The adjective degenerative has no great appeal to the modern
neurologist. It is also not an entirely satisfactory term med­
ically, as it implies an inexplicable decline from a previous
level of normalcy to a lower level of function-an ambigu­
ous conceptualization of disease that satisfies neither a
clinician nor a scientist. Moreover, it gives no hint as to the
fundamental causation of a process and in all likelihood
combines a number of mechanisms under 1 nondescript
term. It would be tempting to attribute all progressive
disease of the nervous system that are of unknown cause
to degeneration. The problem is that many degenerative
diseases of mundane type are caused in a proportion
of cases by germ line genetic changes. All are currently
called degenerative, but this nosology may be a transitional
method of holding a place while awaiting more refined
understanding. What is lacking at the moment is a precise
subcellular mechanism for cellular loss; that is knowledge
that a protein aggregates within or between cells is not
equivalent to understanding the cause of an illness.
Gowers in 1902 suggested the term abiotrophy to encom­
pass the degenerative diseases, by which he meant a lack
of "vital endurance" of the affected neurons, resulting in
their premature death. This concept embodies an unproven
hypothesis-that aging and degenerative changes of cells
are based on the same process. Understandably, contempo­
rary neuropathologists are reluctant to attribute to simple
aging the diverse processes of cellular diseases that are
constantly being revealed by ultrastructural and molecular
genetic techniques. It is increasingly evident that many
of the diseases included in this category depend on
genetic factors. Some appear in more than one member
of the same family, in which case they may be properly
designated as heredodegenerative. Even more diseases,
not differing in any fundamental way from the heredo­
degenerative ones, occur sporadically; that is as isolated
instances but still, genetic factors such as single nucleo­
tide polymorphisms and copy number variations are
often involved in pathogenesis.
Degeneration is nonetheless used as a clinical and
pathologic term that refers to a process of neuronal,
myelin, or tissue breakdown, the degradative products
of which evoke a reaction of phagocytosis and cellular
astrogliosis. What characterizes the degenerative disease
as much as the loss of cells is the concentration of damage
in functionally related cells, or systems; for example the
1 060
cerebral cortex, motor system, extrapyramidal apparatus,
or cerebellum, which are representative of the structures
that are the targets of damage in this class of disease.
The basis of aging changes is also explainable at the
neuronal level, but the nature of these alterations is not
understood. A fundamental problem is the distinction
of these aging deteriorations from degenerative disease.
When a degenerative neurological disease appears in
adult life, one must assume that the clinical presentation
is modified to some extent by life-cycle phenomena-the
patient's function being a sum of both processes. However,
their separation is of fundamental importance in diagnosis
and therapeutics. One has to reconcile the fact that most
degenerative diseases manifest themselves in later life,
leading to the tentative conclusion that some aspect of
the aging process is entwined with the cellular degenera­
tions of disease. This creates a problem for the clinician,
who may be inclined to attribute changes in a person's
function to aging alone rather than searching for a disease
that may allow for treatment or for specific prognostica­
tion and counseling. Moreover, a long-standing uncer­
tainty pertains to certain degenerative conditions such as
Alzheimer disease, which becomes so prevalent in later
age as to offer the possibility that the disease is an invari­
able aspect of aging rather than an acquired perturbation
in cellular function. For most degenerative diseases of the
nervous system, however, this inevitability of occurrence
with aging is clearly not the case. For example, the propor­
tional incidence of Alzheimer pathologic change decreases
continuously from age 70 to age 100 according to Savva
and colleagues. This polemic regarding aging and degen­
erative disease is irresolvable and exposes difficulties with
meaning of the term "disease." If the human being lived
another 50 years beyond the current expectation, would all
nervous structures show the changes of degenerative dis­
ease? The answer is probably "no," as there are distinctive
cellular and subcellular features of degenerative diseases
that are different from the uncomplicated, programmed
loss of cells that is due to aging.
Much new and essential information has been gained
regarding the biologic derangements that lead to neuro­
nal death and dysfunction as a result of investigating the
inherited forms of degenerative diseases. The application
of the techniques of molecular genetics to these diseases
has given stunning results. Even when the hereditary
 CHAPTER 39
form o f a degenerative condition is rare in comparison to
the sporadic type, general principles have been exposed
that are common to the mechanisms of both forms of the
disorder. This approach holds promise for effective treat­
ment of what heretofore have been considered progres­
sive and incurable diseases.
It has been proposed that all degenerative diseases be
classified according to their genetic and molecular abnor­
malities. However, when one notes the diversity of patho­
logic change that may accompany a single, seemingly
unitary gene abnormality or, reciprocally, the diversity of
genetic defects that may underlie a single phenotype, this
type of classification does not prove immediately helpful
to the clinician. In other words, the practice of creating
new disease categories to encompass all the molecular
and pathologic changes associated with a particular type
of neuronal degeneration offers no great advantage in
practice. For example, certain diseases are unified by the
deposition of proteins such as tau and have been termed
"tauopathies," "synucleinopathies," "amyloidopathies,"
and so forth. We endorse a more useful clinical approach
that is based on an awareness of constellations of clinical
features that relate to degeneration of neural systems.
Until such time as the causation of the degenerative neu­
rologic diseases is known, there must be a name and a
place for a group of diseases that are united only by the
common attribute of gradually progressive disintegration
of a part or parts of the nervous system.
General Clinical Characteristics
of Degenerative D iseases
The diseases included in the degenerative category have
2 outstanding characteristics: (1) They affect specific parts or
functional systems of the nervous system and (2) They begin
insidiously, after a long period of normal nervous system func­
tion, and pursue a gradually progressive course . Frequently, it
is impossible to assign a date of onset. The patient or the
patient's family may give a history of the abrupt appear­
ance of disability, particularly if some injury, infection,
surgical procedure, stroke, or other memorable event
coincided with the initial symptoms. A skillfuly l taken
history will reveal that there had been subtle symptoms
for some time but had attracted little attention. Whether
trauma or other stress can actually evoke or aggravate a
degenerative disease is a question that canno t be answered
with certainty; at present, evidence to this effect is largely
anecdotal. Instead, these degenerative disease processes,
by their very nature, appear to develop de novo, without
relation to known antecedent events, and their symptom­
atic expressions are late events in the pathologic process,
occurring only when the degree of neuronal loss exceeds
the ability of a system to function at a clinically acceptable
level. Irreversibility and steady progression of clinical
manifestations when measured over periods of months
or years is another feature common to the neurodegen­
erative conditions. However, several of these diseases
sometimes display periods of relative stability.
Although most degenerative disease do not manifest
expression in other members of the family, the familial
occurrence of degenerative disease is of great importance
Degenerative Diseases of the Nervous System 1 061
both clinically and for scientific reasons as mentioned ear­
lier, but such information is often difficult to obtain. The
family may be small or widely scattered, so that the patient
is unaware of the health of other members. The patient or
the patient's relatives may be reluctant to acknowledge
that a neurologic disease has affected another family
member. Furthermore, it may not be realized that an ill­
ness is hereditary if other members of the family have a
much more or much less severe, or a different form of the
disorder than the patient. Or paternity may be in question.
Even without clear familial occurrence, the patient's eth­
nicity may give clues to a propensity for certain diseases.
Sometimes only the careful examination of other family
members will disclose the presence of a hereditary disease.
Also, it should be remembered that familial occurrence of
a disease does not necessarily mean that it is inherited, but
may indicate instead that more than one member of a fam­
ily had been exposed to the same infectious or toxic agent.
Many symptoms of degenerative disease, while not
currently curable, can be alleviated by skillful management.
The physician's interest and advice are invaluable to the
patient and his family by way of providing support, per­
spective, and information. This accords with the highest
calling of the physician's abilities to relieve suffering.
General Pathologic and Pathogenic Featu res
Most of the degenerative diseases, as emphasized in the
earlier general comments, are characterized by the selective
involvement of anatomically and physiologically related systems
of neurons. This feature is exemplified by amyotrophic
lateral sclerosis (ALS), in which the pathologic process
is virtually limited to motor neurons of the cerebral cor­
tex, brainstem, and spinal cord, and by the progressive
ataxias, in which only the Purkinje cells of the cerebellum
are affected. Many other examples could be cited (e.g.,
Friedreich ataxia, Parkinson disease) in which discrete
neuronal systems disintegrate, leaving others unscathed.
Thus, these degenerative diseases had in the past been
called S1JStem atrophies . The selective vulnerability of cer­
tain systems of neurons is not an exclusive property of
the degenerative diseases; several different processes of
known cause have similarly circumscribed effects on the
nervous system. Contrariwise, in many degenerative dis­
eases, the pathologic changes are somewhat less selective
and eventually quite diffu se. Even then, there is an early
tendency to involve special categories of neurons.
As one would expect of any pathologic process that
is based on the slow wasting and loss of neurons, not
only the cell bodies but also their dendrites, axons, and
myelin sheaths disappear, unaccompanied by an intense
tissue reaction or cellular response. The cerebrospinal
fluid (CSF) shows little, if any, change, or at most a slight
increase in protein content. Moreover, because these dis­
eases invariably result in tissue loss, imaging examina­
tion shows either no change or only a volumetric reduc­
tion (atrophy) with a corresponding passive enlargement
of the CSF compartments. These findings distinguish the
neuronal atrophies from other large classes of progressive
disease of the nervous system, namely, tumors, infec­
tions, and processes of inflammatory type.
1 062 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
At the cellular level, several processes characterize
the death of individual cells. Among these mechanism is
apoptosis, a term borrowed from embryology to specify
the mechanisms that lead to neuronal degeneration. The
original meaning of the term refers to a naturally occur­
ring cell death during development that is driven by the
expression of genes over a short period of time (i.e., "pro­
grammed" cell death), leaving no trace of a pathologic
reaction. The process of neuronal degeneration is quite
different in that it refers to a series of changes in mature
neurons that occur over a protracted period of time,
leading to cell death and often leaving a discrete glial
scar, but not to regional tissue necrosis. In some models
of degenerative disease, cell loss involves activation of
specialized genes, although the time course and cellular
morphology are not apoptotic in the original sense of the
term. It is increasingly apparent that mechanisms other
than programme d cell death will prove central to under­
standing the degenerative diseases, and that the clinical
features of these conditions are manifest even before
cellular destruction occurs. For example, interference
with synaptic signaling and dysfunction of supporting
glia cells are equally important to morphologic neuronal
death.
It will become clear in the following discussion that
the current theme in the study of degenerative diseases
is that of aggregation within specific neurons of normal
cellular proteins such as amyloid, tau, synuclein, ubiq­
uitin, and huntingtin. In some cases, the protein is over­
produced as a result of the simple fact of a triplication or
overactivity of its corresponding gene. In other instances,
enzymatic cleavage of a normal precursor protein yields
a product with physical properties that lead to its aggre­
gation (as happens with amyloid in Alzheimer disease)
or, there may be failure of the normal mechanisms of
protein removal, resulting in its excess accumulation. As
mentioned above, this has resulted in the denomination
of groups of diseases by the type of protein aggregate:
tauopathy, synucleinopathy, etc. Even this is an uncertain
or intermediate classification as it is not known in most
cases if the protein is the cause or the result of cellular
damage, and in any case, the fundamental mechanisms of
cellular destruction are still being determined.
Another characteristic that has guided understand­
ing of degenerative disease is the possible contiguous
"spread" of protein aggregation from one to another
region by synaptic connections. In some cases, this results
in adjacent regions being affected sequentially and in oth­
ers, circuits that are functionally integrated but not nec­
essarily contiguous areas are affected. This geographic
mechanism, proposed by Braak and Braak, conforms to
certain pathologic observations such as the sequential
appearance of synuclein in the olfactory system, thence in
the Meissner- Auerbach plexus of the gut, followed by the
vagus, to involvement of the vagal nuclei in the medulla,
ascending trans-synaptically to the pons and midbrain
nuclei. Whether this accounts for the selectivity of disease
in areas such as the substantia nigra that is most affected
in Parkinson disease, is not entirely known. In any case,
the biologic and the physicochemical properties of these
aggregated proteins have assumed great importance and
the mechanisms by which they interfere with cellular
function and potentially cause cell death are major areas
of research in the degenerative diseases.
CLIN ICAL CLASSI FICATION
Because grouping o f the degenerative diseases i n terms
of etiology is not entirely possible (except that a heredi­
tary or genetic factor can be recognized in some), we
resort for practical purposes to a division based on
the presenting clinical syndromes and their pathologic
anatomy. Although this is the most elementary mode of
classification of naturally occurring phenomena, it is a
necessary prelude to diagnosis and scientific study and
preferable to a purely genetic or molecular classification.
It is certainly an improvement on a haphazard listing of
diseases by the names of the neurologists or neuropa­
thologists who first described them. For reasons given
in the introduction to this chapter, this approach remains
the most effective in analyzing the problem presented by
an individual patient. The main clinical categories are as
follows:
I. Syndrome of progressive dementia, other neurologic
signs absent or inconspicuous
A. Alzheimer disease
B . Some cases of Lewy-body disease
C. Frontotemporal dementias-Pick disease, includ­
ing behavioral variant, primary progressive apha­
sias (several types)
D. Posterior cortical atrophy (visuospatial dementia)
II. Syndrome of progressive dementia in combination
with other neurologic abnormalities
A. Huntington disease (chorea)
B. Lewy-body disease (parkinsonian features)
C. Some cases of Parkinson disease
D. Corticobasal ganglionic degeneration (rigidity,
dystonia)
E. Cortical-striatal-spinal degeneration Gakob disease)
F. Dementia-Parkinson-amyotrophic lateral sclerosis
complex
G. Cerebrocerebellar degeneration
H. Familial dementia with spastic paraparesis, amy­
otrophy, or myoclonus
I. Polyglucosan body disease (neuropathy)
J. Frontotemporal dementia with parkinsonism or
ALS
III . Syndrome of disordered posture and movement
A. Parkinson disease
B . Multiple system atrophy, MSA-P (striatonigral
degeneration, Shy-Drager syndrome)
C. Progressive supranuclear palsy
D. Dystonia musculorum deformans
E. Huntington disease (chorea)
F. Acanthocytosis with chorea
G. Corticobasal ganglionic degeneration
H. Lewy-body disease
I. Restricted dystonias, including spasmodic torti­
collis and Meige syndrome
J. Essential tremor
 CHAPTER 39
IV. Syndrome of progressive ataxia
A. Spinocerebellar ataxias
1. Friedreich ataxia
2. Non-Friedreich, early-onset ataxia (with
retained reflexes, tremor, hypogonadism,
myoclonus, and other disorders)
B. Cerebellar cortical ataxias
1. Holmes type of familial pure cerebellar-oli­
vary atrophy
2. Late-onset cerebellar atrophy
C. Complicated hereditary and sporadic cerebellar
ataxias (later-onset ataxia with brainstem and
other neurologic disorders)
1. Multiple system atrophies (MSA-C) including
olivopontocerebellar degenerations (OPCA)
2. Dentatorubral degeneration (Ramsay Hunt
type)
3. Dentatorubropallidoluysian atrophy (DRPLA)
4. Machado-Joseph (Azorean) disease; SCA-3
5. Other complicated late-onset, autosomal
dominant ataxias with pigmentary retinopa­
thy, ophthalmoplegia, slow eye movements,
polyneuropathy, optic atrophy, deafness,
extrapyramidal features, and dementia
V. Syndrome of slowly developing muscular weak­
ness and atrophy
A. Motor disorders with amyotrophy
1. Amyotrophic lateral sclerosis
2. Progressive spinal muscular atrophy
3. Progressive bulbar palsy
4. Kennedy syndrome and other hereditary
forms of progressive muscular atrophy and
spastic paraplegia
5. Motor neuron disease with frontotemporal
dementia
B. Spastic paraplegia without amyotrophy
1. Primary lateral sclerosis
2. Hereditary spastic paraplegia (Strumpell­
Lorrain)
VI. Sensory and sensorimotor disorders (neuropathies;
see Chap. 46)
A. Hereditary sensorimotor neuropathies-peroneal
muscular atrophy (Charcot-Marie-Tooth);
hypertrophic interstitial polyneuropathy
(Dejerine-Sottas)
B. Pure or predominantly sensory or motor
neuropathic
C. Riley-Day autonomic degeneration
VII. Syndrome of progressive blindness with or without
other neurologic disorders (see Chap. 13)
A. Pigmentary degeneration of retina (retinitis
pigmentosa)
B. Stargardt disease
C. Age-related macular degeneration (ARMD)
VIII. Syndromes characterized by degenerative neuro­
sensory deafness (see Chap . 15)
A. Pure neurosensory deafness
B. Hereditary hearing loss with retinal diseases
C. Hereditary hearing loss with system atrophies
of the nervous system
Degenerative Diseases of the Nervous System 1 063
DISEAS ES CHARACTERIZED MAI N LY
BY PROGR ESSIVE DEM ENTIA
Alzheim er Disease
This is the most common and important degenerative
disease of the brain, having an immense societal impact.
Some aspects of the intellectual deterioration that char­
acterize this disease were described in Chap. 21, under
"The Neurology of Dementia," and the still ambiguous
relationship of this disease to the aging process is men­
tioned above and in Chap. 29. There it was pointed out
that some degree of shrinkage in size and weight of the
brain, that is "atrophy," is an inevitable accompaniment
of advancing age, but that these changes alone are of
relatively slight clinical significance and uncertain struc­
tural basis (e.g., whether the loss of brain weight aging is
the result of a simple depletion of neurons). By contrast,
severe degrees of diffuse cerebral atrophy that evolve
over a few years are associated with dementia, and the
underlying pathologic changes in these cases most often
prove to be those of Alzheimer disease. As also com­
mented on in Chap . 29, the rate of cerebral atrophy, spe­
cifically of the hippocampus and medial parts of the tem­
poral lobes, is accelerated in the early stages of Alzheimer
disease, and longitudinal studies by magnetic resonance
imaging can identify individuals who will subsequently
develop the disease (Rusinick) . Nevertheless, there is not
a continuous increase in the deposition of plaques and
tangles, the pathologic markers of Alzheimer disease,
with increasing age. Therefore, Alzheimer changes are
not an inevitable result of aging.
The now outdated practice of giving Alzheimer dis­
ease and senile dementia the status of separate diseases
is attributable to the relatively young age (51 years) of
the patient originally studied by Alois Alzheimer in 1907.
Such a division is no longer tenable, as the 2 conditions,
except for their age of onset, are clinically and pathologi­
cally indistinguishable. It is probably useful to consider
as related but separable, the several heredofamilial forms
of Alzheimer disease discussed below.
Epidemiology
Although Alzheimer disease has been described a t every
period of adult life, the majority of patients are in their
sixties or older; a relatively small number have been in
their late fifties or younger. It is one of the most frequent
mental illnesses, making up a large proportion of per­
sons in assisted living and skilled nursing facilities. The
incidence of clinically diagnosed Alzheimer disease is
similar throughout the world, and it increases with age,
approximating 3 new cases yearly per 100,000 persons
younger than age 60 years and a staggering 125 new
cases per 100,000 of those older than age 60 years. The
prevalence of the disease per 100,000 population is near
300 in the group aged 60 to 69 years; it is 3,200 in the
70- to 79-year-old group and 10,800 in those older than
age 80. In the year 2008, there were estimated to be more
than 2 million persons with Alzheimer disease in the
1 064 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
United States. (It should be borne in mind that these are
not pathologically proven cases and, while probably cor­
rect as an approximation, are likely combined with other
diseases.) Prevalence rates, which depend also on overall
mortality, are 3 times higher in women, although the inci­
dence of new cases is only slightly disproportionate in
women. The survival of patients with Alzheimer disease
is reduced to half the expected rate, mainly because of
respiratory and cardiovascular causes and inanition, but
also for other reasons that are not entirely clear.
Several putative epidemiologic risk factors for
Alzheimer disease, such as birth order, mother 's age
at birth, and a family history of Down syndrome seem
marginal at best and in some instances may be a result
of selection bias. Depression and possibly head injuries
do seem to confer a somewhat increased risk later in life.
Whether low educational attainment is a risk factor for
the development of Alzheimer disease or, conversely,
whether cognitively demanding occupations or higher
intelligence protects against dementia is still under dis­
cussion. Provocative data indicating that inherent intel­
lectual endowment is important were presented in Chap .
21 (Katzman; Cobb et al). Finally, associations between
diabetes or hyperglycemia and dementia, in general,
have emerged from epidemiologic studies, for example,
one reported by Crane and coworkers, but the ostensible
mechanism by which this confers risk has not been estab­
lished. In their report, a higher than average glucose level
over the preceding 5 years conferred a slightly increased
risk of dementia but not necessarily of Alzheimer disease.
The fam ilial occurrence of Alzheimer disease has been
well established. In less than 1 percent of such cases there
is a dominant inheritance pattern with a high degree of
penetrance and appearance of disease at a younger age
(Nee et al; Goudsmit et al; see further) . Reports of substan­
tial familial aggregations of dementia without a specific
pattern of inheritance also suggest the operation of more
than one genetic factor. Many studies have documented
an increase in the risk of ostensibly sporadic Alzheimer
disease among first-degree relatives of patients with this
disorder. Again, this risk is disproportionately greater in
females, adding to the evidence that women in general are
at slightly higher risk for Alzheimer disease (Silverman
et al) . Li and coworkers have provided evidence that
patients with an earlier age of onset of Alzheimer disease
(before age 70 years) are more likely to have relatives with
the disease than are patients with later onset. Genetic
studies are difficult to carry out because the disease does
not appear at the same age in a given proband. Even in
identical twins, the disease may develop at the age of
60 years in one of the pair and at 80 years in the other.
Death from other causes may prevent its detection. The
other genetic contributions to the occurrence of Alzheimer
disease are discussed extensively further on.
C l i n i c a l Featu res (See also Chap. 21)
The onset of mental changes is usually so insidious that
neither the family nor the patient can date the time of its
beginni ng and most patients come to attention months
or years after the decline began. Occasionally, however,
the process becomes manifest by an unusual degree of
confusion in relation to a febrile illness, an operation,
mild head injury, or the institution of a new medication.
Other patients have as their initial complaints dizzi­
ness, mental fogginess, nondescript headaches, or other
vaguely expressed and changeable somatic symptoms.
The gradual development of forgetfulness is the major
Slj mptom. Small day-to-day happenings are not remem­
bered. Seldom-used names become particularly elusive.
Little-used words from an earlier period of life also tend
to be lost. Appointments are forgotten and possessions
misplaced. Questions are repeated again and again, the
patient having forgotten what was just discussed. It is
said that remote memories are preserved and recent ones
lost (the Ribot law of memory), but this is only relatively
true and it is difficult to check the accuracy of distant per­
sonal memories. For example, Albert and associates, who
tested Alzheimer patients' recognition of dated political
events and pictures of prominent people past and present,
found that some degree of memory loss extends to all
previous decades of the person's life (neuropsychologic
testing is discussed further on) .
Once the memory disorder has become pronounced
in the prototypic disorder, other failures in cerebral
function become increasingly apparent. The patient's
speech is halting because of failure to access the needed
word. The same difficulty interrupts writing. Vocabulary
becomes restricted, and expressive language becomes
stereotyped and inflexible. Comprehension of spoken
words seems at first to be preserved, until it is observed
that the patient does not carry out a complicated request;
even then it is uncertain whether the request was not
understood because of inattention or because it was for­
gotten. Almost imperceptible at first, these disturbances
of language become increasingly apparent as the disease
progresses. The range of vocabulary and the accuracy of
spelling are reduced. Finally; after many years of illness,
there is a failure to speak in full sentences; the finding of
words requires a continuous search; and little that is said
or written is fully comprehended. There is a tendency to
repeat a question before answering it, and later there may
be a rather dramatic repetition of every spoken phrase
(echolalia). The deterioration of verbal skills has by then
progressed beyond a groping for names and common
nouns to an obvious anomie aphasia. Other elements of
receptive and executive aphasia are later added, but dis­
crete aphasias of the Broca or Wernicke type are charac­
teristically lacking. In general, there is a paucity of speech
and a quantitative reduction in mentation.
Skill in arithmetic suffers a similar deterioration.
Faults in balancing the checkbook, mistakes in figuring
the price of items and in making the correct change; all
these and others progress to a point where the patient can
no longer carry out the simplest calculations (acalculia or
dyscalculia).
In some patients, visuospatial orientation becomes
defective. The car cannot be parked; the arms do not
find the correct sleeves of the jacket or shirt; the corners
of the tablecloth cannot be oriented with the corners of
the table; the patient turns in the wrong direction on the
way home or becomes lost. The route from one place to
another cannot be described, nor can given directions
 CHAPTER 39
be understood. As this state worsens, the simplest of geo­
metric forms and patterns cannot be copied.
Late in the course of the illness, the patient forgets
how to use common objects and tools while retaining
the necessary motor power and coordination for these
activities. The razor is no longer correctly applied to the
face; the latch of the door cannot be unfastened; and eat­
ing utensils are used awkwardly. Finally, only the most
habitual and virtually automatic actions are preserved.
Tests of commanded and demonstrated actions cannot be
executed or imitated. Ideational and ideomotor apraxia are
the terms applied to the advanced forms of this motor
incapacity as described in Chaps. 3 and 22.
As these many amnesic, aphasic, agnostic, and
apraxic deficits declare themselves, the patient at first
seems unchanged in overall motility, behavior, tem­
perament, and conduct. Social graces, whatever they
were, are retained in the initial phase of the illness, but
troublesome alterations may gradually appear in this
sphere as well. Imprudent business deals may be made.
Restlessness and agitation or their opposites-inertia and
placidity-become evident. Dressing, shaving, and bath­
ing are neglected. Anxieties and phobias, particularly
fear of being left alone, may emerge. A disturbance of
the normal day and night sleep patterns is prominent in
some patients. A poorly organized paranoid delusional
state, sometimes with hallucinations, may become mani­
fest. The patient may suspect his elderly wife of having
an illicit relationship or his children of stealing his pos­
sessions. A stable marriage may be disrupted by the
patient's infatuation with a younger person or by sexual
indiscretions, which may astonish the community. The
patient's affect coarsens; he is more egocentric and indif­
ferent to the feelings and reactions of others. A gluttonous
appetite sometimes develops, but more often eating is
neglected, resulting in gradual weight loss. Later, grasp­
ing and sucking reflexes and other signs of frontal lobe
disorder are readily elicited (Neary et al), sphincteric con­
tinence fails, and the patient sinks into a state of relative
akinesia and mutism, as described in Chap . 21 .
Difficulty in locomotion, a kind of unsteadiness with
shortened steps but with only slight motor weakness
and rigidity, frequently supervenes. Elements of par­
kinsonian akinesia and rigidity and a fine tremor can be
perceived in patients with advanced stages of the disease.
Ultimately, the patient loses the ability to stand and walk,
being forced to lie inert in bed and having to be fed and
bathed, the legs curled into a fixed posture of paraplegia
in flexion (in essence, a persistent vegetative state).
The symptomatic course of this illness is quite vari­
able but usually extends over a period of 5 or more years,
but judging from pathology studies, the pathologic
course has a much longer asymptomatic duration. This
concept of a preclinical stage is supported by the detailed
studies of Linn and colleagues, who found that a lengthy
period (7 years or more) of stepwise decline in memory
and attention span preceded the clinical diagnosis. In the
dominantly inherited forms of disease, careful studies of
biomarkers in the spinal fluid and by imaging show that
changes occur 15 years or longer before the clinical mani­
festations are apparent (Bateman et al) . Throughout this
Degenerative Diseases of the Nervous System 1 065
period, corticospinal and corticosensory functions, visual
acuity, ocular movements, and visual fields remain intact.
If there is hemiplegia, homonymous hemianopia, and the
like, either the diagnosis of Alzheimer disease is incorrect
or the disease has been complicated by a stroke, tumor,
or subdural hematoma. Exceptions to this statement are
rare. The tendon reflexes are little altered and the plantar
reflexes almost always remain flexor. There is no sensory
or cerebellar ataxia. Convulsions are rare until late in the
illness, when up to 5 percent of patients reportedly have
infrequent seizures. Occasionally, widespread myoclonic
jerks or mild choreoathetotic movements are observed
late in the illness. Eventually, with the patient in a bedfast
state, an intercurrent infection such as aspiration pneu­
monia or some other disease mercifully terminates life.
The sequence of neurologic disabilities may not fol­
low this described order and one or another deficit may
take precedence, presumably because the disease process,
after becoming manifest in the memory cortex of the tem­
poral lobes, affects a particular part of the associative cor­
tex earlier or more severely in one patient than in another.
This allows a relatively restricted deficit to become the
source of early medical complaint, long before the full
syndrome of dementia has declared itself.
There are at least 4 limited deficits that may repre­
sent the opening features of Alzheimer disease but each
of which alone may be mild enough to qualify as mild
cognitive impairment (MCI) . According to Petersen, who
developed this concept, the MCI syndrome is defined by
the presence of cognitive difficulties in one or all spheres
that are not severe enough to interfere with daily life.
The early presentation of Alzheimer disease may
manifest mainly as one of the following syndromes with
the first, memory dysfunction being the most common
and, even as other aspects of the disease advance, it tends
to remain the most prominent.
1. Amnesia The early stages of Alzheimer disease are
usually dominated by a disproportionate failure of
episodic (autobiographical) memory, with integrity
of other cognitive abilities. This may be the sole dif­
ficulty for many years. In such patients, immediate
memory (essentially a measure of attention), tested by
the capacity to repeat a series of numbers or words, is
intact; it is the short-and long-term (retentive) memo­
ry that fails. Memory may become impaired but as a
business executive, for example, the individual may
continue to make acceptable decisions if the work
uses long-established habit patterns and practices.
2. Dysnomia The forgetting of words, especially proper
names, may first bring the patient to a neurologist.
Later the difficulty involves common nouns and pro­
gresses to the point where fluency of speech is seri­
ously impaired. Every sentence is broken by a pause
and search for the wanted word; if the desired word
is not found, a circumlocution is substituted or the
sentence is left unfinished. When the patient is given
a choice of words, including the one that was missed,
there may be a failure of recognition. Repetition of the
spoken words of others, at first flawless, later brings
out a lesser degree of the same difficulty. The defect in
1 066 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
nammg is evident with even simple tests, for example,
asking the patient to generate a list of farm animals or
car brands-a test that may elicit only 3 or 4 responses.
A more extensive examination entails asking the
patient to name as many items as possible in each of
3 categories in 1 min-vegetables, tools, and clothing.
Alzheimer patients fall well below a score of 50 items.
3. Visuospatial disorientation Parietooccipital functions
are sometimes deranged in the course of Alzheimer
disease and in a few cases may fail while other func­
tions are relatively preserved. When it occurs in a pure
form it is termed posterior cortical atrophy, as discussed
in a later section (see Renner et al). As remarked above
and in Chap. 22, prosopagnosia (impaired facial rec­
ognition), losing one's way in familiar surroundings
or inability to interpret a road map, to distinguish
right from left, or to park or garage a car, and diffi­
culty in setting the table or dressing are all manifesta­
tions of a special failure to orient the schema of one's
body with that of surrounding space. Exceptionally,
there is a neglect of stimuli in one visual field. In the
late states, some of these patients develop the Balint
syndrome or Gerstmann syndrome (Tang-Wai et al;
McMonagle et al) .
4. Paranoia and personality changes Occasionally, a t some
point in the development of Alzheimer dementia,
paranoia or bizarre behavior occasionally assumes
prominence. This may appear before the more obvi­
ous memory or language defects announce them­
selves. The patient becomes convinced that relatives
are stealing his possessions or that an elderly and
even infirm spouse is guilty of infidelity. He may
hide his belongings, even relatively worthless ones,
and go about spying on family members. Hostilities
arise, and wills may be altered irrationally. Many
of these patients are constantly worried, tense, and
agitated. Of course, paranoid delusions may be part
of a depressive psychosis and of other dementias,
but most of the elderly patients in whom paranoia
is the presenting problem, seem not to be depressed,
and their cognitive functions are for a time relatively
well preserved. Social indiscretions, rejection of old
friends, embarking on imprudent financial ventures,
or an amorous pursuit that is out of character are
examples of these types of behavioral change.
5. Executive dysfunction This may be the most disabling
of the main aspects of the disease and when it appears
early on, is not specific to Alzheimer dementia as it is
a component of several other processes that affect the
frontal lobes. These patients display early difficulties
in coordinating and planning tasks and following
complex conversations or instructions. They may
become disinclined to participate in social activities
and become withdrawn or quieter than usual. As the
problem advances, simpler and formerly automatic
actions such as driving become problematic for the
patient; the degree of insight varies. Some are able to
express that they feel "confused' but more often, it is
the family that brings these changes to attention.
If one of the foregoing restricted deficits remains
uncomplicated over a long period, one is justified in
suspecting a cause other than Alzheimer disease, such as
one of the lobar atrophies such as frontotemporal demen­
tia (see further on), Binswanger disease, hydrocephalus,
or embolic infarctions of the temporal or parietal lobes.
Each of the restricted clinical disorders described above is
only relatively pure. Careful testing of mental function­
and this is of diagnostic importance-frequently dis­
closes subtle abnormalities in several cognitive spheres.
Initially, most patients have a disproportionate disorder
of the temporoparietal cortices, reflected by an earlier
impairment on the performance parts of the Wechsler
Adult Intelligence Scale. Within a year or two, the
more generalized aspects of mental deterioration become
apparent, and the aphasic-agnosic-apraxic aspects of the
syndrome become increasingly prominent. Although it
is true that most patients with Alzheimer disease walk
normally until relatively late in their illness, infrequently
a short-stepped gait and imbalance draw attention to the
disease and worsen slowly for several years before cogni­
tive manifestations become evident. The general decrepi­
tude in appearance that accompanies the middle and late
stages of the disease in many patients is commented on
in Chap . 21.
For research purposes and t o establish certain inclu­
sive and exclusive criteria for the diagnosis of Alzheimer
disease, a working group of the National Institute of
Neurological and Communicative Disorders and Stroke
(NINCDS) and the Alzheimer 's Disease and Related
Diseases Association (ADRDA) had proposed the fol­
lowing criteria: (1) dementia defined by clinical examina­
tion, the Mini-Mental Scale (see Table 21-6), the Blessed
Dementia Scale, or similar mental status examination; (2)
patient older than age 40 years; (3) deficits in 2 or more
areas of cognition and progressive worsening of memory
and other cognitive functions, such as language, percep­
tion, and motor skills (praxis); (4) absence of disturbed
consciousness; and (5) exclusion of other brain diseases
(McKhann et al, 1984; Tierney et al, 1988). These criteria
have essentially been reaffirmed by more recent consen­
sus panels (see Mci<hann et al, 2011). Using these mea­
sures, the correct diagnosis is achieved in more than 85
percent of patients, but this is not surprising given that
Alzheimer disease is overwhelmingly the most common
cause of adult dementia. Most cases are identifiable with­
out resorting to restrictive lists such as these, especially if
the patient is observed serially over a period of months or
years. There is strong interest in the addition of biomark­
ers to the diagnostic criteria for the disease but these have
not reached the point of general clinical utility and the
diagnosis remains predominantly a clinical one, aided by
imaging and other tests.
Path o l ogy
I n th e advanced stages o f the disease, the brain presents a
diffusely atrophied appearance and its weight is usually
reduced by 20 percent or more. Cerebral convolutions are
narrowed and sulci are widened. The third and lateral
ventricles are symmetrically enlarged to varying degrees.
Usually, the atrophic process involves the frontal, temporal,
and parietal lobes, but cases vary considerably. The extreme
 CHAPTER 39
atrophy of the hippocampus, the most prominent finding
visible on MRI (mainly coronal images), is diagnostic in the
proper clinical circwnstances.
Microscopically, there is widespread loss of nerve
cells. Early in the disease this is most pronounced in
layer II of the entorhinal cortex. In addition to marked
neuronal loss in the hippocampus, adjacent parts of the
medial temporal cortex-namely, the parahippocampal
gyri and subiculum-are affected. The anterior nuclei of
the thalamus, septal nuclei, and diagonal band of Broca,
amygdala, and particular brainstem parts of the mono­
aminergic systems are also depleted. The cholinergic
neurons of the nucleus basalis of Meynert (the substantia
inn ominata) and locus ceruleus are also reduced in num­
ber, a finding that has aroused great interest because of
its putative role of the former in memory function (see
below) . In the cerebral cortex, the cell loss predominantly
affects the large pyramidal neurons. Residual neurons
are observed to have lost volume and ribonucleoprotein;
their dendrites are diminished and crowd one another
owing to the loss of synapses and neuropil. Astrocytic
hypertrophy (more than proliferation) is in evidence as a
compensatory or reparative process, most prominent in
layers III and V.
Moreover, 3 microscopic changes give this disease
its distinctive character: (1) The presence within the
nerve cell cytoplasm of thick, fiber-like strands of silver­
staining material, also in the form of loops, coils, or
tangled masses (Alzheimer neurofibrillary changes or
"tangles" ) (Fig. 39-1). These strands are composed of a
hyperphosphorylated form of the microtubular protein,
tau, and appear as pairs of helical filaments when studied
ultrastructurally. (2) Spherical deposits of amorphous
material scattered throughout the cerebral cortex and
easily seen with periodic acid-Schiff (PAS); the core of the
aggregates is the protein amyloid, surrounded by degen­
erating nerve terminals (neuritic plaques) that stains with
silver. Amyloid is also scattered throughout the cerebral
cortex in a nascent " diffuse" form, without organization
Figure 39- 1 . Photomicrograph of Al zheimer amyloid plaques and
neurofibrillary tangles. Bielchowsky silver stain.
Degenerative Diseases of the Nervous System 1 067
or core formation and then is appreciated mainly by
immunohistochemical methods, as well as deposition
in the walls of small blood vessels near the plaques, so­
called congophilic angiopathy. (3) Granulovacuolar degen­
eration of neurons, most evident in the pyramidal layer
of the hippocampus. This last change is least important
in diagnosis but there is uncertainty regarding its nature;
it had been thought to be simply a reactive process but
recent studies suggest it reflects a defect in phagocytosis
of degraded proteins.
Neuritic plaques and neurofibrillary changes are
found in all the association areas of the cerebral cortex,
but it is the neurofibrillary tangles and quantitative neu­
ronal loss, not the amyloid plaques, that correlate best
with the severity of the dementia (Arriagada et al) . If
any part of the brain is disproportionately affected, it is
the hippocampus, particularly the CAl and CA2 zones
(of Lorente de N6) and the entorhinal cortex, subiculum,
and amygdala. These parts have abundant connections
with other parts of the temporal lobe cortex and dentate
gyrus of the hippocampus and undoubtedly account for
the amnesic component of the dementia. The associative
regions of the parietal lobes are another favored site.
Only a few tangles and plaques are found in the hypo­
thalamus, thalamus, periaqueductal region, pontine teg­
mentum, and granule-cell layer of the cerebellum.
Experienced neuropathologists recognize a form of
Alzheimer disease, particularly in older patients ( 75 years),
in which there are senile plaques but few or no neuro­
nal tangles (about 20 percent of 150 cases reported by
Joachim et al). Increasingly, other pathologic changes are
being appreciated in Alzheimer cases with fewer plaques
and tangles than anticipated for the degree of dementia;
Lewy bodies in particular are found by sophisticated
techniques. Another problem for the neuropathologist is
to distinguish between the normal-aged brain and that of
Alzheimer disease. It is not unusual to find a scattering of
senile plaques in individuals who were ostensibly men­
tally normal during life. Anderson and Hubbard studied
27 demented individuals aged 64 to 92 years and 20 age­
matched nondemented controls. In the former, 3 to 38
percent of the hippocampal neurons contained neurofi­
brillary tangles; in all but 2 of the controls, the number of
hippocampal neurons with tangles fell below 2.5 percent.
Moreover, an increased number of tangles in the aged are
associated with mild cognitive impairment and a higher
likelihood of progression to Alzheimer disease.
Many demented individuals with clinical features
of Alzheimer disease have sufficient neuronal loss and
Lewy bodies in cortex and the substantia nigra to justify
a diagnosis on histopathologic grounds of Parkinson
disease (see further on) . Leverenz and Sumi found
that 25 percent of their Alzheimer patients showed
the pathologic (and clinical) changes of Parkinson dis­
ease, a much higher incidence than can be attributed
to chance. Similarly, of 11 patients with progressive
supranuclear palsy (also discussed further on) reported
by Gearing and coworkers, 10 were demented and 5
had the neuropathologic features of Alzheimer disease.
These mixed cases present problems not only of clas­
sification but also in understanding the neurobiology
1 068 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
of these degenerative diseases. This subject is discussed
further in the section on Parkinson disease.
It is of historical interest that Alzheimer was not
the first to describe plaques, one of the hallmarks of the
pathologic state. Miliary lesions (Herdchen) had been
observed in senile brains by Blocq and Marinesco in 1892
and were named senile plaques by Simchowicz in 1910.
In 1907, Alzheimer described the case of a 51-year-old
woman who died after a 5-year illness characterized by
progressive dementia. Throughout the cerebral cortex he
found the characteristic plaques, but he also noted, thanks
to the use of Bielschowsky' s newly devised silver impreg­
nation method, a clumping and distortion of fibrils in the
neuronal cytoplasm, the neurofibrillary change that now,
appropriately, carries Alzheimer 's name.
Path o g e n es i s
Analyses o f the plaques and neuronal fibrillary changes
have been undertaken in an attempt to elucidate the
mechanism of Alzheimer disease, but so far, to little avail.
Several histologic techniques assist in this endeavor,
including refined methods for silver impregnation that
stain both amyloid and its main constituent (beta-amyloid
protein [A/3]); irnmunostaining using antibodies specific
to such proteins as ubiquitin, neuronal tau protein, and
beta-amyloid protein; and visualization of /3-pleated
protein sheets using thioflavine S and Congo red with
ultraviolet and polarized light. Tau (composed chemically
of beta2 -transferrin) is a discrete cytoskeletal protein that
promotes the assembly of microtubules, stabilizes their
structure, and participates in synaptic plasticity in a yet
to be defined manner. In the pathologic circumstances
of Alzheimer disease, progressive supranuclear palsy,
and frontotemporal dementia (see further on), tau is
hyperphosphorylated and aggregates, resulting in paired
helical filaments that make up the neurofibrillary tangles.
Electrophoretically, tau moves with the /32-globulins and
is thought to function as a transferrin, that is it binds iron
and delivers it to the cell. Its concentration can be mea­
sured in the CSF and serum, but this has not yet proven
clearly to be useful as a diagnostic test.
The A/3 protein is a small portion of a larger entity,
the amyloid precursor protein (APP), which is normally
bound to neuronal membranes. As shown in Fig. 39-2, the
A/3 protein is cleaved from APP by the action of pro teases
termed a, {3, and r secretase. One current hypothesis,
developed by Selkoe and others, focuses on the manner
in which APP is cleaved by these enzymes to give rise to
different-length residues of A/3. During normal cellular
metabolism, APP is cleaved by either a or f3 secretase. The
products of this reaction are then cleaved by the y.secre­
tase isoform of the enzyme. The sequential cleavage by
a and then y produces tiny fragments that are not toxic
to neurons. However, cleavage by f3 and then y results in
a 40-amino-acid product, A/340, and a longer 42-amino­
acid form. The latter A/342 form is toxic in several models
of Alzheimer disease, and it has been proposed that the
ratio of A/342 to A/340 is critical to the neuronal toxicity
of amyloid.
Several pieces of evidence favor the view that eleva­
tion of the levels of Af342 leads to aggregation of amyloid
APP
� Ill c::.
APPsjl jJ stub
Down - D
!�
•
syndrome
AjJ42
!�
Fibril logenesis
*Mutations in APP, .f1 or 1!!1 secretase,
and the Apo E4 allele enhance toxicity.
Figure 39-2. Diagram of proteolysis of amyloid precursor protein
(APP). When APP is cleaved sequentially by {3 secretase and then
secretase, the resulting amyloid protein can be 40 (A/340) or 42
(A/342) amino acids in length. The latter favors the fonnation of
aggregated fibrillary amyloid protein (fibrillogenesis) rather than
normal APP degradation. The fibrillary form of amyloid is neuro­
toxic, a mechanism favored as the cause of cell damage in Alzheimer
disease. Formation of A/342 is promoted by mutations, either in the
APP gene itself or in the presenilins. In Down syndrome, excess
production of APP and its product A/342 is caused by triplication
of the long ann of chromosome 21, the location of the APP gene.
The Apo E4 allele is associated with inadequate clearance of A/342
and is another mechanism that promotes fibrillogenesis. (Modified
by permission from Sisoctia SS, St. George-Hyslop PH: r-Secretase,
notch, A/3 and Alzheimer's ctisease: Where do the presenilins fit in?
Nat Rev Neurosci 3:281-290, 2002.)
and then to neuronal toxicity. It appears that the diffuse
deposition of A/342 precedes the formation of better­
defined neurofibrils and plaques. The fact that the gene
coding for APP is located on chromosome 21, one of the
regions linked to one type of familial Alzheimer disease
and the duplicated chromosome in Down syndrome, in
which Alzheimer changes almost inevitably occur with
aging (see further on), suggests that the overproduction
of amyloid and all its A/3 residues are causative factors
in the disease. Furthermore, the ratio of A /342 to A/340 is
increased in Down syndrome. Another suggestive con­
nection has been the finding that there are genetic defects
in the genes encoding APP and in a pair of endosomal
proteins termed presenilin 1 and 2 in some familial forms
of Alzheimer disease. The presenilins interact with, or
may be a component of, r secretase, the enzyme that
produces the A/342 fragment. Mutations of presenilin 1
and 2 also increase the relative levels of A/342 . It should
be noted that mutations of the APP and presenilin genes
explain a very small proportion of Alzheimer cases
(Terry). Transgenic mice that express human Alzheimer
disease-associated mutations in APP or presenilin genes
 CHAPTER 39
develop plaques with Af342 but not neurofibrillary tan­
gles. Many of the relationships and mechanisms depicted
in Fig. 39-2 are derived from the understanding of genetic
forms of Alzheimer disease; the extent to which they
will be implicated in the idiopathic disease is unknown.
However, some form of disruption in these mechanisms
is likely to be involved in the sporadic disease.
It must be emphasized, however, that there is still
uncertainty regarding the relationship of amyloid deposi­
tion to the loss of neurons and brain atrophy. Alternatively,
soluble oligomers of A/3 amyloid may be the toxic agents,
whereas the emphasis until now has been on the effects of
visible assemblies of insoluble amyloid fibrils. Similarly,
TDP-43, the product of inadequate functioning of the
progranulin gene, is also deposited in neurons and may
play a substantial role in the severity of expression of
Alzheimer disease; this protein has been implicated in the
pathogenesis of frontotemporal dementia and motor neu­
ron disease, both discussed later in the chapter. Others
have questioned the amyloid hypothesis and pointed
to the imprecise relationship between amyloid deposi­
tion and neuronal loss, even suggesting that aggregated
amyloid is in some way a protective mechanism of cells.
The importance of neurofibrillary tangles has also
been questioned, and the manner in which amyloid depo­
sition relates to tangle formation is unclear. Unexplained
also is prominent senile plaque formation in some cases
and neurofibrillary tangles in others. One prevalent view
is that the tangles are a secondary phenomenon. In their
review, Hardy and Selkoe, authoritative investigators
in this field, pointed out that "Although the amyloid
hypothesis offers a broad framework to explain AD
pathogenesis, it is currently lacking in detail, and certain
observations do not fit easily with the simplest version of
the hypothesis." Nonetheless, the amyloid hypothesis is
currently the strongest.
In recent years, some of the subcellular mechanisms
that are deranged by the presence of intracellular or extra­
cellular amyloid have been elucidated. The finding of a
reduced number and enlargement of synapses in affected
cortex early in the disease by DeKosky and Scheff and oth­
ers could be interpreted as either the first sign of neuronal
death or the result of the neuronal loss. Amyloid deposi­
tion would then be a later, secondary phenomenon. These
are complex and uncertain connections but they are among
the most promising findings in this field of research.
It was long ago established that Alzheimer disease is
not caused by any of the usual types of arteriosclerosis.
On the other hand, several studies have indicated that
the presence of cerebral infarctions, small or large, and
nondescript ischemic white matter disease accelerates
the deposition of amyloid and the development of neuro­
fibrillary tangles in the brains of Alzheimer patients (see
further on); the mechanism of these interactions is not
understood. Not surprisingly, cerebrovascular disease
also exaggerates the rate of progression and degree of
dementia. How this relates to the entity of arteriosclerotic,
multiinfarct, or vascular dementia is entirely clear. Without
doubt, as discussed in Chap. 34, multiple cerebral strokes
cause increasing deficits that cumulatively qualify as a
dementia. At least some of the focal lesions that contribute
Degenerative Diseases of the Nervous System 1 069
to the cognitive syndrome can be identified clinically and
there is a stepwise decline in function that corresponds
to strokes. Admittedly, this type of vascular dementia
may be more difficult to recognize when a number of the
infarcts are of the relatively silent lacunar type; the men­
tal capacities of such patients may then appear to fail in
a gradual and continuous fashion. Memory is relatively
spared in the early stages and usually a pseudobulbar
state or deterioration in gait accompanies the dementia.
The subcortical white matter change of Binswanger dis­
ease causes similar diagnostic problems. We are inclined
toward the view expressed in Chap. 21 and summarized
in the commentary by Jagust that there is an undefined,
and perhaps synergistic, interaction between strokes and
progressive mental decline in patients with Alzheimer
disease. Most often, in our experience, it is the degenera­
tive condition of Alzheimer that explains the dementia.
A similar relationship between Alzheimer disease and
previous head injuries is tentative but has led to specula­
tion that several types of brain injuries are conducive to
the development of neurofibrillary tangles and amyloid
deposition, perhaps as if they were part of a reparative
response.
No relationship to premorbid personality traits ear­
lier in life has been established, but an intriguing finding
from what has become known as the "nun study" and
several similar studies suggests that poorer linguistic
capability early in life corresponded to the development
of Alzheimer disease with aging (D.A. Snowden et al) .
In this study, the autobiographies of 93 nuns, written in
their twenties, were rated for linguistic and ideational
complexity. Of 14 sisters who died in late life, dete­
rioration of cognitive function and neuropathologically
proven Alzheimer disease occurred in 7 who had a low
"idea density" in their writings and in none of 7 whose
writings were cognitively more complex. Obviously this
type of correlation is subject to several interpretations,
but the general notion of "cognitive reserve" having
either a protective property or simply hiding mental
decline, has emerged from numerous other studies. Also,
there has been a general perception confirmed by a few
studies such as the one by Verghese and colleagues, that
an active mental life may reduce the severity of mental
decline with aging, but firm conclusions cannot be made
from the available information.
Neurotransmitter Abnormalities Considerable inter­
est was created in the late 1970s by the finding of a
marked reduction in choline acetyltransferase (ChAT)
and acetylcholine in the hippocampus and neocortex of
patients with Alzheimer disease. This loss of cholinergic
synthetic capacity was attributed to a reduction in the
number of cells in the basal forebrain nuclei (mainly the
nucleus basalis of Meynert), from which the major portion
of neocortical cholinergic terminals originate (Whitehouse
et al). However, a 50 percent reduction in ChAT activity
has been found in regions such as the caudate nucleus,
which shows neither plaques nor tangles (see review by
Selkoe). The specificity of the nucleus basalis cholinergic
changes has been questioned for other reasons as well. For
one, Alzheimer brain also shows a loss of monoaminergic
neurons and a diminution of noradrenergic, gabanergic,
1 07 0 P a rt 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
and serotonergic functions in the affected neocortex. The
concentration of ammo acid transmitters, particularly
of glutamate, is also reduced in cortical and subcortical
areas (Sasaki et al) and the concentration of several neuro­
peptide transmitters-notably substance P, somatostatin,
and cholecystokinin are likewise low-but it has not been
deterrrtined whether any of these biochemical abnormali­
ties, including the cholinergic ones, are primary or sec­
ondary to heterogeneous neuronal loss. Nevertheless, the
adrrtinistration of cholinomimetics---either acetylcholine
precursors (e.g., choline or lecithin), degradation inhibi­
tors (e.g., physostigrrtine ), or muscarinic agonists that
act directly on postsynaptic receptors-have had a mild
and unsustained therapeutic effect (see further under
"Treatment").
Chase and associates have demonstrated a 30 percent
reduction in cerebral glucose metabolism in Alzheimer
disease, greatest in the parietal lobes, but this seems most
likely to be secondary to tissue loss in these regions. Even
if not of pathogenic significance, it finds value as a diag­
nostic marker of the disease. The role of alurrtinum in the
genesis of neurofibrillary tangles, as was once proposed,
has never been validated. It has been suggested that the
use of estrogen by postmenopausal women or of antiin­
fl ammatory agents in men or women delayed the onset of
the disease or reduced its occurrence, but neither of these
have been corroborated by other studies.
Genetic Aspects of Alzheimer Disease (Table 39-1)
Of great importance was the aforementioned series of
discoveries in patients with inherited forms of Alzheimer
disease, of defective genes that code for errant APPs
localized to chromosome 21 near the ,8-amyloid gene
(St. George-Hyslop et al). As mentioned, this also pro­
vided an explanation for the Alzheimer changes that
characterize the brains of practically all patients with
the trisomy 21 defect (Down syndrome) who survive
beyond their twentieth year; they overproduce amyloid
as a result of the triplication of the gene. But gene defects
on chromosome 21 are responsible for only a small pro­
portion of familial cases and a rrtinuscule percentage of
disease overall. Other kindreds with familial Alzheimer
disease have been linked to rare dorrtinant mutations
of the presenilin genes on chromosome 14 (presenilin 1;
APP Amyloid precursor protein
PSI Presenilin 1
PS2 Presenilin 2
Apo E Apolipoprotein E
UBQLNl Ubiquilin 1
TREM2 TREM2
AD, autosomal dominant; SNP, single nucleotide polymorphism.
Sherrington et al), accounting in some series for up to 50
percent of familial cases, and on chromosome 1 (preseni­
lin 2), which may account for many of the remaining ones
(Levy-Lahad et al) . These are summarized in Table 39-1.
The age of onset of the disease in these familial forms, as
in the Down cases, is earlier than that in sporadic forms.
These cohorts of patients have provided great insight into
long duration between the appearance of amyloid in the
brain, approximately a decade, and the onset of clinical
disease, and they suggest the potential use of imaging
of chemical biomarkers for the disease (The Dominantly
Inherited Alzheimer Network; see Bateman et al).
It has been clear for some time that an excess or aber­
rant amyloid alone is an incomplete explanation for the
disease. Certain sequence variants in normal genes confer
an increased risk of the disease. The one first discovered
was Apo E, a regulator of lipid metabolism that has an
affinity for A[J in Alzheimer plaques, has been found to
modify the risk of acquiring Alzheimer disease. Of the
several isoforms of Apo E, the presence of E4 (and its
corresponding allele e4 on chromosome 19) is associ­
ated with a tripling of the risk of developing sporadic
Alzheimer disease (Roses; Strittmatter et al; Polvikoski et
al). This is the same allele that contributes to an elevated
low-density lipoprotein fraction in the serum. Possession
of two e4 alleles virtually assures the development
of disease in those who survive to their eighties. The
e4 allele also modifies the age of onset of some of the
familial forms of the disease. In contrast, the e2 allele is
underrepresented among Alzheimer patients. For these
reasons it has been proposed that Apo E, by interact­
ing with APP or tau protein in some way, modifies the
formation of plaques. Indeed, possession of the e4 allele
correlates with increased deposition of A[J in the brain
(McNamara). As pointed out by Hardy, Apo E appears to
act at a point in the pathogenesis that is after the various
genetic mutations have influenced the cellular pathol­
ogy that ostensibly causes Alzheimer disease. However,
these statistical relationships do not invariably connect
an allele to the disease in a particular individual. In other
words, the e4 allele does not act as a mendelian trait but
as a susceptibility (risk) factor. It follows that many, if not
most, individuals who develop Alzheimer disease do not
AD Early Rare but clinically simulates sporadic
Alzheimer disease
AD Early As above
AD Early As above
Haplotype Late Modifies susceptibility to Alzheimer
disease; s-4 allele represents risk
SNP Late Familial cases only
SNP La te E
 CHAPTER 39 Degenerative Diseases of the Nervous System 1 07 1

have the risk allele. Moreover, many individuals with

the e4 allele live into their seventies and eighties without
developing Alzheimer disease. All that can be stated with
certainty is that, on average, the presence of the e4 allele
accelerates the appearance of Alzheimer disease by about
5 years.
Another polymorphism in TREM2 is quite rare in
comparison to the aforementioned Apo E variants but
confers an equivalent risk of Alzheimer disease that has
been shown in several populations in (Guerreiro et al and
Jonsson et al) . In sporadic Alzheimer disease, the TREM2
polymorphism that is implicated in Alzheimer disease
putatively causes inadequate phagocytic clearance of
amyloid. Another rare modifying gene has been found in
familial cases at the UBQLNl (ubiquilin 1) site, coding for
a protein that interacts with PSl and PS2 and participates
in proteasomal degradation.
D i a g n ostic Stu d i e s
Studies with C T and MRI are useful, but not definitive
ancillary tests (Fig. 39-3). In patients with advanced
Alzheimer disease, the lateral and third ventricles are
enlarged to about twice the normal size and the cerebral
sulci are proportionately widened. Coronal MRI of the
medial temporal lobes may reveal a disproportionate
atrophy of the hippocampi and a corresponding enlarge­
ment of the temporal horns of the lateral ventricles. Early
in the disease, however, the changes do not exceed those
found in many mentally intact old persons. For this rea­
son, one cannot rely solely on imaging procedures for
diagnosis and CT and MRI are most valuable in excluding
alternative causes of dementia such as brain tumor, sub­
dural hematoma, cerebral infarction, and hydrocephalus.
The EEG undergoes mild diffuse slowing, but only late
in the course of the illness; it is useful again, in the exclu­
sion of alternative causes of mental decline that manifest
themselves in seizure activity or changes typical of meta­
bolic encephalopathy. The CSF is also normal, although Figure 39-3. Top: Coronal Tl-weighted MRI of a 74-year-old man
occasionally the total protein is slightly elevated. Using "I>V:ith moderate Alzheirner-type dementi a . Diffuse cerebral and
the constellation of clinical data, cerebral imaging in the hippocampal atrophy with ex vacuo ventricular and corti.cal sulcal
context of the age of the patient and time course of the dilation is noted. Bottom: Coronal Tl -weighted MRI of a 70-year-old
disease, the diagnosis of dementia of Alzheimer type is woman with behavioral variant frontotemporal lobar dementia.
Atrophy of the right greater than left temporal lobes is out of pro­
made correctly in 85 to 90 percent of cases.
portion to atrophy of the frontal and parietal lobes.
Of considerable value have been studies of cerebral
blood flow single-photon emission computed tomogra­
phy [SPECT]) and metabolism (positron emission tomog­
raphy [PET] ), which early in the illness often, but not a serial decline in ability. Certain aspects of attention and
always, show diminished activity in the parietal asso­ executive function in Alzheimer disease that also show
ciation regions and the medial temporal lobes. In most changes in Alzheimer disease were reviewed by Perry
cases, when such changes are evident, the diagnosis was and Hodges. The use of these examinations is described
already obvious on clinical grounds. Newer PET ligand in Chap. 2 1 .
agents that bind to amyloid, such as the "Pittsburgh com­ There are n o established biologic markers o f
pound" and tau-ligands are more sensitive in identifying Alzheimer disease with the possible exception o f the
and observing the course of Alzheimer disease. Their ratio of Af3 42 to tau, in the cerebrospinal fluid (the ratio is
main utility may be in detecting changes before brain low in Alzheimer disease). This test is used in some clin­
atrophy is evident and in identifying patients who have ics, but may not be well enough validated for routine use
the earliest changes of Alzheimer disease, whose disease (Maddalena et al) . Schoonenboom and colleagues have
course may be amenable to alteration by medications. shown that the incorporation of CSF phosphorylated tau
Neuropsychologic tests in the typical case show (p-tau) with the typical CSF amyloid/tau ratio may pro­
disproportionate deterioration in memory and verbal vide additional specificity in distinguishing Alzheimer
access skills. Testing is particularly useful when there is from other dementing diseases.
1 072 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
Diffe re nti a l D i a g n os i s of A l z h e i m e r D i sease
(See also Table 21-3)
Formerly, when virtually all forms of dementia were
untreatable, there was little advantage to either the
patient or the family in ascertaining the cause of the
cerebral disease. There are now adequate treatments for
a number of diseases and conditions that cause cognitive
decline, putting a premium on proper diagnosis.
The currently potentially treatable forms of demen­
tia are those caused by normal-pressure hydrocephalus;
chronic subdural hematoma; the dementia of AIDS;
paraneoplastic and related autoimmune encephalitis;
nutritional deficiencies (thiamine-Wernicke-Korsakoff
syndrome, Marchiafava-Bignami disease, pellagra, vita­
min B1 2 deficiency); chronic intoxication (e.g., alcohol,
sedatives); multiple cerebral infarctions; certain endo­
crine and metabolic disorders (myxedema, Hashimoto
encephalopathy), neurosyphilis and other chronic men­
ingitides, Cushing disease, chronic hepatic encephalopa­
thy; frontal and temporal lobe tumors; vascular demen­
tia, cerebral vasculitis; sarcoidosis; progressive multifocal
leukoencephalopathy (PML), Whipple disease; multiple
sclerosis; and sometimes neglected, the pseudodementia
of depression. Exclusion of most of these diseases is read­
ily accomplished by careful history, sequential clinical
evaluations, and testing of blood and CSF, EEG, CT, MRI,
and neuropsychologic testing can be undertaken. We
have regularly but infrequently incorporated the results
of metabolic brain imaging (both FDG-PET and amyloid­
ligand imaging) as well as CSF amyloid-tau ratio. We
anticipate that these tests or similar ones may find more
frequent use. In exceptional situations, brain biopsy may
be justified in the diagnosis of dementia, almost limited
to rapidly progressive cases. A perspective, albeit from
a sample that cannot be generalized to practice, has
been given by Warren and colleagues of 90 consecutive
brain biopsies performed between 1989 and 2003 for the
evaluation of dementia. More than half provided a diag­
nosis, mostly Alzheimer, Creutzfeldt-Jakob disease, and
infl ammatory disorders. However, reasonable assurances
must be given to the neurosurgeon that prion disease is
unlikely.
One problem in differential diagnosis is the distinc­
tion between a late-life depression and a dementia, espe­
cially when some degree of both is present. Observation
over several weeks or more, and the patient's demeanor,
makes the distinction clearer. Multiinfarct dementia is
usually not difficult to separate from Alzheimer demen­
tia, as discussed further on. The dementia of normal­
pressure hydrocephalus may also be confused with
Alzheimer dementia (see Chap. 30) . The problem of
distinguishing Alzheimer disease from a more "benign"
form of memory decline associated with aging comes
up frequently in practice, as discussed further on. These
treatable conditions are discussed in Chaps. 21, 30, and
34 and the important topic of depression is addressed
in Chap. 52. Often we have been confident on clinical
grounds that a patient had Alzheimer disease, only to
have revealed at autopsy that progressive supranuclear
palsy, Lewy-body disease, Pick disease, another non-
Alzheimer degeneration of the frontal lobes, or cortical­
basal-ganglionic degeneration was the cause. All are
discussed later in this chapter.
Tre at m e n t
There i s n o evidence that any o f the formerly proposed
therapies for Alzheimer disease-cerebral vasodilators,
stimulants, L-dopa, massive doses of vitamins B, C, and
E, gingko biloba, hyperbaric oxygen, intravenous immu­
noglobulin, and many others-have any salutary effect.
Trials of oral physostigmine, choline, and lecithin have
yielded mostly negative or uninterpretable results.
The effect of the currently used cholinergic precur­
sors and agonists and acetylcholinesterase inhibitors,
such as donepezil, is modest. With regard to the latter
group of drugs, several large trials have demonstrated a
slight prolongation of the patient's ability to sustain an
independent life, but such evidence generally requires
that the medications be taken for 6 to 12 months. For
example, a meta-analysis of the drugs collectively dem­
onstrated a mean improvement of 2 to 3 points on the
70-point Alzheimer Disease Assessment Scale and a
slight delay in progression. Despite some trials that have
failed to demonstrate benefit (c.f., AD 2000 Collaborative
Group), the balance of evidence favors the use of these
medications in practice, but only in mildly or moderately
affected patients.
Side effects of the aforementioned class of drugs may
include nausea and less often, vomiting. The families of
our patients report from time to time that the medication
caused insomnia or increased confusion. It is worth men­
tioning that when the acetylcholine receptor antagonist
succinylcholine is used prior to general anesthesia, its
effects may be prolonged in patients taking the above
drugs. The use of trazodone, haloperidol, thioridazine,
risperidone, and related drugs may suppress some of
the aberrant behavior and hallucinations when these are
problems, making life more comfortable for both patient
and family, but several trials suggest that their general
application causes more problems than it solves and
they must often be discontinued in response to adverse
effects. The randomized trial conducted by Schneider
and coworkers found that olanzapine, quetiapine, and
risperidone for the treatment of psychosis, aggression, or
agitation with Alzheimer disease were approximately as
good as placebo in relieving these symptoms, but largely
because the drugs were not tolerated. Olanzapine was
slightly preferable in those who continued taking the
medication. The clinician is left with little recourse but
to use this class of medications or haloperidol to control
unmanageable behavior. Small doses of diazepines, such
as lorazepam, are useful when sleep is severely dis­
turbed, but they often increase confusion as well.
The N-methyl-o-aspartate (NMDA) glutarninergic
antagonists, specifically memantine (20 mg daily), have
also been tried. In a study of memantine by Reisberg
and colleagues of 252 patients (187 of whom completed
the trial), there were better results on a few scales that
reflected functional behavior compared to the use of
placebo, but there was no change in 3 main measures
of cognitive performance. Because the side effects were
 CHAPTER 39
ostensibly minor, this drug has been approved for use in
late-stage Alzheimer disease and in conjunction with cho­
linergic drugs. Nevertheless, hallucinations or agitation
may occur and require discontinuation. The combination
of memantine and donepezil in moderately to severely
affected patients offered no benefit over either drug alone
(Howard et al) . The effects of these drugs in later stages of
the disease are, in any case, minimal.
A provocative series of studies using a small mol­
ecule inhibitors of the enzyme y-secretase (semagaces­
tat; see Doody et al, 2013), and a monoclonal antibody
directed at soluble forms of amyloid (solanezumab; see
Doody et al, 2014) have failed to demonstrate clear ben­
efit in early Alzheimer disease. The presumption is that
such agents might be useful if started in the presymptom­
atic stages of disease.
A series of animal experiments that demonstrated
the possibility of removal of plaques by immunization
against amyloid has led to human studies with a similar
vaccination. One trial was stopped because of the occur­
rence of an immune encephalitis in a small number of
patients, but in autopsy material there were indications
that this novel approach may have had the desired effect
of reducing amyloid deposition (Orgogozo et al). Revised
vaccines are being formulated for further testing of this
approach.
Given the state of therapeutics for Alzheimer dis­
ease, always important is the general management of
the demented patient, which should proceed along the
lines outlined in Chap . 21, keeping in mind that the phy­
sician's counsel is often the family's main resource for
important medical and social decisions.
Associ ated Pat h o l og i c States
As indicated earlier, the histologic changes of Alzheimer
disease have a number of interesting associations. Amyloid
plaques and tangle deposition are far more common in the
brains of patients with Parkinson disease (20 to 30 per­
cent) than in the brains of age-matched controls (Hakim
and Mathieson). These findings partly explain the high
incidence of dementia in patients with Parkinson dis­
ease (see further on). As mentioned, with the advance of
Alzheimer disease, extrapyramidal features may emerge.
In such cases, Burns and colleagues have found changes in
the substantia nigra including accumulation of synuclein
and tau representative of Lewy bodies. Another associa­
tion between the 2 diseases is apparent in the Guamanian
Parkinson-dementia complex, which is also discussed below.
In this entity, the symptoms of dementia and parkinsonism
are related to neurofibrillary changes in the cerebral cor­
tex and substantia nigra, respectively; senile plaques and
Lewy bodies are unusual findings. What can be deduced
from the crossover syndromes is that multiple degenera­
tive changes can occur in these diseases and give rise to
heterogeneity in clinical presentation.
The finding of neurofibrillary tangles (and to a lesser
extent of plaques) in boxers ("punch-drunk" syndrome, or
dementia p ugilistica)
is another interesting ramification
of the Alzheimer disease process in that trauma appears
to be able to elicit one of the core features of the disease
as discussed in Chap . 35 . Some cases of primary progres-
Degenerative Diseases of the Nervous System 1 073
sive aphasia (see further on) have Alzheimer change and
amyloid plaque deposition as the primary pathologic
change. There are other unusual and meaningful asso­
ciations, such as dementia with motor neuron disease
or the cases of familial dementia with spastic paraplegia
reported by Worster-Drought and by van Bogaert and
their associates (see later in this chapter) . Here, neuro­
fibrillary change is the most prominent feature whereas
amyloid plaques are negligible in number or absent.
Another provocative connection is the already men­
tioned interrelationship between cerebrovascular disease
and Alzheimer disease. This is a complex area that at one
time, considered the 2 processes to be intimately related
and later, was rejected, only to now be resurrected with
clearer focus, as discussed Chap 34.
Lobar Atroph ies ( Frontotempora l Lobar
Degeneration, Posterior Lobar Degeneratio n )
This broad category o f disease has evolved and the
nosology is confusing because type of selective atrophy
of a cerebral lobe may be caused by several different
histopathologic changes. The notion of lobar atrophy
was introduced in 1892 when Arnold Pick of Prague
described a special form of cerebral degeneration in
which the atrophy was circumscribed (most often in the
frontal or temporal lobes), with involvement of both gray
and white matter; hence the term he applied was lobar
rather than cortical sclerosis. In 1911, Alzheimer presented
the first careful study of the microscopic changes, fol­
lowed by even more complete analyses of the pathologic
changes by the prominent neuropathologists of the age.
As mentioned the pathologic change associated may be
any one of several types: Pick inclusion bodies, neurofi­
brillary tangles, other inclusions, or with no characteristic
changes except for neuronal loss. Contrariwise, gliosis
and mild spongiform changes in the superficial layers
of cortex, and even typical plaque and tangle pathology,
have all been associated with syndromes of gross atrophy
of the frontal or temporal lobes. What has emerged since
his work is that the most common and important of the
lobar atrophies is a group of frontotemporal degenera­
tions that have diverse clinical and pathologic profiles.
In contrast to Alzheimer disease, in which the atro­
phy is relatively diffuse, the pathologic change in lobar
atrophy is circumscribed and often asymmetrical. The
parietal lobes are involved less frequently than the frontal
and temporal lobes. The affected gyri become paper thin,
resembling, in the advanced stages, the kernel of a dried
walnut. The cut surface reveals not only a marked nar­
rowing of the cortical ribbon but a grayish appearance
and reduced volume of the underlying white matter. The
corpus callosum and anterior commissure share in the
atrophy but almost certainly as secondary phenomena.
The overlying pia-arachnoid is often thickened, and the
ventricles are enlarged. The pre- and postcentral, supe­
rior temporal, and occipital convolutions are relatively
unaffected and stand out in striking contrast to the
wasted parts.
The more common frontotemporal lobar degenera­
tions (FTLDs) (to which Pick's name was attached) may
1 07 4 P a rt 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
display any one of several pathologic changes and reflect
different genetic causes. For example, the behavioral or
the aphasic variants of FTD, which are described below,
may be the result of the deposition of tau, progranulin,
amyloid, or synuclein. It is not clear to us if the term "Pick
disease" is worth retaining to denote a unique process
aside from the unusual type that is due to deposition of
argyrophilic intracytoplasmic inclusions (Pick bodies)
and diffusely staining ballooned neurons (Pick cells).
In other respects, it is simply one of the large group of
FTLDs. It is the lobar atrophy and marked changes in the
underlying white matter that provide the unifying ele­
ments of this group of diseases.
C l i n i c a l a n d Pat h o l o g i c Featu res
The descriptive terms frontotemporal lobar atrophy and
frontotemporal dementia are used by neurologists and
neuropathologists to refer to a clinical syndrome that is
associated with degeneration of the frontal and tempo­
ral lobes. Some of the clinical aspects of frontotemporal
dementia were discussed in Chap. 21, but broadly speak­
ing, there are 2 main types: a behavioral variant and a
language variant, the latter being divided into semantic
dementia, progressive nonfluent aphasia, and a logope­
nic variant, all described below.
Behavioral Variant FTLD Patients under consider­
ation with behavioral changes present with personality
and related abnormalities that include apathy, disinhibi­
tion, perseveration, poor judgment and limited ability
for abstraction, loss of empathy, bizarre affect, eating
disorders, and a general disengagement. Insight is almost
always impaired and some subjects become euphoric or
display repetitive compulsive behaviors. An initial diag­
nosis of depression has been common. Other psychiatric
symptoms such as sociopathic and disinhibited behav­
ior with aspects of hyperorality and hyperphagia may
predominate late in the illness. Utilization behavior (the
compulsive use of implements and tools put before the
patient) is also displayed in advanced cases.
CT, MRI, and functional imaging demonstrate a dis­
proportionate atrophy and hypofunction in the frontal
lobes, usually asymmetric. A proportion of patients with
this type of frontotemporal dementia have parkinsonian
features. A form of motor neuron disease is also linked
to frontotemporal dementia in a small number of cases.
This is particularly the case in the Guamanian (now
called western Pacific) variety and in the heredofamilial
frontotemporal atrophy linked to a mutation on chromo­
some 1 7.
In some writings on this subject, the term frontotem­
poral dementia has come to be used in a highly restricted
sense, being assigned to cases that show only tau-staining
material in neurons. Most of the cases are sporadic, but
the inherited variety linked to chromosome 1 7, in which
parkinsonism is prominent, supports its distinction as
a separate entity; it is in these cases that the intraneural
deposition of tau is most striking, in both the frontotem­
poral cortex and the substantia nigra. In a few familial
cases, this process is attributable to mutations in the gene
on chromosome 17 that encodes the tau protein. These
mutations alter the proportions of different isoforrns of
this protein and lead both to tau accumulation and its
hyperphosphorylation. Indeed, many cases of frontotem­
poral dementia are associated with tau gene mutations.
However, abnormal aggregates of tau have been identi­
fied in practically all neurodegenerative atrophies and,
of course, form the main constituent of the paired helical
filaments (neurofibrillary tangles) of Alzheimer disease,
and in progressive supranuclear palsy where they are
abundant, although of slightly different structure. From
the observations of Brun and Passant and of Neary and
associates, pure tau-reactive cases outnumber Pick dis­
ease when the latter is strictly defined by the cortical
white matter degeneration and Pick inclusions.
Nonetheless, a frontotemporal dementia identical to
that of the tau-reactive cases has been observed in others
without any tau or synuclein staining of neurons. Many
of the frontally predominant cases have shown deposi­
tion of the protein progranulin, consisting mainly of a
ubiquitin neuronal inclusion consisting of TDP-43 (TAR
DNA-binding protein), the result of PGRN mutations.
Primary Progressive Aphasias (PPA) Focal distur­
bances, particularly aphasia and apraxia, occur early and
prominently in certain patients with lobar degenerations,
indicating a lesion in the left frontal or temporal lobes.
Viewed from another perspective, a prominent language
disorder has been described in almost two-thirds of all
patients with temporal lobe atrophy.
Several types of this disturbance have been delin­
eated. In the first, progressive nonfluent aphasia, the patient
initially speaks less and has word-finding difficulty (ano­
mia), but language structure is intact (Mesulam, 1982);
later, he may forget and misuse words and soon fails to
understand much of what is heard or read. Sentences
are short and telegraphed. Later, dysarthria and apraxia
become apparent and finally, the patient is virtually
mute, seemingly without impulse to speak, and with an
inability to form words (Snowden et al, 1992).
A second type, semantic dementia, is characterized by
early difficulty naming items, people, and words, fol­
lowed by verbal perseveration, but fluency is retained.
There is considerable difficulty in generating lists of
words of a given category, such as animals. These indi­
viduals are quite aware that they are having trouble
finding words. Eventually the patient loses not just the
use of names of people and objects, but also their mean­
ing, or the conceptual knowledge of the word. Some may
develop severe prosopagnosia, especially if the atrophy
is predominantly right sided. Memory for day-to-day
events is preserved.
A third type has been proposed, logopenic aphasia,
that shares most aspects of nonfluent aphasia but in
which the meaning of words is retained.
According to Mesulam (2003), who has studied the
condition extensively, 60 percent of these cases show no
characteristic pathologic change, 20 percent have Pick
bodies, and a similar proportion show the typical changes
of Alzheimer disease in the affected cortical region. A clear
familial tendency has not been found. Chapter 23 can be
consulted for details of the aphasic disorders.
Posterior Cortical Atrophy This regional variant
of lobar degeneration has been slightly less frequent than
 CHAPTER 39
primary progressive aphasia i n o ur practices. The funda­
mental feature is the progressive loss of the ability to
understand and use visual information. The result is
progressive and ultimately severe visuospatial difficulty
with a relative preservation of memory. Prosopagnosia,
achromatopsia, and dyslexia emerge, or, there may be dif­
ficulty with depth perception, reaching for objects and an
inordinate sensitivity to bright light. Patients under our
care have initially had a vague sense of visual disorientation
followed over months by difficulty in seeing or recognizing
objects in front of them. Many have alexia with agraphia
while others have acalculia or the other elements of the
Gerstmann syndrome. Several eventually become cortically
blind. The syndrome is essentially that of an apperceptive
visual disturbance that includes fragments of the Balint and
the Gerstmann syndromes. The average age of onset is about
60 years. The most common pathologic change in most
reports has been characteristic of Alzheimer disease.
Lewy-body Dem entia
(Diffuse Lewy-body Disease)
Next to Alzheimer disease, diffuse Lewy-body disease, or
Lewy-body dementia, has been the most frequent patho­
logic diagnosis established in many series of globally
demented patients. Reports of this condition have been
increasing steadily since the original communication by
Okazaki and colleagues in 1961 (see review by Kosaka).
The disease is defined by the diffuse involvement of
cortical neurons with Lewy-body inclusions and by an
absence or inconspicuous number of neurofibrillary
tangles and amyloid plaques. To some extent, increased
recognition of this disorder is a result of improved histo­
logic techniques, particularly the ability to detect ubiqui­
tin and synuclein, main components of the Lewy body, by
immunostaining. With this improved detection has come
a better definition of the clinical syndrome and its dis­
tinctions from Alzheimer and other dementias. Because
the Lewy bodies in cortical neurons are not surrounded
by a distinct halo, as they are in the substantia nigra in
cases of Parkinson disease (see further on for discussion
and photomicrograph of a typical Lewy body) they were
not readily appreciated. Aggreagated a-synuclein is the
main component of the Lewy body an observation that
will prove important in understanding both Parkinson
disease and Lewy-body dementia.
C l i n i c a l Featu res
The disease in its typical form is marked by parkinsonian
features, dementia, and a tendency to episodic delirium,
especially nocturnally, and rapid eye movement (REM)
sleep behavior disorder (described below and in Chap. 19).
Diagnostic criteria have been offered by a working group,
requiring 2 of 3 of the following: a parkinsonian syndrome
(usually symmetric), fluctuations in behavior and cognition,
and recurrent hallucinations (McKeith et al). The latest
recursion of this group's criteria emphasizes the presence
of the REM sleep behavior disorder and severe neurolep­
tic sensitivity.
In an analysis of 34 cases of diffuse Lewy-body dis­
ease, Burkhardt and colleagues, found that the most char-
Degenerative Diseases of the Nervous System 1 07 5
acteristic syndrome was one of progressive dementia in
an elderly patient with the additional late onset of parkin­
sonism in many cases. In Lennox's summary of 75 cases,
parkinsonism, particularly with limb and axial rigidity,
was a prominent feature in 90 percent once the illness
was fully developed, and almost half had tremor of the
parkinsonian type (this is somewhat different from other
series). Byrne and associates, as have many others, pointed
out that episodic confusion, hallucinations, and paranoid
delusions were features of Lewy-body dementia; such psy­
chotic aspects are generally uncharacteristic of Alzheimer
and lobar dementias, and only then, in advanced stages. In
Lennox's review, one-third of patients had these swings in
behavior, but as the illness advanced, amnesia, dyscalculia,
visuospatial disorientation, aphasia, and apraxia differed
little from those of Alzheimer disease. In the cases reported
by Fearnley and coworkers, there was a supranuclear gaze
palsy simulating that of progressive supranuclear palsy.
These overlapping clinical features make diagnosis dif­
ficult unless the specific feature of episodic hallucinations
is evident. Difficulty in diagnosis also arises because the
parkinsonian disorder may be either mild or prominent
and may occur as an early or a late manifestation.
The parkinsonian features can respond favorably to
L-dopa, but only for a limited time and sometimes at the
expense of causing an agitated delirium or hallucinations
that would be uncharacteristic of early Parkinson disease
(Hely et al); in others, the response to L-dopa is inconsis­
tent or inapparent. Some patients also have orthostatic
hypotension corresponding to cell loss and Lewy bodies
in the intermediolateral cell column of the spinal cord or
in the sympathetic ganglia, thereby simulating striatoni­
gral degeneration or Shy-Drager syndrome (see further
on) . Others have commented on an extreme sensitivity of
such patients to neuroleptic drugs, including increased
confusion and greatly worsening parkinsonism or the
development of the neuroleptic malignant syndrome.
In our experience with Lewy-body disease, the par­
kinsonian symptoms have been more prominent than
they are in progressive supranuclear palsy, and the most
characteristic feature besides the movement disorder and
a slowly advancing dementia has been a vacuous, anxious
state with intermittent psychotic or delirious behavior.
At least one randomized trial has described benefit
from the anticholinesterase inhibitor, rivastigrnine, in
reducing delusions, hallucinations, and anxiety (McKeith
and colleagues, 2000). With regard to diagnostic testing,
the finding of reduced activity in the posterior parietal
cortical regions on PET scans (as in Alzheimer disease)
has been found as a relatively consistent, but not invari­
able, feature.
Other Degenerative Dementias
Argyro p h i l i c G ra i n D i sease
This obscure entity has been connected with a late­
life dementia in which behavioral disturbances precede
memory difficulty. Whether the finding of argyrophilic
grains in the mediotemporal lobe, different from tau­
laden neurofibrillary tangles and from the glial inclusions
1 07 6 P a rt 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
(putatively a defirung feature of multiple system atrophy),
constitutes a specific entity is not clear to the authors. The
finding overlaps with the deposition of other materials
that are more closely associated with dementing diseases
such as phosphorylated tau and Lewy bodies. Probst and
Tolnay remarked that these small argyrophilic inclusions
are not found in nondemented individuals. It is unlikely
that the condition can be identified in life; if it is a genu­
ine entity, it must be rare. The interested reader may
consult the review by Ferrer.
N e u rose rp i n o pathy
There have been infrequent case reports of dominantly
inherited, adult-onset dementia with a fulminant evolu­
tion suggestive of encephalopathy and the special feature
of seizures. The distinctive feature has been the presence
at autopsy of large eosinophilic, PAs-positive intraneu­
ronal inclusions that contain aggregates of neuroserpin,
thus the initial description of "familial encephalopathy
with neuronal inclusion bodies. " The serpins are a family
of protease inhibitors that include neuroserpin, a protein
expressed exclusively in neurons, and lXt -antitrypsin. The
neuronal inclusions are densest in the deep layers of the
cortex and in the substantia nigra. Missense mutations in
the gene encoding neuroserpin have been identified as
the cause. This entity is reviewed by Lomas and Carrell.
DEM ENTING DISEASES IN WHICH
OTH ER N E U ROLOGIC ABNORMALITI ES
ARE PROM I N ENT
H u nti ngton Disease ( H u ntington Chorea )
This disease, distinguished by the triad of dominant
inheritance, choreoathetosis, and dementia, commemo­
rates the name of George Huntington, a medical practi­
tioner of Pomeroy, Ohio. In 1872, his paper, read before
the Meigs and Mason Academy of Medicine and pub­
lished later that year in the Medical and Surgical Reporter
of Philadelphia, gave a succinct and graphic account of
the disease that was based on observations of patients
that his father and grandfather had made in the course
of their practice in East Hampton, Long Island. Reports
of this disease had appeared previously (see DeJong for
historical background) but they lacked the completeness
of Huntington's description. In 1932, Vessie was able to
show that practically all the patients with this disease
in the eastern United States could be traced to about 6
individuals who had emigrated in 1630 from the tiny East
Anglian village of Bures, in Suffolk, England. One remark­
able family was traced for 300 years through 12 generations,
in each of which the disease had expressed itself.
To quote Huntington, the rule has been that "When
either or both of the parents have shown manifestations
of the disease, one or more of the offspring invariably
suffer of the disease, if they live to adult life. But if by any
chance these children go through life without it, the thread
is broken and the grandchildren and great grandchildren
of the original shakers may rest assured that they are free
from disease." Davenport, in a review of 962 patients with
Huntington chorea, found only 5 who had descended from
unaffected parents. Possibly, in these 5 patients, a parent
had the trait, in very mild form, or parentage was in ques­
tion, because spontaneous mutations are rare.
In university hospital centers, this is a regularly
observed type of hereditary nervous system diseases and
the main cause of progressive chorea at most ages. Its
overall frequency is estimated at 4 to 5 per million, and
30 to 70 per million among whites of northern European
ancestry. The usual age of onset is in the fourth and fifth
decades, but 3 to 5 percent begin before the fifteenth year
and some even in childhood, where it takes on special
form. In approximately 30 percent, symptoms become
apparent after 50 years. The progression of the disease
is generally slower in older patients for reasons noted
below. Once begun, the disease progresses relentlessly,
until only a restricted existence is possible and a medical
disease terminates life.
Exhaustive genealogic documentation many years
ago established the cause to be an autosomal dominant
gene with complete penetrance. Koller and Davenport
made the observation that young patients usually inherit
the disease from their fathers and older patients from
their mothers. It has been observed beginning at almost
the same age in identical twins.
The first important achievement in respect to the
biologic understanding of Huntington disease was the
discovery by Gusella and colleagues of a marker linked
to the Huntington gene and localized to the short arm of
chromosome 4. Subsequently, these investigators and oth­
ers identified the mutation as an excessively long repeat
of the trinucleotide CAG within the Huntington gene,
the length (number) of which determines not only the
presence of the disease, but also the age of onset, longer
repeat lengths being associated with an earlier appear­
ance of signs. At the Huntington gene locus there are
normally 11 to 34 (median: 19) consecutive repetitions of
the CAG triplet, each coding for glutamine. Individuals
with 35 to 39 triplets may eventually manifest the disease
but it tends to be late in onset and mild in degree, or lim­
ited to the below-mentioned "senile chorea. " Those with
more than 42 repeats almost invariably acquire the signs
of disease if they live long enough. The rare alternative
mutation, termed HDL2 (Huntington disease-like-2),
is associated with CATCG repeat expansion of the jun­
tophilin-3 gene, but it is so infrequent that few clinicians
will encounter it (Margolis et al).
These discoveries have made possible the devel­
opment of a genetic test for the measurement of the
repeat length that confirms the diagnosis in symptomatic
patients and allows screening of asymptomatic individu­
als. Because there is no treatment for the disease, testing
raises certain ethical considerations that must be resolved
before its widespread utilization.
C l i n i c a l Featu res
The mental disorder assumes several subtle forms long
before the more obvious deterioration of cognitive func­
tions becomes evident. In approximately half the cases,
 CHAPTER 39
slight but annoying alterations of personality are the first
to appear. Patients begin to find fault with everything,
to complain constantly, and to nag other members of
the family; they may be suspicious, irritable, impulsive,
eccentric, untidy; or excessively religious, or they may
exhibit a false sense of superiority. Poor self-control
may be reflected in outbursts of temper, fits of despon­
dency, slovenliness, alcoholism, or sexual promiscuity.
Disturbances of mood, particularly depression, are com­
mon (almost half of the patients in some series) and may
constitute the most prominent symptoms early in the
disease. Invariably, sooner or later, the intellect begins
to fail globally. The patient becomes less communicative
and socially withdrawn. The emotional disturbances and
changes in personality may reach such proportions as to
constitute a virtual psychosis with persecutory delusions
or hallucinations.
Diminished work performance, inability to manage
household responsibilities, and disturbances of sleep may
prompt medical consultation. There is difficulty in main­
taining attention and concentration and in assimilating
new material. Mental flexibility lessens. Simultaneously;
there is loss of fine manual skills (see further on) . The
performance parts of the Wechsler Adult Intelligence
Scale show greater loss than the verbal parts. Memory is
relatively spared. This gradual dilapidation of intellectual
function has been characterized as a "subcortical demen­
tia," that is elements of aphasia, agnosia, and apraxia are
observed only rarely and memory loss is not profound.
Often the process is so slow, particularly in cases of late
onset, that a fair degree of intellectual capacity seems to
be retained for many years.
The abnormality of movement is subtle at first and most
evident in the hands and face; often the patient is merely
considered to be fidgety, restless, or "nervous. " Slowness
of movement of the fingers and hands, a reduced rate of
finger tapping, and difficulty in performing a sequence
of hand movements are early signs. Gradually these
abnormalities become more pronounced until the entire
musculature is implicated with chorea. The frequency of
blinking is increased (the opposite of parkinsonism), and
voluntary protrusion of the tongue, like other attempts at
sustained posture, is constantly interrupted by unwanted
darting movements. In the advanced stage of the disease
the patient is seldom still for more than a few seconds. The
choreic movements are slower than the brusque jerks and
postural lapses of Sydenham chorea, and they involve
many more muscles. They tend to recur in stereotyped
patterns yet are not as stereotyped as tics. In advanced
cases, they acquire an athetoid or dystonic quality.
Muscle tone is usually decreased until late in the illness,
when there may also be some degree of rigidity, tremor,
and bradykinesia, elements suggestive of Parkinson
disease. Parkinsonism with rigidity characterizes the
Westphal or "rigid" variant, which is more common with
a childhood onset, or the HDL2 genetic variant noted
earlier. Tendon reflexes are exaggerated in one-third of
patients, but only a few have Babinski signs. Voluntary
movements are initiated and executed more slowly than
normal, but there is no weakness and no ataxia, although
speech, which becomes dysarthric and explosive because
Degenerative Diseases of the Nervous System 1 07 7
of incoordination between tongue and diaphragm, may
convey the impression of a cerebellar disorder. Inability to
hold the tongue protruded is characteristic. In late-onset
cases there may be an almost constant rapid movement of
the tongue and mouth, simulating the tardive dyskinesia
that follows the use of neuroleptic drugs. These disorders
of movement that characterize Huntington chorea are
described more fully in Chap. 4.
Oculomotor function is subtly affected in most
patients (Leigh et al; Lasker et al) . Particularly character­
istic are impaired initiation and slowness of both pursuit
and volitional saccadic movements and an inability to
make a volitional saccade without movement of the head.
Excessive distractibility may be noticed during attempted
ocular fixation. The patient feels compelled to glance at
extraneous stimuli even when specifically instructed to
ignore them. Upward gaze is often impaired as the illness
progresses.
As Wilson stated, the relation of the choreic to the
mental symptoms "abides by no general rule. " Most
often the mental symptoms precede the chorea but they
may accompany or follow it, sometimes by many years.
Once the movement disorder is fully established, there
is nearly always some degree of cognitive abnormality.
Exceptional cases have been reported in which the move­
ment disorder existed for 10 to 30 years without mental
changes (Britton et al); this would be most characteristic
of patients with fewer CAG repeats. More typically after
10 to 15 years of symptoms, most patients deteriorate to
a vegetative state, unable to stand or walk and eating
little; in this late stage, a mild amyotrophy may appear.
Noteworthy is the high suicide rate, as pointed out by
Huntington himself (see also Schoenfeld et al) . Because
there is a higher-than-normal incidence of head trauma,
chronic subdural hematoma is another common finding
at autopsy.
The first signs of the disease may appear in child­
hood, before puberty (even younger than the age of
4 years), and several series of such early-onset cases
have been described (Farrer and Conneally; van Dijk
et al) . Mental deterioration at this early age is more often
accompanied by cerebellar ataxia, behavior problems,
seizures, bradykinesia, rigidity, and dystonia than by
chorea (Byers et al) . However, this rigid form of the dis­
ease (Westphal variant) also occurs occasionally in adults
as mentioned above, in some cases because of HDL2.
Functional decline is much faster in children than it is in
adults (Young et al) .
The dementia is generally more severe in cases of early
onset and with correspondingly longer repeat lengths
(15 to 40 years of age) than in those of later onset (55
to 60 years of age) . In adult patients with early onset, the
emotional disturbance tends to be more prominent initially
and precedes the chorea and intellectual loss by years;
with older age of onset, choreiform features are more often
the initial components; in the middle years, dementia and
chorea have their onset at nearly the same age. At the other
extreme of age, the first features may become evident in
the eighties, with orofacial or other dyskinesias that are
mistakenly attributed to an exposure to neuroleptic drugs
or called "senile chorea" (see Chap. 4).
1 07 8 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
Figure 39-4. Axial CT from a 54-year-old mildly demented woman
with a 10-year history of Huntington chorea. The bulge in the infero­
lateral border of the lateral ventricle, normally created by the head
of the caudate nucleus, is obliterated. There is also diffuse enlarge­
ment of the lateral ventricles.
Path o l og y a n d Pat h o g e n e s i s
Gross atrophy bilaterally o f the head o f the caudate
nucleus and putamen is the characteristic abnormality,
usually accompanied by a moderate degree of gyral
atrophy in the frontal and temporal regions. The caudate
atrophy alters the configuration of the frontal horns of the
lateral ventricles in that the inferolateral borders do not
show the usual bulge formed by the head of the caudate
n� cleus. In � ddition, the ventricles are diffusely enlarged
(F1g. 39-4); m CT scans, the bicaudate-to-cranial ratio is
increased, which corroborates the clinical diagnosis in the
moderately advanced case.
The early articles of Alzheimer and Dunlap and
the more recent one of Vonsattel and DiFiglia contain
the most authoritative descriptions of the microscopic
changes. The latter authors have graded the disease into
early, moderately advanced, and far advanced stages. In
5 early but genetically verified cases, no striatal lesion
was found, which suggests that the first clinical mani­
festations are based on a biochemical or infrastructural
change. This view is supported by the observation that
Huntington patients studied with PET show a character­
istic decrease in glucose metabolism in the caudate nuclei,
which precedes the volumetric loss of tissue (Hayden et al).
The striatal degeneration begins in the medial part of
the caudate nucleus and spreads, tending to spare the
nucleus accumbens. Of the 6 cell types in the striatum
(a differentiation based on size, dendritic arborizations
spines, and axon trajectories), the smaller neurons ar�
affected before the larger ones. Loss of dendrites of the
small spiny neurons has been an early finding, while the
large cells are relatively preserved and exhibit no special
alterations.
The anterior parts of the putamen and caudate are
more affected than the posterior parts. Some observers
have noted changes in the globus pallidus, subthalamic
nucleus, red nucleus, cerebellum, and in the pars reticu­
lata of the substantia nigra. In the cerebral cortex, there is
slight neuronal loss in layers 3, 5, and 6, with replacement
gliosis. Cases are reported with typical striatal lesions but
normal cortices in which only chorea had been present
during late life. Several neuropathologists have observed
marked cell loss and gliosis in the subthalamic nuclei
in Huntington-affected children or young adults with
chorea and behavior disorders. However, Hadzi and col­
leagues have determined that the pathologic changes in
the striatum and the cortex evolve differently and have
separate relationships to the CAG repeat length.
Mechanism of Disease As mentioned above, there
is a general relationship between the number of CAG
repeats and the age of onset of symptoms. It has been
found that it is the longer sequence on either of the 2
alleles that determines the age of onset, the size of the
expansion of the normal allele exerting no influence
(Lee et al, 2012). Earlier onset in successive generations
(ant cipation � is well described in the early writings on the
�
subject and 1s now known to be attributable to increasing
lengths of the CAG repeat sequence.
From the molecular perspective, the pathogenesis
of this disease is a direct, but still poorly understood,
consequence of the aforementioned expansion of the
polyglutarnine region of huntingtin (the protein prod­
uct of the Huntington gene) . It has been shown that
the mutant huntingtin protein aggregates in the nuclei
of neurons. Moreover, the protein accumulates prefer­
entially in cells of the striatum and parts of the cortex
affected in Huntington disease. Evidence, particularly
.
that g1ven by Wetz (cited in the review by Bates), sug­
gests that these aggregates may be toxic to neurons, either
directly or in their protofibrillary (unaggregated) form.
The situation is, however, likely to be more complex, as
the bulk of huntingtin deposition is found in cortical neu­
rons, whereas the neuronal loss is predominantly striatal.
One theory supports the concept that the polyglutarnine
complex renders certain cell types unduly sensitive
to glutamate-mediated excitotoxicity. More recently, 2
mechanisms have been proposed based on an interrup­
tion of protein transcription by the binding of mutant
huntingtin to transcription proteins or that mitochondrial
dysfunction occurs directly or through the same tran­
scriptional mechanism, as summarized by Greenamyre.
Because polyglutarnine expansions are implicated in
several neurodegenerative diseases (reviewed in corre­
sponding sections of this chapter), treatments that block
their effects on cellular function may be broadly effective
in several degenerative diseases.
 CHAPTER 39
D i a g n os i s
Once the disease has been observed in its fully developed
form, its recognition requires no great clinical acumen.
The main difficulty arises in patients who lack a fam­
ily history but who display progressive chorea, emo­
tional disturbance, and dementia. This problem has been
largely overcome since the mutation w� iden�ified. It is
now possible to confirm or exclude the diagnosis by anal­
ysis of DNA from a blood sample. The presence of more
than 39 CAG repeats at the Huntington locus essentially
confirms the disease and gives some indication of the
expected time of onset; lesser numbers of repeat length
leave room for equivocation and strings between 39 and
42 may not be manifest if the patient does not live long
enough to express the illness.
Chorea that begins in late life with only mild or ques­
tionable intellectual impairment and without a family his­
tory of similar disease is a source of diagnostic difficulty.
A few cases are the result of the earlier mentioned HDL2
mutation and others derive from alternative degenerative
conditions discussed below. Referring to the problem as
"senile chorea" does not solve the problem. Indeed, senile
chorea has many causes. We have seen it appear with
infections, hyperglycemia, drug therapy, strokes, and
thyrotoxicosis, only to disappear after a few weeks. A
few times we have been confronted with the problem of
an older patient who displays orolingual dyskinesias that
are most characteristic of exposure to neuroleptic drugs
but in whom there was no such history of exposures; test-
ing usually disclosed Huntington dis�ase.
. also help alleviate abnormalities of behavior or emo­
Chorea in early adult life always rruses the question of
a late form of Sydenham chorea, of lupus erythematosus
with antiphospholipid antibodies, or of co� ain� use, but
.
neither familial occurrence nor mental detenoration IS part
of these processes. A "benign inherited chorea," transmit­
ted as an autosomal dominant trait without prolongation
of a triplet sequence, has been traced to chromosome
14q. It is differentiated from Huntington disease by ons� t
before age 5 years, progressing little, and having no assoCI­
ated mental deterioration (Breedveld et al). Other progres­
sive neurologic disorders inherited as autosomal dominant
traits and beginning in adolescence or adult life (e.g.,
polymyoclonus with or without ataxia, ac�thocyt�sis
with progressive chorea, and dentatorubropallidoluysian
degeneration) can closely mimic Huntington dise �se, as
described further on; sometimes only the genetic and
pathologic findings settle the matter. A midlife progres­
sive chorea without dementia (after more than 25 years of
followup) that does not display the Huntington genotype
has been reported. In at least one family in which this
clinical picture is dominantly inherited, the fundamental
defect is a mutation in the gene encoding the light chain of
ferritin (Curtis). Affected individuals have axonal changes
in the pallidum with swollen, ubiquitin- and tau-positive
aggregates; serum ferritin levels may be dep_ressed. !fi e
implication of this mutation is that perturbations of rron
metabolism may be toxic to neurons, a feature that also
characterizes Hallervorden-Spatz disease.
Dentatorubropallidoluysian atrophy (DRPLA), some­
times mistaken clinically for Huntington chorea, was
Degenerative Diseases of the Nervous System 1 079
described in European families by Warner and associ­
ates and is discussed further on. The extrapyramidal
manifestations include chorea, myoclonus, and rigidity.
Adult-onset chorea and dementia has been described
with propionic acidemia; propionic acid is elevated in the
plasma, urine, and CSF. This disorder must be added to
other metabolic diseases described in Chap. 37 as causes
of childhood chorea and dyskinesia-such as glutaric
acidemia, keratin sulfaturia, calcification of basal ganglia,
phenylketonuria, and Hallervorden-Spatz disease, now
called PANK (Hagberg et al) .
Other problems in differential diagnosis include
prion disease, Wilson disease (see Chap. 37), acquired
hepatocerebral degeneration (see Chap. 40), paraneo­
plastic chorea (see Chap. 31), and most often and esp � ­
cially, tardive dyskinesia (see Chap . 41). Man� drugs �
addition to the toxic effects of L-dopa and antipsychotic
medications occasionally cause chorea (amphetamines,
cocaine, tricyclic antidepressants, lithium, isoniazid, line­
zolid). The hyperglycernic-hyperosmolar state is known
for producing a variety of generalized or local movement
disorders, prominent among them being chorea.
Treatm e n t
The dopamine antagonist haloperidol, in daily doses of 2
to 10 mg, is effective partially in suppressing the move­
ment disorder. Because of the danger of superimposing
tardive dyskinesia on the chronic disorder, th� ch� rea
should be treated only if it is functionally disabling,
using the smallest possible dosages. Haloperidol may
tional lability, but it does not alter the progress of the
disease. The authors have not been impressed with the
therapeutic effectiveness of other currently available
�
drugs. Levodopa and other dopamine ago sts make the
chorea worse and, in the rigid form of the disease, evoke
chorea. Drugs that deplete dopamine or block dopamine
receptors-such as reserpine, clozapine, and particularly
tetrabenazine, which has been validated in a controlled
study (Huntington Study Group)-suppress the cho­
rea to some degree, but their side effects (drowsmess,.
akathisia, and tardive dyskinesia) usually outweigh
their desired effects. They may be tried in difficult cases.
The juvenile (rigid) form of the disease is probably best
treated with antiparkinsonian drugs. Preliminary stud­
ies of the transplantation of fetal ganglionic tissue into
the striatum have achieved mixed results. The psycho­
logic and social consequences of the disease require
supportive therapy, and genetic counseling is essential.
Antidepression drugs are widely implemented because
of the high incidence of depression and suicidality but
their efficacy is not clear. Huntington disease pursues
a steadily progressive course and death occurs as �en­
tioned, on average 15 to 20 years after onset, sometimes
much earlier or later.
Aca nthocytosis With Chorea
There are 2 categories of neurologic disease associated with
red blood cell acanthocytosis; one with a defect in the red
cell lipid membrane (represented by Bassen-Komzweig
1 080 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
disease and the HARP [hypobetalipoproteinemia, acan­
thocytosis, retinitis pigmentosa, and pallidal degeneration]
syndrome [see Chap. 37]) and a second group that lacks a
lipid abnormality. This latter type of neuroacanthocyto­
sis enters into the differential diagnosis of Huntington
chorea or unexplained progressive choreas and has the
following characteristics: (1) onset in adolescence or
early adult life of generalized involuntary movements
(described as chorea but including dystonia and tics),
usually beginning as an orofacial dyskinesia and spread­
ing to other parts of the body and to other neural systems;
(2) mild to moderate mental deterioration with behav­
ioral disturbance in some but not all cases; (3) decreased
or absent tendon reflexes and evidence of chronic axonal
neuropathy and denervation atrophy of muscles; and (4)
the defining feature of acanthocytosis (thorny or spiky
appearance of erythrocytes). The main syndrome, and
the one to which the term neuroacanthocytosis had for a
long time been applied, is caused by an autosomal reces­
sive mutation. However, there are now 4 additional sub­
types, one dominantly transmitted and another X-linked
(McLeod type), which is discussed below. These are all in
distinction to Bassen-Kornzweig disease that is caused by
an inherent defect in the lipid layer of the red cell mem­
brane (see further on) .
In the series of 19 cases reported by Hardie and col­
leagues, the manifestations included dystonia, tics, vocal­
izations, rigidity, and lip and tongue biting; more than
half had cognitive impairment or psychiatric features.
The average age of onset was 32 years; 7 of the 19 cases
were sporadic. The disease has been linked in almost all
families to chromosome 9q, where there is a mutation in
the gene encoding a large (3,1 00-amino-acid) protein des­
ignated chorein that is involved in cellular protein sorting
and trafficking (Rampoldi). Some of the families with
dominantly inherited neuroacanthocytosis have muta­
tions in the chorein gene. There is atrophy and gliosis of
the caudate nuclei and putamens but no neuronal loss in
the cerebral cortex or other parts of the brain.
According to Sakai and coworkers, the acanthocyto­
sis is the result of an abnormal composition of covalently
(tightly) bound fatty acids in erythrocyte membrane
proteins (palmitic and docosahexanoic acids increased
and stearic acid decreased). The cells should be examined
in a fresh preparation of blood and isotonic saline; it is
likely to be overlooked in a conventional Wright stain.
More than 5 percent of the red cells have the character­
istic structural abnormality in affected individuals. The
acanthocytosis may also be detected by scanning electron
microscopy. The latter may be necessary to undertake in
cases of unexplained chorea that have the other features
of this disease as genetic testing for the gene (see below)
is not widely available.
McLeod disease, another disorder with acanthocyto­
sis and the gradual development of chorea in middle to
late life, is characterized by degeneration of the caudate
and putamen and a myopathy (elevated serum creatine
phosphokinase [CPK]) . These individuals have fewer
facial tics and orofacial features than those with neuro­
acanthocytosis. McLeod syndrome arises from mutations
in a gene on the X-chromosome that encodes the KX
protein, which binds to surface Kell antigens on red cells.
In addition to the primary KX gene mutations, these indi­
viduals show diminished Kell antigen expression on the
red-cell surface.
Corticostriatospinal Degenerations
Included in this category are a heterogeneous group of
degenerative diseases in which the symptoms of par­
kinsonism and corticospinal degeneration are present in
various combinations. Some of the diseases that make up
this group have not been sharply delineated and are dif­
ficult to separate from one another.
Variants of this category of disease continue to
appear, all rare. The authors have observed several
patients in whom extreme rigidity, corticospinal signs
but no dementia, have developed over a period of several
years. In the later stages of the disease, the patient, while
alert, is totally helpless and unable to speak, swallow, or
move the limbs. Only eye movements are retained, and
even these are hampered by supranuclear gaze palsies
in advanced cases. Intellectual functioning appears to be
better preserved than movement but is difficult to assess.
Other bodily functions are intact. The course is slowly
progressive and ends fatally in 5 to 10 years. There is no
family history of similar disease, and there are no clues
as to causation. Gilbert and colleagues have described
similar cases with signs of Parkinson disease, motor
neuron disease, and dementia; in their cases, there were
no senile plaques or Lewy bodies. The concurrence of
typical motor neuron disease and Parkinson disease may
be coincidental, but Qureshi and colleagues described
13 patients in whom both clinical phenomena began
within a short time and they considered them to be related.
In the variant described by Tandan and colleagues, an
autosomal dominant syndrome of Charcot-Marie-Tooth
polyneuropathy was combined with ptosis, parkinsonism,
and dementia, again without Lewy bodies or amyloid
plaques. Other variants have been described by Schmitt
and coworkers and by Mata and colleagues. Hudson
reviewed 42 sporadic cases in which ALS-parkinsonism­
dementia were combined.
Under the title "Spastic Pseudosclerosis," Jakob, in
1921, described a chronic disease of middle to late adult
life, characterized by abnormalities of behavior and intel­
lect; weakness, ataxia, and spasticity of the limbs (chiefly
the legs); extrapyramidal symptoms such as rigidity,
slowness of movement, tremors, athetotic postures, and
hesitant, dysarthric speech; and normal spinal fluid. The
pathologic changes were diffuse and consisted mainly of
an outfall of neurons in the frontal, temporal, and central
motor gyri, striatum, ventromedial thalamus, and bulbar
motor nuclei. In one of Jakob's cases, there were also
prominent changes in the anterior hom cells and corti­
cospinal tracts in the spinal cord like those of ALS. The
latter finding gave rise to Wilson's concept of the disease
as a corticostriatospinal degeneration. Some restricted cases
bear a resemblance to the type of frontotemporal demen­
tia that occurs with motor neuron disease.
 CHAPTER 39
A degenerative and probably familial disorder that
had been described earlier by Creutzfeldt was consid­
ered by Spielmeyer to be sufficiently similar to the one
of Jakob to warrant the designation Creutzfeldt-Jakob
disease. As discussed in Chap. 33, the disorder originally
described by Creutzfeldt and Jakob has been a source
of endless controversy because of its indeterminate
character. It has been confused with the subacutely
evolving myoclonic dementia, or subacute spongiform
encephalopathy, which is now known to be an infection
caused by a prion agent. The latter disease bears at best
only a superficial resemblance to the one described by
Creutzfeldt and Jakob, and the 2 disorders should be
separated. Unfortunately, the use of the eponym for the
prion-related disease is so entrenched that attempts to
delete it are futile and probably unnecessary. However,
the term Jakob disease has been used for the degenerative
type of corticostriatospinal degeneration.
The Guamanian Parkinson-dementia-ALS complex
deserves separate comment because there have been
many carefully studied cases with almost uniform clini­
cal and pathologic features. The disease occurs in the
indigenous Chamorro peoples of Guam and the Mariana
islands, predominantly in men between the ages of 50
and 60 years. Progressive parkinsonism and dementia
are combined with upper or lower motor neuron disease
(ALS is also common among the Chamorro) leading to
death in 5 years. The pathologic changes, described by
Hirano and associates, consist of severe cortical atrophy
with neurofibrillary tangles and a depopulation of the
substantia nigra, but notably no Lewy bodies or amyloid
plaques, even with sensitive neurochemical staining.
Cases with amyotrophy show a loss of anterior horn cells.
The cause of the Guamanian multisystem degeneration is
not known, although several studies have incriminated
one or more putative neurotoxins in the food supply
(see Chap. 43) . There are some clinical and pathologic
similarities to the form of frontotemporal dementia with
motor neuron disease.
Fam i l i a l Dem entia With Spastic Paraparesis
Occasionally, the authors have encountered families in
which several members developed a spastic paraparesis
and a gradual failure of intellectual function during the
middle adult years. The patient's mental horizon nar­
rowed gradually, and the capacity for high-level think­
ing diminished; in addition, the examination showed
exaggerated tendon reflexes, clonus, and Babinski signs.
In one such family, the illness had occurred in 2 genera­
tions; in another, 3 brothers in a single generation were
afflicted. Skre described 2 recessive types of hereditary
spastic paraplegia in Norway, 1 with onset in childhood,
the other with onset in adult life. In contrast to the domi­
nant form (see further on), the recessive types displayed
evidence of more widespread involvement of the nervous
system, including dementia, cerebellar ataxia, and epi­
lepsy. Also, Cross and McKusick have observed a reces­
sive type of paraplegia accompanied by dementia begin­
ning in adolescence. They named it the Mast syndrome,
after the afflicted family.
Degenerative Diseases of the Nervous System 1 08 1
Worster-Drought and others reported the pathologic
findings in 2 cases of this type. In addition to plaques
and neurofibrillary changes, there was demyelination of
the subcortical white matter and corpus callosum and a
"patchy but gross swelling of the arterioles," which gave
the staining reactions for amyloid ("Scholz's perivascu­
lar plaques"). van Bogaert and associates published an
account of similar cases that showed the characteristic
pathologic features of Alzheimer disease.
Another interesting association of familial spastic
paraplegia is with progressive cerebellar ataxia. Fully
one-third of the cases that we have seen with such a
spastic weakness were also ataxic and would fall into the
category of spinocerebellar degenerations. Yet another
variant of this group of diseases has been described by
Farmer and colleagues; the inheritance in their cases
was autosomal dominant, and the main clinical features
were deafness and dizziness, ataxia, chorea, seizures, and
dementia, evolving in that order. Postmortem examina­
tions of 2 patients disclosed calcification in the globus
pallid us, neuronal loss in the dentate nuclei, and destruc­
tion of myelinated fibers in the centrum semiovale.
Adu lt Polyg lucosan Body Disease
Under this title, Robitaille and colleagues have described
a progressive neurologic disease in adults characterized
clinically by spasticity, chorea, dementia, and a predomi­
nantly sensory polyneuropathy that is reviewed in more
detail in Chap . 39. Structures that closely resembled
Lafora bodies and corpora amylacea were found in large
numbers in both central and peripheral neural processes
(mainly in axons) and also in astrocytes. These basophilic
PAS-positive structures were composed of glucose poly­
mers (polyglucosans) and were readily demonstrated in
sural nerve biopsies and therefore probably best termed
polyglucosan bodies. Some of these structures were also
found in the heart and liver.
More recently, Rifal and associates reviewed the find­
ings in 25 cases of this disease--one observed by them and
24 reported previously. The dementia was relatively mild,
consisting of impairment of retentive memory, dysnomia,
dyscalculia, and sometimes nonfluent aphasia and deficits
of "visual integration"; this was overshadowed by rigid­
ity and spasticity of the limbs and the peripheral nerve
disorder. Bladder dysfunction has been an early sign in
many patients including a middle-aged woman under
our care who had only diffuse white matter changes in
the cerebral MRl and a moderate sensory neuropathy.
Nerve conduction velocities were diminished and the leg
muscles were denervated. Moderate degrees of general­
ized cerebral atrophy, multifocal areas of white matter
rarefaction, and degeneration of the corticospinal system,
disclosed by MRl Some cases simulate motor neuron
.
disease. The finding of polyglucosan axonal inclusion in
biopsied nerves confirms the diagnosis. The disease has
sometimes been misinterpreted as adrenoleukodystrophy.
The disorder appears to be a glycogenosis that is allied
with Anderson disease, as discussed in Chaps. 38 and 48.
Adult forms of metachromatic leukodystrophy, adre­
noleukodystrophy, Krabbe disease, and neuronal ceroid
1 082 Part 4 MAJOR CATEGORIES OF NEU ROLOGIC D ISEASE
lipofuscinosis (Kufs disease) may be present with a simi­
lar clinical picture of progressive dementia (see Chap.
37) as may Whipple disease or the Wernicke-Korsakoff
disease. Quite rare instances of the same syndrome with
adult onset have proved to be caused by phenylketonuria
or other aminoacidopathies (see Chap. 37) .
DISEASES CHARACTERIZED
BY ABNORMALITI ES OF POSTURE
AND MOVEMENT
Parkinson Disease
This common disease, known since ancient times, was
first cogently described by James Parkinson in 1817. In
his words, it was characterized by "involuntary tremu­
lous motion, with lessened muscular power, in parts not
in action and even when supported; with a propensity to
bend the trunk forward, and to pass from a walking to a tremor, stooped posture, axial instability, rigidity, and fes­
runnin g pace, the senses and intellect being uninjured."
Strangely, his essay contained no reference to rigidity
or to slowness of movement and it stressed unduly the
reduction in muscular power. The same criticism can be
leveled against the term paralysis agitans, which appeared
for the first time in 1 841 in Marshall Hall's textbook
Diseases and Derangements of the Nervous System and has
fallen out of use, but was such a common term in the
literature that it is included here.
The natural history of the disease is of interest. As a
rule, it begins between 45 and 70 years of age, with the
peak age of onset in the sixth decade. It is infrequent before
30 years of age, and most series contain a somewhat larger
proportion of men. Trauma, emotional upset, overwork,
exposure to cold, "rigid personality," and so on, were
among many factors that had been suggested over the
years as predisposing to the disease, but there is no evi­
dence to support any such claims. Idiopathic Parkinson
disease is observed in all countries, all ethnic groups, and
all socioeconomic classes, although the incidence in African
Americans is only one-quarter that in whites. There may be
an increased incidence in rural compared to urban areas. In
Asians, the incidence is one-third to one-half that in whites.
The disease is frequent in North America, where there are
approximately 1 million affected patients, constituting
about 1 percent of the population over the age of 65 years.
The incidence in European countries where vital statistics
are kept is similar. A possible relationship to repeated cere­
bral trauma and to the "punch-drunk" syndrome (demen­
tia pugilistica; chronic traumatic encephalopathy) has been
particularly problematic and is unresolved despite several
celebrated cases (Lees). A protective effect of smoking and
coffee drinking has emerged in some epidemiologic studies
but is marginal.
C l i n i c a l Featu res
A tetrad of hypo- and bradykinesia, resting tremor, postural
instability, and rigidity are the core features of Parkinson
disease . These are evident as an expressionless face,
poverty and slowness of voluntary movement, "resting"
I N ITIAL SYM PTOMS IN PATIENTS WITH PARKINSON
DISEASE
Tremor 70%
Gait disturbance 11 %
Stiffness 10%
Slowness 10%
Muscle aches 8%
Loss of dexterity 7%
Handwriting disturbance 5%
Depression, nervousness, other psychiatric 4%
disturbance
Speech disturbance 3%
Source: Adapted from Hoehn and Yahr's study of 183 idiopathic cases, 1967.
tinating gait. Much can still be gained from perusal of the
often-cited study by Hoehn and Yahr, published in 1967
before the widespread use of L-dopa. Table 39-2 is repro­
duced from that paper. The manifestations of basal gangli­
onic disease are fully described in Chap. 4, and only certain
diagnostic problems and variations of the clinical picture
need be considered here.
The early symptoms may be difficult to appreciate
and are often overlooked by family members because
they evolve slowly and tend to be attributed to the natu­
ral changes of aging. Speech becomes soft, monotonous,
and cluttered. For a long time the patient may not be
conscious of the inroads of the disease. At first the only
complaints may be of aching of the back, neck, shoulders,
or hips and of vague weakness. Slight stiffness and slow­
ness of movement or a reduction in the natural swing
of one arm during walking are ignored until one day
it occurs to the physician or to a member of the family
that the patient has the overall cast of Parkinson disease.
Infrequency of blinking, as originally pointed out by
Pierre Marie, is an early sign. The usual blink rate (12
to 20/min) is reduced in the parkinsonian patient to 5
to 10 /min, and with it there is a slight widening of the
palpebral fissures, creating a stare. A reduction in move­
ments of the small facial muscles imparts the character­
istic expressionless "masked" appearance (hypomimia).
When seated, the patient makes fewer small shifts and
adjustments of position than the normal person (hypo­
kinesia), and the fingers straighten and assume a flexed
and adducted posture at the metacarpophalangeal joints.
The characteristic tremor, which usually involves a
hand, is often listed as the initial sign; but in at least half
the cases observant family members will already have
remarked on the patient's relative slowness of movement.
In about one-quarter of cases the tremor is mild and inter­
mittent, or evident in only one finger or one hand. The
tremor of the fully developed case takes several forms, as
was remarked in Chap . 6. The 4-per-second "pill-rolling"
tremor of the thumb and fingers, although most character­
istic, is seen in only about half the patients. It is typically
 CHAPTER 39
present when the hand is motionless, that is not used in
voluntary movement (hence the commonly used term
resting tremor). Complete relaxation, however, reduces or
abolishes the tremor, so that the term tremor in the position
of repose is actually a more accurate description. Volitional
movement dampens it momentarily. The rhythmic beat
coincides with an alternating burst of activity in agonist
and antagonist muscles in the electromyogram (EMG);
hence the description alternating tremor is applied. The
arm, jaw, tongue, eyelids, and foot are less often involved.
Even the least degree of tremor is felt during passive
movement of a rigid part (cogwheel phenomenon, or
Negro sign, or at least this is the ostensible explanation for
cogwheeling) . The tremor shows surprising fluctuations
in severity and is aggravated by walking and excitement,
but its frequency remains constant (Hunker and Abbs). It
bears repetition that one side of the body is tt;pically involved
before the other with tremor and rigidity, and the tremor in
particular remains asymmetrical as the illness advances.
Lance and associates have called attention to the high
incidence of a second essential type of tremor in Parkinson
disease-a fine, 7- to 8-per-second, slightly irregular,
action tremor of the outstretched fingers and hands. This
tremor, unlike the slower one, persists throughout volun­
tary movement, is not evident with the limb in a resting
position, and is more easily suppressed by relaxation.
Electromyographically, it lacks the alternating bursts of
action potentials seen in the typical tremor and resembles,
if not equates with, essential tremor (see Table 6-1) . It is
subject to modulation by different medications than those
used for the alternating Parkinson tremor. The patient
may have either type of tremor or both.
Rigidity is less often an early finding. Once rigidity
develops, it is constantly present and can be felt by the
palpating fingers and as a salience of muscle groups even
when the patient relaxes. When the examiner passively
moves the limb, a mild resistance appears from the start
(without the short free interval that characterizes spastic­
ity) and it continues evenly throughout movement in
both flexor and extensor groups, being interrupted to
a variable degree only by the cogwheel phenomenon.
Rigidity and its cogwheel component are elicited or
enhanced by having the patient engage the opposite limb
in a motor task requiring some degree of concentration,
such as tracing circles in the air (termed Froment sign, or
Noil<a-Froment sign when the patient is asked to raise
the other arm as high as possible, but this maneuver was
actually utilized first to bring out cogwheeling in essen­
tial tremor) or touching each finger to the thumb. In the
muscles of the trunk, postural hypertonus predominates
in the flexor groups and confers on the patient the char­
acteristic flexed posture. Other particulars of the parkin­
sonian appearance of muscle tone, stance, and gait are
discussed in detail in Chaps. 4 and 7. There should be no
pyramidal signs in Parkinson disease.
Here, a few additional points should be made
regarding the quality of volitional and postural move­
ments. The patient is slow and ineffective in attempts to
deliver a quick hard blow; he canno t complete a rapid (bal­
listic) movement. On the EMG, the normal single burst of
agonist-antagonist-agonist sequence of energizing activity
Degenerative Diseases of the Nervous System 1 083
is replaced by several sequential brief bursts, according
to Hallett and Khoshbin. Alternating movements, at first
successful, become progressively impeded if performed
repetitively and, finally, they are blocked completely or
adopt the rhythm of the patient's alternating tremor.
The patient has great difficulty in executing 2 motor acts
simultaneously. In the past the impaired facility of move­
ment had been attributed to rigidity, but the observation
that certain surgical lesions in the brain abolished rigid­
ity without affecting movement refuted this interpreta­
tion. Thus slowness and lack of natural movements (bra­
dykinesia and hypokinesia, respectively) are not derived
from rigidity but are independent manifestations of the
disease. The bradykinetic deficits underlie the character­
istic poverty of movement, reflected also by infrequency
of swallowing, slowness of chewing, a limited capacity
to make postural adjustments of the body and limbs in
response to displacement of these parts, a lack of small
"movements of cooperation" (as in arising from a chair
without first adjusting the feet), absence of arm swing
in walking, and most of the other aspects of the par­
kinsonian countenance. Despite a perception of muscle
weakness, the patient is able to generate normal or near­
normal power, especially in the large muscles; however,
in the small ones, strength is slightly diminished.
As the disorder of movement worsens, all customary
activities show the effects. Handwriting becomes small
(micrographia), tremulous, and cramped, as first noted
by Charcot. Speech softens and seems hurried, monoto­
nous, and mumbling (cluttered): The voice becomes
less audible and, finally, the patient only whispers.
Caekebeke and coworkers refer to the speech disorder as
a hypokinetic dysarthria and attribute it to combined respi­
ratory, phonatory, and articulatory dysfunctions. There is
a failure to fully close the mouth. The consumption of a
meal takes an inordinately long time. Each morsel of food
must be swallowed before the next bite is taken.
Walking becomes reduced to a shuffle; the patient
frequently loses balance, and in walking forward or
backward seems to be "chasing" the body's center of
gravity with a series of increasingly rapid short steps in
order to avoid falling (festination). Defense and righting
reactions are faulty. Falls do occur, but surprisingly infre­
quently given the degree of postural instability. Gait is
improved by sensory guidance, as by holding the patient
at the elbow. Obstacles such as door thresholds have the
opposite effect, at times causing the patient to "freeze" in
place. Getting in and out of a car or elevator or walking
into a room or in a hall becomes particularly difficult.
Difficulty in turning over in bed is a similarly character­
istic feature as the illness advances, but the patient rarely
volunteers this information. Several of our patients have
fallen out of bed at a frequency that suggests a connec­
tion to their reduced mobility combined with slowed
corrective or defensive postural movements. Shaving or
applying lipstick becomes difficult, as the facial muscles
become more immobile and rigid.
Persistent extension or clawing of the toes, jaw
clenching, and other fragments of dystonia, often quite
painful, may enter the picture and are sometimes early
findings. (These are particularly resistant to treatment.)
1 084 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
A special problem of camptocormia occurs in some
Parkinson patients wherein an extreme forward flexion
of the spine and correspondingly severe stooping occur.
It appears to be a type of axial dystonia when it occurs
with Parkinson disease. The deformity resolves when
the patient is supine or pushes upward on the handles
of a walker. This symptom is associated with a variety of
other diseases, some of them muscular. We have not been
impressed that it is ameliorated by L-dopa. Why some
patients with Parkinson disease are extremely bent over
and others are not at all affected is unknown.
As noted above, these various motor impediments
and tremors characteristically begin in one limb (more
often the left) and spread to one side and later to both
sides until the patient is quite helpless. Yet in the excite­
ment of some unusual circumstance (as escaping from
a fire, for example), the patient with all but the most
advanced disease is capable of brief bu t remarkably effec­
tive movement (kinesis paradoxica).
Regarding elicitable neurologic signs, there is an
inability to inhibit blinking in response to a tap over the
bridge of the nose or glabella (Myerson sign) but grasp and
suck reflexes are not present unless dementia supervenes
and buccal and jaw jerks are rarely enhanced. Commonly
there is an impairment of upward gaze and convergence;
if prominent or noted early in the disease, this sign sug­
gests more the possibility of progressive supranuclear
palsy. Bradykinesia may extend to eye movements, in that
there is a delay in the initiation of gaze to one side, slow­
ing of conjugate movements (decreased maximal saccadic
velocity), hypometric saccades, and breakdown of pursuit
movements into small saccades.
There are no sensory findings, but a wide variety of
paresthetic and other sensory complaints and discom­
forts are common. These affect mainly the calves and
abdomen and are among the most distressing of the
nonmotor parkinsonian symptoms. Drooling is troublesome;
an excess flow of saliva has been assumed, but actually
the problem is probably one of failure to swallow with
normal frequency. Seborrhea and excessive sweating
are claimed to be secondary as well, the former due to
failure to cleanse the face sufficiently, the latter to the
effects of the constant motor activity but this explana­
tion seems lacking to us; an autonomic disturbance is
more plausible. Other nonmotor features are mostly
in the category of autonomic disturbances and include
most prominently constipation, abdominal pains and
cramps, erectile dysfunction, joint aches, and various
other sensory experiences that may be difficult for the
patient to describe. There is a tendency in some patients
to have orthostatic hypotension and sometimes syncope;
this has been attributed by Rajput and Rozdilsky to cell
loss in the sympathetic ganglia. However, these features
are not as prominent as in multiple system atrophy (Shy­
Drager syndrome) . It is worth mentioning that several of
our younger Parkinson patients with recurrent syncope
proved to have cardiac arrhythmias; hence other causes
of fainting must be considered.
Postural instability is a core feature of the illness; it
can be elicited by tugging at the patient's shoulders from
behind and noting the lack of a small step backward to
maintain balance often with a fall or the initiation of back­
ward festination. The tendon reflexes vary, as they do in
normal individuals from being barely elicitable to brisk.
Even when parkinsonian symptoms are confined to one
side of the body, the reflexes are usually equal on the two
sides, and the plantar responses are flexor. Exceptionally,
the reflexes on the affected side are slightly brisker, which
raises the question of corticospinal involvement, but
the plantar reflex remains flexor. In these respects, the
clinical picture differs from that of corticobasal gangli­
onic degeneration, in which rigidity, hyperactive tendon
reflexes, and Babinski signs are combined with apraxia
(see further on) .
As mentioned earlier, Parkinson disease may be
complicated by dementia, a feature described by Charcot.
The reported frequency of this combination varies con­
siderably based on the selection of patients and type of
testing. An estimate of 10 to 15 percent (Mayeux et al)
is the generally accepted figure and matches our experi­
ence. The incidence increases with advancing age and
duration of disease, approaching 65 percent in Parkinson
patients older than 80 years of age, but mental decline
may become apparent in patients in their late fifties. The
pathologic basis of the dementia is discussed below.
The overall course of the disease is quite variable. In
the majority of patients, the mean period of time from
inception of the disease to a chairbound state is 7.5 years,
but with a wide range (Hoehn and Yahr; Martilla and
Rinne ). As much as 10 percent of cases remain relatively
mild and only very gradually progressive, and such
patients may remain almost stable for 10 years or more.
These trajectories have been altered somewhat by mod­
em therapies.
Hemiparkinson-Hemiatrophy Syndrome Mentioned
here is a rare syndrome described by Klawans and
elaborated in a series of 30 patients by Wijemanne and
Jankovic. The typical case shows atrophy in one or more
body parts, including at times the face, often since child­
hood, and usually quite subtle. Signs of progressive par­
kinsonism or dystonia begin in midlife on the atrophic
side and, for the most part, are responsive to L-dopa, but
some, such as Klawans' original patients, are resistant.
Several types of early life cerebral injury underlie the syn­
drome, but half of patients have no such lesion evident.
Understanding of the idiopathic cases is limited. Those
with deep brain lesions may be experiencing a slow
degeneration of basal ganglia pathways.
Diag nosis
The 2 main difficulties are t o distinguish typical Parkinson
disease from the many parkinsonian syndromes caused
by other degenerative conditions and by medications
or toxins, and to distinguish the Parkinson tremor from
other types, especially essential tremor. It is worth not­
ing that Parkinson disease is far more common than
any of the degenerative syndromes that resemble it.
Bradykinesia and rigidity of the limbs and axial mus­
culature are symptoms shared with other forms of par­
kinsonism, but it is mainly in Parkinson disease that one
observes an early sign of "resting" alternating tremor that
is more prominent in one arm.
 CHAPTER 39
When not all the typical signs are evident, there is no
alternative but to reexamine the patient at several-month
intervals until it is clear that Parkinson disease is present
or until the characteristic features of another degenera­
tive process become evident; these include early falls and
vertical gaze impairment in progressive supranuclear
palsy; dysautonomia with fainting, bladder, or vocal
cord dysfunction in multiple system atrophy; early and
rapidly evolving dementia or intermittent psychosis in
Lewy-body disease; or apraxia in corticobasal ganglionic
degeneration. Very symmetrical findings, particularly
tremor, suggest an alternative to idiopathic Parkinson
disease. Also, the constellation of features termed "lower
half parkinsonism" consisting of difficulty purely with gait
and stability, as discussed below and in Chap . 7, suggest
a process other than Parkinson disease.
If the symptoms warrant, a beneficial and sustained
response to levodopa or a dopamine agonist also gives a
reasonably secure, although not entirely conclusive, indi­
cation of the presence of Parkinson disease (see further
on) . The other parkinsonian syndromes are for the most
part changed only slightly or only for a few weeks or
months by the drug. Conversely, although some experts
disagree, we have adhered to the notion that complete
resistance of the symptoms to L-dopa early in the ill­
ness makes the diagnosis unlikely. Furthermore, almost
all patients with idiopathic Parkinson disease eventu­
ally acquire dyskinesias in response to L-dopa and the
absence of this sign after approximately 3 to 5 years of
use of the drug brings the diagnosis into question.
The epidemic of encephalitis lethargica (von
Economo encephalitis) that spread over Western Europe
and the United States after the First World War left great
numbers of parkinsonian cases in its wake. No definite
instance of this form of encephalitis had been recorded
before the period 1914 to 1918, and very few have been
seen since 1930; hence, this type of postencephalitic
parkinsonism is no longer a diagnostic consideration.
However, a Parkinson-like syndrome has been described
following other forms of encephalitis, particularly with
Japanese B virus, West Nile virus, and eastern equine
encephalitis. In the few cases caused by these viruses
that we have observed, there has been fairly symmetrical
rigidity, hypokinesia, and little or no tremor.
An "arteriopathic" or " arteriosclerotic" form of
Parkinson disease was at one time much diagnosed but
we have never been entirely convinced of its reality,
referring to damage to the substantia nigra as a result of
vascular disease or to a syndrome that closely resembles
Parkinson disease as a result of atherosclerotic white
matter damage. Nonetheless, a number of authoritative
clinicians are of the opinion that patients with a vascular
cause have a predominantly "lower half" parkinsonism
in which shufflin g gait, stickiness on turning, and fall­
ing are disproportionate to other features. There is no
tremor, and little or no response to L-dopa (see Winikates
and Jankovic) . MRI in such cases has shown substantial
white matter changes in both cerebral hemispheres. In
the few cases attributable to vascular parkinsonism that
have come to our attention with autopsy material, there
have been Lewy bodies in the appropriate locations.
Degenerative Diseases of the Nervous System 1 085
Pseudobulbar palsy from a series of lacunar infarcts or
from Binswanger disease can cause a clinical picture that
simulates certain aspects of Parkinson disease, but uni­
lateral and bilateral corticospinal tract signs, hyperactive
facial reflexes, spasmodic crying and laughing, and other
characteristic features distinguish spastic bulbar palsy
from Parkinson disease. Of course, the elderly parkinso­
nian patient is not impervious to cerebrovascular disease,
and the 2 conditions overlap, but differentiating the pre­
dominantly gait or dementing disorders of widespread
vascular brain damage from idiopathic Parkinson disease
is not difficult.
Normal-pressure hydrocephalus can undoubtedly
produce a syndrome resembling Parkinson disease, par­
ticularly in regard to gait and postural instability, and
at times extending to bradykinesia; but rigid postures,
slowness of alternating movements, hypokinetic ballistic
movements, and resting tremor are not part of the clinical
picture. The gait tends to be short-stepped but not shuf­
fling and there is more of a tendency to retropulsion than
there is in Parkinson disease. Sometimes a lumbar punc­
ture gives surprising benefit, indicating hydrocephalus as
the cause of the motor slowing and gait disorder.
Essential tremor is distinguished by its fine, quick
quality, its tendency to become manifest during voli­
tional movement and to disappear when the limb is in
a position of repose, and the lack of associated slow­
ness of movement or of flexed postures. Cogwheeling
of minor degree may be associated. The head and voice
are more often truly tremulous in essential tremor than
in Parkinson disease. Some of the slower, alternating
forms of essential tremor are difficult to distinguish from
parkinsonian tremor; one can only wait to see whether it
is the first manifestation of Parkinson disease. A mark­
edly asymmetrical or unilateral tremor favors Parkinson
disease. Also as noted, a faster oscillation is often mixed
with the slow alternating Parkinson tremor, but the fast­
frequency tremor is only occasionally an opening feature
of the disease as discussed in Chap . 6.
Progressive supranuclear palsy (discussed in a sec­
tion further on) is characterized by rigidity and dystonic
postures of the neck and shoulders, a staring and immobile
countenance, and a tendency to topple when walking-all
of which are vaguely suggestive of Parkinson disease.
Early and frequent falls are particularly suggestive of this
disease, not being atypical of Parkinson disease until its
late stages. Inability to produce vertical saccades and, later,
paralysis of upward and downward gaze and eventual
loss of lateral gaze with retention of reflex eye movements
establish the diagnosis of PSP in most cases.
Paucity of movement, unchanging attitudes and pos­
tural sets, and a slightly stiff and unbalanced gait may be
observed in patients with an anergic or hypokinetic type
of depression. Because a fair proportion of parkinsonian
patients are depressed, the separation of these 2 condi­
tions is at times diffi cult. The authors have seen patients
who were called parkinsonian by competent neurologists
but whose movements became normal when antidepres­
sant medication or electroconvulsive therapy was given.
Several such patients have nonetheless insisted that
levodopa helps them in some nondescript way.
1 086 Part 4 MAJOR CATEGORIES OF NEU ROLOGIC D ISEASE
The rapid onset of parkinsonism should suggest
exposure to neuroleptic medications (used at times
as antiemetics and gastric motility agents [metoclo­
pramide]), a variant of Creutzfeldt-Jakob disease, an
unusual postinfectious or paraneoplastic illness, or viral
encephalitis. The implicated drugs may also evoke an
irmer restlessness, a "muscular impatience," an inability
to sit still, and a compulsion to move about much like that
which occurs at times in the parkinsonian patient (akathi­
sia). Even the newer antipsychosis medications, favored
specifically because of a putative lack of extrapyramidal
effects, may be at fault.
Strict adherence to the diagnostic criteria for
Parkinson disease also permits its differentiation from
corticostriatospinal, striatonigral, and corticobasal gan­
glionic degeneration, calcification of the basal ganglia,
Wilson disease, the acquired hepatolenticular degenera­
tion of repeated hepatic coma, manganese poisoning, as
well as Machado-Joseph disease, all of which are dis­
cussed in other parts of this chapter.
All in all, if one adheres to the standard definition
of Parkinson disease-bradykinesia, hypokinesia "rest­
ing" tremor, postural changes and instability, cogwheel
rigidity, and response to L-dopa-errors in diagnosis are
few. Yet in a series of 100 cases, studied clinically and
pathologically by Hughes and associates, the diagnosis
was inaccurate in 25 percent. The ostensible explana­
tion for this difficulty is that approximately one-quarter
of Parkinson patients fail to display the characteris­
tic tremor and approximately 10 percent are said to
not respond to L-dopa. These authors noted that early
dementia and autonomic disorder and the presence of
ataxia or corticospinal signs were reliable guides to an
alternate diagnosis.
Path o l ogy a n d Path o g e n es i s
The most constant and pertinent finding i n both idio­
pathic and postencephalitic Parkinson disease is a loss
of pigmented cells in the substantia nigra and other pig­
mented nuclei (locus ceruleus, dorsal motor nucleus of the
vagus). The substantia nigra is visibly pale to the naked
eye; microscopically, the pigmented nuclei show a marked
depletion of cells and replacement gliosis, and some of
the remaining cells have reduced quantities of melanin,
findings that enable one to state with confidence that the
patient must have suffered from Parkinson disease. Also,
many of the remaining cells of the pigmented nuclei con­
tain eosinophilic cytoplasmic inclusions, surrounded by
a faint halo, called Lelvy bodies (Fig. 39-5) . These are seen
in practically all cases of idiopathic Parkinson disease.
They were generally absent in postencephalitic cases, but
there were neurofibrillary tangles within nigral cell in that
disorder. Both these cellular abnormalities appear occa­
sionally in the substantia nigra of aged, nonparkinsonian
individuals. Possibly the individuals with Lewy bodies
would have developed Parkinson disease had they lived a
few more years. Many of the inherited forms of Parkinson
disease also lack Lewy bodies.
Noteworthy is the finding by McGeer and colleagues
that nigral cells normally diminish with age, from a maxi­
mal complement of about 425,000 to 200,000 at age 80 years.
Figure 39-5. Photomicrograph of a round Lewy-body inclusi on in
the cytoplasm of a nigra! neuron . (Hema toxylin and eosin [H&E]
staining.) (Courtesy of Matthew Frosch, MD, PhD.)
Tyrosine-hydroxylase, the rate-limiting enzyme for the syn­
thesis of dopamine, diminishes correspondingly. However,
these authors and others have found that in patients with
Parkinson disease the number of pigmented neurons is
reduced to 30 percent or less of that in age-matched con­
trols. Using more refined counting techniques, Pakkenberg
and coworkers estimated the average total number of pig­
mented neurons to be 550,000 and to be reduced in absolute
numbers by 66 percent in Parkinson patients. (The number
of nonpigmented neurons was reduced in Parkinson cases
by only 24 percent.) Thus aging contributes importantly
to nigral cell loss, but the cell depletion is so much more
marked in Parkinson disease that some factor other than
aging must also be operative.
Other regions of neuronal loss are widespread as
mentioned, but their significance is less clear. There is
neuronal loss in the mesencephalic reticular formation,
near the substantia nigra. These cells project to the thala­
mus and limbic lobes. In the sympathetic ganglia, there
is slight neuronal loss and Lewy bodies are seen. This
is also true of the pigmented nuclei of the lower brain­
stem as well as of neuronal populations in the putamen,
caudatum, pallidum, and substantia irmominata. On the
other hand, doparninergic neurons that project to cortical
and limbic structures, to caudate nucleus and nucleus
accumbens, and to periaqueductal gray matter and spinal
cord are affected little or not at all. The lack of a consis­
tent lesion in either the striatum or the pallidum is note­
worthy. An alternative hypothesis offered by Braak and
Tredici, mentioned in an earlier section of this chapter
and attributed to Braak and Braak, is that the substantia
nigra compacta is affected only late in the pathobiology
of Parkinson disease. Their study found that the earliest
changes in the brain occur in the dorsal glossopharyn­
geal-vagal and anterior olfactory nuclei, and only later
did they appear in the midbrain nuclei. This theory
 CHAPTER 39 Degenerative Diseases of the Nervous System 1 087

accommodates a variety of clinical features and potential
environmental triggers to the disease. Lang has suggested
that this distribution of cell loss explains some of the
nondopaminergic features of the disease and offers other
avenues for therapy.
Statistical data relating Parkinson and Alzheimer dis­
eases are difficult to assess because of different methods
of examination from one series to another. Nevertheless,
the overlap of the 2 diseases is more than fortuitous,
as indicated earlier in this chapter. The majority of the
demented Parkinson patients show some Alzheimer­
type changes but there are some in whom few plaques or
neurofibrillary changes can be found and instead display
cortical neuronal loss accompanied by widespread dis­
tribution of Lewy bodies, marking the process as Lewy­
body dementia and not Parkinson disease.
Of interest had been the observation, both in humans
and in monkeys, that a neurotoxin (known as MPTP
[1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]) produces
irreversible signs of parkinsonism and selective destruc­
tion of cells in the substantia nigra. The toxin, an analogue
of meperidine, which was self-administered by addicts,
binds with high affini ty to monoamine oxidase, an extra­
neural enzyme that transforms MPTP to a toxic metabo­
lite, pyridinium MPP (1 -methyl-4-phenylpyridinium) .
The latter is bound by the melanin in the dopaminergic
nigral neurons in sufficient concentration to destroy the
cells. The mechanism by which MPTP produces the clini­
cal aspects of the Parkinson syndrome is unsettled. One
hypothesis is that the inner segment of the globus pallidus
is rendered hyperactive because of reduction of the influ­
ence of gamma-aminobutyric acid (GABA) of the subtha­
lamic nucleus. The notion of some other environmental
toxin as a cause of Parkinson disease has been stimulated
by the MPTP findings (see Uhl et al; also the review by
Snyder and D'Amato). For example, Parkinson disease is
slightly more frequent in industrialized countries and in
agrarian regions where organophosphates are commonly
used, but its universal occurrence would argue against
this hypothesis. Despite extensive study; no chemical
toxin, heavy metal, or infection has been causally related
to the disease. Some plausible theories hold that a toxin
might be implicated only on a genetic background predis­
posing to the disease. The MPTP disease serves as a model
for the neurophysiologic and neurochemical changes of
Parkinson disease because of destruction of the substantia
nigra, but in most other respects it does not reflect the
naturally occurring disorder (including the absence of
Lewy bodies).
G e n etic As pects
Considering its frequency, coincidence in a family on the
basis of chance occurrence might be as high as 5 percent.
However, careful epidemiologic studies suggest that a
familial occurrence may be as high as 15 percent. A lack
of concordance of Parkinson disease in twins was at first
thought to negate the role of genetic factors, but a study
of dopamine metabolism using PET scanning showed
that 75 percent of asymptomatic twins of Parkinson
patients had evidence of striatal dysfunction, whereas
only a small portion of dizygotic twins showed these
changes (Piccini et al) . These data indicate a substantial
role for inherited traits, even in cases of ostensibly spo­
radic Parkinson disease (see below regarding the better
defined inherited forms). Some mutations and polymor­
phisms are more clearly modifying factors in producing
the disease, but others act as dominant disease genes.
These are summarized in Table 39-3. We have chosen to

Park1 & Park4 SCNA (a-synu clein) AD 30--40 years + Two main m u ta tion s-A53T, A30P-
promote oligomerization of a-synuclein.

Park2 PA R K2 (parkin) AR 20--40 years Accounts for 50% of early-onset inherited

PD; 20% of "sporadic" early-onset cases.

Park3 PA R K3 AD Late onset + Resembles i diopathic PD.

ParkS UCHL-1 (ubiqui tin SNP 50's + Two different polymorphisms confer risk
esterase) of PD.
Mutations decreased recycling of
ubiquitin monomers.

Park6 PINKl (PTEN-in d u ced AR Varies Mitochondrial gene.

putative .kinase 1)

Park7 PARK7 (DJ-1) AR 30's Slow progression; gene plays role in

cellular response to oxida tive stress.

ParkS L.RRK2 (leucine-rich AD Late ± Ashkenazic Jews. Protein also called

repeat kinase 2) dardarin; related to Gaucher ctisease.

Park14 PLA2G6 ? Late Dystonia-parkinsonism; Ia te onset;

(phospholipase A2) other m u ta tions cause neuroaxonal
dystrophy.

NR4A2 NURR l (nuclear recep- AD Confers suscepti- Gene is implicated in the formation and
tor related 1) to PD neurons.

AD, autosomal dominant; AR, autosomal recessive; PD, Parkinson disease.

1 088 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE

retain the nomenclature of the PARK genes for ease of
exposition but, as the genes are sequenced, their names
have replaced this generic notation in many summaries
of the genetics of the disease.
Numerous observations have implicated the nuclear
and synaptic protein a-synuclein, the main component
of Lewy bodies in both the sporadic and inherited forms
of Parkinson disease, as well as in Lewy-body disease.
Synuclein, a normal component of the synapse, exists in a
soluble unfolded form, but in high concentrations it aggre­
gates into filaments, which are the main (but not the only)
constituent of the Lewy body. Irnrnunostaining techniques
disclose additional less-specific proteins, such as ubiquitin
and tau within the Lewy bodies. Furthermore, in fami­
lies with a rare autosomal dominant form of Parkinson
disease, several different mutations on chromosome
code for an aberrant form of synuclein that decreases its
stability and promotes its aggregation (Polyrneropoulos
et al) . A family has also been described in which the
cause of Parkinson disease is an extra nonmutant copy
of the a-synuclein gene (Singleton et al), comparable to
the circumstance or triplication of chromosome 21 in
the Alzheimer disease of Down syndrome. Additionally,
some cases of familial parkinsonism result from muta­
tions that control the removal of a-synuclein from the
cell via proteasomal pathways. Together, these findings
indicate that instability or misfolding of a-synuclein or its
deficient removal may be a primary defect in the disease.
The protofibrillary form of the protein (i.e., a soluble pro­
tein in the cytosol) is also toxic to dopaminergic neurons.
These processes are accelerated by defects in heat shock
proteins that chaperone a-synuclein into and out of the
cell. Curiously, Lewy bodies are not found in patients with
most of the parkin mutations.
Parkin is a ubiquitin protein ligase that participates
in the removal of unnecessary proteins from cells through
the proteasomal system (Fig. 39-6) . Attachment of parkin
4 and ubiquitin to cytosolic proteins is understood to be
an obligatory step in the disposal of proteins by protea­
somes. Mutations in the parkin gene lead either to an
inadequacy or misfolding of synuclein, resulting in its
accumulation, or to the disruption of disposal of proteins
in dopamine-producing cells. The importance of the ubiq­
uitination pathway in this disease is further highlighted

'i!l-synuc/ein mut

---ITJ--
---

--c::J--CJ-
'i!l -synuc/eindup UCH-L 1 mut

y®
Molecular crowding •

---1 I -=
• •,
=-
. ..
parkin mut Hsps +- �� Dopamine

y�®z
...
'i!l -synuclein-dopamine

C) '/,£------
� adduct formation
P rotofibrils

�
Ubiquitinated
protein -

Fibrils Neurotoxicity
P ""Momo

.. /
/
• •• •
"' /
.:.�... . .·-. /
/

Degraded protein

Lewy bodies

Figure 39-6. Schematic d iagram of proposed mechanisms of a-synuclein toxicity .in Parkinson disease. In this model, a-synuclein levels are
elevated by (a) duplicati on of one copy of the a-synuclein gene; (b) point mutati ons in the a-synuclein gene that generate excessi ve accumula­
tions of synuclein; or (c) muta tions in parkin and UCH-Ll genes tha t reduce normal removal of synuclein by the proteosomes. The excess of
synuclein polymerizes to form protofibrils, a process that is enhanced by defects in hea t shock proteins (Hsps) or by the action of dopamine,
which binds to synuclein. In turn , this leads to formation of Lewy bodies. This model attributes the neurotoxici ty to either the protofibril s or
the Lewy bodies. (Ad apted by permi ssion from Eriksen JL, Dawson 1M, Dickson DW, Petrucelli L: Caught in the act: a-Synuclein is the culprit
in Parkinson's disease. Neuron 40:453-456, 2003.)
 CHAPTER 39
by the report that parkinsonian features are present in a
family with mutations in ubiquitin carboxyterminal hydro­
lase L1 (ParkS, UCHL-1; Table 39-3). Figure 39-6 illustrates
these relationships and the processing of synuclein in the
cell. It must be emphasized that most of the mechanisms
illustrated are speculative or are derived from the molec­
ular study of familial Parkinson disease and therefore
may not apply to the sporadic process.
A mutation that has received much attention has
been at the LRRK2 (leucine-rich repeat kinase 2) site.
It is implicated in both genetic and sporadic forms of
the disease, particularly among those of Ashkenazic
Jewish or North African origin. The LRRK2 protein
(dardarin) is a cytoplasmic component that is widely
distributed in the brain and peripheral nerves. It has
been estimated that mutations in the gene (mainly one
common one, G201 95) are responsible for 1 percent of
sporadic cases and are found in 5 to 8 percent of indi­
viduals with a first-degree relative who has the disease.
The gene acts as a dominant trait but penetrance of the
defect increases with age, being 85 percent at 70 years.
Therefore, there may not be a family history. The clinical
syndrome in most respects simulates the sporadic form
of the disease according to Papapetropoulos and col­
leagues, but several other series have noted the absence
of tremor. The genetics of this disorder, also called ParkS,
are reviewed by Brice.
Several other gene defects are of interest in familial
parkinsonism. One is a dominantly inherited mutation
in the gene Nurrl, whose normal function is to specify
the identity of doparninergic neurons. Another is in
recessively inherited parkinsonism caused by defects in
the gene DJ-1, a protein that is essential for the normal
neuronal response to oxidative stress. Also, a disease­
causing mutation in the gene termed PINK, correspond­
ing to Park6, codes for a mitochondrial kinase, therefore
implicating this cellular structure in some forms of
Parkinson disease (Valente et al) . Presumably, doparni­
nergic neurons are compromised in some manner by
these defects.
There has also been emphasis on mutations on 1 of
12 exons in the so-called Park2 gene, which codes for
the protein parkin (see Table 39-3). The most common
types are point mutations or deletions in exon 7, but
abnormalities of the other exons evince similar syn­
dromes. Homozygous mutations generally give rise to
early-onset disease, but certain hemizygous changes (in
exon 7) are associated with a later onset. The resultant
syndromes have been termed parkin disease to distinguish
them from the idiopathic variety. It has been estimated
by Khan and colleagues that 50 percent of families that
display an early onset of Parkinson disease and 18 per­
cent of sporadic cases with early onset (before age 40
years) harbor mutations in this gene. Perhaps of greater
clinical interest is finding that up to 2 percent of late­
onset cases are associated with parkin mutations, and
1 percent due to changes in the aforementioned LRRK2
gene. Sequencing of these genes is now available in com­
mercial laboratories for the purposes of detecting muta­
tions and polymorphisms.
Degenerative Diseases of the Nervous System 1 089
From a clinical perspective, the presentation of the
late-onset cases with parkin mutations has been quite
variable. Collectively, they can often be identified by
an extreme sensitivity to L-dopa, maintaining an almost
complete suppression of symptoms over decades with
only small doses of medication; also, they have a low
threshold for dyskinesias induced by L-dopa. We can also
corroborate from experience with our own patients an
excellent response of tremor, postural changes, and bra­
dykinesia to anticholinergic drugs. A second feature has
been that most of these patients may enjoy a remarkable
restorative benefit from sleep, which creates a diurnal
pattern of symptoms. Several series, particularly those
of Lohmann and associates and of Khan and colleagues,
have indicated that there may be a wide variety of addi­
tional features: hyperreflexia, cervical, foot, or other
focal dystonias, sometimes induced by exercise; and, less
often, autonomic dysfunction, peripheral neuropathy,
and psychiatric symptoms. The sensitivity to medication
and sleep benefit have long been known as the distin­
guishing components of juvenile-onset parkinsonism
with dopa-responsive dystonia (Segawa disease), which
is discussed later in the chapter.
Of similar interest as a modulating factor in the
development of the disease is strong association between
mutations in the glucocerebrosidase gene (other muta­
tions of which causes Gaucher disease) among Ashkenazi
Jews (Sidransky et al), the same population predomi­
nantly affected by polymorphisms of LRRK2. Although
population studies allow only limited conclusions about
clinical correlations, the glucocerebrosidase mutation is
present more often in patients with a family history of
the disease, have an earlier onset that in patients with
a normal gene and a lower incidence of resting tremor.
Mutations have been present in 7 percent of Parkinson
patients who had their genes fully sequenced, making
it so far the most common genetic factor for the disease,
and certainly in this ethnographic population.
It is hoped that the genetic mutations that give rise to
Parkinson disease will expose the molecular pathophysi­
ology of the disease. As discussed earlier, several sites
are implicated in the familial forms of Parkinson disease,
some related to the gene that codes for synuclein, the
main component of the Lewy body.
Tre atm e n t
Although there i s n o current treatment that clearly
halts or reverses the neuronal degeneration underlying
Parkinson disease, methods are now available that afford
considerable relief from symptoms. Treatment can be
medical or surgical, although reliance is placed mainly on
drugs, particularly on L-dopa (Table 39-4). The following
sections are necessarily detailed so as to give the clini­
cian a full comprehension of the use and side effects and
interactions of these drugs.
L-Dopa and L-Dopa-Modifying Drugs At present,
L-dihydroxyphenylalanine (L-dopa) is unquestionably
the most effective agent for the treatment of Parkinson
disease and the therapeutic results, even in those with
1 090 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE

L-Dopa

Carbi dopa-L-dopa 25/ 1 00 mg tid Up to 50/250 mg q3h Reduction of tremor and Nausea, dyskinesias, orthostatic
bradykinesia; less effect hypotension, hallucinati ons,
on postural d i fficul ties confusion

Controlled release 25 / 1 00 mg tid Up to 50/200 mg q4h May prolong L-dopa effects

carbi dopa-L-dopa

Dopamine agonists

Ropini.role 0.25 m g tid 9 to 24 m g / d Moderate effects on all Orthostatic hypotension, excessive

aspects; reduced motor and abrupt sleepiness, confusion,
fluctua tions of L-dopa hallucinations

Pramipexole 0 . 1 25 mg ti d 0.75 to 3 mg/ d As above

Glutamate antagonist

Amantadine 1 00 mg/d 100 mg bid-tid Smoothing of motor Leg swelling, congestive heart
fluctua ti on s failure, prostatic outlet obstruc-
tion, confusion, hallucinations,
insomnia

Anticholinergics

Benz tropine 0.5 mg/d Up to 4 mg/d Tremor reduction, less Atropinic effects: dry mou th,
effect on other features urinary outlet obstruction,
confu s ion, and psychos.is

Trihexypheni d yl 0.5 mg bid Up to 2 mg tid As above A s above

COMT inhibitors

Entacapone 200 mg with Prolonged effect of L-dopa Urine discolorati o n, diarrhea,

L-dopa increased d yskinesias

MAO-inhibitors

Rasagiline 0.5 mg 1 mg daily Reduced "off" time, Hypertensive crisis with tyramine-
Poten ti al neuroprotection rich foods and sympathomimetics

5 bid Potential

far advanced disease, are much better than have been
obtained with other drugs. The levodopa, or a dopamine
agonist preparation as described below, is introduced
when the symptoms begin to interfere with work and
social life or falling becomes a threat, and then these drugs
are used at the lowest possible dose. The theoretical basis
for the use of this compound rests on the observation that
striatal dopamine is depleted in patients with Parkinson
disease but that the remaining diseased nigral cells are
still capable of producing some dopamine by taking up its
precursor, L-dopa. The number of neurons in the striatum
is not diminished and they remain receptive to ingested
dopamine acting through the residual nigral neurons.
Over time, however, the number of remaining nigral neu­
rons becomes inadequate and the receptivity to dopamine
of the striatal target neurons becomes excessive, possibly
as a result of denervation hypersensitivity; this results in
both a reduced response to L-dopa and to paradoxical
and excessive movements (dyskinesias) with each dose.
The drug has an interesting history that includes many
early trials that failed to persuade neurologists of its
effectiveness; Barbeau's paper on this historical subject
may be consulted by the interested reader.
Most patients tolerate the drug initially, experiencing
few serious adverse effects and showing various degrees
of improvement, sometimes dramatic, especially in hypo­
kinesia and tremor after several days or sooner. However,
the side effects and limitations of L-dopa become con­
siderable as the drug therapy continues and the disease
progresses, as discussed below.
By combining L-dopa with a decarboxylase inhibi­
tor (carbidopa or benserazide), which is unable to
penetrate the central nervous system (CNS), decarbox­
ylation of L-dopa to dopamine is greatly diminished in
peripheral tissues. This permits a greater proportion of
L-dopa to reach nigral neurons and, at the same time,
reduces the peripheral side effects of L-dopa and dopa­
mine (nausea, hypotension, confusion) . Combinations
of carbidopa-levodopa are available in a 1 : 10 or 1 : 4 ratio
and the benserazide-levodopa combination is available
in a 1 :4 ratio. The initial dose of carbidopa-levodopa is
typically one-half to one of a 25 / 100-mg tablet given bid
 CHAPTER 39
o r tid and increased slowly until optimum improvement
is achieved, usually up to 4 tablets administered 5 or
more times daily as the disease advances, or a similar
dose of the 25 /250-mg combination.
A class of catechol-0-methyltransferase (COMT)
inhibitors, typified by entacapone, extends the plasma
half-life and the duration of L-dopa effect by preventing
its breakdown (as opposed to increasing its bioavail­
ability, as in the case of carbidopa). A combination of
L-dopa, carbidopa, and a COMT inhibitor is available in
a single pill.
Long-acting preparations of levodopa-carbidopa
may provide slightly longer effect and reduce dyskinesias
in some patients (Hutton and Morris) in the advanced
stages of disease, but our experience with these drugs
given earlier in the course of disease has given less­
predictable results. The absorption of the long-acting
drug, however, is approximately 70 percent and may be
inconsistent, often necessitating a slight increase in total
dose. To facilitate the treatment of morning rigidity and
tremor, the long-acting tablet can be given late in the
previous evening.
For patients who require very frequent but small
doses of the drug because of severe motor fluctuations
and dyskinesias, an oral suspension may be formulated
that allows precisely measured doses to be delivered
orally or through a nasogastric tube. The typical compo­
sition is 500 mg L-dopa (of carbidopa-L-dopa 10/ 100 or
25 /100), 500 mg of ascorbic acid to stabilize the drug, and
250 mL of water, resulting in a concentration of L-dopa
of 2 mg/mL, which is administered in small amounts. A
gel preparation is also available for delivery through a
duodenal tube.
Each patient requires empirical adjustment of the
dose and timing of medication and then generally does
well by maintaining a relatively regular medication
schedule, supplemented by small intercalated doses
when needed. The effect of L-dopa may be virtually
immediate (i.e., after absorption, which occurs over 30 to
40 min) but there is a further cumulative effect over sev­
eral days of consistent dosing. The principles that guide
the adjustment of dosing (end-of-dose wearing off, dys­
kinesias, freezing, confusion) are discussed further on.
Dopamine Agonists These drugs have a direct dopa­
minergic effect on striatal neurons, thereby partially
bypassing the depleted nigral neurons. They have found
a place both as the initial treatment, replacing L-dopa in
this role, and in modulating the effects of L-dopa later in
the illness. However, dopamine agonists are consistently
less potent than L-dopa in managing the main features
of Parkinson disease and, in higher doses and in older
individuals, they produce undesirable motor and cogni­
tive side effects (see further on) . They are favored because
they are associated with fewer dyskinetic motor com­
plications, or at least, delay the need for L-dopa and its
dyskinetic effects. Bromocriptine and lisuride are synthetic
ergot derivatives whose action in Parkinson disease is
explained by their direct stimulating effect on dopamine
(D2) receptors located on striate neurons. The nonergot
dopamine agonists ropinirole and pramipexole have a
similar type and duration of effectiveness and are used
Degenerative Diseases of the Nervous System 1 09 1
more widely because of their minimal ergot-like effects.
Pergolide and the related drug cabergoline are no longer
used because of the risk of cardiac valvular damage, par­
ticularly at higher dose levels.
The dopamine agonists are introduced gradually. For
example, the initial dose of prarnipexole is 0.125 mg tid,
following which the dosage is doubled weekly to a total
of 3 to 4.5 mg/ d if the medication is used without L-dopa.
If an individual is already taking L-dopa, these drugs
usually permit a gradual reduction in levodopa-carbi­
dopa dose by approximately SO percent. Their duration
of action is slightly longer than that of L-dopa and they
cause less nausea. These medications may be also useful
in reducing the motor fluctuations of L-dopa.
Our experience is in general agreement with that of
Marsden, who found that of 263 patients given dopamine
agonists as the sole treatment, 181 had abandoned medi­
cation after 6 months because of lack of effect or adverse
reactions. Nevertheless, the fact that a large enough
proportion of patients continue to benefit for up to 3 to 5
years indicates that the initial use of dopamine agonists
has merit (see also Rascal et al) . A recent development
of some interest is a transdermally absorbed dopamine
agonist such as rotigotine. Several trials suggest that the
transdermal system can maintain a stable plasma level of
the drug. In the study by LeWitt and associates, the main
effect was a doubling of "on" time without unwanted
dyskinesias. The effects on the quality of life in Parkinson
patients appear to be positive but minor in degree. Skin
reactions are common and the sulfites used in the patch
formulation can cause severe systemic reactions in sensi­
tive individuals.
Even small doses of dopaminergic drugs, when first
introduced, may induce orthostatic hypotension, but
most patients are tolerant of them. They may also pro­
duce abrupt and unpredictable sleepiness, and patients
should be warned of this possibility in relation to driving.
In some individuals, particularly the elderly, dopamine
agonists may produce hallucinosis or confusion; these
problems are most profound in patients who are later
determined to have Lewy-body disease (see further on) .
More data are required to judge the efficacy of the cur­
rent trend of initiating therapy with a dopamine agonist
rather than with L-dopa.
Many clinicians initiate treatment with small amounts
of a dopamine agonist, at least as much for the putative
delay of dyskinesias that they offer in comparison to
starting L-dopa. Alternatively, carbidopa/L-dopa tid can
be initiated and supplemented over a month with a dopa­
mine agonist. The side effects and subtleties of dosing are
explained in the sections above on each of these classes of
drug. The issue of also starting an MAO inhibitor such as
rasagiline early in the illness is discussed below.
Adjunctive Medications Because of the side effects
of levodopa and of dopaminergic agents, some neurolo­
gists avoid pharmacotherapies if the patient is in the early
phase of the disease and the parkinsonian symptoms are
not troublesome. When the predominant manifestation is
tremor, very satisfactory results can be obtained in some
patients for up to several years with anticholinergic agents
alone. The anticholinergic drugs have limited effect on the
1 092 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
postural, hypokinetic, and other manifestations of disease.
Koller 's study; which quantified the effect of anticholiner­
gic medication on tremor and compared it to L-dopa, con­
cluded that there was considerable variability in response
between patients but that L-dopa was on average more
effective. Nonetheless, anticholinergic agents have long
been in use for the treatment of tremor in younger patients
and we still use them occasionally; either in conjunction
with L-dopa or in patients who canno t tolerate the latter
drug. The optimum dosage level is the point at which the
greatest relief from tremor is achieved within the limits of
tolerable side effects, mainly dry mouth. In older patients,
one must be alert to changes in cognitive function, hallu­
cinations, and urinary outflow obstruction.
Several synthetic preparations of anticholinergic
drugs are available, the most widely used ones being tri­
hexyphenidyl (beginning with 1 to 2 mg/ d and increased
up to 6 to 8 mg over several weeks) and benztropine
mesylate (1 to 4 mg/ d in divided doses). When it has
been available, we have also had success with the related
agent ethopropazine (50 to 200 mg daily in divided
doses; but it has become difficult to obtain). The effects
on tremor are cumulative and may not be evident for
several days. To obtain maximum benefit from the use of
these drugs, they should be given in gradually increasing
dosage to the point where toxic effects appear: dryness
of the mouth (which can be beneficial when drooling of
saliva is a problem), blurring of vision from pupillary
mydriasis, constipation, and urinary retention as men­
tioned (especially with prostatism). The presence of angle
closure glaucoma is a contraindication to its use. Tremor
abates in several days and most of our patients have
become tolerant to the dry mouth after several weeks.
Pyridostigrnine, propantheline, or glycopyrrolate can be
given to reduce the oral dryness.
With higher dose ranges, mental slowing, confu­
sional states, hallucinations, and impairment of memory
in elderly patients-specifically if there is already some
degree of forgetfulness-are side effects that limit useful­
ness. Occasionally, further benefit may accrue from the
addition of another antihistarninic drug, such as diphen­
hydramine or phenindamine.
The antiviral agent amantadine (100 mg bid) has mild
or moderate benefit for tremor, hypokinesia, and postural
symptoms. In some patients, it reduces L-dopa-induced
dyskinesias (see further on) . Its mechanism of action is
unknown but antagonism of NMDA or release of stored
dopamine has been proposed. It should be noted that
amantadine commonly causes leg swelling, may worsen
congestive heart failure, and can have an adverse effect
on glaucoma, as well as exaggerate the cognitive changes
associated with anticholinergic medications. The use
of the centrally acting anticholinesterase, donepezil, is
being explored for a possible effect on improving gait
stability but requires further study. Finally, the mono­
amine oxidase inhibitors, described just below as puta­
tive neuroprotective agents, have a beneficial effect on
motor fluctuations induced by L-dopa and may have a
slight beneficial effect on the main Parkinson symptoms
as described in several trials, such as the one reported by
Rascol and colleagues.
Neuroprotective Agents An additional approach,
still somewhat controversial, has been to initiate treat­
ment early in the course of the disease with a monoamine
oxidase-B inhibitor (MAO-B inhibitor), with the aim
of reducing oxidative stress in dopaminergic neurons.
The DTAATOP trial conducted by The Parkinson Study
Group (1989) reported a slowing of disease progres­
sion but later followup showed little difference between
treated and untreated groups. Other agents in this class,
notably rasagiline, have given similar mixed results in
brief studies including the ADAGIO trial reported by
Olanow and coworker. The difficulty in assessing the
benefit of these agents has to do with their mild but defi­
nite symptomatic benefit on motor function. A credible
long-term study has reported that early initiation of treat­
ment with bromocriptine (now little used) did not reduce
mortality or motor disability over 14 years and that
any reduction in motor complications was unsustained
(Katzenschlager et al) . Nonetheless, we institute one of
these MAO-B inhibitors in many patients.
Following this same line of reasoning, several stud­
ies, most still disputed or unconfirmed, have suggested
that ropinirole, pramipexole, and even L-dopa have
"neuroprotective" effects in Parkinson disease. However,
slowing of the progression of symptoms, as measured by
a variety of scales, has not been corroborated. Technical
problems in interpreting these results are discussed at
length in the reviews by Wooten and by Clarke and
Guttman. The uncertainties have to do with clinical grad­
ing systems, functional imaging techniques, and points of
comparison to treatment with L-dopa.
The notion that the administration of L-dopa early
in the disease might reduce the period over which it
remains effective has been largely dispelled, but some
neurologists continue to adhere to this idea. Cedarbaum
and colleagues, who reviewed the course of the illness
in 307 patients over a 7-year period, found no evidence
that the early initiation of L-dopa treatment predisposed
to the development of fluctuations in motor response or
to dyskinesia and dementia. In fact, the findings of the
"Elldopa" trial by The Parkinson Study Group (2004)
were that functional and other measures were better in
patients who had taken L-dopa for 40 weeks and then
stopped the medications than in those who received no
medication. Neuropathologic study of the substantia
nigra in the brains of Parkinson patients and their medi­
cation histories also failed to corroborate a reduction in
the number of pigmented neurons (Parkkinen et al) . Also,
the large multicenter study reported by Diamond and
colleagues indicated that patients who were given L-dopa
early in the disease actually survived longer and with
less disability than those who began the medication late
in the course; that is, L-dopa may have itself been neuro­
protective. However, there have been many alternative
interpretations of these data.
Finally, attempts to slow the disease by vitamin
antioxidants such as vitamin E have met with mixed, but
generally negative, results. A possible exception was the
trial of coenzyme Q10 by Shults and colleagues. Massive
doses of this agent, 1,200 mg I d, were found to offer mar­
ginal advantages on the progression over 6 to 18 months
 CHAPTER 39
as measured by certain scores of overall daily function
but not on most neurologic scales. Further study of this
approach is advised.
Side Effects of Dopamine Treatment and Their
Management The side effects of L-dopa are at times
significant to the degree that its continuation cannot be
tolerated. Some patients are at first troubled by nausea,
although this can be mitigated by taking the medica­
tion with meals. Nausea usually disappears after several
weeks of continued use or can be allayed by the specific
dopaminergic chemoreceptor antagonist domperidone. A
few have mild orthostatic hypotensive episodes.
The most troublesome effects of L-dopa as the disease
advances, usually after several years of treatment, are
end-of-dose reduction in efficacy and the induction of
involuntary "dyskinetic" movements-restlessness, head
wagging, grimacing, lingual-labial dyskinesia, blepha­
rospasm, and especially, choreoathetosis and dystonia
of the limbs, neck, and trunk . A decline in efficacy at the
end of the dose interval, typically 2 to 4 h, may be treated
by more frequent dosing, the addition of dopaminergic
agonist, or a COMT inhibitor.
The on-off or off phenomenon is a rapid and sometimes
unpredictable change-in a matter of minutes or from 1 h
to the next-from a state of relative freedom from symp­
toms to one of nearly complete immobility. Both dyski­
nesias and severe "off" periods appear in approximately
75 percent of patients within 5 years. Few patients escape
these opposing effects, forcing an increased frequency of
administration and usually a reduction in dosage.
If involuntary dyskinetic movements are induced by
relatively small doses of L-dopa, the problem may be sup­
pressed to some extent by the addition of direct-acting
dopaminergic agents or by the concurrent administra­
tion of amantadine, or by the use of an oral suspension
of L-dopa as mentioned earlier. The use of lower doses
of long-acting preparations of L-dopa may be helpful
in reducing dyskinesias and the atypical antipsychotic
medications have been said to be useful for this purpose
but carry their own risks.
The onset of psychiatric symptoms coincident with
the use of L-dopa or dopamine agonists may also present
problems and is to be expected eventually in 15 to 25 percent
of patients, particularly in the elderly. Confusion and
outright psychosis (hallucinations and delusions) are seen
in advanced cases of Parkinson disease when high doses
of L-dopa are required and the disease has been present
for many years. This may first be treated by reducing
the dose of the drug. If this is not tolerated, the atypi­
cal neuroleptics olanzapine, clozapine, risperidone, or
quetiapine may be given in low doses. The side effects of
these drugs include sleepiness, orthostatic hypotension,
and sialorrhea. As noted above, clozapine has been said
to provide an additional benefit of suppressing dyskine­
sias in advanced Parkinson disease, but its hematologic
risks have led to limited use. Although useful in the
treatment of frankly psychotic patients, these drugs tend
to be far less effective once dementia has supervened.
The antiepileptic drug, valproate is also said to be useful
in this circumstance, but it has not been as effective as
clozapine and related drugs. Despite its lesser tendency
Degenerative Diseases of the Nervous System 1 093
to produce rigidity, olanzapine, and probably the other
similar agents, in high doses may slightly worsen motor
disability.
Depression, although frequent, is only occasionally a
serious problem, even to the point of suicide. Delusional
thinking may also occur in these circumstances. This
combination of movement and psychiatric disorders
is difficult to treat, and one is faced with instituting an
antidepressant regimen or perhaps using one of the
newer classes of antipsychotic medications that have
the least extrapyramidal side effects (see below). While
the selective serotonin reuptake inhibitors have been
useful in cases of apathetic depression, they may cause
slight worsening of parkinsonian symptoms. Trazodone
has been helpful in treating depression and insomnia,
the latter also being a major problem in some patients.
Excitement and aggressiveness appear in a few. A return
of libido may lead to sexual assertiveness. Other curious
effects of excessive drive from L-dopa and dopamine
agonists have been pathologic gambling (the same has been
seen in treatment of restless legs syndrome) and cross­
dressing (Quinn et al, 1983) .
Anticholinergic agents or L-dopa should not be dis­
continued abruptly in advanced Parkinson disease. If
abruptly discontinued, the patient may become totally
immobilized by a sudden and severe increase of tremor
and rigidity; rarely, a neuroleptic syndrome, sometimes
fatal, has been induced by such withdrawal. Reducing the
medication dose over a week or so is usually adequate.
With progressive loss of nigral cells, there is an
increasing inability to store L-dopa and periods of drug
effectiveness become shorter. In some instances, the
patient becomes so sensitive to L-dopa that 50 to 100 mg
will precipitate dyskinesias; if the dose is lowered by the
same amount, the patient may develop disabling rigidity.
With the end-of-dose loss of effectiveness and the on-off
phenomenon, which with time become increasingly
frequent and unpredictable, the patient may experience
pain, respiratory distress, akathisia, depression, anxiety,
and even hallucinations. Some patients function quite
well in the morning and much less well in the afternoon,
or vice versa. In such cases, and for end-of-dose and on­
off phenomena, one must titrate the dose of L-dopa and
use more frequent dosing during the 24-h day; combining
it with a dopamine agonist or a long-acting preparation
may be helpful. Sometimes temporarily withdrawing
L-dopa and at the same time substituting other medica­
tions may reduce the on-off phenomenon.
Based on the principle that alimentary-derived
amino acids compete for absorption of L-dopa, the use
of a low-protein diet has been advocated as a means of
controlling the motor fluctuations (Pincus and Barry).
Symptoms can sometimes be reduced by the simple expe­
dient of eliminating dietary protein from breakfast and
lunch. Moreover, this dietary regimen may permit the
patient to reduce slightly the total daily dose of L-dopa.
Such dietary manipulation is worth trying in appropriate
patients; it is not harmful, and most of our patients with
advanced disease who have persisted with this diet have
reported improvement in their symptoms or an enhanced
effect of L-dopa. A novel observation by Pierantozzi and
1 094 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
colleagues has been that the absorption of L-dopa may be
influenced by the presence of gastric Helicobacter pylori
infection and that eradication of the organism was associ­
ated with longer "on" time.
S u rg ica l M e a s u res
Until recently, success with L-dopa had replaced the use of
the ablative surgical therapy pioneered by Cooper 50 years
ago. The surgical approaches involved the placement of
lesions in the globus pallidus, ventrolateral thalamus, or
subthalamic nucleus, contralateral to the side of the body
chiefly affected. The best results were obtained in rela­
tively young patients, in whom unilateral tremor or rigid­
ity rather than akinesia were predominant. The symptoms
that responded least well to surgical therapy in Cooper 's
patients were postural imbalance and instability, paroxys­
mal akinesia, bladder and bowel disturbances, dystonia,
and speech difficulties.
More recently, through the work of Laitinen, Leksell,
and others, this mode of therapy has been revived as a
stereotactically guided procedure and advanced by the
newer technique of implanted electrodes (deep brain
stimulation, DBS) . For the treatment of Parkinson dis­
ease, the electrodes are placed in the posterior and ventral
(medial) parts of the subthalamic nucleus or in the internal
segment of the globus pallidus. Most patients who have
DBS experience enhanced responsiveness to L-dopa and a
reduction of drug-induced dyskinesias. Bilateral stimula­
tion of the subthalamic nucleus has produced improve­
ment in all features of the disease, including in bradyki­
nesia, that is lost after several years, but there is generally
little benefit for impaired gait and balance (Limousin
et al; Weaver et al, who conducted a more extensive
study but for only 6 months) . A study by the Deep-Brain
Stimulation for Parkinson's Disease Group demonstrated
at least short-term benefit in motor fluctuations after the
bilateral implantation of stimulating electrodes in the
subthalamic nuclei and the durability of this effect with
continued DBS in subsequent studies ranged from 2 to
7 years.
The ideal candidates for DBS are considered to be
those in whom, after several years, there is a failure of
medications to relieve symptoms but especially because
of unmanageable dyskinesias that result from L-dopa . A
randomized, blinded trial by Deuschl and colleagues con­
firmed this effect and demonstrated an overall improve­
ment in the quality of life at 6 months. The benefit with
bilateral stimulation of the globus pallidus has been
essentially equivalent to results from subthalamic stimu­
lation (Follett et al) . Dystonia, when present as part of
the native disease or as a result of medication, may also
benefit from this treatment, perhaps more so with pal­
lidal stimulation. Several groups have pointed out that
cognitive function may decline slightly with DBS, but
deterioration is not as prominent in some spheres of per­
formance, such as speed of processing, with stimulation
of the globus pallidus. Hemorrhage into the basal ganglia
and local infection near the stimulator has occurred in
a small number of patients so treated. Depression and
suicides also appear as adverse events in some stimula­
tion trials.
The typical patient who will derive benefit from
deep-brain stimulation is considered to be one who, to
maintain mobility, requires a dose of L-dopa that produces
unacceptable dyskinesias and who is constantly cycling
between on and off periods. More recently, DBS has been
introduced earlier in the course of illness, when the patient
is still largely responsive to L-dopa and before severe
motor complications such as dyskinesias arise. These
patients are, of course, younger and have had a shorter
duration of disease. In a trial conducted by Schuepbach
and coworkers, in patients with mean durations of illness
of 7.5 years and 52 years of age, there was a significant
and sustained benefit in quality of life measures, motor
complications and on time, for subthalamic DBS.
The stimulator is inserted in a pouch that is cre­
ated near the rostral pectoral muscle and inferior to the
clavicle. An external controller allows the stimulator to
be adjusted for which 4 electrodes on either side are acti­
vated and their polarity, voltage applied, frequency of
pulses, and pulse duration are manipulated. All patients
with implanted electrodes require frequent initial con­
tact with a physician experienced in programming the
stimulator. Some patients can make minor adjustments
or even turn off the stimulator on their own with a small
control device that has preset limits. The battery must be
exchanged periodically, the duration of service depend­
ing on the voltage used over time and other parameters
of use. A comprehensive review of the subject has been
given by Okun, including comments on the controversies
regarding the differences in cognitive disturbance and the
reduction in L-dopa doses comparing stimulation of the
globus pallidus with the subthalamic nucleus.
Presumably, the high-frequency electrical impulses
cause a disruption of local neuronal activity that is the
functional equivalent of an ablative lesion, but the effects
of deep brain stimulation may be more complex by way
of stimulating neurotransmitter release.
The cerebral implantation of fetal dopaminergic tissue
provided a modest improvement in motor function for
a limited period of time (Spencer et al; Freed et al). The
study by Freed and colleagues found a small improve­
ment on a global scale that measured functional, psycho­
logic, and neurologic aspects only in younger patients but
the effect waned by 1 year. These procedures are ham­
pered by many difficulties, mainly in obtaining tissue
and the failure of grafts to survive but also the problem
of uncontrollable dyskinesias in some patients. Another
provocative approach has been the delivery of neural
trophic factors directly or in a viral vector through a
small catheter; at least 2 trials have failed to show benefit.
Similarly, the implantation of stem cells is being explored
but has several obstacles.
Techniques of focused ultrasound energy to produce
ablative lesions in deep nuclei are being developed. So
far, they have found use for the treatment of essential
tremor, such as in the trial conducted by Elias with tha­
lamic lesions (ventral intermediate nucleus) .
Ancillary Treatments In the management o f the
patient with Parkinson disease, one must not neglect the
maintenance of general health and neuromuscular effi­
ciency by a program of exercise, activity, and rest; physical
 CHAPTER 39
therapy and exercises such as those performed in yoga
may be of help in achieving these ends. Sleep may be aided
by soporific antidepressants. Postural imbalance and falls
can be greatly mitigated by the use of a cane or walking
frame. A number of excellent exercise programs have been
devised specifically for patients with Parkinson disease,
and measures such as massage and yoga have their advo­
cates. Among these mechanical therapies that have been
studied systematically, tai chi has been found to improve
balance and reduce falls as measured by objective criteria
(Li et al), indicating that these approaches are of substan­
tial value. Several of our patients have taken up dancing
and report that their balance in daily circumstances is
improved. Our position has been that any activity that
keeps the patient moving and committed is of great value.
Speech exercises help the motivated patient.
Hypotensive episodes respond to fludrocortisone or
midodrine given each morning. Focal dystonias of the
foot are partially treatable with local injections of botuli­
num toxin. In addition, the patient often needs emotional
support in dealing with the stress of the illness, with the
anxiety that seems to be an integral part of the disease in
some patients, in comprehending the future, and in car­
rying on courageously in spite of it.
M u ltiple System Atrophy (Striaton igral
Degeneration, Shy-Drager Syndro m e,
Olivopontocerebel lar Degeneratio n )
A s the name multiple system atrophy indicates, this depicts
a group of disorders characterized by neuronal degenera­
tion mainly in the substantia nigra, striatum, autonomic
nervous system, and cerebellum. Following a report in
1964 by Adams and colleagues of what was then called
striatonigral degeneration, many patients were recognized
in whom the changes of striatonigral and olivopontocer­
ebellar degeneration were combined and who had symp­
toms and signs of cerebellar ataxia and parkinsonian
manifestations. The pathologic changes were found by
chance in 4 middle-aged patients, in 3 of whom a parkin­
sonian syndrome had been described clinically, none with
a family history of similar disease. Rigidity, stiffness, and
akinesia had begun on one side of the body, then spread
to the other, and progressed over a 5-year period but with
minimal characteristic tremor of idiopathic Parkinson
disease. A flexed posture of the trunk and limbs, slowness
of all movements, poor balance, mumbling speech, and
a tendency to faint when standing were other elements.
There was an early-onset cerebellar ataxia in the fourth
patient that was later obscured by a Parkinson syndrome.
The postmortem examinations disclosed extensive
loss of neurons in the zona compacta of the substantia
nigra, but notably, there were no Lewy bodies or neurofi­
brillary tangles in the remaining cells. Even more striking
were the degenerative changes in the putamina and to
a lesser extent in the caudate nuclei. Secondary pallidal
atrophy (mainly a loss of striatopallidal fibers) was pres­
ent. In the patient with ataxia there was, in addition,
advanced degeneration of the pons, olives, and cerebel­
lum (see below in the discussion of olivopontocerebellar
degeneration).
Degenerative Diseases of the Nervous System 1 095
Recognizing that the clinical and pathologic features
of striatonigral degeneration, with or without autonomic
failure, can coexist with olivopontocerebellar atrophy,
Graham and Oppenheimer proposed the term multiple
Sljstem atrophy (MSA), which has gained wide acceptance.
Several large series of cases of this complex syndrome
have been published, providing a perspective on the fre­
quency and nature of its component syndromes. Either
parkinsonism or cerebellar ataxia may predominate.
In many writings they are categorized as MSA-P and
MSA-C, respectively, depending on whether they display
predominantly parkinsonism or cerebellar ataxia. More
than half of the patients with striatonigral degeneration
have orthostatic hypotension, which proves at autopsy to
be associated with loss of intermediolateral hom cells
and pigmented nuclei of the brainstem. This combined
parkinsonian and autonomic disorder, formerly referred
to as the Shy-Drager syndrome, was alluded to in Chaps.
18 and 26 and is now termed MSA-A, for multiple sys­
tem atrophy with autonomic changes. In addition to
orthostatic hypotension, other features of autonomic
failure include erectile dysfunction loss of sweating, dry
mouth, miosis, and urinary retention or incontinence.
Vocal cord palsy is an important and sometimes initial
manifestation of the disorder; it may cause dysphonia or
stridor and airway obstruction requiring tracheostomy. A
dusky discoloration of the hands as a sign of this disor­
der was ascribed to poor control of cutaneous blood flow
by Klein and colleagues. A diagnostic problem arises in
that orthostatic hypotension is also observed in up to 15
percent of patients with Parkinson disease, a feature that
may be exaggerated by medications, but the degree of
drop in blood pressure is far greater and more frequent in
patients with this form of multiple system atrophy.
In the Brain Tissue Bank of the Parkinson Disease
Society of Great Britain, MSA accounted for 13 percent
of patients who had been identified during life as having
idiopathic Parkinson disease. All the patients with MSA
had one or more symptoms of autonomic failure (pos­
tural hypotension, urinary urgency or retention, urinary
or fecal incontinence, erectile dysfunction) and dyspho­
nia or stridor. Babinski signs were present in half the
patients and cerebellar ataxia in one-third. Tremor was
rare. Males were affected more often than females. In a
comparable series of 100 patients (67 men and 33 women)
studied by Wenning and coworkers (1994), the disease
began with a striatonigral-parkinsonian syndrome in
approximately half; often it was asymmetrical at the
onset. Mild tremor was detected in some but in only
a few was it of the "resting" Parkinson type. In nearly
half, the illness began with autonomic manifestations;
orthostatic hypotension occurred eventually in almost
all patients, but it was disabling in only a few. Cerebellar
features dominated the initial stages of the disease in only
5 percent, but ataxia was eventually obvious in half the
larger group. This ataxic clinical presentation of multiple
system atrophy will be elaborated further in the section
on the degenerative cerebellar ataxias.
The extrapyramidal illness, on the whole, is more
severe than in Parkinson disease, as more than 40 percent
of patients are confined to a wheelchair or otherwise
1 096 Part 4 MAJOR CATEGORIES OF NEU ROLOGIC D ISEASE
severely disabled within 5 years. These observations
generally match the findings in the group described by
Quinn and colleagues (1986), but they emphasized that
pyramidal signs were present in 60 percent.
Colosimo and colleagues reviewed the clinical find­
ings in 16 pathologically verified cases of MSA and found
that several signs, namely, relative symmetry of the signs
and rapid course, the lack of response to L-dopa, absence
or minimal amount of tremor, and the early presence
of autonomic disorders, reliably distinguished this syn­
drome from Parkinson disease. These observations are
in keeping with our own and we would add that abnor­
malities of eye movement are not prominent in MSA.
Additional features occurring occasionally in MSA are
remarked upon in other series; anterocollis or dystonia
of the lower facial muscles, for example, is striking in a
few cases. It is noteworthy that levodopa has had little
or no effect or has made these patients worse early in the
disease but we have seen exceptions. The lack of L-dopa
effect is probably attributable to the loss of striatal dopa­
mine receptors.
The diagnosis of MSA, especially the form with
ataxia, has been aided by imaging techniques. Both MRI
and CT scanning frequently show atrophy of the cer­
ebellum and pons in those with cerebellar features. The
putamina are hypointense on T2-weighted MRI and may
show an increased deposition of iron in the parkinsonian
form. In the cerebellar form, a "hot cross bun" sign has
been emphasized on MRI; it reflects atrophy of the pon­
tocerebellar fibers that manifest high T2 signal intensity
in an atrophic pons. Studies with PET have disclosed
impairment of glucose metabolism in the striatum and to
a lesser extent in the frontal cortex, a reflection, no doubt,
of the loss of functioning neuronal elements in these parts.
Finally, despite the concurrence of striatonigral
degeneration, olivopontocerebellar degeneration, and
the Shy-Drager syndrome, each of these disorders can occur
in almost isolated clinical form; we therefore retain their
original designations.
Although the cause of this process is not known, and
the majority of cases are sporadic, The Multiple System
Atrophy Research Collaboration identified a mutation in
the COQ2 gene, coding for a protein involved in the syn­
thesis of coenzyme Ql O' in both familial cases and a very
small proportion of sporadic ones.
Pathology In recent years, attention has been drawn
to the presence of abnormal staining material in the
cytoplasm of astroglia and oligodendrocytes and in some
neurons as well. These cytoplasmic aggregates have
been referred to as glial cytoplasmic inclusions (Papp et al) .
Although they bear little resemblance morphologically to
other discrete inclusions that have come to be accepted as
characteristic of certain degenerative CNS diseases (e.g.,
Lewy bodies), they nonetheless contain a-synuclein (the
main component of Lewy bodies). It is not clear to us
whether these glial cytoplasmic accumulations represent
a histopathologic hallmark of MSA as suggested by Chin
and Goldman and by Lantos, as their presence is not spe­
cific; they have been identified in practically every degen­
erative disease that has been subjected to sensitive silver
impregnation stains. Many types of inclusions are, of
course, nonspecific, as, for example, a-synuclein-positive
inclusions have been detected in several neurodegenera­
tive syndromes. Appropriate control studies to determine
whether the glial inclusions are found in nondegenerative
lesions in brain (at the edge of an infarct, for example) are
needed. Also lacking is information about the frequency
of these cytoplasmic inclusions in relation to the aging
brain.
Prog ressive Supran uclear Pa lsy
In 1963, Richardson, Steele, and Olszewski crystallized
medical thought about a clinicopathologic entity-pro­
gressive supranuclear palsy (PSP)-to which there had
been only ambiguous reference in the past. The condition
is not rare. By 1972, when Steele reviewed the subject,
73 cases (22 with postmortem examinations) had been
described in the medical literature. Rare familial clusters
have been described in which the pattern of inheritance
is compatible with autosomal dominant transmission
(Brown et al; de Yebenes et al) . Rojo and coworkers
described 12 pathologically confirmed pedigrees and
made note of the variable phenotypical expression of the
disease even within a single pedigree. No toxic, encepha­
litic, racial, or geographic factor has been incriminated.
C l i n i c a l Featu res
The disease has its onset typically in the sixth decade
(range: 45 to 75 years), with some combination of dif­
ficulty in balance, abrupt falls, visual and ocular distur­
bances (giving the syndrome its name), slurred speech,
dysphagia, and sometimes vague changes in personality,
including apprehensiveness and fretfulness suggestive
of an agitated depression. The most common early com­
plaint is unsteadiness of gait and unexplained falling
without loss of consciousness. The patient has difficulty
in describing his imbalance, using terms such as "diz­
ziness," "toppling," or an ambiguous problem with
walking. At first, the neurologic and ophthalmologic
examinations may be unrevealing, and it may take a year
or longer for the characteristic syndrome comprising
supranuclear ophthalmoplegia, pseudobulbar palsy, and
axial dystonia to develop fully.
Difficulty in voluntary vertical movement of the eyes,
often downward but sometimes only upward, and later
impairment of voluntary saccades in all directions are char­
acteristic. A related but more subtle sign has been the find­
ing of hypometric saccades in response to an optokinetic
drum or striped cloth moving vertically in one direction
(usually best seen with stripes moving downward). Later,
both ocular pursuit and refixation movements are delayed
and diminished in amplitude and eventually all voluntary
eye movements are lost, first the vertical ones and then the
horizontal ones as well. However, if the eyes are fixated on
a target and the head is turned slowly, full movements can
be obtained, demonstrating the supranuclear, nonparalytic
character of paralysis of ocular pursuit. Other prominent
oculomotor signs are sudden jerks of the eyes during fixa­
tion, "cogwheel" or saccadic choppiness of pursuit move­
ments, and hypometric saccades of long duration (Troost
and Daroff). The Bell phenomenon (reflexive upturning
 CHAPTER 39 Degenerative Diseases of the Nervous System 1 097

of eyes upon forced closure of the eyelids) and the abil­ frequent and longer than in normal individuals of the
ity to converge are also lost eventually, and the pupils same age. Complaints of urinary frequency and urgency
become small but remain round and reactive to both light have also been frequent in advanced cases under our care.
and to accommodative stimuli. The upper eyelids may be The diagnosis often proves difficult to make if the
retracted, and the wide-eyed, unblinking stare imparts main features are not outstanding. Other features, such
an expression of perpetual surprise. Blepharospasm and as tremor, palilalia, myoclonus, chorea, orofacial dys­
involuntary eye closure are prominent in some cases. In kinesias, and disturbances of vestibular function, are
the late stages, the eyes may be fixed centrally and all observed in some cases. Finally the patient becomes anar­
oculocephalic and vestibular reflexes are lost. It should be thric, immobile, and quite helpless. Dementia of some
emphasized, however, that a proportion of patients do not degree is probably present in many cases, but is mild
demonstrate these eye signs for a year or more after the onset in most. Some patients do become forgetful and appear
of the illness. We have also followed several patients who apathetic and slow in thinking; many others are irritable
had no disorder of eye movement during life but in whom or at times euphoric. Dubois and colleagues proposed an
the typical pathologic changes of PSP were nonetheless "applause sign" as distinctive to this disease; the patient
found. In one such patient, there was a subcortical type fails to stop clapping after being asked to do so only 3
of dementia; in another, focal limb dystonia and parkin­ times, but we are unable to corroborate this.
sonism. Furthermore, other degenerative conditions can By MRl one can, in advanced cases, appreciate atro­
manifest a supranuclear vertical gaze disorder, although phy of the dorsal mesencephalon (superior colliculi, red
never to the extent seen in PSP; these include corticobasal­ nuclei) giving rise to a "mouse ears" configuration (Fig.
ganglionic degeneration, Lewy-body disease, Parkinson 39-7), but these changes may not be evident early in the
disease, and Whipple disease. illness when diagnosis is most diffi cult. Several measure­
The gait disturbance and repeated falling have proved ments of midbrain atrophy have been proposed as aiding
difficult to analyze, as discussed in Chap . 7. Walking diagnosis; for example, there is little overlap between
becomes increasingly awkward and tentative; the patient PSP, multiple system atrophy, and Parkinson disease in
has a tendency to totter and fall repeatedly, but has no the ratio of midbrain-to-pons cross-sagittal area, accord­
ataxia of gait or of the limbs and does not manifest a ing to Oba and colleagues. The CSF remains normal.
Romberg sign or orthostatic tremor. Some patients tend Nonetheless, the diagnosis continues to rest on the clini­
to lean and fall backward (retropulsion) . One of our cal features, mainly affecting eye movements.
patients, a large man, fell repeatedly, wrecking house­ Pathology Postmortem examinations have disclosed a
hold furniture as he went down, yet careful examination bilateral loss of neurons and gliosis in the periaqueductal
provided no clue as to the basic defect in this "toppling" gray matter, superior colliculus, subthalamic nucleus,
phenomenon. Along with the oculomotor and balance
disorders, there is a gradual stiffening and extension of
the neck (in one of our patients it was sharply flexed in a
manner consistent with camptocormia) but this is not an
invariable finding. The face acquires a staring, "worried"
expression with a furrowed brow (a result of the tonic
contraction of the procerus muscle), made more strik­
ing by the paucity of eye movements. A number of our
patients have displayed mild dystonic postures of a hand
or foot, especially as the illness advanced but occasion­
ally early on. The limbs may be slightly stiff and there are
Babinski signs in a few cases.
The stiffness, slowness of movement, difficulty in
turning and sitting down, and hypornimia may suggest
a diagnosis of Parkinson disease. However, the facial
expression of the PSP patient is more a matter of tonic
grimace than of lack of movement, and the lack of tremor,
the erect rather than stooped posture, and prominence
of oculomotor abnormalities serve to distinguish the 2
disorders. The signs of pseudobulbar palsy are eventually
prominent, and this feature, along with the eye move­
ments, distinguishes the process most conspicuously
from other degenerative conditions. The face becomes less
expressive ("masked"), speech is slurred in a slowed spas­
tic fashion, the mouth tends to be held open, and swal­
lowing is difficult. Forced laughing and crying, said to be
infrequent, have been present in about half of our cases
late in the course. Many patients complain of sleep distur­ Figure 39-7. Progressive supranuclear pal sy. T2-weighted axial MRI
bances. The total sleep time and REM sleep are reduced, sho\oving the atrophic d orsal midbrain that gives rise to the "mouse
and spontaneous awakenings during the night are more ears" (also "Mickey mouse") appearance.
1 098 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
red nucleus, pallidurn, dentate nucleus, and pretectal
and vestibular nuclei, and to some extent in the oculo­
motor nucleus. The expected loss of the myelinated fiber
bundles arising from these nuclear structures has also
been commented upon. The remarkable finding has been
the neurofibrillary degeneration of many of the residual
neurons. The neurofibrillary tangles are thick and often
composed of single strands, either twisted or in parallel
arrangement. The neurons of the cerebral cortex have
been involved in some cases (shown by staining of tau
protein), but these changes do not correlate with demen­
tia. The cerebellar cortex is usually spared.
The cause and nature of this disease remain obscure.
Though some clinical and pathologic heterogeneity is
seen, the majority of cases of PSP conform to the typi­
cal pattern as we have just described. These interesting
diagnostic and clinicopathologic aspects are s umma rized
by Willi ams and Lees. Studies with PET demonstrate a
decrease in blood flow, most marked in the frontal lobes,
and a lesser extent of oxygen utilization in central struc­
tures (Leenders et al) . Striatal dopamine formation and
storage are significantly decreased when compared with
control values. Much current interest has been directed to
the neurofibrillary tangles and tau deposition in PSP and
a potential link to the tau pathology displayed in fronto­
temporal dementia and in corticobasalganglionic degen­
eration (see below) . As s ummarized by Golbe, certain
tau gene haplotypes on chromosome 1 7p (the same site
implicated in familial frontotemporal dementia) are more
often associated with PSP than in unaffected individuals,
but other factors, environmental or genetic, must also be
involved. It is intriguing that the tau-gene haplotype of
frontotemporal dementia is not found in PSP. A recent
investigation into the mechanism of postural instability
using functional imaging, showed a correlation between
gait instability and decreased thalamic glucose metabo­
lism and activation (Zwergal) .
PSP should b e suspected whenever an older adult
inexplicably develops a state of imbalance, frequent falls
with preserved consciousness, and variable extrapyrami­
dal symptoms, particularly dystonia of the neck, ocular
palsies, or a picture resembling pseudobulbar palsy. If the
typical abnormalities of eye movements are present, the
diagnosis is not difficult. When only a parkinsonian syn­
drome without tremor is apparent the main diagnostic
consideration is striatonigral degeneration or the cortico­
basalganglionic syndrome, described below.
Treatment L-Dopa has been of slight and unsus­
tained benefit in some of our patients, and combinations
of L-dopa and anticholinergic drugs have been entirely
ineffective in others. A marked response to these drugs
should, of course, suggest the diagnosis of Parkinson
disease. Recently, the drug zolpidem, a gabanergic ago­
nist of benzodiazepine receptors, has been reported to
ameliorate the akinesia and rigidity of PSP (Daniele et al);
however, these observations require corroboration.
Benztropine or trihexyphenidyl has been somewhat help­
ful in reducing dystonia but botulinum injections may be
a better alternative if there are focal signs. Treatments of
the sleep difficulties and urinary incontinence are of great
assistance to the patient and family. A feeding tube becomes
necessary in advanced cases. Observing the decline of
these patients and the limitations of treatment is a frus­
trating ordeal for all involved.
Corticobasal Degeneratio n
Most neurologists have observed elderly patients in
whom the essential abnormality was a progressive asym­
metrical extrapyramidal rigidity combined with signs of
corticospinal disease. Sometimes a mild postural action
tremor beginning unilaterally and suggestive in some
respects of Parkinson disease has been added. The par­
kinsonism is generally unresponsive to L-dopa. These
cases have come to be known by the names corticobasal­
ganglionic or cortical-basal degeneration and like sounding
terms. The clinical relation of such cases is indeterminate
to corticostriatospinal degeneration described earlier, and
based on the finding of tau inclusions, to frontotempo­
ral lobar degeneration and to progressive supranuclear
palsy.
Wenning and colleagues (1998) described a series
of such patients in whom the diagnosis was confirmed
at postmortem examination. The most common early
symptom was an asymmetrical clumsiness of the limbs,
in half of the patients, with rigidity and, in one-fifth, with
tremor; these features are now considered to be the most
characteristic early features of the process. As the illness
progressed, almost all the patients developed an asym­
metric or unilateral akinetic-rigid syndrome, which may
be considered the essential motor disorder of this dis­
ease and various forms of gait disorder and dysarthria.
Stimulus-induced or spontaneous myoclonus and pyra­
midal signs, mentioned in other reports and frequent in
our cases, were not prominent in their series; limitations
of vertical gaze and frontal lobe release signs eventually
became apparent in half.
Eventually, although able to exert considerable mus­
cle power, these patients cannot effectively direct their
voluntary actions. Attempts to move a limb to accom­
plish some purposeful act might result in a totally inap­
propriate movement, always with great enhancement
of rigidity in the limb and in other affected parts, or the
limb may drift off and assume an odd posture, such as
a persistent elevation of the arm without the patient's
awareness-a kind of catalepsy. The disorder of limb
function has some of the attributes of a limb-kinetic or
an ideomotor apraxia (see Chap. 3), but the hand pos­
tures, involuntary movements, and changes in tone are at
times more of the type described as "alien hand. " Some
patients exhibit anosognosia, Babinski signs, impaired
eyelid or ocular motion (upgaze paresis or abnormal
saccadic movements), lingual dyskinesias, frontal release
signs, myoclonus, or dysarthria.
Another distinct group has dementia as an early fea­
ture, as described by Grimes and colleagues, but mental
deterioration is more often late and may not occur in all
patients. There are also rare patients who present with
behavioral disturbance or nonfluent aphasias as early
features, which are difficult to distinguish from sub­
types of frontotemporal dementia (Lee and colleagues,
2011 ). Occasionally, there is some involvement of lower
 CHAPTER 39
motor neurons with resulting amyotrophy. Several of our
patients had myoclonus as an early feature, one display­
ing it only on one side of the face, the other in an arm.
The condition progresses for 5 years or more before some
medical complication overtakes the patient.
Postmortem examination of patients, originally
reported by Rebeiz and colleagues, disclosed a combina­
tion of findings that differentiated the disease process
from other neurodegenerative conditions. Cortical atro­
phy (mainly in the frontal motor-premotor and anterior
parietal lobes) was associated with degeneration of the
substantia nigra and, in one instance, of the dentato­
rubrothalamic fibers. The loss of nerve cells was fairly
marked, but there was no gross lobar atrophy, as occurs
in Pick disease. The neuronal degeneration was more on
one side of the brain than the other. There was moder­
ate gliosis in the cortex and underlying white matter.
The disease is now clearly considered to be related to
tau deposition in specific brain structures; however, the
original authors were more impressed with ballooned
and chromatolytic neurons with eccentric nuclei, a state
that was called neuronal achromasia. The presence of these
achromatic cells in posterior frontal and parietal neu­
rons continues to be considered an essential feature of
the disease, although the rounded areas within neurons
stain for tau and resemble globose tangles that are found
occasionally in Alzheimer disease (corticobasal bodies);
in this way, CBD is connected to the other tau-related
neurodegenerative diseases, " tauopathies." In addition,
adjacent glia are filled with various configurations of tau
protein, thereby linking the disease to frontotemporal
lobar degeneration and PSP. Our colleague Feany, with
Dickson, has identified one type of these as "plaques" in
the cortex that are composed of tau aggregates within the
distal processes of astrocytes.
Both CT and MRl have demonstrated asymmetri­
cal cerebral and pontine atrophy, and PET studies have
revealed thalamoparietal metabolic asymmetries-a
greater reduction of glucose metabolism on the side of
the most extensive lesion (Riley et al).
There are no clues as to the pathogenesis of this dis­
ease. There are rare familial types but no definite genetic
cause has been identified. No organ other than the CNS is
affected. The progression is relentless. None of the drugs
in common use for spasticity, rigidity, and tremor has
been helpful.
Dystonic Disord ers
Dysto n i a M u scu l o r u m Defo r m a n s
(To rs i o n Dysto n i a )
Dystonia as a symptom was discussed in Chaps. 4 and
6. Here we are concerned with a disease or diseases of
which dystonia is the major manifestation. Schwalbe's
account, in 1908, of 3 siblings of a Jewish family who were
afflicted with progressive involuntary movements of
trunk and limbs probably represents the first description
of a disease in which severe and progressive dystonia
was the sole manifestation. In 1911, Oppenheim contrib­
uted other cases and coined the term dystonia musculorum
Degenerative Diseases of the Nervous System 1 099
deformans in the mistaken belief that the disorder was pri­
marily one of muscle and always associated with defor­
mity. Flatau and Sterling, in the same year, first suggested
that the disease might have a hereditary basis and gave
it the more accurate name torsion dystonia of childhood.
At first the condition was considered by some to be a
manifestation of hysteria; only later was it recognized as
a neurologic entity with a predilection for individuals of
Eastern European Jewish origin. Soon thereafter, a second
hereditary form of torsion dystonia, affecting non-Jews,
was observed. The recessive form begins in early child­
hood, is progressive over a few years, and is restricted
to Jewish patients. The dominant form begins later, usu­
ally in late childhood and adolescence, progresses more
slowly, and is not limited to any ethnic group.
As indicated in Chap. 6, most instances of idiopathic
(primary) dystonias that come to our attention, particu­
larly the segmental or restricted types, do not conform
to the classic hereditary disorders as defined above,
although some may represent limited variants of the dis­
ease. In general, these more restricted types have a later
onset and a relatively milder, more slowly progressive
course, with a tendency to involve an axial or a distal
region alone. Only the paravertebral, cervical, or cranial
muscles may be involved (focal dystonia including tor­
ticollis and writer 's cramp), with little change from year
to year. The clinical classification of the predominantly
adult-onset dystonias is made more complex by the fact
that both the restricted and generalized forms may be
sporadic or genetic. Molecular genetic studies, although
still incomplete, hold the promise of clarifying the classifi­
cation of the heritable dystonias. More than 10 types have
been distinguished by genetic mapping, as summarized
by Nemeth. The most important of these is an abnormal
gene (DYT1, also known as TORlA) on chromosome 9q,
which codes for the protein, torsin A in both Jewish and
non-Jewish families. The most common DYTl mutation,
causing deletion of a single glutamate from the torsin A
peptide, is found in most cases of dystonia musculorum
deformans. This disease is inherited in an autosomal
dominant pattern. Although the penetrance of the clinical
trait in these families is low, PET demonstrates hyperme­
tabolism in the cerebellum, lenticular nuclei, and supple­
mentary motor cortex in all carriers of the mutated gene.
The function of torsin A is not fully defined. It is pres­
ent in neurons throughout the brain and has adenosine
triphosphate (ATP) binding and nuclear localization. It
may function as a chaperone protein that shuttles other
proteins in and out of cells. A current speculation, shared
with other degenerative disease, is that the absence of
torsin A renders neurons unduly sensitive to oxidative
stress (Walker and Shashidharan).
Although DYTl mutations account for the majority
of inherited cases of generalized dystonia, they are also
implicated in a small proportion of the more restricted
dystonias, particularly blepharospasm (see further on).
Some individuals in families affected with generalized
dystonia will demonstrate only localized forms (e.g.,
writer 's cramp or torticollis) . The general rule stated
above still holds, namely, that the inherited variety (dys­
tonia musculorum deformans) related to DYTl manifests
1 1 00 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
early in life and begins in one limb and then spreads to
most muscles of the body, while in the common dysto­
nias (mostly sporadic but some heritable) the disease
remains confined to the craniocervical or another region,
does not generalize, and has an adult onset.
Clinical Features The first manifestations of the
generalized disease may be rather subtle. Intermittently,
and usually after activity (late in the day), the patient
(usually a child between 6 and 14 years of age, less often
an adolescent) begins to invert one foot, to extend one
leg and foot in an unnatural way, or to hunch one shoul­
der, raising the question of a nervous tic. As time passes,
the motor disturbance becomes more persistent and
interferes increasingly with the patient's activities. Soon
the muscles of the spine and shoulder or pelvic girdle
become implicated in involuntary spasmodic twisting
movements. The cardinal feature of these severe dystonic
muscle contractions is the simultaneous contraction of
both agonists and antagonists at a joint. These cocontrac­
tion spasms are intermittent at first; in intervals that are
free of the dystonia, muscular tone and volitional move­
ments are normal. In some instances, the muscles are
hypotonic. Gradually, the spasms become more frequent;
finally, they are continuous and the body may become
grotesquely contorted, as shown in Fig. 4-5A. Lateral
and rotatory scoliosis uniformly results as secondary
deformities. For a time, recumbency relieves the spasms,
but later on position has no influence. The hands are
seldom involved, although at times they may be held
in a fisted posture. Cranial muscles do not escape, and
in a few instances a slurring, staccato-type speech was
the initial manifestation. Uncontrollable blepharospasm
was the initial disorder in one of our patients; in two
others, severe dysarthria and dysphagia were the first
signs, caused by dystonia of the tongue, pharyngeal, and
laryngeal muscles.
Other manifestations include torticollis, tortipelvis,
dromedary gait, propulsive gait, action tremor, myo­
clonic jerks during voluntary movement, and mild cho­
reoathetosis of the limbs. Excitement worsens the dysto­
nia and sleep abolishes it. As the years pass the postural
distortion may become fixed to the point where it does
not disappear even in sleep. Tendon reflexes are normal,
corticospinal signs are absent, and there is no ataxia, sen­
sory abnormality, convulsive disorder, or dementia.
Pathology No agreement has been reached concern­
ing the pathologic substrate of the disease. None of the
features of symptomatic dystonia are found, such as the
ferrocalcinosis of PKAN, the lesions of Wilson disease,
kernicterus, etat marbre of neonatal hypoxia, or the
cavitation of familial striatal necrosis, lesions have been
observed in the basal ganglia. However, in the hereditary
forms of dystonia, which are the subject of this section,
one cannot be certain of any specific lesions that would
account for the clinical manifestations. The brain is grossly
normal and ventricular size is not increased. According to
Zeman, who reviewed all the reported autopsy studies up
to 1970, there were no significant changes in the striatum,
pallidum, or elsewhere. This means only that the tech­
niques being used (qualitative analysis of random sec­
tions by light microscopy) are inadequate or the problem
is subcellular. The report by McNaught and colleagues
of perinuclear inclusions in periaqueductal neurons by
the use of special imrnunostaining methods is provoca­
tive. There had been tentative interest in elevations of
dopamine j3-hydroxylase in patients with the autosomal
dominant form of the disease, but the meaning of these
findings is not clear.
Treatment Early in the course of the illness, several
drugs including L-dopa, bromocriptine, carbamazepine,
diazepam, and tetrabenazine seem to be helpful, but only
in a few patients, and the benefit is not lasting. Intrathecal
baclofen has been somewhat more successful in chil­
dren. The rare hereditary form of dystonia-parkinsonism
(described below) responds well to small doses of L-dopa
and dopamine agonists and is exceptional in this respect.
Burke and coworkers advocate the use of very high doses
(up to 30 mg daily or more) of trihexyphenidyl (Artane).
Apparently, dystonic children can tolerate these high
doses if the medication is raised gradually, by 5-mg incre­
ments weekly. In adults, high-dose anticholinergic treat­
ment is less successful but worthy of a trial. Clonazepam
is beneficial in some patients with segmental myoclonus.
Impressive results were obtained in the past by
the use of stereotactic techniques that made lesions
in the ventrolateral nuclei of the thalamus or in the
pallidum-ansa lenticularis region. Some frightfully dis­
abled children, unable to sit or stand, were restored to
near normalcy for a time. Approximately 70 percent of
the patients in Cooper 's series in the 1950s were mod­
erately to markedly improved by unilateral or bilateral
operations and, based on a 20-year followup study, the
improvement was usually sustained. More recent studies
report a somewhat less favorable but nonetheless clear
improvement (see Tasker et al; Andrew et al). The main
risk of the operation was a corticospinal tract lesion, pro­
duced inadvertently by damaging the internal capsule.
Bilateral lesions have sometimes been disastrous, causing
pseudobulbar palsy. The production of lesions has been
supplanted, with success over long periods, by bilateral
stimulation of the internal segments of the globus pal­
lidus (Vidailhet and colleagues) .
H e red ita ry Dysto n i a -Pa rki n s o n i s m
( S e g awa Sy n d ro m e , J u v e n i l e
D o p a - R es p o n s ive Dysto n i a )
This process i s discussed here because its main character­
istic is a dystonia that is responsive to L-dopa, but most
cases also have features of parkinsonism, which is why it
was also mentioned in the earlier discussion of hereditary
forms of Parkinson disease, especially in young patients.
Following the description of the syndrome by Segawa
and colleagues in 1976, others drew attention to this
unique form of hereditary dystonia (Allen and Knopp;
Deonna; Nygaard and Duvoisin). The pattern of inheri­
tance is autosomal dominant and there is no ethnic pre­
dilection. Nygaard and colleagues found a linkage to the
gene on chromosome 14q for the protein GTP cyclohydro­
lase 1 (GCH1 gene) that is implicated in the synthesis of
tetrahydrobiopterin, a cofactor for tyrosine hydroxylase.
It is likely that the mutation impairs the generation of
dopamine, a prediction that accords with responsiveness
 CHAPTER 39
of the parkinsonian and dystonic features to L-dopa.
In one autopsied case (an accidental death), there was
a reduction in the amount of tyrosine hydroxylase in
the striatum and depigmentation but no cell loss in the
substantia nigra (Rajput et al) . The affected enzyme was
reduced in the striatum, as was the level of dopamine.
The dystonic manifestations usually become evi­
dent in childhood, usually between 4 and 8 years of age;
females outnumber males in a ratio of 3:2. Often the legs
are first affected by intermittent stiffening, with frequent
falls and peculiar posturing, sometimes the feet assuming
an equinovarus position. The arms become involved as
well as the truncal muscles; retrocollis or torticollis may
appear. Within 4 to 5 years, all parts of the body, including
the bulbar muscles, are involved. Mild parkinsonian fea­
tures (rigidity, bradykinesia, postural instability) can usu­
ally be detected early in the course of the illness, but more
characteristically they are added to the clinical picture
several years later. In our own patients, and in several of
those of Deanna, there was rigidity of the limbs as well
as slowness of movement and a tremor at rest, all aspects
more parkinsonian than dystonic. In still others, the clini­
cal picture has been one of cerebral spastic diplegia.
A remarkable feature is the disappearance or marked
subsidence of the symptoms after a period of sleep and
worsening as the day progresses. This diurnal variation
is shared with many of the inherited forms of Parkinson
disease listed in Table 39-3. Fluctuations of symptoms
with exercise and menses and in the first month of preg­
nancy have been observed in some cases.
The special feature of this juvenile dystonia-parkin­
sonism syndrome is the dramatic response of both the
dystonic and parkinsonian symptoms to treatment with
L-dopa. As little as 10 mg/kg/ d may eliminate the
movement disorder and permit normal functioning.
Unlike idiopathic Parkinson disease, the medication can
be continued indefinitely without the development of
tolerance, wearing-off effects, or dyskinesias. Segawa
disease accounts for some cases that had in the past been
reported as juvenile Parkinson disease.
To rti co l l i s a n d Ot h e r R estricted Dyski n es i a s
a n d Dysto n i as (See Chap. 6)
With advancing age, a large variety of focal or regional
movement disorders come to light. Various neurophysi­
ologic abnormalities, summarized in Chap. 6, have been
implicated. In the common restricted dystonias, localized
groups of adjacent muscles manifest arrhythmic cocon­
tracting spasms (i.e., agonist and antagonist muscles are
activated simultaneously). The patient's inability to sup­
press the dystonia and the recognition that it is for the
most part beyond voluntary control distinguishes it from
tics, habit spasms, and mannerisms described in Chap. 6.
If the muscle contraction is frequent and prolonged, it
is accompanied by an aching pain that may mistakenly
be blamed for the spasm and the involved muscles may
gradually undergo hypertrophy. Worsening under condi­
tions of excitement and stress and improvement during
quiet and relaxation are typical of this group of disorders
and contributed in the past to the mistaken notion that
the spasms had a psychogenic origin.
Degenerative Diseases of the Nervous System 1 1 01
The most frequent and familiar type is torticollis,
wherein an adult, more often a woman, becomes aware of
a turning of the head to one side while walking. Usually
this condition worsens gradually to a point where it
may be more or less continuous, but in some patients it
remains mild or intermittent for years on end. When fol­
lowed over the years, the condition is observed to remain
limited to the same muscles (mainly the scalene, sterno­
cleidomastoid, and upper trapezius). Rarely, the torticol­
lis is combined with dystonia of the shoulder, arm, and
trunk; tremor; facial spasms; or dystonic writer 's cramp.
Other restricted dyskinesias involve the neck in com­
bination with facial muscles, the orbicularis oculi (bleph£1-
rospasm and bleph£lroclonus), the throat and respiratory
muscles (spastic dysphonia, orofacial dyskinesia, and respira­
tory and phonatory spasms), the hand in writer 's cramp
(graphospasm) or musician and other performing artist's
dystonia, and proximal leg and pelvic-girdle muscles,
where dyskinesia is elicited by walking. All these condi­
tions and their treatments are discussed fully in Chap. 6.
Ot h e r F o r m s of H e red ita ry Dysto n i a
Several familial movement-induced (kinesogenic) dys­
tonic syndromes and a type that is not kinesogenic and
arises suddenly in adolescence, at times with parkin­
sonian features, have been described. There are other
degenerative diseases that combine hereditary dysto­
nia with neural deafness and intellectual impairment
(Scribanu and Kennedy) and with amyotrophy in a
paraplegic distribution (Gilman and Romanul). These are
discussed in greater detail in Chap. 6.
Other important symptomatic dystonias that fall into
the category of hereditary dystonia were described in
Chap. 37. These are PKAN and calcification of the basal
ganglia; of course, Wilson disease may have dystonia as
a central feature. Many extrapyramidal diseases, includ­
ing idiopathic Parkinson disease and progressive supra­
nuclear palsy, may include fragmentary dystonias of the
hand, foot, face, or periorbital muscles.
SYNDROME OF PROG RESSIVE ATAXIA
Wilson wrote that "the group of degenerative conditions
strung together by the common feature of ataxia is one
for which no very suitable classification has yet been
devised," a statement that is not as appropriate today as
when it was written 75 years ago. This topic was intro­
duced in Chap. 5 and some of the congenital and acute
acquired varieties are mentioned there. Here we consider
the chronic, progressive forms of cerebellar disease. Although
most of these are familial and are more or less confined to
this part of the nervous system, a number of other systems
may be involved to varying degrees. Most of the chronic
progressive cerebellar diseases are subsumed under the
"system atrophies," but no one classification designed to
bring order to this category of diseases has proved satis­
factory and a preferable genetic classification is emerging.
Setting aside those of congenital type and those
caused by a metabolic disorder, Harding (1993) grouped
1 1 02 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
the ataxias by age of onset, pattern of heredity, and
associated features. A modification of the classifications
of Greenfield and of Harding, which is included in the
introductory listing of this chapter, still has clinical value.
It divides the progressive cerebellar syndromes into 3
main groups: (1) the spinocerebellar ataxias, with unmis­
takable involvement of the spinal cord (Romberg sign,
sensory loss, diminished tendon reflexes, Babinski signs);
(2) the pure cerebellar ataxias, with no other associated
neurologic disorders; and (3) the complicated cerebellar
ataxias, with a variety of pyramidal, extrapyramidal, reti­
nal, optic nerve, oculomotor, auditory, peripheral nerve,
and cerebrocortical accompaniments including what is
now referred to as multiple system atrophy.
Without doubt, the advances in molecular genetics
of recent years have greatly altered our understanding of
the inherited ataxias and have already disclosed a large
number of unexpected relationships between mutations
and other neural and nonneural disorders. These data
are incorporated at appropriate points in the following
discussion in Table 39-5, later in this section. Inherited
ataxias of early onset (before the age of 20 years) are usu­
ally of recessive type; those of later onset are more likely
to have a dominant pattern but may be autosomal reces­
sive. Table 39-5 lists several types of ataxias that have a
genetic basis. At the time of this writing, 29 types have
been listed in the literature, many of limited clinical con­
sequence and low incidence. We have included the main
varieties that may be of interest to clinicians because
they appear regularly or offer an insight into this class
of disorders. At the same time, it should be emphasized
that many patients with chronic progressive ataxia have
no family history of an ataxia and may have had a spon­
taneous mutation; even then, the genetic aspects of many
cases have not been elucidated.
Early-Onset Spinocerebellar Ataxias
(Pred o m i n a ntly Spinal)
F r i e d re i c h Atax i a
This i s the prototype o f all forms o f progressive spino­
cerebellar ataxias and accounts for about half of all cases
of hereditary ataxias in most large case series (86 of
171 patients collected by Sjogren); its incidence among
Europeans and North Americans is 1 .5 cases per 100,000 per
year. Friedreich, of Heidelberg, began in 1861 to report on
a form of familial progressive ataxia that he had observed
among nearby villagers. It was already known through the
writings of Duchenne that locomotor ataxia was the prom­
inent feature of spinal cord syphilis, that is tabes dorsalis,
but it was Friedreich who demonstrated a nonsyphilitic
hereditary type. This concept was greeted with skepticism,
but soon Duchenne himself affirmed the existence of the
new disease and other case reports appeared in England,
France, and the United States. In 1882, in a thesis on this
subject by Brousse of Montpelier, Friedreich's name was
attached to the entity.
The pattern of inheritance is autosomal recessive.
Genetic linkage studies led to the assignment of the gene
mutation to chromosome 9q13-2 and subsequently, it
was shown that in virtually all cases the mutation is an
expansion of a GAA trinucleotide repeat within a gene
that codes for the protein frataxin. (It is of interest that
this mutation is within an intron) . In a small proportion
of cases, the mutation is a missense mutation rather than
an expansion. In either case, the consequence of the muta­
tion is a reduction in levels of frataxin and loss of its func­
tion. Cases in which the mutation allows the presence of
some residual protein have a milder course. A current
hypothesis is that frataxin is a mitochondrial matrix pro­
tein whose function is to prevent intrarnitochondrial iron
overloading.
Clinical Features Ataxia of gait is nearly always the
initial symptom. Difficulties in standing steadily and in
runnin g are early symptoms. The hands usually become
clumsy months or years after the gait disorder, and dys­
arthric speech appears after the arms are involved (this
is rarely an early symptom). Exceptionally the ataxia
begins rather abruptly after a febrile illness, and one leg
may become clumsy before the other. In some patients,
pes cavus and kyphoscoliosis (scoliosis) are evident well
before the neurologic symptoms; in others, they follow
by several years. The characteristic foot deformity takes
the form of a high plantar arch with retraction of the toes
at the metatarsophalangeal joints and flexion at the inter­
phalangeal joints (hammertoes).
A notable feature in more than half of patients is a
cardiomyopathy. The myocardial fibers are hypertrophic
and may contain iron-reactive granules (Koeppen). Many
of the patients die as a result of cardiac arrhythmia or
congestive heart failure. For this reason, it is essential that
affected individuals have a cardiologic assessment includ­
ing electrocardiography and echocardiography. The car­
diomyopathy of Friedreich disease can develop insidi­
ously but with fulminant consequences. Kyphoscoliosis
and restricted respiratory function are additional impor­
tant contributory causes of death. Harding observed that
approximately 10 percent of these patients have diabetes
mellitus and a higher proportion have impaired glucose
tolerance; there is both insulin deficiency and peripheral
insulin resistance.
In the fully developed syndrome, the abnormality of
gait is of mixed sensory and cerebellar type, aptly called
tabetocerebellar by Charcot. According to Mollaret, the
author of an authoritative monograph on the disease, the
cerebellar component predominates, but in our relatively
small series we have been as impressed almost as much
with the sensory (tabetic) aspect. The patient stands with
feet wide apart, constantly shifting position to maintain
balance. Friedreich referred to the constant teetering and
swaying on standing as static ataxia. In walking, as with
all sensory ataxias, the movements of the legs tend to be
brusque, the feet resounding unevenly and irregularly as
they strike the floor, and closure of the eyes causes the
patient to fall (Romberg sign). This is one component
of the spinal aspect (posterior columns) of the disease.
Attempts to correct the imbalance may result in abrupt,
wild movements. Often there is a rhythmic tremor of the
head. Eventually, the arms are grossly ataxic, and both
action and intention tremors are manifest. Speech is slow,
slurred, explosive, and, finally, almost incomprehensible.
 CHAPTER 39 Degenerative Diseases of the Nervous System 1 1 03

ASSOCIATED WITH SPINOCEREBELLAR ATAXIAS (SCA)

AGE O F C LI N I CAL FEAT U R E S I N ADDITI O N
N OTAT I O N G E N E ( PROTE I N ) I N H E R I TA N C E O N S ET TO ATAXIA

Progressive

Dentatorubropallidoluysian ATNl (atrophin l ) AD' Chi l dhood Chorea, dystoni a, seizures, d ementia
atrophy (DRPLA)

SCA l ATXNl (ataxin-1) AD' Variable 1 0-25% of dominant ataxias; spasticity,

polyneuropathy, ophthalmoparesis,
dementia

SC A2 ATXN2 (ata xin-2) AD' Teens Neuropa thy, ophthalmoparesis, extrapyra-

midal features

SCA3 (Macha do-Joseph) ATXN3 (ataxin-3) AD' Teens 25% of dominant a taxias, spastici ty,
neuropathy, extrapyrami d a l features

ll calcium
SCA6 CACNAlA AD' Adult 20% of dominant a ta xi a s; dysarthria, nystag-
(alpha mus, posterior column signs (see episodic
chann ) ataxia below; gene implicated in familial
hemiplegic migraine)

SCA7 ATXN7 (ata xin-7) AD' La te teens Olivopontocerebellar atrophy and syndrome
of retinal degeneration, hearing l oss,
ophthalmoplegia, spastici ty; genera tional
anti cipation

Infantile Fulminant, with large CAG expansion

SCAB ATXNB (ata xin-8; AD, AR, sporadic Adult Slowly progressive sensory neuropathy;
CTG repeat spasticity; known rapid infantile variant
(non coding)

SC A l O AITCT repeat AD Teens-adult Seizures, personality change

(ataxin-1 0)

SCAll TTBK2 (serine/ AD Ad ult Mild phenotype, nystagmu s, cerebellar

threonine ataxia, neuropathy; dystonia
kinase)

SCA 1 2 PPP2R2B (protein AD Adult Head and hand tremor

phosphatase
2A), CAG
repeat,
non cod ing

SCA 1 3 KCNC3 (Kv3.3 AD Childhood Developmental delay

channel)

SCA14 PR KCG AD Teens-adult Myoclonus, tremor

(protein kinase
C gamma)

SCA 1 5 & 1 6 ITPRl (ITPR1 ) AD Varies Hea d and hand tremor, gaze palsy

SCA 1 7 TATA (TATA box AD' Variable Cognitive d ecline, seizures, extrapyrami d a l
binding features
protein, TBP)

SCA with tremor Fibroblast growth AD Childhood Tremor, cognitive defects, facial dyskinesia
factor 14

Friedreich a ta xi a FXN (frataxin) AR Teens Spinocerebellar ataxia, neuropathy, cardio-

myopa thy, arrhythmia

Vitamin E deficiency TTPA (vitamin E AR Chi ldhood Spinocerebellar a ta xia, neuropathy, card i o-
transfer protein) myopa thy, arrhythmi a

Episodic

Episodic ataxia with myokymia KCNA l (Kvl . l ) AD Teens Limb stiffness, dizziness, visual blurring
(EA1, EAM))

Paroxysmal episodic a taxia CACNA l A AD Teens Nystagmus, vertigo, weakness

(EA2) (Cav2. 1 )

Episodic ataxia (EA5) CACNB4 (calcium AD Teens Seizures, myoclonu s, nystagmus

channel beta-

'CAG expansion. AD denotes autosomal dominant, AR autosomal recessive

1 1 04 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
Breathing, speaking, swallowing, and laughing may be
so incoordinated that the patient nearly chokes while
speaking. Holmes (1907a) remarked on an ataxia of res­
piration that causes "curious short inspiratory whoops."
Facial, buccal, and arm muscles may display tremulous
and sometimes choreiform movements.
Although mentation is generally preserved, emo­
tional lability has been sufficiently prominent to provoke
comment. Torsional and vertical nystagmus is rare but
"square wave jerks" are seen in the early stages of dis­
ease. Horizontal nystagmus may be present late in the
course of the illness, but not early, but it is slight in ampli­
tude. Ocular movements usually remain full, and pupil­
lary reflexes are normal. The facial muscles may seem
slightly weak, and deglutition may become impaired.
Amyotrophy occurs late in the illness and is usually mild,
but it may be extreme in patients with an associated neu­
ropathy (see below). The tendon reflexes are abolished in
nearly every case; rarely, they may be obtainable when
the patient is examined early in the illness (see below) .
Plantar reflexes are extensor and flexor spasms may occur
even with complete absence of tendon reflexes (another
manifestation of the spinal component). The abdominal
reflexes are usually retained until late in the illness. Loss
of vibratory and position sense is invariable from the
beginning; later, there may be some diminution of tactile,
pain, and temperature sensation as well. Sphincter con­
trol is usually preserved.
Variants of Friedreich Ataxia In one important vari­
ant of Friedreich ataxia the tendon reflexes are preserved
or even hyperactive and the limbs may be spastic. It is
the finding of the aberrant frataxin gene that links these
unusual cases to Friedreich ataxia; some are associated
with hypogonadism. Harding (1981) found 20 such cases
among her 200 familial ataxias at the National Hospital,
London. Nevertheless, the distinction between classic
Friedreich ataxia and ataxia with retained tendon reflexes
is an important one clinically, insofar as kyphoscoliosis
and heart disease do not occur in the latter group and the
prognosis is better. Two of our Friedreich patients had
occasional seizures. There are many additional forms of
spinocerebellar ataxia, most displaying mainly a cerebel­
lar atrophy, that may simulate Friedreich disease, but due
to different mutations. These are taken up below.
Laboratory Testing Laboratory tests of diagnostic
value are the measurement of sensory nerve conduc­
tion velocities and amplitudes, which for the most
part are normal because peripheral neuropathy is not
a component of the process. Electrocardiography and
echocardiography may demonstrate the heart block and
ventricular hypertrophy. The CT and MR1 seldom reveal
a significant degree of cerebellar atrophy but the spinal
cord is small. There is no consistent abnormality of blood
or CSF and no biochemical abnormalities have been
demonstrated. Genetic testing for the length of the GAA
trinucleotide repeat segment is available.
Pathology The spinal cord is thin. The posterior
columns and the corticospinal and spinocerebellar tracts
are all depleted of myelinated fibers, and there is a mild
gliosis that does not replace the bulk of the lost fibers. The
nerve cells in the Clarke column and the large neurons
of the dorsal root ganglia, especially lumbosacral ones,
are reduced in number-but perhaps not to a degree that
would fully explain the posterior column degeneration.
The posterior roots are thin. Betz cells are also diminished
in some cases, but the corticospinal tracts are relatively
intact down to the medullary-cervical junction. Beyond
this point, they are degenerated, but to a lesser degree
than the posterior columns . The nuclei of cranial nerves
VIII, X, and XII all exhibit a reduction of cells. Slight to
moderate neuronal loss is seen also in the dentate nuclei,
and the middle and superior cerebellar peduncles are
reduced in size. Some depletion of Purkinje cells in the
superior vermis and neurons in corresponding parts
of the inferior olivary nuclei can be seen. Many of the
myocardial muscle fibers degenerate and are replaced by
fibrous connective tissue.
By way of exploring the anatomic basis of the clini­
cal findings, pes cavus is not different from that seen in
other neuromuscular diseases of early onset with mild
hypertonus of the long extensors and flexors of the feet.
There is also cause of amyotrophy of intrinsic foot mus­
cles and foreshortening of the foot when the bones are
still malleable. The kyphoscoliosis is probably a result of
imbalance of the paravertebral muscles during develop­
ment. The tabetic aspects of the disease are explained by
the degeneration of large cells in the dorsal root ganglia
and the large sensory fibers in nerves, dorsal roots, and
the columns of Goll and Burdach. The loss of neurons
in the sensory ganglia also causes abolition of tendon
reflexes. Cerebellar ataxia is attributable to a combined
degeneration of the superior vermis and the dentato­
rubral pathways but also the spinocerebellar tracts, in
various combinations. Corticospinal lesions account for
the weakness and Babinski signs and contribute to the
pes cavus.
Diagnosis Friedreich disease and its variants must
be distinguished from familial cerebellar cortical atrophy
described next, and from familial spastic paraparesis with
ataxia, as well as from peroneal muscular atrophy and the
Levy-Roussy syndrome, which are discussed also with
the hereditary neuropathies in Chap. 46. It is advisable to
assay serum vitamin E levels, as a rare (except in North
Africa) but treatable inherited deficiency of a vitamin E
transport protein causes a spinocerebellar syndrome with
areflexia in children that resembles Friedreich disease
(see Chap . 41). The absence of dysarthria and of skeletal
or cardiac abnormalities in the vitamin-deficiency illness
may be helpful. Exceptionally, a cardiac disturbance has
been seen in the vitamin deficiency. A form of chronic
infl ammatory demyelinating polyneuropathy has long
since overtaken tabes dorsalis as the most frequent type
of areflexic ataxia. It bears a superficial resemblance to
Friedreich ataxia when the onset is in early life, but lacks
dysarthria and Babinski signs. A form of spinocerebel­
lar degeneration related to human T-cell lymphotrophic
virus type I (HTLV-I), causing so-called tropical spastic
paraparesis, as well as the vacuolar myelopathy of AIDS
multiple sclerosis, syringomyelia, neuroacanthocytosis,
and cervical spondylosis, must be included in the differ­
ential diagnosis of late-onset cases. Genetic testing settles
the matter.
 CHAPTER 39
Treatment Not much can be said on this subject
because there is little effective therapy. A double-blind
crossover study by Trouillas and associates found that the
administration of oral 5-hydroxytryptophan modified the
cerebellar symptoms. This has not been tested in another
study. Apart from this form of treatment, with which
we have had no experience, no therapeutic measures
are known to alter the course of the disease. In several
small trials, idebenone, an antioxidant (the short-chain
analogue of coenzyme Q10), reduced the progression of
left ventricular hypertrophy, a risk factor for arrhythmias
and sudden death in these patients, but this could not be
confirmed in subsequent trials. These results are sum­
marized in an article by Filla and Moss. Heart failure,
arrhythmias, and diabetes mellitus are treated by the
usual medical measures and it bears repetition that care­
ful evaluation of the cardiac disorder may prevent pre­
mature death. Surgery for scoliosis and foot deformities
may be helpful in selected cases.
Pred o m i n a ntly Cerebel l a r
(Cortical, Holmes Type) Hereditary
a n d Sporadic Ataxia
Soon after the publication of Friedreich's descriptions of a
spinal type of hereditary ataxia, reports began to appear of
somewhat different diseases in which the ataxia was related
to degenerative changes in the cerebellum and brainstem
rather than in the spinal cord. Claims of their independence
from the spinal type were based largely on a later age of
onset, a more definite hereditary transmission (usually of
autosomal dominant type), the persistence or hyperactivity
of tendon reflexes, and associations with ophthalmoplegia,
retinal degeneration, and optic atrophy. Several of these
clinical features, particularly briskness of tendon reflexes,
are alien to the classic form of Friedreich ataxia.
By 1893, Pierre Marie thought it desirable to create a
new category of hereditary ataxia that would embrace all
of the non-Friedreich cases. He collated the familial cases
of progressive ataxia that had been described by Fraser,
Nonne, Sanger Brown, and Klippel and Durante (see both
Greenfield and Harding [1993] for references) and pro­
posed that all of them were examples of an entity to which
he applied the name heredo-ataxie cerebelleuse. Marie's
proposition was based almost entirely on clinical observa­
tions not his own but those made by the aforementioned
authors. Later, as members of these families died, post­
mortem examinations disclosed that Marie's hereditary
cerebellar ataxia included not one but several disease enti­
ties. Indeed, as pointed out by Holmes (1907b) and later by
Greenfield, in 3 of the 4 families the cerebellum showed no
significant lesions at all. Yet there was by then no doubt of
the existence of a separate class of predominantly cerebel­
lar atrophies, some purely cortical and others associated
with a variety of noncerebellar disorders.
C l i n i c a l Featu res
Holmes (1907a) described a family of 8 siblings, of whom
3 brothers and 1 sister were affected by a progressive
ataxia, beginning with a reeling gait and followed by
clumsiness of the hands, dysarthria, tremor of the head,
Degenerative Diseases of the Nervous System 1 1 05
and a variable nystagmus, but without additional fea­
tures to implicate disease of the spinal cord or brainstem.
It may be taken as the prototype of pure cerebellar corti­
cal degeneration.
The ataxia begins insidiously; usually in the fourth
decade but with wide variability in age of onset, and
progresses slowly over many years. Ataxia of gait, insta­
bility of the trunk, tremor of the hands and head, and
slightly slowed, hesitant speech is the usual clinical picture.
Nystagmus is rare and intelligence is usually preserved.
The patellar reflexes may be slightly increased but this may
be apparent based on the pendular character of reflexes in
cerebellar disease; the plantar reflexes are flexor and the
ankle jerks are present but there are exceptions and prob­
ably mark the process as one of the other genetic ataxias.
This clinical syndrome probably can result from sev­
eral genetically determined processes, some of which
declare themselves as the illness progresses by displaying
characteristic signs other than ataxia. The differential diag­
nosis in the nonfamilial cases is even broader, including
many acquired types of ataxias discussed in Chap. 5 (see
Table 5-1 ) and at the end of this section.
Pathology Postmortem examination of the Holmes­
type cases discloses symmetrical atrophy of the cerebel­
lum involving mainly the anterior lobe and vermis, the
latter being more affected. Purkinje cells are absent in
the lingula, centralis, and pyramis of the superior vermis
and reduced in number in the quadrangularis, flocculus,
biventral, and pyramidal lobes. The other cerebellar corti­
cal neurons and granule cells and dorsal and medial parts
of the inferior olivary nuclei are diminished less so. The
white matter is slightly pale in myelin stains. The verm­
ian atrophy and that of adjacent parts of the cerebellum
can be visualized with clarity in MRis (Fig. 39-8) .
Figure 39-8. Familial cortical cerebellar atrophy. Tl-weighted MRl
in the sagittal plane showing marked atrophy of vennis and enlarge­
ment of fourth ventricle. The brainstero is only mildly atrophlc and
the posterior fossa is normal is size. Compare with Fig. 39-9 in whlch
the cerebellum and pons are atrophlc.
1 1 06 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
The vague similarity of the pathologic (and clinical)
changes to those of alcoholic cerebellar degeneration is at once
apparent and should raise the question of an alcoholic­
nutritional cause in sporadic cases (see Chap. 41); in seri­
ous alcohol-nutritional disease, there usually is an accom­
panying polyneuropathy and reduced ankle reflexes.
Fragile X Tremor-Ataxic Prem utatio n
Synd rome
This type of developmental delay, caused by an unstable
extended trinucleotide repeat sequence and breakage of
the X-chromosome, is discussed in Chap . 38. Here we
refer to an unusual variant of the degenerative process
with onset in mid- or late adulthood, mainly but not
exclusively in men, and consisting of gait or limb ataxia
and mild tremor. The process affects carriers of a "premu­
tation" who have 50 to 200 CGG repeat sequences in the
FMRl gene. In contradistinction to the full mutation of
over 200 repeats, there is apparently a buildup of messen­
ger ribonucleic acid (mRNA) in the adult form that inter­
feres in some way with cellular function. Aggregating
several studies, the frequency of this genetic abnormality
among otherwise unassignable adult ataxia cases is less
than 10 percent.
The entire clinical spectrum has yet to be defined but
our experience with 2 patients featured mild progressive
gait ataxia in the sixth decade that was misattributed
to normal-pressure hydrocephalus and an intermittent
hand tremor that was probably ataxic in nature. Some
reports have included a parkinsonian syndrome and
more consistently, a mild frontal dementia, making the
distinction from frontotemporal dementia difficult. Many
cases have been confused with multiple system atrophy.
T2 hyperintensity in the cerebellar peduncles are
characteristic of some cases, but this was not found in
our patients, which showed only midline cerebellar atro­
phy. A family history of developmental delay or autistic
spectrum disorder may be a hint to diagnosis and some
proportion of individuals with the premutation also have
a nonprogressive cognitive deficiency.
A study of the neuropathology by Greco and col­
leagues showed cerebral and cerebellar spongiform white
matter changes and both intranuclear and astrocytic
inclusions. Their report demonstrated a correspondence
between the quantity of trinucleotide repeats and the
number of inclusion bodies.
Fa m i l i a l and Sporadic Forms of Combined
Cerebellar Atrophy With Brainstem
a n d Extrapyra m idal Featu res
A sporadically occurring disorder closely resembling the
Holmes type of cortical cerebellar degeneration but with
additional features of brainstem atrophy was described in
1900 by Dejerine and Andre-Thomas, who named it olivo­
pontocerebellar atrophy (OPCA). As more cases of this type
were collected, an autosomal dominant hereditan; pattern
was evident in some, and one or more long tracts in the spi­
nal cord were found to have degenerated. About half the
cases later developed the parkinsonism with degeneration
of nigral cells and, in a few, of striatal cells, thereby mark­
ing the disease as a form of striatonigral degeneration that
is essentially a type of multiple Sljstem atrophy (MSA-C) as
discussed in detail in an earlier section and also below.
Notable findings in both the sporadic and the famil­
ial forms of many of the variants of cerebellar atrophy
are extensive degeneration of the middle cerebellar
peduncles, cerebellar white matter, and pontine, olivary,
and arcuate nuclei; loss of Purkinje cells has been vari­
able. Most likely this degeneration represents a "dying
back" of axons of the cerebellar, pontine, and olivary
nuclei with secondary myelin degeneration. Extreme
atrophy of the medullary olivary nuclei, evident on MRis
(Fig. 39-9), identifies a special process that represents the
aforementioned OPCA.
Although the associated features in each of the inher­
ited cerebellar degenerations do not conform to newer
genetic classifications, certain clinical constellations are
nonetheless recognizable and clinically useful. Many
texts use a genetic system exclusively to categorize these
diseases. In the past, Konigsmark and Weiner subdivided
them into several types, including a dominantly inherited
OPCA (of Menzel); a recessive type (of Pickler-Winkler);
a dominant type with retinal degeneration; one with
spastic paraplegia and areflexia; and with dementia,
ophthalmoplegia, and extrapyramidal signs. To these
had been added cases of OPCA with neuropathy and
slowed eye movements (Wadia type), of which we have
seen 2 cases, and cases with dystonia and a variety of
other clinical findings, most in single families (hemibal­
lismus, athetosis, contractures of the legs, fixed pupils,
ophthalmoplegia, ptosis, gaze palsy, deafness, retinal
degeneration, mental retardation and epilepsy, claw foot
and scoliosis, incontinence, parkinsonian symptoms and
signs, plethora of presentations including a neonatal
type) . Some of these are detailed below.
Figure 39-9. Olivopontocerebel\ar a trophy. MRl in the sagittal plane
demonstrating both vermian atrophy (black arrow) and smallness of
the pons (white arrow). (Reproduced by permission from Bisese JH:
Cranial MRI. New York, McGraw-Hill, 1991.)
 CHAPTER 39
Cases of sporadic olivopontocerebellar atrophy are more
common than the familial variety and tend to occur at an
older age; nystagmus, optic atrophy, retinal degeneration,
ophthalmoplegia, and urinary incontinence are generally
not observed. However, there are numerous cases that
include mild extrapyramidal and neuropathic signs, slow
eye movements, dystonia, impairment of vertical saccadic
eye movements (thus simulating progressive supranuclear
palsy), vocal cord paralysis, all of which probably mark the
process as multiple system atrophy (MSA-C) or Machado­
Joseph-Azorean disease (SCA3, discussed below), and
some cases with deafness. The relationship of olivopon­
tocerebellar atrophy to MSA was discussed in under
"Multiple System Atrophy," but we emphasize that OPCA
occurs as often independently of extrapyramidal degen­
eration for which reason we retain a separate designation.
Cerebellar Atrophy With Pro m i nent Basal
Gang l ionic Featu res
M a c h a d o-J ose p h -Azo rea n D i sease ( S CA3 )
A special form of hereditary ataxia with brainstem and
extrapyramidal signs has been described in patients
mainly, but not exclusively, of Portuguese-Azorean ori­
gin. The disorder is characterized by an autosomal domi­
nant pattern of inheritance and by a slowly progressive
ataxia beginnin g in adolescence or early adult life in
association with hyperreflexia, extrapyramidal features,
dystonia, bulbar signs, distal motor weakness, and oph­
thalmoplegia. There is usually no impairment of intellect
and in the examples the authors have seen, the extrapy­
ramidal symptoms were mainly rigidity and slowness of
movement. Early Machado-Joseph disease characteristi­
cally demonstrates the finding of dysmetric horizontal
and vertical saccades, even before the ataxia is obvious
(Hotson et al) . This conjunction of a parkinsonian syn­
drome with cerebellar ataxia is suggestive of MSA except
for an earlier age of onset and the prominence in some
cases of dystonia, amyotrophy, and ophthalmoplegia in
Machado-Joseph. Postmortem examination discloses a
degeneration of the dentate nuclei and spinocerebellar
tracts and a loss of anterior horn cells and neurons of the
pons, substantia nigra, and oculomotor nuclei. Cancel
and colleagues found an unstable number of CAG repeat­
ing sequences in a gene, ataxin-3, and named the disorder
spinocerebellar ataxia type 3 (SCA3) .
An affected Azorean family named Joseph was
described in 1976 by Rosenberg and colleagues under
the name of autosomal dominant striatonigral degen­
eration. Using the term Azorean disease of the nervous
system (now better known as Machado-Joseph disease),
Romanul and colleagues described yet another family of
Portuguese-Azorean descent, many members of which
were affected by a syndrome comprising a progressive
ataxia of gait, parkinsonian features, limitation of con­
jugate gaze, fasciculations, areflexia, nystagmus, ataxic
tremor, and extensor plantar responses; the pathologic
changes closely resembled those described by Woods
and Schaumburg. Romanul and coworkers compared
the genetic, clinical, and pathologic features of their
Degenerative Diseases of the Nervous System 1 1 07
cases with those described in other Portuguese-Azorean
families and concluded that all of them represent a single
genetic entity with variable expression. This concept of
the disease has been corroborated by the further observa­
tions of Rosenberg and of Fowler who studied 20 patients
with the Machado-Joseph-Azorean disease over a 10-year
period and more recently by genetic testing.
The disease is not limited to Azoreans. Cases con­
forming to the above descriptions have now been
observed among African American, Indian, and Japanese
families (Sakai et al; Yuasa et al; Bharucha et al). There are
no signs of polyneuropathy, which is the main feature of
another disease in Portuguese emigrants caused by amy­
loid deposition, described by Nakano and colleagues as
"Machado disease," this being the name of the progenitor
of the afflicted family.
In fully developed cases, the MRl findings are of
reduced width of the superior and middle cerebellar
peduncles, atrophy of the frontal and temporal lobes, and
smallness of the pons and globus pallidus (Murata et al).
There is no treatment of proven value.
M u lt i p l e System Atro p h y With P red o m i n a nt
Ata x i a (See Section Multiple System Atrophy)
This entity has been discussed with the degenerative
disorders of the basal ganglia earlier in the chapter. Here
it is pointed out that a number of cases of sporadic pro­
gressive ataxia in mid- and late life are attributable to
this process and have been termed MSA-C to signify the
predominant cerebellar feature. The extrapyramidal, cor­
ticospinal, or autonomic aspects of the illness may or may
not become evident only with continued observation or
by pathologic examination. Some guidance as to the fre­
quency of MSA as the cause of otherwise undifferentiated
sporadic ataxia is given in the study by Abele and col­
leagues who found that it accounts for almost one-third
of cases, but the precise number is open to question as
pathologic examinations were not made.
De ntato r u b ro p a l l i d o l u ys i a n At ro p h y ( D R P LA)
This is a rare familial disorder, described mostly in Japan
and in small European pockets, in which symptoms of
cerebellar ataxia are coupled with those of choreoatheto­
sis and dystonia and, in a few instances, parkinsonism,
myoclonus, epilepsy, or dementia. Pathologically there is
degeneration of the dentatorubral and pallidoluysian sys­
tems. The main consideration when chorea is a prominent
feature is the separation of this disorder from Huntington
disease. The gene defect in DRPLA is an unstable CAG
trinucleotide repeat in the gene that codes for the protein
atrophin. This same mutation has been defined in affected
families from throughout the world (e.g., Warner et al).
As with Huntington chorea (where the expanded poly­
glutamine tract is in the protein huntingtin), this disease
is inherited as an autosomal dominant trait and shows
an inverse correlation between the age of onset and the
size of the gene expansion (anticipation). When chorea
predominates early in the illness, there may be difficulty
distinguishing DRPLA from Huntington disease. The
diagnosis is confirmed by sequencing of the affected gene.
1 1 08 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE

De ntato ru b ra l D e g e n e rati o n (Campuzano et al), quite different from the large number
of dominant forms of inherited ataxia. The direct molecu­
1hls is a rare and still nebulous entity but it is probably
lar test for the GAA expansion is useful for diagnosis,
distinct from the condition described above. There are sev­
eral instructive features.In 1921, Ramsay Hunt published
particularly for atypical cases with late ?nset (I?ii
rr et �1).
an account of 6 patients (2 of whom were twin brothers) in
The rarer recessive spinocerebellar ataXIa assocrated with
vitamin E deficiency arises from mutations in the gene
whom myoclonus was combined with progressive cerebel­
that encodes an alpha tocopherol (vitamin E) transport
lar ataxia. The age of onset in the 4 nonfarnilial cases was
protein, as mentioned above.
between 7 and 17 years, and the cerebellar ataxia followed
Among the common autosomal dominant cerebellar
the myoclonus by an interval of 1 to 20 years. Hunt named
ataxias of later onset, molecular and gene studies have
the disorder dyssynergia cerebellaris myoclonica . There were
signs of Friedreich ataxia in the twin brothers; postmortem identified numerous mutations. Of these autosomal dom­
inant ataxias, many are known to be caused by expanded
examination of one showed cerebellar atrophy, degen­
eration of the posterior col umnsand spinocerebellar tracts
CAG-trinucleotide repeats (including SCA types 1, 3, 6,
and 7, 12, 17, as well as DRPLA). Undoubtedly others will
but not of the corticospinal tracts. In 1947, Louis-Bar and
be discovered. However, the mechanisms by which the
van Bogaert reported a similar case and noted, in addition
expanded polyglutamine molecule l� ads to �euronal c:ll
to the above findings, degeneration of the corticospinal .
death or dysfunction remain uncertam. It IS likely �at dif­
tracts and loss of fibers in the posterior roots. Thus the
ferences in the clinical manifestations of these disorders
pathology was identical to that of Friedreich ataxia except
will reflect differences in the patterns of expression of
for the more severe atrophy of the dentate nuclei.
the affected proteins; that is each is expressed in different
Earlier (1914), under the title dyssynergia cerebellaris
progressiva, Hunt had drawn attention to a progress ve � populations of neurons and at different stages in develop­
ment. This raises the possibility that the cascade of events
disease in young individuals manifest by what he consid­
that triggers neuronal degeneration is similar in each of
ered to be a pure cerebellar syndrome but one of his cases
the diseases with a CAG expansion and that a therapy
was revealed at autopsy to be Wilson disease. Hunt's
reports emphasize the hazard of classifying cerebe ar � might be discovered that is effective in all of them.
The special case of fragile X premutation that may
ataxias on the basis of clinical findings alone, a pomt
cause ataxia and tremor in adults is addressed in Chap .
38. Table 39-5 summarizes the genes, terminology; related
made effectively by Holmes.

Pa roxys m a l Ata x i a s (See Chap. 5)
Two adult forms of hereditary cerebellar ataxia are par­
oxysmal in nature. In one (EA-2 for "episodic ataxia,
type 2"), the episodes occur without explanation and
last several hours; vertigo is the prominent feature of the
attacks. Between attacks the patient is normal or has only
minimal ataxia and nystagmus (Griggs et al) . These ataxic
episodes are prevented strikingly by the administration
of oral acetazolamide. The disorder has been found to be
a mutation of the calcium channel gene on chromosome 19
as listed in Table 39-5.
A similar but physiologically and genetically unre­
lated paroxysmal ataxia (EA-1) is characterized by epi­
sodes that may be precipitated by exercise and by the
presence of muscle myokymia (ripplin� ) b � tween attac�s.
Vertigo does not occur and acetazolarrude IS less effective
or not effective at all. The disorder is caused by an abnor­
mality of the potassium channel gene on chromosome
(see Table 39-5). Both of these episodic ataxias are there­
fore "channelopathies" (see Chap . 50). Als � of inter� s is
spinocerebellar atrophy type 6, a progressive con Iho�
in which a mutation has been traced to same gene rmpli­
cated in the EA-2 acetazolamide-responsive paroxysmal
ataxia, but this disorder is not paroxysmal and results in
progressive ataxia, dysarthria, and loss of proprioception.
Genetics of the Heredodegenerative Ataxias
(See Table 39-5)
The many familial degenerative ataxic disorders described
in the preceding pages are genetically distinct. As indi­
cated the autosomal recessive type of Friedreich ataxia is
:
the r sult of an expanded GAA repeat in the frataxin gene
neural abnormalities, and clinical features of the cerebel­
lar atrophies.
Differentia l Diagnosis of the Degenerative
Ataxias in Ad u lts (See also Table 5-1)
Sporadic forms of cerebellar ataxia in adults are in some
instances traceable to strokes involving cerebellar path­
ways (Safe et al) . These are, of course, of acute onset.
Some cases of ataxia are alcoholic-nutritional in origin,
and a few are related to excessive use of drugs or thera­
peutic medications, especially antiepileptic drugs, which
may in a few cases cause a slowly progressive and perma­
nent ataxia. Organic mercury induces subacute cerebel­
lar degeneration, and adulterated heroin causes a mo�e
abrupt and severe ataxic syndrome. The paraneoplastic
variety of cerebellar degeneration often enters into
.
e t_h
differential diagnosis; it occurs mostly m women � Ith
12 breast or ovarian cancers and evolves much more rapidly
�
�
than any of the heredodegenerative forms. he mo �e
.
? rapid onset of ataxia and the presence of anti-PurkinJe
cell antibodies (anti-Yo; see "Paraneoplastic Cerebellar
Degeneration" in Chap . 3 1 ) are central to identifying the
nature of this disease. From time to time one observes a
similar idiopathic variety of subacute cerebellar degener­
ation, particularly in women who have no neo�las� and
lack the specific antibodies of the paraneoplashc disease
(Ropper) . Rare cases of ataxia have been associat�d with
celiac disease and Whipple disease, and metrorudazole
as noted in Chap . 5. Ataxia may also be an early and
prominent manifestation of Creutzfeldt�Jako ?
disease
caused by a prion (see Chap . 33) or of an inhented meta­
bolic disease (see Chap .
37 ) . Of the latter, late-onset G M2
gangliosidosis may simulate cerebellar degeneration in
 CHAPTER 39
adults (see Chap . 37) . Rare cases of aminoacidopathy
manifesting for the first time in adult life have also pro­
voked a cerebellar syndrome (see Chap. 37).
Hereditary Polymyoclonus
The syndrome o f quick, arrhythmic, involuntary single
or repetitive twitches of a muscle or group of muscles
was described in Chap. 6, where it was pointed out that
the condition has many causes. Chapter 37 discusses
those caused by hereditary metabolic diseases. Familial
forms are known, one of which, associated with cerebel­
lar ataxia, was discussed earlier (dyssynergia cerebellaris
myoclonica of Ramsay Hunt) . But there is another dis­
ease, known as hereditary essential benign myoclonus, that
occurs in relatively pure form unaccompanied by ataxia
(termed essential, or familial, myoclonus; see Chap . 6) .
In this condition, it is difficult to evaluate coordination
because willed movement is interrupted by myoclonus
that may be mistaken for intention tremor. Only by
slowing the voluntary movement can the myoclonus be
reduced or eliminated. This myoclonic disease is inher­
ited as an autosomal dominant trait. It becomes manifest
early in life; once established, it persists with little or no
change in severity throughout life, often with rather little
disability. It can, by its natural course, be differentiated
from some of the hereditary metabolic diseases such as
the Unverricht and Lafora types of myoclonic epilepsy,
the lipidoses, tuberous sclerosis, and myoclonic disorders
that follow certain viral infections and anoxic encepha­
lopathy. Of interest is the response of this form of move­
ment disorder to certain pharmacologic agents, notably
clonazepam, valproic acid, and 5-hydroxytryptophan,
the amino acid precursor of serotonin, particularly when
these agents are used in combination (postanoxic myoc­
lonus responds to the same medications).
Another form of nonprogressive myoclonus, domi­
nantly inherited, is associated with dystonia, which is
due to a mutation in a sarcoglycan gene, SGCE.
The main clinical distinctions are from juvenile myo­
clonic epilepsy (see Chap. 16), drug-induced myoclonus,
particularly lithium and opiates; renal failure and other
acquired metabolic disorders; asterixis; and from the startle
responses and some of the diseases that have this sign as
their main characteristic (see Chap. 6) . Creutzfeldt-Jakob
subacute spongiform encephalopathy may cause difficulty
in diagnosis initially but the course of illness clarifies the
situation rapidly. Myoclonus is also one component of the
complex movement disorder in corticobasal-ganglionic
degeneration that was described in an earlier section.
SYN D ROM E OF M U SCU LAR WEAKN ESS
AND WASTING WITHOUT SENSORY
CHANG ES
Motor Neuro n Disease
This general term designates a group of progressive
degenerative disorders of motor neurons in the spinal
cord, brainstem, and motor cortex, manifest clinically by
Degenerative Diseases of the Nervous System 1 1 09
muscular weakness, atrophy, and corticospinal tract signs
in varying combinations. It is for the most part a disease
of middle life and progresses to death in a matter of 2 to
5 years or longer in exceptional cases.
Customarily, motor system disease is subdivided
into several subtypes on the basis of the grouping of
symptoms and signs. The most frequent form, in which
amyotrophy and hyperreflexia are combined, is ALS (amy­
otrophy is the term applied to denervation atrophy and
weakness of muscles). Less frequent are cases in which
weakness and atrophy occur alone, without evidence of
corticospinal tract dysfunction; for these the term progres­
sive spinal muscular atrophy is used. When the weakness
and wasting predominate in muscles innervated by the
motor nuclei of the lower brainstem (i.e., muscles of the
jaw, face, tongue, pharynx, and larynx), it is customary to
speak of progressive bulbar palsy). In a small proportion of
patients, the clinical state is dominated by spastic weak­
ness, hyperreflexia, and Babinski signs, with lower motor
neuron aspects becoming apparent only at a later stage of
the illness, or not at all. This is designated primary lateral
sclerosis, an infrequent form of motor system disease in
which the degenerative process remains confined to the
corticospinal pathways (Pringle et al). The pure spastic
paraplegias without amyotrophy may represent a spe­
cial class of disease hence they are described separately.
There are also relatively common familial forms of spastic
paraplegia in which the disease is confined to the corti­
cospinal tracts or, in some cases, combined with posterior
column or other neurologic signs.
Furthermore, an important group of special spinal
muscular atrophies occurs in infancy and childhood and
are the leading cause of heritable infant mortality and,
after cystic fibrosis, the most frequent form of serious
childhood autosomal recessive disease (Pearn). The best
known is the Werdnig-Hoffmann type of infantile spinal
muscular atrophy (SMA type I); but there are other forms
beginning in later childhood, adolescence, or early adult
life (SMA types II and Ill, or the Wohlfart-Kugelberg­
Welander type) . Despite the clinical heterogeneity of the
heritable childhood spinal muscular atrophies, they all
derive from mutations in the SMN gene (see below; see
Gilliam et al; Brzustowicz et al) . This group of early-onset
spinal muscular atrophies is separate genetically from a
familial form of ALS.
Amyotro p h i c Late ra l S c l e ro s i s
History Credit for the original delineation o f amyo­
trophic lateral sclerosis is appropriately given to Charcot.
With Joffroy in 1869 and Gombault in 1871, he studied the
pathologic aspects of the disease. In a series of lectures
given from 1872 to 1874, he provided a lucid account
of the clinical and pathologic findings. Although called
Charcot disease in France, amyotrophic lateral sclerosis
(the term recommended by Charcot) has been preferred
in the English-speaking world. Duchenne had earlier
(1858) described labioglossolaryngeal paralysis, a term that
Wachsmuth in 1864 changed to progressive bulbar palsy.
In 1869, Charcot called attention to the nuclear origin
of progressive bulbar palsy, and in 1882 Dejerine estab­
lished its relationship to ALS. Most authors credit Aran
1 1 10 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
and Duchenne with the earliest descriptions of progres­
sive spinal muscular atrophy; which they believed to be
of myogenic origin. This interpretation was, of course,
incorrect; Cruveilhier, a few years later, noted the slen­
der anterior roots, and soon thereafter the disease was
brought into line with ALS as a spinal muscular atrophy.
The singular genetic discovery in relation to this disease
has been of the mutation in the superoxide dismutase
(SOD1) gene in familial cases of motor neuron disease.
Epidemiology This is a disease commonly encoun­
tered by neurologists, with an annual incidence rate of 0.4
to 1 . 76 per 100,000 population. Men are affected nearly
twice as often as women. Most patients are older than
age 45 years at the onset of symptoms, and the incidence
increases with each decade of life (Mulder). The disease
occurs in a random pattern throughout the world except
for a dramatic clustering of patients among inhabitants
of the Kii peninsula in Japan and in Guam, where ALS
is often combined with dementia and parkinsonism. In
approximately 10 percent of cases the disease is familial,
being inherited as an autosomal dominant trait with age­
dependent penetrance. The familial cases do not diffe r
fundamentally in their symptoms and clinical course
from nonfamilial ones, although as a group the former
have an earlier age of onset, an equal distribution in men
and women, and a slightly shorter survival. Unusual
environmental associations are reported from time to
time, for example, an increased incidence among Italian
professional football players (Chio et al, 2005) and among
soldiers who had served in various regions. All of these
are questionable on methodologic grounds (they are ret­
rospective case control epidemiologic studies) but further
exploration is warranted.
Clinical Features In the most typical forms of dis­
ease, the onset is perceived by the patient as weakness in
a distal part of one limb. This is noted first as an unex­
plained tripping from slight foot-drop, or by awkward­
ness in tasks requiring fine finger movements (handling
buttons and automobile ignition keys), stiffness of the fin­
gers, and slight weakness or wasting of the hand muscles
on one side. In other words, features related to upper
and to lower motor neuron degeneration (or both) may
appear insidiously in one limb. Cramping beyond what
seems natural and fasciculations of the muscles of the
forearm, upper arm, and shoulder girdle may also arise.
The earliest manifestation of the lower motor neuron
component of this disease is sometimes volitional cramp­
ing-for example, leg cramps as the patient turns in bed
during the early morning hours.
As the weeks and months pass, the other hand and
arm become similarly affected with weakness, stiffness,
slowness, atrophy or cramps. Before long, the triad of
atrophic weakness of the hands and fore arms, fascicula­
tions, slight spasticity of the arms or legs, and generalized
hyperreflexia-all in the absence of sensory change­
leaves little doubt as to the diagnosis. Muscle strength and
bulk diminish in parallel or there is a relative preservation
of power early in the illness. Despite the amyotrophy; the
tendon reflexes are notable for their liveliness. Babinski
and Hoffmann signs are variably present; surprisingly,
they may not appear even as the illness progresses.
Abductors, adductors, and extensors of fingers and thumb
tend to become weak before the long flexors, on which
the handgrip depends, and the dorsal interosseous spaces
become hollowed, giving rise to the "cadaveric" or "skel­
etal" hand. The muscles of the upper arm and shoulder
girdles are typically involved later. There is a general
tendency for adjacent areas to be involved before more
distant ones. When an arm is the first limb affected, all
this occurs while the thigh and leg muscles seem relatively
normal, and there may come a time in some cases when
the patient walks about with useless, dangling arms.
Later the atrophic weakness spreads to the neck, tongue,
pharyngeal, and laryngeal muscles, and eventually those
in the trunk and lower extremities yield to the onslaught
of the disease.
The affected parts may ache and feel cold, but true
paresthesias, except from poor positioning and pressure on
nerves, do not occur or are minor. Sphincteric control is well
maintained even after both legs have become weak and
spastic, but many patients acquire urinary and sometimes
fecal urgency in the advanced stages of the disease. The
abdominal reflexes may be elicitable even when the plantar
reflexes are extensor. Extreme spasticity is rarely seen .
Coarse fasciculations are usually evident in the
weakened muscles but may not be noticed by the patient
until the physician calls attention to them. Fasciculations
are almost never the sole presenting feature of ALS-a
clinical truism with which one can reassure physicians
and medical students who fear, on the basis of persistent
focal muscle twitching in the thumb, face, foot, or fore­
arm, that they are developing the disease.
The course of this illness, irrespective of its particular
mode of onset and pattern of evolution, is progressive.
There may be periods lasting weeks or months during
which the patient observes no advance in symptoms but
clinical changes can nonetheless be detected. Half the
patients succumb within 3 years of onset and 90 percent
within 6 years (Mulder et al) . Several clinical variations
that occur with regularity and have distinguishing clini­
cal features are described below.
Other Patterns of Clinical Evolution In addition to
the special configurations discussed further on, there are
many patterns of neuromuscular involvement other than
the one just described. A leg may be affected before the
hands. A foot-drop with weakness and wasting of the pre­
tibial muscles may be incorrectly attributed to peroneal
nerve compression until weakness of the gastrocnemius
and other muscles betray more widespread involvement
of lumbosacral neurons. In our experience, this crural
amyotrophy has been less frequent than the brachial­
manual type. Another variant is early involvement of
thoracic, abdominal, or posterior neck muscles, the last
being one of the causes of head lolling and camptocormia
(forward bending of the neck and trunk) in older individ­
uals. Yet another pattern is of early diaphragmatic weak­
ness; such cases come to attention because of respiratory
failure. A symmetrical proximal limb or shoulder-girdle
amyotrophy with onset at an early age is also known
and simulates muscular dystrophy (Wohlfart-Kugelberg­
Welander disease, discussed later in this chapter). On
several occasions we have observed a pattern involving
 CHAPTER 39
the ann and leg on the same side, first with spasticity
and then with some degree of amyotrophy; this has been
called the hemiplegic or Mills variant. However, this clini­
cal pattern more often turns out to be a result of multiple
sclerosis of compression of the spinal cord from laterally,
as occurs with a neurofibroma.
The first and dominant manifestations of motor
neuron disease may be a spastic weakness of the legs,
in which case a diagnosis of primary lateral sclerosis is
tentatively made (discussed further on); only after a year
or two do the hand and arm muscles weaken, waste, and
fasciculate, making it obvious that both upper and lower
motor neurons are diseased. Early on, a spastic bulbar
palsy with dysarthria and dysphagia, hyperactive jaw
jerk and facial reflexes, but without muscle atrophy, may
be the initial phase of disease.
As the disease advances, very mild distal sensory
loss may be observed in the feet without explanation,
but, if the sensory loss is a definite and early feature,
the diagnosis must remain in doubt. Approximately 5
percent of cases of ALS are observed in conjunction with
a frontotemporal dementia; less commonly, there is an
association with a Parkinson syndrome.
P rog ressive M u scu l a r Atro p h y
This purely lower motor neuron syndrome i s more com­
mon in men than in women, reportedly in a ratio of 4:1. It
probably encompasses several diseases of the lower motor
neuron, but most of which are manifestations of ALS.
These purely lower motor neuron amyotrophies tend
to progress at a slower pace than the usual case of ALS,
some patients surviving for 15 years or longer. Chio and
colleagues (1985), who analyzed the factors affecting life
expectancy in 155 patients with progressive muscular
atrophy (PMA), found that younger patients had a more
benign course: The 5-year survival was 72 percent in
patients with an onset before age 50 years and 40 percent
in patients with onset after age 50 years. Some of the most
chronic varieties of PMA are familial. It has been revealed
that the original report of a familial variety of this illness
by Willi am Osler described a family now known to have
had a mutation in the SOD1 gene, as discussed below.
In about half the patients, the illness takes the form of a
symmetrical (sometimes asymmetrical) wasting of intrin­
sic hand muscles, slowly advancing to the more proximal
parts of the arms; less often, the legs and thighs are the
sites of the initial atrophic weakness; or the proximal
parts of the limbs are affected before the distal ones.
Fascicular twitchings and cramping are variably present.
Otherwise they differ from ALS only in that the tendon
reflexes are diminished or absent, and signs of corticospi­
nal tract disease cannot be detected. Nonetheless, many
cases of ostensible PMA are found to have indications of
corticospinal tract degeneration at autopsy (Ince et al) .
The main disease to be distinguished from PMA
is an immune-mediated motor neuropathy that occurs
with or without multifocal block of electrical conduction
(see Chap. 46), and various muscle diseases that produce
a similar pattern of weakness, notably, inclusion body
myopathy and polymyositis. The presence of a para­
proteinemia, specifically immunoglobulin (Ig) M with
Degenerative Diseases of the Nervous System 1111
antibodies against G M 1 ganglioside, or the finding of focal
conduction block or sensory nerve abnormalities on the
EMG implies the presence of an autoimmune neuropathy
disease rather than of a degenerative motor neuron type.
P ro g ressive B u l ba r Pa l sy
Here reference is made to a condition in which the first
and dominant symptoms relate to weakness and laxity
of muscles innervated by the motor nuclei of the lower
brainstem, that is muscles of the jaw, face, tongue, phar­
ynx, and larynx. This weakness gives rise to an early
defect in articulation, in which there is difficulty in the
pronunciation of lingual (r, n, 1), labial (b, m, p, f), den­
tal (d, t), and palatal (k, g) consonants. As the condition
worsens, syllables lose their clarity and run together,
until, finally, the patient's speech becomes unintelligible.
In other patients, slurring is a result of spasticity of the
tongue, pharyngeal, and laryngeal muscles; the speech
sounds as if the patient were eating food that is too
hot. Usually the voice is modified by a combination of
atrophic and spastic weakness. Defective modulation
with variable degrees of rasping and nasality is another
characteristic. The pharyngeal reflex is lost, and the pal­
ate and vocal cords move imperfectly or not at all dur­
ing attempted phonation. Mastication and deglutition
become impaired; the bolus of food cannot be manipu­
lated and may lodge between the cheek and teeth and
the pharyngeal muscles do not force it properly into the
esophagus. Liquids and small particles of food find their
way into the trachea or nose. The facial muscles, particu­
larly of the lower face, weaken and sag. Fasciculations
and focal loss of tissue of the tongue are usually early
manifestations; eventually the tongue becomes shriveled
and lies useless on the floor of the mouth. The chin may
also quiver from fascicular twitchings, but the diagnosis
should not be made on the basis of fasciculations alone,
in the absence of weakness and atrophy.
The jaw jerk may be present or exaggerated at a time
when the muscles of mastication are markedly weak. In
fact, spasticity of the jaw muscles may be so pronounced
that the slightest tap on the chin will evoke clonus and
blinking; rarely, attempts to open the mouth elicit a
"bulldog" reflex Gaw snaps shut involuntarily). Spastic
weakness of the oropharyngeal muscles may be the initial
manifestation of bulbar palsy and may at times surpass
signs of atrophic weakness; pseudobulbar signs (patho­
logic laughing and crying) may reach extreme degrees.
This is the only common clinical situation in which spas­
tic and atrophic bulbar palsy coexist. Strangely, the ocular
muscles always escape.
As with other forms of motor system disease,
the course of bulbar palsy is inexorably progressive.
Eventually the weakness spreads to the respiratory
muscles and deglutition fails entirely; the patient dies
of inanition and aspiration pneumonia, usually within
2 to 3 years of onset. Approximately 25 percent of cases
of motor system disease begin with bulbar symptoms,
but rarely, if ever, does the sporadic form of progressive
bulbar palsy run its course as an independent syndrome
(pure heredofamilial forms of progressive bulbar palsy
in the adult are known, e.g., Kennedy disease, discussed
1 1 12 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
further on). In general, the earlier the onset of the bulbar
involvement, the shorter the course of the disease.
P ri m a ry Late ra l Sc l e rosi s
This entity, like ALS, can be a form of motor neuron disease,
although most cases appear to be examples of a unique
degenerative process. Many patients in whom the signs
of corticospinal tract degeneration suggest the presence of
ALS will develop indications of lower motor neuron dis­
ease within 1 year, usually earlier. Approximately 20 per­
cent, however, have a slowly progressive corticospinal tract
disorder that begins with a pure spastic paraparesis; later,
the arms and oropharyngeal muscles become involved
and the disease remains one solely of the upper neurons.
These cases have distinctive neuropathologic features and
are designated as primary lateral sclerosis (PLS), a term
originally suggested by Erb in 1875. A historical review of
the subject appears in the article by Pringle and colleagues.
The typical case begins insidiously in the fifth or
sixth decade with a stiffness in one leg, then in the other;
there is a slowing of gait, with spasticity predominating
over weakness as the years go on. Walking is still possible
with the help of a cane for many years after the onset, but
eventually this condition acquires the characteristic fea­
tures of a severe spastic paraparesis. Over the years, finger
movements become slower, the arms become spastic, and,
if the illness persists for decades, speech takes on a pseu­
dobulbar lilt. There are no sensory symptoms or signs.
The legs are often found to be surprisingly strong, the dif­
ficulty in locomotion being attributable to rigid spasticity.
About half the patients eventually acquire spasticity of the
bladder. Pringle and associates suggest that a diagnostic
criterion of the disease is progression for 3 years without
evidence of lower motor neuron dysfunction.
Pathologic studies in a limited number of cases have
disclosed a relatively stereotyped pattern of reduced
numbers of Betz cells in the frontal and prefrontal motor
cortex, degeneration of the corticospinal tracts, and
preservation of motor neurons in the spinal cord and
brainstem (Beal and Richardson; Fisher; Pringle et al) .
The corticospinal tract lesions are identical to those in
typical ALS. Whether some of these cases are examples of
late-onset familial spastic paraplegia (see further on) has
not been extensively explored with molecular techniques.
Some patients who have only restricted bilateral
signs of upper motor neuron disease prove to have mul­
tiple sclerosis, a slow compression of the spinal cord by
spondylosis or meningioma, spinal dural arteriovenous
fistula, or the myelopathic form of adrenoleukodystro­
phy (affected males or female carriers) . In a few cases,
tropical spastic paraplegia, HN myelopathy, copper
deficiency myelopathy, or a familial type of spastic
paraplegia (described further on) will be uncovered.
Exceptionally, progressive spastic paraparesis has been
linked to an adult onset of phenylketonuria or other arni­
noacidopathies to vitamin B 1 2 deficiency or to the fragile
X premutation syndrome.
L a b o ratory Featu res of M ot o r N e u ro n D i sease
Investigation provides useful confirmatory evidence even
in the typical clinical syndrome. The EMG, as expected,
displays widespread fibrillations (evidence of active
denervation) and fasciculations and enlarged motor units
(denoting reinnervation), and motor nerve conduction
studies reveal only slight slowing, without focal motor
conduction block. If the atrophic paresis is restricted to
an arm or hand, raising the question of cervical spondy­
losis, evidence of denervation in many widely separated
somatic segments favors the diagnosis of ALS. In ques­
tionable cases, it is good practice to insist that denervation
be demonstrated in at least 3 limbs before concluding that
the process is ALS. (The currently favored "El-Escorial"
criteria that are used for the purposes of clinical research
mandate that this finding be present.) Widespread dener­
vation of the paraspinal muscles and of the genioglos­
sus or facial muscles is also strongly suggestive of the
disease but electromyographic testing of these muscles
demands considerable experience and is uncomfortable
for patients. A muscle biopsy is sometimes helpful in cor­
roborating neurogenic denervation. Sensory nerve action
potentials should be normal; tests of motor nerve conduc­
tion have a normal velocity, but the amplitudes become
progressively lower as the disease progresses-in the
earliest stages, they too may be normal. When in a typical
case the amplitudes of sensory nerve action potentials are
reduced, there is usually an underlying entrapment neu­
ropathy, diabetes, or other late-life neuropathy. Sensory
evoked potentials are mildly abnormal in a proportion of
patients, but the explanation for this finding is unclear.
(Sensory complaints and minimal sensory loss have been
commented on above.)
The CSF protein is usually normal or marginally
elevated. Serum creatine kinase is moderately elevated in
patients with rapidly progressive atrophy and weakness,
but it is just as often normal. Motor evoked potentials
elicited from the cortex are also prolonged in patients
with prominent corticospinal signs. In this group, the
MRI may show slight atrophy of the motor cortices and
wallerian degeneration of the motor tracts (Fig. 39-10).
These changes may be diagnostically useful and appear
as increased FLAJR and T2 signal intensity in the pos­
terior limb of the internal capsule, descending motor
tracts of the brainstem, and spinal cord, all of which are
subtle and may be missed. All these laboratory findings,
particularly the degeneration of the lateral columns of
the cord and changes in the internal capsules, pertain
also to primary lateral sclerosis with the notable excep­
tion of EMG findings of denervation and of elevations of
creatine kinase (CK).
Path o l og y
The principal finding i n ALS is a loss o f nerve cells in
the anterior horns of the spinal cord and motor nuclei
of the lower brainstem. Large alpha motor neurons tend
to be affected before small ones. In addition to neuronal
loss, there is evidence of slight gliosis and proliferation
of microglia cells. Many of the surviving nerve cells
are small, shrunken, and filled with lipofuscin. It is not
uncommon to detect ubiquitin inclusions in threads,
skeins, or dense aggregates within the affected neurons
by special stains. Occasionally, there is another ill­
defined cytoplasmic inclusion that is present in neurons
 CHAPTER 39
Figure 39-10. Axial T2-weighted MRI showing abnormal hyperin­
tensi ty reflecting wallerian change in the corticospinal tracts at the
level of the internal capsule (top, arrow) and the pons (bottom) in a
patient with ALS.
and glia. Most studies indicate that these are made up
of TDP-43 and ubiquitin as discussed in the alter section
on "Pathogenesis" . According to some reports, swelling
of the proximal axon is an early finding, presumably
antedating visible changes in the cell body itself. The
anterior roots are thin, and there is a disproportionate
loss of large myelinated fibers in motor nerves (Bradley
et al) . The muscles show typical denervation atrophy
of different ages. Whitehouse and coworkers found a
depletion of muscarinic, cholinergic, glycinergic, and
benzodiazepine receptors in regions of the spinal cord
where motor neurons had disappeared .
The corticospinal tract degeneration is most evident in
the lower parts of the spinal cord, but it can be traced up
through the brainstem to the posterior limb of the internal
capsule and corona radiata by means of fat stains, which
show the macrophages that accumulate in response to
chronic myelin degeneration. There is a loss of Betz cells
in the motor cortex; this is manifest as a slight frontal lobe
atrophy on the MRI, but it is not a prominent finding in
most cases of ALS (Kiernan and Hudson). Other fibers in
the ventral and lateral funiculi are depleted, imparting a
characteristic pallor in myelin stains. Some pathologists
Degenerative Diseases of the Nervous System 1 1 13
have interpreted this as evidence of involvement of non­
motor neurons and hence object to the term motor system
disease. However, this condition of more diffuse pallor may
be a result of a loss of collaterals of motor neurons that
contribute to the lamina propria. One observes the same
effect in long-standing poliomyelitis. In cases of familial
ALS resulting from mutations in the SOD1 gene, the non­
motor systems seem to be more affected (Cudkowicz et al).
Neuropathologic studies of cases of ALS with
dementia are few in number. In addition to the usual loss
of motor neurons, these cases have shown an extensive
neuronal loss, gliosis, and vacuolation involving the
frontal premotor area, particularly the superior frontal
gyri and the inferolateral cortex of the temporal lobes.
The histologic changes of Alzheimer or Pick disease have
not been seen in our cases; neurofibrillary degeneration
has been observed, but is inconsequential in comparison
to that seen in the Guamanian Parkinson-dementia-ALS
complex (Finlayson et al; Mitsuyama). Attempts to trans­
mit this ALS-dementia syndrome to subhuman primates
have been unsuccessful.
D i a g n os i s of ALS
The early clinical picture of motor system disease is
closely simulated by a centrally placed cervical spondy­
lotic bar or ruptured cervical disc, but with these condi­
tions there is usually pain in the neck and shoulders,
limitation of neck movements, and sensory changes,
and the lower motor neuron changes are restricted to 1
or 2 spinal segments. The EMG is helpful if not decisive
in differentiating these disorders. A mild hemiparesis
or monoparesis because of multiple sclerosis may be,
for a time, difficult to distinguish from early ALS and
primary lateral sclerosis. Progressive spinal muscular
atrophy may be differentiated from peroneal muscular
atrophy (Charcot-Marie-Tooth neuropathy) by the lack of
family history, the complete lack of sensory change, and
different EMG patterns, as described in Chap . 46. Motor
system disease beginning in the proximal limb muscles
may be misdiagnosed as an infl ammatory myopathy or a
limb-girdle type of muscular dystrophy.
The main considerations in relation to progres­
sive bulbar palsy are myasthenia gravis and, less often,
inflammatory myopathy, muscular dystrophy, and espe­
cially the inherited (Kennedy) type of bulbospinal atro­
phy, which is discussed further on. The spastic form of
bulbar palsy may suggest the pseudobulbar palsy of
lacunar disease and can be a prominent part of the pro­
gressive supranuclear palsy described earlier in the chap­
ter. A crural form of PMA may be confused with diabetic
polyradiculopathy or polymyositis.
A major consideration is the differentiation of PMA
from a chronic motor polyneuropathy, particularly the
form that displays multifocal conduction block. Extensive
nerve conduction studies and EMG examinations are
necessary to distinguish the two; these neuropathic pro­
cesses are discussed with the peripheral neuropathies in
Chap . 46. The presence of an IgM monoclonal parapro­
teinemia or of specific antibodies directed against the G M 1
ganglioside are usually indicative of the immune motor
neuropathy, but in half of the cases these laboratory
1 1 14 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
tests are negative. There is also a rare form of subacute
poliomyelitis (possibly viral) in patients with lymphoma
or carcinoma; it leads to an amyotrophy that progresses
to death over a period of several months. Chapter
discusses this paraneoplastic variety of motor system
disease in greater detail.
Because it may produce a motor-predominant radic­
ulopathy; chronic Lyme infection is sometimes consid­
ered in the differential diagnosis of ALS. Some clinics
screen for Lyme antibodies using both an enzyme-linked
immunosorbent assay (ELISA) and the more sensitive
and specific Western immunoblot, but we have never
detected such a case and doubt there is much similarity.
Infrequently, we have seen myelopathic motor findings
and motor radiculopathy with vitamin B 1 2 deficiency, and
there are exceptional reports of myeloradiculopathy with
lead poisoning; we sometimes include tests for these con­
ditions. Another entity that may simulate ALS is inclusion
body myositis (IBM), an atypical myopathy that begins
asymmetrically and involves distal muscles, usually with­
out much elevation of serum CPK levels. In a recent series
of 70 patients with this condition, 13 percent were initially
diagnosed as having ALS (Dabby et al) . Features distin­
guishing the IBM cases included normal corticospinal
function, preservation of deep tendon reflexes in weak
muscles, and finger flexor weakness. One concludes from
this series that a detailed, quantitative EMG and possibly
a muscle biopsy are indicated in cases that display pre­
dominantly lower motor features. Fully developed ALS
is difficult to confuse with these conditions. Acid maltase
deficiency may also simulate ALS in causing fatigability
and early respiratory failure.
Over the years, the authors have encountered young
men with localized and asymmetrical amyotrophy of the
leg or forearm that became arrested and did not advance
over a decade or two. Several reports of such a partial
cervical spinal amyotrophy have appeared in recent years
(Hirayama et al; Moreno Martinez et al) . In the type
described by Hirayama and associates, young men are
affected with progressive and asymmetrical amyotrophy of
the forearm and hand that has been traced to ligamentous
SODl Superoxide dismu tase 1 AD
FUS Fused sarcoma AD
TARDPSP AD, rare recessive
DCTN Dynactin AD
CytoC Cytochrome-c oxidase Mitochondrial
ALS2 GEF/alsin AR
SETX Senataxin AD
VAPB Vesicle-associated AD
membrane
AD autosomal dominant; AR autosomal recessive
hypertrophy and buckling in the ventral spinal canal. This
causes a compression of the cervical spinal cord gray mat­
ter, presumably by a chronic ischemic effect as discussed
31 in detail in Chap. 44. In a familial variety of pure restricted
amyotrophy, only the vocal cords became paralyzed over
a period of years in adult life; only later were the hands
affected.
Some patients who have recovered from paralytic
poliomyelitis may develop progressive muscular weak­
ness 30 or 40 years later; the nature of this relationship
is obscure. We favor the explanation that atrophy of
anterior horn cells with aging brings to light a critically
depleted motor neuron population (see further on) . It
appears to progress little if at all.
An observation of interest is the finding of a form
of progressive spinal muscular atrophy in patients with
GM2 gangliosidosis, the storage disease that presents in
infancy as Tay-Sachs disease (Kolodny and Raghavan).
The onset is in late adolescence and early adult life and
the atrophic paralysis is progressive, so that this condi­
tion is often mistaken for Wohlfart-Kugelberg-Welander
disease or ALS. A number of cases of this type have been
discovered in Ashkenazi Jews by the use of lysosomal
enzyme analysis. The rare and incompletely character­
ized entity of polyglucosan disease, discussed in other
sections of the book, has simulated ALS.
The differential diagnosis of the purely spastic state of
primary lateral sclerosis is broad and has been listed ear­
lier. An estimate of the frequency of all the aforementioned
alternative diagnoses may be appreciated from a study of
cases by Visser and colleagues that were initially presumed
to be PMA but turned out to represent another process. In
17 of 89 patients the diagnosis proved to be anti-G M1 motor
conduction block, chronic inflammatory demyelinating
polyneuropathy; and various myopathies. This notwith­
standing, ALS or the more discrete forms of motor system
disease rarely offer any difficulty in diagnosis.
Path o g e n es i s
Insight into the sporadic form o f the disease has been
afforded by analyses of the approximately 10 percent of
Adult Clinically and pathologicaJJy similar to
sporadic ALS
Adult ALS with frontotemporal dementia
Adult Slowly progressive with predominant bulbar
features
Adult Prominent spasticity
Juvenile Very slowly progressive, predominantly
corticospinal
Juvenile Very slowly progressive
Adult Similar to sporadic ALS
 CHAPTER 39
ALS cases that are familial and caused by identifiable
mutations. They are inherited mainly in an autosomal
dominant pattern (Table 39-6) . Of these inherited forms,
approximately 40 percent are associated with a hexa­
nucleotide expansion in the C9orp2 gene, and provoca­
tively, 4 to 8 percent of ostensibly sporadic cases have
mutations in the gene. The mechanism of motor neuron
death that results from this mutation is not known but
may be associated with mishandling of RNA-binding
proteins. Of similar interest are the TARDBP and FUS
genes that each has an association with approximately
5 percent of familial cases and 2 percent of sporadic ones.
These genetic and molecular influences are summarized
by Andersen and Al-Chalabi. All 3 of the aforementioned
genes have also been implicated in degenerative fronto­
temporal dementia and in the combination of this demen­
tia with ALS. The SOD1 mutation, the first to be found
in familial ALS, codes for the cytosolic enzyme Cu-Zn
superoxide dismutase (SOD1; Rosen et al); it has also been
implicated in a small proportion of sporadic cases. There
are yet other mutations in this group that have associa­
tions, not necessarily causal, with small numbers of both
sporadic and inherited cases (Table 39-7).
What has emerged from these genetic studies is the
common feature of the accumulation of the TDP-43 and
FUS proteins in neurons. The mechanisms that lead to
cell death as a result of any of these mutations or the pro­
tein deposition are being sought.
A rare and recessively inherited childhood form
of motor neuron disease (affecting corticospinal more
than spinal motor neurons) has been attributed to muta­
tions in a gene whose protein (alsin) is a component of
the neuronal cell-signaling pathways. Yet another rare
childhood-onset form of disease arises from mutations in
the senataxin gene, a DNA helicase that probably assists
in chromatin folding and unfolding. (It is of interest that a
recessively inherited mutation in the same gene transmits
a recessive form of ataxia with oculomotor disorder.) In
several families, a mutation has been detected in a protein
that is involved in the transport of vesicles in neurons.
Table 39-6 summarizes these various genetic forms of
motor neuron disease.
Trauma, particularly traction injury of an arm, but also
repetitive head and spine injury has been reported occa­
sionally as an antecedent event in patients with ALS, but
a causative relationship has not been established. Younger
and coworkers have found a higher incidence of parapro­
teinemia in patients with motor system disease than can
be accounted for by chance. Many other examples of disor­
dered immune function have been described but a coher­
ent explanation of ALS as an autoimmune disease has
not emerged. It has never been proved that intoxication
with heavy metals (lead, mercury, aluminum) can cause
motor system disease, although there are reports of con­
current myelopathic and radicular motor signs in patients
with lead intoxication. There is little evidence that such
cases represent a reactivation of a virus or the presence
of some other infectious agent. The progressive weakness
that occurs some 30 to 40 years after recovery from polio
should not be confused with PMA, as already indicated.
Finally, we have had occasion to see patients who, many
years after a severe electrical injury that passed through
Degenerative Diseases of the Nervous System 1 1 15
the region of the cord, developed a progressive and severe
amyotrophy of the arms; other such extraordinary cases
are known but the concordance is considered coincidental
by most authorities (see Chap. 44).
Treatm ent
With the exception of riluzole, discussed below, there is no
specific treatment for any of the motor neuron diseases.
Supportive measures, however, are exceedingly important.
In initial office visits, it has been our practice to give the
patient some idea of the seriousness of the condition;
but in early discussions we avoid the devastating state­
ment that ALS is invariably fatal. Typically, patients and
family members will ask explicitly about these matters
in subsequent visits; such data as are appropriate to the
patient's circumstances and character can be conveyed
at that time, usually with the caveat that any individual
may outlive the standard survival statistics.
The antiglutamate agent riluzole was shown by
Bensimon and colleagues to slow the progression of ALS
and improve survival in patients with disease of bulbar
onset. However, it added only 3 months of life at best.
This claim has been confirmed in several followup stud­
ies, although again the benefit has been marginal. Several
additional agents are reported to have been effective in
genetic models of ALS. These are presently undergoing
study in ALS patients. Guanidine hydrochloride and
injections of cobra venom, gangliosides, interferons,
high-dose intravenous cyclophosphamide, and thyro­
tropin-releasing hormone are but some of a long list of
agents that were said to arrest the disease process, but
these claims have been discredited.
An attempt can be made to reduce the spasticity with
medications, such as baclofen or tizanidine, or by subarach­
noid infusions of baclofen via an implanted lumbar pump.
Initial intrathecal test doses are given to predict a response
to the pump infusions of baclofen, but this test may fail;
consequently, in severe cases it may be advisable to pro­
ceed with a constant infusion for several days. Some degree
of improved comfort from a reduction in the extreme rigid­
ity is usually the most that can be expected. Partial relief
from spasticity may also be afforded by the use of benzo­
diazepines or sometimes dantrolene. These approaches are
most suitable for cases of primary lateral sclerosis, which
can be expected to progress slowly and for a long period.
At all stages of ALS, physical therapy is useful in
maintaining mobility, but overwork of the muscles lead­
ing to fatigue and cramps should be avoided. Physical
therapy is invaluable, for example, for avoiding con­
tractures of the fingers and shoulders. Occupational
therapy is likewise helpful, particularly assessments of
the patient's function in the home.
hnportant in the management of ALS is periodic
monitoring of respiratory function. We typically perform
pulmonary function tests every few months after the first
year or so of illness. Our experience has been that the vital
capacity in cubic centimeters can be estimated by multiply­
ing the highest number to which a patient can count with
one deep breath by 100. Thus, the ability to count to 25 with
a full effort in a single breath corresponds to a vital capacity
of approximately 2.5 L. Significant practical advances have
been made in the respiratory management of ALS. The
1 1 16 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE

SMA I (in fantile, Au tosomal recessive Preterm to Neonatal hypotonia (floppy Few survive 1 year
Werdnig-Hoffmann) Two copies of SMN 2 6 months baby}, weakness of suckin g
and swallowing, may have
arthrogryposis, unable to sit
SMA II (intermecliate Autosomal recessive 6 to 15 months Proximal weakness, fasciculation, Variable; death from
type; Dubowitz At least 3 copies of SMN 2 fine hand tremor, unable to respiratory
disease) stand complications
SMA III (Wohlfart- Au tosomal recessive or 1 year to Delayed motor development, Slowly progressive,
Kugelberg-Welander) dominant adolescence proximal leg weakness variable outcome
At least 3 copies of SMN 2
SMA IV Autosomal recessive After age 30 Proximal limb weakness and Slowly progressive;
At least 4 copies of SMN 2 diaphragm eventua.lly wheelchair-
bound but normal life
expectancy
Kennedy syndrome X-linked (CAG repeat Early adulthood Scapuloperoneal or clistal atrophy; Slowly progressive
(bulbospinal atrophy) expansion in the oropharyngeal weakness,
AR gene}, less often gynecomastia, oligospermia
autosomal dominant
Fazio-Londe disease Au tosomal recessive, Childhood to Progressive bulbar and respiratory Survival for years,
rarely dominant, early failure respiratory failure
SLC52A3 gene adolescence

introduction of bilevel positive airway pressure (BiPAP)
has allowed patients to sleep better and reduce daytime
somnolence. Many patients do not initially tolerate the
device, usually because of maladjusted face masks or
excessive applied airway pressures. Almost always, a sea­
soned pulmonary technologist can find solutions to these
problems. It is appropriate to begin BiPAP at (or before)
the earliest sign of carbon dioxide retention, a state that is
heralded by disruption of sleep, nightmares, early morn­
ing headaches, and daytime drowsiness. With noninvasive
respiratory assistance, it may be possible to defer trache­
ostomy for months or years. Ultimately, as the diaphragm
fails, BiPAP is needed not only at night but also during the
day. As BiPAP use approaches 20 to 24 h per day, patients
must usually address the difficult question of tracheostomy
and mechanical ventilation. We broach this subject early
enough in the course of the disease to allow ample time for
discussion and reflection. In practice, most patients elect
not to undergo tracheostomy and full ventilation.
Another important issue regards nutrition. As oro­
pharyngeal palsy progresses, food should be cut into
small pieces and dry foods, such as toast should be
avoided; milk shakes and preparations of the same consis­
tency are ideal at this stage. Speech therapists are capable
of teaching patients methods to adapt to declining bulbar
function and at the same time minimizing aspiration.
Ultimately, in our experience, most ALS patients will need
a feeding tube to maintain normal hydration and caloric
intake. Although we adopt a neutral position in discus­
sions with patients regarding mechanical ventilation, we
tend to urge patients to undergo placement of a feeding
tube at the appropriate time. This presumably increases
survival and improves quality of life by preventing
dehydration and recurrent aspiration. Laparoscopic and
radiologic technologies for the placement of a gastrostomy
tube render the procedure swift and nearly painless. Some
patients have tubes inserted as outpatients and then start
gastric feeding within a day or two.
Other devices, often guided by the physical and
occupational therapist, may be of great assistance to
the patient and family as the disease progresses. These
include a mechanized bed and structural accommoda­
tions in the home that facilitate entry of a wheelchair and
the safe use of the bath or shower as well as thick-handled
utensils. Ambulation aids, beginning with simple canes
(first one, then two) followed by a walker (preferably with
basket and seat) and then a wheelchair (manual or elec­
tric) are of value in maintaining a sense of independence
and assuring safety.
The American Academy of Neurology has published
explicit guidelines for management that have been of
great aid to patients and physicians; they emphasize the
complex and multidisciplinary needs of ALS patients (see
Miller et al 2009a and 2009b).
Heredofa m i l i a l Forms of Prog ressive
M uscu l a r Atrophy
These diverse diseases are the concern mainly of child
neurology. They are presented here because they fall
within the category of system degenerations and are usu­
ally inherited.
S p i n a l M u scu l a r At ro p h y
(We rd n i g - H offm a n Disease)
The classic form of spinal muscular atrophy was described
by Werdnig in 1891 and 1894, by Hoffmann in 1893 and,
at about the same time, by Thomsen and Bruce. The cases
 CHAPTER 39
described by these authors were all in infants. Further
clinical analyses, however, indicated the inadequacy
of this narrow grouping for the large group of spinal
muscular atrophies. Brandt, in his study of 112 Danish
patients, found that in about one-third the weakness
was present at birth, and in 97 the onset was in the first
year of life; in 9 patients, the disease was not recognized
until after the first year of life. In 1956, Walton, and later
Wohlfart and colleagues and Kugelberg and Welander
(see below), identified milder forms of spinal muscular
atrophy in which the onset was between 2 and 1 7 years
and walking was still possible in adult life. Byers and
Banker, in a study of 52 patients, subdivided them into
3 groups on the basis of age of onset; in one group the
disease was recognized at birth or in the first month or
two of life; in a second, between 6 and 12 months; and in
a third, after the first year. In their last group, it was not
unusual for the patient to survive into adolescence and
adult life. In a few of the late-onset types, signs of corti­
cospinal tract involvement are conjoined, and Bonduelle
has also included some patients with areflexia, pes cavus,
Babinski signs, choreiform movements, and developmen­
tal delay in this group. More recently, the designations
SMA I, Il, and Ill have been introduced, based largely on
the age of onset (see Table 39-7) .
GeneticAspects ofSpinalMuscularAtrophies Familial
spinal muscular atrophy that begins in infancy and child­
hood is inherited mainly as an autosomal recessive trait.
All the SMA phenotypes in children have been mapped
to the same chromosome, Sql1 .2-13.3 (Brzustowicz et al;
Gilliam et al; Munsat et al) . The mutations affect the gene
at the "survival of motor neuron" (SMN) site. The SMN
protein participates in forming protein-RNA complexes
(small nuclear ribonucleoproteins and RNA) that are
essential for gene splicing. Within the SMN locus there are
2 alleles: SMN1 , which generates a full-length, fully func­
tional form of SMN, and SMN2, which makes a truncated,
partially functional SMN. The latter can partially compen­
sate for the loss of SMN1 . Making matters more complex,
individuals vary in the number copies of SMN2. As a
result, disease due to loss of both copies of SMN1 causes
very severe SMA in individuals who carry only one copy
of SMN2, while those with multiple copies of SMN2 have
milder disease. Thus, the amount of SMN2 protein deter­
mines the severity and time of onset of disease.
Although affected siblings demonstrate very similar
clinical patterns of disease, the same mutation may give
rise to very different phenotypes in different families, so
that additional modifying posttranscriptional or nonge­
netic attributes must be playing a role. Less often, autoso­
mal dominant and X-linked patterns of inheritance have
been found, resulting from mutations in UBA1, usually
in adults. A rare autosomal dominant adult form is the
result of mutations in VABP and a form that affects only
DYNC1H1 .
the legs is associated with mutations in
Clinical Manifestations of Werdnig-Hoffmann
Disease (SMA I) The most frequent form of these spi­
nal muscular atrophies, the severe infantile type, is a
common disease, occurring once in every 20,000 live
births. After cystic fibrosis, it is also the most frequent
cause of death from a recessively inherited disease.
Degenerative Diseases of the Nervous System 1 1 17
Characteristically the infant, usually born normally, is
noted from birth to be unnaturally weak and limp
("floppy"). Some mothers report that fetal movement in
utero had been less than expected or lacking altogether.
In severe cases, arthrogryposis at the ankles and wrists
or dislocation of the hips is noted at birth (arthrogryposis
and its differential diagnosis is discussed in Chap. 48 in
the section on the congenital neuromuscular disorders).
The muscle weakness in these children is generalized
from the beginning, and death comes early, usually within
the first year. Other infants seem to develop normally for
several months before the weakness becomes apparent. In
these, the trunk, pelvic, and shoulder-girdle muscles are
at first disproportionately affected, while the fingers and
hands, toes and feet, and cranial muscles retain mobility.
Hypotonia accompanies the weakness, and because pas­
sive displacement of articulated parts in testing muscle
tone is easier to judge than power of contraction at this
early age, it may be singled out as the dominant clinical
characteristic. As a rule, the tendon reflexes are unobtain­
able. Volume of muscle is diminished but is difficult to
evaluate in the infant because of the coverings of adipose
tissue. Fasciculations are seldom visible except sometimes
in the tongue. Perception of tactile and painful stimuli
is undiminished, and emotional and social development
measures up to age.
As the months pass, the weakness and hypotonia
progress gradually and spread to all the skeletal muscles
except the ocular ones. Intercostal paralysis with a degree
of collapse of the chest is the rule. Respiratory move­
ments become paradoxical (abdominal protrusion with
chest retraction). The cry becomes feeble, and sucking and
swallowing are less efficient. Such infants are unable to sit
unless propped, and they cann ot hold up their heads with­
out support and cannot roll over or support their weight
when placed on their feet. Their posture is characteristic:
arms abducted and flexed at the elbow, legs in the "frog
position" with external rotation and abduction at hips
and flexion at hips and knees. If the effects of gravity are
removed, all muscles continue to contract; that is there is
paresis, not paralysis. Until late in the illness, these chil­
dren appear bright-eyed, alert, and responsive.
Infants in whom the disease becomes apparent only
after several months of life have a less-rapid decline than
those affected in utero or at birth. Some of the former
become able to sit and creep and even to walk with sup­
port; those with later onset may survive for several years
and even into adolescence or early adult life, as already
mentioned.
Laboratory data of confirmatory value are few.
Muscle enzymes in the serum are usually normal or
rarely elevated. The EMG, if performed at a late enough
stage of development, displays fibrillations, proving the
denervative basis of the weakness. Motor unit poten­
tials are diminished in number and, in the more slowly
evolving cases, some are larger than normal (giant or
polyphasic potentials reflecting reinnervation) . Motor
nerve conduction velocities are normal or fall in the low­
normal range (these are normally slower in infants than
in adults) . Electrophysiologic studies performed in the
first few months of life may give ambiguous results.
1 1 18 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
Pathologic Findings Muscle biopsy after 1 month
of age reveals a typical picture of group atrophy; shortly
after birth this change is difficult to discern. Aside from
denervative atrophy, the essential abnormalities are in the
anterior horn cells in the spinal cord and the motor nuclei
in the lower brainstem. Nerve cells are greatly reduced
in number, and many of the remaining ones are in vary­
ing stages of degeneration; a few are chromatolytic and
contain cytoplasmic inclusions. It is not unusual to see
figures of neuronophagia. There is replacement gliosis
and secondary degeneration in roots and nerves. Other
systems of neurons, including the corticospinal and corti­
cobulbar systems, are entirely unaffected.
Differential Diagnosis The major problem in diag­
nosis is to distinguish Werdnig-Hoffmann disease from
an array of other diseases that cause hypotonia and
delayed motor development in the neonate and infant.
The list of disorders that imitates spinal muscular atro­
phy constitutes a large part of the differential diagnosis
of the so-called floppy infant. The congenital myopathies
(as described in Chap. 48), the glycogenoses, neonatal
myasthenia gravis, Prader-Willi syndrome, and disorders
of fatty acid metabolism frequently present in this way.
The preservation of tendon reflexes and relative lack of
progression of muscle weakness distinguish the latter
disorders. Because of the gravity of the diagnosis, muscle
biopsy should be performed if there is any suspicion of
spinal muscular atrophy. If studied properly, the biopsy
usually yields the correct diagnosis.
Clinical disorders more or less similar to the spi­
nal muscular atrophies may be identified occasionally
in certain hereditary metabolic diseases. For example,
Johnson and coworkers have described a patient who
began experiencing weakness of the legs, cramping, and
fasciculations during adolescence in what proved to be a
variant of hexosaminidase A (GM2 ) deficiency, and biopsy
of rectal mucosa showed nerve cells with the typical
membranous cytoplasmic bodies of Tay-Sachs disease.
Others have reported similar cases. A progressive motor
neuron or motor nerve disorder has also been observed
in glycogen storage disease affecting anterior horn cells.
Motor nerve fibers also suffer damage in metachromatic
and globoid body leukoencephalopathies.
Certain forms of muscular dystrophy, notably myo­
tonic dystrophy, which is about twice as frequent as
Werdnig-Hoffmann disease, may become manifest in the
neonatal period and interfere with sucking and motor
development (see Chap. 48). As a rule, the weakness is
not as severe or diffuse as that in Werdnig-Hoffmann
disease. The mother, but not the child, may display myo­
tonia, either elicitable clinically or, if more subtle, with
EMG recording. Also, a number of polyneuropathies may
cause a serious degree of weakness in early childhood.
Unfortunately, in respect to the latter, adequate sensory
testing is not possible because of the patient's age, but
the CSF protein is often elevated. Again, diagnosis is
greatly facilitated by nerve-muscle biopsy and measure­
ment of nerve conduction velocities. These velocities are
reduced but must be interpreted with caution because
of incomplete development of axons and of myelination
in the first months of life. The needle EMG examination
shows subtle signs of denervation that cannot be easily
distinguished from the finding in the spinal muscular
atrophies. Examination of parents and siblings may dis­
close a clinically inapparent neuropathy. Polymyositis of
childhood may also simulate both muscular dystrophy
and motor neuron disease. Finally nemaline and central
core myopathy can manifest in infancy and early child­
hood and cause a floppy child syndrome.
Developmental delay with a flaccid rather than spas­
tic weakness of the limbs is another major category of
disease that must be distinguished. These include Down
syndrome, cretinism, Prader-Willi syndrome, and achon­
drodysplasia. It should be commented that very sick chil­
dren with celiac disease, cystic fibrosis, and other chronic
diseases may be hypotonic to the point of simulating neu­
romuscular disease. Usually speech is not delayed and ten­
don reflexes are preserved in these purely medical states,
and strength returns as the medical problem is corrected.
Also, certain of the polioencephalopathies and leukodys­
trophies may weaken muscles and abolish tendon reflexes,
but usually there is evidence of cerebral involvement.
There remains, after the assiduous study of the
"floppy infant," a group of cases of hypotonia and motor
underdevelopment that cannot be classified. The term
amyotonia congenita (Oppenheim) was once applied to
this entire group but is now obsolete. Walto proposed the
term benign congenital hypotonia to designate patients who
manifest limp and flabby limbs in infancy and a delay
in sitting up and walking but who improve gradually,
some completely and others incompletely. It is likely that
among this group there are examples of congenital myop­
athy that await differentiation by application of modern
histochemical, ultrastructural, and genetic techniques.
Chronic Childhood and Juvenile Proximal Spinal
Muscular Atrophy (Wohlfart-Kugelberg- We lander
Syndrome; SMA III) This is a somewhat different form
of heredofarnilial spinal muscular atrophy, which, as the
name indicates, involves the proximal muscles of the
limbs predominantly and is only slowly progressive. It
was first separated from other forms of motor system
disease and from muscular dystrophy by Wohlfart and
by Kugelberg and Welander in the mid-1950s. In about
one-third of the cases the onset is before 2 years of age,
and in half, between 3 and 18 years. Males predominate,
especially among patients with juvenile and adult onset.
The usual form of transmission is by an autosomal reces­
sive pattern; most cases result from mutations in the SMN
gene; as mentioned, multiple copies of the SMN2 gene
partly rescue the loss of SMNl and lead to this milder
form of disease. Families with dominant and sex-linked
inheritance have also been described.
The disease begins insidiously; with weakness and
atrophy of the pelvic girdle and proximal leg muscles, fol­
lowed by involvement of the shoulder girdle and upper
arm muscles. Unlike the sporadic form of spinal mus­
cular atrophy, the Wohlfart-Kugelberg-Welander variety
(also listed in other books and monographs as Kugelberg­
Welander disease) is bilaterally symmetrical from the
beginning, and fasciculations are observed in only half
the cases. Ultimately the distal limb muscles are involved
and tendon reflexes are lost. Bulbar musculature and
 CHAPTER 39
corticospinal tracts are spared, although Babinski signs
and an associated ophthalmoplegia (presumably neural)
have been reported in rare instances.
The presence of fasciculations and the EMG and
muscle biopsy findings-all of which show the character­
istic abnormalities of neural atrophy-permit distinction
from muscular dystrophy. Cases that have been exam­
ined postmortem have shown loss and degeneration of
the anterior horn cells.
The disease progresses very slowly, and some patients
survive to old age without serious disability. In general,
the earlier the onset, the less favorable the prognosis;
however, even the most severely affected patients retain
the ability to walk for at least 10 years after the onset.
Admittedly, it is difficult to make a sharp distinction
between these cases of Wohlfart-Kugelberg-Welander dis­
ease and certain milder instances of Werdnig-Hoffmann
disease with onset in late infancy and early childhood
and prolonged survival (Byers and Banker).
A form that is intermediate between the severe
Werdnig-Hoffrnan type and the milder Wohlfart­
Kugelberg-Welander is termed Dubowitz syndrome and
designated SMA II.
Ke n n edy Syn d ro m e (X-Li n ked B u l bos p i n a l
M u scu l a r At ro phy)
An unusual pattern o f distal muscular atrophy with promi­
nent bulbar signs and, less often, ocular palsies was
described by Kennedy and coworkers. The onset has
varied from childhood to adult age, but symptoms typi­
cally begin in the third decade. Most cases have shown an
X-linked pattern of inheritance and a lesser number, an
autosomal dominant pattern. The proximal shoulder and
hip musculature are involved first by weakness and atro­
phy, followed in about half of patients by dysarthria and
dysphagia. Muscle cramps or twitching often precedes
weakness. Facial fasciculations and mild weakness are
characteristic and may be striking. The tendon reflexes
become depressed and may be absent; a mild sensory
neuropathy is almost universal. In the family described
by Kaeser, in which 12 members in 5 generations were
affected, the pattern of weakness was shoulder-shank,
that is scapuloperoneal; it may therefore be mistaken for
muscular dystrophy. Two-thirds of patients have gyne­
comastia, a feature that may first identify affected men
in a kindred; oligospermia and diabetes are additional
associations; therefore, the presence of genuine progeny
virtually excludes the disease in a male. The CK level
is elevated, sometimes tenfold, and physiologic studies
reveal denervation and reinnervation as well as indica­
tions of a mild sensory neuropathy.
As in Huntington disease and certain of the spinocer­
ebellar atrophies, the genetic defect is a CAG expansion,
in this case in the gene (AR) that codes for the androgen
receptor on the short arm of the X-chromosome (La Spada
et al; see Table 39-7). Indeed, the first reported polyglu­
tamine disease was Kennedy syndrome. Lengthened
sequences correlate with an earlier age of onset (anticipa­
tion, as in Huntington disease) but have no relation to the
severity of disease. Androgen receptors have been found
on motor neurons of the spinal cord; the subpopulation
Degenerative Diseases of the Nervous System 1 1 19
of motor neurons that is susceptible to both Kennedy
syndrome and ALS express abundant surface andro­
gen receptors, but it is not clear whether this finding
has direct pathogenic significance. Neuronal inclusions
have been described, composed of aggregations of the
abnormally long polyglutamine protein sequences that
correspond to the CAG expansion. A family with the
bulbospinal phenotype but without the CAG expansion
has also been reported (Paradiso et al). Other features,
such as optic atrophy and sensory neuronopathy, were
present in some members of this kindred but are not fea­
tures of typical cases. The diagnosis can be confirmed by
genetic testing for the lengthened trinucleotide sequence.
Prenatal diagnosis and identification of female carriers
are also possible by this method.
P ro g ressive B u l ba r Pa l sy of C h i l d h oo d
( Fa z i o - La n d e Sy n d ro m e )
Fazio in 1892, and Lande i n 1893, described the develop­
ment of a progressive bulbar palsy in children, adoles­
cents, and young adults. There is progressive paralysis
of the facial, lingual, pharyngeal, laryngeal, and some­
times ocular muscles. The illness usually presents with
stridor and respiratory symptoms, followed by facial
diplegia, dysarthria, dysphagia, and dysphonia. These
features become increasingly pronounced until the time
of death some years later. In a few patients there is a
late development of corticospinal signs and sometimes
ocular palsies. Occasionally, jaw and oculomotor paresis
appears, and in one case, there was progressive deafness.
The disease is rare, only several dozen well-described
examples had been recorded in the medical literature
by 1992 (McShane et al) . Inheritance may be autosomal
dominant, as in Fazio's original case, and rarely X-linked,
but it is more likely to be autosomal recessive. Pathologic
examination has shown a loss of motor neurons in the
hypoglossal, ambiguus, facial, and trigeminal motor
nuclei. In a few cases, the nerve cells in the ocular motor
nuclei also were diminished. This disease, the 2 times we
have encountered it, had to be differentiated from myas­
thenia gravis, a pontomedullary glioma, and brainstem
multiple sclerosis.
The cause of the disease is interesting in that it results
from mutations in SLC52A3, a riboflavin transporter, and
some beneficial effect is derived from the administra­
tion of riboflavin (vitamin B2 ). The disease is allelic with
Brown-Vialetto-Van Laere syndrome, another motor neuron
degeneration, which includes deafness.
Hereditary Forms of Spastic Paraplegia
H e red ita ry S p a stic Pa ra p l e g i a
(Stru m pe i i - L o r ra i n D i sease)
This disease was described by Seeligmuller in 1874 and
later by Striimpell in Germany and Lorrain in France; it
has now been identified in nearly every part of the world.
The pattern of inheritance is usually autosomal domi­
nant, less often recessive (one family has shown X-linked
inheritance), and the onset may be at any age from child­
hood to the senium. Harding (1993) divided the disease
1 1 20 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
3A ATLl (a tlastin) AD
4 Spas tin AD
6 NIPA l AD
10 KIF5A (kinesin-1) AD
13 HSP (heat shock AD
protein)
17 BSCL2 (seipin) AD
7 SPG7 (paraplegin) AR
Sparlin AR
21 SPG21 (maspardin) AR
L1 CAM (Ll cell XR
adhesion molecule)
2 PLP (proteolipid
protein) XR
AD autosomal dontinant; AR autosomal recessive; XR X-linked recessive
into 2 groups, the more common one beginning before
age 35 with a very protracted course and the other with
a late onset (40 to 60 years). The latter type often shows
sensory loss, urinary symptoms, and action tremor.
The clinical picture is that of a gradual development
of spastic weakness of the legs with increasing difficulty
in walking. The tendon reflexes are hyperactive and the
plantar reflexes extensor. In the pure form of the disease,
sensory and other nervous functions are entirely intact.
If the onset is in childhood, as many cases are, the foot
arches become exaggerated, the feet are shortened, and
there is a tightening (pseudocontracture) of calf muscles,
forcing the child or adolescent to "toe-walk." This is a
common orthopedic problem and may require surgical
correction. In children, the legs appear to be underdevel­
oped, and in both children and adults they may become
quite thin . Sometimes the knees are slightly flexed; at
other times the legs are fully extended or hyperextended
(genu recurvatum) and adducted. Weakness is variable
and difficult to estimate. Sphincteric function is usually
retained. Subtle sensory loss in the feet has been reported.
The arms are variably involved. In some patients, the
arms appear to be spared even though the tendon reflexes
are lively. In others, the hands are stiff, movements are
clumsy, and speech is mildly dysarthric. Conjoined find­
ings such as nystagmus, ocular palsies, optic atrophy,
pigmentary macular degeneration, ataxia (both cerebellar
and sensory), sensorimotor polyneuropathy, ichthyosis,
patchy skin pigmentation, epilepsy, and dementia have
all been described in isolated families (see further on) .
The few available pathologic studies have shown
that, in addition to degeneration of the corticospinal
tracts throughout the spinal cord, there is thinning of
the columns of Coil, mainly in the lumbosacral regions,
and of the spinocerebellar tracts, even when no sensory
abnormalities had been detected during life. These were
Childhood Guanylate-binding protein
20 ' s 40-50% of HSP; binds to m.icrotubules
Teens Golgi membrane protein
Childhood Kinesin heavy chain-motor protein
Adult Located in mitochondrial matri x
Variable Silver syndrome: HSP with wasting of hands, feet
Adult Mitochondrial chaperone and metalloprotease;
optic atrophy, neuropathy, myopathy
HSP with wasting of distal limbs, hands, feet
La te teens Endosomal protein involved in protein
transport
Infancy Developmental delay, hydrocephalus, callosal
hypoplasia, spasticity
Infancy Cognitive impainnent, spasticity, a taxia
the pathologic findings described by Strtimpell in his
original (1880) report of 2 brothers with spastic paraple­
gia; one of them, in addition, had a cerebellar syndrome,
but again, there were no sensory abnormalities. A reduc­
tion in the number of Betz and anterior horn cells has also
been reported.
Genetic Aspects of HereditanJ Spastic Paraplegia
Numerous genetic mutations have given rise to this dis­
ease. As of this writing, there were 52 hereditary spastic
paraplegia (HSP) loci many of which are shown in Table
39-8. The disease types have been renamed under the
designation "SPG" (for spastic paraplegia) and num­
bered in order of discovery of the associated gene. The
common uncomplicated autosomal dominant form of
disease has been linked to mutations in many proteins,
the most common being (proteins in parentheses) SPAST
(spas tin) and ALTl (atlastin); and the common recessive
varieties, are in SPG7 (paraplegin); and X-linked in
LlCAM and PLPl (proteolipid protein) . The common
spastin variety, associated with a mutation on chromo­
some 2p, results in great variability of clinical presenta­
tion within and among families (see Nielsen et al) . A
high frequency of partial deletions of the SPAST gene
has been found. The possible subcellular mechanisms
by which these mutations cause degeneration of the
corticospinal tracts have been reviewed by Blackstone.
Differential Diagnosis In the diagnosis of this dis­
order, one should consider an indolent spinal cord or
foramen magnum tumor, cervical spondylosis, a spinal
from of multiple sclerosis (this was the clinical diagnosis
in Strtimpell's original cases), Chiari malformation, com­
pression of the cord by a variety of congenital bony mal­
formations at the craniocervical junction, and a number
of chronic myelitides, among them, lupus erythematosus,
sarcoidosis, AIDS, adrenomyeloneuropathy, primary lat­
eral sclerosis (described earlier in this chapter), hypocupric
 CHAPTER 39
myelopathy, spinal arteriovenous dural fistula, and espe­
cially, tropical spastic paraparesis (caused by the HTLV-1
virus as discussed in Chap. 33).
Va r i a nts of Fa m i l i a l S pastic Pa ra p l e g i a
The literature contains a large number of descriptions of
familial spastic paraplegia combined with other neurologic
abnormalities. Some of the syndromes had developed early
in life in conjunction with moderate degrees of mental r etar­
dation. In these, the rest of the neurologic picture appeared
many years after birth and was progressive. Some idea
of the number of these "hereditary paraplegia-plus" syn­
dromes and the diverse combinations in which they may be
present is conveyed in the review by Gout and colleagues.
Again, it is hardly possible to describe each of these symp­
toms in any degree of detail. The list below includes the
best-known entities but all are rare. But if the term hereditan;
spastic paraplegia is to have any neurologic significance, it
should be applied only to the pure form of the progressive
syndrome. The more common "atypical" or "syndromic"
cases-with amyotrophy; cerebellar ataxia, tremors, dysto­
nia, athetosis, optic atrophy; retinal degeneration, amentia,
and dementia-should be put in separate categories and
their identity retained for nosologic purposes until such
time as additional biochemical and genetic data related to
pathogenesis are forthcoming. The gene mutations found in
some of the variant types have been summarized by Fink,
but-as with all types of uncomplicated hereditary spas­
tic paraplegia-the mechanisms of neuronal loss are not
known. To be separated from these cases are all the congeni­
tal nonprogressive types of spastic diplegia and athetosis.
The following list includes the best-known entities:
1. Hereditary spastic paraplegia with ataxia (Ferguson­
Critchley syndrome) This syndrome is one of a col­
lection of leg spasticity and generalized ataxia syn­
drome that may also be characterized by a disorder of
gaze, or optic atrophy. Most impressive are the mani­
festations of spinocerebellar ataxia beginning during
the fourth and fifth decades of life, accompanied by
weakness of the legs, alterations of mood, pathologic
crying and laughing, dysarthria and diplopia, dyses­
thesias of limbs, and poor bladder control. The ten­
don reflexes are lively; with bilateral Babinski signs.
Sensation is diminished distally in the limbs. The
whole picture resembles a chronic progressive form
of multiple sclerosis. In other cases, running through
several generations of a family, the extrapyramidal
features were more striking; such cases overlap with
the following syndromes. A dominant form of the
disease is due to a mutation in SAX1 .
2. Hereditary spastic paraplegia with extrapyramidal signs
Action and static tremors, parkinsonian rigidity, dys­
tonic tongue movement, and athetosis of the limbs have
all been conjoined with spastic paraplegia. Gilman and
Romanul have reviewed the literature on this subject.
In the authors' experience, the picture of parkinsonism
with spastic weakness and other corticospinal signs
has been the most frequent combination.
3. Hereditary spastic paraplegia with optic atrophy This
is known as Behr syndrome or optic atrophy-ataxia
syndrome, since cerebellar signs are usually con-
Degenerative Diseases of the Nervous System 1 1 21
joined. Some patients also have athetosis. The syn­
drome is transmitted as an autosomal recessive trait,
with onset in infancy and slow progression. The
mutation is in OPA3. There may be a relationship to
decreased excretion of 3-methylglutaconic aciduria
of an optic atrophy and cataract syndrome (Costeff
syndrome) .
4. Hereditary spastic paraplegia with macular degeneration
(Kjellin syndrome) Spastic paraplegia with amyotro­
phy, oligophrenia, and central retinal degeneration
constitutes the syndrome described in 1959 by Kjellin.
Although the developmental delay is stationary,
the spastic weakness and retinal changes are of late
onset and progressive. Mutations have been found in
SPG11 and SPG15.
5. Hereditary spastic paraplegia with developmental delay
or dementia Many of the children with progressive
spastic paraplegia either have been developmentally
delayed since early life or have appeared to regress
mentally as other neurologic symptoms developed.
Examples of this syndrome and its variants are too
numerous to be considered here but are contained in
the review by Gilman and Romanul. The autosomal
recessive syndrome of Sjogren-Larsson, with the onset in
infancy of spastic weakness of the legs in association
with developmental delay, stands somewhat apart
from the others in this large group because of the
associated ichthyosis. The mutation for the latter is
in ALDH3A2 that codes for fatty aldehyde dehydro­
genase. This relates to both dry skin, itchy and dis­
colored skin, and the myelinopathy that characterize
Sjogren-Larsson syndrome.
6. Hereditary spastic paraplegia with polyneuropathy Our
colleagues had observed several patients in whom
a sensorimotor polyneuropathy was combined with
unmistakable signs of corticospinal disease. The age
of onset was in childhood or adolescence, and the dis­
ability progressed to the point where the patient was
chairbound by early adult life. In two of the cases, a
sural nerve biopsy revealed a typical hypertrophic
polyneuropathy; in a third case there was only a deple­
tion of large myelinated fibers. The syndrome resem­
bles the myeloneuropathy of adrenoleukodystrophy.
7. Spastic paraparesis with distal muscle wasting (Troyer
S1Jndrome) This disorder is transmitted as an autoso­
mal recessive trait in the Amish population. Onset is
in childhood with amyotrophy of the hands, followed
by spasticity and contractures of the lower limbs.
Cerebellar signs (mild), athetosis, and deafness may
be added. The mutation is in SPG20.
SYNDROME OF PROGR ESSIVE
BLI N D N ESS (See Chap. 13)
There are 2 main classes of progressive blindness in chil­
dren, adolescents, and adults: progressive optic neuropa­
thy and retinal degenerations (retinitis pigmentosa and
tapetoretinal macular degeneration). Of course, there are
many congenital anomalies and retinal diseases beginning
1 1 22 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
in infancy that result in blindness and microphthalmia.
Some of those of neurologic interest were described briefly
in connection with the hereditary spastic paraplegias and
in Chap. 13.
Leber Heredita ry Optic Atrophy
Although familial amaurosis was known in the early
eighteenth century, it was Leber, in 1871, who gave
the definitive description of this disease and traced
it through many genealogies. The family studies of
Nikoskelainen and coworkers indicate that all daughters
of carrier mothers become carriers themselves, a type of
transmission that is determined by inheritance of defec­
tive mitochondrial DNA from the mother (Wallace et
al). Common to all cases is the presence of a pathogenic
mitochondrial DNA abnormality (Riordan-Eva et al), but
the defect may occur at one of several sites as discussed
in Chap. 37. Thus, Leber optic atrophy has been added
to the growing list of mitochondrial diseases. Mutations
in approximately 20 genes have been detected, together
accounting for about half of cases.
In most patients, the visual loss begins between 18
and 25 years of age, but the range of age of onset is much
broader. Usually the visual loss has an insidious onset
and a subacute evolution, but it may evolve rapidly, sug­
gesting a retrobulbar neuritis; moreover, in these latter
instances, aching in the eye or brow may accompany
the visual loss, just as it does in the demyelinative vari­
ety. Subjective visual phenomena are reported by some.
Usually both eyes are affected simultaneously, although
in some one eye is affected first, followed by the other
after an interval of several weeks or months. In practi­
cally all cases, the second eye is affected within a year of
the first. In the unimpaired eye, abnormalities of visual
evoked potentials may antedate impairment of visual
acuity (Carroll and Mastaglia) .
Once started, the visual loss progresses over a period
of weeks to months. Characteristically, central vision
is lost before peripheral, and there is a stage at which
bilateral central scotomata are readily demonstrated.
Early on, perception of blue-yellow is deficient, while
that of red and green is relatively preserved. In the more
advanced stages, however, the patients are totally color­
blind. Constriction of the fields may be added later. At
first there may be swelling and hyperemia of the discs,
but soon they become atrophic. Peripapillary vasculopa­
thy, consisting of tortuosity and arteriovenous shunting,
is the primary structural change; this has been present
also in asymptomatic offspring of carrier females.
As visual symptoms develop, fluorescein angiogra­
phy shows shunting in the abnormal vascular bed, with
reduced filling of the capillaries of the papillomacular
bundle. Although patients are left with dense central sco­
tomata, it is of some importance that the visual impair­
ment is seldom complete; in some patients, relative
stabilization of visual function occurs. In a few, there may
be a surprising improvement.
Examination of the optic nerve lesion shows the cen­
tral parts of the nerves to be degenerated from papillae
to the lateral geniculate bodies, that is the papillomacular
bundles are particularly affected. Presumably axis cyl­
inders and myelin degenerate together, as would be
expected from the loss of nerve cells in the superficial
layer of the retina. Both astrocytic glial and endoneuria!
fibroblastic connective tissue are increased. Tests for the 3
main mitochondrial mutations that give rise to the disor­
der are now available.
Congenital optic atrophy (of which recessive and
dominant forms are known), retrobulbar neuritis, and
nutritional optic neuropathy are the main considerations
in differential diagnosis.
Retinitis Pigmentosa (See Chap. 13)
This remarkable retinal abiotrophy, known to Helmholtz
in 1851, soon after he invented the ophthalmoscope,
usually begins in childhood and adolescence. Unlike
the optic atrophy of Leber, which affects only the third
neuron of the visual neuronal chain, retinitis pigmentosa
affects all the retinal layers, both the neuroepithelium
and pigment epithelium (see Fig. 13-2) . The incidence
of this disorder is 2 or 3 times greater in males than in
females. Inheritance is more often autosomal recessive
than dominant; in the former, consanguinity plays an
important part, increasing the likelihood of the disease by
approximately 20 times. Sex-linked types are also known.
It is estimated that 100,000 Americans are afflicted with
this disease. Mutations in approximately 60 genes have
been associated with the disorder but the most com­
monly affected in autosomal dominant cases is RHO;
in recessive cases, USH2A, and in X-linked cases, RPGR
and RP2.
The first symptom is usually an impairment of
twilight vision (nyctalopia). Under dim light, the visual
fields tend to constrict; but slowly, as the disease pro­
gresses, there is permanent visual impairment in all
degrees of illumination. The perimacular zones tend to
be the first and most severely involved, giving rise to
partial or complete ring scotomata. Peripheral loss sets in
later. Usually both eyes are affected simultaneously, but
cases are on record where one eye was affected first and
more severely. Ophthalmoscopic examination shows the
characteristic triad of pigmentary deposits that assume
the configuration of bone corpuscles, attenuated vessels,
and pallor of the optic discs. The pigment is caused by
clumping of epithelial cells that migrate from the pig­
ment layer to the superficial parts of the retina as the
rod cells degenerate. The pigmentary change spares only
the fovea, so that eventually the world is perceived by
the patient as though he were looking through narrow
tubes.
The many and diverse syndromes to which retinitis
pigmentosa may be linked include oligophrenia, obe­
sity, syndactyly, and hypogonadism (Bardet-Biedl syn­
drome); hypogenitalism, obesity, and mental deficiency
(Laurence-Moon syndrome); Friedreich and other types
of spinocerebellar and cerebellar ataxia; spastic paraple­
gia and quadriplegia with Laurence-Moon syndrome;
neurogenic amyotrophy, myopia, and color-blindness;
polyneuropathy and deafness (Refsum disease); deaf
mutism; Cockayne syndrome and Bassen-Kornzweig
 CHAPTER 39
disease; and several mitochondrial diseases, particularly
progressive external ophthalmoplegia and Kearns-Sayre
syndromes.
Sta rgardt Disease
This is a bilaterally symmetrical, slowly progressive
macular degeneration, differentiated from retinitis pig­
mentosa by Stargardt in 1 9 0 9 . In essence, it is a heredi­
tary (usually autosomal recessive) tapetoretinal degen­
eration or dystrophy (the latter term being preferred by
Waardenburg), with onset between 6 and 20 years of
age, rarely later, and leading to a loss of central vision.
The macular region becomes gray or yellow-brown with
pigmentary spots, and the visual fields show central
scotomata. Later the periphery of the retina may become
dystrophic. The lesion is well visualized by fluorescein
angiography, which discloses a virtually pathognomonic
"dark choroid" pattern. Activity in the electroretinogram
is diminished or abolished. Both recessively inherited
Stargardt disease and the closely related cone-rod dystro­
phy have been linked to mutations of ABCA4 or ELOVL4
the former codes for a transporter protein (termed ABCR)
of the photoreceptor.
This disease, with its selective loss of cone func­
tion, is in a sense the inverse of retinitis pigmentosa.
According to Cohan and associates, it may be associ­
ated with epilepsy, Refsum syndrome, Keams-Sayre
syndrome, Bassen-Kornzweig syndrome, or Sjogren­
Larsson syndrome, or with spinocerebellar and other
forms of cerebellar degeneration and familial paraplegia.
SYN D ROM E OF CONGEN ITAL
OR PROGRESSIVE DEAFNESS (See Chap. 15)
There is an impressive group of hereditary, progressive
cochleovestibular atrophies that are linked to degenera­
tions of the nervous system. These are the subject of an
informative review by Konigsmark and are summarized
below. Such neurotologic syndromes must be set along­
side a group of 5 diseases that affect the auditory and ves­
tibular nerves exclusively: dominant progressive nerve
deafness; dominant low-frequency hearing loss; domi­
nant midfrequency hearing loss; sex-linked, early-onset
neural deafness; and hereditary episodic vertigo and
hearing loss. The last of these is of special interest to neu­
rologists because both balance and hearing are affected.
It should be pointed out that in 70 percent of cases
of hereditary deafness, there are no other somatic or
neurologic abnormalities. To date, 3 separate autosomal
mutations have been identified that are associated with
this pure "nonsyndromic" type of hereditary deafness,
the most common of which is in the connexin gene, as
discussed in Chap. 15. A number of mitochondrial disor­
ders have been associated with deafness alone as well as
with a number of the better-characterized mitochondrial
syndromes (see Chap. 37) . The age of onset of hearing
loss in the pure forms has been variable, extending well
into adulthood.
Degenerative Diseases of the Nervous System 1 1 23
H e red ita ry H ea ri n g Loss With R eti n a l D i seases
Konigsmark has separated this overall category into 3
subgroups: patients with typical retinitis pigmentosa,
those with Leber optic atrophy, and those with other
retinal changes. With respect to retinitis pigmentosa, 4
syndromes are recognized in which retinitis pigmen­
tosa appears in combination: with congenital hearing
loss (Usher syndrome); with polyneuropathy (Refsum
syndrome); with hypogonadism and obesity (Alstrom
syndrome); and with dwarfism, mental retardation, pre­
mature senility, and photosensitive dermatitis (Cockayne
syndrome) .
Hereditary hearing loss with optic atrophy forms
the core of 4 special syndromes: dominant optic atrophy,
ataxia, muscle wasting, and progressive hearing loss
(Sylvester disease); recessive optic atrophy, polyneu­
ropathy, and neural hearing loss (Rosenberg-Chutorian
syndrome); optic atrophy, hearing loss, and juvenile dia­
betes mellitus (Tun-bridge-Paley syndrome); and optico­
cochleodentate degeneration with optic atrophy, hearing
loss, quadriparesis, and developmental delay (Nyssen­
van Bogaert syndrome).
Hearing loss has also been observed with other
retinal changes, two of which are Norrie disease, with
retinal malformation, hearing loss, and mental retarda­
tion (oculoacousticocerebral degeneration), and Small
disease, with recessive hearing loss, mental retardation,
narrowing of retinal vessels, and muscle atrophy. In the
former, the infant is born blind, with a white vascular­
ized retinal mass behind a clear lens; later the lens and
cornea become opaque. The eyes are small, and the iris is
atrophied. In the latter, the optic fundi shows tortuosity
of vessels, telangiectases, and retinal detachment. The
nature of the progressive generalized muscular weakness
has not been ascertained.
In this group should be included Susac syndrome,
ostensibly a microvasculopathy that causes character­
istic changes in the white matter of the cerebral hemi­
spheres, retinal vasculopathy, and progressive deafness
as discussed in Chap. 34. The later onset and progressive
nature of deafness in this and several other syndromes
are distinguished from forms of congenital deafness that
are typical of the group discussed below.
H e red ita ry H ea ri n g Loss with D i seases of t h e
N e rv o u s Syste m (See Table 15-1)
There are numerous conditions, mostly of childhood and
including developmental abnormalities, in which con­
genital deafness accompanies disease of the peripheral or
central nervous system. Those associated with mitochon­
drial encephalopathies have already been mentioned.
The other main types with autosomal inheritance include
the following:
1. Hereditary hearing loss with epilepsy The seizure disor­
der is mainly one of myoclonus. In one dominantly
inherited form, photomyoclonus is associated with
mental deterioration, hearing loss, and nephropathy
(Hermann disease). In May-White disease, also inher­
ited as an autosomal dominant trait, myoclonus and
1 1 24 Part 4 MAJOR CATEGORIES OF N E U ROLOG IC DISEASE
ataxia accompany hearing loss. Congenital deafness
and mild chronic epilepsy of recessive type have also
been observed (Latham-Monro disease).
2. Hereditary hearing loss and ataxia Here Konigsmark
was able to delineate 5 syndromes, the first 2 of
which show a dominant pattern of heredity, the
last 3 a recessive pattern: piebaldism, ataxia, and
neural hearing loss (Teller-Sugar-Jaeger syndrome);
hearing loss, hyperuricemia, and ataxia (Rosenberg­
Bergstrom syndrome); ataxia and progressive hear­
ing loss (Lichtenstein-Knorr syndrome); ataxia,
hypogonadism, mental deficiency, and hearing loss
(Richards-Rundle syndrome); ataxia, mental retarda­
tion, hearing loss, and pigmentary changes in the
skin Geune-Tommasi syndrome) .
3. Hereditary hearing loss and other neurologic syndromes
These include dominantly inherited sensory radicu­
lar neuropathy (Denny-Brown); progressive polyneu­
ropathy, kyphoscoliosis, skin atrophy, eye defects
(myopia, cataracts, atypical retinitis pigmentosa), bone
cysts, and osteoporosis (Flynn-Aird syndrome); chron­
ic polyneuropathy and nephritis (Lemieux-Neemeh
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