Disorders of Somatic

Sensation

CONTENTS
Approach to diagnosis, 200
Functional anatomy of the
somatic sensory pathways, 201
History, 201
Sensory examination, 202
Sensory changes & their signicance, 203
Distinction of organic & psychogenic sensory disturbances, 207
Peripheral nerve lesions, 208
Polyneuropathies, 212

Metabolic & nutritional neuropathies, 213

Infective & granulomatous
neuropathies, 215
Neuropathies in vasculitis &
collagen vascular disease,
216
Neoplastic & paraproteinemic neuropathies, 217
Drug-induced & toxic neuropathies, 218
Hereditary neuropathies, 219
Entrapment neuropathies, 221
Entrapment syndromes of
upper limbs, 221
Entrapment syndromes of
lower limbs, 222

Root & plexus lesions, 223

Compressive & traumatic
lesions, 223
Tabes dorsalis, 223
Lyme disease, 224
Myelopathies, 224
Syringomyelia, 224
Subacute combined degeneration (vitamin B12 deciency), 225
Cerebral disease, 225
Pain syndromes, 225
Peripheral nerve pain, 225
Radicular pain, 226
Thalamic pain, 226
Back & neck pain, 226

Idiopathic inammatory
neuropathies, 212

KEY CONCEPTS
The distribution of sensory symptoms and signs
often suggests their site of origin in the neuraxis,
and their temporal prole may suggest their
cause.

A dissociated sensory losswith abnormalities

of some but not other sensory modalitiesmay
occur with lesions of the central or peripheral
nervous system.

Sensory symptoms commonly precede sensory

signs; the absence of signs in a patient with sensory symptoms does not imply a psychogenic
basis of symptoms.

In patients with neck or back pain, structural

abnormalities on imaging studies must be interpreted cautiously as they may be an incidental
nding unrelated to the presenting complaint.

properly interpreting the history and clinical signs of

patients with disorders of somatic sensation. As used
APPROACH TO DIAGNOSIS
here, the term includes sensations of touch or
pressure,
vibration, joint position, pain, temperature, and more
An appreciation of the functional anatomy of the sencomplex functions that rely on these primary sensory
sory components of the nervous system is essential
modalities (eg, two-point discrimination,
for
200stereognosis,
Copyright 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.

DISORDERS OF SOMATIC SENSATION / 201

graphesthesia); it excludes special senses such ascells (touch); Krause end-bulbs (cold); and Rufni corsmell,
puscles (heat). The location of the rst central
vision, taste, and hearing.
synapse
depends upon the type of sensation but is either in
FUNCTIONAL ANATOMY OF THE
the
SOMATIC SENSORY PATHWAYS
posterior gray column of the spinal cord or in the upThe sensory pathway between the skin and deeperward extension of this column in the lower brainstem.
The second synapse is located in the anterior part of
structures and the cerebral cortex involves three neuthe anterolateral nucleus of the thalamus, from which
rons, with two synapses occurring centrally. The cell
there
body of the rst sensory neuron of the spinal nerve
is is sensory radiation to the cerebral cortex. In
the
in
spinal cord, bers mediating touch, pressure, and
the dorsal root ganglion (Figure 61). Each cell
poslocated
tural
there sends a peripheral process that terminates in
a sensation ascend in the posterior white columns
to the medulla, where they synapse in the gracile and
free
cuneate
nuclei (see Figure 61). From these nuclei,
nerve ending or encapsulated sensory receptor and
a
bers cross the midline and ascend in the medial
central process that enters the spinal cord. Sensory
lemreniscus to the thalamus. Other bers that mediate
ceptors are relatively specialized for particular sensations and, in addition to free nerve endings (pain),touch
inPrimary
and
those subserving pain and temperature appreciaclude
Meissner
corpuscles,
Merkel
corpuscles,
and
sensory
tion
synapse on neurons in the posterior horns of the
hair
cortex
spinal cord, particularly in the substantia gelatinosa.
The bers from these neurons then cross the midline
and ascend in the anterolateral part of the cord;
Thalamic
radiation
bers
mediating touch pass upward in the anterior
spinothalamic tract, whereas pain and temperature bers
Thalamus
gener(specific sensory
ally travel in the lateral spinothalamic tract (see
relay nuclei)
Figure
61). Fibers from this anterolateral system pass to the
thalamic
HISTORYrelay nuclei and to nonspecic thalamic proGracile and
Medial
jection
and the may
mesencephalic
reticular
formacuneate nuclei
Sensorynuclei
disturbances
consist of loss
of
lemniscus
tion.
Fibers
from
the
lemniscal
and
anterolateral
syssensation,
tems
are
joined
in
the
brainstem
by
bers
subserving
Gracile and
abnormal sensations, or pain.
sensation
from
the head.isCephalic
pain and
temperacuneate fasciculi
The term
paresthesia
used to denote
abnormal
Anterior
(posterior columns)
ture
sensation
are
dependent
upon
the
spinal
nucleus
spontaneous sensations, such as burning, tingling,
or
spinothalamic
of
tract
pins and needles. The term dysesthesia denotes any
Dorsal root
the
ganglion cell
un- trigeminal (V) nerve; touch, pressure, and
postural
pleasant sensation produced by a stimulus that is
Touch,
sensation
are conveyed mostly by the main sensory
Lateral
usupressure,
and
spinothalamic
ally painless. The term numbness is often used by pavibration,
tract
mesencephalic
nuclei
of this
nerve.
joint position
tients to describe
a sense
of heaviness,
weakness, or

deadness in the affected part of the bodyand sometimes to signify any sensory impairment; its meaning
Touch,
must be claried whenever the word is used.
pressure
In obtaining a history of sensory complaints, it is
Pain,
important to determine the location of the symptoms;
Midline
temperature
the mode of onset and progression of the symptoms;
Sensory nerve
whether the symptoms are constant or episodic in nature; whether any factors specically produce,
Figure 61. Sensory pathways conveying touch, pres- enhance,
sure, vibration, joint position, pain, and temperature
or relieve symptoms; and whether there are any
sensation.
accompanying symptoms.
The location of symptoms may provide a clue
to their origin. For example, sensory disturbances involving all the limbs suggest periph-

202 / CHAPTER 6
Posterior column
eral neuropathy, a cervical cord or brainstem lesion,
(touch, pressure,
or
vibration, joint position)
a metabolic disturbance such as hyperventilation syndrome. Involvement of one entire limbor of one side
GracileCuneate
of the bodysuggests a central (brain or spinal cord)
fasciculus fasciculus
lesion. A hemispheric or brainstem lesion may lead to
SL
TC
lateralized sensory symptoms, but the face is also
commonly affected. In addition, there may be other
symptoms and signs, such as aphasia, apraxia, and visual
eld defects with hemispheric disease, or dysarthria,
Lateral
S
weakness, vertigo, diplopia, disequilibrium, and spinothalamic tract
L
(pain,
temperature)
ataxia
T
with brainstem disorders. Involvement of part of a
C
limb
SLTC
or a discrete region of the trunk raises the possibility
of
Anterior spinothalamic tract
a nerve or root lesion, depending upon the precise
(touch, pressure)
distribution. With a root lesion, symptoms may show Figure 62. Location and lamination of sensory pathsome relationship to neck or back movements, and
ways in the spinal cord. C (cervical), T (thoracic), L (lumpain is often conspicuous.
bar), and S (sacral) indicate the level of origin of bers
The course of sensory complaints provides awithin each tract.
guide to their cause. Intermittent or repetitive
transient symptoms may represent sensory
seizures, ischemic phenomena, or metabolic disturbances such as those accompanying
hyperventilation.
Pinprick & Temperature
IntermittentEXAMINATION
localized symptoms that occur at a
SENSORY
Pinprick appreciation is tested by asking the patient
consisto
In
the
investigation
of
sensory
complaints,
various
tent time may suggest the diagnosis or an exogenous
indicate whether the point of a pin (not a hypodermic
modalities
are
tested
in
turn,
and
the
distribution
of
precipitating factor. For example, the pain and pareswhich is likely to puncture the skin and draw
any
abnormality
is
plotted
with
particular
reference
to
thesias of carpal tunnel syndrome (median nerve needle,
blood)
feels
sharp or blunt. Appreciation of pressure
the
normal
root
and
peripheral
nerve
territories.
Comcomor
plete
loss
of
touch
appreciation
is
anesthesia,
partial
pression at the wrist) characteristically occur at night
touch by the pinpoint must not be confused with the
loss
is hypesthesia,
and from
increased
and awaken
the patient
sleep.sensitivity is
appreciation of sharpness. Temperature appreciation
hyperesis
thesia. The corresponding terms for pain appreciation
evaluated by application to the skin of containers of
are analgesia, hypalgesia, and hyperalgesia or hyperpathia; allodynia refers to the misperception of a hot
or cold water. Pinprick and temperature appreciation
trivial
depend upon the integrity of the lateral spinothalamic
1.
PRIMARY
SENSORYas
MODALITIES
tactile
sensation
pain.
tracts (see Figures 61 and 62). The afferent bers
Light Touch
cross
front of the central canal after ascending for
Deepin
Pressure
two or three segments from their level of entry into
The appreciation of light touch is evaluated with a Deep pressure sensibility is evaluated by pressure on
the
wisp of cotton wool, which is brought down carefully
the
cord.
on a small region of skin. The patient lies quietly, with
tendons, such as the Achilles tendon at the ankle.
the eyes closed, and makes a signal each time theVibration
stimVibration appreciation is evaluated with a tuning fork
ulus is felt. The appreciation of light touch depends
(128 Hz) that is set in motion and then placed over a
on
bony prominence; the patient is asked to indicate
bers that traverse the posterior column of the spinal
whether vibration, rather than simple pressure, is felt.
cord in the gracile (leg) and cuneate (arm) fasciculi
Many healthy elderly patients have impaired
ipappreciasilaterally (Figure 61 and Figure 62), passing to the
tion of vibration below the knees.
medial lemniscus of the brainstem (Figure 63), and
on bers in the contralateral anterior spinothalamic
tract.

DISORDERS OF SOMATIC SENSATION / 203

A. Midbrain

Spinothalamic
tract

2. COMPLEX SENSORY FUNCTIONS

Romberg Test

The patient is asked to assume a steady stance with

feet
together, arms outstretched, and eyes closed and is
obMedial
served for any tendency to sway or fall. The test is
lemniscus
positive (abnormal) if unsteadiness is markedly increased
B. Pons
by
eye closureas
occurs, for example, in tabes
Two-Point
Discrimination
dorsalis. A
The
ability
toisdistinguish
touch joint
at two
positive
test
indicative simultaneous
of grossly impaired
neighboring
points
depends
upon
the
integrity
of the
posiSpinothalamic
central
and
peripheral
nervous
system,
the
degree
of
tract
tion sense in the legs.
separation of the two points, and the part of the body
that is stimulated. The patient is required to indicate
whether he or she is touched by one or two compass
Medial
points, while the distance between the points is
lemniscus
varied
in order to determine the shortest distance at which
they are recognized as different points. The threshold
for two-point discrimination approximates 4 mm at
C. Medulla
the
ngertips and may be several centimeters on the
back.
When peripheral sensory function is intact, impaired
Spinothalamic
two-point discrimination
suggests
disorder affecting
Graphesthesia,
Stereognosis,
&aBarognosis
tract
the sensory cortex.
Agraphesthesia, the inability to identify a number
traced on the skin of the palm of the hand despite
Medial
norlemniscus
mal cutaneous sensation, implies a lesion involving
Figure 63. Sensory pathways in the brainstem. In the the
contralateral parietal lobe. The same is true of
medulla, spinothalamic bers conveying pain and teminability
perature sensation are widely separated from medial lemniscal bers mediating touch and pressure; these path- to distinguish between various shapes or textures by
touch
(astereognosis)
or impaired ability to
ways converge as they ascend in the pons and midbrain.
Bilateral
Sensory Discrimination
distinguish
In
some patients
apparently
normal sensation,
between
differentwith
weights
(abarognosis).
simultaneous stimulation of the two sides of the body
reJoint Position
veals an apparent neglect of (or inattention to) sensaJoint position sense is tested by asking the patienttion
to from one side, usually because of some
indicate the direction of small passive movementsunderlying
of
the terminal interphalangeal joints of the ngers and
SENSORY
CHANGES
& THEIR
contralateral
cerebral lesion.
toes. Patients with severe impairment of joint position
SIGNIFICANCE
sense may exhibit slow, continuous movement of the
ngers (pseudoathetoid movement) when attempting It is important to determine the nature and disto hold the hands outstretched with the eyes closed.
tribution of any sensory change. Failure to nd
For clinical purposes, both joint position sense and
clinical evidence of sensory loss in patients with
the
sensory symptoms must never be taken to imply that
ability to appreciate vibration are considered to dethe symptoms have a psychogenic basis. Sensory
pend on bers carried in the posterior columns of the
sympcord, although there is evidence that this is not true
toms often develop well before the onset of sensory
for vibration.
signs.

204 / CHAPTER 6
Peripheral nerve

Nerve root

Ophthalmic branch
Trigeminal
Maxillary branch
Mandibular branch
Anterior cutaneous nerve of neck
Supraclavicular nerves

C3
P o s t.

C4

Mid. Ant.

T2

Axillary nerve

Medial cutaneous nerve of arm

Lateral cutaneous nerve of arm
(branch of radial nerve)

C5

T3
T4
T5
T6 thoracic
LateralAnterior
thoracic
rami rami T7
T8
T9
T10
T11
T12

T2

T1
C6

Medial cutaneous nerve of forearm

Lateral cutaneous nerve of forearm

Radial

L1

L1

C6

L2

Median

C8

Ulnar
Lateral femoral cutaneous
Obturator

C7

L3

Anterior femoral cutaneous

Lateral cutaneous nerve of calf

Saphenous

L4

L5

= Iliohypogastric

= Ilioinguinal

* = Genitofemoral

Superficial peroneal

Dorsal nerve of penis

Perineal nerve of penis

Sural

S1

Lateral and medial plantar

Deep peroneal

Figure 64. A: Cutaneous innervation (anterior view).The segmental or radicular (nerve root) distribution is shown
on the left side of the body, and the peripheral nerve distribution on the right side of the body.
(continued)

dicted on anatomic grounds because of overlap from

adjacent nerves. Moreover, depending upon the type
A. MONONEUROPATHY
of
In patients with a lesion of a single peripheral nerve,
lesion, the bers in a sensory nerve may be affected
sensory loss is usually less than would have been predifferently. Compressive lesions, for example, tend to affect preferentially the large bers that subserve
touch.

Peripheral Nerve Lesions

DISORDERS OF SOMATIC SENSATION / 205

Nerve root

Peripheral nerve

Great occipital
C2

Lesser occipital
Great auricular

C3

Posterior rami of cervical nerves

C4

Supraclavicular

T2

Axillary

T3
T4
T5
T6
T7
T8
T9
T10
T11
T12
L1

C5
T2

T1

Posterior
rami
thoracic rami
Lateral thoracic

Posterior cutaneous nerve of arm

Medial cutaneous nerve of arm
Lateral cutaneous nerve of forearm
Posterior cutaneous nerve of forearm

C6
X

L2

Medial cutaneous nerve of forearm

Posterior lumbar rami
Posterior sacral rami

S3
S4
S5

C6

Lateral cutaneous nerve of arm

Radial
Median
Ulnar

C7

C8

Lateral femoral cutaneous

Obturator
L
3

Anterior femoral cutaneous

S2

Posterior femoral cutaneous

Lateral cutaneous nerve of calf
X

= Iliohypogastric

L5

Superficial peroneal

L4

Saphenous
Sural

Calcaneal
S1

Lateral plantar
Medial plantar

Figure 64. (continued) B: Cutaneous innervation (posterior view).The segmental or radicular (nerve root)
distribution is shown on the left side of the body, and the peripheral nerve distribution on the right side of the body.
For
details of radial median, ulnar, peroneal, and femoral nerves, see Appendix C.

most to the knees before the hands are affected.

B. POLYNEUROPATHY
In patients with polyneuropathies, sensory loss is Certain
metabolic disorders (such as Tangier disease, a
generrecessive
ally symmetric and is greater distally than proximally
trait characterized by the near absence of high
density
as suggested by the term stocking-and-glove sensory
lipoproteins) preferentially involve small nerve bers
loss. As a general rule the loss will have progressed
that subserve pain and temperature appreciation.
alSen-

206 / CHAPTER 6
sory loss may be accompanied by a motor decit and
addition, weakness or paralysis of muscles supplied
reex changes.
by
the involved segments of the cord results from
damage
Root Involvement
to motor neurons in the anterior horn. With more exNerve root involvement produces impairment of cutatensive disease, involvement of the corticospinal
neous sensation in a segmental pattern (Figure 64A,
tracts
B),
in the lateral funiculi may cause a pyramidal decit
but because of overlap there is generally no loss ofbesensalow the lesion. There is relative preservation of postetion unless two or more adjacent roots are affected.
rior column function (Figure 66). Ischemic
In
patients with a cord lesion, there may be a
Pain
myelopathies caused by occlusion of the anterior
transverse
is often a conspicuous feature in patients with
spinal
sensory level. Physiologic areas of increased
compresartery take the form of anterior cord lesions.
sensitivity
sive root lesions. Depending on the level affected, D. POSTERIOR COLUMN LESION
do occur, however, at the costal margin, over the
there
A patient with a posterior column lesion may
breasts,
may
loss of tendon reexes (C56, biceps and braCordbe
Lesion
and in the groin,
and
theseL34,
must knee;
not beS1,
taken
as complain
chioradialis;
C78,
triceps;
ankle),
and
of
a tight or bandlike sensation in the regions correabnorif the anterior roots are also involved, there may be
sponding
to the level of spinal involvement and
mal.
Therefore,
the level
of a sensory
decit
affecting
weakness
and muscle
atrophy
(see Table
511).
somethe trunk is best determined by careful sensory
times also of paresthesias (like electric shocks)
testing
over the back rather than the chest and abdomen.radiating
down the extremities on neck exion (Lhermitte sign).
A. CENTRAL CORD LESION
With a central cord lesionsuch as occurs in sy- There is loss of vibration and joint position sense
below
ringomyelia, following trauma, and with certain cord
the level of the lesion, with preservation of other sentumorsthere is characteristically a loss of pain and
sory modalities. The decit may resemble that
temperature appreciation with sparing of other
resulting
modalifrom
involvement
Brainstem
Lesionof large bers in the posterior
ties. This loss is due to the interruption of bers conroots.
veying pain and temperature that cross from one side
Sensory disturbances may be accompanied by a
E.
CORD HEMISECTION
of
motor
Lateral
hemisection
of the
cord
leadsnerve
to Brownthe cord to the spinothalamic tract on the other. Such
decit, cerebellar
signs,
and
cranial
palsies
Squard
syndrome.
Below
the
lesion,
there is an
a
when
ipsilatloss is usually bilateral, may be asymmetric, and inthe lesion is in the brainstem.
decit
and involving
disturbed the
appreciation
of
volves only the bers of the involved segments. It eral
In pyramidal
patients with
lesions
spinothalamic
vimay
tract in the dorsolateral medulla and pons, pain and
and joint
position sense,
contralateral
be accompanied by lower motor neuron weaknessbration
temperature
in
appreciation
are lostwith
in the
limbs and
loss
the muscles supplied by the affected segments and
trunk on the opposite side of the body. When such a
sometimes by a pyramidal and posterior column of
le- pain and temperature appreciation that begins two
or
three
segments
below
the lesion
67).
decit
sion
is located
in the
medulla,
it also(Figure
typically
below the lesion (Figure 65).
involves
B. ANTEROLATERAL CORD LESION
the spinal trigeminal nucleus, impairing pain and
Lesions involving the anterolateral portion of the temspinal
perature sensation on the same side of the face as
cord (lateral spinothalamic tract) can cause contralatthe leeral impairment of pain and temperature appreciation
sion. The result is a crossed sensory decit that
in segments below the level of the lesion. The
affects
spinothalamic tract is laminated, with bers from the
the ipsilateral face and contralateral limbs. In
sacral segments the outermost. Intrinsic cord (in- contrast,
tramedullary) lesions often spare the sacral bers,spinothalamic lesions above the spinal trigeminal nuwhereas extramedullary lesions, which compress the
cleus affect the face, limbs, and trunk contralateral to
cord, tend to involve these bers as well as those the
lesion. Lesions
With lesions affecting the medial
Thalamic
arising
lemniscus,
Thalamic
lesions
mayand
leadproprioception
to loss or impairment
of all
from more rostral levels.
there is loss
of touch
on the oppoforms
of sensation
onInthe
side ofthe
the
C. ANTERIOR CORD LESION
site side
of the body.
thecontralateral
upper brainstem,
body.
With destructive lesions involving predominantly the
spinothalamic tract and medial lemniscus run
Spontaneous
pain, sometimes with a particularly unanterior portion of the spinal cord, pain and temperatogether
ture appreciation are impaired below the level of the
so that a single lesion may cause loss of all supercial
leand deep sensation over the contralateral side of the
sion from lateral spinothalamic tract involvement. body
In
(see Figure 63).

DISORDERS OF SOMATIC SENSATION / 207

Posterior column

Posterior column

Corticospinal tract

Corticospinal tract

Lateral spinothalamic tract

Lateral spinothalamic tract

Anterior spinothalamic tract

Anterior spinothalamic tract

Figure 66. Anterior cord lesion (blue) associated

with occlusion of the anterior spinal artery. Clinical features are similar to those seen with severe central cord
lesions (Figure 65B), except that posterior column sensory functions are spared and the defect in pain and
temperature sensation extends to sacral levels.

nize objects by touch or to estimate their size,

weight,
consistency, or texture. Cortical sensory disturbances
Figure 65. Central cord lesions (blue) of moderate (A)are usually more conspicuous in the hands than in
or marked (B) extent. Less extensive lesions impair painthe
and temperature appreciation by interrupting incoming trunk or proximal portions of the limbs.
B

DISTINCTION OF ORGANIC
sensory bers as they cross to the contralateral
spinothalamic tract; involvement of anterior horn cells & PSYCHOGENIC SENSORY
causes lower motor neuron weakness.These decits are
DISTURBANCES
restricted to dermatomes and muscles innervated by the
involved spinal cord segments. More extensive lesions Psychogenic disturbances of sensation may be
also produce disturbances of touch, pressure, vibration,associand joint position sense because of involvement of the
ated with such psychiatric disturbances as conversion
posterior columns and cause pyramidal signs because of
corticospinal tract involvement, especially affecting thedisorder. They may take any form but most often are
restricted to loss of cutaneous sensation. There may
arms (see lamination of corticospinal tract in Figure 53).
be
These decits occur below the level of the lesion.
several characteristic features.
Posterior column

Corticospinal tract

pleasant quality, may occur on the affected side. Patients may describe it as burning, tearing, knifelike, or
stabbing, but often have difculty characterizing it.
Any form of cutaneous stimulation can lead to painful
or unpleasant sensations. Such a thalamic syndrome
(Dejerine-Roussy syndrome) can also occasionally result from lesions of the white matter of the parietal
lobe
or from cord lesions.

Lesions of the Sensory Cortex

Lateral spinothalamic tract

Anterior spinothalamic tract

Figure 67. Cord lesion (blue) in Brown-Squard syn-

drome. Hemisection of the cord causes ipsilateral pyramiDisease limited to the sensory cortex impairs
dal dysfunction and impairment of posterior column
discrimisensory function below the level of the lesion and connative sensory function on the opposite side of thetralateral impairment of pain and temperature sensation
body. Thus, patients may be unable to localize stimuli
with an upper limit slightly below the level of the lesion.
on the affected side or to recognize the position of
different parts of the body. They may not be able to
recog-

208 / CHAPTER 6
Nonorganic sensory loss does not conform in itsB. MONONEUROPATHY MULTIPLEX
disIn this disorder, several individual nerves are
tribution to any specic neuroanatomic pattern. It affected,
may
usually at random and noncontiguously. Clinical
surround a bony landmark or involve an area dened
examby surface landmarks rather than innervation.
ination reveals a clinical decit attributable to
Indeed,
involveit is not uncommon for there to be an apparent loss
ment
of of one or more isolated peripheral nerves,
C.
POLYNEUROPATHY
sensation in one or more extremities, with the margin
except
This
denotes a disorder
in which
the function
of
occurring circumferentially in the axilla or groin; orwhenterm
mononeuropathy
multiplex
is extensive
and the
numerous
peripheral
nerves
is affected at the same
ganic sensory loss with such a margin is unusual. Orresulting decits
become
conuent.
time.
ganic peripheral sensory loss over the trunk or face
This leads to a predominantly distal and symmetric
does
not usually extend to the midline but stops 35 cmdecit, with loss of tendon reexes except when small
bers are selectively involved. Polyneuropathies are
besometimes subclassied according to the primary site
fore it, because of overlap in the innervation on the
at
two
which the nerve is affected. In distal axonopathies,
sides; with nonorganic disturbances, apparent
the
sensory
axon is the principal pathologic target; most polyneuloss commonly stops precisely at the midline.
ropathies
fall into this category. Myelinopathies are
There is often a sudden transition between areas
of
connonorganic sensory loss and areas with normal sensathat involve the myelin sheath surrounding
tion. By contrast, with organic disturbances, there ditions
is
the
usually an area of altered sensation between
axon. These disorders include acute idiopathic
insensitive
areas and adjacent areas with normal sensibility. polyneuropathy (Guillain-Barr syndrome), chronic inammaIn nonorganic disturbances, there may be a
tory demyelinating neuropathy, diphtheria, certain
dissociparaated loss that is difcult to interpret on an anatomic
basis. For example, there may be a total loss of neoplastic and paraproteinemic states, and various
hereditary conditions including metachromatic
pinprick
appreciation but preserved temperature sensation.leukodyMoreover, despite the apparent loss of posterior strophy, Krabbe disease, and types 1 and 3 CharcotMarie-Tooth hereditary motor and sensory neuropathy
column
A. SENSORY
DISTURBANCES
Findings
(CMT1
and
3). Finally, certain disorderstermed neufunction, the patient may be able to walk normallyClinical
or Involvement
of sensory bers can lead to
ronopathiesprincipally
affect nerve cell bodies in
maintain the arms outstretched without difculty or
numbness and impaired sensation. It can also
the
pseudoathetoid movements.
lead to abnormal spontaneous sensations, such
anterior horn of the spinal cord or dorsal root
In nonorganic sensory disturbances, appreciation
as pain and paresthesias, and to perverted
ganglion.
of
sensations
are type 2 Charcot-Marie-Tooth hereditary
vibration may be impaired on one side but not theExamples
such as hyperpathia.
motor and sensory neuropathy, pyridoxine-induced
other
1. Pain is a conspicuous feature of certain neuneuside of a bony midline structure, such as the skull or
ropathies, especially if small bers within the nerves
ropathy, and some paraneoplastic syndromes.
sternum.
The vibrations
are LESIONS
in fact conducted to both
PERIPHERAL
NERVE
are
sides by the bone, so that even if there is a
affected. The precise mechanism of its genesis is unhemisensory
clear. Polyneuropathies associated with prominent
Sensory
symptoms
are usually
conspicuous
disturbance,
the vibrations
are a
appreciated
onfeature
either
pain
in
side
include those related to diabetes, alcoholism, porpatients
with
peripheral
nerve lesions
(Table 61).
in patients
with
organic sensory
disorders.
phyria, Fabry disease, amyloidosis, rheumatoid arthriSenFinally, it should be noted that sensory
tis, and acquired immunodeciency syndrome (AIDS),
sory
impairment may be in a distal stocking-anddisturbances
as well as dominantly inherited sensory neuropathy
glove
are often suggested to the patient by the examiners
and
pattern
in patients with polyneuropathies or may folown
paraneoplastic sensory neuronopathy. Pain is also a
Classication
low
the pattern
of individual
peripheral
nerves in paexpectations.
Such
ndings can
be particularly
featients
with mononeuropathies.
misleadA. MONONEUROPATHY SIMPLEX
ture of many entrapment neuropathies and of idioing
they may
be neuroanatomically
correct.
Thisbecause
term signies
involvement
of a single peripheral
pathic brachial plexopathy.
One
helpful approach is to have the patient outline on
nerve.
2. Dissociated sensory loss is impairment of some
the body the extent of any perceived sensory distursensory modalities, such as pain and temperature,
bance before formal sensory testing is undertaken.with
preservation of others, such as light touch, vibration,
and joint position sense. Although the presence of a

DISORDERS OF SOMATIC SENSATION / 209

Table 61. Causes of peripheral neuropathy.
Idiopathic inammatory neuropathies
Drug-induced and toxic neuropathies
Acute idiopathic polyneuropathy (Guillain-Barr
Alcohol
syndrome)
Other drugs (see Table 62)
Chronic inammatory demyelinating polyneuropathy Toxins
Metabolic and nutritional neuropathies
Organic compounds
Diabetes
Hexacarbons
Other endocrinopathies
Organophosphates
Hypothyroidism
Heavy metals
Acromegaly
Arsenic
Uremia
Lead
Liver disease
Thallium
Vitamin B12 deciency
Gold
Infective and granulomatous neuropathies
Platinum
AIDS
Tryptophan (contaminant)
Leprosy
Hereditary neuropathies
Diphtheria
Idiopathic
Sarcoidosis
Hereditary motor and sensory neuropathies
Sepsis and multiorgan failure
Hereditary sensory neuropathies
Vasculitic neuropathies
Friedreich ataxia
Mixed connective tissue disease
Familial amyloidosis
Polyarteritis nodosa
Metabolic
Rheumatoid arthritis
Porphyria
Systemic lupus erythematosus
Metachromatic leukodystrophy
Neoplastic and paraproteinemic neuropathiesc
Krabbe disease
Compression and inltration by tumor
Abetalipoproteinemia
Paraneoplastic syndromes
Tangier disease
Paraproteinemias
Refsum disease
Amyloidosis
Fabry disease
Entrapment neuropathiese

dissociated sensory loss often indicates a spinal cord

C. TENDON REFLEXES
leThese are impaired or lost if reex arcs are
sion, it also occurs in peripheral neuropathies when
interrupted
there is selective involvement of peripheral nerve on either the afferent or efferent side (C56, biceps
bers
and
of a certain size, such as occurs in amyloid
brachioradialis; C78, triceps; L34, knee; S1, ankle).
neuropathy,
The ankle reexes are usually the rst to be lost in
leprous neuritis, or hereditary sensory neuropathy.paIn
D.
DISTURBANCES
such cases, preferential involvement of small bers
tients
isAUTONOMIC
with polyneuropathies,
but may be absent in
Autonomic
disturbances
commonly
associated with disproportionate impairhealthy elderly
subjects. may be particularly
B.
MOTOR DEFICITS
conspicumentmotor
of pain
and temperature
appreciation,
spontaThe
decit
that occurs with
a peripheral
nerve
ous in some peripheral neuropathiesespecially Guilneous
pain,
and
autonomic
dysfunction.
Large-ber
lelain-Barr syndrome and neuropathies related to diadisease,
by
contrast,
results
in
defective
touch,
vibrasion consists of weakness of muscles innervated by
renal failure, porphyria, or amyloidosis.
tion, and joint position sense, early loss of tendon betes,
rethe
Symptoms
include postural hypotension, coldness of
exes, accompanied
and prominentinmotor
symptoms.
nerve,
severe
cases by wasting and
the
extremities,
impaired thermoregulatory sweating,
fascicdisturbances
of
bladder
and bowel function, and
ulation. There may be difculty in the performance of
impone tasks; this is compounded by any accompanying
E. ENLARGED NERVES
tence.
senPalpably enlarged peripheral nerves raise the
sory loss. The clinical ndings reect a lower motor
possibility
neuleprosy, amyloidosis, hereditary motor and sensory
ron decit, and it is the distribution of these signs of
and
neuropathies,
Refsum disease, acromegaly, or
the
chronic
presence of accompanying sensory and reex
inammatory demyelinating polyneuropathy.
changes that
suggest they may be due to peripheral nerve
involvement.

210 / CHAPTER 6
pecially important and may take the form of an
entrapA. TIME COURSE
ment mononeuropathy, acute ischemic mononeuritis,
Polyneuropathy that develops acutely over a few distal sensorimotor polyneuropathy, subacute
days
proximal
usually relates to an inammatory process, as in the
motor polyradiculopathy (diabetic amyotrophy),
Guillain-Barr syndrome. It may also relate to an unthoraderlying neoplasm, to infections such as diphtheria,
coabdominal radiculopathy, or autonomic neuropathy.
to
2. A peripheral neuropathy may also relate to an
metabolic disorders such as acute intermittent por-unphyria, or to exposure to such toxic substances as derlying malignant neoplasm. The peripheral nerves,
thalspinal nerves, and limb plexuses may be compressed
lium or triorthocresyl phosphate. A chronic course or
with
inltrated by extension of primary tumors or
a gradual evolution over several years is typical ofmetastatic
many
lymph nodes. Neoplastic disease can also lead to a
hereditary or metabolic polyneuropathies but also noncharmetastatic (paraneoplastic) sensory or sensorimotor
acterizes chronic inammatory demyelinating
polyneuropathy or to Lambert-Eaton syndrome, a dispolyneuorder of neuromuscular transmission discussed in
B.
AGE AT ONSET
ropathy.
Chapter 5.
Polyneuropathies
develop
during
childhood
or
Mononeuropathythat
of acute
onset
is likely
to be trau3. Certain connective tissue disorders, especially
early
life often
have a whereas
hereditary
basis,
but they
maticadult
or ischemic
in origin,
one
evolving
polyarteritis nodosa, rheumatoid arthritis, Churgmay
grad-also relate to an underlying inammatory
Strauss syndrome, and Wegener granulomatosis, may
disorder.
ually is more likely to relate to entrapment (ie, combe
Those
developing
in lateranatomic
life are more
likely toorbe
pression
by neighboring
structures)
toassociated with mononeuropathy multiplex or, less
due
recurrent minor trauma.
comto a metabolic, toxic, or inammatory disorder or to
monly, polyneuropathy or cranial neuropathy.
an
Polyneuunderlying neoplasm.
ropathy is more common in systemic lupus
Mononeuropathy presenting in the neonatal period
erythematois likely to be developmental in origin or related to
sus. Patients with rheumatoid arthritis are particularly
birth injury; one developing in later life may relate to
likely to develop focal entrapment or compressive
entrapment
or injury
C.
OCCUPATIONAL
HISTORYthat is often occupationally E.
DRUG AND ALCOHOLin
HISTORY
mononeuropathies
the vicinity of the affected
deterVarious industrial substances can lead to peripheral
Some
of
the
drugs
that
cause peripheral neuropathy
joints.
mined.
neuropathy, including carbon disulde, n-hexane, are4. AIDS is commonly associated with a distal, symethshown
Table 62;
there polyneuropathy.
may be selectivePeripheral
metric,in
primarily
sensory
ylene oxide, methyl bromide, acrylamide,
involvement
nerve involvement in AIDS less frequently takes the
F.
Fmotor
AMILY Bor
ACKGROUND
triorthocresyl
of
sensory
bers with
some drugs.
form
of an acute
or chronic
inammatory
demyelinatCertain polyneuropathies have a hereditary basis.
phosphate and certain other organophosphates, DDT,
ing polyneuropathy, polyradiculopathy,
arsenic, lead, and thallium. A mononeuropathy is These
mononeuropaare discussed later in this chapter in the section on
sometimes the rst clinical manifestation of an
thy multiplex, or autonomic neuropathy. Neuropathies
hereditary neuropathies.
occupaare also seen in patients with AIDS-related complex,
tionally related polyneuropathy, but it may also asymptomatic human immunodeciency virus-1
Differential Diagnosis
develop
(HIV-1)
infection,
and HIV-1
Peripheral
neuropathies
canseroconversion.
lead to a motor or
in response to entrapment or recurrent minor occupasensory
tional trauma. For example, carpal tunnel syndrome
decit or both. The preservation of sensation and tenis
don reexes distinguishes the motor decit that
more common in persons who do heavy manual labor
results
or develop repetitive motion injury as a result of comfrom pure pyramidal lesions or is associated with
puter terminal use, and a lesion of the deep palmar
branch
of the
ulnar nerve may relate to repeated spinal
D.
MEDICAL
HISTORY
pres1. Peripheral neuropathy may relate to metabolicmuscular atrophies, myopathies, or disorders of
neurosure on the
palm
the hand
by, for uremia,
example,
disorders
such
as of
diabetes
mellitus,
liver dismuscular transmission from that caused by peripheral
punching
ease,
myxedema, acromegaly, metachromatic
nerve involvement. Other distinguishing features are
down heavily on a stapler or using heavy equipment
leukodysin Chapter 5.
such as or
a pneumatic
roadThat
drill.caused by diabetes discussed
trophy,
Fabry disease.
is
Myelopathies
are characterized by a pyramidal
esdecit below the level of the lesion as well as by
distal
sensory loss.

Evaluation of Patients

DISORDERS OF SOMATIC SENSATION / 211

no evidence of denervation, but there is conduction
block or marked slowing of maximal conduction
velocity in affected nerves. In the axonal neuropathies,
Sensory neuropathy
elecChloramphenicol
tromyography shows that denervation has occurred,
Cisplatin
esPyridoxine
Taxol
pecially distally in the extremities, but maximal nerve
Taxotere
conduction velocity is normal or slowed only slightly.
Predominantly sensory neuropathy
In patients with electrophysiologically conrmed
Ethambutol
peripheral neuropathy, laboratory studies should inHydralazine
clude a complete blood count; erythrocyte
Misonidazole
sedimentaMetronidazole
tion rate; serum urea nitrogen and creatinine, fasting
Motor neuropathy
blood glucose, and serum vitamin B12; serum protein,
Dapsone
protein electrophoresis, and immunoelectrophoresis;
Imipramine
Certain sulfonamides
liver and thyroid function blood tests; serologic tests
Mixed sensory and motor neuropathy
for syphilis (FTA or MHA-TP), rheumatoid factor, and
Amiodarone
antinuclear antibody; and chest x-ray. Depending on
Chloroquine
the clinical circumstances, serologic tests for Lyme
Disulram
disGold
ease, hepatitis, or infection with human immunodeIndomethacin
ciency virus may be required. Genetic studies may
Isoniazid
also
Nitrofurantoin
Treatment of the underlying cause may limit the probe
necessary
counseling.
Penicillamine
gression
of or after
even appropriate
reverse the genetic
neuropathy.
NursingIf
Perhexilene
toxic
causes
are
suspected,
a
24-hour
urine
collection
care
Phenytoin
followed
by
analysis
for
heavy
metals
may
be
is
important in patients with severe motor or sensory
Treatment
Thalidomide
necessary,
decits
to prevent decubitus ulcers, joint
Tryptophan (contaminant)
and
hair
and ngernail clippings can be analyzed for
contractures,
Vincristine
arand additional compressive peripheral nerve damage.
senic.
Examination
a fresh
of urine
for
Respiratory
functionofmust
alsospecimen
be monitored
careporphobilinogen
and

acid
is
fullyparticularly in acute idiopathic polyneuropathy
necessary
(Guillain-Barr syndrome), chronic inammatory deif
porphyria is
suspected.
myelinating
polyneuropathy,
and diphtheritic
neuropaIn tabes dorsalis, there is often a history of
thyand preparations must be made to assist
syphilitic
ventilainfection, and examination reveals other stigmas of
syphilis. In addition, tactile sensation is preserved.tion if the vital capacity falls below about 1 L. In
patients with severe dysesthesia, a cradle (inverted
Radiculopathies are distinguished from peripheral
metal bar frame) can be used to keep the bedclothes
neuropathies by the distribution of motor or sensory
decits (see Figure 64A, B). The presence of neckfrom
or touching sensitive areas of the skin. Treatment
Laboratory
studies
in
patients
with
peripheral
with
phenytoin, 300 mg/d, carbamazepine, up to
back pain that radiates to the extremities in a
neuropa1200
radicular
thy
are directed
at
conrming
the
diagnosis and mg/d, or mexiletine, 600900 mg/d is sometimes
distribution
also
suggests
a root
lesion.
Investigative
Studies
revealhelping any underlying cause. Electromyography may ful in relieving the lancinating pain of certain neureveal
ropathies. If the pain is more constant, burning, or
evidence of denervation in the affected muscles and
dysesthetic, amitriptyline 25100 mg at bedtime is ofcan
ten helpful as are other tricyclic agents. Gabapentin
be used to determine whether any motor units
(300 mg three times daily, with subsequent
remain
increments
under voluntary control. Nerve conduction studies depending on response and tolerance) is effective in
pertreating various neuropathic pain disorders; pain
mit conduction velocity to be measured in motor and
relief
sensory bers. On the basis of electrodiagnostic ormay similarly occur with lamotrigine, topiramate, or
histopathologic studies, peripheral neuropathies can
sodium valproate, but this has been documented less
be
well and in some clinical studies these medications
divided into demyelinating or axonal neuropathies.have
In
the former, electromyography typically reveals little
been ineffective. Topical capsaicin is also helpful in
or
neuropathic pain syndromes.
Table 62. Selected drugs inducing peripheral
neuropathy.

212 / CHAPTER 6
Extremities with sensory loss must be protectedTable 63. Diagnostic criteria for Guillain-Barr
syndrome.1
from repeated minor trauma, such as thermal injury,
that can destroy tissues. The temperature of hot surfaces should be checked with a part of the body inRequired for diagnosis
which sensation is preserved, and the setting of
Progressive weakness of more than one limb
water
Distal areexia with proximal areexia or hyporeexia
heaters must be reduced to prevent scalding. The Supportive of diagnosis
Progression for up to 4 weeks
skin
Relatively symmetric decits
and nails must be cared for meticulously.
Mild sensory involvement
Dysautonomic symptoms may be troublesome, esCranial nerve (especially VII) involvement
pecially in diabetic or alcoholic polyneuropathy.
Recovery beginning within 4 weeks after progression
Waiststops
high elastic hosiery, dietary salt supplementation, Autonomic dysfunction
and
No fever at onset
treatment with udrocortisone, 0.11 mg/d orally, Increased CSF protein after 1 week
may
CSF white blood cell count
help relieve postural hypotension, but the patient Nerve conduction slowing or block by several weeks
must
Against diagnosis
Markedly asymmetric weakness
be monitored carefully to prevent recumbent
Bowel or bladder dysfunction (at onset or persistent)
hypertension. Other medications that may be helpful includeCSF white blood cell count or PMN count
Well-demarcated sensory level
clonidine, midodrine, dihydroergotamine, octreotide,
POLYNEUROPATHIES
diagnosiss
or beta-blockers. Instructing the patient to sleep inExcluding
a
Isolated
sensory
involvement
semierect rather than a recumbent position is helpful
Another polyneuropathy that explains clinical picture
because dysautonomic patients are often unable to
IDIOPATHIC INFLAMMATORY
1
AdaptedfromAsburyAK,CornblathDR:Assess
conNEUROPATHIES
mentofcurrentdiagnosticcriteriaforGuillain
serve salt and water when recumbent at night.

Acute Idiopathic Polyneuropathy

(Guillain-Barr Syndrome)

Barrsyndrome.AnnNeurol
1990;27(Suppl):S21S24.

Guillain-Barr syndrome is an acute or subacute

polyneuropathy that can follow minor infective ill- marked autonomic dysfunction, with tachycardia, cardiac irregularities, labile blood pressure, disturbed
nesses, inoculations, or surgical proceduresor may
sweatocing, impaired pulmonary function, sphincter disturcur without obvious precipitants. Clinical and
bances, paralytic ileus, and other abnormalities.
epidemiB. INVESTIGATIVE STUDIES
ologic evidence suggests an association with
The CSF often shows a characteristic abnormality,
preceding
Campylobacter jejuni infection. Its precise cause iswith
increased protein concentration but a normal cell
uncount; abnormalities may not be found in the rst
clear, but it appears to have an immunologic basis.
week, however. Electrophysiologic studies may reveal
Both
marked slowing of motor and sensory conduction vedemyelinating and axonal forms have been
locity, or evidence of denervation and axonal loss.
recognized,
A. CLINICAL FEATURES
The
with distinctive clinical and electrophysiologic
The features useful for diagnosing Guillain-Barr syntime course of the electrophysiologic changes does
features.
drome are summarized in Table 63. Patients
The demyelinative form is more common in the not
generally
necessarily parallel any clinical developments. When
United
present with weakness that is symmetric, usually HIV-1 infection is suspected because of the clinical
States, but an axonal variant is encountered
begins
context in which the neuropathy has developed or
occasionally
in the legs, is often more marked proximally than disC.
theTREATMENT
(acute motor sensory axonal neuropathy). In northern
tally, and is sometimes so severe that it is lifePlasmapheresis appears to reduce the time required
China a related axonal form occurs frequently and presence of high-risk factors, appropriate serologic
threatening,
for
studies should be performed.
has
especially if the muscles of respiration or swallowing
recovery and may decrease the likelihood of residual
been designated acute motor axonal neuropathy.
are
neuinvolved. Muscle wasting develops if axonal
rologic decits. It is best instituted early, and it is
degeneration
indihas occurred. Sensory complaints, while usually less
cated especially in patients with a severe or rapidly
marked than motor symptoms, are also frequent. The
prodeep tendon reexes are typically absent. There may
gressive decit or respiratory compromise.
be
Intravenous

DISORDERS OF SOMATIC SENSATION / 213

64. Clinical features of chronic
immunoglobulin (400 mg/kg/d for 5 days) appearsTable
to
inammatory demyelinating polyneuropathy.1
be
equally effective and should be used in preference to
plasmapheresis in adults with cardiovascular
Percentage of
instability
Patients
and in children; the two therapies are not additive.
Weakness, hyporeexia, or areexia
94
Therapy is otherwise symptomatic, the aim being
Distal upper extremity
85
to
85
prevent such complications as respiratory failure or Distal lower extremity
Proximal upper extremity
74
vascuProximal lower extremity
68
lar collapse. For this reason, patients who are
Respiratory muscles
11
severely afNeck
4
fected are best managed in intensive care units,
Face
2
where faSensory decit on examination
cilities are available for monitoring and assisted
Distal lower extremity
83
Distal upper extremity
respiration
68
Paresthesia
if necessary (eg, if the vital capacity falls below about
D.
Upper extremity
1 L,PROGNOSIS
79
Symptoms
and
signs
cease
to
progress
by
about
4
the patient is short of breath, or the blood oxygen Lower extremity
72
weeks
Face
satura6
Pain
into
the
illness.Volume
The disorder
is self-limiting,
and imtion
declines).
replacement
orpolyneuropathy
treatment
with
Chronic
inammatory
demyelinating
Lower
extremity
provement
occurs
over the weeks
or months
pressor
agents
is sometimes
required
to counter
17
Upper extremity
is
following
hypoten15
Dysarthria
clinically
similar
to
Guillain-Barr
syndrome
except
onset.
About
7075%
of patients
recover
completely,
sion,
and
low-dose
heparin
may help
to prevent
pul9
Dysphagia
that
25%
areembolism.
left with mild
neurologic decits,
and the
5% outdie,
9
monary
Corticosteroids
may
affect
Impotence
it
follows
progressive
courseor
a course
usually
asaachronic
result
of
respiratory
failure.
The
4
Incontinence
come
adversely
or
delay
recovery,
and
are
not
charprognosis
2
indicated.
acterized
by relapsesand
no improvement
is poorer when
there is evidence
of precedingisCampyapparent
lobacter jejuni infection, and a more protracted 1AdaptedfromDyckPJetal:Chronicinflamma
within
coursethe 6 months after onset. Its cause is not torypolyradiculopathy.MayoClinProc
known.
and less complete recovery are also likely when 1975;50:621637.
Its
clinical features are summarized in Table 64.
axonal
Examidegeneration rather than demyelination is the
is in
another effective immunomodulator therapy, but is
nation
the CSF revealsDemyelinating
ndings resembling those
Chronic
primaryof Inammatory
more
difcult to administer. In nonresponsive
Guillain-Barr
syndrome.
Polyneuropathy
pathology. Advanced
age,The
theelectrophysiologic
need for ventilatory patients,
ndings
suptreatment with azathioprine or cyclophosphamide
indicate
a demyelinative
with
port, or more
rapid onset neuropathy
of symptoms
may also premay be
superimposed
dict a poorer prognosis.
helpful but claims of benet from these agents or
axonal degeneration. The disorder is often responsive
from
to
cyclosporine, interferon-beta, or interferon-alpha
treatment with corticosteroids (prednisone, 60100
METABOLIC
& NUTRITIONAL
require
mg/d
conrmation
by
randomized trials.
NEUROPATHIES
for 24 weeks, then gradually tapered to 520 mg
Diabetes Mellitus
every
other day), which may have to be continued on a
Peripheral nerve involvement in diabetes is common
longand may be characterized by polyneuropathy, which
term basis. Treatment with intravenous
is
immunoglobulin
of mixed (sensory, motor, and autonomic) character
(1 g/kg daily for 2 days with a single additional
in
infusion
at 3 weeks, or 400 mg/kg/d for 5 consecutive daysabout
for 70% of cases and predominantly sensory in
about 30%; mononeuropathy multiplex; or mononeua
total of 2 g, with subsequent courses as needed toropathy simplex (Table 65). Such clinical manifestations can occur in isolation or in any combination. The
mainincidence of peripheral nerve involvement may be intain benet) is also effective as initial or later therapy.
uenced by the adequacy of diabetes control, which
When used as the initial therapy, it has the
A.
CLINICAL
EATURES
should,
in F
any
event, be optimal.
advantage of
fewer side effects (but greater expense) than
prednisone.
Its precise mode of action is unknown. Plasma
exchange

214 / CHAPTER 6
complications of diabetes except when the patient
has
an entrapment neuropathy and may benet from a
deType
Distribution
compressive procedure. The role of growth factors in
treatment is currently under study. Pain is
Polyneuropathy
Mixed sensory, motor, and Symmetric, distal, lower troublesome
autonomic
upper limbs
in some patients and responds to the measures
Primarily sensory
outlined
earlier (p. 211).
Mononeuropathy multiplex
Variable
Postural hypotension may respond to treatment
Polyradiculopathy/plexopathy
with salt supplementation; sleeping in an upright
(Diabetic amyotrophy)
Asymmetric, proximal
posi(pelvic girdle and thighs) tion; wearing waist-high elastic hosiery; udrocortisone, 0.11
mg/d; and midodrine (an 10
Other
Endocrinopathies
Thoracoabdominal
Chest, abdomen
mg
three
times
daily. Treatment is otherwise symptoradiculopathy
Hypothyroidism is a rare cause of polyneuropathy.
matic. Diabetic amyotrophy and mononeuropathy
More commonly, hypothyroidism is associated with
Mononeuropathy simplex
simenPeripheral
Ulnar, median, radial,
plex usually improve or resolve spontaneously.
trapment neuropathy, especially carpal tunnel
lateral femoral cutaneous, sciatic, persyndrome
oneal, other nerves
(see later, under Median Nerve). Polyneuropathy may
Oculomotor (III)
Cranial
be
abducens (VI)
mistakenly diagnosed in patients with proximal limb
trochlear (IV)
weakness caused by hypothyroid myopathy or in paFacial nerve
tients with delayed relaxation of tendon reexes, a
clasThe most common manifestation is a distal sensory
sic manifestation of hypothyroidism that is
or
independent
mixed polyneuropathy, which is sometimes
of neuropathy. Other neurologic manifestations of hydiagnosed,
pothyroidism such as acute confusional state (see
before it becomes symptomatic, from the presenceChapof
depressed tendon reexes and impaired appreciation
ter 1), dementia (see Chapter 1), and cerebellar
of
degenervibration in the legs. Symptoms are generally more
ation (see Chapter 3) are discussed elsewhere.
Uremia
common in the legs than in the arms and consist of Acromegaly also frequently produces carpal tunnel
numbness, pain, or paresthesias. In severe cases, A
symmetric
sensorimotor
polyneuropathy,Because
predomisyndrome
and,
less often, polyneuropathy.
there is
nantly
axonal
in
type,
may
occur
in
uremia.
many acromegalic patients are also diabetic,It ittends
may
distal sensory loss in all limbs and some
to
be
accompanying
affect
the
more than
the
arms and
is more redifcult
to legs
determine
which
disorder
is primarily
motor disturbance. Diabetic dysautonomia leads to
marked
sponsible for polyneuropathy in a given patient.
many symptoms, including postural hypotension, disdistally than proximally. Restless legs, muscle
turbances of cardiac rhythm, impaired thermoregulacramps,
tory sweating, and disturbances of bladder, bowel,and burning feet have been associated with it. The
gasextric, and sexual function. Diabetic mononeuropathy
tent of any disturbance in peripheral nerve function
multiplex is usually characterized by pain and
apweakness
pears to relate to the severity of impaired renal funcand often has a vascular basis. The clinical decit tion.
will The neuropathy itself may improve markedly
depend on the nerves that are affected. Diabetic with
amyrenal transplantation. Carpal tunnel syndrome (see
otrophy is due to radiculoplexopathy, polyradiculopalater)
also been described in patients with renal
Liver has
Disease
thy, or polyradiculoneuropathy. Pain, weakness, and
disPrimary
cirrhosisdistal
may lead
toarteriovenous
a sensory
atease andbiliary
may develop
to the
neuroparophy of pelvic girdle and thigh muscles are typical,
stulas
B. TREATMENT AND PROGNOSIS
thatinisthe
probably
offor
theaccess
axonalduring
type. A
predomiwith absent quadriceps reexes and little sensory thy
placed
forearm
hemodialysis.
No specic treatment exists for the peripheral nerve
nantly
demyelinative
polyneuropathy
can
occur in paloss.
In
tients
with
chronic
liver
disease.
There
does
not to
Diabetic mononeuropathy simplex is typically abrupt
patients on chronic hemodialysis, it often relates
appear
in onset and often painful. Cerebrospinal uid (CSF)
amyloidosis and the accumulation of 2protein is typically increased in diabetic polyneuropamicroglobulin.
thy and mononeuropathy multiplex.
Table 65. Neuropathies associated with
diabetes.

DISORDERS OF SOMATIC SENSATION / 215

to be any correlation between the neurologic ndings
viral infection, as from cytomegalovirus. It is
and the severity of the hepatic dysfunction.
characterized by proximal, and sometimes distal, weakness
with
Vitamin B12 Deciency
less pronounced sensory disturbances and areexia
Vitamin B12 deciency is associated with many
or
features
hyporeexia. The CSF is abnormal, with an elevated
that are characteristic of polyneuropathy, including
protein concentration and often a lymphocytic pleocysymmetric distal sensory and mild motor impairment
tosis (unlike the ndings in Guillain-Barr syndrome
and loss of tendon reexes. Because controversy or
exists
chronic inammatory demyelinating polyneuropathy
about the relative importance of polyneuropathy and
in patients without HIV-1 infection). Some patients
myelopathy in producing this syndrome, vitamin Bimprove
12
spontaneously or stabilize, and others may
deciency is considered in more detail below in the
resecspond to corticosteroids, plasmapheresis, or intration on myelopathies.
INFECTIVE
& GRANULOMATOUS
venous immunoglobulins.
NEUROPATHIES
Lumbosacral polyradiculopathy occurs late in the
course of HIV-1 infection, usually in patients with
AIDS
prior opportunistic infections. Cytomegalovirus infection is thought to be the cause, at least in some inNeuropathy is a common complication of HIV-1 infecClinical features usually develop over
tion (Table 66); involvement of peripheral nerves stances.
is
several
seen at autopsy in about 40% of patients with AIDS.
weeks and include diffuse, progressive leg weakness,
Distal symmetric sensorimotor polyneuropathy is
back pain, painful paresthesias of the feet and perthe most common neuropathy associated with HIV-1
lower extremity areexia, and early urinary
infection. Axons, rather than myelin, are primarily ineum,
afrefected. The cause is unknown, but in some patients
tention. The course may be fulminant, with ascending
viparalysis leading to respiratory failure. The course is
tamin B12 deciency or exposure to neurotoxic drugs
more benign in some patients, however, especially
may be responsible in part. HIV-1 is rarely identied
when the etiology is unclear. CSF ndings include
in
mononuclear or polymorphonuclear pleocytosis, elethe affected nerves. Sensory symptoms predominate
vated protein, and decreased glucose. It is always imand include pain and paresthesias that affect the feet
portant to exclude meningeal lymphomatosis, cord
especially. Weakness is a minor or late feature. Anklecompression, or syphilis as the underlying cause, as
these require specic treatment and affect the
and
sometimes knee reexes are absent. The course isprognosis. Patients with cytomegalovirus infection may retypispond to ganciclovir, 2.5 mg/kg intravenously every 8
cally progressive and no treatment is available, but
hours for 10 days, then 7.5 mg/kg/d 5 days per week.
pain
may be controlled pharmacologically, as describedAn alternative approach is with foscarnet; in severe
cases, both drugs are given. Some worsening in the
earrst
Table
Neuropathies
associated
with
AIDS.
lier on66.
p. 211.
Plasmapheresis
is of no
benet.
two weeks of ganciclovir therapy does not indicate
Inammatory demyelinating polyneuropathy may
treatment failure. The CSF should be re-examined
occur early in HIV-1 infection
and
Stage
of may
HIV-1follow an acute
or chronicType
course. The neuropathy
Infectionmay be immune
Immuneafter
Status
Distribution
3 weeks to determine whether the
mediated, but sometimes results from direct,
Symmetric, distal, lower upper limbs
Sensorimotor
or suppressed
secondary polyneuropathyEarly or late Competent polymorphonuclear
cell count has
declined;
if itlimbs
has not, foscarnet should
Proximal
distal
Inammatory demyelinating Early
Competent
replace
ganciclovir.
polyneuropathy
Mononeuropathy multiplex affects multiple cranial
Lumbosacral polyradiculopathy
Late

Suppressed

Proximal lower limbs, sphincters

Mononeuropathy multiplex

Early or late

Mononeuropathy simplex

Early

Autonomic neuropathy

Early or late

Competent or suppressed
Cranial (eg, facial), peripheral (eg,
peroneal)
Competent
Cranial (eg, facial), peripheral (eg,
peroneal)
Competent or suppressed
Not applicable

216 / CHAPTER 6
and peripheral nerves, resulting in focal weaknessposed areas of the bodyespecially the ears; nose;
and
cheeks; dorsal surfaces of the hands, forearms, and
sensory loss. Some cases may have an autoimmune
feet;
baand lateral aspects of the legsare preferentially insis, whereas others result from neoplastic or
volved. Unlike most polyneuropathies, that caused by
infectious
leprosy tends to spare the tendon reexes.
causes (eg, cytomegalovirus infection) or from vascuAssociated
lopathy. In early HIV-1 infection, mononeuropathy ndings include resorption of the digits, trophic
multiplex may be a self-limited disorder restricted ulcers,
to
a
and cyanosis and anhidrosis of the hands and feet.
single limb, with spontaneous stabilization or
Treatment depends on the type of leprosy, but typiimprovecally involves dapsone, rifampin, and clofazimine. The
ment. Late in AIDS, multiple limbs may be affectedmost
in recent guidelines of the World Health Organizaa progressive fashion.
tion should be followed. In the United States, further
Mononeuropathy simplex tends to occur acutelyinformation
in
can be obtained from the Gillis W. Long
Diphtheria
early HIV-1 infection and improve spontaneously. AHansens Disease Center, in Carville, Louisiana.
vascular cause is probable.
Corynebacterium diphtheriae infects tissues of the
Autonomic neuropathy tends to occur late in theupper
course of HIV-1 infections and may lead to syncopal
respiratory tract and produces a toxin that causes deepisodes, orthostatic hypotension, disturbances ofmyelination of peripheral nerves. Within about 1
sphincter or sexual function, impaired thermoregulamonth
tory sweating, and diarrhea. The dysautonomia may
after infection, patients may develop a cranial motor
reneulate to central or peripheral pathology. Treatment is
ropathy with prominent impairment of ocular
symptomatic
(as
discussed
earlier
under
diabetic
accommoLeprosy is one of the most frequent causes of
neudation. Blurred vision is the usual presenting
peripheral
ropathy).
neuropathy worldwide. In turn, neuropathy is the complaint.
Medication-related neuropathy may result from Extraocular muscles and the face, palate, pharynx,
most
treatment
with the antiretroviral
drugs
zalcitabine and didisabling manifestation
of leprosy.
Mycobacterium
(ddc),
a
may also be affected, but the pupillary light
lep- didanosine (ddI), and stavudine (d4T). Such aphragm
nucleoside
neuropathy
develops
after
about
4
months
rerae affects the skin and peripheral nerves because its
of
treatment
unless other
conditions make
ex is preserved. Recovery typically occurs after
Sarcoidosis
growth
is facilitated
by thecoexisting
cooler temperatures
the
patient
more
susceptible.
It
is
a
distal,
axonal
several
present
Leprosy
Sarcoidosis
candelayed
producesyndrome
mononeuropathy
or, rarely,
senweeks. A more
that commonly
has
at the body surface.
polyneuropathy.
The
mononeuropathy
commonly
insory
neuropathy,
characterized
by
distal
tingling,
its
In tuberculoid leprosy, the immune response is volves cranial nerves, especially the facial nerve, in
numbness,
and pain. Other drugs that may be associonset 23 months following the primary infection
adewhich case the resulting syndrome may be indistinated
with
a
neuropathy
in
AIDS
patients
include
isoniquate to conne the infection to one or more smalltakes
guishable
idiopathicdistal
facialsensorimotor
paralysis (Bell palsy).
azid,
ethambutol,
vincristine,
vinblastine,
taxol, and
the form offrom
a symmetric
patches
of skin and
their associated
cutaneous
In
some
instances,
a
small-ber
neuropathy leads to
thalidomide,
and the statins.
polyneuropasubpain,
dysesthesias,
and
autonomic
involvement.
XMost patients recover completely.
Diphtheritic
cutaneous nerves. This produces a hypopigmentedthy.
rays
neumacule or papule over which sensation is impaired,
of the lungs
and bones
and determination
of serum
ropathy
is discussed
in more
detail in Chapter
5.
with pain and temperature appreciation most
levaffected.
els of angiotensin-converting enzyme are helpful in
Anhidrosis occurs as a result of local involvement of
esautablishing the diagnosis of sarcoidosis. Treatment with
tonomic bers. Sensory decits occur most often in
prednisone, 60 mg/d orally followed by tapering
Sepsis
the
doses,
distribution of the digital, sural, radial, and posterior
Patients
with
sepsis and multiorgan failure may
may speed
recovery.
auricular nerves, whereas motor ndings usually develop
relate
a critical illness polyneuropathy. This is manifest
to involvement of the ulnar or peroneal nerve.
primaInvolved
rily by weakness and is therefore discussed in
nerves are often enlarged.
NEUROPATHIES
IN VASCULITIS
Chapter 5.
Lepromatous leprosy is a more widespread
& COLLAGEN VASCULAR DISEASE
disorder
Systemic vasculitides and collagen vascular diseases
that results in a symmetric, primarily sensory
can
polyneuropathy that disproportionately affects pain and temperature sense. Its distribution is distinctive in that
ex-

DISORDERS OF SOMATIC SENSATION / 217

Table 67. Neuropathies associated with vasculitis and collagen vascular disease.

Disease
Vasculitis
Systemic necrotizing vasculitis2

Polyneuropathy

Mononeuropathy
Simplex or Multiplex1

Entrapment
Neuropathy1

Wegener granulomatosis

Giant cell arteritis

Collagen vascular disease

Rheumatoid arthritis

(III,VI, IV)

Systemic lupus erythematosus

Sjgren syndrome

(V, III,VI)

(M, U, R)

(M)

produce polyneuropathy, mononeuropathy

simplex,

(V)
Progressive systemic sclerosis
mononeuropathy multiplex, or entrapment

(V)
neuropathy
Mixed connective-tissue disease
(Table
67).
1Commonly affected nerves: III, oculomotor; IV, trochlear; V, trigeminal; VI, abducens; M, median; R, radial; U,
Systemic
necrotizing vasculitis includes
ulnar.
2
polyarteritis
Includes polyarteritis nodosa and Churg-Strauss syndrome.
nodosa
and
allergic angiitis and granulomatosis
present;
absent.
(Churg-Strauss syndrome). Neuropathy occurs in
about 50% of patients, most often as
(Guillain-Barr syndrome, see earlier) can also occur,
mononeuropathy
as
multiplex, which may manifest itself with the acute
may mononeuropathy simplex or multiplex, which
onoften
set of pain in one or more cranial or peripheral
affects the ulnar, radial, sciatic, or peroneal nerve.
nerves.
Sjgren syndrome involves the peripheral nerves in
Distal symmetric sensorimotor polyneuropathy is less
about 20% of cases. Distal symmetric sensorimotor
common. Treatment should begin as soon as the
polyneuropathy is most common, entrapment neudiagropathy (affecting especially the median nerve) is
nosis is made; it includes prednisone, 60100 mg/d
also
orally, and cyclophosphamide, 23 mg/d orally.
frequent, and mononeuropathy multiplex can occur.
Plasmapheresis may also be helpful.
Progressive systemic sclerosis (scleroderma) and
Wegener granulomatosis is associated with
mixed connective tissue disease may produce cranial
mononeuropathy multiplex or polyneuropathy in up
mononeuropathy, which most often involves the
to
trigeminal
(V) nerve.
NEOPLASTIC
& PARAPROTEINEMIC
30% of cases. Treatment is the same as for systemic
NEUROPATHIES
necrotizing vasculitis.
Giant cell arteritis is considered in detail in Chapter
Compression & Inltration by Tumor
2. Mononeuropathy affecting cranial nerves innervating the extraocular muscles can occur.
Nerve compression is a common complication of mulRheumatoid arthritis produces entrapment neu-tiple myeloma, lymphoma, and carcinoma. Tumorous
ropathy (most commonly involving the median nerve)
invasion of the epineurium may occur with leukemia,
in about 45% of patients and distal symmetric
lymphoma, and carcinoma of the breast or pancreas.
sensorimotor polyneuropathy in about 30%. MononeuropaParaneoplastic Syndromes
thy multiplex is a frequent feature in cases
Carcinoma (especially oat-cell carcinoma of the lung)
complicated
and lymphoma may be associated with neuropathies
by necrotizing vasculitis.
Systemic lupus erythematosus is discussed in that are thought to be immunologically mediated,
based on the detection of autoantibodies to neuronal
Chapantigens in several cases.
ter 1 as a cause of acute confusional states.
Sensory or sensorimotor polyneuropathy occurs
Neuropathy
occurs in up to 20% of patients. The most commonwith both carcinoma and lymphoma. This can be eipattern is a distal, symmetric sensorimotor
polyneuropathy.
An ascending, predominantly motor polyneuropathy

218 / CHAPTER 6
ther an acute or chronic disorder; it is sometimes with multiple myeloma and may be associated with
asympolyneuropathy. Polyneuropathy is also a feature of
metric and may be accompanied by prominent pain.
hereditary amyloidosis. Amyloid neuropathies are
Carcinoma can also cause sensory neuronopathy,
conwhich primarily affects the cell bodies of sensory sidered below in the section on hereditary neuneurons
ropathies.
in the dorsal root ganglion and is associated with the
presence of anti-Hu (or ANNA-1) antibodies (see DRUG-INDUCED & TOXIC NEUROPATHIES
Chapter 3). This rare condition may be the presenting Alcoholism
manifesPolyneuropathy is one of the most common
tation of cancer. Initial symptoms of pain and
neurologic
numbness
complications of chronic alcoholism; it can occur
usually begin distally but sometimes begin proximally
alone
or
or in combination with other alcohol-related neuroin the face. The disorders often progress over dayslogic
or disorders, such as Wernicke encephalopathy
sev(see
eral weeks, leading to marked sensory ataxia and Chapter 1) or the Korsakoff amnestic syndrome (see
impairChapter 1). Controversy exists concerning the relative
ment of all sensory modalities. Motor involvementcontributions
is
of direct neurotoxicity of alcohol and aslate,
sociated nutritional (especially thiamine) deciency in
and autonomic dysfunction is uncommon. The CSFproducing polyneuropathy.
Paraproteinemias
may
Alcoholic polyneuropathy is typically a symmetric
have an inammatory
formulation.
Treatment,
even
Polyneuropathy
is a common
complication
of multiple
distal sensorimotor neuropathy. The legs are particuof
myeloma.
Patients affected by lytic myeloma are usularly likely to be affected, resulting in defective
the underlying
tumor,picture
is usually
unrewarding.
ally
men. The clinical
is of
a distal symmetric
percepLymphoma polyneuropathy.
may be complicated
by motor
neu- tion of vibration and touch and depressed or absent
sensorimotor
All sensory
modalities
ronopathy,
a pain
disorder
anterior
horn cells,
is indicated in Table 62, a large number of drugs
are affected,
is a of
frequent
feature,
and which
the As
andiscussed
in
Chapter
5.
Hodgkin
disease
and
angioimreexes
kle
reexes.
In someto
cases,
weaknessAisfew
also
have
been reported
causedistal
neuropathies.
munoblastic
lymphadenopathy
are sometimes
associare
depressed.
The disorder is usually
progressive
pronounced and autonomic dysfunction may occur.
merit
ated with Guillain-Barr syndrome.
and
Whencomment.
pain is a prominent feature, it may respond to
brief
leads to death within 2 years. Sclerotic myeloma may
the
same
treatment
described
onleprosy,
p. 211 for
Dapsone,
a drug used
to treat
canpainful
produce
Other Drugs
be accompanied by a chronic demyelinating polyneuneuropathy.
a
ropathy. Motor involvement predominates, but vibraAbstinence
from
alcohol and thiamine
repletion can
primarily
motor
polyneuropathy
that is reversible.
tion and position sense may also be impaired, andhalt
the progression
of symptoms. drug, is
Hydralazine,
an antihypertensive
the
associated
reexes are depressed. Pain is less common than in
on rare occasions with a predominantly sensory
the
polyneuropathy that has been attributed to drugneuropathy of lytic myeloma, and symptoms may induced
impyridoxine deciency and that resolves after
prove with treatment of the underlying cancer or by
the drug is discontinued.
plasmapheresis. The POEMS syndrome (polyneuropa-Isoniazid is a widely used antituberculous agent
thy, organomegaly, endocrinopathy, M protein, and
that
skin changes) may complicate plasma cell dyscrasias,
interferes with pyridoxine metabolism and produces a
espolyneuropathy that principally affects the sensory
pecially osteosclerotic myeloma. The sensorimotorneupolyneuropathy may show certain distinctive electrorons. High doses, hereditary variations in drug
physiologic features, such as conduction slowing that
metabois
lism, and malnutrition predispose to this
more marked in intermediate than distal nerve segcomplication.
ments, and often responds to treatment with corticosSpontaneous recovery is the rule when administration
teroids or cyclophosphamide; irradiation of solitaryof the drug is halted. Isoniazid-induced neuropathy
oscan
teosclerotic lesions may also be worthwhile.
be prevented by concurrent administration of
Amyloidosis
A sensorimotor polyneuropathy similar to that obpyridoxserved
with lytic
myeloma may
also
in WaldenNonhereditary
amyloidosis
occurs
asoccur
an isolated
ine, 100 mg/d orally.
strm
disor- macroglobulinemia or benign monoclonal gam-Phenytoin is often mentioned as a cause of
mopathy.
Treatment
with amyloidosis)
immunosuppressant
drugs
der (primary
generalized
or in patients
polyneuand plasmapheresis is sometimes helpful.
ropathy, but evidence for phenytoin treatment as a
cause of symptomatic neuropathy is sparse.
Pyridoxine (vitamin B6) toxicity has been impli-

DISORDERS OF SOMATIC SENSATION / 219

cated as the cause of a sensory neuronopathy thatadministration of corticosteroids, nonsteroidal antiindisammatory drugs, and analgesics. Most patients improportionately impairs vibration and position sense.
prove or recover fully, but deaths have been
This disorder usually occurs in patients taking at least
reported.
200 mg of pyridoxine dailyabout 100 times the minimum daily requirement. Sensory ataxia, Romberg
HEREDITARY NEUROPATHIES
sign,
Hereditary Motor and Sensory
Lhermitte sign, and ankle areexia are common ndings. Pain is less common, and motor involvementNeuropathies
is
unusual. Symptoms are usually reversible over
months
These are designated Charcot-Marie-Tooth (CMT)
to years if the abuse ceases, but an irreversible synhereditary neuropathies. They constitute a
drome has also been reported following intravenous
genetically
adheterogeneous group of disorders having the same
ministration of high doses of pyridoxine.
cliniVincristine produces a polyneuropathy in most pacal phenotype. There is weakness and wasting of
tients who receive the drug for treatment of (usually
distal
hematologic)
cancer.
The
earliest
manifestations
are
muscles in the limbs, with or without sensory loss;
Organic compounds implicated as causes of polyneudispes
ropathy include hexacarbons present in solvents and
tal
sensory
symptoms
and
loss
of
reexes.
Motor
glues (eg, n-hexane, methyl n-butyl ketone) and cavus and reduced or absent tendon reexes also
decits
occur.
organophosphates
used as plasticizers or insecticides
Toxins
may
predominate
later
in
the
course,
however.
They are divided into demyelinating (CMT1) and neu(eg, triorthocresyl phosphate). Sensory involvement
Constiparonal (CMT2) types, the latter sparing sensory
is
tion
is
a
common
nding
and
may
be
due
to
neurons
most striking in n-hexane neuropathy, whereas neuautonomic
and resembling progressive spinal muscular atrophy
ropathy caused by triorthocresyl phosphate primarily
involvement.
Discontinuing
the
drug
or
administering
(see
affects motor nerves. Organophosphate neuropathy
is Chapter 5). Both types have an autosomal domiit
nant
pattern of inheritance although sporadic cases
discussed in more detail in Chapter 5.
at Heavy
a reduced
dosage
often
leads
to
improvement.
occur.
metals may also be responsible for polyneuCMT1 has its onset in the rst decade, follows a
ropathy. Neuropathy caused by lead, arsenic, and
slowly
progressive course, and is of variable severity.
thalThe
nerves
are palpably thickened in about 50% of
lium is discussed in Chapter 5. Gold, which is used to
cases.
Nerve
conduction velocities are markedly retreat rheumatoid arthritis, may cause a symmetric
duced.
CMT1
is subdivided on the basis of the genetic
polyneuropathy, and cisplatin (a platinum analogue
ndings
(Table
68). An X-linked dominant form
with anticancer activity) may produce a sensory neu(CMTX)
and
autosomal
recessive types (CMT4) have
ropathy.
also
been
described.
Eosinophilia-myalgia syndrome was rst identied
Dejerine-Sottas disease has its onset by 2 years of
in 1989 in patients taking L-tryptophan who
age
with delayed motor milestones and is
developed
characterized
disabling myalgias with blood eosinophil counts
by a severe sensorimotor neuropathy that frequently
above
1,000/L. About 85% of patients are women. The extends to the proximal muscles and is associated with
cause appears to be 1,1-ethylidenebis [tryptophan],
skeletal
abnormalities
suchAutonomic
as scoliosis. There is
Hereditary
Sensory and
a
severe
(HSAN)
contaminant in certain commercial preparations ofNeuropathies
Ldemyelination
of
the nerves. It was previously
tryptophan, which have since been withdrawn. SympThese
neuropathies also take a variety of forms. In
thought
toms include myalgia, arthralgia, dyspnea, cough, HSAN type I, there is a dominant inheritance, a
to have an autosomal recessive mode of inheritance,
rash,
gradubut
fever, and sclerodermiform skin changes. Neurologic
ally
course
from
onset in in
early
adulthood,
it is progressive
now accepted
that it
is inherited
an autosomal
ndings include weakness of distal and proximal limb
and
symmetric
loss
of
distal
pain
and
temperature
dominant manner and the responsible mutations
and bulbar muscles, distal sensory loss, and areexia.
perhave
Eosinophilia, leukocytosis, and elevated liver
ception,
relative
preservation
of light touch.
involved with
the same
genes
as are associated
with
enzymes
PerfoCMT1.
are typical. Nerve conduction studies and
rating ulcers over pressure points and painless infecelectromyogtions of the extremities are common. The tendon
raphy may show evidence of polyneuropathy, myopareexes are depressed, but there is little, if any,
thy, or both. Inammation is prominent in skin biopsy
motor
specimens, but less so in nerve and muscle, whichdisturbance. The gene maps to chromosome 9q22. In
show
HSAN type II, inheritance is recessive, onset is in inprimarily axonal degeneration and muscle ber atrofancy or early childhood, all sensory modalities are afphy. Treatment is discontinuation of L-tryptophan and

220 / CHAPTER 6
Table 68. Hereditary motor and sensory neuropathies of the Charcot-Marie-Tooth (CMT) type.
Disease

Inheritance

Gene

Locus

CMT 1A

AD

PMP22

17p11.2

CMT 1B

AD

MPZ

1q22

CMT 1C

AD

LITAF

16p13

CMT 1D

AD

EGR2

10q21.1q22.1

CMT X

XD

GJB1
CX32

Xq13

Dejerine-Sottas (HMSN 3)

AD

MPZ
PMP22
EGR2
?

1q22
17p11.2
10q21.1q22.1
8q23

CMT 2A

AD

KIF1B

1p36

CMT 2B

AD

RAB7

3q13

CMT 2C

AD

12q23q24

CMT 2D

AD

GARS

7p15

CMT 2E

AD

NEFL

8p21

CMT 2F

AD

7q11q21

CMT 2G

AR

GDAP1

8q13q21.1

CMT 2K

AR

GDAP1

8q13q21.1

CMT 4A

AR

GDAP1

8q13q21.1

CMT 4B1

AR

MTMR2

11q22

CMT 4B2

AR

SBF2

11p15

CMT 4C

AR

KIAA1985

5q32

CMT 4D

AR

NDRG1

8q24

CMT 4E

AR

EGR2

10q21q22

CMT 4F

AR

PRX

19q13

1 AD,

autosomal dominant; AR, autosomal recessive; XD, x-linked dominant.

fected, and tendon reexes are lost. HSAN type III

growth factor at chromosome 1q21q22.
(Riley-Day syndrome, familial dysautonomia) is a recessive disorder that commences in infancy and isPolyneuropathy can occur in both the hereditary and
Amyloidosis
charnonhereditary forms of amyloidosis. Because smallacterized by conspicuous autonomic dysfunction (abdisent tearing, labile temperature and blood pressure),
ameter sensory and autonomic nerve bers are espeaccompanied by absent taste sensation, impaired cially likely to be involved, pain and temperature
pain
sensaand temperature sensation, and areexia. The
tion and autonomic functions are prominently
disorder
affected.
is linked to chromosome 9q31. HSAN type IV is assoClinical presentation is commonly with distal
ciated with congenital insensitivity to pain and absent
paresthesweating, and has been related to recessive
sias, dysesthesias, and numbness; postural
mutations in
hypotension;
the gene encoding a receptor tyrosine kinase for impaired thermoregulatory sweating; and
nerve
disturbances

DISORDERS OF SOMATIC SENSATION / 221

of bladder, bowel, or sexual function. Distal weakness
include abetalipoproteinemia, which is associated
and wasting eventually occur. The tendon reexeswith
are
often preserved until a relatively late stage.
acanthocytosis, malabsorption, retinitis pigmentosa,
Entrapment
and cerebellar ataxia; and Tangier disease, which proneuropathyespecially carpal tunnel syndromemay
duces cataract, orange discoloration of the tonsils,
develop as a consequence of amyloid deposits. There
and
is
hepatosplenomegaly. These are autosomal recessive
no specic treatment.
conditions.
Friedreich Ataxia
Refsum disease is an autosomal recessive disorder
Friedreich ataxia usually has a recessive mode of related to impaired metabolism of phytanic acid. It
inheriproduces polyneuropathy, cerebellar ataxia, retinitis
tance but occasionally occurs with dominant inheripigmentosa, and ichthyosis. It can be treated by retance. It is caused in many cases by a triplet repeat
stricting dietary intake of phytol. Plasmapheresis to
exrepansion in a noncoding region of the frataxin geneduce body stores of phytanic acid may also be helpful
(X25) on chromosome 9q13q21.1, but there is some
at the initiation of treatment.
heterogeneity of phenotype and variation in age of Fabry disease is an X-linked recessive deciency of
onthe enzyme It results in a painful
set among patients with this expansion. This
sensory and autonomic neuropathy, angiokeratomas,
expansion
renal disease, and an increased incidence of stroke.
has not been found in all cases, suggesting that other
The
genetic or environmental factors are sometimes responsible gene has been localized to the long arm
responof
sible. An ataxic gait develops, followed by clumsiness
the X chromosome; mutations causing the disease
of
have
the hands and other signs of cerebellar dysfunction.
been recognized and include gene rearrangements,
Inan
Hereditary Neuropathy with Liability
volvement
peripheral sensory bers leads to
RNA-splicing defect,NEUROPATHIES
and various exonic lesions. PharENTRAPMENT
to PressureofPalsies
sensory
macologic measures (p 211) may be helpful in
This
is aofgenetically
that
decits
the limbs,heterogeneous
with depresseddisorder
or absent
tendon
treating
relates
Certain
nerves are
susceptible
reexes. There may also be leg weakness and
the painperipheral
that characterizes
theparticularly
disorder. Enzyme
remost
commonly
to
deletion
of
the
PMP-22
gene
on
to
extensor
placement therapy is under investigation.
chromosome
17. Inheritance
is motor
as an autosomal
plantar responses
from central
involvement.mechanical injury at vulnerable sites. The term
domientrapThis
nant
trait
with
variable
expression.
Patients
present
ment neuropathy is used when the nerve is comcondition is considered in detail in Chapter 3.
with simple or multiple mononeuropathies that occur
pressed, stretched, or angulated by adjacent
after mild pressure or stretch of nerves, and electroanatomic
In acute intermittent porphyria, which is transmitted
physiologic studies reveal that abnormalities are structures to such an extent that dysfunction occurs.
by recessive inheritance, the initial neurologic
more
There are numerous entrapment neuropathies, and in
Metabolic
manifes- Disorders
widespread than is evident clinically.
many the initial or most conspicuous clinical comtation is often a polyneuropathy that (usually)
plaints are of sensory symptoms or pain. Some of the
involves
ENTRAPMENT
SYNDROMES
more common syndromes
are described below.
motor more than sensory bers. Sensory symptoms
OF UPPER LIMBS
and
Median
Nerve
signs may be predominantly proximal or distal. The
Compression
of Compression
the median nerve can occur in the
pecarpal tunnel at the wrist. Carpal tunnel syndrome is
ripheral nerves may also be affected in variegate porcommon during pregnancy and can occur as a
phyria. Neuropathy caused by porphyria is considered
compliin greater detail in Chapter 5.
cation of trauma, degenerative arthritis,
Two recessive lipidoses are associated with
tenosynovitis,
polyneumyxedema, and acromegaly. Early symptoms are
ropathy with a typical onset in infancy or childhood.
pain
These are metachromatic leukodystrophy, which reand paresthesias conned to a median nerve distribusults from deciency of the enzyme arylsulfatase A,
tion in the hand, ie, involving primarily the thumb, inand
dex, and middle ngers and the lateral half of the
Krabbe disease, which is due to galactocerebroside
ring

nger (see Appendix C). There may be pain in the

galactosidase deciency. Both are inherited in an foreautoarm and, in occasional patients, even in the upper
somal recessive fashion.
arm,
Lipoprotein deciencies that cause polyneuropathy
shoulder, and neck. Symptoms are often particularly

222 / CHAPTER 6
troublesome at night and may awaken the patient An ulnar nerve lesion may develop in the wrist or
from
palm of the hand in association with repetitive
sleep. As the neuropathy advances, weakness andtrauma,
atroarthritis, or compression from ganglia or benign tuphy may eventually develop in the thenar muscles.
mors. Involvement of the deep terminal branch in the
Expalm leads to a motor decit in ulnar-innervated hand
amination reveals impaired cutaneous sensation inmuscles other than the hypothenar group, whereas a
the
more proximal palmar lesion affects the latter
median nerve distribution in the hand and, with muscles
motor
as well; there is no sensory decit. With lesions at the
involvement, weakness and wasting of the abductor
wrist involving either the ulnar nerve itself or its deep
pollicis brevis and opponens pollicis muscles (see Apand supercial branches, both sensory and motor
pendix C). There may be a positive Tinel sign (percuschanges occur in the hand. Sensation over the dorsal
sion of the nerve at the wrist causes paresthesias surface
in
of the hand is unaffected, however, because
its
the
distribution) or a positive response to Phalen
cutaneous branch to this region arises proximal to the
maneuver
wrist. Surgical
treatment is helpful in relieving comRadial
Nerve Compression
(exion of the wrist for 1 minute exacerbates or pression from a ganglion or benign tumor.
The radial nerve may be compressed in the axilla by
reproduces symptoms). The diagnosis can generally be pressure from crutches or other causes; this is
frequently
conseen in alcoholics and drug addicts who have fallen
rmed by electrophysiologic studies, showing sensory
Interdigital
Neuropathy
or motor conduction velocity to be slowed at the asleep with an arm draped over some hard surface.
The
wrist;
Interdigital neuropathy may lead to pain in one or two
resulting decit is primarily motor, with weakness or
there
may
beexamination
signs of chronic
partial
denervation
ngers,
and
reveals
hyperpathia
or in
paralysis occurring in the muscles supplied by the
median-supplied
musclesatofthe
theelbow
hand.leads to
impaired
Ulnar
nerve dysfunction
If the symptoms
fail
respond
to local
corticos-nerve
cutaneous
sensation
into
the
appropriate
distribution
of
paresthe(see Appendix C), but sensory changes may also
teroid
injections
or
simple
maneuvers
such
the affected
nerveand
or nerves.
Such
a neuropathy
sias,
hypesthesia,
nocturnal
pain
in the as
little may
occur,
wearing
renger a
especially in a small region on the back of the hand
nocturnal
wrist
splint,
surgical
decompression
of the
sult
in
the intermetacarpal
tunnel
of
and from
ulnarentrapment
border
of the
hand.
Pain
may also occur
becarpal
tunnel
may
be
necessary.
the
hand,
direct
trauma,
tenosynovitis,
or
arthritis.
about the elbow. Symptoms are often intensied by
tween the thumb and index nger (see Appendix C).
el-Treatment by local inltration with corticosteroids Treatment involves preventing further compression
is sometimes
but arm.
in severe
cases neurolysis
bow
exion orhelpful,
use of the
Examination
may of the nerve. Recovery usually occurs spontaneously
Thoracic Outlet Syndrome
may
reveal
Ulnar Nerve Dysfunction
and completely except when a very severe injury has
be necessary.
sensory
loss on the ulnar aspect of the hand (see In
re-thoracic outlet syndrome, a cervical rib or band or
Appenother
may compress
the lower
sultedanatomic
in axonal structure
degeneration.
Physical therapy
and a
dix C) and weakness of the adductor pollicis, the part
wrist splint may be helpful until recovery occurs.
deep
of the brachial plexus. Symptoms include pain, paresexor muscles of the fourth and fth digits, and the
thesias, and numbness in a C8T1 distribution (Figure
in64). There may be diffuse weakness of the intrinsic
trinsic hand muscles (see Appendix C). The lesion hand muscles, often particularly involving the
may
muscles
result from external pressure, from entrapment within
in the thenar eminence and thereby simulating carpal
the cubital tunnel, or from cubitus valgus deformity
tunnel syndrome. See the section on cervical rib syncausing chronic stretch injury of the nerve.
drome in Chapter 5 for further details.
ElectrodiagENTRAPMENT SYNDROMES
nostic studies may be helpful in localizing the lesion.
OF LOWER LIMBS
Avoiding pressure on or repetitive exion and
Peroneal Nerve Lesions
extension of the elbow, combined in some instances with
Peroneal nerve lesions can occur secondary to
splinting the elbow in extension, is sometimes
trauma
sufcient
or to pressure about the knee at the head of the
to arrest progression and alleviate symptoms.
bula.
Surgical
decompression or ulnar nerve transposition to the The resulting weakness or paralysis of foot and toe
exexor surface of the arm may also be helpful,
tensionand foot eversion (see Appendix C)is acdepending on the cause and severity of the lesion and thecompanied by impaired sensation over the dorsum of
the foot and the lower anterior aspect of the leg (see
duration of symptoms.

DISORDERS OF SOMATIC SENSATION / 223

Appendix C). The ankle reex is preserved, as is foot
sias in the lateral thigh, and examination reveals iminversion.
paired sensation in this region. This syndrome, known
Treatment is purely supportive. It is important toas meralgia paresthetica, is best treated with symptoprotect the nerve from further injury or compression.
matic measures, as its course is often self-limited.
Patients with foot drop may require a brace until
recovObturator Nerve Injury
ery occurs. Recovery occurs spontaneously with time
Trauma to the obturator nerveeg, by pelvic fracture
and is usually complete unless the injury was severe
or a surgical procedurecan lead to pain radiating
enough to cause marked axonal degeneration.
from the groin down the inner aspect of the thigh. An
Tarsal Tunnel Syndrome
obturator hernia or osteitis pubis may cause a similar
The posterior tibial nerve or its branches can be comdisorder; there is accompanying weakness of the
pressed between the oor and the ligamentous roof
adducof
tor thigh muscles (see Appendix C).
the tarsal tunnel, which is located at the ankle
The clinical disturbances resulting from acute
immediinterver- & PLEXUS LESIONS
ately below and behind the medial malleolus. The ROOT
tebral disk prolapse, cervical spondylosis, traumatic
usual
complaint is of burning in the footespecially at plexopathy, cervical rib syndrome, and neuralgic
COMPRESSIVE
& TRAUMATIC LESIONS
amynightsometimes accompanied by weakness of the
otrophy
were
discussed
in Chapter 5. In addition to
inthese
conditions,
patients
with metastatic cancer
trinsic foot muscles. The diagnosis can usually be
may
conFemoral Neuropathy
develop root or plexus lesions from compression by
rmed electrophysiologically.
Isolated
femoral
neuropathy
may occur
in association
If treatment
with
local injection
of steroids
is nottuwith
diabetes
mellitus,
vascular may
disease,
bleeding mor or as a result of trauma induced by radiation
helpful,
surgical
decompression
be necessary.
therdiatheses
apy. Root lesions are typically compressive in nature
(eg, hemophilia, treatment with anticoagulant drugs),
and usually occur in the setting of neoplastic
or
retroperitoneal neoplasms. The most conspicuous meningitis, which is discussed in Chapter 1. Tumors
symp(especially
toms and signs relate to weakness of the quadriceps
lung and breast cancer) can also inltrate the
muscle, with reduced or absent knee reex, but there brachial
plexus, causing severe arm pain and sometimes
may
also
Saphenous
Nerve Injury
be sensory disturbances in the anterior and medialdysesthesia. Because involvement of the lower trunk of the
The
saphenous nerve is the terminal sensory branch
aspects
of the thigh and the medial part of the lower leg. plexus is most common, symptoms usually occur
within the C8 and T1 dermatomes, and Horner syntheTreatment
femoral nerve
andunderlying
supplies cutaneous
sensation
is of the
cause.
drome (see Chapter 4) is present in about 50% of
to
the medial aspect of the leg about and below the cases.
Radiation injuryrather than direct invasion by tuknee
morshould be suspected as the cause when the
(see Figure 64). Mechanical injury to the nerve can
upper
occur at several points along its course; patients then
trunk of the brachial plexus (C5 and C6 nerve roots)
complain of pain or impaired sensation in the
is
distribution of the nerve. Weakness in quadriceps functioninvolved, weakness is a prominent presenting symptom, arm swelling occurs, or symptoms develop
(ie,
within
extension
at
the
knee;
see
Appendix
C)
reects
Lateral Femoral Cutaneous
1 year after completion of radiation therapy with a
femoral
Nerve Dysfunction
total
nerve involvement.
The
lateral
femoral
cutaneous
nerve
dose of more than 6000 R. Lumbosacral plexopathy is
There
is no
specic
treatment,
butsupplies
the nerve
sensation
usually seen
in patients with colorectal, cervical, uterTABES
DORSALIS
should
to
outer border
of the thigh
Its or ovarian carcinoma or sarcoma. Clinical
be the
protected
from further
injury.(see Appendix C). ine,
This type of neurosyphilis, now rare, is characterized
function can be impaired by excessive angulation or
features
mainly by sensory symptoms and signs that indicate
compression by neighboring anatomic structures, that suggest tumor invasion in this setting include
marked involvement of the posterior roots, especially
espeearly
in
cially in pregnancy or other conditions that cause and severe pain, unilateral involvement, leg swelling,
exagand a palpable rectal mass. Radiation injury is more
gerated lumbar lordosis. This leads to pain and
commonly associated with early prominent leg weakparestheness and bilateral symptoms.

dynamic disorder of the CSF pathways. In noncommunicating syringomyelia, there is cystic dilation of the
cord, which is not in communication with the CSF
pathways. The precise clinical disturbance that
224 / CHAPTER 6
results
depends upon the site of cavitation. Typically, there is
the lumbosacral region, with resulting degeneration
a
in
dissociated sensory loss at the level of the lesion; pinthe posterior columns of the spinal cord. Common
prick and temperature appreciation are impaired, but
complaints are of unsteadiness, sudden lancinating
light touch sensation is preserved. The sensory loss
somay
matic pains, and urinary incontinence. Visceral crises
be reected by the presence of painless skin ulcers,
characterized by excruciating abdominal pain also ocscars, edema, hyperhidrosis, neuropathic joints,
cur. Examination reveals marked impairment of vibraresorption and joint position sense in the legs, together with
tion of the terminal phalanges, and other
an ataxic gait and Romberg sign. Deep pain sensation
disturbances.
is impaired, but supercial sensation is generally preWeakness and wasting of muscles occur at the level
served. The bladder is often palpably enlarged;
of
because
the lesion because of the involvement of the anterior
it is accid and insensitive, there is overow incontihorns of the cord. A pyramidal decit and sphincter
nence. Tendon reexes are lost, and the limbs are
disturbances sometimes occur below the level of the
hypoletonic. Sensory loss and hypotonicity may lead to the
sion because of gliosis or compression of the cortioccurrence of hypertrophic (Charcot) joints. In many
cospinal pathways in the lateral columns of the cord.
patients there are other signs of neurosyphilis, includThe tendon reexes may be depressed at the level of
ing Argyll Robertson pupils, optic atrophy, ptosis, a
the
variable ophthalmoplegia, and, in some cases,
lesionbecause of interruption of their afferent, cenpyramiLYME
DISEASE
tral, or efferent pathwaysand increased below it.
dal and mental changes from cerebral involvement
Sco(taboparesis),
in aChapter
1. Treatment
Lyme
disease, as
likediscussed
syphilis, is
spirochetal
infection is
liosis is a common accompaniment of cord cavitation.
of produces both central and peripheral nervous
that
Cavitation commonly occurs in the cervical region;
the underlying infection.
systhis
tem disease. Central nervous system involvement is
can cause a capelike distribution of sensory loss over
manifested by meningitis or meningoencephalitis, as
one or both shoulders, diffuse pain in the neck, and
discussed in Chapter 1. Lyme disease is also
radicular pain in the arms; involvement of the T1 segassociated
ment frequently leads to ipsilateral Horner syndrome.
with inammatory mono- or polyradiculopathy,
If the cavitation involves the lower brainstem (sybrachial plexopathy (see Chapter 5),
ringobulbia), there may also be ipsilateral tongue
mononeuropathy
wast(including facial palsy), and mononeuropathy multiing, palatal weakness, vocal cord paralysis,
plex. The radiculopathy results in pain, sensory loss,
dissociated
or
trigeminal sensory loss, and other evidence of braindysesthesia in affected dermatomes; it also causes
stem involvement.
focal
Communicating syringomyelia is often associated
weakness. One or more cervical, thoracic, or lumbar
with developmental anomalies of the brainstem and
nerve roots may be involved. Electromyography can
foramen magnum region (such as Arnold-Chiari malconrm the presence of radiculopathy, and serologic
formation; see Chapter 3) or with chronic
MYELOPATHIES
testing establishes Lyme disease as the cause.
arachnoiditis
Treatment
of the basal cisterns. Arnold-Chiari malformation can
is described inmay
Chapter
1. with pain or with a variety
Myelopathies
present
lead to hydrocephalus, cerebellar ataxia, pyramidal
of sensory complaints and with motor disturbances.
and
The clinical ndings should suggest the level of the
sensory decits in the limbs, and abnormalities of the
lelower cranial nerves, alone or in any combination.
sion, but further investigation is necessary to
Myelography, magnetic resonance imaging (MRI), or
delineate
computed tomographic (CT) scanning of the foramen
it more fully and determine its nature. Compressive,
magnum region conrms the diagnosis. Treatment is
issurgical.
chemic,
inammatory,
demyelinative,
and
traumatic
Noncommunicating syringomyelia is often due to
SYRINGOMYELIA
myelopathies were discussed in Chapter 5.
trauma, intramedullary tumors, or spinal
Syringomyelia is cavitation of the spinal cord.
arachnoiditis.
CommuPosttraumatic syringomyelia generally occurs in panicating syringomyeliawith communication between
tients with preexisting, severe neurologic decits
the central canal of the cord and the cavityis a from
hydrospinal trauma after an interval of several years,
although
rarely it may develop only a few months after the

DISORDERS OF SOMATIC SENSATION / 225

ringomyelia associated with Arnold-Chiari malformasociated anemia.
tion, removal of the posterior rim of the foramen
magnum and amputation of the cerebellar tonsils are
someCEREBRAL DISEASE
times helpful. The cord cavity should be drained, and,
if necessary,
an outlet may
should
be made
for the fourth
Vitamin
B12 deciency
result
from impaired
abventricle.by
Posttraumatic
syringomyelia
is treated
by
Sensory symptoms may relate to diverse diseases
sorption
the gastrointestinal
tract such
as occurs
surinvolvin
gery
if
it
is
causing
a
progressive
neurologic
decit
or the brainstem or cerebral hemispheres. The
ing
pernicious anemia or because of gastrointestinal surintolerable
pain.
A
variety
of
surgical
approaches
clinical
gery, sprue, or infection with sh tapeworm; it can
have
features of the sensory decit have been described
also
been
used,
including
various
draining
procedures
earbe caused by a strictly vegetarian diet. It may affect
from
lier in this chapter and, together with the nature and
the
the
cord
cavity,
myelotomy,
and
formation
of
surgical
extent of any accompanying neurologic signs, should
spinal
cord,
giving
rise
to
the
syndrome
of
subacute
SUBACUTE COMBINED DEGENERATION
meningocele.
Radicular pain
and
sensory
suggest the probable site of the lesion. The
combined
degeneration.
Onset
is
with
distal
(VITAMIN B12 DEFICIENCY)
disturbances
differential
parestheare usually
helped, in
whereas
spasticity(involvement
responds less
diagnosis
of such lesions is considered separately in
sias
and weakness
the extremities
of
sat- hands occurs relatively early), followed by the Chapter
9.
the
dePAIN SYNDROMES
isfactorily. of spastic paraparesis, with ataxia from
velopment
the
Pain from infective, inammatory, or neoplastic
impairment of postural sensation in the legs.
processes is a feature of many visceral diseases and
Lhermitte
may
sign may be present, and examination reveals a combe a conspicuous component of certain neurologic or
bined posterior column (vibration and joint position
sense) and pyramidal decit in the legs. Plantar re-psychiatric diseases. It can also occur with no obvious
sponses are extensor, but tendon reexes may be cause.
inIn evaluating patients with pain, it is important to
creased or depressed, depending on the site and
determine
the level of the nervous system at which
severity
the
of the involvement. Signs of cord involvement can be
pain arises and whether it has a primary neurologic
accompanied by centrocecal scotoma or optic
baatrophy
from optic (II) nerve involvement, by behavioral orsis. In taking the history, attention should be focused
on the mode of onset, duration, nature, severity, and
psychiatric changes (see Chapter 1), or by peripheral
location of the pain; any associated symptoms; and
neuropathy. The neurologic manifestations are often
facaccompanied by macrocytic megaloblastic anemia,
tors that precipitate or relieve the pain.
but
Treatment depends on the underlying cause and
this is not invariably present.
The serum vitamin B12 level is low in untreated clinical context of the pain and is discussed below. A
cases. If malabsorption of vitamin B12 is the cause,brief comment is necessary, however, about stimulation-produced analgesia and, in particular, about
the
spinal
Schilling test is abnormal, and there is usually gastric
achlorhydria with pernicious anemia. Hematologic cord stimulation (previously known as dorsal column
stimulation) and peripheral nerve stimulation. These
ndings may be normal, however, especially if folic
approaches were based on principles encapsulated
acid
supplements have been given. Electrophysiologic by
the Gate Control theory, in which activation of large
studies may conrm peripheral nerve involvement, andmyelinated bers was held to interrupt nociceptive
median- or tibial-derived somatosensory evoked transmission in the spinal cord, but their precise
PERIPHERAL
NERVE PAIN
mechpotenanism
of action
uncertain.nerve
Spinallesions
cord stimulation
Pain
arising
fromisperipheral
is usually is
tials may show abnormalities indicative of posterior
known to affect certain neurotransmitter systems,
column dysfunction. Spinal MRI sometimes shows loparcalized
to the region that is affected pathologically or
abnormalities in the posterior columns.
ticularly substance
P andof

acid It may
conned
to the territory
the affected nerve.
Treatment is with vitamin B12 given by intramuscu(GABAergic)
systems.
have
a
burning
quality,
and
when
mixed
(motor
and
lar injection daily (501000 for 2 weeks, then
sensory)
nerves
are
involved,
there
may
be
an
weekly (100 for 2 months, and monthly (100
thereafter. Note that folic acid supplements do notaccompanying motor decit. Painful peripheral neuropathies
help
inthe neurologic disorder; in addition, they may mask
as-

226 / CHAPTER 6
clude those caused by diabetes, polyarteritis,
have difculty describing. It is aggravated by
alcoholicemotional
nutritional deciency states, and the various entrapstress and tends to develop during partial recovery
ment neuropathies. Treatment of pain associated with
from
peripheral neuropathies is discussed earlier. The term
a sensory decit caused by the underlying thalamic
causalgia correctly is used for the severe persistent
lepain,
sion. Mild cutaneous stimulation may produce very
often burning in quality, that results from nerve unpleasant and painful sensations. This combination
trauma. Such pain often radiates to a more extensive
of
territory than is supplied by the affected nerve andsensory
is
loss, spontaneous pain, and perverted cutaassociated with exquisite tenderness. Onset of pain
neous sensation has come to be called Dejerinemay
Roussy
be at any time within the rst 6 weeks or so after syndrome. Similar pain can be produced by a lesion
nerve
that involves the parietal lobe or the sensory
injury. The cause is uncertain, but it has been attribpathways
uted to ephaptic transmission between efferent at any point in the cord (posterior columns or
BACK
& NECKtract)
PAINor in the brainstem. Treatment
sympaspinothalamic
thetic and afferent somatic bers at the site of injury.
with analgesics, anticonvulsants (carbamazepine or
Spinal disease occurs most commonly in the neck or
Pain may be accompanied by increased sweating and
phenytoin), or antidepressants and phenothiazines in
low back and can cause local or root pain or both. It
vasoconstriction of the affected extremity, which iscombination is occasionally helpful.
can also lead to pain that is referred to other parts of
commonly kept covered up and still by the patient.
the involved dermatomes. Pain from the lower lumbar
Respine, for example, is often referred to the buttocks.
ex sympathetic dystrophy is a more general term
Conversely, pain may be referred to the back from
that
the
denotes sympathetically mediated pain syndromes
viscera, especially the pelvic organs. Local pain may
prelead to protective reex muscle spasm, which in turn
cipitated by a wide variety of tissue injuries, including
causes further pain and may result in abnormal
soft tissue trauma, bone fractures, and myocardial inposture,
farction. Medical approaches to treatment include
limitation of movement, and local spinal tenderness.
symThe history may provide clues to the underlying
pathetic blockade by injection of local anesthetics
cause, and physical examination will dene any
RADICULAR
PAIN
into
neurothe sympathetic
or by
infusionof
ofone
reserRadicular
pain is chain
localized
to regional
the distribution
or
logic involvement.
pine or
guanethidine.
such
procedure may
more
nerve
roots and One
is often
exacerbated
by proDiagnostic studies that can help in evaluating paduce permanent cessation of painor repeated
coughing,
tients include x-rays of the affected region and a
sympa- and other maneuvers that increase
sneezing,
comthetic blocks may be required. Surgical
intraspinal
plete blood count and erythrocyte sedimentation rate
sympathectomy
pressure.
It is also exacerbated by maneuvers that
(especially if infective or inammatory disorders or
is benecial
in up to roots.
75% of
cases.straight
Spinal cord
stretch
the affected
Passive
leg raising
myeloma is suspected); determination of serum
stimulaleads
to stretching of the sacral and lower lumbar
protein
tion has also been successful in some instances for
roots,
and protein electrophoresis; and measurement of
thedoes passive exion of the neck. Spinal
as
serum
treatment
of reex sympathetic dystrophy or
movements
calcium, phosphorus, alkaline and acid phosphatase,
causalgia.
that narrow the intervertebral foramina can
and uric acid. Electromyography may be helpful in
aggravate
deroot pain. Extension and lateral exion of the head to
termining the extent and severity of root
the affected side may thus exacerbate cervical root
involvement;
symptoms. In addition to pain, root lesions can cause
1.
LOW provides
BACK PAIN a guide to prognosis. A CT scan, MRI
it also
paresthesias and numbness in a dermatomal distribuLow
back
pain
common cause
of time
lost from
of the spine,
orisa amyelogram
may be
necessary,
tion (see Figure 64); they can also cause segmental
work.
It
has
many
causes.
espeweakness and reex changes, depending upon the
cially if neoplasm is suspected, neurologic decits are
THALAMIC
PAIN
level
progressive,
pain persists despite conservative
Trauma
affected (see
Table
511).
Useful
treatment
Depending
upon
their
extent
andmodes
preciseoflocation,
treatment
include immobilization, nonsteroidal antiinammatory
Unaccustomed exertion or activityor lifting heavy
thalmeasures, or there is evidence of cord involvement.
drugslesions
or other
analgesics,
andin
surgical
obamic
may
lead to pain
all or part of the conAt
decompression.
bracing of the spinecan
tralateral
half of the body. The pain is of a burning jects
na- without adequate
myelography,
CSF can be obtained for laboratory excause
ture with a particularly unpleasant quality that
amination.
musculoskeletal pain that improves with rest. Clinical
patients

DISORDERS OF SOMATIC SENSATION / 227

examination commonly reveals spasm of the lumbar
The detection of structural abnormalities by
muscles and restricted spinal movements.
these imaging procedures does not mandate
Management
surgical treatment unless the clinical circumincludes local heat, bed rest on a rm mattress, nonsstances are appropriatedegenerative abnormalities
teroidal antiinammatory drugs or other analgesics,
are
and
common in asymptomatic subjects, especially with
muscle-relaxant drugs, eg, diazepam, 2 mg three adtimes
This most commonly affects the L5S1 or the L45vancing age, and may therefore be of no clinical reledaily,
increased
gradually
untiltosymptoms
vance.
disk. The
prolapse
may relate
injury, butare
in many
relieved
patients it commonly follows minor strain or normal The persistence of low back and root pain despite
(or
to the
highest dose
tolerated).
Vertebral
fractures
may have several causes including
activity.
Protruded
disk material
may
press on
one surgery
or
that
follow
more
severe
injury
and
lead
to
local
pain
inadequate
more nerve roots and thus produce radicular pain,
a
and
segmental motor or sensory decit, or a sphincter decompression, recurrent herniation of disk material,
tenderness
can be visualized at radiography. If cord
root compression or damage as a result of the
disinoperative
turbance inLumbar
addition Intervertebral
to a painful stiffDisk
back. The pain
Prolapsed
volvement
is
suspectedeg,
because
of
leg
procedure, surgery at the wrong level, infective or inmay be reproduced by percussion over the spine or
weakness
folammatory complications of surgery, or spinal
scilowing
injurythe
patient
must
be
immobilized
until
atic nerve, by passive straight leg raising, or by instabilradiographed
to determine whether fracture
ity. In many instances, however, no specic cause can
extendislocation
be
identied
and most patients do not require further
sion of the knee while the hip is exed. The presence
Lumbar
Osteoarthropathy
of
the
vertebral
column
has
occurred.
surgery.
Chronic
pain in this setting may, however, reof
This
tends
to
occur
later life and
mayiscause
low
There
a high
risk
bilateral symptoms and signs suggests that disk spond to spinal cordinstimulation.
back
that patients will not return to work.
material
pain that is increased by activity. Radiologic
has protruded centrally, and this is more likely to be
abnormaliassociated with sphincter involvement than is lateralties vary in severity. In patients with mild symptoms,
a
prosurgical corset is helpful, whereas in more severe
trusion. An L5 radiculopathy causes weak dorsiexion
cases
of the foot and toes, while an S1 root lesion leads to
a
depressed ankle reex and weakness of plantar operative treatment may be necessary. Even minor
changes may cause root or cord dysfunction in
exion
of the foot (see Table 511). In either case, spinal patients
with a congenitally narrowed spinal canal (spinal
movements are restricted, there is local tenderness,
stenosis), leading to the syndrome of intermittent
and
Lasgue sign (reproducing the patients pain on claudication of the cord or cauda equina. This is characterized by painsometimes accompanied by weakstretchness
or radicular
sensory disturbances in the legs
Ankylosing
Spondylitis
ing the sciatic nerve by straight leg raising) is
that
positive.
Backache
and
stiffness,
followed
bypostures
progressive
occurs with
activity
or with
certain
and is reThe L4 root is occasionally affected, but involvement
limitalieved
by
rest.
In
such
circumstances,
spinal
of a higher lumbar root should arouse suspicion oftion of movement, characterize this disorder, which
other causes of root compression. Pelvic and rectaldecompresocsion is indicated.
excurs predominantly in young men. Characteristic
amination and plain x-rays of the spine help to
early
exclude
radiologic ndings consist of sclerosis and narrowing
other diseases, such as local tumors or metastaticof
neothe sacroiliac joints. Treatment is with nonsteroidal
plastic deposits. Symptoms often resolve with simple
anNeoplastic Disease
analgesics, diazepam, and bed rest on a rm
tiinammatory agents, especially indomethacin or asmattress
Extradural
malignant
tumors
are postural
an important
causeis
pirin. Physical
therapy,
including
exercises,
for 23 days, followed by gradual mobilization. Bedof
also important.
rest for longer than 23 days provides no additional
back pain and should be suspected if there is
benet. Nonsteroidal antiinammatory drugs may persistent
be
helpful for acute back pain but are often ineffective
pain
or that worsens despite bed rest. They may
provide only minor or transient benets in patientseventually
with symptoms or signs of root compression. The utillead to cord compression or a cauda equina
ity of epidural steroid injection is uncertain.
syndrome,
Persisting pain, an increasing neurologic decit,depending
or
upon the level of involvement. There may
any evidence of sphincter dysfunction should leadinitially
to
be no change on plain radiographs of the
MRI, CT scanning, or myelography, and surgical treatspine,
ment if indicated by the results of these procedures.
but a bone scan is sometimes revealing. Benign os-

228 / CHAPTER 6
teogenic tumors also produce back pain, and plainCongenital
xAnomalies
rays then show a lytic lesion; treatment is by
Minor spinal anomalies can cause pain because of alexcision.
tered mechanics or alignment or because reduction in
Infections
the size of the spinal canal renders the cord or roots
more liable to compression by degenerative or other
Tuberculous and pyogenic infections of the vertebrae
changes. Children or young adults with congenital deor
fects in spinal fusion (spinal dysraphism) occasionally
intervertebral disks can cause progressive low back
present with pain, a neurologic decit in one or both
pain
legs, or sphincter disturbances. Treatment is of the
and local tenderness. Although there are sometimes
unno
derlying disorder.
systemic signs of infection, the peripheral white cell
count and erythrocyte sedimentation rate are raised.Congenital spinal stenosis may lead to the syndrome of neurogenic claudication, but symptoms usuXally develop only in later life when minor
rays may show disk space narrowing and a soft tissue
degenerative
mass, but they are frequently normal initially.
changes have come to be superimposed on the
The osteomyelitis requires long-term antimicrobial
congenitherapy; surgical debridement and drainage may also
Arachnoiditis
tal anomaly, as discussed on p 227.
be
Severe pain in the back and legs can result from
needed. Spinal epidural abscess (see Chapter 5) similarly presents with localized pain and tenderness, inammation and brosis of the arachnoid layer of the
somespinal
times associated with osteomyelitis. Cord
meninges (arachnoiditis), which may be idiopathic or
compression
may occur with the onset of a rapidly progressive causally related to previous surgery, infection,
Osteoporosis
myelogacLow
back
pain
is
a
common
complaint
in
patients
or long-standing disk disease. There is no adecid paraplegia. MRI, CT scanning, or myelography raphy,
and
with
quate
treatment,
but operation may be possible if the
operative treatment are undertaken urgently if there
osteoporosis,
and
vertebral
fractures
may
occur
arachnoiditis
is
localized.
Spinal cord stimulation may
is
spontaprovide
symptomatic
relief.
This condition is considReferred Pain
evidence of cord compression. In early cases without
neously
or
after
trivial
trauma.
Pain
may
be
helped
by
ered
in
more
detail
in
Chapter
5.
neurologic involvement, treatment with antibioticsDisease of the hip joints may cause
pain in the back
a
alone may be sufcient.
and
thighs
that
is
enhanced
by
activity;
examination
brace to support the back. It is important that
repatients
keep active and take a diet containing adequate veals limitation of movement at the joint with a positive Patrick sign (hip pain on external rotation of the
Paget
disease,
whichvitamin
is characterized
by excessive
amounts
of calcium,
D, and protein.
Estrogen
hip),
bone
therapy
may be of
helpful
in postmenopausal women.
In and x-rays show degenerative changes. Aortic
Paget Disease
the Spine
aneurysms,
cardiac ischemia, visceral and
destruction
and repair, calcitonin,
is of unknown
cause
but may
special circumstances,
sodium
uoride,
or
have
a familial
basis. Pain
is helpful.
commonly the rst genitourinary
phosphate
supplements
are
disease (especially pelvic disorders in women), and
sympretroperitoneal masses also cause back pain. There
tom. Vertebral involvement may also lead to
are
evidence
often other symptoms and signs that suggest the
of cord or root compression. The serum calcium and
underphosphorus levels are normal, but the alkaline phoslying
disorder.Chronic
Moreover,
there
is no localized spinal
phatase is markedly increased. Urinary
Nonspecic
Back
Pain
tenderness
or
restriction
of
motility.
hydroxyproline
In many
patients
chronic back
pain poses a
Treatment
is ofwhose
the underlying
cause.
and calcium are increased when the disease is active.
difXcult management problem, there are no objective
rays show expansion and increased density of the inclinivolved bones, and ssure fractures may be evident in
cal signs or obvious causes of pain despite detailed
the long bones.
inTreatment includes prescription of a high-protein
vestigations. In some cases, the pain may have a
diet with vitamin C supplements. Calcium intake
postural basis; in others, it may be a somatic
should be high in active patients and restricted in immanifestamobilized patients. Vitamin D supplements50,000
tion of a psychiatric disorder. Pain that initially had an
units three times a weekand anabolic hormones
organic basis is often enhanced or perpetuated by
may
nonorganic factors and leads to disability out of proalso be helpful. In active, progressive disease,
portion to the symptoms.
treatment
Nonsteroidal antiinammatory drugs may provide
with calcitonin, diphosphonates, or mithramycin reshort-term symptomatic relief. There is some controduces osteoclastic activity.

DISORDERS OF SOMATIC SENSATION / 229

versy about the chronic use of narcotic analgesics function,
in
can occur as a result of cord involvement.
paThe diagnosis is conrmed by CT scan, MRI, or myeltients with persisting low back pain, but such agents
ography. However, these imaging studies may show
are
abgenerally
best
avoided.
Treatment
with
tricyclic
normalities in asymptomatic subjects in middle or
2. NECK PAIN
antidelater
Neck pain is a common problem in the general
pressant
drugs
is
sometimes
helpful,
and
psychiatric
life, so that any disk protrusion may be incidental and
populaevaluation
may
be
worthwhile.
Unnecessary
surgical
to patients symptoms. Electromyography
tion; surveys indicate that approximately one-thirdunrelated
of
procedures
must
be
avoided.
may
help
to
establish that anatomic abnormalities
the adult population have experienced it over the
are
previof functional relevance.
ous year and in many instances it lasts for more than
In mild cases, bed rest or intermittent neck
6
traction,
months.
Congenital abnormalities of the cervical spine, followed by immobilization of the neck in a collar for
several
weeks,
often helps. If these measures fail or if
such
3. HERPES
Z
OSTER (SHINGLES)
Cervical
Spondylosis
there
is
a
signicant
neurologic
decit, surgical
treatas hemivertebrae or fused vertebrae, basilar
This viral disorder becomes
increasingly
common
ment
may
be
necessary.
This
is
an
important
cause
of
pain
in
the
neck
and
impression,
with
sometimes
accompanied
by a segmental
motor
and instability of the atlantoaxial joint, can cause arms,
advancing
age, causing
an inammatory
reaction
in
or
neck
one
sensory
in the arms
orcranial
by spastic
paraparesis.
pain. The traumatic, infective, and neoplastic
or more decit
of the dorsal
root or
nerve
ganglia, in
It
is
disorders
the affected root or nerve itself, and in the CSF. There
discussed
in Chapter
5. reactivation of varicella
mentioned above as causes of low back pain can also
seems to be
spontaneous
afvirus
fect the cervical spine and then produce pain in the
that remained latent in sensory ganglia after previous
neck.
infection. Herpes zoster is common in patients with
Rheumatoid arthritis may involve the spine,
lymphoma, especially following regional radiotherapy.
especially in
The initial complaint is of a burning or shooting pain
the cervical region, leading to pain, stiffness, and in the involved dermatome, followed within 25 days
reduced
by the development of a vesicular erythematous
mobility; cord compression may result from displacerash.
ment of vertebrae or atlantoaxial subluxation and The
can pain may diminish in intensity as the rash develbe
ops. The rash becomes crusted and scaly after a few
life-threatening if not treated by xation.
days and then fades, leaving small anesthetic scars.
Cervical injuries are an important cause of neckSecpain. Whiplash exion-extension injuries have
ondary infection is common. The pain and
become
dysesthesias
especially common as a result of automobile
may last for several weeks or, in some instances,
accidents.
may
Other occult cervical injuries such as disk clefts and
persist for many months (postherpetic neuralgia) besfore subsiding, especially in the elderly. The increased
sures may be responsible for symptoms in some inincidence and severity of postherpetic neuralgia with
stances, but are difcult to recognize. Management
age
of may reect an age-related reduction in virus-spepersistent symptoms following whiplash injuries is cic cell-mediated immunity. It is not clear whether
conimmunocompromise secondary to HIV infection or
Acute Cervical Disk Protrusion
troversial. Conservative therapeutic measures are connective tissue disease predisposes to postherpetic
Patients
appro- may present with neck and radicular arm neuralgia. Pain is exacerbated by touching the
pain
priate. Other approaches sometimes advocated involved
that
is exacerbated by head movement. The
include
area. Supercial sensation is often impaired in the afmechanism
block of cervical facet joints with bupivacaine and fected
indermatome, and focal weakness and atrophy
responsible
for the
pain
unclear;
pressure onbut
nerve
jection into the
joints
of is
depot
corticosteroids,
can
the
roots
is unlikely
to beand
theoften
sole cause
because
painalso occur. Signs are usually limited to one
response
is variable
short-lived.
Subluxed
may
cerdermatome,
resolve
with
timeare
andanother
conservative
measures despite
vical facet
joints
well-recognized
but more are occasionally involved. Mild pleocytosis
persisting
complica- compression. With lateral herniation of the
and an increased protein concentration sometimes
disk,
there
may also
be segmental
sensory,
or
tion of
automobile
accidents.
Even motor,
minor trauma
may
ocrelead to cervical fractures in an apparently ankylosed
cur in the CSF. The most commonly involved sites are
ex
af- thoracic dermatomes, but involvement of the rst
re- changes, usually at the C6 or C7 level, on the the
fected
side.
With
more
centrally
directed
herniations,
gion in patients with diffuse idiopathic skeletal hyperdivision of the fth cranial nerve, also common, is esspastic
and a sensory
disturbance
in the
ostosis, paraparesis
but major neurologic
decits
are common
pecially
in
distressing and may lead to corneal scarring
legs,
sometimes accompanied by impaired sphincter
such circumstances.
and anesthesia, as well as to a variety of other ocular

230 / CHAPTER 6
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Movement
Disorders
CONTENTS
Types of abnormal
movements, 234
Tremor, 234
Chorea, 235
Hemiballismus, 235
Dystonia & athetosis, 236
Myoclonus, 237
Tics, 237
Clinical evaluation
of patients, 238
History, 238

Diseases & syndromes

manifested by abnormal
movements, 241
Familial, or benign, essential
tremor, 241
Parkinsonism, 241
Progressive supranuclear
palsy, 248
Corticobasal degeneration,
249
Huntington disease, 249
Dentatorubral-pallidoluysian
atrophy, 251
Sydenham chorea, 252
Idiopathic torsion dystonia,
252

Dopa-responsive dystonia,
253
Dystonia-parkinsonism, 253
Myoclonic dystonia, 253
Focal torsion dystonia, 253
Heredodegenerative dystonia, 254
Paroxysmal dyskinesias, 254
Wilson disease, 254
Drug-induced movement
disorders, 256
Gilles de la Tourette syndrome, 258
Acquired hepatocerebral
degeneration, 259
Restless legs syndrome, 259

Examination, 239
Investigative studies, 240

KEY CONCEPTS
The characterization of abnormal movements is
the rst step in identifying their cause; age at
onset, mode of onset, and clinical course are then
diagnostically helpful.
The relationship of tremor to activity may suggest its cause.
A variety of medications induce movement disorders. Neuroleptic-induced dyskinesias take many

forms; some occur months or years after the start

of treatment or after withdrawal of the causal
agent, and may be irreversible.

Pharmacologic treatment of Parkinson disease

should be planned so as to reduce the risk of late
management problems related to levodopa
therapy.

Movement disorders (sometimes called

tion of deep subcortical gray matter structures
extrapyramidal
termed
disorders) impair the regulation of voluntary motorthe basal ganglia. Although there is no universally acaccepted anatomic denition of the basal ganglia, for
tivity without directly affecting strength, sensation,clinical
or
purposes they may be considered to comprise
cerebellar function. They include hyperkinetic disorthe caudate nucleus, putamen, globus pallidus,
ders associated with abnormal, involuntary
subthalmovements
amic nucleus, and substantia nigra. The putamen and
233the
and hypokinetic disorders characterized by poverty
of globus pallidus are collectively termed the
movement. Movement disorders result from dysfunclentiform
Copyright 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.

234 / CHAPTER 7
nucleus; the combination of lentiform nucleus andclassied as tremor, chorea, athetosis or dystonia,
cauballisdate nucleus is designated the corpus striatum. mus, myoclonus, or tics. Such movements can arise
The basic circuitry of the basal ganglia consists for
of
three interacting neuronal loops (Figure 71). The rst
a variety of reasons. In many disorders, abnormal
is a corticocortical loop that passes from the cerebral
movements
TREMOR are the sole clinical features.
cortex, through the caudate and putamen, the
A tremor is a rhythmic oscillatory movement
internal
best characterized by its relationship to volunsegment of the globus pallidus, and the thalamus,
tary motor activityie, according to whether it
and
then back to the cerebral cortex. The second is a occurs at rest, during maintenance of a particular
posnigrosture, or during movement. The major causes of
triatal loop connecting the substantia nigra with the
caudate and putamen. The third, a striatopallidal tremor
are listed in Table 71. Tremor is enhanced by emoloop,
tional stress and disappears during sleep. Tremor that
projects from the caudate and putamen to the
occurs when the limb is at rest is generally referred to
external
as
segment of the globus pallidus, then to the
static tremor or rest tremor. If present during
subthalamic
nucleus, and nally to the internal segment of the sustained
globus pallidus. In some movement disorders (eg, posture, it is called a postural tremor; while this
TYPES
ABNORMAL
tremor
ParkinsonOF
disease),
a discrete site of pathology within
may continue during movement, movement does not
these pathways can be identied; in other cases (eg,
MOVEMENTS
increase its
severity. When present during movement
esPostural
Tremor
sential tremor), the precise anatomic abnormality but
is not at rest, it is generally called an intention
A.
PHYSIOLOGIC
TREMOR and intention tremors are also
Categorizing an abnormal movement is genertremor.
Both postural
unAn
8to
12-Hz
tremor of the outstretched hands is a
ally
the
rst
step
toward
arriving
at
the
neurocalled action tremors.
known.
nding. Its physiologic basis is uncertain.
logic diagnosis. Abnormal movements can normal
be

Cerebral
cortex

Caudate and
putamen

Thalamus

Subthalamic
nucleus
Globus
pallidus

Substantia
nigra

Figure 71. Basic neuronal circuitry of the basal

ganglia.

Table 71. Causes of tremor.

Postural tremor
Physiologic tremor
Enhanced physiologic tremor
Anxiety or fear
Excessive physical activity or sleep deprivation
Sedative drug or alcohol withdrawal
Drug toxicity (eg, lithium, bronchodilators, sodium
valproate, tricyclic antidepressants)
Heavy metal poisoning (eg, mercury, lead,
arsenic)
Carbon monoxide poisoning
Thyrotoxicosis
Familial (autosomal dominant) or idiopathic (benign
essential) tremor
Cerebellar disorders
Wilson disease
Intention tremor
Brainstem or cerebellar disease
Drug toxicity (eg, alcohol, anticonvulsants,
sedatives)
Wilson disease
Rest tremor
Parkinsonism
Wilson disease
Heavy metal poisoning (eg, mercury)

MOVEMENT DISORDERS / 235

B. ENHANCED PHYSIOLOGIC TREMOR
Rest Tremor
Physiologic tremor may be enhanced by fear or
A. PARKINSONISM
anxiety.
A more conspicuous postural tremor may also be Rest tremor usually has a frequency of 46 Hz and is
characteristic of parkinsonism whether the disorder is
found
idfollowing excessive physical activity or sleep deprivaiopathic or secondary (ie, postencephalitic, toxic, or
tion. It can complicate treatment with certain drugs
(notably lithium, tricyclic antidepressants, sodium druginduced in origin). The rate of the tremor, its
valrelationship
proate, and bronchodilators) and is often conspicuous
to activity, and the presence of rigidity or hypokinesia
in patients with alcoholism or in alcohol or drug withusually distinguish the tremor of parkinsonism from
drawal states. It is common in thyrotoxicosis, and it
other forms of tremor. Tremor in the hands may
can
also result from poisoning with a number of sub- appear
as a pill-rolling maneuverrhythmic, opposing
C.
OTHER C
AUSES
stances,
including
mercury, lead, arsenic, and carbon
circular
The
most common type of abnormal postural tremor
monoxide.
movements of the thumb and index nger. There may
is There is no specic medical therapy.
be OTHER CAUSES
benign essential tremor, which often has a familialB.
Less
common
causes
rest tremor
include
Wilson
alternating
exion
andofextension
of the
ngers
or
badishand,
sis. Postural tremor may also be conspicuous in
ease
and poisoning
with and
heavy
metals such
as
or alternating
pronation
supination
of the
patients
mercury.
Asterixis
forearm;
with Wilson disease or cerebellar disorders.
CHOREA
in the feet, rhythmic alternating exion and extension
Asterixis may be associated with postural tremor, but
The
are word chorea denotes rapid irregular muscle jerks
is
that
occurParkinsonism
involuntarily is
and
unpredictably
in detail
different
common.
discussed
in more
itself more properly considered a form of myoclonus
parts
later. of the body. In orid cases, the often forceful in(see below) than of tremor. It is seen most commonly
voluntary movements of the limbs and head and the
in patients with metabolic encephalopathy such as
acoccompanying facial grimacing and tongue movements
curs with hepatic or renal failure.
are unmistakable. Voluntary movements may be disTo detect asterixis, the examiner asks the patient
torted by the superimposed involuntary ones. In mild
to
cases, however, patients may exhibit no more than a
hold the arms outstretched with ngers and wrists expertended. Episodic cessation of muscular activity
sistent restlessness and clumsiness. Power is
causes
generally
sudden exion at the wrists followed by a return to
full, but there may be difculty in maintaining muscuexIntention Tremor
lar contraction such that, for example, hand grip is retension, so that the hands ap in a regular or, more
laxed intermittently (milkmaid grasp). The gait
Intention
tremor occurs during activity. If the patient
ofbecomes
is
ten, an irregular rhythm. The asterixis resolves with
irregular and unsteady, with the patient suddenly dipasked
to of
touch
his or her nose
with a nger, for
clearing
the metabolic
encephalopathy.
ping or lurching to one side or the other (dancing
examgait).
ple, the arm exhibits tremor during movement, often
Speech often becomes irregular in volume and tempo
more marked as the target is reached. This form ofClassication & Pathology
and may be explosive in character. In some patients,
tremor is sometimes mistaken for limb ataxia, but The
the pathologic basis of chorea is unclear, but in some
athetotic
movements or dystonic posturing may also
latter has no rhythmic oscillatory component.
cases
it is associated with cell loss in the caudate
be
Intention tremor results from a lesion affecting the
nucleus
prominent. Chorea disappears during sleep.
superior cerebellar peduncle. Because it is often very
and putamen, and it can be provoked by
coarse, it can lead to severe functional disability. No
dopaminergic
satisfactory medical treatment exists, but stereotactic
agonist drugs. The important causes of chorea are
surgery of the contralateral ventrolateral nucleus of
shown
the
in Table 72 and are discussed later in this chapter.
thalamus or high-frequency thalamic stimulation When chorea is due to a treatable medical disorder,
through an implanted device is sometimes helpful such
HEMIBALLISMUS
when patients are severely incapacitated.
as polycythemia vera or thyrotoxicosis, adequate
Intention tremor can also occurtogether with Hemiballismus
is unilateral chorea that is especially
treatother signs of cerebellar involvementas a
viment of the primary disorder abolishes the
manifestaolent
because the proximal muscles of the limbs are
dyskinesia.
tion of toxicity of certain sedative or anticonvulsant
indrugs (such as phenytoin) or alcohol; it is seen in patients with Wilson disease.

236 / CHAPTER 7
Table 72. Causes of chorea.

Factors Inuencing Dystonia

The abnormal movements are not present during

Hereditary
sleep.
Huntington disease
They are generally enhanced by emotional stress and
Dentatorubro-pallidoluysian atrophy
by
Benign hereditary chorea
voluntary activity. In some cases, abnormal
Wilson disease
movements
Paroxysmal choreoathetosis
or postures occur only during voluntary activity and
Familial chorea with associated acanthocytosis
Static encephalopathy (cerebral palsy) acquired
sometimes
Etiology only during specic activities such as writantenatally
ing, speaking, or chewing.
or perinatally (eg, from anoxia, hemorrhage, trauma, Table 73 lists some of the conditions in which these
kermovement disorders are encountered. Perinatal
nicterus)
anoxia,
Sydenham chorea
birth trauma, and kernicterus are the most common
Chorea gravidarum
causes. In these circumstances, abnormal
Drug toxicity
movements
Levodopa and other dopaminergic drugs
usually develop before age 5 years. Careful
Antipsychotic drugs
questioning
Lithium
usually discloses a history of abnormal early developPhenytoin
ment and often of seizures. Examination may reveal
Oral contraceptives
Miscellaneous medical disorders
signs of mental retardation or a pyramidal decit in
Thyrotoxicosis, hypoparathyroidism, or Addison disease
adHypocalcemia, hypomagnesemia, or hypernatremia dition to the movement disorder.
Hyperglycemia, hypoglycemia
Torsion dystonia may occur as a manifestation of
Polycythemia vera
Wilson disease or Huntington disease or as a sequela
Hepatic cirrhosis
of
Systemic lupus erythematosus, lupus anticoagulant
encephalitis.
syndrome
Dystonic movements and postures are the cardinal
Encephalitis
features
of the disorder known as idiopathic torsion
Acquired immunodeciency syndrome
dystonia (discussed at length later).
Cerebrovascular disorders
Vasculitis
Acute dystonic posturing may result from
Ischemic or hemorrhagic stroke
treatment
Table 73. Causes of dystonia and athetosis.
Subdural hematoma
with dopamine receptor antagonist drugs (discussed
Structural lesions of the subthalamic nucleus
on
Static perinatal encephalopathy (cerebral
p 356).
palsy)
Lateralized dystonia
may occasionally relate to
Pelizaeus-Merzbacher
disease
volved. It is due most often to vascular disease in the
focal
Neuroacanthocytosis
contralateral subthalamic nucleus and commonly reWilson disease
solves spontaneously in the weeks following its onset.
Huntington disease
It
Parkinson disease
is sometimes due to other types of structural disease;
Drugs
in
Levodopa and dopamine agonists
the past, it was an occasional complication of
Antipsychotic drugs
thalamoSerotonin reuptake inhibitors
tomy. Pharmacologic treatment is similar to that for Others (see text)
Toxins (eg, methanol, manganese)
DYSTONIA
ATHETOSIS
chorea (see &
later).
The term athetosis generally denotes abnormal Encephalitis
moveIschemic anoxia
ments that are slow, sinuous, and writhing in
Focal intracranial disease
Progressive supranuclear palsy
character.
Idiopathic torsion dystonia
When the movements are so sustained that they are
Hereditary
better regarded as abnormal postures, the term
Sporadic
dystoFormes frustes of idiopathic torsion dystonia
nia is used, and many now use the terms
Dopa-responsive dystonia
interchangeMyoclonic dystonia
ably. The abnormal movements and postures may Psychogenic
be
factors

generalized or restricted in distribution. In the latter

circumstance, one or more of the limbs may be
affected
(segmental dystonia) or the disturbance may be restricted to localized muscle groups (focal dystonia).

MOVEMENT DISORDERS / 237

intracranial disease, but the clinical context in which
Table 74. Causes of generalized myoclonus.
it
occurs usually identies the underlying cause.
Physiologic myoclonus

Nocturnal myoclonus
Hiccup
Myoclonic jerks are sudden, rapid, twitchlike muscle
Essential myoclonus
Epileptic myoclonus
contractions. They can be classied according to their
distribution, relationship to precipitating stimuli, orSymptomatic myoclonus
etiology. Generalized myoclonus has a widespread Degenerative disordersi
Dentatorubrothalamic atrophy (Ramsay Hunt
dissyndrome)
tribution, whereas focal or segmental myoclonus is
Storage diseases (eg, Lafora body disease)
reWilson disease
stricted to a particular part of the body. Myoclonus Huntington disease
can
Myoclonic dystonia
be spontaneous, or it can be brought on by sensory Alzheimer disease
stimulation, arousal, or the initiation of movement Infectious disorders
Creutzfeldt-Jakob disease
(action myoclonus). Myoclonus may occur as a normal AIDS dementia complex
phenomenon (physiologic myoclonus) in healthy per-Subacute sclerosing panencephalitis
Encephalitis lethargica
sons, as an isolated abnormality (essential
Viral encephalitis
myoclonus),
Metabolic disorders
or as a manifestation
of epilepsy (epileptic
Generalized
Myoclonus
Drug intoxications (eg, penicillin, antidepressants,
myoclonus).
bismuth, levodopa, anticonvulsants)
The
causes
of generalized
myoclonus
are of
It can
also occur
as a feature
of a variety
Drug withdrawal (ethanol, sedatives)
summarized
degeneraHypoglycemia
in
Table
74. Physiologic
myoclonus
includes the my- Hyperosmolar nonketotic hyperglycemia
tive,
infectious,
and metabolic
disorders
oclonus
that occurs upon falling asleep or awakeningHyponatremia
(symptomatic
(nocturnal
myoclonus), as well as hiccup. Essential Hepatic encephalopathy
myoclonus).
myUremia
oclonus is a benign condition that occurs in the ab- Hypoxia
Focal brain damage
sence of other neurologic abnormalities and is someHead injury
times inherited. Epileptic myoclonus may be
Stroke
impossible to differentiate clinically from nonepileptic
Tumors

MYOCLONUS

forms. It may be possible to distinguish the two types

electrophysiologically, however, by the duration of
the
electromyographic burst associated with the jerking,
by
Treatment
demonstrating an EEG correlate with a consistent
Although myoclonus can be difcult to treat, it sometemSegmental Myoclonus
times responds to anticonvulsant drugs such as
Segmental
myoclonus
can
arise
lesions affecting
poral relationship
to the
jerks,
orfrom
by determining
valproic
the
cerebral
cortex,
brainstem,
or
spinal
cord.
For
exwhether muscles involved in the same jerk are
acid, 250500 mg orally three times daily, or to
ample,
involvement
of
the
dentatorubroolivary
pathactivated
benzoway
by
stroke,
multiple
sclerosis,
tumors,
or
other
synchronously.
diazepines such as clonazepam, 0.5 mg orally three
disdaily, gradually increased to as much as 12
orders can produce palatal myoclonus, which maytimes
be
mg/d.
associated with an audible click or synchronous
Postanoxic action myoclonus has been found to be removemarkably responsive to 5-hydroxytryptophan, the
ments of ocular, facial, or other bulbar muscles. Segmetabolic precursor of the neurotransmitter 5mental myoclonus can result from many of the same
hydroxdisturbances that produce symptomatic generalized
ytryptamine (serotonin). The dosage of 5myoclonus (see Table 74). Metabolic disorders such
hydroxytrypas
hyperosmolar nonketotic hyperglycemia can causetophan
TICS is increased gradually to a maximum of 11.5
mg/d orally and may be combined with carbidopa
epilepsia partialis continua, in which a repetitive focal
are sudden,
recurrent,
quick,
coordinated
abnor(maximum,
400 mg/d
orally)
to inhibit
metabolism
in
epileptic discharge occurs from the contralateral Tics
mal
movements
that can usually be imitated without
peripheral
tissues.
sensorimotor cortex and leads to segmental myoclonus.
Segmental myoclonus is usually unaffected by external
stimuli and persists during sleep.

238 / CHAPTER 7
difculty. The same movement occurs again and Mode of Onset
again
Abrupt onset of dystonic posturing in a child
and can be suppressed voluntarily for short periods,
or young adult should raise the possibility of a
aldrug-induced reaction; a more gradual onset of
though doing so may cause anxiety. Tics tend to
dystonic
movements and postures in an adolescent
worsen
sugwith
stress, diminish during voluntary activity or menClassication
gests the possibility of a chronic disorder such as idiotal concentration, and disappear during sleep.
Tics can be classied into four groups depending pathic torsion dystonia or Wilson disease. Similarly,
the
upon
onset of severe chorea or ballismus suggests
whether they are simple or multiple and transient abrupt
or
a
chronic.
vascular cause, and abrupt onset of severe
Transient simple tics are very common in children,
parkinsonism
usually terminate spontaneously within 1 year (often
Course
suggests a neurotoxic cause; more gradual, insidious
within a few weeks), and generally require no treatThe manner
in which the process.
disorder progresses
onset suggests
a degenerative
ment.
from
its
onset
may
also
be
helpful diagnostiChronic simple tics can develop at any age but ofcally. For example, Sydenham chorea usually
ten begin in childhood, and treatment is unnecessary
resolves
within about 6 months after onset and
in
should,
most cases. The benign nature of the disorder must
therefore, not be confused with other varieties of
be
chorea that occur in childhood.
explained to the patient.
Persistent simple or multiple tics of childhood orMedical History
adolescence generally begin before age 15 years. A. DRUG HISTORY
There
It is important to obtain an accurate account
may be single or multiple motor ticsand often vocal of all drugs that have been taken by the
ticsbut complete remission occurs by the end of patient
adoover the years, since many of the movement
lescence.
disorders are iatrogenic. The phenothiazine and butyThe syndrome of chronic multiple motor and vocal
rophenone drugs may lead to the development of abtics is generally referred to as Gilles de la Tourettenormal movements either while patients are taking
synthem or after their use has been discontinued, and
drome, after the
French physician who was one of the
the
CLINICAL
EVALUATION
rst to describe its clinical features. It is discusseddyskinesia
in
may be irreversible. These drugs and the
OF
PATIENTS
dedyskinesias associated with their use are discussed
tail later.
later

HISTORY
Age at Onset

in this chapter.
Reversible dyskinesia may develop in patients
taking
certain other drugs, including oral contraceptives,
The age at onset of a movement disorder may
suggest the underlying cause. For example,levodopa, and phenytoin. Several drugs, especially
onlithium, tricyclic antidepressants, valproic acid, and
set in infancy or early childhood suggests birth
B.
GENERAL MEDICAL
BACKGROUND
bronchodilators,
can
cause tremor. Serotonin
trauma, kernicterus, cerebral anoxia, or an inherited
1.
Chorea
may
be
symptomatic
of the disease in
reuptake
disorder; abnormal facial movements developing in
painhibitors have been associated with a number of
childhood are more likely to represent tics than involtients
move-with a history of rheumatic fever, thyroid
untary movements of another sort; and tremor
disease,
ment disorders including parkinsonism, akathisia,
presentsystemic
lupus erythematosus,
chorea, dystonia,
and bruxism. polycythemia, hying in early adult life is more likely to be of the benign
poparathyroidism,
or cirrhosis of the liver.
essential variety than due to Parkinson disease.
2.
Movement
disorders,
including tremor, chorea,
The age at onset can also inuence the prognosis.
hemiballismus, dystonia, and myoclonus, have been
In
deidiopathic torsion dystonia, for example, progression
to severe disability is much more common when scribed in patients with acquired immunodeciency
syndrome (AIDS). Opportunistic infections such as
symptoxoplasmosis appear to be the cause in
toms develop in childhood than when they developcerebral
in
some
later life. Conversely, tardive dyskinesia is more likely
but infection with human immunodeciency
to be permanent and irreversible when it developscases,
in
virus
type
1 (HIV-1) may also have a direct pathothe elderly than when it develops in the adolescent
genetic
role.
years.

MOVEMENT DISORDERS / 239

3. A history of birth trauma or perinatal distresspersonal scrutiny of close relatives. Any possibility of
may suggest the cause of a movement disorder that
consanguinity should be noted.
develops during childhood.
4. Encephalitis lethargica is no longer encountered
EXAMINATION
clinically; it was epidemic in the 1920s, however, and
was often followed by a wide variety of movement Clinical examination will indicate the nature of the
abnormal movements, the extent of neurologic
disinvolveorders, including parkinsonism. It is therefore imporment, and the presence of coexisting disease; these
tant to inquire about this disease when elderly
in
patients
Family History
turn may suggest the diagnosis.
are being evaluated.
Some movement disorders have an inherited basis The mental status examination may suggest
psychi(Taatric disease, raising the possibility that the abnormal
bles 75 and 76), and it is essential that a complete
movements are related to the psychiatric disorder or
family history be obtained, supplemented if possible
to
by
its treatment
with psychoactive drugsor that the
Table 75. Selected hereditary nonparkinsonian movement
disorders.
patient has a disorder characterized by both abnormal
Disorder

Gene

Locus

Inheritance1

Benign hereditary chorea

BCH

14q13

AD

Dentatorubro-pallidoluysian atrophy

DRPLA

12p13

AD

Dopa-responsive dystonia

GCH1 (DYT5)

14q22.1q22.2

AD

Dopa-responsive dystonia

DYT14

14q13

AD

Dystonia-parkinsonism

DYT3

Xq13.1

XLR

Dystonia-parkinsonism, rapid onset

DYT12

19q13

AD

Essential tremor 1

ETM1

3q13

AD

Essential tremor 2

ETM2

2p22p25

AD

Familial chorea-acanthocytosis

CHA

9q21

AD, AR

Gilles de la Tourette syndrome

GTS

18q22.1

AD

Huntington disease

HD

4p16.3

AD

Myoclonic dystonia, alcohol-responsive

SGCE (DYT11)

7q21

AD

Myoclonic dystonia, alcohol-responsive

DYT15

18p11

AD

Paroxysmal nonkinesigenic dyskinesia

PNKD (DYT8)

2q33q35

AD

Torsion dystonia2

DYT1

9q34

AD

Torsion dystonia, adult onset

DYT6

8p21q22

AD

Torsion dystonia, focal adult onset

DYT7

18p

AD

Choreoathetosis/spasticity, episodic

CSE (DYT9)

1p

AD

Paroxysmal kinesigenic choreoathetosis

PKC (DYT10)

16p11.2q12.1

AD, ?AR

Torsion dystonia, juvenile focal onset

DYT13

1p36.32p36.13

AD

Wilson disease

ATP7B

13q14.3q21.1

AR

1AD,

autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.

forms with autosomal or X-linked recessive inheritance have been described, but the responsible genes have not
been identied.
2Other

240 / CHAPTER 7
Table 76. Hereditary parkinsonism.
Designation

Gene Locus

Gene

Inheritance

PARK1

4q21

SNCA

AD

PARK3

2p13

AD

PARK4

4q21

SNCA triplicate

AD

PARK5

4p14

UCHL1

AD

PARK8

12p11.2q13.1

AD

PARK11

2q36q37

AD

PARK2

6q25.2q27

Parkin

AR

PARK6

1p35p36

AR

PARK7

1p36

DJ1

AR

PARK9

1p36

AR

PARK10

1p

Other genes that have been implicated include NR4A2 on 2q22q23 and SNCA1P on 5q23. Mitochondrial defects or
mutations may also be involved in the pathogenesis of parkinsonism.

movements and behavioral disturbances, such as always be excluded by appropriate serologic tests in
Huntpatients with neurologic disease of uncertain etiology.
ington disease or Wilson disease.
Focal motor or sensory decits raise the possibility
Electroencephalography
of a structural space-occupying lesion, as does paAn EEG is sometimes helpful in diagnosing patients
pilledema. Kayser-Fleischer rings suggest Wilson diswith myoclonus; otherwise, it is of limited usefulness.
ease. Signs of vascular, hepatic, or metabolic disease
may suggest other causes for a movement disorder,
such
Imaging
as acquired hepatocerebral degeneration or
Radiologic studies are occasionally helpful in
vasculitis.
INVESTIGATIVE STUDIES
evaluating
patients with movement disorders. In some patients,
Several investigations may be of diagnostic
Serum
help. and urine copper and serum ceruloplasmin intracranial calcication may be found by skull x-rays
or computed tomography (CT) scans; the signicance
levBlood & Urine Tests
of this nding, however, is not clear. CT scans or
els are important in diagnosing Wilson disease.
magComplete blood count and sedimentation rate are
netic resonance imaging (MRI) may also reveal a
helpful in excluding polycythemia, vasculitis, or systumor
temic lupus erythematosus, any of which can
or other lesion associated with focal dyskinesia or
occasiondystoally lead to a movement disorder.
Genetic Studies
nia,
caudate atrophy
due to Huntington
Blood chemistries may reveal hepatic dysfunction
Recombinant
DNA technology
has been disease,
used to or
basal
related to Wilson disease or acquired hepatocerebral
generganglia
abnormalities
associated
withcertain
Wilson disease.
deate probes
for genes that
determine
generation; hyperthyroidism or hypocalcemia as ainheritable
cause
movement disorders. In this manner, the gene
of chorea; or a variety of metabolic disorders
responsiassociated
ble for Huntington disease has been localized to the
with myoclonus.
terminal band of the short arm of chromosome 4, and
Serologic tests are helpful for diagnosing
the gene for Wilson disease to the long arm of
movement
chromodisorders caused by systemic lupus erythematosussome
or 13. Genetic markers are therefore of diagnostic
luvalue in such disorders (see Tables 75 and 76).
pus anticoagulant syndrome. Neurosyphilis can beTheir
manifested clinically in a variety of ways and should
use may be limited, however, by the genetic hetero-

MOVEMENT DISORDERS / 241

geneity of some diseases, imprecise gene localization
patients respond to alprazolam, up to 3 mg/d in diby
vided doses. Some patients benet from gabapentin,
certain probes, ethical concerns about adverse
topiramate, or intramuscular injections of botulinum
psychotoxin. Anecdotal reports of benet from mirtazapine
logical reactions to the presymptomatic diagnosis were
of
not conrmed in a double-blind study, which
fafound no effect on the tremor in most patients.
tal disorders, and the potential for misuse of such
Some patients have disabling tremor that is unreinforsponsive to pharmacologic measures. Thalamotomy
mation by prospective employers, insurance
may be helpful, but a signicant morbidity is
DISEASES
companies, & SYNDROMES
associated
and government agencies.
with bilateral procedures. High-frequency thalamic
MANIFESTED
BY ABNORMAL
stimulation by an implanted electrode is an effective
MOVEMENTS
alternative to thalamotomy and has a low morbidity. It
may be particularly useful for treatment of the
The
more
common
and
well-dened
diseases
or
synA postural tremor may be prominent in otherwise nordromes
characterized
by
abnormal
movements
are
mal subjects. Although the pathophysiologic basis unoperof
ated side in patients who have already undergone
disthis disorder is uncertain, it often has a familial basis
cussed
with the
principles
of their
treatment. uniPARKINSONISM
with an here
autosomal
dominant
mode
of inheritance.
lateral thalamotomy. Benet is maintained over the
Two
FAMILIAL, OR BENIGN, ESSENTIAL
Parkinsonism
in with
all ethnic
groups;
in the
years in most occurs
patients
severe
disability.
responsible
TREMOR genes have been identied.
United
Symptoms may develop in the teenage or early
States and western Europe it has a prevalence of
adult
12/1000 population, with an approximately equal
years but often do not appear until later. The tremor
sex
typically involves one or both hands or the head and
distribution. The disorder becomes increasingly comvoice, whereas the legs tend to be spared.
mon with advancing age. It is characterized by
Examination
tremor,
Etiology
usually reveals no other abnormalities. Although the
hypokinesia, rigidity, and abnormal gait and posture.
tremor may become more conspicuous with time, it
A. IDIOPATHIC
generally leads to little disability other than cosmetic
and social embarrassment. In occasional cases, The most common variety of parkinsonism occurs
without obvious cause; this idiopathic form is called
tremor
Parkinson disease or paralysis agitans.
interferes with the ability to perform ne or delicate
tasks with the hands; handwriting is sometimes
B. ENCEPHALITIS LETHARGICA
severely
impaired. Speech is affected when the laryngeal In the rst half of the twentieth century, parkinsonism
often developed in patients with a history of von
muscles
Economo encephalitis. Because this type of infection
are involved. Patients commonly report that a small
is
quantity of alcohol provides remarkable but transient
C. DRUG- OR TOXIN-INDUCED PARKINSONISM
not
encountered,
cases ofdrugs,
postencephalitic
relief; the mechanism is not known.
1. now
Therapeutic
drugsMany
such as pheparkinIf treatment is warranted, propranolol, 40120 mg
nothiazines, butyrophenones, metoclopramide, resersonism
aretetrabenazine,
becoming increasingly
orally twice daily, can be prescribedbut it will need
pine, and
can causerare.
a reversible
to be taken for an indenite period. Alternatively, if
parkintremor is particularly disabling under certain pre- sonian syndrome (see p 256).
dictable circumstances, it can be treated with a single
2. Toxic substancesEnvironmental toxins such as
oral dose of 40120 mg of propranolol taken in anticimanganese dust or carbon disulde can lead to
pation of the precipitating circumstances. Primidone
parkinhas also been effective, but patients with essentialsonism, and the disorder may appear as a sequela of
tremor are often very sensitive to this drug, so that
seit
must be introduced more gradually than when it isvere carbon monoxide poisoning or exposure to
used to treat epilepsy. Patients are therefore started
fumes
on
during welding. Experimental studies suggest that
50 mg/d and the daily dose is increased by 50 mg pesevery
ticide exposure is also associated with the
2 weeks until benet occurs or side effects limit development
further
of parkinsonism.
increments. A dose of 100 or 150 mg three times a 3. MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahyday
dropyridine)A drug-induced form of parkinsonism
is often effective. There is no evidence that high has been described in individuals who synthesized
doses
and
(750mg daily) provide any added benet. Occasional
self-administered a meperidine analogue, MPTP. This

242 / CHAPTER 7
compound is metabolized to a toxin that selectively
Caudate and putamen
destroys dopaminergic neurons in the substantia nigra
and adrenergic neurons in the locus ceruleus and inACh
GABA
(+)
duces a severe form of parkinsonism in humans and
in
subhuman primates. The ability of this drug to reproduce neurochemical, pathologic, and clinical features
of
DA ()
Parkinson disease suggests that an environmental
toxin
could be responsible for the idiopathic disorder.
MPTP-induced parkinsonism has been used as a
D.
PARKINSONISM ASSOCIATED WITH OTHER
model
N
EUROLOGIC DISEASES
to assist in the development of new drugs for
Parkinsonism
that occurs in association with
treatment
symptoms
Substantia nigra
of this disease. Rotenone, a mitochondrial toxin, also
and
signs
of
other
neurologic
disorders
is
considered
produces a model of parkinsonism in animals.
Figure 72. Simplied neurochemical anatomy of the
briey under Differential Diagnosis (p 244).
basal ganglia. Dopamine (DA) neurons exert a net
E. FAMILIAL PARKINSONISM
Rarely, parkinsonism occurs on a familial basis. In inhibitory effect and acetylcholine (ACh) neurons a net
excitatory effect on the GABAergic output from the
some
cases with autosomal dominant inheritance, this striatum.
results
from mutations in the gene (4q21). Mutations in the parkin gene (6q25.2q27) are a major system (Figure 73). Other neurotransmitters, such as
cause of early-onset, autosomal recessive, familialnorepinephrine, are also depleted in the brains of patients with parkinsonism, but the clinical relevance of
parkinsonism and of sporadic juvenile-onset
this deciency is less clear.
Parkinson
Disorder of the balance of inhibition and excitation
disease. A number of different rearrangements of
exons
and different point mutations have been found in
Caudate and putamen
such
patients. Several other genes or chromosomal
regions
Pathology
ACh
GABA
have been implicated in different familial forms of the
(+)
In
idiopathic
parkinsonism,
pathologic
examination
disease (Table 76), and a genetic susceptibility locus
shows
loss
of pigmentation
and cells
in the
has also
been
identied in patients
with
thesubstantia
typical
nigra
and
other
brainstem
centers,
cell
loss
in the
lateglobus
pallidus and
putamen,
and the presence of
onset, apparently
sporadic
disorder.
laDA ()
mentous eosinophilic intraneural inclusion granules
(Lewy bodies), containing the protein in
the basal ganglia, brainstem, spinal cord, and sympathetic ganglia. These inclusion bodies are not seen in
postencephalitic parkinsonism; instead there may be
nonspecic neurobrillary degeneration in a number
of
Substantia nigra
diencephalic structures as well as changes in the substantia nigra.
Pathogenesis
Figure 73. Neurochemical pathology of basal ganglia in Parkinson disease. Dopamine (DA) neurons
Both dopamine and acetylcholine are present in the
degenerate (black circle and dashed line), upsetting the
corpus striatum, where they act as neurotransmitters
normal balance between dopaminergic inhibition and
(Figure 72). In idiopathic parkinsonism, it is generally
cholinergic (ACh) excitation of striatal output (GABA)
believed that the normal balance between these two
neurons.The net effect is to increase GABAergic output
anfrom the striatum.
tagonistic neurotransmitters is disturbed because of
dopamine depletion in the dopaminergic nigrostriatal

MOVEMENT DISORDERS / 243

may ultimately be present in all of the limbs, it is not
uncommon for the tremor to be conned to one
limbor to the two limbs on one sidefor months or
Cortex
Cortex
years before it becomes more generalized. In some
patients tremor never becomes prominent.
Putamen
B. RIGIDITY
Putamen
D2
D1
Rigidity or increased toneie, increased resistance to
passive movementis a characteristic clinical feature
of
SNc
SNc
I
D
parkinsonism. The disturbance in tone is responsible
for the exed posture of many patients with
parkinsonGPe
GPe
VL
ism. The resistance is typically uniform throughout
VL
the
STN
STN
range of movement at a particular joint and affects
agonist and antagonist muscles alikein contrast to the
GPi/SNr
GPi/SNr
ndings in spasticity, where the increase in tone is
often
greatest at the beginning of the passive movement
Brainstem
(clasp-knife phenomenon) and more marked in some
Spinal cord
muscles
than in others. In some instances, the rigidity
C.
HYPOKINESIA
in
parkinsonism
is described
cogwheel
beThe
most
disabling
feature ofas
this
disorderrigidity
is
Figure 74. A model of the basal ganglia and its concause
of
ratchetlike
interruptions
of
passive
hypokinenections under normal conditions (A) and in the setting
sia (sometimes called bradykinesia or akinesia)a
of parkinsonism (B). I refers to the indirect pathway andmovement
that may of
bevoluntary
due, in part,
to the presence
of tremor.
slowness
movement
and a reduction
in
D refers to the direct pathway. Blue arrows indicate
inhibitory connections; white arrows indicate excitatory auconnections.The thickness of the arrows indicates the tomatic movement, such as swinging the arms while
amount of activity in the various projections. GPe, exter-walking. The patients face is relatively immobile
nal segment of the globus pallidus; GPi, internal seg- (masklike facies), with widened palpebral ssures, inment of the globus pallidus; SNr, substantia nigra pars
frequent blinking, a certain xity of facial expression,
reticulata; SNc, substantia nigra pars compacta; STN,
and a smile that develops and fades slowly. The voice
subthalamic nucleus; VL, ventrolateral thalamus.
is
(ReproducedwithpermissionfromWichmann
of low volume (hypophonia) and tends to be poorly
T,VitejJL,DeLongMR:TheNeuroscientist
modulated. Fine or rapidly alternating movements are
1995;1:236.)
impaired, but power is not diminished if time is allowed
for it to
develop.
The handwriting is small,
D.
ABNORMAL
GAIT
AND POSTURE
tremulous,
hard tonds
read.
The
patientand
generally
it difcult to get up from
bed or an easy chair and tends to adopt a exed
within the basal ganglia and its connections via direct
posture
and indirect pathways has been proposed to explain
on standing (Figure 75). It is often difcult to start
the
walking, so that the patient may lean farther and farimpaired motor function in Parkinson disease. These
ther forward while walking in place before being able
pathways are illustrated in Figure 74.
to advance. The gait itself is characterized by small,
Clinical Findings
shufing steps and absence of the arm swing that
norA. TREMOR
mally accompanies locomotion; there is generally
The 4- to 6-Hz tremor of parkinsonism is characteristisome
cally most conspicuous at rest; it increases at times
unsteadiness on turning, and there may be difculty
of
in
emotional stress and often improves during voluntary
stopping. In advanced cases, the patient tends to
activity. It commonly begins in the hand or foot, E.
walk
OTHER CLINICAL FEATURES
where
with increasing
speed
to prevent a (uttering
fall (festinating
There
is often mild
blepharoclonus
of the
it takes the form of rhythmic exion-extension of the
gait) eyelids) and occasionally blepharospasm
closed
ngers or of the hand or footor of rhythmic pronabecause of the altered center of gravity that results
(involtion-supination of the forearm. It frequently involves
from
untary closure of the eyelids). The patient may drool,
the face in the area of the mouth as well. Althoughthe
it abnormal posture.
A. Normal

B. Parkinsonism

same patient. A trial of antidepressant drug

treatment
may be helpful if diagnostic uncertainty cannot be resolved by the presence of more widespread
244 / CHAPTER 7
neurologic
signs indicative of parkinsonism.
Essential (benign, familial) tremor has been considered separately (see earlier). An early age at onset, a
family history of tremor, a benecial effect of alcohol
on the tremor, and a lack of other neurologic signs
distinguish this disorder from parkinsonism.
Furthermore,
essential tremor commonly affects the head (causing
a
nod or head shake); parkinsonism typically affects
the
face and lips rather than the head.
Diffuse Lewy body disease is a disorder of recently
evolving denition. It occurs especially in patients
aged
between 60 and 80 years and is marked clinically by
the
combination of a rapidly progressing neurobehavioral
syndrome of dementia and hallucinations and extrapyramidal motor features characteristic of
Parkinson
disease. Myoclonus may also be seen. There is only
an
incomplete response to levodopa, but patients are extremely sensitive to parkinsonian complications of
neuroleptics as well as to the side effects of
antiparkinsonian drugs.
Wilson disease can also lead to a parkinsonian syndrome,
but other varieties of abnormal movements
Figure 75. Typical exed posture of a patient with
are
parkinsonism.
usually present as well. Moreover, the early age at
onset
perhaps because of impairment of swallowing. There
and the presence of Kayser-Fleischer rings should disis
tinguish Wilson disease from Parkinson disease, as
typically no alteration in the tendon reexes
should the abnormalities in serum and urinary copper
(although
and serum ceruloplasmin that occur in Wilson
a mild hyperreexia may occur on the affected side
in
disease.
asymmetrical parkinsonism), and the plantar
Huntington disease may occasionally be mistaken
responses
for parkinsonism when it presents with rigidity and
are exor. Repetitive tapping (about twice per
akinesia, but a family history of Huntington disease or
second)
an accompanying dementia, if present, should
over the bridge of the nose produces a sustained suggest
blink
the correct diagnosis, which can be conrmed by geresponse (Myerson sign); the response is not
netic studies.
sustained
Shy-Drager syndrome (multisystem atrophy) is a
in normal subjects. Cognitive decline sometimes degenerative disorder characterized by parkinsonian
occurs
features, autonomic insufciency (leading to postural
but
is
usually
mild
and
late.
Depression
and
visual
hypotension, anhidrosis, disturbance of sphincter
Differential Diagnosis
halconThe
diagnosis
be difcult
to make in
mild cases.
lucinations
aremay
frequent.
Dysautonomic
symptoms
trol, impotence, etc), and signs of more widespread
Depression may be accompanied by a somewhat
are
neurologic involvement (pyramidal or lower motor
exfrequent, especially urinary urgency and urge incontineuron signs and often a cerebellar decit). There is
pressionless
face, poorlypostural
modulated
voice, andrelates
reducnence and constipation;
hypotension
no
tion
voluntary to
activity;
it can thus
simulate
parkinmostincommonly
dopaminergic
therapy
or inactivity
treatment for the motor decit, but the postural hysonism.
two diseases
often coexist in
but mayMoreover,
also reectthe
baroreex
failure.
potension may respond to a liberal salt diet;
the
udrocortisone, 0.11 mg/d; midodrine (an 10 mg

MOVEMENT DISORDERS / 245

Progressive supranuclear palsy is a disorder in
Caudate and putamen
which there may be bradykinesia and rigidity, but its
characteristic features are early postural instability
1
and
ACh
GABA
falls, loss of voluntary control of eye movements
(+)
(espe2
cially vertical gaze), frontotemporal dementia,
pseudobulbar palsy, dysarthria, and axial dystonia. The
DA ()
disorder
responds poorly, if at all, to antiparkinsonian drugs. It
is discussed on p 248.
Corticobasal degeneration is characterized
clinically
by both cortical and basal ganglionic dysfunction.
Rigidity, bradykinesia, tremor, postural disturbances,
Substantia nigra
and dystonia are accompanied by such additional
decits as cortical sensory loss, apraxia, focal reex
Figure 76. Therapeutic approaches in Parkinson dismyease.The balance between dopaminergic (DA) and
oclonus, dementia, or aphasia. Symptoms are often
cholinergic (ACh) inuences on striatal output (GABA)
strikingly asymmetric. Treatment with
neurons can be restored by (1) blockade of cholinergic
antiparkinsonian
transmission with muscarinic anticholinergic drugs or
medication is usually unrewarding, although some(2)
pa-enhancement of dopaminergic transmission with
the dopamine precursor levodopa, dopamine-agonist
tients do respond to Sinemet (p 249).
or amantadine (which stimulates the release of
Creutzfeldt-Jakob disease may be accompanied drugs,
by
dopamine from surviving nerve terminals).
parkinsonian features, but dementia is usually
present,
myoclonic jerking is common, and ataxia is
sometimes
prominent; there may be pyramidal signs and visual
in parasympathetic end organs. Confusion, especially
disturbances, and the EEG ndings of periodic dis-in the elderly, is due to antimuscarinic effects in the
charges are usually characteristic.
brain. Treatment is started with a small dose of one of
Normal-pressure hydrocephalus leads to a gait disthe anticholinergics; the dosage is then gradually inturbance (often mistakenly attributed to parkinsoncreased until benet occurs or side effects limit
Treatment
ism), urinary incontinence, and dementia. CT scan-further
ning
dilationrequires
of the ventricular
system ofbut
the
Earlyreveals
parkinsonism
no drug treatment,
it
increments.
If treatment is not helpful, the drug is
brain
without
cortical
atrophy.
The
disorder
may
is important to discuss with the patient the naturewithdrawn
of
and another anticholinergic preparation is
follow
the disorder and the availability of medical treatment
tried.
B. AMANTADINE
head
injury, intracranial hemorrhage, or meningoenif
cephalitis,
but
the
cause
is
often
obscure.
Surgical
symptoms become more severe and to encourageAmantadine can be given for mild parkinsonism
shunting
procedures to bypass any obstruction to either
the
activalone
or in combination with an anticholinergic agent.
ow
of
cerebrospinal
uid
(CSF)
are
often
benecial.
ity. Treatment, when indicated, is directed toward
Its
precise
mode of action is unclear. Its advantages
restoring the dopaminergic:cholinergic balance in the
are
striatum
by blocking
the effect of acetylcholine with
A.
ANTICHOLINERGIC
DRUGS
that it improves all the clinical features of parkinsonanticholinergic
drugs
or bydrugs
enhancing
dopaminergic
Muscarinic anticholinergic
are more
helpful in
ism, its side effects (restlessness, confusion, skin
transmission
(Figure 76).
alleviating tremor and rigidity than hypokinesia but rashes,
are
edema, disturbances of cardiac rhythm) are relatively
generally less effective than dopaminergic drugs (see
uncommon, its effects are exerted rapidly, and it is
below). A number of preparations are available, and given in a standard dose of 100 mg orally twice daily.
Unfortunately, however, many patients fail to respond
indito this drug, or its benet is short-lived. Amantadine
vidual patients tend to favor different drugs. Among
C.
LEVODOPA
may
also be useful in reducing iatrogenic dyskinesias
the most commonly prescribed drugs are triLevodopa, which is converted in the body to
in
hexyphenidyl and benztropine (Table 77). Common
dopamine
(Figure 77),
ameliorates all the mapatients
with advanced
disease.
side effects include dryness of the mouth,
jor clinical features of parkinsonism and, unlike
constipation,
urinary retention, and defective pupillary
accommodation; these are caused by muscarinic receptor
blockade

the anticholinergic drugs, is often particularly helpful

against hypokinesia. There is controversy about the
best
time to introduce dopaminergic therapy. Concerns
246 / CHAPTER 7
that
levodopa loses its effectiveness with time in some paTable 77. Drugs used in the treatment
tients are probably misplaced, but response
of Parkinson disease.
uctuations
sometimes occur after it has been used for several
Total Daily Dose (mg)1
Drug
years,
and these may be particularly disabling and difcult
Anticholinergics
to
Benztropine (Cogentin)
16
manage. It may be wise to defer its introduction as
Trihexyphenidyl (Artane)
620
long
Amantadine (Symmetrel)
100200
as possible and then use dopamine agonists
Levodopa (Sinemet; Stalevo)
30010002
(discussed
Dopamine agonists
Ergolides
below) in conjunction with it to keep the levodopa
Bromocriptine (Parlodel)
dose as low as possible.
1530
Pergolide (Permax)
The most common side effects of levodopa are
35
Nonergolides
nauPramipexole (Mirapex)
sea, vomiting, hypotension, abnormal movements
1.54.5
Ropinirole (Requip)
824
(dyskinesias), restlessness, and confusion. Cardiac arrhythmias occur occasionally. The late dyskinesias
MAO-B inhibitor
and
Selegiline (Eldepryl)
10
behavioral side effects occur as dose-related
phenomCOMT inhibitor
Entacapone (Comtan)
6001000
ena, but reduction in dose may diminish any
Tolcapone (Tasmar)
300600
therapeu1 Doses are range for total daily maintenance; all drugs aretic benet. Treatment with clozapine, a dibenzodiadministered in divided doses. Introduction is at a lower azepine derivative that does not block the
dose, which is gradually increased. Drug interactions are therapeutic
common; the addition of one drug may mandate reductioneffects of dopaminergic medication, may relieve
of another. Psychoactive side effects are common with all confuof these agents.
sion and psychotic mental disturbances and, in some
2 Refers to the levodopa component of the carbidopa/levinstances, the dyskinesias. Clozapine requires regular
odopa combination (eg, 25/250 represents 250 mg of levmonitoring of the leukocyte count. Olanzapine, quetiodopa).
apine, and risperidone are alternative agents that
may
be less effective but do not affect the blood count.
Another late complication of levodopa therapy is
response
uctuation such as the wearing-off effect, in which
deterioration occurs shortly before the next dose is to
OH
HO
be
C
O
H
taken, or the on-off phenomenon, in which abrupt but
transient uctuations in the severity of parkinsonism
HO
NH2
C
C
occur at frequent intervals during the day, apparently
without any relationship to the last dose of levodopa.
H
H
This sometimes disabling problem is unaffected by
Levodopa
concomitant administration of carbidopa. It can be
DOPA DECARBOXYLASE
controlled only partly by varying the dosing intervals,
administering levodopa 1 hour before meals,
HO
restricting
H
H
dietary protein intake, or providing treatment with
HO
NH2
C
C
dopamine agonists.
Carbidopa is a drug that inhibits dopa decarboxyH
H
lase, the enzyme responsible for the breakdown of
Dopamine
levodopa to its active metabolite, dopamine (see Figure
Figure 77. Metabolism of levodopa to dopamine.
77), but does not cross the blood-brain barrier. Accordingly, if levodopa is given in combination with
carbidopa, the breakdown of levodopa is limited outside
the central nervous system. The daily dose of

D. DOPAMINE AGONISTS
The older agonists are ergot derivatives.
Bromocriptine
stimulates dopamine D2 receptors. It is perhaps
MOVEMENT DISORDERS / 247
slightly
less effective than levodopa in relieving the
Levodopa therapy (either alone or in conjunctionsponse and tolerance. A common maintenance dose
symptoms
with carbidopa) is contraindicated in patients with is
of parkinsonism but is less likely to cause dyskinesias
narbetween 0.5 and 1.5 mg three times daily. Ropinirole
or
row-angle glaucoma or psychotic illness and should
is
the on-off phenomenon. In consequence, it has been
be
started at 0.25 mg three times daily and the total
recommended that when dopaminergic therapy is to
avoided in patients receiving monoamine oxidase daily
A
be
indose increased at weekly intervals by 0.75 mg until
introduced, the patient be started on Sinemet, 25/100
hibitors. It should also be used with care in patients
the
three times daily, with bromocriptine then added and
with active peptic ulcers or suspected malignant fourth week and by 1.5 mg thereafter. Most patients
gradually increased. The starting dose of
melanomas.
need between 2 and 8 mg three times daily for
bromocriptine
A controlled-release (CR) formulation of Sinemetbenet.
is 1.25 mg/d for 1 week and 2.5 mg/d for the next
may reduce response uctuations and the dosing freAdverse effects of these medications include fatigue,
week, after which the daily dose is increased by 2.5E. CATECHOL-O-M
ETHYLTRANSFERASE
quency.
somnolence,
nausea,
peripheralINHIBITORS
edema, dyskinesias,
mg
These
inhibitors
may
be
used
to
reduce the dose reconfusion, hallucinations, and orthostatic
increments every 2 weeks, depending on the
quirements
of
and
any
response
uctuations to
hypotension.
response
Sinemet.
An irresistible urge to sleep at inappropriate times
and the development of side effects. MaintenanceTheir use leads to more sustained plasma levels of
has
doses
levalso been reported and may lead to injury.
are usually between 2.5 and 10 mg orally three times
odopa, with improved transport into the blood and
daily. Side effects are similar to those associated with
across the blood-brain barrier. Side effects include
levodopa therapy, but psychiatric effects such as diardelurhea, confusion, dyskinesias, and abnormalities of
sions or hallucinations are especially common, andliver
bromocriptine is therefore contraindicated in patients
function tests. Two of these inhibitors are in
with a history of psychotic disorders. Relative con-widespread
traindications to its use are recent myocardial infarcuse. Tolcapone is taken in a daily dose of 100 or 200
tion, severe peripheral vascular disease, and active
mg
pepthree times daily. Acute hepatic necrosis has occurred
tic ulceration. Pericardial, pleural, or retroperitoneal
in
brosis are rare, ergot-related side effects.
rare instances in patients receiving this medication
Pergolide also is an ergot derivative and dopamine
and,
receptor agonist; unlike bromocriptine, it activatesaccordingly, entacapone (200 mg) taken with
both
Sinemet
D1 and D2 receptors. Its indications, side effects, and
up to ve times daily is generally preferred.
contraindications are similar to those described
A commercial preparation named Stalevo is now
above
available that combines levodopa with both
for bromocriptine, and it is unclear whether either F.
carbidopa
SELEGILINE
compound is clinically superior to the other. The startand entacapone.
In addition
to or
thedeprenyl)
convenience
Selegiline
(also called
eldepryl
is a of
ing dose is 0.05 mg orally daily for 2 days, increased
simmonoamine
oxidase type B inhibitor and therefore inby
plifying
the
drug regime
and requiring
the
hibits
the
metabolic
breakdown
of dopamine
(Figure
0.10.15 mg/d every 3 days for 12 days and by 0.25
consumption
78).
It thus enhances the antiparkinsonian effect of
mg/d every 3 days thereafter. The average
of
a lesserand
number
of tablets
than
otherwise,
it is in
levodopa
may reduce
mild
on-off
uctuations
maintenance
priced
redose is 1 mg orally three times daily. Pergolide
at or below theSome
price clinical
of its individual
components.
sponsiveness.
studies suggest
that It
recently
is
selegihas been associated with the development of valvular
available
in three
combinations:
Stalevo
50 (50 mg
line
may also
delay
the progression
of Parkinson
heart disease in about one-third of patients,
levdisease,
suggesting
odopa plus
12.5
mg carbidopa
and 200
mg regard;
although
the
evidence
is incomplete
in this
that a non-ergot agonist is to be preferred.
entacapone),
when
The new dopamine agonists, pramipexole and G.
Stalevo
(100 mg, 25 mg,
and 200
mg, kept for
used
for100
neuroprotection,
selegiline
is best
SURGERY
ropinirole, are not ergot derivatives. They seem toSurgical
be
respectively),
patreatment of parkinsonism by thalamotomy
as
and Stalevo
150disease.
(150 mg,37.5
mg,isand
200
mg).twice
tients
with mild
The dose
5 mg
orally
or
effective as the older agonists but are without their
daily, usuallyisgiven
in when
the day
to avoid
pallidotomy
often early
helpful
patients
become
poinsomnia.
unretential ergot-related adverse effects, and may be sponsive to pharmacologic measures or develop
used in
intoleraearly or advanced Parkinson disease. Pramipexole ble
is adverse reactions to antiparkinsonian medication.
started at 0.125 mg three times daily; the daily dose
Leis
sions of the internal segment of the globus pallidus
doubled after one week and again after another (GPi), for example, will attenuate its unbalanced inweek; it

248 / CHAPTER 7
tation of human embryonic mesencephalic tissue
containing dopaminergic neurons, benet occurred in
HO
NH2
CH2
CH2
young patients (less than 60 years old) but not in
older
subjects; among those initially responding favorably,
Dopamine
severe uncontrolled dyskinesias and dystonias
Selegiline
developed
MONOAMINE OXIDASE
more than 1 year later in some patients despite
(type B)
reducHO
tion or discontinuation of antiparkinsonian medication
O
and was attributed to a relative excess of dopamine
from continued ber outgrowth from the transplant.
HO
CH2
C
OH
In
a second such trial, benet was inconsequential but,
again, dyskinetic complications occurred and were
Dihydroxyphenylacetic acid
J.
PROTECTIVEincapacitating.
THERAPY
sometimes
Clearly, more fundamental
Attempts
have
been before
made to
slowtrials
the progression
studies are required
other
of cellular of
Figure 78. Metabolic breakdown of dopamine.
the
disease
by
inuencing
the
mechanisms
involved
Selegiline interferes with the breakdown of dopamine therain
by inhibiting the enzyme monoamine oxidase type B. pies in this disease. Thus, these approaches remain
cell
in- death. In addition to treatment with monoamine
oxidase
inhibitors
suchwithout
as selegiline,
vestigational,
are not
hazard,mentioned
and involve unearlier,
certain
mechanisms.
hibitory output (see Figure 74). Treatment by surgery
there are reasons to examine whether benet may
is
folsometimes helpful in relatively young patients withlow treatment that enhances mitochondrial function
pre(such as with coenzyme Q10), limits glutamate
dominantly unilateral tremor and rigidity that havetoxicity,
failed to respond to medication; thalamotomy is more
inhibits inammatory responses (eg, minocycline), or
helpful for tremor, and pallidotomy for hypokinesia.
has an anti-apoptotic effect. Certain monoamine oxiDiffuse vascular disease or dementia is a
dase inhibitors such as selegiline and rasagiline have
contraindication
anti-apoptotic properties, as also do certain
to this approach. The rate of signicant complications
dopamine
is
K.
PHYSICAL
THERAPY
ANDalso
AIDShave
FOR Ddirect
AILY LIVING
agonists
(which
may
antioxidant efless than 5% after unilateral pallidotomy or thalamoPhysical
therapy
and
speech
therapy
are benecial to
fects).
A
number
of
clinical
trials
are
currently
H.
DEEPbut
BRAIN
STIMULATION
tomy,
about
20% or more after bilateral
many
patients with parkinsonism, and the quality of
examinHigh-frequency
thalamic stimulation is effective for
procedures,
life
ing these therapeutic possibilities, and also the
the
which are therefore best avoided. Thus, deep braincan
often be improved by providing simple aids to
regenerrelief
stim- of parkinsonian tremor. Deep brain stimulation
daily
of
the globus
pallidus
subthalamic
nucleus mayative role of the replacement of growth factors.
ulation
is generally
theorpreferred
approach.
living. Such aids may include extra rails or banisters
help
placed strategically about the home for additional
all the cardinal features of the disease and reduces
supthe
port, table cutlery with large handles, nonslip rubber
time spent in the off-state in patients with response
table mats, devices to amplify the voice, and chairs
uctuations. This approach has the advantage of
that
PROGRESSIVE SUPRANUCLEAR PALSY
being
Progressive
supranuclear
palsyatisthe
an push
idiopathic
will gently eject
the occupant
of a button.
reversible, of having a lower morbidity than ablative
degenersurgical procedures (especially when bilateral proceative disorder, a tauopathy, that primarily affects
I.
CELLULAR
THERAPIES
dures
are contemplated),
and of causing minimal subAutologous
or fetal adrenal medullary tissue or fetal
damcortical gray matter regions of the brain. There is
substantia
nigra
transplanted
the
age to the brain. has
It is been
contraindicated
in to
patients
with
much
putamen
atypical parkinsonism or dementia.
overlap clinically and pathologically with corticobasal
or caudate nucleus, in the belief that the transplanted
degeneration. The principal neuropathologic nding is
tissue can continue to synthesize and release
neuronal degeneration with the presence of
dopamine.
neurobrilResults from preliminary studies have been contradiclary tangles in the midbrain, pons, basal ganglia, and
tory, and this approach is highly controversial. In one
dentate nuclei of the cerebellum. Associated neurorecent controlled trial involving intracerebral
chemical abnormalities include decreased concentratransplantions of dopamine and its metabolite homovanillic
acid
HO

MOVEMENT DISORDERS / 249

in the caudate nucleus and putamen. The classic erative disorder, a tauopathy that occurs in middlecliniaged
cal features are gait disturbance with early falls, or elderly persons of either sex. It is characterized
supranuclear ophthalmoplegia, pseudobulbar palsy,
pathologically by the presence intracellularly of
axabnorial dystonia with or without extrapyramidal rigiditymal
of lamentous deposits containing tau protein. It
the limbs, and dementia. Men are affected twice as
sometimes simulates Parkinson disease when
ofbradykiClinical
Findings
ten as women,
and the disorder has its onset
nesia and rigidity are conspicuous features. Posturalbetween
acSupranuclear ophthalmoplegia is characterized by
ages 45 and 75 years.
tion tremor may also occur, but the usual cause of
prominent failure of voluntary vertical gaze, with later
proparalysis of horizontal gaze; oculocephalic and
found disability is apraxia and clumsiness rather than
oculovestibular reexes are preserved. Postural
extrapyramidal decits. Other features of the estabinstability
lished disorder include speech disturbances (aphasic,
and unexplained falls also occur early and may
apraxic, or dysarthric), acalculia, cortical sensory
precede
decits (such as neglect syndromes), stimulusvertical gaze palsies. In addition, the neck often
sensitive
assumes
myoclonus, alien limb phenomenon (the tendency for
an extended posture (axial dystonia in extension),
a limb to move semipuposefully, involuntarily, and
with
without
the knowledge
Differential
Diagnosisof its owner), dysphagia, posresistance to passive exion. Rigidity of the limbs and
tural disturbances, dystonic features, and ultimately
bradykinesia may mimic Parkinson disease, but The disorder is distinguished from Parkinson disease
cognitive decline and behavioral changes. Frontal retremor
by
lease signs, brisk tendon reexes, and extensor
is rare. A coexisting pseudobulbar palsy produces the marked apraxia that often leads to a useless limb,
plantar
facial
difculty
opening
or closing
the eyes, or speech
responsesinmay
also be
encountered.
weakness, dysarthria, dysphagia, and often
disexaggerated
turbances. The presence of pyramidal and cortical
jaw jerk and gag reexes; there may also be
decits in addition to any extrapyramidal dysfunction
exaggerated
and the relative preservation of cognitive function, at
Differential
Diagnosis
and inappropriate
emotional responses
least until late in the course of the disorder, also help
(pseudobulbar
in
Parkinson disease differs in that voluntary downward
affect). Hyperreexia, extensor plantar responses,this regard, but denitive diagnosis can be made only
and
and
Treatment
horizontal gaze are not usually lost, axial posture at
cerebellar signs are sometimes seen. The dementia
autopsy. MRI may show cortical and midbrain atrophy
tends to
Antiparkinsonian
generally unhelpful
of
enlargement medication
of the third is
ventricle.
be characterized by exion rather than extension, and
progressive supranuclear palsy is characterized bybut
tremor
is certainly worthy of trial. No specic therapy exists.
forgetTreatment
is common, the course is less fulminant, and
fulness, slowed thought processes, alterations of Treatment is purely supportive.
antiparkinDopaminergic
preparations are occasionally of benet
mood
Prognosis
sonian medications are more often effective.
for
and bradykinesia.
andrigidity
personality,
and impairedAnticholinergics
calculation and such as
amitriptyline,
5075 mg orally at bedtime, or ben- The disorder follows a progressive course, leading to
abstracinztropine,
mg/d
orally, have
tion. Focal610
cortical
dysfunction
is been
rare. reported to imcreasing disability and dependence. Death typically
prove speech, gait, and pathologic laughing or crying,
foland methysergide, 812 mg/d orally, may ameliorate
lows within 10 years, often sooner, from aspiration
dysphagia. There is no treatment for the dementia.
pneumonia.
Treatment is supportive.

Prognosis

HUNTINGTON DISEASE
Epidemiology

The disorder typically follows a progressive course,Huntington disease is a hereditary disorder of the
with
nervdeath from aspiration or inanition within 212 (usually
ous system characterized by the gradual onset and
47) years.
subsequent progression of chorea and dementia. It
CORTIC0BASAL DEGENERATION
occurs
Corticobasal degeneration is a rare, nonfamilial, throughout the world and in all ethnic groups. Its
prevalence rate is about 5 per 100,000 population.
degenSymptoms usually do not appear until adulthood
(typically between 30 and 50 years of age), by which time

250 / CHAPTER 7
these patients have often started families of their tyric acid (GABA) and enkephalin and project to the
own;
external segment of the globus pallidus are affected
thus, the disease continues from one generation toearthe
liest, but other classes of neurons are eventually innext.
volved as well. Biochemical studies have shown that
Genetics
the
Huntington disease is an autosomal dominant
concentrations of the inhibitory neurotransmitter
disorder
GABA, its biosynthetic enzyme glutamic acid decardue to a mutation in the huntingtin gene on chromoboxylase (GAD), and acetylcholine and its
some 4p16.3. The disease shows complete
biosynthetic
penetrance,
enzyme choline acetyltransferase are all reduced in
so that offspring of an affected individual have a 50%
the
chance of developing it. Additional features of the basal
inganglia of patients with Huntington disease.
heritance of Huntington disease include anticipation,
The
meaning that there is a trend toward earlier onset concentration
in
of dopamine is normal or slightly insuccreased. Changes in the concentrations of neuropepcessive generations, and paternal descent, which tides in the basal ganglia have also been found,
refers
includto the tendency for anticipation to be most
ing decreased substance P, methionine enkephalin,
pronounced
dynorphin, and cholecystokinin and increased
Pathophysiology
in individuals who inherit the disease from their somatoHow
expanded
CAG repeat
in huntingtin
leads to
father.
statinan
and
neuropeptide
Y. Neurons
containing
Huntington
disease
is
unknown,
but
at
least
twoemisfacBoth of these phenomena are related to the unstable
NADPH diaphorase activity are spared. Positron
tors
may
contribute.
First,
like
other
autosomal
dominasion tomography has shown reduced glucose
nant
disorders, Huntington disease is likely to involve
ture of the mutation responsible for Huntington disutilization
a
easeexpansion of a CAG trinucleotide repeat that
in an anatomically normal caudate nucleus.
codes
for a polyglutamine tract. The repeat can toxic gain in function of the mutant protein. Mutant
Pathology
huntingtin is cleaved by proteases and conjugated
expand
Postmortem
examination
of patients
withmale
the disease
with
during gametogenesis,
especially
in the
reveals
cell
loss,
particularly
in
the
cerebral
cortex
ubiquitin, then transported in a complex called the
germline.
and
This leads to an abnormal protein with longer and proteasome to the cell nucleus, where it may disrupt
corpus
striatum (Figure
79). Normal
In the latter
region,
longer polyglutamine
tracts.
subjects
havethe gene transcription machinery and thereby
medium-sized
spiny
neurons
that
contain

promote
becell death. However, loss of the normal function of
tween 11 and 34 CAG repeats whereas nearly all patients with Huntington
Caudate anddisease
putamen have more than 40.huntingtin, which has not yet been dened but may
inClinical Findings
clude an inhibitory effect on programmed cell death,
Symptoms
usually begin
in the pathogenesis.
fourth or fth decade,
may also contribute
to disease
ACh
GABA
and
the
disease
is
progressive,
with
an average life
(+)
span
after
onset
of about 15 years.
A.
INITIAL
SYMPTOMS
Either abnormal movements or intellectual changes
may be the initial symptom, but ultimately both are
present.
DA ()
1. DementiaThe earliest mental changes often
consist of irritability, moodiness, and antisocial
behavior, but a more obvious dementia subsequently develops. This is characterized at an early stage by
selective
Substantia nigra
and progressive impairment of attention and
executive
Figure 79. Neurochemical pathology of the basal
function, consistent with frontostriatal pathology.
ganglia in Huntington disease. GABAergic neurons with
2. ChoreaMovement disturbance may be characcell bodies in the striatum degenerate (black square
terized initially by no more than an apparent
and dashed line), decreasing GABAergic output from
dgetiness
the striatum. ACh, acetylcholine; DA, dopamine.
or restlessness, but grossly abnormal choreiform
movements are eventually seen.
3. Atypical formsEspecially in cases developing
during childhoodbut occasionally in adult-onset

MOVEMENT DISORDERS / 251

cases as wellthe clinical picture is dominated by peripheral blood.
proParoxysmal choreoathetosis may occur on a
gressive rigidity and akinesia, with little or no chorea.
familial
This is known as the Westphal variant, and the
basis, but the intermittent nature of the symptoms
correct
and
diagnosis is suggested by the accompanying
their relationship to movement or emotional stress
dementia
usuand positive family history.
ally distinguish this disorder from Huntington disease.
B. Epilepsy
FAMILY HISTORY
and cerebellar ataxia are frequent
The age at onset of symptoms usually
In
cases in which a positive family history cannot be
features
distinguishes
obtained,
it must
bebut
remembered
that
the early Huntington disease from certain rare inherited childof the juvenile
form
not of adult
cases.
death
hood disorders characterized by choreoathetosis.
of a parent may make the history incomplete and
Wilson disease can be distinguished from Huntingthat
ton disease by the mode of inheritance, the presence
relatives often conceal the familial nature of the of
disorKayser-Fleischer rings, and abnormal serum copper
der. In addition, a certain degree of eccentric
and
behavior,
ceruloplasmin levels.
clumsiness, or restlessness may be regarded as
Dentatorubral-pallidoluysian atrophy, another
normal
dominantly inherited CAG repeat disorder that is cliniby lay people and medical personnel unfamiliar with
cally similar to Huntington disease, is distinguished
the disorder. The family history cannot therefore be
by
C.
re-GENETIC TESTING
genetic testing.
& Prognosis
Genetic
testing
nowuntil
provides
an accurate
garded as
negative
all close
relativesand
of the Treatment
When the early symptoms constitute progressive
denitive
patient
There
is no cure for Huntington disease, which, as a
inmeans
of establishing
the
diagnosis
and
also permits
have been
examined by
the
physician
personally.
rule,
terminates
aftertoclinical
tellectual failure,fatally
it may1020
not beyears
possible
distinguish
the
Neveronset.
Huntington
disease
from
other
varieties
of
dementia
D.
IMAGING
presymptomatic
detection
ofcases
the disease.
theless,
apparently
sporadic
are occasionallyThere
isthe
nofamily
treatment
for is
the
dementia, but
the
unless
history
characteristic
or
the
Conditions
that
should
bedemonstrates
considered in atrophy
the
CT
or MRI
often
ofmoveen-scanning
movedifferential
the
cerebral cortex and caudate nucleus in
countered.
ment disorder
respond
to drugs that interfere
disorder may
becomes
noticeable.
diagnosis
of Huntington disease are listed in Table ment
7
established
with
2.
cases.
dopaminergic inhibition of striatal output neurons.
Tardive dyskinesia, which is most common, can
Differential Diagnosis
These include dopamine D2-receptor-blocking drugs
usually
such as haloperidol, 0.54 mg orally four times daily,
be identied from the history. Laboratory studies can
or chlorpromazine, 2550 mg orally three times daily;
exclude most medical disorders associated with
and drugs that deplete dopamine from nerve
chorea.
terminals,
Other hereditary disorders in which chorea is a consuch as reserpine, 0.55 mg/d orally, or tetrabenazine
spicuous feature are described below.
(unavailable in the United States), 12.550 mg orally
Benign hereditary chorea is a recently recognized
three times daily. Drugs that potentiate GABAergic or
disorder that is inherited in either an autosomal domicholinergic neurotransmission are generally
nant or recessive manner and is characterized by
ineffective.
chorSelective serotonin-reuptake inhibitors may help to
eiform movements that develop in early childhood,Prevention
redo
Patients
should be advised
of the risk
of role
transmitting
duce aggressiveness
and agitation.
The
of
not progress during adult life, and are not associated
the
disease,
and
living
offspring
should
receive
surgical
with dementia.
genetic
treatment involving the intrastriatal transplantation
Familial chorea sometimes occurs in associationcounseling. The use of genetic markers for detection
of
with circulating acanthocytes (spiny red blood cells),
of
fetal striatal neuroblasts is currently being
but examination of a wet blood lm will clearly distinpresymptomatic
Huntington disease and the
investigated.
guish this disorder. Other clinical features of choreaproblems
acanthocytosis include orolingual ticlike dyskinesias,
associated with this approach are discussed on p 240.
DENTATORUBRAL-PALLIDOLUYSIAN
vocalizations, mild intellectual decline, seizures, ATROPHY
peripheral neuropathy, and muscle atrophy. ParkinsonianThis disorder, which is inherited in an autosomal
domfeatures are sometimes present. Unlike certain other inant manner, is rare except in Japan. It is
characterized
disorby dementia, choreoathetosis, ataxia, and myoclonic
ders associated with circulating acanthocytes, there
is
no disturbance of
concentration in the

252 / CHAPTER 7
epilepsy. The mutant gene is distinct from that in dominantly inherited disorder, which has been identiHuntington disease, despite the similarity of clinical
ed, named DYT1, and encodes torsin A, an ATPphenotype. The gene maps to 12p13.31, where there
binding protein. Other cases seem to occur on a spois
radic basis. Changes in the concentrations of
an expanded trinucleotide repeat. The size of the norepinephrine, serotonin, and dopamine have been
(CAG)n repeat expansion correlates with age on onset
demonstrated in a variety of brain regions, but their
and disease severity. Treatment is symptomatic, asrole in the pathogenesis of dystonia is uncertain.
for
Onset
Huntington disease.
may be in childhood or later life, and this disorder reSYDENHAM CHOREA
mains as a lifelong afiction. The diagnosis is made
on
This disorder occurs principally in children and
clinical grounds.
adolesClinical Findings
cents as a complication of a previous group A heA. HISTORY
molytic streptococcal infection. The underlying pathologic feature is probably arteritis. In about 30% of When onset is in childhood, a family history is usually
cases, it appears 2 or 3 months after an episode ofobtainable. Symptoms generally commence in the
legs.
rheuProgression is likely, and it leads to severe disability
matic fever or polyarthritis, but in other patients no
such history can be obtained. There is usually no from generalized dystonia.
With onset in adult life, a positive family history is
recent
not likely to be obtained. The initial symptoms are
history of sore throat and no fever. The disorder may
have an acute or insidious onset, usually subsidingusually in the arms or axial structures. Generalized
within the following 46 months. It may recur during
dystopregnancy, however, or in patients taking oral contrania may ultimately develop in about 20% of patients
ceptive preparations.
EXAMINATION
with
adult-onset dystonia, but severe disability does
Sydenham chorea is characterized by abnormalB.
The
disorder
is characterized by abnormal
not
choreiform movements that are sometimes unilateral
movements
usually
occur.
and, when mild, may be mistaken for restlessness or
and postures that are typically exacerbated by
dgetiness. There may be accompanying behavioral
voluntary
changes, with the child becoming irritable or
activity. For example, the neck may be twisted to one
disobediside (torticollis), the arm held in a hyperpronated
ent. Obsessive-compulsive symptoms and emotional
posilability also occur. In 30% of cases there is evidencetion
of with the wrist exed and ngers extended, the
leg
cardiac involvement, but the sedimentation rate and
held extended with the foot plantar-exed and
antistreptolysin O titer are usually normal.
inverted,
The traditional treatment is bed rest, sedation, and
prophylactic antibiotic therapy even if there are noor the trunk held in a exed or extended position.
There is often facial grimacing, and other
other signs of acute rheumatism. A course of
characteristic
intramusfacial abnormalities may also be encountered,
cular penicillin is generally recommended, and
including
continIDIOPATHIC TORSION DYSTONIA
blepharospasm (spontaneous, involuntary forced clouous prophylactic oral penicillin daily until about age
sure of the eyelids for a variable period of time) and
20 years
is also
frequently advised
to prevent
This
disorder
is characterized
by dystonic
movements
dystonia. This consists of spasms of
streptoand
postures and an absence of other neurologic oromandibular
It is important
to exclude other causes of dystonia
Differential
Diagnosis
the
coccal infections.
signs.
(see
about the mouth, causing, for example,
The
prognosis
is essentiallyhistories
that of the
The
birth
and developmental
arecardiac
normal.muscles
Be- 73)
Table
before a diagnosis of idiopathic torsion
involcom-the diagnosis can be made, other possible
fore
dysuntary opening or closing of the mouth; pouting,
plications.
causes
of
tonia is made. A normal developmental history prior
dystonia must be excluded on clinical grounds andpurstoby
ing, or retraction of the lips; retraction of the
laboratory investigations.
the onset of abnormal movements, together with the
platysma
Idiopathic torsion dystonia may be inherited as an
absence of other neurologic signs and normal results
and roving or protruding movements of the
autosomal dominant (with variable penetrance of muscle;
of
tongue.
3040%), autosomal recessive, or X-linked recessive
laboratory investigations, is important in this regard.
disorder, and the defective genes have been localized
In
in
patients with primary torsion dystonia that begins besome cases (see Table 75). Molecular genetic techfore the age of 30 years, genetic testing, especially
niques permit identication of carriers of the
for
responsiDYT1, in conjunction with genetic counseling is helpble trinucleotide (GAG) deletion on the gene for the
ful by obviating the need for other diagnostic studies

MOVEMENT DISORDERS / 253

and facilitating further advice and management. Testsive dystonia probably merit a trial of levodopa
ing patients who are older at onset may also be wartherapy.
ranted in those with a family history of early-onsetDYSTONIA-PARKINSONISM
disAn X-linked recessive form of dystonia-parkinsonism
ease.
(sometimes called Lubag) has been identied in men
Treatment
from the Philippines, and the responsible gene
The abnormal movements may be helped, at leastlocalized
in
part, by drugs. A dramatic response to levodopa sugto Xq13. Female heterozygotes are reported to have
gests a variant of classic torsion dystonia, discussed
mild dystonia or chorea. The response to pharmasepcotherapy is often disappointing.
arately below. Anticholinergic drugs given in the highAnother variety with autosomal-dominant inheriest doses that can be tolerated (typically,
tance has been described in the United States, with
trihexyphenidyl, 4050 mg/d orally in divided doses)
rapid evolution of symptoms and signs over hours,
may be very effective. Diazepam is occasionally days, or weeks, but slow progression thereafter. It
helpful.
may
Phenothiazines, haloperidol, or tetrabenazine
rst manifest during childhood or adulthood, often af(unavailter a period of stress. Levodopa therapy is ineffective.
able in the United States) may be worthwhile;
Genetic linkage has been described to markers on
however,
chroMYOCLONIC DYSTONIA
at effective doses, these drugs usually lead to a mild
mosome 19q13.
This is an autosomal dominant disorder (see Table 7
parkinsonian syndrome. Other drugs that are some5)
times helpful are baclofen and carbamazepine.
with incomplete penetrance and variable expression
Stereoin
tactic thalamotomy may help patients with predominantly
dystonia that particularly involveswhich patients exhibit rapid jerks in addition to more
Courseunilateral
& Prognosis
A
number abnormal
of the dystonic
features
of idiopathic
sustained
postures.
The legs
are often
the
torsion
spared.
If
all
cases
are
considered
together,
about
one-third
limbs. Deep brain stimulation of the globus pallidus
dystonia
may also occur as isolated phenomena.
of
has shown benet in a limited number of patients The
and jerks may respond to alcohol. The EEG is normal.
They
are
The disorder
appears to be distinct from classic idiopatients
eventually
become so severely disabled that
is currently
under study.
probably
best
regarded
occur
pathic
torsion
dystonia. as
Its focal
onsetdystonias
is usuallythat
before
the
they are conned to chair or bed, and another oneInherited
in
an
autosomal
dominant
manner
with
inas
age
of
20
years,
and
it
usually
has
a
benign,
slowly
third are affected only mildly. In general, severe
complete
formes
frustes of idiopathic torsion dystonia in
prodisabil- penetrance, the gene causing this disorder
maps
to
chromosome
14q.
Autosomal
recessive
patients
gressiveTORSION
course over
many years. Genetic studies
ity is more likely to occur when the disorder com- FOCAL
DYSTONIA
inheriwith
a positive family history or that represent a focal
suggest
mences in childhood.
tance occurs in rare instances
and has been
manifestation
its adult-onset
form when
there isare
no
DOPA-RESPONSIVE
DYSTONIA
that myoclonicofdystonia
and essential
myoclonus
associated
family
history.
In
addition,
focal
adult-onset
dystonia
allelic disorders.
with mutations in the tyrosine hydroxylase (TH) gene
may have a familial basis related to a genetic
on 11p15.5. Symptom onset is typically in childhood
abnormality
but may occur later. Girls are affected more
(DYT7) at 18p31 with autosomal dominant
commonly
inheritance.
than boys. Disabling dystonia may be accompanied Both blepharospasm and oromandibular dystonia
by
can occur as isolated focal dystonias. Familial blebradykinesia and rigidity that sometimes leads to a
pharospasm inherited as an autosomal dominant trait
mishas been described, but the gene remains
taken diagnosis of juvenile Parkinson disease; diurnal
unmapped.
worsening of symptoms is common. Extensor plantarSpasmodic torticollis usually begins in the fourth or
response or other evidence of upper motor neuronfth
in- decade and is characterized by a tendency for
volvement may occur. Some patients have focal the
dystoneck to twist to one side. This often occurs
nias or minor functional decits, whereas others beepisodically
come chairbound if untreated. Remarkable recovery
in early stages, but eventually the neck is held
occurs with low doses of levodopa, to which patients
continuare particularly sensitive. Because of the wide
ously to one side. Although the disorder is usually
variation
lifein age and manner of presentation, all children with
long once it develops, spontaneous remission does
an
ocunexplained extrapyramidal motor disorder and allcur occasionally, especially in the rst 18 months
paafter
tients with symptoms that might relate to dopa- onset. Medical treatment is generally unsatisfactory.
responA

254 / CHAPTER 7
trial of the drugs used in treating idiopathic torsion(Non-Kinesigenic Dyskinesia)
dystonia is worthwhile, as some patients do obtain
Dystonia, chorea, and athetosis lasting from a few
unmindoubted benet. Selective section of the spinal accesutes to several hours characterize this disorder,
sory nerve (cranial nerve XI) and the upper cervical
which is
nerve roots is sometimes helpful for patients in whom
inherited as an autosomal dominant trait with incomthe neck is markedly deviated to the side, but recurplete penetrance. The gene has been mapped to 2q.
rence of the abnormal posture is frequent. Local injection of botulinum toxin into the overactive musclesAttacks
may also produce benet for up to several months;
it may occur several times daily and are
precipitated
can be repeated as needed. It is the most effective
by
caffeine, alcohol,
fatigue,
and emotional stress but
Paroxysmal
Kinesigenic
Choreoathetosis
treatnot
by
movement.
Onset
may
be in childhood or early
ment available for this disorder.
This
disorder
occurs on abetween
sporadicepisodes
basis or is
asnormal.
an
adulthood.
Examination
Writers cramp is characterized by dystonic posturautoing of the hand and forearm when the hand is used
somal dominant trait. The gene has been mapped to
for
chromosome 16. Attacks begin in the rst or second
writing and sometimes other tasks such as playingdecade, last for seconds to minutes, and are
the
precipitated
piano
usingof
a disorders
screwdriver
table cutlery.by
Drug by sudden movement. They often respond to anticonA largeorgroup
areorcharacterized
treatment
vulsant medication.
dystonia is usually unrewarding, and it is often Paroxysmal
Exercise-induced Dyskinesias
necesand
other
neurologic
features,
such
as
dementia,
HEREDODEGENERATIVE
sary
for patients to learn to DYSTONIA
use the other hand forIn this rare disorder, which may be sporadic or
ataxia,
these
dyskinesias, or parkinsonism. This includes Wilsonfamilial,
leg dystonia is brought on by exercise (as opposed to
tasks.
dis- Injections of botulinum toxin into the involved
muscles
are
sometimes
helpful.
ease, which is discussed separately. Fahr disease the initiation of movement). Onset is usually before
the
consists
of idiopathic basal ganglia calcication associated age of 30, attacks last for several minutes to hours,
and
WILSON DISEASE
with
are poorly responsive to medication.
dystonia, parkinsonism, and behavioral disturbances;
Wilson disease is an autosomal recessive disorder of
aucopper metabolism that produces neurologic and hetosomal dominant inheritance occurs in some
patic dysfunction. The gene localizes in the region of
families.
chromosome 13q1421, but the disease is caused by
Hallervorden-Spatz disease, which is now desig-a
nated panthokenate kinase-associated
number of different mutations, two of which are enneurodegeneracountered fairly frequently in affected patients. Altion, is characterized by extrapyramidal and cognitive
though the precise nature of the biochemical
abnormalities, dysarthria, dysphagia, and ocular abnormalabnority in Wilson disease is unknown, its pathogenesis
malities (eg, gaze palsies, optic atrophy). Deposition
appears to involve decreased binding of copper to the
of
transport protein ceruloplasmin. As a result, large
iron and other pigments in the globus pallidus leads
amounts of unbound copper enter the circulation and
to
are subsequently deposited in tissues, including the
a characteristic MRI appearance on T2-weighted MRI
brain, liver, kidney, and cornea. Studies of
called the eye of the tiger sign. The disorder has
mitochondrautoial function and aconitase activity suggest that free
somal recessive inheritance, with the gene (PANK2)
radilocal formation
and oxidative damage, perhaps through
Clinical
Findings
calized to 20p12.3-p13.
mitochondrial copper accumulation, are important in
Chorea-acanthocytosis is characterized by someA.
ODE OF PRESENTATION
theMpathogenesis
of the disease.
combination of dystonia, chorea, orofacial
Wilson disease usually presents in childhood or young
PAROXYSMAL
DYSKINESIAS
dyskinesias,
adult life. The average age at onset is about 11 years
tics,
hyporeexia,
amyotrophy,
andand
cognitive
abnorIn
this
group of disorders,
dystonia
dyskinesias
for
malities. The peripheral blood contains circulating patients presenting with hepatic dysfunction and 19
ocacanthocytes
(spiny
red
but abasis.
normal lipid years for those with initial neurologic manifestations,
cur
episodically,
often
oncells)
a familial
prole.
but the disease may begin as late as the sixth
Paroxysmal Dystonic Choreoathetosis
The disorder has autosomal recessive inheritance decade.
and
the responsible gene maps to 9q21. Certain
Hepatic and neurologic presentations are about
mitochonequally
drionopathies may also be associated with dystonia,
such as Leber hereditary optic atrophy.

MOVEMENT DISORDERS / 255

common, and most patients, if untreated, eventually
to predominate when the disease begins before age
develop both types of involvement. Rare
20
presentations
yearsand for older patients to exhibit wild tremor,
include joint disease, fever, hemolytic anemia, andchorea, or ballismus. Symptoms may progress
berapidly,
B.
NONNEUROLOGIC
FINDINGS
havioral
disturbances.
especially in younger patients, but are more often
Ocular and hepatic abnormalities are the most promigradnent nonneurologic manifestations of Wilson disease.
ual
in development
with periods of remission and
Differential
Diagnosis
The most common ocular nding is Kayser-Fleischer
exacrings (Figure 710): bilateral brown corneal rings that
When
Wilson disease presents as a neurologic
erbation.
result from copper deposition in Descemet
disorder,
membrane.
other conditions that must be considered in the differThe rings are present in virtually all patients with ential diagnosis include multiple sclerosis and
neujuvenilerologic involvement but may be detectable only byInvestigative
onset Huntington
disease.
Studies
slit
lamp examination. Hepatic involvement leads to Investigation may reveal abnormal liver function
chronic cirrhosis, which may be complicated by blood
tests and aminoaciduria as a result of renal tubular
splenomegaly, esophageal varices with hematemesis,
damage. The levels of serum copper and
C.
N
EUROLOGIC
F
INDINGS
or
ceruloplasmin
Neurologic
ndings
in
Wilson
disease
reect
the
disfulminant hepatic failure. Splenomegaly may cause
(an 2-globulin to which 90% of the circulating copper
proportionate
involvement
of
the
caudate
nucleus,
heputamen,
cerebral
cortex,
and
cerebellum.
Neurologic
is bound) are low, and 24-hour urinary copper excremolytic anemia and thrombocytopenia.
signs include resting or postural tremor, choreiform
tion is generally increased. Liver biopsy reveals a
movements of the limbs, facial grimacing, rigidity,huge
hypokinesia, dysarthria, dysphagia, abnormal (exed)
excess of copper; it also usually reveals cirrhosis. No
The
optimal
means
of removing
copper
from theBrain
possingle
laboratory
feature
is reliable
in isolation.
brain
tures, and ataxia. Seizures may also occur.
CT scanning or MRI may show cerebrocortical atrophy
and other
organs isindisputed.
physicians
use
Psychologic
abnormalities
the basalMost
ganglia.
The MRI
abpenidisorders in Wilson disease include dementia, characnormalities include the face of the giant panda sign
cillamine,
a copper-chelating agent that promotes exterized by mental slowness, poor concentration, and
in
Treatment
of copper
from tissueadeposition
sites,
even
memory impairment; disorders of affect, behavior,traction
or midbrain
the
and sometimes
face of the
miniature
though
of penicillamine-induced
worsening
personality; and (rarely) psychosis with
panda instances
in the pontine
tegmentum.
have been described. Treatment should be started as
hallucinations.
There is a tendency for a dystonic or parkinsonian early as possible and customarily employs 1.52 g/d
of
picorally administered penicillamine. The response to
ture with hyperreexia and extensor plantar
treatment may take several months and can be moniresponses
tored by serial slit lamp examinations and blood
chemistries. Side effects of penicillamine include nausea, nephrotic syndrome, myasthenia gravis,
arthropathy, pemphigus, diverse blood dyscrasias, and a
lupuslike syndrome; moreover, penicillamine may cause an
additional worsening of neurologic symptoms. Treatment with tetrathiomolybdate is sometimes helpful.
Restriction of dietary copper and administration of
zinc
sulfate (200 mg/d orally) can decrease copper
absorpFigure 710. Kayser-Fleischer ring in Wilson disease.
tion. Treatment must be continued for the lifetime of
This corneal ring (between arrows) was golden brown
the patient, and most patients treated early can
and contrasted clearly against a gray-blue iris. Note that
the darkness of the ring increases as the outer border expect a
complete or nearly complete recovery. Liver
(limbus) of the cornea is approached (right arrow).
transplan(PhotocourtesyofWFHoyt.)
tation may be required in cases with fulminant
hepatic
failure.
Siblings of affected patients should be screened for
presymptomatic Wilson disease with neurologic and

256 / CHAPTER 7
slit lamp examinations and determination of serumdrug ingestion, often point to the iatrogenic nature of
ceruloplasmin levels. If no abnormalities are found,the disorder. Signs usually develop within 3 months
serum copper and urinary copper excretion shouldafter
be
assayed and liver biopsy performed if necessary. Ifstarting the offending drug and disappear over weeks
these
or
investigations reveal preclinical Wilson disease, months following discontinuance.
therapy
Depending on the severity of symptoms and the
should be instituted as described above for symptonematic disease.
cessity for continuing antipsychotic drug therapy,
DRUG-INDUCED MOVEMENT DISORDERS
several strategies are available for treating drug-induced
Parkinsonism
parkinsonism. These include slow tapering and evenParkinsonism frequently complicates treatment
tual withdrawal of the antipsychotic drug, substituting
with dopamine-depleting agents such as reseran antipsychotic agent less likely to cause
pine or dopamine-receptor antagonists suchextrapyramias
phenothiazines or butyrophenones. In the case of andal reactions (see Table 78), or adding an anticholintipsychotic drugs, the risk of this complication is ergic drug such as trihexyphenidyl or benztropine
greatest
(FigAcute Dystonia or Dyskinesia
when agents are used that are potent D2-receptor ure 711). Levodopa is of no help if the neuroleptic
antagoAcute
dystonia
or dyskinesia
(such
as blepharospasm,
drugs are
continued;
it may be
helpful
if these drugs
nists with little anticholinergic effect, such as
torticollis,
or
facial
grimacing)
is
an
occasional
are
piperazine
complidiscontinued but may aggravate the psychotic
phenothiazines, butyrophenones, and thioxanthenes
cation
of dopamine receptor antagonist treatment,
disorder
(Table 78). In addition, women and elderly patients
genfor which they were originally prescribed.
aperally occurring within 1 week after introduction of
pear to be at somewhat increased risk. Tremor is relasuch medication and often within 48 hours. Men and
tively uncommon, while hypokinesia tends to be symyounger patients show increased susceptibility to this
Table
drug-induced
metric78.
andAntipsychotic
the most conspicuous
neurologic feature
complication. The pathophysiologic basis of the
Caudate and putamen
extrapyramidal
side effects.
of
disturparkinsonism. These points, together with the history
2
of
Relative EPS
Risk1

Drug
Conventional antipsychotics
Fluphenazine(Prolixin)
(Haldol)

High

Perphenazine

(Trilafon)

High

Thiothixene

(Navane)

High

Triuoperazine

(Stelazine)

High

Chlorpromazine

(Thorazine)

Intermediate

(Mellaril)

Intermediate

(Risperdal)

Intermediate

Other antipsychotics
Risperidone
Aripiprazole

(Abilify)

Low

Clozapine

(Clozaril)

Low

Olanzapine

(Zyprexa)

Low

Quetiapine

(Seroquel)

Low

Ziprasidone

(Geodon)

Low

1Extrapyramidal

GABA
1

High

Haloperidol

Thioridazine

ACh
(+)

symptoms (dystonia, parkinsonism,

akathisia, tardive dyskinesia).

DA

()

Substantia nigra

Figure 711. Mechanisms and treatment of druginduced parkinsonism. Symptoms result from pharmacologic blockade of dopamine receptors by antipsychotic drugs (1), which mimics the degeneration of
nigrostriatal dopamine (DA) neurons seen in idiopathic
parkinsonism. Symptoms may be relieved by the
administration of muscarinic anticholinergic drugs (2)
or by substituting an antipsychotic drug with anticholinergic properties.These measures restore the normal balance between dopaminergic and cholinergic
(ACh) transmission in the striatum.

sure is obtained.
Tardive dyskinesia is easier to prevent than to cure.
Antipsychotic drugs should be prescribed only on
clear
MOVEMENT DISORDERS / 257
indication, and their long-term use should be monitored, with periodic drug holidays to determine
bance is unclear, but intravenous treatment with an
whether the need for treatment continues. Drug holiandays may also help to unmask incipient dyskinesias
ticholinergic drug (eg, benztropine, 2 mg, or
which, curiously, tend to worsen when the drug is
diphenhywithdrawn. Antipsychotic medication should be
dramine, 50 mg) usually alleviates it.
Akathisia
gradually withdrawn if possible when dyskinesia appears
Akathisia is a state of motor restlessness
Tardive
dyskinesia may develop after long-term treatdurcharacterized
ment
antipsychotic
(dopamine-receptor-antagoby an with
inability
to sit or stand
still, which is relieveding
by a drug holiday, as this may allow remission to ocnist)
drugs
or with
It is commonlycur.
moving
about.
It is metaclopramide.
a very common movement
enTreating the established disorder is generally
disorder
countered
chronically
institutionalized
psychiatric
unsatisinduced byinchronic
treatment
with antipsychotic
patients,
and the risk of developing tardive
factory, though it sometimes resolves spontaneously,
drugs
dyskinesia
esand occurs more often in women than in men. It may
appears
to
increase
with
advancing
age.
The
manner
pecially in children or young adults. Antidopaminergic
be seen as a tardive phenomenon after the
in
agents such as haloperidol or phenothiazines
discontinuawhich
chronic
drug
treatment
promotes
a
movement
suppress
Tardive
Dyskinesia Akathisia is treated in the same
tion of neuroleptics.
disorder
is
unknown.
the abnormal movements, but their use for this purmanner as drug-induced parkinsonism.
Drug-induced supersensitivity of striatal dopamine
pose is not recommended since they may aggravate
receptors has been proposed but is unlikely to be rethe
sponsible for several reasons. Supersensitivity always
underlying disorder. Treatment with reserpine, 0.25
acmg
companies chronic antipsychotic drug treatment, gradually increased to 24 mg/d orally, or
whereas tardive dyskinesia does not. Supersensitivity
tetrabenazine
may occur early in the course of treatment, while tar(not available in the United States), 12.5 mg
dive dyskinesia does not develop for at least 3
gradually
months.
increased to as much as 200 mg/d orally, may be
In addition, supersensitivity is invariably reversiblehelpwhen drugs are discontinued; tardive dyskinesia isful. Both these drugs deplete monoamine neurotransnot.
mitters, including dopamine. A number of other pharThe clinical features of tardive dyskinesia, particularly
macologic approaches have been suggested and may
its persistent nature, are more suggestive of an help in individual cases; these include treatment with
underlycarbamazepine, baclofen, lithium, clonazepam, and
ing structural abnormality. Such an abnormality may
alinvolve GABA neurons, because GABA and its syntheprazolam. Calcium-channel blockers have also been
sizing enzyme, glutamic acid decarboxylase, are deadpleted in the basal ganglia following chronic
vocated but there is no evidence of their utility. Antitreatment
cholinergic drugs should be avoided as they may
of animals with antipsychotic drugs and GABA levels
exacerbate the dyskinesia. In patients requiring
in CSF are decreased in patients with tardive dyskinecontinsia. No consistent pathologic features have been ued treatment for psychosis, clozapine, risperidone,
found
olanzapine, or quetiapine should be used in place of
in the brains of patients with tardive dyskinesia, al-the
though inferior olive atrophy, degeneration of the typical antipsychotics.
subA variety of other late and often persistent movestantia nigra, and swelling of large neurons in the ment disorders may appear during the course of ancautipsychotic drug treatment. Tardive dystonia is usudate nucleus have been described in some cases. ally
The segmental (affecting two or more contiguous
clinical disorder is characterized by abnormal
body parts, such as the face and neck or arm and
choreoatrunk) in nature. It is less often focal; when this is the
thetoid movements that are often especially
case, the head and neck are particularly apt to be afconspicufected, producing blepharospasm, torticollis, or oroous about the face and mouth in adults and tend to
mandibular dystonia. Generalized dystonia is least
be
common and tends to occur in younger patients.
more obvious in the limbs in children. The onset ofTreatment is as for tardive dyskinesia, except that andyskinesia is generally not until monthsor years
ticholinergic drugs may also be helpful; focal dystoafnias may also respond to local injection of botulinum
ter the start of treatment with the responsible agent.
A toxin. Tardive akathisia (characterized by a feeling
Tardive dyskinesia may be impossible to distinguish
of restlessness and a need to move about, with an infrom such disorders as Huntington disease or idio-ability to sit or stand still) can also occur; it is treated
pathic torsion dystonia unless a history of drug expoin the same manner as drug-induced parkinsonism.

258 / CHAPTER 7
dive myoclonus may also occur. Rabbit syndrome is
Most
a cases are sporadic, although there is
neuroleptic-induced disorder characterized by rhythoccasionally a
mic vertical movements about the mouth, resembling
family history, and partial expression of the trait may
the chewing movements of a rabbit; the tongue is occur in siblings or offspring of patients. Inheritance
spared. Anticholinergic drugs may be helpful in its has been attributed to an autosomal dominant gene
treatment.
with variable penetrance. Males are affected more
commonly than females. The prevalence in the United
Neuroleptic Malignant Syndrome
States has been estimated to be 0.05%.
This rare complication of treatment with antipsychotic
The pathophysiology is obscure, but the corticodrugs (neuroleptics) is manifested by rigidity, fever,
striato-thalamo-cortical pathways seem to be
alinvolved.
tered mental status, and autonomic dysfunction. Dopaminergic excess in the brains of patients with
Haloperidol is implicated most often, but the syn- Gilles de la Tourette syndrome has been postulated,
drome can complicate treatment with any
mainly because of the benecial effects that
antipsychotic
dopaminedrug; whether concomitant treatment with lithiumblocking
or
drugs can have on the tics. The administraanticholinergic drugs increases the risk is uncertain.
tion of dopamine receptor agonists often fails to proSymptoms typically develop over 13 days and can
duce
the exacerbation
of symptoms
thatages
might
be 21
Symptoms
usually commence
between
2 and
ocanticipated
from
this
hypothesis,
however.
years. The rst signs consist of motor tics in 80% of
cur at any time during the course of treatment. The
No structural
the there
clinical
disorder
has a
Clinical
Findings
cases
and
vocal basis
tics infor
20%;
may
be either
difbeen
single
ferential diagnosis includes infection, which must be
recognized.
Only
a When
few cases
have come
tic or multiple
tics.
the initial
sign istoa autopsy,
motor tic,
excluded in any febrile patient. Neuroleptic malignant
and
it
most
commonly
involves
the
face,
taking
the
form
syndrome resembles malignant hyperthermia (seethe ndings are conicting.
of
Chapter 5), but the latter disorder develops over minsnifng, blinking, forced eye closure, etc. It is
utes to hours rather than days and is associated with
generally
the
not possible to make the diagnosis at this stage.
administration of inhalational anesthetics or
All patients ultimately develop a number of differneuromusent
motor tics and involuntary vocal tics, the latter
cular blocking agents rather than antipsychotics.
commonly
consisting of grunts, barks, hisses, throatTreatclearing
or
coughing, and the like, and sometimes
ment of neuroleptic malignant syndrome includes
takwithdrawal
of antipsychotic
drugs, Disorders
lithium, and antiOther
Drug-Induced
Movement
ing the form of verbal utterances including coprolalia
cholinergics; reduction of body temperature with anLevodopa
produces
a
wide
variety
of
abnormal
movetipyretics and articial cooling; and rehydration. (vulgar or obscene speech). There may also be
echolalia
ments
as a dose-related
in patients
Dantrolene
(see Chapter phenomenon
5) may be benecial,
as with
may
(parroting the speech of others), echopraxia
parkinsonism.
They
can
be
reversed
by
withdrawing
bromocriptine, levodopa preparations, or
(imitation
the
amantadine.
of others movements), and palilalia (repetition of
medication
or
reducing
the
dose.
Chorea
may
also
The mortality rate is as high as 20%.
words or phrases). The tics vary over time in severity,
decharacter, and the muscle groups involved. In 40
velop in patients receiving dopamine agonists,
50%
anticholinof cases, some of the tics involve self-mutilation with
ergic drugs, phenytoin, carbamazepine,
such activities as severe nail-biting or hair-pulling,
amphetamines,
lithium, and oral contraceptives; it resolves with picking at the nose, or biting the lips or tongue. Sensory
discontics, consisting of pressure, tickling, and warm or cold
tinuance of the responsible drug. Dystonia has
sensations, also occur. Behavioral disorders, including
resulted
obsessive-compulsive disorder and attention decit
from
administration
of
dopamine
agonists,
lithium,
GILLES DE LA TOURETTE SYNDROME
hyperactivity disorder, are common in patients with
seroGilles
de la Tourette
syndrome,
characterized
tonin reuptake
inhibitors,
carbamazepine,
andby Gilles de la Tourette syndrome, but their precise relachronictypically
lifelongmultiple motor and verbal
tionship to the tic disorder is uncertain.
metoclotics,
is of unknown
cause
and does
relate to social
pramide;
and postural
tremor
from not
administration
of Physical examination usually reveals no other
class,
ethnic group,
perinatal
birth abnortheophylline,
caffeine,
lithium,abnormalities,
thyroid hormone,
Differential Diagnosis
trauma,
tricyclic or birth order. Symptoms begin before 21 malities, but there is a higher than expected
differential diagnosis includes the various moveyears
incidence
antidepressants, valproic acid, and isoproterenol. The
of age, and the course is one of remission and
of left-handedness or ambidexterity. In about 50% of
relapse.
cases, the EEG shows minor nonspecic
abnormalities
of no diagnostic relevance.

MOVEMENT DISORDERS / 259

ment disorders that can present in childhood. Other
et with a minimum of side effects or until side
disorders characterized by tics (see Tics, p 237) are
effects
dislimit further increments. A total daily dose of 28 mg
tinguished by resolution of the tics by early adulthood
is usually optimal, but higher doses are sometimes
or by the restricted number of tics.
necWilson disease can simulate Gilles de la Touretteessary. Side effects include extrapyramidal
syndrome; it must be excluded because it responds
movement
well
disorders, sedation, dryness of the mouth, blurred vito medical treatment. In addition to a movement sion, and gastrointestinal disturbances. Pimozide, andisorother dopaminergic-receptor antagonist, may be
der, Wilson disease produces hepatic involvement,helpKayser-Fleischer corneal rings, and abnormalities of
ful in patients who are either unresponsive to or
serum copper and ceruloplasmin, which are absentcannot
in
Gilles de la Tourette syndrome.
tolerate haloperidol. Treatment is started with 1 mg/d
Sydenham chorea can be difcult to recognize ifand the dose is increased by 1 mg every 5 days; most
there is no recent history of rheumatic fever or polypatients require 716 mg/d.
arthritis and no clinical evidence of cardiac involve- Phenothiazines such as uphenazine are
ment, but this disorder is a self-limiting one, usually
sometimes
clearing in 36 months.
helpful for the management of tics, as also are
Bobble-head syndrome, which can be difcult todopamine agonists. Recent reports suggest that injecdistinguish from Gilles de la Tourette syndrome, is tion of botulinum toxin A at the site of the most probcharacterized by rapid, rhythmic bobbing of the head
lematic tics may be worthwhile. Treatment of any
Complications
in children with progressive hydrocephalus.
associated attention decit disorder may include the use
Gilles de la Tourette syndrome is often unrecognized
for years, the tics being attributed to psychiatric of
a clonidine patch, guanfacine, pemoline, methylillness
phenidate, or dextroamphetamine, whereas
or mistaken for some other form of abnormal movement. Indeed, in many cases the correct diagnosisobsessiveis
compulsive disorder may require selective serotonin
reuptake
inhibitors or clomipramine
nally made by the family rather than the physician.
In
Patients occasionally respond favorably to clonconsequence, patients are often subjected to
azepam, risperidone, desipramine, or carbamazepine,
unnecesACQUIRED HEPATOCEREBRAL
but diazepam, barbiturates, phenytoin, and
sary and expensive treatment before the true nature
DEGENERATION
cholinergic
of
agonists (such
as deanol)degeneration
are usually not
helpful.a
the disorder is recognized. Psychiatric disturbances,
Acquired
hepatocerebral
produces
Neurosurgical treatment, for example, by prefrontal
sometimes culminating in suicide, may occur because
neuleucotomy,
anterior
cingulotomy,
or thalamotomy
has
of the cosmetic
and social and,
embarrassment
Treatment
is symptomatic
if effective, produced
must be
rologic
disorder
associated
with extrapyramidal,
cerebeen
helpful,
but
preliminary
results
suggest
that
by
continued
indenitely. Education of the patient, not
bellar, and pyramidal signs as well as dementia. ExTreatment
bilateral
thalamic
may be
worthwhile
the tics.
family
trapyramidal
signsstimulation
include rigidity,
rest
tremor, in
otherwise
intractable
cases.
Drug therapy
can lead is
toimportant.
a number Extra
of sidebreak
effects,
members,
and teachers
chorea,
as
periathetosis, and dystonia. This condition is discussed in
discussed
below.
ods at school
and additional time for test taking are
Chapter
1. LEGS SYNDROME
RESTLESS
ofRestless legs syndrome is characterized by an
ten helpful.
unpleasClonidine has been reported to ameliorate motor
or
vocal tics in roughly 50% of children so treated. It ant creeping discomfort that is perceived as arising
deep
may
act by reducing activity in noradrenergic neurons within the legs and occasionally in the arms as well.
Such symptoms tend to occur when patients are rearislaxed, especially while lying down or sitting, and lead
ing in the locus ceruleus. It is started in a dose of 23
increasing after 2 weeks to 4 and to a need to move about. They are often particularly
troublesome at night and may delay the onset of
then, if necessary, to 5 It may cause an initial
transient fall in blood pressure. The most frequentsleep.
A sleep disorder associated with periodic movements
side
sleep may also occur and can be documented
effect is sedation. Other adverse reactions includeduring
reby
duced or excessive salivation and diarrhea.
polysomnographic recording. The cause is unknown,
Haloperidol is often effective. It is started at a low
the disorder may have a genetic predisposidaily dose (0.25 mg), which is gradually increasedalthough
by
0.25 mg every 4 or 5 days until there is maximumtion; it seems especially common among pregnant
women and is not uncommon among uremic or diaben-

260 / CHAPTER 7
Parkinsonism
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