Neurology

Dementia
 Diagnostic criteria based on DSM-IV placed considerable weight on memory impairment.
o Memory impairment defined either as
 Inability to learn new information
 Inability to recall previously learned information
o Cognitive disturbances often accompany memory impairment
 Apraxia—inability to plan or execute a learned task despite having relatively preserved
primary neurologic function
 IE motor, sensory, hearing, visual, etc.
 Agnosia—inability to process and comprehend sensory information despite having
preserved sensory function
 EX: visual or tactile
 Aphasia—inability to take in, process, understand, and/or express language
 Impaired Executive Functioning—inability to organize and regulate information that
allows for goal directed behavior, independence, and quality of life
 ^ The three As have an inability of cortex (gray matter) to sort out, process, interpret
basic function of daily activities
 Newer Criteria (DSM V) calls for multiple domains to carry equal weight, not just memory impairment
o Learning/memory
o Language
o Executive function
o Complex attention
o Perception/motor
o Social cognition
 Criteria must be associated with a significant decline from previous functional state and must be
present in the absence of delirium
 Severity is gauged by numerous scoring systems
o Most commonly used ones
 Mini mental status examination (MMSE)
 Clinical dementia rating (CDR)
o Based on the MMSE, dementia is graded as
 Normal: 27-30
 Mild: 20-26
 Moderate: 10-20
 Severe: <10
o CDR grading
 Normal: 0
 Mild: 1
 Moderate: 2
 Severe: 3
 Role of Genetic Testing for Alzheimer Dementia
o Early onset (age < 60) with an autosomal dominant component: consider presenilin 1 testing
o Late onset inherited cases may be from various mutations, most commonly apolipoprotein E
(e4 allele).
 While testing is commercially available, the lack of disease modifying therapy may limit
its use
 Pathogenesis is incompletely defined but seems to focus on accumulation of neurotoxic particles
 o Amyloid precursor peptide is likely converted into beta-A4 amyloid particles by secretase
enzymes
o Beta-A4 amyloid may then aggregate into plaques or activate caspase enzymes to cleave tau
proteins, leading to their abnormal phosphorylation and aggregation into neurofibrillary tangles
 After diagnosing dementia and gauging its severity, the next issue to address is reversibility.
o 80-90% cases are irreversible and most of these are related to Alzheimer dementia (DAT)
o Selected Reversible Causes
 Nutritional deficiency (mostly B12)
 Endocrine/metabolic disorders
 Think hypothyroidism
 Infection
 Autoimmunity
 Neoplasm
 Sleep disorders
 Certain space-distorting processed
 Subdural hematoma
 Normal-pressure hydrocephalus
o Selected Irreversible Causes
 Dementia of Alzheimer’s type
 Dementia with Lewy bodies
 Frontotemporal dementia
 Vascular dementia
 Stroke not required to have dementia of this type as once thought
 Prion disease
o By clinical probability and by published guidelines, serum TSH (for hypothyroidism) and vitamin
B12 (even if CBC normal) MUST be obtained in all patients. Further testing is based on clinical
suspicion.
 Clues on the Illness Script to Suggest non-Alzheimer Dementia
o Epidemiology
 Age of Onset
 DAT is very uncommon prior to 60 years of age
 Younger, less likely Alzheimer’s
 Medical History
 Vascular risk factors
 Autoimmune disease
 Patterns of Inheritance
 Check out family history
 You may learn person has frontotemporal dementia syndrome or Huntington’s
 Social History
 Tobacco, alcohol, and drugs are strong contributors to neuronal injury
o Signs and Symptoms
 Most important word for all these is “early”
 All these can happen in Alzheimer’s if they make it long enough
 They tend to be very late manifestations of Alzheimer’s
 If any of these are present early in the cognitive decline, seek a different cause of
dementia
 Sensorimotor
 Gait
  Language
 Behavior/Personality
 Hallucinations/Delusions
 Dream Enactment
 Dysautonomia
 Movement Disorder
 Parkinsonism
 Chorea/Athetosis
 Myoclonus
 Tremor
 Dystonia
 Radiologic/Laboratory Findings
o Tempo
 Rapid progression
 Alzheimer’s is a slow progression
 Fluctuating
 Alzheimer’s is a slow, steady decline lasting years
 Frequent fluctuations in function and behavior is more classic for say dementia
with Lewy bodies
 Stepwise Decline
 They are stable for some time then abruptly have a set back
 Beware of things like vascular dementia
 Overview Dementia Syndromes
o Creutzfeldt-Jakob Disease and other Prion Diseases
 Prion particles are part of normal neurons, but certain exposures may create a
structurally abnormal form that is directly neurotoxic.
 Most cases are sporadic, and prognosis is dismal
 Features
 Rapidly progressing dementia IE weeks to months
 Myoclonus and other motor disturbances
 Akinetic mutism
o Won’t move, won’t talk
 Visual/cerebellar problems
 EEG with periodic sharp-wave discharges
 CSF with increased levels of 14-3-3 protein
 Suggestive MRI abnormalities
o Pulvinar sign—high intensity signal from thalamus
o Other areas including basal ganglia
o Dementia with Lewy Bodies
 Lewy bodies are abnormal aggregates of alpha synuclein and other particles that
accumulate in particular catecholaminergic areas of the CNS
 Relatively preserved insight
 They know something is going wrong with them
 Clinical features include
 Dementia, especially with early parkinsonism
o As opposed to Parkinson’s disease, where dementia may not develop for
several years after the onset of the movement disorder
o In Alzheimer’s memory is affected first
 o In dementia with Lewy bodies, executive function and visuospatial
function are affected before memory
 Getting lost in familiar places
 Poor clock drawing
 Cannot copy figures
 Cannot spell “world” backwards
 Unusual structured visual hallucinations
o HaLEWYcinations
o May be simple or even as complex as thinking their reflection in the
mirror is a stranger
 Fluctuating degrees of dysfunction
o Can last seconds to days and be quite abrupt to where they are mistaken
for seizure or stroke
 REM sleep-related behavior disturbances
o Normally, in REM we dream but our muscles are paralyzed except for
eyes and respiratory
o “acting out dreams”
 Loss of REM sleep muscle atonia
o Melatonin or clonazepam may be useful
 Memory and insight relatively preserved early on
 Medication sensitivity: exaggerated or paradoxical responses
o Antipsychotics
 Especially haloperidol
 May get rebound worsening psychosis or a worsening
neuromuscular adverse effect
o Anticholinergics
o Dopaminergic Agents
 Core Features of Disease
 Three Core
o Dementia
o Visual hallucinations
o Fluctuations
 REM sleep disturbances not considered a core feature but is quite common and
may precede the diagnosis by years
 There may be a role for neuroimaging in helping distinguish Alzheimer’s from Lewy body
 SPECT scanning with decreased dopamine transporter uptake in basal ganglia as
well as altered perfusion/metabolism in occipital regions
 123MIBG scanning with poor myocardial uptake
o Normal Pressure Hydrocephalus
 Triad: ataxia, dementia, urinary incontinence
 Wet, wobbly, whacky
 Occurs because ventricular expansion damages periventricular structures that
control coordination, cognition, and continence
 Most cases are idiopathic and some are secondary to an ongoing or a prior CNS insult
that has created impaired CSF resorption
 Early recognition may allow for shunting and likely improvement
 Gait disturbance (ataxia) is the earliest and most responsive of the three abnormalities
and even office-based testing (Miller-Fisher test)
  Assess gait before and after withdrawal of CSF
o Frontotemporal Dementia
 Heterogenous group of degenerative disorders that affect the frontal and temporal
lobes to varying degrees
 May appear as early as 30, 40, 50 years
 Typical presentation encompasses early social, behavioral, and language disturbances
(IE fluent and non-fluent aphasias) that rapidly progresses to more extensive cognitive
dysfunction
 Memory may be preserved early and patients tend to NOT have insight as to
their problems. In fact, the Mini Mental Status Examination score tends to be
normal early.
 Hallucinations are NOT common (unlike Lewy body)
 Disinhibition, unusual eating patterns, hoarding, emotional blunting, and other
behavioral disturbances may lead to patients often labeled as having a primary
psychiatric disease.
 10-20 % may have coexisting pyramidal and extrapyramidal motor disorders,
including motor neuron disease and various Parkinson-like syndromes
 Compared to Alzheimer’s, age of onset is earlier and rate of progression is faster
 Only 10% are diagnosed after 70 years old
 Up to 40% may be inherited
o Vascular Dementia
 This form should be considered in patients with numerous atherothrombotic risk factors
who present with relatively abrupt onset, fluctuating, and/or stepwise decline in
cognitive function
 Since it can be the result of large or (more commonly) small vessel disease, presentation
can be quite variable (tempo, localization, and even mechanism) and diagnostic criteria
are still evolving.
 Complicating this is that vascular dementia can often coexist with Alzheimer’s,
plus they share some similar risk factors.
 Due to the diverse clinical scenarios, this category is now thought of as “vascular
neurocognitive disorder”
 Treatment
o Treatment Issues in Degenerative Dementias
 Intellectual Decline
 Preventative therapy has not been found to be successful as rate of progression
from mild cognitive impairment, the precursor to dementia, is 10-15% a year
even if pharmacotherapy is attempted.
 Role of Cholinergic Augmentation
o Loss of cholinergic neurons, mostly in basal forebrain, is felt to play a role
in cognitive decline and even behavioral aspects of dementia
 Irrespective of the cause, a lot of neurons decline early in memory
impairment are cholinergically dependent
o We have come up with drugs that are central cholinesterase inhibitors,
trying to prolong the half-life and effect of Ach on the hippocampal,
limbic system, and other deep structures that are responsible for basic
cognition
o Currently used agents
 Donepezil
  Galantamine
 Rivastigmine
 Tacrine—no longer used because severe neutropenia
o These drugs are only symptomatic therapy.
 Improved quality of life and cognition to a small extent
 There is no effect on survival, delay nursing home placement, or
disability
 These drugs do not prolong life
o In advanced dementia, benefit is minimal, and drug should be tapered.
Think to start decreasing drug when
 No longer benefiting from it
 Have intolerable side effects
o May have some peripheral effects that can be adverse effects:
 Bradycardia
 Altered bowel and bladder habits
o May be useful in some non-Alzheimer dementias
 Dementia with Lewy bodies
 Vascular dementia
 Parkinson disease
 ^most robust risk factor for all 4 is age
 Possible Neuroprotective Agents
o Glutamate normally binds many receptors in the brain to provide more of
a stimulant and maintenance effect.
 In the setting of degenerative neurologic disease like dementia,
too much of a good thing becomes a bad thing. In patients with
ongoing dementia syndrome, when glutamate binds the NMDA
receptor, it tends to create worsening neuronal injury, so we have
to come up with an antagonist called memantine
o Memantine inhibits the action of glutamate at the NMDA receptor
 May be used alone or with cholinergic augmentation in patients
with moderate to severe dementia (MMSE of 3-14)
 Could be continued even as patient progresses
 Other agents to be considered include
o Vitamin E
o Selegiline
o Neither of these have data to back them up though
 Behavioral Decline
 This includes psychosis, depression, and anxiety
 Issues with antidepressants
o In general, SSRIs are first line
o TCA should be avoided due to their anticholinergic effects
o Trazodone and other atypical antidepressants may be useful
 Trazodone specifically is helpful with insomnia
 Role of Antipsychotic Drugs
o Think of dopamine and acetylcholine as a seesaw.
 If I take away dopamine, I will have both
 Anti-dopaminergic side effects
 Cholinergic excess side effects
  If a patient has Parkinson’s disease and is also psychotic, the anti-
psychotic drug of choice is quetiapine because it is the least
antidopaminergic antipsychotic.
o First Generation Agents
 These are the more anti dopaminergic
 EX: haloperidol, chlorpromazine, and prochlorperazine
 Neurologic side effects are based on dopamine inhibition and
procholinergic activity
 Early: < 3 months
o Parkinsonism, akathisia, rigidity, dystonia,
neuroleptic malignant syndrome
o Dystonia is Ach excess and the rest are lack of
dopamine
 Late: > 3 months
o Tardive dyskinesia
 Up to 25% a year in the elderly
 Endocrine effects include hyperprolactinemia
 QT prolongation is also a problem
o Second Generation Agents
 Less anti dopamine; also cover serotonin, histamine, etc. that can
also contribute to psychosis
 EX: risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole,
and clozapine
 Extrapyramidal effects are far less likely than with first generation
agents IE lower risk neuro AE
 Quetiapine (by being the least dopaminergic of these
agents) is likely the preferred agent in patients with
parkinsonism
 Clozapine is a more effective agent than others but its
associated severe leukopenia (agranulocytosis) limits its
use to those who fail numerous other drugs
 Endocrine effects relate to severe insulin resistance IE metabolic
syndrome
 Weight gain
 Hyperlipidemia
 Diabetes mellitus
 QT prolongation is also a problem
 Sleep Decline
 Insomnia
 Sleep apnea
 REM sleep due to behavioral or motor things
 Abrupt Decline
 Source control!
 Try to find a source before you blame it on “progression of dementia”
o Adding a medication
o Mild dehydration
o Bladder infection
o Fecal impaction
 o Misplacing hearing aids
o Being put in a new environment
 Lifestyle Decline
 Protect from harm!
 Frequent falls, hip fractures, etc. are major causes of morbidity/mortality in
patients with dementia of any etiology
o AGAIN: If a patient with established dementia has a relatively abrupt clinical decline, do NOT
just blame it on the progression of dementia. There could be other simply reversible factors
that could be targeted to change and bring patients back to baseline. It is all about that source
and symptom control.