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MOTOR NEURON DISEASE
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Motor Neuron Disease
Loss of upper and lower motor neuron
function
The relative degree of upper vs. lower
motor neuron loss and the distribution of
the loss between bulbar and spinal
functions determine the various clinical
categories
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Classification
Amyotrophic Lateral Sclerosis
Progressive Bulbar Palsy
Progressive Muscular Atrophy
Primary Lateral Sclerosis Multifocal Motor Neuropathy
Spinal Muscular Atrophy
Kennedys Disease
Monomelic Amyotrophy
Brachial Amyotrophic Diplegia
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Amyotrophic Lateral Sclerosis
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General Information
ALS is disease of part of the nervous system
that controls voluntary movements
Amyotrophic = without muscle nourishment,
resulting in loss of nerve signals to muscles Lateral = to the side, referring to location of
damage in spinal cord (corticospinal tract)
Sclerosis = hardened nature of spinal cord
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Statistics
Incidence 0.4-1.76/ 100,000, and increases witheach decade of life
Usually begins in mid to later life; rare in age
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Familial ALS
Between 5 and 10% of ALS cases are familial,
the majority autosomal dominant
Younger age at presentation, lacks male
predominance, has shorter disease duration,and predilection for lower extremity onset
Up to 20% of familial ALS patients are
associated with mutation in the Cu/Zn SOD1
mutation on chromosome 21
More than 60 different mutations described
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Pathology
Loss of neurons in anterior horn of spinal cord
and motor nuclei of lower brainstem
Pathologic features include cell body shrinkage,
pyknosis, ghost cells, neuronophagia, andgliosis
Loss of Betz cells in precentral motor cortex
Corticospinal tracts depleted of large myelinatedfibers, and most readily observed in anterior and
lateral columns of spinal cord
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ALS
UMN exerts complex control over LMNs
that allows smooth, directed movements
(e.g. picking up a glass)
When UMN is lost, spasticity develops
In ALS, death of UMN and LMN results in
tight, weak, and atrophic muscles;
fasciculations and cramps
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ALS Symptoms
Stiffness, weakness, wasting in hand muscles;
impaired fine finger movements (e.g. buttoning,
turning ignition keys)
Cramping, fasciculations (muscle twitches) Exaggerated reflexes (e.g. biceps, knees)
Positive Babinskis
Spasticity Sensory symptoms (numbness, tingling) rare
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ALS Symptoms
Finger abductors, adductors, extensors
weak before finger flexors (resulting in
clawed hand with hollowing of dorsal
interosseus spaces)
Weakness spreads to neck, tongue,
pharynx, larynx, trunk,
Affected parts may feel cold
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ALS Symptoms
Leg involvement with foot drop
In some, early involvement of thoracic,
abdominal, neck muscles
Gait disorder
Shortness of breath
Weight loss
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ALS Symptoms
Weakness usually painless
Patient may notice atrophy before
functional loss
Weakness frequently asymmetric
Sensory symptoms may be reported in up
to 25%, but objective clinical sensory signsuncommon
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ALS and Dementia
Historically, ALS was not felt to beassociated with cognitive or memoryimpairment.
Recent studies suggest 20-25% of ALSpatients have frontotemporal lobedementia
Progressive condition that results indegeneration of the frontal and temporallobes of the brain
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Frontotemproal Dementia
Initial symptoms include changes in
personality, language, and behavioral
disturbances
Difficulties with executive function (e.g.,
planning a party)
Differentiate from Alzheimers Disease,
which typically begins with short term
memory impairment
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Frontotemporal Dementia
Etiology unclear, possibly related to
abnormal tau protein metabolism
Risk factors include advanced age, family
history of dementia, bulbar symptoms,
diminished vital capacity
Associated with reduced life span
Diagnosis assisted by formal
neuropsychological testing
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ALS Symptoms
Dutch researchers examined 14 studies ofcognition in ALS patients without obvious
dementia. Findings revealed loweraverage scores on tests of global cognitiveability, immediate verbal memory, visualmemory, executive functioning, (e.g.,planning a series of events), verbalfluency and processing speed
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ALS Symptoms
Extraocular muscles, bowel/bladder
function typically spared
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Prognosis
Rate of anterior horn cell deterioration varies
from patient to patient
50% die within 3 years, usually from
respiratory complications; 90% within 6
years
Rare cases survive decades
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Evaluation
NCS/EMG integral part of evaluation ofALS patients
NCS findings:
Normal SNAPs (sensory nerve actionpotentials)
Low amplitude CMAPs (compound muscleaction potentials) when significant axon loss
occurs; may accompany modest slowing ofNCVs
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ALS Evaluation
Median motor distal latencies may beprolonged
EMG findings:
Active denervation (fibrillations and positivewaves)
Fasciculations
Chronic denervation (large amplitude,prolonged duration polyphasic MUAPs)
MUAPs fire with rapid rate (>10 Hz)
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ALS Evaluation
NCS/EMG changes should be found in at
least 2 regions (bulbar, cervical, thoracic,
lumbosacral)
In cervical and lumbosacral regions, at
least two muscles from different roots and
peripheral nerves must be involved
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ALS Evaluation
Exclusion criteria:
Marked conduction slowing
Conduction blockAbnormal sensory responses
otherwise unexplained by advanced
age or coexisting neuropathy
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ALS Evaluation
MRI of spine to exclude structural cause(e.g. spinal stenosis).
Serum and urine studies to exclude other
metabolic causes (lead toxicity,paraproteinemia)
Lumbar puncture usually yields normal
CSF CK usually normal or slightly elevated
Muscle biopsy occasionally useful
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El Escorial Criteria for Diagnosis
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Treatments
Rilutek, glutamate inhibitor, extends
survival a few months
OT, PT may utilize AFOs, walker,
manual/power wheelchair, scooter
ST electronic speech device; may also
assist with swallowing
evaluation/treatment
Patients eventually require PEG/G-Tube
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Progressive Muscular Atrophy
Pure lower motor neuron syndrome
Patients develop distal limb wasting,
weakness, fasciculations, cramps; no
sensory symptoms/signs
Asymmetric weakness
Reflexes usually reduced or absent
Long clinical course, with slow progression
to proximal limb muscles
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PMA
Bulbar involvement unusual
Upper motor neuron dysfunction usually
absent
Need to rule out multifocal motor
neuropathy (treatable)
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Progressive Bulbar Palsy
Variant of ALS
Patients present with dysarthria,
dysphagia, sialorrhea, aspiration, and
pseudobulbar signs
Upper motor neuron dysfunction may
result in spastic dysarthria with slow oral
and tongue movements, and strained
voice
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Progressive Bulbar Palsy
Dysphagia, often initially more for liquids
than solids
Hyperactive gag and jaw-jerk reflexes
Pseudobulbar affect with inappropriate
laughing, crying, and yawning
Lower motor neuron dysfunction leads to
greater degree of weakness affecting the
face, palate, and tongue
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Primary Lateral Sclerosis
2-3.7% of ALS patients present with this
pure UMN syndrome
Age of onset typically 50-55 years
May have very slow progression
Commonly present with spastic
paraparesis, progressing rostrally to
eventually cause pseudobulbar palsy
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Multifocal Motor Neuropathy
May mimic PMA or ALS
Usually affects only motor fibers, sparing
sensory fibers
Slowly progressive, begins distally
Absence of upper motor neuron signs
Usually seen in younger patients (
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MMN
Individual motor nerve affected out of proportionto adjacent nerves with same myotomalinnervation (e.g., median vs. ulnar)
Respiratory and bulbar weakness rare
No shortening of life span
Weakness out of proportion to atrophy,suggesting demyelination as primary pathology
Non-regional spread of weakness (e.g., rightarm to left leg)
Associatied with AntiGM1 antibodies
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MMN
Some improvement in up to 80%
Significant useful functional benefit in 50-
60%
Despite improvement in strength, IVIg
treatment usually does not reduce titers of
serum anti-GM1 antibodies
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MMN
Cyclophosphamide is the only
immunosuppressive treatment reported to
produce sustained long-term relief in 50-
80% of patients with MMN
Limited use due to side effects and
increased risk of neoplasm
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Spinal Muscular Atrophy
Most cases are genetic, autosomal
recessive, and linked to chromosome 5
Classification based on age of onset:
SMA I: Werdnig-Hoffman, acute infantile
SMA II: intermediate, chronic infantile
SMA III: Kugleberg-Welander, chronic juvenile
SMA IV: adult onset
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SMA
Characteristic clinical presentation is
progressive, symmetric proximal
weakness and atrophy without UMN signs
Werdnig-Hoffman most severe form, death
by age 2
Diagnosis suggested by history of
impaired motor development or loss ofmotor skills
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SMA
Findings on physical exam include
weakness, hypotonia, and absent deep
tendon reflexes
CK 1-2X normal, but may be 10X normal
in type III
Positive DNA test for deletion ofsurvival
motor neuron gene (SMN)
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SMA
EMG findings reveal regular spontaneous
motor unit action potentials
Fasciculations more common in types II
and III than type I
Fibrillations and positive waves in all
patients
Normal sensory nerve action potentials
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SMA
Compound nerve action potentials may be
low in amplitude, velocities normal
Motor unit action potentials large
amplitude, prolonged duration, with
decreased recruitment
Muscle biopsy reveals grouped atrophy of
type I and II muscle fibers, as opposed tonormal checkerboard pattern
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SMA
Prognosis
SMA I: weakness before 6 months, never sit
independently, lie expectancy less than 2
years SMA II: onset after 6 months, can sit
independently, may survive to 2nd or 3rd
decade
SMA III: manifest weakness after 18 months,
walk independently, survive to 6th decade
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SMA
Scoliosis, contractures, and pneumonia
are predictable complications
Some children with Werdnig-Hoffman do
not suck or swallow well, so feeding
gastrostomy may be necessary
Forced vital capacity decreased in all
patients, so respiratory support should bediscussed before it is needed
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SMA
Development of orthopedic deformities in
patients with SMA II and III necessitates team
approach
SMA I patients rarely survive long enough todevelop spinal deformities
SMA patients who walked, but never normally,
typically lose walking ability by 15 years. Those
who developed weakness after walking normallycan walk until the 30s or 40s
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Kennedys Disease
Fasciculations frequent in limb muscles
DTRs depressed or absent
Hand tremors found in up to 80 percent,
characteristic of essential tremors; may
respond to propranalol
Facial fasciculations in more than 90%,
best elicited by having patients whistle or
blow out of cheeks
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Kennedys Disease
Dysarthria and dysphagia rare
Sensory loss/symptoms rare, but most
patients have absent or low amplitude
sensory nerve action potentials (SNAPs)
Gynecomastia and impotence in most
patients due to androgen insensitivity
Diabetes mellitus occurs in small
percentage of patients
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Kennedys Disease
Diagnosis suggested by clinical
presentation and positive family history,
confirmed by genetic testing
Serum CK usually elevated, sometimes up
to 8,000
CMAP amplitudes may be normal or low
SNAP amplitudes low or absent
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Kennedys Disease
EMG reveals large amplitude, prolongedduration polyphasic MUAPs withdecreased recruitment
EMG of facial muscles reveal grouped,repetitive motor unit discharges whichoccur with mild activation of facial muscles
Diagnosis confirmed by DNA analysis ofthe CAG mutation within the first exon ofthe androgen receptor gene
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Kennedys Disease
Slowly progressive, with normal or slightly
reduced life expectancy
Bulbar weakness late in the disease
course
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Monomelic Amyotrophy
Etiology unknown
Most cases sporadic
Most patients 18-22 years
Slow onset of unilateral weakness and
atrophy of hand muscles
Weakness progresses slowly over 1-3years, then stabilizes
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Monomelic Amyotrophy
Atrophy usually limited to hand and
forearm muscles (brachioradialis often
spared)
Postural tremor in 10%
DTRs usually normal
UMN signs absent
Sensation usually preserved
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Brachial Amyotrophic Diplegia
Differentiate from monomelic amyotrophy,
which usually occurs in younger age
group, restriction to hand and forearm
muscles, and asymmetric
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Reference
Murray B., Mitsumoto H., Russman B.,
Shapiro B.E. Neuronopathies (Motor
Neuron and Dorsal Root Ganglion
Disorders). In B. Katirji, H. Kaminski, D.Preston, R. Ruff, B. Shapiro (eds),
Neuromuscular Disorders in Clinical
Practice. Butterworth-Heinemann, 2002;417-477.
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