MND & Atypical MNDs

7/28/2019 MND & Atypical MNDs

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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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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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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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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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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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MND & Atypical MNDs