Motor Syndromes

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MOTOR SYNDROMES

Motor
Differential diagnosis
Hereditary

Amyotrophic lateral sclerosis
Hereditary
Sporadic
ALS variants
EOM & Extrapyramidal change
Primary lateral sclerosis (PLS)
Primary muscular atrophy (PMA)
Western Pacific ALS

Amyotrophy
Lower extremity, benign
Monomelic
Diabetic amyotrophy
Hand weakness
Hopkins
Infections
Insulinoma
Mitochondrial: SCO2
Motor Neuron Disorders
Hereditary
Bulbar
Lower motor neuron
Upper motor neuron
Asymmetric
Symmetric
Motor Neuropathy
Distal
Hereditary
Antibodies
IgG vs GM1
IgM vs GM1
IgM vs GalNAc-GD1a
IgM vs NS6S
Multifocal motor (MMN)

Myopathies
Painful
Paraneoplastic
Lymphoma
Breast
Poliomyelitis & Post-polio syndrome
Rapid onset
Acute Axonal Motor Neuropathy
Poliomyelitis
Porphyria
Spinal muscular atrophy: Hereditary
SMN (5q)
Androgen Receptor (Bulbar SMA)
Distal SMA (Distal HMN)
Hexosaminidase A (Tay-Sachs)
Scapuloperoneal
Spinal muscular atrophy 2
X-linked Infant & Arthrogryposis
Spastic paraparesis
Toxic

From: Quain

Motor Neuron Disorders: Differential Diagnoses

Asymmetric
- Upper + Lower Motor Neuron Signs
  - Amyotrophic Lateral Sclerosis (ALS)
    - Sporadic ALS
    - Hereditary ALS
      - Superoxide Dismutase; Chromosome 21; Dominant
      - Other ALS: Recessive & Dominant
  - Sporadic motor neuron disorders with dementia
    - Western Pacific ALS
    - Frontal Dementia followed by motor system disease
      - Upper motor neuron: Especially bulbar
      - Lower motor neuron: Fasciculations; Mild weakness
      - ? Atypical Creutzfeld-Jacob syndromes
  - Multi-system disorders
- Lower Motor Neuron Signs only (Asymmetric)
  - Distal Lower Motor Neuron (LMN) Syndrome
    - IgM vs GM1 ganglioside
    - IgM vs GalNAc-GD1a ganglioside
    - Also see: Multifocal motor neuropathy
  - Proximal Lower Motor Neuron Syndromes
    - Brachial amyotrophic diplegia
    - ? Associated with IgM vs asialo-GM1
    - Rare: Upper > Lower limbs with anti-Hu antibodies
  - Lower Motor Neuron Syndrome without antibodies (PMA)
  - ALS variants
    - Hereditary
    - Sporadic
  - Focal motor neuron disease
    - Monomelic Amyotrophy
    - Paraspinous muscle amyotrophy
    - Cervical amyotrophy
  - Paraneoplastic motor neuro(no)pathy
    - Mild weakness: With lymphoma
    - Severe weakness: With breast cancer
  - Hopkins' syndrome: Acute post-asthmatic amyotrophy
  - Polio & Post-polio syndrome
  - SMN2 (SMN^C) deletions
  - Neurofibromatosis, Type 2 ⁵
Symmetric & Proximal: Hereditary Spinal Muscular Atrophy
- SMN: Chromosome 5q; Recessive
- Androgen Receptor (Bulbo-spinal Muscular Atrophy): X-linked; Recessive
- Hexosaminidase A (Tay-Sachs): Chromosome 15; Recessive
Hand weakness
- Motor neuron disease & motor neuropathies
- Myopathies: Distal; Myotonic Dystrophy; Inclusion Body Myositis
- Myasthenia Gravis
- Peripheral nerve lesion
  - Median: Recurrent motor branch; Anterior interosseus
  - Ulnar: Guyon canal
  - Radial: Posterior interosseus
- Brachial Plexopathy
- Distal SMA
Bulbar involvement

From: Quain
- Bulbo-spinal Muscular Atrophy
  - Androgen Receptor: X-linked
  - Dominant
- Amyotrophic Lateral Sclerosis (ALS)
- Hereditary Bulbar syndromes
  - Brown-Vialetto-van Laere
  - Fazio-Londe
- Congenital Bulbar syndrome
  - Worster-Drought syndrome: Congenital suprabulbar paralysis
- SCA 36
Painful: Diabetic amyotrophy
Rapid Onset
- Acute Axonal Motor Neuropathy
- Poliomyelitis
- Porphyria
  - 4 types cause neurologic attacks
    - Acute intermittent
    - Variegate Porphyria
    - Coproporphyria
    - δ-amino-levulinic acid dehydratase deficiency
  - Urine: During attacks
    - All types produce increased δ-amino-levulinic acid
Acquired
- Toxic: Lead; Dapsone; Botulism; Tick Paralysis
- Infections
  - Polio
  - West Nile
  - Central European encephalitis
  - Creutzfeld-Jacob
    - Amyotrophy
    - Polyneuropathy (± Demyelinating)
Other

Paraneoplastic Motor Neuropathy

Ramon y Cajal

Onset: After diagnosis of tumor
Epidemiology: Majority male & > 50 years
Clinical
- Weakness
  - Asymmetric; Arms > Legs
  - Mild
  - Lower motor neuron only
  - Normal bulbar
- Cramps: Painful
- Painless in some patients
- Course: Progressive then stabilizes or improves
Associated with
- Non-Hodgkin Lymphoma
- Also other lymphomas & myeloproliferative disorders⁴
Laboratory
- CSF: No cells; Mildly increased protein
- MRI: Spinal cord normal
- ? Neuronopathy
Animal model: Similar disorder in mice 2° murine leukemic virus
Also see: Paraneoplastic Lower Motor Neuron Syndrome

Paraneoplastic Lower Motor Neuron Syndrome⁸

Epidemiology: Single patient, 72 year old female
Onset: 4 months before diagnosis of tumor
Clinical
- Weakness
  - Asymmetric at onset
  - Arms & Legs
  - Severe
  - Lower motor neuron only
  - Bulbar: Hypophonia; Dysphagia; Unilateral facial paresis
- Painless
- Course
  - Progressive over months
  - Improvement after tumor removal
  - Long-term residual disability
- Sensation: Normal
- Tendon reflexes: Absent
- CNS: Transient dizziness & Nystagmus
Associated with
- Ductal adenocarcinoma of breast
Laboratory
- Antibodies
  - Serum binding to βIV spectrin, isoform I (Bands at MW 250kD & 140kD)
  - Serm binding to axon initial segments & nodes of Ranvier in rat brain
- Electrophysiology
  - EMG: Denervation
  - NCV: Small CMAPs; No conduction block
- MRI: Spinal cord with high signal spots on T2
- ? Neuronopathy
Immunosuppressive treatment: No response
Also see: Paraneoplastic Motor Neuropathy

HOPKINS' SYNDROME: Acute post-asthmatic amyotrophy

Clinical
- Onset
  - Age: 1 to 13 years
  - After acute asthmatic attack: Latency 1 to 18 days
  - Mild pain: Limb, neck or meningismus
  - Rapid onset weakness
- Weakness
  - Single limb; Asymmetric; May be Proximal > Distal
  - Severity: Mild to severe
  - Arm or leg
- Wasting: Affected limb
- Sensory: Normal
- Tendon reflexes: Reduced
- Prognosis: Permanent paralysis
Laboratory
- EMG: Denervation
- CSF
  - Pleocytosis
  - Protein: ± Increased
- MRI: May show signal (T2) in spinal cord

Post-Polio Syndrome

Old Polio
Asymmetric atrophy & weakness
Atrophic right leg (arrow) in patient
with paralytic polio 70 years in past

Diagnostic Criteria: Clinical
- History of polio
  - Partial or complete neurological & functional recovery
  - Stable function > 15 years
- Onset of
  - Fatigue
  - Muscle pain
  - Functional loss
    - Usually 2° Musculoskeletal disorder
    - New weakness is rare
- Neurological examination
  - Lower motor neuron syndrome (confirmed by EMG or MRI)
    - Measurable loss of strength is rare
  - Decreased or absent tendon reflexes
  - No sensory loss
- Other
  - No other explanation for symptoms
  - Joint pain & cold intolerance may accompany the syndrome
Laboratory features
- CK: Elevated
- Electrophysiology
  - Very large motor units (up to 10 times normal)
  - Some fibrillations & positive sharp waves even in stable patients
- Muscle pathology
  - Near full recovery of strength & stable
    - Type I muscle fiber predominance
  - Persistent or new weakness
    - 50% type I fibers
    - Angular fibers; Atrophy + hypertrophy
  - New weakness & high CK
    - More small angular fibers
    - Muscle fiber necrosis
Recommended exercise
- Mild paresis: Resistance training
- Moderate paresis: Submaximal endurance
- Severe paresis: None; Joint bracing

Monomelic Amyotrophy

Nosology
- Hirayama's disease
  - Course: Progressive weakness over 1 to 4 years; Then plateau
  - More related to flexion myelopathy
- O'Sullivan-McLeod syndrome
  - Course: Slow progression over decades
Epidemiology
- Male > Female: Up to 10:1
- Family history
  - Usually sporadic
  - Occasional familial occurrence
    - Dominant¹³ or Recessive
- Geographic: Common in
  - Eastern India ⁷
  - Taiwan
  - Other: Japan, Sri Lanka, Indonesia, Korea, Hong Kong, Malaysia
- Association: Heavy physical activity before onset
Possible etiologies
- Cervical myelopathy, central: Neck flexion induced
- Motor neuron disease
- Genetic associations (Koreans) ¹⁶
  - KIAA1377 : G668S
  - C5ORF42 : P1794L
Clinical ¹⁷
- Onset
  - Age: Young adult; 13 to 25 years; Up to 40 years in India
  - Weakness: Distal; Single limb
- Weakness
  - Asymmetric
    - Often predominant in one arm
    - Subclinical involvement of other arm: Common
  - Distal predominant (97%): Proximal > Distal in 3% to 10%
  - Hand & Forearm
    - C8 & T1 ± C7, innervated muscles
  - Side: Right 1x to 3x > Left
  - Cold paresis: More weakness & stiffness in cold
- Atrophy
  - Hands
  - "Oblique amyotrophy": Wasted C7 muscles with preserved brachioradialis belly (C6)
- Tremor or Minipolymyoclonus (80%)
  - On finger extension
  - Irregular & Coarse
- Occasional other features
  - Weakness: Other
    - Ipsilateral shoulder
    - Progression to opposite limb
      - Frequency: 18% - 40%
      - Latency: Range 2 to 120 months; Mean 43 months
      - Usually milder weakness than 1st limb
    - Worsening on exposure to cold
  - Fasciculations
    - On affected side (47% to 66%)
    - May not be symptomatic
    - Contractile fasciculation
  - Sensory loss
    - Mild or none in affected limb on exam
    - Rarely prominent on examination
    - Subjective numbness (20%)
  - Discomfort
    - Cramps & Spasms (30%)
    - Neck pain
  - Autonomic: Hyperhidrosis
- Tendon reflexes: Usually normal
- No cranial nerve, leg or pyramidal changes
- Disease course
  - Typical monomelic amyotrophy¹⁰
    - Progression: Over 1 month to 5 years; 7% as long as 8 years
    - Static after progression phase: May persist for decades
    - Disability: Mild or none in 73%
  - O'Sullivan-McLeod syndrome⁶: Progression over decades
Laboratory
- EMG
  - Location of pathology
    - Most common: C8-T1
    - Partial involvement: C7
    - Spared: C5-C6
    - Occasional: Legs
    - May be present in asymptomatic limbs
  - Chronic denervation
    - In affected limb(s) (100%)
    - Opposite arm or lower extremities: 30% to 100%
    - Signs of acute denervation in 45%
  - Ongoing denervation
- NCV
  - CMAPs: Small in affected limbs; Especially ulnar nerve
  - Velocities: Normal
  - Sensory: Normal
- Sympathetic skin response: May be abnormal
- MRI
  - Cervical pathology
    - Spinal cord atrophy (30% to 50%): C6 & C7
    - Anterior horns, gray matter: T2 signal
    - Neck flexion
      - Posterior epidural venous plexus: Engorgement
      - Posterior dura: Anterior shifting
    - ? Some patients with inelastic dura
      - Spinal cord compression with neck flexion ¹
  - Other studies³
    - No major spinal anomalies
    - Mild flexion-induced cord displacement
Differential diagnosis: HMN & Distal SMA, especially HMN Type 5

Amyotrophy: Benign Lower Extremity¹¹

Epidemiology
- 16 cases described
- Male > Female: 5:1
Onset: Mean age 41 years
Clinical
- Weakness: Posterior legs
  - Usual: Posterior calf; Peronei; Hamstrings
  - Rare: Quads
  - Often bilateral (50%)
    - Clinical or subclinical
    - Asymmetry: Some
- No sensory, bulbar or upper motor neuron signs
- Course
  - Insidious onset
  - Slow progression: Few years
  - Stabilization
Laboratory
- MRI
  - Loss of muscle with fat replacement
  - Distribution: Lower extremities
    - Distal leg: Posterior compartment
    - Thigh: Long head of biceps
- EMG: Denervation
- Muscle biopsy: Denervation; Grouped atrophy

Benign lower limb amyotrophy: MRI
From: M Al-Lozi Legs: Involvement of posterior muscle groups	From: M Al-Lozi Thigh: Long head of biceps involvement

Putnam	Gowers
	Primary muscular atrophy Note wasting, including paraspinous muscles.

"Primary Muscular Atrophy" (PMA)¹⁵

Epidemiology
- Frequency: 7% to 11% of ALS-like disorders
- Male in 74%: vs 55% in ALS
Lower Motor Neuron Syndrome: Widespread
- Weakness: Distribution
  - Distal & Proximal: Either may be more prominent
  - Asymmetric
  - Often involves paraspinous & respiratory muscles
  - Often spares bulbar musculature
- Spontaneous motor activity
  - Cramps: Common in legs, at night
  - Fasciculations
- Upper motor neuron signs
  - Not present at diagnosis
  - After 5 years: 20%
    - More with younger onset age
    - 50% develop in 1st year after diagnosis
- Pain: Related to immobility
- Time course
  - Progressive
  - Survival
    - Mean = 4 years: vs 3 years in ALS
    - Range: Similar to, more rapid, or slower than, typical ALS
    - Overall mortality: 68%
Laboratory
- Muscle pathology: Grouped atrophy > Fiber type grouping
- No serum antibodies
- No conduction block
No evidence for response to treatment
Differential diagnosis
- Proximal lower motor neuron syndrome
- ALS
  - Sporadic
  - Hereditary
    - SOD mutations: A4V, Leu84Val, D101N
    - CHMP2B
Pathology
- Loss of motor neurons in anterior horn of spinal cord
- Shrinkage of remaining motor neurons
- Inclusion bodies: Intracytoplasmic, Hyaline

Primary Lateral Sclerosis ²

Dominant, Adult onset
4p16
FIG4: 6q21
PLS + FTD
Recessive, Childhood onset
ALS2
ERLIN2
SIGMAR1
SPG11
Sporadic, Adult onset

From Bramwell: Diseases of the Spinal Cord

PLS: "Sclerosis" of pyramidal tracts (Upper thoracic cord)

PLS : Sporadic, Adult onset ¹⁴

Nosology: ? Discrete syndrome vs ALS variant
Genetics
- Family history: Usually none
- No mutations in Alsin gene in sporadic cases
Clinical
- Onset
  - Spasticity
    - Legs before arms
    - Slowly progressive
  - Age: Most commonly in 5th decade
- Motor dysfunction
  - Corticospinal ± corticobulbar tract dysfunction
    - Spasticity: Legs > Arms
    - Tendon reflexes: Brisk
    - Plantar reflex: Normal or upgoing
    - Pseudobulbar signs: Especially with disease onset > 45 years
  - Symmetric
  - No lower motor neuron change
- Sensory: Normal
- Frontal lobe dysfunction: Mild
- Progression
  - Gradual
  - Slow
  - > 3 years; Up to 3 decades
  - 40% develop Lower motor neuron signs 3 to 10 years after onset
- Bladder function: Normal until late in disease
- Differences from ALS: PLS has less
  - Bulbar onset
  - Weakness
    - Focal
    - Limb
  - Weight loss
  - Vital capacity reduction
Laboratory
- Magnetic stimulation: Absent or prolonged cortical motor evoked latencies
- MRI: Focal atrophy of precentral gyrus
- PET scan: Reduced glucose consumption in pericentral region
- Central motor conduction times: Prolonged
- Normal: Serum; CSF; EMG; Spinal cord imaging; Serum CK; CSF protein
Disease association: ? Breast cnacer
Pathology
- Corticospinal tract: Axonal loss
- Normal: Anterior horn cells ± Betz cells
Differential diagnosis
- Structural disorders: Spinal; Foramen magnum; Hydrocephalus
- Hereditary spinal disorders
- Infections

PLS: Recessive, Juvenile onset⁹

l Alsin (ALS2)

; Chromosome 2q33.1; Recessive

Epidemiology: Cypriot family
Genetics
- Mutation
  - Deletion: In Exon 9
  - Homozygous c.2980-2A>G mutation at splice acceptor site of intron 17: Frameshift
- Allelic with
  - ALS2: Mutations in another region of alsin gene
  - Familial spastic paraparesis, infantile onset (IAHSP)
Clinical
- Onset: Childhood
- Spasticity: Bulbar; Extremities
- Gaze paresis: Saccadic
- Normal: Cognition; Sensation
- Progression: Slow; Some remain ambulatory for decades
Laboratory
- Central motor conduction times: Delayed or Unrecordable
- EMG: No denervation
- Brain imaging: Normal

PLS: Dominant, Adult onset

l Chromosome 4p16; Dominant

Epidemiology
- Single French-Canadian family
- Male:Female = 1:1
Onset
- Age: 30 to 60 years
- Spasticity: Leg; Asymmetric
Clinical
- Spasticity: Arms & Legs; Asymmetric
- Strength: Normal
- Reflexes
  - Tendon: Diffusely increased
  - Plantar: Extensor
- Dysphagia: 60%
- Sensation: Normal
Laboratory
- EMG: Denervation, mild, distal, chronic
- MRI: Normal or Spinal cord atrophy, mild

PLS with Frontotemporal dementia¹²
l Sporadic

Epidemiology: 2 patients
Differential diagnosis: See ALS-FTD2
Onset
- Age: 6th to 8th decade
- Dementia
- Dysarthria
Clinical
- Cortical
  - Dementia
  - Aphasia
- Motor
  - Spasticity
  - Bulbar dysfunction: 1 patient
  - Strength: Normal
  - Tendon reflexes: Brisk
  - Plantar responses: Extensor
- Course
  - Slow progression
  - Death after 7 years
Pathology
- Neuronal loss: Frontotemporal & Motor cortex
- Inclusions: Ubiquitin & TDP-43 positive cytoplasmic

Patient information

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8/20/2012