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MOTOR SYNDROMES

Differential diagnosis Hereditary Amyotrophic lateral sclerosis   Hereditary   Sporadic ALS variants   EOM & Extrapyramidal change   Primary lateral sclerosis   Primary muscular atrophy   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     IgM vs GM1 ganglioside     IgM vs GalNAc-GD1a ganglioside   Multifocal motor neuropathy (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 SMA & Arthrogryposis Spastic paraparesis Toxic

From Bramwell:  Atlas of Clinical Medicine ALS with Bulbar involvement

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
      • ALS with Ophthalmoplegia & Extrapyramidal Disorders
      • Polyglucosan body disease
      • Motor neuronopathy with cataracts and skeletal abnormalities
      • Multiple system atrophy
      • AAA syndrome
  • 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 2⁵
• 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
  • Bulbo-spinal Muscular Atrophy
    • Androgen Receptor: X-linked
    • Dominant
  • Amyotrophic Lateral Sclerosis (ALS)
    • Sporadic ALS
    • Hereditary ALS
    • ALS with Bulbar onset, Benign course & Bunina bodies
  • Hereditary Bulbar syndromes
    • Brown-Vialetto-van Laere
    • Fazio-Londe
  • Congenital Bulbar syndrome
    • Worster-Drought syndrome: Congenital suprabulbar paralysis
• Painful: Diabetic amyotrophy
• Rapid Onset
  • Acute Axonal Motor Neuropathy
    (with Campylobacter jejuni or serum IgG vs GM1)
  • Poliomyelitis
  • Porphyria
    • 4 types cause neurologic attacks
      
      • Acute intermittent
      • Variegate Porphyria
      • Coproporphyria
      • δ-amino-levulinic acid dehydratase deficiency
    • Urine: All types produce increased δ-amino-levulinic acid during attacks
• Acquired
  • Toxic: Lead; Dapsone; Botulism; Tick Paralysis
  • Infections
    • Polio
    • West Nile
    • Central European encephalitis
      
    • Creutzfeld-Jacob
      • Amyotrophy
      • Polyneuropathy (± Demyelinating)
• Other
  • Distal SMA
  • SMA & motor neuron syndromes: Other hereditary
  • Multifocal Motor Neuropathy (MMN)

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

• Age: 1 to 13 years
• Onset
  • 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
• Sensory: Normal
• CSF
  • Pleocytosis
  • Protein: ± Increased
• MRI: May show signal (T2) in spinal cord
• Prognosis: Permanent paralysis

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

• Eponyms
  • Hirayama's disease: Progressive weakness over 1 to 4 years, then plateau
  • O'Sullivan-McLeod syndrome: Slow progression
• Epidemiology
  • Male > Female: Up to 10:1
  • Family history
    • Usually sporadic
    • Occasional familial occurrence
  • Common in Eastern India⁷, Taiwan
  • Association: Heavy physical activity before onset
• Onset
  • Age: Young adult; 15 to 25 years; Up to 40 years in India
  • Weakness: Distal; Single limb
• Clinical
  • Weakness
    • Often confined to a single arm
    • Distal involvement (97%): C7, C8 & T1 innervated muscles; Hand & Forearm
    • Proximal > Distal: 10%
    • Side: Right 1x to 3x Left
  • Atrophy: "Oblique amyotrophy"; Sparing brachioradialis
  • Tremor (80%): On finger extension; Irregular & Coarse (Minipolymyoclonus)
  • 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
    • Cramps & Spasms (30%)
    • Sensory loss
      • Mild in affected limb
      • Rarely prominent on examination
    • Hyperhidrosis
    • Neck pain
  • 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: C7-T1
      • Occasional: Legs
      • May be present in asymptomatic limbs
    • Chronic denervation
      • In affected limb(s) (100%)
      • Opposite arm or lower extremities in some patients
      • Signs of acute denervation in 45%
    • Ongoing denervation
  • NCV
    • CMAPs: Small in affected limbs; Especially ulnar nerve
    • Sensory: Normal
  • Sympathetic skin response: May be abnormal
  • MRI
    • Cervical pathology
      • ? Some patients with inelastic dura
        • Spinal cord compression with neck flexion¹
      • Anterior shifting of posterior dura: Engorged posterior venous plexus
      • Spinal cord atrophy: C6 & C7
      • T2 signal in anterior horns of gray matter
    • Other studies³
      • No major spinal anomalies
      • Mild flexion-induced cord displacement

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

"Primary Muscular Atrophy" (PMA)

Gowers

Primary muscular atrophy Note wasting, including paraspinous muscles.

• Widespread Lower Motor Neuron Syndrome
  • 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
  • No upper motor neuron signs
  • Pain: Related to immobility
  • Time course
    • Progressive
    • Similar to, more rapid, or slower than, typical ALS
• 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
• Pathology
  • Loss of motor neurons in anterior horn of spinal cord
  • Shrinkage of remaining motor neurons
  • Inclusion bodies: Intracytoplasmic, Hyaline

Primary Lateral Sclerosis²

PLS : Sporadic, Adult onset

• ? Discrete syndrome vs ALS variant
• Genetics
  • Family history: Usually none
  • No mutations in Alsin gene
• 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
  • Bladder function: Normal until late in disease
• 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

• Gene mutations
  • PLS: Deletion in exon 9
  • ALS2: Mutation in another region of alsin gene
  • Familial spastic paraparesis, infantile onset
• Clinical
  • Onset: Childhood
  • Spasticity: Bulbar; Extremities
  • Gaze paresis
  • Normal: Cognition; Sensation
• Laboratory
  • Central motor conduction times: Delayed or Unrecordable
  • EMG: No denervation

• 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

• Epidemiology: 2 patients
• 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