MOTOR NEURON DISEASES. James B. Caress, MD Wake Forest University School of Medicine

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1 MOTOR NEURON DISEASES James B. Caress, MD Wake Forest University School of Medicine

2 Motor Neuron Diseases progressive selective degeneration of upper and/or lower motor neurons proximal and distal weakness tend to spare eye movements and bladder/bowel function.

3 Anatomy: UMN upper (UMN) and lower (LMN) motor neurons UMNs form the pyramidal tract which terminate by synapsing on anterior horn cells (LMN) in the anterior horn of spinal cord gray matter

4 Anatomy: LMN LMNs coalesce into spinal nerve roots as they are combined with sensory fibers LMNs traverse the plexus and innervate muscles 50 to >200 LMNs innervate each muscle each LMN divides into branches as it pierces the muscle membrane each terminal branch forms a bulb called the presynaptic terminal

5 Clinical Findings in MNDs LMN signs weakness, atrophy, fasciculations, cramps UMN signs weakness, spasticity, brisk reflexes, clonus, and extensor plantar responses unusual laughing or crying spells not associated with appropriate emotions (pseudobulbar affect)

6 Classification of MNDs Acute Polio Subacute/Chronic SMA I (Werdnig-Hoffman) Amyotrophic Lateral Sclerosis Chronic other Spinal Muscular Atrophy syndromes Monomelic Amyotrophy Multifocal Motor Neuropathy with Conduction Block

7 Acute MND: Polio most infections are asymptomatic abrupt onset following poliovirus infection fever and lethargy progressive paralysis 1-2 weeks after fever self limited with nadir at 1 month recovery may be full or partial Salk/Sabin vaccine nearly eradicated polio polio occurs in infants in modern era following oral polio vaccine (1 in 2.5 million) inadequate vaccination

8 Polio: Sequelae scoliosis of the spine atrophy of one or more limbs post-polio syndrome may occur years later pain, fatigue, subjective weakness no evidence for disease recrudescence possibly related to overuse of abnormal muscles post-polio muscular atrophy

9 Spinal Muscular Atrophy affect only LMNs and in adults are very slowly progressive autosomal recessive with a few exceptions infantile, childhood, and adult onset forms most AR SMA cases are due to abnormalities in SMN gene (chr 5q) function of SMN is unknown

10 SMA: Early onset SMA I (Werdnig-Hoffman) decreased fetal movements, onset < 6 months never sit up unassisted death occurs before age 2 SMA II (Kugelberg-Welander) onset 6-18 months, never walk death occurring in childhood SMA III onset after 18 months, walk until certain age progress or arrest after a period of years

11 SMA: Adult onset SMA IV proximal weakness and fasciculations abnormal gait normal life expectancy Kennedy s disease (X-linked SBMA) LMN + sensory neuropathy + gynecomastia trinucleotide repeat in androgen receptor gene monomelic amyotrophy teenage onset of unilateral limb atrophy self limited

12 Multifocal Motor Neuropathy with Conduction Block progressive LMN syndrome typically affects unilateral arm > leg M >> F minimal sensory involvement conduction blocks seen on NCS dramatic response to IVIG, plasmapheresis probable motor variant of CIDP

13 Amyotrophic Lateral Sclerosis (ALS) affects UMNs and LMNs progressive spasticity, weakness, atrophy of the limb and bulbar muscles 65% have UMN/LMN signs at presentation 75% have limb onset distal > proximal, commonly asymmetrical 25% bulbar onset gradual dysarthria and/or dysphagia fasciculations (90%) and cramps (50%) sensory complaints are not present

14 ALS: Epidemiology 1-2 / 100,000 incidence average age of onset is 59 but may occur at any age 5-10% are familial ALS (FALS) 20% of FALS cases have deletion in Cu/Zn superoxide dismutase gene (Chr 21)

15 ALS: Course progresses at a variable rate but often marked by plateaus and extremely rare reports of spontaneous regression average life expectancy is around 3 years 10% survive longer than 10 years better prognosis in younger persons and those with limb onset

16 ALS: Diagnosis diagnosis is clinical with supportive evidence from NCS/EMG negative neuroimaging CK may be elevated <1000 CSF protein may be mildly increased and OCBs are positive in 10% autopsy reveals atrophy of MNDs without inflammation

17 ALS: Etiology cause of this disease is unknown glutamate toxicity immunological Cu/Zn superoxide dismutase

18 ALS: Variants Progressive Muscular Atrophy (PMA) limb LMNs affected Progressive Bulbar Palsy CNs 7-12 LMNs affected 1-2 year survival Primary Lateral Sclerosis/Pseudobulbar Palsy UMN only, avg 15 year survival

19 ALS: Differential Diagnosis cervical spine disease myelopathy + radiculopathy B12 deficiency peripheral neuropathy + myelopathy other MNDs rare cancers, paraneoplastic syndromes myopathies hyperparathyroidism/ hyperthyroidism myasthenia gravis bulbar onset inflammatory neuropathies lead toxicity multiple sclerosis

20 ALS: Treatment Riluzole (rilutek) has been shown to extend survival by several months insulin like growth factor, gabapentin palliative care patient/family education physical therapy, assistive devices anti-depressants, -spasticity, -salivation? gastrostomy? tracheostomy with ventilation

21 MNDs: Summary pure motor syndromes hereditary or sporadic LMN involvement weakness, atrophy, fasciculations UMN involvement spasticity, weakness ALS combines UMN and LMN signs rapidly developing therapeutic strategy supportive treatment, counseling