Neuromuscular Diseases

Anatomy

upper motor neuron – cell bodies in grey matter of precentral gyrus

axons: cerebrum to brainstem (crossover lower medulla – pyrimidal decussation) to lateral corticospinal tract
synapse on alpha-motor neurons (lower motor) in anterior horn of spinal cord

lower motor (alpha) – ventral root, peripheral nerve bifurcates, innervate 3 (extraoc) to 2000 (gastrocnemius)

one nerve per muscle (except extraocular), and only one muscle type per nerve (not adjacent – checkerboard)
cell body, axon, neuromuscular junction, or muscle fibers can be affected by disease

sensory – with motor in peripheral nerves to dorsal root gangl. (cell bodies), process to dorsal horn (spinal)

synapse then cross to other side OR synapse and cross in lower brainstem and synapse again in thalamus

Clinical Disorders Associated with Various Anatomical Structures

upper motor – strokes, brain tumors, spinal cord injury, vitamin B₁₂ deficiency, degenerative disease

weakness, increased muscle tone (hypertonia) of a particular type (spasticity), ipsi- or contralateral
increased deep tendon reflex – Babinsky’s sign (toe ext.), Hoffman’s sign (flick finger, thumb flex), clonus
usually not pure (other systems affected which affect neuron)
site determined by sensory (small stroke – mild isolated weakness; spinal cord transection – no feeling)

lower motor – peripheral nerve damage (trauma, neuropathy), spinal root compression (disc herniation), degenerative disease (Amyotrophic Lateral Sclerosis)

weakness, decreased or absent deep tendon reflexes, decreased muscle tone (hypotonia), atrophy
fasciculations (whole motor units – unkn) and fibrillations (single muscle fiber – too many Na⁺ and Ca⁺⁺ channels)
site determined by sensory (peripheral nerve produces isolated sensory, spinal root only in distribution)
muscle cells denervated and fibers degenerate (to small angular cells); fiber type grouping observed

neuromuscular junction – myasthenia gravis, Lambert-Eaton, congenital myasthenic syndromes, botulism

fatiguing weakness (repetitive activity leads to loss of power) – safety factor smaller
otherwise normal reflexes, tone, sensation, no atrophy

muscle disorders – polymyositis, muscular dystrophies, metabolic myopathies

proximal weakness, myalgias, muscle atrophy, otherwise normal reflexes, tone, sensation
damage to membrane: elevated serum creatine phosphokinase and aldolase, myoglobinuria, renal failure
more varied histological changes than nerve (variations in fiber size, central nuclei, necrosis of fibers)

peripheral neuropathy – sensory or motor, often polyneuropathy – diffuse (longest most affected)

weakness, atrophy, sensory loss, paresthesia, dyesthesia (unpleasant paresthesia), decreased reflexes
muscle biopsy indicates neurogenic atrophy (alpha-motor neurons destroyed)
three pathologic changes in peripheral nerve:

(1) Wallerian degeneration—interrupt axon transport, myelin degenerates and phago. by macrophage, chromatolysis, Schwann cells proliferate (bands of Bungner), regeneration by slow axonal transport

(2) segmental demyelination—primary destruction of myelin, no atrophy or chromatolysis, starts at nodes, rapid and complete recovery (although thinner myelin)

(3) axonal degeneration—metabolic derangement of axon, Schwann cell proliferate (not as much), lose myelin, atrophy, chromatolysis, slowed conduction velocity, regenerate by slow axonal transport

Electromyography (EMG)

Nerve Conduction—stimulate nerve, measure amplitude, distal latency time (compute conduction velocity)

Needle Examination—insert needle electrode into muscle, measure electrical activity (volitional and spont.)

called compound muscle action potential

Repetitive Nerve Stimulations—stimulate neuromuscular junction repeatedly (usually 3-5 Hz, to 20-50 Hz)

Neuromuscular Diseases

Lower Motor Neuron Diseases

(1) Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease) 1/100,000; mean age 56 yrs; death in 2-5 years

progressive selective degeneration of upper and lower motor neurons
associated with lateral sclerosis (hardening of lateral corticospinal tract by astrogliosis)
10% autosomal dominant mutation of superoxide dismutase gene (free radical damage?)
clinical presentation: variable presentation (degree involvement may differ at various levels of the spinal cord and brain)

altered deep tendon reflexes, Babinski reflex, atrophy, fasciculations, but normal sensation

EMG: widespread fibrillation and fasciculation, normal sensory potentials
biopsy shows neurogenic atrophy

(2) Poliomyelitis

polio enterovirus enters intestine, sometimes causes diarrhea and fever
in 1 to 2 percent of cases virus infects and destroys anterior horn and brain stem motor neurons
clinical presentation: widespread paralysis (limbs, respiratory, face, and brainstem-innervated), atrophy, decreased reflexes
EMG: fibrillations and fasciculations

(3) Guillian-Barre Syndrome (Acute Demyelinating Polyradiculoneuropathy)

most common acute paralytic disease in Western countries (1.8/100,000, increases with age)
segmental demyelination of spinal roots and proximal nerves, less commonly of distal nerves
clinical presentation: symmetrical weakness/numbness, distally (hands, feet) progresses proximally (hip/shoulder muscles)

autonomic instability (orthostatic hypotension, tachycardias, hypertension, gastrointestinal atony)
cranial nerve involvement of facial and bulbar musculature

EMG: slowed nerve conduction and multiple conduction blocks
increased cerebrospinal fluid protein without increase in white blood cells
Treatment: plasma exchange, intravenous immunoglobulins, ventilation (90% recover after 3 weeks)

(4) Tick Paralyis

tick saliva toxins cause conduction block and slowed conduction time
clinical presentation: weakness, respiratory failure, parasthesias (numbness; sensory exam usually normal)
EMG: slowed nerve conduction and conduction blocks
Treatment: careful removal of tick, improvement within hours of tick removal, complete in days

Neuromuscular Junction: Postsynaptic Diseases

(1) Myasthenia Gravis – 50-142 per million, affects young women (frequency increases with age in both sexes)

AchR antibodies destroy endplate function (less depolarization in mepp and epp)
a decrease in epp amplitude is normal, but this causes epp to start low
clinical presentation: fatiguing weakness (esp. repetitive activity: combing hair, speaking, chewing, walking)

normal strength if tested without first fatiguing, normal reflexes, normal sensation and mentation (thinking)
ptosis and diplopia of ocular muscles
dysphagia, dysarthria, dysphonia, respiratory muscle weakness, and general limb weakness

EMG: normal compound muscle action potentials and sensory potentials, except with repetitive stimuli
Diagnosis: AChR antibodies in sera; also tensilon (AChE inhibitor) corrects strength
Treatment: anticholinesterase agents, immune modulating treatments (plasma exchange, intravenous immunglobulin, corticosteriods, azathioprine, cyclosporine)

(2) Congenital Myasthenic Syndromes – rare inherited defects in neuromuscular transmission

too much endplate causes Ca⁺⁺-mediated proteases to destroy endplate – loss of syn folds, fewer AchR
clinical presentation: like MG, but manifest in childhood: fatiguing weakness (droopy eyelids), normal sensory, reflexes, tone
anti-cholinesterase inhibitors (pyridostigmine for example) correct the problem
EMG: decremental response to repetitive stimulation, prolonged MEPP depolarization

repeated action potentials from single stimulus (EPP beyond absolute refractory period)

no AChR antibodies detected (to rule out myesthenia gravis)
two congenital myasthenic syndromes with similar clinical presentation:

(1) AChE Deficiency – not enough AChE, so ACh acts too long

(2) Slow Channel Syndrome – AChR open too long

Neuromuscular Junction – Presynaptic Diseases

(1) Botulism

Clostridium botulinum toxin – anaerobic organism (improper canning) – thermolabile (thermal inactivation)
toxin paralyzes organs innervated by cholinergic neurons, including smooth and skeletal muscle
botulinum and tetanus toxins – structurally homologous proteases, cleave distinct presynaptic proteins involved in vesicle fusion, block formation of docking complex
tetanus toxin, botulinum toxins B, D, F, and G cleave synaptobrevin
botulinum A and E cleave SNAP-25
botulinum C1 cleaves syntaxin
clinical presentation:

early: difficulty talking and swallowing, and diplopia
later: generalized paralysis of voluntary muscles
sensation is normal

postganglionic parasympathetic (dry mouth, blurred vision, no pupil constrict., constipation, and urinary retention)
Treatment: supportive with artificial respiration if required, antitoxin

NOTE: Botulism toxins can be used to produce transient (2-5 months) paralysis in muscles to treat movement disorders like torticollis or blepharospasm, or to paralyze ocular muscles to treat ocular misalignment (strabismus)

(2) Lambert-Eaton Myasthenic Syndrome – rare

synaptic vesicle release is decreased (antibodies to presynaptic Ca⁺⁺ channels?)
associated with small cell carcinoma of the lung, may occur as autoimmune disease.
clinical presentation: autonomic effects (dry mouth, urinary retention and orthostatic hypotension)
EMG: reduced response to single stimulus, but 20 Hz leads to an incremental response, recover action pot.

MEPP amplitude normal, but fewer quanta released so epp reduced

Treatment: guanidine HCl increases the number of quanta released

Muscular Diseases

(1) Duchenne Muscular Dystrophy – 20-30/100,000 male births, X-linked recessive, 1/3 of cases are sporadic

missing dystrophin protein (if truncated: milder – Becker’s Muscular Dystrophy)
clinical presentation: normal at birth, progressive proximal weakness by age 2, obvious by 3-5, wheel chair by 12, die early 20’s

no sensory symptoms, development of a cardiomyopathy is common, sometimes cognitive abnormalities
proximal muscles initially (walking/climbing stairs), eventually all but extraocular
extreme atrophy, but pseudohypertrophy early (calf muscles); enzymes elevated to more than 10⁴

EMG: nerve conduction normal, needle examination shows compound muscle action potential is small
muscle biopsy: central nuclei, variations in fiber size, type II fibers degenerate preferentially early

muscle degeneration and regeneration, eventually replaced with fat and connective tissue

Treatment: physical therapy and orthopedic bracing, surgery to relieve contractures, genetic counseling

(2) Polymyositis – 1-10 per million

probably autoimmune, significant elevations in muscle enzymes
clinical presentation: proximal weakness, sometimes muscle pain, cardiac muscle—congestive heart failure and arrhythmias

usually normal reflexes and sensation

EMG: decrease in amplitude and duration of motor unit potentials (fibrillations in severe disease)
muscle biopsy: inflammation, necrosis of muscle fibers, regeneration of fibers
Treatment: immunosuppression (prednisone, intravenous immunoglobulin, azathioprine)