Peripheral nervous system (PNS) includes those portions of motor neurons, autonomic neurons and sensory neurons that extend outside the central nervous system (CNS) and have Schwann cell or ganglionic satellite cell associations. PNS has CNS components, such as cell bodies of motor neurons and central projections of many sensory neurons in the spinal cord. Separation of PNS from CNS is helpful because (1) many diseases affect one or the other and (2) the PNS has regenerative capacity.
Structure: Axons, including motor (large myelinated), sensory (all sizes) and autonomic (unmyelinated).
Schwann cells, both myelinating and unmyelinating.
Connective tissue; epineurium around nerve, perineurium around nerve fascicle, and endoneurium around axons within a perineurial limited fascicle.
Pathologic mechanisms: Axonal degeneration
1. Metabolic derangement of neuron, usually manifest distally where neuronal cell body's influence is weakest (distal axonopathy).
2. Myelin degenerates because of the axonopathy (secondary demyelination).
3. Schwann cells proliferate within their surviving basement membrane tubes, preparing for possible axonal regrowth (axonal "sprouting").
4. Innervated (now denervated) muscles undergo denervation atrophy. Muscles can be repaired if denervation is not prolonged or severe.
5. Neuronal chromatolysis (cell body changes) in severe cases.
6. In the specific case of nerve transection, these processes are referred to as Wallerian degeneration (after Dr. Waller).
Primary (segmental) demyelination
1. Primary myelin destruction often leaves axon intact (naked axon).
2. Remyelination is of short "fetal" length since the axon is no longer stretching (as in somatic growth), and short internodes result, and with fewer myelin lamellae than previously.
3. Repeated cycles of demyelination/remyelination result in Schwann cells in excess because most of their axonal spouts degenerate, so the now "extra" Schwann cells form loose concentric rings around the remaining axon ("onion bulb").
1. Inflammation, amyloid deposition, immunoglobulin deposition, infection, vasculitis, fibrosis, metabolic storage, tumor metastasis.
2. Compromise of connective tissue compartments can lead to axonal degeneration, demyelination or both.
Nerve biopsy: Usually of sural nerve on lateral aspect of ankle; pure sensory nerve, so no motor loss. Routine sections of limited value. Special stains for myelin and neurofilaments very helpful. Most valuable are plastic 1 ΅m sections to evaluate relative amounts of (or actually count) large and small myelinated fibres, while these as well as unmyelinated fibres can be identified by electron microscopy.
PNS diseases; the following are examples to show various types of pathologic findings.
1. Entrapment/compression neuropathy: Most commonly of median and ulnar nerves.
a. Median n. usually involved in the carpal tunnel of the wrist ("carpal tunnel syndrome").
(1) Often tenderness over median n. at compression site; tap causes pain (Tinel's sign).
(2) Associated with hypothyroidism, acromegaly, amyloidosis, rheumatoid arthritis, tuberculosis, leprosy, and repeated movement disorders (like doing this typing).
b. Ulnar n. where it passes over distal head of humerus.
(1) Weakness and atrophy of ulnar aspect of hand, sensory loss over 4th & 5th digits.
(2) May be caused by trauma or arthritis.
c. "Saturday Night Palsy" from radial n. compression after falling asleep with an arm over the edge of a bench, sofa, auditorium seat, etc., with wrist drop & paralysis of finger extensors; slow recovery is the rule.
2. Toxic neuropathy: Heavy metal intoxication (Pb, As, Hg, Bi), therapeutic agents (isoniazid), solvents (N hexane, ketones), others (acrylamide in electrophoresis gels). Pathology often axonal, but some cause primary demyelination.
3. Alcoholic polyneuropathy: Common.
a. Pain & paresthesia most severe in feet, then sensory loss & weakness.
b. Biopsy may show scattered axonal degeneration & axon loss.
4. Diabetic neuropathy: Very common in diabetics.
a. May be symmetrical, may involve only one nerve, may include autonomic nerves (e.g., incontinence, impotence).
b. Mostly distal axonal degeneration & regeneration; blood vessels walls often thick.
5. Vasculitic neuropathy: Primary vasculitis [periarteritis nodosa, systemic lupus erythematosus (SLE), scleroderma, giant cell arteritis], hypersensitivity angiitis, & intravenous drug use.
a. May be distal, symmetrical, sensory & motor deficit or isolated single nerve involvement.
b. Biopsy may show inflamed small epineurial (usually) or endoneurial arteries (occasionally), or damage may be proximal to the biopsy site and only axonal degeneration is seen.
6. Inflammatory neuropathy: Lymphocytic inflammation is variable, but macrophages enter the nerve from the blood and strip myelin off axons; immune mediated.
a. Guillain Barrι syndrome (GBS; acute). Severe axonal loss associated with evidence of Campylobacter jejuni infection; many possible causes of GBS, generally post infection.
b. Chronic inflammatory demyelinating polyneuritis. May be chronic GBS.
a. M. leprae in Schwann cells & macrophages in leprosy.
b. C. diphtheriae endotoxin (from a bacteriophage) causes demyelination by interfering with Schwann cell myelin protein chain elongation.
c. Varicella zoster virus (herpes zoster) causes shingles and chickenpox. It remains dormant in dorsal root ganglia & some cranial nerve ganglia and then is transported anterograde to cutaneous distribution of the nerve where vesicles & rash form.
8. Hereditary neuropathies (prominent "onion bulbs").
a. Hereditary motor and sensory neuropathies (HMSN).
(1) Hypertrophic Charcot Marie Tooth (CMT) disease with chromosomal duplications, deletions or point mutations involving myelin proteins is HMSN 1.
(2) Neuronal CMT disease is HMSN 2; tends to be more severe then HMSN 1, with distal axonopathy. Pathogenesis not well known.
(3) Dejerine Sottas syndrome (HMSN 3) is varied, with altered myelin proteins (dysmyelination).
b. Familial dysautonomia (Riley Day syndrome): Loss of unmyelinated and some myelinated axons; impaired pain & temperature sensation (carried by unmyelinated & small myelinated axons) as well as loss of autonomic function, including gastrointestinal motility, impaired blood pressure regulation.
I. General Considerations of Muscle Disease
A. Histologic criteria of muscle disease
1. Fibre size.
a. Atrophic (small, angular, flattened).
b. Hypertrophic (large).
2. Fibre shape (normally polygonal).
a. Round ("myopathic" as in muscular dystrophy).
b. Angular ("neurogenic" as in denervation atrophy).
3. Nuclear position.
a. Normal, or subsarcolemmal (sarcolemma = plasma membrane + cell's basement membrane).
b. Central (can be from myopathic or neurogenic causes).
4. Atrophy is degeneration (rather than representing necrosis).
5. Fibre necrosis can be partial, followed by regeneration.
6. Inflammation (cause or response to muscle disorder).
7. Connective tissue (normal amount or fibrosis).
8. Adipose tissue in nerve fascicle (normally not within perimysium).
B. Observations using histochemistry
1. Fibre size and distribution.
a. Atrophy of one or both fibre types (grouped atrophy).
b. Grouping of fibres of one type (histochemical fibre type grouping).
2. Alterations within individual fibres.
a. Targets, targetoids, cores (deficiency of mitochondria & other organelles).
b. Nemaline "rods" (enlarged, elongated, rod-shaped Z discs).
II. Congenital Myopathies (non progressive; often floppy babies)
A. Central core disease
1. Delayed motor maturation; mild findings, and many patients do not think of themselves as impaired.
2. Central defect (core) in most muscle fibres.
3. EM of core shows decrease in mitochondria & other organelles.
4. Oxidative enzymes (mitochondria) decreased in core.
B. Nemaline myopathy (nemaline Ί thread)
1. Facial weakness, facial elongation, prognathism, kyphoscoliosis, high arched palate, temporomandibular ankylosis, pes cavus or planus, pectus excavatum.
2. Clusters of threads or rods immediately beneath sarcolemma, best seen in trichrome stained frozen sections; EM shows filamentous arrays of proliferated, enlarged Z bands.
C. Centronuclear myopathy
1. Thin weak face, ptosis, distal > proximal limb weakness, foot drop; less weakness when onset later.
2. Type 1 fibre predominance and atrophy.
3. Single central or slightly eccentric nucleus in most fibres.
4. EM shows perinuclear sarcoplasmic disorganization.
III. Muscular Dystrophies (unremittingly progressive)
A. Congenital muscular dystrophy
1. Fukuyama congenital muscular dystrophy: weakness, seizures common, mental retardation; variation in fibre size, myofibre necrosis & endoneurial fibrosis.
2. Other types of congenital muscular dystrophy.
B. Duchenne muscular dystrophy
1. Most common form of muscular dystrophy; prevalence of 1:3500 live male births.
2. Onset 2 5 years; fatal by age 20 years.
3. Delayed motor control in young boys evenually becomes progressive weakness.
4. Pseudohypertrophy characteristic: deltoid, calf and other muscles enlarged and weak when replaced by fat and fibrosis.
5. X linked recessive; DMD gene located at Xp21; largest known human gene at 2500 Kb.
6. Large DMD gene has high mutation rate; usually a deletion is found, and patients lack the DMD gene product, dystrophin (430 kd protein of all muscle types).
7. Postulated that dystrophin stabilizes sarcolemma, and its lack during contraction allows Ca2+ to enter myofibres, activating cellular proteases that lead to myofibre necrosis.
8. Respiratory and cardiac muscles affected; serum creatine kinase elevated.
9. Hyaline fibres (early necrosis), phagocytosis of myofibres, regeneration, endomysial fibrosis, ringed fibres (peripheral myofibrils perpendicular to normal orientation).
C. Becker dystrophy
1. Similar to Duchenne muscular dystrophy, but milder.
2. Dystrophin adequate in amount but abnormal in size or deformed in structure.
3. Atrophic & hypertrophic fibres, endomysial fibrosis, internal nuclei, some necrosis and regeneration.
D. Facioscapulohumeral dystrophy (face, shoulder, upper arm)
1. Mild and slowly progressive; life span not particularly shortened.
2. Cannot whistle well, speech becomes indistinct; trunk and legs eventually involved.
3. Fibre atrophy and hypertrophy, with moth eaten fibres in oxidative enzyme stains; EM shows mitochondrial loss & myofilament disruption (non specific).
4. Unusual for a dystrophy in having chronic inflammatory response early in its course.
E. Limb girdle syndrome: proximal axial muscle weakness, often pseudohypertrophy, frequent cardiac involvement, slow progression; non specific dystrophic biopsy changes.
1. Scapulohumeral (Erb's) dystrophy: early adulthood onset with weakness first in upper extremities.
F. Myotonic muscular dystrophy
1. Most frequent myotonic disorder; others include myotonia congenita & acquired myotonia (drug induced, malignancy associated).
2. Incidence 5:100,000 population in adults; onset early adulthood, disabling in 15 20 years.
3. MyD gene on 19q13.3; dominant inheritance, variable penetrance with variable clinical features.
4. Facial weakness, ptosis, then limb weakness.
5. Myotonia is a delay in muscle relaxation after normal contraction, so that patient grasps an object and has difficulty letting go (in a Viet Nam case, a soldier held a hand grenade and threw it over his unit, except he could not let it go in time and it fell down on his own men).
6. EMG shows excessive insertional activity and repetitive (myotonic) discharges that build and decline.
7. Cardiomyopathy; sudden death can be seen (evaluation for pacemaker commonly done).
8. Smooth muscle affected: dysphagia, spastic colon, megacolon.
9. CNS and endocrine functional deficits, including insulin resistance without overt diabetes.
10. Biopsy shows internal nuclei and type 1 fibre atrophy; necrosis, regeneration, interstitial fibrosis, ringed fibres.
IV. Metabolic Myopathies
A. Carbohydrate storage diseases
1. Acid maltase deficiency (type II glycogenosis): glucose cannot be liberated from glycogen.
a. Infantile: Pompe's disease; early infantile onset, fatal in 2 years.
1) Glycogen accumulation in CNS, heart, muscle, liver.
2) Glycogen stain identifies storage in vacuoles.
b. Adult onset: more localized in skeletal muscle, with fatigue and eventually respiratory failure.
2. McArdle's disease (type V glycogenosis or myophosphorylase deficiency).
a. Slowly progressive early onset with exercise intolerance, myalgia, stiffness and muscle cramps.
b. Myoglobinuria can follow vigorous exercise, and renal failure is a complication.
c. Serum creatine kinase usually elevated at rest.
d. Biopsy: glycogen in subsarcolemmal vacuoles, absence of phosphorylase activity.
B. Lipid storage diseases: lipid containing vacuoles in muscle cells
C. Mitochondrial myopathies
1. Generalized weakness, ptosis and ophthalmoplegia; involvement of multiple organs besides muscle sometimes called ophthalmoplegia plus or Kearns Sayre syndrome (includes ptosis, ocular muscle weakness, retinitis pigmentosa, short stature, mental retardation, deafness & heart conduction defects).
2. Sporadic or inherited from nuclear DNA or mitochondrial (maternal) DNA.
3. Biochemical defects in mitochondria include substrate transport or utilization, oxidation, respiratory chain function, and ATP synthesis.
4. Biopsy: ragged red fibres (trichrome stain), consisting of enlarged, crowded, misshapen mitochondria under the sarcolemmal surface (electron microscopy).
D. Malignant hyperthermia
1. Familial, 1:15,000 anesthetic administrations (especially halothane or succinylcholine [depolarizing muscle relaxants]).
2. Markedly increased muscle metabolism associated with generalized rigidity as O2 consumption increases and lactate is produced; acidosis results in membrane permeability and K+ loss, with myoglobinuria and possible renal failure; heat results from excessive muscular metabolism.
3. Mutations in RYR1 gene encoding calcium ion release channel of muscle sarcoplasmic reticulum has been shown; inappropriate Ca2+ release may promote sustained muscle contraction.
V. Inflammatory Myopathies
A. Bacterial myositis: pyomyositis, or abscess
1. Hematogenous or following closed trauma.
2. Fever, muscle tenderness, mixed inflammatory infiltrate and necrosis of all cellular elements.
B. Viral myositis: Influenza, coxsackievirus, ECHO virus & adenovirus: rhabdomyolysis in gravely ill patients, can be renal failure and death.
C. Polymyositis: most common inflammatory myopathy in adults; 10 per million population annually
1. Fairly abrupt onset of general weakness over a few weeks, with fever, malaise, dysphagia.
2. Antinuclear antibodies commonly found, along with elevated serum creatine kinase.
3. Autoimmune disease with probable cell mediated mechanism; T cells may be sensitized by muscle antigens, leading to complement activation with membrane attack complex formed, causing myofibre necrosis.
4. Biopsy: mature lymphocytes surround muscle cells; macrophages enter necrotic myofibres.
D. Dermatomyositis: can "merge" with findings of polymyositis, but generally distinct findings
1. Cutaneous rash (butterfly facial rash or violaceous eyelid rash and periorbital edema).
2. Rash can be extensive over neck, shoulders and extremities; in children multiple organs often involved with angiopathy of skin, muscle, viscera and peripheral nerve.
3. Immune complex mediated vasculopathy found; humoral rather than cell mediated immunity.
4. Biopsy: lymphocytes around blood vessels (where immune complexes are) instead of around muscle cells; fibre atrophy typically at periphery of fascicles (perifascicular atrophy) due to ischemia of fascicle edges.
5. Polymyositis and dermatomyositis associated (10%) with malignancies; such perineoplastic myositis is not as responsive to corticosteroid therapy.
E. Drug induced inflammatory myopathy: d penicillamine, methyldopa, cimetidine, hydralazine, and L tryptophan (eosinophilia myalgia syndrome; could be caused by contaminant since all cases from one Japanese company) form part of the differential diagnosis
VI. Disorders of the Neuromuscular Junction
A. Myasthenia gravis: acquired, immune mediated disease of neuromuscular transmission
1. Prevalence about 50 per million; more often seen after age 50.
2. Easy fatigability, often beginning in extraocular muscles & with other cranial nerves.
3. Ptosis, expressionless face, open mouth, inability to smile (myasthenic snarl), difficulty chewing, nasal speech, dysphonia and a tendency to choke on food.
4. Serum IgG antibodies to nicotinic acetylcholine receptor (AChR) in 90% of cases, with complement activation at motor end plate region, and destruction of neuromuscular junction.
5. Association of thymic hyperplasia (65%) and thymoma (15%): possible sensitization to AChR in thymus gland.
6. Positive response to short acting AChEase inhibitors (edrophonium in Tensilon test).
7. Biopsy: non specific.
B. Eaton Lambert syndrome: autoimmune presynaptic disorder of neuromuscular transmission
1. Fatigue, weakness, hyporeflexia, autonomic symptoms (dry mouth, constipation, impotence).
2. Decrease in quanta of ACh released from motor nerve terminals causes impaired transmission.
3. EM: depletion of presynaptic membrane active zones and active zone particles (the voltage sensitive Ca2+ channels), probably causing reduced Ca2+ entry into nerve and reduced ACh release.
4. Strong association with pulmonary carcinoid tumors; IgG autoantibodies may be to carcinoid cell antigens.
VII. Denervating Diseases
A. Injury to peripheral nerve causes neurogenic atrophy of muscle fibres
B. Neuronal muscular atrophies: death of lower motor neurons (anterior horn cells)
1. Amyotrophic lateral sclerosis (ALS).
2. Werdnig Hoffmann disease (autosomal recessive; common cause of floppy baby).
Spinal dysraphism Failure of neural groove to form midline spinal structures, including spinal cord and vertebral column. This often occurs at the L1 level where the neural plate/tube ends, with the caudal blastema forming the more caudal midline neural elements. Failure of proper blastema formation or of mesenchyme induction surrounding the blastema is common, with spina bifida occulta (defect in spinal arch laminae seen on X ray), meningocele, or meningomyelocele resulting.
Syringomyelia A syrinx is a cavity in the cord parenchyma that forms from unknown cause and can continually enlarge, destroying white matter tracts as it does so. It is often associated with trauma such as constant lifting of heavy boxes, or with tumor not too distant in the brainstem or cord, or with other developmental anomalies when present at birth. It is outside the central canal, but they can end up in communication. Enlargement of the syrinx often begins at a cervical level and interrupts the anterior grey commissure (bilateral destruction of crossing pain & temperature axons going to lateral spinothalamic tracts). Hydromyelia is simple dilation of the central canal.
Spinal cord degenerative diseases:
Friedreich's ataxia Most frequent hereditary ataxia. Usually autosomal recessive with onset by 20 years of age, and progressive incapacitating course can last up to 30 years. Mutation at 9q13.3 21.1. Neuronal loss in Clarke's column (thoracic cord levels) and axonal loss in anterior and posterior spinocerebellar tracts. Upper limb relay of spinocerebellar axons is through the accessory cuneate nucleus of the medulla, which has neuronal loss. Cerebellar dentate nucleus also has neuronal loss. Motor axons degenerate, mostly distally, seen as corticospinal tract degeneration in the lower cord. The most prominent symptom is ataxia, first of gait, then of clumsiness of the hands and later dysarthria. Death is often from cardiomyopathy associated with cardiac arrhythmias.
Werdnig Hoffmann disease (infantile spinal muscular atrophy) "Floppy baby" with hypotonia and muscle weakness evident shortly after birth; usually die by age of 2 years. Loss or degenerated appearance of spinal motor neurons, with axonal loss resulting in skeletal muscle atrophy.
Amyotrophic lateral sclerosis (ALS; Lou Gehrig disease) Usually sporadic (5 10% familial), male pre-dominance, midlife onset, 2 6 year course, about 6 cases per 100,000 population. Loss of spinal cord motor neurons and usually corticospinal tract degeneration. In familial ALS, there are mutations in the Cu/Zn super-oxide dismutase (SOD) gene (SOD1) that alter folding of SOD, resulting in decreased activity, thus preventing the enzyme from destroying tissue free radicals (superoxides). Presumably, this causes neuronal damage.
Vertebral arteries and intercostal arteries from the aorta are the main vascular supplies to the spinal cord. Occlusion at the aortic arch interrupts half the vertebal a. blood flow to the spinal cord, while suprarenal occlusion of any intercostal a. may compromise the cord. However, anastomotic channels are plentiful. The main problem is in hypotension involving the systemic circulation generally or the aorta in particular, such as following rupture of an aortic aneurysm. In such cases, the entire spinal cord is at risk of infarction. If the hypoxic and hypotensive insult is relatively minor, the superior and inferior parts of the spinal cord may be adequately supplied, but the zone in between the upper and lower boundaries can be infarcted (boundary zone infarct). For the spinal cord, the vascular boundary zone is at the T4 level. Embolic disease can cause infarction at any level.
A. For unknown reason, there appears to be reflexive vascular spasm when physical trauma involves the spinal cord. Thus, the major pathology has a vascular appearance, with infarction in the area. Any direct trauma that transects axons has direct consequences for the resulting neural disconnections.
B. Brown-Sιquard syndrome (rare but instructive): Hemisection of the spinal cord.
1. Loss of sensory input in the posterior columns below the lesion ipsilaterally.
2. Upper motor neuron lesion below the injury ipsilaterally.
3. Lower motor neuron lesion (and vasomotor paralysis with SNS involvement) in the area of supply of injured segment ipsilaterally.
4. Bilateral loss of pain & thermal sense at the level of the lesion.
5. Loss of pain & thermal sense below the lesion contralaterally.
The same diseases that affect the brain also affect the spinal cord. Clinically, since the cord is relatively small, most of these entities result in a condition termed transverse myelitis, with bilateral loss of motor output and sensory input below the lesion. Transverse myelitis as a clinical condition can be caused by many diseases such as vascular malformations, infarcts, metastatic cancer, radiation changes, multiple sclerosis or heroine injections, and clinically the etiology may be problematic if there is no associated systemic disease. Inflammatory conditions causing transverse myelitis include viral infection or hypersensitivity response to a virus, vaccination or immunization, as well as SLE and isolated bacterial myelitis. Seldom seen is Pott's paraplegia as a result of tuberculous osteitis of the vertebral column with an extradural abscess that compresses the cord anteriorly. Tabes dorsalis seen in tertiary syphilis is caused by inflammation of posterior thoracolumbar nerve roots and spinal ganglia, with degeneration in the ascending midline tracts of the posterior columns and ataxia (involvement of position related sensory axons for lower extremities).
Subacute combined degeneration of the cord Caused by deficiency of vitamin B12 (and possibly folic acid). Combined motor (corticospinal tract) and sensory (posterior column) symptoms are found. A vacuolar distension of myelin sheaths, mostly in cervical and thoracic levels, is followed by demyelination of axons and gliosis. Advanced cases have significant axonal loss, but the motor and sensory loss can be largely reversed in most cases by timely B12 supplementation.
Ependymoma is the most common cord neoplasm, followed by astrocytoma. Ependymomas at the caudal end of the cord are usually myxopapillary ependymomas, which are rarely malignant. Epidermoid cysts, vascular malformations, lipomas and schwannomas also occur, and they can all present with cord compression. Therefore, in the spinal cord the biologic potential (e.g., for metastasis) of the lesion is not the immediate concern; the immediate problem faced by the physician, and by the patient, is spinal cord decompression.