Introduction
The spinal nerves are peripheral nerves, which compose of both motor and sensory nerve fibers that exit the spinal canal through the interverbal foramen. A single Schwann cell wraps a neuronal axon segment to form a myelin sheath.
The neuromuscular motor unit is a combination of peripheral motor neurons with their axons & innervated muscle fibers. These peripheral motor neurons are either in the anterior horn of spinal cord or brain stem cranial nerve nuclei.
The implications of injuries on the peripheral nerves & skeletal muscles
Diseases which cause injuries to the peripheral nerves may primarily affect the Schwann cells or the axons. Segmental demyelination is the loss of myelin due to Schwann cell dysfunction or myelin sheath damage.
Axonal degeneration is the primary loss of axon with secondary myelin loss due to disease affecting the neurons and axons. It may be due to ischemia, trauma, neuronopathy (disease affecting neuronal cell body) or axonopathy (disease affecting axons).
Denervation atrophy is a reduction in muscle fiber size resulting from axonal degeneration. Myopathy is the primary disorder of the muscle fiber.
How nerve regeneration and muscle reinnervation occur
Nerve regeneration occurs when proximal stumps of degenerated axons spread and elongate. These proximal stumps use neighboring Schawn cells as growth cones for guidance. Regeneration is slow at about 1mm/day and can be accelerated by marrow stromal cell transplant for nerve function recovery.
The reinnervation of an atrophic skeletal muscle happens when the neuron in an unaffected motor unit extends branches to the denervated muscle fiber motor unit. Normally, muscle fibers within a skeletal muscle consist of randomly dispersed type 1 & 2 fibers. Their properties are determined by an innervating neuron of the motor unit.
Type 1 fibers are slow-twitch fibers, rich in myoglobin & oxidative enzymes, & have many mitochondria. Type 2 fibers are fast-twitch fibers, rich in glycolytic enzymes. After reinnervation, both fiber types are grouped together, with the newly adopted muscle fiber type taking up same feature as the neighboring fiber.
Next, we shall discuss a variety of the disorders of the peripheral nerve and skeletal muscle.
Guillain-Barre Syndrome
This is an acute onset immune-mediated demyelinating neuropathy that causes ascending paralysis of the limbs. It is a life-threatening condition with an annual incidence of 3 in 100,000 individuals world-wide.
Predisposing factors: Influenza-like illness; Campylobacter jejuni; cytomegalovirus; EBV; Mycoplasma pneumoniae; prior vaccination.
Pathogenesis: segmental demyelination following a T-cell mediated immune response. Inflammation occurs in the spinal & cranial motor roots, & their adjacent peripheral nerves. There are perivenular & endoneurial infiltrates of lymphocytes, macrophages, with a few plasma cells.
Clinical manifestations: weakness beginning in distal extremities & rapidly progressing to affect proximal parts; absence of deep tendon reflexes; radiculoneuropathy. Complications include respiratory paralysis; cardiac arrest; autonomic instability.
Laboratory findings: elevation of CSF proteins; little/no CSF pleocytosis. Management require plasmapheresis; respiratory care and support.
Chronic inflammatory demyelinating polyradiculoneuropathy
This is a subacute or chronic inflammatory demyelinating polyradiculoneuropathy with relapsing and remissive episodes over several years.
It often presents as symmetrically mixed sensorimotor polyneuropathy, & management includes plasmapheresis and steroid therapy. Nerve biopsies reveal onion bulb formation.
Hansen disease (Leprosy)
This is an infectious, symmetrical polyneuropathy resulting from mycobacterium leprae infection. The two forms include: lepromatous and tuberculoid leprosy. In both forms, peripheral nerves are variably affected.
In lepromatous leprosy, M. leprae infects Schwan cells resulting in demyelination, axonal loss, endoneurial fibrosis, & perineurial thickening. Infection occurs in cool extremities & affects pain fibers, with resulting large ulcers in the extremities due to sensation loss.
Tuberculoid leprosy results from an active cell-mediated immune response against M. leprae with granulomatous lesions in the dermis, and cutaneous nerve damage. In this form, there is a significant local nerve damage.
Diphtheric polyneuropathy
This condition arises from damage of peripheral nerve by the exotoxin of Corynebacterium diphtheriae. It presents as early proprioception & vibratory sensation loss; paresthesia, & weakness.
There is segmental demyelination affecting axons of motor & sensory roots, alongside mixed sensorimotor nerves. Early damages are seen in the sensory ganglia.
Shingles
Painful, vesicular rashes following reactivation of varicella zoster virus within neurons in the sensory ganglia of spinal cord & brain stem. These rashes are commonly seen along the dermatomes of the thorax and trigeminal nerve.
Predisposing factor includes immunosuppression. In this condition, there is sensory neuronal loss, with peripheral nerve axonal degeneration. Motor neuron & cranial nerve motor nuclei damage may be seen in a few patients. Weakness along the affected dermatomes may occur in a few individuals.
Hereditary sensory and autonomic neuropathies
These are a heterogeneous group of genetic diseases discovered in infancy and young adulthood. They may present as numbness, pain, & orthostatic hypotension.
Charcot-Marie-Toot disease 1A (Hereditary Motor and Sensory Neuropathy type 1A)
This is a demyelinating neuropathy that causes a progressive muscular atrophy of the leg below the knee (peroneal muscular atrophy). It is often autosomal dominant & presents in childhood and adulthood.
Causes: Segmental trisomy in Chr. 17p11.2, resulting in abnormal peripheral myelin protein 22 (PMP22). PMP22 is a transmembrane protein found in compacted myelin.
Clinical manifestation: distal muscle weakness; atrophy of the leg below the knee; sensorimotor deficits; pes cavus.
Diabetic peripheral neuropathy
This is a peripheral nerve damage that results from diabetes mellitus, with accompanying sensorimotor or autonomic dysfunction or both.
Pathogenesis: vascular insufficiency (esp. endoneurial arterioles)> peripheral nerve ischemia> axonal injury> loss of myelinated & unmyelinated fibers.
Clinical manifestation: In patients with symmetric sensorimotor dysfunction, there is an accompanying decreased sensation in distal extremities with especially loss of pain sensation; distal ulcers. Motor abnormalities are less significant. In patients with autonomic dysfunction there is postural hypotension; incomplete emptying of bladder; recurrent infections; sexual dysfunction.
Metabolic and nutritional peripheral neuropathies
Metabolic peripheral neuropathies may occur in patients with renal failure (uremic neuropathy); chronic respiratory insufficiency; thyroid dysfunction & chronic liver disease.
Patients with uremic neuropathy typically have distal symmetric axonal degeneration with accompanying muscle cramps; distal dysesthesias; reduced deep tendon reflexes.
Nutritional peripheral neuropathies may arise from thiamine deficiency (neuropathic beriberi); Vit. B6, B12 & E deficiency; chronic ethyl alcohol consumption.
Neoplastic and paraneoplastic neuropathy
Neoplastic neuropathy commonly causes mononeuropathy & arises from direct infiltration or compression of peripheral nerves by a tumor.
Examples include: brachial plexopathy from neoplasms of lung apex; cranial nerve palsies from intracranial tumor or tumors of skull base; polyradiculopathy from meningeal carcinomatosis of cauda equina.
Paraneoplastic neuropathy causes a diffuse, symmetric sensorimotor neuropathy due to a distant tumor. Patients present with weakness & sensory dysfunctions (numbness, paresthesias). Causes may include: small cell lung cancer; plasma cell neoplasms (via deposition of light chain {AL type-amyloid proteins} or immunoglobulins neutralizing myelin-associated glycoprotein).
Carpal tunnel syndrome, Saturday night palsy
These are compression neuropathies that arise from the compression of peripheral nerve with an anatomical compartment.
Carpal tunnel syndrome results from compression of median nerve at the level of the wrist within the compartment of the transverse carpal ligament. It is frequently bilateral & affects more women than men.
Causes of carpal tunnel syndrome include: pregnancy, tissue edema; amyloidosis (β2 -microglobulin deposition in patients on renal dialysis); diabetic mellitus; repetitive wrist motion; acromegaly. Patients present with numbness & paresthesias in the first three digits.
Saturday night palsy affects the radial nerve in the upper arm, & results from sleeping with the arm in an awkward position.
Spinal muscular atrophy
This is an autosomal recessive motor neuron disease that causes denervation skeletal muscle atrophy in children and adolescence.
Causes: Homozygous deletion of survival motor neuron 1 (SMN1) gene on chromosome 5. SMN protein promotes motor neuron survival & are also expressed in all tissues.
Clinical manifestation: Werdnig-Hoffmann disease (SMA type 1) presents at birth or within the first 4 months of life with severe hypotonia. Death occurs within first 3 yrs. of life. SMA 2 presents btw 3 to 15 months of life, & death occurs after age 4. SMA 3 presents after age 2, & children often survive into adulthood.
Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD)
These are X-linked disorders, & are the most common forms of muscular dystrophy. The cause includes genetic abnormalities- mainly deletions or frame shift/point mutation in DMD gene on Xp22, that encodes dystrophin.
Cytoplasmic dystrophin-associated protein complex including contractile actin, transmembrane sarcoglycan & dystroglycan form an interface btw. cytoskeletal protein & extracellular matrix. Myocyte degeneration occurs in the presence of abnormal dystrophin.
Pathogenesis: variation in muscle fiber size> increased numbers of internalized nuclei beyond normal range of 3-5%> degeneration, necrosis, & phagocytosis> muscle fibers regeneration> proliferation of endomysial connective tissue> fat and collagen deposit.
Clinical manifestation: weakness in pelvic girdle muscle (initially) & shoulder girdle muscle (later); pseudohypertrophy; delayed walking; dilated cardiomyopathy; heart failure; arrhythmias; mental retardation.
Complications: respiratory insufficiency; pulmonary infection; cardiac decompensation. In patients with BMD, symptoms develop in later childhood or adolescence. DMD develops by age 5, & patients are confined on wheel chair by age 10-12.
Diagnosis: Muscle biopsy by staining & western blot analysis; elevated serum creatine level. In DMD, there is little to no dystrophin, while in BMD there is reduction in dystrophin amount.
Myotonic dystrophy
This is an autosomal dominant disorder, with late childhood presentation, that results in involuntary contraction of a muscle group. The cause includes: trinucleotide expansion of CTG on chr. 19q13.2-13.3, which affects mRNA for dystrophia myotonia protein kinase (DMPK).
Pathogenesis: ring fibers (subsarcolemmal longitudinal fibers circumferentially surrounded by myofibrils)> fiber splitting, necrosis & regeneration.
Clinical manifestation: weakness of foot dorsiflexors with abnormal gait; weakness of hand intrinsic muscles & wrist extensors; hand stiffness; atrophy of muscles of the face & ptosis; cataract; frontal balding; gonadal atrophy; cardiomyopathy; smooth muscle involvement; reduced plasma IgG, abnormal glucose tolerance; dementia.
Hyperkalemic, Hypokalemic, & Normokalemic periodic paralysis
These are ion channel myopathies that are familial, & which arise from changes in serum potassium levels. Predisposing factors include: vigorous exercise, high-carbohydrate meal, & cold. They clinically manifest as hypotonia.
Hyperkalemic periodic paralysis occurs with high serum potassium level. It results from a mutation in the gene that encodes a skeletal muscle sodium channel protein (SCN4A). SCN4A regulates Na entry into cell during contraction.
Hypokalemic periodic paralysis occurs with low serum potassium level. It results from mutation in the gene that encodes voltage-gated L-type calcium channel. Normokalemic periodic paralysis is associated with normal serum potassium level.
Malignant hyperthermia
This is also a channelopathy, with a clinical syndrome marked by a hypermetabolic state including tachycardia, tachypnoea, tetany, muscle spasms, hyperpyrexia.
Predisposing factors: halogenated inhalational anesthetics; succinylcholine; patients with dystrophinopathies, congenital & metabolic myopathies; mutations in L-type voltage-gated calcium channel (rynodine receptor- RyR1).
Exposure of the mutant receptor- RyR1 to anesthetics causes uncontrolled efflux of calcium from the sarcoplasm resulting in the clinical syndrome.
Polymyositis, Dermatomyositis, & Inclusion body myositis
These are immune mediated inflammatory myopathies. Polymyositis is common in adults, & presents as symmetric proximal muscle weakness & myalgias, excluding cutaneous rash. Patient may also present with interstitial lung disease, myocarditis, & vasculitis.
Dermatomyositis affects the skin and skeletal muscles. It presents as a lilac or heliotrope cutaneous rash on the upper eyelid with periorbital edema; scaling erythematous rash over the knuckles, elbows, & knees (Grotton lesions); bilaterally symmetric proximal muscle weakness & myalgias; difficulty standing up & climbing stairs.
Other clinical manifestations of dermatomyositis include: distal muscle weakness and myalgias later in the course of disease; dysphagia; interstitial lung disease; vasculitis; myocarditis; risk of visceral cancer.
Juvenile dermatomyositis in youths may present in addition, as calcinosis; abdominal pain, G.I tract mucosal ulceration, bleeding, & perforation due to vasculopathy.
Inclusion body myositis affects individuals >50 years old. It may present as asymmetric muscle weakness affecting distal muscles. Such distal muscles include knee extensors (quadriceps); wrists & finger flexors.
Pathogenesis: In dermatomyositis, there is immune-complex deposit around small blood vessels & perimysium, with peripheral perifascicular atrophy. In polymyositis, CD8+ T cells & macrophages invade healthy muscle fibers. Inclusion body myositis contains intracellular vacuolated fibers made of β- amyloid or hyperphosphorylated tau, with CD8+ T cells & macrophages attacking myocytes.
Diagnosis: electromyography, muscle biopsy, & elevated serum creatine kinase. Management requires immunosuppressive agents for all, except inclusion-body myositis.
Ethanol myopathy
This is the damage of skeletal muscle fiber by excessive drinking of alcohol. This disorder causes myocyte swelling> fiber necrosis> myophagocytosis> regeneration> neuropathy.
Signs/symptoms: proximal muscle weakness; localized or generalized muscle pain; rhabdomyolysis; myoglobinuria; renal failure; denervation of muscle.
Drug-induced myopathies
They are structurally abnormal muscle changes caused by drugs including steroids, statins, chloroquine & hydrochloroquine.
Clinical manifestations: proximal muscle weakness; muscle atrophy (esp. in steroid use); myocyte necrosis (esp. in chloroquine use).
Myasthenia gravis
This disorder results from an immune-mediated loss of acetylcholine receptor in the post synaptic membrane. It commonly affects women <40 years old. Patients often & occasionally present with thymic hyperplasia & thymoma respectively.
Pathogenesis: autoantibodies bind to acetylcholine receptor> complement activation> injury & degradation of acetylcholine receptors> inhibition of acetylcholine binding. anticholinesterase agents can be used for diagnosis.
Clinical manifestation: reduced motor response; generalized weakness; extraocular muscle weakness; ptosis; diplopia; type 2 fiber atrophy; complicated by respiratory insufficiency.
Management: anticholinesterase agents; prednisone; plasmapheresis; thymectomy.
Lambert-Eaton Myasthenic syndrome
This is a neuromuscular junction disease that can’t be improved by an anticholinesterase agent. They present as proximal muscle weakness & autonomic dysfunction.
Predisposing factors: underlying malignancy (esp. small cell lung cancer); autoantibodies against presynaptic PQ-type voltage-gated calcium channels.
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