Online newspaper of professor Yasser Metwally

1 am professor Yasser Metwally, porofessor of neurology, Ain Shams university, Cairo, Egypt, Visit my web site at: www.yassermetwally.com

This post contains simple medical information to neurological patients (vist my site at http://patients.yassermetwally.com)

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INTRODUCTION

The peripheral nervous system refers to the cranial nerves and spinal nerves from their origin to their end. The afferent (sensory) system begins in the periphery and ends in the CNS; the efferent (motor) system begins in the CNS and ends at the target muscle.

• Anatomy and Physiology

Thirty of the 31 pairs of spinal nerves consist of an anterior (ventral) motor root and a posterior (dorsal) sensory root; C1 has no sensory root. Efferent motor fibers emerge from anterior horn cells located in the gray matter of the spinal cord. A motor unit consists of an anterior horn cell, its motor axon, the muscle fibers it innervates, and the connection between them (neuromuscular junction). The cell bodies of the afferent sensory fibers lie in dorsal root ganglia, located outside the spinal cord. The ventral and dorsal roots combine to form a spinal nerve, which exits via an intervertebral foramen. Because the spinal cord is shorter than the vertebral column, the more caudal the spinal nerve, the further the foramen is from the corresponding cord segment. Thus, in the lumbosacral region, nerve roots from lower cord segments descend within the spinal column in a near-vertical sheaf, forming the cauda equina.

The cervical and lumbosacral spinal nerves anastomose peripherally into plexuses, then branch into nerve trunks that terminate up to 1 m away in peripheral structures. The intercostal nerves are segmental.

The term peripheral nerve refers to the part of a spinal nerve distal to the root and plexus. Peripheral nerves are bundles of nerve fibers ranging in diameter from 0.3 to 22 µm. Schwann cells form a thin cytoplasmic tube around each fiber and further wrap larger fibers in a multilayered insulating membrane (myelin sheath), which enhances impulse conduction. The largest and most heavily myelinated fibers conduct quickly; they convey motor, touch, and proprioceptive impulses. The less myelinated and unmyelinated fibers conduct more slowly; they convey pain, temperature, and autonomic impulses. Because nerves are metabolically active tissues, they require nutrients, supplied by blood vessels called the vasa nervorum.

• Etiology and Pathophysiology

Disorders can result from damage to or dysfunction of the cell body, myelin sheath, axons, or neuromuscular junction. Disorders can be genetic or acquired (due to toxic, metabolic, traumatic, infectious, or inflammatory conditions—see Table 1: Peripheral Nervous System Disorders: Causes of Peripheral Nerve Disorders). Peripheral neuropathies may affect one nerve (mononeuropathy), several discrete nerves (multiple mononeuropathy, or mononeuritis multiplex), or multiple nerves diffusely (polyneuropathy). Some conditions involve a plexus (plexopathy) or nerve root (radiculopathy). More than one site can be affected (eg, in the most common variant of Guillain-Barré syndrome).

Table 1. Causes of Peripheral Nerve Disorders

Site	Type	Examples
Motor neuron	Inherited	Spinal muscular atrophy types I–IV
	Acquired, acute	Polio, infections by coxsackievirus and other enteroviruses (rare disorders)
	Acquired, chronic	Amyotrophic lateral sclerosis, paraneoplastic syndrome, postpolio syndrome, progressive bulbar palsy
Nerve root	Acquired	Herniated disk, infections, metastatic cancer, neurofibroma, trauma
Plexus	Acquired	Acute brachial neuritis, diabetes mellitus, hematoma, local tumors (eg, schwannoma), metastatic cancer, neurofibromatosis (rare), traction during birth, severe trauma
Peripheral nerve	Hereditary	Hereditary adult-onset neuropathies, hereditary sensorimotor neuropathies, hereditary sensory and autonomic neuropathies
	Infectious	Hepatitis C, HIV infection, Lyme disease, syphilis. In undeveloped nations, diphtheria, parasites
	Inflammatory	Chronic inflammatory demyelinating polyradiculoneuropathy, Guillain-Barré syndrome and variants, vasculitis
	Metabolic	Amyloidosis, diabetes mellitus, dysproteinemic neuropathy, ethanol with undernutrition (particularly deficiency of B vitamins), ICU neuropathy, leukodystrophies (rare), renal insufficiency
Neuromuscular junction	Congenital and acquired	Botulism in infants, congenital myasthenia (very rare), Eaton-Lambert syndrome, myasthenia gravis, toxic neuromuscular junction disorders (eg, due to nerve agents)
Muscle fiber	Dystrophies	Distal muscular dystrophy (late distal hereditary myopathy; rare), Duchenne’s muscular dystrophy and related dystrophies, fascioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, oculopharyngeal dystrophy (rare)
	Channelopathies (myotonic)	Familial periodic paralysis, myotonia congenita (Thomsen’s disease), myotonic dystrophy (Steinert’s disease)
	Congenital	Central core disease, centronuclear myopathy, nemaline myopathy (very rare)
	Endocrine	Diabetes mellitus, hypothyroidism, thyrotoxic myopathy, acromegaly, Cushing’s syndrome
	Inflammatory	Infection (viral more than bacterial), polymyositis/dermatomyositis
	Metabolic	Acid maltase deficiency, carnitine deficiency, glycogen storage and lipid storage diseases (rare)

Because sensory and motor cell bodies are in different locations, a nerve cell body disorder typically affects either the sensory or motor component but rarely both.

Damage to the myelin sheath slows nerve conduction. Demyelination affects predominantly heavily myelinated fibers, causing large-fiber sensory dysfunction (buzzing and tingling sensations), motor weakness, and diminished reflexes. Profound motor weakness with minimal atrophy is a hallmark of an acquired demyelinating polyneuropathy.

Because the vasa nervorum do not reach the center of a nerve, centrally located fascicles are most vulnerable to vascular disorders (eg, vasculitis, ischemia). These disorders result in small-fiber sensory dysfunction (sharp pain and burning sensations), motor weakness proportional to atrophy, and less severe reflex abnormalities than in other nerve disorders. The distal 2/3 of a limb is affected most. Initially, deficits tend to be asymmetric because the vasculitic or ischemic process is random. However, multiple infarcts may later coalesce, causing symmetric deficits (multiple mononeuropathy).

Toxic-metabolic or genetic disorders usually begin symmetrically. Immune-mediated processes may be symmetric or, early in rapidly evolving processes, asymmetric.

Damage to the axon transport system for cellular constituents, especially microtubules and microfilaments, causes significant axon dysfunction. First affected are the smaller fibers (because they have greater metabolic requirements) and the most distal part of the nerve. Then, axonal degeneration slowly ascends, producing the characteristic distal-to-proximal pattern of symptoms (stocking-glove sensory loss, weakness).

Recovery: Damage to the myelin sheath (eg, by injury or Guillain-Barré syndrome) can often be repaired by surviving Schwann cells in about 6 to 12 wk.

After axonal damage, the fiber regrows within the Schwann cell tube at about 1 mm/day once the pathologic process ends. However, regrowth may be misdirected, causing aberrant innervation (eg, of fibers in the wrong muscle, of a touch receptor at the wrong site, or of a temperature instead of a touch receptor). Regeneration is virtually impossible when the cell body dies and is unlikely when the axon is completely lost.

• Evaluation

History and physical examination should determine whether one or more limbs are affected, whether symptoms involve one or several nerve territories, and whether deficits are pure motor, pure sensory, or mixed (sensorimotor). These determinations narrow diagnostic possibilities and guide further testing.

Onset site (eg, distal vs proximal) and tempo (eg, rapid vs slowly progressive), distribution (symmetric vs asymmetric), and presence or absence of cranial nerve, limb girdle, and autonomic function involvement are determined. Family history, toxic exposures, and past medical history are also important.

Sensation (using pinprick and light touch for small fibers and vibration for large fibers), proprioception, motor strength, and deep tendon reflexes are evaluated. Proportionality of motor weakness to the degree of atrophy is noted, as are type and distribution of reflex abnormalities.

Generally, nerve conduction velocity studies and electromyography (collectively called EMG) are done. These tests help identify level of involvement (nerve, plexus, root) and distinguish demyelinating disorders (very slow conduction) from axonal disorders.

CERVICAL SPONDYLOSIS

Cervical spondylosis is degenerative changes in the intervertebral disk and annulus and formation of bony osteophytes, which narrow the cervical canal or neural foramina, causing radiculopathy and sometimes myelopathy.

A congenitally narrow canal increases the risk of cervical spondylosis. If the spinal cord is compressed, progressive myelopathy and a spastic gait typically develop. Pain may predominate with radicular signs in the dermatome most affected, usually between C5 and C6 or C6 and C7. Neural foraminal root compression causes arm weakness and atrophy with segmental reflex loss; spinal cord compression causes hyperreflexia, increased muscle tone, vibratory impairment, and extensor plantar responses in the legs.

• Diagnosis and Treatment

If symptoms of cervical root or cord impingement occur, MRI and electrodiagnostic tests (eg, electromyography, somatosensory evoked potentials, motor evoked potentials) are indicated. Spinal x-rays, including oblique views of the neural foramina, may show degenerative changes with osteophytes and narrowing of disk space, but these findings are neither sensitive nor specific. If the sagittal diameter of the cervical canal is < 10 mm, risk of cord compression is higher.

• Degenerative Changes of the Cervical Spine

Occasionally, signs lessen or stabilize spontaneously. Conservative treatment includes a soft collar and NSAIDs or other mild analgesics. Decompressive laminectomy is indicated for patients with myelopathy and cord compression or, if conservative treatment is ineffective, for patients with radiculopathy and electrodiagnostic evidence of neurologic dysfunction.

DISORDERS OF THE NEUROMUSCULAR JUNCTION

Disorders of neuromuscular transmission affect the neuromuscular junction. They may involve postsynaptic receptors (eg, in myasthenia gravis), or breakdown of acetylcholine within the synapse (eg, due to drugs or neurotoxic chemicals). Common features of these disorders include fluctuating fatigue and muscle weakness.

Eaton-Lambert syndrome is due to impaired acetylcholine release from presynaptic nerve terminals.

Botulism is also due to impaired release of acetylcholine from presynaptic nerve terminals. Botulism develops when toxin produced by Clostridium botulinum spores irreversibly binds to the terminal cholinergic nerve twigs, resulting in severe weakness, sometimes with respiratory compromise. Other systemic symptoms may include mydriasis, dry mouth, constipation, urinary retention, and tachycardia due to unopposed sympathetic nervous system activity. These systemic findings are absent in myasthenia gravis. In botulism, electromyography (EMG) shows a mild decremental response to low-frequency (2- to 3-Hz) repetitive nerve stimulation but a pronounced incremental response after 10 sec of exercise or with rapid (50-Hz) repetitive nerve stimulation.

Drugs or toxic chemicals may block neuromuscular junction function. Cholinergic drugs, organophosphate insecticides, and most nerve gases block neuromuscular transmission by excessive acetylcholine action that depolarizes postsynaptic receptors. Miosis, bronchorrhea, and myasthenic-like weakness result. Aminoglycoside and polypeptide antibiotics decrease presynaptic acetylcholine release and sensitivity of the postsynaptic membrane to acetylcholine. At high serum levels, these antibiotics may increase neuromuscular block in patients with latent myasthenia gravis. Long-term penicillamine treatment may cause a reversible syndrome that clinically and electromyographically resembles myasthenia gravis. Excessive Mg po or IV (with blood levels approaching 8 to 9 mg/dL) can also induce severe weakness resembling a myasthenic syndrome. Treatment consists of eliminating the drug or toxic chemical and providing necessary respiratory support and intensive nursing care. Atropine 0.4 to 0.6 mg po tid decreases bronchial secretions in patients with cholinergic excess. Higher doses (eg, 2 to 4 mg IV q 5 min) may be necessary for organophosphate insecticide or nerve gas poisoning.

Stiff-person syndrome is characterized by insidious onset of progressive stiffness in the trunk and abdomen and, to a lesser degree, in the legs and arms. Patients are otherwise normal, and examination detects only muscle hypertrophy and stiffness. EMG shows only the electrical activity of normal contraction. The syndrome may be autoimmune and can occur as a paraneoplastic syndrome (most often with breast, lung, or colon cancer or with Hodgkin lymphoma). Autoantibodies against several proteins involved with GABA (?-aminobutyric acid)-glycine synapses are present, affecting primarily inhibitory neurons that originate in the anterior horn of the spinal cord. Only symptomatic therapy is available. Diazepam is the only drug that consistently relieves muscle stiffness. Results of plasmapheresis are inconsistent.

Isaacs’ syndrome produces predominantly limb symptoms. Cause is unknown. Abnormalities are thought to originate in a peripheral nerve because they are abolished by curare but usually persist after general anesthesia. The sine qua non is myokymia—continuous muscle twitching described as “bag of worms” movements. Other symptoms include carpopedal spasms, intermittent cramps, increased sweating, and pseudomyotonia (impaired relaxation after a strong muscle contraction but without the typical waxing-and-waning EMG abnormality of true myotonia). Carbamazepine may relieve these symptoms.

MYASTHENIA GRAVIS

Myasthenia gravis is an autoimmune disorder of episodic muscle weakness and easy fatigability caused by antibody- and cell-mediated destruction of acetylcholine receptors. It is more common among young women and older men but may occur at any age. Symptoms worsen with muscle activity and lessen with rest. Diagnosis is by IV edrophonium challenge, which briefly lessens the weakness. Treatment includes anticholinesterase drugs, immunosuppressants, corticosteroids, thymectomy, and plasmapheresis.

Myasthenia gravis results from an autoimmune attack on postsynaptic acetylcholine receptors, which disrupts neuromuscular transmission. The trigger for autoantibody production is unknown, but the disorder is associated with abnormalities of the thymus, thyrotoxicosis, and other autoimmune disorders. The role of the thymus in myasthenia is unclear, but 65% of patients have thymic hyperplasia, and 10% have a thymoma. Precipitating factors include infection, surgery, and certain drugs (eg, aminoglycosides, quinine, Mg sulfate, procainamide, Ca channel blockers).

Rare forms: Ocular myasthenia gravis involves only extraocular muscles. Congenital myasthenia is a rare autosomal recessive disorder that begins in childhood; it results from structural abnormalities in the postsynaptic receptor rather than an autoimmune disorder. Ophthalmoplegia is common.

Neonatal myasthenia affects 12% of infants born to women with myasthenia gravis. It is due to IgG antibodies that passively cross the placenta. It causes generalized muscle weakness, which resolves in days to weeks as antibody titers decline. Thus, treatment is usually supportive.

• Symptoms and Signs

The most common symptoms are ptosis, diplopia, and muscle weakness after exercise. Weakness resolves when the affected muscles are rested but recurs when they are used again. Ocular muscles are affected initially in 40% of patients and eventually in 85%. If generalized myasthenia is going to develop after ocular symptoms, it usually does so within the 1st 3 yr. Proximal limb weakness is common. Some patients present with bulbar symptoms (eg, altered voice, nasal regurgitation, choking, dysphagia). Sensation and deep tendon reflexes are normal. Manifestations fluctuate in intensity over hours to days.

Myasthenic crisis, a severe generalized quadriparesis or life-threatening respiratory muscle weakness, occurs in about 10% of patients. It is often due to a supervening infection that reactivates the immune system. Once respiratory insufficiency begins, respiratory failure may occur rapidly.

• Diagnosis

Diagnosis is suggested by symptoms and signs and confirmed by tests. An anticholinesterase test using the short-acting (< 5 min) drug edrophonium is positive in most patients who have myasthenia with overt weakness. A muscle with obvious weakness is tested. Patients are asked to exercise the affected muscle until fatigue occurs (eg, hold the eyes open until ptosis occurs or count aloud until slurred speech develops); then, edrophonium 2 mg IV is given. If no adverse reaction (eg, bradycardia, atrioventricular block) occurs within 30 sec, another 8 mg is given. Rapid (< 2 min) recovery of muscle function is a positive result. However, a positive result is not definitive for myasthenia gravis because such improvement may occur in other neuromuscular disorders. The test may cause weakness due to cholinergic crisis to worsen (see below). Resuscitation equipment and atropine (as an antidote) must be available during the test.

Even if the anticholinesterase test is unequivocally positive, serum acetylcholine receptor antibody levels, electromyography (EMG), or both are required to confirm the diagnosis. The antibodies are present in 90% of patients with generalized myasthenia but in only 50% with the ocular form. Antibody levels do not correlate with disease severity.

EMG using repetitive stimuli (2 to 3/sec) shows a significant decrease in amplitude of the compound muscle action potential response in 60% of patients. Single-fiber EMG can improve the yield to > 95%.

Once myasthenia is diagnosed, CT or MRI of the thorax should be done to check for a thymoma. Other tests should be done to screen for autoimmune disorders frequently associated with myasthenia gravis (eg, vitamin B12 deficiency, hyperthyroidism, RA, SLE). Bedside pulmonary function tests (eg, forced vital capacity) help detect impending respiratory failure. Patients in myasthenic crisis require evaluation for an infectious trigger.

• Treatment

Patients with respiratory failure require intubation and mechanical ventilation. Anticholinesterase drugs and plasmapheresis relieve symptoms; corticosteroids, immunosuppressants, and thymectomy lessen the severity of the autoimmune reaction. In patients with congenital myasthenia, anticholinesterase drugs and immunomodulating treatments are not beneficial and should be avoided.

Symptomatic treatment: Anticholinesterase drugs are the mainstay of symptomatic treatment but do not alter the underlying disease process. Moreover, they rarely relieve all symptoms, and myasthenia may become refractory to these drugs. Pyridostigmine is begun at 30 to 60 mg po q 3 to 4 h and titrated up to a maximum of 180 mg/dose based on symptoms. Patients who have severe dysphagia particularly in the morning can take 180-mg long-acting capsules at night, but these capsules tend to be less effective. When parenteral therapy is necessary (eg, because of dysphagia), neostigmine (1 mg = 60 mg of pyridostigmine) may be substituted. Anticholinesterase drugs can cause abdominal cramps and diarrhea, which are treated with oral atropine 0.4 to 0.6 mg or propantheline 15 mg tid to qid.

Cholinergic crisis is muscular weakness caused by a dose of neostigmine or pyridostigmine that is too high. A mild crisis may be difficult to differentiate from worsening myasthenia. Severe cholinergic crisis usually results in excess lacrimation, salivation, tachycardia, and diarrhea, which do not result from myasthenia gravis. The approach to deterioration in patients who have been responding well to treatment is controversial. Some experts believe an edrophonium test is useful because strength improves only in myasthenic crisis. Others recommend simply initiating respiratory support and stopping anticholinesterase drugs for several days.

Immunomodulating treatment: Immunosuppressants interrupt the autoimmune reaction and slow the disease course, but they do not relieve symptoms rapidly. When given IV immune globulin 400 mg/kg once/day for 5 days, 70% of patients improve in 1 to 2 wk. Effects may last 1 to 2 mo.

Corticosteroids are necessary as maintenance therapy in many patients but have little immediate effect in myasthenic crisis. Over 1/2 of patients worsen acutely after starting high-dose corticosteroids. Initially, prednisone 20 mg po once/day is given; dose is increased by 5 mg q 2 to 3 days up to 60 or 70 mg, which is then given every other day. Improvement may take several months; then, the dose should be reduced to the minimum necessary.

Azathioprine 2.5 to 3.5 mg/kg po once/day may be as effective as corticosteroids, although significant benefit may not occur for many months. Cyclosporine 2 to 2.5 mg/kg po bid may allow the corticosteroid dose to be reduced. These drugs require the usual precautions. Other drugs that may be beneficial include methotrexate, cyclophosphamide, and mycophenolate mofetil.

Thymectomy is an option for most patients < 60 yr with generalized myasthenia and should be done in all patients with a thymoma. Subsequently, for 80%, remission occurs or the maintenance drug dose can be lowered.

Plasmapheresis may be useful during myasthenia crisis and before thymectomy in refractory patients.

HEREDITARY NEUROPATHIES

Hereditary neuropathies are a variety of congenital degenerative neurologic disorders.

Hereditary neuropathies are classified as sensorimotor neuropathies or sensory neuropathies.

Sensorimotor neuropathies: There are 3 main types (I, II, and III); all begin in childhood. Some less common types begin at birth and result in greater disability.

Types I and II (Charcot-Marie-Tooth disease, peroneal muscular atrophy) are the most common; they are usually autosomal dominant disorders characterized by weakness and atrophy, primarily in peroneal and distal leg muscles. Patients may also have other degenerative disorders (eg, Friedreich’s ataxia) or a family history of them. Patients with type I present in middle childhood with footdrop and slowly progressive distal muscle atrophy, producing “stork legs.” Intrinsic muscle wasting in the hands begins later. Vibration, pain, and temperature sensation decreases in a stocking-glove pattern. Deep tendon reflexes are absent. High pedal arches or hammertoes may be the only signs in less affected family members who carry the disease. Nerve conduction velocities are slow, and distal latencies are prolonged. Segmental demyelination and remyelination occur. Enlarged peripheral nerves may be palpated. The disease progresses slowly and does not affect life span. Type II evolves more slowly; weakness usually develops later in life. Patients have relatively normal nerve conduction velocities but low amplitude sensory nerve action potentials and compound muscle action potentials. Biopsies detect axonal (wallerian) degeneration.

Type III (hypertrophic interstitial neuropathy, Dejerine-Sottas disease), a rare autosomal recessive disorder, begins in childhood with progressive weakness and sensory loss and absent deep tendon reflexes. Although initially it resembles Charcot-Marie-Tooth disease, the motor weakness progresses more quickly. Demyelination and remyelination occur, producing enlarged peripheral nerves and onion bulbs, detected by nerve biopsy.

Sensory neuropathies: In hereditary sensory neuropathies, which are rare, loss of distal pain and temperature sensation is more prominent than loss of vibratory and position sense. The main complication is pedal mutilation due to pain insensitivity, resulting in a high risk of infections and osteomyelitis.

• Diagnosis and Treatment

The characteristic distribution of motor weakness, foot deformities, and family history suggests the diagnosis, which should be confirmed by electrophysiologic testing. Genetic analysis is available, but there are no specific treatments. Bracing helps correct footdrop; orthopedic surgery to stabilize the foot may help. Vocational counseling to prepare young patients for disease progression may be useful.

Hereditary Motor Neuropathy With Liability to Pressure Palsies

Hereditary motor neuropathy with liability to pressure palsies is a hereditary disorder in which nerves become increasingly sensitive to pressure and stretch.

In hereditary motor neuropathy with liability to pressure palsies (HNPP), nerves lose their myelin sheath and do not conduct nerve impulses normally. The cause is loss of one copy of peripheral myelin protein-22 gene (PMP22), located on the short arm of chromosome 17. A duplication (extra copy) results in Charcot-Marie-Tooth disease type I. Two copies of the gene are needed for normal function. Incidence of HNPP is estimated to be 2 to 5/100,000.

The pressure palsies can be mild or severe and last from minutes to months. Numbness and weakness occur in affected areas.

HNPP should be suspected in patients with recurrent demyelinating polyneuropathy, compression mononeuropathy, multiple mononeuropathy of unknown origin, or a family history of carpal tunnel syndrome. Electromyography, nerve biopsy, and genetic testing aid in diagnosis, but biopsy is rarely required. Treatment is symptomatic and involves avoiding or modifying activities that cause symptoms. Wrist splints and elbow pads can reduce pressure, prevent reinjury, and allow the nerve to repair the myelin over time. Surgery is rarely indicated.

MOTOR NEURON DISEASE

Motor neuron disorders are characterized by steady, relentless, progressive degeneration of corticospinal tracts, anterior horn cells, bulbar motor nuclei, or a combination. Symptoms vary in severity and may include muscle weakness and atrophy, fasciculations, emotional lability, and respiratory muscle weakness. Diagnosis involves nerve conduction velocity studies, electromyography, and exclusion of other disorders via neuroimaging and laboratory tests. Treatment is supportive.

Several motor neuron disorders (MNDs) exist. Usually, etiology is unknown. Nomenclature and symptoms vary according to the part of the motor system most affected. Myopathies, which mimic findings of MNDs, are disorders of the muscle membrane, contractile apparatus, or organelles.

Classification, Symptoms, and Signs

MNDs can be classified as upper and lower; some disorders (eg, amyotrophic lateral sclerosis) have features of both.

Upper MNDs (eg, primary lateral sclerosis) affect neurons between the motor cortex and brain stem (corticobulbar tracts) or spinal cord (corticospinal tracts). Generally, symptoms consist of stiffness, clumsiness, and awkward movements, usually affecting first the mouth, throat, or both, then spreading to the limbs.

Lower MNDs affect the anterior horn cells or their efferent axons to the skeletal muscles. In bulbar palsies, only the cranial nerve motor nuclei in the brain stem (bulbar nuclei) are affected. Patients usually present with facial weakness, dysphagia, and dysarthria. When anterior horn cells of spinal (not cranial) nerves are affected, as in spinal muscular atrophies, symptoms usually include muscle weakness and atrophy, fasciculations (visible muscle twitches), and muscle cramps, initially in a hand, a foot, or the tongue. Poliomyelitis, an enteroviral infection that attacks anterior horn cells, and postpolio syndrome are also lower MNDs.

Physical findings help differentiate upper and lower MND (see Table 2: Peripheral Nervous System Disorders: Distinguishing Upper from Lower Motor Neuron Lesions) and weakness from lower MND from myopathy (see Table 3: Peripheral Nervous System Disorders: Distinguishing Neurogenic* from Myogenic† Muscle Weakness).

Table 2. Distinguishing Upper from Lower Motor Neuron Lesions

Feature	Reflexes	Atrophy	Tone	Fasciculations
Upper Lesion	Hyperactive	Absent*	Increased	Absent
Lower Lesion	Diminished or absent	Present	Decreased or absent	Present

*May appear with prolonged limb disuse.

Table 3. Distinguishing Neurogenic* from Myogenic† Muscle Weakness

Feature	Distribution	Fasciculations	Reflexes	Sensory signs/symptoms
Due to Neuropathy	Distal > proximal	May be present	Diminished	May be present
Due to Myopathy	Proximal > distal	Absent	Often preserved	Absent

*Weakness due to neuropathy: lower motor neuron.

†Weakness due to myopathy: nerve function intact.

Amyotrophic lateral sclerosis (ALS): ALS (Lou Gehrig disease, Charcot’s syndrome) is the most common MND. Patients present with random, asymmetric symptoms, consisting of cramps, weakness, and muscle atrophy of the hands (most commonly) or feet. Fasciculations, spasticity, hyperactive deep tendon reflexes, extensor plantar reflexes, clumsiness, stiffness of movement, weight loss, fatigue, and difficulty controlling facial expression and tongue movements soon follow. Other symptoms include hoarseness, dysphagia, slurred speech, and a tendency to choke on liquids. Late in the disorder, inappropriate, involuntary, and uncontrollable excesses of laughter or crying (pseudobulbar affect) occur. Sensory systems, consciousness, cognition, voluntary eye movements, sexual function, and urinary and anal sphincters are usually spared. Death is usually caused by failure of the respiratory muscles; 50% of patients die within 3 yr of onset, 20% live 5 yr, and 10% live 10 yr. Survival > 30 yr is rare.

Progressive bulbar palsy: The muscles innervated by cranial nerves and corticobulbar tracts are predominantly affected, causing progressive difficulty with chewing, swallowing, and talking; nasal voice; reduced gag reflex; fasciculations and weak movement of the facial muscles and tongue; and weak palatal movement. A pseudobulbar affect, with emotional lability, may occur if the corticobulbar tract is affected. Patients with dysphagia have a very poor prognosis; respiratory complications due to aspiration frequently result in death within 1 to 3 yr.

Progressive muscular atrophy: In many cases, especially those with childhood onset, inheritance is autosomal recessive. Other cases are sporadic. The disorder can develop at any age. Anterior horn cell involvement occurs alone or is more prominent than corticospinal involvement, and progression tends to be more benign than that of other MNDs. Fasciculations may be the earliest manifestation. Muscle wasting and marked weakness begin in the hands and progress to the arms, shoulders, and legs, eventually becoming generalized. Patients may survive = 25 yr.

Primary lateral sclerosis and progressive pseudobulbar palsy: Muscle stiffness and signs of distal motor weakness gradually increase, affecting the limbs in primary lateral sclerosis and the lower cranial nerves in progressive pseudobulbar palsy. Fasciculations and muscle atrophy may follow many years later. These disorders usually take several years to produce total disability.

• Diagnosis

Diagnosis is suggested by progressive, generalized motor weakness without significant sensory abnormalities. Other neurologic disorders that cause pure muscle weakness include disorders of neuromuscular transmission and various myopathies. Acquired causes of pure motor weakness include noninflammatory myopathies, polymyositis, dermatomyositis, thyroid and adrenal disorders, electrolyte abnormalities (hypokalemia, hypercalcemia, hypophosphatemia), and various infections (eg, syphilis, Lyme disease, hepatitis C).

When cranial nerves are affected, a secondary treatable cause is less likely. Upper and lower motor neuron signs plus weakness in facial muscles strongly suggest ALS.

Electrodiagnostic tests should be done to check for evidence of disorders of neuromuscular transmission or demyelination. Such evidence is not present in MNDs; nerve conduction velocities are usually normal until late in the disease process. Needle electromyography (EMG) is the most useful test, showing fibrillations, positive waves, fasciculations, and sometimes giant motor units, even in unaffected limbs.

Brain MRI is required. MRI of the cervical spine is indicated when there is no clinical or EMG evidence of cranial nerve motor weakness.

Laboratory tests are done to identify treatable disorders. Tests include CBC, electrolytes, creatine phosphokinase, thyroid tests, serum and urine protein electrophoresis with immunofixation for monoclonal antibodies, anti-myelin-associated glycoprotein (MAG) antibodies, and a 24-h urine collection to check for heavy metals in patients who may have been exposed to them. A lumbar puncture should be done; elevated WBCs or protein levels strongly suggest an alternative diagnosis.

Serum Venereal Disease Research Laboratories (VDRL) tests, ESR, and measurement of certain antibodies (rheumatoid factor, Lyme titer, HIV, hepatitis C virus, antinuclear [ANA], anti-Hu paraneoplastic) are indicated only if suggested by risk factors or history. Genetic testing (eg, superoxide dismutase gene mutation) and enzyme measurements (eg, hexosaminidase A) should not be done unless patients are interested in genetic counseling; disorders detected by these tests have no known treatment.

• Treatment

There is no specific treatment. However, an antiglutamate drug, riluzole 50 mg po bid, prolongs life in patients with bulbar-variant ALS. A multidisciplinary team approach helps patients cope with progressive neurologic disability. Physical therapy may help maintain muscle function. Occupational therapists can recommend adaptive braces and walking devices to help with activities of daily living. Speech and language therapists may provide alternative communication devices. Patients with pharyngeal weakness should be fed with extreme care and may require percutaneous endoscopic gastrostomy. Pulmonary specialists are crucial as respiratory weakness develops; they may recommend noninvasive respiratory support (eg, bilevel positive airway pressure) or tracheostomy and full ventilatory support.

Baclofen may help reduce spasticity; quinine or phenytoin may help decrease cramps. A strong anticholinergic drug (eg, glycopyrrolate, amitriptyline , benztropine , trihexyphenidyl, transdermal hyoscine, atropine) may be used to decrease saliva production. Amitriptyline and fluvoxamine are options for managing pseudobulbar affect. Pain in late stages of these disorders may require opioids and benzodiazepines. Surgery to improve swallowing has had limited success in patients with progressive bulbar palsy.

Early in the disorder, health care practitioners must talk frankly with patients, family members, and caregivers to determine the level of intervention acceptable. These decisions should be reviewed and confirmed at various stages of the disorder.

NERVE ROOT DISORDERS

Nerve root disorders result in predictable segmental radicular symptoms (pain or paresthesias in a dermatomal distribution, weakness of muscles innervated by the root). Diagnosis may require neuroimaging, electromyography, and systemic testing for underlying disorders. Treatment depends on cause but includes symptomatic relief with NSAIDs and other analgesics.

Nerve root disorders (radiculopathies) are precipitated by chronic pressure on a root in or adjacent to the spinal column. The most common cause is a herniated intervertebral disk. Bone changes due to RA or osteoarthritis, especially in the cervical and lumbar areas, may also compress isolated nerve roots. Less commonly, carcinomatous meningitis produces patchy multiple root dysfunction. Rarely, mass spinal lesions (eg, epidural abscesses and tumors, spinal meningiomas, neurofibromas) may manifest with radicular symptoms instead of the usual spinal cord dysfunction. Diabetes can cause a painful thoracic or extremity radiculopathy. Infectious disorders, such as fungal (eg, histoplasmosis) and spirochetal diseases (eg, Lyme disease, syphilis), sometimes affect nerve roots. Herpes zoster infection usually causes a painful radiculopathy with dermatomal sensory loss and characteristic rash, but it may cause a motor radiculopathy with myotomic weakness and reflex loss.

• Symptoms and Signs

Nerve root disorders tend to cause characteristic radicular syndromes of pain and segmental neurologic deficits based on the affected cord level (see Table 4: Peripheral Nervous System Disorders: Symptoms of Common Radiculopathies by Cord Level). Muscles innervated by the affected motor root become weak and atrophy; they also may be flaccid with fasciculations. Sensory root involvement causes sensory impairment in a dermatomal distribution. Corresponding segmental deep tendon reflexes may be diminished or absent.

Table 4. Symptoms of Common Radiculopathies by Cord Level

Level	Symptoms
C6	Pain in the trapezius ridge and tip of the shoulder, often radiating to the thumb, with paresthesias and sensory impairment in the same areas; weakness of biceps; and decreased biceps brachii and brachioradialis reflexes
C7	Pain in the shoulder blade and axilla, radiating to the middle finger; weakness of triceps; and decreased triceps brachii reflex
T (any)	Bandlike dysesthesias around thorax
L5	Pain in the buttock, posterior lateral thigh, calf, and foot; footdrop with weakness of the anterior tibial, posterior tibial, and peroneal muscles; and sensory loss over the shin and dorsal foot
S1	Pain along posterior aspect of the leg and buttock, weakness of the medial gastrocnemius muscle with impaired ankle plantar flexion, loss of ankle jerk, and sensory loss over the lateral calf and foot

Pain may be exacerbated by movements that transmit pressure to the nerve root through the subarachnoid space (eg, moving the spine, coughing, sneezing, Valsalva maneuver). Lesions of the cauda equina, which affect multiple lumbar and sacral roots, cause radicular symptoms in both legs and may impair sphincter and sexual function.

Findings indicating spinal cord compression include a sensory level (an abrupt change in sensation below a horizontal line across the spine), flaccid paraparesis or quadriparesis, reflex abnormalities below the site of compression, early-onset hyporeflexia followed later by hyperreflexia, and sphincter dysfunction.

• Diagnosis and Treatment

Radicular symptoms require CT or MRI of the affected area. Myelography is sometimes used if multiple levels are affected. The area imaged depends on symptoms and signs; if the level is unclear, electromyography (EMG) should be done to localize the affected root, but EMG cannot identify the cause.

If imaging does not detect an anatomic abnormality, CSF analysis is done to check for infectious or inflammatory causes, and fasting blood glucose is measured to check for diabetes.

Specific causes are treated. Acute pain requires appropriate analgesics (eg, NSAIDs, sometimes opioids). Use of low-dose tricyclic antidepressants at bedtime may help. Muscle relaxants, sedatives, and topical treatments rarely provide additional benefit. Chronic pain can be difficult to manage; NSAIDs are often only partly effective, and opioids have a high risk of addiction. Tricyclic antidepressants and anticonvulsants may be effective, as may physical therapy and consultation with a mental health practitioner. For a few patients, alternative medical treatments (eg, transdermal electrical nerve stimulation, spinal manipulation, acupuncture, medicinal herbs) may be helpful.

•  

  • Herniated Nucleus Pulposus

(Herniated, Ruptured, or Prolapsed Intervertebral Disk)

Herniated nucleus pulposus is prolapse of the central area of an intervertebral disk through the surrounding annulus. Symptoms occur when the disk impinges on an adjacent nerve root, causing segmental radiculopathy with paresthesias and weakness in the distribution of the affected root. Diagnosis is by CT, MRI, or CT-myelography. Treatment of mild cases is with NSAIDs and other analgesics if needed. Bed rest is rarely indicated. Patients with progressive neurologic deficits, intractable pain, or sphincter dysfunction may require urgent surgery (eg, diskectomy, laminectomy).

Spinal vertebrae are separated by cartilaginous disks consisting of an outer annulus fibrosus and an inner nucleus pulposus. When degenerative changes (with or without trauma) result in protrusion or rupture of the nucleus through the annulus fibrosus in the lumbosacral or cervical area, the nucleus is displaced posterolaterally or posteriorly into the extradural space. Radiculopathy occurs when the herniated nucleus compresses or irritates the nerve root. Posterior protrusion may compress the cord or cauda equina, especially in a congenitally narrow spinal canal (spinal stenosis). In the lumbar area, > 80% of disk ruptures affect L5 or S1 nerve roots; in the cervical area, C6 and C7 are most commonly affected. Herniated disk is common, often causing no symptoms.

Symptoms and signs are similar to those of other nerve root disorders (see Table 4: Peripheral Nervous System Disorders: Symptoms of Common Radiculopathies by Cord Level), although pain is somewhat more likely to develop suddenly if the disk herniates, and the cord may be compressed. In patients with lumbosacral herniation, straight-leg raises, which stretch the roots, may cause back or leg pain (bilateral if disk herniation is central); with cervical herniation, neck flexion or tilting is painful. Cervical cord compression may cause spastic paresis of the lower limbs. Cauda equina compression often results in urine retention or incontinence due to loss of sphincter function.

• Diagnosis and Treatment

CT, MRI, or CT-myelography of the affected area is done. Electromyography may help identify the involved root. Because asymptomatic herniated disk is quite common, the clinician must carefully correlate symptoms with MRI abnormalities before invasive procedures are considered.

Because up to 95% of patients with herniated disk recover without surgery within about 3 mo, treatment should be conservative, unless neurologic deficits are progressive or severe. Heavy or vigorous physical activity is restricted, but ambulation and light activity (eg, lifting objects < 5 to 10 lb) are permitted as tolerated; prolonged bed rest (including traction) is contraindicated. NSAIDs and other analgesics should be used as needed to relieve pain.

If lumbar radiculopathies result in persistent or worsening objective neurologic deficits (weakness, sensory deficits) or in severe, intractable nerve root pain, invasive procedures should be considered. Microscopic diskectomy and laminectomy with surgical removal of herniated material are usually the procedures of choice. Percutaneous approaches to remove bulging disk material are being evaluated. Dissolving herniated disk material with local injections of the enzyme chymopapain is not recommended. Lesions acutely compressing the spinal cord or cauda equina (eg, producing urine retention or incontinence) require immediate surgical evaluation.

If cervical radiculopathies result in signs of spinal cord compromise, surgical decompression is needed immediately; otherwise, it is done electively when nonsurgical treatments are ineffective.

PERIPHERAL NEUROPATHY

Peripheral neuropathy is dysfunction of a spinal nerve or nerves distal to a plexus or root. It includes numerous syndromes characterized by varying degrees of sensory disturbances, pain, muscle weakness and atrophy, diminished deep tendon reflexes, and vasomotor symptoms, alone or in any combination. Initial classification is based on history and physical examination and must be confirmed with electromyography and nerve conduction velocity studies. Treatment is aimed mainly at the cause.

Peripheral neuropathy may affect a single nerve (mononeuropathy), = 2 discrete nerves in separate areas (multiple mononeuropathy), or many nerves simultaneously (polyneuropathy).

• Mononeuropathies

Single and multiple mononeuropathies are characterized by sensory disturbances and weakness in the distribution of the affected nerve or nerves. Diagnosis is clinical but should be confirmed with electrodiagnostic tests. Treatment is directed at the cause, sometimes with splinting, NSAIDs, corticosteroid injections, and, for severe cases of nerve entrapment, surgery.

Trauma is the most common cause of acute mononeuropathy. Violent muscular activity or forcible overextension of a joint may cause focal neuropathy, as may repeated small traumas (eg, tight gripping of small tools, excessive vibration from air hammers). Prolonged, uninterrupted pressure at bony prominences can cause pressure neuropathy, usually affecting superficial nerves (ulnar, radial, peroneal), particularly in thin people; such pressure may occur during sound sleep, intoxication, bicycle riding, or anesthesia. Compression of nerves in narrow canals causes entrapment neuropathy (eg, in carpal tunnel syndrome). Nerve compression by a tumor, bony hyperostosis, a cast, crutches, or prolonged cramped postures (eg, during gardening) may cause compression paralysis. Hemorrhage into a nerve, exposure to cold or radiation, or direct tumor invasion may cause neuropathy.

Multiple mononeuropathy (mononeuritis multiplex) is usually secondary to connective tissue disorders (eg, polyarteritis nodosa, SLE, Sjögren’s syndrome, RA), sarcoidosis, metabolic disorders (eg, diabetes, amyloidosis), or infectious disorders (eg, Lyme disease, HIV infection, leprosy). Diabetes usually causes sensorimotor distal polyneuropathy.

• Symptoms and Signs

Single and multiple mononeuropathies are characterized by pain, weakness, and paresthesias in the distribution of the affected nerve or nerves. Pure motor nerve involvement begins with painless weakness; pure sensory nerve involvement begins with sensory disturbances without weakness. Multiple mononeuropathy is often asymmetric at its onset; nerves may be involved all at once or progressively. Extensive involvement of many nerves may simulate polyneuropathy.

Ulnar nerve palsy of the elbow is often caused by trauma to the nerve in the ulnar groove of the elbow by repeated leaning on the elbow or by asymmetric bone growth after a childhood fracture (tardy ulnar palsy). The ulnar nerve can also be compressed at the cubital tunnel. Compression at the level of the elbow can cause paresthesias and a sensory deficit in the 5th digit and medial half of the 4th digit; the thumb adductor, 5th digit abductor, and interosseous muscles are weak and may be atrophied. Severe chronic ulnar palsy causes a clawhand deformity.

Carpal tunnel syndrome may be unilateral or bilateral. It results from compression of the median nerve in the volar aspect of the wrist between the transverse superficial carpal ligament and the flexor tendons of the forearm muscles. The compression causes paresthesias in the radial-palmar aspect of the hand and pain in the wrist and palm. Pain may also occur in the forearm and shoulder. Pain may be more severe at night. A sensory deficit in the palmar aspect of the 1st 3 fingers may follow, and the muscles that control thumb abduction and opposition may become weak and atrophied. Sensory symptoms due to this syndrome should be distinguished from C6 root dysfunction due to cervical radiculopathy, by electromyography (EMG) if needed.

Peroneal nerve palsy is usually caused by compression of the nerve against the lateral aspect of the fibular neck. It is most common among emaciated bedbound patients and thin people who habitually cross their legs. It causes footdrop (weakened dorsiflexion and eversion of the foot) and, occasionally, a sensory deficit in the anterolateral aspect of the lower leg and the dorsum of the foot or in the web space between the 1st and 2nd metatarsals.

Radial nerve palsy (Saturday night palsy) is caused by compression of the nerve against the humerus, as when the arm is draped over the back of a chair for a long time (eg, during intoxication or deep sleep). Typical symptoms include wristdrop (weakness of the wrist and finger extensors) and sensory loss in the dorsal aspect of the 1st dorsal interosseous muscle.

• Diagnosis and Treatment

Electrodiagnostic tests are generally obtained, either to clarify diagnosis or to assess severity and prognosis.

Underlying disorders are treated. Treatment of compression neuropathy depends on cause. Often, fixed compression (eg, by tumor) must be relieved surgically. Symptoms of transient compression usually resolve with rest, heat, NSAIDs, and avoidance or modification of causative activity. Patients with carpal tunnel syndrome sometimes benefit from corticosteroid injections. For all types, braces or splints are often used pending resolution. Surgery should be considered when progression occurs despite conservative treatment.

• Polyneuropathy

A polyneuropathy is a diffuse peripheral nerve disorder not confined to the distribution of a single nerve or a single limb. Electrodiagnostic tests should always be performed to classify the nerve structures involved, distribution, and severity of the disorder in order to focus the search for the underlying cause. Treatment is directed toward attenuating or removing the underlying cause.

Some polyneuropathies (eg, due to lead toxicity, dapsone use, tick bite, porphyria, or Guillain-Barré syndrome) affect primarily motor fibers; others (eg, due to dorsal root ganglionitis of cancer, leprosy, AIDS, diabetes mellitus, or chronic pyridoxine intoxication) affect primarily sensory fibers. Some disorders (eg, Guillain-Barré syndrome, Lyme disease, diabetes, diphtheria) can also affect cranial nerves. Certain drugs and toxins can affect sensory or motor fibers or both (seeTable 5: Peripheral Nervous System Disorders: Toxic Causes of Neuropathies).

Table 5. Toxic Causes of Neuropathies

Type	Drugs & Toxins
Axonal motor	Gangliosides; with prolonged exposure, lead, mercury, misoprostol, tetanus, tick paralysis
Axonal sensorimotor	Acrylamide, alcohol (ethanol), allyl chloride, arsenic, cadmium, carbon disulfide, chlorphenoxy compounds, ciguatoxin, dapsone, colchicine, cyanide, DMAPN, disulfiram, ethylene oxide, lithium, methyl bromide, nitrofurantoin, organophosphates, podophyllin, polychlorinated biphenyls (PCBs), saxitoxin, Spanish toxic oil, taxol, tetrodotoxin, thallium, trichloroethylene, TOCP, vacor (PNU), vinca alkaloids Almitrine, bortezomib, chloramphenicol, dioxin, doxorubicin, ethambutol, ethionamide, etoposide, gemcitabine, glutethimide, hydralazine, ifosfamide, interferon-a, isoniazid, lead, metronidazole, misonidazole, nitrous oxide, nucleosides (didanosine[ddI], stavudine[d4T], zalcitabine[ddC]), phenytoin, platinum analogs, propafenone, pyridoxine, statins, thalidomide
Demyelinating	Buckthorn, chloroquine, diphtheria, hexachlorophene, muzolimine, perhexiline, procainamide, tacrolimus tellurium, zimeldine
Mixed	Amiodarone, ethylene glycol, gold, hexacarbons, n-hexane, Na cyanate, suramin DMAPN = dimethylaminopropionitrile; TOCP = triorthocresyl phosphate; PNU = N-3 pyridilmethyl-N´-nitrophenyl urea.

• Symptoms and Signs

Because pathophysiology and symptoms are related, polyneuropathies are often classified by area of dysfunction: myelin, vasa nervorum, or axon. Hereditary neuropathies are discussed below.

Myelin dysfunction: Myelin dysfunction polyneuropathies most often result from a parainfectious immune response triggered by an encapsulated bacterium (eg, Campylobacter sp), virus (eg, enteric or influenza viruses, HIV), or vaccine (eg, influenza vaccine). Presumably, antigens in these agents cross-react with antigens in the peripheral nervous system, causing an immune response (cellular, humoral, or both) that culminates in varying degrees of myelin dysfunction. In acute cases (eg, in Guillain-Barré syndrome), rapidly progressive weakness and respiratory failure may develop.

Myelin dysfunction usually results in large-fiber sensory disturbances (paresthesias), significant muscle weakness greater than expected for degree of atrophy, and significantly diminished reflexes. Trunk musculature and cranial nerves may be involved. Abnormalities typically occur along the entire length of a nerve, producing proximal and distal symptoms. There may be side-to-side asymmetries, and more rostral parts of the body may be affected before distal extremities. Muscle bulk and tone are relatively preserved.

• Vasa nervorum compromise:

Chronic arteriosclerotic ischemia, vasculitis, and hypercoagulable states can compromise the vascular supply to the nerves.

Usually, small-fiber sensory and motor dysfunction occurs first. Patients typically have painful, often burning sensory disturbances. Abnormalities tend to be asymmetric early in the disorder and rarely affect the proximal 1/3 of the limb or trunk muscles. Cranial nerve involvement is rare, except in diabetes, which commonly affects the 3rd cranial (oculomotor) nerve. Later, symptoms and signs may appear symmetric if nerve lesions coalesce. Dysautonomia and skin changes (eg, atrophic, shiny skin) sometimes occur. Muscle weakness tends to be proportional to atrophy, and reflexes are rarely lost completely.

• Axonopathy:

Axonopathies tend to be distal; they may be symmetric or asymmetric.

Symmetric axonopathies result most often from toxic-metabolic disorders. Common causes include diabetes mellitus, chronic renal insufficiency, and adverse effects of chemotherapy drugs (eg, vinca alkaloids). Axonopathy may result from nutritional deficiencies (most commonly, of vitamin B) or from excess intake of vitamin B6 or alcohol. Less common metabolic causes include hypothyroidism, porphyria, sarcoidosis, and amyloidosis. Other causes include certain infections (eg, Lyme disease), drugs (eg, nitrous oxide), and exposure to certain chemicals (eg, to Agent Orange, n-hexane) or heavy metals (eg, lead, arsenic, mercury). In a paraneoplastic syndrome associated with small-cell lung cancer, loss of dorsal root ganglia and their sensory axons results in subacute sensory neuropathy.

Primary axon dysfunction may begin with symptoms of large- or small-fiber dysfunction or both. Usually, the resulting neuropathy has a distal symmetric, stocking-glove distribution; it evenly affects the lower extremities before the upper extremities and progresses symmetrically from distal to proximal areas.

Asymmetric axonopathy can result from parainfectious or vascular disorders.

• Diagnosis

Clinical findings, particularly tempo of onset, aid in diagnosis and identification of the cause. Asymmetric neuropathies suggest a disorder affecting the myelin sheath or vasa nervorum. Symmetric, distal neuropathies suggest toxic or metabolic causes. Slowly progressive, chronic neuropathies tend to be inherited or due to long-term toxic exposure or metabolic disorders. Acute neuropathies suggest an autoimmune response, vasculitis, or a postinfectious cause. Rash, skin ulcers, and Raynaud’s phenomenon in patients with an asymmetric axonal neuropathy suggest a hypercoagulable state or parainfectious or autoimmune vasculitis. Weight loss, fever, lymphadenopathy, and mass lesions may suggest a tumor or paraneoplastic syndrome.

Electrodiagnostic tests: Regardless of clinical findings, electromyography (EMG) and nerve conduction velocity studies are necessary to classify type of neuropathy. At a minimum, EMG of both lower extremities should be done to assess for asymmetry and full extent of axon loss. Because EMG and nerve conduction studies assess primarily large myelinated fibers in distal limb segments, EMG may be normal in patients with proximal myelin dysfunction (eg, early in Guillain-Barré syndrome) and in patients with primarily small-fiber dysfunction. In such cases, quantitative sensory or autonomic testing or both may be done depending on the presenting symptoms.

Laboratory tests: Baseline laboratory tests for all patients include CBC, electrolytes, renal function tests, rapid plasma reagin test, and measurement of fasting blood sugar, hemoglobin A1C, vitamin B12, folate, and thyroid-stimulating hormone. Some clinicians include serum protein electrophoresis. The need for other tests is determined by polyneuropathy subtype.

The approach to patients with acute myelin dysfunction neuropathies is the same as that to those with Guillain-Barré syndrome; forced vital capacity is measured to check for incipient respiratory failure. In acute or chronic myelin dysfunction, tests for infectious disorders and immune dysfunction, including tests for hepatitis and HIV and serum protein electrophoresis, are done. In addition, anti-myelin-associated glycoprotein (MAG) antibodies are measured if motor dysfunction predominates; anti-sulfatide antibodies are measured if primary sensory dysfunction is present. A lumbar puncture should also be done; myelin dysfunction due to an autoimmune response often causes albuminocytologic dissociation: increased CSF protein (> 45 mg%) but normal WBC count (= 5/µL).

For asymmetric axonal polyneuropathies, tests for hypercoagulable states and parainfectious or autoimmune vasculitis, particularly if suggested by clinical findings, should be done; the minimum is ESR, serum protein electrophoresis, and measurement of rheumatoid factor, antinuclear antibodies, and serum CPK. CPK may be elevated when rapid onset of disease results in muscle infarction. Coagulation studies (eg, protein C, protein S, antithrombin III, anticardiolipin antibody, homocysteine levels) should be done only if suggested by personal or family history. Tests for sarcoidosis, hepatitis C, or Wegener’s granulomatosis should be done only if suggested by symptoms and signs. If no cause is identified, nerve and muscle biopsy should be done. An affected sural nerve is usually biopsied. A muscle adjacent to the biopsied sural nerve or a quadriceps, biceps brachii, or deltoid muscle may be biopsied. The muscle should be one with moderate weakness that has not been tested by needle EMG. Yield is higher if the contralateral muscle has EMG abnormalities. Nerve biopsies tend to be more useful in asymmetric axonopathies than in other polyneuropathy subtypes.

If initial tests do not identify the cause of distal symmetric axonopathies, a 24-h urine collection is tested for heavy metals, and urine protein electrophoresis is done. If chronic heavy metal poisoning is suspected, testing of hairs from the pubis or axillary region may help. History and physical examination should determine whether tests for other causes are needed. 

• Treatment

Treatment focuses on correcting the causes when possible; a causative drug or toxin can be eliminated, or a dietary deficiency corrected. Although these actions may halt progression and lessen symptoms, recovery is slow and may be incomplete. If the cause cannot be corrected, treatment focuses on minimizing disability and pain. Physical and occupational therapists can recommend useful assistive devices. Amitriptyline, gabapentin, mexiletine, and topical lidocaine may relieve neuropathic pain (eg, diabetic burning feet).

For myelin dysfunction polyneuropathies, immune system–modifying treatments are usually used: plasmapheresis or IV immune globulin for acute myelin dysfunction and corticosteroids or antimetabolite drugs for chronic myelin dysfunction.

GUILLAIN BARRE SYNDROME

(Acute Idiopathic Polyneuritis; Landry’s Paralysis; Acute Inflammatory Demyelinating Polyradiculoneuropathy)

Guillain-Barré syndrome is an acute, usually rapidly progressive inflammatory polyneuropathy characterized by muscular weakness and mild distal sensory loss. Cause is thought to be autoimmune. Diagnosis is clinical. Treatment includes plasmapheresis, ?-globulin, and, for severe cases, mechanical ventilation.

Guillain-Barré syndrome is the most common acquired inflammatory neuropathy. Although the cause is not fully understood, it is thought to be autoimmune. There are several variants. In some, demyelination predominates; others affect the axon.

In about 2/3 of patients, the syndrome begins 5 days to 3 wk after a banal infectious disorder, surgery, or vaccination. Infection is the trigger in > 50% of patients; common pathogens include Campylobacter jejuni, enteric viruses, herpesviruses (including cytomegalovirus and those causing infectious mononucleosis), and Mycoplasma sp. A cluster of cases followed the swine flu vaccination program in 1975.

• Symptoms and Signs

Flaccid weakness predominates in most patients; it is always more prominent than sensory abnormalities and may be most prominent proximally. Relatively symmetric weakness with paresthesias usually begins in the legs and progresses to the arms, but it occasionally begins in the arms or head. In 90% of patients, weakness is maximal at 3 wk. Deep tendon reflexes are lost. Sphincters are usually spared. Facial and oropharyngeal muscles are weak in > 50% of patients with severe disease. Respiratory paralysis severe enough to require endotracheal intubation and mechanical ventilation occurs in 5 to 10%.

A few patients (possibly with a variant form) have significant, life-threatening autonomic dysfunction causing BP fluctuations, inappropriate ADH secretion, cardiac arrhythmias, GI stasis, urinary retention, and pupillary changes. An unusual variant (Fisher variant) may cause only ophthalmoparesis, ataxia, and areflexia.

• Diagnosis

Diagnosis is clinical. Similar acute weakness can result from myasthenia gravis, botulism, poliomyelitis (primarily outside the US), tick paralysis, West Nile virus infection, and metabolic neuropathies, but these disorders can be distinguished. Myasthenia gravis is intermittent and worsened by exertion. Botulism may cause fixed dilated pupils (in 50%) and prominent cranial nerve dysfunction with normal sensation. Poliomyelitis usually occurs in epidemics. Tick paralysis causes ascending paralysis but spares sensation. West Nile virus causes headache, fever, and asymmetric flaccid paralysis but spares sensation. Metabolic neuropathies occur with a chronic metabolic disorder.

If Guillain-Barré syndrome is suspected, patients should be admitted to a hospital for electromyography (EMG), CSF analysis, and measurement of forced vital capacity every 6 to 8 h. Initial EMG detects slow nerve conduction velocities and evidence of segmental demyelination in 2/3 of patients; however, a normal EMG does not exclude the diagnosis and should not delay treatment. CSF analysis may detect albuminocytologic dissociation (increased protein but normal WBC count), but it may not appear for up to 1 wk and does not develop in 10% of patients.

• Prognosis

Most patients improve considerably over a period of months, but about 30% of adults and even more children have some degree of residual weakness at 3 yr. Patients with residual defects may require retraining, orthopedic appliances, or surgery. This syndrome is fatal in < 2%.

After initial improvement, 3 to 10% of patients develop chronic relapsing polyneuropathy. Pathology and laboratory findings are similar to those in the acute syndrome, but weakness may be more asymmetric and progress more slowly. Eventually, nerves may become palpable because of repeated episodes of segmental demyelination and remyelination.

• Treatment

Guillain-Barré syndrome is a medical emergency, requiring constant monitoring and support of vital functions, typically in an ICU. Forced vital capacity should be measured frequently so that respiration can be assisted if necessary; if vital capacity is < 15 mL/kg, endotracheal intubation is indicated. Inability to lift the head off the pillow by flexing the neck is another danger sign; it frequently develops simultaneously with phrenic nerve (diaphragm) weakness.

Fluid intake should be sufficient to maintain a urine volume of at least 1 to 1.5 L/day. Extremities should be protected from trauma and from the pressure of bed rest. Heat helps relieve pain, making early physical therapy possible. Immobilization, which may cause ankylosis, should be avoided. Passive full-range joint movement should be started immediately, and active exercises should be initiated when acute symptoms subside. Heparin 5000 units sc bid helps prevent deep vein thrombosis in bedbound patients.

Corticosteroids do not improve the outcome and should not be used. Plasmapheresis helps when done early in the syndrome and is the treatment of choice in acutely ill patients. It is relatively safe, shortens the disease course and hospital stay, and reduces mortality risk and incidence of permanent paralysis. Immune globulin (?-globulin) 400 mg/kg IV once/day for 5 consecutive days is equally effective when given early, with benefit demonstrated up to 1 mo from disease onset. However, because plasmapheresis removes any previously administered ?-globulin, negating its benefits, ?-globulin is typically used if plasmapheresis is ineffective or unavailable.

In chronic relapsing polyneuropathy, corticosteroids lessen weakness and may be needed for a long time. Immunosuppressants (eg, corticosteroids, azathioprine), ?-globulin, and plasmapheresis benefit some patients.

PLEXUS DISORDERS

Disorders of the brachial or lumbosacral plexus cause a painful mixed sensorimotor disorder of the corresponding limb.

Because several nerve roots intertwine within the plexus, the symptom pattern does not fit the distribution of individual roots or nerves. Disorders of the rostral brachial plexus affect the shoulders, those of the caudal brachial plexus affect the hands, and those of the lumbosacral plexus affect the legs.

Plexus disorders (plexopathies) are usually due to physical compression or injury. In infants, traction during birth may cause plexopathy. In adults, the cause is usually trauma (typically, for the brachial plexus, a fall that forces the head away from the shoulder) or invasion by metastatic cancer (typically, breast or lung cancer for the brachial plexus and intestinal or GU tumors for the lumbosacral plexus). In patients receiving anticoagulants, a hematoma may compress the lumbosacral plexus. Neurofibromatosis occasionally involves a plexus. Other causes include postradiation fibrosis (eg, after radiation therapy for breast cancer) and diabetes.

Acute brachial neuritis (neuralgic amyotrophy) occurs primarily in men and typically in young adults, although it can occur at any age. Cause is unknown, but viral or immunologic inflammatory processes are suspected.

• Symptoms and Signs

Manifestations include extremity pain and motor or sensory deficits that do not correspond to an isolated nerve root. For acute brachial neuritis, symptoms include severe supraclavicular pain, weakness, and diminished reflexes, with minor sensory abnormalities in the distribution of the brachial plexus. Weakness and decreased reflexes usually occur as pain resolves. Severe weakness develops within 3 to 10 days, then typically regresses over the next few months. The most commonly affected muscles are the serratus anterior, other muscles innervated by the upper trunk, and muscles innervated by the anterior interosseus nerve (in the forearm).

• Diagnosis and Treatment

Diagnosis is suggested clinically. Electromyography and somatosensory evoked potentials should be done to clarify the anatomic distribution (including possible nerve root involvement). MRI of the appropriate plexus and adjacent spine is indicated for all nontraumatic plexopathies that are not a typical case of brachial neuritis.

Treatment is directed at the cause. Corticosteroids, although commonly prescribed, have no proven benefit. Surgery may be indicated for injuries, hematomas, and benign or metastatic tumors. Metastases should also be treated with radiation therapy, chemotherapy, or both. Glycemic control can benefit patients with a diabetic plexopathy.

SPINAL MUSCULAR ATROPHY

Spinal muscular atrophies include several types of hereditary disorders characterized by skeletal muscle wasting due to progressive degeneration of anterior horn cells in the spinal cord and of motor nuclei in the brain stem. Manifestations may begin in infancy or childhood. They vary by the specific type and may include hypotonia; hyporeflexia; difficulty sucking, swallowing, and breathing; unmet developmental milestones; and, in more severe types, very early death. Diagnosis is by genetic testing. Treatment is supportive.

Spinal muscular atrophies usually result from autosomal recessive mutations of a single gene locus on the short arm of chromosome 5, causing a homozygous deletion. There are 4 main types.

Type I spinal muscular atrophy (Werdnig-Hoffmann disease) is present in utero or becomes symptomatic by about age 6 mo. Affected infants have hypotonia (often notable at birth), hyporeflexia, tongue fasciculations, and pronounced difficulty sucking, swallowing, and eventually breathing. Death, usually due to respiratory failure, occurs within the 1st yr in 95% and by age 4 yr in all.

In type II (intermediate) spinal muscular atrophy, symptoms usually manifest between age 3 and 15 mo; < 25% of affected children learn to sit, and none walk or crawl. Children have flaccid muscle weakness and fasciculations, which may be hard to see in young children. Deep tendon reflexes are absent. Dysphagia may be present. The disorder is often fatal in early life, frequently resulting from respiratory complications. However, progression can stop spontaneously, leaving children with permanent, nonprogressive weakness and a high risk of severe scoliosis and its complications.

Type III spinal muscular atrophy (Wohlfart-Kugelberg-Welander disease) usually manifests between age 15 mo and 19 yr. Findings are similar to those of type I, but progression is slower and life expectancy is longer; some patients have a normal life span. Some familial cases are secondary to specific enzyme defects (eg, hexosaminidase deficiency). Symmetric weakness and wasting progress from proximal to distal areas and are most evident in the legs, beginning in the quadriceps and hip flexors. Later, arms are affected. Life expectancy depends on whether respiratory complications develop.

Type IV spinal muscular atrophy can be recessive, dominant, or X-linked, with adult onset (age 30 to 60 yr) and slow progression of primarily proximal muscle weakness and wasting. Differentiating this disorder from amyotrophic lateral sclerosis that involves predominantly lower motor neurons may be difficult.

• Diagnosis and Treatment

EMG and nerve conduction velocity studies should be done; muscles innervated by cranial nerves should be included. Conduction is normal, but affected muscles, which are often clinically unaffected, are denervated. Definitive diagnosis is by genetic testing, which detects the causative mutation in about 95% of patients. Muscle biopsy is done occasionally. Serum enzymes (eg, CK, aldolase) may be slightly increased. Amniocentesis is often diagnostic.

There is no specific treatment. Physical therapy, braces, and special appliances can benefit patients with static or slowly progressive disease by preventing scoliosis and contractures. Adaptive devices available through physical and occupational therapists may improve children’s independence and self-care by enabling them to feed themselves, write, or use a computer.

THORACIC OUTLET SYNDROME

Thoracic outlet compression syndromes are a group of poorly defined disorders characterized by pain and paresthesias in the hand, neck, shoulder, or arms. They appear to involve compression of the lower trunk of the brachial plexus (and perhaps the subclavian vessels) as it traverses the thoracic outlet below the scalene muscles and over the 1st rib before entering the axilla, but this involvement is unclear. Diagnostic techniques have not been established. Treatment includes physical therapy, analgesics, and, in severe cases, surgery.

Pathogenesis is often unknown but sometimes involves compression by a cervical rib, an abnormal 1st thoracic rib, abnormal insertion or position of the scalene muscles, or a malunited clavicle fracture. These syndromes are more common among women and usually develop between age 35 and 55.

Pain and paresthesias usually begin in the neck or shoulder and extend to the medial aspect of the arm and hand and sometimes the adjacent anterior chest wall. Many patients have mild to moderate sensory impairment in the C8 to T1 distribution on the painful side; a few have prominent vascular-autonomic changes in the hand (eg, cyanosis, swelling). In even fewer, the entire affected hand is weak. Rare complications include Raynaud’s phenomenon and distal gangrene.

• Diagnosis and Treatment

Diagnosis is suggested by distribution of symptoms. Various maneuvers are alleged to demonstrate compression of vascular structures (eg, by extending the brachial plexus), but sensitivity and specificity are not established. Auscultating bruits at the clavicle or apex of the axilla or finding a cervical rib by x-ray can aid in diagnosis. Although angiography may detect kinking or partial obstruction of axillary arteries or veins, neither finding is incontrovertible evidence of disease. Other testing is controversial, but evaluation as for brachial plexopathy (eg, electrodiagnostic tests, MRI) may be reasonable.

Most patients without objective neurologic deficits respond to physical therapy, NSAIDs, and low-dose tricyclic antidepressants. If cervical ribs or subclavian artery obstructions are identified, an experienced specialist should decide whether surgery is necessary. With few exceptions, surgery should be reserved for patients who have significant or progressive neurovascular deficits and who do not respond to conservative treatment.

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The author,

Professor Yasser Metwally