24-29: Polyneuropathies & Mononeuritis Multiplex

General Considerations

Diffuse polyneuropathies lead to a symmetric sensory, motor, or mixed deficit, often most marked distally. They include the hereditary, metabolic, and toxic disorders; idiopathic inflammatory polyneuropathy (Guillain-Barré syndrome); and the peripheral neuropathies that may occur as a nonmetastatic complication of malignant diseases. Involvement of motor fibers leads to flaccid weakness that is most marked distally; dysfunction of sensory fibers causes impaired sensory perception. Tendon reflexes are depressed or absent. Paresthesias, pain, and muscle tenderness may also occur. Multiple mononeuropathies (mononeuropathy multiplex) suggest a patchy multifocal disease process such as vasculopathy (eg, diabetes, arteritis), an infiltrative process (eg, leprosy, sarcoidosis), radiation damage, or an immunologic disorder (eg, brachial plexopathy).

Clinical Findings

The cause of polyneuropathy or mononeuritis multiplex is suggested by the history, mode of onset, and predominant clinical manifestations. Laboratory workup includes a complete blood count, serum protein electrophoresis with reflex to immunofixation or immunotyping, determination of plasma urea and electrolytes, liver biochemical tests, thyroid function tests, vitamin B₁₂ level, tests for rheumatoid factor and antinuclear antibody, HBsAg determination, a serologic test for syphilis, fasting blood glucose level and hemoglobin A_1c, urinary heavy metal levels, cerebrospinal fluid examination, and chest radiography. These tests should be ordered selectively, as guided by symptoms and signs. Measurement of nerve conduction velocity can confirm the peripheral nerve origin of symptoms and provides a means of following clinical changes, as well as indicate the likely disease process (ie, axonal or demyelinating neuropathy). Cutaneous nerve biopsy may help establish a precise diagnosis (eg, polyarteritis, amyloidosis). In about half of cases, no specific cause can be established; of these, slightly less than half are subsequently found to be familial.

Treatment

Treatment is of the underlying cause, when feasible, and is discussed below under the individual disorders. Physical therapy helps prevent contractures, and splints can maintain a weak extremity in a position of useful function. Anesthetic extremities must be protected from injury. To guard against burns, patients should check the temperature of water and hot surfaces with a portion of skin having normal sensation, measure water temperature with a thermometer, and use cold water for washing or lower the temperature setting of their hot-water heaters. Shoes should be examined frequently during the day for grit or foreign objects in order to prevent pressure lesions.

Patients with polyneuropathies or mononeuritis multiplex are subject to additional nerve injury at pressure points and should therefore avoid such behavior as leaning on elbows or sitting with crossed legs for lengthy periods.

Neuropathic, burning pain may respond to simple analgesics, such as aspirin or nonsteroidal anti-inflammatory agents, and to gabapentin (300 mg orally three times daily, titrated up to a maximum of 1200 mg orally three times daily as necessary) or pregabalin (50–100 mg orally three times daily). Duloxetine (60 mg orally once or twice daily), venlafaxine (start 37.5 mg orally twice daily, and titrate up to 75 mg orally two to three times daily), or tricyclic antidepressants (eg, amitriptyline 10–150 mg orally at bedtime daily) may be helpful, especially in painful diabetic neuropathy. Medical cannabis may provide some relief, but long-term safety data are lacking. The use of a frame or cradle to reduce contact with bedclothes may be helpful. Many patients experience episodic stabbing pains, which may respond to gabapentin, pregabalin, carbamazepine (start 100 mg orally twice daily, and titrate up to 400 mg orally twice daily), or tricyclic antidepressants. Opioids may be necessary for severe hyperpathia or pain induced by minimal stimuli, but their use generally should be avoided.

Symptoms of autonomic dysfunction are occasionally troublesome. Treatment of postural hypotension is discussed earlier in this chapter. Erectile dysfunction can be treated with phosphodiesterase inhibitors; a flaccid neuropathic bladder may respond to parasympathomimetic medications such as bethanechol chloride, 10–50 mg three or four times daily.

A. Charcot-Marie-Tooth Disease (HMSN Type I, II)

There are several distinct varieties of Charcot-Marie-Tooth disease, usually with an autosomal dominant mode of inheritance, but occasional cases occur on a sporadic, recessive, or X-linked basis. Clinical presentation may be with foot deformities or gait disturbances in childhood or early adult life. Slow progression leads to the typical features of polyneuropathy, with distal weakness and wasting that begin in the legs, a variable amount of distal sensory loss, and depressed or absent tendon reflexes. Tremor is a conspicuous feature in some instances. Hereditary motor and sensory neuropathy (HMSN) type I is characterized by demyelination on electrodiagnostic studies and is usually caused by mutations in the peripheral myelin protein 22 or myelin protein zero gene. In HMSN type II, electrodiagnostic studies show axonal loss rather than demyelination; one-third of cases are due to mutations in the gene mitofusin 2.

A similar disorder may occur in patients with progressive distal spinal muscular atrophies, but there is no sensory loss; electrophysiologic investigation reveals that motor conduction velocity is normal or only slightly reduced, and nerve action potentials are normal.

B. Dejerine-Sottas Disease (HMSN Type III)

The disorder may occur on a sporadic, autosomal dominant or, less commonly, autosomal recessive basis. Onset in infancy or childhood leads to a progressive motor and sensory polyneuropathy with weakness, ataxia, sensory loss, and depressed or absent tendon reflexes. The peripheral nerves may be palpably enlarged and are characterized pathologically by segmental demyelination, Schwann cell hyperplasia, and thin myelin sheaths. Electrophysiologically, there is a slowing of conduction, and sensory action potentials may be unrecordable.

C. Friedreich Ataxia

This disorder, the only known autosomal recessive trinucleotide repeat disease, is caused by expansion of a poly-GAA locus in the gene for frataxin on chromosome 9, leading to symptoms in childhood or early adult life. The gait becomes ataxic, the hands become clumsy, and other signs of cerebellar dysfunction develop accompanied by weakness of the legs and extensor plantar responses. Involvement of peripheral sensory fibers leads to sensory disturbances in the limbs and depressed tendon reflexes. There is bilateral pes cavus. Pathologically, there is a marked loss of cells in the posterior root ganglia and degeneration of peripheral sensory fibers. In the central nervous system, changes are conspicuous in the posterior and lateral columns of the cord. Electrophysiologically, conduction velocity in motor fibers is normal or only mildly reduced, but sensory action potentials are small or absent. Cardiac disease is the most common cause of death.

In the differential diagnosis for Friedreich ataxia are other spinocerebellar ataxias, a growing group of at least 30 inherited disorders, each involving a different identified gene. These heterogeneous disorders, which frequently (but not exclusively) exhibit an autosomal dominant inheritance pattern and poly-CAG expansion of the affected gene, typically cause cerebellar ataxia and varying combinations of other symptoms (such as peripheral neuropathy, ophthalmoparesis, dysarthria, and pyramidal and extrapyramidal signs).

D. Refsum Disease (HMSN Type IV)

This autosomal recessive disorder is due to a disturbance in phytanic acid metabolism. Pigmentary retinal degeneration is accompanied by progressive sensorimotor polyneuropathy and cerebellar signs. Auditory dysfunction, cardiomyopathy, and cutaneous manifestations may also occur. Motor and sensory conduction velocities are reduced, often markedly, and there may be electromyographic evidence of denervation in affected muscles. Dietary restriction of phytanic acid and its precursors may be helpful therapeutically. Plasmapheresis to reduce stored phytanic acid may help at the initiation of treatment.

E. Porphyria

Peripheral nerve involvement may occur during acute attacks in both variegate porphyria and acute intermittent porphyria. Motor symptoms usually occur first, and weakness is often most marked proximally and in the upper limbs rather than the lower. Sensory symptoms and signs may be proximal or distal in distribution. Autonomic involvement is sometimes pronounced. The electrophysiologic findings are in keeping with the results of neuropathologic studies suggesting that the neuropathy is axonal in type (see Chapter 40).

F. Familial Amyloid Polyneuropathy

Sensory and autonomic symptoms are especially conspicuous, whereas distal wasting and weakness occur later. The polyneuropathy is axonal and likely results from amyloid deposition within the peripheral nerves due to mutations in the genes encoding transthyretin, apolipoprotein A1, or gelsolin. Transthyretin amyloidosis is the most common; is associated with cardiomyopathy, nephropathy, leptomeningeal involvement, and vitreous opacity; and is treatable with liver transplantation, the small interfering ribonucleic acid patisiran (0.3 mg/kg up to 30 mg intravenously once every 3 weeks), or the antisense oligonucleotide inotersen (284 mg subcutaneously weekly). Tafamidis helps transthyretin amyloid cardiomyopathy and may slow the progression of the neuropathy.

A. Diabetes Mellitus

In this disorder, involvement of the peripheral nervous system may lead to symmetric sensory or mixed polyneuropathy, asymmetric motor radiculoneuropathy or plexopathy (diabetic amyotrophy), thoracoabdominal radiculopathy, autonomic neuropathy, or isolated lesions of individual nerves. These may occur singly or in any combination and are discussed in Chapter 27.

B. Uremia

Uremia may lead to a symmetric sensorimotor polyneuropathy that tends to affect the lower limbs more than the upper limbs and is more marked distally than proximally (see Chapter 22). The diagnosis can be confirmed electrophysiologically because motor and sensory conduction velocity is moderately reduced. The neuropathy improves both clinically and electrophysiologically with kidney transplantation and to a lesser extent with chronic dialysis.

C. Alcoholism and Nutritional Deficiency

Many patients with alcoholism have an axonal distal sensorimotor polyneuropathy that is frequently accompanied by painful cramps, muscle tenderness, and painful paresthesias and is often more marked in the legs than in the arms. Symptoms of autonomic dysfunction may also be conspicuous. Motor and sensory conduction velocity may be slightly reduced, even in subclinical cases, but gross slowing of conduction is uncommon. Treatment is similar to diabetic polyneuropathy but also includes abstinence from alcohol. A similar distal sensorimotor polyneuropathy is a well-recognized feature of beriberi (thiamine deficiency). In vitamin B₁₂ deficiency, distal sensory polyneuropathy may develop but is usually overshadowed by central nervous system manifestations (eg, myelopathy, optic neuropathy, or intellectual changes).

D. Paraproteinemias

A symmetric sensorimotor polyneuropathy that is gradual in onset, progressive in course, and often accompanied by pain and dysesthesias in the limbs may occur in patients (especially men) with plasma cell myeloma (formerly multiple myeloma). The neuropathy is of the axonal type in classic lytic myeloma, but segmental demyelination (primary or secondary) and axonal loss may occur in sclerotic myeloma and lead to predominantly motor clinical manifestations. Both demyelinating and axonal neuropathies are also observed in patients with paraproteinemias without myeloma. A small fraction will develop myeloma if serially followed. The demyelinating neuropathy in these patients may be due to the monoclonal proteins reacting to a component of the nerve myelin. The neuropathy of classic plasma cell myeloma is poorly responsive to therapy. The polyneuropathy of benign monoclonal gammopathy may respond to immunosuppressant medications and plasmapheresis.

Polyneuropathy may also occur in association with monoclonal gammopathy of unknown significance, macroglobulinemia, and cryoglobulinemia and sometimes responds to plasmapheresis. Many patients with an IgM M-protein will have antibodies to myelin-associated glycoprotein (MAG); these patients may respond to treatment with rituximab. Entrapment neuropathy, such as carpal tunnel syndrome, is more common than polyneuropathy in patients with (nonhereditary) generalized amyloidosis.

A. Leprosy

Leprosy is an important cause of peripheral neuropathy in certain parts of the world. Sensory disturbances are mainly due to involvement of intracutaneous nerves. In tuberculoid leprosy, they develop at the same time and in the same distribution as the nerve; trunks lying beneath the lesion are also involved. In lepromatous leprosy, there is more extensive sensory loss, and this develops earlier and to a greater extent in the coolest regions of the body, such as the dorsal surfaces of the hands and feet, where the bacilli proliferate most actively. Motor deficits result from involvement of superficial nerves where their temperature is lowest, eg, the ulnar nerve in the region proximal to the olecranon groove, the median nerve as it emerges from beneath the forearm flexor muscle to run toward the carpal tunnel, the peroneal nerve at the head of the fibula, and the posterior tibial nerve in the lower part of the leg; patchy facial muscular weakness may also occur owing to involvement of the superficial branches of the seventh cranial nerve.

Motor disturbances in leprosy are suggestive of multiple mononeuropathy, whereas sensory changes resemble those of distal polyneuropathy. Examination, however, relates the distribution of sensory deficits to the temperature of the tissues; in the legs, for example, sparing frequently occurs between the toes and in the popliteal fossae, where the temperature is higher. Treatment is with antileprotic agents (see Chapter 33).

B. AIDS

A variety of neuropathies occur in HIV-infected patients (see Chapter 31). Patients with AIDS may develop a chronic symmetric sensorimotor axonal polyneuropathy associated usually with no abnormal cerebrospinal fluid findings. Treatment is symptomatic. AIDS patients may also develop progressive polyradiculopathy or radiculomyelopathy that leads to leg weakness and urinary retention; sensory loss is less conspicuous than in polyneuropathy. The cerebrospinal fluid may show mononuclear pleocytosis and increased protein and low glucose concentrations. Cytomegalovirus is responsible in at least some cases. The prognosis is generally poor, but some patients respond to intravenous ganciclovir (2.5 mg/kg every 8 hours for 10 days, then 7.5 mg/kg daily 5 days per week).

An inflammatory demyelinating polyradiculoneuropathy sometimes occurs in HIV-seropositive patients without AIDS and may follow an acute, subacute, or chronic course. Weakness is usually more conspicuous distally than proximally and tends to overshadow sensory symptoms. Tendon reflexes are depressed or absent. The cerebrospinal fluid shows an increased cell count and protein concentration. Treatment with plasmapheresis has helped some patients. Spontaneous improvement may also occur. Seropositive patients without AIDS may also develop a mononeuropathy multiplex that sometimes responds to treatment with plasmapheresis.

C. Lyme Borreliosis

The neurologic manifestations of Lyme disease include meningitis, meningoencephalitis, polyradiculoneuropathy, mononeuropathy multiplex, and cranial neuropathy. Serologic tests establish the underlying disorder. Lyme disease and its treatment are discussed in depth in Chapter 34.

D. Sarcoidosis

Cranial nerve palsies (especially facial palsy), multiple mononeuropathy and, less commonly, symmetric polyneuropathy may all occur, the latter sometimes preferentially affecting either motor or sensory fibers. Improvement may occur with use of corticosteroids.

E. Polyarteritis

Involvement of the vasa nervorum by the vasculitic process may result in infarction of the nerve. Clinically, one encounters an asymmetric sensorimotor polyneuropathy (mononeuritis multiplex) that pursues a waxing and waning course. Corticosteroids and cytotoxic agents—especially cyclophosphamide—may be of benefit in severe cases (Chapter 20).

F. Rheumatoid Arthritis

Compressive or entrapment neuropathies, ischemic neuropathies, mild distal sensory polyneuropathy, and severe progressive sensorimotor polyneuropathy can occur in rheumatoid arthritis.

Patients in intensive care units with sepsis and multiorgan failure sometimes develop polyneuropathies. This may be manifested initially by unexpected difficulty in weaning patients from a mechanical ventilator and in more advanced cases by wasting and weakness of the extremities and loss of tendon reflexes. Sensory abnormalities are relatively inconspicuous. The neuropathy is axonal in type. Its pathogenesis is obscure, and treatment is supportive. The prognosis is good provided patients recover from the underlying critical illness.

Axonal polyneuropathy may follow exposure to industrial agents or pesticides such as acrylamide, organophosphorus compounds, hexacarbon solvents, methyl bromide, and carbon disulfide; metals such as arsenic, thallium, mercury, and lead; and medications such as phenytoin, amiodarone, perhexiline, isoniazid, nitrofurantoin, vincristine, and pyridoxine in high doses. Detailed occupational, environmental, and medical histories and recognition of clusters of cases are important in suggesting the diagnosis. Treatment is by preventing further exposure to the causal agent. Isoniazid neuropathy is prevented by pyridoxine supplementation.

Diphtheritic neuropathy results from a neurotoxin released by the causative organism and is common in many areas. Palatal weakness may develop 2–4 weeks after infection of the throat, and infection of the skin may similarly be followed by focal weakness of neighboring muscles. Disturbances of accommodation may occur about 4–5 weeks after infection and distal sensorimotor demyelinating polyneuropathy after 1–3 months.

A variety of neuropathies have been associated with nonmetastatic complications of malignancy and were discussed earlier.

General Considerations

This acute or subacute polyradiculoneuropathy sometimes follows infective illness, inoculations, or surgical procedures. There is an association with preceding Campylobacter jejuni enteritis. The disorder probably has an immunologic basis, but the precise mechanism is unclear.

Clinical Findings

A. Symptoms and Signs

The main complaint is of weakness that varies widely in severity in different patients and often has a proximal emphasis and symmetric distribution. It usually begins in the legs, spreading to a variable extent but frequently involving the arms and often one or both sides of the face. The muscles of respiration or deglutition may also be affected. Sensory symptoms are usually less conspicuous than motor ones, but distal paresthesias and dysesthesias are common, and neuropathic or radicular pain is present in many patients. Autonomic disturbances are also common, may be severe, and are sometimes life-threatening; they include tachycardia, cardiac irregularities, hypotension or hypertension, facial flushing, abnormalities of sweating, pulmonary dysfunction, and impaired sphincter control. The axonal subtypes of the syndrome (acute motor axonal neuropathy [AMAN] and acute motor and sensory axonal neuropathy [AMSAN]) are caused by antibodies to gangliosides on the axon membrane, including anti-GM1, anti-GM1b, anti-GD1a, anti-GD1b, and (in AMAN) anti-GalNAC-GD1a antibodies. The Miller Fisher syndrome, another subtype, is characterized by the clinical triad of ophthalmoplegia, ataxia, and areflexia, and is associated with anti-GQ1b antibodies.

B. Laboratory Findings

The cerebrospinal fluid characteristically contains a high protein concentration with a normal cell count, but these changes may take up to 2 weeks to develop; white blood cell counts greater than 50 cells/mcL should prompt consideration of alternative diagnoses. Electrophysiologic studies may reveal marked abnormalities, which do not necessarily parallel the clinical disorder in their temporal course.

Differential Diagnosis

When the diagnosis is made, the history and appropriate laboratory studies should exclude the possibility of porphyric, diphtheritic, or toxic (heavy metal, hexacarbon, organophosphate) neuropathies, and of HIV infection. The temporal course excludes other peripheral neuropathies. Poliomyelitis, botulism, and tick paralysis must also be considered as they cause weakness of acute onset. The presence of pyramidal signs, a markedly asymmetric motor deficit, a sharp sensory level, or early sphincter involvement should suggest a focal cord lesion.

Treatment

Treatment with prednisone is ineffective and may prolong recovery time. Plasmapheresis is of value; it is best performed within the first few days of illness and is particularly useful for clinically severe or rapidly progressive cases or those with ventilatory impairment. IVIG (400 mg/kg/day for 5 days) is equally helpful. Patients should be admitted to intensive care units if their forced vital capacity is declining, and intubation is considered if the forced vital capacity reaches 15 mL/kg, the maximum inspiratory pressure reaches –30 mm Hg, or dyspnea becomes evident. Declining oxygen saturation is a late indicator of neuromuscular respiratory failure. Respiratory toilet and chest physical therapy help prevent atelectasis. Marked hypotension may respond to volume replacement or pressor agents. Thromboprophylaxis is important.

Prognosis

Most patients eventually make a good recovery, but this may take many months, and about 20% of patients are left with persisting disability. Approximately 3% of patients with acute idiopathic polyneuropathy have one or more clinically similar relapses, sometimes several years after the initial illness.

When to Refer

All patients should be referred.

When to Admit

All patients should be hospitalized until their condition is stable and there is no respiratory compromise.

Chronic inflammatory demyelinating polyneuropathy, an acquired immunologically mediated disorder, is clinically similar to Guillain-Barré syndrome except that it has a relapsing or steadily progressive course over months or years and that autonomic dysfunction is generally less common. It may present as an exclusively motor disorder or with a mixed sensorimotor disturbance. In the relapsing form, partial recovery may occur after some relapses, but in other instances there is no recovery between exacerbations. Although remission may occur spontaneously with time, the disorder frequently follows a progressive downhill course leading to severe functional disability.

Electrodiagnostic studies show marked slowing of motor and sensory conduction, and focal conduction block. Signs of partial denervation may also be present owing to secondary axonal degeneration. Nerve biopsy may show chronic perivascular inflammatory infiltrates in the endoneurium and epineurium, without accompanying evidence of vasculitis. However, a normal nerve biopsy result or the presence of nonspecific abnormalities does not exclude the diagnosis.

Corticosteroids may arrest or reverse the downhill course. Treatment is usually begun with prednisone, 60–80 mg orally daily, continued for 2–3 months or until a definite response has occurred. If no response has occurred despite 3 months of treatment, a higher dose may be tried. In responsive cases, the dose is gradually tapered, but most patients become corticosteroid-dependent, often requiring prednisone, 20 mg daily on alternate days, on a long-term basis. IVIG can be used in place of, or in addition to corticosteroids, and is best used as the initial treatment in pure motor syndromes (2 g/kg over 2–5 days followed by 1 g/kg every 3 weeks); a weekly regimen of 0.2–0.4 g/kg of a 20% subcutaneous immunoglobulin solution is an effective alternative but has not been compared directly to corticosteroids or IVIG. When both IVIG and corticosteroids are ineffective, plasma exchange may be worthwhile. Consistent with the notion that the condition is antibody mediated, rituximab has shown promise. Immunosuppressant or immunomodulatory medications (such as azathioprine) may be added when the response to other measures is unsatisfactory or to enable maintenance doses of corticosteroids to be lowered. Symptomatic treatment is also important.