3489Peripheral Neuropathy CHAPTER 446

sudomotor axon reflex testing. Sensory and motor NCS generally

demonstrate features described above with DSPN.

Diabetic Radiculoplexus Neuropathy (Diabetic Amyotrophy

or Bruns-Garland Syndrome) Diabetic radiculoplexus neuropathy is the presenting manifestation of DM in approximately one-third

of patients. Typically, patients present with severe pain in the low

back, hip, and thigh in one leg. Rarely, the diabetic polyradiculoneuropathy begins in both legs at the same time (Pattern 4, Table 446-2).

Atrophy and weakness of proximal and distal muscles in the affected

leg become apparent within a few days or weeks. The neuropathy

is often accompanied or heralded by severe weight loss. Weakness

usually progresses over several weeks or months but can continue to

progress for 18 months or more. Subsequently, there is slow recovery,

but many are left with residual weakness, sensory loss, and pain. In

contrast to the more typical lumbosacral radiculoplexus neuropathy,

some patients develop thoracic radiculopathy or, even less commonly, a cervical polyradiculoneuropathy. CSF protein is usually

elevated, while the cell count is normal. ESR is often increased. EDx

reveals evidence of active denervation in affected proximal and distal

muscles in the affected limbs and in paraspinal muscles. Nerve biopsies may demonstrate axonal degeneration along with perivascular

inflammation. Patients with severe pain are sometimes treated in the

acute period with glucocorticoids, although a randomized controlled

trial has yet to be performed, and the natural history of this neuropathy

is gradual improvement.

Diabetic Mononeuropathies or Multiple Mononeuropathies

The most common mononeuropathies are median neuropathy at the

wrist and ulnar neuropathy at the elbow, but peroneal neuropathy

at the fibular head and sciatic, lateral femoral, cutaneous, or cranial

neuropathies also occur (Pattern 3, Table 446-2). In regard to cranial

mononeuropathies, seventh nerve palsies are relatively common but

may have other, nondiabetic etiologies. In diabetics, a third nerve

palsy is most common, followed by sixth nerve and, less frequently,

fourth nerve palsies. Diabetic third nerve palsies are characteristically

pupil-sparing (Chap. 32).

■ HYPOTHYROIDISM

Hypothyroidism is more commonly associated with a proximal myopathy, but some patients develop a neuropathy, most typically CTS.

Rarely, a generalized sensory polyneuropathy characterized by painful

paresthesias and numbness in both the legs and hands can occur. Treatment is correction of the hypothyroidism.

■ SJÖGREN’S SYNDROME

Sjögren’s syndrome, characterized by the sicca complex of xerophthalmia, xerostomia, and dryness of other mucous membranes,

can be complicated by neuropathy (Chap. 361). Most common is

a length-dependent axonal sensorimotor neuropathy characterized mainly by sensory loss in the distal extremities (Pattern 2,

Table 446-2). A pure small-fiber neuropathy or a cranial neuropathy, particularly involving the trigeminal nerve, can also be seen.

Sjögren’s syndrome is also associated with sensory neuronopathy/

ganglionopathy. Patients with sensory ganglionopathies develop

progressive numbness and tingling of the limbs, trunk, and face in a

non-length-dependent manner such that symptoms can involve the

face or arms more than the legs. The onset can be acute or insidious.

Sensory examination demonstrates severe vibratory and proprioceptive

loss leading to sensory ataxia.

Patients with neuropathy due to Sjögren’s syndrome may have

ANAs, SS-A/Ro, and SS-B/La antibodies in the serum, but most do not.

NCS demonstrate reduced amplitudes of sensory studies in the affected

limbs. Nerve biopsy demonstrates axonal degeneration. Nonspecific

perivascular inflammation may be present, but only rarely is there

necrotizing vasculitis. There is no specific treatment for neuropathies

related to Sjögren’s syndrome. When vasculitis is suspected, immunosuppressive agents may be beneficial. Occasionally, the sensory

neuronopathy/ganglionopathy stabilizes or improves with immunotherapy, such as intravenous immunoglobulin.

■ RHEUMATOID ARTHRITIS

Peripheral neuropathy occurs in at least 50% of patients with rheumatoid arthritis (RA) and may be vasculitic in nature (Chap. 358).

Vasculitic neuropathy can present with a mononeuropathy multiplex

(Pattern 3, Table 446-2), a generalized symmetric pattern of involvement (Pattern 2, Table 446-2), or a combination of these patterns

(Chap. 363). Neuropathies may also result from drugs used to treat RA

(e.g., tumor necrosis blockers, leflunomide). Nerve biopsy often reveals

thickening of the epineurial and endoneurial blood vessels as well as

perivascular inflammation or vasculitis, with transmural inflammatory

cell infiltration and fibrinoid necrosis of vessel walls. The neuropathy is

usually responsive to immunomodulating therapies.

■ SYSTEMIC LUPUS ERYTHEMATOSUS

Between 2 and 27% of individuals with SLE develop a peripheral

neuropathy (Chap. 356). Affected patients typically present with a

slowly progressive sensory loss beginning in the feet. Some patients

develop burning pain and paresthesias with normal reflexes, and

NCS suggest a pure small-fiber neuropathy (Pattern 2, Table 446-2).

Less common are multiple mononeuropathies presumably secondary to necrotizing vasculitis (Pattern 3, Table 446-2). Rarely, a generalized sensorimotor polyneuropathy meeting clinical, laboratory,

electrophysiologic, and histologic criteria for either GBS or CIDP

may occur. Immunosuppressive therapy may be beneficial in SLE

patients with neuropathy due to vasculitis. Immunosuppressive

agents are less likely to be effective in patients with a generalized

sensory or sensorimotor polyneuropathy without evidence of vasculitis. Patients with a GBS or CIDP-like neuropathy should be treated

accordingly (Chap. 447).

■ SYSTEMIC SCLEROSIS (SCLERODERMA)

A distal symmetric, mainly sensory polyneuropathy complicates

5–67% of scleroderma cases (Pattern 2, Table 446-2) (Chap. 360).

Cranial mononeuropathies can also develop, most commonly of the

trigeminal nerve, producing numbness and dysesthesias in the face.

Multiple mononeuropathies also occur (Pattern 3, Table 446-2). The

EDx and histologic features of nerve biopsy are those of an axonal

sensory greater than motor polyneuropathy.

■ MIXED CONNECTIVE TISSUE DISEASE (MCTD)

A mild distal axonal sensorimotor polyneuropathy occurs in ~10% of

patients with MCTD.

■ SARCOIDOSIS

The peripheral nervous system or CNS is involved in ~5% of patients

with sarcoidosis (Chap. 367). The most common cranial nerve involved

is the seventh nerve, which can be affected bilaterally. Some patients

develop radiculopathy or polyradiculopathy (Pattern 4, Table 446-2).

With a generalized root involvement, the clinical presentation can

mimic GBS or CIDP. Patients can also present with multiple mononeuropathies (Pattern 3, Table 446-2) or a generalized, slowly progressive,

sensory greater than motor polyneuropathy (Pattern 2, Table 446-2).

Some have features of a pure small-fiber neuropathy. EDx reveals an

axonal neuropathy. Nerve biopsy can reveal noncaseating granulomas

infiltrating the endoneurium, perineurium, or epineurium along with

lymphocytic necrotizing angiitis. Neurosarcoidosis may respond to

treatment with glucocorticoids or other immunosuppressive agents.

■ HYPEREOSINOPHILIC SYNDROME

Hypereosinophilic syndrome is characterized by eosinophilia associated with various skin, cardiac, hematologic, and neurologic abnormalities. A generalized peripheral neuropathy or a mononeuropathy

multiplex occurs in 6–14% of patients (Pattern 2, Table 446-2).

■ CELIAC DISEASE (GLUTEN-INDUCED ENTEROPATHY OR NONTROPICAL SPRUE)

Neurologic complications, particularly ataxia and peripheral neuropathy, are estimated to occur in 10% of patients with celiac disease

(Chap. 325). A generalized sensorimotor polyneuropathy, pure motor

neuropathy, multiple mononeuropathies, autonomic neuropathy,

3490 PART 13 Neurologic Disorders

small-fiber neuropathy, and neuromyotonia have all been reported

in association with celiac disease or antigliadin/antiendomysial antibodies (Patterns 2, 3, and 9; Table 446-2). Nerve biopsy may reveal a

loss of large myelinated fibers. The neuropathy may be secondary to

malabsorption of vitamins B12 and E. However, some patients have no

appreciable vitamin deficiencies. The pathogenic basis for the neuropathy in these patients is unclear but may be autoimmune in etiology.

The neuropathy does not appear to respond to a gluten-free diet. In

patients with vitamin B12 or vitamin E deficiency, replacement therapy

may improve or stabilize the neuropathy.

■ INFLAMMATORY BOWEL DISEASE

Ulcerative colitis and Crohn’s disease may be complicated by GBS,

CIDP, generalized axonal sensory or sensorimotor polyneuropathy, small-fiber neuropathy, or mononeuropathy (Patterns 2 and 3,

Table 446-2) (Chap. 326). These neuropathies may be autoimmune,

nutritional (e.g., vitamin B12 deficiency), treatment related (e.g., metronidazole), or idiopathic in nature. An acute neuropathy with demyelination resembling GBS, CIDP, or multifocal motor neuropathy may

occur in patients treated with tumor necrosis factor α blockers.

■ UREMIC NEUROPATHY

Approximately 60% of patients with renal failure develop a polyneuropathy characterized by length-dependent numbness, tingling, allodynia, and mild distal weakness (Pattern 2, Table 446-2). Rarely, a

rapidly progressive weakness and sensory loss very similar to GBS can

occur that improves with an increase in the intensity of renal dialysis or

with transplantation (Pattern 1, Table 446-2). Mononeuropathies can

also occur, the most common of which is CTS. Ischemic monomelic

neuropathy (see below) can complicate arteriovenous shunts created

in the arm for dialysis (Pattern 3, Table 446-2). EDx in uremic patients

reveals features of a length-dependent, primarily axonal, sensorimotor

polyneuropathy. Sural nerve biopsies demonstrate a loss of nerve fibers

(particularly large myelinated nerve fibers), active axonal degeneration, and segmental and paranodal demyelination. The sensorimotor

polyneuropathy can be stabilized by hemodialysis and improved with

successful renal transplantation.

■ CHRONIC LIVER DISEASE

A generalized sensorimotor neuropathy characterized by numbness,

tingling, and minor weakness in the distal aspects of primarily the

lower limbs commonly occurs in patients with chronic liver failure.

EDx studies are consistent with a sensory greater than motor axonopathy. Occasionally patients with severe liver disease develop a combined

neuropathy and myopathy. Sural nerve biopsy reveals both segmental

demyelination and axonal loss. It is not known if hepatic failure in isolation can cause peripheral neuropathy, as the majority of patients have

liver disease secondary to other disorders, such as alcoholism or viral

hepatitis, which can also cause neuropathy.

■ CRITICAL ILLNESS POLYNEUROPATHY

The most common causes of acute generalized weakness leading to

admission to a medical intensive care unit (ICU) are GBS and myasthenia gravis (Pattern 1, Table 446-2) (Chaps. 447 and 448). However,

weakness developing in critically ill patients while in the ICU is usually

caused by critical illness polyneuropathy (CIP) or critical illness myopathy (CIM) or, much less commonly, by prolonged neuromuscular

blockade. From a clinical and EDx standpoint, it can be quite difficult

to distinguish these disorders. Most specialists believe that CIM is

more common. Both CIM and CIP develop as a complication of sepsis

and multiple organ failure. They usually present as an inability to wean

a patient from a ventilator. A coexisting encephalopathy may limit the

neurologic examination, in particular the sensory examination. Muscle

stretch reflexes are absent or reduced.

Serum creatine kinase (CK) is usually normal; an elevated serum

CK would point to CIM as opposed to CIP. NCS reveal absent or

markedly reduced amplitudes of motor and sensory studies in CIP,

whereas sensory studies are relatively preserved in CIM. Needle EMG

usually reveals profuse positive sharp waves and fibrillation potentials,

and it is not unusual in patients with severe weakness to be unable to

recruit motor unit action potentials. The pathogenic basis of CIP is

not known. Perhaps circulating toxins and metabolic abnormalities

associated with sepsis and multiorgan failure impair axonal transport

or mitochondrial function, leading to axonal degeneration.

■ LEPROSY (HANSEN’S DISEASE)

Leprosy, caused by the acid-fast bacteria Mycobacterium leprae, is

the most common cause of peripheral neuropathy in Southeast Asia,

Africa, and South America (Chap. 179). Clinical manifestations range

from tuberculoid leprosy at one end of the spectrum to lepromatous

leprosy at the other end, with borderline leprosy in between. Neuropathies are most common in patients with borderline leprosy. Superficial

cutaneous nerves of the ears and distal limbs are commonly affected.

Mononeuropathies, multiple mononeuropathies, or a slowly progressive symmetric sensorimotor polyneuropathy may develop (Patterns 2

and 3, Table 446-2). Sensory NCS are usually absent in the lower limb

and are reduced in amplitude in the arms. Motor NCS may demonstrate reduced amplitudes in affected nerves but occasionally can reveal

demyelinating features. Leprosy is usually diagnosed by skin lesion

biopsy. Nerve biopsy can also be diagnostic, particularly when there

are no apparent skin lesions. The tuberculoid form is characterized

by granulomas, and bacilli are not seen. In contrast, with lepromatous

leprosy, large numbers of infiltrating bacilli, TH2 lymphocytes, and

organism-laden, foamy macrophages with minimal granulomatous

infiltration are evident. The bacilli are best appreciated using the Fite

stain, where they can be seen as red-staining rods often in clusters free

in the endoneurium, within macrophages, or within Schwann cells.

Patients are generally treated with multiple drugs: dapsone, rifampin,

and clofazimine. Other medications that are used include thalidomide,

pefloxacin, ofloxacin, sparfloxacin, minocycline, and clarithromycin.

Patients are generally treated for 2 years. Treatment is sometimes complicated by the so-called reversal reaction, particularly in borderline

leprosy. The reversal reaction can occur at any time during treatment

and develops because of a shift to the tuberculoid end of the spectrum,

with an increase in cellular immunity during treatment. The cellular

response is upregulated as evidenced by an increased release of tumor

necrosis factor α, interferon γ, and interleukin 2, with new granuloma

formation. This can result in an exacerbation of the rash and the neuropathy as well as in appearance of new lesions. High-dose glucocorticoids blunt this adverse reaction and may be used prophylactically at

treatment onset in high-risk patients. Erythema nodosum leprosum

(ENL) is also treated with glucocorticoids or thalidomide.

■ LYME DISEASE

Lyme disease is caused by infection with Borrelia burgdorferi, a spirochete usually transmitted by the deer tick Ixodes dammini (Chap. 186).

Neurologic complications may develop during the second and third

stages of infection. Facial neuropathy is most common and is bilateral

in about half of cases, which is rare for idiopathic Bell’s palsy. Involvement of nerves is frequently asymmetric. Some patients present with a

polyradiculoneuropathy or multiple mononeuropathies (Pattern 3 or 4,

Table 446-2). EDx is suggestive of a primary axonopathy. Nerve biopsies can reveal axonal degeneration with perivascular inflammation.

Treatment is with antibiotics.

■ DIPHTHERITIC NEUROPATHY

Diphtheria is caused by the bacteria Corynebacterium diphtheriae

(Chap. 150). Infected individuals present with flulike symptoms of

generalized myalgias, headache, fatigue, low-grade fever, and irritability within a week to 10 days of the exposure. About 20–70% of patients

develop a peripheral neuropathy caused by a toxin released by the

bacteria. Three to 4 weeks after infection, patients may note decreased

sensation in their throat and begin to develop dysphagia, dysarthria,

hoarseness, and blurred vision due to impaired accommodation. A

generalized polyneuropathy may manifest 2 or 3 months following the

initial infection, characterized by numbness, paresthesias, and weakness of the arms and legs and occasionally ventilatory failure (Pattern 1,

Table 446-2). CSF protein can be elevated with or without lymphocytic

3491Peripheral Neuropathy CHAPTER 446

pleocytosis. EDx suggests a diffuse axonal sensorimotor polyneuropathy. Antitoxin and antibiotics should be given within 48 h of symptom

onset. Although early treatment reduces the incidence and severity of

some complications (i.e., cardiomyopathy), it does not appear to alter

the natural history of the associated peripheral neuropathy. The neuropathy usually resolves after several months.

■ COVID-19

GBS (Chap. 447) has been reported in the setting of acute COVID-19

infection.

■ HUMAN IMMUNODEFICIENCY VIRUS

HIV infection can result in a variety of neurologic complications,

including peripheral neuropathies (Chap. 202). Approximately 20%

of HIV-infected individuals develop a neuropathy as a direct result of

the virus itself or as a result of other associated viral infections (e.g.,

CMV) or neurotoxicity secondary to antiviral medications (see below).

The major presentations of peripheral neuropathy associated with

HIV infection include (1) distal symmetric polyneuropathy (DSP),

(2) inflammatory demyelinating polyneuropathy (including both GBS

and CIDP), (3) multiple mononeuropathies (e.g., vasculitis, CMVrelated), (4) polyradiculopathy (usually CMV-related), (5) autonomic

neuropathy, and (6) sensory ganglionitis.

HIV-Related Distal Symmetric Polyneuropathy DSP is the

most common form of peripheral neuropathy associated with HIV

infection and usually is seen in patients with AIDS. It is characterized

by numbness and painful paresthesias involving the distal extremities

(Pattern 2, Table 446-2). The pathogenic basis for DSP is unknown but

is not due to actual infection of the peripheral nerves. The neuropathy

may be immune mediated, perhaps caused by the release of cytokines

from surrounding inflammatory cells. Vitamin B12 deficiency may

contribute in some instances but is not a major cause of most cases

of DSP. Older antiretroviral agents (e.g., dideoxycytidine, dideoxyinosine, stavudine) are also neurotoxic and can cause a painful sensory

neuropathy.

HIV-Related Inflammatory Demyelinating Polyradiculoneu- ropathy Both acute inflammatory demyelinating polyneuropathy

(AIDP) and CIDP can occur as a complication of HIV infection

(Pattern 1, Table 446-2). AIDP usually develops at the time of seroconversion, whereas CIDP can occur any time in the course of the infection. Clinical and EDx features are indistinguishable from idiopathic

AIDP or CIDP (Chap. 447). In addition to elevated protein levels,

lymphocytic pleocytosis is evident in the CSF, a finding that helps distinguish this HIV-associated polyradiculoneuropathy from idiopathic

AIDP/CIDP.

HIV-Related Progressive Polyradiculopathy An acute, progressive lumbosacral polyradiculoneuropathy usually secondary

to CMV infection can develop in patients with AIDS (Pattern 4,

Table 446-2). Patients present with severe radicular pain, numbness,

and weakness in the legs, which is usually asymmetric. CSF is abnormal, demonstrating a high protein level, along with a reduced glucose

concentration and notably a neutrophilic pleocytosis. EDx studies

reveal features of active axonal degeneration. The polyradiculoneuropathy may improve with antiviral therapy.

HIV-Related Multiple Mononeuropathies Multiple mononeuropathies can also develop in patients with HIV infection, usually

in the context of AIDS. Weakness, numbness, paresthesias, and pain

occur in the distribution of affected nerves (Pattern 3, Table 446-2).

Nerve biopsies can reveal axonal degeneration with necrotizing

vasculitis or perivascular inflammation. Glucocorticoid treatment is

indicated for vasculitis directly due to HIV infection.

HIV-Related Sensory Neuronopathy/Ganglionopathy Dorsal root ganglionitis is a very rare complication of HIV infection,

and neuronopathy can be the presenting manifestation. Patients

develop sensory ataxia similar to idiopathic sensory neuronopathy/

ganglionopathy (Pattern 9, Table 446-2). NCS reveal reduced amplitudes

or absence of sensory nerve action potentials (SNAPs).

■ HERPES VARICELLA-ZOSTER VIRUS

Peripheral neuropathy from herpes varicella-zoster (HVZ) infection

results from reactivation of latent virus or from a primary infection

(Chap. 193). Two-thirds of infections in adults are characterized by

dermal zoster in which severe pain and paresthesias develop in a dermatomal region followed within a week or two by a vesicular rash in

the same distribution (Pattern 3, Table 446-2). Weakness in muscles

innervated by roots corresponding to the dermatomal distribution

of skin lesions occurs in 5–30% of patients. Approximately 25% of

affected patients have continued pain (postherpetic neuralgia [PHN]).

A large clinical trial demonstrated that vaccination against zoster

reduces the incidence of HVZ among vaccine recipients by 51% and

reduces the incidence of PHN by 67%. Treatment of PHN is symptomatic (Table 446-6).

■ CYTOMEGALOVIRUS

CMV can cause an acute lumbosacral polyradiculopathy and multiple mononeuropathies in patients with HIV infection and in other

immune deficiency conditions (Pattern 4, Table 446-2) (Chap. 195).

■ EPSTEIN-BARR VIRUS

EBV infection has been associated with GBS, cranial neuropathies,

mononeuropathy multiplex, brachial plexopathy, lumbosacral radiculoplexopathy, and sensory neuronopathies (Patterns 1, 3, 4, and 9,

Table 446-2) (Chap. 194).

■ HEPATITIS VIRUSES

Hepatitis B and C can cause multiple mononeuropathies related to

vasculitis, AIDP, or CIDP (Patterns 1 and 3, Table 446-2) (Chap. 341).

NEUROPATHIES ASSOCIATED WITH

MALIGNANCY

Patients with malignancy can develop neuropathies due to (1) a

direct effect of the cancer by invasion or compression of the nerves,

(2) remote or paraneoplastic effect, (3) a toxic effect of treatment, or

(4) as a consequence of immune compromise caused by immunosuppressive medications. The most common associated malignancy is

lung cancer, but neuropathies also complicate carcinoma of the breast,

ovaries, stomach, colon, rectum, and other organs, including the lymphoproliferative system.

■ PARANEOPLASTIC SENSORY NEURONOPATHY/

GANGLIONOPATHY

Paraneoplastic encephalomyelitis/sensory neuronopathy (PEM/SN)

usually complicates small-cell lung carcinoma (Chap. 94). Patients

usually present with numbness and paresthesias in the distal extremities that are often asymmetric. The onset can be acute or insidiously

progressive. Prominent loss of proprioception leads to sensory ataxia

(Pattern 9; Table 446-2). Weakness can be present, usually secondary

to an associated myelitis, motor neuronopathy, or concurrent LEMS.

Many patients also develop confusion, memory loss, depression, hallucinations or seizures, or cerebellar ataxia. Polyclonal antineuronal

antibodies (IgG) directed against a 35- to 40-kDa protein or complex

of proteins, the so-called Hu antigen, are found in the sera or CSF in

the majority of patients with paraneoplastic PEM/SN. CSF may be

normal or may demonstrate mild lymphocytic pleocytosis and elevated

protein. PEM/SN is probably the result of antigenic similarity between

proteins expressed in the tumor cells and neuronal cells, leading to an

immune response directed against both cell types. Treatment of the

underlying cancer generally does not affect the course of PEM/SN.

However, occasional patients may improve following treatment of the

tumor. Unfortunately, plasmapheresis, intravenous immunoglobulin,

and immunosuppressive agents have not shown benefit.

■ NEUROPATHY SECONDARY TO

TUMOR INFILTRATION

Malignant cells, in particular leukemia and lymphoma, can infiltrate

cranial and peripheral nerves, leading to mononeuropathy, mononeuropathy multiplex, polyradiculopathy, plexopathy, or even a generalized

symmetric distal or proximal and distal polyneuropathy (Patterns 1, 2,

3492 PART 13 Neurologic Disorders

3, and 4; Table 446-2). Neuropathy related to tumor infiltration is often

painful; it can be the presenting manifestation of the cancer or the heralding symptom of a relapse. The neuropathy may improve with treatment of the underlying leukemia or lymphoma or with glucocorticoids.

■ NEUROPATHY AS A COMPLICATION OF BONE

MARROW TRANSPLANTATION

Neuropathies may develop in patients who undergo bone marrow

transplantation (BMT) because of the toxic effects of chemotherapy,

radiation, infection, or an autoimmune response directed against the

peripheral nerves. Peripheral neuropathy in BMT is often associated

with graft-versus-host disease (GVHD). Chronic GVHD shares many

features with a variety of autoimmune disorders, and it is possible that

an immune-mediated response directed against peripheral nerves is

responsible. Patients with chronic GVHD may develop cranial neuropathies, sensorimotor polyneuropathies, multiple mononeuropathies,

and severe generalized peripheral neuropathies resembling AIDP or

CIDP (Patterns 1, 2, and 3; Table 446-2). The neuropathy may improve

by increasing the intensity of immunosuppressive or immunomodulating therapy and resolution of the GVHD.

■ LYMPHOMA

Lymphomas may cause neuropathy by infiltration or direct compression of nerves or by a paraneoplastic process. The neuropathy can be

purely sensory or motor but most commonly is sensorimotor. The

pattern of involvement may be symmetric, asymmetric, or multifocal,

and the course may be acute, gradually progressive, or relapsing and

remitting (Patterns 1, 2, and 3; Table 446-2). EDx can be compatible with either an axonal or demyelinating process. CSF may reveal

lymphocytic pleocytosis and an elevated protein. Nerve biopsy may

demonstrate endoneurial inflammatory cells in both the infiltrative

and the paraneoplastic etiologies. A monoclonal population of cells

favors lymphomatous invasion. The neuropathy may respond to treatment of the underlying lymphoma or immunomodulating therapies.

■ MULTIPLE MYELOMA

MM usually presents in the fifth to seventh decade of life with fatigue,

bone pain, anemia, and hypercalcemia (Chap. 111). Clinical and

EDx features of neuropathy occur in as many as 40% of patients. The

most common pattern is that of a distal, axonal, sensory, or sensorimotor polyneuropathy (Pattern 2; Table 446-2). Less frequently, a

chronic demyelinating polyradiculoneuropathy may develop (Pattern 1;

Table 446-2) (see POEMS, Chap. 447). MM can be complicated by

amyloid polyneuropathy and should be considered in patients with

painful paresthesias, loss of pinprick and temperature discrimination,

and autonomic dysfunction (suggestive of a small-fiber neuropathy)

and CTS. Expanding plasmacytomas can compress cranial nerves and

spinal roots as well. A monoclonal protein, usually composed of γ or μ

heavy chains or κ light chains, may be identified in the serum or urine.

EDx usually shows reduced amplitudes with normal or only mildly

abnormal distal latencies and conduction velocities. A superimposed

median neuropathy at the wrist is common. Abdominal fat pad, rectal,

or sural nerve biopsy can be performed to look for amyloid deposition.

Unfortunately, the treatment of the underlying MM does not usually

affect the course of the neuropathy.

■ NEUROPATHIES ASSOCIATED WITH

MONOCLONAL GAMMOPATHY OF UNCERTAIN

SIGNIFICANCE (SEE CHAP. 447)

Toxic Neuropathies Secondary to Chemotherapy Many of

the commonly used chemotherapy agents can cause a toxic neuropathy

(Table 446-7). The mechanisms by which these agents cause toxic

neuropathies vary, as does the specific type of neuropathy produced.

The risk of developing a toxic neuropathy or more severe neuropathy

appears to be greater in patients with a preexisting neuropathy (e.g.,

CMT disease, diabetic neuropathy) and those who also take other

potentially neurotoxic drugs (e.g., nitrofurantoin, isoniazid, disulfiram,

pyridoxine). Chemotherapeutic agents usually cause a sensory greater

than motor length-dependent axonal neuropathy or neuronopathy/

ganglionopathy (Patterns 2 and 9; Table 446-2).

OTHER TOXIC NEUROPATHIES

Neuropathies can develop as complications of toxic effects of various

drugs and other environmental exposures (Table 446-8). The more

common neuropathies associated with these agents are discussed here.

■ CHLOROQUINE AND HYDROXYCHLOROQUINE

Chloroquine and hydroxychloroquine can cause a toxic myopathy

characterized by slowly progressive, painless, proximal weakness

and atrophy, which is worse in the legs than the arms. In addition,

neuropathy can also develop with or without the myopathy leading

to sensory loss and distal weakness. The “neuromyopathy” usually

appears in patients taking 500 mg daily for a year or more but has been

reported with doses as low as 200 mg/d. Serum CK levels are usually

elevated due to the superimposed myopathy. NCS reveal mild slowing

of motor and sensory NCVs with a mild to moderate reduction in the

amplitudes, although NCS may be normal in patients with only the

myopathy. EMG demonstrates myopathic muscle action potentials

(MUAPs), increased insertional activity in the form of positive sharp

waves, fibrillation potentials, and occasionally myotonic potentials,

particularly in the proximal muscles. Neurogenic MUAPs and reduced

recruitment are found in more distal muscles. Nerve biopsy demonstrates autophagic vacuoles within Schwann cells. Vacuoles may also

be evident in muscle biopsies. The pathogenic basis of the neuropathy

is not known but may be related to the amphiphilic properties of the

drug. These agents contain both hydrophobic and hydrophilic regions

that allow them to interact with the anionic phospholipids of cell

membranes and organelles. The drug-lipid complexes may be resistant to digestion by lysosomal enzymes, leading to the formation of

autophagic vacuoles filled with myeloid debris that may in turn cause

degeneration of nerves and muscle fibers. The signs and symptoms of

the neuropathy and myopathy are usually reversible following discontinuation of medication.

■ AMIODARONE

Amiodarone can cause a neuromyopathy similar to chloroquine

and hydroxychloroquine. The neuromyopathy typically appears after

patients have taken the medication for 2–3 years. Nerve biopsy demonstrates a combination of segmental demyelination and axonal loss.

Electron microscopy reveals lamellar or dense inclusions in Schwann

cells, pericytes, and endothelial cells. The inclusions in muscle and

nerve biopsies have persisted as long as 2 years following discontinuation of the medication.

■ COLCHICINE

Colchicine can also cause a neuromyopathy. Patients usually present

with proximal weakness and numbness and tingling in the distal

extremities. EDx reveals features of an axonal polyneuropathy. Muscle

biopsy reveals a vacuolar myopathy, whereas sensory nerves demonstrate axonal degeneration. Colchicine inhibits the polymerization of

tubulin into microtubules. The disruption of the microtubules probably leads to defective intracellular movement of important proteins,

nutrients, and waste products in muscle and nerves.

■ THALIDOMIDE

Thalidomide is an immunomodulating agent used to treat MM,

GVHD, leprosy, and other autoimmune disorders. Thalidomide is

associated with severe teratogenic effects as well as peripheral neuropathy that can be dose-limiting. Patients develop numbness, painful

tingling, and burning discomfort in the feet and hands and less commonly muscle weakness and atrophy. Even after stopping the drug for

4–6 years, as many as 50% patients continue to have significant symptoms. NCS demonstrate reduced amplitudes or complete absence of

SNAPs, with preserved conduction velocities when obtainable. Motor

NCS are usually normal. Nerve biopsy reveals a loss of large-diameter

myelinated fibers and axonal degeneration. Degeneration of dorsal root

ganglion cells has been reported at autopsy.

3493Peripheral Neuropathy CHAPTER 446

■ PYRIDOXINE (VITAMIN B6

) TOXICITY

Pyridoxine is an essential vitamin that serves as a coenzyme for transamination and decarboxylation. However, at high doses (116 mg/d),

patients can develop a severe sensory neuropathy with dysesthesias and

sensory ataxia. NCS reveal absent or markedly reduced SNAP amplitudes with relatively preserved CMAPs. Nerve biopsy reveals axonal

loss of fiber at all diameters. Loss of dorsal root ganglion cells with

subsequent degeneration of both the peripheral and central sensory

tracts have been reported in animal models.

■ ISONIAZID

One of the most common side effects of isoniazid (INH) is peripheral

neuropathy. Standard doses of INH (3–5 mg/kg per day) are associated

with a 2% incidence of neuropathy, whereas neuropathy develops in

at least 17% of patients taking in excess of 6 mg/kg per d. The elderly,

malnourished, and “slow acetylators” are at increased risk for developing the neuropathy. INH inhibits pyridoxal phosphokinase, resulting in

pyridoxine deficiency and the neuropathy. Prophylactic administration

of pyridoxine 100 mg/d can prevent the neuropathy from developing.

■ ANTIRETROVIRAL AGENTS

The nucleoside analogues zalcitabine (dideoxycytidine or ddC),

didanosine (dideoxyinosine or ddI), stavudine (d4T), lamivudine

(3TC), and antiretroviral nucleoside reverse transcriptase inhibitor

(NRTI) are used to treat HIV infection. One of the major doselimiting side effects of these medications is a predominantly sensory,

length-dependent, symmetrically painful neuropathy (Pattern 2;

Table 446-2). Zalcitabine (ddC) is the most extensively studied of the

nucleoside analogues, and at doses >0.18 mg/kg per d, it is associated

with a subacute onset of severe burning and lancinating pains in the

feet and hands. NCS reveal decreased amplitudes of the SNAPs with

normal motor studies. The nucleoside analogues inhibit mitochondrial DNA polymerase, which is the suspected pathogenic basis for

the neuropathy. Because of a “coasting effect,” patients can continue to

worsen even 2–3 weeks after stopping the medication. Following dose

reduction, improvement in the neuropathy is seen in most patients

after several months (mean time ~10 weeks).

■ HEXACARBONS (n-HEXANE, METHYL n-BUTYL

KETONE)/GLUE SNIFFER’S NEUROPATHY

n-Hexane and methyl n-butyl ketone are water-insoluble industrial

organic solvents that are also present in some glues. Exposure through

inhalation, accidentally or intentionally (glue sniffing), or through

skin absorption can lead to a profound subacute sensory and motor

polyneuropathy (Pattern 2; Table 446-2). NCS demonstrate decreased

amplitudes of the SNAPs and CMAPs with slightly slow CVs. Nerve

biopsy reveals a loss of myelinated fibers and giant axons that are filled

with 10-nm neurofilaments. Hexacarbon exposure leads to covalent

cross-linking between axonal neurofilaments that results in their

aggregation, impaired axonal transport, swelling of the axons, and

eventual axonal degeneration.

■ LEAD

Lead neuropathy is uncommon, but it can be seen in children who

accidentally ingest lead-based paints in older buildings and in industrial workers exposed to lead-containing products. The most common

presentation of lead poisoning is an encephalopathy; however, symptoms and signs of a primarily motor neuropathy can also occur.

TABLE 446-7 Toxic Neuropathies Secondary to Chemotherapy

DRUG MECHANISM OF NEUROTOXICITY CLINICAL FEATURES NERVE HISTOPATHOLOGY EMG/NCS

Vinca alkaloids

(vincristine,

vinblastine, vindesine,

vinorelbine)

Interfere with axonal microtubule

assembly; impairs axonal transport

Symmetric, S-M, large-/smallfiber PN; autonomic symptoms

common; infrequent cranial

neuropathies

Axonal degeneration of

myelinated and unmyelinated

fibers; regenerating clusters,

minimal segmental demyelination

Axonal sensorimotor PN; distal

denervation on EMG; abnormal

QST, particularly vibratory

perception

Cisplatin Preferential damage to dorsal root

ganglia:

? binds to and cross-links DNA

? inhibits protein synthesis

? impairs axonal transport

Predominant large-fiber

sensory neuronopathy; sensory

ataxia

Loss of large > small myelinated

and unmyelinated fibers; axonal

degeneration with small clusters

of regenerating fibers; secondary

segmental demyelination

Low-amplitude or unobtainable

SNAPs with normal CMAPs and

EMG; abnormal QST, particularly

vibratory perception

Taxanes (paclitaxel,

docetaxel)

Promotes axonal microtubule

assembly; interferes with axonal

transport

Symmetric, predominantly

sensory PN; large-fiber

modalities affected more than

small-fiber

Loss of large > small myelinated

and unmyelinated fibers; axonal

degeneration with small clusters

of regenerating fibers; secondary

segmental demyelination

Axonal sensorimotor PN; distal

denervation on EMG; abnormal

QST, particularly vibratory

perception

Suramin

Axonal PN Unknown; ? inhibition of

neurotrophic growth factor

binding; ? neuronal lysosomal

storage

Symmetric, length-dependent,

sensory-predominant PN

None described Abnormalities consistent with an

axonal S-M PN

Demyelinating PN Unknown; ? immunomodulating

effects

Subacute, S-M PN with diffuse

proximal and distal weakness;

areflexia; increased CSF protein

Loss of large and small

myelinated fibers with primary

demyelination and secondary

axonal degeneration;

occasional epi- and endoneurial

inflammatory cell infiltrates

Features suggestive of an acquired

demyelinating sensorimotor PN

(e.g., slow CVs, prolonged distal

latencies and F-wave latencies,

conduction block, temporal

dispersion)

Cytarabine (ARA-C) Unknown; ? selective Schwann

cell toxicity; ? immunomodulating

effects

GBS-like syndrome; pure

sensory neuropathy; brachial

plexopathy

Loss of myelinated nerve fibers;

axonal degeneration; segmental

demyelination; no inflammation

Axonal, demyelinating, or mixed

S-M PN; denervation on EMG

Etoposide (VP-16) Unknown; ? selective dorsal root

ganglia toxicity

Length-dependent, sensorypredominant PN; autonomic

neuropathy

None described Abnormalities consistent with an

axonal S-M PN

Bortezomib (Velcade) Unknown Length-dependent, sensory,

predominantly small-fiber PN

Not reported Abnormalities consistent with an

axonal sensory neuropathy with

early small-fiber involvement

(abnormal autonomic studies)

Abbreviations: CMAP, compound motor action potential; CSF, cerebrospinal fluid; CVs, conduction velocities; EMG, electromyography; GBS, Guillain-Barré syndrome; NCS,

nerve conduction studies; PN, polyneuropathy; QST, quantitative sensory testing; S-M, sensorimotor; SNAP, sensory nerve action potential.

Source: From AA Amato, JA Russell (eds): Neuromuscular Disorders, 2nd ed. McGraw-Hill Education, 2016, Table 19-3, p. 439; with permission.

3494 PART 13 Neurologic Disorders

TABLE 446-8 Toxic Neuropathies

DRUG

MECHANISM OF

NEUROTOXICITY CLINICAL FEATURES NERVE HISTOPATHOLOGY EMG/NCS

Misonidazole Unknown Painful paresthesias and loss of largeand small-fiber sensory modalities

and sometimes distal weakness in

length-dependent pattern

Axonal degeneration of

large, myelinated fibers;

axonal swellings; segmental

demyelination

Low-amplitude or unobtainable

SNAPs with normal or only slightly

reduced CMAP amplitudes

Metronidazole Unknown Painful paresthesias and loss of largeand small-fiber sensory modalities

and sometimes distal weakness in

length-dependent pattern

Axonal degeneration Low-amplitude or unobtainable

SNAPs with normal CMAPs

Chloroquine and

hydroxychloroquine

Amphiphilic properties may

lead to drug-lipid complexes

that are indigestible and

result in accumulation of

autophagic vacuoles

Loss of large- and small-fiber sensory

modalities and distal weakness

in length-dependent pattern;

superimposed myopathy may lead to

proximal weakness

Axonal degeneration with

autophagic vacuoles in nerves

as well as muscle fibers

Low-amplitude or unobtainable

SNAPs with normal or reduced

CMAP amplitudes; distal denervation

on EMG; irritability and myopathicappearing MUAPs proximally in

patients with superimposed toxic

myopathy

Amiodarone Amphiphilic properties may

lead to drug-lipid complexes

that are indigestible and

result in accumulation of

autophagic vacuoles

Paresthesias and pain with loss

of large- and small-fiber sensory

modalities and distal weakness

in length-dependent pattern;

superimposed myopathy may lead to

proximal weakness

Axonal degeneration and

segmental demyelination with

myeloid inclusions in nerves

and muscle fibers

Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes; can also have prominent

slowing of CVs; distal denervation

on EMG; irritability and myopathicappearing MUAPs proximally in

patients with superimposed toxic

myopathy

Colchicine Inhibits polymerization of

tubulin in microtubules and

impairs axoplasmic flow

Numbness and paresthesias with loss

of large-fiber modalities in a lengthdependent fashion; superimposed

myopathy may lead to proximal in

addition to distal weakness

Nerve biopsy demonstrates

axonal degeneration; muscle

biopsy reveals fibers with

vacuoles

Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes; irritability and myopathicappearing MUAPs proximally in

patients with superimposed toxic

myopathy

Podophyllin Binds to microtubules and

impairs axoplasmic flow

Sensory loss, tingling, muscle

weakness, and diminished muscle

stretch reflexes in length-dependent

pattern; autonomic neuropathy

Axonal degeneration Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

Thalidomide Unknown Numbness, tingling, and burning pain

and weakness in a length-dependent

pattern

Axonal degeneration; autopsy

studies reveal degeneration of

dorsal root ganglia

Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

Disulfiram Accumulation of

neurofilaments and impaired

axoplasmic flow

Numbness, tingling, and burning pain

in a length-dependent pattern

Axonal degeneration with

accumulation of neurofilaments

in the axons

Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

Dapsone Unknown Distal weakness that may progress to

proximal muscles; sensory loss

Axonal degeneration and

segmental demyelination

Low-amplitude or unobtainable

CMAPs with normal or reduced SNAP

amplitudes

Leflunomide Unknown Paresthesias and numbness in a

length-dependent pattern

Unknown Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

Nitrofurantoin Unknown Numbness, painful paresthesias, and

severe weakness that may resemble

GBS

Axonal degeneration; autopsy

studies reveal degeneration of

dorsal root ganglia and anterior

horn cells

Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

Pyridoxine (vitamin B6

) Unknown Dysesthesias and sensory ataxia;

impaired large-fiber sensory

modalities on examination

Marked loss of sensory axons

and cell bodies in dorsal root

ganglia

Reduced amplitudes or absent SNAPs

Isoniazid Inhibits pyridoxal

phosphokinase leading to

pyridoxine deficiency

Dysesthesias and sensory ataxia;

impaired large-fiber sensory

modalities on examination

Marked loss of sensory axons

and cell bodies in dorsal root

ganglia and degeneration of the

dorsal columns

Reduced amplitudes or absent SNAPs

and, to a lesser extent, CMAPs

Ethambutol Unknown Numbness with loss of large-fiber

modalities on examination

Axonal degeneration Reduced amplitudes or absent SNAPs

Antinucleosides Unknown Dysesthesia and sensory ataxia;

impaired large-fiber sensory

modalities on examination

Axonal degeneration Reduced amplitudes or absent SNAPs

Phenytoin Unknown Numbness with loss of large-fiber

modalities on examination

Axonal degeneration and

segmental demyelination

Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

Lithium Unknown Numbness with loss of large-fiber

modalities on examination

Axonal degeneration Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

 (Continued)

3495Peripheral Neuropathy CHAPTER 446

TABLE 446-8 Toxic Neuropathies

DRUG

MECHANISM OF

NEUROTOXICITY CLINICAL FEATURES NERVE HISTOPATHOLOGY EMG/NCS

Acrylamide Unknown; may be caused by

impaired axonal transport

Numbness with loss of large-fiber

modalities on examination; sensory

ataxia; mild distal weakness

Degeneration of sensory

axons in peripheral nerves

and posterior columns,

spinocerebellar tracts,

mammillary bodies, optic tracts,

and corticospinal tracts in the

CNS

Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

Carbon disulfide Unknown Length-dependent numbness and

tingling with mild distal weakness

Axonal swellings with

accumulation of neurofilaments

Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

Ethylene oxide Unknown; may act as

alkylating agent and bind

DNA

Length-dependent numbness

and tingling; may have mild distal

weakness

Axonal degeneration Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

Organophosphates Bind and inhibit neuropathy

target esterase

Early features are those of

neuromuscular blockade with

generalized weakness; later axonal

sensorimotor PN ensues

Axonal degeneration along

with degeneration of gracile

fasciculus and corticospinal

tracts

Early: repetitive firing of CMAPs and

decrement with repetitive nerve

stimulation; late: axonal sensorimotor

PN

Hexacarbons Unknown; may lead to

covalent cross-linking

between neurofilaments

Acute, severe sensorimotor PN that

may resemble GBS

Axonal degeneration and

giant axons swollen with

neurofilaments

Features of a mixed axonal and/or

demyelinating sensorimotor axonal

PN—reduced amplitudes, prolonged

distal latencies, conduction block, and

slowing of CVs

Lead Unknown; may interfere with

mitochondria

Encephalopathy; motor neuropathy

(often resembles radial neuropathy

with wrist and finger drop); autonomic

neuropathy; bluish-black discoloration

of gums

Axonal degeneration of motor

axons

Reduction of CMAP amplitudes with

active denervation on EMG

Mercury Unknown; may combine with

sulfhydryl groups

Abdominal pain and nephrotic

syndrome; encephalopathy; ataxia;

paresthesias

Axonal degeneration;

degeneration of dorsal root

ganglia, calcarine, and

cerebellar cortex

Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

Thallium Unknown Encephalopathy; painful sensory

symptoms; mild loss of vibration;

distal or generalized weakness may

also develop; autonomic neuropathy;

alopecia

Axonal degeneration Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes

Arsenic Unknown; may combine with

sulfhydryl groups

Abdominal discomfort, burning

pain, and paresthesias; generalized

weakness; autonomic insufficiency;

can resemble GBS

Axonal degeneration Low-amplitude or unobtainable

SNAPs with normal or reduced CMAP

amplitudes; may have demyelinating

features: prolonged distal latencies

and slowing of CVs

Gold Unknown Distal paresthesias and reduction of

all sensory modalities

Axonal degeneration Low-amplitude or unobtainable

SNAPs

Abbreviations: CMAP, compound motor action potential; CVs, conduction velocities; EMG, electromyography; GBS, Guillain-Barré syndrome; MUAP, muscle action potential;

NCS, nerve conduction studies; PN, polyneuropathy; S-M, sensorimotor; SNAP, sensory nerve action potential.

Source: From AA Amato, JA Russell (eds): Neuromuscular Disorders, 2nd ed. McGraw-Hill Education, 2016, Table 20-1, p. 449-451; with permission.

The neuropathy is characterized by an insidious and progressive onset

of weakness usually beginning in the arms, in particular involving the

wrist and finger extensors, resembling a radial neuropathy. Sensation

is generally preserved; however, the autonomic nervous system can be

affected (Patterns 2, 3, and 10; Table 446-2). Laboratory investigation

can reveal a microcytic hypochromic anemia with basophilic stippling

of erythrocytes, an elevated serum lead level, and an elevated serum

coproporphyrin level. A 24-h urine collection demonstrates elevated

levels of lead excretion. The NCS may reveal reduced CMAP amplitudes, while the SNAPs are typically normal. The pathogenic basis may

be related to abnormal porphyrin metabolism. The most important

principle of management is to remove the source of the exposure.

Chelation therapy with calcium disodium ethylene-diaminetetraacetic

acid (EDTA), British anti-Lewisite (BAL), and penicillamine also demonstrates variable efficacy.

■ MERCURY

Mercury toxicity may occur as a result of exposure to either organic

or inorganic mercurials. Mercury poisoning presents with paresthesias

in hands and feet that progress proximally and may involve the face

and tongue. Motor weakness can also develop. CNS symptoms often

overshadow the neuropathy. EDx shows features of a primarily axonal

sensorimotor polyneuropathy. The primary site of neuromuscular

pathology appears to be the dorsal root ganglia. The mainstay of treatment is removing the source of exposure.

■ THALLIUM

Thallium can exist in a monovalent or trivalent form and is primarily

used as a rodenticide. The toxic neuropathy usually manifests as burning paresthesias of the feet, abdominal pain, and vomiting. Increased

thirst, sleep disturbances, and psychotic behavior may be noted.

Within the first week, patients develop pigmentation of the hair, an

acne-like rash in the malar area of the face, and hyperreflexia. By the

second and third weeks, autonomic instability with labile heart rate and

blood pressure may be seen. Hyporeflexia and alopecia also occur but

may not be evident until the third or fourth week following exposure.

With severe intoxication, proximal weakness and involvement of the

cranial nerves can occur. Some patients require mechanical ventilation

due to respiratory muscle involvement. The lethal dose of thallium is

variable, ranging from 8 to 15 mg/kg body weight. Death can result in

 (Continued)

3496 PART 13 Neurologic Disorders

<48 h following a particularly large dose. NCS demonstrate features of

a primarily axonal sensorimotor polyneuropathy. With acute intoxication, potassium ferric ferrocyanide II may be effective in preventing

absorption of thallium from the gut. However, there may be no benefit

once thallium has been absorbed. Unfortunately, chelating agents are

not very efficacious. Adequate diuresis is essential to help eliminate

thallium from the body without increasing tissue availability from the

serum.

■ ARSENIC

Arsenic is another heavy metal that can cause a toxic sensorimotor

polyneuropathy. The neuropathy manifests 5–10 days after ingestion of

arsenic and progresses for several weeks, sometimes mimicking GBS.

The presenting symptoms are typically an abrupt onset of abdominal

discomfort, nausea, vomiting, pain, and diarrhea followed within several days by burning pain in the feet and hands. Examination of the skin

can be helpful in the diagnosis as the loss of the superficial epidermal

layer results in patchy regions of increased or decreased pigmentation

on the skin several weeks after an acute exposure or with chronic low

levels of ingestion. Mee’s lines, which are transverse lines at the base of

the fingernails and toenails, do not become evident until 1 or 2 months

after the exposure. Multiple Mee’s lines may be seen in patients with

long fingernails who have had chronic exposure to arsenic. Mee’s lines

are not specific for arsenic toxicity as they can also be seen following

thallium poisoning. Because arsenic is cleared from blood rapidly, the

serum concentration of arsenic is not diagnostically helpful. However,

arsenic levels are increased in the urine, hair, and fingernails of patients

exposed to arsenic. Anemia with stippling of erythrocytes is common,

and occasionally, pancytopenia and aplastic anemia can develop.

Increased CSF protein levels without pleocytosis can be seen; this can

lead to misdiagnosis as GBS. NCS are usually suggestive of an axonal

sensorimotor polyneuropathy; however, demyelinating features can be

present. Chelation therapy with BAL has yielded inconsistent results;

therefore, it is not generally recommended.

NUTRITIONAL NEUROPATHIES

■ COBALAMIN (VITAMIN B12)

Pernicious anemia is the most common cause of cobalamin deficiency.

Other causes include dietary avoidance (vegetarians), gastrectomy,

gastric bypass surgery, inflammatory bowel disease, pancreatic insufficiency, bacterial overgrowth, and possibly histamine-2 blockers and

proton pump inhibitors. An underappreciated cause of cobalamin

deficiency is food-cobalamin malabsorption. This typically occurs in

older individuals and results from an inability to adequately absorb

cobalamin in food protein. No apparent cause of deficiency is identified in a significant number of patients with cobalamin deficiency. The

use of nitrous oxide as an anesthetic agent or as a recreational drug

can produce acute cobalamin deficiency neuropathy and subacute

combined degeneration.

Complaints of numb hands typically appear before lower extremity

paresthesias are noted. A preferential large-fiber sensory loss affecting

proprioception and vibration with sparing of small-fiber modalities

is present; an unsteady gait reflects sensory ataxia. These features,

coupled with diffuse hyperreflexia and absent Achilles reflexes, should

always focus attention on the possibility of cobalamin deficiency

(Patterns 2 and 6; Table 446-2). Optic atrophy and, in severe cases,

behavioral changes ranging from mild irritability and forgetfulness

to severe dementia and frank psychosis may appear. The full clinical

picture of subacute combined degeneration is uncommon. CNS manifestations, especially pyramidal tract signs, may be missing, and in fact,

some patients may only exhibit symptoms of peripheral neuropathy.

EDx shows an axonal sensorimotor neuropathy. CNS involvement

produces abnormal somatosensory and visual evoked potential latencies. The diagnosis is confirmed by finding reduced serum cobalamin

levels. In up to 40% of patients, anemia and macrocytosis are lacking. Serum methylmalonic acid and homocysteine, the metabolites

that accumulate when cobalamin-dependent reactions are blocked,

are elevated. Antibodies to intrinsic factor are present in ~60% and

antiparietal cell antibodies in ~90% of individuals with pernicious

anemia.

Cobalamin deficiency can be treated with various regimens of

cobalamin. One typical regimen consists of 1000 μg cyanocobalamin

IM weekly for 1 month and monthly thereafter. Patients with food

cobalamin malabsorption can absorb free cobalamin and therefore can

be treated with oral cobalamin supplementation. An oral cobalamin

dose of 1000 μg/d should be sufficient. Treatment for cobalamin deficiency usually does not completely reverse the clinical manifestations,

and at least 50% of patients exhibit some permanent neurologic deficit.

■ THIAMINE DEFICIENCY

Thiamine (vitamin B1

) deficiency is an uncommon cause of peripheral

neuropathy in developed countries. It is now most often seen as a consequence of chronic alcohol abuse, recurrent vomiting, total parenteral

nutrition, and bariatric surgery. Thiamine deficiency polyneuropathy

can occur in normal, healthy young adults who do not abuse alcohol but who engage in inappropriately restrictive diets. Thiamine is

water-soluble. It is present in most animal and plant tissues, but the

greatest sources are unrefined cereal grains, wheat germ, yeast, soybean

flour, and pork. Beriberi means “I can’t, I can’t” in Singhalese, the language of natives of what was once part of the Dutch East Indies (now

Sri Lanka). Dry beriberi refers to neuropathic symptoms. The term wet

beriberi is used when cardiac manifestations predominate (in reference

to edema). Beriberi was relatively uncommon until the late 1800s when

it became widespread among people for whom rice was a dietary mainstay. This epidemic was due to a new technique of processing rice that

removed the germ from the rice shaft, rendering the so-called polished

rice deficient in thiamine and other essential nutrients.

Symptoms of neuropathy follow prolonged deficiency. These begin

with mild sensory loss and/or burning dysesthesias in the toes and

feet and aching and cramping in the lower legs. Pain may be the predominant symptom. With progression, patients develop features of a

nonspecific generalized polyneuropathy, with distal sensory loss in the

feet and hands.

Blood and urine assays for thiamine are not reliable for diagnosis

of deficiency. Erythrocyte transketolase activity and the percentage

increase in activity (in vitro) following the addition of thiamine

pyrophosphate (TPP) may be more accurate and reliable. EDx shows

nonspecific findings of an axonal sensorimotor polyneuropathy. When

a diagnosis of thiamine deficiency is made or suspected, thiamine

replacement should be provided until proper nutrition is restored.

Thiamine is usually given intravenously or intramuscularly at a dose of

100 mg/d. Although cardiac manifestations show a striking response

to thiamine replacement, neurologic improvement is usually more

variable and less dramatic.

■ VITAMIN E DEFICIENCY

The term vitamin E is usually used for α-tocopherol, the most active

of the four main types of vitamin E. Because vitamin E is present in

animal fat, vegetable oils, and various grains, deficiency is usually due

to factors other than insufficient intake. Vitamin E deficiency usually

occurs secondary to lipid malabsorption or in uncommon disorders of

vitamin E transport. One hereditary disorder is abetalipoproteinemia,

a rare autosomal dominant disorder characterized by steatorrhea, pigmentary retinopathy, acanthocytosis, and progressive ataxia. Patients

with cystic fibrosis may also have vitamin E deficiency secondary to

steatorrhea. There are genetic forms of isolated vitamin E deficiency

not associated with lipid malabsorption. Vitamin E deficiency may

also occur as a consequence of various cholestatic and hepatobiliary

disorders as well as short-bowel syndromes resulting from the surgical

treatment of intestinal disorders.

Clinical features may not appear until many years after the onset of

deficiency. The onset of symptoms tends to be insidious, and progression is slow. The main clinical features are spinocerebellar ataxia and

polyneuropathy, thus resembling Friedreich’s ataxia or other spinocerebellar ataxias. Patients manifest progressive ataxia and signs of posterior column dysfunction, such as impaired joint position and vibratory

sensation. Because of the polyneuropathy, there is hyporeflexia, but

3497Peripheral Neuropathy CHAPTER 446

plantar responses may be extensor as a result of the spinal cord involvement (Patterns 2 and 6; Table 446-2). Other neurologic manifestations

may include ophthalmoplegia, pigmented retinopathy, night blindness,

dysarthria, pseudoathetosis, dystonia, and tremor. Vitamin E deficiency may present as an isolated polyneuropathy, but this is very rare.

The yield of checking serum vitamin E levels in patients with isolated

polyneuropathy is extremely low, and this test should not be part of

routine practice.

Diagnosis is made by measuring α-tocopherol levels in the serum.

EDx shows features of an axonal neuropathy. Treatment is replacement

with oral vitamin E, but high doses are not needed. For patients with

isolated vitamin E deficiency, treatment consists of 1500–6000 IU/d in

divided doses.

■ VITAMIN B6

 DEFICIENCY

Vitamin B6

, or pyridoxine, can produce neuropathic manifestations

from both deficiency and toxicity. Vitamin B6

 toxicity was discussed

above. Vitamin B6

 deficiency is most commonly seen in patients treated

with isoniazid or hydralazine. The polyneuropathy of vitamin B6

 is

nonspecific, manifesting as a generalized axonal sensorimotor polyneuropathy. Vitamin B6

 deficiency can be detected by direct assay.

Vitamin B6

 supplementation with 50–100 mg/d is suggested for

patients being treated with isoniazid or hydralazine. This same dose is

appropriate for replacement in cases of nutritional deficiency.

■ PELLAGRA (NIACIN DEFICIENCY)

Pellagra is produced by deficiency of niacin. Although pellagra may be

seen in alcoholics, this disorder has essentially been eradicated in most

Western countries by means of enriching bread with niacin. Nevertheless, pellagra continues to be a problem in a number of underdeveloped

regions, particularly in Asia and Africa, where corn is the main source

of carbohydrate. Neurologic manifestations are variable; abnormalities

can develop in the brain and spinal cord as well as peripheral nerves.

When peripheral nerves are involved, the neuropathy is usually mild

and resembles beriberi. Treatment is with niacin 40–250 mg/d.

■ COPPER DEFICIENCY

A syndrome that has only recently been described is myeloneuropathy

secondary to copper deficiency. Most patients present with lower limb

paresthesias, weakness, spasticity, and gait difficulties (Pattern 6;

Table 446-2). Large-fiber sensory function is impaired, reflexes are

brisk, and plantar responses are extensor. In some cases, light touch

and pinprick sensation are affected, and NCS indicate sensorimotor

axonal polyneuropathy in addition to myelopathy.

Hematologic abnormalities are a known complication of copper

deficiency; these can include microcytic anemia, neutropenia, and

occasionally pancytopenia. Because copper is absorbed in the stomach

and proximal jejunum, many cases of copper deficiency occur in the

setting of prior gastric surgery. Excess zinc is an established cause of

copper deficiency. Zinc upregulates enterocyte production of metallothionine, which results in decreased absorption of copper. Excessive

dietary zinc supplements or denture cream containing zinc can produce this clinical picture. Other potential causes of copper deficiency

include malnutrition, prematurity, total parenteral nutrition, and

ingestion of copper-chelating agents.

Following oral or IV copper replacement, some patients show neurologic improvement, but this may take many months or not occur

at all. Replacement consists of oral copper sulfate or gluconate 2 mg

one to three times a day. If oral copper replacement is not effective,

elemental copper in the copper sulfate or copper chloride forms can

be given as 2 mg IV daily for 3–5 days, then weekly for 1–2 months

until copper levels normalize. Thereafter, oral daily copper therapy

can be resumed. In contrast to the neurologic manifestations, most of

the hematologic indices normalize in response to copper replacement

therapy.

■ NEUROPATHY ASSOCIATED WITH

GASTRIC SURGERY

Polyneuropathy may occur following gastric surgery for ulcer, cancer, or weight reduction. This usually occurs in the context of rapid,

significant weight loss and recurrent, protracted vomiting. The clinical

picture is one of acute or subacute sensory loss and weakness. Neuropathy following weight loss surgery usually occurs in the first several

months after surgery. Weight reduction surgical procedures include

gastrojejunostomy, gastric stapling, vertical banded gastroplasty, and

gastrectomy with Roux-en-Y anastomosis. The initial manifestations are

usually numbness and paresthesias in the feet (Pattern 2; Table 446-2).

In many cases, no specific nutritional deficiency factor is identified.

Management consists of parenteral vitamin supplementation, especially including thiamine. Improvement has been observed following

supplementation, parenteral nutritional support, and reversal of the

surgical bypass. The duration and severity of deficits before identification and treatment of neuropathy are important predictors of final

outcome.

CRYPTOGENIC (IDIOPATHIC) SENSORY

AND SENSORIMOTOR POLYNEUROPATHY

Cryptogenic (idiopathic) sensory and sensorimotor polyneuropathy

(CSPN) is a diagnosis of exclusion, established after a careful medical, family, and social history; neurologic examination; and directed

laboratory testing. Despite extensive evaluation, the cause of polyneuropathy in as many as 50% of all patients is idiopathic. CSPN should

be considered a distinct diagnostic subset of peripheral neuropathy.

The onset of CSPN is predominantly in the sixth and seventh decades.

Patients complain of distal numbness, tingling, and often burning

pain that invariably begins in the feet and may eventually involve the

fingers and hands (“burning feet syndrome”). Patients exhibit a distal

sensory loss to pinprick, touch, and vibration in the toes and feet, and

occasionally in the fingers (Pattern 2; Table 446-2). It is uncommon

to see significant proprioception deficits, even though patients may

complain of gait unsteadiness. However, tandem gait may be abnormal in a minority of cases. Neither subjective nor objective evidence

of weakness is a prominent feature. Most patients have evidence of

both large- and small-fiber loss on neurologic examination and EDx.

Approximately 10% of patients have only evidence of small-fiber

involvement. The ankle muscle stretch reflex is frequently absent, but

in cases with predominantly small-fiber loss, this may be preserved.

The EDx findings range from isolated SNAP abnormalities (usually

with loss of amplitude), to evidence for an axonal sensorimotor neuropathy, to a completely normal study (if primarily small fibers are

involved). Therapy primarily involves the control of neuropathic pain

(Table 446-6) if present. Recently, a large comparative effectiveness

study in CSPN showed that the drugs nortriptyline and duloxetine outperformed pregabalin and mexiletine. These drugs should not be used

if the patient has only numbness and tingling but no pain.

Although no treatment is available that can reverse an idiopathic

distal peripheral neuropathy, the prognosis is good. Progression often

does not occur or is minimal, with sensory symptoms and signs progressing proximally up to the knees and elbows. The disorder does not

lead to significant motor disability over time. The relatively benign

course of this disorder should be explained to patients.

MONONEUROPATHIES/PLEXOPATHIES/

RADICULOPATHIES (PATTERN 3;

TABLE 446-2)

■ MEDIAN NEUROPATHY

CTS is a compression of the median nerve in the carpal tunnel at the

wrist. The median nerve enters the hand through the carpal tunnel by

coursing under the transverse carpal ligament. The symptoms of CTS

consist of numbness and paresthesias variably in the thumb, index,

middle, and half of the ring finger. At times, the paresthesias can

include the entire hand and extend into the forearm or upper arm or

can be isolated to one or two fingers. Pain is another common symptom and can be located in the hand and forearm and, at times, in the

proximal arm. CTS is common and often misdiagnosed as thoracic

outlet syndrome. The signs of CTS are decreased sensation in the

median nerve distribution; reproduction of the sensation of tingling

when a percussion hammer is tapped over the wrist (Tinel sign) or the