Color Atlas of Neurology

Peripheral Nerve and Muscle

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Peripheral Neuropathies

Diabetic Neuropathies

Pathogenesis. Distal symmetric polyneuropathy, a form of diabetic polyneuropathy (DPN), is due to generalized peripheral nerve damage. It is a complication of continuous hyperglycemia and the related metabolic changes ( polyols, phospholipids, fatty acids, oxidative radicals, lack of nerve growth factors). Normalization of the blood glucose concentration by medical treatment can prevent DPN (at least partially) but, long-standing severe DPN, once established, cannot be completely reversed by euglycemia. Pathological examination reveals extensive axon loss, which is thought to be due either to the chronic hyperglycemia itself or to the resulting (perhaps inflammatory) microvascular changes. Repeated episodes of hypoglycemia (p. 308) can also cause neuropathy.

Symptoms and signs. DPN produces both negative neurological signs (sensory loss, sensory ataxia, thermanesthesia, hypalgesia, autonomic dysfunction, paresis) and positive neurological signs (paresthesia, dysesthesia, pain). The manifestations of DPN are classified in Table 59 (p. 395). They may be present in varying combi-

324nations.

Diagnosis. DPN is diagnosed in diabetic patients

with distal, symmetric, sensorimotor poly-

neuropathy of the lower limbs, after the exclusion of other causes (e. g., diabetic lumbosacral or radicular lesions ( Table 59), other neuropathies or primary illnesses); it is usually accompanied by diabetic retinopathy or nephropathy of comparable severity. Other neuropathic syndromes found in diabetes (some symmetric, some asymmetric) require the use of specialized tests for their differential diagnosis (p. 391).

Treatment. The main objective of treatment is normoglycemia. Pain (p. 108) due to diabetic neuropathy usually responds to tricyclic antidepressants (amitryptiline, clomipramine), anticonvulsants (carbamazepine, gabapentin, lamotrigine), antiarrhythmics (lidocaine, mexiletine), capsaicin (administered locally as a 0.075% cream), or transdermal clonidine. Autonomic dysfunction of various types is treated symptomatically. Other factors that may worsen the neuropathy should be avoided (alcohol, vitamin deficiency, medication side effects). The complications of DPN (diabetic foot ulcer, infection, weakness, falls) may require specific treatment.

Uremic Neuropathy

Uremic neuropathy is a distal, symmetrical, sensorimotor, axonal peripheral neuropathy that mainly affects the legs. Paresthesiae and a “restless legs” sensation are typical. Uremic neuropathy may complicate renal failure of any etiology and is treated by therapy of the underlying disease.

Peripheral Neuropathies

Generalized autonomic dysfunction

Distal symmetrical sensorimotor neuropathy

Diabetes mellitus

Paresthesia (tingling)

Proximal diabetic neuropathy (left)

External oculomotor nerve palsy (right)

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Peripheral Neuropathies

Incomplete bilateral peripheral facial palsy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

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Peripheral Neuropathies

!Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)

! Multifocal Motor Neuropathy (MMN)

MMN is characterized by progressive asymmetrical weakness, which usually begins in the upper limbs. The underlying lesion is usually in isolated peripheral nerves (most often radial, median, ulnar, and common peroneal). Muscle spasms and fasciculations are common. Sensory loss, if any, is mild, and muscle atrophy is mild or absent even if weakness is marked. The reflexes may be absent, diminished, or (rarely) brisk. Nerve conduction studies reveal a motor conduction block. There may be an elevated serum concentration of IgM antibodies to GM1. Repeated intravenous administration of immunoglobulin or cyclophosphamide is an effective treatment. The differential diagnosis includes amyotrophic lateral sclerosis, distal spinal muscular atrophy (p. 385), and CIDP.

! Paraproteinemic Polyneuropathies

These disorders are most commonly due to nonmalignant monoclonal gammopathies, usually of IgM type, rarely IgG or IgA, though there is progression to plasmocytoma or Waldenström macroglobulinemia in some 20% of cases. The main features of monoclonal gammopathy of undetermined significance (MGUS) include: κ-type, M protein !25 g/l, Bence Jones proteinuria

328(rare), no skeletal or organ involvement, normal blood smear. The clinical manifestations are of

slowly progressive, distal, symmetrical, sen-

sorimotor polyneuropathy, which is sometimes painful. Serum antibodies to myelin-associated glycoprotein (MAG) may be present, and the CSF protein concentration may be elevated. The treatment is by immune suppression, but the ideal type of agent, timing, and dosage have not yet been determined. POEMS syndrome (PNP + organomegaly + endocrinopathy + M protein + skin changes; Crow–Fukase syndrome) is a rare systemic manifestation of osteosclerotic myeloma.

! Neuropathy of Infectious Origin

Leprosy, HIV infection, herpes zoster infection, borreliosis, tetanus, botulism, diphtheria, or other infectious diseases may cause neuropathy. Leprosy is the most common cause of peripheral neuropathy around the world. Its pathogenic organism (Mycobacterium leprae) attacks peripheral nerves in the cooler parts of the body, such as the skin, nose, anterior portion of the eye, and testes. There is segmental thickening of peripheral nerves (elbow, wrist, ankle). Areas of skin become depigmented and anhidrotic, with dissociated sensory loss. There are different types of leprosy, each of which is associated with a characteristic type of neuropathy.

! Neuralgic Amyotrophy

This disorder involves acute, usually nocturnal attacks of severe pain in the shoulder for several days or weeks, followed by weakness and muscle atrophy. Sensory deficits are rare (axillary nerve distribution). The symptoms usually resolve spontaneously.

! Vasculitic Neuropathy

Peripheral neuropathy due to connective tissue disease is usually multifocal, rarely symmetric (p. 180). Early treatment by immune suppression improves the outcome. Various connective tissue diseases can produce an isolated sensory trigeminal neuropathy.

Predominantly distal paresis, muscular atrophy and cramps

metrical PNP

Neuralgic amyotrophy

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Peripheral Neuropathies

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Peripheral Neuropathies

Nonmetabolic Hereditary Neuropathies

(Tables 62 and 63, p. 396 f)

For neuropathies associated with systemic disease, see p. 280.

! Hereditary Motor–Sensory Neuropathy

The type I phenotype is produced by three different genotypes: CMT1 (autosomal domi-

(X-linked).

HMSN type II. CMT2A and B resemble HMSN type I but begin later, with only rare areflexia and no palpable thickening of peripheral nerves. CMT2C is characterized by vocal cord paralysis (hoarseness, inspiratory stridor), proximal and distal weakness, distal muscle atrophy, and areflexia.

HMSN type III. This rare polyneuropathy (eponym: Dejerine–Sottas disease) becomes manifest at birth or in childhood with generalized weakness, areflexia, and palpable nerve thickening. Hearing loss, skeletal deformity, and sensory deficits ( ataxia) ensue as the disease progresses.

!Hereditary Neuropathy with Pressure Palsies (HNPP)

HNPP is characterized by recurrent, transient episodes of weakness and sensory loss after relatively mild compression of a peripheral nerve (ulnar, peroneal, radial, or median nerve). There may be evidence of a generalized polyneuropathy or a painless plexopathy. The “sausagelike” pathological changes seen on sural nerve biopsy are the origin of the alterna-

332 tive name, tomaculous neuropathy (from Latin tomaculum, “sausage”).

Metabolic Hereditary Neuropathies

Other members of this class are listed in the section on metabolic diseases (p. 306 ff).

! Porphyria

Among the known porphyrias, four hepatic types are associated with encephalopathy and peripheral neuropathy: variegate porphyria, acute intermittent porphyria, hereditary coproporphyria, and δ-aminolevulinic acid dehydrase deficiency (autosomal recessive; the others are autosomal dominant). The porphyrias are hereditary enzymopathies affecting the biosynthesis of heme. Severe peripheral neuropathy is seen during attacks of acute porphyria, which are most often precipitated by medications and hormonal influences (also fasting, alcohol, and infection). The manifestations of porphyria include colicky abdominal pain, pain in the limbs, paresthesiae, tachycardia, and variable degrees of weakness. Encephalopathy is manifest as confusion, lack of concentration, somnolence, psychosis, hallucinations and/or epileptic seizures. The diagnosis of porphyria is based on the demonstration of porphyrin metabolites in the urine and feces.

!Neuropathy Due to Hereditary Disorders of Lipid Metabolism

Polyneuropathy occurs in metachromatic leukodystrophy (p. 306), Krabbe disease (p. 307), abetalipoproteinemia (p. 300), adrenomyeloneuropathy (p. 384), Tangier disease (tonsillar hypertrophy, hepatosplenomegaly, low serum cholesterol, serum HDL deficiency), Fabry disease (punctate red angiokeratoma on buttocks and in the genital and periumbilical areas, retinovascular changes, corneal deposits, nephropathy, painful neuropathy; glycosphingolipid deposition due to α-galactosidase deficiency), and Refsum disease. The last is an autosomal recessive disorder of phytanic acid metabolism in which phytanic acid accumulation leads to tapetoretinal degeneration, night blindness, and a distal, symmetric polyneuropathy with peripheral nerve thickening. The CSF protein concentration is markedly elevated, but the CSF cell count is normal. The serum phytanic acid concentration is elevated.