Peripheral Neuropathies

Epidemiology

As a group, peripheral neuropathies are among the most common neurologic problems encountered in medical practice. The prevalence of peripheral neuropathy increases with age from 2 to 3% in individuals who are 50 to 60 years of age to 13% among individuals who are 70 to 80 years of age and greater than 30% among individuals over age 80 years. The population prevalence of peripheral polyneuropathy in the United States is 2.4% overall but rises to as high as 50% among individuals over 85 years of age. The most common cause of polyneuropathy is diabetes, which accounts for approximately 50% of cases. Most of the remainder have cryptogenic sensory peripheral neuropathy, although over 50% of this population has prediabetes. Other common causes of neuropathy include genetic, inflammatory, metabolic, and toxic etiologies.

Pathobiology

Motor neurons extend from their cell body in the ventral horn of the spinal cord through the ventral nerve roots and peripheral nerves to the neuromuscular junctions at the muscle that they innervate. The cell bodies of primary sensory neurons lie outside the spinal cord in the dorsal root ganglia, where they extend peripherally to specialized sensory end organs, including nociceptors (pain receptors), thermoreceptors, and mechanoreceptors. Central projections from dorsal root ganglia enter the spinal cord through the dorsal roots to carry sensory information to the central nervous system (CNS). At each spinal segment, the ventral roots, which carry motor axons, and the dorsal roots, which carry sensory axons, join to form mixed sensorimotor nerves. In the proximal upper and lower extremities, the mixed spinal nerves form the brachial and lumbar plexuses from which arise the major anatomically defined limb nerves. Each mixed nerve is composed of a spectrum of nerve fibers, damage to which causes specific but overlapping symptoms and signs. Large-diameter myelinated fibers are responsible for motor function, proprioception, and touch sensation, whereas small-diameter lightly myelinated and unmyelinated axons are responsible for pain and autonomic function. Preganglionic sympathetic autonomic fibers begin in the intermediolateral column of the spinal cord and synapse in ganglia of the sympathetic trunk. Preganglionic parasympathetic fibers travel long distances from their cell bodies in the brain stem or sacral spinal cord to reach terminal ganglia near the organs that the parasympathetic fibers innervate.

Although positive sensory symptoms occur with injury to both large- and small-diameter fibers, severe painful sensations, particularly burning, usually suggests preferential injury to small-diameter axons. Because motor axons are capable of reinnervating denervated muscle fibers via collateral sprouting, weakness does not develop in axonal neuropathies until about 50% of axons have been injured.

Clinical Manifestations

The clinical features of a peripheral neuropathy are dependent on the involved regions. Most patients with peripheral neuropathy have a chronic axonal sensory greater than motor peripheral polyneuropathy and present with slowly progressive sensory symptoms.

Sensory and motor symptoms may be divided into negative (loss of function) and positive (abnormal function). Common negative sensory symptoms include a general sense of numbness or loss of sensation, such as feeling as if feet are “walking on pebbles” or “ice cold,” difficulty determining whether bath water is hot or cold with the foot, and loss of balance, particularly in the dark when visual compensation is difficult. Positive symptoms include painful dysesthesias, such as feeling as though the feet are “on fire,” “on hot coals,” or “stuck with pins.” If severe, the symptoms may reach the level of the knee, at which point the fingers may become involved. Motor symptoms and signs are typically mild and limited to subtle weakness of toe extension and flexion, with atrophy of foot muscles. There may be mild gait instability that does not require the use of assistive devices. Foot ulceration is absent. Gait imbalance owing to a sensory ataxia (instability worse with eyes closed) indicates large fiber involvement or dysfunction of the dorsal columns of the spinal cord. Sensory ataxia involving the upper extremities is manifest by impaired coordination and finger-nose-finger testing that is worse with eyes closed, when there are often writhing, “pseudoathetoid” movements of the fingers with arms outstretched.

Involvement of motor nerves results in muscle weakness and, over time, atrophy. In peripheral polyneuropathies weakness involves distal muscles in the legs more than the arms. Deep and superficial muscles that are innervated by the peroneal nerve, such as the tibialis anterior and peroneus brevis and longus muscles, are usually affected first. As a result, tripping on a carpet or curb and ankle sprains are frequent symptoms. In the hands, symptoms typically involve fine movements, such as using buttons or zippers and inserting and turning keys in locks.

Peripheral neuropathies that involve nerve roots (polyradiculopathies, such as acute inflammatory demyelinating polyradiculoneuropathy, the most common cause of the Guillain-Barré syndrome) usually cause proximal muscle weakness that results in difficulty arising from a chair, climbing stairs, or working with the arms over the head (e.g., washing or combing hair). Positive motor symptoms, which are less common, include cramps and fasciculations, which are characteristic of disorders involving the motor neuron (e.g., amyotrophic lateral sclerosis) but also may be seen in peripheral neuropathies.

Careful examination of deep tendon reflexes is an important part of the clinical examination. Absence of reflexes often reflects a demyelinating neuropathy. In patients with acute numbness or weakness, this finding suggests Guillain-Barré syndrome. Length-dependent reduction or loss of reflexes (e.g., in Achilles tendons) is common in peripheral polyneuropathies. Because both the afferent and efferent limbs of the deep tendon reflexes involve large myelinated fibers, reflexes are often normal in neuropathies that preferentially involve small-diameter lightly myelinated and unmyelinated axons.

Autonomic symptoms ( Chapter 386 ) are frequent in neuropathies associated with diabetes ( Chapter 210 ) or amyloidosis ( Chapter 174 ) and include urinary retention or incontinence, abnormalities of sweating, constipation alternating with diarrhea, and lightheadedness when standing. Erectile dysfunction is frequent in men.

Diagnosis

A Systematic Approach to Patients with Neuropathy

Diagnosis of peripheral neuropathies is founded on neuroanatomical localization ( Table 388-1 ). The pattern of involvement is often appreciable with a careful history. The most common form of neuropathy is peripheral polyneuropathy. Polyneuropathies cause length-dependent, “stocking glove” symptoms and signs. Most polyneuropathies are sensory predominant, although some forms, particularly inherited polyneuropathies, cause more weakness than sensory loss. Multifocal and asymmetrical distal predominant motor and sensory signs and symptoms usually suggest a disorder involving multiple individual peripheral nerves (“mononeuritis multiplex”). Polyradiculopathies, which involve multiple nerve roots, cause non–length-dependent motor and sensory signs and symptoms that involve both proximal and distal locations. Recognition of a specific pattern can suggest a diagnosis. For example, a patient with stepwise development of asymmetrical distal weakness, pain, and numbness likely has a mononeuritis multiplex, which is usually caused by a vasculitis ( Chapter 249 ).

TABLE 388-1

TYPES OF NEUROPATHIES

PERIPHERAL NERVOUS SYSTEM LOCALIZATION	SYSTEMS INVOLVED	ANATOMIC DISTRIBUTION	EXAMPLES
Acquired peripheral polyneuropathy	Positive sensory symptoms and sensory signs; usually less motor involvement	Symmetrical and length dependent (“stocking glove”) sensory loss and weakness	Diabetes, cryptogenic sensory peripheral neuropathy, chemotherapy-induced peripheral neuropathy
Genetic peripheral polyneuropathy	Motor often greater than sensory, with primarily negative sensory symptoms (numbness), high arched feet, and hammer toes	Symmetrical and length-dependent (“stocking glove”) weakness and sensory loss	Charcot-Marie-Tooth disease
Mononeuritis multiplex	Motor and sensory, often painful	Asymmetrical, usually distal predominant	Vasculitis (systemic and primary peripheral nervous system)
Polyradiculopathy	Motor greater than sensory involvement	Proximal and distal; usually symmetrical but may be asymmetrical	Acute or chronic inflammatory demyelinating polyradiculoneuropathy (symmetrical); diabetic radiculoplexus neuropathy (asymmetrical)
Sensory neuronopathy (dorsal root ganglionopathy)	Sensory only, usually with ataxia and often painful	Proximal and distal, and asymmetrical	Sjögren syndrome, paraneoplastic (anti-Hu), idiopathic

Approximately 50% of patients with an acquired peripheral polyneuropathy have diabetes ( Chapter 210 ), and most of the remainder have cryptogenic sensory peripheral neuropathy. Over half of patients with cryptogenic sensory peripheral neuropathy have prediabetes or previously unrecognized mild diabetes, and up to 80% have the metabolic syndrome. Every patient with this pattern of polyneuropathy should be evaluated for diabetes and prediabetes, paraproteinemia ( Chapter 173 ), and vitamin B ₁₂ deficiency ( Chapter 199 ). In the absence of clinical evidence of a systemic disorder or history of toxic exposure associated with peripheral polyneuropathy ( Table 388-2 ), additional diagnostic evaluation is usually unhelpful.

TABLE 388-2

SELECTED CAUSES FOR TOXIC NEUROPATHIES

TOXIN CATEGORY	SPECIFIC AGENTS
Antineoplastic agents	Paclitaxel, cisplatin, oxaliplatin, bortezomib, thalidomide
Antimicrobials	Chloroquine, dapsone, isoniazid, metronidazole, nitrofurantoin
Cardiac medications	Amiodarone, perhexiline, hydralazine
Other medications	Colchicine, gold salts, phenytoin, disulfiram, pyridoxine
Heavy metals	Lead (wrist drop), arsenic, thallium (alopecia), mercury
Organic solvents	Hexane, acrylamide, vacor

Disorders of the peripheral nervous system usually conform to one of ten patterns, which reflect the underlying neuroanatomic pattern of impairment of sensory, motor, and/or autonomic function caused by the specific disorder. Recognition of a specific pattern narrows the differential diagnosis and focuses the diagnostic evaluation ( Table 388-3 ).

TABLE 388-3

TEN TYPICAL PATTERNS OF NERVOUS SYSTEM DISORDERS

ANATOMIC PATTERN	NEUROANATOMIC LOCALIZATION	DIFFERENTIAL DIAGNOSIS
1. Symmetrical proximal and distal weakness with sensory loss	Polyradiculoneuropathy	Acute inflammatory demyelinating polyradiculoneuropathy if acute and maximal involvement within the first 4 weeks, chronic inflammatory demyelinating polyneuropathy if progressive over >8 weeks
2. Symmetrical distal sensory loss with or without distal weakness	Peripheral polyneuropathy	Cryptogenic sensory peripheral neuropathy, diabetes or other metabolic disorders, toxic, hereditary such as Charcot-Marie-Tooth
3. Asymmetrical distal weakness with sensory loss	Mononeuritis multiplex	Vasculitis, hereditary neuropathy with predisposition to pressure palsies, multifocal acquired demyelinating sensory and motor neuropathy, infections (e.g., leprosy)
	Mononeuropathy or radiculopathy	Compression, trauma, or tumor
4. Asymmetrical proximal and distal weakness with sensory loss	Polyradiculopathy	Polyradiculopathy or plexopathy due to diabetes (diabetic lumbosacral radiculoplexus neuropathy) or a meningeal disorder (carcinoma, lymphoma, sarcoidosis, chronic infection)
5. Asymmetrical distal weakness without sensory loss	Motor neuronopathy with upper motor neuron signs (brisk reflexes, spasticity, Babinski responses)	Amyotrophic lateral sclerosis Progressive muscular atrophy, multifocal motor neuropathy, monomelic amyotrophy (Hirayama disease)
	Motor neuronopathy (lower motor neurons) or motor neuropathy
6. Symmetrical sensory loss with distal areflexia with upper motor neuron findings	Mixed myelopathy and polyneuropathy	Severe combined degeneration due to vitamin B 12 or copper deficiency or to inherited disorders (adrenomyeloneuropathy, metachromatic leukodystrophy, Friedreich ataxia)
7. Symmetrical weakness without sensory loss	Motor neuronopathy	Proximal and distal: spinal muscular atrophy or progressive muscular atrophy
	Motor neuropathy	Distal predominant: hereditary motor neuropathy
8. Focal midline proximal weakness	Motor neuronopathy, neuromuscular junction disorder, myopathy	Neck extensor weakness (head drop): amyotrophic lateral sclerosis, myasthenia gravis, myopathy
		Bulbar weakness: amyotrophic lateral sclerosis, myasthenia gravis
9. Asymmetrical sensory loss with sensory ataxia without weakness	Sensory neuronopathy/ganglionopathy	Sjögren, paraneoplastic (anti-Hu antibody), idiopathic
	Sensory polyradiculoneuropathy	Chronic immune sensory polyradiculoneuropathy
10. Autonomic symptoms and signs	Autonomic neuropathy	Diabetes, amyloid, autoimmune autonomic neuropathies

Any pattern other than typical neuropathy, or the presence of any atypical “red flag” (e.g., an acute onset suggestive of inflammatory, infectious, or toxic causes; proximal involvement; motor predominance; significant ataxia; or asymmetry), should prompt additional diagnostic evaluation to assess the neuroanatomic localization, underlying physiology (demyelinating versus axonal), and structural changes ( Fig. 388-1 ).

Nerve and Skin Biopsy

The most common indications for biopsy of a distal sensory nerve, usually the sural or superficial peroneal sensory nerve, is peripheral nerve vasculitis ( Fig. 388-2 ). Among patients referred for suspected peripheral nerve vasculitis, a simultaneous muscle biopsy increases diagnostic yield from approximately 50% to 60 to 70%. The second most common indication for nerve biopsy is evaluation for suspected light chain amyloidosis ( Chapter 174 ). Nerve masses usually require a biopsy to diagnose a potential tumor. Rarely, nerve biopsy may be useful in the diagnosis of other infiltrative or inflammatory disorders.

Skin biopsies are routinely performed to confirm the presence of a small fiber neuropathy in patients with distal symmetrical sensory loss with neuropathic pain ( Fig. 388-3 ), in which nerve conduction studies are usually normal, with an antibody that binds to all axons (PGP 9.5). The diagnosis of small fiber neuropathy is based on demonstrating a reduced density of intraepidermal nerve fibers.

Epidemiology and Pathobiology

Charcot-Marie-Tooth disease has a prevalence of 1 : 2500 and is caused by mutations that affect myelin formation. Autosomal dominant Charcot-Marie-Tooth is subdivided into demyelinating (CMT1) and axonal (CMT2) forms based on electrophysiologic criteria. Many patients have de novo mutations. X-linked (CMTX) and autosomal recessive demyelinating (CMT4) and axonal (CMT-AR2) forms are also seen. Each type is further subdivided by the specific genetic cause. The most common form, CMT1A, is caused by a duplication of a fragment of chromosome 17 containing the peripheral myelin protein 22-kD (PMP22) gene. The most common form of CMT2 is a mutation in the mitofusin gene (CMT2A). Overall, CMT1A accounts for roughly 50% of all cases of Charcot-Marie-Tooth disease, CMT1X accounts for 10 to 20%, CMT1B for less than 5%, and CMT2 for 20%. However, mutations have been identified in more than 100 genes, and this number is likely to increase substantially in the future.

Clinical Manifestation

Classic Charcot-Marie-Tooth disease causes slowly progressive distal weakness and sensory loss, often beginning in the first 2 decades of life, but an increasing number of patients are being identified well into adulthood and even in later years of life. Children are often slow runners and have impaired balance (e.g., skating, walking across a log). Ankle-foot orthoses are frequently required by the third decade. Fine hand movements (e.g., fastening jewelry, turning a key, or using buttons and zippers) may be impaired. Most patients have distal leg atrophy (inverted champagne bottle) with high arched feet (pes cavus) and hammer toes ( Fig. 388-4 ). Nevertheless, many patients remain ambulatory throughout life, and most have a normal lifespan. A minority of patients have a more severe phenotype with delayed motor milestones and onset in infancy (Dejerine-Sottas neuropathy).

Patients with hereditary motor neuropathies sometimes have mild sensory abnormalities, and patients with hereditary sensory and autonomic neuropathies usually have some weakness. The extent of motor or sensory loss can sometimes alter the classification. For example, the same mutations in the same gene ( GARS ) may cause both CMT2D and hereditary motor neuropathy type V ( Video 388-1 ).

Diagnosis

Genetic testing is the gold standard for accurately diagnosing patients with inherited neuropathies, but it should be combined with a careful family history, clinical examination, and neurophysiologic testing. The diagnostic yield of genetic testing is highest among patients with clinical onset at a young age and a positive family history. For CMT1A, which comprises about 50% of cases of Charcot-Marie-Tooth disease, genetic testing must specifically search for a PMP22 duplication, which will not be diagnosed by next-generation sequencing. If this test is negative or in patients with axonal variants (CMT2), next-generation sequencing is typically performed. Since not all variants are pathogenic and many are described as variants of uncertain significance, it is essential to determine, if possible, whether a given variant tracks with neuropathy in a family, whether the variant is common in population databases, and whether it is predicted to be pathogenic in animal or in silico models.

Treatment

Prognosis

A detailed family history and examination of family members may be required for prognosis and genetic counseling. In general, Charcot-Marie-Tooth is a slowly progressive disorder that does not affect longevity, although many patients experience progressive gait difficulties with aging. The prognosis and degree of disability vary among specific forms.

Treatment

Prognosis

Death has typically occurred within a decade of diagnosis owing to cardiac or autonomic failure unless patients underwent liver transplantation. As noted earlier, however, new molecular therapies, including inotersen and patisiran, can substantially slow progression, with their long-term benefits still to be determined.

Definition

Guillain-Barré syndrome refers to acquired, inflammatory polyradiculoneuropathies that share an acute onset, elevated cerebrospinal fluid (CSF) protein levels with low cell counts (cytoalbuminologic dissociation), and a monophasic course. Guillain-Barré syndrome is subdivided into demyelinating (acute inflammatory demyelinating polyradiculoneuropathy), and axonal (acute motor and sensory axonal neuropathy and acute motor axonal neuropathy) variants, and the Miller-Fisher syndrome.

Epidemiology

The annual incidence of Guillain-Barré syndrome is 1 to 2 per 100,000, although in some areas the incidence may be higher. Acute inflammatory demyelinating polyradiculoneuropathy accounts for 97% of cases in North America and Europe with an incidence of 0.6 to 1.9 cases per 100,000. Men are more often affected than women (1.4 : 1). In 60% of patients, a respiratory tract infection or gastroenteritis precedes Guillain-Barré syndrome. Patients with axonal variants are particularly likely to have had a prior Campylobacter jejuni diarrheal illness. In Belgium and the Netherlands, 5 to 10% of patients have a preceding hepatitis E infection ( Chapter 134 ), thereby emphasizing the regional variability in infectious triggers. Guillain-Barré syndrome does not appear to be substantially associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination ( Chapters 335 to 337 ), aside from a slight increase in risk of 0.6 cases/100,000 doses for the ChADOx1nCoV-19 vaccine, and the incidence of Guillain-Barré syndrome actually declined during the pandemic likely due to a reduced incidence of communicable diseases known to provoke Guillain-Barré syndrome. In contrast, Zika virus ( Chapter 352 ) has been associated with a significantly increased risk of all forms of Guillain-Barré syndrome, as well as a transient polyneuritis pattern of mild distal sensory symptoms (acute peripheral polyneuropathy).

Pathobiology

All forms of Guillain-Barré syndrome probably result from postinfectious molecular mimicry, in which the immune system attacks peripheral nerve antigens because they resemble antigens presented by microbes, in particular, C. jejuni . For example, the HS/0:19 serotype of C. jejuni is common in patients with the acute motor axonal neuropathy form of Guillain-Barré syndrome in northern China and other countries. However, it is not clear that molecular mimicry causes acute inflammatory demyelinating polyradiculoneuropathy, which is the most common form in the United States and Europe.

Clinical Manifestations

Weakness is the most common initial symptom. It can be mild, such as difficulty walking, or severe, with total quadriplegia and respiratory failure. The most common manifestation is leg weakness that progresses into the arms. Bilateral facial weakness occurs in 50% of patients and may lag behind limb weakness. Although Guillain-Barré syndrome has been described as an “ascending paralysis,” proximal weakness is common, and 5% of patients have isolated cranial nerve involvement that subsequently descends into the limbs. Slight sensory loss occurs in most patients. The autonomic nervous system is involved in about 65% of cases.

Acute motor sensory axonal neuropathy is clinically similar to acute inflammatory demyelinating polyradiculoneuropathy except it is typically more severe because of primary injury to axons rather than to myelin. Autonomic dysfunction is more common. Weakness without sensory loss develops in acute motor axonal neuropathy, including cranial nerve involvement in about 25% of patients.

The Miller-Fisher syndrome consists of the triad of ophthalmoplegia, ataxia, and areflexia. Facial weakness, ptosis, and pupillary abnormalities may be present. Nerve conduction velocities in Miller-Fisher syndrome are normal, unlike acute inflammatory demyelinating polyradiculoneuropathy.

Diagnosis

The diagnosis of acute inflammatory demyelinating polyradiculoneuropathy and acute motor sensory axonal neuropathy is based on the history, physical examination, CSF evaluation, and nerve conduction studies. Weakness is symmetrical, and deep tendon reflexes are decreased or absent. The presence of other CNS abnormalities should cast doubt on the diagnosis.

CSF analysis typically reveals high protein with a paucity of white blood cells (WBCs). The CSF should have fewer than 5 WBCs/mL; a CSF cell count greater than 50 WBCs/mL suggests HIV seroconversion ( Chapters 355 and 359 ) or infections such as Lyme disease ( Chapter 296 ). Acute inflammatory demyelinating polyradiculoneuropathy is distinguished from acute motor sensory axonal neuropathy by nerve conduction studies. Because elevated CSF protein level and abnormal nerve conduction studies may not be apparent in the first 7 to 10 days of the illness and because CSF protein remains normal in up to 10% of cases, the initial treatment decision often must be made based on clinical judgment. Most Miller-Fisher syndrome patients (>85%) have polyclonal antibodies that react to the ganglioside GQ _1b .

Treatment

Prognosis

Fifty percent of patients progress to maximum disability within 2 weeks of the onset of symptoms, 75% within 3 weeks, and greater than 90% within 4 weeks. With supportive care, mortality is 3% at 6 months, primarily in the elderly and severely affected patients, and especially during the recovery phase. After a brief period of stabilization, slow recovery occurs over weeks to months. Most patients recover completely or are left with minor sequelae; 20% have a persistent disability. The prognosis is poorer in patients who present with weakness, have axonal variants, or have acute inflammatory demyelinating polyradiculoneuropathy with significant axonal loss as reflected by reduced compound muscle action potential amplitudes in the upper extremities. Other predictors of a poor prognosis include older age, preceding diarrheal illness, and the severity of weakness.

Definition

Chronic inflammatory demyelinating polyradiculoneuropathy is usually slowly progressive but may be monophasic or relapsing. By definition, it develops over at least 2 months and more slowly than acute inflammatory demyelinating polyradiculoneuropathy, which it otherwise resembles.

Epidemiology

Chronic inflammatory demyelinating polyradiculoneuropathy occurs in all age groups, with a mean age of 30 to 50 years. Women are more likely to be affected. Antecedent events in about 30% of patients include upper respiratory infections, gastrointestinal infections, vaccinations, surgery, and trauma. In some patients it is a paraneoplastic phenomenon, especially with non-Hodgkin lymphoma ( Chapter 171 ).

Pathobiology

Chronic inflammatory demyelinating polyradiculoneuropathy is considered an autoimmune disorder based on its pathology and experimental models, in which a similar disorder follows immunization with peripheral nervous system myelin components and Freund adjuvant. Nerve biopsy shows macrophage-mediated segmental demyelination, occasional endoneurial lymphocytic T-cell infiltrates, and endoneurial edema. Major histocompatibility complex class I and II antigens are upregulated, and there are often deposits of immunoglobulins and complement on the outer Schwann cell membranes or myelin sheaths. Chronic inflammatory demyelinating polyradiculoneuropathy can be passively transferred to animals by patient sera, but no clear autoantigen has been identified.

Clinical Manifestations

Weakness and sensory loss begin insidiously and progress over a period of months to years. Weakness, which involves both proximal and distal muscles, is usually symmetrical. The absence of proximal weakness suggests a polyneuropathy. Patients often require assistance with ambulation. Loss of proprioception from damage to large-diameter sensory nerves may affect balance. Deep tendon reflexes are usually absent or markedly decreased. Facial weakness (15%), ptosis, or ophthalmoparesis (5%) may occur. Variants include pure motor, pure sensory, and multifocal forms (multifocal acquired demyelinating sensory and motor neuropathy).

Diagnosis

Diagnosis is based on clinical symptoms and signs, CSF examination, and electrodiagnostic studies. CSF results resemble those of acute inflammatory demyelinating polyradiculoneuropathy: WBC counts are usually fewer than 10 cells/µL, and the level of protein is greater than 60 mg/dL. A CSF WBC count greater than 50/µL suggest another diagnosis, such as HIV infection or hematologic malignancy.

Nonuniform, asymmetrical slowing of motor nerve conduction velocity with prolonged minimal F wave latencies is typical. Compound muscle action potential amplitudes are generally reduced because of secondary axonal degeneration. Sensory nerve action potential amplitudes are usually reduced or absent.

Many patients, however, do not meet formal electrophysiologic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. The combination of symmetrical onset of weakness involving all four limbs with proximal weakness in at least one limb has a comparable diagnostic accuracy (sensitivity 83%, specificity 97%).

A subset of patients with severe disability, subacute onset, tremor, sensory ataxia, and poor response to IVIG have antibodies reactive against contactin or neurofascin. These antibodies, which are usually of the immunoglobulin (Ig) G4 isotype, bind to the nodal and paranodal region.

Treatment