Structure of Peripheral Nerves

The peripheral nerve is a cable-like structure containing bundles of both unmyelinated and myelinated fibers and their supporting elements. The unmyelinated axons are surrounded only by the plasma membrane of a Schwann cell. The myelinated axons are engulfed by a Schwann cell that wraps around the axons multiple times, thereby insulating the axon with multiple layers of lipid-rich cell membrane. The myelinated axon is surrounded completely by myelin and Schwann cells except at regular gaps called the nodes of Ranvier, which measure approximately 1 µm in adults. The propagation of action potentials from one node of Ranvier to the next (saltatory conduction) is maintained by a thick myelin sheath with low capacitance and high resistance to electric current and by a high concentration of voltage-gated sodium channels at the nodes of Ranvier.

Pathological Processes Involving Peripheral Nerves

Despite the large number of causes for neuropathy, the pathological reactions of peripheral nerves to various insults remain limited. In general, these pathological processes can be divided into four main categories: (1) wallerian degeneration, which is the response to axonal interruption, (2) axonal degeneration or axonopathy, (3) primary neuronal (perikaryal) degeneration or neuronopathy, and (4) segmental demyelination or myelinopathy. The patient’s symptoms, the type and pattern of distribution of signs, and the characteristics of nerve conduction study abnormalities provide information about the underlying pathological changes.

Any type of mechanical injury that causes interruption of axons leads to wallerian degeneration—that is, distal degeneration of axons and their myelin sheaths. Immediately following injury, motor weakness and sensory loss occur in the distribution of the damaged nerve, as well as complete loss of voluntary activity (with a complete lesion) or a decrease in motor unit action potential (MUAP) recruitment (with a partial lesion) on needle electromyogram (EMG). However, the axons remain excitable distally, since distal conduction failure is not completed until 10 to 11 days later as the distal nerve trunk becomes progressively unexcitable. On nerve conduction studies, the amplitude of the compound muscle action potential (CMAP) begins to decline by the second day after injury and reaches its nadir by the fifth to sixth. For sensory axons, the loss of sensory nerve action potential (SNAP) is delayed by another 2 to 3 days; distal SNAP remains normal for 5 to 6 days and then decreases rapidly to reach its nadir by 10 to 11 days after injury (see Fig. 32B.9 in Chapter 32B). The temporal sequence of wallerian degeneration is length dependent, occurring earlier in shorter than in longer distal nerve stumps. Denervation potentials (fibrillation potentials) are typically seen on needle EMG in some affected muscles 10 to 14 days after injury and become full after 3 weeks from acute nerve injury. Axonal interruption initiates secondary morphological changes of the nerve cell body, termed chromatolysis, and the proximal axonal caliber becomes smaller. Regeneration from the proximal stump begins as early as 24 hours following transection but proceeds slowly at a maximal rate of 2 to 3 mm/day and is often incomplete. The quality of recovery depends on the degree of preservation of the Schwann cell/basal lamina tube and the nerve sheath and surrounding tissue, the distance of the site of injury from the cell body, and the patient’s age.

Axonal degeneration (or axonopathy), the most common pathological reaction of peripheral nerve, signifies distal axonal breakdown and is presumably caused by metabolic derangement within neurons or ischemia. Systemic metabolic disorders, toxin exposure, vasculitis, and some inherited neuropathies are the usual causes of axonal degeneration. The myelin sheath breaks down concomitantly with the axon in a process that starts at the most distal part of the nerve fiber and progresses toward the nerve cell body, hence the term dying-back or length-dependent polyneuropathy (Fig. 76.1). A similar sequence of events may occur simultaneously in centrally directed sensory axons, resulting in distal degeneration of rostral dorsal column fibers. The selective length-dependent vulnerability of distal axons could result from failure of the perikaryon to synthesize enzymes or structural proteins, from alterations in axonal transport, or from regional disturbances of energy metabolism. In some axonopathies, alterations in axon caliber, either axonal atrophy or axonal swelling, may precede distal axonal degeneration. Clinically, dying-back polyneuropathy presents with symmetrical distal loss of sensory and motor function in the lower extremities that extends proximally in a graded manner. The result is sensory loss in a stocking-like pattern, distal muscle weakness and atrophy, and loss of distal limb myotatic reflexes. Axonopathies result in low-amplitude SNAPs and CMAPs, but they affect distal latencies and conduction velocities only slightly. Needle EMG of distal muscles shows acute and/or chronic of denervation changes (see Chapter 32B). Because axonal regeneration proceeds at a maximal rate of 2 to 3 mm/day, recovery may be delayed and is often incomplete.

Fig. 76.1 Diagram of the main pathological events of distal axonal degeneration or axonopathy. Jagged lines indicate that either a toxin or a metabolic insult acts at multiple sites along motor and sensory axons in the peripheral nervous system (PNS) and central nervous system (CNS). Axonal degeneration begins at the most distal part of the nerve fiber and progresses proximally by the late stage. Recovery occurs by axonal regeneration but is impeded by astroglial proliferation in the CNS.

(Adapted from Schaumburg, H.H., Spencer, P.S., Thomas, P.K., 1983. Disorders of Peripheral Nerves. Davis, Philadelphia.)

Neuronopathy designates loss of nerve cell bodies with resultant degeneration of their entire peripheral and central axons. Either anterior horn or dorsal root ganglion cells may be affected. When anterior horn cells are affected, as in anterior poliomyelitis or motor neuron disease, focal weakness without sensory loss results. Sensory neuronopathy, or dorsal polyganglionopathy, means damage to dorsal root ganglion neurons that results in sensory ataxia, sensory loss, and diffuse areflexia (Fig. 76.2). A number of toxins such as organic mercury compounds, doxorubicin, and high-dose pyridoxine produce primary sensory neuronal degeneration. Immune-mediated inflammatory damage of dorsal root ganglion neurons occurs in paraneoplastic sensory neuronopathy and Sjögren syndrome. It is often difficult to distinguish between neuronopathies and axonopathies on clinical grounds alone. Once the pathological processes are no longer active, sensory deficits become fixed, and little or no recovery takes place.

Fig. 76.2 Diagram of the main pathological events of a sensory neuropathy or gangliopathy. A toxin (jagged lines) produces destruction of dorsal root ganglion (DRG) neurons, which results in degeneration of the peripheral-central axonal processes. Recovery is poor, as no axonal regeneration can take place. CNS, Central nervous system; PNS, peripheral nervous system.

(Adapted from Schaumburg, H.H., Spencer, P.S., Thomas, P.K., 1983. Disorders of Peripheral Nerves. Davis, Philadelphia.)

The term segmental demyelination (or myelinopathy) implies injury of either myelin sheaths or Schwann cells, resulting in breakdown of myelin with sparing of axons (Fig. 76.3). This occurs mechanically by acute nerve compression or chronic nerve entrapment and in immune-mediated demyelinating neuropathies and hereditary disorders of Schwann cell/myelin metabolism. Primary myelin damage may be produced experimentally by myelinotoxic agents such as diphtheria toxin or by acute nerve compression. Remyelination of demyelinated segments usually occurs within weeks. The newly formed remyelinated segments have thinner-than-normal myelin sheaths and internodes of shortened length. Repeated episodes of demyelination and remyelination produce proliferation of multiple layers of Schwann cells around the axon, termed an onion bulb. The physiological consequence of acquired demyelination, such as in inflammatory or compressive demyelination but not hereditary myelinopathies, is conduction block, which results in loss of the ability of the nerve action potential to reach the muscle, thereby producing weakness. Because the axon remains intact, there is little muscle atrophy. Relative sparing of temperature and pinprick sensation in many demyelinating polyneuropathies reflects preserved function of unmyelinated and small-diameter myelinated fibers. Early generalized loss of reflexes, disproportionately mild muscle atrophy in the presence of proximal and distal weakness, neuropathic tremor, and palpably enlarged nerves are all clinical clues that suggest demyelinating polyneuropathy. Nerve conduction studies or analysis of single teased nerve fiber preparations stained with osmium can confirm demyelination. Demyelination is present if motor and sensory nerve conduction velocities (NCVs) are reduced to less than 70% of the lower limits of normal, with relative preservation of response amplitudes. The presence of partial motor conduction block, temporal dispersion of CMAPs, and marked prolongation of distal motor and F-wave latencies are all features consistent with acquired demyelination (see Chapter 32B). Recovery depends on the extent of remyelination, and therefore clinical improvement may occur within days to weeks. It should be noted that in many demyelinating neuropathies, axonal degeneration may also coexist.

Fig. 76.3 Diagram of the main pathological events of primary segmental demyelination in immune-mediated inflammatory polyradiculoneuropathies. Attack by inflammatory cells causes patchy multifocal demyelination along nerve fibers but spares their axons. Recovery occurs by remyelination. Demyelinated segments become invested by several Schwann cells, resulting in a decrease in internodal length of those areas. CNS, Central nervous system; PNS, peripheral nervous system.

(Adapted from Schaumburg, H.H., Spencer, P.S., Thomas, P.K., 1983. Disorders of Peripheral Nerves. Davis, Philadelphia.)

Classification of Peripheral Nerve Disorders

There are several patterns of peripheral nerve disease (Box 76.1). Brachial, lumbar, and sacral plexopathy are discussed in Chapter 75, and radiculopathies are discussed in Chapter 74.

A mononeuropathy means focal involvement of a single nerve and implies a local process. Direct trauma, compression, entrapment, vascular lesions, and neoplastic compression or infiltration are the most common causes. Electrophysiological studies provide a more precise localization of the lesion than may be possible by clinical examination, can distinguish axonal loss from focal segmental demyelination, and sometimes may reveal a more widespread change indicating an underlying generalized polyneuropathy that has made the nerve susceptible to entrapment, as occurs in diabetes mellitus, hypothyroidism, acromegaly, alcoholism, and hereditary neuropathy with liability to pressure palsy (HNPP).

Multiple mononeuropathies, or mononeuropathy multiplex, signify simultaneous or sequential damage to multiple noncontiguous nerves. Confluent multiple mononeuropathies may give rise to motor weakness with sensory loss that can simulate a length-dependent peripheral polyneuropathy.

Polyneuropathy is most commonly characterized by symmetrical distal motor and/or sensory deficits that typically have a graded increase in severity distally and distal attenuation of reflexes. The sensory and motor deficits generally follow a length-dependent stocking-glove pattern. Most polyneuropathies are fairly symmetrical, but some are asymmetrical and may be confused with confluent mononeuropathy multiplex. A small number of polyneuropathies (e.g., that associated with acute intermittent porphyria [AIP]) can be predominantly proximal. It is helpful to determine the relative extent of sensory, motor, and autonomic neuron involvement, although most polyneuropathies produce mixed sensorimotor deficits and some degree of autonomic dysfunction.

Diagnostic Clues from the History

The symptoms of peripheral nerve disorders fall under the general headings of motor, sensory, or autonomic disturbances. The inquiry should seek both negative and positive symptoms. Negative motor symptoms are weakness, atrophy, and walking difficulties. Muscle cramps, fasciculations, myokymia, or tremor are positive manifestations of motor nerve dysfunction. In polyneuropathies, negative motor symptoms include early distal toe and ankle extensor weakness, resulting in tripping on rugs or uneven ground. However, a complaint of difficulty walking in itself does not distinguish muscle weakness from sensory, pyramidal, extrapyramidal, or cerebellar disturbance. If the fingers are weak, patients may complain of difficulty opening jars or turning a key in a lock.

Positive sensory symptoms include prickling, searing, burning, and tight band-like sensations. Paresthesias are unpleasant sensations arising spontaneously without apparent stimulus. The presence of spontaneously reported paresthesias is helpful in distinguishing acquired (>60% of patients) from inherited (≈17% of patients) polyneuropathies. Allodynia refers to the perception of nonpainful stimuli as painful, and hyperalgesia is painful hypersensitivity to noxious stimuli. Neuropathic pain, the extreme example of a positive symptom, is a cardinal feature of many neuropathies. Neuropathic pain often has a deep, burning, or drawing character that may be associated with jabbing or shooting pains that typically increases at night or during periods of rest.

Symptoms of autonomic dysfunction can be helpful in directing attention toward specific neuropathies that have prominent autonomic symptoms. It is important to ask about orthostatic intolerance (lightheadedness, presyncopal symptoms or syncope), reduced or excessive sweating, heat intolerance, and bladder, bowel, and sexual dysfunctions. Anorexia, early satiety, nausea, and vomiting are symptoms suggestive of gastroparesis. The degree of autonomic involvement can be documented by noninvasive autonomic function studies (see Chapter 77).

Historical information regarding onset, duration, and evolution of symptoms provides important clues to diagnosis. Knowledge about the time course of disease (acute, subacute, or chronic) and the course (monophasic, progressive, or relapsing) narrows diagnostic possibilities. Guillain-Barré syndrome (GBS), acute porphyria, vasculitis, neuralgic amyotrophy and some forms of toxic neuropathies have acute presentations. A relapsing course is found in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), acute porphyria, Refsum disease, hereditary neuropathy with liability to pressure palsies (HNPP), familial brachial plexus neuropathy, and repeated episodes of toxin exposure.

In patients with a chronic indolent course over many years, inquiries about similar symptoms and bony deformities (such as pes cavus) in immediate relatives often point to a familial polyneuropathy. Inherited polyneuropathies are a major cause of undiagnosed polyneuropathies, accounting for about 30% of patients referred to tertiary centers for diagnosis. Molecular genetic testing or the clinical and electrophysiological evaluation of relatives of patients with undiagnosed neuropathy may corroborate that the disorder is familial. The presence of constitutional symptoms such as weight loss, malaise, and anorexia suggests an underlying systemic disorder as a cause of the polyneuropathy. Inquiry should be made about preceding or concurrent associated medical conditions (diabetes mellitus, hypothyroidism, chronic renal failure, liver disease, intestinal malabsorption, malignancy, connective tissue diseases, human immunodeficiency virus [HIV] seropositivity); drug use, including over-the-counter vitamin preparations (vitamin B₆); alcohol and dietary habits; and exposure to solvents, pesticides, or heavy metals.

Diagnostic Clues from the Examination

The first step in the examination of patients with neuropathy is to determine the anatomical pattern and localization of the disease process and whether motor, sensory, or autonomic nerves are involved.

In mononeuropathy, the neurological deficit follows the distribution of a single nerve. For example, in a patient with foot drop due to a common fibular (peroneal) nerve lesion, the neurological examination reveals weakness of ankle and toe dorsiflexion and ankle eversion, but ankle inversion, toe flexion, and plantar flexion are normal, since muscles controlling these functions are innervated by the tibial nerve. Similarly, sensory loss is restricted to the lower two-thirds of the lateral leg and dorsum of the foot, but sensation on the sole of the foot is normal.

In multiple mononeuropathies (mononeuropathy multiplex), the neurological findings should point to simultaneous or sequential damage to two or more noncontiguous peripheral nerves. Confluent multiple mononeuropathies, such as with involvement of the fibular and tibial nerves or median and ulnar nerves, may give rise to motor weakness with sensory loss that can simulate a length-dependent peripheral polyneuropathy. EDX studies ascertain whether the primary pathological process is axonal degeneration or segmental demyelination (Box 76.2). Approximately two-thirds of patients with multiple mononeuropathies display a picture of axonal damage. Ischemia caused by systemic or nonsystemic vasculitis or microangiopathy in diabetes mellitus should be considered. Other less common causes are disorders affecting interstitial structures of nerve, namely infectious, granulomatous, leukemic, or neoplastic infiltration, including Hansen disease (leprosy) and sarcoidosis. In the event focal demyelination or motor conduction block leads to multiple mononeuropathies, multifocal acquired demyelinating sensory and motor neuropathy (Lewis-Sumner syndrome), multifocal motor neuropathy, or HNPP should be considered.

In polyneuropathy, the sensory deficits generally follow a length-dependent stocking-glove pattern. By the time sensory disturbances of the longest nerves in the body (lower limbs) have reached the level of the knees, paresthesias are usually noted in the distribution of the second-longest nerves (i.e., those in the upper limbs) at the tips of the fingers. When sensory impairment reaches the midthigh, involvement of the third-longest nerves, the anterior intercostal and lumbar segmental nerves, gives rise to a tent-shaped area of hypoesthesia on the anterior chest and abdomen. Involvement of the recurrent laryngeal nerves may occur at this stage, with hoarseness. Motor weakness follows a dying-back pattern and usually is greater in extensor foot muscles than in corresponding flexors. For example, heel walking is affected earlier than toe walking in most polyneuropathies. It is helpful to determine the relative extent of sensory, motor, and autonomic fiber involvement, although most polyneuropathies produce mixed sensorimotor deficits and some degree of autonomic dysfunction.

Motor deficits tend to dominate the clinical picture in acute and chronic inflammatory demyelinating polyneuropathies, hereditary motor and sensory neuropathies, and in neuropathies associated with osteosclerotic myeloma, porphyria, lead toxicity, organophosphate intoxication, and hypoglycemia (Box 76.3). The distribution of weakness provides important information. Asymmetrical weakness without sensory loss suggests a motor neuronopathy such as motor neuron disease or multifocal motor neuropathy. The facial nerve can be affected in several peripheral nerve disorders (Box 76.4). In most polyneuropathies, the legs are more severely affected than the arms, with several notable exceptions (Box 76.5). Polyradiculoneuropathies cause both proximal and distal muscle weakness. For example, proximal and distal weakness is encountered in acute and chronic inflammatory demyelinating polyradiculoneuropathies, osteosclerotic myeloma, porphyria, and diabetic lumbar radiculoplexopathy. Nerve root involvement is confirmed by denervation in paraspinal muscles on needle EMG.

Autonomic dysfunction of clinical importance is seen in association with specific acute (e.g., GBS) or chronic (e.g., amyloid and diabetic) sensorimotor polyneuropathies. Rarely, an autonomic neuropathy can be the exclusive manifestation of a peripheral nerve disorder, without somatic nerve involvement (Box 76.6).

Predominant sensory involvement may be a feature of polyneuropathies caused by diabetes, carcinoma, Sjögren syndrome, dysproteinemia, acquired immunodeficiency syndrome (AIDS), vitamin B₁₂ deficiency, celiac disease, inherited and idiopathic sensory neuropathies, and intoxications with cisplatin, thalidomide, or pyridoxine. Loss of sensation in peripheral neuropathies often involves all sensory modalities. However, the impairment may be restricted to selective sensory modalities in many situations, which makes it possible to correlate the type of sensory loss with the diameter size of affected afferent fibers (Fig. 76.4). Pain and temperature sensation are mediated by unmyelinated and small myelinated Aδ fibers, whereas vibratory sense, proprioception, and the afferent limb of the tendon reflex are subserved by large myelinated Aα and Aβ fibers. Light touch is mediated by both large and small myelinated fibers. In polyneuropathies preferentially affecting small fibers, diminished pain and temperature sensation predominate, along with spontaneous burning pain, painful dysesthesias, and autonomic dysfunction. There is preservation of tendon reflexes, balance, and motor strength, and hence few abnormal objective neurological signs are found on examination. A pattern of sensory loss that is very characteristic is distal loss of pinprick sensation, above which is a band of hyperalgesia (exaggerated pain from noxious stimuli), with normal sensation above this level. Relatively few disorders cause selective small-fiber neuropathies (Mendell and Sahenk, 2003) (Box 76.7). Selective large-fiber sensory loss is characterized by areflexia, sensory ataxia, and loss of joint position and vibration sense. Loss of joint position may also manifest as pseudoathetosis (involuntary sinuous movements of fingers and hands when the arms are outstretched and the eyes are closed) and/or a Romberg sign (disproportionate loss of balance with eyes closed compared with eyes open). Striking sensory ataxia, together with pseudoathetosis or asymmetrical truncal or facial sensory loss, directs attention to a primary disorder of sensory neurons or polyganglionopathies. The differential diagnosis of ataxic sensory neuropathies is limited (Box 76.8).

Fig. 76.4 Myelinated fiber (MF) and unmyelinated fiber (UF) size-frequency histograms of a normal sural nerve. Fiber size distribution is bimodal for MF but unimodal for UF. MF density in normal sural nerve ranges from 6000 to 10,000 fibers/mm² of fascicular area. Number of UFs is normally about four times that of MFs. Corresponding compound nerve action potential recorded from the sural nerve in vitro is shown at top. Three distinct peaks indicated by arrows are, from left to right, Aa, Aa, and C-potentials, which correspond to large MF, small MF, and UF peaks, respectively.

Palpation of peripheral nerves is an important though unreliable part of the examination. Hypertrophy of a single nerve trunk suggests either a neoplastic process (e.g., neurofibroma, schwannoma, malignant nerve sheath tumor) or localized perineurial hypertrophic neuropathy. Generalized or multifocal nerve hypertrophy is found in a limited number of peripheral nerve disorders including leprosy, neurofibromatosis, Charcot-Marie-Tooth (CMT) disease types 1 and 3, acromegaly, Refsum disease, and rarely CIDP.

Certain telltale signs of the skin and its appendages may direct the experienced examiner to a specific diagnosis (Table 76.1): alopecia is seen in thallium poisoning, tightly curled hair in giant axonal neuropathy; white transverse nail bands termed Mees lines in arsenic or thallium intoxications; purpuric skin eruptions of the legs in cryoglobulinemia and some vasculitides; skin hyperpigmentation or hypertrichosis in POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes); telangiectasias over the abdomen and buttocks in Fabry disease; enlarged yellow-orange tonsils in Tangier disease; pes cavus and hammer toes in CMT disease; and overriding toes and ichthyosis in Refsum disease.

Table 76.1 Neuropathies with Skin, Nail, or Hair Manifestations

POEMS, Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.

Electrodiagnostic Studies

It is helpful to follow a decision-making pathway based initially on the overall pattern of distribution of deficits, followed by the electrophysiological findings, and finally the clinical course (Fig. 76.5). EDX studies, carefully performed and directed to the particular clinical situation, play a key role in the evaluation by (1) confirming the presence of neuropathy, (2) precisely locating focal nerve lesions, and (3) giving information as to the nature of the underlying nerve pathology (Gooch and Weimer, 2007; Wilbourn, A.J., 2002) (see Chapter 32B).

Fig. 76.5 Diagnostic approach to evaluation of a patient with peripheral neuropathy. Electromyography (EMG) denotes electrodiagnostic studies. DNA diagnostic testing or specific biochemical tests are available for conditions marked with asterisks. CIDP, Chronic inflammatory demyelinating polyradiculoneuropathy; CMT, Charcot-Marie-Tooth disease; CMTX, Charcot-Marie-Tooth disease X-linked; GBS, Guillain-Barré syndrome; HNPP, hereditary liability to pressure palsies; NP, neuropathy.

Because routine sensory nerve conduction studies assess only large myelinated fibers, such studies may be entirely normal in selective small fiber neuropathies. Quantitative sensory testing assessing cold and heat-pain thresholds, tests of sudomotor function, and skin biopsy with analysis of intraepidermal nerve fiber density may be helpful in confirming the unmyelinated nerve fiber abnormalities (Devigili et al., 2008). Since sweating mediated by unmyelinated sympathetic cholinergic fibers is often impaired, the quantitative sudomotor axon reflex (QSART) that evaluates sweating is a highly specific and sensitive method (sensitivity of 80%) to confirm small nerve fiber damage. Quantitative sensory testing assessing both vibratory and thermal detection thresholds has become a useful addition to the bedside sensory examination in controlled clinical trials. Its use in routine clinical practice remains limited because the test is still subjective in that it requires patient cooperation and is time consuming.

Nerve and Skin Biopsy

Skin punch or blister biopsies that demonstrate loss of intraepidermal nerve fibers is an alternative method for documenting small fiber neuropathy (Panoutsopoulou, 2009). Only unmyelinated intraepidermal networks of nerve fibers can be demonstrated by immunostaining with the panaxonal marker protein gene product 9.5, studied best with the use of confocal microscopy. Age, gender, and site of skin biopsy have a profound effect on epidermal nerve fiber density. The density of intraepidermal nerve fibers is reduced in skin biopsies obtained from patients with idiopathic, HIV-associated, diabetic, and other sensory neuropathies (Kennedy, 2004). Skin punch biopsy is most useful in patients with suspected small fiber neuropathy, when nerve conduction studies, are normal. The diagnosis of small-fiber neuropathy is best accomplished when at least two abnormal results are met, including positive clinical findings, quantitative sensory testing, QSART, and skin biopsy examinations (Devigili et al., 2008). Skin punch biopsy only detects the presence of skin nerve abnormalities and rarely leads to a specific etiological diagnosis. The skin biopsy also does not permit the study of myelinated fibers unless a thicker biopsy including dermis is obtained. Finally, unlike sural nerve biopsy, the interstitial pathological processes of the nerves cannot be studied.

Nerve biopsy (other than for the diagnosis of vasculitis and neoplasia) should be performed only in centers with established experience with the surgical procedure, handling of nerve specimens, and pathological technique; otherwise little useful information is likely to be obtained. The sural nerve is selected most commonly for biopsy, because the resultant sensory deficit is restricted to a small area over the heel and dorsolateral aspect of the foot, and because its morphology has been well characterized in health and disease. The superficial fibular nerve is an alternative lower-extremity cutaneous nerve suitable for biopsy and has the advantage of allowing simultaneous biopsy of the peroneus brevis muscle through the same incision. This combined distal nerve and muscle biopsy procedure increases the yield of identifying suspected vasculitis (Collins et al., 2000; Vital et al., 2006). In contrast, adding a proximal muscle (e.g., quadriceps) to a cutaneous nerve biopsy (e.g., sural) does not significantly increase the diagnostic yield compared to nerve biopsy alone (Bennett et al., 2008). In patients with proximal involvement of the lower limbs, the intermediate cutaneous nerve of the thigh combined with a muscle biopsy can be performed. When the risk of complication is increased from a biopsy of the lower limbs (e.g., in significant distal leg ischemia, edema) or the neuropathy is preferentially more pronounced in the upper limbs, a cutaneous nerve biopsy of superficial radial or antebrachial nerves may be performed. When the imaging studies indicate a plexus or nerve root pathological process (e.g., inflammatory, infiltrative), a fascicular biopsy of the affected nerve by an expert surgeon may provide invaluable information. Nerve biopsy has proved to be particularly informative when techniques such as single teased fiber preparations, semithin sections, ultrastructural studies, and morphometry are applied to quantitate the nerve fiber pathology. Nowadays, relatively few disorders remain in which a nerve biopsy is essential for diagnosis (Pleasure, 2007; Said, 2002) (Box 76.9). In general, nerve biopsy is most frequently diagnostic in suspected vasculitis, amyloid neuropathy, and leprosy. It is helpful in the recognition of CIDP, inherited disorders of myelin, and some rare axonopathies in which distinctive axonal changes occur, such as in giant axonal neuropathy and polyglucosan body disease. The availability of molecular genetic tests for several CMT neuropathies, HNPP, and familial transthyretin amyloidosis has decreased the necessity for nerve biopsy in these conditions.

Nerve biopsy is an invasive procedure and is associated with as high as 15% complication rate—particularly minor wound infections, wound dehiscence, and stump neuromas. Approximately one-third of patients (particularly those without much sensory loss initially) report unpleasant sensory symptoms at the sural nerve biopsy site that are still present 1 year after the biopsy (Gabriel et al., 2000). The area of the original sensory deficit declines by 90% after 18 months because of collateral reinnervation (Theriault et al., 1998). The complications may be greater if substantial foot ischemia is present or if the patient smokes cigarettes.

Other Laboratory Tests

The clinical neuropathic patterns and the results of EDX studies guide the experienced clinician to select the most appropriate laboratory tests. A few laboratory tests should be obtained routinely in all patients with peripheral polyneuropathy. These include complete blood cell count (CBC), sedimentation rate (with or without C-reactive protein), renal functions, fasting blood sugar, thyroid studies, vitamin B₁₂ level, and serum protein electrophoresis with immunofixation electrophoresis. It is important to screen for monoclonal proteins in all patients with chronic undiagnosed polyneuropathy, particularly those older than 60 years, because 10% of such patients have a monoclonal gammopathy. Cerebrospinal fluid (CSF) examination is helpful in the evaluation of suspected demyelinating neuropathies and polyradiculopathies related to meningeal carcinomatosis or lymphomatosis.

Several serum autoantibodies with reactivity to various components of peripheral nerve have been associated with peripheral neuropathy syndromes, and reference laboratories offer panels of nerve antibodies for sensory, sensorimotor, and motor neuropathies. It must be emphasized that the clinical relevance of most autoantibodies has not been established for patient treatment, and their use is not cost-effective (Vernino and Wolfe, 2007). Those of greatest clinical utility are listed in Table 76.2 (Kissel, 1998). An ever-increasing number of molecular genetic tests for inherited neuropathies is available at reference laboratories (see Hereditary Neuropathies, later).

Table 76.2 Neuropathies Associated with Serum Autoantibodies

Ig, Immunoglobulin.

In patients with initially undiagnosed peripheral neuropathy referred to specialized centers, a definite diagnosis can be made in more than 75% of cases. Inherited neuropathies, CIDP, and neuropathies associated with other systemic diseases accounted for most diagnoses. The improved diagnostic rate resulted in large measure from detailed clinical, EDX and laboratory evaluations and study of relatives of patients with undiagnosed neuropathy.

Definition and Classification of Mononeuropathies

Mononeuropathy is defined as a disorder of a single peripheral nerve. This may result from compression, traction, laceration, thermal, or chemical injury. The damage may involve one or more structural components of the peripheral nerve, while the pathophysiological responses to peripheral nerve lesions include axon loss, demyelination, or a combination of both.

Peripheral nerve injuries are classified based on functional status of the nerve and histological findings. Seddon divided peripheral nerve injury into three classes: neurapraxia, axonotmesis, and neurotmesis. This classification remains popular, particularly among surgeons, because of its correlation to outcome (Seddon, 1975). Later, Sunderland (1991) revised the classification into five degrees that have better prognostic implications.

Mononeuropathies of the Upper Extremities

Entrapment neuropathies of the upper extremities are shown in Table 76.3.

Median Nerve

Applied Anatomy

The median nerve, formed from contributions of the lateral cord (C6 and C7 fibers) and medial cord (C8 and T1 fibers) of the brachial plexus, runs into the forearm between the two heads of the pronator teres. It then gives off branches to the pronator teres, flexor carpi radialis, flexor digitorum sublimis, and the palmaris longus muscles and the anterior interosseous nerve. The anterior interosseous nerve is the largest branch of the median nerve and is a pure motor nerve. It arises from the median nerve distal to these motor branches in the upper forearm and innervates the flexor pollicis longus, pronator quadratus, and flexor digitorum profundus muscles of the index and middle fingers. The median nerve then enters the wrist through the carpal tunnel, formed by the carpal bones and the transverse carpal ligament, the latter forming its roof. Before reaching the wrist, the median nerve gives off the palmar cutaneous sensory branch which runs subcutaneously (not through the carpal tunnel) to innervate the skin over the thenar eminence. Distal to the carpal tunnel, the median nerve divides into motor and sensory divisions. The motor division innervates the first and second lumbricals and most muscles of the thenar eminence including the opponens pollicis, abductor pollicis brevis, and superficial head of the flexor pollicis brevis. The sensory fibers of the median nerve innervate the skin of the thumb, index, middle, and lateral half of the ring fingers.

Median Nerve Entrapment at the Wrist (Carpal Tunnel Syndrome)

Carpal tunnel syndrome (CTS) is by far the most common entrapment neuropathy. This entrapment occurs in the tunnel through which the median nerve and long finger flexor tendons pass. Because the transverse carpal ligament is an unyielding fibrous structure forming the roof of the tunnel, tenosynovitis or arthritis in this area often produces pressure on the median nerve. The syndrome is frequently bilateral and usually of greater intensity in the dominant hand.

Symptoms consist of nocturnal pain and paresthesias, most often confined to the thumb, index, and middle fingers, but may be reported to involve the entire hand. Patients complain of tingling numbness and burning sensations, often awakening them from sleep. Referred pain may radiate to the forearm and even as high as the shoulder (Stevens et al., 1999). Symptoms are often provoked after excessive use of the hand or wrist or during ordinary activities such as driving or holding a phone, book, or newspaper, in which the wrist is assumed in either a flexed or extended posture. Objective sensory changes may be found in the distribution of the median nerve, most often impaired two-point discrimination, pinprick and light touch sensation, or occasionally hyperesthesia in the thumb, index, and middle fingers, with sparing of the skin over the thenar eminence. Thenar (abductor pollicis brevis muscle) weakness and atrophy may be present in advanced cases of CTS (Fig. 76.6). Flexing the patient’s hand at the wrist for 1 minute (Phalen maneuver) or hyperextension of the wrist (reversed Phalen maneuver) can reproduce the symptoms, is present in about 80% of patients, and is rarely false positive. A positive Tinel sign, in which percussion of the nerve at the carpal tunnel causes paresthesias in the distribution of the distal distribution of the median nerve, is present in approximately 60% of affected patients but is not specific for CTS and may be false positive.

Fig. 76.6 Thenar atrophy in chronic bilateral carpal tunnel syndrome.

Work-related wrist and hand symptoms (repetitive motion injury) from cumulative trauma in the workplace have received increasing attention by the general public in recent years (Thomsen et al., 2002). Although a proportion of these cases have bona fide CTS, longitudinal natural history data suggest that the majority of industrial workers do not develop symptoms of CTS (Nathan et al., 1998). Symptoms consistent with hand and wrist arthritis in a variety of occupational settings are now recognized as being much more common than CTS (Dillon et al., 2002). CTS appears to occur in work settings that include repetitive forceful grasping or pinching, awkward positions of the hand and wrist, direct pressure over the carpal tunnel, and the use of handheld vibrating tools. Increased risk for the syndrome has been found in meat packers, garment workers, butchers, grocery checkers, electronic assembly workers, musicians, dental hygienists, and housekeepers. The highest reported incidence of work-related CTS, based on the number of carpal tunnel surgeries performed, was 15% among a group of meat packers. Although computer keyboard use has long been thought to be related to developing carpal tunnel symptoms, recent data provide no convincing correlation between intensive keyboard use and the subsequent development of CTS (Papanicolaou et al., 2001; Stevens et al., 2001).

Diseases and conditions that have been found to predispose to the development of CTS include pregnancy, diabetes, obesity, age, rheumatoid arthritis, hypothyroidism, amyloidosis, gout, acromegaly, certain mucopolysaccharidoses, arteriovenous shunts for hemodialysis, old fractures at the wrist, and inflammatory diseases involving tendons or connective tissues at the wrist level (Becker et al., 2002). On rare occasions, CTS may be familial, and some patients with CTS have carpal canals that are significantly narrower than average.

The most commonly performed EDX test for CTS are the median nerve sensory and motor conduction studies, which exhibit delayed sensory or motor latencies across the wrist in about 70% of patients. However, these studies are not sensitive enough in the diagnosis of CTS and fail to detect up to a third of patients with CTS, particularly those with mild and early symptoms. Recording the median latency at short distances over the course of the median nerve from palm to wrist and/or comparing this latency with the latency for the ulnar or radial nerve at the same distance (internal comparison nerve conduction studies) increase the sensitivity of these nerve conduction studies (Stevens, 1997) (Table 76.5).

Table 76.5 Internal Comparison Nerve Conduction Studies in the Evaluation of Carpal Tunnel Syndrome

Mild CTS must be distinguished from proximal median neuropathies, upper brachial plexopathy, C6 or C7 radiculopathies, and polyneuropathy involving the hands. Occasionally, a transient ischemic attack may mimic the symptoms of CTS.

In cases with only mild sensory symptoms, treatment with splints in neutral position, nonsteroidal antiinflammatory drugs (NSAIDs), and local corticosteroid injection often suffice. Withdrawal of provoking factors is also important. Although nonoperative treatments have been advocated (Osterman et al., 2002), a comparison of splinting versus surgery suggested that the latter may have a better long-term outcome than the former (Gerritsen et al., 2002). Use of a range of devices and appliances to protect the hand against CTS, including gel-padded gloves, has shown little if any improvement in objective measures of nerve function. Severe sensory loss and thenar atrophy suggest the need for surgical carpal tunnel release. Open surgical sectioning of the volar carpal ligament or fiberoptic techniques are often successful, with more than 90% of patients having prompt resolution of pain and paresthesias (Mirza and King, 1996). Improvement in distal latencies may lag behind the relief of symptoms. Comparing with preoperative values, nerve conduction studies demonstrate improvement in those with moderate abnormalities preoperatively, whereas patients with severe or no abnormalities on baseline nerve conduction studies had poorer results (Bland, 2001). A correlation between patients seeking workers’ compensation who hire attorneys and poorer operative outcomes has also been reported (Katz et al., 2001a). Older individuals may not improve as much as younger patients (Porter et al., 2002), and factors such as poor mental health, significant alcohol consumption, longer disease duration, and male gender also portend a poorer outcome. Rarely, symptoms persist after operation. Poor surgical results usually are associated with incomplete sectioning of the transverse ligament, surgical damage of the palmar cutaneous branch of the median nerve by an improperly placed skin incision, scarring within the carpal tunnel, or an incorrect preoperative diagnosis. Surgical reexploration may be required in diagnostically certain cases with poor response to the initial operation (Steyers, 2002).

Median Nerve Compressions at the Elbow

Anterior Interosseous Nerve Syndrome

In the relatively rare anterior interosseous nerve syndrome, the nerve may be compressed by fibrous bands attached to the flexor digitorum superficialis muscle, an anomalous muscle such as accessory head of the flexor pollicis longus (Gantzer muscle), or by an external compression such as with anterior elbow dislocations or complex elbow fractures. Isolated involvement of this nerve more often may suggest a partial neuralgic amyotrophy (idiopathic brachial plexus neuropathy, Parsonage-Turner syndrome) or less commonly a restricted form of multifocal motor neuropathy with conduction block. However, a careful and detailed electrophysiological study may reveal involvement of other nerves. Patients often complain of an acute or subacute onset of pain in the forearm or elbow. The patient is unable to flex the distal phalanges of the thumb and index finger, making it impossible to form a circle with those fingers (pinch or O sign). Sensory and motor nerve conduction studies of the median nerve are usually normal. Needle EMG reveals denervation in muscles innervated by the anterior interosseous nerve, including the flexor pollicis longus, pronator quadratus, and flexor digitorum profundus muscles of the index and middle fingers. Spontaneous recovery usually occurs within 3 to 12 months, and therefore surgery may not be necessary unless penetrating injury, fracture, or progressive deterioration and weakness are detected.

Pronator Teres Syndrome

In the pronator teres syndrome, the median nerve is compressed in the proximal forearm between the two heads of pronator teres muscle, a fibrous arcade of the flexor digitorum superficialis muscle, or the lacertus fibrosus (a thick fascial band extending from the biceps tendon to the forearm fascia). This extremely rare and controversial entrapment may develop in individuals engaged in repetitive pronating movements of the forearm. Patients usually experience a vague aching pain in the volar aspect of the elbow and forearm, beginning or worsening during activities involving grasping or pronation or both. There is also an insidious onset of paresthesias and numbness of the palm of hand, mimicking CTS but without the nocturnal symptoms. Resistance to pronation produces pain in the proximal forearm. The pronator teres may be firm and tender on palpation, and the Tinel sign may be elicited over the median nerve in the region of the elbow. Weakness of median-innervated muscles such as the flexor pollicis longus, pronator quadratus, and abductor pollicis brevis (but not of pronator teres) is rarely demonstrated, in contrast to traumatic cases such as following elbow dislocation, forearm fracture, or intracompartmental hemorrhage. Nerve conduction studies in the median nerve are usually normal and do not show the distal median motor and sensory latencies at the wrist that accompany CTS. Needle EMG is also usually normal, with no definite signs of denervation. Injection of corticosteroids into the pronator teres muscle, NSAIDs, and immobilization of the arm with the elbow flexed to 90 degrees and in mild pronation often provide relief of symptoms. On occasion, surgery is controversial but may be necessary, but patients may gain only partial relief.

Median Nerve Entrapment at the Ligament of Struthers

An often bilateral supracondylar spur of the humerus is present in approximately 1% of normal individuals. This beadlike bony or cartilaginous projection arises from the anteromedial surface of the humerus, located about 5 cm above the medial epicondyle. A fibrous band, the ligament of Struthers, extends from this spur to the medial epicondyle and may rarely compromise the median nerve and the brachial artery above the elbow. Clinical symptoms resemble the pronator teres syndrome, but the radial pulse diminishes when the forearm is fully extended in supination because of the concomitant entrapment of the brachial artery. Elbow extension causes aggravation of the pain. On needle EMG, there is usually denervation in the abductor pollicis brevis, flexor pollicis longus, pronator quadratus, and pronator teres. Involvement of the pronator teres muscle theoretically allows differentiation of the ligament of Struthers syndrome from the pronator teres syndrome. Treatment consists of surgical excision of the spur and ligament.

Mononeuropathies of the Lower Extremities

Entrapment neuropathies of lower limbs are shown in Table 76.4.

Localized Perineurial Hypertrophic Mononeuropathy

A slowly progressive painless mononeuropathy that cannot be localized to entrapment sites and is caused by a focal fusiform enlargement of the affected nerve, termed localized hypertrophic neuropathy or perineurioma, is an uncommon condition affecting young adults (Simmons et al., 1999). Although any nerve may be involved, it often occurs in the radial, posterior interosseous, tibial, and sciatic nerves. The fusiform enlargement is mainly composed of “onion bulblike whorls” formed by layers of perineurial cells (Fig. 76.7, B). The lamellae of the whorls stain for epithelial membrane antigen. The cause of the perineurial cell proliferation is unknown. It typically results in painless, slowly progressive weakness and atrophy in the distribution of the affected nerve. Sensory symptoms are minor, although sensory nerve fibers are obviously involved. EDX study results show an axonal mononeuropathy and help in the precise localization of the focal nerve lesion. MRI shows a focal enlargement of the affected nerve, increased signal on T2-weighted images, and enhancement with gadolinium (see Fig. 76.7, A).

Fig. 76.7 A, Axial magnetic resonance imaging of right upper arm 10 cm proximal to epicondyles demonstrates a focal enhancing enlargement of the median nerve after gadolinium administration. Fusiform enlargement of the nerve extended approximately 4 cm in length and measured 7 mm in diameter at its greatest thickness on serial axial cuts. B, Fascicular biopsy specimen of the enlarged median nerve segment shows numerous onion-bulblike structures. By immunochemistry, onion bulbs consist of epithelial membrane antigen–positive cells, confirming their perineurial cell origin. (Hematoxylin and eosin; ×80; bar = 20 µm.)

(Courtesy Dr. P.J. Dyck, Mayo Clinic, Rochester, MN.)

Surgical exploration and a fascicular biopsy by a surgeon experienced in peripheral nerve microsurgery may confirm the diagnosis and exclude malignant peripheral nerve sheath tumors, which are difficult to exclude without biopsy. Surgical resection of the involved nerve segment with graft repair has been proposed, but because of the benign nature of the “tumor” and its very slow progression, the involved nerve should be preserved if it has even partial function.

Charcot-Marie-Tooth Disease (Hereditary Motor and Sensory Neuropathy)

The syndrome of peroneal muscular atrophy, or CMT disease, was first described in 1886 by Charcot and Marie in Paris and Tooth in London (Charcot and Marie, 1886; Tooth, 1886). CMT disease is the most common inherited neuropathy, with an estimated prevalence of 10 to 41 per 100,000 (Martyn and Hughes, 1997). Clinical studies combined with electrophysiological and sural nerve biopsy findings of a large number of families with peroneal muscular atrophy have allowed a separation into two main groups: (1) the demyelinating form, or CMT1 (hereditary motor and sensory neuropathy [HMSN-I]), in which there are marked reductions in motor NCVs and nerve biopsy findings of demyelination and onion bulb formation; and (2) the axonal form of CMT disease, or CMT2 (HMSN-II), in which motor NCVs are normal or near normal, and nerve biopsy reveals axonal loss without prominent demyelination (Harding, 1995). The peroneal muscular atrophy phenotype without sensory involvement on either clinical or electrophysiological examination has been classified as hereditary distal spinal muscular atrophy. A more severe form of demyelinating neuropathy with onset occurring in early childhood is referred to as Dejerine-Sottas disease.

CMT1 and the vast majority of subtypes of CMT2 display autosomal dominant inheritance. A minority of cases occur sporadically or in siblings only and have therefore been attributed to autosomal recessive inheritance or to de novo gene mutations. Because a great variability in clinical expression exists among affected kin in the dominant disorders, a recessive inheritance can only be accepted if the clinical and electrophysiological examinations of both parents have proved to be normal. Even when the cause is nonparental, most of these patients phenotypically resemble CMT1. For all of these groups, an ever-increasing number of genetic subtypes have been elucidated.

Charcot-Marie-Tooth Disease Type 1

In CMT1, symptoms often begin during the first or second decade of life. It is characterized by slowly progressive weakness, muscular wasting, and sensory impairment predominantly involving the distal legs. Foot deformities and difficulties in running or walking resulting from symmetrical weakness and wasting in the intrinsic foot, peroneal, and anterior tibial muscles are often present. In two-thirds of patients, the upper limbs are involved later in life. Inspection reveals pes cavus and hammer toes in nearly three-quarters of adult patients, mild kyphosis in approximately a tenth, and palpably enlarged hypertrophic peripheral nerves in a quarter (Fig. 76.8). The foot deformities occur because of long-term muscular weakness and imbalance between the intrinsic extensor and long extensor muscles of the feet and toes (a similar process causes clawing of the fingers in more advanced cases). Absent ankle reflexes are universal and frequently associated with absent or reduced knee and upper limb reflexes. Some degree of distal sensory impairment (diminished vibration sense and light touch in the feet and hands) is usually discovered by examination but rarely gives rise to symptoms. Occasionally, patients have an essential or postural upper-limb tremor. Such cases have been referred to as Roussy-Lévy syndrome, but current evidence suggests that this is not a separate clinical or genetic entity.

Fig. 76.8 Leg atrophy, pes cavus, and enlarged great auricular nerve (arrow) are evident in a patient with Charcot-Marie-Tooth type 1 disease.

Severity of neuropathy in affected family members varies considerably. Approximately 10% of patients with slowed NCVs may remain asymptomatic. In women with CMT1, the disease may exacerbate during pregnancy. Such worsening is temporary in about a third of patients but becomes progressive in the remainder. Slow deterioration in strength and decline in axonal function continues throughout adulthood, although much of this deterioration likely represents the effects of aging superimposed on decreased reserves (Verhamme et al., 2009).

Motor nerve conduction studies show uniform slowing by more than 25% of the lower limits of normal in all nerves. Motor conduction of upper-limb nerves proves more useful than studies of lower-extremity nerves because distal denervation in the feet is often severe and virtually complete. A conduction velocity below 38 m/sec in the forearm segment of the median nerve is proposed as a cutoff value to distinguish between CMT1 and CMT2. Although this cutoff is useful, it can be misleading if applied too rigidly. SNAPs are usually absent with surface recordings. Routine hematological and biochemical studies are normal. CSF is also normal, which helps differentiate the condition from chronic inflammatory demyelinating polyneuropathy, in which the CSF protein is usually elevated. Sural nerve biopsy typically shows the changes of a hypertrophic neuropathy, characterized by onion bulb formation, increased frequency of fibers with demyelinated and remyelinated segments, an increase in endoneurial area, and loss of large myelinated fibers (Fig. 76.9).

Fig. 76.9 Charcot-Marie-Tooth type 1 disease. A, Semi-thin transverse section of sural nerve showing numerous onion bulbs. (Toluidine blue; bar = 20 µm.) B, Electron micrograph of an onion bulb formation; two small myelinated fibers are surrounded by multiple layers of Schwann cell processes. (Bar = 0.5 µm.)

Gene mutations, predominantly affecting genes for myelin and Schwann cell proteins, have been recognized that account for about three-quarters of families with CMT1 (see Chapter 40).

Molecular Advances of Charcot-Marie-Tooth Disease and Related Disorders

Major advances have been made in recent years in the molecular genetics of CMT or hereditary motor and sensory neuropathies (Bennett and Chance, 2001; Berger et al., 2002; Kamholz et al., 2000) (Fig. 76.10; also see Chapter 40). Most CMT1 patients have DNA rearrangements on chromosome 17p11.2. A 1.5-megabase tandem duplication accounts for 70% of CMT1A cases. As the gene for peripheral myelin protein 22 (PMP22) lies within the CMT1A duplication, it results in three copies of the dosage-sensitive PMP22 gene. PMP22 is a membrane glycoprotein found in the compact portion of the peripheral myelin sheath. The precise function of PMP22 in normal nerve remains unknown. A minority of CMT1A patients have PMP22 missense mutations similar to the natural mouse mutants, trembler and trembler-J, which feature a severe hypomyelinating neuropathy. Deletion of the same 1.5-megabase region on chromosome 17p11.2 results in a single copy of the normal PMP22 gene, a finding observed in 85% of patients with HNPP. The CMT1A duplication or HNPP deletion is caused by reciprocal recombination events that occur in male germ cell meiosis. The PMP22 duplication or deletion can be detected in blood samples using pulse-field electrophoresis followed by hybridization with specific CMT1A duplication junction fragments or cytogenetic testing with a PMP22 probe by fluorescence in situ hybridization.

Fig. 76.10 A, Charcot-Marie-Tooth disease (CMT) and related disorders: CMT1, CMT with X-linked inheritance (CMTX), hereditary neuropathy with liability to pressure palsies (HNPP), Dejerine-Sottas syndrome (DSS), and CMT4 are inherited disorders of myelin. CMT2 is a primary axonal disorder. Alterations in dosage of peripheral myelin protein 22 (PMP22) gene account for the majority of patients with CMT1A and HNPP. B, Point mutations of these genes (connexin-32 [Cx32], myelin protein zero [MPZ, P0], PMP22, EGR2, periaxin) result in CMTX, CMT1B, CMT1A, DSS, and CMT4. Mutations of the LITAF gene result in CMT1C. C, Point mutations of the KIF1B and NFL genes and specific MPZ missense mutations result in CMT2. NCV, Nerve conduction velocity.

(Adapted with permission from Lupski, J.R., 1998. Molecular genetics of peripheral neuropathies. In: Martin, J.D. (Ed.), Molecular Neurology. Scientific American, New York. All rights reserved.)

Myelin protein zero (P0; gene symbol, MPZ) is the major peripheral myelin glycoprotein and is thought to function as an adhesion molecule in the formation and compaction of peripheral myelin. It is a member of the immunoglobulin superfamily, with distinct extracellular transmembrane and intracellular domains. Mutations in the gene encoding for MPZ, located on chromosome 1q22-23, have been associated with CMT1B, DSS, and congenital hypomyelination neuropathy. Different MPZ mutations result in divergent morphological effects on myelin sheaths, consisting of uncompacting of myelin or focal myelin foldings (Gabreëls-Festen et al., 1996). Specific MPZ missense mutations have also been reported with a CMT2 phenotype, showing only mild slowing of NCVs (Marrosu et al., 1998). The Thr124 Met mutations in the MPZ gene have been detected in several families with a distinct CMT2 phenotype (CMT2J) characterized by late onset, marked sensory loss, and sometimes deafness, chronic cough, and pupillary abnormalities (De Jonghe et al., 1999).

The early growth response 2 gene (EGR2), located on chromosome 10q21-q22, encodes a zinc-finger transcription factor expressed in myelinating Schwann cells that regulates the expression of myelin proteins including PMP22, P0, Cx32, and periaxin (Kamholz et al., 2000). EGR2 gene missense mutations have been reported in patients with CMT1D, DSS, or congenital hypomyelination neuropathy (Timmerman et al., 1999; Warner et al., 1998). Respiratory compromise and cranial nerve dysfunction are commonly associated with EGR2 mutations (Szigeti, 2007).

Connexin 32 (Cx32) is a gap junction protein found in noncompacted paranodal loops and Schmidt-Lanterman incisures of Schwann cell cytoplasm, which is encoded by a four-exon gene located on chromosome Xq. As a gap junction protein, Cx32 forms small channels that facilitate transfer of ions and small molecules between Schwann cells and axons. Cx32 is also expressed in oligodendroglial cells in the CNS. This may explain the common abnormal brainstem auditory evoked potentials and other CNS abnormalities found in affected males. More than 200 different mutations in Cx32 have been identified in CMTX families. Genotype-phenotype correlations among patients with Cx32 mutations suggest that most missense mutations result in a mild clinical phenotype, whereas nonsense and frameshift mutations produce more severe phenotypes (Ionasescu et al., 1996a). Mutation analysis of Cx32 should be considered in any patient whose family history does not suggest a male-to-male transmission.

The designation CMT1C is reserved for autosomal dominant CMT1 families not linked to either CMT1A or CMT1B. Three such families showed linkage to chromosome 16p13. Missense mutations were found in the LITAF (lipopolysaccharide-induced tumor necrosis factor alpha) gene, which encodes a lysosomal protein that may play a role in protein degradation pathways (Street et al., 2003). Affected individuals in these families manifest characteristic CMT1 symptoms.

Periaxin is a cytoskeleton-associated protein that links the cytoskeleton of the Schwann cell with the basal lamina, a necessary function to stabilize the mature myelin sheath. Periaxin frameshift and nonsense mutations have been found in families with DSS and also those with autosomal recessive CMT4F (Takashima et al., 2002).

Point mutations of signal transduction proteins such as myotubularin-related protein 2 (MTMR2), N-myc downstream regulated gene 1 (NDRG1), and ganglioside-induced differentiation-associated protein 1 (GDAP1) are found in severe childhood-onset, autosomal-recessive demyelinating neuropathies or CMT4. Mutations of MTMR2 give rise to a severe demyelinating neuropathy characterized by redundant loops of focally folded myelin (Houlden et al., 2001b). GDAP1 mutations may be the most common cause of autosomal recessive CMT and can result in demyelinating as well as axonal phenotypes (Nelis et al., 2002).

In general, DNA rearrangements such as PMP22 duplication or deletion result in milder clinical phenotypes than point mutations for structural myelin proteins or the transcription factor gene, EGR2. Most known mutations cause disease manifestations in the heterozygous state, behaving as either gain-of-function or loss-of-function dominant mutations. Rare recessive mutations in PMP22, EGR2, MTMR2, NDRG1, and periaxin have been reported (Lupski, 2000). DNA sequencing tests are available for PMP22, Cx32, MPZ, EGR2, and periaxin in commercial laboratories.

CMT can also be classified by mode of inheritance (autosomal dominant, X-linked, and rarely autosomal recessive), chromosomal locus, or causative genes (Table 76.6). The classification remains fluid and may change as experts alter and revise these designations based on new molecular findings. An up-to-date listing of loci and genes can be found at the CMT mutation database (www.molgen.ua.ac.be/cmtmutations). DSS, formerly CMT3, may no longer be a useful designation because it is genetically heterogeneous, caused by different structural myelin protein and transcription factor gene mutations. One proposal is to reserve CMT3 for rare axonal types of autosomal recessive neuropathy (Vance, 2000).

Table 76.6 Molecular Genetic Classification of Charcot-Marie-Tooth Disease and Related Disorders (2002)

Hereditary Neuropathy with Liability to Pressure Palsies

HNPP is an autosomal dominant disorder of peripheral nerves leading to increased susceptibility to mechanical traction or compression. It occurs with an estimated prevalence of 16 per 100,000 population. Patients have recurrent episodes of isolated mononeuropathies, typically affecting, in order of decreasing frequency, the fibular nerve, ulnar nerve, brachial plexus, radial nerve, and median nerves. Painless brachial plexopathy is seen in up to a third of patients. Recurrent plexopathy can also be caused by another condition, hereditary neuralgic amyotrophy, which is often preceded by severe ipsilateral limb pain. Most HNPP patients experience the initial episode in the second or third decade of life. Attacks usually are provoked by compression, slight traction, or other minor trauma. Most episodes are of sudden onset, painless, and usually followed by complete recovery within days or weeks. Less-common presentations include transient positionally induced sensory symptoms, progressive mononeuropathy, chronic sensory polyneuropathy, CMT phenotype with pes cavus, and a diffuse chronic sensorimotor neuropathy resembling chronic inflammatory demyelinating polyneuropathy (Mouton et al., 1999). About 15% of mutation carriers remain asymptomatic.

Nerve conduction studies in patients with HNPP associated with PMP22 deletion typically demonstrate a characteristic pattern of prolonged distal motor latencies with only mild slowing in forearm segments of median and ulnar nerves, focal slowing of median, ulnar, and fibular nerves at compression sites, and diffuse reduction of SNAP amplitudes (Dubourg et al., 2000; Mouton et al., 1999). The median motor nerve conduction is typically above 38 m/sec, but sensory studies demonstrate velocities in the demyelinating range and reduced or absent SNAPs. Prolonged median distal motor latencies and abnormal sensory conduction studies are frequently found in asymptomatic carriers (Infante et al., 2001).

Sural nerve biopsy specimens demonstrate focal sausagelike thickenings of myelin termed tomacula (Fig. 76.11), segmental demyelination, and axonal loss.

Fig. 76.11 Single teased nerve fibers from a patient with hereditary liability to pressure palsies, showing examples of focal sausage-shaped enlargements of the myelin sheath (large arrows) in two fibers (A-B). Fiber A shows thinly remyelinated internodes. Successive nodes of Ranvier (thin arrows) can be followed from left to right. (Bar = 100 µm.)

(Reprinted with permission from Bosch, E.P., Chui, H.C., Martin, M.A., et al., 1980. Brachial plexus involvement in familial pressure-sensitive neuropathy: electrophysiological and morphological findings. Ann Neurol 8, 620-624.)

Linkage studies show a 1.5-megabase deletion of chromosome 17p11.2-12 that includes the PMP22 gene and corresponds to the duplicated region in CMT1A in 85% of affected patients with HNPP. The remaining patients have a variety of mutations in PMP22 that lead to frameshift or nonsense mutations causing functional changes in the protein (Lenssen et al., 1998; van de Wetering et al., 2002). Exactly how the deletion of PMP22 causes HNPP remains unclear. One small study of PMP22 expression in dermal nerve myelin from patients with CMT1A or HNPP as well as healthy controls found that levels of PMP22 were highly variable in patients with CMT1A but not in patients with HNPP or in healthy controls, although most patients with HNPP did exhibit PMP22 overexpression. The investigators’ hypothesis was that the variability in PMP22 levels plays an important role in the differences in pathology and disability seen in CMT1A versus HNPP (Katona et al., 2009). Molecular diagnosis of the 17p11.2 deletion is available in reference laboratories and has replaced nerve biopsy for the diagnosis of HNPP. Testing should be considered regardless of family history in any patient presenting with painless multiple mononeuropathies, brachial plexopathy, or recurrent demyelinating neuropathy (Tyson et al., 1996). The primary treatment strategy is to prevent nerve injury by avoiding pressure damage.

Giant Axonal Neuropathy

Giant axonal neuropathy (GAN) is a rare autosomal recessive multisystemic neurodegenerative disorder of intermediate filaments affecting the peripheral and CNS. GAN presents as a slowly progressive axonal sensorimotor neuropathy in early childhood and leads to death by late adolescence. Most affected children have tightly curled hair and distal leg weakness. Some develop a peculiar gait disturbance with a tendency to walk on the inner edges of the feet (Fig. 76.12). With disease progression, evidence of CNS involvement occurs, including optic atrophy, nystagmus, cerebellar ataxia, upper motor neuron signs and intellectual decline, and abnormal visual, auditory, and somatosensory evoked potentials. MRI of the brain demonstrates cerebellar and cerebral white-matter abnormalities. Nerve conduction studies show reduced CMAP and SNAP amplitudes with normal to only slightly reduced conduction velocities. Sural nerve biopsy demonstrates the pathognomonic changes of large focal axonal swellings that contain densely packed disorganized neurofilaments (Fig. 76.13). Axonal function and axoplasmic transport are impaired. The disease locus was mapped to chromosome 16q24. GAN is caused by mutations of the GAN gene, which encodes a novel protein called gigaxonin (Bomont et al., 2000; Kuhlenbäumer et al., 2002). Gigaxonin is a ubiquitously expressed cytoskeletal protein and a member of the BTB/kelsch superfamily, which is involved in diverse cellular functions and may be important in the cross-linking of intermediate filaments (Herrmann and Griffin, 2002).

Fig. 76.12 Tightly curled hair in a young child with giant axonal neuropathy.

Fig. 76.13 Giant axonal neuropathy. Electron micrograph of a giant axon filled with neurofilaments and with an attenuated myelin sheath. (Bar = 1 µm.)

Hereditary Sensory and Autonomic Neuropathy

Hereditary sensory and autonomic neuropathies (HSANs) are a clinically and genetically heterogenous group of neuropathies characterized by prominent sensory loss and variable autonomic features but without significant motor involvement (Verhoeven et al., 2006). Currently these neuropathies are divided into five main groups based on the inheritance, clinical features, and type of sensory neurons involved (Table 76.8). Compared with CMT, HSANs are distinctly rare. Molecular genetic studies have identified seven disease-causing gene mutations in these disorders. More genetic discoveries are likely forthcoming; a study of 100 patients with familial HSAN and isolated patients diagnosed with HSAN found that only 14% of the isolated cases and 31% of the familial cases were found to have mutations in the known causative genes (Rotthier et al., 2009). The pronounced sensory loss in HSAN predisposes these patients to unnoticed recurrent trauma, leading to neuropathic (Charcot) joints, nonhealing ulcers, infections, and osteomyelitis resulting in acral mutilations (acrodystrophic neuropathy). These complications are preventable by careful avoidance of trauma to the insensitive extremities.

Hereditary Sensory and Autonomic Neuropathy Type I

HSAN type I is an autosomal dominant disorder and the most common hereditary sensory neuropathy (Houlden et al., 2006). Symptoms begin in the second to fourth decade with sensory loss and subsequent tissue injury mainly affecting the feet and legs. Sensory loss initially affects pain and temperature perception more than touch-pressure sensation, but it involves all modalities as the disease progresses. Autonomic involvements are limited to hypohidrosis. Patients present with calluses on the soles, painless stress fractures of the feet, neuropathic foot and ankle joints, and recurrent plantar ulcers. If ulcers are neglected and become infected, severe acromutilation may result (acrodystrophic neuropathy) (Fig. 76.14). Lancinating or shooting pains are often prominent and are considered the hallmark feature of HSAN-I. Distal muscle weakness and wasting are present in advanced cases. Such motor involvement, albeit without the lancinating pain, may create diagnostic confusion with CMT2B with dense sensory loss (linked to chromosome 3q13) or with certain axonal MPZ gene mutations. Variable neural hearing loss or rarely spastic paraparesis may be seen in HSAN-I. Some families present with burning feet or neurogenic arthropathy, suggesting clinical as well as genetic heterogeneity both within and between families with HSAN-I (Dyck et al., 2000a; Houlden et al., 2006).

Fig. 76.14 Nonhealing foot ulcer in a 33-year-old man with hereditary sensory and autonomic neuropathy type I. In his kinship, 10 individuals are affected in three generations.

SNAP amplitudes are reduced late in the disease. Motor conduction velocities remain normal, but CMAP amplitudes are reduced in advanced cases. Sural nerve biopsy confirms a severe loss of small myelinated axons and, to a lesser degree, of unmyelinated and large myelinated fibers (Fig. 76.15). Pathological evidence of regenerative activity is usually minimal. HSAN-I has been mapped to chromosome 9q22.1-22.3. Mutations in the SPTLC1 gene encoding a subunit of serine palmitoyltransferase are identified in 90% of patients (Dawkins et al., 2001). These mutations result in increased de novo ceramide synthesis. Since ceramide plays a role in the regulation of programmed cell death, the neuronal degeneration in HSAN-I may be caused by ceramide-induced apoptosis. Molecular genetic testing for HSAN-I is clinically available. Families without linkage to chromosome 9q22 have been described, suggesting genetic heterogeneity (Auer-Grumbach et al., 2000). A subtype, HSAN-IB, is associated with paroxysmal cough, cough syncope, and gastroesophageal reflux (Spring et al., 2005). Additional features include hoarseness of voice and hearing deficit; motor involvement, acral mutilations and ulceration are usually absent. The association of cough and gastroesophageal reflux is not unique to HSAN-IB, as it has also been associated with CMT2 with MPZ mutation.

Fig. 76.15 Semi-thin transverse section of sural nerve from a patient with hereditary sensory and autonomic neuropathy type I. Note loss of large and small myelinated fibers. (Toluidine blue; bar = 50 µm.)

Hereditary Sensory and Autonomic Neuropathy Type II

HSAN-II is recessively inherited and rarely begins later than infancy. All sensory modalities of distal upper and lower limbs and, to a lesser extent, of trunk and face are affected. The hands, feet, lips, and tongue are at risk for mutilation because of generalized sensory loss and insensitivity to pain. Autonomic symptoms are minimal, and mental development is normal. There is loss of tendon reflexes. Rarely, associations with spastic paraplegia, retinitis pigmentosa, mild motor weakness, or neurotrophic keratitis have been described. The clinical course is slowly progressive, with progressive axonal loss. SNAPs are absent. Sural nerve biopsy specimens show almost complete absence of myelinated fibers and reduced unmyelinated fiber populations (Fig. 76.16). Mutations in the HSN2 nervous-system-specific exon of the with-no-lysine(K)-1 (WNK1) gene on chromosome 12q13.33 causes HSAN-II (Shekarabi et al., 2008). All mutations result in a truncation of the HSN2 protein, with the protein loss or inactivation (or both) causing the peripheral neuropathy. The exact function of HSN2 protein remains unknown, but it may play a role in the development or maintenance of sensory neurons or accompanying Schwann cells.

Fig. 76.16 Sural nerve fiber size-frequency histograms of myelinated fibers (MF) (left) and unmyelinated fibers (UF) (right) of two affected siblings with hereditary sensory and autonomic neuropathy type II (green bars) and control nerve (white bars). In the patients, the number of myelinated fibers was less than 500/mm² and that of the unmyelinated fibers less than 10,000/mm².

Neuropathy Associated with Spinocerebellar Ataxias

Friedreich ataxia is an autosomal recessive neurodegenerative disease characterized by degeneration of large sensory neurons and spinocerebellar tracts, cardiomyopathy, and increased incidence of diabetes (see Chapter 72). Even in the early stages of the disease, examination reveals lower-limb areflexia and impaired joint position and vibration sense, with preserved pain and temperature sensation. Pes cavus and hammer toes occur in approximately 90% of cases.

Motor NCVs are normal or slightly reduced, and SNAPs are invariably reduced or absent. A selective loss of large myelinated fibers occurs in the sural nerve. Friedreich ataxia is the result of a large GAA triplet repeat expansion on chromosome 9q13-q21.1, leading to loss of frataxin expression (see Chapter 72).

Peripheral nerve involvement has been found in association with other spinocerebellar ataxias (SCAs), most notably SCA3 in older patients, SCA4, SCA18, and prominently in SCA25. An autosomal recessive SCA and peripheral neuropathy with raised serum α-fetoprotein unrelated to ataxia telangiectasia has been reported (Izatt et al., 2004).

Primary Erythromelalgia

Inherited or primary erythromelalgia is a rare autosomal dominant neuropathic condition characterized by recurrent attacks of erythema and intense burning pain of the hands and feet in response to mild warmth or moderate exercise. To get relief, patients often attempt to cool the affected areas. These symptoms may lead to significant disability. Patients function normally between episodes. Mutations in the voltage-gated sodium channel Na(v)1.7, encoded by the gene SCN9A, is responsible for this syndrome. Na(v)1.7 is preferentially expressed in small dorsal-root ganglia neurons. Its mutations result in the increased activity of dorsal root ganglion neurons and enhanced sensation of pain (Choi et al., 2006; Waxman, 2007). Other mutations in SCN9A that cause a loss of Na(v)1.7 function result in the opposing condition of “congenital inability to experience pain,” emphasizing the importance of sodium channels in nociception (Cox et al., 2006). A third disorder has also been linked to Na(v)1.7: paroxysmal extreme pain disorder, which was formerly known as familial rectal pain syndrome (Fertleman et al., 2007). The linkage between pain and temperature in erythromelalgia is in keeping with other diseases of sodium channels. No treatment is consistently effective. Aspirin, lidocaine (gel, patch, or infusion), anticonvulsants, tricyclic antidepressants, and vasoactive drugs have been used with varying success. Paroxysmal extreme pain disorder almost universally responds to carbamazepine, although the response is often incomplete.

A secondary form of erythromelalgia is caused by polycythemia vera and other myeloproliferative disorders.

Familial Amyloid Polyneuropathy

Familial amyloid polyneuropathy (FAP) is a group of autosomal dominant disorders characterized by the extracellular deposition of amyloid proteins in peripheral nerves and other organs. Amyloid is a fibrillar conformation of a protein characterized by (1) green birefringence of Congo red–stained sections viewed in polarized light, (2) the presence of nonbranched 10-nm amyloid fibrils on electron microscopy, and (3) a β-pleated sheet structure on x-ray diffraction. More than 20 different proteins are known to undergo conformational changes leading to the generation of amyloid deposits in tissues. These deposits may be widespread or restricted to certain organs (localized amyloidosis). The clinical presentation depends on the organs involved and the size of amyloid fibrils. In FAP, one of three aberrant proteins (transthyretin, apolipoprotein A1, or gelsolin [Falk et al., 1997]) can be found in the peripheral nerves. The latter two are rare and restricted to a few families. In acquired primary systemic amyloidosis, polypeptides of immunoglobulin light-chain origin are deposited in tissues as amyloid, which leads to the term AL amyloid (see Primary Systemic Amyloidosis, later).

The classification of FAP was traditionally based on clinical presentation. Progress in understanding the protein composition and molecular genetics of these disorders justifies a different approach (Table 76.9).

Porphyric Neuropathy

Acute hepatic porphyrias are a group of autosomal dominant inherited metabolic disorders that manifest as acute or subacute severe life-threatening motor neuropathy, abdominal pain, autonomic dysfunction, and neuropsychiatric manifestations (Albers and Fink, 2004). Its gene is thought to be present in 1 in 80,000 people, although only one-third of affected persons ever manifest symptoms of the disease. The main forms of porphyria include AIP, variegate porphyria, and hereditary coproporphyria. The basic defects are a 50% reduction in hydroxymethylbilane synthase (also known as porphobilinogen deaminase) in AIP, of protoporphinogen IX oxidase in variegate porphyria, and of coproporphinogen oxidase in coproporphyria, all of which result in abnormalities of heme synthesis. Each abnormality of enzyme activity provokes a compensatory overproduction of porphyrins and their precursors through the negative feedback regulation by heme of the first and rate-limiting enzyme of the heme biosynthetic pathway, δ-aminolevulinic acid synthase (ALAS). A fourth disorder referred to as plumboporphyria is inherited as an autosomal recessive trait and is caused by a deficiency of δ-aminolevulinic acid dehydratase (ALAD) (Table 76.10). More than 90 mutations in the porphobilinogen deaminase (PBGD) gene have been identified that decrease enzyme activity and cause AIP (Elder et al., 1997). These partial enzyme defects remain latent until precipitating factors trigger acute attacks. Precipitating factors include certain drugs, the menstrual cycle, alcohol, hormones, and fasting (either intentional or during an intercurrent illness). Precipitating factors induce hepatic δ-ALAS, the rate-limiting enzyme in heme biosynthesis, leading to the overproduction and overexcretion of PBG and δ-ALA.

Treatment and Management

The treatment of patients with acute hepatic porphyria involves three important steps: (1) prevention of attacks, (2) attempts to repress hepatic ALAS activity, thereby reducing porphyrin production, and (3) supportive care. Ideally, attacks should be prevented by avoiding drugs and situations that induce them. Among the inducing drugs, barbiturates are the most common precipitants, followed by sulfonamides, analgesics, nonbarbiturate hypnotics, anticonvulsants, and female sex hormones. Intentional fasting and alcohol consumption should be avoided. Gonadotropin-releasing hormone agonists may benefit women with recurrent attacks related to the menstrual cycle. The attack must be treated promptly as outlined in Fig. 76.17. First, all offending drugs are removed, and any intercurrent infection is treated. A high-carbohydrate diet orally or by nasogastric feeding (at least 400 g daily or the equivalence of glucose or levulose infusions) results in reduced porphyrin precursor production. Persistent symptoms or neurological deficits that progress for 24 hours after carbohydrate loading are indications for treatment with hematin (a hydroxide of heme), which represses the activity of hepatic ALAS and may restore cytochrome functions by replenishing an endogenous heme deficit. Hematin therapy at the recommended dose of 6 infusions of 4 mg/kg body weight at 12-hour intervals has resulted in consistent reduction of porphyrin precursors in serum and urine and clinical improvement in more than 80% of attacks. The only placebo-controlled study suggested a more modest clinical benefit of IV hematin. Early administration of hematin is advocated to correct the metabolic insult before neuronal damage becomes irreversible.

Fig. 76.17 Management of acute porphyric attack. PRN, As needed.

(Adapted from Bosch, E.P., Pierach, C.A., 1987. Acute hepatic porphyria, in: Johnson, R.T. (Ed.), Current Therapy in Neurologic Disease. Decker, Toronto.)

Supportive treatment consists of the correction of fluid imbalance, close attention to respiratory function, and physical therapy. Supplemental vitamin B₆ and beta-blockers for control of tachycardia may become necessary. Abdominal pain can often be controlled with simple analgesics but may require narcotics. Sedation with chlorpromazine is often helpful. The treatment of seizures poses a difficult therapeutic problem because most anticonvulsants may exacerbate the disease. Intravenous diazepam and parental magnesium sulfate are both effective and safe for immediate seizure control. All at-risk relatives should be screened for latent disease.

Fabry Disease

Fabry disease (angiokeratoma corporis diffusum) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A, which results in the accumulation of the glycolipid globotriacylceramide (ceramide trihexoside) within vascular endothelial cells of the kidneys, heart, brain, and skin. Over time, progressive vascular disease leads to renal failure, cardiac disease, and strokes. Skin involvement gives rise to the typical angiokeratomas, which are dark red, punctate telangiectasias found mainly over the lower part of the trunk, buttocks, and scrotum (Fig. 76.18). A painful small-fiber neuropathy develops in childhood or adolescence. In fact, any boy or young man with severe painful sensory neuropathy should be suspected as having Fabry disease, and any skin lesions should be carefully scrutinized because they are usually sparse and may be easily overlooked. Distal paresthesias and lancinating pain are intensified by exertion, fever, or hot environments. Autonomic dysfunction includes diminished sweating, impaired tear and saliva formation, and decreased intestinal motility. Some patients have hearing loss (Barras and Maire, 2006; Vibert et al., 2006). Except for impairment of temperature sensation, overt neurological signs are absent. Female carriers often show clinical involvement but rarely develop renal failure, which is characteristically seen in affected men.

Fig. 76.18 Fabry disease. Typical angiokeratomas are clustered over the lower part of the trunk.

On nerve conduction studies, the conduction velocities are mildly reduced in two-thirds of patients. Deposition of glycolipid in small neurons of sensory and peripheral autonomic ganglia results in neuronal degeneration and selective loss of small myelinated and unmyelinated fibers in sural nerve biopsy specimens. Ultrastructurally, perineurial, endothelial, and perithelial cells contain characteristic lamellated glycolipid inclusions. Leukocyte preparations or skin fibroblasts are used for the diagnostic α-galactosidase assay. Screening for Fabry disease is recommended for patients with small-fiber neuropathy of unknown cause (Tanislav et al., 2011).

Analgesics, phenytoin, or carbamazepine, along with avoidance of aggravating factors, are effective for pain relief. Recombinant α-galactosidase-A replacement therapy with recombinant α-galactosidase A (agalsidase beta) has been shown to be safe and effective in the removal of microvascular endothelial deposits of globotriacylceramide from target organs (Eng et al., 2001) and in improvement of autonomic function (Ries et al., 2006). Agalsidase alfa has also been shown to be beneficial in cardiac, renal, neuropathic pain, and quality-of-life measures (Mehta et al., 2009). Renal transplantation may correct the biochemical defect, resulting in relief from pain and partial restoration of sweating.

Leukodystrophies with Neuropathy

The leukodystrophies result from inherited abnormalities of myelin metabolism that may affect both the CNS and PNS. Overall incidence of the leukodystrophies in the United States is 1 in 7663 live births (Bonkowsky et al., 2010). Peripheral nerve involvement is seen in metachromatic leukodystrophy (MLD), Krabbe disease, adrenomyeloneuropathy, and Cockayne syndrome. Recognition of an associated neuropathy may be helpful in the differential diagnosis of the underlying leukodystrophy. Missense mutations in proteolipid protein, a major protein component of CNS myelin, cause a spectrum of X-linked CNS disorders without peripheral neuropathy, including Pelizaeus-Merzbacher disease and hereditary spastic paraparesis. Proteolipid protein is also expressed in Schwann cells and compact peripheral myelin. Absence of proteolipid protein expression caused by a frameshift mutation has been reported to produce a demyelinating neuropathy with less severe CNS manifestations (Gabern et al., 1997).

Phytanic Acid Storage Disease (Refsum Disease)

Refsum disease, heredopathia atactica polyneuritiformis, is a rare autosomal recessive disorder of phytanic acid metabolism. The gene defect has been localized to chromosome 10 and encodes the peroxisomal enzyme, phytanoyl-CoA-hydroxylase. The defect in the enzyme that initiates the alpha-oxidation pathway of β-methyl substituted fatty acids leads to phytanic acid accumulation in serum and tissues. Phytanic acid is derived exclusively from dietary sources, mainly chlorophyll, dairy products, meats, and fish oils. Clinical onset spans from childhood to the third decade of life. The cardinal manifestations include pigmentary retinal degeneration with night blindness or visual-field constriction, chronic hypertrophic neuropathy, ataxia, and other cerebellar signs such as nystagmus and intention tremor. Initially, the neuropathy affects the lower limbs with distal leg atrophy, weakness, areflexia, large-fiber sensory impairment, and sometimes palpably enlarged nerves. Weakness becomes generalized later in the illness. In addition to pes cavus, overriding toes caused by symmetrically short fourth metatarsals are a helpful sign for Refsum disease. Progressive sensorineural hearing loss, anosmia, cardiomyopathy, and ichthyosis are common. The course may be either progressive or fluctuating with exacerbations and remissions. Exacerbations are often precipitated by fasting, which mobilizes phytanic acid from endogenous fat stores.

Motor conduction velocities are markedly slowed, and SNAPs are reduced or absent. CSF protein is increased in the range of 100 to 700 mg/dL. Sural nerve biopsy reveals a hypertrophic neuropathy with prominent onion bulb formation. The diagnosis is confirmed by elevated serum levels of phytanic acid.

Chronic dietary treatment, by restricting the exogenous sources of phytanic acid (<10 mg/day) and its precursor, phytol, results in reduction of serum phytanic acid levels and clinical improvement. The diet should provide sufficient calories to avoid weight loss. Plasma exchange has been used to lower toxic serum phytanic acid levels more rapidly in critically ill patients. Docosahexaenoic acid has been found to be deficient in peroxisomal disorders, but supplementation does not lead to clinical improvement even though docosahexaenoic acid plasma levels do increase (Parker et al., 2010).

Tangier Disease

Tangier disease is an autosomal recessive disorder named after Tangier Island, Virginia, the origin of the first described cases. It is characterized by severe deficiency of plasma α- or high-density lipoproteins, resulting in the deposition of cholesterol esters in many tissues, including the reticuloendothelial system and peripheral nerves. The accumulation of lipids leads to enlarged yellow-orange tonsils, which may provide a clue to the diagnosis. In adolescence or adult life, approximately half of affected patients develop one of two distinct neuropathic syndromes. The first is a progressive symmetrical neuropathy with dissociated loss of pain and temperature sensation in the face, arms, and upper trunk, combined with faciobrachial muscle wasting and weakness. These findings bear a superficial resemblance to syringomyelia. The second syndrome consists of relapsing multifocal mononeuropathies involving the cranial, trunk, or limb nerves.

High-density lipoprotein and serum cholesterol are markedly reduced, whereas triglyceride concentrations are elevated. A neuropathic disorder is confirmed by absent or low-amplitude SNAPs and reduced conduction velocities. Nerve biopsy specimens from patients with the multiple mononeuropathy variant have shown segmental demyelination and remyelination. By contrast, small myelinated and unmyelinated axons are preferentially lost in the syringomyelia-like variant. Typically abundant lipid vacuoles in Schwann cells are present in both. No specific treatment is known.

Abetalipoproteinemia (Bassen-Kornzweig Syndrome)

Abetalipoproteinemia is a rare autosomal recessive disorder of lipoprotein metabolism. The condition is associated with gene defects coding for the microsomal triglyceride transfer protein, resulting in abnormal very-low-density lipoprotein secretion. Fat malabsorption is present from birth and results in a severe deficiency of the fat-soluble vitamins A, E, and K. Steatorrhea, hypocholesterolemia, and abnormally spiky red cells (acanthocytes) are present from birth. Most untreated patients develop retinitis pigmentosa, peripheral neuropathy, and spinocerebellar degeneration during the first 2 decades of life. A progressive, mainly large-fiber sensory neuropathy occurs, with gait ataxia, areflexia, impaired proprioceptive sensation, and modest distal weakness; the condition must be considered in the differential diagnosis of the spinocerebellar ataxias. Patients have absence of serum β-lipoproteins and very low levels of vitamin E.

Clinical manifestations of vitamin E deficiency can also be found in familial vitamin E deficiency caused by mutations of the α-tocopherol transfer protein gene. These gene mutations result in the failure to incorporate α-tocopherol in very-low-density lipoprotein in the liver and lead to low vitamin E levels in the absence of malabsorption (Martinello et al., 1998).

Dietary fat restriction and large oral doses of vitamin E (100 mg/kg/day) can prevent the onset of symptoms or arrest progression of neurological complications in abetalipoproteinemia and familial vitamin E deficiency.

Mitochondrial Cytopathies and Polyneuropathy

Inborn errors of mitochondrial metabolism encompass a heterogenous group of multisystemic disorders caused by mutations in either mitochondrial or nuclear DNA. These mutations impair cellular energy metabolism of virtually every organ, but in particular the CNS and muscles. Involvement of the PNS also occurs in several mitochondrial cytopathies (Bouillot et al., 2002; Stickler et al., 2006). However, mitochondrial cytopathy remains an uncommon cause for isolated and progressive neuropathy. A mixed demyelinating and axonal neuropathy is seen in MERRF (myoclonic epilepsy and ragged red fibers). In the syndrome of neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) caused by a mutation of the ATP6 gene, an axonal neuropathy predominates and may be the presenting feature. In fact, the first case of an established mitochondrial cytopathy and neuropathy was described in this syndrome. In sensory ataxic neuropathy, dysarthria, and ophthalmoplegia (SANDO), a multiple mitochondrial depletion disorder, a severe sensory axonal neuropathy and ophthalmoplegia associated with other features such as migraine, depression, and cyclooxygenase (COX)-deficient muscle fibers develops after age 30 (Fadic et al., 1997). Mutations in the nuclear DNA polymerase (POLG), crucial for mitochondrial DNA replication, results in epilepsy, ataxia, headache, myoclonus, late-onset ophthalmoplegia, and a sensorimotor neuropathy (Tzoulis et al., 2006).

A demyelinating neuropathy, at times severe, is seen in MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). The majority of patients (≈75%) have a predominantly axonal neuropathy, half predominantly sensory; the remainder have only electrophysiological abnormalities (Kaufmann et al., 2006). Endocrine involvement, especially of thyroid and pancreas, is common, and impaired glucose metabolism and hypothyroidism may contribute to the development and severity of neuropathy in MELAS. The neuropathy of MELAS appears to be more common in men than women.

In the syndrome of myoneurogastrointestinal encephalopathy (MNGIE), an autosomal recessive condition with a loss-of-function mutation in the thymidine phosphorylase gene, a mixed axonal and demyelinating neuropathy may be present. At times, the neuropathy may follow a course mimicking CIDP (Bedlack et al., 2004). However, these patients often have no proximal weakness, suffer from gastrointestinal dysfunction due to intestinal pseudo-obstruction, may have CNS demyelination or lactic acidosis, exhibit extraocular abnormalities, and show no response to immunomodulatory treatments. Measurement of thymidine level in the serum or activity of thymidine phosphorylase in buffy coat supports the diagnosis. DNA sequencing will confirm the diagnosis by demonstrating mutations in the thymidine phosphorylase gene. A presentation similar to CMT with distal muscle atrophy and pes cavus has also been observed in patients with MNGIE (Said et al., 2005). The course of neuropathy in MNGIE, however, may become rapid and pain may be prominent. The role of nutritional factors secondary to gastrointestinal dysmotility in the development and intensity of the neuropathy in such patients should not be ignored. Nerve biopsies performed in few patients with MNGIE has shown variable abnormalities including reduction in myelinated fiber density, demyelination and remyelination, myelin sheath irregularity, and a high proportion of fibers with axonal degeneration and axonal atrophy. Schwann cells, axons, and endothelial cells may contain abnormal mitochondria, including paracrystalline inclusions. Recent reports suggest that allogenic stem cell transplantation corrects biochemical derangements in the blood of MNGIE patients, but its clinical efficacy remains unproven (Hirano et al., 2006).

In another mitochondrial disorder commonly observed in children, Leigh disease, a demyelinating-remyelinating neuropathy and hypomyelination of nerves is observed. This is particularly prominent when mutations occur in nuclear genes (e.g., SURF1 and SCO2) encoding the assembly of complex IV of the respiratory chain. Navajo neurohepatopathy, a unique autosomal recessive, multisystemic, progressive syndrome prevalent in Navajo children of the southwest United States, is caused by a mutation in the mitochondrial MPV17 gene, which is believed to be involved in mitochondrial DNA maintenance and in the regulation of oxidative phosphorylation (Karadimas et al., 2006). These children develop a severe sensorimotor neuropathy associated with corneal ulcerations, acral mutilation, poor weight gain, short stature, sexual infantilism, serious systemic infections, and liver derangement, including Reye syndrome–like episodes, leading to cirrhosis and hepatic failure. Mitochondrial cytopathies should be considered in the differential diagnoses of any patient with a peripheral neuropathy and a multisystemic condition.

Acute Inflammatory Demyelinating Polyradiculoneuropathy (Guillain-Barré Syndrome)

In 1916, Guillain, Barré, and Strohl emphasized the main clinical features of GBS: motor weakness, areflexia, paresthesias with minor sensory loss, and increased protein in CSF without pleocytosis (albuminocytological dissociation). Our current understanding of the pathology was greatly enhanced when multifocal inflammatory demyelination of spinal roots and peripheral nerves were described. The frequent finding of motor conduction blocks and reduced conduction velocities provided further electrophysiological confirmation of the widespread demyelination. Improvement in modern critical care has dramatically changed outcomes in GBS, including a reduction in the mortality rate from 33% before the introduction of positive-pressure ventilation to the current rate of approximately 5% to 10%. The diagnosis of GBS depends on clinical criteria supported by electrophysiological studies and CSF findings (Box 76.10). These diagnostic criteria define AIDP, which is the most common form of GBS in Europe and North America. However, in recent years it has been recognized that GBS is a heterogeneous disorder, and not all GBS cases are due to demyelination. An axonal immune-mediated injury may also produce a similar clinical presentation. This axonal variant of GBS is called acute motor-sensory axonal neuropathy (AMSAN) because of involvement of both motor and sensory fibers and is known for its severity and poor recovery. A second, pure motor axonal form called acute motor axonal neuropathy (AMAN) has been described in northern China, where it occurs in summer epidemics in children and young adults. The Miller Fisher syndrome (MFS) variant accounts for 6% of total GBS cases in Western countries, whereas in Taiwan the proportion is as high as 18%, suggesting a geographical difference. Other variants of GBS such as acute pandysautonomia and the pharyngeal-cervical-brachial variant occur so infrequently that no exact figure on their prevalence and incidence can be given. The classification of GBS subtypes and variants is based on the clinical picture and electrophysiological and pathological findings (Griffin et al., 1996) (Box 76.11).