Michael J. Polydefkis
In previous editions, Gary J. Romano, MD, PhD, and Ralph Kuncl, MD, PhD, contributed to this chapter.
Definitions and Pathophysiology
Peripheral neuropathies result from disease processes that involve the peripheral nervous system. The peripheral nervous system includes cranial nerves III through XII, dorsal and ventral spinal roots, dorsal root ganglia, spinal nerves, and most autonomic ganglia and nerves.
Peripheral nerves consist of a bundle of fibers called axons; the large- and medium-sized axons are normally covered with a layer of myelin. Most peripheral nerves are mixed nerves that carry both incoming sensory information (afferent fibers) and outgoing motor and autonomic impulses (efferent fibers). Large-diameter afferent fibers convey information about position and vibration; large-diameter efferent fibers innervate the muscles themselves. Small-diameter, often unmyelinated fibers convey pain and temperature sensation and autonomic information.
Based on the primary site of involvement of the peripheral nerves, peripheral neuropathies can be classified into three categories: neuronopathies, axonopathies, and melanopathies. Neuronopathies result from processes affecting primarily the sensory cell bodies in the dorsal root ganglia or motor neuron cell bodies in the spinal cord. By convention, because motor neuron cell bodies are in the central nervous system (CNS), motor neuronopathies are not usually classified among the peripheral neuropathies. Axonal neuropathies result from processes affecting primarily the axon, whereas myelinopathies (also called demyelinating neuropathies) result from processes affecting primarily the myelin sheath. In some chronic disorders such as diabetes mellitus (DM), irrespective of the primary pathologic process, the interdependence between axon and myelin produces secondary changes that, on biopsy, reveal a mixed pathologic picture. The etiologic diagnosis of peripheral neuropathies, therefore, depends on both the clinical features and the supportive laboratory and pathologic findings.
Three major anatomic patterns of peripheral nerve disease may be distinguished by clinical presentation: mononeuropathy, mononeuropathy multiplex (multifocal neuropathies), and polyneuropathy. Mononeuropathies are lesions of individual nerve roots or peripheral nerves; they usually are because of local causes such as trauma or entrapment (compression of a nerve by adjacent structures). Mononeuropathy multiplex refers to involvement of two
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or more named nerves, usually asymmetrically and not contiguously, either at the same time or sequentially. This less common pattern is usually caused by systemic diseases such as the necrotizing vasculitides (e.g., polyarteritis nodosa) or DM, which may affect several nerves focally. Polyneuropathy is the result of a generalized disease process affecting many peripheral nerves, often in a symmetric distribution.
In both axonal and demyelinating diseases, the longer larger nerves are generally involved earlier and more severely than the shorter nerves. In demyelinating neuropathies, this vulnerability of the longer axons may reflect the increased number of potential sites for demyelination; in axonal neuropathies, the longer axons require more metabolic support and therefore may be more susceptible to disruption of this support. In axonal neuropathies, the distal ends of the nerve fibers—those that project to the feet—tend to be affected first producing a stocking pattern of involvement. Subsequently, the distal upper extremities become involved in a “glove” pattern. Demyelinating neuropathies generally begin in the lower extremities but can have a more patchy pattern of involvement. Most polyneuropathies indiscriminately affect both the sensory and the motor nerve fibers (mixed polyneuropathies or sensorimotor neuropathies); some affect peripheral autonomic nerves. However, clinically (and occasionally pathologically) in some patients there is a predilection for the sensory nerves (sensory neuropathies), motor nerves (motor neuropathies), or autonomic nerves.
Approach to the Patient
History and Physical Examination
Symptoms of peripheral neuropathy include reduced sensitivity to stimuli (hypesthesia); spontaneous unusual sensations such as tingling, burning, or pain (paresthesias or dysesthesias); weakness; and muscle cramps. If autonomic nerves are involved, impotence, urinary retention or overflow incontinence, constipation or diarrhea, diminished sweating, and orthostatic hypotension are common symptoms. In patients with polyneuropathy, paresthesias in the feet are the most common presenting complaint. Often, patients are bothered by nonnoxious sensory stimuli such as light touch perceived as pain (allodynia) and may report that symptoms of restless legs syndrome that are relieved by pacing the floor or by firm massage. Complaints of heaviness or coldness of the extremities are also common. Diminished joint position sense (proprioception) may be reported as unsteady gait, particularly on uneven surfaces or in the dark.
The major signs of peripheral neuropathy are sensory loss, weakness, muscle atrophy, diminished or absent tendon reflexes, and, if autonomic nerves are involved, trophic changes in the skin. The most common sensory modalities affected in polyneuropathy are pain and vibration, in a symmetric stocking–glove distribution. Thermal sensation is usually affected, but this is harder to document in the clinical setting. In polyneuropathies the weakness is most often distal, affecting the intrinsic muscles of the feet (e.g., inability to spread or extend the toes). In long-standing and inherited neuropathies the muscle imbalance causes high arched feet and hammer toes. Eventually, the shin may appear prominent because of atrophy of the tibialis anterior muscle (sharp shin sign), and there may be striking wasting of the small muscles of the hand. Marked loss of proprioception in the feet may be manifest as unsteadiness, ataxia, or a positive Romberg test (seeChapter 86 for additional details about neurologic signs).
Causes and Distinctive Features
Whereas a limited number of conditions produce mononeuropathy and mononeuropathy multiplex (Table 92.1), there are many causes of polyneuropathy (Table 92.2). Diagnosis often depends on obtaining a thorough history (e.g., of alcoholism or of occupational exposure to toxins) or finding a relevant systemic condition (e.g., DM). Table 92.3 lists the three features most useful in the differential diagnosis of a polyneuropathy—time course, selective functional involvement, and distribution—and the causes associated with these features.
Time Course
Mononeuropathies are often acute in onset; that is, the patient remembers the time of onset. The most common of the acute polyneuropathies, the Guillain-Barré syndrome, and other processes—metabolic, vasculitic, or toxic—may cause rapid onset of severe neurologic dysfunction, sometimes within hours. Most toxic neuropathies (e.g., lead poisoning) develop more slowly (within weeks), as do neuropathies associated with malnutrition (e.g., thiamine deficiency). The most common of the chronic neuropathies
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in the United States (gradual progression over months to years) are associated with DM (see Chapter 79) and alcoholism (see below). Neuropathies related to infections such as leprosy or HIV also tend to be chronic in nature.
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TABLE 92.1 Common Causes of Mononeuropathy and Mononeuropathy Multiplex |
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TABLE 92.2 Polyneuropathy: Causes and Modes of Predominant Involvement |
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Patients with hereditary neuropathies sometimes may be unaware that they have a long-standing progressive disorder. A history of a lack of athletic ability in school or problems fitting shoes may be useful clues. Irreducibly high-arched feet and hammer toes reflect long-standing disease occurring during foot development and may therefore suggest a hereditary process.
Selective Functional Involvement
Mononeuropathy usually produces both motor and sensory involvement in the distribution of the affected nerve root or peripheral nerve. Most polyneuropathies produce both sensory and motor disturbances. Polyneuropathy with predominantly sensory involvement suggests DM, carcinoma, amyloidosis, and dysproteinemia. Occasionally, sensory losses are dissociated, that is, the patient has diminished pain and temperature sensation but preserved vibration and joint position sense; this pattern is typical of small fiber neuropathies. In diabetes, it is not unusual for the neuropathy to start as a small fiber predominant process that then progresses to involve large fiber sensory and then motor nerves. When position and vibratory sense are lost but pain sense is preserved, vitamin B12 deficiency (usually pernicious anemia) or, much more rarely, Friedreich ataxia should be considered. In polyneuropathy, predominantly motor involvement suggests inflammatory demyelinating neuropathy, hereditary neuropathies, lead intoxication, or acute intermittent porphyria. Predominantly autonomic involvementsuggests DM, amyloidosis, familial dysautonomia, or dysproteinemia.
Investigations
Clinical Laboratory
The cause of a peripheral neuropathy must be identified because often neurologic dysfunction persists unless the underlying disease can be treated. The common causes of polyneuropathy (shown in italics in Table 92.3) may be obvious to a patient's physician, but sometimes even these require direct questioning (e.g., concerning alcoholism) or specific laboratory tests (e.g., oral glucose tolerance testing) before they are appreciated. If the cause of the neuropathy is not obvious, one should consider the following screening tests that may point to a cause: erythrocyte sedimentation rate, fasting blood glucose level, oral glucose tolerance testing, serum creatinine concentration, a complete blood count, serum B12 level, a chest radiograph, and a serum and urine immunofixation electrophoresis. Many unusual conditions may be associated with neuropathy,
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but an extensive screening program to rule out all these processes would be expensive and almost always unrewarding unless there is some clue in the history or physical examination to warrant a particular test (e.g., measurement of blood lead levels in a patient with a possible history of occupational exposure). If no cause of the process is identified on evaluation, consultation with a neurologist should be considered.
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TABLE 92.3 Polyneuropathy: Differential Diagnosis |
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Nerve Conduction Studies
The measurement of nerve conduction is useful as an initial diagnostic screen because it can distinguish major categories of disease (axonal versus demyelinating) and can localize entrapments and other mononeuropathies. A baseline measurement makes it possible to differentiate progression of the peripheral neuropathy from other clinical conditions in the future.
Nerve conduction measurements involve stimulating a nerve at one point and recording the response, either at the muscle (motor nerve) or at some distance along the nerve (sensory nerve). The results of nerve conduction studies usually include latency of response, conduction velocity, and amplitude of response. The latency of response refers to the time elapsed between the start of the stimulus and the muscle response (muscle fiber depolarization) or nerve response (sensory nerve action potential). The conduction velocity between two points along the nerve is expressed in meters per second.
Conduction disturbances of the peripheral nerve may be localized, as in an entrapment syndrome, or may involve nerves more diffusely, as in polyneuropathies. Generally, early axonal degenerations are associated with normal conduction and the presence of denervation on electromyography (see Electromyography), whereas early demyelination is characterized by slowing of nerve
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conduction and normal EMG studies. Nerve conduction velocities are normal, and sensory nerve action potentials are spared in cervical or lumbar disk disease with radiculopathy, because the potential site of nerve root compression at the neural foramina is proximal to the sensory cell body in the ganglion and therefore does not cause degeneration of the distal sensory nerve fiber. This is an important point because spondylitic radiculopathy is common and may mimic polyneuropathy (see Chapters 70 and 71).
The procedure has several limitations. First, nerve conduction studies test directly only the portion of the nerve between the stimulating and recording electrodes; they generally do not detect damage more distal than (e.g., intramuscular nerve) or more proximal to (e.g., nerve root) the segment tested. Long latency responses such as F waves or H reflexes can provide information about conduction over long segments of nerve, including proximal nerve segments. Second, electrophysiologic studies reflect the function of a subset of peripheral nerve fibers, namely the largest and fastest conducting fibers. Therefore, a patient with a selective small fiber neuropathy can test normally on nerve conduction studies.
Patient Experience
With the patient comfortably positioned, surface electrodes are placed over the nerves and muscles to be tested. Nerves are stimulated with shocks applied to the skin. The shocks are mildly unpleasant. Nerves on both sides of the body may be compared. Testing takes approximately 20 to 60 minutes.
Electromyography
EMG involves the insertion of a needle electrode into a muscle to record muscle electrical activity. By observing muscle activity at rest (spontaneous discharges) and during muscle contraction (volitional activity), much can be inferred about the integrity of motor nerves and the muscle itself.
Spontaneous fibrillation potentials are the action potentials of single myofibers that are twitching spontaneously. Fibrillation potentials and positive waves are usually, but not invariably, a good indication of denervation (they also occur in polymyositis and more rarely in other myopathic processes). Fasciculations are the spontaneous firings of whole motor units (all the muscle fibers innervated by a single motor neuron and its branches). Fasciculations may be seen in normal subjects, although they are more frequent and likely to be more polyphasic in states of denervation.
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TABLE 92.4 Electromyography: Patterns Typical of Nerve and Muscle Disorders |
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Voluntary motor unit potentials are examined individually by asking the patient to contract a given muscle slightly. Long-duration, large-amplitude, polyphasic potentials suggest a denervating process with subsequent reinnervation through axonal sprouting. Brief, small-amplitude, polyphasic potentials are associated with myopathic processes. Graded increasing effort is used to analyze the orderly recruitment of motor unit potentials, including their number and firing rates. Recruitment of a reduced repertoire of large-amplitude motor unit potentials firing at rapid rates is indicative of denervation and reinnervation. Early recruitment of numerous brief small-amplitude motor unit potentials indicates a myopathic process.
One important use of EMG is to detect denervation in muscles that are clinically of normal strength. Because of the process of collateral reinnervation, significant numbers of motor axons may be lost before clinical muscle weakness is detectable. For example, in a slowly progressive chronic entrapment neuropathy such as carpal tunnel syndrome (CTS), more than 50% of the motor axons may be lost before thenar muscles become weak. By revealing such denervation changes, EMG studies help the clinician to determine the severity of the lesion and make informed decisions about prognosis and management. The EMG can also recognize denervation in muscles that are difficult to assess on physical examination. Another use of EMG is to help define entrapment neuropathies (e.g., radial nerve entrapment) and differentiate these from more proximal radicular compression (e.g., apparent carpal tunnel syndrome that is actually caused by C6 radiculopathy: normal nerve conduction velocity [NCV] for the median nerve with abnormal EMG reflecting nerve root pathology). EMG can also help differentiate the muscle wasting of neuropathic or myopathic disorders from disuse atrophy. Table 92.4 summarizes the changes found in denervation and myopathic conditions.
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The EMG electrodes mildly inflame the muscles into which they have been inserted though the serum creatine phosphokinase activity is rarely altered by this procedure. Thus, if a muscle biopsy is being considered, EMG should not be performed in the muscle to be biopsied.
Patient Experience
There is usually discomfort with the initial insertion of the recording needles and during movement of the muscles when the needles are in place. Because the needles are very thin and penetrate only skin and muscle, the risks of infection or hemorrhage are almost nil. The procedure takes 30 to 60 minutes.
Nerve Biopsy
Nerve biopsy is a useful last step that should be reserved for patients in whom a specific histologic diagnosis and a management decision that may help the patient are possible (e.g., amyloidosis, demyelination, inflammation, or necrotizing vasculitis). Its use should be guided by the history and electrophysiology. The nerve studied by biopsy is almost always a sensory nerve (the sural) and sometimes may not reflect a disease process that appears to affect only the motor nerves. The biopsy always leads to a fixed numbness in the distribution of the excised nerve (usually the sural distribution on the lateral heel and ankle) but rarely may lead to painful sequelae such as neuroma formation. If a nerve biopsy is done, it should be done at a center where it is performed frequently, where plastic embedded nerve histopathology and electron microscopy are routinely available, and where a pathologist with special expertise in nerve morphology can interpret it, so that maximum information can result from this invasive procedure. Consultation with a neurologist is helpful in determining whether a nerve biopsy is indicated.
Skin Biopsy
The advent of skin biopsy as a diagnostic and research tool has provided an attractive option to the assessment of small caliber unmyelinated sensory nerve fibers. These fibers have historically been difficult to measure as they are not assessed by conventional nerve conduction testing (1). Skin biopsies are well tolerated, relatively noninvasive and can be used to pathologically sample nerve at different locations repeatedly over time. Epidermal nerve fibers are unmyelinated C fiber nociceptors and are typically affected early in the course of sensory neuropathies before large fiber involvement is apparent (2,3). As a result, the skin biopsy technique has become a useful diagnostic tool for small fiber neuropathies in patients who present with distal dysesthesias and normal nerve conduction test results (4). The technique has recently also been adapted to investigate the myelinated nerve fibers within the deep dermis providing insight into demyelinating and inherited neuropathies (5).
Patient Experience
Biopsy sites are numbed with subcutaneous 2% lidocaine producing transient burning. 3 mm punch skin biopsies are performed under sterile conditions using a circular knife identical to ones used for routine dermatologic biopsies. Hemostasis is achieved through local pressure without the need for suture placement—the exception being patients with international normalized ratio (INR) values greater than 2.5. The sites heal by a process of granulation most often with little or no scar formation. People with darkly pigmented skin or those with a predilection to keloid formation can have more prominent scarring. The procedure takes 15 minutes.
Specific Causes
Diabetic Neuropathy
Diabetic neuropathy is one of the most common neuropathies seen in primary care settings (6,7). The diabetic polyneuropathies have protean manifestations. They may present as a symmetric polyneuropathy or as a focal neuropathy. The former include sensory or sensorimotor polyneuropathy and autonomic polyneuropathy. The focal neuropathic syndromes include asymmetric lower limb mononeuropathy (diabetic amyotrophy), mononeuropathy multiplex, cranial neuropathy, entrapment neuropathies, and isolated trunk radiculopathies. Chapter 79 discusses the problem in detail (see Femoral Neuropathy).
Alcoholic Neuropathy
The neuropathy associated with alcoholism and related vitamin deficiencies is a sensorimotor axonal polyneuropathy (8). The presenting symptoms are often pain and paresthesias in the feet and legs though many patients are asymptomatic. Examination often shows diminished ankle jerks and a stocking–glove pattern of decreased sensation to all modalities. Autonomic features, including impotence, bladder dysfunction, and orthostatic hypotension, may rarely be seen. Electrodiagnostic studies commonly reveal reduced amplitudes of the sural sensory nerve action potentials and abnormal H reflexes. Sural nerve sections show primary axonal degeneration. Malnutrition and vitamin deficiencies (particularly thiamine deficiency) probably make a major contribution to the neuropathy, although there is evidence that alcohol has a direct toxic effect on peripheral nerves.
Treatment is aimed toward improved nutrition and vitamin replacement and effective treatment for the alcoholism (see Chapter 28). The paresthesias can improve
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with treatment in the setting of mild disease but often persist in cases with moderate to severe neuropathy.
Carcinomatous Neuropathies
The most common form of neuropathy associated with malignancies is a distal sensorimotor polyneuropathy. Compression or infiltration of nerves by tumor or a pure sensory neuronopathy occurs less commonly. Both the distal sensorimotor neuropathy and pure sensory neuronopathy are most often associated with carcinoma of the lung, and the onset of the neuropathic symptoms can either precede, follow, or coincide with the diagnosis of the malignancy (9,10).
Distal Sensorimotor Neuropathy
Distal sensorimotor neuropathy is primarily an axonal process with sensory loss and weakness appearing initially in the feet. It is more common in men, develops over weeks or months, and is generally progressive in its course. If the underlying cancer responds to treatment, the neuropathy may improve.
Carcinomatous Sensory Neuropathy
Carcinomatous sensory neuropathy has a distinctive pattern beginning subacutely, often with pain and paresthesias involving legs, arms, or, rarely, the face. Over many weeks a profound proprioceptive sensory loss develops, accompanied by pseudoathetosis (seemingly purposeless movements caused by loss of position sense). Areflexia is common. The patient may be unable to stand or walk unassisted despite normal strength. Nerve conduction studies may show reduced or unobtainable sensory potentials. It occurs more typically in women (9). The underlying tumor is most often small cell carcinoma of the lung, but this neuropathy also may accompany breast, ovarian, uterine, and gastrointestinal tract tumors. The neuropathy is usually progressive. Common chemotherapeutic agents including cis-platinum and oxaliplatin can produce a similar picture.
Paraneoplastic Vasculitis of Nerve and Muscle
This disorder is a nonsystemic vasculitic neuropathy that usually affects older men, has a subacute onset, and is progressive. It may present as a painful symmetric or asymmetric sensorimotor polyneuropathy or, less commonly, as a mononeuritis multiplex. The tumors most frequently involved are lymphoma and small-cell lung cancer. Electrodiagnostic studies reveal axonal degeneration affecting motor and sensory fibers. The erythrocyte sedimentation rate may be elevated, and the cerebrospinal fluid protein content is increased. Nerve biopsy reveals intramural and perivascular infiltrates without a necrotizing vasculitis. Muscle is often involved as well. It may respond to treatment of the tumor or to immunosuppression (11,12).
Paraproteinemic Neuropathies
An association between peripheral neuropathies and monoclonal gammopathies has been increasingly recognized. In patients with idiopathic peripheral neuropathy, a monoclonal gammopathy can be identified in nearly 10%. In half of these a plasma cell dyscrasia is diagnosed, whereas in the other half the monoclonal gammopathy is of undetermined significance and the relevance of the association with the neuropathy is unclear (13). In the event of a plasma cell dyscrasia, the treatment of the neuropathy is superceded by treatment of the tumor. The malignancies associated with monoclonal gammopathies include multiple myeloma, osteosclerotic myeloma, Waldenström macroglobulinemia, B-cell lymphoma, and chronic B-cell lymphocytic leukemia. Peripheral neuropathy may be the presenting symptom in plasma cell dyscrasias, such as in primary amyloidosis or the rare osteosclerotic form of myeloma. Patients with multiple myeloma may develop a mild distal sensorimotor neuropathy, a pure sensory neuropathy, or a subacute monophasic or relapsing and remitting neuropathy. Amyloid deposition may occur in these patients, usually causing a distal sensorimotor neuropathy, but may also present as CTS, multiple mononeuropathies, or autonomic dysfunction. Neuropathic symptoms typical in primary amyloidosis are prominent burning dysesthesias and autonomic dysfunction. Like the amyloidosis, the neuropathy generally does not respond to treatment.
Nearly 50% of patients with osteosclerotic myeloma have a neuropathy characterized as a symmetric, demyelinating, primarily motor neuropathy. All or some of the features of the POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome may be present (14). Although the course is usually one of steady progression, improvement in the neuropathy occurred in nearly 50% of patients in one series in response to successful treatment of osteosclerotic myeloma.
Five to ten percent of patients with Waldenström macroglobulinemia have a demyelinating sensorimotor polyneuropathy that predominantly affects large sensory fibers. Postural tremor and pseudoathetosis are common. Those patients with demyelinating neuropathy and immunoglobulin (Ig)M to myelin-associated protein (MAG) may respond to therapy with plasma exchange or intravenous Ig, but most require chemotherapy. In patients that are refractory to these treatments, high-dose Cytoxan therapy has provided encouraging results and is a growing focus of research protocols (15).
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TABLE 92.5 Toxins and Drugs Associated with Peripheral Neuropathies |
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Neuropathy Caused by Toxins and Drugs
Toxic neuropathies, including those caused by drugs, are becoming increasingly recognized. Toxic neuropathies are potentially reversible if the toxin can be identified and the exposure to the toxin eliminated. The diagnosis may be made easily if there is a history of drug exposure (e.g., colchicine, isoniazid, hydralazine, vincristine) or industrial exposure (Table 92.5). Because these neuropathies have no distinguishing features on routine history or physical examination, a detailed history of exposure to drugs and the patient's occupation and recreational habits is important. Axonal involvement in the spinal cord may also occur and be masked by the toxic neuropathy. In these cases, a residual spastic paraparesis becomes apparent when the peripheral neuropathy has resolved. Toxic neuropathies are classically associated with chronic low-dose exposure (months to years), although they may appear within days to weeks with high-level exposure. The syndrome of proximal muscle weakness and axonal polyneuropathy caused by colchicine may appear after the patient has taken this drug for years, usually because of elevated drug levels caused by altered renal function. A delayed neuropathy associated with organophosphates develops 10 to 14 days after exposure, whereas Vacor, a rodenticide, produces an acute toxic neuropathy within 2 to 3 days.
Toxicity caused by megadose pyridoxine (vitamin B6) consumption produces a gradually progressive sensory ataxia with profound distal limb impairment of position and vibratory sense (16). General public acceptance of vitamin B6 therapy makes direct questioning about vitamin habits necessary. Neuropathy has been reported in patients consuming dosages as low as 200 mg/day.
Patients with familial neuropathy, pre-existing peripheral neuropathy or prominent risk factors such as diabetes or uremia represent a vulnerable population and can experience rapid neuropathy progression in the setting of toxin exposure. This underscores the importance of investigating potential toxic exposures in patients with rapid neuropathy disease courses and not attributing it to a known diagnosis.
Human Immunodeficiency Virus Infection
There are many peripheral nervous system manifestations of human immunodeficiency virus (HIV) infection (17). A painful sensory neuropathy, usually confined to the feet, is the most common neurologic complication, affecting 30% of patients with the acquired immunodeficiency syndrome, and typically occurs in the setting of advanced infection. Often reduction in unmyelinated nerve fiber density is the most sensitive pathologic marker, though nerve conduction studies can show reduced or absent sensory potentials. Treatment is currently limited to symptomatic relief using tricyclic antidepressants such as amitriptyline (Elavil) or antiepileptic agents such as lamotrigene (Lamictal), gabapentin (Neurontin), or carbamazepine (Tegretol), described below.
Multiple mononeuropathies have been described, most often in HIV-infected patients who have not yet developed AIDS. Both acute Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) have been seen, usually in the early stages of HIV infection, in otherwise asymptomatic seropositive patients. Treatment for these demyelinating conditions is generally identical to seronegative patients.
Progressive polyradiculopathy is a cytomegalovirus (CMV) infection-related syndrome that usually occurs late in the course of HIV disease and causes radiating pain and numbness in the low back and buttocks. This is typically followed by progressive flaccid paraparesis, lower extremity areflexia, sphincter dysfunction and occasionally, a thoracic sensory level. Urinary retention occurs in most patients. Cranial nerves and the upper extremities are rarely involved, though many patients have a history of CMV retinitis. The mortality rate is nearly 100% if untreated, with a very rapid and progressive course (measured in days). Cerebrospinal fluid (CSF) findings include a marked polymorphonuclear pleocytosis, and polymerase chain reaction (PCR) for CMV deoxyribonucleic acid (DNA) is highly sensitive and specific. Treatment with ganciclovir is effective if initiated early (18,19).
Compression and Entrapment Neuropathies
When a peripheral neurologic abnormality occurs in one upper or lower extremity, the abnormality is usually caused by nerve entrapment or compression caused by anatomic abnormalities or trauma, although polyneuropathy and
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mononeuropathy multiplex may present initially as a focal deficit in one extremity. With clinical evaluation, it is usually possible to determine whether the patient's problem is caused by nerve root damage or damage to a peripheral nerve or one of its branches. Tables 92.6, 92.7, and 92.8 and Figures 92.1 and 92.2 summarize the information needed to make this distinction: distribution of sensory, motor, and reflex deficits; common causative factors; and critical anatomic relationships.
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TABLE 92.6 Comparative Data on Root and Nerve Lesions in the Upper Extremity |
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TABLE 92.7 Comparative Data on Root and Nerve Lesions in the Lower Extremity |
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Several common compression and entrapment neuropathies and specific approaches to treatment are discussed here. Nerve conduction testing is needed to confirm the diagnosis, and distinguish between several possible conditions as well as to support the decision to recommend
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surgery. People with diabetes are at increased risk of developing entrapment neuropathies and generally do not recover axonal loss to the degree that nondiabetic counterparts do. This has prompted some to argue for aggressive early diagnosis and treatment of entrapment neuropathies in people with diabetes—before significant axon loss occurs. Additional general aspects of prognosis and treatment are described in a later section (see Therapeutic Principles). Chapters 70 and 71 discuss root compression symptoms caused by cervical and lumbar spine disease.
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TABLE 92.8 Entrapment Neuropathies: Common Causative Factors |
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Median Nerve (Carpal Tunnel Syndrome)
Causes
CTS is the most common of all the entrapment neuropathies. In CTS, symptoms and signs result from compression by neighboring anatomic structures on the median nerve as it passes from the forearm to the palm (Fig. 92.1). The median nerve and nine digital flexor tendons pass through the carpal tunnel, a rigid compartment formed by the concave arch of the carpal bones and roofed by the transverse carpal ligament. Conditions that cause a decrease in the size of the carpal tunnel (e.g., Colles fracture, rheumatoid arthritis, congenital carpal tunnel stenosis), enlargement of the median nerve (e.g., amyloid, neuroma, endoneural edema in DM), or increase in the volume of other structures within the tunnel (e.g., tenosynovitis, ganglion, lipoma, urate deposits in gout, hematoma, fluid retention in pregnancy) may all result in compression of the median nerve. CTS in the workplace is associated with occupations requiring wrist extension/flexion or hand force in all wrist positions (e.g., meat processing, fruit packing, upholstering, and waiting on tables). Median nerve compression can also be caused by sustained or repeated stress over the base of the palm, such as that caused by the use of hand-tools. Vibration exposure (low frequency, 10 to 40 Hz) is another well-recognized risk factor for CTS (typically from air-powered tools). Repetitive wrist and hand movements in activities such as knitting, crocheting, hooking rugs, playing a musical instrument, painting, woodworking, gardening, lifting weights, or typing when the keyboard is too high may also lead to CTS.
Manifestations and Evaluation
The onset of symptoms of CTS is usually insidious and nocturnal because of sustained posture of wrist flexion during sleep. Symptoms in the hand may initially be described as episodic tingling and numbness with gradual progression to more severe symptoms, such as burning, aching, or a painful numbness in the fingers and deep in the palm. The fingers are sometimes described as feeling swollen, even though little swelling is apparent on inspection. Many patients have accompanying dull aching pain in the forearm, sometimes reaching the shoulder, which can be confused with a C6 radiculopathy.
As CTS progresses, the nocturnal pain and tingling may wake the patient. Relief may be obtained by hanging the arm or shaking or rubbing the hand. Episodic tingling may develop during the day, but the associated pain in the arm occurs less often during the day than at night. Additionally, there can be a subjective feeling of weakness and clumsiness in the fingers with difficulty performing tasks such as unscrewing bottle tops, turning a key, or crocheting.
Objective changes in sensation and strength may appear in the hand, but some patients may have severe attacks of pain for years without developing neurologic signs. Sensory signs within the median nerve distribution (Table 92.6) precede motor signs and are most pronounced in the fingertips. Rarely, instead of decreased sensation, hyperesthesia in the median distribution may occur. Isolated
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sensory impairment in the distribution of one of the lateral three digital (thumb and digits 2, 3, lateral half of 4) nerves may be unusual presenting features of median nerve lesions at the wrist. Mild weakness of the abductor pollicis brevis (to test, patient abducts thumb at right angle to palm, against resistance) or of the opponens pollicis muscle (to test, patient touches base of little finger with thumb, against resistance) is often present with no visually apparent atrophy. Prolonged hyperflexion of the wrist may reproduce sensory symptoms (Phalen sign). Tinel sign,
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consisting of shock-like pain and tingling elicited by percussion of the median nerve at the wrist, is a less specific finding. In a systematic review of the accuracy of the physical examination to diagnose CTS, hypalgesia in the median nerve territory, a classic pattern of pain with hand symptom diagrams, and weak thumb abduction were the strongest predictors of electrodiagnostic CTS (20).
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FIGURE 92.1. Anatomic relationships of nerves to the upper extremity. (Modified from Patten J. Neurological differential diagnosis. 2nd ed. New York: Springer-Verlag, 1995. ) |
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FIGURE 92.2. Anatomic relationships of nerves to the lower extremity. (Modified from Patten J. Neurological differential diagnosis. 2nd ed. New York: Springer-Verlag, 1995. ) |
Nerve conduction studies in CTS are invaluable in confirming the diagnosis and qualifying the degree of axon loss if any. In addition, because central nervous system
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or root lesions can occasionally result in similar sensory symptoms, confirmation of a peripheral nerve lesion by electrophysiologic testing is important. Typically changes in the sensory axons of the median nerve, including segmental reduction in conduction velocity across the wrist segment and axon loss, are the most sensitive measures. Motor axon changes, such as prolonged distal latencies, occur later in the course of entrapment. EMG is important to confirm localization of median nerve entrapment, to look for evidence of associated axonal degeneration and to rule out possible coexistent cervical radiculopathy (double crush syndrome).
Treatment
Immobilization of the wrist with a close-fitting anterior splint (extends from the upper part of the forearm to the metacarpophalangeal joints), which is worn by the patient at night or when resting, holds the wrist immobilized in a neutral position. This is often sufficient, but if symptoms persist after a few weeks, additional therapy is indicated. Medications such as NSAIDS, pyridoxine, or diuretics are commonly prescribed but the efficacy of such treatments has not been supported by clinical trials. Steroid injection beneath the transverse carpal ligament has been used for over 60 years to treat CTS though care must be taken not to directly inject the nerve which can result in axonal injury. Several, randomized clinical trials demonstrated that injection with steroids was superior to placebo injection in patients with CTS refractory to splinting. The benefit was frequently short-lived and required repeat injections in many patients (21,22). Two recent RCTs comparing surgical therapy to steroid injection found surgery to be superior for both symptomatic and electrophysiologic improvement (23,24). Steroid injection has an important role as a predictor of treatment success as patients responding transiently to local injection were much more likely to experience relief following surgery (25,26), but likely carries increased risk when used repeatedly in the chronic management of CTS.
Indications for carpal tunnel release include the failure of nonoperative treatment or clinical evidence of thenar atrophy. A relative indication is constant sensory loss, especially if it is long standing. Surgery for CTS is one of the most successful operations that can be performed on the hand. The operation demands care and skill by an orthopedic, plastic, or neurologic surgeon who performs hand surgery regularly. Complications of the operation or poor results such as reflex sympathetic dystrophy, injury to median nerve branches, hypertrophic scar or adherent flexor tendons are almost always related to poor surgical technique. The usual postoperative recovery time is 6 to 8 weeks. An additional month may be needed for occupational rehabilitation. Most patients with jobs that involve repetitive wrist motion such as typing are able to return to their preoperative activities after a work-hardening program.
Ulnar Nerve
Causes
Ulnar nerve compression occurs most often at the elbow (Fig. 92.1). The cubital tunnel refers to the area of potential entrapment of the ulnar nerve at the elbow as it runs beneath the aponeurosis of the flexor carpi ulnaris muscle just distal to the medial epicondyle. Minor pressure directly over the cubital tunnel during anesthesia, intoxication, stupor, coma, or by trauma may subsequently cause symptoms.
Compression of the ulnar nerve at the elbow may occur with activities requiring repeated or sustained flexion of the elbow because the cubital tunnel is at its smallest when the elbow is at 90% flexion. Hypermobility of the ulnar nerve can result in subluxation over the medial epicondyle and repeated trauma.
Manifestations and Evaluation
Patients may awaken at night with elbow pain, shooting pain in the hand or fifth digit, and paresthesias and hypesthesia in the ulnar nerve distribution. These symptoms usually improve with elbow extension. The amount of pain and paresthesia varies.
Ulnar sensory loss (Table 92.6) is easiest to establish with two-point discrimination over the distal two phalanges of the little finger. Transition between the ulnar territory over the hypothenar eminence and the medial antebrachial cutaneous nerve (branch from the brachial plexus) of the forearm is often detected at the skin crease at the wrist. Motor disability is usually manifested as decreased grip and pinch strength, which is related to the degree of atrophy of the involved intrinsic muscles, especially the palmar and dorsal interossei and flexor digitorum profundus to the fourth and fifth digits. One of the earliest signs of ulnar nerve entrapment is weakness of fifth finger adduction with a tendency to catch the finger on a pants pocket.
Ulnar neuropathy distal to the elbow occurs at the wrist or in the hand and must be considered if there is no weakness in the flexor digitorum profundus. This is most often caused by a ganglion, rheumatoid arthritis, or trauma (e.g., long-distance bicycling). Often lesions in the wrist or hand produce no paresthesias or sensory loss. Depending on the level of entrapment at the wrist, either all of the ulnar innervated muscles may be weak or there may be selective preservation of hypothenar function, i.e., abductor digiti minimi.
Electrodiagnostic study involves focal slowing of the ulnar motor or sensory nerve conduction across the elbow
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to localize the nerve damage, depending on the severity. False-positive findings may be obtained, so close correlation with the clinical findings is mandatory. Increased distal latencies are found with entrapment at the wrist but must be correlated with needle electrode examination (see Nerve Conduction Studies) to determine the actual site of the lesion.
Treatment
Nonsurgical treatment is indicated for the patient with intermittent symptoms, acute or chronic mild neuropathy, or mild neuropathy associated with an occupational cause. For a mild ulnar neuropathy, wearing elbow pads during the day and splinting the elbow at night in an extended position may be helpful. An easy way to splint the elbow during sleep is to strap a pillow around it. Elbow protection should be continued for 2 to 3 months, especially if the symptoms are intermittent or show improvement. For ulnar compression at the wrist, whether caused by a single traumatic event or by chronic trauma, conservative treatment with a wrist splint (see Median Nerve [Carpal Tunnel Syndrome], above) is generally adequate.
Surgical intervention is generally not necessary. If symptoms progress or if motor involvement develops, surgery can be considered. Surgical approaches to lesions of the ulnar nerve at the elbow depend on the cause and the surgeon. These include simple release of the cubital tunnel, medial epicondylectomy, and anterior transposition of the nerve. Complications from any of the surgical approaches include persistent or recurrent symptoms caused by inadequate surgery or recurrent scarring around the nerve.
Radial Nerve
Causes
Radial nerve lesions are the least common of the major upper extremity nontraumatic compression neuropathies and usually involve the nerve at or proximal to the elbow (Fig. 92.1). Besides traumatic conditions such as humeral fractures, more proximal radial nerve injuries can occur when the arm has been held in a hyperabducted position that causes traction to the nerve, as in surgery or sleep. Proximal nerve injury may also follow axillary pressure caused by incorrect use of a crutch. The middle third of the nerve is compressed against the humerus in the so-called Saturday night palsy, as when an intoxicated person sleeps with the arm draped over a chair. Compression of the posterior interosseous nerve (a motor branch of radial nerve in the forearm) can result from a variety of masses, such as lipomas, fibromas, or calluses from old fractures.
Manifestations and Evaluation
The radial nerve is predominantly a motor nerve. Depending on the location of a high radial compression, the triceps function (elbow extension) may or may not be affected. Elbow flexion and supination may be slightly affected by brachioradialis weakness. The most obvious finding in a radial palsy is wrist drop and digital extensor paralysis (finger drop). A lesion of the posterior interosseous nerve results in finger drop alone.
High radial nerve lesions may produce sensory loss over the dorsum of the hand. Pain and tenderness in the area of nerve damage may be present. Nerve conduction studies and electromyography (see Nerve Conduction Studies) are helpful in localizing and quantifying radial nerve compression. For example, acutely, a Saturday night palsy can cause focal slowing of conduction at the site of pressure injury but normal motor and sensory conduction below this lesion.
Treatment
The treatment of traumatic radial nerve compression is generally conservative and recovery of function occurs within a few weeks to months. To prevent flexor contractures, a cock-up splint for the wrist joint should be accompanied by a spring-loaded extensor brace for the fingers if the weakness is severe and long lasting. Individually constructed splints made by an occupational therapist are superior to those obtained from a surgical supply house. For compression of the posterior interosseus nerve with no obvious cause, imaging of the nerve should be performed to investigate for possible masses. If no mass is identified, surgical exploration is indicated if there has not been spontaneous recovery within 2 to 3 months.
Peroneal Nerve
Causes
The most common site of compression of the peroneal nerve is at the fibular head (Fig. 92.2). Such compression may result from improperly applied plaster casts or tight stockings and garters or from falling asleep with the side of the leg resting against a protruding object, as in a drug- or alcohol-induced stupor or in the weakened bedridden patient. Prolonged leg crossing, squatting, or kneeling may also result in peroneal compression. Entrapment of the peroneal nerve can also occur in the fibular tunnel formed by the peroneus longus muscle.
Manifestations and Evaluation
Symptoms of peroneal palsy consist of painless weakness of ankle dorsiflexion (foot drop) and foot eversion and sensory loss over the lateral calf and dorsum of the foot. Electrodiagnostic studies and nerve conduction studies can detect focal slowing or conduction block in the peroneal nerve segment across the fibular head. The superficial peroneal sensory potential may be absent. Needle electrode examination may demonstrate denervation in peroneal innervated muscles with sparing of the short
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head of the biceps femoris muscle, the most distal of the peroneal innervated muscles above the fibular head. Peroneal palsy with loss of motor function and no clear history of trauma or external compression should be investigated with appropriate physical examination and imaging of the popliteal fossa to rule out a mass lesion.
Treatment
Mild compressive peroneal lesions can be treated conservatively. Patients should be advised to avoid potentially injurious positions for the nerve (e.g., leg crossing, squatting). A custom-fitted ankle–foot orthotic is recommended for increased ankle stability and prevention of plantar flexion contractures. Most patients with a transient compressive insult recover peroneal function within weeks to months. Surgical exploration should be considered in severe cases with no clear cause.
Tibial Nerve (Tarsal Tunnel Syndrome)
Causes
The tarsal tunnel is located at the inferoposterior margin of the medial malleolus (Fig. 92.2) and is formed by bones of the ankle and the flexor retinaculum (fibrous sheath from medial malleolus posteroinferior to the medial side of the calcaneus) (see Chapter 72). In addition to the posterior tibial nerve, the tunnel contains the posterior tibial artery and three long flexor tendons (27).
Enlarged tortuous veins within the tarsal tunnel, fracture or dislocation at the ankle, and tenosynovitis may lead to compression of the tibial nerve trunk. Prolonged standing and walking often aggravate the pain, indicating that stasis or engorgement within the tunnel is likely to play some role. Also, sensory symptoms are made worse by the venous stasis and engorgement that occur at night during sleep. Except for a high prevalence in jockeys, no common occupational factors have been identified.
Manifestations and Evaluation
The primary symptom of tarsal tunnel syndrome is pain and dysesthesia in the sole of the foot. The burning pain (descriptions by patients may vary, e.g., walking on knives or pins, sole feels very thick) worsens with rest after a day of activity. Nocturnal pain is characteristic. Any or all the three terminal divisions of the tibial nerve (medial plantar, lateral plantar, and calcaneal) may be affected, resulting in sensory disturbance over the entire plantar surface or only one portion of it.
Tinel sign, consisting of shooting pain to the plantar surface produced by gentle percussion over the tarsal tunnel, may be present. Sensory loss, if present, is localized to the plantar surface of the foot and over the tips of the toes (the sural and peroneal territories on the dorsum of the foot do not include the tips of the toes). Weakness in the intrinsic muscles of the foot may lead to a change in configuration of the foot and to instability of the phalanges, which impairs the pushing-off phase of walking. Tarsal tunnel syndrome is usually unilateral.
In the tarsal tunnel syndrome, sensory nerve conduction studies of medial and lateral plantar nerves are the most sensitive electrodiagnostic measures, showing reduced sensory nerve action potential amplitudes or absent responses. Reduced motor or sensory conduction velocities across the flexor retinaculum are found less commonly. Electromyography demonstrates chronic partial denervation in the tibial innervated intrinsic muscles of the feet (e.g., abductor hallucis and abductor digiti quinti). Symptoms of tarsal tunnel syndrome may mimic those of a small fiber neuropathy and often require electrodiagnostic and skin biopsies to distinguish the two.
Treatment
It is important to identify and remove any source of external pressure at the flexor retinaculum. Definitive treatment of tarsal tunnel syndrome is surgical release of the flexor retinaculum, which can result in dramatic relief of symptoms.
Femoral Nerve
Causes
The femoral nerve may be injured by stab wounds to the groin or hip, pelvic fractures, inguinal surgery (inguinal hernia, vascular repair, node resection), angiography, or retraction during pelvic surgery (Fig. 92.2). Stretch injuries can occur with prolonged lithotomy position, during child birth, or with hyperextension during gymnastics or dance. Pressure on the femoral nerve can also be produced at the psoas muscle by hematoma or abscess.
Manifestations and Evaluation
The patient often complains about buckling of the knee (quadriceps weakness), and falls are common. Pain in the groin radiating into the thigh may be severe. Sensory loss is present in the anterior medial thigh and medial leg. Weakness of the quadriceps (knee extension) and loss of the knee jerk are noted on examination. Weakness of hip flexors indicates a more proximal lumbar plexus or root lesion. Electromyography helps differentiate these problems.
Femoral neuropathy is to be distinguished from diabetic lumbar plexopathy (diabetic amyotrophy). The latter disorder, seen most commonly in people with diabetes over 50 years of age, begins abruptly with severe pain in the thigh and buttocks, and progresses to produce proximal weakness which can be severe and require the use of a wheelchair. Classically, these patients have significant concomitant weight loss. With electromyography a wider distribution of involvement can be appreciated.
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Sensory signs are mild. The prognosis for recovery over 2 to 6 months is variable but generally good (see Chapter 79).
Treatment
Treatment depends on accurate diagnosis (e.g., discontinuation of anticoagulants when a psoas hematoma has been identified as the cause of the neuropathy). Physiotherapy may be required to maintain the mobility of the hip joint. The outcome and extent of rehabilitation measures are determined by the cause and extent of injury.
Saphenous Nerve
The saphenous nerve is one of three sensory branches of the femoral nerve (Fig. 92.2). It is most often injured at Hunter canal (10 cm proximal to the medial condyle of the femur). Vein stripping and knee surgery are common causes. A small medial nerve branch can be injured by knee surgery. The patient has pain and numbness at the medial aspect of the knee and leg. The pain may worsen with walking and climbing. Manual pressure over the Hunter canal produces pain that radiates. If the pain becomes chronic, local anesthetic can be injected to the area of injury.
Sciatic Nerve
Causes
The sciatic nerve is often injured as a complication of trauma (Fig. 92.2), including hip fractures, dislocations, and arthroplastic surgery. Compression of the nerve can occur in comatose or chronically bedridden patients or after sitting on a hard edge. Hematoma, endometriosis, lipoma, and aneurysms of the gluteal artery are other causes of compression. Injections into the buttock are now less common causes of sciatic nerve injury. Injections usually cause immediate dysfunction with poor recovery.
Manifestations and Evaluation
Symptoms of sciatic nerve compression may mimic L5–S1 radiculopathy caused by disk disease (see Chapter 71). The lateral trunk or peroneal division of the sciatic nerve is often affected more severely than the tibial division. Therefore, the distinction between a proximal sciatic injury and a more distal peroneal injury (e.g., after awakening from hip surgery) may be difficult clinically and require electromyography evaluation in order to distinguish the two.
Lateral Femoral Cutaneous Nerve (Meralgia Paresthetica)
The lateral femoral cutaneous nerve may be compressed or stretched at the anterior superior iliac spine at the lateral end of the inguinal canal (see lateral cutaneous nerve of the thigh; Fig. 92.2), causing burning pain, paresthesia, and decreased sensation over the lateral thigh in a distribution that roughly corresponds to the pockets of pants. There is no motor involvement or loss of patellar reflex. Point tenderness can usually be elicited at the passage of the nerve at the ipsilateral anterior iliac crest. Common causes include obesity, acute abdominal enlargement (ascites, pregnancy), external mechanical trauma (girdle, utility belt, climbing with body against utility pole), and DM. The nerve compression may be relieved by weight loss or correction of the aggravating condition. Pain may respond to medical management (seeTherapeutic Principles), but generally resolves spontaneously over months. If the pain is severe, local injection of an anesthetic may provide relief for long periods; sectioning of the ligament over the canal or sectioning of the nerve is rarely needed. Paresthesias and pain usually disappear gradually, but a painless sensory loss in the lateral thigh may persist.
Bell Palsy
Paralysis of the facial muscles caused by inflammation and swelling of the seventh (the facial) cranial nerve (Bell palsy) is seen occasionally in a general medical practice. One large series reported an incidence of 23 cases per 100,000 population per year (28). There is no predilection for a particular sex, age group, or race. In most patients, the cause of the condition is unknown. Two specific causes for seventh nerve neuropathy that have been recognized in recent years are Lyme disease (29,30) (see Chapter 38) and HIV infection (seeChapter 39). Bilateral involvement also raises the possibility of sarcoidosis or carcinomatous meningitis. Several small studies have suggested that asymptomatic reactivation of varicella zoster virus is responsible for a substantial proportion of cases of Bell palsy (31).
Manifestations
Usually, patients note the sudden onset, within hours, of a unilateral facial weakness: the eyebrow sags, the eyelid cannot be closed, the nasolabial fold disappears, and the mouth is drawn to the unaffected side. Less commonly, there is loss of taste on the anterior two thirds of the tongue and there is hyperacusis (an accentuation of sounds) in the affected ear. There may be pain behind the ear. Most patients recover spontaneously within weeks to a few months; approximately 15% recover incompletely, but severe residual weakness is rare (28). Patching of the unclosed eye should be performed to avoid corneal injury. Rarely, synkinesis (a contraction of all the facial muscles on the affected side when the patient attempts to move just one or a few of them) caused by aberrant reinnervation can complicate recovery.
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Management
Therapeutic trials of treatment for Bell palsy have lacked sufficient power to be conclusive, but meta-analysis of several trials show that corticosteroid therapy early in the course improves facial outcomes (32,33). Combined acyclovir–prednisone was found to improve recovery over prednisone alone in one trial (34). The current standard of treatment when the palsy has been present less than 4 days is prednisone 60 to 80 mg/day for 1 week, and valacyclovir (because of improved oral absorption) 1 g three times a day for 1 week (35).
Less Common Problems
Hereditary Motor and Sensory Neuropathies
Of the heritable disorders affecting the peripheral nervous system, the hereditary motorsensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) disease are the most common. As a group, the HMSN are a heterogeneous group of neuropathy syndromes affecting an estimated 1 per 2,500 people (see http://www.hopkinsbayview.org/PAMreferences). The nomenclature of these disorders has historically been confusing, though the identification of individual gene mutations has greatly clarified the situation. Patients are now generally classified into four types: CMT 1 refers to patients with reduced conduction velocities and a dominant pattern of inheritance; CMT II if there is a dominant pattern of inheritance and normal nerve conduction velocities but reduced motor or sensory amplitudes; CMTX if they have an X-linked inheritance pattern; and CMT 4 if the inheritance pattern is autosomal recessive. Past eponyms such as Dejerine Sottas disease and the Roussy-Levy syndrome are now appreciated to be phenotypic variants of CMT 1 rather than distinct disease entities.
The most common type, CMT I, is characterized by slowly progressive distal weakness, muscle wasting; foot abnormalities that can include pes cavus and hammer toe, and mildly diminished distal sensation. Symptoms are usually manifest by the fourth decade; however, many patients have few or no symptoms. Sensory symptoms are rarely the presenting complaint and when present suggest an acquired rather than inherited neuropathy.
Physical examination demonstrates a wide range of clinical severity and may include distal weakness, thin peroneal muscles, diminished deep tendon reflexes in the legs, characteristic abnormalities of the feet (see above), and mildly reduced distal sensation. Occasionally, enlarged nerves can be palpated. Electrophysiologic studies of sensory and motor nerves show diffuse involvement, with severely reduced conduction velocities uniformly along the nerve segment. Nerve pathology shows onion bulb formation composed of redundant Schwann cell processes resulting from recurrent demyelination and remyelination. Diagnosis is established by identifying a history of childhood onset and by physical examination, characteristic electrophysiologic findings, electrodiagnostic evaluation of family members, and genetic testing. Genetic mutations have been identified on chromosomes 1, 10, and 17. The most common treatment required is the use of custom-fitted ankle–foot orthotics.
Guillain-Barré Syndrome
GBS or acute inflammatory polyradiculoneuropathy is a rapidly progressive paralytic syndrome affecting all ages. Evidence is strong for an immune-mediated pathogenesis. Most cases of GBS follow a mild viral illness (by 10 to 12 days) (36). The syndrome also may be associated with pregnancy, the postoperative period, recent influenza immunization, and HIV infection. A link between preceding Campylobacter jejuniinfection and GBS is particularly strong, involving approximately 20% of cases. Molecular mimicry has been implicated as the mechanism and might explain why such cases tend to be more severe. Other prognostic indicators for severe disease are older than 60 years, ventilator dependence, and a rapid progression from initial symptoms to respiratory insufficiency. Diagnosis of C. jejuni infection is based on isolation of C. jejuni from stool. The differential diagnosis for GBS includes acute intermittent porphyria, botulism, diphtheria, poliomyelitis, Lyme disease, and toxic neuropathies (arsenic, thallium).
Manifestations
There is rapid progression of ascending symmetric weakness (usually moving from the lower extremities to the upper extremities) accompanied by loss of deep tendon reflexes. Although acute pain or paresthesias in the back and proximal limbs may be prominent early symptoms, objective evidence of sensory loss is generally limited to mild impairment of distal joint position sense and vibratory sensation. Cranial muscle weakness may be present, with bilateral facial nerve palsy in 40% of patients. Nerve conduction studies show changes of demyelination (prolonged distal motor and F-wave latencies and reduced motor conduction velocities). The CSF may show an increased protein concentration with normal cell counts (cytoalbumin dissociation).
Management and Course
Because of rapid progression of the disease, patients suspected of having this disorder should be admitted to the hospital for close monitoring for potential respiratory failure and autonomic instability (hypotension, hypertension, cardiac arrhythmias, or hyperpyrexia occur in two thirds of patients with GBS). Treatment with either plasmapheresis or intravenous human immunoglobulin early in the
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course shortens the period of disability, and the combination is no better than either treatment alone (37). Recovery is complete in approximately 50% of patients (although it may take 6 to 18 months); most of the remainder have only mild residual deficits, but 10% have severe permanent disability. Splints (to prevent contractures) and physiotherapy should be used until the recovery period is complete.
Chronic Inflammatory Demyelinating Polyneuropathy
CIDP is an acquired motor and sensory neuropathy of unknown cause but with strong evidence for an immune-mediated pathogenesis. CIDP can occur in the absence of systemic disease or, less commonly, in association with such disorders as systemic lupus erythematosus (SLE), HIV infection, or dysproteinemias. Clinically, CIDP is a predominantly motor polyneuropathy. It may affect all ages and may have either a chronic progressive or relapsing course. Weakness typically develops over at least 2 months (distinguishing CIDP from acute inflammatory demyelinating neuropathy or GBS) and generally begins in the legs. Sensory involvement is variable. Most patients experience some degree of numbness or paresthesia; occasionally, there may be painful dysesthesias. On examination, weakness may be both proximal and distal, and the tendon reflexes are reduced or absent in all four limbs.
Electrodiagnostic studies demonstrate features of demyelination, including prolonged distal and F-wave latencies, reduced conduction velocities variably along nerve segments, abnormal temporal dispersion, and conduction block. CSF protein is often elevated. Sural nerve pathology may show evidence of demyelination and remyelination with onion bulb formation, subperineurial and endoneurial edema, and mononuclear cell infiltration.
Management
Common practice is to begin treatment with prednisone 1 mg/kg/day (38) and to use either plasmapheresis or intravenous human Ig as adjuvants (39). Each of these immunomodulating therapies has been demonstrated to be effective in randomized placebo-controlled trials, and most patients respond. Long-term corticosteroid therapy usually is effective but is limited by side effects. Steroid-sparing therapy with azathioprine or mycophenolate are also effective but have a long latency period. The effect of either plasmapheresis or human immunoglobulin is large and of equal likelihood, but for most patients is short-lived and requires continued intermittent treatment (39). For plasmapheresis, improved motor conduction velocities and reversal of conduction block predict improvement in motor function (40). Plasma exchange treatments should be given two to three times per week until improvement is established, then tapered in frequency; concurrent immunosuppressive drug treatment is usually required (40). Human immunoglobulin treatment is effective in about two thirds of patients, most often in patients with acute relapse or disease duration less than 1 year (41). Improvement after a dose of 2 g/kg lasts a median 6 weeks and is reproducible, so that followup pulses of 1 g/kg as single infusions can maintain a stable benefit (41). Of the two adjuvants, both are extraordinarily expensive, but intravenous Ig infusion may be preferable because it does not require expensive medical devices and can be given at home (39).
Multifocal Motor Neuropathy
Patients with multifocal motor neuropathy have progressive, predominantly distal, asymmetric weakness that usually begins in the arms. Early in the disease course, multifocal motor neuropathy can mimic CIDP or the lower motor neuron presentation of amyotrophic lateral sclerosis. Nerve conduction studies show multiple areas of persistent partial motor conduction block, and many patients have high IgM anti-GM 1 ganglioside antibody titers. Most patients with multifocal motor neuropathy respond variably to immunomodulatory therapy with human immune globulin (42). Recently, therapy with rituximab has also been demonstrated to be effective in some patients that became refractory to human immune globulin (43). Corticosteroids are ineffective.
Therapeutic Principles
General Measures that Improve Nerve Function
Treatment of peripheral neuropathies first requires identifying and treating any underlying cause, if possible. For type 1 DM, for example, it is now known that intense efforts at tight glucose control dramatically reduce the incidence of neuropathy (see Chapter 79). Efforts should be made also to prevent further damage; for example, patients with an underlying generalized polyneuropathy are more prone to pressure palsies, and it is important to educate them about habits that could be injurious (e.g., leaning on elbows or crossing legs). The daily administration of multivitamins is necessary only in patients whose nutrition may be poor. For entrapment and compression neuropathies, eliminating pressure on the affected nerve is the primary mode of treatment. Pain and paresthesias may be relieved rapidly within hours or days. The prognosis for recovery depends on the pathophysiology of the nerve injury. When little or no denervation is demonstrated by electromyography, which suggests that the predominant pathophysiology is edema or demyelination, recovery of function over weeks is expected. In more severe cases with marked denervation indicating axonal injury, recovery is more prolonged (months).
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The most important prognostic indicators for traumatic nerve injuries are the site, mechanism, and completeness of the injury. Traumatic injuries can occur at the level of the root, plexus, or peripheral nerve. Root avulsion has the worst prognosis. Electrodiagnostic studies are helpful in localizing the site of injury; however, because denervation may not be evident for at least 14 days, electromyography studies should be done approximately 3 to 4 weeks after injury. Complete nerve transections caused by sharp penetrating injury, although rare, more often benefit from early primary anastomosis than do complicated nerve injuries such as gunshot wounds. Physical therapy, particularly range-of-motion exercises, should be initiated early after injury to prevent contractures. The onset of spontaneous recovery can vary from weeks to 6 months or more after injury. In cases of persistent loss of function or severe pain, surgical exploration should be considered.
Symptomatic Treatment for Irreversible Damage
Polyneuropathy is often irreversible and progressive. Symptomatic therapy and rehabilitative measures are therefore fundamental in helping these patients.
Motor Neuropathies
In most polyneuropathies, weakness usually affects ankle dorsiflexors early (causing foot drop); ambulation can be greatly improved by a custom-fitted ankle–foot orthotic, such as a rigid plastic splint worn in the shoe or a spring-loaded brace attached to the shoe. Fine motor weakness in the hands can be aided by special tools, such as large-handled utensils and other devices, provided by occupational therapists.
Sensory Neuropathies
Small hard objects (keys, faucet handles) can be built up with soft materials. Occupational therapists can make useful suggestions in this regard. Anesthetic limbs are vulnerable to repeated unrecognized trauma. The patient should always check the temperature of bath water, pot handles, and so on with parts of the body that have normal sensation. Meticulous care should be given to feet and toenails to prevent ulceration or infection. Moisturizing cream for dry insensitive skin will reduce serious abrasions.
Pain associated with sensory neuropathies is usually chronic though rewarding to treat. Simple analgesics (aspirin, acetaminophen, or NSAIDS), whirlpool, and massage may help relieve mild pain but are generally of limited benefit. Effective agents generally are from three classes of drugs: anticonvulsants, antidepressants and opiate or opiate-like medications. Gabapentin (Neurontin) was initially developed as an anticonvulsant but its membrane stabilizing properties also renders it quite effective at reducing neuropathic pain and dysesthesias (44). It is generally well tolerated but may be sedating in elderly patients. Therefore, it is usually best to begin gabapentin therapy with a small dose in the evenings (100 to 300 mg) and gradually titrate the dose upwards to the lowest effective dose or a maximum of 3,600 mg/day. Similar approaches can be used for other anticonvulsant medications with efficacy in neuropathic pain such as lamotrigene (Lamictal) and pregabalin (Lyrica). Tricyclic antidepressants (e.g., amitriptyline or nortriptyline, 25 to 75 mg at bedtime) are often effective. The selective serotonin reuptake inhibitor (SSRI)/NERI drugs duloxetine and fluoxetine are also effective and have the advantage of being dosed once per day and not requiring a titration period. Duloxetine doses greater than 60 mg/day are generally not associated with improved symptom relief and are complicated by higher side effect rates (45). Tramadol (Ultram), a nonaddictive synthetic analgesic structurally related to opiates, or a combination of tramadol and acetaminophen (Ultracet), both have demonstrated efficacy for treatment of neuropathic pain (46). These agents have the advantage that they can be dosed on an as-needed basis while the other agents discussed above generally require constant blood levels for optimum effect. Long-acting opiate preparations such as the fentanyl patch are another attractive option and have the advantage of being dosed every three days. Topical agents such as the Lidoderm patch is another option and is not associated with systemic absorption (47). It most helpful for focal, well-circumscribed neuropathic pain. Another topical agent worth mention is capsaicin cream. While effective (48), the mechanism of action may be associated with epidermal nerve fiber injury (49) from which patients may not fully recover (50). The newer antidepressant and anticonvulsant compounds are so efficacious that their use has supplanted that of the more historical drugs carbamazepine and phenytoin for treatment of neuropathic pain. These historical agents have similar degrees of symptom relief but are associated with much higher rates of side effects.
Autonomic Neuropathies
Autonomic dysfunctions should also be approached symptomatically (51). The hypotonic bladder may be treated by drugs that increase bladder tone (Urecholine, 10 to 25 mg every 8 hours), by self-catheterization, or occasionally with surgery to decrease resistance to bladder emptying. For male sexual impotence, penile prostheses and pharmacologic erections produced by intracavernous injection or intraurethral suppositories have represented significant advances. The knowledge that sexual dysfunction has a neurologic basis may relieve the anxiety that often accompanies the problem. A check for medications that may be contributing to impotence is important.
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TABLE 92.9 Measures that May Help Patients with Orthostatic Hypotension Caused by Autonomic Neuropathy |
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Orthostatic hypotension may be treated with salt supplementation and a volume-expanding mineralocorticoid (fludrocortisone 0.1 to 0.2 mg/day) in patients without congestive heart failure or hypertension. A recently released expensive α1-adrenergic agonist, midodrine (ProAmatine), has been shown to help patients with orthostatic hypotension. The dosage is 10 mg three times per day. Contraindications are the same as those for fludrocortisone (52). Support stockings with pressure gradients may be helpful to prevent venous pooling, but many patients do not tolerate these stockings well. Arising slowly from recumbent or sitting positions, maintaining active ambulation, and sleeping with the head of the bed elevated on blocks (to stimulate renin release) are other measures that may help. Table 92.9 summarizes the practical ways to manage orthostatic hypotension caused by autonomic dysfunction.
Other Problems
Restless Legs Syndrome
Restless legs syndrome is common, affecting perhaps 5% of the general population. It is an important cause of insomnia (see Chapter 7). Patients complain of an aching or painful crawling sensation deep inside the legs at rest, especially in the evening or in bed. Walking provides some relief, but the dysesthesias often return quickly upon resting (53,54).
The exact pathophysiology has not been elucidated; both peripheral and central mechanisms have been proposed. The syndrome has been related in some patients to the peripheral neuropathies of DM and uremia. An association has also been found with iron and folate deficiency anemias, calcium and potassium deficiency, pregnancy, postgastric surgery state, excessive caffeine, sedative drug withdrawal, and exposure to neuroleptic medication. An idiopathic form is associated with periodic movements during sleep and a positive family history.
These patients should be evaluated for associated conditions for specific treatment. Restricting caffeine use and performing regular exercise before bedtime may be helpful recommendations. Simple analgesics (aspirin, acetaminophen) at bedtime may help early symptoms. In other patients, nonsedating dosages of clonazepam (Klonopin, 0.5 to 2 mg) or triazolam (Halcion, 0.125 mg) may relieve nocturnal symptoms. The drug of choice for people with severe restless leg syndrome is Sinemet (a combination of L-dopa and carbidopa) at dosages of one-half to two 25-/100-mg tablets at bedtime. If the patient is typically awakened later during the night, the controlled-release form of Sinemet is preferable. Sinemet is generally well tolerated (see details in Chapter 90). Dopamine agonists such as ropinirole and pramipexole have also been reported to be useful in treating this disorder (54).
Muscle Cramps
Cramps are localized involuntary painful contractions of skeletal muscles that produce a visible, palpable, hard, and bulging muscle. They must be distinguished from the sensation of cramp such as that described with intermittent claudication; the latter is not associated with a palpable hard and bulging muscle.
Ordinary muscle cramps are common and may be stopped by stretching the affected muscles. Frequent cramps are most often associated with denervating diseases, fatiguing exercises, salt depletion, dehydration, pregnancy, hypothyroidism, alcoholism, uremia, or hypomag-nesemia. Patients with frequent daytime cramps related to exercise or fasting should be referred to a neurologist for evaluation for one of the rare muscle enzymatic defects (e.g., myophosphorylase, phosphofructokinase, or carnitine palmitoyltransferase deficiency). If no correctable associated condition exists, these patients may be given a therapeutic trial of phenytoin, carbamazepine, or amitriptyline (seeSensory Neuropathies).
Nocturnal cramps occur in 15% of healthy young adults and are even more common in the elderly. Regular passive stretching of leg muscles often prevents nocturnal cramps. If this is not effective, empiric trial of medicine can be considered. Meta-analysis of published and unpublished controlled trials showed that quinine, which requires a prescription (usual dose 325 mg at bedtime), reduced by about 21% the frequency of night cramps (55). Another drug reported to be effective is single-dose clonazepam, 0.25 to 0.5 mg at bedtime.
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Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.