Chapter 10: Sensory Disorders

In order to interpret the history and clinical signs of patients with disorders of somatic sensation, the functional anatomy of the sensory components of the nervous system must be understood. As used here, somatic sensation refers to the sensations of touch or pressure, vibration, joint position, pain, and temperature, and to more complex functions that rely on these primary sensory modalities (eg, two-point discrimination, stereognosis, graphesthesia); it excludes special senses such as smell, vision, taste, and hearing.

FUNCTIONAL ANATOMY OF THE SOMATIC SENSORY PATHWAYS

The sensory pathway between peripheral tissues (eg, skin or joints) and the cerebral cortex involves three neurons and two central synapses (Figure 10-1).

First-order sensory neurons from the limbs and trunk have cell bodies in the dorsal root ganglia. Each of these neurons sends a peripheral process that terminates in a free nerve ending or encapsulated sensory receptor and a central process that enters the spinal cord. Sensory receptors are relatively specialized for particular sensations and, in addition to free nerve endings (pain, itch), include Meissner corpuscles, Merkel corpuscles, and hair cells (touch); Krause end-bulbs (cold); and Ruffini corpuscles (heat). First-order sensory neurons synapse centrally at a site that depends on the type of sensation. Fibers mediating touch, pressure, or postural sensation in the limbs and trunk ascend in the posterior columns of the spinal cord to the medulla, where they synapse in the gracile and cuneate nuclei. Other fibers that mediate touch and those subserving pain, temperature, and itch appreciation in the limbs and trunk synapse on neurons in the posterior horns of the spinal cord, particularly in the substantia gelatinosa. First-order sensory neurons from the face, which have cell bodies in the trigeminal (gasserian) ganglion, travel in the trigeminal (V) nerve and enter the pons. Fibers mediating facial touch and pressure synapse in the main trigeminal (V) nerve sensory nucleus, whereas those conveying facial pain and temperature synapse in the spinal trigeminal (V) nerve nucleus.

Second-order sensory neurons with cell bodies in the gracile and cuneate nuclei cross the midline and ascend in the medial lemniscus. Second-order sensory neurons that arise in the posterior horns of the spinal cord cross the midline and ascend in the anterolateral part of the cord: fibers mediating touch pass upward in the anterior spinothalamic tract, whereas pain, itch, and temperature fibers generally travel in the lateral spinothalamic tract. Second-order sensory neurons from the limbs and trunk are joined in the brainstem by fibers from the face: those that mediate facial touch and pressure sensation project from the main trigeminal (V) nerve sensory nucleus via the trigeminal lemniscus, and those that convey facial pain, itch, and temperature project from the spinal trigeminal (V) nerve nucleus via the trigeminothalamic tract, to the ipsilateral thalamus. In the thalamus, medial lemniscal and spinothalamic fibers synapse in the ventral posterolateral (VPL) nucleus; spinothalamic fibers also synapse in the ventral posteroinferior (VPI) nucleus and intralaminar (ILa) nuclei; and fibers in the trigeminal lemniscus and trigeminothalamic tract synapse in the ventral posteromedial (VPM) nucleus. In addition, some second-order spinothalamic sensory neurons send collaterals to the reticular formation.

Third-order sensory neurons project from the thalamus to the ipsilateral cerebral cortex. Fibers from VPL, VPI, and VPM travel primarily to the primary somatosensory cortex in the postcentral gyrus; fibers from ILa also project to the striatum, cingulate gyrus, and prefrontal cortex.

HISTORY

Sensory disturbances may consist of loss of sensation, abnormal sensations, or pain. The term paresthesia denotes abnormal spontaneous sensations, such as burning, tingling, or pins and needles, whereas dysesthesia denotes any unpleasant sensation produced by a stimulus that is normally painless. The term numbness is often used by patients to describe a sense of heaviness, weakness, or deadness in part of the body—and sometimes to signify any sensory impairment; the meaning must be clarified whenever this word is used.

It is important to determine the location of sensory symptoms; their mode of onset and progression; whether they are constant or episodic in nature; whether any factors specifically produce, enhance, or relieve them; and whether there are any accompanying symptoms.

The location of symptoms may reflect their origin. For example, sensory disturbances involving all the limbs suggest peripheral neuropathy, a cervical cord or brainstem lesion, or a metabolic disturbance such as hyperventilation syndrome. Involvement of one entire limb, or of one side of the body, suggests a central (brain or spinal cord) lesion. A hemispheric or brainstem lesion may cause lateralized sensory symptoms, but the face is also commonly affected. In addition, there may be other symptoms and signs, such as aphasia, apraxia, and visual field defects with hemispheric disease, or dysarthria, weakness, vertigo, diplopia, disequilibrium, and ataxia with brainstem disorders. Involvement of part of a limb or a discrete region of the trunk raises the possibility of a nerve or root lesion, depending on the precise distribution. With a root lesion, symptoms may show some relationship to neck or back movements, and pain is often conspicuous.

The course of sensory complaints provides a guide to their cause. Intermittent or repetitive transient symptoms may represent sensory seizures, ischemic phenomena, or metabolic disturbances such as those accompanying hyperventilation. Intermittent localized symptoms that occur at a consistent time may suggest the diagnosis or an exogenous precipitating factor. For example, the pain and paresthesias of carpal tunnel syndrome (median nerve compression at the wrist) characteristically occur at night and awaken the patient from sleep.

SENSORY EXAMINATION

Various sensory modalities are tested in turn, and the distribution of any abnormality is plotted with particular reference to the normal root and peripheral nerve territories. Complete loss of touch appreciation is anesthesia, partial loss is hypesthesia, and increased sensitivity is hyperesthesia. The corresponding terms for pain appreciation are analgesia, hypalgesia, and hyperalgesia or hyperpathia; allodynia refers to the misperception of a trivial tactile sensation as pain.

PRIMARY SENSORY MODALITIES

Light Touch

The appreciation of light touch is evaluated with a wisp of cotton wool that is brought down carefully on a small region of skin. The patient lies with eyes closed, and indicates each time the stimulus is felt. The appreciation of light touch depends on fibers that traverse the posterior column of the spinal cord in the gracile (leg) and cuneate (arm) fasciculi ipsilaterally (Figures 10-1 and 10-2), passing to the medial lemniscus of the brainstem (Figure 10-3), and on fibers in the contralateral anterior spinothalamic tract.

Pinprick & Temperature

Pinprick appreciation is tested by asking the patient to indicate whether the point of a pin (not a hypodermic needle, which may puncture the skin and draw blood) feels sharp or blunt. Appreciation of sharpness must be distinguished from appreciation of pressure or touch. The pin—a potential source of infection—should be handled with care and discarded after use. Temperature appreciation is evaluated by applying containers of hot or cold water to the skin. For convenience, cold can be tested by application of the side of a metal tuning fork to different bodily regions; testing of heat is usually omitted from the routine examination. Pinprick and temperature appreciation depend on the integrity of the lateral spinothalamic tracts (see Figures 10-1 and 10-2). The afferent fibers cross in front of the central canal after ascending for two or three segments from their level of entry into the cord.

Deep Pressure

Deep pressure sensibility is evaluated by pressure on the tendons, such as the Achilles tendon at the ankle.

Vibration

A tuning fork (128 Hz) is set in motion and then placed over a bony prominence; the patient is asked to indicate whether vibration, rather than simple pressure, is felt. Many healthy elderly patients have impaired appreciation of vibration below the knees.

Joint Position

The patient is asked to indicate the direction of small passive movements of the terminal interphalangeal joints of the fingers and toes. Patients with severe impairment of joint position sense may exhibit slow, continuous movement of the fingers (pseudoathetoid movement) when attempting to hold the hands outstretched with eyes closed. For clinical purposes, both joint position sense and the ability to appreciate vibration are considered to depend on fibers carried in the posterior columns of the spinal cord, although this is not strictly true for vibration.

COMPLEX SENSORY FUNCTIONS

Romberg Test

The patient assumes a steady stance with feet together, arms outstretched, and eyes closed and is observed for any tendency to sway or fall. The test is positive (abnormal) if unsteadiness is markedly increased by eye closure—as occurs, for example, in tabes dorsalis. A positive test is indicative of grossly impaired joint position sense in the legs.

Two-Point Discrimination

The ability to distinguish simultaneous touch at two neighboring points depends on the integrity of the central and peripheral nervous system, the degree of separation of the two points, and the part of the body that is stimulated. The patient indicates whether he or she is touched by one or two compass points, while the distance between the points is varied in order to determine the shortest distance at which they are recognized as different points. The threshold for two-point discrimination approximates 4 mm at the fingertips and may be several centimeters on the back. When peripheral sensory function is intact, impaired two-point discrimination suggests a disorder affecting the sensory cortex.

Graphesthesia, Stereognosis, & Barognosis

Agraphesthesia, the inability to identify a number traced on the skin of the palm of the hand despite normal cutaneous sensation, implies a lesion involving the contralateral parietal lobe. The same is true of inability to distinguish between various shapes or textures by touch (astereognosis) or impaired ability to distinguish between different weights (abarognosis).

Bilateral Sensory Discrimination

In some patients with apparently normal sensation, simultaneous stimulation of the two sides of the body reveals an apparent neglect of (or inattention to) sensation from one side, usually because of an underlying contralateral cerebral lesion.

SENSORY CHANGES & THEIR SIGNIFICANCE

The nature and distribution of any sensory change must be determined. Failure to find clinical evidence of sensory loss in patients with sensory symptoms should not imply that the symptoms necessarily have a psychogenic basis. Sensory symptoms often develop well before the onset of sensory signs.

PERIPHERAL NERVE LESIONS

Mononeuropathy

In patients with a lesion of a single peripheral nerve, sensory loss is usually less than predicted on anatomic grounds because of overlap from adjacent nerves. Moreover, depending on the type of lesion, the fibers in a sensory nerve may be affected differently. Compressive lesions, for example, tend to affect preferentially the large fibers subserving touch.

Polyneuropathy

In patients with polyneuropathies, sensory loss is generally symmetric and is greater distally than proximally (stocking-and-glove sensory loss or length-dependent neuropathy). The loss generally will have progressed almost to the knees before the hands are affected. Sensory loss may then be accompanied by a motor deficit and reflex changes. Diabetes mellitus, amyloidosis, and certain other metabolic disorders (eg, Tangier disease, a recessive trait characterized by the near absence of high-density lipoproteins) preferentially involve small nerve fibers subserving pain and temperature appreciation; in a pure small-fiber sensory neuropathy, the tendon reflexes are unaffected and no motor deficit occurs.

ROOT LESIONS

Nerve root involvement produces impaired cutaneous sensation in a segmental pattern (Figure 10-4), but because of overlap there is generally no sensory loss unless two or more adjacent roots are affected. Pain is often a conspicuous feature with compressive root lesions. Depending on the level affected, there may be loss of tendon reflexes (C5-C6, biceps and brachioradialis; C7-C8, triceps; L3-L4, knee; S1, ankle), and if the anterior roots are also involved, weakness and muscle atrophy may occur.

SPINAL CORD LESIONS

In patients with spinal cord lesions, there may be a transverse sensory level. Physiologic areas of increased sensitivity do occur, however, at the costal margin, over the breasts, and in the groin, and these must not be taken as abnormal. Therefore, the level of a sensory deficit affecting the trunk is best determined by careful sensory testing over the back rather than the chest and abdomen.

Central Cord Lesion

With a central cord lesion, such as occurs in syringomyelia, after trauma, and with certain tumors, there is characteristically a loss of pain and temperature appreciation with sparing of other modalities. This loss is due to the interruption of fibers conveying pain and temperature that cross from one side of the cord to the spinothalamic tract on the other. Such a loss is usually bilateral, may be asymmetric, and involves only the fibers of the involved segments. It may be accompanied by lower motor neuron weakness in the muscles supplied by the affected segments and sometimes by a pyramidal and posterior column deficit below the lesion (Figure 10-5).

Anterolateral Spinal Cord Lesion

Lesions involving the anterolateral portion of the spinal cord (lateral spinothalamic tract) can cause contralateral impairment of pain and temperature appreciation in segments below the level of the lesion. The spinothalamic tract is laminated, with fibers from the sacral segments the outermost. Intrinsic cord (intramedullary) lesions often spare the sacral fibers, whereas extramedullary lesions, which compress the cord, tend to involve these fibers as well as those arising from more rostral levels.

Anterior Spinal Cord Lesion

With destructive lesions involving predominantly the anterior portion of the spinal cord, pain and temperature appreciation are impaired below the level of the lesion from lateral spinothalamic tract involvement. In addition, weakness or paralysis of muscles supplied by the involved segments of the cord results from damage to anterior horn cells. With more extensive disease, involvement of the corticospinal tracts in the lateral funiculi may cause a pyramidal deficit below the lesion. There is relative preservation of posterior column function (Figure 10-6). Ischemic myelopathies caused by occlusion of the anterior spinal artery take the form of anterior spinal cord lesions.

Posterior Column Lesion

A patient with a posterior column lesion may complain of a tight or bandlike sensation in the regions corresponding to the level of spinal involvement and sometimes also of paresthesias (like electric shocks) radiating down the extremities on neck flexion (Lhermitte sign). There is loss of vibration and joint position sense below the level of the lesion, with preservation of other sensory modalities. The deficit may resemble that resulting from involvement of large fibers in the posterior roots.

Spinal Cord Hemisection

Lateral hemisection of the spinal cord leads to Brown–Séquard syndrome. Below the lesion, there is an ipsilateral pyramidal deficit and disturbed appreciation of vibration and joint position sense; contralateral loss of pain and temperature appreciation begins two or three segments below the lesion (Figure 10-7). Hyperalgesia and spontaneous pain are sometimes prominent ipsilaterally.

BRAINSTEM LESIONS

With brainstem lesions, sensory disturbances may be accompanied by a motor deficit, cerebellar signs, and cranial nerve palsies.

With lesions involving the spinothalamic tract in the dorsolateral medulla and pons, pain and temperature appreciation are lost in the limbs and trunk on the opposite side of the body. When such a lesion is medullary, it also typically involves the spinal trigeminal nucleus, impairing pain and temperature sensation on the same side of the face as the lesion. The result is a crossed sensory deficit that affects the ipsilateral face and contralateral limbs. In contrast, spinothalamic lesions above the spinal trigeminal nucleus affect the face, limbs, and trunk contralateral to the lesion. With lesions affecting the medial lemniscus, there is loss of touch and proprioception on the opposite side of the body. In the upper brainstem, the spinothalamic tract and medial lemniscus run together so that a single lesion may cause loss of all superficial and deep sensation over the contralateral side of the body (see Figure 10-3).

THALAMIC LESIONS

Thalamic lesions may lead to loss or impairment of all forms of sensation on the contralateral side of the body, and this may have a distribution that differs from the area of symptomatic involvement. Spontaneous pain, sometimes with a particularly unpleasant quality, may occur on the affected side. Patients may describe it as burning, tearing, knifelike, or stabbing, but often have difficulty characterizing it. Any form of cutaneous stimulation can lead to painful or unpleasant sensations. Such a thalamic syndrome (Dejerine–Roussy syndrome) can also occasionally result from lesions of the white matter of the parietal lobe or from spinal cord lesions, as discussed later.

LESIONS OF THE SENSORY CORTEX

Disease limited to the sensory cortex impairs discriminative sensory function on the opposite side of the body. Patients may be unable to localize stimuli on the affected side or to recognize the position of different parts of the body. They may not be able to recognize objects by touch or to estimate their size, weight, consistency, or texture. Cortical sensory disturbances are usually more conspicuous in the hands than in the trunk or proximal portions of the limbs.

DISTINCTION BETWEEN ORGANIC & PSYCHOGENIC SENSORY DISTURBANCES

Psychogenic disturbances of sensation may be associated with such psychiatric disturbances as conversion disorder. They may take any form but most often are restricted to loss of cutaneous sensation. There may be several characteristic features.

Nonorganic sensory loss does not conform in its distribution to any specific neuroanatomic pattern. It may surround a bony landmark or involve an area defined by surface landmarks rather than innervation. Indeed, it is not uncommon for there to be an apparent loss of sensation in one or more extremities, with circumferential margins in the axilla or groin; organic sensory loss with such a margin is unusual. Organic peripheral sensory loss over the trunk or face does not usually extend to the midline but stops 3 to 5 cm before it, because of overlap in the innervation on the two sides; with nonorganic disturbances, apparent sensory loss commonly stops precisely at the midline.

There is often a sudden transition between areas of nonorganic sensory loss and areas with normal sensation. By contrast, with organic disturbances, there is usually an area of altered sensation between insensitive areas and adjacent areas with normal sensibility.

In nonorganic disturbances, there may be a dissociated loss that is difficult to interpret on an anatomic basis. For example, there may be a total loss of pinprick appreciation but preserved temperature sensation. Moreover, despite the apparent loss of posterior column function, the patient may be able to walk normally or maintain the arms outstretched without difficulty or pseudoathetoid movements.

In nonorganic sensory disturbances, appreciation of vibration may be impaired on one side but not the other side of a bony midline structure, such as the skull or sternum. The vibrations are in fact conducted to both sides by the bone, so that even if there is a hemisensory disturbance, the vibrations are appreciated on either side in patients with organic sensory disorders.

Finally, it should be noted that sensory disturbances are often suggested to the patient by the examiner’s own expectations. Such findings can be particularly misleading because they may be neuroanatomically correct. One helpful approach is to have the patient outline on the body the extent of any perceived sensory disturbance before formal sensory testing is undertaken.

Sensory symptoms are usually a conspicuous feature in patients with peripheral nerve lesions (Table 10-1). Sensory impairment may be in a distal stocking-and-glove pattern in patients with polyneuropathies or may follow the pattern of individual peripheral nerves in patients with mononeuropathies (see Figure 10-4).

CLASSIFICATION

MONONEUROPATHY SIMPLEX

This term signifies involvement of a single peripheral nerve.

MONONEUROPATHY MULTIPLEX

In this disorder, several individual nerves are affected, usually at random and noncontiguously. Clinical examination reveals a clinical deficit attributable to involvement of one or more isolated peripheral nerves, except when mononeuropathy multiplex is extensive and the resulting deficits become confluent.

POLYNEUROPATHY

The term polyneuropathy denotes a disorder in which the function of several peripheral nerves is affected at the same time. This leads to a predominantly distal and symmetric deficit, with loss of tendon reflexes except when small fibers are selectively involved. Polyneuropathies are sometimes subclassified according to the primary site at which the nerve is affected.

In distal axonopathies (axonal neuropathies), the axon is the principal pathologic target; most polyneuropathies fall into this category.

Myelinopathies (demyelinating neuropathies) are conditions that involve the myelin sheath surrounding the axon. These disorders include acute idiopathic polyneuropathy (Guillain–Barré syndrome), chronic inflammatory demyelinating neuropathy, diphtheria, certain paraneoplastic and paraproteinemic states, and various hereditary conditions including metachromatic leukodystrophy, Krabbe disease, and types 1 and 3 Charcot–Marie–Tooth hereditary motor and sensory neuropathy (CMT-1 and 3).

Finally, certain disorders, termed neuronopathies, principally affect nerve cell bodies in the anterior horn of the spinal cord or dorsal root ganglion. Examples are type 2 CMT hereditary motor and sensory neuropathy, pyridoxine-induced neuropathy, and some paraneoplastic syndromes.

CLINICAL FINDINGS

SENSORY DISTURBANCES

Involvement of sensory fibers can lead to numbness and impaired sensation; abnormal spontaneous sensations, such as pain and paresthesias; and perverted sensations such as hyperpathia (amplified response to a normally painful stimulus).

Pain

Pain is a conspicuous feature of certain neuropathies, especially if small fibers within the nerves are affected. The precise mechanism of its genesis is unclear. Polyneuropathies associated with prominent pain include those related to diabetes, alcoholism, porphyria, Fabry disease, amyloidosis, rheumatoid arthritis, and acquired immunodeficiency syndrome (AIDS), as well as dominantly inherited sensory neuropathy and paraneoplastic sensory neuronopathy. Pain is also a feature of many entrapment neuropathies and of idiopathic brachial plexopathy.

Dissociated Sensory Loss

Dissociated sensory loss is impairment of some sensory modalities, such as pain and temperature, with preservation of others, such as light touch, vibration, and joint position sense. Although the presence of a dissociated sensory loss often indicates a spinal cord lesion, it also occurs in peripheral neuropathies when there is selective involvement of peripheral nerve fibers of a certain size, such as occurs in amyloid neuropathy, leprous neuritis, or hereditary sensory neuropathy. Small fiber disease is commonly associated with disproportionate impairment of pain and temperature appreciation, spontaneous pain, and autonomic dysfunction. Large fiber disease, by contrast, results in defective touch, vibration, and joint position sense, early loss of tendon reflexes, and prominent motor symptoms.

MOTOR DEFICITS

Peripheral nerve lesions may cause weakness of muscles innervated by the nerve, accompanied in severe cases by wasting and fasciculation. There may be difficulty in the performance of fine tasks; this is compounded by any accompanying sensory loss. The clinical findings reflect a lower motor neuron deficit, and it is the distribution of these signs and the presence of accompanying sensory and reflex changes that suggest they may be due to peripheral nerve involvement.

TENDON REFLEXES

These are impaired or lost if reflex arcs are interrupted on either the afferent or efferent side (C5-C6, biceps and brachioradialis; C7-C8, triceps; L3-L4, knee; S1, ankle). The ankle reflexes are usually the first to be lost in patients with polyneuropathies, but may also be absent in healthy elderly subjects.

AUTONOMIC DISTURBANCES

Autonomic disturbances are particularly conspicuous in some peripheral neuropathies—especially Guillain–Barré syndrome and neuropathies related to diabetes, renal failure, porphyria, certain paraneoplastic disorders, and amyloidosis. Symptoms include postural hypotension, tachycardia, cold extremities, impaired thermoregulatory sweating, bladder and bowel dysfunction, and impotence.

ENLARGED NERVES

Palpably enlarged peripheral nerves raise the possibility of leprosy, amyloidosis, hereditary motor and sensory neuropathies, Refsum disease, acromegaly, or chronic inflammatory demyelinating polyneuropathy.

EVALUATION OF PATIENTS

TIME COURSE

Polyneuropathy that develops acutely over a few days usually relates to an inflammatory process, as in the Guillain–Barré syndrome. It may also relate to an underlying neoplasm, to infections such as diphtheria, to metabolic disorders such as acute intermittent porphyria, or to exposure to such toxic substances as thallium or triorthocresyl phosphate. A chronic course with a gradual evolution over several years is typical of many hereditary or metabolic polyneuropathies but also characterizes chronic inflammatory demyelinating polyneuropathy.

Mononeuropathy of acute onset is likely to be traumatic or ischemic in origin, whereas one evolving gradually is more likely to relate to entrapment (ie, compression by neighboring anatomic structures) or to recurrent minor trauma.

AGE AT ONSET

Polyneuropathy that develops during childhood or early adult life often has a hereditary basis, but may also relate to an underlying inflammatory disorder. Polyneuropathy developing later is more likely to result from a metabolic, toxic, or inflammatory disorder, or from an underlying neoplasm.

Mononeuropathy presenting in the neonatal period is likely to be developmental in origin or related to birth injury; one presenting in later life may relate to entrapment or injury that is often occupationally determined.

OCCUPATIONAL HISTORY

Various industrial toxins can lead to peripheral neuropathy, including carbon disulfide, n-hexane, ethylene oxide, methyl bromide, acrylamide, triorthocresyl phosphate and certain other organophosphates, DDT, arsenic, lead, and thallium. A mononeuropathy is sometimes the first clinical manifestation of an occupationally related polyneuropathy, but it may also develop in response to entrapment or recurrent minor occupational trauma. For example, carpal tunnel syndrome is more common in persons who do heavy manual labor or develop repetitive motion injury as a result of computer terminal use, and a lesion of the deep palmar branch of the ulnar nerve may relate to repeated pressure on the palm of the hand by, for example, punching down heavily on a stapler or using heavy equipment such as a pneumatic road drill.

MEDICAL HISTORY

Metabolic Disorders

Peripheral neuropathy may relate to metabolic disorders such as diabetes mellitus, uremia, liver disease, myxedema, acromegaly, metachromatic leukodystrophy, or Fabry disease. That caused by diabetes is especially important and may take the form of an entrapment mononeuropathy, acute ischemic mononeuropathy, distal sensorimotor polyneuropathy, subacute proximal motor polyradiculoplexopathy (diabetic amyotrophy), thoracoabdominal radiculopathy, or autonomic neuropathy.

Neoplasm

The peripheral nerves, spinal nerves, and limb plexuses may be compressed or infiltrated by extension of primary tumors or metastatic lymph nodes. Neoplastic disease can also lead to a nonmetastatic (paraneoplastic) sensory or sensorimotor polyneuropathy or to Lambert–Eaton syndrome, a disorder of neuromuscular transmission discussed in Chapter 9, Motor Disorders.

Connective Tissue Disorders

Polyarteritis nodosa, rheumatoid arthritis, Churg–Strauss syndrome, and granulomatosis with polyangiitis (formerly Wegener granulomatosis) may be associated with mononeuropathy multiplex or, less commonly, polyneuropathy or cranial neuropathy. Polyneuropathy is more common in systemic lupus erythematosus. Rheumatoid arthritis may cause focal entrapment or compressive mononeuropathies in the vicinity of affected joints.

Infection With Human Immunodeficiency Virus

Acquired immune deficiency syndrome (AIDS) is commonly associated with a distal, symmetric, primarily sensory polyneuropathy. Less frequently, AIDS is associated with an acute or chronic inflammatory demyelinating polyneuropathy, polyradiculopathy, mononeuropathy multiplex, or autonomic neuropathy. Neuropathies are also seen with asymptomatic human immunodeficiency virus-1 (HIV-1) infection and HIV-1 seroconversion.

DRUG & ALCOHOL HISTORY

Some of the drugs that cause peripheral neuropathy are listed in Table 10-2; motor or sensory fibers are involved selectively with certain drugs.

FAMILY HISTORY

Polyneuropathies may have a hereditary basis, as is discussed later in this chapter in the section on hereditary neuropathies.

DIFFERENTIAL DIAGNOSIS

Peripheral neuropathies can lead to a motor or sensory deficit or both. The preservation of sensation and tendon reflexes distinguishes the motor deficit of pure pyramidal lesions, spinal muscular atrophies, myopathies, or disorders of neuromuscular transmission from that caused by peripheral nerve involvement. Other distinguishing features are discussed in Chapter 9, Motor Disorders.

Myelopathies are characterized by a pyramidal deficit below the level of the lesion as well as by distal sensory loss. In tabes dorsalis, there is often a history of syphilitic infection, and examination reveals other stigmas of syphilis. In addition, tactile sensation is preserved.

Radiculopathies are distinguished from peripheral neuropathies by the distribution of motor or sensory deficits (see Figure 10-4). The presence of neck or back pain that radiates to the extremities in a radicular distribution also suggests a root lesion.

INVESTIGATIVE STUDIES

Laboratory studies in patients with peripheral neuropathy are directed at confirming the diagnosis and revealing any underlying cause.

Electromyography may reveal evidence of denervation in the affected muscles and can be used to determine whether any motor units remain under voluntary control. Nerve conduction studies permit conduction velocity to be measured in motor and sensory fibers (see Chapter 2, Investigative Studies). On the basis of electrodiagnostic or histopathologic studies, peripheral neuropathies can be divided into demyelinating or axonal neuropathies. In demyelinating neuropathies, electromyography typically reveals little or no evidence of denervation, but there is conduction block or marked slowing of maximal conduction velocity in affected nerves. In axonal neuropathies, electromyography shows that denervation has occurred, especially distally in the extremities, but maximal nerve conduction velocity is normal or slowed only slightly.

Determination of a complete blood count, erythrocyte sedimentation rate, serum urea nitrogen and creatinine, fasting blood glucose, serum vitamin B₁₂, serum protein, protein electrophoresis and immunoelectrophoresis, liver and thyroid function blood tests, and serologic test for syphilis (FTA or MHA-TP), rheumatoid factor, and antinuclear antibody may help to identify the cause of a peripheral nerve disorder, as also may chest x-ray. Depending on the clinical circumstances, serologic tests for Lyme disease, hepatitis, infection with HIV, or paraneoplastic antibodies may be required. Genetic studies may also be necessary after appropriate genetic counseling.

If toxic causes are suspected, a 24-hour urine collection followed by analysis for heavy metals may be helpful, and hair and fingernail clippings can be analyzed for arsenic. Examination of a fresh specimen of urine for porphobilinogen and δ-aminolevulinic acid is necessary when porphyria is suspected.

TREATMENT

DISEASE-SPECIFIC TREATMENT

Treatment of the underlying cause may limit the progression of or even reverse the neuropathy. Disease-specific treatments are discussed later under individual disorders.

VENTILATORY ASSISTANCE

Respiratory function must be monitored—particularly in acute idiopathic polyneuropathy (Guillain–Barré syndrome), chronic inflammatory demyelinating polyneuropathy, and diphtheritic neuropathy—and preparations made to assist ventilation if the forced vital capacity reaches 15 mL/kg, the mean inspiratory force reaches –40 mm Hg, dyspnea becomes evident, or the oxygen saturation of arterial blood declines.

TRAUMA PREVENTION

Nursing care is important in patients with severe motor or sensory deficits to prevent decubitus ulcers, joint contractures, and additional compressive peripheral nerve damage. In patients with severe dysesthesia, a cradle (metal bar frame) can be used to keep the bedclothes from touching sensitive areas of the skin.

Extremities with sensory loss must be protected from repeated minor trauma, such as thermal injury, that can destroy tissues. The temperature of hot surfaces should be checked with a part of the body in which sensation is preserved, and the setting of water heaters must be reduced to prevent scalding. The skin and nails must be cared for meticulously.

PAIN RELIEF

Patients with sensory disorders may suffer from especially severe pain, which can impair quality of life. Treatment of this pain is important.

Duloxetine (60 mg once daily) or venlafaxine (titrated up to 75 mg two to three times daily in standard formulation or as the equivalent dose once daily in the extended release formulation) is often helpful; both are selective serotonin and norepinephrine reuptake inhibitors.

Pregabalin (150 mg increasing after 1 week to 300 mg daily in divided doses; maximum, 600 mg daily) also relieves neuropathic pain.

Phenytoin 300 mg/d, carbamazepine up to 1200 mg/d, or mexiletine 600 to 900 mg/d can sometimes relieve the lancinating pain of certain neuropathies. If the pain is constant, burning, or dysesthetic, amitriptyline 25 to 100 mg at bedtime is often helpful, as are other tricyclic agents.

Gabapentin (300 mg three times daily, with subsequent increments depending on response and tolerance) is effective in treating various neuropathic pain disorders; pain relief may similarly occur with lamotrigine, topiramate, or sodium valproate, but this has been documented less well. Lamotrigine requires slow dose titration to avoid skin rashes and other complications. Combined gabapentin and nortriptyline may be more effective than either drug given alone for neuropathic pain (diabetic neuropathy or postherpetic neuralgia). This drug combination is therefore recommended in patients who show a partial response to either drug given alone and require additional pain relief.

Topical capsaicin is also helpful in neuropathic pain syndromes.

AUTONOMIC DISTURBANCES

Dysautonomic symptoms may be troublesome in some polyneuropathies, especially diabetic polyneuropathy. Waist-high elastic hosiery, dietary salt supplementation, and treatment with fludrocortisone 0.1 to 0.5 mg/d orally may relieve postural hypotension, but the patient must be monitored to prevent recumbent hypertension. Other medications that may be helpful include clonidine, midodrine, dihydroergotamine, octreotide, or β-blockers. The utility of droxidopa in peripheral dysautonomias is unclear. Instructing the patients to sleep in a semierect rather than recumbent position is helpful because dysautonomic patients are often unable to conserve salt and water when recumbent.

IDIOPATHIC INFLAMMATORY NEUROPATHIES

ACUTE IDIOPATHIC POLYNEUROPATHY (GUILLAIN–BARRÉ SYNDROME)

Guillain–Barré syndrome is an acute or subacute polyneuropathy that can follow minor infective illnesses, inoculations, or surgical procedures or may occur without obvious precipitants. Clinical and epidemiologic evidence suggests an association with preceding Campylobacter jejuni infection. It may also occur in association with Zika virus infection. Its precise cause is unclear, but an immunologic basis is likely. Both demyelinating and axonal forms occur, with distinctive clinical and electrophysiologic features. The demyelinative form is more common in the United States, but an axonal variant is encountered occasionally (acute motor sensory axonal neuropathy). In northern China, a related axonal form occurs frequently (acute motor axonal neuropathy or AMAN). The axonal variants are caused by antibodies to gangliosides on the axon membrane, including anti-GM1, anti-GM1b, anti-GD1a, anti-GD1b, and (in AMAN) anti-GalNAC-GD1a antibodies. The Miller Fisher syndrome, another subtype, is characterized by ophthalmoplegia, ataxia, and areflexia, and is associated with anti-GQ1b antibodies (see Chapter 8, Disorders of Equilibrium); it is sometimes associated with a brainstem encephalitis (Bickerstaff encephalitis).

Clinical Features

Diagnostic features are summarized in Table 10-3. Patients commonly present with ascending weakness that is symmetric, usually begins in the legs, is often more marked proximally than distally, and may be life-threatening, especially if the muscles of respiration or swallowing are involved. Some patients present instead with weakness about the bulbar, neck, and shoulder muscles, or with an acute pandysautonomia. Muscle wasting develops if axonal degeneration has occurred. Sensory complaints, although usually less marked than motor symptoms, are also frequent. The deep tendon reflexes are typically absent. There may be marked autonomic dysfunction, with tachycardia, cardiac irregularities, labile blood pressure, disturbed sweating, impaired pulmonary function, sphincter disturbances, paralytic ileus, and other abnormalities.

Investigative Studies

The cerebrospinal fluid (CSF) often shows an increased protein concentration but normal cell count (cytoalbuminologic dissociation), but abnormalities may not occur in the first week. Electrophysiologic studies may reveal marked slowing of motor and sensory conduction velocity or evidence of denervation and axonal loss. The time course of the electrophysiologic changes does not necessarily parallel any clinical developments. When HIV-1 infection is suspected because of the clinical context in which the neuropathy has developed, the presence of high-risk factors, or a CSF pleocytosis, appropriate serologic studies should be performed.

Treatment

Plasmapheresis reduces the time required for recovery and may decrease the likelihood of residual neurologic deficits. It is best instituted early, and it is indicated especially in patients with a severe or rapidly progressive deficit or respiratory compromise. Intravenous immunoglobulin (400 mg/kg/d for 5 days) is equally effective and should be used in preference to plasmapheresis in adults with cardiovascular instability and in children; the two therapies are not additive.

Therapy is otherwise symptomatic, the aim being to prevent such complications as respiratory failure or vascular collapse. For this reason, patients who are severely affected are best managed in intensive care units, where facilities are available for monitoring and assisted respiration if necessary (eg, if the forced vital capacity reaches 15 mL/kg, the mean inspiratory force reaches –40 mm Hg, the patient is short of breath, or the blood oxygen saturation declines). Paroxysmal hypertension may necessitate treatment with labetalol or nitroprusside. Volume replacement or treatment with pressor agents is sometimes required to counter hypotension, and low-dose heparin may help to prevent pulmonary embolism. Cardiac arrhythmias are common and—depending on their nature—may require treatment. Corticosteroids may affect the outcome adversely or delay recovery, and are not indicated. Physical therapy and rehabilitation are important aspects of treatment.

Prognosis

Symptoms and signs cease to progress by approximately 4 weeks into the illness. The disorder is self-limiting, and improvement occurs over the weeks or months after onset. Approximately 70% of patients recover completely, 25% are left with mild neurologic deficits, and 5% die, usually as a result of respiratory failure. The prognosis is poorer when there is evidence of preceding Campylobacter jejuni infection, and a more protracted course and less complete recovery are also likely when axonal degeneration is the primary pathology. Advanced age, the need for ventilatory support, or more rapid onset of symptoms may also predict a poorer prognosis.

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

Chronic inflammatory demyelinating polyneuropathy is clinically similar to Guillain–Barré syndrome except that it follows a chronic progressive course, or a course characterized by relapses, and no improvement is apparent within the 6 months after onset. Its cause is not known. Its clinical features are summarized in Table 10-4. It must be distinguished from certain hereditary demyelinating neuropathies, discussed later in this chapter.

Examination of the CSF reveals findings resembling those in Guillain–Barré syndrome: the protein is elevated while the white cell count is normal. The electrophysiologic findings indicate a demyelinative neuropathy with superimposed axonal degeneration. Laboratory studies may help to identify disorders causing neuropathy, such as diabetes.

The disorder is often responsive to treatment with corticosteroids (prednisone 60-100 mg/d for 2-4 weeks, then gradually tapered to 5-20 mg every other day), which may be required on a long-term basis. Treatment with intravenous immunoglobulin (1 g/kg daily for 2 days with a single additional infusion at 3 weeks, or 400 mg/kg/d for 5 consecutive days for a total of 2 g, with subsequent courses as needed to maintain benefit) is also effective as initial or later therapy. When used as initial therapy, it has the advantage of fewer side effects (but greater expense) than prednisone. Its precise mode of action is unknown. Plasma exchange is another effective immunomodulator therapy, but is more difficult to administer. In nonresponsive patients, treatment with methotrexate, azathioprine, or cyclophosphamide may be helpful, but claims of benefit from these agents or from cyclosporine, interferon-β, or interferon-α require confirmation by randomized trials.

METABOLIC & NUTRITIONAL NEUROPATHIES

DIABETES MELLITUS

Peripheral nerve involvement in diabetes is common and may take several forms (Table 10-5), which can occur in isolation or in any combination. The incidence of peripheral nerve involvement may be influenced by the adequacy of diabetes control, which should, in any event, be optimized.

Clinical Features

Distal polyneuropathy is the most common manifestation and may be mixed (sensory, motor, and autonomic; 70% of cases) or predominantly sensory (30%). Symptoms are generally more common in the legs than arms and consist of numbness, pain, or paresthesias. It may be diagnosed presymptomatically by the presence of depressed tendon reflexes and impaired appreciation of vibration in the legs. In severe cases, there is distal sensory loss in all limbs and some accompanying motor disturbance.

Diabetic dysautonomia leads to many symptoms, including postural hypotension, disturbances of cardiac rhythm, impaired thermoregulatory sweating, and disturbances of bladder, bowel, gastric, and sexual function.

Diabetic mononeuropathy multiplex is usually characterized by pain and weakness and often has a vascular basis. The clinical deficit depends on the nerves that are affected.

Diabetic amyotrophy is due to radiculoplexopathy, polyradiculopathy, or polyradiculoneuropathy. Pain, weakness, and atrophy of pelvic girdle and thigh muscles are typical, with absent quadriceps reflexes and little sensory loss.

Diabetic mononeuropathy simplex is typically abrupt in onset and often painful.

CSF protein concentration is typically increased in diabetic polyneuropathy and mononeuropathy multiplex.

Treatment & Prognosis

No specific treatment exists for the peripheral nerve complications of diabetes except when the patient has an entrapment neuropathy and may benefit from a decompressive procedure. The treatment of pain or autonomic disturbances was outlined earlier. Diabetic amyotrophy usually improves spontaneously. It is important that the control of diabetes is optimized.

OTHER ENDOCRINOPATHIES

Hypothyroidism

Hypothyroidism is associated with entrapment neuropathy, especially carpal tunnel syndrome (median nerve entrapment; see later), but rarely causes a polyneuropathy. Polyneuropathy may be mistakenly diagnosed in patients with proximal limb weakness caused by hypothyroid myopathy or in patients with delayed relaxation of tendon reflexes, a classic manifestation of hypothyroidism that is independent of neuropathy. Other neurologic manifestations of hypothyroidism include an acute confusional state (see Chapter 4, Confusional States), dementia (see Chapter 5, Dementia & Amnestic Disorders), and cerebellar ataxia (see Chapter 8, Disorders of Equilibrium).

Acromegaly

This also frequently produces carpal tunnel syndrome and, less often, polyneuropathy. Because many acromegalic patients are also diabetic, it may be difficult to determine which disorder is primarily responsible for polyneuropathy in a given patient.

UREMIA

A symmetric sensorimotor polyneuropathy, predominantly axonal in type, may occur in uremia. It affects the legs more than the arms, is more marked distally than proximally, and relates to the severity of impaired renal function. Restless legs, muscle cramps, and burning feet may be associated. The neuropathy may improve markedly with renal transplantation. Carpal tunnel syndrome (see later) may also occur with renal disease and may develop distal to the arteriovenous fistulas placed in the forearm for access during hemodialysis. In patients on chronic hemodialysis, it often relates to amyloidosis and the accumulation of β₂-microglobulin.

LIVER DISEASE

Primary biliary cirrhosis may lead to a sensory neuropathy that is probably of the axonal type. A predominantly demyelinative polyneuropathy can occur with chronic liver disease. There does not appear to be any correlation between the neurologic findings and the severity of the hepatic dysfunction.

VITAMIN B₁₂ DEFICIENCY

Vitamin B₁₂ deficiency is associated with symmetric distal sensory and mild motor impairment and loss of tendon reflexes. Because controversy exists about the relative importance of polyneuropathy and myelopathy in producing this syndrome, vitamin B₁₂ deficiency is considered in more detail later, in the section on myelopathies. Polyradiculoneuropathy, polyneuropathy, and myelopathy may follow bariatric surgery and relate to nutritional deficiencies, including but not limited to vitamin B₁₂.

INFECTIVE & GRANULOMATOUS NEUROPATHIES

HIV INFECTION

Neuropathy is a common complication of HIV-1 infection (Table 10-6); involvement of peripheral nerves is seen at autopsy in approximately 40% of patients with AIDS. It may be a consequence of HIV infection or of secondary infection with other organisms (eg, cytomegalovirus, varicella-zoster virus, Treponema pallidum), have an immunologic basis, or relate to nutritional deficiency or medication.

Distal symmetric sensorimotor or predominantly sensory polyneuropathy is the most common neuropathy associated with HIV-1 infection. Axons, rather than myelin, are primarily affected. The cause is unknown, but in some patients, vitamin B₁₂ deficiency or exposure to neurotoxic drugs (which should be discontinued if possible) may be responsible in part. Other causes of neuropathy should be excluded. HIV-1 is rarely identified in the affected nerves. Sensory symptoms predominate and include pain and paresthesias affecting especially the feet. Weakness is a minor or late feature. Ankle and sometimes knee reflexes are absent. The course is typically progressive. Combination antiretroviral therapy (cART) may help in improving sensory function. Pain may be controlled pharmacologically, as described earlier. Plasmapheresis is of no benefit.

Inflammatory demyelinating polyneuropathy may occur early in HIV-1 infection and follow an acute course (symptoms reaching their nadir within 4 weeks) or, in patients with severe infection, a chronic course (progression for longer than 4 weeks). The neuropathy may be immune mediated, but sometimes results from direct, secondary viral infection, as from cytomegalovirus. It is characterized by proximal, and sometimes distal, weakness with less pronounced sensory disturbances, and areflexia or hyporeflexia. The CSF is abnormal, with an elevated protein concentration and often a lymphocytic pleocytosis (unlike the findings in Guillain–Barré syndrome or chronic inflammatory demyelinating polyneuropathy in patients without HIV-1 infection). Some patients improve spontaneously or stabilize, and others may respond to corticosteroids, plasmapheresis, or intravenous immunoglobulin.

Lumbosacral polyradiculopathy occurs late in the course of HIV-1 infection, usually in patients with prior opportunistic infections. Cytomegalovirus infection is the cause, at least in some instances. Clinical features usually develop over several weeks and include diffuse, progressive leg weakness, back pain, painful paresthesias of the feet and perineum, lower extremity areflexia, and early urinary retention. The course may be fulminant, with ascending paralysis leading to respiratory failure, but is sometimes more benign, especially when the etiology is unclear. CSF findings include mononuclear or polymorphonuclear pleocytosis, elevated protein concentration, and decreased glucose level; a positive test for cytomegalovirus by polymerase chain reaction provides further support. It is always important to exclude meningeal lymphomatosis, cord compression, or syphilis as the underlying cause, as these require specific treatment and affect the prognosis. Patients with cytomegalovirus infection may respond to ganciclovir 2.5 mg/kg intravenously every 8 hours for 10 days, then 7.5 mg/kg/d 5 d/wk. An alternative approach is with foscarnet; in severe cases, both drugs are given. Some worsening in the first 2 weeks of ganciclovir therapy does not indicate treatment failure. The CSF should be re-examined after 3 weeks to determine whether the polymorphonuclear cell count has declined; if it has not, foscarnet should replace ganciclovir.

Mononeuropathy multiplex affects multiple cranial and peripheral nerves, resulting in focal weakness and sensory loss. This may have an autoimmune basis or neoplastic or infectious causes (eg, cytomegalovirus infection), or result from vasculopathy. In early HIV-1 infection, mononeuropathy multiplex may be a self-limited disorder restricted to a single limb, with spontaneous stabilization or improvement. Late in AIDS, several limbs may be affected in a progressive fashion.

Mononeuropathy simplex tends to occur acutely in early HIV-1 infection and improve spontaneously. It may present as unilateral or bilateral facial palsy. A vascular cause is probable.

Autonomic neuropathy tends to occur late in HIV-1 infections and may lead to syncopal episodes, orthostatic hypotension, disturbances of sphincter or sexual function, impaired thermoregulatory sweating, and diarrhea. The dysautonomia may relate to central or peripheral pathology. Treatment is symptomatic (as discussed in an earlier section).

Medication-related neuropathy may result from treatment with the antiretroviral drugs zalcitabine (ddC), didanosine (ddI), and stavudine (d4T), after approximately 4 months unless other coexisting conditions make the patient more susceptible. It is an axonal sensory neuropathy, characterized by distal tingling, numbness, and pain. Other drugs that may be associated with a neuropathy in AIDS patients include isoniazid, ethambutol, vincristine, vinblastine, Taxol, thalidomide, and the statins.

LEPROSY

Leprosy is one of the most frequent causes of peripheral neuropathy worldwide. In turn, neuropathy is the most disabling manifestation of leprosy. Mycobacterium leprae affects the skin and peripheral nerves because its growth is facilitated by the cooler temperatures present at the body surface.

In tuberculoid leprosy, the immune response is adequate to confine the infection to one or more small patches of skin and their associated cutaneous and subcutaneous nerves. This produces a hypopigmented macule or papule over which sensation is impaired; pain and temperature appreciation are most affected. Anhidrosis occurs with involvement of autonomic fibers. Sensory deficits occur most often in the distribution of the digital, sural, radial, and posterior auricular nerves, whereas motor findings usually relate to involvement of the ulnar or fibular (peroneal) nerve. Involved nerves are often enlarged.

Lepromatous leprosy is a more widespread disorder that results in a symmetric, primarily sensory polyneuropathy that disproportionately affects pain and temperature sense. Its distribution is distinctive in that exposed areas of the body—especially the ears; nose; cheeks; dorsal surfaces of the hands, forearms, and feet; and lateral aspects of the legs—are preferentially involved. Unlike most polyneuropathies, that caused by leprosy tends to spare the tendon reflexes. Associated findings include resorption of the digits, trophic ulcers, and cyanosis and anhidrosis of the hands and feet.

Treatment depends on the type of leprosy, but typically involves dapsone, rifampicin, and clofazimine. The most recent guidelines of the World Health Organization (http://www.who.int/lep/mdt/regimens/en/index.html) should be followed. In the United States, further information can be obtained from the National Hansen’s Disease Program of the US Department of Health and Human Services (http://www.hrsa.gov/hansensdisease/).

DIPHTHERIA

Corynebacterium diphtheriae infects tissues of the upper respiratory tract and produces a toxin that causes demyelination of peripheral nerves. Within approximately 1 month after infection, patients may develop a cranial motor neuropathy with prominent impairment of ocular accommodation. Blurred vision is the usual presenting complaint. Extraocular muscles and the face, palate, pharynx, and diaphragm may also be affected, but the pupillary light reflex is preserved. Recovery typically occurs after several weeks. A more delayed syndrome that commonly has its onset 2 to 3 months after the primary infection takes the form of a symmetric distal sensorimotor polyneuropathy. Most patients recover completely. Diphtheritic neuropathy is discussed in more detail in Chapter 9, Motor Disorders.

SARCOIDOSIS

Sarcoidosis can produce mononeuropathy or, rarely, polyneuropathy. The mononeuropathy commonly involves cranial nerves, especially the facial nerve. In some instances, a small-fiber neuropathy leads to pain, dysesthesias, and autonomic involvement. Clinical evaluation for extraneural disease, x-rays of the lungs and bones, examination of the CSF, and determination of serum levels of angiotensin-converting enzyme are helpful in establishing the diagnosis of sarcoidosis. Treatment with prednisone, 60 mg/d orally followed by tapering doses, may speed recovery.

SEPSIS & MULTIORGAN FAILURE

Patients with sepsis and multiorgan failure may develop a critical illness polyneuropathy. This manifests primarily by weakness and is therefore discussed in Chapter 9, Motor Disorders.

NEUROPATHIES IN VASCULITIS & COLLAGEN VASCULAR DISEASE

Systemic vasculitides and collagen vascular diseases can produce polyneuropathy, mononeuropathy simplex, mononeuropathy multiplex, or entrapment neuropathy (Table 10-7).

SYSTEMIC NECROTIZING VASCULITIS

This includes polyarteritis nodosa and allergic angiitis and granulomatosis (Churg–Strauss syndrome). Neuropathy occurs in approximately 50% of patients, most often as mononeuropathy multiplex, which may manifest with pain of acute onset in one or more cranial or peripheral nerves. Distal symmetric sensorimotor polyneuropathy is less common. Treatment should begin as soon as the diagnosis is made; it includes prednisone 60 to 100 mg/d orally and cyclophosphamide 2 to 3 mg/d orally.

GRANULOMATOSIS WITH POLYANGIITIS (WEGENER GRANULOMATOSIS)

Mononeuropathy multiplex or polyneuropathy occurs in up to 30% of cases. Treatment is the same as for systemic necrotizing vasculitis.

GIANT CELL ARTERITIS

This disorder is considered in detail in Chapter 6, Headache & Facial Pain. Mononeuropathy affecting cranial nerves innervating the extraocular muscles can occur.

RHEUMATOID ARTHRITIS

Rheumatoid arthritis produces entrapment neuropathy (most commonly involving the median nerve) in approximately 45% of patients and distal symmetric sensorimotor polyneuropathy in about 30%. Mononeuropathy multiplex is a frequent feature in cases complicated by necrotizing vasculitis.

SYSTEMIC LUPUS ERYTHEMATOSUS

This is discussed in Chapter 4, Confusional States, as a cause of acute confusional states. Neuropathy occurs in up to 20% of patients. The most common pattern is a distal, symmetric sensorimotor polyneuropathy. An ascending, predominantly motor polyneuropathy (Guillain–Barré syndrome, see earlier) can also occur, as may mononeuropathy simplex or multiplex, which often affects the ulnar, radial, sciatic, or fibular (peroneal) nerve.

SJÖGREN SYNDROME

Sjögren syndrome involves the peripheral nerves in approximately 20% of cases. Distal symmetric sensorimotor polyneuropathy is most common, entrapment neuropathy (affecting especially the median nerve) is also frequent, and mononeuropathy multiplex can occur.

SCLERODERMA & MIXED CONNECTIVE-TISSUE DISEASE

Progressive systemic sclerosis (scleroderma) and mixed connective-tissue disease may produce cranial mononeuropathy, which most often involves the trigeminal (V) nerve.

NEOPLASTIC & PARAPROTEINEMIC NEUROPATHIES

COMPRESSION & INFILTRATION BY TUMOR

Nerve compression is a common complication of multiple myeloma, lymphoma, and carcinoma. Tumorous invasion of the epineurium may occur with leukemia, lymphoma, and various cancers, particularly carcinoma of the breast or pancreas.

PARANEOPLASTIC SYNDROMES

Carcinoma (especially small-cell cancer of the lung) and lymphoma may be associated with neuropathies that are thought to be immunologically mediated, based on the detection of autoantibodies to neuronal antigens in several cases.

Sensory or Sensorimotor Polyneuropathy

This occurs with both carcinoma and lymphoma. It can be either an acute or chronic disorder, is sometimes asymmetric, and may be accompanied by prominent pain. The CSF is typically acellular but protein concentration may be mildly elevated. Among patients with a chronic sensorimotor polyneuropathy of uncertain cause, approximately 10% have a monoclonal gammopathy; many such patients eventually develop a hematologic malignancy, as discussed later. Treatment of the malignancy may improve the neuropathy.

Sensory Neuronopathy

Carcinoma can also cause sensory neuronopathy, which primarily affects the cell bodies of sensory neurons in the dorsal root ganglion and is associated with the presence of anti-Hu (or ANNA-1) antibodies (see Chapter 8, Disorders of Equilibrium). This rare condition may be the presenting manifestation of cancer. Initial symptoms of pain and numbness usually begin distally but sometimes begin proximally or in the face. The disorders often progress over days or several weeks, leading to marked sensory ataxia and impairment of all sensory modalities. Motor involvement is late, and autonomic dysfunction is uncommon. The CSF may have an inflammatory formula. Treatment of the underlying tumor is usually unrewarding.

Motor Neuronopathy, Guillain–Barré Syndrome, & Other Motor Disorders

Lymphoma may be complicated by motor neuronopathy, a disorder of anterior horn cells. Hodgkin disease and angioimmunoblastic lymphadenopathy are sometimes associated with Guillain–Barré syndrome, which responds to treatment as in patients without malignancy. These and other paraneoplastic motor disorders (including the Lambert–Eaton myasthenic syndrome, neuromyotonia, and stiff-person syndrome) are discussed in Chapter 9, Motor Disorders.

Autonomic Neuropathy

An autonomic neuropathy may occur as a paraneoplastic disorder, especially in patients with small-cell lung cancer. It relates most often to anti-Hu antibodies but may also occur with an antibody against ganglionic acetylcholine receptors (anti-nAChR). It is underdiagnosed, often develops in the setting of other paraneoplastic syndromes, and has a poor prognosis. Symptoms may include hypotension, orthostatic hypotension, hypoventilation, abnormal thermoregulatory sweating, sleep apnea, gastroparesis, intestinal pseudo-obstruction, and cardiac arrhythmias, sometimes leading to sudden death. Affected patients do not improve with immunotherapy even after treatment of the underlying tumor.

PARAPROTEINEMIAS

Patients with paraproteinemic demyelinating neuropathy, especially a chronic distal sensory neuropathy, may have a malignant plasma cell dyscrasia. The paraprotein is likely to underlie the neuropathy when it is an immunoglobulin (Ig)M. When it is IgG or IgA, the neuropathy may be clinically and electrophysiologically indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy and similar in its response to treatment.

Polyneuropathy is a common complication of multiple myeloma. Patients affected by lytic myeloma are usually men. The clinical picture is of a distal symmetric sensorimotor polyneuropathy. All sensory modalities are affected, pain is a frequent feature, and the reflexes are depressed. The disorder is usually progressive and leads to death within 2 years.

Sclerotic myeloma may be accompanied by a chronic demyelinating polyneuropathy. Motor involvement predominates, but vibration and position sense may also be impaired, and the reflexes are depressed. Pain is less common than in the neuropathy of lytic myeloma, and symptoms may improve with treatment of the underlying cancer or by plasmapheresis.

The POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) may complicate plasma cell dyscrasias, especially osteosclerotic myeloma. The sensorimotor polyneuropathy may show certain distinctive electrophysiologic features, such as conduction slowing that is more marked in intermediate than distal nerve segments, and often responds to treatment. Local irradiation or resection of an isolated plasmacytoma should be considered, as should melphalan with or without corticosteroids.

A sensorimotor polyneuropathy similar to that observed with lytic myeloma may also occur in Waldenström macroglobulinemia or benign monoclonal gammopathy. Treatment with immunosuppressant drugs and plasmapheresis is sometimes helpful.

AMYLOIDOSIS

Nonhereditary amyloidosis occurs as an isolated disorder (primary generalized amyloidosis) or in patients with multiple myeloma and may be associated with polyneuropathy. Polyneuropathy is also a feature of hereditary amyloidosis. Amyloid neuropathies are considered later in the section on hereditary neuropathies.

DRUG-INDUCED & TOXIC NEUROPATHIES

ALCOHOLISM

Polyneuropathy is one of the most common neurologic complications of chronic alcoholism; it can occur alone or in combination with other alcohol-related neurologic disorders, such as Wernicke encephalopathy (see Chapter 4, Confusional States) or the Korsakoff amnestic syndrome (see Chapter 5, Dementia & Amnestic Disorders). Controversy exists concerning the relative contributions of direct neurotoxicity of alcohol and associated nutritional (especially thiamine) deficiency in producing polyneuropathy.

Alcoholic polyneuropathy is typically a symmetric distal sensorimotor neuropathy. The legs are most affected, resulting in defective perception of vibration and touch and depressed or absent ankle reflexes. In some cases, distal weakness is pronounced, and autonomic dysfunction may occur. When pain occurs, it may respond to the treatment described earlier for painful neuropathy.

Abstinence from alcohol and thiamine repletion can halt the progression of symptoms.

OTHER DRUGS

As indicated in Table 10-2, a large number of drugs may cause neuropathies and most merit no additional comment here. With regard to isoniazid, a widely used antituberculous agent that interferes with pyridoxine metabolism, the polyneuropathy principally affects the sensory neurons. High doses, hereditary variations in drug metabolism, and malnutrition predispose to this complication. Spontaneous improvement occurs when administration of the drug is halted. Isoniazid-induced neuropathy can be prevented by concurrent administration of pyridoxine 100 mg/d orally.

Pyridoxine (vitamin B₆) toxicity may cause a sensory neuronopathy that disproportionately impairs vibration and position sense. This disorder usually occurs in patients taking at least 200 mg of pyridoxine daily—approximately 100 times the minimum daily requirement. Sensory ataxia, Romberg sign, Lhermitte sign, and ankle areflexia are common findings. Pain is less common, and motor involvement is unusual. Symptoms are usually reversible over months to years if the abuse ceases, but an irreversible syndrome has also been reported after intravenous administration of high doses of pyridoxine.

TOXINS

Organic compounds implicated as causes of polyneuropathy include hexacarbons present in solvents and glues (eg, n-hexane, methyl n-butyl ketone) and organophosphates used as plasticizers or insecticides (eg, triorthocresyl phosphate). Sensory involvement is most striking in n-hexane neuropathy, whereas neuropathy caused by triorthocresyl phosphate primarily affects motor nerves. Organophosphate neuropathy is discussed in more detail in Chapter 9, Motor Disorders.

Heavy metals may also be responsible for polyneuropathy. Neuropathy caused by lead, arsenic, and thallium is discussed in Chapter 9, Motor Disorders. Gold, which is used to treat rheumatoid arthritis, may cause a symmetric polyneuropathy, and cisplatin (a platinum analogue with anticancer activity) may produce a sensory neuropathy.

HEREDITARY NEUROPATHIES

HEREDITARY MOTOR & SENSORY NEUROPATHIES

These are designated Charcot–Marie–Tooth (CMT) hereditary neuropathies. They constitute a genetically heterogeneous group of disorders having a similar clinical phenotype. There is weakness and wasting of distal muscles in the limbs, with or without sensory loss; pes cavus and reduced or absent tendon reflexes also occur. They are divided into demyelinating (CMT-1) and neuronal (CMT-2) types, the latter sparing sensory neurons and resembling progressive spinal muscular atrophy (see Chapter 9, Motor Disorders). Both types have an autosomal dominant pattern of inheritance, although apparently sporadic cases occur.

CMT-1 has its onset in the first decade, follows a slowly progressive course, and is of variable severity. The nerves are often palpably thickened. Nerve conduction velocities are markedly reduced. CMT-1 is subdivided on the basis of the genetic findings, but the most common forms result from duplication of or mutations in the gene for peripheral myelin protein-22 (PMP22) in CMT1A or for myelin protein zero (MPZ) in CMT1B.

CMT-2 is generally less severe than CMT-1, is associated with normal or near-normal nerve conduction velocities, and does not cause nerve enlargement. The most common mutations are in the gene for mitofusin 2 (MFN2), but mutations in various other genes, including MPZ, have also been reported. X-linked dominant (CMT-X) and autosomal recessive (CMT-4) variants have been described.

Dejerine–Sottas disease (HMSN3; CMT-3) has its onset by 2 years of age with delayed motor milestones, is characterized by a severe sensorimotor neuropathy that frequently extends to the proximal muscles, and is associated with skeletal abnormalities such as scoliosis. There is severe demyelination of the nerves. It has autosomal recessive or dominant inheritance, and the responsible mutations involve the same genes associated with CMT-1.

HEREDITARY SENSORY & AUTONOMIC NEUROPATHIES

These neuropathies also take a variety of forms. In hereditary sensory and autonomic neuropathy (HSAN) type I, there is dominant inheritance, a gradually progressive course from onset in early adulthood, and symmetric loss of distal pain and temperature perception, with relative preservation of light touch. Perforating ulcers over pressure points and painless infections of the extremities are common. The tendon reflexes are depressed, but there is little, if any, motor disturbance. This phenotype is associated with mutations in the genes coding for serine palmitoyltransferase long-chain subunits (SPTLC1 and SPTLC2), the GTPase atlastin family (ATL1 and ATL3), or DNA methyltransferase 1 (DNMT1).

In HSAN type II, inheritance is recessive, onset is in infancy or early childhood, progression is slow, all sensory modalities are affected, autonomic involvement is variable, and tendon reflexes are lost. Four subtypes are recognized. The affected genes are lysine-deficient protein kinase 1 (WNK1); family with sequence similarity 134, member B (FAM134B); kinesin family member 1A (KIF1A); and voltage-gated sodium channel type IX, alpha subunit (SCN9A).

HSAN type III (Riley–Day syndrome, familial dysautonomia) is a progressive recessive disorder that commences in infancy. It is characterized by conspicuous autonomic dysfunction (absent tearing, and labile temperature and blood pressure), absent taste sensation, impaired pain and temperature sensation, and areflexia. The disorder, which has an increased prevalence in persons of Ashkenazi Jewish origin, is linked to mutations in the gene for inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP).

HSAN type IV is associated with congenital insensitivity to pain and absent sweating and has been related to recessive mutations in the gene encoding a receptor tyrosine kinase for nerve growth factor (NTRK1). Many of these patients have cognitive dysfunction. Death from hyperpyrexia may occur.

HSAN type V resembles type IV, but cognitive abnormalities do not occur. The mutation is in the nerve growth factor β-subunit gene (NGFB).

Other, less common forms have also been described.

AMYLOIDOSIS

Polyneuropathy can occur in both hereditary and nonhereditary forms of amyloidosis. Because small-diameter sensory and autonomic nerve fibers are especially likely to be involved, pain and temperature sensation and autonomic functions are prominently affected. Clinical presentation is commonly with distal paresthesias, dysesthesias, and numbness; postural hypotension; impaired thermoregulatory sweating; and disturbances of bladder, bowel, or sexual function. Distal weakness and wasting eventually occur. The tendon reflexes are often preserved until a relatively late stage. Entrapment neuropathy, especially carpal tunnel syndrome, may develop as a consequence of amyloid deposits.

In primary amyloidosis, the diagnosis is made by identifying amyloid deposits in the tissues; examination of abdominal fat aspirate is usually the initial step. Treatment has included alkylating agents or autologous peripheral blood stem-cell transplantation. In hereditary (familial) amyloidosis, genetic testing for transthyretin (TTR) mutations is more useful for establishing the diagnosis than analysis of tissues for amyloid deposition. Treatment by orthotopic liver transplantation is effective.

FRIEDREICH ATAXIA

Friedreich ataxia usually has an autosomal recessive mode of inheritance but occasionally occurs with dominant inheritance. It is usually caused by an expanded GAA trinucleotide repeat in a noncoding region of the gene for frataxin (FXN), a mitochondrial protein. An ataxic gait develops, followed by clumsiness of the hands and other signs of cerebellar dysfunction. Involvement of peripheral sensory fibers leads to sensory deficits of the limbs, with depressed or absent tendon reflexes. There may also be leg weakness and extensor plantar responses from central motor involvement. This condition is considered in detail in Chapter 8, Disorders of Equilibrium.

HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES

This is a genetically heterogeneous disorder that relates most commonly to deletion in the peripheral myelin protein 22 (PMP22) gene. Inheritance is as an autosomal dominant trait with variable expression. Patients present with simple or multiple mononeuropathies that occur after mild pressure or stretch of nerves, and electrophysiologic studies reveal that abnormalities are more widespread than is evident clinically. Patients should be advised to avoid prolonged sitting with legs crossed or leaning on the elbows, and not to engage in activities involving repetitive movements of the wrist. Protective pads worn at the elbows or knees are sometimes worthwhile.

METABOLIC DISORDERS

In acute intermittent porphyria, which is transmitted by recessive inheritance, the initial neurologic manifestation is often a polyneuropathy that usually involves motor more than sensory fibers. Sensory symptoms and signs may be predominantly proximal or distal. The peripheral nerves may also be affected in variegate porphyria. Neuropathy caused by porphyria is considered further in Chapter 9, Motor Disorders.

Two autosomal recessive lipidoses are associated with polyneuropathy with a typical onset in infancy or childhood. These are metachromatic leukodystrophy, which results from deficiency of the enzyme arylsulfatase A, and Krabbe disease, due to galactocerebroside β-galactosidase deficiency.

Lipoprotein deficiencies that cause polyneuropathy include abetalipoproteinemia, which is associated with acanthocytosis, malabsorption, retinitis pigmentosa, and cerebellar ataxia, and Tangier disease, which produces cataract, orange discoloration of the tonsils, and hepatosplenomegaly. These are autosomal recessive conditions.

Refsum disease (previously HMSN IV) is an autosomal recessive disorder related to impaired metabolism of phytanic acid, resulting from mutations in the PHYH gene (encoding phytanoyl-CoA hydroxylase) in 90% of cases and from mutations in the PEX7 gene (encoding the PTS2 receptor) in 10% or less of cases. The disorder is characterized by polyneuropathy, cerebellar ataxia, retinitis pigmentosa, and ichthyosis. Sensorineural deafness, anosmia, and cardiac arrhythmias may also occur. Treatment is by restricting dietary intake of phytol. Plasmapheresis to reduce body stores of phytanic acid may also help at the initiation of treatment, especially if there is acute weakness or a cardiac arrhythmia.

Fabry disease is an X-linked recessive disease caused by deficiency of the enzyme α-galactosidase-A, which leads to the accumulation of α-D-galactosyl moieties in different cells and tissues. This results in a painful sensory and autonomic (ie, a small-fiber) neuropathy, angiokeratomas, renal and cardiac disease, and an increased incidence of stroke. White matter lesions may be present on brain MRI. Multiple mutations of the α-galactosidase-A (GLA) gene have been found. The diagnosis can be confirmed in males by a low α-galactosidase-A activity in leukocytes or plasma. Mutation analysis is required for the diagnosis of female carriers.

Pharmacologic measures (discussed earlier) may be helpful in treating pain, especially treatment with gabapentin or amitriptyline. Enzyme replacement therapy with agalsidase β or α, a recombinant human α-galactosidase A enzyme, also merits consideration. It should probably be given to all hemizygous males with low or undetectable levels of α-galactosidase-A, regardless of whether clinical features of the disease are present, but there is no agreement about this. Enzyme replacement therapy is important in reducing pain and, once started, should be continued indefinitely; it may help to stabilize or improve cardiac and renal function, although this remains unclear. Antiplatelet agents help to prevent ischemic stroke, as discussed in Chapter 13, Stroke.

Certain peripheral nerves are particularly susceptible to mechanical injury at vulnerable sites. The term entrapment neuropathy is used when the nerve is compressed, stretched, or angulated by adjacent anatomic structures to such an extent that dysfunction occurs. There are numerous entrapment neuropathies, and in many the initial or most conspicuous clinical complaints are of sensory symptoms or pain. Some of the more common syndromes are described next.

UPPER LIMB ENTRAPMENT SYNDROMES

MEDIAN NERVE COMPRESSION

Compression of the median nerve is common in the carpal tunnel at the wrist. Carpal tunnel syndrome may occur during pregnancy and as a complication of trauma, degenerative arthritis, tenosynovitis, diabetes mellitus, myxedema, and acromegaly. Early symptoms are pain and paresthesias confined to a median nerve distribution in the hand, that is, involving primarily the thumb, index, and middle fingers and the lateral half of the ring finger (see Appendix). There may be pain in the forearm and, in occasional patients, more proximally. Symptoms are often particularly troublesome at night and may awaken the patient from sleep. As the neuropathy advances, weakness and atrophy may eventually develop in the thenar muscles.

Examination reveals impaired cutaneous sensation in the median nerve distribution in the hand and, with motor involvement, weakness and wasting of the abductor pollicis brevis and opponens pollicis muscles (see Appendix). There may be a positive Tinel sign (percussion of the nerve at the wrist causes paresthesias in its distribution) or a positive response to the Phalen maneuver (flexion of the wrist for 1 minute exacerbates or reproduces symptoms).

The diagnosis can generally be confirmed by electrophysiologic studies. If the symptoms fail to respond to local corticosteroid injections or simple maneuvers such as wearing a nocturnal wrist splint, surgical decompression of the carpal tunnel may be necessary.

INTERDIGITAL NEUROPATHY

Interdigital neuropathy may lead to pain in one or two fingers, and examination reveals hyperpathia or impaired cutaneous sensation in the appropriate distribution of the affected nerve or nerves. Such a neuropathy may result from entrapment in the intermetacarpal tunnel of the hand, direct trauma, tenosynovitis, or arthritis.

Treatment by local infiltration with corticosteroids is sometimes helpful, but in severe cases neurolysis may be necessary.

ULNAR NEUROPATHY

Ulnar nerve dysfunction at the elbow leads to paresthesias, hypesthesia, and nocturnal pain in the little finger and ulnar border of the hand. Pain may also occur about the elbow. Symptoms are often intensified by elbow flexion or use of the arm.

Examination may reveal sensory loss on the ulnar aspect of the hand and weakness of the adductor pollicis, the deep flexor muscles of the fourth and fifth digits, and the intrinsic hand muscles (see Appendix). The lesion may result from external pressure, from entrapment within the cubital tunnel, or from cubitus valgus deformity causing chronic stretch injury of the nerve. Electrodiagnostic studies may localize the lesion.

Avoiding pressure on or repetitive flexion and extension of the elbow, combined in some instances with splinting the elbow in extension, is sometimes sufficient to arrest progression and alleviate symptoms. Surgical decompression or ulnar nerve transposition to the flexor surface of the arm may also be helpful, depending on the cause and severity of the lesion and duration of symptoms.

An ulnar nerve lesion may also develop in the wrist or palm of the hand in association with repetitive trauma, arthritis, or compression from ganglia or benign tumors. Involvement of the deep terminal branch in the palm leads to a motor deficit in ulnar-innervated hand muscles other than the hypothenar group, whereas a more proximal palmar lesion affects the latter muscles as well; there is no sensory deficit. With lesions at the wrist involving either the ulnar nerve itself or its deep and superficial branches, both sensory and motor changes occur in the hand. Sensation over the dorsal surface of the hand is unaffected, however, because the cutaneous branch to this region arises proximal to the wrist. Surgical treatment is helpful in relieving compression from a ganglion or benign tumor.

RADIAL NEUROPATHY

The radial nerve may be compressed in the axilla by pressure from crutches or other causes; this is frequently seen in alcoholics and drug addicts who have fallen asleep with an arm draped over some hard surface (so-called “Saturday night palsy”). The resulting deficit is primarily motor, with weakness or paralysis occurring in the muscles supplied by the nerve, but sensory changes may also occur, especially in a small region on the back of the hand between the thumb and index finger (see Appendix).

Treatment involves preventing further compression of the nerve. Recovery usually occurs spontaneously and completely, except when a very severe injury has resulted in axonal degeneration. Physical therapy and a wrist splint may be helpful until recovery occurs.

THORACIC OUTLET SYNDROME

A cervical rib or band or other anatomic structure may compress the lower part of the brachial plexus. Symptoms include pain, paresthesias, and numbness in a C8 and T1 distribution (see Figure 10-4). There may be diffuse weakness of the intrinsic hand muscles, often particularly involving the muscles in the thenar eminence and thereby simulating carpal tunnel syndrome. The section on cervical rib syndrome in Chapter 9, Motor Disorders, contains further details.

LOWER LIMB ENTRAPMENT SYNDROMES

FIBULAR (PERONEAL) NEUROPATHY

Fibular (peroneal) nerve lesions can follow trauma or pressure about the knee at the fibular head. The resulting weakness or paralysis of foot and toe extension—and foot eversion—is accompanied by impaired sensation over the dorsum of the foot and the lower anterior aspect of the leg (see Appendix). The ankle reflex is preserved, as is foot inversion.

Treatment is purely supportive. The nerve must be protected from further injury or compression. Patients with foot drop may require a brace until recovery occurs. Recovery occurs spontaneously with time and is usually complete unless the injury was severe enough to cause marked axonal degeneration.

TIBIAL NEUROPATHY

The posterior tibial nerve or its branches can be compressed between the floor and the ligamentous roof of the tarsal tunnel, which is located at the ankle immediately below and behind the medial malleolus. The usual complaint is of burning in the foot, especially at night, sometimes accompanied by weakness of the intrinsic foot muscles. The diagnosis can usually be confirmed electrophysiologically. If treatment with local injection of corticosteroids is not helpful, surgical decompression may be necessary.

FEMORAL NEUROPATHY

Isolated femoral neuropathy may occur in association with diabetes mellitus, vascular disease, bleeding diatheses (eg, hemophilia or treatment with anticoagulant drugs), or retroperitoneal neoplasms. Weakness of the quadriceps muscle is accompanied by a reduced or absent knee reflex, and sensory disturbances may also occur in the anterior and medial aspects of the thigh and medial part of the lower leg. Treatment is of the underlying cause.

SAPHENOUS NEUROPATHY

The saphenous nerve is the terminal sensory branch of the femoral nerve and supplies cutaneous sensation to the medial aspect of the leg about and below the knee (see Figure 10-4). Mechanical injury to the nerve can occur at several points along its course; patients complain of pain or impaired sensation in the distribution of the nerve. Weakness in quadriceps function (ie, extension at the knee; see Appendix) indicates femoral, rather than saphenous, nerve involvement. There is no specific treatment, but the nerve should be protected from further injury.

LATERAL FEMORAL CUTANEOUS NEUROPATHY

The lateral femoral cutaneous nerve supplies sensation to the outer border of the thigh (see Appendix). Its function can be impaired by excessive angulation or compression by neighboring anatomic structures, especially in pregnancy or other conditions that cause exaggerated lumbar lordosis. This leads to pain and paresthesias in the lateral thigh, where examination reveals impaired sensation. This syndrome, known as meralgia paresthetica, is best treated with symptomatic measures such as simple analgesics taken orally. Its course is often self-limited, but in occasional cases it progresses to a patch of permanent, painless numbness.

OBTURATOR NEUROPATHY

Trauma to the obturator nerve—for example, by pelvic fracture or a surgical procedure—can lead to pain radiating from the groin down the inner aspect of the thigh. An obturator hernia or osteitis pubis may cause a similar disorder; there is accompanying weakness of the adductor thigh muscles (see Appendix).

COMPRESSIVE & TRAUMATIC LESIONS

The clinical disturbances resulting from acute intervertebral disk prolapse, cervical spondylosis, traumatic plexopathy, cervical rib syndrome, and neuralgic amyotrophy are discussed in Chapter 9, Motor Disorders. In addition to these conditions, patients with metastatic cancer may develop root or plexus lesions from compression by tumor or as a result of trauma induced by radiation therapy.

Root lesions are typically compressive in nature and usually occur in the setting of neoplastic meningitis, which is discussed in Chapter 4, Confusional States.

Brachial plexopathy can result from tumor infiltration, especially by lung or breast cancer, causing severe arm pain and sometimes dysesthesia. Because involvement of the lower trunk of the plexus is most common, symptoms usually occur within the C8 and T1 dermatomes, and Horner syndrome (see Chapter 7, Neuro-Ophthalmic Disorders) is present in approximately 50% of cases. Radiation injury, rather than direct invasion by tumor, should be suspected when the upper trunk of the brachial plexus (C5 and C6 nerve roots) is involved, weakness is a prominent presenting symptom, arm swelling occurs, or symptoms develop within 1 year after completion of radiation therapy with a total dose of more than 60 Gy. MRI findings of thickening and diffuse enhancement of the brachial plexus without a focal mass lesion support a radiation-induced plexopathy, as does the finding of myokymic discharges on electromyography.

Lumbosacral plexopathy is usually seen in patients with colorectal, cervical, uterine, or ovarian carcinoma or sarcoma. Clinical features that suggest tumor invasion include early and severe pain, unilateral involvement, leg swelling, and a palpable rectal mass. Radiation injury is more commonly associated with early prominent leg weakness and bilateral symptoms.

TABES DORSALIS

This type of neurosyphilis, now rare, is characterized mainly by sensory symptoms and signs that indicate marked involvement of the posterior roots, especially in the lumbosacral region, with resulting degeneration in the posterior columns of the spinal cord. Common complaints are of unsteadiness, sudden lancinating somatic pains, and urinary incontinence. Visceral crises characterized by excruciating abdominal pain also occur.

Examination reveals marked impairment of vibration and joint position sense in the legs, together with an ataxic gait and Romberg sign. Deep pain sensation is impaired, but superficial sensation is generally preserved. The bladder is often palpably enlarged; because it is flaccid and insensitive, there is overflow incontinence. Tendon reflexes are lost, and the limbs are hypotonic. Sensory loss and hypotonicity may lead to the occurrence of hypertrophic (Charcot) joints. In many patients, there are other signs of neurosyphilis, including Argyll Robertson pupils, optic atrophy, ptosis, a variable ophthalmoplegia, and, in some cases, pyramidal and mental changes from cerebral involvement (taboparesis), as discussed in Chapter 5, Dementia & Amnestic Disorders. Treatment is of the underlying infection.

LYME DISEASE

Lyme disease, like syphilis, is a spirochetal infection that produces both central and peripheral nervous system disease. Central nervous system involvement is manifested by meningitis or meningoencephalitis (see Chapter 4, Confusional States). Lyme disease is also associated with inflammatory mono- or polyradiculopathy, brachial plexopathy, mononeuropathy (including facial palsy), and mononeuropathy multiplex. The radiculopathy results in pain, sensory loss, or dysesthesia in affected dermatomes; it also causes focal weakness. One or more cervical, thoracic, or lumbar nerve roots may be involved. Electromyography can confirm the presence of radiculopathy, and serologic testing establishes Lyme disease as the cause. Treatment is described in Chapter 4.

Myelopathies may present with pain or various sensory complaints and with motor disturbances. The clinical findings should suggest the level of the lesion, but further investigation is necessary to delineate it more fully and determine its nature. Compressive, ischemic, inflammatory, demyelinative, and traumatic myelopathies are discussed in Chapter 9, Motor Disorders.

SYRINGOMYELIA

Syringomyelia is cavitation of the spinal cord. Communicating syringomyelia, with communication between the central canal of the cord and the cavity, is a hydrodynamic disorder of the CSF pathways. In noncommunicating syringomyelia, there is cystic dilation of the cord, which is not in communication with the CSF pathways.

Syringomyelia may be asymptomatic, being discovered incidentally on imaging studies. When symptomatic, the clinical disturbance depends on the site of cavitation. Typically, there is a dissociated sensory loss at the level of the lesion; pinprick and temperature appreciation are impaired, but light touch sensation is preserved (see Figure 10-5). The sensory loss may be reflected by the presence of painless skin ulcers, scars, edema, hyperhidrosis, neuropathic joints, resorption of the terminal phalanges, and other disturbances. Weakness and wasting of muscles occur at the level of the lesion because of the involvement of the anterior horns of the spinal cord (see Figure 10-5).

A pyramidal deficit and sphincter disturbances sometimes occur below the level of the lesion because of gliosis or compression of the descending corticospinal pathways. The tendon reflexes may be depressed at the level of the lesion—because of interruption of their afferent, central, or efferent pathways—and increased below it. Scoliosis is a common accompaniment of cord cavitation.

Cavitation commonly occurs in the cervical region, causing a capelike distribution of sensory loss over one or both shoulders, diffuse pain in the neck, and radicular pain in the arms; involvement of the T1 segment frequently leads to ipsilateral Horner syndrome. If the cavitation involves the lower brainstem (syringobulbia), there may also be ipsilateral tongue wasting, palatal weakness, vocal cord paralysis, dissociated trigeminal sensory loss, and other evidence of brainstem involvement.

Communicating syringomyelia is often associated with developmental anomalies of the brainstem and foramen magnum region (such as Arnold–Chiari malformation; see Chapter 8, Disorders of Equilibrium) or with chronic arachnoiditis of the basal cisterns. Arnold–Chiari malformation can lead to hydrocephalus, cerebellar ataxia, pyramidal and sensory deficits in the limbs, and abnormalities of the lower cranial nerves, alone or in any combination. CT scans reveal a small posterior fossa and enlarged foramen magnum; other skeletal abnormalities may be present at the base of the skull and upper cervical spine. MRI reveals the syrinx and the Arnold–Chiari malformation, with caudal displacement of the fourth ventricle and herniation of the cerebellar tonsils through the foramen magnum.

Noncommunicating syringomyelia is often due to trauma, intramedullary tumors (such as ependymomas or hemangioblastomas), or spinal arachnoiditis (Figure 10-8). Posttraumatic syringomyelia generally occurs in patients with preexisting, severe neurologic deficits from spinal trauma after an interval of several years, although rarely it develops after only a few months. Presentation is with increase in a previously stable deficit; weakness, impaired sensation, and spasticity are often conspicuous, and pain, often radicular, may be distressing. Focal cord enlargement is found on MRI in patients with cavitation related to previous injury or to intramedullary neoplasms. The presence of arachnoiditis, cord compression, or spinal stenosis implies a worse prognosis than otherwise.

Treatment depends on the underlying cause. Decompression of a distended syrinx may provide transient benefit. In the case of communicating syringomyelia associated with Arnold–Chiari malformation, removal of the posterior rim of the foramen magnum and amputation of the cerebellar tonsils are sometimes helpful. The cord cavity should be drained, and, if necessary, an outlet should be made for the fourth ventricle; the use of syrinx shunts is more controversial. Posttraumatic syringomyelia is treated by surgery if it is causing a progressive neurologic deficit or intolerable pain. A variety of surgical approaches have been used, including various draining procedures from the cord cavity, myelotomy, and formation of surgical meningocele. Radicular pain and sensory disturbances are usually helped, whereas spasticity and motor deficits respond less satisfactorily.

SUBACUTE COMBINED DEGENERATION

Vitamin B₁₂ deficiency (Figure 10-9) may result from impaired absorption by the gastrointestinal tract such as occurs in pernicious anemia or because of gastrointestinal surgery, sprue, or infection with fish tapeworm; it can also be caused by a strictly vegetarian diet. Vitamin B₁₂ deficiency can lead to subacute combined degeneration of the posterior and lateral columns of the spinal cord.

Clinical onset is with distal paresthesias and weakness in the extremities (involvement of the hands occurs relatively early), followed by the development of spastic paraparesis, with ataxia from impaired postural sensation in the legs. Lhermitte sign may be present, and examination reveals a combined posterior column (vibration and joint position sense) and pyramidal deficit in the legs. Plantar responses are extensor, but tendon reflexes may be increased or depressed, depending on the site and severity of the involvement. Signs of cord involvement can be accompanied by centrocecal scotoma or optic atrophy from optic (II) nerve involvement, by behavioral or psychiatric changes, or by peripheral neuropathy. The neurologic manifestations are often accompanied by macrocytic megaloblastic anemia, but this is not invariably present.

The serum vitamin B₁₂ level is low in untreated cases, and serum homocysteine and methylmalonic acid levels are elevated. In pernicious anemia, gastric achlorhydria is usual, and anti-intrinsic factor and gastric parietal cell antibodies confirm the diagnosis. Hematologic findings may be normal, however, especially if folic acid supplements have been given. Electrophysiologic studies may confirm peripheral nerve involvement, and median- or tibial-derived somatosensory evoked potentials may show abnormalities indicative of posterior column dysfunction. Spinal MRI sometimes shows abnormalities in the posterior columns.

Treatment is with vitamin B₁₂ given by intramuscular injection daily (1,000 μg) for 2 weeks, then weekly (100 μg) for 2 months, and monthly (100 μg) thereafter. Note that folic acid supplements do not help the neurologic disorder; in addition, they may mask associated anemia.

A similar disorder may result from nitrous oxide abuse, which leads to inactivation of vitamin B₁₂. Management is focused on the prevention of further exposure to nitrous oxide.

Copper deficiency can also lead to subacute combined degeneration. The copper deficiency may follow total parenteral hyperalimentation, copper insufficiency with enteral feeding, malabsorption, gastric surgery, or excessive zinc ingestion, which inhibits the intestinal absorption of copper. Low serum copper and ceruloplasmin levels and urinary copper excretion confirm the diagnosis. Treatment involves copper supplementation and modification of any risk factors, which leads to stabilization of the neurologic deficit.

CEREBRAL DISORDERS

Sensory symptoms may relate to diverse diseases involving the brainstem or cerebral hemispheres (eg, stroke). The clinical features of the sensory deficit have been described earlier in this chapter and, together with the nature and extent of any accompanying neurologic signs, should suggest the probable site of the lesion.

Pain from infective, inflammatory, or neoplastic processes is a feature of many visceral diseases and may be a conspicuous component of certain neurologic or psychiatric diseases. It can also occur with no obvious cause.

In evaluating patients with pain, it is important to determine the level of the nervous system at which the pain arises and whether it has a primary neurologic basis. In the history, attention is focused on the mode of onset, duration, nature, severity, and location of the pain; on any associated symptoms; and on factors that precipitate or relieve the pain.

Treatment depends on the underlying cause and clinical context of the pain and is discussed later. A brief comment is necessary, however, about stimulation-produced analgesia and, in particular, about spinal cord stimulation (“dorsal column stimulation”) and peripheral nerve stimulation. These approaches were based on principles encapsulated by the gate control theory, in which activation of large myelinated fibers was held to interrupt nociceptive transmission in the spinal cord, but their precise mechanism of action is uncertain. Spinal cord stimulation is known to affect certain neurotransmitter systems, particularly substance P and γ-aminobutyric acid (GABAergic) systems.

PERIPHERAL NERVE PAIN

Pain arising from peripheral nerve lesions is usually localized to the site of nerve injury or confined to the territory of the affected nerve. It may have a burning quality, and when mixed (motor and sensory) nerves are involved, there may be an accompanying motor deficit. Painful peripheral neuropathies include those caused by diabetes, polyarteritis, alcoholic-nutritional deficiency states, and the various entrapment neuropathies. Treatment of pain associated with peripheral neuropathies was discussed earlier.

Reflex sympathetic dystrophy is a general term that denotes sympathetically mediated pain syndromes precipitated by a wide variety of tissue injuries, including soft tissue trauma, bone fractures, and myocardial infarction. The designation complex regional pain syndrome (CRPS), type 1, is now used (in preference to reflex sympathetic dystrophy) for pain that follows injury but spreads beyond the site of trauma in a distribution that does not conform to that of an individual peripheral nerve, is greater than would be expected from the injury, and may progress with time (sometimes to the opposite limb). It has been attributed to a post-traumatic neuralgia associated with distal degeneration of small-diameter peripheral axons. CRPS type 2, or causalgia, designates the severe persistent pain, often burning in quality, that results from nerve trauma. Such pain is associated with exquisite tenderness. Onset of pain may be at any time within the first 6 weeks or so after nerve injury. The cause is uncertain, but it has been attributed to ephaptic transmission between efferent sympathetic and afferent somatic fibers at the site of injury. Other proposed mechanisms involve inflammatory reactions and changes in the central mechanisms subserving pain.

In both types of CRPS, pain may be accompanied by swelling, increased sweating, and vasoconstriction of the affected extremity, which is commonly kept covered up and still by the patient; allodynia, hyperalgesia, muscle atrophy, and osteoporosis may also occur. No other cause for the symptoms and signs is apparent.

Treatment is largely empirical; studies to support specific therapeutic regimens are lacking. Medical approaches to treatment include physical and occupational therapy, with emphasis on increasing activity of the involved limb. Relaxation therapy or biofeedback may help, as also may topical lidocaine or capsaicin cream. Various pharmacologic approaches have been tried singly or in combination, with doses tailored to the individual. These include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (eg, duloxetine or venlafaxine), nonsteroidal anti-inflammatory drugs, gabapentin, pregabalin, lamotrigine, and opioids. If these measures do not provide satisfactory relief, a therapeutic trial of prednisone (starting with 1 mg/kg daily for 3 days) is sometimes undertaken. Addition of calcitonin or a bisphosphonate may be useful.

Sympathetic blockade by injection of local anesthetics into the sympathetic chain or by regional infusion of reserpine or guanethidine provides temporary benefit to some patients. One such procedure sometimes produces permanent cessation of pain; in other instances, repeated sympathetic blocks may be required. Surgical sympathectomy is beneficial in up to 75% of cases. Spinal cord stimulation has been effective in some instances for the treatment of either type of CRPS when other measures, including opiates, have been unhelpful.

RADICULAR PAIN

Radicular pain is caused most commonly by mechanical root compression from disk protrusion, spinal stenosis, or congenital anomalies, but infective, inflammatory, and neoplastic causes require exclusion. Herpes zoster infection is considered separately. The pain is localized to the distribution of one or more nerve roots and is often exacerbated by coughing, sneezing, and other maneuvers that cause increased intraspinal pressure. It is also exacerbated by maneuvers that stretch the affected roots. Passive straight-leg raising leads to stretching of the sacral and lower lumbar roots, as does passive flexion of the neck. Spinal movements that narrow the intervertebral foramina can aggravate root pain. Extension and lateral flexion of the head to the affected side may thus exacerbate cervical root symptoms. In addition to pain, root lesions can cause paresthesias and numbness in a dermatomal distribution (see Figure 10-4); they can also cause segmental weakness and reflex changes, depending on the level affected (see Chapter 9, Motor Disorders, Table 9-12). Useful modes of treatment for mechanical causes include immobilization, nonsteroidal anti-inflammatory drugs or other analgesics, and surgical decompression.

THALAMIC PAIN

Depending on their extent and precise location, thalamic lesions may lead to a burning, unpleasant pain in all or part of the contralateral half of the body. It is aggravated by emotional stress and tends to develop during partial recovery from a sensory deficit caused by the underlying thalamic lesion. Mild cutaneous stimulation may produce very unpleasant and painful sensations. This combination of sensory loss, spontaneous pain, and perverted cutaneous sensation is called Dejerine–Roussy syndrome. Similar pain can be produced by a lesion of the parietal lobe or the sensory pathways at any point in the cord (posterior columns or spinothalamic tract) or brainstem. Treatment with analgesics, anticonvulsants (carbamazepine, phenytoin, gabapentin, pregabalin, and lamotrigine), or tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, mexiletine, baclofen, and phenothiazines, either alone or in combination, is occasionally helpful, according to anecdotal observations. Opioids are sometimes used but carry the risk of dependency and addiction.

BACK & NECK PAIN

Spinal disease occurs most commonly in the neck or low back and can cause local or root pain, or both, and pain referred to other parts of the involved dermatomes. Pain from the lower lumbar spine, for example, is often referred to the buttocks. Conversely, pain may be referred to the back from the viscera, especially the pelvic organs. Local pain may lead to protective reflex muscle spasm, which in turn causes further pain and may result in abnormal posture, limitation of movement, and local spinal tenderness.

The history may suggest the underlying cause, and physical examination will define any neurologic involvement. Investigative studies may include complete blood count and erythrocyte sedimentation rate (especially if infective or inflammatory disorders or myeloma is suspected); determination of serum protein and protein electrophoresis; and measurement of serum calcium, phosphorus, alkaline and acid phosphatase, and uric acid. Electromyography may indicate the extent and severity of root involvement and provides a guide to prognosis. A CT scan, MRI of the spine, or CT myelogram may be necessary, especially if neoplasm is suspected, neurologic deficits are progressive, pain persists despite conservative treatment measures, or there is evidence of cord involvement. At myelography, CSF can be obtained for laboratory examination.

LOW BACK PAIN

Low back pain is a common cause of time lost from work. It has many causes. Routine immediate imaging of patients with acute or subacute low back pain who have no clinical features suggestive of serious underlying disorder does not improve the clinical outcome and is therefore unnecessary.

Trauma

Unaccustomed exertion or activity—or lifting heavy objects without adequate bracing of the spine—can cause musculoskeletal pain that improves with rest. Clinical examination commonly reveals spasm of the lumbar muscles and restricted spinal movement. Management includes local heat, bed rest on a firm mattress, nonsteroidal anti-inflammatory drugs or other analgesics, and muscle-relaxant drugs (eg, diazepam 2 mg three times daily, increased gradually until symptoms are relieved or to the highest dose tolerated). Vertebral fractures that follow more severe injury and lead to local pain and tenderness can be visualized at radiography. If spinal cord involvement is suspected—for example, because of leg weakness after injury—the patient must be immobilized until imaged to determine whether fracture dislocation of the vertebral column has occurred.

Prolapsed Lumbar Intervertebral Disk

This most commonly affects the L5-S1 or the L4-L5 disk. The prolapse may relate to injury, but commonly follows minor strain or normal activity. Protruded disk material may press on one or more nerve roots and thus produce radicular pain, a segmental motor or sensory deficit, or a sphincter disturbance in addition to a painful stiff back. The pain may be reproduced by percussion over the spine or sciatic nerve, by passive straight leg raising, or by extension of the knee while the hip is flexed. Bilateral symptoms and signs suggest that disk material has protruded centrally, and this is more likely to cause sphincter involvement than is lateral protrusion.

An L5 radiculopathy causes weak dorsiflexion of the foot and toes, whereas an S1 root lesion leads to a depressed ankle reflex and weakness of plantar flexion of the foot (see Chapter 9, Motor Disorders, Table 9-12). In either case, spinal movements are restricted, there is local tenderness, and Lasègue sign (reproduction of the patient’s pain on stretching the sciatic nerve by straight leg raising) is positive. The L4 root is occasionally affected, but involvement of a higher lumbar root should arouse suspicion of other causes of root compression.

Pelvic and rectal examination and spinal MRI or CT and CT myelography help to exclude other diseases, such as local tumors or metastatic neoplastic deposits.

Symptoms often resolve with simple analgesics, diazepam, and bed rest on a firm mattress for 2 to 3 days, followed by gradual mobilization. Bed rest for longer than 2 to 3 days provides no additional benefit. Nonsteroidal anti-inflammatory drugs may be helpful for acute back pain but are often ineffective or provide only minor or transient benefits in patients with root compression. Epidural steroid injection is of uncertain benefit and associated with potentially serious adverse effects.

Persisting pain, an increasing neurologic deficit, or any evidence of sphincter dysfunction should lead to MRI, CT scanning, or CT myelography, and surgical treatment if indicated by the results of these procedures. The presence of structural abnormalities does not mandate surgical treatment unless the clinical circumstances are appropriate—degenerative abnormalities are common in asymptomatic subjects, especially with advancing age, and may therefore be of no clinical relevance.

Continuing pain despite surgery may result from inadequate decompression, recurrent herniation of disk material, root compression or damage relating to the operative procedure, surgery at the wrong level, infective or inflammatory complications of surgery, or spinal instability. Often, however, no specific cause can be identified, and most patients do not require further surgery. Chronic pain in this setting may, however, respond to spinal cord stimulation. There is a high risk that patients will not return to work.

Lumbar Osteoarthropathy

This tends to occur in later life and may cause low back pain that is increased by activity. MRI is the preferred mode of imaging; abnormalities vary in severity, and their clinical relevance is not always clear. Many asymptomatic elderly subjects have degenerative changes of the lumbar spine. In patients with mild symptoms, a surgical corset is helpful, whereas in more severe cases operative treatment may be necessary.

Even minor changes may cause root or cord dysfunction in patients with a congenitally narrowed spinal canal (spinal stenosis), leading to the syndrome of intermittent claudication of the spinal cord or cauda equina. Similar symptoms may result from ossification of the ligamentum flavum, epidural lipomatosis, Pott disease, osteomyelitis, rheumatoid arthritis, or post-traumatic stenosis of the spinal canal. They may also occur with dural arteriovenous fistulas. The syndrome is characterized by pain, sometimes accompanied by weakness or radicular sensory disturbances in the legs, that occurs with activity or with certain postures and is relieved by rest.

Patients with mild to moderate symptoms related to spinal stenosis should be treated conservatively with pain medication, nonsteroidal anti-inflammatory agents, and physical therapy to reduce the lumbar lordosis. Muscle relaxants and antidepressant drugs are often prescribed also. Studies to examine the relative merits and cost-effectiveness of these approaches are lacking. Bed rest is to be avoided. If symptoms are severe, decompressive surgery is indicated when conservative treatment for 3 to 6 months has been unhelpful or there is a significant motor deficit or symptoms of cauda equina syndrome (compression of lumbosacral nerve roots in the spinal canal, below the end of the spinal cord [conus medullaris]). Such surgery leads to pain relief, but the rapidity and extent of recovery is variable. Complications include epidural hematomas, inadequate decompression with residual stenosis, instability, and reossification with renewed nerve compression. Up to 25% of patients undergoing surgical decompression will require reoperation in the following 10 years.

Ankylosing Spondylitis

Backache and stiffness, followed by progressive limitation of movement, characterize this disorder, which occurs predominantly in young men. Characteristic early radiologic findings consist of sclerosis and narrowing of the sacroiliac joints. Treatment is with nonsteroidal anti-inflammatory agents, especially indomethacin or aspirin. Physical therapy, including postural exercises, is also important.

Neoplastic Disease

Extradural malignant tumors are an important cause of back pain and should be suspected if there is persistent pain that worsens despite bed rest. They may eventually lead to spinal cord compression or a cauda equina syndrome, depending on the level of involvement. The diagnosis is confirmed by spinal MRI or CT and CT myelography. CSF cytology may be diagnostic with leptomeningeal involvement, but is sometimes negative initially. Benign osteogenic tumors also produce back pain; treatment is by excision.

Infections

Tuberculous and pyogenic infections of the vertebrae or intervertebral disks can cause progressive low back pain and local tenderness. Although there are sometimes no systemic signs of infection, the peripheral white cell count and erythrocyte sedimentation rate are elevated. Spinal imaging may show disk space narrowing and a soft tissue mass, but is sometimes normal initially.

Bone infection (osteomyelitis) requires long-term antimicrobial therapy; surgical debridement and drainage may also be needed. Spinal epidural abscess (see Chapter 9, Motor Disorders) similarly presents with localized pain and tenderness, sometimes associated with osteomyelitis. Cord compression may occur with the onset of a rapidly progressive flaccid paraplegia. MRI, CT scanning, or CT myelography, followed by operative treatment, are undertaken urgently if there is cord compression. In early cases without neurologic involvement, treatment with antibiotics alone may be sufficient.

Osteoporosis

Low back pain is a common complaint in patients with osteoporosis, and vertebral fractures may occur spontaneously or after trivial trauma. Pain may be helped by a brace to support the back. It is important that patients keep active, stop tobacco smoking, and take a diet containing adequate amounts of calories, calcium, vitamin D, and protein. Estrogen therapy may be helpful in postmenopausal women, but is less widely used than previously. The bisphosphonates alendronate and risedronate may be helpful and have reduced the incidence of fractures in randomized trials. Other antiresorptives include raloxifene, a selective estrogen receptor modulator, and the bisphosphonate zoledronic acid. In special circumstances, parathyroid hormone, calcitonin, or strontium is helpful.

Paget Disease of the Spine

Paget disease, which is characterized by excessive bone destruction and repair, is of unknown cause but may have a familial basis. Pain is commonly the first symptom. Vertebral involvement may also lead to evidence of cord or root compression. The serum calcium and phosphorus levels are normal, but the alkaline phosphatase is markedly increased. Urinary hydroxyproline and calcium are increased when the disease is active. X-rays show expansion and increased density of the involved bones, and fissure fractures may be evident in the long bones.

In active, progressive disease, treatment with calcitonin or bisphosphonates reduces osteoclastic activity. Decompressive surgery is sometimes necessary for neurologic complications.

Congenital Anomalies

Minor spinal anomalies can cause pain because of altered mechanics or alignment or because reduction in the size of the spinal canal renders the cord or roots more liable to compression by degenerative or other changes. Children or young adults with congenital defects in spinal fusion (spinal dysraphism) occasionally present with pain, a neurologic deficit in one or both legs, or sphincter disturbances. Treatment is of the underlying disorder.

Congenital spinal stenosis may lead to the syndrome of neurogenic claudication, but symptoms usually develop only in later life when minor degenerative changes have come to be superimposed on the congenital anomaly, as discussed earlier.

Arachnoiditis

Severe pain in the back and legs can result from inflammation and fibrosis of the arachnoid layer of the spinal meninges (arachnoiditis), which may be idiopathic or causally related to previous surgery, infection, myelography, or long-standing disk disease. There is no adequate treatment, but operation may be possible if the arachnoiditis is localized. Spinal cord stimulation may provide symptomatic relief. This condition is considered in more detail in Chapter 9, Motor Disorders.

Referred Pain

Disease of the hip joints may cause pain in the back and thighs that is enhanced by activity; examination reveals limitation of movement at the joint with a positive Patrick sign (hip pain on external rotation of the hip), and radiographs show degenerative changes. Aortic aneurysms, cardiac ischemia, visceral and genitourinary disease (especially pelvic disorders in women), and retroperitoneal masses can also cause back pain. There are often other symptoms and signs that suggest the underlying disorder. Moreover, there is no localized spinal tenderness or restriction of motility. Treatment is of the underlying cause.

Nonspecific Chronic Back Pain

In many patients with chronic back pain, there are no objective clinical signs or obvious causes of pain despite detailed investigations. In some cases, the pain may have a postural basis; in others, it may be a somatic manifestation of a psychiatric disorder. Pain that initially had an organic basis is often enhanced or perpetuated by nonorganic factors and leads to disability out of proportion to the symptoms.

Nonsteroidal anti-inflammatory drugs may provide short-term symptomatic relief. There is some controversy about the chronic use of narcotic analgesics in patients with persisting low back pain, but such agents are generally best avoided. Treatment with tricyclic antidepressant drugs is sometimes helpful, and psychiatric evaluation may be worthwhile. Bedrest is not recommended and provides no greater benefit than symptom-limited activity. Unnecessary surgical procedures must be avoided.

NECK PAIN

Neck pain is a common problem in the general population; surveys indicate that approximately one-third of the adult population has experienced it over the previous year, and in some instances, it lasts for more than 6 months.

Congenital abnormalities of the cervical spine, such as hemivertebrae or fused vertebrae, basilar impression, and instability of the atlantoaxial joint, can cause neck pain. The traumatic, infective, and neoplastic disorders mentioned previously as causes of low back pain can also affect the cervical spine, producing pain in the neck. Rheumatoid arthritis may involve the spine, especially in the cervical region, leading to pain, stiffness, and reduced mobility; spinal cord compression may result from displacement of vertebrae or atlantoaxial subluxation and can be life-threatening if not treated by fixation.

Cervical injuries are an important cause of neck pain. Whiplash flexion-extension injuries commonly result from automobile accidents. Other occult cervical injuries such as disk clefts and fissures may be responsible for symptoms in some instances, but are difficult to recognize. Management of persistent symptoms after whiplash injuries is controversial. Conservative therapeutic measures are appropriate. Other approaches sometimes advocated include block of cervical facet joints with bupivacaine and injection into the joints of depot corticosteroids, but the response is variable and often short-lived. Subluxed cervical facet joints are another well-recognized complication of automobile accidents. Even minor trauma may lead to cervical fractures in an apparently ankylosed region in patients with diffuse idiopathic skeletal hyperostosis, but major neurologic deficits are common in such circumstances.

Acute Cervical Disk Protrusion

Patients commonly present with neck and radicular arm pain that is exacerbated by head movement, accompanied by muscle spasm. The pathophysiology of the pain is unclear; pressure on nerve roots is unlikely to be the sole cause because pain may resolve with time and conservative measures despite persisting compression. With lateral herniation of the disk, there may also be segmental motor, sensory, or reflex changes, usually at the C6 or C7 level, on the affected side (see Figure 9-9 and Table 9-12). With more centrally directed herniations, spastic paraparesis and a sensory disturbance in the legs, sometimes accompanied by impaired sphincter function, can occur as a result of spinal cord involvement. The diagnosis is confirmed by CT scan, MRI, or CT myelography. However, these imaging studies often show abnormalities in asymptomatic subjects in middle or later life, so that any disk protrusion may be incidental and unrelated to patients’ symptoms. Electromyography may help to establish that anatomic abnormalities are of functional relevance.

Treatment recommendations have limited objective evidence and are based on anecdotal experience. In mild cases, postural modification, the temporary nocturnal use of a soft collar, and immobilization of the neck in a collar for brief periods during the day often helps. Activities that provoke pain should be avoided. Acetaminophen or nonsteroidal anti-inflammatory drugs may relieve pain, and—when pain persists and disturbs sleep—a tricyclic antidepressant and muscle relaxants are often also worthwhile. A short course of oral corticosteroids can be helpful when pain is severe. Physical therapy is of uncertain benefit, as is intermittent neck traction. If these measures fail and there is persistent radicular pain for more than 2 months or a significant progressive neurologic deficit, surgical treatment may be necessary.

Cervical Spondylosis

This is an important cause of pain in the neck and arms, sometimes accompanied by a segmental motor or sensory deficit in the arms or by spastic paraparesis. It is discussed in Chapter 9, Motor Disorders.

HERPES ZOSTER (SHINGLES)

This viral disorder becomes increasingly common with advancing age, causing an inflammatory reaction in one or more of the dorsal root or cranial nerve ganglia, in the affected root or nerve itself, and in the CSF. There seems to be spontaneous reactivation of varicella virus that remained latent in sensory ganglia after previous infection. Herpes zoster is common in patients with lymphoma, especially after regional radiotherapy.

The initial complaint is of a burning or shooting pain in the involved dermatome, followed within 2 to 5 days by the development of a vesicular erythematous rash. The pain may diminish in intensity as the rash develops. The rash becomes crusted and scaly after a few days and then fades, leaving small anesthetic scars. Secondary infection is common. The pain and dysesthesias may last for several weeks or, in some instances, persist for many months (postherpetic neuralgia) before subsiding.

Postherpetic neuralgia is most likely to occur in the elderly, when the rash is severe, with a longer duration of the rash before medical consultation, and with involvement of the first division of the trigeminal (V) nerve. The increased incidence and severity of postherpetic neuralgia with age may reflect an age-related reduction in virus-specific cell-mediated immunity. It is not clear whether immune compromise secondary to HIV infection or connective tissue disease predisposes to postherpetic neuralgia.

Pain is exacerbated by touching the involved area. Superficial sensation is often impaired in the affected dermatome, and focal weakness and atrophy can also occur. Signs are usually limited to one dermatome, but more are occasionally involved. Mild pleocytosis and an increased protein concentration sometimes occur in the CSF. The most commonly involved sites are the thoracic dermatomes, but involvement of the first division of the trigeminal (V) nerve, also common, is especially distressing and may lead to corneal scarring and anesthesia, as well as to a variety of other ocular complications.

Facial (VII) nerve palsy occurring in association with a herpetic eruption that involves the ear, palate, pharynx, or neck is called Ramsay Hunt syndrome. Other rare complications of herpes zoster include other motor neuropathies, meningitis, encephalitis, myelopathy, and cerebral angiopathy.

Unless otherwise contraindicated, the administration of live-attenuated zoster vaccine to patients over the age of 50 years is an important approach to preventing the occurrence of herpes zoster and reducing the risk of post-herpetic neuralgia. There is no specific treatment once herpes zoster has developed. Analgesics provide symptomatic relief—acetaminophen or nonsteroidal anti-inflammatory drugs for mild pain, and opioid analgesics when pain is more severe. Antiviral therapy (with oral acyclovir, valacyclovir, or famciclovir for 1 week) speeds recovery of the cutaneous lesions and helps the acute pain; they are generally used when patients are seen within 72 hours of symptom onset or new skin lesions are continuing to develop. It is unsettled whether their use reduces the incidence of postherpetic neuralgia. Corticosteroids are of uncertain value and do not affect the incidence of postherpetic neuralgia. Although postherpetic neuralgia can be very distressing, duloxetine (60 mg once daily) or pregabalin (150 mg increasing after 1 week to 300 mg daily in divided doses; maximum, 600 mg daily) may be helpful for relief of pain. It sometimes responds also to treatment with carbamazepine, up to 1,200 mg/d; phenytoin 300 mg/d; gabapentin, up to 3,600 mg/d; or amitriptyline 10 to 100 mg at bedtime.

Attempts at relieving postherpetic neuralgia by peripheral nerve section are generally unrewarding, but treatment with topically applied local anesthetics is sometimes helpful, as is topically applied capsaicin cream, perhaps because of depletion of pain-mediating peptides from peripheral sensory neurons. Intrathecal methylprednisolone may be helpful for intractable pain.