Chapter 32. Pain in the Extremities

Extremity pain can have many causes. This chapter provides a comprehensive differential diagnosis of such pain. The reader should consult the individual chapters dealing with particular pain syndromes to find specific treatment options.

Acute Arterial Insufficiency

(See Chap. 50)

The pain of acute arterial insufficiency is characterized by its sudden onset. Emboli lodge at artery branch points, which are also more likely to be affected by atherosclerosis. Emboli may occlude more than one vessel at a branch point and thereby limit collateral flow. Muscle necrosis and irreversible changes may occur if blood flow is not reestablished within 4 to 6 hours.1

The five cardinal features of arterial insufficiency (the five “Ps”) consist of pain, pallor, paresthesias, paralysis, and pulselessness. The pain is well localized to an extremity and severe. It may be attenuated by good collateral circulation; that is, occlusion of a brachial artery may not produce as dramatic a clinical picture as occlusion of a common femoral artery or popliteal artery. Nerve endings and muscle tissue are extremely sensitive to hypoxia, and acute obstruction soon leads to anesthesia and paralysis in an affected extremity.2

Pulses usually, but not always, are absent distal to the site of obstruction. Therefore, pain and associated signs and symptoms of ischemia in the presence of detectable pulses warrant further investigation.2 Conversely, pulses may be unusually strong proximal to the site of the occlusion.

Acute ischemia in an extremity also is accompanied by a change in the skin temperature distal to the site of occlusion. The extremity appears pale, and the veins may seem to be empty. Palpation along the course of the artery may reveal tenderness over the site of occlusion. The muscles begin to feel hard and inelastic as the ischemia progresses.2 Muscular fatigue and weakness are apparent.

Chronic Arterial Insufficiency

Chronic arterial insufficiency can produce a wide variety of painful symptoms. Affected patients can have numbness, coldness, tingling, or total paresis. The degree of insufficiency determines the type of pain in the lower extremity (intermittent claudication or rest pain). Atherosclerosis is the most common cause of chronic lower limb ischemia. Hypertension, diabetes mellitus, hypercholesterolemia, and cigarette smoking increase the incidence and severity of atheroma formation.3 Thromboangiitis obliterans (Buerger’s disease), popliteal artery entrapment, and cystic adventitial disease can also cause lower limb ischemia.

Claudication refers to cramping pain that occurs when blood flow cannot be increased to a muscle mass in response to the increased metabolic demands of exercise. Blood flow is adequate in the extremity at rest. Claudication has several diagnostic features: (1) it is always relieved by rest after exercise, (2) it is produced by a consistent amount of exercise, and (3) it is always experienced in a functional muscle group.4

Ischemic rest pain occurs when blood flow in the extremity falls below resting tissue requirements. It is a manifestation of severe chronic arterial insufficiency. Pain can occur in the toes and metatarsal joints and is not confined to functional muscle groups. These patients may experience relief by hanging the affected limb over the side of the bed. The pain is constant and aggravated by limb elevation and exposure to cold.5 Differentiating between intermittent claudication and ischemic rest pain becomes important because nondiabetic patients with claudication rarely require extremity amputation, although many patients with ischemic rest pain do.6,7

Measurement of systolic blood pressure at the ankle facilitates the diagnosis of arterial insufficiency of the lower limbs. The cuff encircles the ankle, and a Doppler probe is placed over the dorsalis pedis or posterior tibial arteries. The ratio of the ankle to arm blood pressure is known as the ankle pressure index. Normally, systolic augmentation occurs, and the ankle pressure should exceed the arm pressure by 10 to 20 mm Hg,8 which yields an ankle pressure index of 1.10 to 1.20. An index less than 1.0 suggests some degree of arterial insufficiency. Angiographic data correlate with these indices.9–11 Recently, magnetic resonance angiography has been used to study vascular insufficiency.12

Popliteal Artery Entrapment

Popliteal artery entrapment can result in unilateral claudication in even young patients.13,14 The popliteal artery, instead of coursing downward between the two heads of the gastrocnemius muscle, passes medially to the muscle. Its compression by muscle or fiber spans results in calf and foot claudication. The symptoms of numbness, paresthesias, and cramping associated with exercise may mimic chronic arterial insufficiency. The unilateral nature of the symptoms and the young age of the patient should suggest the diagnosis. Physical examination may reveal either present or absent popliteal and dorsalis pedis pulses, or the latter may disappear with exercise. Palpation may show increased collateral blood flow (palpable geniculate arteries) near the knee. This distinguishes entrapment from chronic arterial insufficiency. Active plantar flexion or passive dorsiflexion may obliterate the pedal pulses and aid the diagnosis. A bruit also may be heard over the popliteal artery.

Arteriography is essential for diagnosis and should be done bilaterally (25% of cases will be bilateral, even in asymptomatic patients).15 Angiographic confirmation relies on medial deviation of the popliteal artery and segmental occlusion of the popliteal artery.

Adventitial Cystic Disease of the Popliteal Artery

Adventitial cystic disease of the popliteal artery is a rare cause of claudication in young patients.16 The symptoms are produced by a cyst within the adventitial layer of the popliteal artery, leading to gradual occlusion. These mostly male patients describe a rapid onset of severe claudication. A murmur in the popliteal fossa and the absence of pedal pulses help make the diagnosis. If pedal pulses are present, they can be eliminated by acute knee flexion. The cysts contain mucoproteins and mucopolysaccharides; their exact cause is unclear. Radiographic evidence for the diagnosis includes an “hourglass” appearance using angiography.16

Thromboangiitis Obliterans (Buerger’s Disease)

Buerger’s disease involves the entire neurovascular bundle of the small vessels of the hands and feet. It appears as an intermittent claudication of the arch of the foot and can progress to ischemic digital pain at rest and frank gangrene. Buerger’s disease usually affects more than one limb of men younger than 40 who are heavy smokers.17,18 In contrast to atherosclerosis, Buerger’s disease can cause ischemic lesions of the fingers, and recurrent episodes of superficial thrombophlebitis. Angiography shows many small artery occlusions with tapering proximal to the occlusion and the absence of plaques.19 Its pathologic features include a panangiitis that preserves vessel architecture and infiltration of the vessel walls by giant cells and lymphocytes.

Raynaud’s Disease

Raynaud’s disease is defined as episodic digital vasospasm precipitated by cold or stress that affects mostly the fingers and hands. It also may affect the feet and toes. The classic attack has three components: (1) initial blanching with relative numbness secondary to arterial vasoconstriction, (2) cyanosis resulting from the desaturation that occurs because of insufficient blood entering the capillaries and small veins, and (3) reactive hyperemia.20 Usually, neither pallor nor cyanosis predominates. Between 70% and 90% of patients with Raynaud disease are women.21 The pain, which initially may be mild, becomes more severe and constant as the condition progresses.

The underlying pathophysiology in an attack is digital artery closure.22 This closure may occur secondary to a vasoconstrictive mechanism (generally in younger women with connective tissue disease) or an obstructive mechanism (usually in older patients with atherosclerosis). The former may be caused by abnormal arterial adrenoreceptors or adrenoreceptor-immune complex interactions. Baseline proximal luminal obstructions are found in the latter group.

Raynaud’s phenomenon is associated with various other diseases23 (Table 32-1) and with occupational hazards, such as operating a chain saw or pneumatic drill. The vibration frequency of these tools (110–140 Hz) presumably causes severe sheer stresses in the arteries of the hands and fingers.24 Pathologic studies show subintimal fibrosis after long-term exposure to these tools.

The diagnosis is confirmed by the ice-water immersion test. Using a thermistor probe, a baseline digital tip pulp temperature is determined (which must be greater than 32°C, even if external warming must be used). The patient’s fingers are submerged in ice water for 30 seconds. Pulp temperature recordings are then made every 5 minutes for up to 45 minutes.25 A normal patient’s digital temperature returns to baseline within 10 minutes. In contrast, patients with Raynaud’s syndrome have a prolonged return to baseline temperature.

Other laboratory diagnostic tests include an erythrocyte sedimentation rate, complete blood count, antinuclear antibody, and rheumatoid factor. Hand radiographs are useful for detecting subcutaneous calcinosis typical of scleroderma or CRST syndrome (Calcinosis cutis, Raynaud phenomena, Sclerodactyly, and Telangiectasia).

Thrombophlebitis

Thrombophlebitis of the superficial venous system can occur in either the upper or the lower extremities. The factors responsible for both thrombosis of the superficial venous system and deep vein thrombosis are defined in the Virchow triad: stasis, abnormalities of the vessel wall, and hypercoagulability. Thrombophlebitis may occur after an injury to a limb or secondary to intravenous cannulation. Other causes include varicose veins and carcinoma. Patients may experience pain and redness along the course of a superficial vein, which may feel firm to the touch. Doppler studies show diminished or absent flow through the vein. Treatment is directed toward the underlying disease process and should involve bed rest, elevation of the extremity, and application of moist compresses.

Deep Venous Thrombosis (DVT)

DVT develops commonly near valves in the lower extremity. Initial platelet aggregation elicits fibrin thrombus formation. Both platelets and fibrin contribute to the growing thrombus. In the calf, venous thrombosis usually produces tenderness but minimal swelling. The skin temperature may be increased in the extremity secondary to diversion of blood flow from the deep veins to the superficial veins. Increased tenderness with dorsiflexion (Homan’s sign) is notoriously unreliable in the diagnosis of DVT.26 Femoral vein thrombosis usually results in both calf and popliteal fossa tenderness, and leg swelling. Ileofemoral vein thrombosis is accompanied by sudden severe pain, edema, and discoloration. Patients also may feel tingling, numbness, and weakness. The pain begins in the area of the femoral triangle or in the calf, but rapidly involves the entire leg. This acute venous outflow obstruction can progress to venous gangrene with interference of arterial inflow and limb cyanosis (phlegmasia cerulea dolens).

Conditions that predispose to DVT include obesity, the postpartum state, pelvic surgery, lower extremity fractures, prolonged bed rest, estrogen use, and carcinoma. Detection depends on the following noninvasive laboratory tests.27–30

• 1. Doppler ultrasonography recognizes the distorted flow patterns
• 2. Impedance plethysmography quantifies venous obstruction by measuring the rate at which a vein empties when a pneumatic cuff at the thigh is released
• 3. Radioactive fibrinogen uptake tests involve the use of labeled fibrinogen that is taken up by newly formed thrombi. This is the most sensitive test to detect below-the-knee thrombi.

Ascending contrast phlebography also can be used to diagnose DVT, but it is invasive, often painful, and difficult to interpret.

Cellulitis in an extremity, although it does not have a vascular cause, must be differentiated from both superficial and deep venous thrombi. These infections occur after trauma to the skin and subcutaneous tissue. Inflammation is accompanied by edema, hyperemia, and leukocytic infiltration. The hallmarks of infection (swelling, tenderness, heat, and redness) are apparent. Lymphangitis may be evident, with reddish painful streaks and regional node tenderness and enlargement. These patients generally have more systemic symptoms than those with superficial thrombophlebitis. Gram staining of needle aspirates is helpful in diagnosing this disorder and is crucial for further therapy.

Compartment Syndrome

Compartment syndrome is defined as a condition in which increased tissue pressure in a confined space compromises the circulation, resulting in muscle necrosis and neurologic injury. Of the compartment syndromes described (acute, subacute, and chronic Volkmann’s contracture), only the acute compartment syndromes are painful. Acute compartment syndromes are seen after tibial fractures, supracondylar fractures, brachial arteriograms, gunshot wounds, circumferential burns, snake bites, reflow after limb reattachment, and crush injuries.

The pathophysiology involves raised tissue pressure leading to altered microcirculation in the compartment.31–33 Early investigators believed the increased tissue pressure led to arterial spasm and subsequent compromised tissue perfusion. However, newer hypotheses describe increasing tissue pressure that compromises transmural pressure across the walls of the arterioles. At a critical transmural pressure, the vessels close. Small arterioles close at a lower transmural pressure than larger arteries. Hence, tissue ischemia may occur in the presence of palpable pulses. Another hypothesis involves a rise in venous pressure in a compartment in response to the rise in tissue pressure. The venous pressure increase allows blood flow to continue. However, this venous hypertension in the compartment soon disturbs the normal capillary arteriovenous gradient. This, in turn, compromises capillary blood flow and tissue perfusion. Disruption of the Starling gradients leads to decreased extracellular fluid absorption, increased extracellular fluid transudation, and a further increase in compartment tissue pressure.

Acute compartment syndromes usually provoke intense pain, which is well localized to the involved muscle groups. Passive stretching of the involved muscle groups greatly aggravates the pain. For example, passive finger extension in a patient who has flexor forearm compartment syndrome leads to excruciating pain. The second typical finding is induration over the involved muscle groups. Less importantly, patients may have weakness of the involved muscles and paresthesias in the distribution of the involved nerves. Palpable pulses are an unreliable clinical sign (see earlier discussion).

Measuring the tissue pressure in the compartment can aid in the diagnosis. Normal tissue pressure is between 0 and 10 mm Hg. Permanent nerve dysfunction can occur with tissue pressures as low as 30 mm Hg for 6 to 8 hours. The tissue pressure may be measured by the injection method of Whitesides and associates,34 the wick catheter method of Owen and colleagues,35 or the continuous infusion method of Matsen and colleagues.36,37

Arterial Thrombosis in the Drug Abuser

Extremity pain after drug injection can result from a number of complications38 (Table 32-2). Intraarterial injection of many agents can result in extremity pain and gangrene. The theoretical mechanisms cited include (1) vasospasm, (2) norepinephrine release, (3) intimal damage, (4) necrotizing arteritis, and (5) particulate embolism. However, the final common pathway is arterial thrombosis. Diluents used in street drugs (lactose, quinine, starch, and talcum powder) compound the vascular insult.39

The diagnosis requires eliciting the appropriate history. For example, with an intraarterial injection, patients may describe a so-called hand trip that begins with a burning from the point of insertion of the needle to the tip of the fingers.40,41 This burning is followed immediately by blanching, severe pain, and cyanosis. Addicts also use belts or other vigorous tourniquets for injections; these inadvertently may be left on during the postinjection stupor and further compromise the vascular supply. Pressure necrosis from an abnormal posture after sedation may lead to muscle breakdown and ischemia. Finally, the needle itself, which causes perivascular hematomas, production of an intimal flap, or a false aneurysm, can also lead to thrombosis.42

The so-called puffy hand syndrome results from widespread destruction of lymphatic vessels and veins in an extremity used for injections.43,44 Extremity drainage depends on the deep venous system after the superficial lymphatic vessels and veins are destroyed. When perivascular injection or hematomas compromise the deep venous system, swelling and venous hypertension can lead to gangrene. The diagnosis of extremity pain in drug abusers depends on the history and signs of acute ischemia. Identification of the drug used may be helpful. Laboratory tests that may be helpful include Doppler ultrasonography, digital temperature readings, plethysmography, and angiography.

Mycotic Aneurysm

Mycotic aneurysms in the extremities can arise through several recognized mechanisms.45,46,47,48

• 1. Septic embolization in the arterial lumen, such as occurs with bacterial endocarditis, causes a gradual weakening of the arterial wall, subsequent aneurysm formation, and enlargement of the artery.49
• 2. Local spread from an abscess or area of cellulitis destroys the arterial wall with resulting aneurysm formation.50
• 3. Trauma to an artery and subsequent contamination can cause the formation of a mycotic aneurysm. This commonly occurs after penetrating trauma, radiologic procedures, or inadvertent arterial injection by drug abusers.51

Most mycotic aneurysms are arterial, rather than venous, because the high pressure promotes dilation. Aneurysms that result from repeated punctures of arteriovenous dialysis fistulas constitute an exception to this rule. The venous punctures coupled with the high venous pressure seen in these fistulas can cause aneurysm formation.

Patients with a history of rheumatic fever, intravenous drug abuse, immunosuppression, prolonged illness, penetrating trauma, and invasive radiologic procedures may develop mycotic aneurysms. A warm, tender, palpable, pulsatile mass should alert the physician to the diagnosis. A systolic bruit heard over the mass distinguishes aneurysms from arteriovenous fistulas, which have both systolic and diastolic components to their bruits. Signs and symptoms of generalized sepsis also may be present. Occasionally, septic arthritis or petechial skin lesions can develop from emboli originating in the aneurysms. An arteriogram is a useful aid to confirm the diagnosis. Needle aspiration also may be warranted.

Traumatic Aneurysms

Traumatic aneurysms are actually false aneurysms produced by arterial penetration. The perivascular hematomas that result may be classified as follows: (1) acute traumatic hematomas, in which through-and-through disruption of the arterial wall leads to a gradual enlarging hematoma contained by surrounding tissue; or (2) chronic traumatic aneurysms, in which the perivascular hematoma is absorbed, and a tissue sac and surrounding fibrosis provide boundaries.52,53

Traumatic aneurysms result from penetrating trauma, invasive radiologic procedures, placement of intra-aortic balloon pumps, vascular procedures, orthopedic reconstructive procedures, and internal fixation of bones.53

The interval from initial insult to aneurysm detection is longer than 1 month in more than 50% of cases. Affected patients have a tender pulsatile mass near the course of the artery. As in mycotic aneurysms, a systolic bruit is present. Occasionally, compression by the expanding aneurysm leads to a secondary peripheral neuropathy or venous occlusion. Suspected traumatic aneurysms in the extremity can be evaluated using percutaneous angiography.

Brachial Plexus Lesions

Several anatomic relationships become important when referring to brachial plexus disorders. The plexus is superficial in the supraclavicular fossa and protected by skin, subcutaneous tissues, and fascia. Also, the brachial plexus is in close proximity to the subclavian artery in the fossa, and both structures lie near the apex of the lung. More distally, the plexus lies close to the first and second parts of the axillary artery, and a thick pad of fat and connective tissue surrounds both. Therefore, many causes can lead to brachial plexus neuropathies (Table 32-3). For example, traction on the upper cervical roots when the shoulder is depressed forcibly and the head turned to the opposite side can lead to neuropathy. Apical lesions of the lung also may depress both the plexus and the vessels that run close to it.

Generally, all lesions of the brachial plexus cause partial or total paralysis of the shoulder. Any lesion involving the T1 root or sympathetic trunk will be accompanied by Horner’s syndrome. Sensory deficits will be combined with disturbances of sweating. Most plexus lesions also have long-term complications54 (Table 32-4).

Plexus lesions can be classified based on anatomic location regardless of their etiology. Superior plexus lesions (Duchenne-Erb) result from damage to the fifth and sixth cervical roots. The deltoid, biceps, brachioradialis, and brachialis muscles are affected. There is an inability to abduct and externally rotate the shoulder and an inability to flex the elbow or pronate the forearm. The arm hangs loose, internally rotated, and the palm is visible from behind (so-called porter’s-tip position). Sensory loss may be apparent over the deltoid and radial side of the forearm. An isolated middle brachial plexus lesion (C7) is unusual. It is manifested by sensory deficits on the back of the forearm or the radial aspect of the dorsum of the hand. Inferior plexus lesions (C8 to T1) include paralysis of small hand muscles and finger flexors with preservation of finger and wrist extensors. These lesions, therefore, result in hyperextension at the metacarpophalangeal joints and flexion at the interphalangeal joints. Horner’s syndrome may be seen. These inferior plexus lesions may result from sudden upward pulling on the shoulder.

Lower plexus lesions are divided anatomically into three types. Firstly, posterior cord lesions cause sensory deficits along the distribution of the axillary and radial nerves, weakness of abduction of the arm, and inability to extend the wrist or fingers. Secondly, medial cord lesions cause weakness of the muscles innervated by the ulnar nerve and medial head of the median nerve, thereby leading to severe hand disability. Sensory deficits produce dysfunction of the medial cutaneous nerve of the upper arm and forearm. Isolated medial cord lesions are rare except after radiotherapy. Thirdly, lateral cord lesions involve the lateral part of the median nerve and musculocutaneous nerve, causing weakness of flexion and pronation of the forearm, wrist, and fingers. Sensory loss is limited to the radial aspect of the forearm (Table 32-5).

Because of its superficial position in the supraclavicular fossa, the brachial plexus can be susceptible to traction and exogenous compression. Upper brachial plexus injuries have been reported in laborers who carry heavy loads on their shoulders and U.S. football players. Paralysis from the heavy backpacks carried by soldiers (so-called rucksack paralysis) has been recognized since World War 11.55–57 The whole plexus (usually on the nondominant side) is affected initially. However, soon only the upper plexus lesions remain, and it is common to see involvement of the nerve to the serratus anterior with winging of the scapula.

Hematomas after anticoagulation or percutaneous axillary artery cannulation may lead to plexus injuries.58,59 Of special concern to physicians are brachial plexus injuries occurring during general anesthesia. There are three causes. Firstly, shoulder braces may be placed too far medially near the posterior triangle, injuring the plexus before it descends behind the clavicle. Secondly, if the arm is abducted to 90 degrees or more, the head of the humerus descends into the axilla and presses into the plexus as it passes from the supraclavicular area to the axilla. Thirdly, excessive depression of the shoulder girdle with the patient in the Trendelenburg position can stretch the upper roots of the brachial plexus.60,61

Vascular insufficiency is a rare cause of brachial plexus injury, but may occur after acute axillary artery occlusions secondary to emboli. Intravenous injection of contaminated heroin can lead to a painless paresis of muscles supplied by the posterior and medial cord.62 Radiotherapy to the clavicular region or axilla can injure the brachial plexus. Distinguishing radiation injury from direct tumor infiltration can be difficult. Post-radiation intervals shorter than 3 months or longer than 5 years favor metastases. Intense pain, lower plexus lesions, and Horner’s syndrome also favor metastases. Skin changes, lymphedema of the extremity, induration over the supraclavicular fossa, and upper plexus lesions favor radiotherapy as the source of the neuropathy. Paresthesias frequently can be elicited by tapping the supraclavicular fossa after radiation-induced lesions63,64 (Table 32-6).

Inherited Brachial Plexus Neuropathy

A form of recurrent brachial plexus neuropathy can display familial predilection.65–69 It is similar to neuralgic amyotrophy except for several distinguishing features. In contrast to neuralgic amyotrophy, the familial form of brachial plexus neuropathy is characterized by recurrent episodes over several years separated by intervals of full recovery. Both diseases occur most commonly during the third and fourth decades of life, but in the familial form, affected patients may have their first attacks during the first decade of life. The familial form does not seem to be precipitated as commonly by infections as is neuralgic amyotrophy. However, several authors have reported a dramatic onset of attacks in women several hours after childbirth.67,70 There may be minor dysmorphic features (e.g., hypotelorism, epicanthic folds, and cleft palate) associated with the familial form of the disease.67 Finally, there is nerve involvement outside the brachial plexus with such diverse manifestations as Horner’s syndrome, Bell’s palsy, and lumbosacral weakness in the familial form of the disease.

Pain is the initial manifestation of a familial attack. It is described as sharp and burning, particularly in the shoulder. Movement exacerbates the pain; therefore, affected patients keep their shoulders immobile. Weakness soon follows, and although any muscles controlled by the plexus may be involved, those innervated by the upper trunk of the plexus generally are affected. Sensory dysfunction is not a prominent feature. Affected patients usually have an excellent recovery of strength, but they may accumulate deficits after multiple attacks.68

Guillain-Barré Syndrome

Guillain-Barré syndrome occurs worldwide, with an incidence of 1 to 1.5 cases per 100,000 persons annually. There is no age or gender preference; 60% to 70% of cases are preceded by an upper respiratory or gastrointestinal illness 1 to 3 weeks before the onset of the syndrome.71 An ascending weakness involving both proximal and distal muscles distinguishes Guillain-Barré syndrome. The weakness generally begins in the lower extremities and then can progress to upper extremity, intercostal, and neck muscles. Affected patients also have decreased sensation and possibly transient autonomic dysfunction.

Pain occurs in one third of the cases of Guillain-Barré syndrome as a result of involvement of the posterior roots. There may be tenderness after deep pressure on the muscles. Paresthesias are common. Affected patients also describe a burning, radiating pain.

The clinical diagnosis is aided by examination of cerebrospinal fluid. Normal pressures, increased protein, and acellular fluid are found. Nerve conduction studies show slowing after the paralysis begins.72 A syndrome identical to Guillain-Barré can occur after infectious mononucleosis.

Fabry’s Disease (Angiokeratoma Corporis Diffusum)

Fabry’s disease is an X-linked recessive disorder characterized by accumulation of a lipid, ceramide trihexoside, in many organs. Patients are young boys or men with intense burning pain in their feet and lower legs.73

The enzymatic defect in Fabry’s disease is a deficiency of the enzyme ceramide trihexosidase; the terminal molecule of galactose is missing from this enzyme.74 Stored glycolipid accumulates in different organ systems. Renal involvement initially is characterized by albuminuria and inability to concentrate urine, which progresses to uremia. Glycolipid accumulates in the endothelial cells of the glomeruli and distal tubular cells. The first manifestations of this disease, angiokeratomas, are found over the perineum, upper thighs, and buttocks. Less commonly, they may be seen on the lip and oral mucosa.75

The vascular elements that supply the ganglions of the peripheral nervous system accumulate the lipid. The ganglion cells themselves and the perineural cells may contain the storage material, possibly causing the anhidrosis and pain that are features of this disease.76

Other systems that accumulate glycolipid include the eye, liver, and reticuloendothelial system. The diagnosis can be confirmed by enzyme assays done on biopsy specimens of small intestinal mucosa.74 Tissue α-galactosidase activity is decreased in patients with Fabry’s disease.

Compression Neuropathies

Compression neuropathies are caused by pressure damage to peripheral nerves. The pressure may be external (a brace or cast), or the nerves may be compressed by adjacent body tissues (tumors, muscle, or synovial thickening). Entrapment neuropathies occur at sites where the nerves normally would be somewhat confined (Table 32-7).

Three degrees of compression neuropathy can be described: neurapraxia, axonotmesis, and neurotmesis. In neurapraxia, functional impairment without axonal structural loss can recover in days to weeks by removing the inciting compressing stimulus. In axonotmesis, wallerian degeneration follows axonal loss and functional restoration may occur only after axonal regeneration, which takes months or years. In neurotmesis, severance of the entire nerve and supporting connective tissue occurs. Such injuries spontaneously regenerate poorly, if at all.

Individual peripheral nerves are more susceptible to compression when already involved by disease states associated with generalized peripheral neuropathies (e.g., diabetes mellitus, renal failure, or alcoholism).77,78 Affected patients have symptoms of sensory nerve dysfunction. Paresthesias and numbness usually are confined to the cutaneous distribution of the nerve. Pain can occur at rest and is localized, but may be referred to other sites.

Electrophysiologic studies can help localize and assess these neuropathies.79 Nerve conduction studies may reveal (1) slowing of conduction secondary to focal demyelination, (2) reduced amplitudes of both sensory action potentials and compound muscle potentials secondary to axonal damage, and (3) the presence of a generalized polyneuropathy. Electromyographic studies may show (1) denervation potentials in the muscle secondary to anterior horn cell loss, and (2) motor unit potential variation secondary to reinnervation of the muscle by axons. Computed tomography (CT) scans and radiography may reveal bone or joint abnormalities responsible for compression.80

Ulnar Nerve Syndromes

The ulnar nerve derives from the C7, C8, and T1 roots. It courses medially in the upper arm without giving off any branches. At the elbow, it lies behind the medial epicondyle in the ulnar groove. It then descends under a roof formed by the aponeurosis of the flexor carpi ulnaris muscle in the cubital tunnel. Motor branches arise in the cubital tunnel and supply the flexor carpi ulnaris. The nerve then gives off branches to the flexor digitorum profundus of the fourth and fifth digits. The palmar cutaneous branch arises and supplies the hypothenar region. More distally, the dorsal cutaneous branch arises and innervates the medial half of the back of the hand and half of the fourth and fifth digits. The nerve enters the hand superficial to the flexor retinaculum and runs between the hook of the hamate and pisiform bone into Guyon’s canal, where it bifurcates and gives rise to a superficial terminal branch and deep motor branch that supplies the hypothenar muscles, third and fourth lumbricales, adductor pollicis, and all the interossei.

Compression above the Elbow and at the Elbow

The elbow is the most common site of ulnar nerve entrapment, particularly in the condylar groove and cubital tunnel. The nerve lies superficially in the groove and is susceptible to compression by leaning on the elbow or improper arm positioning during general anesthesia. Deformities from injuries to the elbow can cause the ulnar nerve to stretch, with a neuropathy appearing long after the actual time of injury (so-called tardy ulnar palsy).81 The ulnar nerve also may be compressed in the cubital tunnel (so-called idiopathic cubital tunnel syndrome); this may be caused by prolonged flexion tightening of the aponeurosis at the proximal end of the tunnel.82,83

Ulnar nerve injuries during anesthesia may result when the patient’s arm is adducted along the side of the body and the hand supinated. The patient’s elbow may slip out of the restraints, and with the ulnar groove located posteromedially, the edge of the table may compress the nerve. Pronating the forearm will rotate the ulnar groove more posteriorly and laterally and prevent compression by the table or equipment rail.84 Patients with entrapment neuropathies at or above the elbows may have pain at the elbow, which may spread to other parts of the arm. Tingling and numbness along the medial portion of the palm and the fourth and fifth digits also occurs. Muscle wasting is prominent in the hypothenar eminence, and affected patients have weakness of the interossei. Severe ulnar neuropathy at the elbow results in a so-called claw-hand deformity. Proximal ulnar entrapment is characterized by weakness of the flexor carpi ulnaris and flexor digitorum profundus muscles; this distinguishes it from more distal entrapments.

Ulnar Nerve Compression in the Wrist or Hand

Ulnar nerve compression in the wrist or hand may result in intermittent paresthesias along the volar aspect of the fifth digit and half or all the volar aspect of the ring finger.85 The sensory branch of the ulnar nerve to the hand courses through Guyon’s canal encased by fibrous tissue. Repetitive trauma to the area (e.g., striking a stapler) can lead to compression. Other causes include pressure from a wristwatch band or overuse of the flexor carpi ulnaris. Finally, space-occupying lesions (e.g., ganglions or lipomas), thrombosis of the ulnar artery, or a rapid weight gain may cause nerve compression at the edge of Guyon’s canal.

Radial Nerve Syndromes

The radial nerve receives contributions from the C5 to T1 roots. It spirals around the shaft of the humerus in the spiral groove and descends along the lateral aspect of the humerus superficially. It passes distally in front of the lateral epicondyle and divides into the deep motor nerve (posterior interosseous nerve) and superficial radial nerves variably 4 to 5 cm above or below the lateral epicondyle. The deep motor branch (posterior interosseous nerve) passes into the supinator muscle through the arcade of Frohse and finally supplies the extensor muscles of the digits. The superficial radial nerve passes over the supinator and pronator teres muscles along the lateral forearm and supplies sensation to the dorsal aspect of the hand, the thumb, and adjacent fingers.

The radial nerve may be compressed in the axilla secondary to the misuse of crutches. Along with the signs and symptoms described subsequently for more distal radial neuropathies, these patients characteristically have triceps weakness.

Most radial nerve compressions occur between the mid to upper arm and elbow, where the nerve courses laterally around the spiral groove and then passes superficially along the humerus. Improper positioning of the arm during sleep or intoxication (so-called Saturday-night palsy) results in involvement of the extensors of the wrist and fingers and the brachioradialis muscles, with resultant wrist drop and associated variable sensory disturbances.86 Misuse of tourniquets, external pressure from ether screens and Mayo stands, and failure to pad the dependent arm when a patient is in the lateral decubitus position can produce a radial nerve palsy during anesthesia. Fractures of the shaft of the humerus with callus formation may compress the nerve and cause a neuropathy.

The posterior interosseous nerve (deep motor branch) can be compressed in the radial tunnel between the superficial and deep heads of the supinator. Radial tunnel syndrome is characterized by deep aching pain of the extensor supinator muscles in the dorsal forearm. Affected patients are unable to extend their thumbs and fingers at the metacarpophalangeal joints and cannot deviate their hands in the ulnar direction. Superficial radial nerve compressions can be caused by wearing handcuffs or watchbands or by fractures of the radius. Affected patients feel pain and paresthesias on the dorsum of the thumb and index finger.

Median Nerve Syndromes

The median nerve receives contributions from the C5 to T1 roots. It courses medially in the upper arm where it gives off no branches. The nerve crosses the elbow anteriorly and passes between the two heads of the pronator teres. It then passes deep to the tendon (so-called subliminis bridge) and runs distally between the flexor digitorum profundus muscles and flexor digitorum superficialis muscles. Motor nerves branch off before the median nerve passes between the pronator teres, the muscles responsible for wrist and finger flexion. A purely motor branch, the anterior interosseous nerve, is given off just after the median nerve emerges from the pronator teres. It innervates the flexor digitorum profundus to the second and third digits. The median nerve passes under the flexor retinaculum at the wrist and innervates the first two lumbrical muscles and the adductor pollicis brevis. The digital nerves then provide sensory innervation to the distal palm and palmar surfaces of the first through fourth digits.

Compression in the Carpal Tunnel

Compression of the median nerve in the carpal tunnel is the most common compression neuropathy of the upper extremity.87 Women between the ages of 40 and 60 years are affected predominantly. Any condition that reduces the capacity of the carpal tunnel can precipitate the symptoms.88 These conditions include (1) fractures, (2) ganglions, (3) xanthomas, and (4) synovial disorders. Systemic conditions predisposing to carpal tunnel syndrome include (1) obesity, (2) pregnancy, (3) hypothyroidism, (4) acromegaly, (5) myeloma, (6) amyloidosis, (7) Raynaud’s disease, (8) chronic renal failure, and (9) diabetes mellitus.

Paresthesias and pain occurring during sleep characterize the syndrome. The paresthesias usually are localized to the palmar aspects of the fingers and hands. These patients, however, may complain of wrist and forearm pain. The paresthesias and pain are aggravated by repeated wrist and finger flexion. Affected patients also may feel clumsy and have hand weakness. The symptoms usually begin in the dominant hand, although in more than half of the cases, the disorder is bilateral.89

Physical examination reveals decreased sensation over the palmar aspect of the thumb through the ring finger. Atrophy of the thenar muscles can occur as a late sign of median neuropathy. Tinel’s sign and Phalen’s test help make the diagnosis. Tinel’s sign refers to distal paresthesias elicited by percussion of the median nerve either proximal to the flexor retinaculum in the wrist or distally at the base of the palm. Phalen’s test is performed by applying a tourniquet to the arm at 60 mm Hg pressure.90 The venous congestion will elicit paresthesias in patients with carpal tunnel syndrome. Alternatively, acute flexion of the wrist for 60 seconds will accomplish the same goal.

Median Nerve Compression Proximal to the Carpal Tunnel

The median nerve may be compressed proximally, too. For example, compression in the axilla may result from the misuse of crutches. The pronator syndrome, which may appear spontaneously or be caused by excessive forearm pronation (e.g., in tennis players), results from median nerve entrapment between the two heads of the pronator teres.91 These patients have unlocalized forearm pain combined with numbness in the fingers innervated by the median nerve.92 Anterior interosseous syndrome is caused by damage to this purely motor branch from fractures or fibrous band compression. Affected patients have proximal forearm pain that increases with exercise.93

Diagnostically, these proximal nerve compressions can be distinguished from carpal tunnel syndrome by the characteristic weakness of the flexor digitorum muscles and flexor pollicis longus. These patients are asked to oppose the tip of the thumb to the second digit and are unable to flex both distal phalanges (so-called circle test). Weakness of pronation also is characteristic of proximal median nerve entrapment.93,94

Digital Nerve Compression of the Thumb and Fingers

So-called bowler’s thumb is caused by constant irritation of the digital nerve at the thumb. Perineural fibrosis and painful nodule formation results. So-called harp player’s thumb is caused by strumming musical instruments; painful nodules or hypersensitivity to touch may occur.

Suprascapular Nerve

The suprascapular nerve is a purely motor nerve arising from the upper branch of the brachial plexus. It runs under the trapezius muscle through a notch on the upper border of the scapula and supplies the supraspinatus and infraspinatus muscles.

Damage to the scapula may injure the nerve to produce a syndrome characterized by weakness confined to spinatus muscles without sensory loss. Affected patients have pain after shoulder abduction.95,96 Tenderness may be elicited by palpating the suprascapular notch. Needle electromyography (EMG) shows denervation of the spinatus muscles.

Femoral Nerve Entrapment Syndrome

The femoral nerve is formed from the posterior branches of L2 to L4 behind the psoas muscle. It then courses around the lateral wall of the psoas muscle into the iliacus compartment located between the psoas and iliacus muscles and covered by the iliacus fascia. It then gives off branches that supply the quadriceps and sensation to the anterior thigh. The nerve terminates as the saphenous nerve, which supplies sensation to the skin on the medial aspect of the leg.

Femoral neuropathy leads to wasting of the quadriceps muscles and sensory disturbances over the anteromedial aspect of the thigh and medial aspect of the lower leg. The patellar reflex also is diminished or absent.

Diabetes is the most common cause of femoral neuropathy.97 Other causes include injury of the nerve beneath the inguinal ligament as a result of scar tissue or prolonged lithotomy position98 and compression of the nerve in the iliacus compartment from hematomas secondary to trauma or anticoagulants.99

Femoral neuropathy must be differentiated from L3 to L4 radiculopathy. EMG studies can help determine whether motor dysfunction is confined to the femoral nerve distribution. CT scans and radiographs of the lumbosacral spine may help exclude disk disease.

Meralgia Paresthetica or Lateral Femoral Cutaneous Nerve Entrapment (Roth’s Disease or Bernhardt’s Disease)

The lateral femoral cutaneous nerve, which supplies the anterolateral aspect of the thigh, is a purely sensory nerve formed from the posterior division of the L2 and L3 roots. The nerve emerges along the lateral border of the psoas muscle and courses peripherally around the pelvis between the iliac muscle and its overlying fascia (Fig. 32-1). The nerve then descends under the lateral aspect of the inguinal ligament to the anterior-superior iliac spine; finally, it runs beneath the deep fascia and subcutaneous tissue of the upper thigh.100 The nerve divides into anterior and posterior branches, which supply the anterolateral and posterior aspect of the thigh, respectively. Affected patients have burning pain and dysesthesias along the lateral aspect of the thigh, which are exacerbated by prolonged walking or standing.

The most common site of lateral femoral cutaneous nerve entrapment occurs as the nerve passes from the pelvis into the thigh.101 Thus, pressure from belts, girdles, and tight pants is cited as a precipitating cause. Also, direct trauma to the area of the anterior-superior iliac spine can lead to increased tension on the nerve. The diagnosis can be confirmed by blocking the nerve with a local anesthetic. A wheal is raised medially and inferiorly to the anterior-superior iliac spine. After the fascia above the inguinal ligament is pierced, 10 to 12 mL of a local anesthetic are injected in a fanlike distribution.

Sciatic Nerve Syndromes

Two distinct nerves, the tibial and common peroneal, comprise the sciatic nerve. The latter arises from the posterior divisions of L4, L5, S1, and S2. The former arises from the anterior divisions of L4 and L5, and S1 to S3. The sciatic nerve leaves the pelvis through the sciatic notch below the piriformis muscle, where it may be compressed by masses. Then it courses between the greater trochanter and ischial tuberosity covered by the gluteus maximus muscle and hamstrings. The fact that the superior and inferior gluteal nerves and posterior cutaneous nerve of the thigh pass with the sciatic nerve through the notch can help to localize sites of sciatic compression.

Aside from penetrating trauma, most injuries to the sciatic nerve occur as a result of fracture dislocations of the hip joint and hip arthroplasty. Deep injections into the buttock may directly injure the nerve or cause muscle fibrosis that compresses the nerve.102 Masses, such as endometriomas, may compress the nerve at the sciatic notch.103 In addition to the buttock pain and paresthesias along the back of the leg, a sciatic nerve injury can cause foot drop, impaired hip extension, and decreased sensation over the lateral leg and foot.

Piriformis syndrome is caused by spasm or scarring of the piriformis muscle. Affected patients have symptoms similar to “sciatica,” such as buttock pain and burning dysesthesias down the back of the leg.104,105

The common peroneal nerve diverges from the tibial nerve in the upper popliteal fossa and passes laterally to the head of the fibula, close to the median margin of the tendon of the biceps femoris. Then it passes superficially to the neck of the fibula. Distal to this, it divides into the superficial peroneal nerve (musculocutaneous nerve) and the deep peroneal nerve. The superficial peroneal nerve courses along the shaft of the fibula with the peroneal muscles that it supplies. Its cutaneous nerve innervates the skin of the lateral and distal portion of the lower leg and the dorsal aspect of the foot. The deep peroneal nerve descends in the anterior compartment of the leg and supplies the tibialis anterior, extensor hallucis longus, and extensor digitorum brevis muscles in the foot.

The common peroneal nerve may be compressed near the neck of the fibula during general anesthesia or coma. Less common causes include prolonged squatting106 or crossing of the legs.107 The nerve also may be compressed by ganglions or cysts in the knee joint. Affected patients have foot drop and sensory deficits over the anterolateral aspect of the lower leg and dorsum of the foot (Fig. 32-2).

Anterior tibial syndrome involves compression of the deep peroneal nerve caused by muscle swelling in the anterior compartment of the leg. These patients have exquisite anterior lower leg pain and motor dysfunction. The syndrome may occur after trauma, reperfusion after arterial occlusion, or excessive exercise.

Tibial nerve syndromes involve the tibial nerve, which branches from the sciatic nerve, descends through the popliteal fossa, and passes deep between the heads of the gastrocnemius muscle, which it supplies. The nerve becomes superficial along the medial aspect of the ankle and passes under the flexor retinaculum into the foot. The flexor retinaculum forms the roof of the tarsal tunnel. Distal to this site, the tibial nerve divides into plantar nerves and sensory branches that supply the sole of the heel. The plantar nerve innervates motor and sensory elements of the anterior two thirds of the sole. The sural nerve leaves the tibial nerve in the popliteal fossa and descends in the middle of the calf to supply the skin over the lateral aspect of the ankle.

Compression of the distal part of the tibial nerve or two plantar nerves can cause diffuse foot pain and paresthesias in the sole of the foot. Weakness of foot muscles may be noticed, and physical examination shows plantar nerve sensory abnormalities. Compression or palpation over the medial aspect of the Achilles tendon may elicit pain and paresthesias. This syndrome is called the tarsal tunnel syndrome, and it can result from ill-fitting footwear or compression by tendon sheaths.108,109

Morton’s neuroma (or neuralgia) is caused by compression of the interdigital nerves by adjacent metatarsal heads (generally between the third and fourth toes). The pain radiates from the site of the neuroma into the toes. Initially, the pain occurs while walking, but eventually it becomes continuous.

Sural neuropathy causes paresthesias and pain over the lateral aspect of the ankle and foot. This results from prolonged pressure over the posterior lower calf.110

Complex Regional Pain Syndrome

(See Chap. 39)

In 1994, the International Association for the Study of Pain (IASP) recommended two important changes in the taxonomic classification of pain to reflect more accurately current understanding of the entities. For example, the constellation of signs and symptoms eliciting the diagnosis of reflex sympathetic dystrophy seemed to imply an underlying mechanism, which investigations have so far failed to support. Hence, the terms complex regional pain syndrome (CRPS), types 1 and 2, have replaced reflex sympathetic dystrophy and causalgia, respectively. At one time, clinicians made the diagnosis of CRPS only if a trial of sympathetic blockade ameliorated the pain. Subsequently, it has been discovered that the role of the sympathetic nervous system may vary during the natural course of the chronic pain syndrome. For example, in some patients, early sympatholysis may obliterate the perceived pain, whereas the same intervention later in the course of the disease fails to produce a positive response. Hence, for the same CRPS, a period of sympathetically maintained pain may be followed by a phase of sympathetically independent pain.

Normally, injury stimulates afferent sensory fibers that travel to the dorsal root ganglia and synapse in the posterior horn of the spinal cord. The impulse is relayed as well to sympathetic neurons in the lateral columns, which send efferent impulses through the anterior root. After synapsing in the sympathetic ganglion, these efferent signals can mediate vasoconstriction in the affected extremity. Over time, however, the role of the sympathetic nervous systems becomes less clear.111

Pain, swelling, discoloration, and stiffness comprise the four major hallmarks of CRPS. Patients commonly experience constant pain, which has a burning, cramping, or cutting quality. Passive motion of the extremity aggravates the pain. Hyperpathia and tenderness elicited over the joints commonly develop. Swelling often begins at the point of initial trauma and initially feels soft. Eventually it can involve the whole extremity and usually becomes firm. Skin tone changes from red to white as early capillary vasodilation gives way to later vasoconstriction. Stiffness results from the combination of increased swelling and disuse because of the intense pain caused by motion.112 As the disease progresses, fibrosis of ligamentous structures and adhesion formation further limit joint motion. Forearm and shoulder motion are limited to a much greater extent than elbow motion.

Affected patients also have other signs and symptoms, such as cool skin and positive responses to cold and the ice-water immersion test, and there is decreased skin temperature in the affected extremity. Trophic skin changes may be seen as tight, shiny skin. Later features include atrophy of subcutaneous tissue producing tight, shiny skin and tapering of the pulp area of the fingers (the so-called pencil-pointing sign).

CRPS, type 2 (causalgia), was first described in 1864 among Union soldiers when gunshot wounds to extremities directly injured peripheral nerves. A so-called major form involved proximal nerve injury with resultant pain in the entire extremity.113,114 Minor causalgia involved injury to distal sensory nerves and is generally confined to one or several fingers.

Hypothyroid Neuropathy

The peripheral nervous system manifestations of myxedema are well described. Affected patients may have either mononeuropathy or polyneuropathy.

The most common mononeuropathy involves compression of the median nerve as it passes through the carpal tunnel at the wrist. With myxedema, the extracellular tissue in the perineurium, endoneurium, and tendons acquires increased amounts of acid mucopolysaccharides. These attract fluid and diminish the available space for nerve in the carpal tunnel.115

The extremity pain associated with the polyneuropathy of hypothyroidism has two distinct origins: (1) skeletal muscle, and (2) peripheral nerve. In the first case, affected patients may have edema of the skeletal muscle that is manifested as cramping.116 Prolonged relaxation and contraction times produce slowed movement. Patients display proximal weakness. The relaxed muscles feel firmer and larger than normal. In the second case, distal extremity pain has a neuropathic origin marked by slowed conduction velocity, decreased tendon reflexes, dysesthesias, and sensory deficits.

A distinct type of muscle cramping has been noticed in patients with both hypo- and hyperthyroidism. These patients experience an undulatory muscular twitching, or so-called myokymia, which may be produced by repetitive discharges from many single motor nerve fibers. The cramping is accompanied by excessive sweating.117

Neuropathy in Acromegaly

Patients with acromegaly may have intense pain and tingling in their extremities as a result of hypertrophic neuropathy.118 In addition, bilateral carpal tunnel syndrome has been reported to be associated with acromegaly.119 Presumably, the overabundance of growth hormone causes proliferation of the connective tissue and synovium, diminishing the available space in the carpal tunnel. Hypertrophic connective tissue also may compress axons, resulting in sensorimotor disturbances.

Thoracic Outlet Syndrome

Thoracic outlet syndrome results from compression or irritation of the brachial plexus and subclavian vessels as they pass through the costoclavicular space and thoracic outlet.120,121 Actual compression of the plexus accounts for the symptoms in most patients. Therefore, the disease probably should be viewed as a neuropathy122 (Fig. 32-3). The syndrome primarily affects young and middle-aged women. The history is essential to separate thoracic outlet syndrome from other causes of upper extremity pain, such as carpal tunnel syndrome and cervical disc disease123 (Table 32-8). The symptoms may occur spontaneously or after trauma124 to the shoulder and neck, resulting in chronic muscle spasms.124,125 The pain initially is unilateral and intermittent, but it increases in severity and frequency with time. It begins over the anterior and posterior shoulder region and radiates down the lateral arm to the hand. The pain also may radiate up the back of the neck to the mastoid and occipital region of the skull and cause severe headaches. Paresthesias accompany the pain, and because the compression typically involves C8 to T1 of the plexus, affected patients localize their numbness and tingling to the ulnar nerve distribution.

A striking feature of the history is that elevating the arm and increased arm activity can initiate or aggravate the symptoms. Muscle cramping, per se, is not a feature of the syndrome. The hands may or may not show increased sensitivity to cold.

Frank arterial occlusion rarely, if ever, accounts for the signs and symptoms of thoracic outlet syndrome. Exertion, which can cause cyanosis and edema of the extremity, may produce subclavian vein thrombosis126 (the so-called effort thrombotic syndrome of Paget and Schroetter). The physical examination should include blood pressure measurement in both arms to identify any differences. Muscle atrophy of ulnar-innervated interosseous muscles can be assessed by an interphalangeal card test or by spreading the digits against resistance. Triceps strength may be diminished. Bruits may be heard over the supraclavicular fossa. Moderate pressure over the supraclavicular fossa for 15 seconds may reproduce the symptoms. The reflexes generally are normal. Pinprick sensation may be diminished over the C8 to T1 dermatome.

Several maneuvers that have questionable diagnostic value should be mentioned.127 Adson’s maneuver consists of monitoring the radial pulse while patients take deep breaths, extend their necks, and then turn their chin toward the affected side. A decrease or disappearance of the pulse is a positive test result. A bruit may be heard over the supraclavicular area using this maneuver. The deep breath elevates the first rib, and turning the neck narrows the interscalene triangle. The costoclavicular compressive maneuver consists of monitoring the radial pulse while the patient throws back the shoulders and presses them downward. A positive test result is a decrease or disappearance of the radial pulse with or without a bruit. This maneuver compresses the subclavian artery between the clavicle and the first rib.

By contrast, the elevated-arm stress test described by Roos125 seems to have some diagnostic value. This test involves a 90-degree abduction and external rotation of the arms. The patient is then instructed to open and close the hands for 3 minutes. A reproduction of symptoms of the thoracic outlet syndrome constitutes a positive test result.

In addition to the history and physical examination, some other tests should be discussed when diagnosing thoracic outlet syndrome. Although thoracic outlet syndrome can be considered an ulnar neuropathy, the actual irritation of the plexus is intermittent and rarely results in neuropathic changes. Hence, nerve conduction studies generally are not useful.128,129 Also, because the C8 to T1 part of the plexus is both inferior and deep, stimulation would be difficult technically. Only a small minority of patients with thoracic outlet syndrome has disease that involves subclavian arterial compression; therefore, angiograms generally are not indicated. The two exceptions to this rule are when there is (1) a large differential blood pressure between the arms, or (2) interest in excluding a subclavian artery aneurysm. Cervical spine films generally are valuable in patients with thoracic outlet syndrome to exclude any coexisting cervical disc disease.

Cervical Disc Disease

(See Chap. 27)

Cervical disc disease is another common cause of neck, shoulder, and arm pain. The root or cord compression may result from ruptured disc material or a degenerative osteophytic lesion. The radiculopathy usually involves, in descending order, C7, C6, C5, and C8. The symptoms may occur after trauma or sudden hyperextension.130,131

One common syndrome involving lateral disc lesions between C5 and C6 includes pain felt at the trapezium ridge, tip of the shoulder, radial forearm, and thumb. Affected patients have sensory loss and paresthesias in the same distribution. Unilateral paracervical muscle spasm is present. The patient may experience biceps tenderness in the supraclavicular regions, motor deficit, and loss of deep tendon reflex. The patient has a secondary weakness after forearm flexion.

Another common syndrome is caused by lateral protrusion between the sixth and seventh cervical vertebrae, with involvement of the seventh cervical root. The pain occurs in the shoulder and radiates down the elbow and dorsal forearm to the index and middle fingers. There is tenderness over the third and fourth thoracic spinous processes and the triceps region. The patient has sensory deficits and paresthesias in the second and third fingers. Physical examination shows an absent triceps reflex, with weakness in forearm extension, wrist extension, and hand grip Regardless of the cervical root involved, affected patients relate a history of chronic sharp pain. Events such as coughing or sneezing tend to exaggerate the pain. Most changes in head position (particularly hyperextension) intensify the pain. On examination, turning the head to one side and hyperextending the neck produce neck pain and characteristic radicular paresthesias (Table 32-9).

Neuralgic Amyotrophy

Neuralgic amyotrophy is a syndrome characterized by the acute onset of shoulder pain, which can be severe or aching. Although it frequently affects the shoulder alone, it may also involve the arm, neck, and back. The pain is worse at night and intensifies with movement.132 The syndrome involves mostly the right side, but almost 25% of cases are bilateral.

Proximal motor weakness in the shoulder and arms, particularly affecting the muscles innervated by the axillary and suprascapular nerves, follows the pain at varying intervals.133 Complete limb paralysis is rare. Pain relief often occurs after resting the limb with the elbow flexed and the shoulder adducted; however, this may aggravate the weakness. Sensory involvement is not a characteristic feature of this syndrome. The cause remains unknown. However, a brachial neuritis similar to neuralgic amyotrophy may appear after serum inoculations or infections caused by influenza, typhus, or variola viruses.

The diagnosis depends on obtaining a history consistent with neuralgic amyotrophy. The physical diagnosis is aided by eliciting pain after arm abduction, external rotation at the shoulder, and then extension of the elbow (the so-called flexion-adduction sign described by Waxman).134 EMG studies show a peripheral plexus lesion with normal spinal roots.135

Neuropathy of Serum Sickness

Before the age of antibiotics, bacterial infections often were treated with large volumes of horse or rabbit antisera. The serum sickness that patients developed occasionally was accompanied by neuropathy, usually of the brachial plexus.136 Heterologous serum rarely is used today, but neuropathies still may occur as a sequela of typhoid or paratyphoid vaccinations or from drugs that form complexes with serum proteins.137

The usual clinical features of serum sickness (e.g., lymph node swelling, joint pain, myalgias, and albuminuria) generally are present when the neuropathy appears. There is no relationship between the amount of serum given, the severity of systemic manifestations, and the development of neuropathy.

Pain onset occurs suddenly. It generally starts in the shoulder girdle or upper arm. The pain should be distinguished from more typical myalgic or arthritic types seen during serum sickness in other joints and muscles. Physical examination may reveal tenderness over the brachial plexus. Weakness involving the shoulder muscles soon follows the onset of pain, and affected patients may be paralyzed totally and have striking atrophy. The reflexes also are decreased or absent, and vasomotor changes may appear. Sensory signs are not prominent, a feature that is found in other brachial neuropathies. The radial nerve is a less common site of involvement.

The pathologic basis of the neuropathy of serum sickness seems to be that immune-complex deposition causes vasculitis and perivascular edema. This, in turn, leads to edema of the nerves. This swelling impinges on the nerves as they exit from the foramina. If the swelling progresses, it may compromise flow further and lead to frank necrosis of the nerves, which explains why severe lancinating pain can be such a prominent feature of this neuropathy.136,137

Neuropathy in Connective Tissue Diseases

Peripheral neuropathy may occur in conjunction with various connective tissue diseases. The clinical manifestations and histopathologic findings are similar regardless of the disease. The pathogenic lesion is arteritis involving the small nutrient arteries of the nerves. Thus, it is described as an angiopathic neuropathy that occurs with varying frequencies in rheumatoid arthritis, polyarteritis nodosa, Churg-Strauss vasculitis, systemic lupus erythematosus, and giant cell arteritis.138

Patients with rheumatoid arthritis and peripheral neuropathy have certain distinguishing features. Firstly, they usually have had rheumatoid arthritis for an average of 10 years before the onset of neuropathy. Secondly, rheumatoid nodules and destructive joint changes are present. Thirdly, elevated titers of rheumatoid factor are common.139 Fourthly, these patients have other complications of arteritis (such as nail-bed infarctions, skin ulcers, and Raynaud’s phenomenon). Finally, these patients often describe a change in their clinical status involving fever, anorexia, or weight loss. It previously was believed that patients receiving corticosteroids were at risk for an increased incidence of neuropathy. However, these are patients with severe disease, and it is thought currently that corticosteroids may help to check the progression of the arteritis. Thus, rapid tapering of these drugs may exacerbate the arteritis and precipitate the onset of the neuropathy.

The latter usually includes a gradual onset of numbness and tingling confined to the lower extremities. The sensory deficits are symmetric and not accompanied by motor deficits. Patients with rheumatoid arthritis and other connective tissue diseases also may have mononeuritis multiplex or a sudden onset of pain and paresthesias along the course of a peripheral nerve, followed by wrist or foot drop.

Although only a small percentage of patients with rheumatoid arthritis have symptomatic neuropathy, a large percentage have histologic evidence of disease involving the peripheral nerves at autopsy.139 The range of arterial pathologic changes in the peripheral nerves includes perivascular infiltration with mononuclear cells, fibrinoid necrosis of the media with infiltration of eosinophils and mononuclear cells, intimal proliferation and reduplication of the internal elastic lamina, and hemorrhage around the vessel walls. The damage to nutrient vessels results in both segmental demyelination and wallerian degeneration in the affected nerves.140

The diagnosis of rheumatoid arthritis generally is well established before the neuropathy appears. However, patients with neuropathy have an elevated erythrocyte sedimentation rate; mild normochromic, normocytic anemia; and significantly elevated titers of rheumatoid factor.

Polyarteritis nodosa is a multisystem disease characterized by a vasculitis of small and medium-sized muscular arteries, with particular involvement of the kidneys and gastrointestinal tract. Clinical neuropathy is a common manifestation of this disease. The clinical presentation may be similar to that of rheumatoid arthritis. One important distinguishing feature is that the neuropathy of polyarteritis nodosa involves the upper extremities as frequently as the lower extremities. The neuropathy may occur in conjunction with other manifestations of this disease, such as fever, weight loss, renal insufficiency, and skin lesions.141 Patients with both polyarteritis nodosa and rheumatoid arthritis also may have an accompanying arthritis. The arthritis of polyarteritis nodosa is mild and of short duration. It does not cause the extensive joint destruction and nodule formation seen with rheumatoid arthritis.

The pathologic changes seen in the peripheral nerves involve an arteritis of nutrient arteries that is similar to that described in rheumatoid arthritis. The diagnosis depends on a histologic demonstration of vasculitis in the involved organs. Peripheral neuropathy may be associated with Churg-Strauss vasculitis (eosinophilic granulomatosus). It is considered a variant of polyarteritis nodosa that is characterized by peripheral eosinophilia and a strong association with severe asthma.142 Both systemic lupus erythematosus and giant cell arteritis (involving the temporal arteries) may include secondary neuropathy.

Porphyric Neuropathy

The porphyrias are a group of metabolic disorders characterized biochemically by an overproduction of porphyrins and porphyrin precursors. Recurrent attacks, which are often precipitated by drugs (such as barbiturates, phenytoin, sulfonamides, and estrogens), are common. The neuropathy and extremity pain is a feature only of one subgroup, the so-called hereditary hepatic porphyrias, which include (1) acute intermittent porphyria, (2) variegate porphyria, and (3) hereditary coproporphyria.143

Acute intermittent porphyria, inherited as an autosomal dominant trait, is most common in women of English and Scandinavian origin.144 Attacks are rare before puberty and are distinguished temporally by three phases: (1) abdominal pain, (2) psychologic disturbances, and (3) polyneuropathy. Abdominal pain initiates the attack. The pain is described as colicky and may be diffuse or confined to one region of the abdominal wall. It often radiates to the back but is not accompanied by abdominal wall guarding or tenderness. Tachycardia is a constant physical sign during attacks.145 Radiographic studies show distended loops of bowel. Psychologic manifestations follow the acute abdominal attacks. This phase is characterized by restlessness, insomnia, hallucinations, and confusion.146 Neuropathy is the final phase of the attack. It is symmetric, progressive, and initially involves mostly motor nerves. The upper extremities are affected more than the lower extremities and the proximal, more so than the distal muscles. Tendon reflexes are diminished or absent.147,148 The extremity pain that occurs can result from various factors. Proximal muscle aching and cramps are common. Paresthesias and dysesthesias also occur in half the cases.

The diagnosis depends on the characteristic history and is confirmed by demonstrations of increased levels of porphobilinogen and δ-aminolevulinic acid in the urine. Variegate porphyria is most common among European descendants in South Africa. The acute attacks are similar to those of acute intermittent porphyria, but in addition, they are accompanied by cutaneous photosensitivity. Hereditary coproporphyria is a rare cause of neuropathy and is distinguished by a predominantly fecal excretion of porphyrins.

Hepatic Neuropathy

Several types of peripheral neuropathy may accompany hepatic dysfunction. These are distinct from alcoholic neuropathy or illnesses that affect both the liver and peripheral nervous system concomitantly.149 Specifically, the conditions are (1) a painless demyelinating neuropathy that accompanies hepatic dysfunction, regardless of the cause150,151; (2) an acute polyneuritis identical to that seen with Guillain-Barré syndrome occurring late in the course of viral hepatitis as jaundice is regressing152,153; and (3) a rare but painful neuropathy that occurs with biliary infections.154

Patients with biliary cirrhosis and neuropathy have the other common manifestations of this disease: hepatomegaly, pruritus, jaundice, and cutaneous xanthomatosis. Hypersensitivity and paresthesias have been recognized for a long time as a feature of biliary cirrhosis. However, Thomas and Walker154 also documented the presence of sensory deficits. Xanthomatous involvement of the connective tissue sheaths of the cutaneous nerves is the cause of the painful dysesthesias.

Burning Feet Syndrome

Investigators initially thought that the so-called burning feet syndrome described among prisoners of war after World War II represented a distinct deficiency syndrome. Currently, experts agree that it is merely one manifestation of vitamin B deficiency and can be found in patients with (1) alcoholic neuropathy, (2) beriberi, (3) pellagra, and (4) Strachan’s syndrome. The symptom of burning feet, or acrodysesthesia, begins as a persistent burning pain over the metatarsals on the soles of the feet. Various other dysesthesias, tingling, electric shocks, or coldness may accompany this pain. Soon, the entire soles and dorsal surface of the feet are involved symmetrically. The pain worsens at night. Affected patients try a number of methods to relieve the burning: immersing their feet in ice water, constant massage, or walking (despite pain caused by contact). Many authors believed the syndrome had a causalgic basis as a result of findings such as cyanosis and hyperhidrosis. Other features of peripheral neuropathy (e.g., absent reflexes, impairment of sensation, and muscle wasting) may or may not be present. Occasionally, the patient’s hands may be involved, too.

Isoniazid- or Hydralazine-Induced Neuropathy

The occurrence of isoniazid-induced neuropathy was discovered shortly after the drug was first used to treat tuberculosis. The neuropathy generally involved the motor function, sensation, and reflexes of the lower extremities. The initial symptoms consisted of numbness and tingling, which began in the toes and feet, followed by calf tenderness, and finally continuous burning paresthesias and painful dysesthesias caused by contact stimuli. Increasing severity of symptoms paralleled proximal spread of the neuropathy to the knees. Patients displayed weak toe movements and dorsiflexion and loss of the Achilles reflex.155 The incidence of the neuropathy varies with the dose of drug administered. It ranges from less than 10% of patients treated with a dose of 4 to 9 mg/kg per day to 40% with doses of 20 mg/kg per day.156 Vitamin B6 deficiency causes the neuropathy, which can be prevented by vitamin B6 supplementation.157 Isoniazid produces marked excretion of pyridoxine.

Pyridoxine deficiency presumably is the basis for the neuropathy that complicates therapy with hydralazine, which is chemically related to isoniazid.158

Pellagra

The first description of pellagra among peasants in northwestern Spain whose diet consisted almost entirely of corn appeared in 1730. The role of sunlight, the seasonal variation (highest in the spring), and the rash that appeared on exposed areas (so-called Casal’s collar) were noticed. The first reports of pellagra in the United States were made in the late 1800s, and the disease soon attained epidemic proportions among alcoholic and farming populations. Currently, the disease rarely is seen in the continental United States (except among food faddists). It does occur commonly among poorer vegetarians and the black population of South Africa.

Initially, it was believed that pellagra was caused solely by a niacin-deficient diet. Subsequently, it was shown that (1) administration of tryptophan to humans resulted in increased urinary excretion of niacin metabolites, and (2) the dermal and gastrointestinal manifestations of pellagra responded to large doses of tryptophan. Thus, currently, investigators believe that pellagra is the result of a deficiency of niacin and its amino acid precursor, tryptophan.

Pellagra shows the clinical triad of dermal, gastrointestinal, and neurologic lesions. The skin lesions first appear erythematous, then become brown and hyperkeratotic. They are seen on the face, neck, sternum, and dorsum of the hands and feet. Affected patients have anorexia, diarrhea, weight loss, and dysphagia. The neurologic manifestations consist variously of depression, insomnia, irritability, and signs of spinal cord involvement. The neuropathy, which is identical to that observed with beriberi, is the most common neurologic finding. Affected patients have exquisite tenderness to palpation of the muscles of their calves and feet. Many also feel an intense burning pain in a so-called glove-and-stocking distribution. Diminution or loss of vibratory sensation and deep tendon reflexes occur.

The Syndrome of Amblyopia, Painful Neuropathy, and Orogenital Dermatitis (Strachan’s Syndrome)

Strachan (in 1888) and Scott (in 1918) both described a deficiency syndrome among Jamaicans—consisting of amblyopia, painful neuropathy, and orogenital lesions—that was distinct from beriberi and pellagra. These manifestations since have been described among World War II prisoners in Johore and Singapore, in survivors of German concentration camps, and in natives in Trinidad and Senegal. Currently, the syndrome has not been related to a specific vitamin deficiency, although a riboflavin deficiency has been suggested. The few neuropathologic studies performed reveal spinal cord posterior column demyelination, particularly in the cervical region.

Patients with pellagra classically have numbness and tingling in their hands and feet. The dysesthesias consist of severe burning in the soles and palms, which often is worse at night. The numbness extends progressively to the knees or hips, and the patient’s gait may be impaired. Often, the symptoms are confined to the lower extremities, or alternatively, they may begin in the fingertips and involve the hands and arms symmetrically. Muscle wasting is progressive, and extremity cramps are common.

Amblyopia is the other constant feature of this syndrome. Visual impairment is accompanied by central and centrocecal scotomas that progress to complete blindness. Ophthalmologic evaluation shows little, except occasionally disc hyperemia is found.

The dermatitis involves the corners of the mouth and eyes, prepuce, anus, and vulva. Deafness and vertigo (so-called camp dizziness) are common features of some outbreaks of the syndrome.

Alcoholic Neuropathy

In a consecutive series of 1,030 alcoholic patients admitted to Boston City Hospital,159 a 9% incidence of peripheral neuropathy was observed, with a disproportionately higher incidence in women. Nutritional deficiency and the toxic effect of the alcohol, per se, account for the major findings of alcoholic neuropathy. Alcoholic patients not only subsist on a diet of carbohydrates, they also have an impaired capacity to absorb folate and thiamine and to digest fats. Axonal degeneration, with destruction of both myelin and axons, results. The changes are seen predominantly in the longest and largest myelinated fibers. As the neuropathy advances, anterior and posterior nerve root involvement occurs.

Alcoholic neuropathy is a progressive symmetric disorder of the extremities that generally spares both the cranial and truncal nerves. The lower extremities (particularly the feet and ankles) are affected more than the upper extremities; in one study 70% of patients had lower extremity involvement alone. Motor disability and sensory deficits occur concomitantly. These signs can range from mild asymptomatic depression of the Achilles reflex to gross motor deficits (wrist and foot drop). All sensory modalities, both superficial and deep, may be affected with a characteristic distribution (so-called glove and stocking).

The pain that accompanies alcoholic neuropathy typically occurs in several areas. Affected patients have a characteristic tenderness when pressure is applied to the muscles of their feet and calves. The distal lower extremity dysesthesias may have a dull aching quality or a sharp, lancinating, tabes-like pain. These patients also describe a burning feet syndrome that consists of severe paresthesias of the soles aggravated by contact stimuli. Excessive sweating on the volar surfaces of the feet and hands may occur, which presumably is related to postganglionic sympathetic involvement. Other signs, such as stasis edema, glossiness, and pigmentation changes of the skin, and dystrophic changes in the feet, may be present.

Herpes Zoster

(See Chap. 40)

Herpes zoster, or shingles, is an infection by the DNA virus varicella-zoster that occurs with an annual incidence of approximately 125 cases per 100,000. Herpes zoster is thought to be a reactivation of the varicella-zoster virus that also causes chickenpox in children, which has remained dormant in the dorsal root ganglia for many years.

When viral antibody titers decline in elderly or immunocompromised patients, the virus may reactivate and begin to replicate. A painful neuralgia results from damage to the sensory ganglia. The virus then spreads peripherally to cutaneous sensory nerve endings, causing vesicular eruptions. Most affected patients are healthy, but the course may be more severe in immunosuppressed patients (Table 32-10).

Zoster-affected patients usually have pain and dysesthesias along the dermatomal distribution of a single spinal or cranial sensory nerve. The pain at first is usually mild, but it increases in intensity over the succeeding days. Occasionally, patients have accompanying systemic symptoms such as fever, malaise, adenopathy, or headache. After 4 to 5 days, the typical skin lesions appear. Swelling and erythema give way to red papules that progress to clear vesicles, blebs, and pustules that crust over in 2 to 3 weeks. The lesions are unilateral in a dermatomal distribution. The most common dermatomes affected are the thoracic, followed by the cranial, lumbosacral, and cervical. During the acute phase, patients feel continuous dysesthesias that are aggravated by movement or pressure on the skin. As the blebs begin to dry and scale, the intense pain subsides, but many patients still have hyperesthesias and, only gradually, become asymptomatic.

Paresis may accompany the rash, particularly in elderly patients. It follows the appearance of the rash and usually occurs with cervical and lumbosacral eruptions rather than thoracic. Involvement of the facial nerves is common (Ramsay Hunt syndrome). The virus may be recovered from early vesicles, cerebrospinal fluid, and blood. The base of the skin lesions contains multinucleated giant cells and eosinophilic intranuclear inclusions.

Postherpetic neuralgia develop in 10% to 50% of patients with acute herpes zoster; the incidence increases with advancing age. The syndrome consists of pain persisting for 4 to 6 weeks after the skin lesions have disappeared. Such patients generally suffer from a burning pain associated with hyperesthesia.

Introduction

(See Chap. 37)

Peripheral neuropathies are a common source of extremity pain. Several unique features of the peripheral nervous system make it particularly susceptible to trauma or metabolic derangements. Firstly, it is composed of long axons (1–2 m). Secondly, the spinal roots pass through narrow foramina centrally and many ligaments and tendon sheaths peripherally, making them susceptible to compression. Thirdly, the axons depend on a complex longitudinal network of nutrient arteries that run in the epineurium and perineurium.

The peripheral neuropathies involving smaller afferent fibers are usually painful. Those affecting large-diameter afferent fibers and Schwann cells are generally painless. The pain of a peripheral neuropathy is usually not distinctive, and the diagnosis must, therefore, be based on other criteria.

Regardless of their cause, peripheral neuropathies have several characteristics: (1) paresthesias and dysesthesias, (2) sensory loss, (3) loss or diminution of tendon reflexes, and (4) impaired motor function. Paresthesias and dysesthesias commonly accompany certain types of neuropathies, such as those resulting from diabetes and alcohol. The paresthesias can manifest as tingling, lancinating pain, or numbness. Perversion of sensation may also occur, such as when a tactile stimulus causes a burning or tingling. Commonly, the pain persists after the stimulus is withdrawn. Hyperpathia may be prominent.

The cause of paresthesias remains poorly understood. One hypothesis suggests that the loss of large touch-pressure fibers no longer inhibits pain-sensing cells in the posterior horn. Another states that ectopic discharges may result from regenerated nociceptive fibers. Some type of sensory loss accompanies most neuropathies. Only one or all sensory modalities (touch-pressure, vibratory, joint position, pain, and temperature) may be affected. Deep tendon reflex loss or diminution characterizes peripheral neuropathy, especially when both sensory and motor involvement exists. The Achilles reflex serves as a particularly sensitive index of polyneuropathy. Tremors and disorders of autonomic function also may be seen with peripheral neuropathies. Useful diagnostic laboratory tests include nerve conduction studies, nerve biopsies, and cerebrospinal fluid examination.160,161

Diabetic Neuropathy

Diabetic neuropathy includes a wide range of clinical manifestations. Traditionally, it has been categorized anatomically (Table 32-11). For our purposes, the diabetic neuropathies can be classified into separate pain syndromes: polyneuropathy, mononeuropathy, radiculopathy, and amyotrophy162,163 (Table 32-12).

Depending on the criteria used to establish the diagnosis, the incidence of diabetic neuropathy varies from 5% to 60% of patients with the disease. Pirart noticed that the neuropathy rarely occurred in the young, and its prevalence increased from 7.5% at the time of discovery of diabetes mellitus to almost 50% after 25 years.164 Neuropathy may accompany both type 1 and type 2 diabetes mellitus. It also may occur in patients with diabetes after pancreatectomy and hemochromatosis. Several authors have noted the common concurrence of neuropathy, nephropathy, and retinopathy (diabetic triopathy).165

Symmetric Sensory Polyneuropathy

A symmetric sensory polyneuropathy is the most frequent form of peripheral nerve disorder in diabetic patients. It may occur acutely after a diabetic coma, as a result of poor serum glucose control, after initiation of therapy, or during periods of emotional stress.166

A loss of ankle jerks and vibratory sense in the feet should direct the clinician toward the diagnosis. Symptoms, which consist of tingling, numbness, and burning paresthesias, are generally confined to the lower extremities. A deep aching pain (described by patients as “arising from the bones”) that intensifies at night can affect the feet and legs. Symmetric distal sensory impairment occurs in a glove-and-stocking distribution.

Signs and symptoms of diabetic sensory neuropathy display considerable variability. At one extreme, patients show loss of position sense, decreased reflexes, and no pain. At the other end, they manifest cutaneous hyperesthesia, distal burning pain, and autonomic dysfunction but preserved reflexes and large fiber sensory function. Sural nerve biopsies from these patients reveal the involvement of both small myelinated and unmyelinated fibers.167

Other less common variants have been described. For example, Archer168 documented severe distal burning pain without sensory loss or autonomic features that occurred after rapid weight loss in men. The neuropathy subsided after these patients gained weight and had improved diabetic control.

The term diabetic pseudotabes refers to a variant that includes symmetric distal loss of cutaneous sensibility, joint position, and vibration, all leading to gait abnormalities and foot ulcers. Autonomic signs and symptoms, including atonic bladder and Argyll Robertson pupils, also may occur.

Neuropathy arthropathy, seen in advanced cases of sensory polyneuropathy, affects mainly the joints of the feet and, less commonly, the ankle. The interphalangeal and metatarsophalangeal joints are affected.169

Autonomic dysfunction almost always accompanies the sensory polyneuropathy in diabetes and has a wide range of clinical manifestations (Table 32-13). The disease affects both the longer sensory and autonomic fibers first. Some of the earliest changes involve vascular and sudomotor innervation of the legs. Hence, anhidrosis and an absence of piloerection may be first detected in the feet, but eventually ascend the legs in a symmetric fashion. Peripheral edema of unknown origin also frequently occurs with diabetic neuropathy.170

Focal and Multifocal Neuropathies

Diabetes most commonly affects the ulnar, median, radial, femoral, lateral femoral cutaneous, and peroneal nerves. The onset may be abrupt or insidious. These isolated peripheral nerve lesions often occur at sites common for external pressure palsies (e.g., carpal tunnel).

Diabetic Amyotrophy and Proximal Motor Neuropathy

Diabetic amyotrophy connotes a syndrome usually encountered in older patients that consists of asymmetric proximal muscle wasting in the lower limbs. The muscles commonly affected include the iliopsoas, quadriceps, and adductor muscles but not the hamstrings.171,172 Patients complain of pain, which is generally most severe at night, in the thigh muscles and lumbar region. The patellar reflex may be depressed, but sensation is maintained.

Uremic Neuropathy

Sixty to 70% of patients about to begin dialysis for chronic renal failure display neuropathic features.173,174 The progression of the neuropathy depends solely on the duration and severity of renal failure. Men seem to have a several-fold higher incidence than women.

The combined motor and sensory dysfunction that occurs with uremic neuropathy invariably occurs in a distal, symmetric distribution.175 The legs are affected before and more often than the upper extremities. This correlates with histopathologic studies that show a distal axonal degeneration, with shrinkage and nerve fiber loss predominantly involving larger fibers.

The exact cause of the neuropathy is unknown, although the accumulation of toxic substances with molecular weights of 300 to 2000 Daltons (the so-called middle-molecule hypothesis) that are not removed during hemodialysis have been implicated.176 Two other observations support the middle-molecule hypothesis as the source of neuropathy. One entails the striking remission of neuropathy after successful renal transplantation and the other the fact that peritoneal dialysis, which presumably passes toxic molecules more selectively than hemodialysis, is not associated with neuropathy despite having higher blood levels of urea and creatinine.

Uremic patients can have extremity pain from various causes. Nielsen177 noticed muscular cramps and the restless-leg syndrome in two thirds of patients in his series. The cramps, which also can occur during acute uremia, probably reflect muscular irritability in the presence of uremic toxins. They are not necessarily associated with any other signs and symptoms of neuropathy (e.g., slowing of conduction velocity). The restless-leg syndrome of Ekbom,178 characterized by night pain relieved by movement, is associated with clinical neuropathy. Dysesthesias can occur that range from the burning-feet type identical to that seen in alcoholic patients to painful tingling, electric shocks, or constrictive feelings around the ankles and feet. The diagnosis depends on demonstrating a neuropathy with symptomatic uremia and excluding other causes of neuropathy, such as toxins.

Gold Neuropathy

Gold has been used traditionally to treat rheumatoid arthritis. Common side effects of this drug include fever and rashes. The incidence of patients who have peripheral neuropathy after gold therapy is less than 1%. Such patients have painful paresthesias, followed by sudden onset of asymmetric weakness. They may have fever and rashes before the onset of the neuropathy.179 Controversy exists as to whether the neuropathy results from the direct toxic effect of the drug or from a hypersensitivity reaction.180

Perhexiline Neuropathy

Perhexiline maleate was introduced for the treatment of angina in the early 1970s. Peripheral neuropathy was seen in some patients who were treated with doses of 300 to 400 mg/day for 4 months to 1 year. These patients had pain and distal paresthesias, followed by severe distal and proximal muscle weakness. They also had a high incidence of bilateral papilledema, abnormal liver function tests, and weight loss. Perhexiline apparently causes cellular accumulation of abnormal gangliosides, particularly in Schwann cells and liver cells.181

Nitrofurantoin Neuropathy

Nitrofurantoin may cause peripheral neuropathy characterized by distal weakness and sensory loss. Pain and paresthesias are the common presenting symptoms.182 The neuropathy may occur soon after drug therapy begins. It is most commonly seen in patients with impaired renal function who have higher blood levels of the drug.183

Disulfiram Neuropathy

Disulfiram therapy for alcohol abuse rarely causes neuropathy.184 Affected patients generally have taken 1.0 or 1.5 g/day of this drug. They have paresthesias beginning in the lower extremities. The mechanism is unclear; however, carbon disulfide, a by-product of disulfiram, is a known neurotoxin.185

Carcinomatous Neuropathy

An association between malignant disease and peripheral neuropathy independent of metastases has been recognized for a long time. In 1948, Denny-Brown186 described two patients with carcinoma of the lung and sensory neuropathy from degeneration of dorsal root ganglion cells. Studies among different groups of workers revealed an incidence of clinical peripheral neuropathy in the range of 1.7% to 5% of patients with cancer.187,188 The highest incidence occurs among those with carcinoma of the lung, followed by those with carcinoma of the stomach, colon, and breast.

Most commonly, a combined sensorimotor neuropathy develops, but a pure sensory type also may occur.188 Painful dysesthesias that begin distally and spread proximally and aching pains characterize the sensory component. Tendon reflexes are depressed, and position and vibratory sense may be impaired. The neuropathy often precedes other symptoms of the neoplasm by a year. Women more commonly display this type of neuropathy. Its course is unaffected by the underlying disease state.

Pathologic changes associated with the sensory neuropathy include severe degeneration of dorsal nerve roots and the posterior columns.186 Axonal degeneration and segmental demyelination occur with the sensorimotor neuropathy.189 The etiology of these neuropathies remains unclear.

Vincristine Neuropathy

Casey and associates190 demonstrated that vincristine, a cancer chemotherapeutic agent, predictably produced a peripheral neuropathy distinct from that caused by the malignancy per se. Affected patients developed finger paresthesias, then painful cramping and weakness in the extensor muscles of their hands and wrists, and commonly lost their ankle reflexes. Symptoms improved somewhat after decreasing or discontinuing the drug. Presumably, the vincristine-induced breakdown of neurotubules and proliferation of neurofilaments in nerve cells plays a role in its neuropathic mechanism.191

Polymyalgia Rheumatica

(See Chap. 31)

Polymyalgia rheumatica is a clinical syndrome characterized by morning stiffness in the proximal portion of the extremities or torso.192 It occurs relatively commonly in persons older than 50; one study documented an annual incidence of 53.7 cases per 100,000 persons and a prevalence of 500 per 100,000.193 A close relationship exists between polymyalgia rheumatica and giant cell arteritis; polymyalgia rheumatica occurs in 40% to 60% of patients with giant cell arteritis.194 Hence, some authors suggest that polymyalgia rheumatica may be an expression of an underlying arteritis.

The presence of symptoms in two of the three commonly affected areas (neck, hip, or shoulder) for at least 1 month and evidence of a systemic process, such as an increased erythrocyte sedimentation rate (>40 mm/hour using the Westergren method) confirm the diagnosis.195 Some definitions also require a rapid response to small doses of corticosteroids. The presence of other diseases, such as rheumatoid arthritis, polymyositis, malignancy, or chronic infection, excludes the diagnosis.

The cause remains unknown. Reports of familial aggregation and the finding that the disease appears almost exclusively in whites suggest a genetic predisposition. Several results suggest a humoral or cellular immune basis. These include (1) the granulomatous histopathologic features of giant cell arteritis, (2) the presence of immunoglobulins and complement deposits adjacent to the elastic lamina in some involved temporal arteries, and (3) the finding that sera from patients with polymyalgia rheumatica contains increased levels of circulating immune complexes during active disease.196

These patients are generally in good health before polymyalgia rheumatica develops. Arthralgias and myalgias may occur either slowly or abruptly; they generally begin in one shoulder girdle. However, the disease soon becomes bilateral and eventually involves most of the tendinous attachments, and there is proximal muscle pain with movement (compare the joint pain in rheumatoid arthritis).197,198 Muscular strength is normal. Synovitis in the knees or sternoclavicular joints may be found. More than half the patients have systemic symptoms such as weight loss or a low-grade fever before the onset of muscle pain.197,198

Laboratory findings during the active phase include (1) a markedly elevated erythrocyte sedimentation rate (>100 mm/hour using the Westergren method), (2) a mild-to-moderate normochromic anemia, and (3) an increase in α2-globulin and fibrinogen.199 Significant normal laboratory values include serum creatine kinase, muscle biopsies, and EMG studies.

The differential diagnosis of polymyalgia rheumatica includes rheumatoid arthritis, polymyositis, and systemic processes (such as bacterial endocarditis). The absence of swelling and peripheral joint pain should distinguish polymyalgia rheumatica from arthritis. Polymyositis is characterized by muscle weakness, elevated muscle enzyme studies, and abnormal EMG studies.

Psoriatic Arthritis

Psoriatic arthritis is an inflammatory asymmetric polyarthritis found in patients with psoriasis. The cause is unknown, but up to 30% of patients are positive for HLA-B27 antigen.200 The onset of the arthritis generally follows the psoriasis by months or years. The course of arthritis may or may not parallel that of the skin lesions. The pattern of the arthritis is that of a typical inflammatory arthritis that affects predominantly the upper extremities. The proximal joints of the hands and feet are tender and swollen. The arthritis is limited to several joints and is asymmetric. There are no rheumatoid nodules. Laboratory tests do not show rheumatoid factor. Affected patients may have an increased erythrocyte sedimentation rate and anemia.200

The radiologic features of psoriatic arthritis include erosions of the articular surfaces and the so-called pencil-in-cup deformity observed in joints of the fingers and toes. The diagnosis depends on findings consistent with psoriasis and an accompanying inflammatory arthritis without rheumatoid factor or nodules.

Reiter’s Syndrome

Reiter’s syndrome is an asymmetric inflammatory arthritis coupled with urethritis or cervicitis. Classically, the syndrome also included conjunctivitis. The syndrome has two clinical forms. The postvenereal form occurs predominantly in young men; the postdysenteric form affects both sexes in all age groups. The actual pathogenesis of the disease involves infection of the urogenital tract or gut with one of several organisms in genetically susceptible patients. Sufferers generally have the HLA-B27 alloantigen.201

Clinically, the syndrome begins with an asymptomatic serous urethral discharge usually followed by conjunctivitis.201 Finally, the patient has an acute onset of inflammatory arthritis of the lower extremities. Keratoderma blennorrhagia frequently appear on the palms or soles. Painless mucocutaneous lesions may appear in the mouth, on the palms and soles, or on the glans penis.201

Synovial fluid analysis reveals an increased leukocyte count and inflammatory arthritis. The diagnosis, therefore, relies on documenting nonspecific urethritis or cervicitis without rheumatoid factor.

Gout

Gout is a painful disorder of the joints secondary to deposition of crystals of monosodium urate monohydrate. Urate values greater than 7.0 mg/dL in the plasma cause saturation; chronically elevated uric acid leads to gouty attacks. Hyperuricemia, per se, is not synonymous with gout, and most hyperuricemic patients are asymptomatic. Men tend to have higher serum uric acid levels, and more than 95% of cases occur in adult men. Hyperuricemic patients also are prone to acute nephrolithiasis, and approximately 20% of gout sufferers have attacks of renal colic before gouty attacks.202

The pathogenesis of an acute gouty attack after years of chronically elevated uric acid levels probably involves crystal deposition and resultant phagocytosis by leukocytes, leading to activation of Hageman factor, coating of crystals with gamma globulins, and complement activation.202 Lowering the local tissue pH then results in additional precipitation of urate crystals.

Initially, gouty arthritis usually attacks a single joint and is exquisitely painful. Affected patients may describe prior mild attacks (twinges). The distal lower extremities, particularly the great toe (podagra), bear the brunt of the attacks. The following are involved in order of decreasing frequency: instep, ankle, heel, knee, and upper extremities. The attacks may be triggered by trauma, alcohol, surgery, or dietary excesses. Affected patients may have accompanying systemic signs, such as fever, increased erythrocyte sedimentation rate, and leukocytosis. The attacks abate spontaneously and are separated by periods when the patient is completely asymptomatic.203

In untreated patients, the hyperuricemia causes deposits of monosodium urate (tophi) in tendons, membranes, and soft tissues. However, these tophi rarely occur before the onset of acute gouty attacks.

Monosodium urate crystals detected using polarized-light microscopy in the leukocytes from synovial aspirates confirms the diagnosis. These crystals appear needle shaped and negatively birefringent. The leukocyte count of the synovial fluid during attacks may vary from 1,000 to 70,000/dL. Extracellular crystals may be found in the synovial fluid during asymptomatic periods. In the absence of microscopic confirmation, the diagnosis can be presumed by the combination of (1) the presence of hyperuricemia, (2) a history typical of gout, and (3) response to colchicine.

Pseudogout

Pseudogout is a crystalline arthritis seen in elderly patients that is characterized by calcium deposits in articular cartilage and caused by release of calcium pyrophosphate crystals into the joint space. There is a definite association with hyperparathyroidism, osteoarthritis, and hemochromatosis. Pseudogout also is seen in metabolic disorders such as Wilson’s disease, hypothyroidism, gout, and ochronosis.204

Patients with pseudogout have elevated fluid levels of inorganic pyrophosphate. Crystals then form in articular cartilage (chondrocalcinosis). The crystals found in synovial fluid are released from the cartilage, possibly after trauma that disrupts the cartilage or as a result of lowering the Ca2+ levels in the synovium. Regardless, the presence of calcium pyrophosphate crystals then causes a classic inflammatory response, and polymorphonuclear leukocytes enter the joint.204

The acute arthritic attacks of pseudogout are usually monoarticular. The knee is the most common site. The joint is warm, swollen, and painful. The attacks may be preceded by surgery or trauma.

Showing calcium pyrophosphate dihydrate crystals in the synovial fluid during acute attacks confirms the diagnosis. Under a polarized-light microscope, the crystals appear as positive birefringent blunt rods. They may be intra- or extracellular. Radiologically, these patients have calcium deposits in their articular cartilage.204

Osteoarthritis

Osteoarthritis affects predominantly older patients. Articular cartilage absorbs the bulk of joint stress, but over time degenerates. Increased mechanical pressure appears to provoke an elaboration of chondrocytes and synovial fluid. The water and proteoglycan content decreases, and focal cartilage erosions appear. Eventually, joint margins reveal new bone and thickened synovium. The end point of this process is a progressive loss of chondrocytes, development of fissures, osteophyte formation, and replacement of cartilage with bone.205

Patients complain of a diffuse, aching pain that usually is limited to one or several joints. Rest relieves the pain, and activity aggravates it. Affected individuals may describe an increase in symptoms with changes in weather. Stiffness generally does not become a major symptom.206

Painless Heberden’s nodes, which are prominent knobs along the medial and lateral aspect of distal interphalangeal joints, and Bouchard’s nodes, which are found on the proximal interphalangeal joints, are a common finding. Occasionally, the joints may appear swollen and warm as a result of the inflammatory synovitis that accompanies an exacerbation of symptoms. The pattern of joint involvement (proximal interphalangeal and distal interphalangeal involvement with sparing of the wrist joint) helps distinguish osteoarthritis from rheumatoid arthritis.206

Radiologic findings typical of osteoarthritis include loss of joint space, presence of osteophytes, and subchondral sclerosis. Synovial fluid aspirate shows a low leukocyte count and predominantly mononuclear cells.

Rheumatoid Arthritis

Inflammatory synovitis, which results in eventual cartilage and bone destruction, distinguishes rheumatoid arthritis. The cause remains unknown, but genetics plays a role, as witnessed by its association with HLA-DR4.207 Women are affected threefold more than men. Symptoms most frequently begin between the ages of 35 and 50 years.

Systemic symptoms, such as fatigue, generalized weakness, and anorexia, generally precede the joint pain of rheumatoid arthritis. The pain affects joints in a symmetric distribution and is aggravated by passive or active motion.208 Morning stiffness is a universal feature and is an important criterion for the diagnosis. Physical examination reveals synovitis with accompanying swelling, tenderness, and increased warmth in the joints. The pain is secondary to joint swelling, which stretches the joint capsule. The wrist joints, proximal interphalangeal joints, and metacarpophalangeal joints usually are involved, but rarely the distal interphalangeal joints. Hand involvement with destruction of cartilage, tendons, and ligaments can cause a number of typical deformities: (1) boutonnäire deformity (which results from flexion deformity of the proximal interphalangeal joints and extension of the distal interphalangeal joints), (2) swan-neck deformity (which results from hyperextension of proximal joint and flexion of distal interphalangeal joints), and (3) radial deviation at the wrist with ulnar deviation at the digits.

Although no specific diagnostic tests exist, the American Rheumatism Association has developed a list of criteria to aid in the diagnosis (Table 32-14). Affected patients may carry the rheumatoid factor (autoantibodies to immunoglobulin G) in their serum. In addition, there may be a normochromic normocytic anemia. Most patients also have increased erythrocyte sedimentation rates. Evaluation of the synovial fluid shows increased leukocytes with polymorphonuclear leukocytes, suggesting an inflammatory process.

Muscular Disorders: Introduction

Most skeletal muscle pain is associated with exercise or trauma.209 The pain is related temporally to exercise and is of limited duration. Muscle pain is transmitted by the thin myelinated fibers (group III or Aδ) and unmyelinated fibers (group IV or C). These afferent fibers have unencapsulated branching endings throughout the muscle with increasing density in the region of fascia, tendons, and aponeuroses. There are two types of muscle pain receptors: chemoreceptors and mechanoreceptors. The former respond to chemical changes in the environment; the latter are affected by mechanical changes. These receptors can be stimulated by potassium ions, hydrogen ions, histamine, serotonin, or bradykinin.210–213

Patients most often describe muscle pain or myalgia as dull or aching in quality. The term cramp214 refers to an acute onset of a painful contraction, and although they can be intensely painful, the quality of pain is described as dull. A muscle contracture is similar to a cramp, but of longer duration; it is seen in disorders of muscle metabolism. Muscle spasms are reflex contractions of muscles surrounding injured tissues or structures (e.g., abdominal muscle spasm associated with an inflamed appendix). Myotonia is tonic spasm of a muscle after voluntary contraction caused by a high-frequency firing of muscle fibers. Tetany refers to involuntary cramplike spasms associated with reductions in ionizable calcium or magnesium and attributed to repetitive firing in motor axons. Dystonia is an involuntary contraction of muscle that involves both agonist and antagonist activities.

Myalgias can be difficult to distinguish from pain arising from other sites. Pain from the joints is well localized and exacerbated by movement. Patients poorly localize bone pain, but it tends to have a deep, boring quality that generally worsens at night. One must determine whether the muscle pain is accompanied by weakness (failure to achieve strength) or fatigue (failure to maintain strength). As a rule, proximal muscle weakness suggests primary muscle disease; peripheral and localized pain and weakness tend to occur with nerve entrapments. Excessive fatigability is seen in disorders of muscle metabolism, myotonic disorders, and mitochondrial myopathies.

The relationship of diet, alcohol intake, and fasting to muscle pain should be determined. Drinking bouts may precipitate myopathy and myoglobinuria in alcoholic patients. Fasting or prolonged exercise with fasting may precipitate pain and weakness in patients with carnitine palmityl transferase deficiency. A diet lacking in vitamin D may lead to osteomalacic myopathy with bone and muscle pain.

Signs of muscle pain are confined to weakness, fatigability, tenderness, and swelling. Muscle swelling per se is rare, but it may occur in the polymyositis-dermatomyositis complex, acute alcoholic myopathy, phosphofructokinase deficiency, and myophosphorylase.

Useful clinical tests to evaluate muscle pain and disease include (1) presence of myoglobinemia and myoglobinuria, (2) serum creatine kinase levels, (3) erythrocyte sedimentation rate, (4) EMG, (5) quantitation of muscle force generation, (6) exercise testing, (7) ischemic forearm tests, and (8) muscle biopsy.

Myoglobin is a muscle protein involved in oxygen storage. Muscle breakdown or rhabdomyolysis can release myoglobin molecules, which may pass into the urine as a result of their small size (molecular weight 17,500 Daltons) and precipitate oliguric renal failure. Myoglobinemia and myoglobinuria also may arise from various other causes.215

Creatine kinase is a muscle enzyme that catalyzes the breakdown and synthesis of phosphoryl creatine. Abnormal increases in serum levels of creatine kinase may indicate muscle damage; however, exercise and intramuscular injections may also cause elevated serum levels.216 This enzyme is elevated in muscular dystrophies, acute rhabdomyolysis, McArdle’s disease, and polymyositis-dermatomyositis complex.

EMG helps distinguish myopathic from neuropathic diseases. Fibrillation and giant action potentials characterize denervation from entrapment; myopathies are associated with brief, small-amplitude motor unit potentials. EMG can also provide information about which nerve roots are involved.

Quantitation217 of muscle force generation can be done using a hand-held dynamometer or muscle-testing chair. The latter involves electrical activation of the quadriceps with large surface electrodes and provides data concerning muscle fatigability and frequency characteristics. These tools can track the progression of the disease or the distribution of muscle weakness.

Exercise testing uses submaximal effort at approximately 70% of previously determined maximal rate while simultaneously measuring heart rate and blood pressure and levels of blood lactate and pyruvate. Exercise testing can elicit symptoms in patients with muscle disorders, and it is a particularly useful tool in those with suspected metabolic disorders.

The simplicity and advantages of muscle biopsy, particularly in the diagnosis of inflammatory myopathies and mitochondrial myopathies, have been well described. Percutaneous needle biopsy is atraumatic and appears to be as reliable clinically as an open biopsy of muscle.

Muscle Pain and Exercise

Normally, muscle pain with exercise can occur under two situations. Firstly, it can occur with exercise and increase in intensity until the muscle relaxes. When the voluntary contraction stops, the pain disappears immediately. This type of concentric contraction or positive work has a high metabolic cost.218 The mechanism for this type of ischemic pain appears to be an accumulation of metabolites that occludes blood vessels and stops the blood supply to the muscle. Secondly, vigorous exercise leads to delayed muscle pain. This results from eccentric muscle contractions or negative work where the muscle is lengthened during a contraction.219 The mechanism of this delayed soreness after eccentric contraction is unknown; however, the muscles show evidence of damage, both biochemically and morphologically.220

Cramps are painful involuntary contractions of acute onset that occur more often at night. Stretching of voluntary muscle produces an involuntary contraction that cannot be relaxed. The cramping results from spontaneous firing of groups of anterior horn cells with motor unit contractions. Cramps in the calf muscles generally are considered benign. More generalized cramps, however, may be a sign of muscle disease.214 Cramps that recur and are confined to one specific muscle group may indicate nerve root entrapment. They also occur with increasing frequency during pregnancy, with electrolyte imbalances, and in patients undergoing hemodialysis. Physical examination during muscle cramping shows a taut, contracted muscle. This can be a distinguishing feature of the cramps caused by intermittent claudication, in which patients have cramplike pain without muscle contraction. The cause of the pain is not understood completely, but it may involve an accumulation of metabolites or a relative ischemia of the muscle. There is a benign form of muscle cramping (idiopathic cramp syndrome) in which no neuromuscular disorder is apparent.

The stiff-person syndrome refers to a progressive form of painful muscle spasm.221,222 These patients have a boardlike stiffness of their muscles, paroxysms of cramping, and a normal sensory examination. The muscle stiffness resolves during sleep or after the administration of large doses of diazepam. Isaac’s syndrome is manifested by excessive sweating, widespread fasciculations, generalized stiffness, and continuous motor unit activity that persists during sleep and anesthesia.223

Tetany results from a reduction in ionizable calcium and magnesium. This leads to increased neuromuscular irritability and involuntary, cramplike spasms. The actual level of ionizable calcium needed to produce tetany varies individually and is related to the concentration of other electrolytes in the extracellular fluid. Hyperventilation and ischemia increase the tendency for spasm to occur. The full clinical spectrum of tetany is manifested by perioral and peripheral paresthesias, carpal spasm, pedal spasm, laryngospasm, Chvostek’s and Trousseau’s signs, and Q-T prolongation on an electrocardiogram. Hypocalcemia causes unstable depolarization of the nerve fiber axons. Thus, there is increased sensitivity of the facial nerve to percussion (Chvostek’s sign) and spasm with ischemia (Trousseau’s sign).

Drugs also may be a source of muscle pain. Focal myopathy may occur after intramuscular injections from local irritation (e.g., paraldehyde) or after histamine release (opiates).

Painful proximal myopathy with tenderness and weakness can occur after administration of clofibrate, aminocaproic acid, and emetine, particularly after prolonged treatment and elevated serum blood levels. Serum levels of muscle enzymes are elevated, and myoglobinuria may occur. Muscle biopsy reveals multifocal muscle-fiber necrosis. A painful, necrotizing proximal myopathy with an associated peripheral neuropathy has been reported in patients treated with vincristine.224 Chronic hypokalemia from drug use generally results in painless weakness and hypotonia. However, painful quadriparesis and myoglobinuria have been reported after administration of amphotericin B and chlorthalidone.224 Finally, some drugs may cause myalgias and cramps from unknown mechanisms. These drugs include lithium carbonate, danazol, isoetharine, cimetidine, and the diuretics metolazone and bumetanide.224

The glycogen storage diseases constitute a group of diseases in which an inborn error of glycogen metabolism exists. When the energy supply for muscle contractions is compromised, muscle fatigue and pain may result.

McArdle’s disease, or type V, first manifests during adolescence with cramps, weakness, and contractions induced by vigorous exercise. The cramps and pain are relieved by rest, but the contractions may persist for hours. Moderate exercise may be well tolerated. This disorder is caused by a deficiency of the enzyme myophosphorylase. Tarui’s disease, or type VII, is a rare enzyme deficiency that begins during early childhood and is characterized by exercise-induced pain without muscle contractions.

Idiopathic Polymyositis and Dermatomyositis

Idiopathic polymyositis and dermatomyositis refer to a category of relatively common diseases that may affect striated muscle only (polymyositis) or skin and muscle (dermatomyositis). They also may occur associated with arthritis, connective tissue diseases, or malignancy. Pain may be a prominent feature.225

The cause of polymyositis-dermatomyositis is unknown. Theories include autoimmune processes or a possible viral mechanism.226 Polymyositis-dermatomyositis may have several different clinical presentations. Polymyositis, confined to striated muscles, begins with an insidious onset over 3 to 6 months of a symmetric weakness of the proximal limb and trunk muscles. In a minority of patients, a febrile illness precedes this subacute muscle weakness. Women outnumber men by 2 to 1, and the age range is generally 30 to 60 years.226 Rarely, severe muscle weakness occurs acutely with associated myoglobinuria.

Affected patients first notice weakness of the proximal limb muscles when climbing steps, rising from chairs, or combing their hair. The muscle pain that occurs in a minority of patients is of a constant aching quality and follows the same distribution as the weakness.227

Physical examination shows a symmetric weakness of the muscles of the hips, shoulders, and thighs. Weakness of the facial and pharyngeal muscles is also common. The muscles are not tender to examination, and atrophy is not a prominent feature.

Dermatomyositis is characterized by skin lesions that may precede, accompany, or follow the muscle involvement. The rash may take one of several forms: localized erythema, maculopapular eruption, or exfoliative dermatitis. The areas most predisposed include the eyelids, the bridge of the nose, and the cheeks. The extensor surfaces of elbows, knees, and knuckles may develop flat plaques known as Gottron’s papules.228 The myositis that accompanies these skin changes is indistinguishable from polymyositis.

Polymyositis or dermatomyositis may occur associated with an underlying neoplasm (group 3) (Table 32-15). The muscle and skin manifestations may antedate the discovery of a carcinoma by 1 to 2 years. This generally occurs with bronchogenic carcinoma.229 The actual incidence of underlying carcinomas with polymyositis is 2% to 3%; it rises to 15% to 20% with dermatomyositis. Idiopathic polymyositis and dermatomyositis occur less frequently in children than in adults. The childhood form constitutes 8% to 22% of cases in most large series. The clinical features of the disease in children are similar to those in adults; however, children have a high incidence of vasculitis.230

Finally, polymyositis or dermatomyositis may occur in collagen vascular disease. Mixed connective tissue diseases also may have an accompanying arthritis that limits joint motion and further diminishes strength.

Laboratory findings common to all the clinical subsets of dermatomyositis-polymyositis include (1) elevated serum levels of skeletal muscle enzymes, particularly creatine kinase (which may be elevated 10–80 times normal); (2) sometimes positive tests for circulating rheumatoid factor and antinuclear antibody; (3) myoglobinuria; (4) EMG studies showing an increase in the insertional activity of the muscle with numerous fibrillation potentials and positive sharp waves at rest231; and (5) resultant muscle biopsy consisting of inflammatory infiltrates (lymphocytes and histiocytes) between the muscle fibers and around the small blood vessels in the muscle.232

Other Forms of Polymyositis

Trichinosis in humans is contracted by ingesting meat (usually pork) containing the larvae of Trichinella spiralis. Once freed from their cysts by gastric digestion, the larvae migrate into the intestinal mucosa, where copulation occurs. The offspring (up to 1,500 per female) enter the circulation and are distributed to muscles throughout the body. After entering the muscle, the larvae grow and become encysted and eventually calcified. The life cycle then ends. The muscles most affected include the eye muscles, diaphragm, deltoid, pectorals, and gastrocnemius.233

The clinical severity of the symptoms correlates well with the number of larvae disseminated to the tissues. Patients with less than 10 larvae per gram of muscle are asymptomatic; those with greater than 50 larvae per gram of muscle display gastrointestinal symptoms (e.g., diarrhea and abdominal pain) 1 to 2 days after the infected meat is eaten. This brief period is followed by a stage of muscular invasion that may last up to 6 weeks. Affected patients have muscle pain and tenderness with accompanying weakness. They also may have fever, periorbital edema, conjunctivitis, and a maculopapular rash. Severe cases develop various central nervous system manifestations. Finally, myocarditis may occur, with resultant congestive heart failure and electrocardiographic changes.

Laboratory findings include an eosinophilic leukocytosis (>500 eosinophils/μL) within the first few weeks. Serologic tests may turn positive within the first month and remain positive for years. A definitive diagnosis is made by muscle biopsy. A portion of muscle is excised from the gastrocnemius or deltoid and examined microscopically for the presence of larvae or calcified cysts.234

Eosinophilic Myositis

Eosinophilic myositis consists of three separate clinical entities: (1) eosinophilic fasciitis, (2) eosinophilic monomyositis, and (3) eosinophilic polymyositis.235 The first entity involves tenosynovitis with local pain and stiffness of unknown cause. It progresses from one muscle to another but generally is confined to an extremity. These patients have no systemic manifestations. The muscle, per se, is not involved, and biopsy of fascia and tendon sheaths reveals an inflammatory process with eosinophilic leukocytes.

The second entity includes muscle pain confined to one calf muscle and associated with a tender mass. A muscle biopsy shows an inflammatory necrosis and edema of interstitial tissues. Eosinophilic polymyositis, as described by Layzer and colleagues,236 is characterized by multiple systemic problems (congestive heart failure, anemia, and pulmonary infiltrates) plus painful proximal muscle weakness. The muscles themselves are swollen and exquisitely tender.237