Neuropathic Joint Disease
Neuropathic joint disease (Charcot's joint) is a progressive destructive arthritis associated with loss of pain sensation, proprioception, or both. Normal muscular reflexes that modulate joint movement are decreased. Without these protective mechanisms, joints are subjected to repeated trauma, resulting in progressive cartilage and bone damage. Neuropathic arthropathy was first described by Jean-Martin Charcot in 1868 in patients with tabes dorsalis. The term Charcot joint is commonly used interchangeably with neuropathic joint. Today, diabetes mellitus is the most frequent cause of neuropathic joint disease (Fig. 336-1). A variety of other disorders are associated with neuropathic arthritis including leprosy, yaws, syringomyelia, meningomyelocele, congenital indifference to pain, peroneal muscular atrophy (Charcot-Marie-Tooth disease), and amyloidosis. An arthritis resembling neuropathic joint disease has been reported in patients who have received frequent intraarticular glucocorticoid injections into a weight-bearing joint, but this is a rare complication. The distribution of joint involvement depends on the underlying neurologic disorder (Table 336-2). In tabes dorsalis, knees, hips, and ankles are most commonly affected; in syringomyelia, the glenohumeral joint, elbow, and wrist; and in diabetes mellitus, the tarsal and tarsometatarsal joints are most commonly affected.
Charcot arthropathy associated with diabetes mellitus. Lateral foot radiograph demonstrating complete loss of the arch due to bony fragmentation and dislocation in the midfoot. (Courtesy of Andrew Neckers, MD and Jean Schils, MD; with permission.)
Table 336-2 Disorders Associated with Neuropathic Joint Disease |Favorite Table|Download (.pdf)
Table 336-2 Disorders Associated with Neuropathic Joint Disease
|Meningomyelocele||Congenital indifference to pain|
|Syringomyelia||Peroneal muscular atrophy|
Pathology and Pathophysiology
The pathologic changes in the neuropathic joint are similar to those found in the severe osteoarthritic joint. There is fragmentation and eventual loss of articular cartilage with eburnation of the underlying bone. Osteophytes are found at the joint margins. With more advanced disease, erosions are present on the joint surface. Fractures, devitalized bone, intraarticular loose bodies, and microscopic fragments of cartilage and bone may be present.
At least two underlying mechanisms are believed to be involved in the pathogenesis of neuropathic arthritis. An abnormal autonomic nervous system is thought to be responsible for the dysregulated blood flow to the joint with subsequent resorption of bone. Loss of bone, particularly in the diabetic foot, may be the initial finding. With the loss of deep pain, proprioception, and protective neuromuscular reflexes, the joint is subjected to repeated microtrauma, resulting in ligamental tears and bone fractures. The mechanism of injury that occurs following frequent intraarticular glucocorticoid injections is thought to be due to the analgesic effect of glucocorticoids leading to overuse of an already damaged joint, which results in accelerated cartilage damage, although steroid-induced cartilage damage be more common in some animal species than in humans. It is not understood why only a few patients with neuropathy develop clinically evident neuropathic arthritis.
Neuropathic joint disease usually begins in a single joint and then becomes apparent in other joints, depending on the underlying neurologic disorder. The involved joint progressively becomes enlarged due to bony overgrowth and synovial effusion. Loose bodies may be palpated in the joint cavity. Joint instability, subluxation, and crepitus occur as the disease progresses. Neuropathic joints may develop rapidly, and a totally disorganized joint with multiple bony fragments may evolve in a patient within weeks or months. The amount of pain experienced by the patient is less than would be anticipated based on the degree of joint damage. Patients may experience sudden joint pain from intraarticular fractures of osteophytes or condyles.
Neuropathic arthritis is encountered most often in patients with diabetes mellitus, with the incidence estimated in the range of 0.5%. The usual age of onset is ⩾50 years, following several years of diabetes, but exceptions occur. The tarsal and tarsometatarsal joints are most often affected, followed by the metatarsophalangeal and talotibial joints. The knees and spine are occasionally involved. Patients often attribute the onset of foot pain to antecedent trauma such as twisting their foot. Neuropathic changes may develop rapidly following a foot fracture or dislocation. Swelling of the foot and ankle are often present. Downward collapse of the tarsal bones leads to convexity of the sole, referred to as a “rocker foot.” Large osteophytes may protrude from the top of the foot. Calluses frequently form over the metatarsal heads and may lead to infected ulcers and osteomyelitis. The value of protective inserts and orthotics, as well as regular foot examination, cannot be overstated. Radiographs may show resorption and tapering of the distal metatarsal bones. The term Lisfranc fracture-dislocation is sometimes used to describe the destructive changes at the tarsometatarsal joints.
The diagnosis of neuropathic arthritis is based on the clinical features and characteristic radiographic findings in a patient with an underlying sensory neuropathy. The differential diagnosis of neuropathic arthritis depends upon the severity of the process and includes osteomyelitis, osteonecrosis, advanced osteoarthritis, stress fractures, and CPPD. Radiographs in neuropathic arthritis initially show changes of osteoarthritis with joint space narrowing, subchondral bone sclerosis, osteophytes, and joint effusions followed later by marked destructive and hypertrophic changes. The radiographic findings of neuropathic arthritis may be difficult to differentiate from those of osteomyelitis, especially in the diabetic foot. The joint margins in a neuropathic joint tend to be distinct, while in osteomyelitis, they are blurred. Imaging studies may be helpful, but cultures of tissue from the joint are often required to exclude osteomyelitis. MRI and bone scans using indium 111–labeled white blood cells or indium 111–labeled immunoglobulin G, which will show an increased uptake in osteomyelitis but not in a neuropathic joint may be useful. A technetium bone scan will not distinguish osteomyelitis from neuropathic arthritis, as increased uptake is observed in both. The joint fluid in neuropathic arthritis is noninflammatory; may be xanthochromic or even bloody; and may contain fragments of synovium, cartilage, and bone. The finding of calcium pyrophosphate dihydrate crystals supports the diagnosis of crystal-associated arthropathy. In the absence of such crystals, an increased number of leukocytes may indicate osteomyelitis.
Treatment: Neuropathic Joint Disease
The primary focus of treatment is to stabilize the joint. Treatment of the underlying disorder, even if successful, does not usually affect established joint disease. Braces and splints are helpful. Their use requires close surveillance, because patients may be unable to appreciate pressure from a poorly adjusted brace. In the diabetic patient, early recognition and treatment of a Charcot's foot by prohibiting weight bearing of the foot for at least eight weeks may possibly prevent severe disease from developing. Fusion of an unstable joint may improve function and reduce pain, but nonunion is frequent, especially when immobilization of the joint is inadequate.
Hypertrophic Osteoarthropathy and Clubbing
Hypertrophic osteoarthropathy (HOA) is characterized by clubbing of digits and, in more advanced stages, by periosteal new bone formation and synovial effusions. HOA may be primary or familial and begin in childhood. Secondary HOA is associated with intrathoracic malignancies, suppurative and some hypoxemic lung diseases, congenital heart disease, and a variety of other disorders. Clubbing is almost always a feature of HOA but can occur as an isolated manifestation (Fig. 336-2). The presence of clubbing in isolation may be congenital or represent either an early stage or one element in the spectrum of HOA. The presence of isolated acquired clubbing has the same clinical significance as clubbing associated with periostitis.
Clubbing of fingers. (Reprinted from the Clinical Slide Collection on the Rheumatic Diseases, Copyright 1991, 1995. Used by permission of the American College of Rheumatology.)
Pathology and Pathophysiology of Acquired Hoa
In HOA, the bone changes in the distal extremities begin as periostitis followed by new bone formation. At this stage, a radiolucent area may be observed between the new periosteal bone and subjacent cortex. As the process progresses, multiple layers of new bone are deposited, which become contiguous with the cortex and result in cortical thickening. The outer portion of bone is laminated in appearance, with an irregular surface. Initially, the process of periosteal new bone formation involves the proximal and distal diaphyses of the tibia, fibula, radius, and ulna and, less frequently, the femur, humerus, metacarpals, metatarsals, and phalanges. Occasionally, scapulae, clavicles, ribs, and pelvic bones are also affected. The adjacent interosseous membranes may become ossified. The distribution of the bone manifestations is usually bilateral and symmetric. The soft tissue overlying the distal third of the arms and legs may be thickened. Proliferation of connective tissue occurs in the nail bed and volar pad of digits, giving the distal phalanges a clubbed appearance. Small blood vessels in the clubbed digits are dilated and have thickened walls. In addition, the number of arteriovenous anastomoses is increased.
Several theories have been suggested for the pathogenesis of HOA, but many have been disproved or have not explained the development in all clinical disorders associated with HOA. Previously proposed neurogenic and humoral theories are no longer considered likely explanations for HOA. Recent studies have suggested a role for platelets in the development of HOA. It has been observed that megakaryocytes and large platelet particles, present in venous circulation, were fragmented in their passage through normal lung. In patients with cyanotic congenital heart disease and in other disorders associated with right-to-left shunts, these large platelet particles bypass the lung and reach the distal extremities, where they can interact with endothelial cells. Platelet-endothelial activation in the distal portion of extremities may result in the release of platelet-derived growth factor (PDGF) and other factors leading to the proliferation of connective tissue and periosteum. Stimulation of fibroblasts by PDGF and transforming growth factor β results in cell growth and collagen synthesis. Elevated plasma levels of von Willebrand factor antigen have been found in patients with both primary and secondary forms of HOA, indicating endothelial activation or damage. Abnormalities of collagen synthesis have been demonstrated in the involved skin of patients with primary HOA. Other factors are undoubtedly involved in the pathogenesis of HOA, and further studies are needed to better understand this disorder.
Primary or familial HOA, also referred to as pachydermoperiostitis or Touraine-Solente-Golé syndrome, usually begins insidiously at puberty. In a smaller number of patients, the onset is in the first year of life. The disorder is inherited as an autosomal dominant trait with variable expression and is nine times more common in boys than in girls. Approximately one-third of patients have a family history of primary HOA.
Primary HOA is characterized by clubbing, periostitis, and unusual skin features. A small number of patients with this syndrome do not express clubbing. The skin changes and periostitis are prominent features of this syndrome. The skin becomes thickened and coarse. Deep nasolabial folds develop, and the forehead may become furrowed. Patients may have heavy-appearing eyelids and ptosis. The skin is often greasy, and there may be excessive sweating of the hands and feet. Patients may also experience acnevulgaris, seborrhea, and folliculitis. In a few patients, the skin over the scalp becomes very thick and corrugated, a feature that has been descriptively termed cutis verticis gyrata. The distal extremities, particularly the legs, become thickened owing to proliferation of new bone and soft tissue; when the process is extensive, the distal lower extremities resemble those of an elephant. The periostitis is usually not painful, because it may be in secondary HOA. Clubbing of the fingers may be extensive, producing large, bulbous deformities and clumsiness. Clubbing also affects the toes. Patients may experience articular and periarticular pain, especially in the ankles and knees, and joint motion may be mildly restricted owing to periarticular bone overgrowth. Noninflammatory effusions occur in the wrists, knees, and ankles. Synovial hypertrophy is not found. Associated abnormalities observed in patients with primary HOA include hypertrophic gastropathy, bone marrow failure, female escutcheon, gynecomastia, and cranial suture defects. In patients with primary HOA, the symptoms disappear when adulthood is reached.
HOA secondary to an underlying disease occurs more frequently than primary HOA. It accompanies a variety of disorders and may precede clinical features of the associated disorder by months. Clubbing is more frequent than the full syndrome of HOA in patients with associated illnesses. Because clubbing evolves over months and is usually asymptomatic, it is often recognized first by the physician and not the patient. Patients may experience a burning sensation in their fingertips. Clubbing is characterized by widening of the fingertips, enlargement of the distal volar pad, convexity of the nail contour, and the loss of the normal 15° angle between the proximal nail and cuticle. The thickness of the digit at the base of the nail is greater than the thickness at the distal interphalangeal joint. An objective measurement of finger clubbing can be made by determining the diameter at the base of the nail and at the distal interphalangeal joint of all 10 digits. Clubbing is present when the sum of the individual digit ratios is >10. At the bedside, clubbing can be appreciated by having the patient place the dorsal surface of the distal phalanges of the fourth fingers together with the nails of the fourth fingers opposing each other. Normally, an open area is visible between the bases of the opposing fingernails; when clubbing is present, this open space is no longer visible. The base of the nail feels spongy when compressed, and the nail can be easily rocked on its bed. When clubbing is advanced, the finger may have a drumstick appearance, and the distal interphalangeal joint can be hyperextended. Periosteal involvement in the distal extremities may produce a burning or deep-seated aching pain. The pain can be quite incapacitating and is aggravated by dependency and relieved by elevation of the affected limbs. Pressure applied over the distal forearms and legs or gentle percussion of the distal long bones like the tibia may be quite painful.
Patients may experience joint pain, most often in the ankles, wrists, and knees. Joint effusions may be present; usually, they are small and noninflammatory. The small joints of the hands are rarely affected. Severe joint or long bone pain may be the presenting symptom of an underlying lung malignancy and may precede the appearance of clubbing. In addition, the progression of HOA tends to be more rapid when associated with malignancies, most notably bronchogenic carcinoma. Noninflammatory but variably painful knee effusions may occur prior to the appearance of clubbing and symptoms of distal periostitis. Unlike primary HOA, excessive sweating and oiliness of the skin and thickening of the facial skin are uncommon in secondary HOA.
HOA occurs in 5–10% of patients with intrathoracic malignancies, the most common being bronchogenic carcinoma and pleural tumors (Table 336-3). Lung metastases infrequently cause HOA. HOA is also seen in patients with intrathoracic infections, including lung abscesses, empyema, bronchiectasis, and chronic obstructive lung disease, but uncommonly in pulmonary tuberculosis. HOA may also accompany chronic interstitial pneumonitis, sarcoidosis, and cystic fibrosis. In the latter, clubbing is more common than the full syndrome of HOA. Other causes of clubbing include congenital heart disease with right-to-left shunts, bacterial endocarditis, Crohn's disease, ulcerative colitis, sprue, and neoplasms of the esophagus, liver, and small and large bowel. In patients with congenital heart disease with right-to-left shunts, clubbing alone occurs more often than the full syndrome of HOA.
Table 336-3 Disorders Associated with Hypertrophic Osteoarthropathy |Favorite Table|Download (.pdf)
Table 336-3 Disorders Associated with Hypertrophic Osteoarthropathy
Bronchogenic carcinoma and other neoplasms
Lung abscesses, empyema, bronchiectasis
Chronic interstitial pneumonitisCystic fibrosis
Chronic obstructive lung disease
Inflammatory bowel disease
Neoplasms: esophagus, liver, bowel
Cyanotic congenital heart disease
Subacute bacterial endocarditis
Infected arterial graftsa
Aneurysm of major extremity arterya
Patent ductus arteriosusb
Arteriovenous fistula of major extremity vessela
Thyroid (thyroid acropachy)
Hyperthyroidism (Graves' disease)
Unilateral clubbing has been found in association with aneurysms of major extremity arteries, with infected arterial grafts, and with arteriovenous fistulas of brachial vessels. Clubbing of the toes but not fingers has been associated with an infected abdominal aortic aneurysm and patent ductus arteriosus. Clubbing of a single digit may follow trauma and has been reported in tophaceous gout and sarcoidosis. While clubbing occurs more commonly than the full syndrome in most diseases, periostitis in the absence of clubbing has been observed in the affected limb of patients with infected arterial grafts.
Hyperthyroidism (Graves' disease), treated or untreated, is occasionally associated with clubbing and periostitis of the bones of the hands and feet. This condition is referred to as thyroid acropachy. Periostitis may be asymptomatic and occurs in the midshaft and diaphyseal portion of the metacarpal and phalangeal bones. Significant hand joint pain may occur; this may respond to successful therapy of the thyroid dysfunction. The long bones of the extremities are seldom affected. Elevated levels of long-acting thyroid stimulator are found in the serum of these patients.
The laboratory abnormalities reflect the underlying disorder. The synovial fluid of involved joints has <500 white cells per microliter, and the cells are predominantly mononuclear. Radiographs show a faint radiolucent line beneath the new periosteal bone along the shaft of long bones at their distal end. These changes are observed most frequently at the ankles, wrists, and knees. The ends of the distal phalanges may show osseous resorption. Radionuclide studies show pericortical linear uptake along the cortical margins of long bones that may be present before any radiographic changes.
Treatment Hypertrophic Osteoarthropathy
The treatment of HOA is to identify the associated disorder and treat it appropriately. The symptoms and signs of HOA may disappear completely with removal or effective chemotherapy of a tumor or with antibiotic therapy and drainage of a chronic pulmonary infection. Vagotomy or percutaneous block of the vagus nerve leads to symptomatic relief in some patients. NSAIDs or analgesics may help control symptoms of HOA.
Reflex Sympathetic Dystrophy Syndrome
The reflex sympathetic dystrophy syndrome is now referred to as complex regional pain syndrome, type 1, by the new Classification of the International Association for the Study of Pain. It is characterized by pain and swelling, usually of a distal extremity, accompanied by vasomotor instability, trophic skin changes, and the rapid development of bony demineralization. Reflex sympathetic dystrophy syndrome, including its treatment, is covered in greater detail in Chap. 376.
Tietze Syndrome and Costochondritis
Tietze syndrome is manifested by painful swelling of one or more costochondral articulations. The age of onset is usually before 40, and both sexes are affected equally. In most patients, only one joint is involved, usually the second or third costochondral joint. The onset of anterior chest pain may be sudden or gradual. The pain may radiate to the arms or shoulders and is aggravated by sneezing, coughing, deep inspirations, or twisting motions of the chest. The term costochondritis is often used interchangeably with Tietze syndrome, but some workers restrict the former term to pain of the costochondral articulations without swelling. Costochondritis is observed in patients over age 40; tends to affect the third, fourth, and fifth costochondral joints; and occurs more often in women. Both syndromes may mimic cardiac or upper abdominal causes of pain. Rheumatoid arthritis, ankylosing spondylitis, and reactive arthritis (Reiter's syndrome) may involve costochondral joints but are distinguished easily by their other clinical features. Other skeletal causes of anterior chest wall pain are xiphoidalgia and the slipping rib syndrome, which usually involves the tenth rib. Malignancies such as breast cancer, prostate cancer, plasma cell cytoma, and sarcoma can invade the ribs, thoracic spine, or chest wall and produce symptoms suggesting Tietze syndrome. Patients with osteomalacia may have significant rib pain, with or without documented micro fractures. These conditions should be distinguishable by radiographs, bone scanning, vitamin D measurement, or biopsy. Analgesics, anti-inflammatory drugs, and local glucocorticoid injections usually relieve symptoms of costochondritis/Tietze syndrome. Care should be taken to avoid overdiagnosing these syndromes in patients with acute chest pain syndromes; many patients will be tender to overly vigorous palpation of the costochondral joints.