Acute necrotizing hemorrhagic leukoencephalitis
Acute hemorrhagic leukoencephalitis of Weston Hurst is at the extreme end of the spectrum of demyelinating diseases. It typically follows a viral upper
Mar. 26, 2021
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Rheumatoid arthritis is a systemic disease that can potentially affect any organ. Neurologic complications in particular are well recognized, causing distinct increase in morbidity and mortality. Multidisciplinary conservative therapies include disease activity control with disease-modifying antirheumatic drugs, glucocorticoids, and new biological agents, in addition to symptomatic treatments such as rest, restriction of activity, moist heat, NSAIDs, gentle massage, etc. Neurologic complications of newer biological therapies and immunosuppressive drugs represent an increasing clinical challenge. Cervical collar, physical therapy, and occupational therapies also have a role. Survival rate is significantly decreased in patients with rheumatoid arthritis and neurologic complications.
• Patients with rheumatoid arthritis have a reduced survival rate in general.
• Rheumatoid arthritis of the cervical spine is a common complication that is often under-appreciated.
• Neurologic complications related to rheumatoid arthritis affect the central nervous system, peripheral nervous system, muscles, and neuromuscular junction.
• Neurologic complications of newer biological therapies and immunosuppressive drugs are an increasing concern.
Neurologic complications of rheumatoid arthritis have been known for many years. In the 19th century Piters and Villard (107) and later Bannatyne (08) described peripheral neuropathy due to rheumatoid arthritis. Bannatyne described infiltration of small round cells in the nerve sheath, in the perivascular region, and among nerve fibers, as well as thickening of intima of blood vessels with encroachment on the vascular luminal wall (08). In 1942 Freund and colleagues reviewed the earlier reports on the rheumatoid arthritis neuropathy and reported “perineuritic nodules” in autopsied specimens of rheumatoid arthritis patients (45). These nodules consisted of chronic inflammatory cells in peripheral nerves. However, the significance of these observations was unknown until Ball described the presence of systemic arteritis that included peripheral neuropathy, which could complicate rheumatoid arthritis (07). Three years later, Hart and colleagues reported 10 rheumatoid arthritis patients with peripheral neuropathy and attributed it to diffuse arteritis (54). Neuropathy, therefore, was considered as an important complication of rheumatoid arthritis. Lastly, Ferguson and Slocumb indicated that development of peripheral neuropathy in rheumatoid arthritis has prognostic values (43). In their view, rheumatoid arthritis patients with peripheral neuropathy due to vasculitis had decreased survival compared to patients without neuropathy. With introduction of modern neurology in the last 25 years, other neurologic complications of rheumatoid arthritis such as cerebral vasculitis and cervical myelopathy have also been recognized.
Rheumatoid arthritis is a chronic inflammatory arthropathy, often occurring as part of a more systemic immunopathological syndrome, of unknown etiology. It is characterized by persistent inflammatory synovitis that usually involves peripheral joints in a symmetric distribution. The hallmark of rheumatoid arthritis is synovial inflammation that causes cartilage destruction, bone erosion, and subsequent alterations of joint structure. The course of rheumatoid arthritis can be variable. Some patients have only a mild oligoarticular disease of short duration with minimal joint damage, whereas a larger group of patients experience a destructive and progressive disease with remarkable functional impairment. Other patients manifest involvement of other organ systems including the nervous system. The 1987 revised criteria for the classification and diagnosis of rheumatoid arthritis are presented in Table 1.
• At least 4 of the 7 criteria are required to classify a patient as having rheumatoid arthritis.
• Morning stiffness*
- Rheumatoid nodules
* Must be present for at least 6 weeks
In two thirds of patients, rheumatoid arthritis manifests with systemic presentations such as fatigue, anorexia, generalized weakness, and vague musculoskeletal symptoms followed by synovitis. This prodrome may last for weeks or months before specific symptoms appear. The specific symptoms of rheumatoid arthritis gradually develop and involve several joints, especially those of the hands, wrists, knees, and feet in a symmetric fashion. In approximately 10% of patients, the onset of rheumatoid arthritis is more acute, with a rapid manifestation of polyarthritis, frequently accompanied by constitutional symptoms such as fatigue, lymphadenopathy, and splenic enlargement. In one third of individuals, symptoms may be limited to one or a few joints.
Synovitis causes swelling, tenderness, and restriction of movement of joints. Joint swelling is due to accumulation of synovial fluid associated with inflammation, synovial hypertrophy, and thickening of joint capsule. Pain predominantly originates from the joint capsule, which is richly supplied by pain fibers and is sensitive to distension. Rheumatoid arthritis most frequently affects specific joints such as the proximal interphalangeal and metacarpophalangeal joints. Synovitis of the wrist joint is almost a uniform feature of rheumatoid arthritis and leads to restriction of motion, deformity, and median nerve entrapment (carpal tunnel syndrome). Synovial inflammation of the elbow joint may appear early in the course of disease. The knee joint is often affected with synovial hypertrophy, effusion, and ligamentous laxity. Arthritis in the forefoot, ankles, and subtalar joints can cause severe pain during ambulation. Axial involvement is generally limited to the cervical spine. Using pulsed arterial spine labeling MRI technique joint pain seems to involve neural processing in the medial frontal cortex (75).
Persistent inflammation of the joints leads to a number of characteristic joint deformities. These can be attributed to a variety of pathologic events, including laxity of supporting soft tissue structures (weakening of ligaments, tendons, and the joint capsule) cartilage degradation, and muscle imbalance.
Extra-articular manifestations of rheumatoid arthritis. Rheumatoid arthritis is a systemic disease with a number of extra-articular manifestations. Generally, they occur in patients with high titers of autoantibodies to the Fc component of immunoglobulin G (rheumatoid factors). Extra-articular manifestations of rheumatoid arthritis are present in 10% to 20% of patients. These extra-articular sites include skin (livido reticularis, purpura, skin infarcts, and ulcerations), heart (pericarditis, myocarditis, endocarditis, and coronary vasculitis), lung (pulmonary nodules, pleuritis, and interstitial disease), eye (episcleritis and keratoconjunctivitis sicca), and the nervous system. In patients with advanced rheumatoid arthritis, almost all organs are affected. Of these various complications, we will only focus on nervous system involvement in rheumatoid arthritis. Neurologic complications of rheumatoid arthritis may occur in: (1) the central nervous system, (2) the peripheral nervous system, (3) neuromuscular junction, and (4) muscle (see Table 2). Involvement of the peripheral nervous system is the most common clinically manifest neurologic complication of rheumatoid arthritis, but the frequency of cervical spine abnormalities is underestimated.
Central nervous system and psychiatric complications
• Cerebral vasculopathy/vasculitis
• Subaxial cervical spine involvement
- Subaxial subluxation
Peripheral nervous system
• Compression/entrapment neuropathies
- Carpal tunnel syndrome
• Peripheral neuropathy due to necrotizing vasculitis
- Upper extremity neuropathy secondary to involvement of digital nerves or “digital neuropathy:
Myasthenia gravis and myopathies
Central nervous system and psychiatric complications. CNS involvement is uncommon in rheumatoid arthritis. CNS inflammation can be caused by cerebral vasculopathy/vasculitis, which seems to be uncommon if one requires pathologic confirmation as well as direct CNS involvement by the inflammatory cells, also rarely documented (Spath et al 2012), and rheumatoid nodules. Nearly all patients who develop CNS vasculitis have severe erosive joint disease of long duration, high rheumatoid factor titers, and prominent extra-articular features. There have been rare cases with early involvement of the meninges (76; 85). CNS manifestations are believed to occur later in the disease course as a result of the accumulation of inflammatory changes (115). Increased levels of several inflammatory markers seem to increase the chances of stroke (146). Various lacunar stroke syndromes are thought to be secondary to thrombotic microangiopathy rather than to active vasculitis causing occlusion. Patients with rheumatoid arthritis may develop strokes unrelated to the specific pathology of rheumatoid arthritis, just as can be seen in other individuals when related to the more common risk factors for classic atherosclerotic disease. There is also some evidence that certain parameters of disease of large and midsize intracranial vessels are more advanced than controls. In one study patients treated with newer biological agents had less involvement than those treated with methotrexate (98; 131). In another study examining database of rheumatoid arthritis patients versus controls there was a slight increase in ischemic stroke compared to controls. In this study there was a suggestion that methotrexate might have some protective effect when compared to treatment with hydroxychloroquine and sulfasalazine, which had no effect compared to no treatment (133). Nonsteroidal anti-inflammatory drugs increased the incidence of stroke in rheumatoid arthritis patients by 1.4-fold (27). Rheumatoid arthritis also appeared to increase the risk of recurrent strokes and transient ischemic attacks (28). All of these risk factors in rheumatoid arthritis need to be kept in mind in planning treatment of patients with rheumatoid arthritis, particularly in the presence of other risk factors for ischemic stroke.
CNS involvement in rheumatoid arthritis may be symptomatic or asymptomatic. Clinical manifestations include altered sensorium, motor defects, seizures, and cranial neuropathies (141; 50; 09). Abnormalities in MRI suggesting anatomic changes in deep gray matter, an increase in volume (140), and in brain metabolism by magnetic resonance spectroscopy (41) have been reported, but the histologic pathologic substrate for these changes is not known. In asymptomatic cases, the inflammatory syndrome, however, is usually diagnosed during postmortem examination. Hypoglossal nerve palsy is a rare complication associated with rheumatoid arthritis of the cervical spine. Blankenship and colleagues report 3 cases of hypoglossal nerve palsy with rheumatoid arthritis, the mechanism of which they attribute to pannus formation, or vertical subluxation of the odontoid process, or both (12).
Histopathologic findings in brain, meninges, or spinal cord, when there is pathologically confirmed CNS pathology, include rheumatoid nodules, meningeal inflammation, and vasculopathy/vasculitis. Rheumatoid nodules of the brain are located in the meninges and do not invade cerebral parenchyma. Histologically, rheumatoid nodules consist of a central zone of necrotic material including collagen fibrils, noncollagenous filaments, and cellular debris; a midzone of palisading macrophages that express human leukocyte antigen-DR antigens, and an outer zone of granulation tissue. The meningeal nodules are usually asymptomatic. However, rheumatoid nodules of spine can cause nerve compression, spinal canal stenosis, and weakness of lower extremities (82).
The next most frequent abnormality is lymphocytic infiltration of leptomeninges or pachymeninges. Lymphocytic vasculitis appears in 37% of autopsy cases with involvement of brain, spinal cord, and meninges (09). Gadolinium-enhanced brain MRI, combined with CSF examination, can increase the diagnostic accuracy of CNS vasculitis in patients with CNS vasculitis of various etiologies between 92% and 100% (128). However, owing to the relative rarity of vasculitis/vasculopathy in rheumatoid arthritis, the percentages for rheumatoid arthritis are not known. MRI findings in cerebral rheumatoid vasculitis and pachymeningitis include nonenhancing and enhancing white matter lesions of hypointense signals on T1-weighted images and hyperintense signals on proton density and T2-weighted images in frontal and parietal lobes along with meningeal enhancement and thickening (26). Although it is rarely the cause of pachymeningitis and optic neuritis, rheumatoid arthritis should always be kept in mind in these two conditions in the appropriate clinical setting (03). Granulomatous meningitis can occur as the only CNS manifestation of rheumatoid arthritis and needs to be distinguished from infections, particularly in patients being treated with immunosuppressive agents (60; 40).
A rare manifestation of the CNS involvement in rheumatoid arthritis is normal pressure hydrocephalus (see Table 2): a triad of urinary incontinence, gait difficulty, and dementia. Its occurrence in the context of rheumatoid arthritis is likely due to impairment of resorption of the cerebrospinal fluid following inflammation of the meninges. Normal pressure hydrocephalus associated with rheumatoid arthritis may improve with corticosteroid therapy or insertion of a ventricular shunt (83).
Hashimoto encephalopathy affects patients with autoimmune thyroid disease most commonly and has been associated with rheumatoid arthritis, among other autoimmune disorders. It is a distinct form of encephalopathy, which can manifest itself with purely psychiatric symptoms. It is characterized by the presence of high serum level of TPO antibodies, exclusion of other possible causes of encephalopathy, and typical EEG findings with general slowing – and the degree of slowing corresponds to clinical severity. Atypical EEG findings include epileptiform discharges or triphasic waves. Reversal of clinical and EEG abnormalities occur on corticosteroid treatment. Several mechanisms have been proposed including antigen-antibody complex accumulation, intrathecal thyroid antibodies, global cerebral perfusion, and vasculitis (125). Some have questioned whether the elevated antibodies are simply a marker of “autoimmunity” and might have no direct relationship to the various clinical syndromes reported with Hashimoto encephalopathy. There is no relationship to thyroid function itself, and the neurologic manifestations are more related to the associated autoimmune disease (99). Recent papers have raised the issue if Hashimoto encephalopathy actually exists or can be denied by response to corticosteroids or titer of thyroid peroxidase antibodies (84).
Symptoms of involvement of cerebral hemispheres and brain stem and/or cranial nerves in a patient with rheumatoid arthritis undergoing immunosuppressive drugs or treatment with monoclonal antibodies should always raise the possibility of opportunistic infections, including mycobacterial, fungal, or viral (including progressive multifocal leukoencephalopathy and Epstein-Barr virus-associated lymphoma), or inflammatory and presumed demyelinating involvement of white matter, particularly with treatment with rituximab. In addition, although corticosteroid use in patients with rheumatoid arthritis is not as frequent as was the case many years ago, the possibility of psychosis and other neuropsychiatric symptoms induced by corticosteroids or withdrawal of corticosteroids needs to be considered (50). A recent study using MRI spectroscopy did not find specific changes in rheumatoid arthritis patients compared to controls, but there was a trend in abnormal metabolism that could explain some of the complaints of fatigue in patients (91). Inflammatory mediators could affect CNS function without necessarily causing histologic inflammatory changes in the vessel walls or within the CNS parenchyma.
Cervical myelopathy of rheumatoid arthritis is due to cord compression, or so-called “kinking” of the cord, and occurs in over half of patients with rheumatoid arthritis in some series (17). Unlike the thoracic and lumbosacral spines, the cervical spine is particularly prone to damage by the destructive inflammatory process of rheumatoid arthritis. This is caused by a chronic inflammatory infiltrative process that involves the synovial joints of the cervical spine and the surrounding connective tissue structures (see Table 2). Both the atlantoaxial complex and the subaxial spine can be involved. Proliferative synovitis or pannus formation affecting the atlantoaxial, atlanto-odontoid, and atlantooccipital joints, and also the synovial-covered bursa located between the odontoid process and the transverse ligament, occurs in almost half of the cases of rheumatoid arthritis with cervical myelopathy. Involvement of the cervical joints below C2 accounts for the rest (18). Cervical spine involvement usually occurs in association with severe destructive peripheral rheumatoid arthritis, formation of rheumatoid nodules, and a high titer of rheumatoid factor. Although one of the most threatening neurologic manifestations of rheumatoid arthritis, the development of compressive myelopathy due to rheumatoid arthritis is less common than often thought. This may relate to earlier and more effective treatments (112).
Under normal circumstances, the anterior arch of the atlas is separated from the odontoid process by a distance of less than 3 mm. This distance is kept during neck flexion, as the transverse ligament tightly keeps the odontoid process within the articular notch on the anterior arch of the atlas. The transverse ligament, which is located posterior to the odontoid process, is crucial in preventing the posterior protrusion of the odontoid process into the spinal cord during head flexion. Loosening of the transverse ligament results in horizontal atlantoaxial subluxation. Two other ligaments, the apical and alar, attaching the dens superiorly and superolaterally to the edge of the foramen magnum, also participate in maintaining the positional integrity of the odontoid process in relationship to the atlas and cranium. Complete severance of the transverse ligament results in a subluxation of no more than 5 mm; involvement of the apical and alar ligaments is required for subluxation of more than 5 mm. When this occurs during head flexion, the cervical cord may be compressed against the posterior arch of atlas, a condition known as anterior atlantoaxial subluxation. Abnormalities in apparent diffusion coefficient has been proposed to be an indicator of spinal cord compression in patients with rheumatoid arthritis (81).
Chronic proliferative inflammatory infiltrative processes that involve synovial joints of the cervical spine and the surrounding connective tissue structures can damage or loosen the transverse ligament and erode or fracture the odontoid process, which can cause subluxation. In addition, a rheumatoid pannus around the odontoid process may further limit the available space in the spinal cord. Destruction of the lateral atlantoaxial facet and atlanto-occipital joints and their associated ligaments can also contribute to the neurologic complications of the C1-C2 spine. Subluxations of C1-C2 may occur in various directions: anteriorly, posteriorly, vertically, laterally, or a combination of these (52; 142). Each one of these subluxations depends on the position and nature of the atlantoaxial complex.
Anterior subluxation is usually associated with prolonged disease duration, presence of rheumatoid factor, presence of rheumatoid nodules, male sex, erosive peripheral joint disease, and joint instability (126; 144).
Anterior subluxations are common radiologic findings in patients with severe rheumatoid arthritis, however, many are asymptomatic. This radiologic abnormality has been reported in 9.5% to 36% of rheumatoid arthritis patients (126; 120; 105; 144).
Movement of the atlas posterior to the axis results in posterior atlantoaxial subluxation. It may happen if the odontoid process is severely eroded, fractured, destroyed, or congenitally absent. Posterior atlantoaxial subluxation is an uncommon lesion and includes only 6.7% of all rheumatoid arthritis cervical subluxations. Interestingly, this type of subluxation is rarely associated with clinical manifestations of cervical myelopathy.
Vertical subluxations at the C1-C2 level are due to destruction of the osseous structures and cartilage in the region of the atlanto-occipital or lateral atlantoaxial facet joints. Lateral radiographs will disclose what seems to be an upward movement of the odontoid through the foramen magnum into the posterior fossa when, in fact, it is the cranium that settles down on the odontoid as the disease process advances. Vertical subluxations are less frequent than anterior atlantoaxial subluxation, with reported prevalence of 3% to 4% in the overall rheumatoid arthritis patient population (55; 144) and 22% of rheumatoid arthritis patients with some form of cervical subluxation (142). Like anteroposterior atlantoaxial subluxation, vertical subluxations correlate with longer disease duration and more severe peripheral joint disease (55; 120).
Lateral atlantoaxial subluxation is a consequence of atlantoaxial facet joint involvement with resultant lateral displacement of the lateral masses of the atlas (52; 53). Contributing factors to the development of this kind of subluxation include synovitis of the joints, bone erosions, and capsular and ligamentous laxity. Rotatory subluxation of the atlas on the axis may accompany lateral subluxations, although it does not appear to exist in isolation (52). Severe lateral facet involvement can lead to lateral mass collapse of the atlas with or without lateral subluxations. Most patients with lateral mass collapse in rheumatoid arthritis have unilateral disease that causes a clinical syndrome known as “nonreducible rotational head tilt” (52; 53). In these patients, the head is always tilted to the side of the lateral mass. Lateral facet joint disease is frequently associated with other subluxations. Bilateral facet joint arthritis with unilateral collapse of the axis can cause or worsen vertical subluxations.
Subaxial cervical spine involvement occurs as often as atlantoaxial subluxation (144). The inflammatory process of the subaxial spine involves the longitudinal ligaments, vertebral endplates, apophyseal joints, and intervertebral discs leading to subaxial subluxation, spondylodiscitis, and apophyseal changes. It may cause an unstable spine, radiologically demonstrated as a staircase or stepladder deformity. Root compression, or cord compression, or both under these circumstances may occur at the level of the cervical cord or thoracic cord as well (127). Encasement of the spinal cord with inflammatory tissue at the cervical and thoracic spine has also been reported (62).
Most of the patients with rheumatoid arthritis cervical myelopathy present with neck pain or headaches. Pain usually results from compression and irritation of the second cervical roots and typically causes localized neck pain with radiation up to the occiput. This is characteristic of anterior and posterior atlantoaxial subluxation. Other clues to cervical myelopathy include paresthesia, numbness of arms and feet, jumping legs, and weakness most frequently beginning in hands. These manifestations may be confused with peripheral neuropathy or cord or nerve root compression. With further progression of pathologic process, other signs and symptoms such as spastic quadriparesis, episodic loss of consciousness, dizziness with bending neck forward, and Lhermitte sign develop. Extensor plantar responses are significant clues to the presence of cervical myelopathy in rheumatoid arthritis patients. Cranial neuropathy due to brainstem involvement is rare (88), as is brain stem compression itself (15). Severe medullary compression can cause respiratory insufficiency (58). Increasing weakness of upper extremities, occipital headache, nausea, and incontinence are clinical evidence of evolving compression, which may cause sudden death (102). Myelitis has been reported in a patient with rheumatoid arthritis who was being treated with inhibitor of TNF-alpha (34). Patients with rheumatoid arthritis may also suffer from fracture of the odontoid even in the absence of overt trauma. MRI is the initial procedure for diagnosis. If a fracture is seen, a CT scan is helpful in planning surgery; however, maneuvering the cervical spine for x-rays with flexion and extension should be avoided to prevent causing myelopathy or worsening an already present myelopathy (132).
A sizable number of patients with rheumatoid arthritis suffer from depression (31; 103). Depressive symptoms are both common and associated with reduced health status (65). It has been shown that higher depression is related to more pain, excessive fatigue, and decreased quality of life in patients with rheumatoid arthritis (65). Depression in rheumatoid arthritis patients is treated like other forms of depression, with antidepressants (103).
Peripheral neuropathy. Peripheral neuropathy occurs in 10% of patients with rheumatoid arthritis. The gender distribution is similar to that of the underlying disease (see Table 2). Rheumatoid arthritis patients develop upper extremity neuropathy secondary to involvement of digital nerves or “digital neuropathy,” lower extremity neuropathy with involvement of major nerves, lower extremity distal sensory neuropathy, and distal sensory/motor polyneuropathy of upper and lower extremities. As is the case with peripheral neuropathies in some other autoimmune diseases, including systemic lupus erythematosus, the more symmetric distal neuropathies may represent “merged” mononeuropathy multiplex (78). Recent studies have emphasized the different patterns of neuropathy seen in patients with rheumatoid arthritis (63; 77).
The estimated prevalence of carpal tunnel syndrome in the general population is 220 per 100,000 (35). The prevalence of carpal tunnel syndrome in the rheumatoid arthritis population is almost twice as high. It may be the presenting sign of rheumatoid arthritis and is secondary to median nerve compression in the wrist by tenosynovitis of the flexor tendons of the fingers. Carpal tunnel syndrome and other entrapment neuropathies do not correlate with duration of rheumatoid arthritis, male gender, or seropositivity. Carpal tunnel syndrome presents with intermittent pain, numbness, and tingling in the fingers that is dependent on the position of the hand and wrist and commonly associated with subjective weakness of grip. The symptoms initially occur only at night and may awaken the patient. In more severe cases the symptoms also occur during the day. They are frequently provoked by hyperextension or hyperflexion of the wrist during activities such as driving, or during work-related repeated hand movements. The pain can extend from the wrist into the forearm or even to the shoulder. The patient will often shake the hand and fingers in an effort to obtain relief from the discomfort (flick sign). Although positive sensory symptoms such as pain and tingling predominate, occasionally the only symptom is loss of dexterity. Gentle tapping of the median nerve at the wrist produces pain or paresthesia in the distribution of the median nerve (Tinel sign). Forced flexion of the wrist may reproduce symptoms (the Phalen maneuver). Atrophy of the thenar eminence and weakness of abductor pollicis brevis may be present in more severe and longstanding cases. A review of the experience of a group in Hungary has suggested that carpal tunnel syndrome is not more common in patients with rheumatoid arthritis than in the general population (113). They found little evidence of anatomic changes that differed from controls. The prevalence of carpal tunnel syndrome was 5.5% of rheumatoid arthritis patients and those with subclinical carpal tunnel syndrome (clinical neurophysiologic changes only) was 14.0%. There was no correlation with other clinical parameters of rheumatoid arthritis and the presence of carpal tunnel syndrome (113). It should be noted that because of more and more use of computers with repetitive motion at the wrists in the general population, one could speculate findings might represent an increase in carpal tunnel syndrome in the general control population rather than a decrease in patients with rheumatoid arthritis.
Ulnar neuropathy is the next most common compressive neuropathy encountered in rheumatoid arthritis patients (see Table 2). Ulnar nerve lesions at the elbow cause weakness of the flexor carpi ulnaris, flexor digitorum profundus of the ring and little fingers, and the intrinsic hand muscles. Pinch strength is reduced by weakness of adductor pollicis, flexor pollicis brevis, and first dorsal interosseous muscles. As a compensatory maneuver during attempted pinch of the thumb and index finger (such as when a sheet of paper is grasped between the thumb and index finger and pulled), the proximal phalanx of the thumb is extended and the distal phalanx is flexed (Froment sign). Weakness of the interossei muscles results in inability to produce a forceful extension of the interphalangeal joints as used in finger-flicking movements. Remarkable atrophy of the first dorsal interosseous muscle causes lumbricals weakness with secondary hyperextension of the metacarpophalangeal joints, together with clawing of the fourth and fifth fingers. The small muscles of the hand are always more severely affected than the forearm muscles. Sensory loss involves the fifth digit, and often the ulnar side of the fourth digit, and extends to the dorsum of the hand.
Compression of the posterior tibial nerve as it traverses the fibroosseous tarsal tunnel can cause tarsal tunnel syndrome (see Table 2). Tarsal tunnel is formed by the medial malleolus and the flexor retinaculum in the medial aspect of the foot and ankle. Tarsal tunnel syndrome in rheumatoid arthritis patients is due to tenosynovitis. Electrophysiologic studies show abnormalities consistent with tarsal tunnel syndrome in 5% to 25% of rheumatoid arthritis patients (10; 49). However, most patients are asymptomatic. Clinical manifestations of tarsal tunnel syndrome include paresthesia, pain, and burning in the toes and soles, which are initially intermittent and later constant (49). Pain and paresthesia are aggravated at night, with physical activity, and by wearing tight shoes. Weakness and atrophy of the intrinsic toe muscles are late manifestations. Other less common causes that should be excluded are inflammation of the flexor retinaculum, posttraumatic edema and fibrosis, valgus deformities, and adjacent bone dislocation or fracture (49).
There is growing evidence that some forms of neuropathy in rheumatoid arthritis are secondary to an immune-mediated vasculitis including, as noted above, the more symmetric sensory and sensory-motor “fiber length pattern” neuropathies. This view is supported by immunofluorescence studies suggesting that immune complexes with fixation of complement initiate the arteritis associated with neuropathy. In a sural nerve biopsy performed 8 days after the onset of neuropathic symptoms, IgG and IgM were observed in the vascular wall in areas corresponding to those of fibrinoid necrosis (30). The cellular infiltrate in this specimen consisted of a mixture of polymorphonuclear and mononuclear cells. Reports also describe a deposition of IgG, IgM, complement, and fibrin in areas of acute vascular damage (108). Vasculitic neuropathy is the most common peripheral manifestation of systemic necrotizing vasculitis, seen in as many as 60% of patients (97).
Upper extremity neuropathy involves a sensory syndrome characterized by insidious numbness affecting one or more digits of either hand randomly, unlike the characteristic pattern observed with ulnar or median lesions. The numbness is usually limited to the terminal phalanges of the affected digits. The thumb is rarely affected and generally pain and paresthesia are uncommon. Neurologic examination may disclose decreased perception to touch and pinprick as well as loss of proprioception. Many such patients also have signs of neuropathy in the lower extremities.
Lower extremity involvement of major nerves presents with lesions of lateral popliteal, sciatic, or other single large nerves, with both sensory and motor manifestations. This type of neuropathy, mononeuropathy, or mononeuropathy multiplex is usually of acute onset, and in most cases is indicative of neuropathy secondary to vascular occlusion.
Lower extremity distal sensory neuropathy manifests with purely sensory symptoms that appear slowly. The numbness and occasionally paresthesia involve the feet up to malleoli. Neurologic examination discloses hypalgesia, loss of vibratory sense, and decrease or loss of deep tendon reflexes.
Distal sensory and motor polyneuropathy of upper and lower extremities presents the smallest subgroup, but the most severe form of neuropathy. Patients present with symmetrical distal weakness, wasting, and impairment of all sensory modalities. The neuropathy of these patients is either a widespread polyneuropathy or a severe mononeuritis multiplex. One case of Miller Fisher syndrome in a patient with adult onset Still disease has been reported (38). Whereas both are autoimmune/immunopathologically mediated diseases, it is not clear if this is simply a chance occurrence. Certainly, a causal relationship seems unlikely. Adult-onset Still disease is a multisystem inflammatory disorder that is characterized by high spiking fevers, salmon-colored rash, arthralgia or arthritis, hepatic and splenic enlargement, lymphadenopathy, and sore throat. Often a leukocytosis is present, whereas other rheumatologic markers such as rheumatoid factor and antinuclear antibody are negative. There are not any specific lab tests or combination of tests that support the diagnosis of adult-onset Still disease; however, in the presence a compatible clinical scenario, serum ferritin level more than 3200 ng/mL is strongly suggestive of the disorder. Like rheumatoid arthritis, almost all organ system involvement has been observed in patients with adult-onset Still disease.
There have been reports that patients with rheumatoid arthritis may develop autonomic neuropathy. In a cross-sectional study of cardiovascular autonomic functions in patients with rheumatoid arthritis, an increase in abnormalities in autonomic functions was not more common than in control subjects. Other autonomic functions were not examined (95). Patients with rheumatoid arthritis have been shown to have abnormalities of parasympathetic, sympathetic, and sudomotor function, and this was seen more often in these patients than in normal controls (130; 01).
Demyelinating peripheral neuropathies, seemingly identical to chronic inflammatory demyelinating polyneuropathy (CIDP) or subacute inflammatory demyelinating neuropathy, have been reported in patients with autoimmune diseases treated with inhibitors of TNF-alpha, as have CNS demyelinating syndromes and other neuropathies (05).
Myasthenia gravis and myopathies. Patients with rheumatoid arthritis frequently develop muscle weakness and atrophy, which have been attributed to disuse atrophy secondary to joint pain, synovitis, and immobility. Decrease in muscle performance is seen with increasing disease activity in rheumatoid arthritis patients (136). However, the amount of muscle atrophy does not correlate with the degree of disuse. Intramuscular inflammatory cells, mainly lymphocytes and plasma cells, have been described in rheumatoid arthritis. Though not specific for rheumatoid arthritis, interstitial inflammatory cells are detected in almost 25% of muscle biopsies of rheumatoid arthritis patients with rheumatoid vasculitis (108). Increase in proinflammatory cytokines in muscle, which did not correlate with blood levels, has been reported, as has evidence of calcium and free radical signaling (59; 147). An increase with skeletal muscle fat has been demonstrated on computerized tomography, which seems to be associated with worse muscle function (68). In addition, arteritis of the small arteries is detected in 8% of random muscle biopsies of rheumatoid arthritis patients without extra-articular manifestations (121). Voskuyl and colleagues detected perivascular infiltrates in randomly obtained muscle biopsies in 75% of patients with rheumatoid vasculitis versus 14% of those rheumatoid arthritis patients without vasculitis (139). The exact mechanism of myopathy associated with rheumatoid arthritis remains to be established but appears to be immune mediated. In these studies there was not always a clinical correlation with the findings on muscle biopsy. There are many case reports and small series describing inflammatory myopathies, including polymyositis and inclusion body myositis (93; 92; 94). In some cases, the patients were being treated with monoclonal antibodies, and the possibility that myositis might also be caused by these agents, which clearly cause lesions in the CNS and PNS, was suggested. Additionally, patients with one autoimmune/immunopathologically mediated disease have an increase in concomitant other autoimmune/immunopathologically mediated diseases.
Myopathy in rheumatoid arthritis patients may also be due to medications such as corticosteroids (see Table 2). Corticosteroids may cause a slowly progressive proximal myopathy. Weakness is associated with normal or uncommonly elevated serum muscle enzymes and EMG evidence of myopathy. The treatment is lowering the dose of corticosteroids slowly.
It has been reported that changes occur in muscles of patients with rheumatoid arthritis that do not fit readily into classic inflammatory myopathies but rather seem to relate in general to overall disease activity, disability, and physical inactivity (59).
D-penicillamine, a second-line antirheumatic agent, can induce myasthenia gravis (33; 56) (see Table 2). This syndrome is characterized by predominance of oculomotor symptoms in 90% of cases, a slowly progressive proximal muscle weakness, decreased or absent deep tendon reflexes (unusual in otherwise uncomplicated idiopathic myasthenia gravis), the presence of antibodies to acetylcholine receptors in 75% of cases, striated muscles in 53%, and an increased prevalence of the DR1 DW35 human leukocyte antigen haplotype (143; 22). The myasthenia resolves with cessation of D-penicillamine in most instances. When it does not, it raises the possibility that the treatment with penicillamine simply uncovered concomitant myasthenia gravis. There is an increase in concomitant autoimmune diseases in patients with myasthenia gravis including thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and B12 deficiency (119).
Neurologic complications of treatment of rheumatoid arthritis. Infectious complications, including those that involve the nervous system, of classical immunosuppressive therapy with corticosteroids, and cytotoxic and cytotoxic agents, are well recognized and occur in patients with rheumatoid arthritis. These include infections with mycobacteria, fungi (145), and viruses. Included in these complications are lymphomas (46), some involving the CNS along with other organs (67), including those caused by viruses, particularly with Epstein-Barr virus (90). Although monoclonal antibodies are more focused in their effects on the immune system than corticosteroids and agents such as cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil, they clearly have immunosuppressive effects and are associated with an increase in infections including progressive multifocal encephalopathy (PML).
PML has been reported with treatment with several of the monoclonal antibodies used in rheumatologic autoimmune disorders including rheumatoid arthritis (29; 06; 72), systemic lupus erythematosus, psoriasis and psoriatic arthritis, and multiple sclerosis (14). There is no proven effective therapy for PML, and discontinuation of the suppressive therapy is advisable. When plasma exchange has been used to reduce circulating levels of natalizumab in patients with multiple sclerosis who have or are suspected to have PML, some patients develop immune reconstitution inflammatory syndrome (IRIS) (89; 110).
In addition to PML and lymphomas, patients treated with inhibitors of tumor necrosis factor-alpha (TNF-alpha) have been reported to develop both demyelinating peripheral neuropathy (109; 129; 42; 122) and CNS disorders. The CNS disorders have symptoms referable to the cerebral hemispheres or optic nerves, less commonly to the spinal cord (114). The MRI is characterized by multiple lesions in the white matter, which on T2/FLAIR shows increased signal and gadolinium enhancement on T1 sequences (Magnano et al 2004; 135; 42; 122; 36). This inflammatory syndrome has been reported with all of the monoclonal antibodies directed against TNF-alpha, as well as to fusion proteins that inhibit TNF-alpha receptors. Pathologic examination of brain obtained by biopsy from a patient with CNS demyelination secondary to TNF-a inhibition was indistinguishable from multiple cross (64). Because only 1 lesion was biopsied, one cannot be absolutely certain that the other lesions would be identical in appearance. There have also been reports of new onset inflammatory myopathies with these agents (20; 61; 138; 19), but it is harder to be certain of the relationship to the inhibition of TNF-alpha because inflammatory myopathies are seen in patients with rheumatoid arthritis, systemic lupus erythematosus, and Sjogren syndrome in the absence of treatment with inhibitors of TNF-alpha. It is of interest that treatment with inhibitors of TNF-alpha in patients with relapsing-remitting multiple sclerosis (RRMS) was associated with worsening of multiple sclerosis by both clinical and MRI criteria (137; 134). The reasons for this effect in multiple sclerosis, the opposite of what was expected in the clinical trials, is not clear, but in animal models may have to do with membrane bound versus secreted TNF-alpha and different receptors for TNF-alpha.
Patients with rheumatoid arthritis CNS vasculopathy/vasculitis, which as noted above are rarely documented by pathologic findings, have decreased survival compared with the general rheumatoid arthritis population. The survival rate in rheumatoid arthritis in general is reduced (117; 16; 51), and with cervical myelopathy from rheumatoid atlantoaxial subluxation it is reduced even further (111). Often these patients die when arteritis involves the coronary or mesenteric arteries, causing infarction.
The natural history of rheumatoid arthritis cervical spine disease is variable, but the prognosis is relatively favorable unless cervical myelopathy occurs. One study of anterior subluxations in 84 patients without cord or brainstem compression over a 5- to 14-year period revealed that only 1 in 4 worsened, 1 in 4 improved, and1 in 2 remained unchanged by radiographic criteria (120). Another prospective study by Winfield showed an absence of neurologic signs or symptoms in 36 rheumatoid arthritis patients with anterior or subaxial subluxations over a 7-year time period (144). Therefore, although radiographic progression seems common, it does not correspond with a higher rate of neurologic deterioration. Supportive data suggest, however, that the risk for developing upper cervical spinal cord compression secondary to anterior atlantoaxial subluxation may be related to certain factors such as male sex, an anterior subluxation greater than 9 mm, coexistence of atlantoaxial impaction, and possibly the presence of lateral atlantoaxial subluxation (142).
The overall 5-year mortality rate of patients with radiographic evidence of cervical subluxations, with or without neurologic manifestations, has been calculated to be 17%. This is higher than the rate in the cohort healthy population but similar to other patients with severe rheumatoid arthritis without cervical involvement (105). In contrast, untreated rheumatoid arthritis patients with cervical myelopathy have a more severe course and higher mortality rate.
The cause of rheumatoid arthritis is unknown. It has also been hypothesized that rheumatoid arthritis is a manifestation of the response to an infectious agent in a genetically susceptible individual. Because rheumatoid arthritis has a worldwide distribution, this agent must be ubiquitous. Alternatively, if the disease is triggered by an infection, different infectious agents could be involved. Certainly in Guillain Barre syndrome more than one agent has been associated with this disorder. A number of possible causative agents have been suggested, including mycoplasma, Epstein-Barr virus, cytomegalovirus, parvovirus, and rubella virus, but solid evidence in favor of any of these candidates is lacking. The role of “superantigens” in pathogenesis of rheumatoid arthritis remains speculative.
Another controversial issue is the process by which an infectious agent might cause chronic inflammatory arthritis in susceptible hosts. It is possible that persistent infection of articular structures or retention of microbial products in the synovial tissues generates a state of chronic inflammatory response and immune activation. Another hypothesis is that the microorganism or response to the microorganism might induce an immune response to components of the joints by changing its integrity and revealing antigenic self-peptides that are usually buried. In this regard, reactivity to type II collagen and heat shock protein has been shown in rheumatoid arthritis. A third hypothesis suggests that an infecting microorganism may prime the host to cross-reactive determinants expressed within the joint as a result of “molecular mimicry.” Evidence of similarity between the human leukocyte antigen-DR4 molecule itself and products of certain gram-negative bacteria and Epstein-Barr virus has lent support to this possibility. The final hypothesis is that products of the infecting microorganism, such as hsp65 class of heat shock protein of E. coli, may induce rheumatoid arthritis. Though external events such as surgery or trauma, infections, or childbirth seem to trigger the onset of rheumatoid arthritis, a clear relationship has not been established (Gordon et al 2003).
Synovial inflammation is central to the pathophysiology of rheumatoid arthritis. Synovitis of rheumatoid arthritis is characterized by microvascular injury along with hyperplasia and hypertrophy of the synovial lining cells. This is followed by perivascular infiltration of mononuclear cells consisting of human leukocyte antigen-DR-positive antigen presenting cells in close contact with T cells, most of which express the helper/memory phenotype (CD4+CD45+) and belong to the T helper Th1 type (100). Other histopathologic features are vascular thrombosis, microvascular injury, neovascularization, and edema of the synovial membrane (74).
Genetic studies have demonstrated an association between rheumatoid arthritis and MHC class II antigens human leukocyte antigen-DRB1*0404 and DRB1-*0401 (73). Human leukocyte antigen class II molecules on macrophages and dendritic cells present specific antigen peptides to CD4+ T cells. The antigen could be either an exogenous antigen, such as viral protein, or an endogenous protein. Possible endogenous antigens include citrullinated protein (keratin, profilaggrin, and filaggrin), human cartilage protein glycoprotein 39, and heavy-chain-binding protein (13).
Scattered throughout the inflamed tissue are both CD4+ and CD8+ T cells, which express the early activation antigen, CD69. Besides the T cells, a variable number of activated B cells and antibody-producing plasma cells are also present. The activation of B cells by CD4+ T cells occurs through cell-surface contact and through binding of alphaL-beta2 integrin, CD154 (CD40 ligand), and CD28 (79). Both polyclonal immunoglobulin and the autoantibody rheumatoid factor are produced inside the synovium, which results in the local formation of immune complexes. Rheumatoid factors are autoantibodies reactive with the Fc portion of IgG and are found in the sera of approximately 80% of rheumatoid arthritis patients. Rheumatoid factor is a prominent constituent of immune complexes in the sera and synovial fluids, synovial tissue, and cartilage. Lastly, the activated synovial fibroblasts produce a variety of enzymes such as collagenase, cathepsins, and matrix metalloproteinases that can degrade the articular matrix (116).
Activated lymphocytes, macrophages, and fibroblasts produce cytokines and chemokines that appear to account for many of the histopathologic and clinical manifestations of rheumatoid arthritis synovitis. These effector molecules include T cell products such as interleukin-2, interferon-gamma, interleukin-6, interleukin-10, interleukin-13, interleukin-16, interleukin-17, granulocyte-macrophage colony stimulating factor, tumor necrosis factor-alpha, transforming growth factor-beta; activated myeloid cell products, such as interleukin-1, tumor necrosis factor-alpha, interleukin-6, interleukin-8, interleukin-10, interleukin-12, granulocyte-macrophage colony stimulating factor, macrophage CSF, platelet-derived growth factor, insulin-derived growth factor, and transforming growth factor-beta; and synovial endothelial cell and fibroblast products, such as interleukin-1, interleukin-6, interleukin-8, granulocyte-macrophage colony stimulating factor, interleukin-15, interleukin-16, interleukin-18, and macrophage-CSF (57).
In addition to the generation of proinflammatory cytokines that propagate the inflammation, anti-inflammatory pathways are also being activated during the course of rheumatoid inflammation by release of various cytokines and mediators such as interleukin-1 receptor antagonist, soluble tumor necrosis factor-alpha p75 and p55 receptors, soluble interleukin-1 receptor type I and receptor type II, interleukin-10, interleukin-11, interleukin-13, and interleukin-16 (71). Clearly, the ongoing anti-inflammatory pathways are insufficient to down-regulate the inflammation in many patients.
The prevalence of rheumatoid arthritis in the United States is 0.8% of the population. All races are affected, and women are 3 times more likely than men to be affected. In older patients the prevalence increases but the sex difference decreases. The onset of rheumatoid arthritis is most often during the fourth or fifth decade of life. The extra-articular manifestations of rheumatoid arthritis can occur at any age after onset. Siblings of affected individuals are 2 to 4 times more likely to develop rheumatoid arthritis than are unrelated persons (MacGregor et al 2003).
Genetic studies have demonstrated a genetic predisposition. Genes in the major histocompatibility complex have been linked with rheumatoid arthritis in addition to their potential genetic markers that may confer susceptibility to rheumatoid arthritis independently of the major histocompatibility complex (Nepom et al 2003). Monozygotic twins are 4 times more likely to be concordant for rheumatoid arthritis than dizygotic twins, who have a similar risk of developing rheumatoid arthritis as nontwin siblings. Only 15% to 20% of monozygotic twins are concordant for rheumatoid arthritis, a point that implies the role of other nongenetic factors in the pathogenesis of rheumatoid arthritis.
The highest risk of concordance for rheumatoid arthritis is observed in twins who have 2 human leukocyte antigen-DRB1 alleles known to be associated with rheumatoid arthritis. The class II major histocompatibility complex allele human leukocyte antigen-DR4 and related alleles are major genetic risk factors for rheumatoid arthritis. Earlier studies have demonstrated that as many as 70% of patients with classic rheumatoid arthritis carry human leukocyte antigen-DR4 compared to 28% of control individuals. Various populations such as North American and European whites, Japanese, and native populations of India, Mexico, South America, and Southern China have demonstrated the association between human leukocyte antigen-DR4 and rheumatoid arthritis (149; 150). However, such an association has not been detected in other populations such as Israeli Jews and Asian Indians. There is an association between human leukocyte antigen-DR1 and rheumatoid arthritis in Israeli Jews (37).
From a molecular viewpoint, human leukocyte antigen-DR consists of 2 chains, alpha and beta. The alpha chain is nonpolymorphic, whereas the beta chain is highly polymorphic. Differences in the amino acids of the beta chain are responsible for allelic variations in the human leukocyte antigen-DR molecule. The major amino acids are located in the 3 hypervariable regions of the molecule. Each of the human leukocyte antigen-DR molecules associated with rheumatoid arthritis has a similar sequence of amino acids in the third hypervariable region of the beta chain of the molecule. The beta chains of the human leukocyte antigen-DR molecules clustered with rheumatoid arthritis, including human leukocyte antigen-Dw4 (DRB1*0401), human leukocyte antigen-DRw14 (DRB1*0404), human leukocyte antigen-Dw15 (DRB1*0405), human leukocyte antigen-DR1 (DRB1*0101), and human leukocyte antigen-Dw16 (DRB1*1402), contain the same amino acids at positions 67 through 74, with the exception of a single change of one basic amino acid for another (arginine--> lysine) in position 71 of human leukocyte antigen-Dw4 (106). All other human leukocyte antigen-DR beta chains have amino acid changes in this region that change either their charge or hydrophobicity. These findings indicate that a particular amino acid sequence in the third hypervariable region of the human leukocyte antigen-DR molecule is a major genetic component conveying susceptibility to rheumatoid arthritis, regardless of whether it happens in human leukocyte antigen-DR4, human leukocyte antigen-DR1, or human leukocyte antigen-Dw16.
The genes in the human leukocyte antigen-D complex that may protect an individual against rheumatoid arthritis include human leukocyte antigen-DR5 (DRB1*1101), human leukocyte antigen-DR2 (DRB1*1501), human leukocyte antigen-DR3 (DRB1*0301), and human leukocyte antigen-DR7 (DRB1*0701). These genes have been detected at a lower frequency in rheumatoid arthritis patients compared to controls. Early aggressive disease and extra-articular manifestations are observed in those with DRB1*0401 or DRB1*0404.
Rheumatoid cervical spine disorders are so common that cervical spine radiographs should be taken in every patient with rheumatoid arthritis during the disease course; they all carry a high risk for atlantoaxial subluxation (17). There are no specific measures for prevention of rheumatoid arthritis-related myelopathy, although immunosuppression of the underlying disease may be effective in delaying the progression of the underlying myelopathic process by slowing the changes in the spinal canal.
Considerations in the differential diagnosis of rheumatoid arthritis are numerous and depend in part on the clinical presentation. A list of diseases that can mimic rheumatoid arthritis include acute rheumatic fever, acute viral arthritis (rubella, hepatitis B, parvovirus), amyloidosis, bacterial endocarditis, inflammatory bowel disease, osteoarthritis, systemic lupus erythematosus, polymyalgia rheumatica, reactive arthritis, sarcoidosis, serum sickness, primary Sjogren syndrome, vasculitis syndromes, and Whipple disease. Obtaining a detailed history, a laboratory work-up, and adherence to the diagnostic criteria of rheumatoid arthritis should allow the accurate diagnosis in the majority of patients.
The cerebral angiogram may be normal in as many as 40% of biopsy-proven cases of primary CNS vasculitis (21). Emmer and colleagues found that MR spectroscopy was useful in identifying whether rheumatoid arthritis was active because systemic inflammation in the disease was associated with brain metabolic abnormalities (41). As noted, in some of these studies the MRI changes might represent the response of the patient to the illness rather than being causative.
Diagnosis of cervical spine disease is based on the patient’s clinical manifestations in the context of radiographic evidence of abnormalities. It should be suspected in rheumatoid arthritis patients with neck pain associated with increasing weakness and sensory loss in extremities. The degree of atlantoaxial subluxation can be measured by lateral plain cervical radiographs in the flexion and extension. Anterior atlantoaxial subluxation is present if the distance between the posterior-inferior aspect of the anterior arch of the atlas and the most anterior point of the odontoid process is greater than 2.5 mm in females and greater than 3.0 mm in males. The maximum value should be applied, which can be measured from lateral flexion views, as this allows the odontoid process to move posteriorly away from the anterior arch of atlas. Subluxations more than 10 to 12 mm probably imply compromise to the apical and alar ligaments superimposed on transverse ligament laxity (44). Posterior atlantoaxial subluxation can be diagnosed if the posterior margin of the anterior arch of C1 is located posterior to the anterior aspect of the body of the axis (142).
Vertical subluxation is more difficult to diagnose and various diagnostic methods have been devised to define this entity on lateral plain radiographs. Kauppi and colleagues proposed a method for screening and grading that determines cranial settling by the presence of superior migration of the superior aspect of the body of C2 beyond a line drawn between the most inferior point of the anterior and posterior arches of the atlas (66).
Lateral atlantoaxial subluxation can be observed on open-mouthed, anteroposterior views when the lateral mass of C1 lies laterally by 2 mm or more than the lateral mass of C2 (142). Diagnosis of subaxial subluxations demand lateral radiographs that include extension and flexion films maximally visualizing the horizontal dislocations of the vertebral bodies. Displacements between adjacent vertebral bodies of greater than 1 mm or 15% of the anteroposterior vertebral diameter are consistent with subaxial subluxation.
MRI is currently the neurodiagnostic procedure of choice for localizing and identifying the underlying pathology in the cervical spine involvement in rheumatoid arthritis. It can visualize the cervical spine in sagittal plane, is noninvasive, and lacks ionizing radiation. Good resolution of the posterior fossa, foramen magnum, spinal cord, cerebrospinal fluid, bones, and pannus is obtained by using MRI.
Somatosensory evoked potentials can also be helpful in detecting spinal cord dysfunction as well as differentiating CNS involvement from brachial plexus and cervical cord lesions (47). Somatosensory evoked potentials can be performed serially in documenting progression or improvement of cervical myelopathy.
Clinical neurophysiologic studies are useful in assessing patients with rheumatoid arthritis with sensory complaints (118). Sensory nerve conduction studies can establish the diagnosis of carpal tunnel syndrome. The most significant parameter is an increased distal sensory latency or absence of measurable action potential. Increased sensory conduction velocity, decreased amplitude, and increased duration are also useful but less sensitive. Electrodiagnostic examinations usually include motor and sensory nerve conduction studies of both median nerves and at least one ulnar nerve. Needle examination of the abductor pollicis brevis muscles is routinely performed to detect denervation. Needle examination of several other upper extremity muscles and the cervical paraspinal muscles is often necessary to evaluate for other entrapment neuropathies, plexopathy, or radiculopathy. Cervical radiculopathy and diffuse peripheral polyneuropathy can be excluded by electrodiagnostic examinations.
Electrodiagnostic studies are significant in confirming ulnar nerve involvement and localizing the lesion. EMG is the most important electrodiagnostic examination for evaluation of suspected ulnar neuropathy at the elbow. In certain patients, plain films, MRI of the elbow, or a laboratory evaluation to screen for an underlying susceptibility to compression neuropathy may be helpful. Nerve conduction studies/EMG are useful in patients with mononeuropathy, mononeuropathy multiplex, as well as in patients who appear to have a more diffuse bilateral symmetric sensory or sensory motor neuropathy. This is particularly true because such studies, when carefully done, can demonstrate an underlying asymmetric neuropathy that is characteristic of neuropathy with rheumatoid arthritis, systemic lupus erythematosus, and other rheumatologic and vasculitis diseases (70; 78).
In rheumatoid arthritis patients with cervical myelopathy, the aims of clinical and surgical treatment consist of identifying patients at risk of paralysis or death and starting treatment before such complications happen. Treatment consists of differentiating nonoperative from operative patients so that surgical intervention can be offered and serious neurologic complications prevented or ameliorated.
Indications for surgical intervention and stabilization are intractable pain and clinical manifestations of myelopathy. Generally, surgery causes symptomatic relief in those with cervical or radicular pain. The surgical outcome for patients with neurologic defects is less certain (86). Nonetheless, once cervical myelopathy has developed, it may assume a rapid course with unfavorable prognosis. Meijers and colleagues followed 43 patients, 34 of whom were judged fit to undergo a surgical fusion (87). Five years later, 10 were alive and 24 had died. All 9 patients who were managed medically died within 1 year; 4 deaths were attributable to spinal cord compression. Therefore, appropriate surgical intervention can remarkably improve the survival of these patients. Because there is a poor correlation between the degree of subluxation, age, gender, and neurologic complications, surgical fusion in asymptomatic patients with atlantoaxial subluxation is contentious. Many authors support early “prophylactic” fusion for rheumatoid arthritis patients in good health if mobile atlantoaxial subluxation is greater than 6 mm (101). The main purpose of the early intervention is to stabilize the subluxation and prevent progression. The recurrence rate of cervical instability following fusion is 5.5% in those with only atlantoaxial subluxation, whereas the recurrence rate increases to 36% in rheumatoid arthritis patients with more advanced disease (those with coexisting horizontal and vertical atlantoaxial subluxation due to chronic inflammation and severe weakness of ligaments and other supporting structures who required fusion from the occiput to C3) (02). The prognosis of surgery for those in end-stage disease is not favorable (23; 24). One of the largest series prospectively reported the outcomes of 2 groups of rheumatoid arthritis patients: one group who had surgery of the cervical spine and was ambulant at the time of presentation, versus the other group who was unable to walk. The second group had a significantly greater proportion of surgical complications, poorer survival rate, and less functional recovery compared to the first group (25). This report further supports the concept of early surgical intervention. The principal targets of surgical intervention are the relief of spinal cord compression and associated neurologic defects, amelioration of pain, and the stabilization of the cervical spine (151). In the absence of pannus behind the dens, simple posterior fusion and repositioning of the C1-C2 subluxation is an appropriate choice. In cases that pannus behind the dens causes constant cord compression, transoral removal of the odontoid process has been suggested (32). There is currently no other alternative to surgical treatment. Paus and colleagues recommended consideration of early surgery for rheumatoid arthritis with associated subluxation of the cervical spine in the hope of decreasing morbidity and mortality as well as improving longevity (104).
Except for relief of entrapment syndromes, there are no known proven effective treatments for rheumatoid peripheral neuropathy. Nevertheless, if a patient with rheumatoid arthritis develops mononeuropathy, mononeuropathy multiplex, or a peripheral neuropathy with clinical (history or neurologic examination), neurophysiologic (NCS/EMG) or pathologic (nerve biopsy) evidence of an underlying asymmetric process highly suspicious of a vasculitic etiology, treatment with a course of corticosteroids, immunosuppressive therapy (78) or, if necessary, a biological agent shown to be useful for other aspects of rheumatoid arthritis should be strongly considered. Continuous physical therapy and supportive measures are crucial to prevent contracture, which can become disabling. Pain in vasculitic neuropathy may also be influenced by a differential expression of pain-related neurotrophic factors and their concomitant soluble receptors (148).
In a patient with refractory rheumatoid arthritis, treatment with adalimumab, a fully humanized IgG1 monoclonal antibody against TNF-a, might have contributed to meningoencephalitis, with brain and meningeal biopsy suggestive of hypertrophic pachymeningitis. This is a rare complication of rheumatoid arthritis and, thus, may have had nothing to do with the adalimumab. However, this patient had recurrence of neurologic symptoms on repeated administration of adalimumab and resolution of symptoms after withdrawal (04), thus, in this instance, a role for adalimumab in the development of pachymeningitis cannot be discounted.
There is overwhelming evidence that pregnancy has a beneficial effect on rheumatoid arthritis. Approximately 75% of patients improve during pregnancy (11; 124). Improvement often begins in the first trimester, and, with few exceptions, is maintained throughout pregnancy. However, fluctuation in disease activity is common, even in those whose rheumatoid arthritis improves or goes into remission. Therapy based on the immunosuppressive factors in pregnancy is an obvious research path to cure rheumatoid arthritis. This approach is currently under investigation in multiple sclerosis where improvement in the third trimester is well established (69).
Stroke prevention. In assessing risk for stroke in patients with rheumatoid arthritis, the role of systemic inflammation associated with the arthritis should be considered along with other well known risk factors, including age, hypertension, hyperlipidemia, genetics, and diabetes. An argument can be made that reducing systemic inflammation to help lower the risk of stroke should be considered another reason for early control of inflammation in patients with rheumatoid arthritis. Paradoxically, lower levels of lipids have been reported in patients with active rheumatoid arthritis, and although statins may help reduce the effects of inflammation, the use of statins should be based on a patient's lipid levels. The increase in cardiovascular complication of NSAIDs should also be considered in patients with rheumatoid arthritis. Exercise, important in the general reduction of cardiovascular disease, may be problematic for patients whose mobility is reduced by rheumatoid arthritis (39).
Robert P Lisak MD
Dr. Lisak of Wayne State University School of Medicine received consulting fees from GLG Consulting, Insight Consulting, Clearview Consulting, Guidepoint Consulting, Haven Consulting, Slingshot Consulting, and Resources Decision Group; research support from Alexion, Novartis, Hoffman-LaRoche, Sanofi-Aventis, Argenx, and Genzyme; and honorariums from Argenx, Novartis, and Mallinckrodt for advisory board membership.See Profile
Francesc Graus MD PhD
Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.See Profile
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