NEUROLOGY OF RHEUMATOLOGY, IMMUNOLOGY, AND TRANSPLANTATION

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CHAPTER 119 NEUROLOGY OF RHEUMATOLOGY, IMMUNOLOGY, AND TRANSPLANTATION

Evaluation of patients with rheumatic, inflammatory, or post-transplantation neurological syndromes is challenging because these patients can have a wide variety of disease-specific neurological pathological processes, adverse effects of medications, or, if they have been immunosuppressed, opportunistic infections. They often need a thorough evaluation that might include characterizing the activity of their systemic illness, imaging of brain or spinal cord, electrodiagnostic studies, and spinal fluid examination.

PRIMARY SJÖGREN’S SYNDROME

Sjögren’s syndrome is an autoimmune disease that affects exocrine glands and has protean neurological effects.¹ The sicca syndrome of dry eyes and dry mouth is its signature characteristic, but other systemic manifestations include arthralgias and myalgias, fatigue, and weight loss. Sjögren’s syndrome can affect the lungs, kidneys, and thyroid; can cause small- or medium-vessel vasculitis; and can have hematological manifestations, such as anemia, lymphoma, neutropenia, and monoclonal gammopathy. The diagnosis is supported by objective evidence of sicca syndrome, such as positive results of Schirmer’s test for tear production, findings from lip biopsy, and the presence of specific autoantibodies (anti-Ro [SSA] and anti-La [SSB]). Sjögren’s syndrome can be associated with other inflammatory diseases, such as rheumatoid arthritis, in which case it is termed secondary Sjögren’s syndrome. The neurological aspects discussed as follows are associated with primary Sjögren’s syndrome.

Central Nervous System Manifestations

Mild deficits on psychometric testing are the most common cerebral abnormalities in patients with Sjögren’s syndrome. In rare cases, the neuropsychological impairment is severe enough to cause dementia. Deficits are sometimes correlated with specific areas of brain hypoperfusion, demonstrable with techniques such as single photon emission computed tomography (SPECT), even in patients who have normal magnetic resonance imaging (MRI) brain scans and no other manifestations of central nervous system (CNS) disease.²

A wide variety of focal brain lesions can occur in patients with Sjögren’s syndrome. The findings can appear gradually or as suddenly as a stroke. Sjögren’s syndrome affects either gray or white matter, above or below the tentorium; thus, clinical manifestations are diverse and include hemiparesis or hemisensory loss, ataxia, eye movement abnormalities, and dysarthria.

At times, CNS disease in Sjögren’s syndrome follows a relapsing-remitting multifocal pattern, mimicking the course of multiple sclerosis. Nonetheless, surveys in multiple sclerosis clinics suggest that the incidence of sicca syndrome among patients with multiple sclerosis approximates that in the general population. Clues that a relapsing-remitting CNS illness might be associated with Sjögren’s syndrome include older age at onset; associated peripheral neuropathy; lesions on spinal MRI that span multiple spinal segments; atypical brain MRI appearance for multiple sclerosis, such as gray matter lesions or absence of lesions in the corpus callosum; and lack of cerebrospinal fluid (CSF) oligoclonal bands.

Sjögren’s syndrome is rarely associated with aseptic meningitis, which is sometimes recurrent. Pleocytosis, usually mild, can also be found in some patients with focal or multifocal CNS syndromes. CSF protein level is sometimes increased, and glucose level is usually normal. Oligoclonal bands are present in CSF in a minority of patients.

Myelopathy caused by intramedullary spinal cord lesions is among the most common of CNS abnormalities in Sjögren’s syndrome. The clinical varieties include acute, subacute, or chronic transverse myelopathies; lateralized spinal cord inflammation leads to hemicord syndromes, such as hemiplegia; motor syndromes resembling motor neuron disease or primary lateral sclerosis; and predominantly posterior cord abnormalities.

Spinal cord MRI is abnormal in approximately 75% of patients with clinical myelopathies, usually showing areas of hyperintensity on T2-weighted scans. On occasion, the cord appears swollen. In some cases, the lesions are enhanced with gadolinium. The MRI lesions usually extend over multiple spinal levels, in contrast to the localized appearance that is typical of the plaques of multiple sclerosis.

Peripheral Nervous System Manifestations

Symmetrical length-dependent neuropathy is the most common peripheral nervous system finding in patients with Sjögren’s syndrome and can be the presenting clinical finding. Manifestations include small- or mixed-fiber sensory axonal neuropathy or sensorimotor neuropathies. Motor neuropathies resembling Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy are infrequent. Clinical peripheral nervous system disease probably occurs in 10% to 20% of patients with primary Sjögren’s syndrome; a higher incidence of peripheral nerve abnormalities is noted among patients with Sjögren’s syndrome who are carefully screened with quantitative sensory and electrodiagnostic testing. Conversely, if patients with idiopathic axonal neuropathies are screened for Sjögren’s syndrome, a few meet definite diagnostic criteria for Sjögren’s syndrome, and more have isolated features of Sjögren’s syndrome, such as symptoms of sicca syndrome or a positive findings on lip biopsy.³ Most patients with peripheral neuropathy and sicca syndrome do not eventually develop other extraglandular manifestations of Sjögren’s syndrome.⁴

Nerve biopsy findings in patients with peripheral neuropathy and Sjögren’s syndrome are generally no more specific than those in other axonal neuropathies. Nonspecific epineurial inflammatory cells are often present, but there is rarely definite evidence of vasculitis.⁴

Sensory neuronopathy, apparently caused by inflammation in the dorsal root ganglia, is an uncommon but distinctive manifestation of Sjögren’s syndrome. The sensory findings can manifest acutely or indolently, often in a proximal, asymmetrical pattern. Dysfunction of large-fiber functions can cause loss of joint position sense and of tendon reflexes, pseudoathetosis and ataxia, and low-amplitude or unobtainable sensory nerve action potentials. Pain and temperature fiber dysfunction can cause sensory loss and neuropathic pain. The sensory neuronopathy often is the presenting manifestation of Sjögren’s syndrome in these patients; however, investigation shows typical diagnostic findings such as sicca syndrome symptoms, abnormal results of tests of tear and saliva production, and positive lip biopsy findings. Nonetheless, patients with Sjögren’s sensory neuronopathy usually do not have systemic extraglandular disease. MRI of the spinal cord often reveals bright signal intensity on the posterior columns on T2-weighted images.

Sjögren’s syndrome can cause branch trigeminal sensory neuropathies, unilaterally or bilaterally, with a predilection for the mandibular or maxillary divisions of the nerve. Pathology is probably inflammation of the gasserian ganglion, analogous to disease of the dorsal root ganglion in sensory neuronopathy, which sometimes accompanies the trigeminal neuropathy. Sjögren’s syndrome can also affect the olfactory, facial, and audiovestibular nerves.

Severe autonomic neuropathy with manifestations such as orthostatic syncope and nocturnal diarrhea is an unusual accompaniment of Sjögren’s syndrome. The autonomic neuropathy can be the sole neurological abnormality or can co-occur with sensory neuronopathy or peripheral neuropathy. When patients with Sjögren’s syndrome are questioned closely, they often reveal milder symptoms of autonomic dysfunction, such as orthostatic lightheadedness. Furthermore, detailed autonomic testing, such as tilt-table testing or comparison of heart rates during inspiration and expiration, often reveals asymptomatic autonomic dysfunction.

Mononeuritis multiplex is unusual in patients with Sjögren’s syndrome. When it does occur, systemic manifestations of Sjögren’s syndrome, such as cutaneous vasculitis or Raynaud’s phenomenon, are usually present. Many such patients have cryoglobulinemia. Nerve biopsy sometimes demonstrates evidence of vasculitis or nonspecific lymphocytic proliferation.

In rare cases, patients with Sjögren’s syndrome have prominent disease of α motor neurons, which differs from classic amyotrophic lateral sclerosis by the presence of other neurological changes such as CNS disease beyond the pyramidal tract.

Many patients with Sjögren’s syndrome complain of mild weakness or myalgias but have no serious muscle pathology. They usually have normal creatine kinase levels and electromyograms. Infrequently, Sjögren’s syndrome coexists with polymyositis or dermatomyositis. A rare complication of Sjögren’s syndrome is reversible hypokalemic paralysis caused by distal renal tubular acidosis.

Information on neurological responses to treatment is limited to uncontrolled observations in small series of patients. Steroids are rarely helpful in patients with axonal polyneuropathies.¹ The neuronopathy is poorly responsive to steroids or immunosuppression.^5,⁶ Myelopathy and other CNS syndromes are more likely to improve with steroid treatment. In patients with severe myelopathy or mononeuritis multiplex, cyclophosphamide in combination with steroid therapy sometimes yields apparent benefit.¹ Case reports suggest improvement in myelopathy treated with steroids and azathioprine or chlorambucil or in sensory neuronopathy treated with intravenous immunoglobulin. Responses to plasmapheresis have been mixed.⁷ A least one patient experienced improvement after treatment with the anti–tumor necrosis factor antibody infliximab.⁸

PROGRESSIVE SYSTEMIC SCLEROSIS

Progressive systemic sclerosis is an uncommon illness that causes excessive tissue fibrosis and vascular changes. It is often referred to as scleroderma, which more precisely is the skin thickening and fibrosis caused by the disease. Localized forms of scleroderma can occur without progressive systemic sclerosis and do not have the same prognostic or neurological implications. In progressive systemic sclerosis, the skin is affected in a number of other ways, including calcifications, telangiectasias, finger swelling, and sclerodactyly (tightening of the skin of the digits). Raynaud’s phenomenon occurs in as many as 90% of patients with progressive systemic sclerosis. Other systemic manifestations are gastrointestinal disease, especially impaired esophageal motility; pulmonary disease, such as fibrosis or pulmonary hypertension; renal or cardiac involvement, especially with hypertension; hypothyroidism; sicca syndrome; and arthralgias and tenosynovitis. Dysphagia is often present because of esophageal disease and is usually not an indication of bulbar neurological dysfunction. The syndrome of subcutaneous calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia (CREST) may be present with less systemic involvement.

More than half the patients with progressive systemic sclerosis have evidence of autoimmunity such as antinuclear antibodies or, less common but more specific, antibodies against centromeres, topoisomerase I, RNA polymerase III, or Scl-70. These provide some prognostic clues: anti–SCL-70 antibody is more often associated with fully developed progressive systemic sclerosis, whereas anticentromere antibodies are associated with CREST.

Neurological complications are relatively limited in patients with progressive systemic sclerosis. These include headache, myopathy, trigeminal neuropathy, peripheral neuropathy, autonomic neuropathy, ectopic calcifications, and stroke.

Patients with progressive systemic sclerosis may have nonspecific cerebral calcifications in the basal ganglia and dentate nuclei. These are best visualized by computed tomography and are present in about one third of patients with progressive systemic sclerosis in a consecutive series. In rare cases, focal cerebral gyral or spinal ligamentous calcifications occur. Cervical or even thoracic paraspinal calcifications are also unusual. These can adjoin the facet joints and extend into neuroforamina, at times compressing nerve roots.

Patients with progressive systemic sclerosis are at increased risk of peripheral vascular disease, including extracranial carotid artery stenosis, in comparison with controls. This risk is independent of additional stroke risk if they are hypertensive. In a few instances, patients with progressive systemic sclerosis have developed a diffuse or multifocal encephalopathy associated with a diffuse cerebral vasculopathy, in which angiography demonstrates multifocal narrowing of medium-sized intracerebral arteries. Reports of cerebral aneurysms in patients with progressive systemic sclerosis are so few that it is unclear whether the concurrent conditions are coincidental or pathogenically linked.

Trigeminal sensory neuropathy, clinically similar to trigeminal neuropathy that is found in Sjögren’s syndrome, occurs in approximately 4% of patients with progressive systemic sclerosis. There are isolated reports of acute myelitis in patients with progressive systemic sclerosis.

Peripheral nerve abnormalities in patients with progressive systemic sclerosis are varied and uncommon and include carpal tunnel syndrome, distal axonal sensory neuropathy, transverse myelitis, and mononeuritis multiplex. For example, in a series of 125 patients, four had carpal tunnel syndrome. Symmetrical distal sensory neuropathy, lumbar or brachial plexopathies, and mononeuritis multiplex were even less frequent. An occasional patient has asymptomatic mildly abnormal nerve conduction. Some patients have focal abnormalities of cutaneous sensation.

Some patients with progressive systemic sclerosis have autonomic nervous system deficits, such as decreased sudomotor sweating, evident on autonomic testing. Clinical autonomic neuropathy, with manifestations such as orthostatic hypotension or impotence, can also occur.

Patients with progressive systemic sclerosis often have mild symmetrical weakness, especially proximally. Some have mild elevation of creatine kinase levels and mild electromyographic abnormalities, such as decreased motor unit duration. Less frequently, progressive systemic sclerosis and inflammatory myopathy can occur in the same patient.

RHEUMATOID ARTHRITIS

Rheumatoid arthritis is a chronic (duration, >6 weeks), symmetrical, inflammatory polyarthritis with a predilection for metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. The prevalence is 1% to 2% in many population groups; women are more commonly affected. Joints develop synovial proliferation and erosion of cartilage and bone, which lead to chronic deformities. Modern disease-modifying antirheumatic drugs can prevent or decrease the proliferative, erosive process. Rheumatoid arthritis can have nonarticular manifestations, including subcutaneous rheumatoid nodules; sicca syndrome; Felty’s syndrome of hypersplenism; amyloidosis; scleritis or episcleritis; lung or heart involvement; anemia of chronic disease; eosinophilia; thrombocytosis; and vasculitis. Rheumatoid arthritis can be accompanied by autoantibodies. For example, rheumatoid factor is present in about 80% of patients, but this finding is nonspecific. Important neurological issues in patients with rheumatoid arthritis are headache, spinal disease especially at the atlantoaxial joint, peripheral nerve disease, muscle weakness, and, in rare cases, rheumatoid vasculitis or pachymeningitis. The neurological complications of rheumatoid arthritis are indications of advanced or severe disease. Serological testing for rheumatoid factor is not useful for investigating neurological disease in patients who do not have clinical arthritis.

Headache

Neck or head pain, particularly occipital headache, is common among patients with rheumatoid arthritis. For some, this is independent of specific cervical spine pathology, but for others, pain is correlated with lateral subluxation of the atlantoaxial joint. In patients with severe intractable neck or occipital pain and demonstrable atlantoaxial joint lateral subluxation, surgical stabilization of the joint can decrease the pain.

Brown’s Syndrome

Tendonitis of the superior oblique tendon (Brown’s syndrome) can cause eye pain, intraorbital clicking with eye movement, and decreased eye elevation, especially when the eye is abducted. It is important to distinguish this rare complication of rheumatoid arthritis from neurological causes of impaired eye movement.

Atlantoaxial Disease

Rheumatoid arthritis can affect the cervical spine, where ligamentous inflammatory changes lead, in particular, to atlantoaxial joint subluxation (Fig. 119-1). Subluxation is usually anterior but can also occur vertically, laterally, or posteriorly. Anterior atlantoaxial subluxation was found in fewer than 3% of patients who had had rheumatoid arthritis for less than 5 years, 15% of those who had had the disease for 10 to 15 years, and 26% of those who had had the disease for more than 15 years.⁹ Once present, the subluxation may not increase; however, in a decade, at least 25% of those with subluxation have progression in subluxation, varying from 1 to 7 mm.