Rheumatoid Arthritis with Associated CNS Vasculitis
Patient #29 presented with the gradual onset of weight loss, rash, joint pains, and an elevated rheumatoid factor consistent with a diagnosis of rheumatoid arthritis and the rapid onset of neurological compromise evidenced by gait difficulty, diffuse and focal weakness, and impaired cognition. She demonstrated evidence of bilateral pyramidal dysfunction (bilateral weakness, worse on the left with right-sided hyper-reflexia and a left-sided Babinski sign), frontal lobe compromise (palmomental, snout reflexes, etc.), and diffuse cortical (apraxias, language dysfunction) and subcortical (bradyphrenia, poverty of speech) involvement. These findings support a diffuse cerebral insult, resulting in a rapidly progressive dementia.
The differential diagnosis of rapidly progressive dementia is broad, including diffuse demyelinating processes such as multiple sclerosis or acute demyelinating encephalomyelitis; frontal lobe tumors (benign and malignant); prion diseases, such a Creutzfeldt-Jakob; bilateral subdural hematomas; chronic meningitis due to AFB or fungal agents; various metabolic disorders; and CNS vasculitis. Generally, each of these processes demonstrates various levels of pyramidal dysfunction as seen in this case. Unfortunately, there were few historical features that could unequivocably distinguish between the possibilities, though the lack of a low-grade fever argues against chronic meningitis and the lack of myoclonus, parkinsonism, and cerebellar dysfunction argues against Creutzfeldt-Jakob disease. Therefore, supporting laboratory and radiologic evidence was needed to further differentiate the possibilities.
Further evidence against Creutfeldt-Jakob disease included relatively non-specific findings of diffuse slow activity on routine EEG (there was no finding of one per second generalized sharp waves as may be seen in CJ disease). While this does not exclude CJ disease from the possibilities, it provides no further supporting evidence. This, taken with the clinical picture and the MRI findings of diffuse subcortical white matter hyperintensities on T2-weighted images essentially excludes CJ disease from consideration. The MRI in Creutfeldt-Jakob disease is usually non-specific, showing only mild atrophy. Similarly, the CSF findings do not support a diagnosis of chronic meningitis. While there is evidence of an inflammatory process, by CSF, there is no evidence to support an ongoing infection. Metabolic causes were eliminated by the findings of relatively normal metabolic screening labs. The MRI did not show evidence of a frontal lobe tumor or bilateral subdural hematomas, rejecting these possibilities.
The remaining possibilities of a diffuse demyelinating process or CNS vasculitis could not be differentiated on the basis of the foregoing tests, however. Both processes might present with evidence of diffuse, patchy white matter involvement on MRI, an inflammatory process by CSF examination, and pyramidal and cognitive compromise. Both possibilities would be unusual in this clinical setting, though, since the process clearly progressed over time eliminating acute demyelinating encephalomyelitis (a monophasic illness without progression). Multiple sclerosis would be unusual in this age group, especially presenting in such a fulminant manner. And CNS vasculitis secondary to rheumatoid arthritis is extremely rare, with only a few cases reported in the literature. There was, however, evidence to support the latter diagnosis, as the patient showed a markedly elevated rheumatoid factor (considered a prognostic indicator of disease by some investigators), and a possible systemic vasculitis (lower extremity rash, fever, chills). Cerebral angiogram was performed to investigate this possibility, but the results were normal. The angiogram was, therefore, neither helpful nor harmful in establishing a diagnosis, as it is normal in up to 50% of small and medium vessel vasculitides. Frontal lobe biopsy was, therefore, performed. This showed the classic small vessel changes associated with rheumatoid arthritis vasculitis with transmural, predominantly lymphocytic infiltration with focal intimal proliferation. There were no macrophages, viral inclusions, plaques, tangles, neoplastic cells, or cytoplasmic inclusions. These findings are in contrast to what is seen in cases of CNS inflammatory demyelinating diseases, where there is lymphocytic cuffing of small and medium sized vessels but no invasion of the vessel walls.
The patient was treated with eight days of intravenous Cytoxan. By discharge from the hospital, her mental status had improved markedly with increased alertness and improved interaction with her environment. The patient continued to improve and from her family's standpoint regained her previous level of cognitive functioning and personality. Her ambulation improved from the inability to walk to assistance with a walker. She currently lives in a nursing home where her daughters visit frequently and has no evidence of progressive CNS
Rheumatoid arthritis is a systemic autoimmune disease generally manifested by a symmetric polyarticular erosive inflammation of the joints. Criteria for the classification includes four of the seven which have been present for at least six weeks:
The presence of a positive Rheumatoid arthritis titer in a patient with Rheumatoid arthritis is of clinical value because its presence tends to correlate with severe unremitting disease and the development of extraarticular manifestations. There is a loose correlation with severity of disease and titer. Extraarticular manifestations include subcutaneous nodules, vasculitis, pericarditis, pulmonary nodules or interstitial fibrosis, mononeuritis multiplex, episcieritis, Sjogren's and Felty's syndromes. The vasculitis is most frequently evidenced as skin infarctions/ulcerations and a mononeuritis multiplex. Bowel ulceration and cardiac involvement are other manifestations of the vasculitis associated with Rheumatoid arthritis, but renal involvement is seldom seen. Besides the mononeuritis multiplex associated with RA-vasculitis, CNS manifestations include myelopathies associated with C-spine instability and entrapment neuropathies. The occurrence of inflammatory CNS involvement is rare and is always in the setting of the vasculitis associated with Rheumatoid arthritis. Many rheumatologists believe the vasculitis is an underdiagnosed occurrence in rheumatoid arthritis. This may also be true of the CNS vasculitis manifestation.
In one review of the literature through 1987, only 19 cases of inflammatory CNS disease associated with RA with proven RA diagnosis and sound clinical and histopathological data were documented. Of these 19, the most frequent finding was a CNS nodule in the meninges histologically identical to the rheumatoid nodule seen systemically. The second most frequent finding was a nonspecific inflammation of the pachymeninges or leptomeninges. Only nine patients had evidence of CNS parenchymal vasculitis.
Six of the nine literature reported cases of rheumatoid CNS vasculitis were female. Ages ranged between 47-75 with the majority being in their sixties. Subcutaneous nodules were reported in half of the cases. Seven reported positive RA titers (two did not report the finding). Four of those seven titers were 1:5,120 or greater. Most had evidence of severe joint deformities and several had cutaneous problems such as ulcers or gangrene. An alteration in mental status was the most common presentation reported in eight of the cases. Fever was common. Seizure, focal neurologic deficit, and cranial nerve findings were also reported.
As mentioned above, elevated rheumatoid factor titers are a consistent if not absolute finding. A review of CSF findings showed four of the nine with moderate elevations in protein, three did not report CSF findings, and the most recent two cases reported normal protein values. Only one case reported an abnormal white blood cell count. None of the cases besides our own reported the findings associated with electrophoresis. This case revealed an increased IgG synthesis rate and IgG index with faint oligoclonal band staining. Only this case and the other more recent case have suggested a predominant white matter process. Neither case revealed enhancement by MRI. These two cases reported cerebral angiograms negative for vasculitis. CT findings in the other cases are not available, but when reviewing the cases with meningeal involvement, CT scans reported meningeal enhancement and ventricular enlargement. EEGs may be abnormaI (reported in four of the nine cases) and may show uniform slowing or focal slowing.
All nine reviewed cases provided histopathological confirmation of the diagnosis by brain biopsy or autopsy. All cases reported vessel wall infiltration of predominantly lymphocytic and plasma cell proliferation. Polymorphonuclear cells were reported in two. Gliosis was noted in the two most recent cases. Four of the nine cases had meningeal involvement either as CNS nodules or meningeal inflammation or vasculitis.
Of the reported cases, death occurred from 4-120 months after the initial CNS presentation with the median death occurring less than two months after CNS symptoms. Six of these patients received either steroid therapy or no therapy. One patient received steroid and cyclophosphamide (dose unknown) with death occurring at two months. The more recently reported patient died at 14 months from causes felt to be unrelated to the CNS vasculitis. This patient received steroids and oral cyclophosphamide followed by azathioprine. Our case, now lost to follow-up, was still alive greater than three years after her initial symptoms. Her therapy consisted of aggressive high dose intravenous cyclophosphamide.
Treatment of the systemic vasculitis associated with rheumatoid arthritis has typically consisted of steroid therapy. Although various immunosuppressive agents have been used there have been few controlled studies and none have shown a definite advantage. One small, underpowered study using azathioprine did not show a benefit over steroids. D-penicillamine, cyclosporine, cyclophosphamide, and methotrexate have all been used. This small sample size of nine patients with rheumatoid arthritis manifesting a cerebral vasculitis suggests aggressive therapy is warranted. Death was relentless in all but the last two cases and both of these cases used fairly aggressive immunosuppressive approaches. Because of the small number of documented cases and rapid occurrence of death, little is known about the course of this vasculitis. The question remains in the face of aggressive therapy whether this is an indolent, progressive disease process or a monophasic insult.
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