Vancouver, B.C.. Summary: A studyof 170 patientswithjuvenilerheumatoid arthritis and a review of the literature indicate that this disease can significantlyaffect ...
ORIGINAL ARTICLES
Cerebral complications in juvenile rheumatoid arthritis
James E. Jan, m.d., f.r.c.p.[c], Robert H. Hill, m.a., b.m., b.ch., cr.cp.[c] and Morton D. Low, m.d., ph.d., Vancouver, B.C. Summary: A study of 170 patients with juvenile rheumatoid arthritis and a review of the literature indicate that this disease can significantly affect the central nervous system. Signs of CNS dysfunction were observed in 13 children. During the acute toxic stages the EEG is abnormal in many cases. Other manifestations of toxic encephalopathy such as irritability, drowsiness, stupor, convulsions and marked meningismus may be evident in severe cases. Meningitis is often suspected but ruled out by the finding of normal CSF. Steroids can rapidly improve the condition of these children. If 'unexplained' seizures occur during the chronic stage, the diagnosis of cerebral vasculitis should be entertained. Resume: Les complications ce're'brales d'arthrite rhumatoide
juve'nile L'etudede 170 enfants souffrant d'arthrite rhumatoide juvenile et une revue de la litterature pertinente montre que cette
maladie peut affecter notablement le systdme nerveux central (SN C). Des signes de ce trouble fonctionnel du SN C ont ete observes chez 13 enfants. Durant les phases toxiques aigues, I'EEG est anormal en de nombreux cas. Dans des cas particulierement sevdres, d'autres manifestations
Although rheumatoid arthritis is known to involve multiple systems in the body, there has been little dis¬ cussion in the pediatric literature of the central nervous system disturbances. No specific encephalopathy asso¬ ciated with juvenile rheumatoid arthritis has been de¬ scribed. The occurrence of convulsions in the very young has been commented upon1 but there has been a tendency to describe these simply as febrile seizures. Electroencephalographic changes have been documented in cases of juvenile rheumatoid arthritis in the eastern European literature,2"4 but no autopsy reports are available. From a review of the available literature and our own experience, it is evident that signs of central nervous system (CNS) involvement may be seen in both the acute and chronic stages of juvenile rheumatoid arthritis. An encephalopathy may accompany acute toxic exacerba¬ tions, whereas cerebral complications appearing late, commonly after prolonged steroid therapy, may be due to vasculitis.
Methods and case reports The charts* of 170 children in whom juvenile rheuma¬ notamment irritabilite, somnolence, stupeur, convulsions et toid arthritis was diagnosed within the 12-year period meningisme important. On soupgonne frequemment la 1958 to 1970 were reviewed. meningite, mais cette pathologie peut §tre ecartee par la Of the 170 patients, eight (4.7%) had signs of men¬ decouverte de liquide cerebro-rachidien normal. La corticotherapie ingismus ranging from neck stiffness to intense general permet d'ameliorer rapidement l'6tat de ces enfants. Si des muscular rigidity during acute stages of disease. Lumbar convulsions "inexplicables" surviennent pendant la phase was done in 11 patients (6.4%) to exclude men¬ puncture chronique, il faudrait envisager le diagnostic de vasculite which was suspected because of meningismus, ingitis cerebrale. hyperpyrexia and/or extreme irritability (Table I). Three children with seizures during their illness are presented in From the Departments of Pediatrics and Medicine, University of British the following case reports. Columbia and Vancouver General Hospital, Vancouver, B.C. d'encephalopathies toxiques peuvent se manifester,
Reprint requests to: Dr. J. E. Jan, Children's Hospital Diagnostic Centre, 901 West 10th Avenue, Vancouver 9, B.C.
Casel In May 1970 a 2,/2-year-old North American Indian boy became severely ill with pain in the knees and ankles, a fleeting erythe¬ matous itchy rash and intermittent fever up to 40°C. Juvenile rheumatoid arthritis was diagnosed and he was given aspirin up to 1800 mg. daily (120 mg./kg.) without improvement. On July
*Charts were obtained from the records of the Vancouver General Hospital and the Canadian Arthritis and Rheumatism
Society, Vancouver, B.C.
C.M.A. JOURNAL/OCTOBER 7,
1972/VOL. 107
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a five-minute-long generalized convulsion followed by a left-sided seizure. With the exception of marked irritability and drowsiness, there were no abnormal neurological signs and he was afebrile at the time. He was subsequently transferred to the Vancouver General Hospital where he ap¬ peared extremely ill with arthritis, fever to 40°C, hepatosplenomegaly, lymphadenopathy and itchy rash. He had pancytopenia; phagocytosis of myeloid and erythroid elements by histiocytes was seen in the bone marrow. Electroencephalogram (EEG) showed a marked paroxysmal frontal dominant general¬ ized slow dysrhythmia without consistent focal or lateralizing signs (Fig. 1). Lumbar puncture yielded normal cerebrospinal fluid under normal pressure. With steroid medication the patient improved dramatically. Bone marrow became normal in two weeks and waking EEG in two and one-half weeks (Fig. 2). His subsequent course has been one of exacerbations and remissions with continuing arthritis and it has not been possible to discontinue steroids. There have been no further seizures despite periods of hyperpyrexia up to 40° C. Case 2 This Caucasian boy developed normally until the age of 13 months at which time the diagnosis of juvenile rheumatoid arthritis was made and salicylate therapy started. He responded well but relapsed after several months and was in and out of hospital for the rest of his life. On one occasion, while his tem¬ perature was 39°C, his extremities twitched repeatedly. The EEG showed episodic slow wave activity lateralized to the right hemisphere. A few months later, his whole body became rigid as a board for about 24 hours; marked drowsiness, irritability and hyperreflexia were noted. The CSF and radiographs of the spine were normal. At the age of two years he developed pericarditis with bronchopneumonia and was treated with prednisone (10 to 40 mg. daily). Shortly before his fourth birthday, 10 days after halothane anesthesia for dental extraction, he developed hepatomegaly followed by hepatic coma. After two months of critical illness he died. A thorough autopsy examination was performed. Sections of the brain showed While there was generalized congestion but no vasculitis.a decrease in myelin preservation of the neurons in the pons, with extensive macrophage infiltration was evident. This was thought to represent central pontine myelinolysis. When t|ie ankle and knee joints were opened, a fine granular pattern was visible on the articular surfaces which was consistent with pannus formation seen in rheumatoid arthritis.
20, 1970, he had
Case 3 This Caucasian
of age when he developed rheumatoid arthritis. It was progres¬ sive with severe flare-ups. One day at the age of 14 years, while he was doing school work, his right hand began to shake, his mouth started twitching and he lost consciousness and had a generalized seizure for three to five minutes. Examination in hospital showed a severely deformed cushingoid boy, well aware of his circumstances. He was afebrile. He had been taking prednisone 2.5 mg. daily for several months and ASA 2400 mg. daily. Laboratory findings and x-rays were con¬ sistent with the clinical diagnosis. Salicylate level was 15.1 mg./lOO ml. Oral phenylhydantoin was added to his medications. Two weeks later he had another generalized seizure which started in the left arm and lasted for two and one-half minutes. Again there were no abnormal neurological findings. Lumbar puncture revealed normal CSF and the EEG tracing was mildly abnormal with a mixed slightly slow and slightly fast diffuse dysrhythmia. There have been no further convul¬ sions and the prednisone and phenylhydantoin were eventually discontinued. He remains severely handicapped with wide¬ spread deformities of the joints, typical of advanced rheuma¬ toid disease.
Discussion In Case 1 the painful and swollen major joints, the high intermittent fever,1 the fleeting erythematous macular rash5 and the clinical course were all characteristic fea¬ tures of juvenile rheumatoid arthritis. The drowsiness and extreme irritability, the convulsions and the associated EEG changes all indicated an acute CNS disturbance. The second patient had similar acute CNS dysfunction
boy was healthy until four and one-half years
Table I CNS complications
FIG. 1.EEG in child aged 2 years, 10 months in acute stage of rheumatoid arthritis. Diffuse and paroxysmal slowing. AGEi 2 yr. 11
mo
C4P4
100
jiV_
FIG. 2.EEG in same child as in Fig. 1, approximately one month later. Normal for age. 624 C.M.A. JOURNAL/OCTOBER 7,
1972/VOL.
107
several times during the exacerbations of his illness focal seizures, marked meningismus, drowsiness, hyperreflexia and EEG changes. He died of fulminant hepatic necrosis following halothane anesthesia. Central pontine myelinolysis was believed to have occurred just before death. Acute toxic encephalopathy can accompany severe infections which do not directly involve the CNS. Diphtheria, scarlet fever, erysipelas, typhoid fever, dysentery and a variety of poisons8 are known to cause occasionally this indirect disturbance of function of the cerebral neurons. Other organs of the body may also be affected by the toxic process. The neurological manifestations include irritability, drowsiness, stupor, meningismus, convulsions and EEG changes, but the CSF is normal, although occasionally the pressure is increased. At autopsy there is usually swelling of the brain but microscopic examination shows no definite cellular changes.9 Our first two cases showed the above manifestations of encephalopathy during their acute illnesses. Indeed, in 4.7% of the patients whose records were reviewed, meningismus was found during acute exacerbations and 6.4% were subjected to lumbar puncture to exclude meningitis. Cervical spine involvement occurs in juvenile rheumatoid arthritis10 and may simulate nuchal rigidity. Our cases did not have clinical or radiographic evidence of cervical spine disease at the time of these acute episodes and the meningismus was severe enough to cause generalized muscular rigidity in some cases. Ford has stated that such muscular rigidity in encephalopathy is of cerebral origin.8 In contrast to the first two cases the third child, who was afflicted with chronic severe juvenile rheumatoid arthritis, did not have seizures during the acute exacerbation of his illness, but after prolonged use of steroid therapy, and he showed none of the signs of acute CNS involvement. The association of systemic vasculitis with corticosteroid therapy6' 7 is well known and it could have been the basis for the seizures in this case. EEGs were done on only three of our patients because they had seizures but others have described EEG changes in both the acute and chronic stages of juvenile rheumatoid arthritis.24 Kozina and Bacia,2 examining 50 cases, concluded that 48% had abnormal, 20% borderline and 32% normal tracings. The abnormalities were not specific and varied from diffuse to focal. Various neurological complications have been described in adults with chronic rheumatoid arthritis. Peripheral neuropathy secondary to systemic vasculitis is often seen after prolonged steroid therapy7' 1-13 and rarely without.7' 11
Cerebral vasculitis, 15 rheumatoid nodules"2 15, 16I pressing on the brain or spinal cord and pachymeningitiS12' 17 have been documented only in chronic cases. Reports of generalized"8 and cerebral vasculitis"4 in children with chronic juvenile disease have also been published. ,
The authors wish to express their gratitude to Dr. H. G. Dunn and to Dr. S. Israels for their advice.
References 1. CALABRO JJ, MARCHESANO JM: Fever associated with juvenile rheumatoid arthritis. N EnglJ Med 276: 11-18, 1967 2. KOZINA W, BACIA R: Electroencephalographic alterations in the course of rheumatoid arthritis in children. Reumatologia 5: 131-140, 1967 3. BREZINOVA V, BARDFELD R, MEUR J: Results of electroencephalographic examination in cases with juvenile form of rheumatoid arthritis. Ibid: 65-67, 1967 .. 4. SOMOGYI I, BENCZE GY: Uber die epileptoide wellentatigkeit im belastungs-EEG bei lupus erythematosus und rheumatoid-arthritis in remission. A cta Med A cad Sci Hung 26: 225-231, 1969 5. CALABRO JJ, MARCHESANO JM: Rash associated with juvenile rheumatoid arthritis.JPediatr 72: 611-619, 1968 6. OGRYZLO MA: Diffuse systemic rheumatoid disease. Ann Rheum Dis 12: 323-326, 1953 7. FERGUSON RH, SLOCUMB CH: Peripheral neuropathy in rheumatoid arthritis. Bull Rheum Dis 11: 251-254, 1961 8. FORD FR: Diseases of the Nervous System in Infancy, Childhood and Adolesence, fifth ed. Springfield, Charles C Thomas, 1966, pp 593-596 9. LYON G, DODGE PR, ADAMS RD: The acute encephalopathies of obscure origin in infants and children. Brain 84: 680-708, 1961 10. GROKOEST AW, SNYDER AL, SCHLAEGER R: Juvenile Rheumatoid Arthritis, first ed. Boston, Little, Brown and Company, 1961, pp 42-52 11. SCHMID FR, COOPER NS, ZIFF M, et al: Arteritis in rheumatoid arthritis. Am J Med 30: 56-83, 1961 12. PEARSON CM: (The UCLA Interdepartmental Conference) Rheumatoid arthritis and its systemic manifestations. Ann Intern Med 65: 1101-1130, 1966 13. HART FD, GOLDING JR, MACKENZIE DH: Neuropathy in rheumatoid disease. Ann Rheum Dis 16: 471480, 1957 14. SIEVERs K, NISSILA M, SIEVERS UM: Cerebral vasculitis visualised by angiography in juvenile rheumatoid arthritis simulating brain tumor. Acta Rheumatol Scand 14: 222-232, 1968 15. STEINER JW, GELBLOOM AJ: Intracranial manifestations in two cases of systemic rheumatoid disease. Arthritis Rheum 2: 537-545, 1959 16. ELLMAN P, CUDKOWICZ B, ELWOOD JS: Widespread serous membrane involvement by rheumatoid nodules. J Clin Pathol 7: 239-244, 1954 17. GUTMAN L, HABLE K: Rheumatoid pachymeningitis. Neurology (Minneap) 13: 901-905, 1963 18. REID, MM, FANNIN TF: Extensive vascular calcification in association with juvenile rheumatoid arthritis. Arch Dis Child 43: 607-610, 1968
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