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Acute Encephalomyelitis: Extending the Neurological Manifestations of Acute Rheumatic Fever? By R. Munn l , K. Farrell J and N. Cimolai2 1Division of Neurology,

Department of Paediatrics, and 2Department of Pathology, University of British Columbia, Vancouver, Canada

The clinical course of a five-year-old boy who developed meningeal irritation, encephalomyelitis, and optic neuritis four weeks after Streptococcus pyogenes pharyngitis is detailed. The patient responded to therapy with corticosteroids and recovered fuHy. Review of the literature reveals that a wide range of neurological disorders have been described in association with rheumatic fever. We suggest that disseminated encephalomyelitis in this child most probably was related to the streptococcal infection and that the spectrum of post-infectious neurological disorders associated with Streptococcus pyogenes may be broader than is currently appreciated.

Keywords

Streptococcus pyogenes - Encephalomyelitis - Rheumatic fever

Introduction The neurological manifestations associated with Streptococcus pyogenes (Group A streptococcus) infection may be the result of direct infection (e.g., meningitis) or of a post-infectious, presumably immune-mediated reaction. Sydenham's chorea is the major post-infectious neurological complication and is part of the clinical spectrum of acute rheumatic fever. Other post-infectious neurological complications have been associated with rheumatic fever but are not widely recognized (3, 11, 15). Miller et al (10) have reviewed the descriptions of varied neurologic disorders after clinical scarlet fever. However, these prior reports have lacked laboratory evidence to support Streptococcus pyogenes infection. We describe a child who developed acute encephalomyelitis and optic neuritis associated with serological and culture evidence of Streptococcus pyogenes infection, and suggest that the spectrum of postinfectious neurological disorders associated with the Group A streptococcus may be more broad than is generally appreciated. Received August 15, 1991; accepted January 10, 1992 Neuropediatrics 23. (1992) 196-198 © Hippokrates Verlag Stuttgart

A five-year-old male acutely developed a sore throat, fever (39.0°C), headache, photophobia and purulent nasopharyngitis. He received oral cotrimoxazole but did not improve. Physical examination eight days after the onset of these symptoms revealed pharyngitis in addition to anterior and posterior cervicallymphadenopathy. Meningismus was not apprec.iable and the neurological examination was normal. Laboratory investigations yielded the following: WBC 23 x 109/L (predominance of polymorphonuclear ceIls), erythrocyte sedimentation rate 78, anti-streptolysin 0 titer (ASOT) > 6400 Todd units. A throat culture yielded Streptococcus pyogenes. The patient was treated with oral erythromycin for two weeks and his symptoms resolved over several days. The patient remained weIl until 1-2 weeks later at which time he developed a progressive abnormality of gait. Two days later, he complained of blurred vision in his left eye. The child was afebrile but manifested marked meningismus, decreased visual acuity in the left eye (O.S. 20/40, O.D. 20/20), spasticity of aIl four limbs, symmetrically brisk deep tendon reflexes and bilateral extensor plantar responses. Examination of the cerebrospinal fluid (CSF) revealed the foHowing: 2 x 106/L red blood ceHs and 150 x 106/L nucleated ceIls (12 % neutrophils, 60 % lymphocytes, 24 % monocytes, 4 % eosinophils), glucose 2.3 mmoVL (blood glucose 4.4 mmoVL), protein 0.83 g/L (normal 0.15-0.45 g/L), IgG 0.14 g/L (normal 0.005-0.095 g/L) with an IgG synthesis index of 0.56 (normal< 1.02). There was no evidence of CSF oligoclonal banding and the total serum IgG was elevated at 22.6 g/L. Bacterial and viral cultures of CSF were negative. Serology excluded infection by cytomegalovirus, herpes simplex, Epstein-Barr virus, measles, mumps, rubella, Mycoplasma pneumoniae, Influenza A and B, Borrelia burgdorferi, and Borrelia hermsii. A visual evoked potential (VEP) revealed a weIl formed and reproducible P-1 00 peak at 105 msec of the right eye and a poorly formed P-100 peak at 120 msec of the left eye compatible with left optic neuritis. Computer tomographic (CT) scan with contrast enhancement and magnetic resonance imaging of the head were both normal. The patient was treated with intravenous methylprednisolone (30 mg/kg/day) for three days and a tapering course of prednisone (1 mg/kg/day) for two weeks. The child was normal neurologicaIly four days after starting the corticosteroid therapy but developed increasing neck and back stiffness towards the end of the course of prednisone requiring an additional eight weeks of oral prednisone. He subsequently made a fuIl recovery. Follow-up streptococcal serologywas consistent with Streptococcus pyogenes infection (Table 1).

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Case report Abstract

labre 1

Patient serological anti-streptococcal profile. I

ASOT AntiDNAse B

Neuropediatrics 23 (1992)

March 23

1

April 10

>6400

I

April 26

3200 > 1/1360

I

May 3

6400

IJune 29 800 > 1/1360

ASOT = anti-streptolysin titer in Todd units Anti-DNAase B = antibody titer to deoxyribonuclease B of Streptococcus

pyogenes

Discussion Our patient developed clinical signs of meningeal irritation, encephalomyelitis and optic neuritis four weeks after an apparent Streptococcus pyogenes pharyngitis. He was previously weIl and had no other evidence of systemic disease during the two weeks interval prior to admission to hospital. The CSF pleocytosis and increased protein in CSF are consiste.nt with meningeal inflammation. The abnormal VEP supports the clinical diagnosis of optic neuritis. These observations are consistent with a diagnosis of acute disseminated encephalomyelitis.

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subthalamic and caudate nuclei have been demonstrated in patients with Sydenham's chorea and the presence of these antibodies appears to correlate with the severity and duration of clinical attacks (8). Neuropathological examination of patients with Sydenham's chorea demonstrates an arteritis which is probably immune mediated (2). Given the diffuse localization of pathological abnormalities in the central nervous system (4), it is surprising that acute rheumatic fever has not been associated with a broader neurological spectrum of disease. The limitations of using predominantly clinical criteria (i. e. Iones' criteria) for the definition of acute rheumatic fever may account for this narrow spectrum. The pathogenesis and certain pathological features of post-infectious encephalomyelitis resemble those observed in Sydenham's chorea. The pathogenesis of postinfectious encephalomyelitis also involves presumably an autoimmune mechanism. The disorder occurs typically in children following a presumed infectious illness. As in Sydenham'schorea, there is a lag between the infection and the onset of the acute neurological disease (13). Although the preceding infectious illness is often presumed to be viral, a clearly defined etiologic agent is rarely demonstrated. Finally, a perivascular inflammatory reaction is one of the pathological features of post-infectious encephalomyelitis (1).

The diagnosis of Streptococcus pyogenes infecThe temporal profile of our patient's illness, tion preceding the neurological illness was confirmed by culture and by streptococcal serology. Both the ASOT and anti-DNase the history of delayed appropriate therapy, and the strongly B titer were markedly elevated for several months, and there supportive laboratory evidence of Streptococcus pyogenes infecwas a decline in the ASOT titre by the third month (Tab. 1). AI- tion lead us to hypothesize that acute encephalomyelitis may though the level of ASOT titre does not correlate strongly with represent a post-infectious complication of Streptococcus the severity of a streptococcal infection (5), patients with acute pyogenes infection. Although non-nephritic post-infectious rheumatic fever tend to have higher titers compared to patients sequelae are termed acute rheumatic fever when a set of predewith simple streptococcal infections (12). The interval between termined, predominantly clinical criteria are satisfied, we proonset of pharyngitis and development of neurological features is pose that the rigid definition of acute rheumatic fever will exalso in the range documented for acute rheumatic fever. Finally, clude a bonafide spectrum of post-infectious sequelae that may cotrimoxazole, which is generally ineffective for treatment of still be associated with substantiallaboratory evidence of infecStreptococcus pyogenes pharyngitis, was used initially and treat- tion. The restrictive nature of predominantly clinical definitions ment with erythromycin was not begun until 9 days following is often evident after a laboratory measure of infection becomes the onset of symptoms. The failure to treat the Streptococcus -established, and this issue is exemplified by the impact of labopyogenes infection promptly may have played a role in the devel- ratory diagnosis upon the toxic shock and acquired opment of what may have been a neurological variant of acute immunodeficiency syndromes prior to the recognition of the rerheumatic fever. spective etiologic agents. The spectrum of postinfectious neurological complications associated with Streptococcus pyogenes Although Sydenham's chorea is the only weIl may be more diverse than is currently accepted. recognized neurological manifestation of acute rheumatic fever, other neurological disorders have been reported in association with rheumatic fever (3, 7, 10, 11, 15). Encephalitis and Acknowledgment meningoencephalitis were described in a review of the "nonchoreaI" cerebral manifestations of rheumatic fever in adults We thank Tammy Groening for preparation of (11). The signs and symptoms included headache, vomiting, the manuscript. disturbances of consciousness, pyramidal tract signs, aphasia, seizures and meningismus. Histopathological studies in fifteen of these patients revealed widespread cerebral vasculitis. Psychiatric disease (3) and seizures (15) have also been reported as References possible late manifestations of rheumatic fever. Thus, a number of neurological disorders in addition to Sydenham's chorea have been described in patients with rheumatic fever as diag- 1 Allen, 1. V.: Demyelinating diseases. In: Adams,]. H.,]. A. N. Corsellis, L. W. Duchen (Eds.) Greenfield's Neuropathology. 4th ed., New York, nosed by Iones' criteria. The majority of previous reports, howJohn Wiley and Sons (1984) 338-384 ever, lack laboratory evidence which would support preceding 2 Aron, A. M., }. M. Freeman, S. Carter: The natural history of streptococcal infection. Sydenham's chorea. Am. J. Med. 38 (1965) 83-95 3 Bruetsch, W. L.: Late cerebral sequelae of rheumatic fever. Arch. Intern. The pathophysiology of Sydenham's chorea Med. 73 (1944)472-476 most probably involves an autoimmune process triggered by 4 Colony, H. 5., N. Malamud: Sydenham's chorea: a clinicopathologic streptococcal antigens (6, 14). Immunoglobulin Gantibodies to study. Neurology 6 (1956) 672-676

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Streptococcus Pyogenes - Associated Encephalomyelitis

Neuropediatrics 23 (1992) Femeri, P.: Immune responses to streptococcal infections. In Rose, N. R., H. Friedman,]. L. Fahey (Eds.). Manual of Clinical Immunology. 3rd ed., Washington, American Society for Microbiology (1985) 336-341 6 Fischetti, V. A.: Streptococcal M protein: molecular design and biological behaviour. Clin. Microbiol. Rev. 2 (1989) 285-314 7 Hodson, A. K., R. A. Doughty, M. E. Norman: Acute encephalopathy, streptococcal infection, and cryglobulinemia. Arch. Neurol. 35 (1978) 43-44 8 Husby, G., 1. Van De Rijn,]. B. Zabriskie, Z. H. Abdin, R. C. Williams: Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J. Exp. Med. 144 (1976) 1094-1110 9 ]ohnson, R. T.: The pathogenesis of acute viral encephalitis and postinfectious encephalomyelitis. J. Infect. Dis. 155 (1987) 359-364 10 Miller, H. G.,]. B. Stanton,]. L. Gibbons: Para-infectious encephalomyelitis and related syndromes. Q. J. Med. 25 (1956) 427-505 11 Mitkov, V.: Cerebral manifestations of rheumatic fever. World Neurol. 2 (1961) 920-924 12 Quinn, R. W., S. ]. Liao: A comparative study of antihyaluronidase, antistreptolysin "0", antistreptokinase, and streptococcal agglutination

R. Munnetal

5

13

14 15

titers in patients with rheumatic fever, acute hemolytic streptococcal infections, rheumatoid arthritis and non-rheumatoid forms of arthritis. J. Clin. Invest. 29 (1950) 1156-1166 Reik, L.: Disorders that mimic CNS infections. Neurol. CIin. 4 (1986) 223-248 Senitzer, D., E. H. Freimer: Autoimmune mechanisms in the pathogenesis of rheumatic fever. Rev. Infect. Dis. 6 (1984) 832-839 Whitman,]. F., L.]. Karnosh: Rheumatic brain disease as a cause of convulsions. Cleve. Clin. Q. 16 (1949) 136-141

Dr. Nevio Cimolai Program of Microbiology Department of Pathology B.C. 's Children's Hospital 4480 Oak Street Vancouver, B.C. Canada V6H 3V4

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Acute encephalomyelitis: extending the neurological manifestations of acute rheumatic fever?

The clinical course of a five-year-old boy who developed meningeal irritation, encephalomyelitis, and optic neuritis four weeks after Streptococcus py...
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