Rheumatology 2002; 41: 216-222
© 2002 British Society for Rheumatology
 

Miller Fisher syndrome in adult onset Still's disease: case report and review of the literature of other neurological manifestations

S. S. Desai, E. Allen and A. Deodhar

Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, CR 119, Portland, OR 97201, USA

Abstract

Adult-onset Still's disease (AOSD) is a multi-system inflammatory disorder characterized by high spiking fevers, evanescent salmon-coloured rash, arthralgias or arthritis, hepatosplenomegaly, lymphadenopathy and sore throat. There is no specific test or combination of tests that can establish the diagnosis of AOSD and patients may present with other systemic involvement including neurological manifestations in 7–12% of cases. We present a complex case of a patient with AOSD who developed the Miller-Fisher variant of Guillain–Barré syndrome. This immunological disorder of the nervous system has not been described in association with AOSD before. We also review the literature on other neurological manifestations in AOSD. AOSD mimics different disease processes and its multi-system manifestations may complicate the picture further.

KEY WORDS: Miller Fisher syndrome, Still's disease, Guillain–Barré syndrome, Neurological manifestations, Adult Still's disease, gangliosides.

Introduction

Adult onset Still's disease (AOSD) is a multi-system, inflammatory disorder characterized by high spiking fevers, evanescent salmon-coloured rash, arthralgias or arthritis, hepatosplenomegaly, lymphadenopathy and sore throat (Table 1). Patients often have a marked leucocytosis while other markers of rheumatological disorders, such as rheumatoid factor and antinuclear antibody, are negative. Other laboratory manifestations observed in AOSD include elevations in liver enzymes, abnormalities in haematological function ranging from anaemia to disseminated intravascular coagulation and markedly elevated levels of ferritin in the active stage of disease [1–4]. There is no specific test or combination of tests that can establish the diagnosis of AOSD. However, in the presence of a compatible clinical scenario, serum ferritin higher than 3200 ng/ml is highly suggestive of AOSD [5].

 
Almost all organ system involvement has been noted in patients with AOSD. These include pulmonary manifestations ranging from pleuritis to pneumonitis, cardiac abnormalities such as pericarditis, pericardial tamponade and myocarditis, and renal manifestations presenting as proteinuria during the febrile phase as well as microscopic haematuria and nephrotic syndrome [2]. We describe a complex case of AOSD who developed the Miller-Fisher variant of Guillain–Barré syndrome and review the literature on neurological manifestations of AOSD.

A 19 yr-old Hispanic female with an unremarkable medical history, who was 4 months pregnant, presented to the obstetrics service in late 1995 with arthralgias and a maculopapular rash during her second pregnancy. She complained of sore throat and pain and swelling in the wrists, metacarpophalangeal joints and proximal interphalangeal joints of both hands. Her elbows, shoulders, knees, and toes were involved to a lesser degree. The rash was diffuse and mildly pruritic.

On examination, she was febrile to 38°C with normal blood pressure and pulse. An erythematous maculopapular rash was evident over the forearms, thighs, abdomen and back. There was diffuse muscle tenderness but no synovitis. The remainder of her examination was unremarkable apart from the pregnancy. Her erythrocyte sedimentation rate was 103 mm/h; antinuclear antibody, rheumatoid factor and serologies for human immunodeficiency virus, rubella and Epstein–Barr virus were all negative. The titre of parvovirus B19 IgM was positive at 1:56. She was diagnosed with acute parvovirus B19 arthritis and was treated with prednisone 10 mg daily with dramatic improvement in her aches and pains as well as rash.

Over the next 3 months, however, she continued to have intermittent arthralgias, rash and fevers. She also complained of fatigue and began losing weight during her third trimester. This as well as evidence of fetal hydrops, necessitated delivery by Caesarian section at 7 months. The baby was diagnosed with congenital cytomegalovirus infection and required prolonged admission to the intensive care unit.

Post-partum, she continued to complain of febrile episodes, arthralgias and diffuse myalgias severe enough to interfere with her ability to care for her two small children. She denied oral ulcers, alopecia, shortness of breath, pleuritic chest pain, abdominal pain, Raynaud's phenomenon, photosensitivity, numbness, paraesthesias and focal weakness. The macular rash was apparent during febrile episodes and again involved primarily the proximal limbs and trunk. A new finding was posterior cervical and axillary lymphadenopathy. Laboratory investigations revealed haemoglobin of 7.9 g/dl, which was attributed to her recent Caesarian section as well as poor nutritional status. The white blood cell count was in the range of 13000 mm³. Repeat parvovirus B19 IgM and IgG were negative.

Six months after her initial presentation, she was admitted for further work up of persistent arthralgias, intermittent fevers, progressive weight loss and profound anaemia, which had proven refractory to iron supplementation. This was the first of many admissions and the beginning of a very thorough and expensive evaluation. Over the course of the next 18 months, multiple investigations were undertaken, as outlined in Tables 2–4. In August 1996 she underwent a laparotomy with liver biopsy, sampling of multiple abdominal lymph nodes and repeat bone marrow biopsy. Splenectomy was performed for ‘lymphoma staging’ and possible idiopathic thrombocytopenic purpura as her platelets dropped as low as 20000 mm³. Serum and urine protein electrophoresis was non-specific and did not suggest a monoclonal gammopathy. The liver biopsy and histopathology of lymph nodes and spleen did not show evidence of lymphoma. She developed a leucocytosis in the range of 20000–49000 cells/mm³ and her serum ferritin levels were noted to be markedly elevated, to between 2400 and 9850 ng/ml (normal value 16–400 ng/ml).

 
A diagnosis of AOSD was made (Table 1). In addition to diagnostic criteria, supportive features included the high serum ferritin concentration and wrist radiographs showing non-erosive bony fusion of the carpal bones (Fig. 1).

View larger version (108K): [in this window] [in a new window]   FIG. 1.  X-ray demonstrating non-erosive fusion of carpal bones in a pericapitate pattern, a distinctive feature of AOSD.

 
She was treated initially with non-steroidal anti-inflammatory drugs and then with prednisone at doses of 10–20 mg/day, though doses in the range of 1 mg/kg/day were often required for flares. Methotrexate was added in November 1996. However, despite doses up to 20 mg per week, she remained symptomatic. Methotrexate was stopped in October 1997 because of treatment failure.

Over a 2-yr period, she needed more than 20 admissions to the medical ward for flares of AOSD. These were manifested as high fevers, evanescent rash, arthralgias, abdominal pain, an impressive leucocytosis (average 20 000–30 000 cells/mm³) and high serum ferritin levels. A typical admission lasted 2–3 days and consisted of multiple investigations, primarily aimed at ruling out an infectious aetiology in a splenectomized patient. After another flare in May 1998, however, she experienced an 8-month period during which her disease was quiescent. In January 1999, her disease flared again, requiring admission almost monthly for management of flares.

In May 1999, she was admitted with generalized weakness, postural dizziness, painful oral ulcers, facial paraesthesias and an acute onset of watery diarrhoea. Initial examination confirmed severe orthostatic hypotension (standing blood pressure 50/25 mmHg). She was afebrile and there was no rash. Ragged-edged and shallow based ulcers were noted on the tongue, buccal mucosa and gingiva. Neurological examination was remarkable for diffuse and symmetric weakness (graded 4-5 throughout) and absence of both deep tendon and corneal reflexes. During the next 2 days, she developed diplopia (without objective extraocular muscle dysmotility), dysphagia and facial diplegia. Magnetic resonance imaging of the brain showed no significant abnormality. Examination of cerebrospinal fluid revealed markedly elevated protein (421 mg/dl) but a normal opening pressure, cell count and glucose. Gram stain and bacterial and fungal cultures were negative. Stool cultures were negative. Biopsy of the oral lesions was consistent with aphthous ulcer and the Tzanck smear for herpes infection was negative. Nerve conduction studies demonstrated a substantial lag time in combined potentials, suggestive of a demyelinating process (Fig. 2).

View larger version (52K): [in this window] [in a new window]   FIG. 2.  F response abnormality: right tibial F response, 13 traces. Minimal F response is prolonged at 61.8 ms (normal <50 ms).

 
These findings were consistent with the Miller Fisher variant of GBS. She was treated with pooled intravenous immunoglobulin 2 mg/kg/day for 3 days. Her cranial nerve palsies resolved within 1 week and she was discharged to a nursing home for rehabilitation.

After discharge, the areflexia has persisted and her strength has improved only marginally. Her course has been complicated by malnutrition and weight loss, necessitating gastrostomy tube feeding. She is ambulatory, but has been unable to work or independently care for herself and her two children.

Discussion

Still's disease, first described by George Still in 1896, is the systemic form of juvenile rheumatoid arthritis [6]. Bywaters in 1971 described fourteen adults with an illness resembling Still's disease and coined the term AOSD [7].

Nervous system involvement has been described in approximately 7–12% of patients with AOSD [1, 4]; however, neither the GBS nor the Miller Fisher syndrome (MFS) has been described before in a patient with AOSD. We present the first case report of a patient with AOSD who developed the Miller Fisher variant of GBS. Our patient had the characteristic findings of MFS confirmed by electromyographic studies.

GBS is characterized by progressive symmetrical limb weakness, areflexia, absent or mild sensory signs and variable autonomic dysfunctions. C. Miller Fisher described a syndrome consisting of ophthalmoplegia, ataxia and areflexia [8]. He regarded this syndrome as a variant of GBS; however, the relationship between MFS and GBS is controversial. Many patients with GBS and MFS report an antecedent, acute infectious illness or gastroenteritis that often resolves at the onset of neurological symptoms, such as our patient demonstrated. Campylobacter jejuni has been recognized as the most frequent antecedent pathogen for GBS and has also been reported in the Miller Fisher variant syndrome [9, 10]. Immune responses against C. jejuni have been postulated to be involved in both GBS and MFS by induction of a specific anti-ganglioside antibody which cross-reacts with neural tissues [11]. In GBS the specificity of anti-ganglioside antibodies is very variable and the presence of anti-GM1 ganglioside IgG antibodies may be associated with a more severe form of GBS. High titres of anti-GQ1b antibodies were found in MFS patients, as opposed to control subjects [12, 13]. Although we did not detect the anti-ganglioside antibody we believe that our patients' antecedent diarrhoeal illness was probably related to the subsequent development of the MFS. It is not possible to speculate whether this patient's MFS was causally related to her AOSD as the immunological basis of AOSD still remains unclear. It is interesting to postulate that the two disorders may share an infectious trigger, thus allowing the presentation of one with another.

A review of literature on neurological manifestations of AOSD revealed multiple problems with the case reports (Table 5). It is notable that in many case reports the neurological manifestations have no relationship to AOSD. Neurological syndromes, such as encephalopathy, delerium and decreased mentation, are often described in the literature as neurological complications of AOSD when they could be the manifestations of acute liver failure secondary to AOSD. Some neurological manifestations are reported during the acute phase of AOSD but resolve prior to appropriate therapy with anti-inflammatory medication, making it less likely to be related to the original disease. In most references it is difficult to distinguish a neurological complication associated with AOSD from a separate complication entirely. Overall, the review of the literature shows that there is a trend for some neurological complications, such as cranial nerve paresis, peripheral neuropathy and meningoencephalitis, to be associated with AOSD or a flare.

 
The diagnosis of AOSD is often difficult as it mimics systemic infections, systemic vasculitis or even neoplastic conditions such as lymphoma. As our case demonstrates, neurological manifestations can complicate the picture further.

Acknowledgments

The authors are indebted to Cari A. Gandrud for her assistance in preparation of the manuscript.

Notes

Correspondence to: S. S. Desai.

References

1. Pouchot J, Sampalis JS, Beaudet F et al. Adult Still's disease: manifestations, disease course and outcome in 62 patients. Medicine1991;70:118–36.[Medline]
2. Reginato A, Schumacher HR, Baker DG, O'Connor CR, Ferreiros J. Adult onset Still's disease: experience in 23 patients and literature review with emphasis on organ failure. Semin Arthritis Rheum1987;17:39–57.[Medline]
3. Ohta A, Yamaguchi M, Kaneoka H, Nagayoshi T, Hiida M. Adult Still's disease: review of 228 cases from the literature. J Rheumatol1987;14:1139–46.[Medline]
4. Ohta A, Yamaguchi M, Tsunematsu T et al. Adult Stills disease: a multicenter survey of Japanese patients. J Rheumatol1990;17:1058–63.[Medline]
5. Gonzalez-Hernandez T, Martin-Mola E, Fernandez-Zamorano A, Balsa-Criado A, de Miguel-Mendieta E. Serum ferritin can be useful for diagnosis in adult onset Still's disease. J Rheumatol1989;163:412–3.
6. Still GF. On a form of chronic joint disease in children. Med Clin Trans1897;80:47.
7. Bywaters EGL. Still's disease in the adult. Ann Rheum Dis1971;30:121–32.[Medline]
8. Fisher M. An unusual case of acute idiopathic polyneurites (syndrome of ophthalmoplegia, ataxia, and areflexia). N Engl J Med1956;255:57–65.
9. Jacobs BC, Endtz H, van der Meche FGA, Hazenberg MP, Achtereekte HAM, van Doorn PA. Serum anti-GQ1b IgG antibodies recognize surface epitopes on Campylobacter jejuni from patients with Miller Fisher syndrome. Ann Neurol1995;37:260–4.[Medline]
10. Hahn A. Guillain–Barré syndrome. Lancet1998;352:635–41.[Medline]
11. Rees J, Gregson NA, Hughes RAC. Anti-ganglioside GM1 antibodies in Guillain–Barré syndrome and their relationship to Campylobacter jejuni infection. Ann Neurol1995;38:809–16.[Medline]
12. Chiba A, Kusunoki S, Obata H, Machinami R, Kanazawa I. Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain–Barré syndrome: clinical and immunohistochemical studies. Neurology1993;43:1911–7.[Abstract]
13. Willison HJ, Veitch J, Paterson G, Kennedy PGE. Miller Fisher syndrome is associated with serum antibodies to GQ1b ganglioside. J Neurol Neurosurg Psychiatry1993;56:204–6.[Abstract]
14. Garrote F, Marco J, Obeso G, Rodriguez E, del Ser T. Aseptic meningitis and focal central nervous system involvement in a case of adult onset Still's disease. J Rheumatol1993;20:765–7.[Medline]
15. Denault A, Dimopoulos M, Fitzcharles MA. Meningoencephalitis and peripheral neuropathy complicating adult Still's disease. J Rheumatol1990;17:698–700.[Medline]
16. Wouters JM, Froeling PG, van de Putte LB. Adult onset Still's disease complicated by hypercalcemia: possible relationship with rapidly destructive polyarthritis. Ann Rheum Dis1985;44:345–8.[Abstract]
17. Baker DG, Shumacher HR, Reginato AJ. Fifteen patients with adult onset Still's disease: life threatening liver failure in two. Arthritis Rheum1979;22:590.
18. Kaplinksky N, Pras M, Frankl O. An adult form of juvenile rheumatoid arthritis. Arch Intern Med1980;140:1073–4.[Abstract]
19. Marie I, Levergue H, Perraudin N, Cailleux N, Lecomte F, Courtois H. Aseptic meningitis and cranial nerve palsy revealing adult-onset Still's disease. Clin Infect Dis1999;29:220–1.[Medline]
20. Markusse HM, Stolk B, van der Mey AGL, de Jonge-Bok JM, Heering KJ. Sensorineural hearing loss in adult onset Still's disease. Ann Rheum Dis1988;47:600–2.[Abstract]
21. Scully RE, Mark EJ, McNeely WF, McNeely BU. Case records of the Massachusetts General Hospital: case 27-1989. N Engl J Med1989;321:34–43.[Medline]
22. Cush JJ, Leibowitz IH, Friedman SA. Adult-onset Still's disease and inflammatory orbital pseudotumor. NY State J Med1985;85:110–1.
23. Kurabayashi H, Kubota K, Tamura K, Shirakura T. Cerebral hemorrhage complicating adult-onset Still's disease: a case report. J Int Med Res1996;24:492–4.[Medline]
24. Mok CC, Lau CS, Wong RWS. Clinical characteristics, treatment, and outcome of adult onset Still's disease in Southern Chinese. J Rheumatol1998;25:2345–51.[Medline]
25. Cush JJ, Medsger TA, Christy WC, Herbert DC, Cooperstein LA. Adult-onset Still's disease clinical course and outcome. Arthritis Rheum1987;30:186–94.[Medline]
26. Baker DG. Adult-onset Still's disease. NY State J Med1985;85:92–3.
27. Goldman JA, Beard MR, Case HL. Acute febrile juvenile rheumatoid arthritis in adults: cause of polyarthritis and fever. Southern Med J1980;73:555–63.[Medline]
28. Yamaguchi M, Ohta A, Tsunematsu T et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol1992;19:424–30.[Medline]

Submitted 2 July 2001; Accepted 22 August 2001

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