Home

Current Issue

Archives

Guidelines for Authors

Classified Ads

Links

Search PubMed

Subscriptions

Subscriber Registration

Guidelines for Website Users

JRheum Update Service

Contact Info

Letters

Intrathecal Corticosteroids for Systemic Lupus Erythematosus with Central Nervous System Involvement

To the Editor:

High dose corticosteroids or immunosuppressants are frequently administered systemically for the treatment of systemic lupus erythematosus (SLE) with central nervous system (CNS) involvement. We describe 2 cases of CNS lupus where CNS symptoms and abnormalities in the cerebrospinal fluid (CSF) persisted and corticosteroids were successfully administered intrathecally without serious adverse reactions.

Case 1. A 29-year-old woman was diagnosed elsewhere as having SLE from the presence of facial rash, arthralgia, and serum anti-DNA antibody, and was successfully treated with 40 mg/day prednisolone. Two months later, she was found unconscious with convulsions, and referred to hospital. There was no rash, and no arthritic signs or symptoms. Neurological examination revealed somnolence, but no meningeal or focal signs. Magnetic resonance image (MRI) of the brain was normal. In the CSF, mononuclear cell count was 4/µl; CSF IgG index [(CSF/serum IgG ratio)/(CSF/serum albumin ratio)] was 1.1 and interleukin 6 (IL-6) was 30.5 pg/ml (undetectable normally). Bacterial cultures, serum antibodies to herpes simplex virus, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus were negative. White blood cell (WBC) count was 7800/µl, serum anti-DNA antibody titer was 16 U/ml (normal < 7 U/ml), and complement activity (CH50) was normal. Intravenous administration of 1000 mg methylprednisolone was repeated for 3 days (pulse therapy); then she became alert and the CSF-IgG index (0.6) and IL-6 levels normalized in 4 weeks, and prednisolone was reduced to 30 mg/day. However, headache occurred and the CSF cell count increased to 24/µl, and the CSF IgG level and CSF-IgG index and IL-6 concentration rose to the previous levels. Because the patient had insulin resistant diabetes and there was no evidence for intracranial infection, 20 mg prednisolone was administered intrathecally 3 times with an interval of one week. Headache disappeared in a week, and CSF findings normalized in 3 weeks without recurrence for 8 months.

Case 2. A 39-year-old woman was diagnosed as having SLE without CNS involvement and was successfully treated with corticosteroids plus cyclosporine A. Twenty-eight months later, she had convulsions and was referred to the hospital. There were no systemic findings such as fever, rash, or proteinuria, but she was somnolent without focal or meningeal signs. WBC was 5400/µl, the serum anti-DNA antibody was 20 U/ml, and CH50 was normal. In the CSF, cell count was 754 (polymorphonuclear, 451; mononuclear, 303)/µl, CSF IgG index was 1.7, and IL-6 was 83 pg/ml. There was no evidence for bacterial or viral infections. The serum anti-DNA level and MRI of the brain were normal. Pulse therapy was followed by 100 mg prednisolone/day; she soon became alert and the CSF cell count decreased to 23/µl. However, headache and high CSF IgG indices (1.2-1.6) and intrathecal IL-6 levels (80-99 pg/ml) persisted for a month without extra-CNS symptoms, and the serum anti-DNA and CH50 were normal. Intrathecal injection of prednisolone (20 mg) was done 6 times with an interval of one week; headache subsided in 3 weeks, the CSF findings normalized in 5 weeks, and no remarkable adverse reactions occurred, and the dose of prednisolone was reduced to 15 mg with no flare for 6 months.

It has been reported that lymphocytic activation, local production of immunoglobulins^1,2, or various inflammatory cytokines such as IL-6 or IL-8 are associated in the pathogenesis of CNS lupus^3,4, as well as intrathecal synthesis of various autoantibodies⁵. In the current cases, CSF IgG indices and IL-6 concentrations paralleled the symptoms of CNS lupus.

Intrathecal administration of corticosteroids is often used for prevention of leukemic infiltration in the CNS, but rarely in patients with CNS lupus, while intrathecal administration of dexamethasone and methotrexate has been reported to be effective in SLE⁶. On the other hand, transfer of corticosteroids from blood to CSF is limited if the blood-brain barrier is intact⁷. When 0.8 mg/kg prednisolone was administered intravenously in patients with rheumatoid arthritis, the peak intrathecal concentration was only 55-85 ng/ml after 100-200 min⁸. Since the CSF-serum albumin quotient (Q albumin), an indicator of blood-brain barrier function, was normal in the current cases, administration of 20 mg prednisolone into the intrathecal space of 90-150 ml could cause high concentrations in the CSF. Further, it is expected that doses of corticosteroids will be spared by this method. On the other hand, intrathecal therapy has various complications, such as dural leak, spinal abscess, or thromboembolism⁹, and intraorbital hematoma¹⁰ by intrathecal corticosteroids has been reported. Therefore, this therapy should be indicated when systemically administered corticosteroids or immunosuppressants are not effective. Although the possibility exists that improvement of the CNS lupus was a natural course, intrathecal administration of corticosteroids might be useful in some cases of CNS lupus. Evaluation of this therapy, including combination with immunosuppressants such as methotrexate, should be studied in a larger number of cases.

MASANORI FUNAUCHI, MD; MOTOKI OHNO, MD; YUJI NOZAKI; MASAFUMI SUGIYAMA, MD; KOJI KINOSHITA, MD; AKIHISA KANAMARU, MD, Department of Hematology, Nephrology and Rheumatology, Kinki University School of Medicine, Osaka, Japan.

REFERENCES

1. Winfield JB, Shaw M, Silverman LM, Eisenberg RA, Wilson HA 3rd, Koffler D. Intrathecal IgG synthesis and blood-brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction. Am J Med 1983;74:837-44.

2. West SG, Emlen W, Wener MH, Kotzin BL. Neuropsychiatric lupus erythematosus: a 10-year prospective study on the value of diagnostic tests. Am J Med 1995;99:153-63.

3. Tsrysberg E, Carlsten H, Tarkowski A. Intrathecal cytokines in systemic lupus erythematosus with central nervous system involvement. Lupus 2000;9:498-503.

4. Gruol DL, Nelson TE. Physiological and pathological roles of interleukin-6 in the central nervous system. Mol Neurobiol 1997;15:307-39.

5. Mevorach D, Raz E, Steiner I. Evidence for intrathecal synthesis of autoantibodies in systemic lupus erythematosus with neurological involvement. Lupus 1994;3:117-21.

6. Valesini G, Priori R, Francia A, et al. Central nervous system involvement in systemic lupus erythematosus: a new therapeutic approach with intrathecal dexamethasone and methotrexate. Springer Semin Immunopathol 1994;16:313-21.

7. Marynick SP, Havens WW 2nd, Ebert MH, Loriaux DL. Studies on the transfer of steroid hormones across the blood-cerebrospinal fluid barrier in the Rhesus monkey. Endocrinology 1976;99:400-5.

8. Buhrer M, Frey FJ, Frey BM. Prednisolone concentrations in cerebrospinal fluid after different prednisolone prodrugs. Br J Clin Pharmacol 1991;31:111-3.

9. Ergan M, von Hansen BF, Courtheoux P, Viader F, Prouzeau S, Marcelli C. Cerebral vein thrombosis after an intrathecal glucocorticoid injection. Rev Rhum Engl Ed 1997;64:513-6.

10. Hoeffel C, Gaucher H, Chevrot A, Hoeffel JC. Complications of lumbar puncture with injection of hydrosoluble material. J Spinal Disord 1999;12:168-71.

Lupus-like Syndrome and Vasculitis Induced by Valpromide

To the Editor:

Valpromide is a thymoregulator drug approved for bipolar disorders and epilepsy. It is a prodrug biotransformed into valproid acid and used as antiepileptic drug, which has been implicated in cases of Stevens-Johnson syndrome and toxic epidermal necrolysis¹. Rare cases of cutaneous vasculitis or lupus-like syndrome have been described in association with valproid acid but not to valpromide^2-4. We describe the observations of 2 patients in whom lupus-like syndrome and glomerulonephritis associated vasculitis developed while taking valpromide.

Case 1 is a 34-year-old man hospitalized in March 2000, because of acute polyarthritis. He had a medical history of chronic psychosis treated with haloperidol 7.5 mg/day, levomepromazine 100 mg/day, alprazolam 1 mg/day, and valpromide 600 mg/day for 12 months. He had no family history of autoimmune or connective tissue diseases. He described the occurrence, 2 weeks before hospitalization, of acute and symmetrical polyarthritis of the hands, wrists, shoulders and knees with fever up to 39°C. Clinical examination was normal except for his polyarthritis. Laboratory data confirmed inflammation (C-reactive protein 259 mg/l) and moderate hyperleukocytosis. Investigations for infectious or tumoral causes were negative (blood and urine cultures, echocardiography, computerized tomographic scan, serologies for cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis B and C, HIV, Coxsackies, Chlamydiae, Mycoplasma, Rickettsiae, Yersinia, Salmonella, Brucella, Lyme, polymerase chain reaction detection for EBV, CMV, HCV, HIV, osteomedullar biopsy). Puncture of the right knee showed an inflammatory fluid without infectious agent. Immunologic data found positive antinuclear antibodies at 1/1000 without specificity. Complement levels were normal and we found no cryoprecipitate, rheumatoid factor, or antineutrophil antibodies. According to valpromide metabolism and a previous description of lupus-like diseases under valproate, valpromide was discontinued and nonsteroidal antiinflammatory drugs initiated: the course of the disease was favorable in the following 2 weeks, and antiinflammatory drugs where stopped 6 weeks after. Eighteen months later, no sign of the disease recurred and antinuclear antibodies titer had normalized to 1/250.

Case 2. A 49-year-old woman was hospitalized for purpura of the legs in September 2001. She had a medical history of beta thalassemia, tobacco related chronic bronchopneumonia, and manic-depressive psychosis for 10 years treated with lithium and clomipramine for several years. She had no family history of connective tissue diseases. Twenty days before hospitalization, valpromide, 600 mg twice a day, had been introduced. Four days later she developed a maculopapular rash on her legs, with progressive extension to her trunk and arms. In the same period of time, she described the occurrence of edema of her legs, myalgias, arthralgia, paresthesia of the right foot and constitutional symptoms. The patient was subsequently hospitalized. Clinical examination showed necrotizing purpura. There were extensive soft tissue edemas in both legs. Her temperature was normal. Blood pressure was 140/70 mmHg. Biological data showed anemia (hemoglobinemia 9.4 g/100 ml) with microcytosis (64 µ³) and hyperleukocytosis from 11,900 to 18,500/mm³ related to lithium therapy. Baseline creatininemia was 146 µmol/l and progressively increased up to 430 µmol/l 12 days later. Proteinuria was found to be 1.5 g/day with microscopic hematuria (499,500 red cells/min) and aseptic leukocyturia (33,300 leukocytes/min). C-reactive protein was between 50 and 69 mg/l). Immunologic testing (antinuclear, anti-DNA, antineutrophil, and antiphospholipid antibodies, total complement activity and plasma levels of C3 and C4 factors, cryoglobulinemia, rheumatoid factor, electrophoresis, and immunoelectrophoresis of serum protides) did not show abnormality. A cutaneous biopsy of the purpura showed moderate inflammatory infiltration of vessels, and direct immunofluorescence study revealed C3 and IgA deposits. A percutaneous renal biopsy was performed and showed extracapillary glomerulonephritis with epithelial proliferation. Interstitial and tubular lesions (with some eosinophiliac infiltration) were also observed. There was no vasculitis or immunoglobulin or complement deposit on glomerules, but biopsy was performed 4 days after beginning of oral corticosteroid therapy initiated because of the rapid progression of the renal insufficiency. Pulse methylprednisolone (500 mg over 3 days) was then given, followed by oral prednisolone at 20 mg/day. Creatininemia rapidly decreased from 430 µmol/l to 177 µmol/l in 10 days, and purpura disappeared. C-reactive protein decreased to 3.5 mg/l. One and 6 months later, creatininemia was measured at 142 and 120 µmol/l. Proteinuria remained elevated from 1.2 to 1.6 g/day.

Our 2 cases of systemic inflammatory reactions can be reasonably attributed to valpromide, due to the clinical features and the temporal association with drug initiation. Although other therapies could have caused inflammatory reactions in our patients, we do not think they were causative because in our 2 observations, clinical and biological improvement was observed after only valpromide was discontinued, without relapse after 6 and 18 months of followup. Previous descriptions of vasculitis and lupus-like syndrome under valproate, a metabolism product of valpromide, also support the implication of valpromide^2-4. To our mind, valpromide should be added to the list of drugs that induce vasculitis or lupus-like syndromes.

FABRICE BONNET, MD; PHILIPPE MORLAT, MD, PhD; STEN de WITTE, MD, Service de Médecine Interne et Maladies Infectieuses; CHRISTIAN COMBE, Service de Néphrologie, Hôpital Saint-André; JACQUES BEYLOT, MD, Service de Médecine Interne et Maladies Infectieuses, Hôpital Saint-André, Bordeaux, France.

REFERENCES

1. Rzany B, Correira O, Kelly JP, Naldi L, Auquier A, Stern R, for the Study Group of the International Case-Control Study on Severe Cutaneous Adverse Reactions. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Lancet 1999;353:2190-4

2. Kamper AM, Valentijn RM, Stricker BHC, Purcell PM. Cutaneous vasculitis induced by sodium valproate [letter]. Lancet 1991;337:497-8.

3. Asconape JJ, Manning KR, Lancman ME. Systemic lupus erythematosus associated with use of valproate. Epilepsia 1994;35:162-3.

4. Bleck TP, Smith MC. Possible induction of systemic lupus erythematosus by valproate. Epilepsia 1990;31:343-5.