Ethosuximide-associated systemic lupus erythematosis in childhood

J Epilepsy 1994;7:23-26 © 1994 Butterworth-Heinemann

Ethosuximide-Associated Systemic Lupus Erythematosis in Childhood James J. Riviello, Jr., Steven A. Raphael, Lawrence W. Brown, and Donald P. Goldsmith

Systemic lupus erythematosis (SLE) is an autoimmune disorder that may be associated with antiepileptic drugs (AEDs). The postulated mechanisms of drugrelated lupus (DRL) include either an unmasking of idiopathic SLE or the actual induction of autoantibodies. Although ethosuximide (ETH) is one of the drugs most implicated in childhood DRL, our treatment of a 13-year-old girl with ETHassociated DRL prompted a literature search that revealed only 15 other cases. Many of these were on multiple AEDs. We subsequently became aware of two other cases. The relationship of ETH to SLE in these three children is discussed, and clinical and laboratory features useful in the differentiation of various types of SLE are reviewed. Key Words: Ethosuximide--Systemic lupus erythematosis-Pediatrics--Epilepsy.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that occurs spontaneously or may follow treatment with various drugs. SLE is therefore classified as either idiopathic or drug-related (DRL) (1,2). The drugs associated with DRL have been divided into three groups. Group I includes those with a definite association, proven by controlled prospective studies; Group 2 includes those with a possible association; and Group 3 includes those with an unlikely association or with only a rare case of DRL. The postulated mechanisms of DRL include either an unmasking of latent SLE or actual induction of autoantibodies (2). Hydralazine and procainamide are the drugs most Received June 15, 1993; accepted July 3, 1993. From the Sections of Child Neurology and Allergy and Rheumatology, St. Christopher's Hospital for Children, the Departments of Pediatrics and Neurology, Temple University School of Medicine, and the Section of Child Neurology, Department of Pediatrics and Neurology, Medical College of Pennsylvania, Philadelphia, PA, U.S.A. Address correspondence and reprint requests to Dr. J. J. Riviello, Jr., at Epilepsy Program, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, U.S.A.

often associated with adult DRL, whereas the antiepileptic drugs (AEDs), phenytoin (PHT), ethosuximide (ETH), and trimethadione (TRI) are the ones most often associated with childhood DRL (3-5). Our treatment of an adolescent girl with ETH-associated DRL prompted a literature search that revealed only 15 other cases of ETH-associated DRL in children (Table 1) (3-10). However, the majority of these children had been on multiple AEDs, specific case information was lacking in many, and specific antibody testing was not available. We subsequently became aware of two other children with ETH-associated DRL. We report these three children, document their immunologic studies, and review the clinical and laboratory features useful in differentiating the various forms of SLE.

Case Reports Case 1 This 12-year-old girl received ETH for absence seizures. Headaches, myalgias, and arthralgias developed after several weeks; the ETH was stopped and J EPILEPSY, VOL. 7, NO. 1, 1994

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Table 1.

Ethosuximide-associated DRL

Age/sex

AED on presentation

Past AEDs

5/F NG/F 5/M 6/F

ETH; methylphenobarbital ETH; recurrence of DRL ETH; phenobarbital ETH

Phenobarbital TRI

10/M

ETH

PHT Phenobarbital Methsuximide DRL on: Phenobarbital ETH PHT PRM

10/F 21/F

TRI Recurrence on: PHT PRM

NG NG NG NG NG NG NG NG

ETH ETH ETH/PHT ETH/PHT ETH/PHT PHT/ETH/TRI PHT/ETH/TRI PHT/ETH/TRI

Laboratory values + LE prep ANA: 1/100 +LE prep + ANA +LE prep

Reference 6 6,8 6 9 7

+ LE prep + LE prep +ANA

3 10

NG NG NG NG NG NG NG NG

5 5 5 5 5 4 4 4

Abbreviations: ETH,ethosuximide; PHT, phenytoin; TRI, trimethadione; PRM, primidone; DRL, drug-related lupus; LE, lupus erythematosus, ANA, antinuclear antibodies; NG, not given.

then restarted 4 weeks later. However, after 6 months, myalgias and arthralgias recurred along with arthritis of the left knee and chest pain associated with cough and fever. Her past medical history had been unremarkable, and there was no family history of autoimmune disorders. The physical examination was remarkable for minimal respiratory distress, basilar rates, distant heart sounds, a soft, grade 2/6 systolic ejection murmur, and 1+ bilateral pitting edema. Initial abnormal laboratory values included an erythrocyte sedimentation rate (ESR) of 127 m m / h (normal: 0-10); antinuclear antibody (ANA) of 1/10,240 (homogeneous) (normah ~1/40); C4 of 10.5 mg/dl (normal: 15-45); and CH50 of 17 U/ml (normal: 51-150). Chest radiography demonstrated cardiomegaly and bilateral pleural effusions, electrocardiography (ECG) revealed voltage reduction in all leads, and echocardiography showed a large pericardial effusion. The diagnosis of probable drug-induced SLE was made, and the ETH was discontinued; 500 ml of serosanguinous pericardial fluid was removed, daily aspirin therapy was started, and clonazepam was added for seizure control. Subsequent laboratory values included elevated anti-double-stranded (anti-DS) DNA antibodies 19 U/ml (normal: ~1, done by radioim24

J EPILEPSY, VOL. 7, NO. 1, 1994

munoassay, but the antihistone antibodies and lupus panel [antibodies to ENA, RNP, Sm, SS-A/RO, SSB/LA, SCL-70, and PM-1 (11)] were negative. Six weeks after discharge, she developed arthralgias and myalgias and corticosteroids were started. When her absence seizures recurred, she was then treated with valproic acid (VPA). Her subsequent rheumatologic examination and ESR, complement studies, and double-stranded DNA antibodies have been unremarkable, but the ANA titer has remained elevated (1/640-1/1,280) with a homogeneous pattern. Case 2

This 8-year-old girl has been started on ETH for absence epilepsy that developed at age 6 years. Although excellent seizure control was achieved, persistent nausea and vomiting had occurred, the ETH was stopped, and acetazolamide was started. This did not control her seizures, clonazeparn was then substituted, but caused a behavior change, and ETH was then restarted. Because a cousin had developed SLE while receiving PHT and an aunt had developed SLE while receiving quindine,, a periodic ANA had been requested by her family, although she was

ETHOSUXIMIDE-ASSOCIATED SLE IN CHILDREN

asymptomatic. At the time she was back on ETH, the ANA had risen to 1/1,280 (~1/40). However, the lupus panel, antihistone antibodies, and serum complement values were normal; the ESR was not available. Because of the elevation in the ANA titer, she was then switched to VPA. Subsequent ANAs, the first drawn after 6 months, have been negative, and she has since been successfully tapered off VPA. Case 3

This 7-year-old boy received ETH for absence epilepsy. The dose was increased after 1 year, and he developed chronic skin lesions that were treated with corticosteroids and acne medications. However, he subsequently developed a rash on his nose after exposure to the sun, and a diagnosis of discoid lupus was made. The physical examination was otherwise unremarkable, and there was no family history of autoimmune disorders. Laboratory values revealed an ANA of 1/160 with a nucleolar pattern (<1/40), normal serum complement values, a negative rheumatoid factor, lupus panel, and antihistone antibodies; the ESR was not available. He was then switched to VPA. After 6 months, the skin lesion was smaller but remained red after exposure to the sun, and he continued with no joint symptoms. A repeat ANA, done after I year, was then negative. After remaining seizure-free for 2 years and following an unremarkable EEG, the VPA was successfully tapered. He has a very small pink residual lesion on the nose.

Dis~:ussion Despite the fact that ETH is one of the drugs most implicated in childhood DRL, a literature search identiffed only 15 children with ETH-associated DRL (Table 1). Specific case information was given in only six, two boys and four girls, aged 5 months to 21 years. Only one of these, a 10-month-old girl, was on ETH alone at the onset of her DRL, but she had been previously treated with other AEDs. Two of them had developed DRL while receiving previous AEDs and five had been treated with other AEDs prior to ETH. In the other eight without specific case information, ages, gender, and follow-up information were not given; two were on ETH alone, three were on ETH and PHT, and three were on ETH, PHT, and TRI. The patient with DRL may be predisposed to native SLE or it could have been drug-induced. It is estimated that 10% of the cases of SLE are drug-related (1). The following criteria are necessary for the diagnosis of DRL: no history suggestive of SLE prior to

therapy; a positive ANA with at least one clinical feature of SLE; and rapid clinical improvement should occur when the offending drug is withdrawn and the ANA should gradually decrease. In DRL, the onset of symptoms is abrupt, cutaneous manifestations may be absent, clinical symptoms are milder in most cases, and multisystem disease, particularly involving the renal or central nervous system, is rare. Symptomatic drug-induced SLE is rare in blacks (1,2). Although the best screening test for active SLE is the presence of ANA, these are nonspecific and may be found in other inflammatory disorders, certain infections, and malignancies. Antibodies to doublestranded DNA (DS-DNA) and to anti-SM are relatively specific for native SLE; ds-DNA is associated with renal involvement, and anti-SM occurs with isolated central nervous system involvement (2,11). Antihistone antibodies are more common in DRL (2,11), occurring in 82-92% of such cases (12), compared to 20-30% of those with idiopathic SLE (13). The presence of IgG antibodies to the histone complex H2AH2B has recently been reported as a specific marker for procainamide-induced SLE (14). However, the presence of markers for autoantibodies alone is not sufficient to diagnose DRL, since many patients with drug-related autoantibodies are asymptomatic. For example, the ANA may be positive in up to 80% of patients on procainamide, but only one-third will develop clinical manifestations (14). Genetic factors may contribute to the development of both forms of SLE. Inherited complement deficiency states have been associated with SLE. C2 deficiency is the most prevalent, with SLE seen in 33% of individuals with homozygous C2 deficiency; a partial C2 deficiency (heterogeneous C2 deficiency) may also be a risk factor (15). Drug-induced forms of SLE result from the deposition of immune complexes, which is facilitated by the inhibition of the C4 component of complement. Hydralazine and INH have been demonstrated to inhibit the binding of C4, and null alleles for C4 have been associated with both native and drug-induced SLE (16,17). The results of HLA typing in SLE have been inconsistent, but HLA-D region antigens have been associated with SLE (18), and HLA regions DR2 and DR3 have been associated with increased autoantibody production (19). Our first and third cases demonstrate that ETH alone can be implicated in DRL, since these two children had not been previously treated with other AEDs. The absence of antihistone antibodies in both of these and the subsequent deterioration in our first child after the discontinuation of the ETH suggests that the DRL was idiopathic SLE rather than purely DRL. Our second case was on ETH monotherapy at J EPILEPSY, VOL. 7, NO. 1, 1994

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j. j. RrVIELLO, JR., ET AL. the onset of his symptoms, but had been previously treated with other AEDs and had a family history of DRL, suggesting a genetic predisposition. The infrequent occurrence of ETH-associated DRL makes a prospective study difficult. No AED is yet included in Group 1, ETH, mephytoin, PHT, primidone, and TRI have long been included in Group 2, and carbamazepine has recently been added to Group 2 (20-23). Of the primary AEDs, phenobarbital and VPA have not yet been included in these three groups. However, four patients from the literature review (Table 1) were either on both phenobarbital and ETH u p o n presentation or had previously been treated with a barbiturate. In addition, primidone, which is included in Group 2, is metabolized to phenobarbital. There is also a recent report of DRL in two patients treated with VPA, one of w h o m had idiopathic SLE (24). The benzodiazepines have not yet been implicated. In summary, strict classification of both seizure type and epileptic syndrome is important in determining the appropriate choices for AEDs. A family history of SLE, DRL, or autoimmune disease should be sought before starting therapy with AEDs, and if positive, a Group 2 drug may then be avoided. However, in a specific patient, it may be difficult to differentiate between idiopathic SLE and DRL with certainty.

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