Prospective Study of New-Onset Seizures in Patients with Human Immunodeficiency Virus Infection Etiologic and Clinical Aspects

ORIGINAL CONTRIBUTION Prospective Study of New-Onset Seizures in Patients With Human Immunodeficiency Virus Infection Etiologic and Clinical Aspects

Berta Pascual-Sedano, MD; Alejandro Iranzo, MD; Joan Martı´-Fa`bregas, MD; Pere Domingo, MD; Antonio Escartin, RN, MD; Montserrat Fuster, MD; Josep L. Barrio, MD; Maria A. Sambeat, MD

Objective: To determine the frequency and etiologic and Expanded AIDS Definition. Mean latency (±SD) clinical aspects of new-onset seizures in patients with hu- between diagnosis of HIV infection and the first sei- man immunodeficiency virus (HIV) infection. zure was 60.7 ± 37.6 months. Seizure cause was drug toxicity in 8 patients (47%) and intracranial lesion in Design: A prospective survey of an HIV-infected pa- 6 patients (35.3%). Two patients had seizures related tient cohort. to metabolic derangements. No cause was found in 1 case. The first seizure was generalized in 12 patients Setting: Outpatients and inpatients in a university hos- (70.6%), simple partial motor seizure in 2 (11.8%), pital in Barcelona, Spain. and simple partial seizure evolving to generalized seizure in 3 (17.6%). We found partial seizures in 66.6% Patients: Five hundred fifty HIV-infected patients re- of patients who had intracranial lesions. Most patients cruited over 1 year. were treated with phenytoin, which was well tolerated and effective in controlling seizures. Main Outcome Measure: Analysis of new-onset seizures, with detailed medical history and appropriate Conclusions: New-onset seizures are infrequent in pa- workup. tients with HIV. In most cases a definite or probable cause is identified, which is usually related to toxic and/or meta- Results: Seventeen HIV-infected patients (3%) had a bolic factors. Most seizures are generalized, and partial new-onset seizure during the study period. Fourteen seizures suggest a focal cerebral lesion. (82%) of 17 patients had acquired immunodeficiency syndrome diagnosed according to the 1993 CDC Arch Neurol. 1999;56:609-612

ERVOUS SYSTEM clinical women, with a mean age (± SD) of 32.8 ± involvement, both cen- 5.7 years (age range, 22-45 years). Human tral and peripheral, is immunodeficiency virus risk factors were found in about 40% to intravenous drug use (IVDU) in 10 pa- 65% of patients infected tients (5 men), homosexual activity in 4 (all Nwith human immunodeficiency virus men), and heterosexual transmission in 3 (HIV) sometime during the disease (1 woman). At the time of first seizure, 14 course.1,2 Postmortem studies show 70% (82.3%) had an AIDS-defining condition (13 to 80% of cases have nervous system in- stage C3, 1 stage C2); mean latency be- volvement.1 Retrospective studies3,4 esti- tween HIV diagnosis and the first seizure mate that 11% to 17% of HIV-infected pa- was 60.7 ± 37.6 months (range,1-120 tients will have seizures sometime during months). Mean CD4+ cell count was 0.115 their course. We prospectively studied the ±.016 ϫ 109/L (115 ± 16/mm3) (range, clinical and etiologic spectrum of sei- 0.002-0.56 ϫ 109/L [2-560 mm3]). Eight pa- zures in HIV-infected patients. tients (47%) died, with a mean survival period from first seizure of 3 months. All From the Departments RESULTS deaths were in patients who were in an ad- of Neurology vanced HIV infection stage (mean CD4+ cell (Drs Pascual-Sedano, Iranzo, ϫ 9 Martı´-Fa`bregas, and Escartı´n) PATIENTS count of 0.018 10 /L) at the time of first and Internal Medicine seizure. Mean follow-up was 5.0 ± 2.9 (Drs Domingo, Fuster, Barrio, Of 550 patients, 17 (3%) had a new-onset months for all patients (range, 1-10 and Sambeat), Hospital de Sant seizure during the study (Table). Eleven months), and 6.8 ± 3.2 months for survi- Pau, Barcelona, Spain. (64.7%) were men and 6 (35.3%) were vors (range, 1-10 months).

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 2 (11.8%), and simple partial seizure evolving to generalized seizure in 3 (17.6%). During follow-up, the 2 patients PATIENTS AND METHODS with initial simple partial seizure evolved to generalized seizure. All 17 patients had a generalized seizure at some time. We studied 550 HIV-infected patients older than 18 All generalized seizures were tonic-clonic, except for 1 years whose disease was diagnosed with standard patient who had myoclonic seizures. No complex partial methods5 and staged according to the Centers for Dis- seizures were observed. Three patients (17.6%) had status ease Control and Prevention’s Revised Classifica- epilepticus: 2 with simple partial motor status (1 with tion System for HIV Infection.6 Over a 1-year pe- cerebralTXPand1withanunknowncause)and1withmyo- riod, patients infected with HIV were consecutively clonic status (IV infusion of diacetylmorphine hydrochlo- seen in the AIDS Unit of the Department of Internal ride). Four patients (23.5%) had a single seizure (3 with Medicine of the Hospital de Sant Pau, Barcelona, generalized tonic-clonic [GTC] seizure and 1 with simple Spain.The Hospital de Sant Pau is one of 4 reference partial seizure with secondarily generalized seizure). Fo- hospitals in Barcelona and has an active acquired im- cal seizures were most frequently seen in patients with ce- munodeficiency syndrome (AIDS) unit. Any patient with prior seizures (with or without relation to HIV) rebral mass lesions (4/6 [66%]). Seizures were refractory was excluded from the study. Any patient with a first to therapy in 3 patients (17.6%): 1 with PML, 1 with relaps- seizure during this 1-year period was examined by ing cerebral TXP, and 1 with myoclonic status due to IV in- physicians from the Department of Neurology and fusion of diacetylmorphine. followed up quarterly until death or study end. Clinical data recorded for each patient were age, THERAPY sex, HIV risk factors, first seizure date, toxic drug use, latency between diagnosis of HIV infection and first Seven patients (41.1%) were not treated as having a single seizure, stage of disease, prior anti-HIV treatments, first seizure and/or the seizure was related to a toxic- neurologic complications related to HIV, nonneuro- metabolic cause. Two untreated patients had cerebral TXP: logic complications, and seizure characteristics (du- ration, interval between seizures, precipitating drugs, 1 died within a few hours of cerebral edema and1 responded frequency, and clinical seizure type based on the In- to anti-TXP therapy, without recurrence of seizures. ternational Classification of Epileptic Seizures of Phenytoin was initially prescribed for 8 patients (47%) 19817). Examination included testing glucose and se- and carbamazepine for 2 (11.8%). Carbamazepine therapy rum electrolyte levels, liver and renal function, blood was discontinued in both patients because of adverse ef- cell count, serologic tests for Toxoplasma gondii and fects (severe skin reaction and ataxia) and was changed cytomegalovirus, computed tomographic or mag- to phenytoin. No serious adverse effects were observed in netic resonance imaging brain scans, and, if re- patients who received phenytoin, except in 1 patient with quired, toxicologic screens, electroencephalo- ataxia and nystagmus because the dosage was too high. graphic and cerebrospinal fluid studies (biochemical Seizures were well controlled with treatment. tests, serologic tests for syphilis and T gondii, Gram stain, cultures for Cryptococcus neoformans and My- cobacterium, stains for acid-fast Bacillus, and poly- COMMENT merase chain reaction for herpes simplex virus). New-onset seizures were relatively infrequent in our HIV- infected patients (3%). A cause was identified in most of our patients (94.1%), with toxic-metabolic factors the main CAUSE cause (nearly 60%). Fourteen patients (82.3%) had AIDS at the time of the first seizure, confirming, as in previous Seizures were attributed to drug toxicity in 8 patients reports,3,8-10 that seizures usually occur in patients with se- (47%): infusions of intravenous (IV) foscarnet sodium vere immunodepression. Generalized tonic-clonic sei- (n = 2) ceftazidime (n = 1), oral sulfonamides and zid- zures were the most common, and a focal seizure sug- ovudine (n = 1), infusions of IV imipenem (n = 1), IV gested a structural cerebral lesion. In our series, seizure was cocaine (n = 1), IV heroin (n = 1), and medazepam hy- never the presenting feature of HIV infection. Patients who drochloride withdrawal (n = 1). Drug toxicity was con- had seizures responded well to therapy. sidered a definite or probable cause when the time was In the literature, HIV represents 8% of the cause in close between use of the drug and the seizure. Six pa- adults who have a first epileptic seizure. In the 15- to 45- tients (35.3%) had intracranial lesions: 5 had cerebral year age group, this number increases to 20%.11 Fre- toxoplasmosis (TXP) and 1 had progressive multifocal quency of first seizure in HIV-infected patients ranges from leukoencephalopathy (PML). Metabolic derangements 11% to 17% in retrospective studies.3,4 We found a fre- (hypoglycemia and hypomagnesemia) were observed in quency of 3%. Van Paesschen et al8 report 4% in hospi- 2 patients (11.7%). Toxic-metabolic factors were thus the talized patients. The reported higher percentages are pos- cause of the seizure in 10 patients (58.8%). No cause was sibly because of the inclusion of only inpatients in the found in 1 patient, despite a thorough examination. advanced disease stages and a longer follow-up than in our study. We studied patients (both outpatients and inpa- CLINICAL SEIZURE TYPE tients) for only 1 year; if the inclusion period had been longer, the occurrence might have been higher. Since the First seizure was generalized in 12 patients (70.6%), simple number of HIV-infected patients with first seizure in our partial seizure without generalization (both motor type) in study is relatively low, seizure characterization is limited.

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Findings of Patient No./ Risk Latency, Neurological Sex/Age, y Factor mo CD4+؋109L Examination Dementia CSF Results EEG Results Presumed Cause 1/M/27 HT 58 0.008 Focal deficit (H, S) No Elevated protein Focal spikes Progressive multifocal leukoencephalopathy 2/F/27 IVDU 16 0.014 Normal No ND ND Ceftazidime 3/M/40 HM 44 0.067 Residual focal deficit (H) Yes Elevated protein, ND Sulfonamides and zidovudine VDRL+ 4/F/30 HT 21 0.002 Normal No ND ND Imipenem 5/M/45 HM 36 0.030 Normal Yes ND ND Cerebral toxoplasmosis 6/M/39 IVDU 72 0.064 Focal deficit (H, S) No Elevated protein ND Foscarnet sodium 7/M/22 IVDU 84 0.393 Tremor No ND Normal Medazepam hydrochloride withdrawal 8/M/27 HT 60 0.004 Coma No ND ND Cerebral toxoplasmosis 9/F/30 IVDU 72 0.446 Normal No Normal Focal spikes Heroin 10/F/33 IVDU 120 0.074 Normal No Normal ND Foscarnet 11/M/34 HM 1 0.011 Normal No ND ND Cerebral toxoplasmosis 12/M/34 IVDU 21 0.012 Focal deficit (H) No ND ND Cerebral toxoplasmosis 13/M/38 IVDU 45 0.260 Normal No ND Normal Unknown (HIV?) 14/M/33 HM 72 0.005 Normal No ND ND Hypomagnesemia 15/F/32 IVDU 120 0.010 Focal deficit (E) Yes Normal ND Hypoglycemia 16/M/31 IVDU 84 0.560 Tremor No ND Normal Cocaine 17/F/37 IVDU 90 0.003 Focal deficit (H, B) No Elevated protein ND Cerebral toxoplasmosis

*Latency refers to the time between the diagnosis of human immunodeficiency virus infection and the first seizure. CD4+ cell count is the cell count at the time of first seizure. CSF indicates cerebrospinal fluid; EEG, electroencephalogram; HT, heterosexual transmission; H, hemiparesis; S, sensory disturbance; IVDU, intravenous drug use; ND, not done; HM, homosexual transmission; E, extensor plantar response; and B, brisk reflexes.

The HIV-infected population treated at our hospital has estimated that 18% to 25% of patients with cerebral TXP characteristics similar to other HIV-infected populations in will have epileptic seizures.4,16 Spain. In our series the main HIV risk factor was IVDU One patient had simple partial seizures with PML. This (58.8%), reflecting the nature of our population.12 Van Paes- disease was first described as a cause of seizures in 1983.18 schen et al8 also report IVDU as the most common risk fac- Since then other cases9,10,13,19-21 have been reported. Wong tor (46%). In other reports, sexual transmission was the most et al3 found no PML in 70 patients who had seizures, but 2 common risk factor.3,9 Mode of exposure to HIV seemed to studies21,22 have reported seizure as an initial manifesta- influence the cause of seizures in our study: 3 (30%) of 10 tion of HIV infection in 20% of patients with PML. patients had seizures that were related to IVDU. A variety of other causes have been associated with Prior to their first seizure, 14 patients (82.3%) had al- HIV-infected patients who have seizures (infection, neo- ready been diagnosed as having AIDS. Previous studies have plasm, and stroke),3,8-10,13,23-26 but we did not see these ranged from 55.7% to 91.0%.3,8-10 Mean CD4+ cell count at causes in our patients. the time of first seizure in our series was low (0.155 ϫ 109/ Unlike previous studies3,10 according to our study, L), confirming that seizures more commonly appear in ad- toxic-metabolic factors accounted for more than half vanced stages of the disease. (58.8%) the seizures patients experienced. Surpris- In the literature, seizures have been reported as a ingly, in series with larger groups of patients,9,13 no sei- presenting manifestation of HIV-related disease in 3.8% zures caused by toxic-metabolic factors were observed. to 18% of patients.3,9,10 In our series, we did not observe The cause of seizures in 2 patients was hypoglycemia a seizure as the initial manifestation of HIV infection. and hypomagnesemia. Hypomagnesemia can induce epi- We were able to identify the cause of seizure in 94.1% leptic seizures,27,28 and Van Paesschen et al8 emphasize meta- of cases. Previous studies3,9,10,13,14 have been unable to es- bolic causes as important in HIV-infected patients. Van Paes- tablish cause of seizure in 23% to 46% of patients, and the schen et al found hyponatremia to be a common disorder seizure was attributed to the HIV infection. The HIV stage (46%) in their patients and reported an association between was less advanced in those with no identifiable cause than hypomagnesemia, renal failure, and status epilepticus. None in those with an identifiable cause. In our series, we were of the patients with status epilepticus had these disorders. unable to identify a presumed cause in only 1 patient in The cause of 1 partial seizure (dysphasia), which evolved whom the HIV infection alone was the presumed cause. to a generalized seizure, was hypomagnesemia. Opportunistic infections may affect up to 20% of Neurotoxicity due to use of zidovudine has been long HIV-infected patients15,16 and cause 40% of neurologic recognized as a cause of epileptic seizures.29-35 One of our manifestations.14,17 Six (35.3%) of our patients had a cen- patients attempted suicide with an overdose of sulfon- tral nervous system infection as the underlying seizure amides and zidovudine, both of which may have con- cause, although most seizures were partial. Only 1 pa- tributed to the GTC seizure. In 1 patient, imipenem pro- tient with cerebral TXP had refractory seizures. It has been duced a GTC seizure, a well-known adverse effect.36 Two

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 of our patients had seizures with an IV infusion of fos- 8. Van Paesschen W, Bodian C, Maker H. Metabolic abnormalities and new-onset seizures in human immunodeficiency virus-seropositive patients. Epilepsia. 1995; carnet, and in both cases, seizures reappeared with fur- 36:146-150. ther foscarnet treatment. Calcium and magnesium lev- 9. Bartolomei F, Pellegrino P, Dhiver C, Quilichini R, Gastaut JA, Gastaut JL. Crises els in 1 patient were normal. Seizure frequency related d’epilepsie au cours de l’infection par le VIH: 52 observations. Presse Med. 1991; 37-39 20:2135-2138. to the use of foscarnet is about 3% to 15%. 10. Holtzman DM, Kaku DA, So YT. New-onset seizures associated with human im- Seizures directly related to substance use, abuse, and munodeficiency virus infection: causation and clinical features in 100 cases. 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