Clinical features of status epilepticus in patients with HIV ... - Neurology

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Abstract—The authors reviewed the records of 42 patients with HIV infection and status epilepticus (SE). Brain tumor and infection were the most common.
Clinical features of status epilepticus in patients with HIV infection

Abstract—The authors reviewed the records of 42 patients with HIV infection and status epilepticus (SE). Brain tumor and infection were the most common etiologies. The median duration of SE was 2.0 ⫾ 10 hours. Most patients (37 [88%]) responded to IV benzodiazepine or phenytoin treatment. Nevertheless, 12 (29%) patients died and 15 (36%) developed new neurologic deficits. In patients with HIV infection, aggressive management of seizures may limit the risk of SE. NEUROLOGY 2005;65:314–316

Kelly C. Lee, PharmD, BCPP; Paul A. Garcia, MD; and Brian K. Alldredge, PharmD

HIV infection and AIDS are risk factors for seizures with the incidence between 4 and 11%.1,2 Although seizures commonly occur late in HIV disease, patients may present with seizures at any time.1-3 Status epilepticus (SE) occurs in 8 to 14% of HIV patients with new-onset seizures; however, little is known regarding the causes, clinical features, and outcomes of this serious complication.2,4 Methods. We retrospectively reviewed the records of patients admitted to the University of California, San Francisco (UCSF) Medical Center and San Francisco General Hospital (SFGH). Potential cases were identified initially by selecting patients with 1) concomitant diagnoses of HIV/AIDS (International Classification of Diseases, Revision 9 [ICD-9] code: 042) and SE (ICD-9 code: 345.3) and 2) discharge date between January 1, 1989, and August 31, 2000. For UCSF, we also identified all cases involving convulsions, not otherwise specified (ICD-9 code: 780.3) in addition to HIV codes to detect possible code errors for SE. However, less than 3% of patients were undetected using ICD-9 codes for SE and HIV. Therefore, the second search strategy was not repeated for SFGH. We classified a patient as having SE if he or she had a seizure lasting 15 minutes or longer or at least two seizures occurring over a 15-minute period without recovery of consciousness between events. Demographic information, clinical SE details, history of HIV illness (HIV/AIDS diagnoses, most recent CD4 counts, opportunistic infections), treatment response to antiepileptic drugs (AEDs), changes in neurologic function, and overall outcome were recorded for each patient. A FileMaker Pro 5.0 Version 3 database was used for data collection. Outcome was categorized as death, neurologic/functional change, or no change from baseline functioning before the index SE episode. Outcome was based on the patient’s condition at the time of hospital discharge. We classified function at discharge as independent (no neurologic deficit and able to live independently), impaired, independent (neurologic deficit but able to live independently), or impaired, dependent (requiring assistance with activities of daily living). This study was approved by the UCSF and SFGH Committees on Human Research.

Results. A total of 203 potential cases of SE in patients with HIV infection were identified using ICD-9 codes. Forty-two patients met inclusion/exclusion criteria. Demographic and clinical characteristics of these patients are

School of Pharmacy (Dr. Lee), Loma Linda University, Loma Linda, CA; Schools of Medicine (Drs. Garcia and Alldredge) and Pharmacy (Dr. Alldredge), University of California, San Francisco. Received December 23, 2004. Accepted in final form April 7, 2005. Address correspondence and reprint requests to Dr. Kelly C. Lee, School of Pharmacy, Loma Linda University, 11262 Campus Street, West Hall 1333, Loma Linda, CA 92350; e-mail: [email protected] 314

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shown in table 1. Nine patients (21%) received antiretroviral drug therapy. Etiologies and provocative factors are listed in table 2. In approximately one-third of patients, CNS infection was the likely cause of SE. Toxoplasma infections accounted for approximately 40% of CNS infections. Other common potential etiologies were CNS tumors (two patients with confirmed CNS lymphoma) and AED withdrawal. In seven patients, there was no reasonable laboratory, radiologic, or historical evidence to explain the cause of SE, and their etiologies were classified as “unknown.” The median interval from the onset of SE to initiation of drug treatment was 0.53 hours (range 0 to 6.3). The median interval from treatment initiation to cessation of SE was 1.3 hours (range 0 to 57). The median (⫾ SD) total duration of SE was 2.0 ⫾ 10 hours (range 0.25 to 57). In 21 (50%) patients, the total duration of SE was 2 hours or longer. SE was terminated with IV benzodiazepine with or without phenytoin in 36 patients (86%). In five of the remaining patients, seizures were terminated with phenobarbital with or without continuous infusion of midazolam or pentobarbital. SE ceased spontaneously in one patient before drug treatment. Thirty of the 42 patients (71%) were admitted to the intensive care unit for management. The figure shows the change from baseline neurologic function to functional status at the time of discharge. At baseline, patients were relatively evenly distributed between the three function groups (independent, impaired independent, impaired dependent). However, after the index SE episode, there was a decline in neurologic function in 15 patients (36%). Twelve patients (29%) died during the acute hospitalization. Patients who died did not differ in age from those who survived. The median duration of SE in those who died was longer (4.4 ⫾ 18 hours; mean 11 ⫾ 17.6) than in those who survived (1.3 ⫾ 4.0 hours; mean 3.1 ⫾ 4.0) (p ⫽ 0.0240). There was a trend toward lower average CD4 counts in patients who died (18.25 ⫾ 20.20/mm3) compared with those who survived (151.95 ⫾ 297.73/mm3), but the difference was not significant (p ⫽ 0.1311). The most common etiology of the SE in both groups was CNS infection. Autopsy information was available for only one patient whose death was due to a CNS lymphoma involving the caudate and parietal and frontal cortex. Fourteen patients had multifocal or diffuse neuroimaging abnormalities and 13 had normal studies. Fifteen patients (36%) had focal imaging abnormalities (seven left, eight right). All but one were in extratemporal regions.

Table 1 Characteristics of HIV-infected patients with status epilepticus (n ⫽ 42)*

Table 2 Etiologies of status epilepticus in 42 patients with HIV infection

Sex, n (%)

Etiology

Male

38 (91)

Female

4 (10)

Median age SD (y)

39.5 ⫾ 7.4 (range 30–61)

Ethnicity, n (%) African-American

9 (21)

Native American/Alaska Native Asian/Pacific Islander

0 1 (2)

White

21 (50)

Hispanic

8 (18)

Other

2 (5)

Unknown

1 (2)

Seizure history, n (%) Previous seizures

19 (45)

Location at time of SE onset, n (%)

Frequency*

CNS infection Toxoplasma infection

5

Cryptococcal meningitis

4

Cytomegalovirus infection

1

HSV infection

1

Other infections

2

Subtotal for CNS infections

13

CNS tumor

8

Unknown

7

Antiepileptic drug withdrawal or noncompliance

6

Acute trauma

3

Metabolic abnormality

3

Alcohol withdrawal

2

Refractory epilepsy†

2

Nonspecific HIV disease

2 1

Out of hospital

28 (67)

Drug toxicity

In hospital

14 (33)

Acute stroke

1

Anoxia/cardiopulmonary arrest

0

HIV disease status, n (%) HIV infected, non-AIDS AIDS CD4 count at the time of SE†

6 (14)

Total for all etiologies

36 (86)

* Patients may have had more than one etiology. † History of medically refractory epilepsy and admission antiepileptic drug blood levels within the usual therapeutic range.

Mean 103.9/mm3 ⫾ 181.9 (range 0–929/mm3, median 27/mm3) ⬍200/mm3: 28 patients 200–500/mm3: 5 patients ⬎500/mm3: 1 patient

* Percentages of patients may not equal 100% due to rounding. AIDS defined as HIV-infected and CD4 ⬍200/mm3 and/or presence/history of AIDS-defining diagnosis.10 † Represents only 34 patients in whom CD4 counts were documented. SE ⫽ status epilepticus, CD4 ⫽ CD4⫹ lymphocyte.

Localization and lateralization of the focal findings did not predict response to therapy or neurologic outcome.

Discussion. To our knowledge, this is the first report on the treatment response and outcomes of SE in the HIV/AIDS population. Previous studies in the general population have shown that advanced age and acute etiologies are associated with greater morbidity and mortality.5,6 Additionally, studies have consistently shown an association between SE duration and neurologic outcome. The type and severity of the underlying pathology undoubtedly confound this observation. Nevertheless, animal studies suggest that SE of longer duration may result in poorer response to initial treatment.7 Although we found an association between SE duration and mortality, our study design does not allow us to determine whether there is an independent association. Although there

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was no clear difference in etiology for our patients who died compared with those who survived, the trend toward lower CD4 counts in patients who died is suggestive of a more severe underlying disease in these patients. Perhaps due to our more homogeneous population, age did not predict mortality in our series. Despite the fact that most patients received effective treatment promptly, many patients died or developed new neurologic disability. The mortality rate was approximately twice that found in a previous study of unselected patients with SE from the same

Figure. Overall neurologic function at discharge compared with baseline July (2 of 2) 2005

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hospitals.8 This may be due to the underlying HIVrelated disease process being more likely to cause permanent neurologic injury. It is also possible that SE may cause lasting neurologic dysfunction in patients with severe HIV-related brain injuries. Regardless, it suggests that patients with HIV/AIDS who survive SE will likely need discharge plans appropriate to a new functional level. SE often occurs in patients with advanced HIV disease. Thus, patients and caregivers may have previously preferred less aggressive medical treatment. Although the idea of hospitalization in the intensive care unit may be controversial for this high-risk population, we found no factors that absolutely predicted severe morbidity or mortality. Based on this observation and the fact that SE was quickly and easily treated in this group, we believe that nonaggressive management of SE would be inappropriate for most patients. Indeed, many patients were discharged without new neurologic problems. Because even a single, unprovoked seizure is associated with a high recurrence rate in patients with HIV/AIDS, many patients with new seizures are treated with AEDs.9 Nevertheless, patients with previous seizures comprised nearly half of our patients with SE, suggesting that suboptimal seizure treatment may contribute to SE in HIV-infected patients. Although AEDs do not provide absolute protection

against SE as evidenced by two patients who had recurrent seizures and SE despite adequate drug levels, most patients with previous seizures were either untreated or noncompliant with their treatments. Perhaps more aggressive medical management, patient counseling, and the use of rescue medicines would decrease the incidence of SE in these patients who can ill afford added neurologic disability. References 1. Wong MC, Suite ND, Labar DR. Seizures in human immunodeficiency virus infection. Arch Neurol 1990;47:640–642. 2. Van Paesschen W, Bodian C, Maker H. Metabolic abnormalities and new-onset seizures in human immunodeficiency virus-seropositive patients. Epilepsia 1995;36:146–150. 3. Garg RK. HIV infection and seizures. Postgrad Med J 1999;75:387–390. 4. Sagduyu A, Tarlaci S, Sirin H. Generalized tonic-clonic status epilepticus: causes, treatment, complications and predictors of case fatality. J Neurol 1998;245:640–646. 5. Logroscino G, Hesdorffer DC, Cascino G, Annegers JF, Hauser WA. Short-term mortality after a first episode of status epilepticus. Epilepsia 1997;38:1344–1349. 6. Walton NY. Systemic effects of generalized convulsive status epilepticus. Epilepsia 1993;34(suppl 1):S54–S58. 7. Walton NY, Treiman DM. Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam. Exp Neurol 1988; 101:267–275. 8. Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43:483–488. 9. Holtzman DM, Kaku DA, So YT. New-onset seizures associated with human immunodeficiency virus infection: causation and clinical features in 100 cases. Am J Med 1989;87:173–177. 10. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992;41:1-19.

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