Up to 70% of HIV patients develop neurologic complications.114 Neurologic symptoms herald acquired immunodeficiency syndrome (AIDS) in up to 20% of HIV patients, though neurologic disease more commonly occurs within the context of other AIDS-defining illnesses.115

The spectrum of neurologic disorders that complicate HIV-1 infection is extremely diverse. CNS complications, including seizures, can be divided into those due to HIV infection itself and those secondary to opportunistic infections, drug toxicity, or other HIV-related causes.

Neurologic complications of HIV with seizure risk

Disorders directly related to HIV:

  • Acute meningitis
  • Chronic meningitis
  • Persistent or recurrent meningeal pleocytosis with or without meningeal symptoms
  • Acute encephalitis
  • Chronic encephalitis
  • HIV-1 minor encephalopathy (cognitive/motor abnormalities)
  • HIV-1 major encephalopathy (cognitive/motor abnormalities)
  • AIDS dementia complex

Secondary neurologic syndromes:

  • Opportunistic infections
  • Cytomegalovirus
  • Toxoplasmosis
  • Cryptococcus
  • Progressive multifocal leukoencephalopathy (PML)
  • Herpes simplex virus encephalitis
  • Candidiasis
  • Herpes zoster virus encephalitis
  • Histoplasmosis
  • Tuberculosis
  • Aspergillosis
  • Neoplasms
  • Primary central nervous system (CNS) lymphoma
  • Metastatic disease (including Kaposi’s sarcoma)
  • Vascular disease
  • CNS hemorrhage (secondary to thrombocytopenia, vasculitis, etc.)
  • CNS ischemic stroke
  • Metabolic disorders
  • Drug toxicity
  • Antiretroviral drugs
  • Neuroleptic malignant syndrome

Epidemiology of seizures in patients with HIV infection Seizures can occur at any disease stage. For example, although seizures were the presenting symptom of HIV infection in 18 of 100 cases described by Holtzman et al.,116 all 7 patients with status epilepticus described by Aronow and colleagues died within 1 month of the episode.117

Early work suggested that approximately half of seizures associated with HIV infection were due to the direct toxic effects of HIV infection of the brain, and secondary-process complications of AIDS contributed to the remainder. More recent studies, however, have emphasized that several potential seizure-causing processes can operate simultaneously.118

Reviewing together 276 patients described in four large series, Labar and Harden found that generalized convulsions constituted 75% of seizures.13 Status epilepticus, typically generalized convulsive, occurred in 13% of cases.13

Pesola and Westfal conducted a retrospective review of all patients with new-onset generalized seizures presenting to an academic medical center emergency department (ED) in New York City over 2 years to determine the leading causes of new-onset generalized seizures in AIDS patients:119

  • idiopathic (31%)
  • HIV encephalopathy (31%)
  • CNS toxoplasmosis (18%)
  • alcohol withdrawal (8%)
  • progressive multifocal leukoencephalopathy (8%)
  • CNS lymphoma (4%)

In a comparison group of HIV-negative patients similarly presenting with new-onset seizures, idiopathic (36%) and alcohol withdrawal (24%) were the most common etiologies.119

The same study119 tested whether American College of Emergency Physicians guidelines for ED workup of new-onset seizures were applicable to AIDS patient populations. Using those guidelines, only one-third of patients with CNS lesions requiring admission (e.g., toxoplasmosis and lymphoma) manifested findings meeting those guidelines’ threshold criteria for admission. Thus, two-thirds of HIV-positive patients with admission-requiring CNS lesions contributing to their seizure presentation would have been inappropriately discharged under then-existing American College of Emergency Physicians guidelines. Based on such studies, the guidelines have been amended to require neuroimaging and lumbar puncture (LP) in the ED (or admission for in-patient workup) for all patients with AIDS or suspected AIDS presenting with new-onset seizure.203

In a related study performed at Johns Hopkins Medical Center, aiming to formulate a decision guideline for ED use of noncontrast head CT in HIV-infected patients, investigators sought to determine which neurologic signs or symptoms are predictive of new focal lesions on head CT in HIV-infected patients. New-onset seizure was the most strongly associated with new focal lesions (relative risk of 73.5%).120 The most common intracranial lesion among patients in this study with CD4 counts less than 200 was toxoplasmosis, whereas strokes (ischemic or hemorrhagic) were most common in those with CD4 counts greater than 200.120

Pascual-Sedano et al. also performed a prospective study of new-onset seizures in an HIV-infected patient cohort (n >500).121A new-onset seizure occurred during the study period in 3% of subjects. Of these, 82% had AIDS per the 1993 CDC AIDS definition. The mean latency between HIV diagnosis and first seizure was 60.7 months. The leading causes of seizures were:

  • drug toxicity (47%)
  • intracranial lesion (35%)
  • metabolic derangement or unknown (18%)

In the Pascual-Sedano study,121 the type of first seizure was:

  • generalized (71%)
  • simple partial motor (12%)
  • simple partial with secondary generalization (18%)

Partial seizures occurred in 67% of the patients with an intracranial lesion.

Consistent with AIDS’ protean character, seizure comorbidity can also have varied phenomenology. There are multiple reports of epilepsia partialis continua (EPC) complicating HIV infection. In an HIV patient with chronic focal myoclonus described by Bartolomei and coworkers, serial MRI demonstrated increasing left rolandic T2-weighted signal, and histopathologic study of a brain biopsy specimen demonstrated inflammation characterized by perivascular mononuclear cell infiltration; the only detectable cause was HIV infection. An EEG-electromyography back-averaging study demonstrated that focal motor activity was indeed of cortical origin. High-dose steroid and antiretroviral therapy led to marked radiologic and clinical improvement. This first reported case of HIV-related “inflammatory” EPC emphasizes the importance of including CNS-HIV involvement in the differential diagnosis of EPC.122 More commonly, HIV-1 infection presenting with new-onset EPC can be an early manifestation of PML or secondary focal mass lesion.123

Seizure diagnosis in HIV infection

Neurodiagnostic testing (neuroimaging, LP) demonstrates abnormalities compatible with HIV infection and associated secondary complications.

EEGs in HIV infection and AIDS frequently show epileptiform features.13 Harden and colleagues found low-amplitude, slow, monotonous EEGs associated with AIDS dementia complex.124

Gabuzda and coworkers described routine EEGs in a series of AIDS patients:125

  • generalized slowing (38%)
  • focal slowing (19%)
  • epileptiform activity (6%)
  • unremarkable (37%)

About 13% of patients had clinically diagnosed seizures. Of these, half had EEGs with sharp waves, and 17% had focal slowing. The remainder had unremarkable interictal EEGs.125

Treatment of seizures in HIV infection

Multidrug HIV regimens frequently include medications with a high potential for interactions with anticonvulsants (see Table: Anticonvulsant and antimicrobial cytochrome P-450 effects and Table: Major antimicrobial-anticonvulsant interactions. Meticulous attention to these interactions and tight monitoring of anticonvulsant levels is required.

It has been demonstrated that valproate may increase the viral burden by potentiating replication, so clinicians should be cautious when using valproate in HIV-positive patients.126

The relatively high risk of seizure recurrence imposed by HIV or AIDS and secondary complications increases the need for anticonvulsant maintenance therapy. In one series of HIV patients with new-onset seizure, the average number of seizures per patient was 2.3 during a mean follow-up of 4 months.116 Other reports note seizure recurrence rates of 30–50%.127

The need for anticonvulsants has to be balanced with reports that HIV or AIDS patients have an increased tendency to develop adverse drug effects. In two studies,116,127 26% and 14% of patients with HIV infection who were treated with phenytoin had to discontinue that medication secondary to toxicity (e.g., dermatologic, hematologic, hepatic). Among patients without HIV infection or AIDS, no more than 12% discontinue the anticonvulsant secondary to adverse effects. In contrast, Koppel et al. found that rashes, hepatic dysfunction, and hematologic abnormalities were equally common in AIDS patients without seizures and not taking anticonvulsants as in AIDS patients taking anticonvulsants.128 Whether to institute maintenance anticonvulsant treatment after a first seizure in an HIV patient remains a clinical decision to be made on a case-by-case basis.

Data from JR Berger, DM Simpson. Neurologic Complications of AIDS. In WM Scheld, RJ Whitley, DT Durack (eds), Infections of the Central Nervous System. Philadelphia: Lippincott–Raven, 1997;255–271; and CB Britton. Acquired immunodeficiency syndrome. In LP Rowland (ed), Merritt’s Textbook of Neurology. Baltimore: Williams & Wilkins, 1995;179–193.
Adapted from: Goldstein MA and Harden CL. Infectious states. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;83-133.
With permission from Elsevier (www.elsevier.com). 

Reviewed By: 
Steven C. Schachter, MD
Sunday, February 29, 2004