New-onset seizures are frequent manifestations of central nervous system disorders in patients infected with human immunodeficiency virus (HIV). Seizures are more common in advanced stages of the disease, although they may occur early in the course of illness. In the majority of patients, seizures are of the generalised type. Status epilepticus is also frequent. Associated metabolic abnormalities increase the risk for status epilepticus. Cerebral mass lesions, cryptococcal meningitis, and HIV-encephalopathy are common causes of seizures. Phenytoin is the most commonly prescribed anticonvulsant in this situation, although several patients may experience hypersensitivity reactions. The prognosis of seizure disorders in HIV-infected patients depends upon the underlying cause.
- human immunodeficiency virus
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Disorders of the central nervous system (CNS) in patients with human immunodeficiency virus (HIV) type-1 infection is often associated with severe morbidity and mortality. Seizures are relatively common manifestations of HIV infection itself and of its several complications involving the brain.1-6
Available data on the incidence of new-onset seizures in HIV-infected persons are derived from hospital-based studies. Wonget al 3 observed an incidence of 11% among 630 HIV-infected patients. In a more recent study, Van Paesschen et al 4 observed that 4% of AIDS patients had new-onset seizures. In their study, the incidence of seizures was much lower than in the former study, presumably because strict inclusion criteria were applied. All patients were admitted, or were already in-patients, on the day of first seizure. Out of 68 selected patients, 62 had acquired immunodeficiency syndrome (AIDS), only six (9%) patients had AIDS-related complex or were asymptomatic HIV-seropositive.4 In the study by Wong et al, 3 28% of the patients had AIDS-related complex or were asymptomatic HIV-seropositive.
Associated seizure disorders
In most AIDS patients, seizures are seen in advanced stages of the disease.3 4 Dore et al 5 in a case-control study observed that 84% of such patients had prior AIDS-defining illness, and mean CD4 T-cell count was 8 × 106 cells/μl, while in a control group (patients without seizures) mean CD4 T-cell count was 14 × 106 cells/μl, and AIDS-defining illness was present in 80% of the patients.
Seizures may be the presenting clinical symptom of HIV disease. In a few patients seizures can occur early in the course of HIV-infection. The majority of patients have generalised seizures; partial seizures are less frequently observed and do not necessarily imply the presence of focal mass lesions.1-6 Both simple and complex partial seizures are seen in patients with diffuse brain disease, such as HIV encephalopathy and meningitis.3 The incidence of convulsive status epilepticus has been reported as between 8% and 18% in different studies,2-4 and is often associated with poor prognosis. The frequent occurrence of generalised seizures and status epilepticus suggests that the HIV-infected brain has a low cortical excitability and impaired mechanisms for terminating seizure activity. Electroencephalographic (EEG) findings are usually non-specific, diffuse slowing being the most common abnormality. Focal slowing and epileptiform activities are infrequently seen.2 3
Work-up for HIV-infected patients presenting with new-onset seizures includes neuroimaging studies (computed tomography (CT), magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis), as well as blood chemistry and, in some patients, neuropathological studies of biopsied brain tissue. In a few patients, diagnosis may not be clear until post-mortem neuropathological evaluation. Approximately 50–60% of patients have an apparent secondary disease process to which the seizures can be attributed; at rest, no demonstrable cause is seen (table).1-7 Various electrolyte and metabolic disturbances, such as hyponatraemia, hypomagnesaemia and renal failure, are associated with an increased risk of seizure recurrence and increased occurrence of convulsive status epilepticus.2 4
Intracranial mass lesions account for nearly half the neurological disorders in AIDS patients. The nature of these mass lesions can be broadly divided into three distinct groups: opportunistic infections, neoplasms, and cerebrovascular diseases. Seizures are dominant manifestations of most of these disorders (boxFB1).8
Toxoplasmosis is the most common cause of intracranial mass lesions in AIDS and occurs in 3–10% of patients in the USA and in up to 50% of patients in Europe and Africa.8 Seizures have been reported as an early manifestation in 15–40% of patients with cerebral toxoplasmosis.1 9 The diagnosis is usually made by demonstrating the presence of ring-enhancing lesions on CT scan, positive toxoplasma antibody titre, and clinical improvement with antitoxoplasma treatment which is confirmed by repeat CT brain scan.10 Various studies have described different incidences (12–28%) of toxoplasmosis in patients with new-onset seizures among HIV infected persons.2 4 5 Identification of cerebral toxoplasmosis is important because timely treatment with sulfadiazine and pyrimethamine is most likely to result in rapid clinical improvement.
Primary CNS lymphoma, the second most common cause of AIDS-related intracranial mass lesions, occurs in up to 2% of patients with AIDS.8 It is also the second most common mass lesion producing seizures in HIV-infected persons. A number of imaging features are helpful in distinguishing this condition from cerebral toxoplasmosis. Involvement of, and extension across, the corpus callosum is frequent in primary CNS lymphoma. Exclusive involvements of white matter, periventricular location and sub-ependymal spread (seen as contrast enhancement along the ventricular surface) are also common in lymphoma.10
Other causes of intracranial mass lesions which are likely to produce seizures in AIDS patients include tuberculous abscesses11and tuberculomas,12 cryptococcal abscesses,10nocardial abscesses,13 syphilitic gummas and cerebrovascular diseases when accompanied by oedema.14
Other focal lesions
Other focal lesions without significant mass effect, such as progressive multifocal leukoencephalopathy (PML) may also be responsible for new-onset seizures in several AIDS patients (figure). Moulignier et al 15 reported on 10 HIV-infected patients with PML in whom partial or generalised seizures were the presenting neurological manifestations. They suggested that demyelinated lesions adjacent to the cerebral cortex acting as irritative foci, axonal conduction abnormalities, or disturbance of the neuron–glia balance are the possible reasons for a pure white matter disease producing seizures. Confirmation of the diagnosis of PML requires neuropathological studies of biopsied brain tissue from the lesion (box FB2).
Meningitis and encephalitis
In patients without mass lesions, meningo-encephalitis caused by some opportunistic infections is a frequent source of seizures. The incidence of meningitis and encephalitis in HIV-infected patients with new onset seizures varies from 12% to 16%. Cryptococcal meningitis is the most frequent meningo-encephalitis producing seizures.2-6 To confirm the diagnosis, an India ink preparation of CSF should be examined for cryptococcal antigen; fungal culture may increase the diagnostic yield.
Infrequent causes include aseptic meningitis, neurosyphilis, Herpes zoster leukoencephalitis, toxoplasma and cytomegalovirus encephalitis.5 In the developed countries, subacute sclerosing panencephalitis has re-emerged in children infected with HIV and can present with seizures and encephalopathy. The diagnosis is confirmed with characteristic periodic electroencephalographic changes and high measles antibody titre in CSF.16
Approximately half of HIV-infected patients with seizures have no definite identifiable disease of the brain, and cerebral HIV infection seems to be the most likely cause of the seizures.1-7Navia et al 17 reported nine patients with AIDS–dementia complex who had new-onset seizures and in whom autopsies did not reveal any secondary infections or neoplastic processes. The authors considered direct HIV infection of brain to be the cause of the seizures. In the study by Holtzmanet al,2 HIV encephalopathy was responsible for seizures in 24% of the patients. The diagnosis was established with the help of characteristic clinical features and histopathology of brain tissues. Later, in a series by Wonget al, 3 17 patients within an unidentified group underwent post-mortem neuropathological examination of brain; six of them had microglial nodules or multinucleated cells or both, suggesting the diagnosis of HIV infection as a primary cause of seizures. In a series by Van Paesschen et al,4 41% of patients had cerebral atrophy on CT scan without meningitis or other demonstrable CT lesions. Autopsies of two patients from the latter group who died after seizure onset revealed subacute HIV-associated encephalitis in one patient, and cytomegalovirus encephalitis in the other. In a more recent study, Doreet al 5 observed that 42% of cases had no identifiable cause of seizures, although 18% of patients were receiving foscarnet therapy. They suggested that foscarnet therapy and subclinical HIV-1 involvement of the brain may be factors responsible for seizure activity. Thus, available data strongly suggest an epileptogenic role of HIV infection of the brain.
Among the various pathologies reported in the brain of patients of AIDS is neuronal injury and loss, however, neurons themselves are not infected by HIV. There is strong evidence for the existence of HIV- or immune-related toxins that produce injury or death of neurons via a potentially complex interaction between macrophages, microglia, or monocytes, especially after interacting with astrocytes. These neurotoxic substances can lead to increased glutamate release or decreased glutamate re-uptake. This mechanism involves the activation of voltage-dependent calcium channels andN-methyl-d-aspartate (NMDA) receptor-operated channels and influx of calcium inside the neurons and other cells. The same mechanisms which have been proposed for the pathogenesis of the AIDS–dementia complex are considered responsible for early and late occurrences of seizures in these patients (boxFB3).18 19
HIV-related seizures may also be provoked by concurrently administered drugs, for example, foscarnet therapy.20Solomon et al 21 reported one HIV-infected patient who developed new-onset generalised seizures following a single topical application of lindane for scabies.
Seizure recurrences are frequent among these patients. Long-term anti-epileptic therapy needs to be considered, even after a single seizure. Phenytoin has been the most widely prescribed anti-epileptic drug for these patients, but a significant number of patients are likely to experience undesirable side-effects, including skin rashes, leucopenia, thrombocytopenia and hepatic dysfunction. Phenobarbitone and valproate are satisfactory alternatives in this situation.2 3 19 Patients with mass lesions may experience seizure recurrence despite adequate plasma concentrations of anti-epileptic drug.3 As patients with HIV disease are likely to take long-term anti-epileptic medication, this may lead to drug interactions as a result of hepatic enzyme induction. Anti-epileptic drugs may also reduce the plasma concentrations of the protease inhibitors and so reduce their antiviral efficacy.22
Seizures are frequently associated with neurological manifestations of HIV infection. Correct diagnosis of underlying causes and their treatment along with anticonvulsant therapy is required for proper management. Proper control of seizures will help to improve the quality of life in these patients who are already suffering from a dreaded disease.