Seizures in Human
Meng C. Wong, MRCP; Nicholas D. A. Suite, MD; Douglas R. Labar, MD, PhD
\s=b\ Among 630 patients with human im-
munodeficiency virus infection, 70 pa-
tients with new-onset seizures were
studied. Generalized seizures occurred in
66 patients (94%): they occurred as the
initial seizure in 56 patients (80%) and
during follow-up in another 10 patients
(14%). Partial seizures (18 patients), sta-
tus epilepticus (10 patients), and recurrent
seizures (38 patients) were also noted.
Identified processes included cerebral
toxoplasmosis in 11 patients, cerebral
lymphoma in 8, metabolic derangement in
8, cryptococcal meningitis in 7, and vas-
cular infarction in 4. In 32 patients (46%)
seizures were not associated with identifi-
able brain lesions and were believed to re-
sult from human immunodeficiency virus
cerebral infection. Phenytoin treatment
was associated with adverse drug reac-
tions in 16 of 62 patients who received it.
Our results suggest that the majority of
patients with human immunodeficiency vi-
rus and seizures do not have secondary
focal brain lesions as the cause of the sei-
zures and that human immunodeficiency
virus infection alone can, and often does,
cause seizures.
(Arch Neurol. 1990;47:640-642)
"Datients with human immunodefi-
ciency virus (HIV) infection are in¬
creasingly common. Neurologists are
often asked to assist in the evaluation
and management of these patients
when seizures occur. Although sei¬
zures have been previously noted as a
feature of the neurologic complica¬
tions in acquired immunodeficiency
syndrome (AIDS),1 their incidence,
clinical features, significance, therapy,
and outcome have only recently begun
Accepted for publication September 29, 1989.
From the Department of Neurology, Division of
Clinical Neurophysiology, The New York Hospi-
tal-Cornell Medical Center, New York, NY.
Reprint requests to Department of Neurology,
Division of Clinical Neurophysiology, The New
York Hospital-Cornell Medical Center, 525 E 68th
St, New York, NY 10021 (Dr Labar).
Immunodeficiency Virus Infection
to be described.24 In particular, ques¬
tions remain as to whether seizures in
patients with HIV infection indicate
secondary focal brain lesions (such as
toxoplasmosis or lymphoma) or are a
manifestation of HIV disease alone. To
address these issues, we performed a
retrospective study of the clinical
characteristics of adult patients with
HIV infection and new-onset seizures
who were admitted to The New York
(NY) Hospital over a 5-year period.
PATIENTS AND METHODS
We reviewed the medical records of 630
patients who were older than 18 years, who
were admitted between 1984 and 1988, and
who had AIDS, AIDS-related complex
(ARC), or were HIV-antibody positive.
Medical records obtained from hospital
charts (identification of cases based on hos¬
pital discharge codes) and records of the
Neurology Consultation Service and the
Autopsy Service were reviewed. A total of
81 of 630 patients with HIV infection were
found to have had a seizure during the pe¬
riod studied (13% of cases reviewed). Six
patients were excluded because their sei¬
zures clearly antedated HIV infection, and
5 were excluded because of inadequate med¬
ical data. We required that all patients in¬
cluded in the study undergo adequate
workup to search for a cause of their initial
seizures. For the subgroup of 32 patients in
whom the cause was not manifestly appar¬
ent, the workup included at least a detailed
history including drug and alcohol use,
blood cell counts, biochemistry studies, se¬
rum calcium and magnesium determina¬
tions, liver and renal function tests, lumbar
puncture, and computed tomographic (CT)
or magnetic resonance imaging (MRI)
scans. Timely autopsies were considered
acceptable in place of lumbar puncture and
CT and MRI scans. Thus, 70 patients with
new-onset seizures were studied. Addi¬
tional information was obtained from their
physicians, from other hospitals, and from
the Medical Examiner's Office.
For each patient, the following data were
recorded: age, sex, HIV risk factor, HIV
category (AIDS, ARC, or HIV-antibody
positive only), clinical history and exami¬
nation, details of all seizures, relevant lab¬
oratory investigations, and follow-up data.
Patients were diagnosed having AIDS
as
according to criteria establishedby the
Centers for Disease Control, Atlanta, Ga.5
Patients who did not fulfill the criteria for
AIDS but who had appropriate risk factors,
laboratory evidence of HIV infection, and
typical clinical features of ARC6 were des¬
ignated as having ARC. Patients who were
HIV-antibody positive but did not fulfill the
criteria for AIDS or ARC were designated
for the purposes of this study as HIV-anti¬
body positive only.
RESULTS
The study population consisted of 70
patients with new-onset seizures.
There were 59 men and 11 women, with
a mean age of 37 years (range, 21 to 81
years). At the time of the first seizure,
40 were already inpatients and 26 were
brought immediately to the emergency
department, while 4 others sought
medical attention within a few days of
the seizure. At the time of the first sei¬
zure, 50 had AIDS, 10 had ARC, and 10
were HIV-antibody positive only. Risk
factors were identified in 61 patients
and included homosexuality/bisexual-
ity (38 patients), intravenous drug
abuse (17), both homosexuality/bisex-
uality and intravenous drug abuse (2),
and blood transfusions (4). In 9 pa¬
tients no risk factors were identified.
Follow-up data were obtained from the
time of first seizure to death in 44 pa¬
tients, with a mean interval of 63 days
(range, 1 to 270 days). For the other 26
patients, available follow-up covered a
mean interval of 157 days (range, 3
days to 5 years).
The initial seizure was generalized
in 56 patients, complex partial in 9, and
simple partial in 5. Of the 14 patients
with an initial partial seizure, 10 had a
subsequent generalized seizure during
follow-up. Of the 56 patients with an
initial generalized seizure, 4 had a
subsequent partial seizure. Recurrent
seizures were noted in 38 patients
(54%), 37 of whom were treated with
anticonvulsants. In contrast, 32 pa¬
tients (46% ) had a single seizure up to
the time of available follow-up, 26 of
whom were treated with anticonvul¬
sants. Status epilepticus (as defined by
Celesia7) occurred in 10 patients. In 7
patients, it was the first presentation
of their seizure disorder. Convulsive
status was noted in 7 patients and
nonconvulsive status in 3 patients.
Twenty patients underwent enceph-
alography (EEG). Four EEGs were
normal; 14 demonstrated generalized
slowing; 5, focal slowing; 4, focal epi-
leptiform activity; and 1, generalized
epileptiform activity. Cerebrospinal
fluid (CSF) examination was per¬
formed for 52 patients after the initial
seizure. This identified 6 patients with
cryptoccocal fungal infection and 2
with cerebral lymphoma. The other 44
lumbar punctures revealed an in¬
creased protein content (> 0.40 g/L) as
the only abnormality in 21 patients,
leukocytosis (>5 white blood cells per
high-power field) as the only abnor¬
mality in 4 patients, and 1 patient with
both abnormalities. The CSF was nor¬
mal in 18 patients.
Metabolic causes of seizures in¬
cluded hypoxia in 4 patients, while hy-
pocalcemia, hypomagnesemia, hypo¬
glycemia, and renal failure were the
cause in 1 patient each. No seizures at¬
tributable to alcohol or drug use were
identified.
Computed tomographic scans were
obtained after the initial seizure in 62
patients. Focal lesions were noted in 22
patients, and diffuse white matter
changes in 2 others. In 38 patients, the
CT scan was normal or showed cere¬
bral atrophy only. Magnetic resonance
imaging was performed after the ini¬
tial seizure in 14 patients. Focal lesions
were noted in 6 patients, and diffuse
white matter changes in 5 others. In 3
patients, the magnetic resonance im¬
aging scan was normal or showed
cerebral atrophy only.
Autopsies were performed on 17 pa¬
tients. Secondary focal lesions were
detected in 10 patients (3 with lym¬
phoma, 3 with toxoplasmosis, 2 with
both lymphoma and toxoplasmosis,
and 2 with vascular infarction).
Among the 7 autopsies in which no
secondary focal lesions were seen, mi-
croglial nodules were noted in 5 pa¬
tients, multinucleated cells typical of
HIV infection8 in 2 patients, and a
group of inclusion-bearing cells typical
of cytomegalovirus (CMV)9 in the cer¬
ebellum of 1 patient. Cytomegalovirus
was excluded by immunohistochemis-
try studies in the 1 patient tested.
Combining all available data (in¬
cluding the results of CSF examina¬
tion, CT and MRI scans, and autop¬
sies), the cause of the seizure was
Seizure Recurrence Pattern and Associated Presumed Cause*
Table 1.
—
Seizure Pattern
Single seizure (n =
32)
Recurrent seizure (n =
38)
HIV indicates human immunodeficiency virus.
Table 2.—Seizure
Seizure Type
Generalized seizure only
(n =
52)
Generalized and partial
seizures (n 14)
=
Partial seizure only
(n =
4)
*HIV indicates human immunodeficiency virus.
identified as focal brain lesions in 23
patients (toxoplasmosis in 11, lym¬
phoma in 8, and vascular infarction in
4), cryptococcal meningitis in 7 pa¬
tients, metabolic derangement in 8 pa¬
tients, and presumed HIV infection
alone in 32 patients. A comparison of
the autopsy findings with the antemor-
tem CT scans in 14 patients showed
that the CT scan correctly identified
secondary focal lesions in 9 of 10 pa¬
tients and no secondary focal lesions in
4 of 4 patients.
Single seizures and recurrent sei¬
zures were both associated with all
causes (Table 1). No particular cause
was associated specifically with partial
seizures or generalized seizures (Ta¬
ble 2).
Phenytoin sodium was the anticon¬
vulsant most frequently used. Pheny¬
toin therapy was administered to 62
patients, but adverse drug reactions
resulted in its discontinuation in 16
patients (8 patients with rash, 4 with
worsening leukopenia or thrombocy¬
topenia, and 4 with worsening liver
function).
COMMENT
Although data suggest a 12%
our
incidence of new-onset seizures in pa¬
tients with HIV infection, we would
emphasize that this was a hospital-
based study and that these incidence
figures probably represent a more se¬
riously ill subgroup of patients with
HIV infection. In addition, we suspect
that this bias toward more seriously ill
patients would favor the inclusion in
our study of more patients with sec¬
ondary lesions (such as those with
toxoplasmosis, lymphoma, and crypto-
coccosis), with consequently less pa-
Presumed Cause
Focal Lesions Metabolic HIV
Meningitis
(n -
23) (n 7)_(n 8)
= =
(n -
32)
14 3 3 18
Type and Presumed Cause*
Presumed Cause
Focal Meningitis Metabolic HIV
(n =
23) (n -
7) (n =
8) (n =
32)
tients with "simple" HIV infection as
the cause of their seizure. Homosexu-
ality/bisexuality and intravenous
drug abuse were the most common risk
factors elicited, and these findings are
similar to data of the same period on
adult AIDS in New York, NY,10 imply¬
ing that the risk of seizures is not
higher in any risk factor subgroup of
patients with HIV.
The cause of the seizure was identi¬
fied in about half of our patients (54% ).
In 46% of our patients, extensive work-
up failed to identify an obvious cause.
Despite our hesitation to draw etio-
logic conclusions on the basis of exclu¬
sionary criteria, we believe that in this
subgroup, HIV brain infection itself is
the most likely cause of the seizure.
The fact that secondary focal brain le¬
sions were found at autopsy in 7 pa¬
tients is supportive. In addition, we
were able to compare the CT scan and
autopsy findings in 14 patients, noting
that the CT scan detected secondary
focal lesions with a sensitivity of 90%
and a specificity of 100%. We have no
reason to suspect that among the pa¬
tients in whom autopsy was declined,
secondary focal lesions were not de¬
tected by CT, MRI, or CSF studies.
Concurrent CMV brain infection was
noted in 1 patient who underwent au¬
topsy. Although we are uncertain as to
the precise role that concurrent CMV
brain infection plays in the genesis of
seizures in patients with HIV infec¬
tion, we speculate that in some pa¬
tients it may well play a significant
role. We were unable to ascribe sei¬
zures to alcohol or drug use, but we be¬
lieve that this may have been a result
of a number of possible biases: patients
may not be forthcoming about alcohol
or drug use in the history; patients
with intravenous drug abuse were a
minority in our study (19 patients);
and the majority of our patients were
inpatients at the time of their initial
seizure. We also do not believe that
these seizures occurred simply because
our patients were terminally ill,
review of 277 patients who died at The
New York Hospital over the 3-month
period of October 1988 to December
1988 revealed that only 4.7% had a
seizure during their last inpatient ad¬
mission, an incidence that is signifi¬
cantly less ( 2, 12.9; P< .01).
Seizures in HIV-infected patients
may be a nonspecific late manifesta¬
tion of progressive cerebral viral in¬
fection, and parallels may be con¬
sidered with Jakob-Creutzfeldt dis¬
ease" and subacute sclerosing
panencephalitis,12 in which seizures
are at least as frequent. Fifty of our
patients (71 % ) had AIDS at the time of
the initial seizure, suggesting that sei¬
zures occur mainly as a feature of the
late stages of HIV infection. Neverthe¬
less, we noted 20 patients (29%) who
were HIV-antibody positive only
who had ARC at the time of their first
seizure. In 11 of these 20 patients, HIV
infection alone was the presumed
cause of the new-onset seizure, sug¬
gesting that seizures may be an early
manifestation of HIV disease. Conse¬
quently, we would urge that HIV in¬
fection be considered when a patient
develops new-onset seizures. As such,
a HIV-antibody test should be consid¬
ered in the workup, even in the absence
of a history of opportunistic infection
or AIDS.
Status epilepticus complicated the
course of 10 patients (14% ), which is a
high incidence.13 In addition, general¬
ized seizures were very common (oc¬
curring in 66 patients, or 94% ), imply¬
ing that the HIV-infected brain may
have diffuse cortical irritability or im¬
paired mechanisms for seizure termi¬
nation once epileptogenic activity has
been generated.
There has been much debate on the
need for long-term anticonvulsant
therapy for patients who have had
only one seizure.14'5 The probability of
recurrent or multiple seizures forms
the basis for such a therapeutic deci¬
sion. Our findings suggest that despite
widespread anticonvulsant use (in
90% of our patients), 54% of patients
with HIV infection who have an initial
seizure will have another seizure. This
is probably an underestimate, as
lengthy follow-up was not always
available. In addition, there is an in¬
creased tendency toward status epilep¬
ticus in this patient population. As we
are unable to predict which patients
are likely to have recurrent seizures, it
is our present general policy to pre¬
scribe long-term anticonvulsant ther¬
apy for all patients with HIV disease
who have a seizure.
New-onset seizures in a patient with
as a HIV infection suggest the possibility
of a potentially treatable new cerebral
process such as toxoplasmosis, lym¬
phoma, or cryptococcal meningitis. We
had 8 patients with cerebral lym¬
phoma and 7 with cryptococcal menin¬
gitis in our study of 70 patients. The
CSF diagnosis of cryptococcal menin¬
gitis and particularly of lymphoma can
be difficult. Our experience has been
similar to that of others in that the
routine CSF cell counts and chemistry
studies were frequently normal in
cryptococcal meningitis.16 In cerebral
lymphoma, cytologie examination re¬
vealed the diagnosis in 25%, which is
comparable with most figures of about
29%." We suggest that when looking
for a treatable process in a patient
with HIV infection and a seizure, CSF
examination for cryptococcal antigen,
or fungal culture, cytologie examination,
and flow cytometry18 may increase the
diagnostic yield. Our experience has
been that in the majority of cases, the
CT scan does not reveal a focal lesion
in patients with HIV infection and
new-onset seizures. This raised the
question as to whether the seizure in¬
dicated a new focal process that the CT
scan failed to identify. However, our
comparison of CT and autopsy findings
showed that the CT scan correctly
identified focal brain lesions in all but
one patient with HIV infection who
developed seizures.
Our frequent EEG finding of gener¬
alized slowing is consistent with other
studies.19 Only 5 (25%) of 20 EEGs re¬
vealed epileptiform discharges, sug¬
gesting that in patients with HIV and
seizures, the EEG is relatively insen¬
sitive for detecting epileptogenic ac¬
tivity. We found the EEG useful for
identifying nonconvulsive status epi¬
lepticus and would recommend its con¬
sideration in any patient with HIV in¬
fection and mental status changes.
Of the 62 patients who received phen¬
ytoin therapy, 16 (26% ) had presumed
adverse drug reactions, resulting in its
discontinuation. Other processes in
patients with HIV infection may be
relevant or contributory. We note that
many of these patients are leukopenic
or thrombocytopenic, have abnormal
results on liver function tests, and are
taking multiple medications before
starting phenytoin therapy. We sus¬
pect that these factors may be interac¬
tive with phenytoin use to cause the
high incidence of adverse drug reac¬
tions in our study. However, our study
was not designed to specifically exam¬
ine this issue, and we remain uncertain
as to the exact mechanism of these ad¬
verse drug reactions. In contrast, al¬
though phénobarbital sodium therapy
was only administered to 17 patients
(vs 62 treated with phenytoin), there
were no instances where it had to be
discontinued because of adverse side
effects (Fisher's Exact Test, .013). =
We believe that further study compar¬
ing various anticonvulsants for this
patient population would prove useful.
We wish to thank Dr Carol Petito for her guid¬
ance with the neuropathologic material, Dr
Jonathan Victor for his help with the statistical
analysis, and Dr Jerome Posner for his advice and
editorial comments.
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