Intra-Arterial Papaverine-Induced
Seizures: Case Report and Review
of the Literature
Juan R. Carhuapoma, M.D.,* Adnan I. Qureshi, M.D.,* Rafael J. Tamargo, M.D.,†
John M. Mathis, M.D., M.Sc.,‡ and Daniel F. Hanley, M.D.*
Divisions of *Neurosciences Critical Care, †Neuroradiology and ‡Department of
Neurological Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland

Carhuapoma JR, Qureshi AI, Tamargo RJ, Mathis JM, Hanley DF.
Intra-arterial papaverine-induced seizures: case report and review of the literature. Surg Neurol 2001;56:159 – 63.

KEY WORDS

Papaverine, seizures, subarachnoid hemorrhage.

BACKGROUND

Microcatheter-guided intra-arterial (IA) papaverine infusion in conjunction with balloon angioplasty is an available therapy for patients with symptomatic vasospasm
after subarachnoid hemorrhage (SAH) that is refractory
to hypertensive, hypervolemic therapy. However, side
effects and complications have been reported in association with its use.
CASE DESCRIPTION

We report on a patient who developed symptomatic vasospasm after subarachnoid hemorrhage due to rupture
of a left terminal internal carotid artery (ICA) saccular
aneurysm. Seven days after the hemorrhage and 4 days
after surgical clipping, the patient developed aphasia and
right hemiparesis due to vasospasm, which was refractory to maximal medical treatment with volume and
blood pressure elevation. Cerebral angiography identified severe narrowing of distal ICA and proximal middle
cerebral artery segments bilaterally. These findings partially resolved after balloon angioplasty. However, after
300 mg of IA papaverine, the patient developed generalized convulsions. This occurred despite therapeutic serum levels of phenytoin. Twenty-four hours later, after
brief neurologic improvement, recurrent neurologic deficits prompted repeat papaverine administration. Seizures again occurred after the administration of 240 mg of
IA papaverine and prevented administration of the full
dose. The patient did not develop further seizures and
her neurologic deficits continue to resolve.
CONCLUSIONS

IA papaverine-induced seizures are infrequently reported. This potential complication should be considered
when papaverine administration is entertained in the
treatment of anterior circulation refractory symptomatic
vasospasm after SAH. © 2001 by Elsevier Science Inc.

Address reprint requests to: Dr. Juan R. Carhuapoma, Division of Critical Care Neurology, Columbia University College of Physicians and Surgeons, Neurological Institute, 710 West 168th Street, Box 209, New York,
NY 10032.
Received August 18, 2000; accepted February 27, 2001.
© 2001 by Elsevier Science Inc.
655 Avenue of the Americas, New York, NY 10010

fter nontraumatic subarachnoid hemorrhage
(SAH), angiographically defined cerebral vasospasm occurs in up to 70% of patients [14]. Its
clinical correlate, delayed cerebral ischemia (DCI)
develops in 33 to 37.5% of them [1,11]. Nonpharmacological therapies for DCI include induced hypervolemia and hypertension, which attempt to improve collateral blood flow to brain at risk for
ischemia [2,28,29]. Nevertheless, a subgroup of patients will remain refractory to such interventions.
Two neurointerventional approaches have become
available to prevent permanent cerebral ischemia
in this patient cohort: balloon angioplasty and
microcatheter-guided intra-arterial (IA) papaverine
injection [3,12,22–24,30].
Papaverine hydrochloride, a benzylisquinoline
that inhibits cAMP and cGMP phosphodiesterase
[21], has been used as the primary treatment of
refractory vasospasm in addition to balloon angioplasty. Although a potent vasodilator, the effects of
the drug are shorter lasting compared with mechanical angioplasty [9]. Several side effects associated with rapid administration of papaverine,
such as hemiparesis, midriasis, hypotension, elevated intracranial pressure (ICP), and cardiorespiratory depression have been identified since it was
first introduced in neurocritical care [17,19]. The
development of seizures as a side effect of its IA
administration in the treatment of cerebral vasospasm, however, has not been thoroughly studied
thus far.
We describe a patient treated with IA papaverine
for symptomatic vasospasm after SAH who developed recurrent seizures during repeated adminis-

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160 Surg Neurol
2001;55:159 –63

Carhuapoma et al

tration of papaverine hydrochloride, and review the
pertinent literature.

Case Report
A 35-year-old woman developed sudden onset of
severe headache and altered level of consciousness
2 days before admission. Her medical history was
remarkable for remote, mild renal dysfunction (admission creatinine: 0.6 mg/dL), inactive systemic
lupus erythematosus (SLE) and recent (2 months)
normal vaginal delivery. Upon admission, only neck
rigidity was elicited on examination. Initial head
computed tomography (CT) scan was normal. Nevertheless, an elevated number of red blood cells
and cerebrospinal fluid (CSF) xanthochromia suggested the diagnosis of SAH. Cerebral angiography
performed 1 day after admission showed a left internal carotid artery (ICA) termination aneurysm.
Seizure and vasospasm prophylaxis was instituted
with phenytoin (PHT) and nimodipine, respectively.
The patient underwent an uncomplicated left frontal craniotomy for aneurysm clipping. Her immediate postoperative neurologic examination showed
normal cognitive and motor functions.
Two days later, she developed clonic movements
of the right facial muscles, followed by brief postictal lethargy. Total serum PHT level was 19.4 mcg/
dL. Gabapentin was added to her anticonvulsant
regimen (900 mg PO tid) and the daily dose of PHT
was increased. Four days after surgery and 7 days
after the original bleed, the patient experienced
abrupt onset of lethargy, severe right hemiparesis
and aphasia, with elevated transcranial Doppler velocities in the left anterior circulation. Repeat head
CT scan identified a subtle hypodense area in the
left frontal white matter. Symptomatic vasospasm
was suspected and volume expansion (intravenous
fluids, 5.6 – 6.8 liters/day; pulmonary capillary
wedge pressure, 18 –22 mmHg), and hypertensive
therapy with dobutamine and phenylephrine (mean
arterial pressure, 115–120 mmHg) were instituted.
Eight hours later, in the absence of observable improvement, cerebral angiography was performed
that demonstrated narrowing of the bilateral distal
ICA, proximal middle cerebral artery (MCA), and
anterior cerebral artery (ACA) A1 segments, compatible with severe vasospasm (Figure 1). After successful bilateral angioplasty of the proximal segments of the MCA and distal ICA (Figure 2), an
injection of papaverine was started in the left anterior circulation, but it was interrupted by 90 seconds of generalized tonic-clonic seizure activity after the administration of 300 mg of papaverine over

Diagnostic cerebral angiogram demonstrating arterial narrowing in the left distal ICA, proximal MCA,
and ACA A1.

1

30 minutes. The seizure was rapidly controlled with
5 mg of intravenous midazolam. The levels of total
and free PHT were 18.8 and 6.2 mcg/dL, respectively, and no further adjustments were made. Initial improvement in comprehension and motor
function was noted, but because right hemiparesis
recurred after 24 hours, cerebral angiography was
repeated, revealing persistent bilateral ACA-A1 segment narrowing. No attempt to angioplasty these
segments was made. After administration of 240 mg
of papaverine in the left anterior circulation, the
patient developed a new generalized convulsion,
which ceased shortly after the papaverine infusion
was discontinued. After the second procedure, the
neurologic deficits improved gradually and no further clinical ictal activity was recorded.

Discussion
We report the occurrence of recurrent seizures in a
patient with SAH during repeated IA infusions of
papaverine for the treatment of refractory cerebral
vasospasm. A similar occurrence has been previously reported in only six other cases of cerebral
vasospasm treated with IA papaverine injection
[4,10,16,23,26,27]. In our patient, the close temporal

Papaverine-Induced Seizures

Cerebral angiogram demonstrating successful balloon angioplasty of the left distal ICA and proximal
MCA segment. Persistent, mild ACA A1 segment vasospasm is also noted.

2

association between papaverine infusion and onset
of seizures on two separate occasions suggests a
causal relationship.
Use of papaverine hydrochloride in the treatment
of vasospasm was first reported in 1992 [6,13].
Since then, it has been used in refractory cases,
either alone or in combination with balloon angioplasty, and with different rates of success [9]. Although papaverine is capable of reversing angiographic vasospasm, its effects are shorter lasting
than those of proximal, large vessel cerebral angioplasty [9,15,21,26]. Clinically, papaverine is administered via microcatheter in the compromised circulation. When vasospasm affects anterior
circulation vessels, the catheter tip is usually positioned distal to the ophthalmic artery, in the supraclinoid ICA, whereby papaverine exerts its effects
on both ACA and MCA territories. When the posterior circulation is treated, the catheter tip is placed
proximal to the vasospastic segment [12,19]. The
dose of papaverine commonly used is 300 mg of the
drug diluted in 100 cc of normal saline (0.3% papaverine), and is administered in the affected vascular
territory over 30 to 60 minutes. In situations where
more than one vascular territory is affected, additional doses of papaverine may be infused, but side

Surg Neurol 161
2001;55:159 –63

effects such as hypotension or increased ICP can
limit the procedure [5,19].
Some of the side effects reported with use of
papaverine in patients with cerebral vasospasm are
clearly dose-related. Hypotension has been directly
associated with large doses and with too rapid administration of the drug [19]. Because hypotension
in the setting of refractory vasospasm can have
devastating neurologic consequences, blood pressure should be closely monitored during IA administration of papaverine when vasospasm affects several vascular territories. The rise in ICP during the
administration of the drug has been reported previously and it has been linked to the rate and total
dose of drug given [5]. Although the mechanism of
increased ICP is independent of blood pressure
changes in these patients and is likely the result of
vasodilatory effects of the drug on cerebral vasculature, a decrease in the mean arterial pressure can
clearly complicate papaverine treatment and lead
to additional vasodilatation of cerebral blood vessels, increased cerebral blood volume, and subsequent worsening of an already elevated ICP. Finally,
Miller et al have described severe thrombocytopenia after the IA administration of papaverine for
treatment of cerebral vasospasm [20].
Mathis et al reported their experience with 36
patients treated with papaverine for symptomatic
vasospasm and found transient neurologic events
complicating therapy in six (16.7%) of them [19]:
pupillary dilatation (four patients), transient hemiparesis (one patient), and respiratory arrest (one
patient). Because there is a risk of microcrystal
formation, some investigators have postulated that
precipitation of papaverine can occur and subsequent distal embolization may affect an already
challenged vascular territory [18]. However, to the
best of our knowledge, this hypothesis has never
been validated in vivo.
Papaverine hydrochloride has been used in epilepsy research as an anticonvulsant agent because
of its inhibitory effects on adenosine uptake. Dragunow et al have shown that adenosine modulates
the kindling process in neuronal structures involved in the generation of seizure discharges [7,8].
Furthermore, adenosine may also belong to an inherent control system that prevents seizure spreading. However, in a rodent model of theophyllineinduced seizures, Ramzan reported the only
available study that presents papaverine as proconvulsant [25]. Apparently, this effect of papaverine
could be mediated by reducing threshold concentrations of theophylline required to generate seizures, and perhaps by acting as proconvulsant in
itself if sufficiently high concentrations are reached.

162 Surg Neurol
2001;55:159 –63

1

Carhuapoma et al

Review of Papaverine-Associated Seizures in SAH Patients Reported since 1993

AGE/SEX

VESSELS
TREATED

H&H

DOSE OF
PAPAVERINE

ANGIOGRAPHIC
RESULTS

OUTCOME

42/M
37/M
Not reported
40/F
44/F
40/F

ICA
MCA
MCA
ACA/MCA
ACA/MCA
ICA

II
I
Not reported
III
II
III

30 mg
20 mg
200 mg
120 mg
200 mg
Not reported

Resolved vasospasm
No effect
Not reported
Resolved vasospasm
Resolved vasospasm
Minimal improvement

No neurologic deficit
Severely disabled
Not reported
Mildly disabled
Died
Minimally improved

AUTHOR, YEAR
27

Tsurushima et al , 2000
Terada et al26, 1997
Numaguchi et al23, 1997
Marks et al16, 1993
Clouston et al4, 1995
Firlik et al10, 1999

M, Male; F, Female; H & H, Hunt and Hess score; ICA, Internal carotid artery; MCA, Middle cerebral artery; ACA, Anterior cerebral artery.

A review of six other cases of papaverine-induced
seizures reported since 1992 seems to suggest that
this drug may trigger seizures through a mechanism unrelated to the total administered dose, the
initial neurologic status, or the final effect on vessel
patency (Table 1). Interestingly, in every case
where this complication was reported, the drug was
being administered in the anterior circulation (ICA
or MCA), as in our patient. Although only six cases
have been reported thus far, the analysis of these
data portrays direct proconvulsant effect of papaverine during its IA administration in metabolically
challenged neuronal tissue as a conceivable pathophysiologic mechanism. This and other hypotheses, however, have never been specifically tested.
Underlying conditions such as SLE (although inactive), recent surgical trauma, cerebral ischemia secondary to cerebral vasospasm, an already existing
predisposition to seizure activity (as demonstrated
by an early postoperative seizure), and perhaps
supra-therapeutic levels of PHT could also have
contributed to further reduce the seizure threshold
in this case.

Conclusion
The case presented in this report shows a clear-cut
instance of seizures reproducibly associated with
the IA administration of papaverine. The mechanism leading to this manifestation of altered neuronal function remains unknown. As in this case, concomitant conditions that can further decrease the
seizure threshold, if present, have the potential to
aggravate this risk when the cerebral anterior circulation is the target of this form of therapy.
Dr. Carhuapoma is supported partly by the David A. Dana
Research Prize in Neurosciences Critical Care, Johns Hopkins University School of Medicine, and by the Daland Fellowship for Clinical Research Award from the American
Philosophical Society.

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COMMENTARY

Although this is not the first case of seizures occurring after intra-arterial administration of papaverine, I find it to be very valuable because the patient
was re-challenged with papaverine, eliciting another
seizure episode. Re-challenge is the best proof of
cause/effect association. This case is a good reminder to clinicians of this possible side effect, especially when considering this line of treatment in a
patient in whom a seizure might have devastating
consequences. In addition, this case report confirms once more the lack of antipileptogenic effect
of phenytoin, as the serum free phenytoin level in
this patient was two times the maximum therapeutic level.
Carlota Andrews, PharmD, Ph.D.
Department of Pharmacy Practice
University of Illinois at Chicago
Chicago, Illinois