Brain & Development 28 (2006) 336–338

www.elsevier.com/locate/braindev

Case report
Benign angiopathy of the central nervous system associated with
phenytoin intoxication
Hiroyuki Wakamoto a,b,*, Aya Kume b, Naoko Nakano b, Hideo Nagao c
a
Division of Pediatric Nurology, Children’s Hospital of Michigan, Wayne State University, 3901 Beaubien Street, Detroit, Michigan 48201, USA
b
Department of Pediatrics, Ehime Prefecture Niihama Hospital, 3-1-1 Hongo, Niihama city, Ehime 792-0042, Japan
c
Department of Pathology for the Handicapped, Faculty of Education, Ehime University, Ehime, Japan
Received 29 May 2005; received in revised form 5 September 2005; accepted 11 October 2005

Abstract
We report a patient with epilepsy who presented with acute onset of left hemiparesis associated with phenytoin intoxication due to
interaction with clobazam. Magnetic resonance angiography of the head revealed stenosis of the M2 segment of the right middle cerebral
artery, whereas an erythrocyte sedimentation rate and cerebrospinal fluid analysis were normal, being consistent with a diagnosis of benign
angiopathy of the central nervous system. The patient exhibited an elevated plasma level of thrombin-antithrombin III complex along with a
marginally increased plasma concentration of soluble E-selectin. The present case suggests that phenytoin intoxication can cause cerebral
vasospasm, which may be associated with some inflammatory endothelial injury accompanied by activated intravascular coagulation.
q 2006 Elsevier B.V. All rights reserved.

Keywords: Benign angiopathy of the central nervous system; Reversible segmental arterial vasoconstriction; Phenytoin intoxication

1. Introduction resonance angiography (MRA) revealed focal vasospasm of

Benign angiopathy of the central nervous system
(BACNS) is a rare cerebrovascular disorder with clinical
and angiographic features similar to those of cerebral
angiitis [1–3]. The presenting symptoms are a severe
headache with vomiting, seizures, and a focal neurological
deficit, which occur following diverse associated conditions
such as migraine, closed head injury, pregnancy, neuro-
surgical procedures, and intake of vasoactive drugs [1–3].
Because there have been rare laboratory and pathological
evidence of significant inflammatory process, the mechan-
ism of BACNS is considered to be reversible cerebral
arterial vasoconstriction [1–3]. In this report, we describe a
patient with sudden onset of hemiparesis in association with
phenytoin (PHT) intoxication, in whom cranial magnetic
* Corresponding author. Address: Division of Pediatric Nurology,
Children’s Hospital of Michigan, Wayne State University, 3901 Beaubien
Street, Detroit, Michigan 48201, USA. Tel.: C1 313 745 5547; fax: C313
745 0955.
E-mail address: hwakamot@dmc.org (H. Wakamoto).
0387-7604/$ - see front matter q 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2005.10.003
the branches of a middle cerebral artery. Although transient
hemiparesis has previously been reported in PHT toxicity,
the pathophysiological mechanism has remained unknown
[4–6]. This is the first report demonstrating reversible
cerebral segmental vasoconstriction as a possible compli-
cation of PHT intoxication.
2. Case report
A 25-year-old man was referred to our hospital because
of gait disturbance. The patient had been treated for epilepsy
at another hospital since age 5 years. He was born
uneventfully after a full-term, uncomplicated pregnancy.
The family history was noncontributory. The developmental
milestones had been normal until about 5 years of age, when
he became hyperactive and attention-deficient. His complex
partial seizures with secondary generalization and atypical
absence seizures had been resistant to various antiepileptic
drugs, except for PHT and ethosuximide (ESM). Initial EEG
(electroencephalogram) was reported to show frequent
diffuse polyspikes or generalized irregular 3 Hz spike and
wave bursts. Magnetic resonance imaging (MRI) of the head
at age 15 years revealed no abnormalities. Four months
 H. Wakamoto et al. / Brain & Development 28 (2006) 336–338
before admission, in an attempt to control the seizures, the
dosage of PHT was increased from 400 to 450 mg per day,
which caused truncal ataxia. The serum concentration of
PHT and ESM were 41.0 and 38.2 mg/ml (therapeutic range:
PHT, 10–20 mg/ml; ESM, 40–80 mg/ml). The dosage
of PHT was decreased to 400 mg per day, resulting in a
rapid improvement of ataxia. Thereafter, 5 mg per day of
clobazam (CLB) was added. However, 3 days later, the
patient became unable to walk, and then he was referred to
our hospital. He denied having used any sympathomimetic
or serotonergic medication. Neurologic examination
showed the presence of horizontal nystagmus, intention
tremor, and increased deep tendon reflexes. The serum
concentrations of PHT and ESM were 51.4 and 34.0 mg/ml,
but the serum level of CLB was not measured. Routine
blood examination and urinalysis were normal. Interictal
EEG showed occasional generalized irregular slow spike
and waves. Cranial MRI revealed mild atrophy of the
cerebellum and cerebrum. After admission, CLB was
discontinued and the dosage of PHT was gradually
decreased to 300 mg per day. On the 2nd hospital day, left
hemiparesis suddenly developed without any preceding
seizures. The patient was alert and oriented. Neurologic
examination showed muscle weakness and decreased
sensation to touch in the left extremities with mild left
facial palsy. Deep tendon reflexes were symmetric and
brisk, and plantar reflexes were flexor. Computed tomogra-
phy of the head revealed no abnormalities. A lumbar
puncture revealed a protein level of 46 m/dl (normal, 10–
45 mg/dl) with a normal cell count, and no detectable
myelin basic protein or oligoclonal IgG band. On the 12th
hospital day, myoclonic seizures were noted only in the
right-sided body. Fluid-attenuated inversion recovery MRI
of the head performed on the 17th hospital day showed the
same findings as those seen on admission, while MRA
revealed stenosis of the M2 segment of the right middle
cerebral artery (Fig. 1A). The results of laboratory
examinations were as follows: serum C-reactive protein
Fig. 1. (A) Cranial MRA performed during the left hemiparesis showed narrowing of the M2 segment of the right middle cerebral artery (arrows). (B) Repeat
MRA performed after disappearance of the hemiparesis with the administration of methylprednisolone showed improvement, although mild stenotic changes
were still noted.
337
level, 2.1 mg/dl (normal, !0.5 mg/dl); erythrocyte sedi-
mentation rate, 11 mm/h (normal, !18 mm/h); serum
complement 3 level, 127 mg/dl (normal, 80–140 mg/dl);
serum complement 4 level, 38 mg/dl (normal, 11–38 mg/
dl); plasma soluble E-selectin (sE-selectin) level,
61.0 ng/ml, (normal, !50.0 ng/ml); and plasma thrombin-
antithrombinIII complex (TAT) level, 33.0 mg/l (normal,
!4.1 mg/l). Tests for antiphospholipid antibodies, anti-
nuclear antibodies, and antineutrophilic cytoplasmic anti-
bodies were negative. Treatment with high-dose
methylprednisolone (MPS) was initiated as follows; 1 g
per day for 3 days, 0.5 g per day for 2 days, 0.25 g per day
for 2 days, and 0.1 g per day for the remaining 2 days.
During the treatment period, hemiparesis began to resolve,
and the patient became able to walk 2 weeks after the start of
the MPS therapy. He refused medication with oral
predonisolone following the MPS therapy. Repeat MRA
showed improvement of the previously recognized findings,
although mild stenosis was still apparent (Fig. 1B). The
plasma levels of sE-selectin and TAT returned to be normal.
At the time of discharge, his medication comprised PHT
300 mg per day and ESM 600 mg per day, and the serum
concentrations of PHT and ESM were 25.1 and 41.6 mg/ml,
respectively. At follow-up visit, the patient had remained
well, except for epileptic seizures occurring once per week,
for the last 2 years.
3. Discussion
The MR angiographic features of this patient could be
interpreted as either findings of cerebral vasculitis or ones of
cerebral vasospasm. First, the normal results of an
erythrocyte sedimentation rate and cerebrospinal fluid
analysis made a diagnosis of vasculitis most unlikely
[1–3]. Secondly, the clinical improvement with a short-
term corticosteroids treatment was inconsistent with a
diagnosis of cerebral vasculitis, which usually requires
338 H. Wakamoto et al. / Brain & Development 28 (2006) 336–338
more aggressive, long-term immunosupressive therapy
[1–3]. Therefore, the present case illustrates the develop-
ment of reversible cerebral segmental vasoconstriction in
the setting of PHT intoxication in combination with CBL
and ESM. Although there have previously been a few
reports of transient hemiparesis associated with PHT
intoxication [4–6], this is the first report of MRA-
demonstrated BACNS in a patient with PHT toxicity.
Reversible cerebral vasocontriction has been reported to
occur with or after exposure to various vasoactive drugs:
cocaine, serotonergic drugs, catecholaminergic agents,
ergot derivatives, and a combination of sumatriptan and
midrin [3]. While most of the drug-induced BACNS usually
involves multiple small or middle-sized cerebral arteries,
MRA of our patient showed vascular changes limited to
the branches of the right middle cerebral artery. Although
the precise reason for this focal involvement is unknown,
one possible speculation is that the vasoactive effect of PHT
might be much less potent than that of the other
medications. Despite this, our case still fulfills the
diagnostic criteria, which include involvement of at least
one major branch of anterior and posterior carotid arteries or
subbranches with areas of stenosis and dilatation (i.e.,
vascular beading or alternating areas of stenosis and ectasia
in multiple cerebral vessels) [2,9]. Besides, unlike the usual
cases of drug-induced BACNS [3], our patient exhibited a
significantly elevated plasma level of TAT along with a
marginally increased plasma concentration of sE-selectin,
which is known as a marker of inflammatory endothelial
activation [8]. These findings suggest the presence of
moderately activated intravascular coagulation as well as
mild inflammatory endothelial injury following cerebral
vasospasm. There is evidence that, in experimental studies,
PHT can cause severe endothelial injury accompanied by
thrombosis in the cerebral vasculature of the rats [10]. Thus
the residual mild stenotic changes seen in the repeat MRA
might represent the process of such subtle vascular
inflammation associated with cerebral vasoconstriction
(Fig. 1B). These underlying vascular injuries probably
accounted for the slow recovery of the hemiparesis in our
patient, although it remains difficult to explain the
discrepancy between the delayed clinical recovery and
normal serial MRI findings.
Finally, a precipitating role of the concomitantly
prescribed CLB and ESM in the onset of BACNS cannot
be ruled out, but there is no available evidence from the
literature or our own case to support this possibility.
Nevertheless, it should be mentioned that the addition of
CLB was obviously a contributing factor to the PTH toxicity
because this drug increases the serum PHT levels by direct
interference with hepatic degradation of PHT [7].
In summary, taken together with the previously
published reports of PHT intoxication-related hemiparesis
[4–6], the present case suggests that BACNS can be a rare
neurological complication of PHT intoxication. The PHT-
induced cerebral vasospasm may be associated with some
inflammatory endothelial injury accompanied by activated
intravascular coagulation. Further studies are needed to
confirm our conclusion based on this single case of PHT
intoxication.
References
[1] Calabrese LH, Gragg LA, Furlan AJ. Benign angioapthy: a distinct
subset of angiographically defined primary angiitis of the central
nervous system. J Rheumatol 1993;20:2046–50.
[2] Calabrese LH. Vasculitis of the central nervous system. Rheum Dis
Clin North Am 1995;21:1059–76.
[3] Singhal AB. Cerebral vasoconstriction syndromes. Top Stroke
Rehabil 2004;11:1–6.
[4] Morris JV, Fischer E, Bergin JV. Rare complication of phenytoin
sodium treatment. Br Med J 1956;44:1529.
[5] Findler G, Lavy S. Transient hemiparesis: a rare manifestation of
diphenylhydantoin toxicity. Report of two cases. J Neurosurg 1979;
50:685–7.
[6] Sandyk R. Transient hemiparesis—a rare complication of phenytoin
toxicity. Postgrad Med J 1983;59:601–2.
[7] Zifkin B, Sherwin A, Andermann F. Phenyotoin toxicity due to
interaction with clobazam. Neurology 1991;41:313–4.
[8] Fassbender K, Bertsch T, Mielke O, Muhlhauser F, Hennerici M.
Adhesion molecules in cerebrovascular diseases. Evidence for an
inflammatory endothelial activation in cerebral large-and small-vessel
disease. Stroke 1999;30:1647–50.
[9] Duna GF, Calabrese LH. Limitations of invasive modalities in the
diagnosis of primary angiitis of the central nervous system.
J Rheumatol 1995;22:662–7.
[10] Tani S, Shimizu T, Kasuya H, Iwasaki H, Takashima K. Induction of
cerebral thrombosis with phenytoin in rats. Stroke 1995;26:2081–6.