CLINICAL REPORT

Sporadic Multiple Cerebral Cavernomatosis
Report of a Case and Review of Literature
Arzu Coban, MD,* Candan Gurses, MD,* Bilge Bilgic, MD,† Serra Sencer, MD,‡ Aykut Karasu, MD,§
Nerses Bebek, MD,* Betul Baykan, MD,* Kemal T. Hepgul, MD,§ and Aysen Gokyigit, MD*

Objective: Cerebral cavernous malformations (CCM) are vascular
malformations causing seizures and cerebral hemorrhages. They
occur in sporadic and familial forms. Familial cases are associated
with a high frequency of multiple lesions, which are less frequently
associated with sporadic cases.
Case Report: We report a 46-year-old woman presenting with epilepsy with multiple cerebral cavernomatosis on MRI. Because she had
had a previous liver transplantation operation, and received immunosuppressants, she was not advised to have a brain operation. However, she
had to be operated as a result of a bleeding in one of her cerebral
cavernomas. The histologic diagnosis was cavernoma. She has been seizure
free after the operation with levetiracetam therapy for the last 17 months.
She had no positive family history for both epilepsy and cavernomatosis.
Conclusion: When multiple cerebral cavernomatosis are identified in
a patient, a detailed neurologic family history should be sought despite
the possibility of its being a sporadic case. Our main intention is to
present a patient who is surgically controversial and to point out the
importance of genetic heredity.
Key Words: cavernoma, sporadic multiple malformation, liver
transplantation, seizure, levetiracetam
(The Neurologist 2008;14: 46 – 49)

The typical appearance of cavernomas is
heterogeneous “popcorn-like” lesions of
different sizes with a mixed signal intensity core
and a peripheral rim of hypointense signal
intensity reflecting a zone of hemosiderin.

From the Departments of *Neurology; †Pathology; ‡Radiology; and §Neurosurgery, Istanbul School of Medicine, University of Istanbul, Millet
Cad, Çapa, TR-34390, Istanbul, Turkey.
Part of this study was presented as a poster presentation in V National
Congress of Epilepsy (June 2006, Bursa, Turkey).
Reprints: Dr. Arzu Coban, Merdivenköy Mah. Nazenin Sok. Kadribey Ap. No. 23/9,
Kadiköy, Istanbul 34732, Turkey. E-mail: arzucoban2002@yahoo.com.
Copyright © 2008 by Lippincott Williams & Wilkins
ISSN: 1074-7931/08/1401-0046
DOI: 10.1097/NRL.0b013e31813e343f

46

T

here are 4 major cerebral vascular malformations: cavernous angioma (cavernoma), parenchymal arteriovenous
malformation, venous angioma, and capillary telangiectasia.1
Cerebral cavernous malformations (CCM) are non-neoplastic
congenital anomalies that present in a variety of clinical patterns,
ranging from asymptomatic to fatal intracranial hemorrhage.2
The prevalence of cavernomas has been estimated as 0.5% to
0.7% in the population.3,4 They are characterized by abnormally
enlarged capillary cavities without intervening normal brain
parenchyma or muscular tissue.5,6 Magnetic resonance imaging
(MRI) is more sensitive than computed tomography (CT) for the
detection of cavernomas.7,8 The typical appearance of cavernomas is heterogeneous “popcorn-like” lesions of different sizes
with a mixed signal intensity core and a peripheral rim of
hypointense signal intensity reflecting a zone of hemosiderin.7,8
A supratentorial location of lesions has been reported to be more
frequent than an infratentorial location.9 –13 In this report, we
present a patient who had a history of liver transplantation with
multiple cerebral cavernomatosis presenting with disturbances
of consciousness and generalized seizures.

CASE REPORT
A 46-year-old woman presenting with vertigo, nausea,
vomiting, and disturbances of consciousness due to a seizure
attack at home was admitted to the Emergency Department of
Neurology. After a seizure attack at home, she had a second
generalized tonic-clonic seizure 3 hours after admission. Her
CT scan showed hyperdense lesions in the right temporal, right
parietal, and left frontal lobes (Fig. 1). These findings indicated
that there was a hemorrhage with minimal mass effect. In the
following week, while she was still in the hospital, she had her
third seizure. After the seizure, her neurologic examination was
unremarkable except for a postictal short period of confusion.
She had a history of hepatitis B virus (HBV) infection 10 years
ago. Liver transplantation was performed 2 years ago. Her
brother had hepatic cirrhosis and her sister was a HBV transporter. She has used Cyclocyphorine 175 mg/d, Lamuvidin 300
mg/d, Acyclovir 2400 mg/d, Acetylsalicylic acid 80 mg/d, and
Omeprazole 40 mg/d. Physical examination revealed mild hepatomegaly and splenomegaly. Routine blood findings included a
low platelet count (93,000/mm3), hemoglobin (9.7 gr/dL), hematocrit (28.6%), and leukocyte count (2800/mm3). The results
of other laboratory tests (BUN, creatinine, AST, ALT, ALP,
lipid profile, electrolytes, PT, PTT, and INR) and electroencephalography (EEG) examination were unremarkable. Her
brain MRI, done a few days later, revealed subacute to chronic
The Neurologist • Volume 14, Number 1, January 2008

The Neurologist • Volume 14, Number 1, January 2008

Multiple Cerebral Cavernomatosis

DISCUSSION
The most frequent symptoms of cavernomas are epileptic seizures, hemorrhage, focal neurologic deficits, and
headaches.7,8,14,15 However, many patients are entirely
asymptomatic.16 –20 Clinical presentation usually occurs between the third and fifth decades, but the first symptoms may
appear at any age.4,8 We report a patient with multiple
cerebral lesions. She had 3 seizures. Cerebral cavernomatosis
and hemorrhagic neoplasms were taken into consideration in
the differential diagnosis. MRI delineated discrete lesions,
typical of cavernous angiomas, with a mixed hyperintense,
reticulated, central core surrounded by a hypointense rim.
Diagnosis is based on typical findings on MRI in combination with angiography presenting a normal vascular anatomy.
This patient with multiple cerebral cavernomatosis was considered for surgery and it was decided that she would not be
operated unless it was urgent because she had had a liver
transplantation and was using immunosuppressants. Levetiracetam was administered because of its pharmacokinetic profile
that includes minimal protein binding, lack of hepatic metabolism, and no interaction with other drugs.21 Her seizures discontinued with levetiracetam. However, she had to be operated upon
the recurrence of bleeding and extension of severe edema in one
of her cavernomas.

FIGURE 1. Diagnostic images of patient. Cranial CT show
hyperdense lesions in the right temporal, right parietal, and
left frontal lobar areas.

hemorrhagic lobar hyperintense-hypointense mixed lesions on
T2 and FLAIR-weighted images and hyperintense lesions on
T1-weighted images in the right temporal (2.3 cm in diameter),
right parietal (1.6 cm in diameter), and left frontal (1.2 cm in
diameter) areas, which were not contrast-enhancing. The right
temporal region is surrounded by edema (Figs. 2– 4). Intracranial
MR angiography was normal. Thus cerebral cavernomatosis
was considered in the differential diagnosis. The patient was
treated with levetiracetam 1000 mg/d and seizures were controlled. She was discharged from hospital because surgeons
were conservative about operating on her finding it risky due to
her previous history of liver transplantation. Moreover, because
the result her neurologic examination was normal and hemorrhagic lesion was limited, surgery was not thought to be crucial.
Nine months after the initial presentation, she presented
with nausea and headache. Her MRI showed recurrence of
hemorrhage, extension of the lesion size, and severe edema in
the right temporal lesion, for which the patient was operated
urgently. Surgical excision via a right temporal craniotomy
for the entire right temporal lesion was undertaken. Histopathological examination revealed thick-walled, hyalinized
vascular channels. Some had occluded lumens. Surrounding
brain parenchyma showed reactive astrogliosis. Hemosiderin
deposition was also evident adjacent to large vessels (Fig. 5).
The histopathological diagnosis was cavernoma. Now she has
been seizure-free for 17 months.
© 2008 Lippincott Williams & Wilkins

In a recent study, the authors reported the favorable
neurologic and seizure outcomes after surgical
resection of patients with supratentorial cerebral
cavernous malformations and epileptic seizures.

The surgical treatment of cerebral cavernomas remains to
be controversial.12 Most surgeons would agree on surgery in
symptomatic patients with a readily accessible and isolated
lesion that has produced repetitive or progressive symptoms.12,22
A conservative approach is best adopted when there is a clinically silent lesion in an eloquent area or there are stable neurologic deficits.12 However, surgery for supratentorial CCM in
noneloquent locations is safe and curative.23 In a recent study,
the authors reported the favorable neurologic and seizure outcomes after surgical resection of patients with supratentorial
CCM and epileptic seizures.24 Eventually, the optimal management of cavernous malformations should be determined on a
case-by-case basis and, when indicated to be favorable, surgery
provides good outcome. Unlike our patient’s initial hemorrhage,
which was limited, the second hemorrhage was extensive and
lethal, thus, she was operated despite its risks.
The reported overt annualized bleeding rate is slightly less
than 1% in patients with cavernoma although repeated, often
occult, hemorrhagic episodes are common.3 Her age being close
to the upper limit for the most frequent bleeding from cavernomas, ie, the fifth decade of life, the annualized bleeding rate

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Coban et al

The Neurologist • Volume 14, Number 1, January 2008

FIGURES 2– 4. Diagnostic images of patient. Cranial T2 (2A, 2B, 2C, 2D) and FLAIR (3A, 3B) and T1 (4A, 4B)-weighted images show
multiple lesions of mixed signal with subacute and chronic hemorrhagic content in the right temporal (2.3 cm in diameter), right parietal
(1.6 cm in diameter), and left frontal (1.2 cm in diameter) regions. The right temporal region is surrounded with edema.

being less than 1%, and her using immunosuppressants led us
refrain from the operation of her other cavernomas.
Cavernomas occur in sporadic and familial forms.14,25
The familial form is characterized by multiple lesions and
autosomal dominant transmission. However, in sporadic form,
patients usually have a single lesion.25 In some patients with no
positive family history, multiple lesions (usually 2 or 3) can be
found sporadically.26 –28 Our patient’s parents were deceased
and she had 5 (3 men, 2 women) siblings and 3 children (1 boy,
2 girls). Her siblings and her son did not agree to an investigation. Therefore only 2 family members (26-year-old and 20year-old daughters) were scanned by MRI and were found to be
normal. Hence, in our case, a family history of multiple cavernomas, epilepsy and focal neurologic deficits were not detected.
It was concluded that our case was most probably sporadic.

Mutations in Krit 1, a gene located at the
cerebral cavernous malformations 1 locus on
chromosome 7q21, account for the majority of
familial cavernoma cases.

48

FIGURE 5. Histopathologic appearance of lesion. Figure
shows reactive gliosis of the surrounding pathologic vessel
with thick-hyalinized walls. (Hematoxylin-eosin stain).
© 2008 Lippincott Williams & Wilkins

The Neurologist • Volume 14, Number 1, January 2008

In the genetic investigations on the CCM gene 3 different gene regions were observed.29 Three CCM loci were
previously mapped on 7q (CCM1), 7p (CCM2), and 3q
(CCM3).29 –31 Mutations in Krit 1, a gene located at the
CCM1 locus on chromosome 7q21, account for the majority
of familial cavernoma cases.32 These mutations are seldom a
cause of sporadic cases.33,34 Recently, Verlaan et al screened
for the CCM1 gene in 35 sporadic cases with either single or
multiple cavernomas.27 They detected that 29% of the cases
with multiple CCM have a CCM1 mutation, whereas cases
with only 1 malformation have none.27 Sporadic cases with
multiple malformations warrant the same approach as
individuals who have a familial history of CCM.27
Genetic confirmation of our patient and family members has not been completed yet. There are no recent results.
However, we believe that early identification of symptomatic
and asymptomatic family members may prevent life-threatening complications. When multiple cerebral cavernomatosis
are identified in a patient, a detailed neurologic family history
should be sought despite the possibility of the patient being a
sporadic case. In conclusion, our main intention is to present
a patient who is surgically controversial and to point out the
importance of genetic heredity.
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