Subarachnoid haemorrhage due to cervical spinal cord
haemangioblastomas in a patient with von Hippel-Lindau disease
A. Berlis1 , M. Schumacher1, J. Spreer1, H. P. H. Neumann2 , and V. van Velthoven3
1

Section of Neuroradiology, University of Freiburg, Freiburg, Germany
Department of Nephrology and Hypertension, University of Freiburg, Freiburg, Germany
3
Department of Neurosurgery, University of Freiburg, Freiburg, Germany
2

Summary

Case report

A case is presented with severe infra- and supratentorial subarachnoid haemorrhage (SAH) caused by intramedullary haemangioblastomas of the cervical spinal cord. The patient initially had a
typical SAH symptomatology without neurological deficit. The cerebral angiogram was nondiagnostic. After admission the patient developed slightly progressive right sensorimotor paresis. Angiography of
the cervical spine and MRI delineated three intramedullary haemangioblastomas. Retrospectively the diagnosis of von Hippel-Lindau
(VHL) disease was made by multiple haemangioblastomas and a
positive family history. The three lesions were surgically completely
removed.

This previously healthy 47 year old women suddenly collapsed during
shopping in March 2001. After a few minutes she recovered spontaneously and complained of severe headache, nuchal pain, nausea, and
pronounced neck rigidity (Hunt þ Hess Grading I, GCS 14). Initially no
other abnormalities were found on neurological examination. After
admission the patient developed a slightly progressive right hemihypesthesia and a paresis of the right arm.

Introduction
The incidence of SAH is about six cases per 100 000
people annually [14]. The reason for SAH is predominantly a ruptured aneurysm in about 85% of cases. Nonaneurysmal perimesencephalic haemorrhage is found in
10% and other rare conditions in 5% [14]. SAH of spinal
origin is rare and accounts for less than 1% of cases [3].
Common sources are arteriovenous malformations and
tumours predominantly neurinomas and ependymomas.
In the literature only nine cases of spinal haemangioblastomas with SAH have been reported [3, 4, 6, 8–
11]. We present a case of three haemangioblastomas of
the cervical spine causing intracranial SAH associated
with a positive family history for von Hippel-Lindau
disease (VHL).

Examination
Cranial CT showed severe infra- and supratentorial as
well as cervical SAH at level C0=1 SAH Fisher-Grading
3 (Fig. 1). Initial cerebral angiography showed no pathological findings. Three days later an additional cervical
spinal angiography revealed three tumours: one with a
diameter of about 10 mm at level C1=2 and the others at
level C3=4 to C5 and C5 to C6 with a total length of
about 45 mm (Fig. 2). MRI of the whole spine and head
confirmed the three intramedullary tumours, one of them
reaching the cord’s surface at level C5. There was an
extraordinarily severe swelling of the medulla oblongata, the cervical and upper thoracic spinal cord
(Fig. 3). Other haemangioblastomas could be detected
at level D3 and in the left cerebellar hemisphere, both
with a diameter of about 3 mm.
Family history and genetic analysis
A few years ago the son of the patient was found to
have multiple haemangioblastomas and a cerebellar

1010

Fig. 1. Initial plain CT with infra- and supratentorial SAH

Fig. 2. Angiogram of right vertebral artery with intense tumour stain at C3–C6 (A, B) and lateral view of left vertebral artery with tumour stain at
C1=2 (C, D). Typical tumour vascularization via segmental arteries C4–6 on the right side and C2, C4–5 on the left side to pial branches of the
spinal arteries

haemangioblastoma was operated on. In the genetic
analysis no VHL-tumour suppressor gene was detected.
Other family members including the patient presented
refused further examinations such as MRI and genetic
screening. Following the actual detection of the multiple haemangioblastomas the genetic analysis was neg-

ative in the whole family. Consecutive MRI of the
family showed multiple haemangioblastomas in a
daughter of the patient.
In order to detect germline mutations of the VHL
gene, molecular genetic analysis of constitutional DNA
was performed. The DNA was extracted from peripheral

1011

Fig. 3. Initial MRI with high signal of medulla oblongata, cervical and upper thoracic spinal cord caused by severe cord swelling (T2-weighted
images – A). Delineation of intramedullary haemangioblastomas after contrast (T1-weighted images – B)

blood leucocytes by standard protocols. In order to
detect point mutations and small deletions and insertions, we performed PCR followed SSCP as recently
published [7]. To detect large germline deletions and
insertions, we used southern analysis. This method has
also been previously described [7].
Operation
The cervical lesions were approached by laminotomy
C2 to C6 and total removal was achieved. Because of

severe swelling of the cord the laminotomy block was
not replaced instantly but frozen for subsequent reimplantation. Typical haemangioblastomas were found
intraoperatively and confirmed histopathologically.
Postoperative course
Early postoperative MRI revealed a small subdural
bleeding and swelling of the cervical spinal cord without
pathological contrast enhancement. Neurological examination showed severe sensory ataxia, hyperhidrosis,

Fig. 4. MRI three months after complete tumour resection with complete restitution of cord swelling, but with postoperative spinal cord defect at
level C3–C5 (T2-weighted images – A). T1-weighted images (B) revealed no pathological contrast enhancement in the cervical spinal cord but cord
adhesions at level C5 and C6

1012

disturbance of the epicritic sensory system as well as
impaired skilled movements of both hands and a slight
paresis of the right arm. Three months later the neurological impairment of the patient had improved with a
residual slight impairment of skilled movement of the
right hand, a slight ataxia and minor paresis of the right
arm. MRI revealed complete restitution of cord swelling,
a residual cyst at level C3 to C5 and the complete resection of the cervical spinal cord tumours (Fig. 4). In a
second operation three months later frozen laminae C2–
C6 were re-implanted and the cord adhesions at level C5
and C6 were detached. The further postoperative course
was uneventful with finally recovery of the neurological
deficits ten months after SAH.

Discussion
Haemangioblastomas of the spinal cord are benign
tumours representing 1.6%–6.4% of spinal cord tumours
[5] and are the third most frequent intramedullary spinal
cord tumour besides ependymoma and astrocytoma [1].
About 60% of spinal haemangioblastomas are intramedullary, 11% are combined intramedullary and extramedullary tumours, 21% are intradural extramedullary,
and 8% are extradural [5]. Most frequently, spinal cord
haemangioblastomas occur in the thoracic region (50%),
followed by the cervical region in 40% [10]. Up to now
only nine cases with SAH due to a spinal haemangioblastoma have been published, one patient without
description of tumour site [3, 4, 6, 8–11]. Including
the case presented the lesion sites were the cervical
spine in seven of nine patients, the thoracic and lumbar
spine in one patient each. The tumours were located
intramedullarily in five of nine cases and extramedullary
in four cases.
Approximately 25% of haemangioblastomas are associated with VHL disease (incidence of VHL: 1:36000–
45500) [2]. The diagnostic criteria of VHL are based
on presence of haemangioblastoma in the CNS or retina,
and the presence of one of the typical VHL-associated
tumours like clear cell renal carcinoma, pheochromocytoma, pancreatic and inner ear tumours or a positive family
history. Multiple haemangioblastomas are almost exclusively found in VHL patients [13]. The syndrome is caused
by germline mutations of the VHL tumour suppressor gene
located on chromosome 3p25–26. In VHL disease germline VHL mutations were identified in 86% [7]. In the
present patient the diagnosis of VHL was proved by multiple haemangioblastomas in the spinal cord and cerebellum, and a positive family history in two of three children

with detection of multiple haemangioblastomas. It is of
major interest that a mutation of the VHL-tumour suppressor gene could not be detected in this family. This was the
reason not to insist on a refused MRI-examination of the
whole family even though haemangioblastomas in the son
of the patient were known. An early family examination
with MRI could have proved the VHL-disease and the
multiple asymptomatic tumours of the mother could have
been detected earlier.
Regular MRI screenings can detect changes in tumour
size. In our institution tumour growth in MRI follow up
is considered as an indication for operation. In the case
described here there is a chance that applying this strategy the operation would have been performed before
SAH occurred. The indication for operation is debatable.
In our experience tumour progression justifies the surgical removal also in asymptomatic patients. Even without
tumour progression the knowledge of the existence of
the tumours in this patient would have had resulted in
earlier diagnostic steps after detection of SAH with the
possibility to avoid the aggravation of the neurological
condition.
Complete removal of spinal cord haemangioblastomas is possible in most cases with a low rate of surgical
complications and good prognosis [11, 12]. In our case
the large cervical tumours were excised totally with
finally recovery of neurological deficits.
This case points out that a SAH, particularly if the
posterior fossa is involved, requires angiography of the
supra-aortic cervical vessels when the cerebral angiogram is nondiagnostic. Furthermore in patients with
haemangioblastomas negative for VHL tumour suppressor gene a thorough investigation should be performed.
Current recommendation is to search for constitutional
mutations of the VHL gene. However, in a certain fraction (about 14%) the mutation could not be detected in
our center [7]. A recent report has now detected 100% of
mutations in VHL patients by improved detection methods [13]. The methodological innovation of this report is
a quantitative Southern blot, which will also be established in our center. Finally, all cases with hereditary
haemangioblastomas should undergo a screening program including MRI of the brain, spinal cord, kidney,
pancreas and adrenal glands as well as measurement of
catecholamines in order to detect further tumours in time.
Acknowledgments
The authors thank Ralf Kubalek, M.D., Peter Reinacher, M.D., and
Sven Gl€asker, M.D. for reviewing and thoughtful contributions to the
manuscript.

1013

References
1. Baleriaux DL (1999) Spinal cord tumors. Eur Radiol 9:
1252–1258
2. B€
ohling T, Plate KH, Maltia M, Alitalo K, Neumann HPH (2000)
Von Hippel-Lindau disease and capillary haemangioblastoma.
Pathology and genetics of tumours of the nervous system, 2nd
edn, chapter 14. In: Kleihues P, Cawenee WK (eds) International
agency for research on cancer. World Health Organization, Lyon,
pp 223–226
3. Cerejo A, Vaz R, Feyo PB, Cruz C (1990) Spinal cord hemangioblastoma with subarachnoid hemorrhage. Neurosurgery 28:
991–993
4. Cervoni L, Franco C, Celli P, Fortuna A (1995) Spinal tumors and
subarachnoid hemorrhage: pathogenetic and diagnostic aspects in 5
cases. Neurosurg. Rev. 18: 159–162
5. Chu B-C, Terae S, Hida K, Furukawa M, Abe S, Miyasaka K (2001)
MR findings in spinal hemangioblastoma: Correlation with symptoms and with angiographic and surgical findings. AJNR Am J
Neurorad 22: 206–217
6. Djindjian M, Djindjian R, Houdart R, Hurth M (1978) Subarachnoid hemorrhage due to intraspinal tumors. Surg Neurol 9:
223–229
7. Gl€asker S, Bender BU, Apel TW, van Velthoven V, Mulligan LM,
Zentner J, Neumann HP (2001) Reconsideration of biallelic inactivation of the VHL tumour suppressor gene in hemangioblastomas
of the central nervous system. J Neurol Neurosurg Psychiatry 70:
644–648
8. Irie K, Kuyama H, Nagao S (1998) Spinal cord hemangioblastoma
presenting with subarachnoid hemorrhage. Neurol Med Chir 38:
355–358
9. Kormos RL, Tucker WS, Bilbao JM, Gladstone RM, Bass AG
(1980) Subarachnoid hemorrhage due to a spinal hemangioblastoma: case report. Neurosurgery 6: 657–660
10. Minami M, Hanakita J, Suwa H, Suzui H, Fujita K, Nakamura T
(1998) Cervical hemangiblastoma with a past history of subarchnoid hemorrhage. Surg Neurol 49: 278–281
11. Neumann HPH, Eggert HR, Weigel K, Friedburg H, Wiestler OD,
Schollmeyer P (1989) Hemangioblastomas of the central nervous
system. J Neurosurg 70: 24–30

12. Roonprapunt C, Silvera VM, Setton A, Freed D, Epstein FJ, Jallo G
(2001) Surgical management of isolated hemangioblastomas of the
spinal cord. Neurosurgery 49: 321–327
13. Stolle C, Glenn G, Zbar B, Humphrey JS, Choyke P, Walther M,
Pack S, Hurley K, Andrey C, Klausner R, Linehan WM (1998)
Improved detection of germline mutations in the von Hippel-Lindau
disease tumor suppressor gene. Hum Mutat 12: 417–423
14. van Gijn J, Rinkel GJE (2001) Subarachnoid haemorrhage: diagnosis, causes and management. Brain 124: 249–278

Comment
This manuscript reports a rare case if spinal haemangioblastomas causing Subarachnoid haemorrhage (SAH) with a family history of von Hippel
Lindau disease. Although this is an interesting article that shows the
importance of cervical evaluation in SAH patients with negative conventional angiograms, nine cases of spinal haemangioblastoma with SAH
have already been reported. Thus, this report does not provide remarkable
contributions on diagnosis and treatment of spinal cord haemangioblastomas. Another important point of this article is negative gene analysis in a
patient with typical VHL-disease. Inactivation of the VHL tumor suppressor gene at 3p25–26 is considered to be a common oncogenic mechanism
in VHL-associated tumors, and germline mutations of this gene are
reported to be present in 63 to 100% of VHL-related haemangioblastomas.
Improved detection of germline mutation in the VHL tumor suppressor
gene was previously reported using sophisticated methods [1].

Reference
1. Stolle C, Gleen G, Humphrey JS et al (1998) Improved detection of
germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 12: 417–423
S. Nagao
Kagawa
Correspondence: Dr. Ansgar Berlis, Section of Neuroradiology,
University of Freiburg, Breisacherstr. 64, D-79106 Freiburg. e-mail:
BERLIS@nz.ukl.uni-freiburg.de