Childs Nerv Syst (2006) 22:1487–1491
DOI 10.1007/s00381-006-0155-y

CASE REPORT

Spontaneous posterior fossa hemorrhage associated
with low-molecular weight heparin in an adolescent
recently diagnosed with posterior reversible
encephalopathy syndrome: case report
and review of the literature
Theofilos G. Machinis & Kostas N. Fountas &
Vassilios G. Dimopoulos & E. Christopher Troup
Received: 5 August 2005 / Published online: 8 September 2006
# Springer-Verlag 2006

Abstract
Background Posterior reversible encephalopathy syndrome
(PRES) constitutes a well-described clinical entity, classically entailing characteristic edematous lesions on imaging
studies in a patient with altered mental status, visual
disturbances, headache, and seizures. PRES is reversible
in the vast majority of cases, although progression to
ischemia and hemorrhage has been documented.
Methods We report a case of a 16-year-old male with
chronic renal failure who developed PRES during a
hypertensive crisis. The hypertension was successfully
managed and PRES-associated symptomatology showed
complete regression. However, approximately 2 months
later, the patient returned with a spontaneous posterior fossa
hemorrhage. Two weeks before this second admission,
treatment with low-molecular weight heparin had been
initiated. The patient finally succumbed, despite surgical
evacuation. The pertinent literature is reviewed.
Conclusion We suggest that the administration of lowmolecular weight heparin in the setting of recent PRES
might increase the risk for the development of intracranial
hemorrhage.
Keywords Hemorrhage . Heparin . Low-molecular weight .
Magnetic resonance imaging . Posterior fossa . PRES .
Reversible encephalopathy

T. G. Machinis : K. N. Fountas (*) : V. G. Dimopoulos :
E. C. Troup
Department of Neurosurgery, Medical Center of Central Georgia,
Mercer University School of Medicine,
Macon, GA, USA
e-mail: knfountasmd@excite.com

Introduction
Posterior reversible encephalopathy syndrome (PRES) is a
well-recognized clinical entity characterized mainly by
headache, blurred vision, altered mental status, and seizures, along with typical imaging features, primarily in the
territories of the brain supplied by the posterior circulation
[1]. An associated factor, most commonly hypertension, is
identified in the vast majority of cases.
Prompt treatment usually reverses the clinical symptoms
and the radiological findings and the patients have an
overall good prognosis. However, PRES may be complicated during its course by ischemia, infarcts, and less
commonly, hemorrhage in the posterior fossa [2–4].
In our current communication, we present a case of a 16year-old male with chronic renal failure, who developed a
left cerebellar hemorrhage more than 2 months after the
successful management of a hypertensive crisis complicated
with PRES. The patient was started on low-molecular
weight heparin 2 weeks before the incident. The possible
association between anticoagulation in the setting of recent
PRES and intracerebral hemorrhage is discussed and the
pertinent literature is reviewed.

Case report
A 16-year-old African American male with a history of
chronic renal failure, due to focal glomerular sclerosis,
presented with increasing headache, blurred vision, and
difficulty of breathing. The patient was receiving dialysis
three times a week and had undergone bilateral nephrectomy 2 months earlier. He was diagnosed with hypertension
6 months before this episode and was receiving antihyper-

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tensive treatment. Upon admission, his blood pressure was
220/160 mmHg. Neurological examination revealed no
focal deficits. The patient became progressively incoherent
and combative. No seizure activity was documented. Chest
X-ray showed signs of pulmonary edema. Antihypertensive
treatment was initialized and dialysis was planned for the
following day. The patient showed progressive clinical
improvement and his blood pressure was normalized. A
magnetic resonance imaging (MRI) showed subtle zones of
increased signal intensity in the cerebellar hemispheres and
over the occipital lobes bilaterally on T2-weighted images
(Figs. 1 and 2) and on fluid-attenuated inversion recovery
(FLAIR) images (Figs. 3 and 4), consistent with PRES. The
patient was discharged 2 days after admission free of
symptoms and with a blood pressure of 140/80 mmHg.
Two months later, the patient returned to the ER; his
mother gave an account of severe headache and vomiting that
had started a few hours ago. He was started on low-molecular
weight heparin 2 weeks ago due to clotting of the tip of his
dialysis catheter in the right atrium. On admission, the patient
was unresponsive and intubation was required. His pupils
were dilated and nonreactive, and his blood pressure was
130/76 mmHg. According to the patient’s mother, his blood
pressure had been well controlled since the previous
hypertensive crisis. Prothrombin time, partial thromboplastin time, and platelet count were within normal limits and no
electrolyte disturbances were noted. Computerized tomography (CT) of the brain revealed a left cerebellar hemorrhage
measuring 3.4×4.8 cm with mass effect (Figs. 5 and 6).
Administration of Vitamin K and protamine was initiated.
The patient was immediately taken to the operating room
and posterior fossa craniectomy for evacuation of the
hematoma was undertaken. A right occipital external
ventricular drain was left at the conclusion of the case.
There were no complications during the procedure. The

Fig. 1 Axial T2-weighted MR images showing areas of increased
signal intensity bilaterally in the cerebellar hemispheres

Childs Nerv Syst (2006) 22:1487–1491

Fig. 2 Axial T2-weighted MR images showing areas of increased
signal intensity bilaterally in the cerebellar hemispheres

patient’s condition did not improve postoperatively, and he
succumbed to the disease 3 days after admission.

Discussion
Hypertensive encephalopathy as a distinct clinical entity was
described as early as 1928 by Oppenheimer and Fishburg
[5]. In recent years, a variety of diseases and therapeutic
agents have been found to produce a similar clinical
syndrome and imaging findings, leading to the introduction
of a large number of terms used to describe the same
syndrome. In 1996, Hinchey et al. [1] suggested the term
reversible posterior leukoencephalopathy syndrome to
describe a disorder in a group of patients with neurological

Fig. 3 Axial FLAIR MR images demonstrating patchy zones of
increased signal intensity in the cerebellar hemispheres

Childs Nerv Syst (2006) 22:1487–1491

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Fig. 4 Axial FLAIR MR images demonstrating patchy zones of
increased signal intensity in the cerebellar hemispheres

Fig. 6 Axial CT images without contrast demonstrating left cerebellar
hemisphere hemorrhage with significant mass effect, obliteration of
the fourth ventricle, and midline structure shift

findings and CT and MRI abnormalities in the posterior
regions of the brain; those patients had associated hypertension or renal insufficiency or were immunocompromised. They called it “leuko”-encephalopathy, based on
their belief that only the white matter was involved, and
“reversible” due to the reversibility of symptoms after the
treatment of the underlying disorder or the withdrawal of
the triggering agent. A few months later, Pavlakis et al. [6]
suggested that the term occipital–parietal encephalopathy is
more appropriate because the gray matter can also be
affected. The nomenclature has further been complicated by
terms such as reversible posterior cerebral edema syndrome
[7] and vascular autoregulatory dysfunction [8]. In 2002,
Schwartz [9] suggested the introduction of “hyperperfusion
encephalopathy” as a general term for describing hyperten-

sive encephalopathy and all other related encephalopathies
sharing the same pathophysiologic mechanism regardless of
the causative agent, in an effort to simplify the existing
nomenclature. The term posterior reversible encephalopathy
syndrome has become widely accepted in the last few
years, and this is the term used by the authors in their text.
The clinical spectrum of PRES comprises mainly the
classical tetrad of altered mental status, headache, seizures,
and visual disturbances; Pavlakis et al. [10] reported that
three of these four symptoms are present in 76% of patients.
Altered mental status may range from somnolence to stupor
and coma. Visual disturbances usually occur in the form of
blurred vision and papilledema, but visual hallucinations,
hemianopia, and cortical blindness may develop [11].
Antunes et al. [12] have described a patient who presented
with occulogyric crisis as the sole clinical manifestation of
the syndrome. Seizures are usually multiple and often
become generalized [1]. Bakshi et al. [13] reported on two
cases, where occipital lobe seizures were the major
manifestations of PRES. Other associated symptoms include vomiting, nausea, weakness, and incoordination of
the limbs [14], whereas focal neurological signs may
occasionally appear [11].
PRES is most commonly encountered in the setting of
hypertension [1, 9, 10], but a variety of associated
conditions and triggering factors have been recently
identified. Renal insufficiency, eclampsia, immunosuppression with cyclosporine or tacrolimus, and various cytotoxic
agents, such as cisplatin, cyclophosphamide, and granulocyte colony stimulating factor are not infrequently encountered [15, 16]. Porphyria [17], systemic lupus erythematosus
[3], hemolytic uremic syndrome [18], and thrombotic
thrombocytopenic purpura [19] have also been implicated.
Kastrup et al. [15] reported two cases in which the only

Fig. 5 Axial CT images without contrast demonstrating left cerebellar
hemisphere hemorrhage with significant mass effect, obliteration of
the fourth ventricle, and midline structure shift

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identifiable abnormality was elevated serum calcium
levels.
The pathophysiology behind the reversible changes seen
in PRES is not thoroughly understood. Earlier findings of
cerebral vasospasm in patients with eclampsia led to the
hypothesis that cerebral vasoconstriction in response to
systemic hypertension was the mechanism of PRES [20].
There is not much support for this theory today. Contrariwise, the changes observed in PRES are attributed mostly
to vasodilation. Autoregulatory mechanisms in the brain
result in constriction of cerebral arterioles in the setting of
systemic hypertension. There is a threshold though, after
which this mechanism is lost and the arterioles are forced to
dilate, leading to extravasation of fluid and formation of
edema [3, 4, 20, 21]. Results obtained by MR perfusion
imaging performed on a patient in a study reported by Jones
et al. [20] provide further evidence in support of vasodilation. Cytotoxic and immunosuppressive agents might
disrupt the blood brain barrier, thus facilitating the
development of edema [10]. When hypertension is adequately managed and possible causative agents removed,
fluid reenters the vessels and edema disappears. The
predilection for the territories supplied by the posterior
circulation is further explained by the sparse distribution of
adrenoreceptors in the posterior circulation, resulting in a
decreased contractility, thus easier hyperperfusion and
development of vasogenic edema [3, 4].
The diagnosis of PRES requires positive imaging
findings, primarily attributed to brain edema, mainly, but
not exclusively, in the white matter [4, 22]. Casey et al. [23]
demonstrated in a study utilizing FLAIR MRI that 94% of
patients with PRES had cortical involvement. CT reveals
hypodense areas in the posterior regions of the cerebral
hemispheres. The diagnostic modality of choice in cases of
PRES is MRI. The lesions demonstrate high signal intensity
on T2-weighted and FLAIR images [3]. They are usually
symmetrical, most often in the parieto–occipital region. It is
interesting to note that Covarrubias et al. [2] documented
frontal lobe affection in 82% of patients. The brain stem
may also be involved, though isolated brain stem affection
is rare [17]. The lesions appear isointense on diffusionweighted images (DWI) and show increased signal intensity
on apparent diffusion coefficient (ADC) maps. These
findings are of paramount importance because they aid in
the differentiation from infarction, which shows high signal
intensity on DWI and low on ADC maps [3, 24]. “Top of
the basilar” embolism may also mimic PRES; sparing of the
calcarine and paramedian occipital lobe, typical of PRES,
contributes to establishing the correct diagnosis in these
cases. Thrombosis of the superior sagittal or the transverse
sinus may also pose diagnostic difficulties; magnetic
resonance angiography (MRA) is then the modality of
choice [4]. Vasogenic edema produced due to neoplastic

Childs Nerv Syst (2006) 22:1487–1491

and inflammatory abnormalities may be differentiated from
edema in PRES mainly due to its asymmetric and unilateral
extension, its typical gadolinium enhancing, as well as its
irreversibility with treatment [9].
Management of PRES consists of removal of the
suspected causative agent, such as immunosuppressive
and cytotoxic medication, and treatment of the underlying
disorder, usually hypertension. Reversal of neurologic
symptoms is then expected to occur within a few days to
weeks. Rarely, progression to ischemia, infarction, or
hemorrhage may occur [2–4]. However, Covarrubias et
al. [2] reported that as high as 27% of their patients had
evidence of ischemia on DWI. In the same study, a
correlation between the extent of lesions on T2-weighted
images or DWI and prognosis was noted. Furthermore, it
has been suggested that chronic hypertension leads to
elevation of the upper limit of cerebral autoregulation;
aggressive antihypertensive treatment may, in these cases,
result in persistence of cerebral vasoconstriction, which,
in combination with the decreased systemic blood
pressure is responsible for paradoxical ischemia in the
brain [4].
In our patient, posterior fossa hemorrhage occurred more
than 2 months after reversal of the neurological symptoms.
Furthermore, the patient’s blood pressure had been within
normal limits and dialysis was being regularly performed
during that period of time. Jones et al. [20] supported in
their article that children have a lower range of cerebral
blood flow autoregulation than adults. Lower blood
pressure, in the range of 180/130 mmHg, could thus
precipitate hypertensive encephalopathy in younger
patients. Our patient presented the second time with a
blood pressure of 130/76 mmHg, which by no means can
be considered beyond the range of autoregulation. Conclusively, at the time of hemorrhage, our patient had neither
the clinical findings of PRES, nor a blood pressure that
could trigger another episode of PRES.
One could postulate that our patient’s hemorrhage was a
result of hemodialysis, which is a well-known risk factor
for hemorrhagic complications, especially subdural hematomas [25, 26]. Although this is a valid suggestion, we do
not feel comfortable with attributing a spontaneous posterior fossa hemorrhage in a young patient solely to renal
failure and hemodialysis, without taking into consideration
the recent PRES findings in the very same anatomical
region.
Our patient was started on low-molecular weight heparin
2 weeks before the fatal hemorrhage. Intracranial hemorrhage associated with administration of low-molecular
weight heparin has been reported in children [27]. However, clotting studies in our patient were within normal limits
at the time of the second admission to the hospital. This, in
association with the fact that the hemorrhage occurred at

Childs Nerv Syst (2006) 22:1487–1491

exactly the same region of the brain where the edematous
changes of PRES had been noted some 2 months earlier,
raises the suspicion that low-molecular weight heparin in
the setting of recent PRES might have precipitated the
hemorrhagic event, even with normal clotting studies. MRI
of the brain before the bleeding would have demonstrated
any possible findings in the posterior fossa. Unfortunately,
such an MRI was not obtained.
In conclusion, we have presented a case of fatal
intracranial hemorrhage in a patient receiving low-molecular weight heparin, almost 2 months after an episode of
PRES. Although the exact mechanism of hemorrhage
cannot be fully elucidated, we suggest that the administration of low-molecular weight heparin may increase the risk
of intracranial hemorrhage in patients recently diagnosed
with PRES.

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