Cerebral Venous Thrombosis in
Patients with Nephrotic Syndrome
Case Reports

Sheng-Feng Sung, MD
Jiann-Shing Jeng, MD
Ping-Keung Yip, MD
and Kou-Mau Huang, MD*
TAIPEI, TAIWAN

ABSTRACT
The authors describe two cases of cerebral venous thrombosis (CVT) in patients with
nephrotic syndrome. The main clinical features of CVT were persistent headache, hemiparesis, and seizure, and the diagnosis was based on magnetic resonance imaging and
magnetic resonance angiography. Both showed acquired deficiency of free protein S. The
neurologic symptoms remained stationary in the first patient, who received no anticoagulation therapy, but resolved rapidly in the second, treated with intravenous heparin and
supplemented with fresh frozen plasma. CVT should be suspected in patients with
nephrotic syndrome who present with symptoms of intracranial hypertension or any focal
neurologic deficit.

From the Departments of Neurology and ~~Radiology, National Taiwan University Hospital, Taipei, Taiwan.
©1999 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A.

427

Introduction
The association between nephrotic syndrome and
thromboembolic complications is well established.l2 The overall incidence of renal vein
thrombosis in patients with nephrotic syndrome is
35% and that of thromboembolism other than
renal vein thrombosis (including deep vein
thrombosis, pulmonary embolism, cerebral infarction, and peripheral arterial thrombosis) is
20%.22 However, cerebral venous thrombosis
(CVT) has been rarely reported in patients with
nephrotic syndrome. Over a period of 12 years
(1984-1995), 38 patients, aged 15 years and
over, with CVT documented by conventional an-

giography or magnetic resonance imaging
(MRI) /angiography (MRA) were seen in our hospital. In two of them, the etiology of CVT was
probably a hypercoagulable state secondary to
nephrotic syndrome.

sistent headache, for 3 days and was transferred to
our hospital 2 weeks after onset. Her medical history showed hypertension and hypoalbuminemia
over the previous 2 months. She did not take oral
contraceptives. The family history was unremarkable. On arrival, vital signs and physical examination produced normal findings except for pitting
edema in the lower legs. Neurologic examination
showed left hemiparesis and decreased sensory
perception on the left side. MRI demonstrated an
area of abnormal signal intensity in the right
frontal region and thrombosis of the superior
sagittal sinus (Figure 1A). MRA confirmed thrombosis of the superior sagittal sinus with establishment of collateral circulation (Figure 1B). Routine
blood biochemistry results were normal, except for

hypercholesterolemia and hypoalbuminemia (24
g/L, normal 37-52). The 24-hour urine protein
content was 3 g. Coagulation studies, including
prothrombin time, partial thromboplastin time,
thrombin time, fibrinogen, antithrombin III, protein C, total protein S, and plasminogen yielded
normal results, except for a slightly lowered free
protein S level (71%, normal 75%-136%).
Antinuclear antibody titers were mildly elevated

Case Reports
Case l. A 45-year-old woman had sustained progressive left-sided weakness, accompanied by per-

Figure 1. A. Parasagittal T1-weighted image shows low signal intensity in the right frontal region
with high signal intensity along the gyri (arrow) indicating petechial hemorrhage.
B. Axial three-dimensional phase contrast magnetic resonance angiography reveals frayed appearance
in the posterior portion of the superior sagittal sinus (arrow) and prominent cortical veins.

428

(320 x ) . Serum complements were normal.
Anticardiolipin antibody were negative for both
immunoglobulin G (IgG) and IgM.
A renal biopsy, taken 1 month after admission, demonstrated chronic tubulointerstitial
nephritis. Prednisolone (100 mg on alternate

days) was initially prescribed, and the proteinuria
gradually decreased. She was maintained on aspirin and low-dose prednisolone and has remained stable for 2 years.
Case 2. A 16-year-old man was admitted to our
hospital because of a 5-day history of headache,
nausea, and vomiting, followed by an episode of
generalized seizure. A diagnosis of nephrotic
syndrome had been made 7 months earlier, and
he had received corticosteroid therapy; otherwise his medical history was not remarkable.
Upon initial evaluation, he was afebrile with
normal vital signs. Physical examination revealed mild peripheral edema. No abnormal
neurologic signs were present.
MRI

demonstrated

thrombosis

in

the

superior sagittal sinus, straight sinus, and bilateral lateral sinuses (Figure 2A). MRA confirmed

absence of flow in the straight sinus and superior sagittal sinus (Figure 2B). The levels for
blood urea nitrogen, creatinine, and total cholesterol were elevated. Serum albumin concentration was decreased to 14 g/L. The 24-hour urine
protein loss was 24 g. Complete blood counts,
electrolytes, other blood chemistry parameters,
antinuclear antibody, and serum complements
yielded normal results. He had normal levels of
fibrinogen, total protein S, and protein C.
Plasminogen activity was 66% (normal 74%134%). Free protein S content was decreased to
66%, functional protein S activity to 51%
(normal 72%-124%), and antithrombin III to
56% (normal 76%-135%). The prothrombin
time and partial thromboplastin time were
normal, but the thrombin time was prolonged.
Lupus anticoagulant was negative. Anticardiolipin antibody levels were increased for IgM and
negative for IgG.
He was initially treated with intravenous heparin and fresh frozen plasma to replace antithrombin III, then was gradually shifted to oral
warfarin. Glycerol was administered to relieve intracranial hypertension. Pulse therapy with

A. Midsagittal Tl-weighted image shows slightly heterogeneous iso- to low-signal intensity
the
along
straight sinus (arrow) and the posterior two thirds of the superior sagittal sinus (arrowhead).
B. Axial three-dimensional phase contrast magnetic resonance angiography shows complete loss of flow
signal from the superior sagittal sinus.

Figure 2.

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methylprednisolone (1,000 mg three times a day
on alternate days) was used to treat his nephrotic syndrome. The response was favorable, with
resolution of the peripheral edema and improvement of the proteinuria. A follow-up MRI and
MRA 2 weeks later showed partial recanalization
of the thrombosed sinuses. He has now been well
during 8 months of outpatient follow-up.

Discussion

Nephrotic syndrome is associated with a hypercoagulable state, resulting in venous or arterial
infarction of various organs.2Several disorders
of hemostasis have been demonstrated in patients with nephrotic syndrome, including
thrombocytosis and platelet hyperaggregability;
increased plasma levels of factors V, VII, VIII, X,
and XIII and fibrinogen; hyperviscosity of blood;
lowered fibrinolytic activity; and decreased plasma concentrations of natural anticoagulants,
such as free protein S and antithrombin III.2-5
The mechanisms responsible for these hemostatic disorders probably involve the urinary loss of
anticoagulants, increased liver synthesis of procoagulants stimulated by hypoalbuminemia, or
consumption of coagulation factors by intravascular thrombin formation.5
Free protein S, but not bound protein S, acts
as a cofactor for activated protein C, a major inhibitor of blood coagulation.6Urinary loss of free
protein S and increased synthesis of C4b binding
protein, which shifts free protein S to bound
form, contribute to low free protein S levels in patients with nephrotic syndrome.7 Reduction of
plasma volume and hemoconcentration due to
nephrotic syndrome may also account for thrombosis. The risk of thrombosis is higher at the onset
of the disease or during relapse.8 Intensity of hypercoagulability is related to the degree of hypoalbuminemia, and these hemostatic abnormalities tend to revert toward normal on clinical remission of the nephrotic syndrome.4
In our first patient, illness began when she
did not receive any treatment for nephrotic syndrome. In the other patient, the thrombotic
events began during a period of poorly controlled
nephrosis, as shown by marked proteinuria, low
albumin concentration, and high cholesterol levels, despite taking corticosteroid. Both had some
kind of clotting disorder. Reduced free protein S

431

or functional

protein S activity was a consistent

feature in both patients. The second patient
showed additional deficiencies in antithrombin III
and plasminogen.
In reviewing the English literature, six additional adult cases of CVT accompanying nephrotic syndrome were found (Table 0.9-12 The common clinical features included headache, seizure,
diplopia, and disturbance of consciousness.
Superior sagittal sinus was involved in most of
them. Only five cases (including our two cases)
had available data on protein S. Among them,
three had deficiency of free protein S. Other
common coagulation abnormalities are decreased antithrombin III and increased fibrinogen. The loss of free protein S may be an important factor in the pathogenesis of CVT in patients
with nephrotic syndrome.

Conclusion
Dural sinus thrombosis is a rare complication of
nephrotic syndrome, often resulting in significant
neurologic deficits and even death. In our series
of 38 cases of CVT, 5.3% were due to nephrotic
syndrome, and it seems that complications such
as CVT may not be uncommon, but, being difficult to diagnose, may have simply gone unnoticed in the past. We suggest that any neurologic deficits, or even headache, in a nephrotic patient should prompt the clinician to search for
possible CVT and to start treatment as soon as

possible. Acquired protein S deficiency is a common finding in patients of nephrotic syndrome
who develop CVT and may play an important
role in the pathogenesis of CVT.
Ping-Keung Yip, MD
Department of Neurology
National Taiwan University Hospital
7, Chung-Shan South Road
Taipei, 100, Taiwan

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