Case report

A case of isolated cortical venous thrombosis
presenting radiographically as a subacute multifocal
leukoencephalopathy, and review of literature
Charles Francis Palmer,1 Farnaz Khalighinejad,2 Adalia Jun-O’Conell,2 Carolina Ionete2
1

Department of Neurology,
Medical University of South
Carolina, Charleston, South
Carolina, USA
2
Department of Neurology,
University of Massachusetts
Medical School, Worcester,
Massachusetts, USA
Correspondence to
Dr Farnaz Khalighinejad;
​Farnaz.​Khalighinejad@​
umassmed.​edu
Accepted 19 September 2019

SUMMARY
A 55-year-old man presented with brief seizure
with associated acute aphasia, right head turn and
subsequent generalised convulsion. On imaging, he
was found to have patchy juxtacortical and cortical
T2 hyperintensity with high radiographic suspicion for
subacute multifocal leukoencephalopathy. Serum and
cerebrospinal fluid testing were unremarkable. Clinically,
the patient recovered completely and had no recurrence
of symptoms. On follow-up MRI 1 month later, the
T2 hyperintensity had resolved almost entirely while
hypointensity on susceptibility-weighted angiography
MRI remained, suggesting isolated cortical venous
thrombosis.

Background

There are no documented cases that describe isolated
cortical venous thrombosis (ICVT) presenting
radiographically similarly to subacute multifocal
leukoencephalopathy. ICVT is a rare condition
representing a minuscule fraction of all strokes that
typically presents as an occlusion of anastomotic
surface vessels. Because of the condition’s rarity and
its propensity to mimic other conditions, in addition to the non-specific symptoms such as headache
or seizure that are typical for first presentation, this
can be a very difficult diagnosis to make.

Case presentation

We describe a case of a 55-year-old homosexual
man on HIV preventative therapy with emtricitabine/tenofovir disoproxil and a history of stable
bipolar 1 disorder who presented to the emergency
department after an episode of transient, 2–4 min
episode of clinical seizure with associated transient
aphasia, followed by right head turn and subsequent generalised convulsion. He had been started
on Truvada 6 months previous to the presentation
for HIV prevention due to anticipation of becoming
sexually active with multiple partners.
© BMJ Publishing Group
Limited 2019. No commercial
re-use. See rights and
permissions. Published by BMJ.
To cite: Palmer CF,
Khalighinejad F,
Jun-O’Conell A, et al. BMJ
Case Rep 2019;12:e230915.
doi:10.1136/bcr-2019230915

Investigations

Initial examination demonstrated normal vital signs
with non-focal neurological examination. Initial
head CT scan was unremarkable, and the head
and neck CT angiogram showed no major vascular
abnormalities. The subsequent brain MRI with and
without contrast showed patchy juxtacortical and
cortical T2 hyperintensity with swelling, as well as

associated curvilinear susceptibility within the overlying cortex and minimal superficial enhancement
(figure 1A–D). This finding suggested a radiological pattern for a multifocal leukoencephalopathy
or encephalitis. Urine toxicology screen, thyroid
function panel, liver enzymes, B12 and complete
blood count were all unremarkable, excluding
other causes for encephalopathy. Lumbar puncture
was normal, with a CSF protein count of 36 mg/dL
and normal cell counts, decreasing the suspicion for
encephalitis. Oligoclonal bands were not present in
the cerebrospinal fluid (CSF). Infectious tests from
CSF were all unremarkable for JC virus antibody,
syphilis, Epstein-Barr virus and varicella zoster.
The patient was negative for HIV, but positive for
antibody to JC virus in the blood, reflecting past
exposure to the virus. Serum was unremarkable
with C-reactive protein, erythrocyte sedimentation
rate, lactic acid, complement 3 c and 4 c, and antinuclear antibody, all in the normal ranges and slight
elevation of c-ANCA titre of 1:40, without clear
significance.

Differential diagnosis

Findings on MRI suggested progressive multifocal
leukoencephalopathy (PML) or encephalitis, with
cortical laminar necrosis and iron susceptibility
signal considered less likely to support these entities. However, the patient was not immunosuppressed, HIV negative and afebrile, assuaging the
concern for the former two options.

Treatment

The patient was started on 150 mg oxcarbazepine
twice daily for seizure prophylaxis. This treatment has been ongoing. Continued antiepileptic
drug therapy will be reevaluated at future visits,
and discontinued if there is no new clinical seizure
activity or changes on electroencephalogram.

Outcome and follow-up

Although CSF results were reassuring, and his
clinical seizures completely resolved, there was
still a concern for possible PML given the atypical radiological pattern. Thus, subsequent close
surveillance was pursued, including close clinical
follow-ups and subsequent follow-up serum tests
for leukaemia/lymphoma evaluation, anti-dsDNA,
anticardiolipin, anti-ribonucleoprotein, anti-Lyme
and human T-lymphotropic virus PCR which all

Palmer CF, et al. BMJ Case Rep 2019;12:e230915. doi:10.1136/bcr-2019-230915

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Unusual association of diseases/symptoms

haemosiderin staining, and was also slightly improved. MRI of
the cervical spine showed no evidence of demyelinating lesions.
Due to the resolution on imaging and his benign clinical
picture, the final diagnosis was ICVT. The patient underwent
workup by haematology for occult causes of hypercoagulability.
The patient had no family history of clotting disorders and no
prior personal history of thromboembolic events. Hypercoagulability workup, including prothrombin gene mutation, factor
V Leiden, protein C, protein S and antithrombin III deficiency,
was negative. Lupus anticoagulant and anticardiolipin antibody were negative as well. While laboratory tests were benign,
the patient admitted to taking over-the-counter testosterone
supplementation for a number of months which the thrombosis
was attributed to. As there was no worsening of the patient’s
neurological condition and no clear high risk of reoccurrence in
the setting of negative workup, the patient was not started on
anticoagulation.

Discussion

Figure 1 The initial lesion as seen on (A) T2 fluid-attenuated
inversion recovery (FLAIR), (B) T1 with contrast, (C) MRI-SWAN and (D)
diffusion-weighted imaging (DWI). Patchy juxtacortical and cortical T2
hyperintensity with swelling and curvilinear susceptibility within the
overlying cortex with minimal superficial enhancement can be seen. This
pattern is common in multifocal leukoencephalopathy or encephalitis.
SWAN, susceptibility-weighted angiography.
were unremarkable. His repeat MRI 1 month after his initial
presentation showed near complete resolution of the T2 FLAIR
hyperintensity in the left frontal cortical-subcortical region, with
possible trace residual T2 hyperintensity in the left precentral
gyrus (figure 2A and B) which was unusual for possible PML.
The hypointensity seen on susceptibility-weighted angiography
(SWAN) imaging in the precentral gyrus probably represented

Figure 2 The lesion as seen on follow-up on (A) T2 FLAIR and (B)
MRI-SWAN. Near-complete resolution of the previous findings are seen
on both images, with some residual hypointensity in the precentral
gyrus on MRI-SWAN. SWAN, susceptibility-weighted angiography.
2

ICVT is a rare and poorly understood condition that has only
been documented in case reports or case series (116 total patients
studied in a comprehensive 2014 review of the literature)1 and
represents less than 0.063% of all cerebral strokes.2 It frequently
involves anastomotic surface vessels such as the vein of Trolard,
the vein of Labbé, the superficial Sylvian vein and the precentral,
postcentral and central veins. It has been known to mimic other
conditions on MRI, such as subarachnoid haemorrhage, transient ischaemic attack3 or even brain tumour.4 ICVT has subtle
findings on CT, occasionally presenting with hyperdense vein
sign within 7-14 days,5 but frequently found to be normal. CT
venogram can be useful to visualise a filling defect.6 On MRI,
a clot will display T1 isointensity and T2 hypointensity, with
T1 hyperintensity from a subacute clot and cerebral oedema
will typically be present.6 Magnetic susceptibility effect can be
a valuable tool for diagnosis; a study showed that in ICVT, a
venous occlusion could be seen as a homogeneous well-delineated hyposignal which was tubular, serpentine or rounded.7
In addition, parenchymal abnormalities were seen close to the
occluded vein, including cortical–subcortical hyperintensities.7
Both haemorrhagic and edematous parenchymal involvement is
frequently seen,1 7 and lesion regresses. Clinically, ICVT often
presents similarly to dural venous sinus thrombosis, with headache or seizure as the most common symptoms on presentation.1
However, it should be on the differential diagnosis whenever a
patient presents with any acute central nervous system symptomatology, as it is frequently missed or misdiagnosed.8 Headache
and papilledema are less common than in dural venous sinus
thrombosis, and elevated opening pressure on lumbar puncture
is less likely, while haemorrhagic or edematous lesions are more
likely.1 Mortality reportedly range from 2.8% to 6%, but most or
all deaths are seen in patients with other intracranial pathology,
such as meningitis or encephalitis. In patients presenting with
ICVT as a solitary diagnosis, the mortality rate is 0%; with good
outcome.1 While most patients who are diagnosed with ICVT
receive anticoagulation and it is considered the standard of care,
outcomes may not be different between patients who receive
anticoagulation and those who do not.2
In juxtaposition to associated good outcome with ICVT, PML
is another rare condition (incidence of 1–4 per 1000 personyears) that is a demyelinating disease of the white matter caused
by reactivation of latent JC virus in immunocompromised individuals.9 Contrary to ICVT, PML is known to be rapidly progressive, with consistent worsening of symptoms and no remission
Palmer CF, et al. BMJ Case Rep 2019;12:e230915. doi:10.1136/bcr-2019-230915

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Unusual association of diseases/symptoms

on subsequent imaging, and a devastating expected outcome.9 In
PML, typical lesions consist of T1 hypo/T2 hyperintensity in a
multifocal, asymmetric pattern involving subcortical structures.
Subcortical U-fibres and peripheral white matter are known to
be commonly involved, and the disease is frequently seen in the
parieto-occipital region.10 There is typically little mass effect and
no contrast enhancement.10
In our patient’s images, the rounded appearance of the thrombosis mimicked the subcortical U-fibre involvement seen in
PML which was further supported by the presence of patchy
subcortical T2 hyperintensity. The small amount of swelling and
oedema could be typical of either PML or ICVT. The haemosiderin deposition seen as a hypointensity on MRI-SWAN
(susceptibility-weighted angiography) is more typical in cases
of thrombosis, especially as clot deteriorates or ischaemic cells
apoptose, but as the literature shows, it is an occasional finding
in PML as well.10 The presence of low-intensity susceptibility-weighted imaging signal are frequently seen in ICVT,7 and
while it is a possible finding in PML, the mechanism is unclear
and this is not a typical finding.11
Even though the initial read on imaging was highly suspicious for PML especially given the patient’s higher risk for HIV
infection, overall the aetiologies outside of our final diagnosis
of ICVT were thought to be very unlikely, due to the lack of
progressive symptoms, the absence of immunosuppression,
the grossly normal laboratory tests, the reassuring findings on
lumbar puncture and the marked resolution on follow-up MRI.
ICVT is known to mimic other neurological conditions radiographically,3 4 but to our current knowledge, we believe that this
is the first case report demonstrating ICVT mimicking PML.
This is an important finding, as the former disease has a good
outcome, while the latter is rapidly progressive and fatal.
One other point to highlight is testosterone supplementation
as our patient’s identified cause of ICVT in the absence of other
causes of hypercoagulability. Testosterone products are known
as a cause of hypercoagulability,12 with the US Food and Drug
Administration (FDA) and Canada Health both adding warnings
for increased risk of venous thromboembolism in 2014,13 14 and
the FDA also issuing a warning in 2015 for increased risk of heart
attack and stroke with testosterone supplementation.15 In addition, over-the-counter supplements are notoriously under-regulated as to their contents,16 and the actual dose of testosterone in
the supplement as well as the presence of any other ingredients
known to incite hypercoagulability is unknown.

Learning points
►► Isolated cortical venous thrombosis (ICVT) is a rare condition

that can present in a radiographically diverse manner.

Contributors CFP contributed to data acquisition, interpretation of data, drafting
of article and critical revision of the manuscript for important intellectual content.
FK contributed to data acquisition, interpretation of data, drafting of article and
critical revision of the manuscript for important intellectual content. AJ contributed
to data acquisition, interpretation of data, drafting of article and critical revision of
the manuscript for important intellectual content. CI contributed to data acquisition,
interpretation of data, drafting of article and critical revision of the manuscript for
important intellectual content.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.

References

1 Coutinho JM, Gerritsma JJ, Zuurbier SM, et al. Isolated cortical vein thrombosis:
systematic review of case reports and case series. Stroke 2014;45:1836–8.
2 Kitamura Y, Hara K, Tsunematsu K. Isolated superficial sylvian vein thrombosis
with long cord sign: case report and review of the literature. Neurol Med Chir
2014;54:253–9.
3 Morris JG, Fisher M, Carandang RA. Cortical vein thrombosis as a mimic for isolated
cortical subarachnoid hemorrhage and transient ischemic attack. Case Rep Neurol
2010;2:63–8.
4 Yu Y, Ren M, Yao S, et al. Pathological confirmation of 4 cases with isolated cortical
vein thrombosis previously misdiagnosed as brain tumor. Oncol Lett 2016;11:649–53.
5 Zeina A-R, Kassem E, Klein A, et al. Hyperdense cerebral sinus vein thrombosis on
computed tomography. West J Emerg Med 2010;11:217.
6 Rodallec MH, Krainik A, Feydy A, et al. Cerebral venous thrombosis and multidetector
CT angiography: tips and tricks. Radiographics 2006;26 Suppl 1:S5–18.
7 Boukobza M, Crassard I, Bousser MG, et al. Mr imaging features of isolated cortical
vein thrombosis: diagnosis and follow-up. AJNR Am J Neuroradiol 2009;30:344–8.
8 Sasidharan PK. Cerebral vein thrombosis misdiagnosed and mismanaged. Thrombosis
2012;2012:1–11.
9 Pavlovic D, Patera AC, Nyberg F, et al. Progressive multifocal leukoencephalopathy:
current treatment options and future perspectives. Ther Adv Neurol Disord
2015;8:255–73.
10 Sarbu N, Shih RY, Jones RV, et al. White matter diseases with Radiologic-Pathologic
correlation. Radiographics 2016;36:1426–47.
11 Yap SM, Murray B, Lynch T, et al. A role for susceptibility weighted imaging in
progressive multifocal leukoencephalopathy. Ir Med J 2017;110:549.
12 Glueck CJ, Goldenberg N, Wang P. Testosterone therapy, thrombophilia, venous
thromboembolism, and thrombotic events. J Clin Med 2018;8. doi:10.3390/
jcm8010011
13 Information Update - Possible cardiovascular problems associated with testosterone
products: Health Canada; 2014, 2014. Available: http://​healthycanadians.​gc.​ca/​recall-​
alert-r​ appel-​avis/h​ c-​sc/2​ 014/​40587a-e​ ng.​php/
14 Testosterone Products: FDA/CDER Statement - Risk of Venous Blood Clots: ​
SafetyAlertRegistry.​com, 2014. Available: http://www.​safetyalertregistry.​com/​alerts/​
2558
15 FDA Drug Safety Communication. Fda cautions about using testosterone products
for low testosterone due to aging; requires labeling change to inform of possible
increased risk of heart attack and stroke with use ​FDA.​gov, 2015. Available: https://
www.f​ da.​gov/​Drugs/​DrugSafety/u​ cm436259.​htm?a​ ttorney_​name=​Brett%​20Hollett?​
PageSpeed=​noscript
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Science and Nutrition 2018:1–12.

►► ICVT frequently presents idiopathically and resolves

spontaneously, with no lasting sequelae.

►► Patients with higher risk of HIV infection presenting with a

first onset of seizure and an abnormal subcortical U-fibre
involvement leads to the challenging differential diagnosis
of progressive multifocal leukoencephalopathy (PML) which
can have potential serious implications for morbid outcome.
However, ICVT can also mimic PML from neuroradiological
perspective, as demonstrated by our case, with a completely
different outcome, especially in the absence of nonradiological abnormal findings.
►► MRI with susceptibility-weighted imaging can be a useful
diagnostic tool in cases of ICVT as it shows haemosiderin
deposition after resolution of the acute clot.
Palmer CF, et al. BMJ Case Rep 2019;12:e230915. doi:10.1136/bcr-2019-230915

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Palmer CF, et al. BMJ Case Rep 2019;12:e230915. doi:10.1136/bcr-2019-230915

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Unusual association of diseases/symptoms