Kapur et al. Journal of Medical Case Reports
https://doi.org/10.1186/s13256-019-1988-9

(2019) 13:36

CASE REPORT

Open Access

An uncommon presentation of
hyperhomocysteinemia and vitamin B12
deficiency: a case report
Vinay Kapur1*, Sanjay D’Cruz2 and Ravinder Kaur3

Abstract
Introduction: Cerebral venous thrombosis is relatively rare and characterized by a wide spectrum of clinical features. It
is more common in young adults with women affected more than men. The diagnosis of cerebral venous thrombosis
is easier nowadays due to easy access to advanced neuroimaging techniques. Abnormalities in thrombophilic profile
are associated with enhanced risk of cerebral venous thrombosis. It has varied etiologies such as hypercoagulable
states, infection, dehydration, pregnancy, and substance abuse. Hyperhomocysteinemia is found to be closely
associated with an enhanced risk of cerebral venous thrombosis.
Case presentation: Here we report a case of cerebral venous thrombosis secondary to hyperhomocysteinemia
caused by vitamin B12 deficiency in a 32-year-old Indo-Aryan man. A detailed coagulation workup led us to find
the etiology of cerebral venous thrombosis in this patient who followed a strict vegetarian diet and had vitamin
B12 deficiency leading to hyperhomocysteinemia.
Conclusion: There are conflicting reports in the literature about the association of hyperhomocysteinemia, B12
deficiency, and cerebral venous thrombosis but some reports point to a significant association. We conclude that
further studies with a large sample size are required to analyze the effect of hyperhomocysteinemia and low
vitamin B12 on the risk of cerebral venous thrombosis.
Keywords: Hyperhomocysteinemia, Thrombophilia, Venous thrombosis, Vitamin B12

Introduction
Cerebral venous thrombosis represents 0.5–3% of all
cases of stroke affecting mainly the younger population
with an incidence of 3–4 per million in adults [1]. It is a
severe thrombotic manifestation resulting in marked
disability and has a tendency to recur. It has varied etiologies such as hypercoagulable states, infection, dehydration, pregnancy, drugs such as oral contraceptive pills
and substance abuse. This case report highlights the importance of hyperhomocysteinemia (Hhcy) secondary to
vitamin B12 deficiency leading to cerebral venous thrombosis. The patient mentioned here developed B12 deficiency as he followed a strict vegetarian diet and had
poor socio-economic status. This case report is significant in the present era when people around the world
* Correspondence: vinay.kapur99@gmail.com
1
Department of General Medicine, Dr HS Judge Institute of Dental Sciences
& Hospital, Panjab University, Chandigarh, India
Full list of author information is available at the end of the article

are changing dietary habits and shifting to a vegan diet
which is likely to increase the prevalence of vitamin B12
deficiency and subsequently Hhcy. Therefore, it is prudent to include vitamin B12 and homocysteine levels in
workups of patients presenting with cerebral venous
thrombosis.

Case presentation
A 32-year-old Indo-Aryan man presented to our emergency department with history of frequent vomiting,
moderate to severe headache and giddiness for past 5
days. He also developed weakness of the right side of his
body along with altered sensorium over last 24 hours
prior to presentation. There was also history of one episode of generalized tonic-clonic seizures prior to onset
of weakness. His past medical history was not suggestive
of any major illness/drug treatment. His family history
was non-contributory and he had no addictions. He was
afebrile with pulse 86/minute and blood pressure of 126/

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Kapur et al. Journal of Medical Case Reports

(2019) 13:36

74 mmHg. On neurological examination, he was drowsy
and was responding poorly to verbal commands. He was
having hypertonia and grade III power in his right upper
limb and lower limb. Deep tendon reflexes were mildly
exaggerated and Babinski sign was positive on right side.
His chest, abdomen, and cardiovascular system examination were unremarkable. His preliminary blood examination revealed macrocytic anemia with hemoglobin (Hb)
of 11.4 g/dl and mean corpuscular volume (MCV) of
110 fl. Peripheral blood film showed macrocytes and
macro-ovalocytes with hypersegmented neutrophils. He
had low serum cobalamin levels 68 pg/ml (200–600)
with normal folate levels. Test for anti-intrinsic factor
antibodies was negative and there was no evidence of
gastric atrophy on stomach biopsy. Cerebrospinal fluid
(CSF) examination was normal along with negative immunological profile: antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), lupus
anticoagulant and antiphospholipid antibodies. A detailed thrombophilic workup showed normal prothrombin time 12.8 seconds (11.4–13.7), activated partial
thromboplastin time 32.6 seconds (27.8–41.8), protein C
106% (70–140%), protein S 98% (70–140%), and antithrombin III 88% (80–120%). His fibrinogen levels were
normal and assays for factor V Leiden and prothrombin
gene mutation were negative. The only abnormality was
raised fasting total serum homocysteine levels of
36 μmol/l (5.0–13.9). A non-contrast computed tomography (CT) scan of his head was inconclusive. Magnetic
resonance imaging (MRI) of his brain showed mixed signal intensity lesion in right posterior parieto-occipital
lobe with areas of hypointensity in T2-weighted images
(Figs. 1 and 2). T1-weighted axial images at the same
levels showed areas of hyperintensity in the above lesion
due to hemorrhage (Figs. 3 and 4). Magnetic resonance
(MR) venography showed no signal in right transverse
and sigmoid sinus due to venous thrombosis (Fig. 5). A
diagnosis of cerebral venous thrombosis due to Hhcy
secondary to cobalamin deficiency was made.
He was treated with sodium valproate 20 mg/kg administered intravenously followed by orally administered
valproate 20 mg/kg in two divided doses which was
gradually escalated on follow-up visits. He was also administered cerebral decongestants, initially mannitol
100 ml 8 hourly for 2 days followed by orally administered glycerol 30 ml 8 hourly for 1 week. In addition, he
was administered parenteral cyanocobalamin 1000 μg
once daily for 7 days along with low molecular weight
heparin. Gradually he regained sensorium, his power improved, and he was discharged on orally administered
sodium valproate, warfarin, and methylcobalamin. On
subsequent monthly follow-ups, his international normalized ratio (INR) was regularly monitored and maintained between 2.0 and 3.0. He remained seizure free

Page 2 of 5

Fig. 1 T2-weighted axial images of the brain show mixed signal
intensity lesion in right posterior parieto-occipital lobe with areas
of hypointensity

Fig. 2 T2-weighted axial images of the brain show mixed signal
intensity lesion in right posterior parieto-occipital lobe with areas
of hypointensity

Kapur et al. Journal of Medical Case Reports

(2019) 13:36

Fig. 3 T1-weighted axial images at the same levels show the areas of
hyperintensity in the above lesion due to hemorrhage. The normal
flow void in the posterior part of superior sagittal sinus is replaced by a
hyperintense signal on both T1-weighted and T2-weighted images
due to thrombosis

Page 3 of 5

Fig. 4 T1-weighted axial images at the same levels show the areas of
hyperintensity in the above lesion due to hemorrhage. The normal
flow void in the posterior part of superior sagittal sinus is replaced by a
hyperintense signal on both T1-weighted and T2-weighted images
due to thrombosis

thereafter and was continued on sodium valproate 750
mg twice a day. On neurological examination he showed
significant improvement, initially he was walking with
support and later he was fully ambulatory on his own.
Repeat investigations done at 6 months after stopping
anticoagulants showed normal serum cobalamin 364 pg/ml
(200–600) and fasting total homocysteine levels 8.4 μmol/l
(5.0–13.9). The rest of the thrombophilia profile was within
normal limits.

Discussion
This case report describes an unusual association between Hhcy, low vitamin B12 levels and cerebral venous
thrombosis as our patient had no other apparent risk
factor for venous sinus thrombosis. The prevalence of
Hhcy in the general population is approximately 1%, although it may vary from place to place [2]. Hhcy can be
caused by genetic and acquired factors, including folate
and cobalamin deficiency and methylcobalamin acts as a
cofactor with enzyme methionine synthase required for
remethylation of homocysteine to methionine. During
remethylation, 5-methyltetrahydrofolate, formed from
5,10-methylenetetrahydrofolate in the presence of
5,10-methylenetetrahydrofolate reductase (MTHFR), is
converted to tetrahydrofolate (Fig. 6). Hhcy is known to

Fig. 5 Coronal magnetic resonance venography image shows loss of
flow-related signal in transverse and sigmoid sinus due to thrombosis

Kapur et al. Journal of Medical Case Reports

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Page 4 of 5

Fig. 6 Pathways of homocysteine metabolism

increase arterial thrombotic events in coronary, cerebral,
and peripheral arteries [3–5]. Studies have also shown
increased risk of venous thrombotic events associated
with Hhcy [6, 7]. The main hypotheses put forward to
explain the pathogenesis of thrombotic events resulting
from increased homocysteine levels include injury to
vascular endothelium and adverse effects on clotting
cascade. It can lead to increased platelet aggregation, increased low-density lipoprotein (LDL) as well as LDL
oxidation, abnormalities of fibrinolysis including decreased activity of antithrombin III and protein C, increased smooth muscle proliferation, activation of
inflammatory pathways and thrombocyte dysfunction [8,
9]. Our patient had cerebral venous thrombosis secondary to Hhcy caused by vitamin B12 deficiency as he
followed a strict vegetarian diet, was from a low
socio-economic stratum and apparently had no other risk
factors for venous thrombosis. There have been very few
studies in the literature which have shown this association.
Martinelli et al. showed in their study that Hhcy is associated with fourfold increased risk of cerebral venous
thrombosis [10]. Patil et al. showed that Hhcy was a
causative factor for cerebral venous thrombosis in 24% of
their patients [11]. Tufano et al. reported that frequency
of Hhcy was not significantly different between patients
with cerebral venous thrombosis and controls [12]. Investigations in our patient revealed low serum B12 and Hhcy.
On review of the literature, few studies have looked at the
issue of B12 deficiency and increased thrombotic tendency.
Remacha et al. indicated that serum vitamin B12 levels
were moderately related to thromboembolism and vitamin
B12 deficiency was common among patients with Hhcy
and thrombosis [13]. In another study by the same
authors, multivariate analysis demonstrated that vitamin
B12 deficiency was a significant risk factor for arterial
thrombosis but when Hhcy was included in the analysis,
Hhcy was found to be to be responsible for thrombosis
and it was concluded that as a consequence of Hhcy,

patients with acquired vitamin B12 deficiency had a high
risk of thrombosis [14]. Soltani et al. revealed in their
study that patients with cerebral venous thrombosis had
higher levels of homocysteine with low vitamin B12 levels
as compared to controls [15]. Cantu et al. found that there
is an independent association of low levels of folic acid,
vitamin B12 as well as Hhcy with risk of cerebral venous
thrombosis and mechanisms other than Hhcy should be
analyzed for cerebral venous thrombosis risk [16]. There
are anecdotal case reports suggesting correlation between
Hhcy, vitamin B12 deficiency and cerebral venous thrombosis, deep vein thrombosis and acute porto-mesenteric
vein thrombosis [17–19]. Ming-Ching Shen et al. reported
that Hhcy caused deep vein thrombosis in a vitamin
B12-deficient metformin-treated patient with diabetes [20].
There are conflicting reports in the literature about the
association of Hhcy, B12 deficiency and cerebral venous
thrombosis; however, most of the studies pointed to a
significant association.

Conclusion
We conclude that Hhcy is an independent risk factor for
cerebral venous thrombosis in patients with cobalamin
deficiency, especially those who follow a strict vegetarian
diet. Hhcy can be easily reversed with vitamin supplementation, cobalamin and folic acid. Although there are
conflicting reports in the literature about the association
between Hhcy, B12 deficiency and cerebral venous
thrombosis, in our view homocysteine levels should be
checked in all patients with cerebral venous thrombosis
for whom there is no other obvious predisposing factor
for venous thrombosis. Further studies with large sample
size are required to analyze the effect of Hhcy and low
vitamin B12 on the risk of cerebral venous thrombosis.
Acknowledgements
Not applicable.

Kapur et al. Journal of Medical Case Reports

(2019) 13:36

Funding
Not applicable.
Availability of data and materials
All data analyzed during this study are included in this article and are
available from the corresponding author on reasonable request.
Authors’ contributions
VK: Case presentation design, literature search, and preparation of
manuscript. SDC: review of manuscript and literature review. RK: review of
manuscript and radiological assessment. All the authors read and approved
final manuscript.
Ethics approval and consent to participate
Not applicable as no experimental intervention was undertaken.
Consent for publication
Written informed consent was obtained from the patient for publication of
this case report and accompanying images. A copy of the written consent is
available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.

Publisher’s Note
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published maps and institutional affiliations.
Author details
1
Department of General Medicine, Dr HS Judge Institute of Dental Sciences
& Hospital, Panjab University, Chandigarh, India. 2Department of General
Medicine, Government Medical College & Hospital, Chandigarh, India.
3
Department of Radiodiagnosis & Imaging, Government Medical College &
Hospital, Chandigarh, India.
Received: 16 October 2018 Accepted: 21 January 2019

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