Headache presenting as cerebral venous thrombosis associated with heterozygous methylenetetrahydrofolate reductase gene mutation: A case report

Muhammed Jasim Abdul Jalal; Murali Krishna Menon

doi:10.4103/0975-9727.185016

CASE REPORT

Year : 2016 | Volume : 7 | Issue : 2 | Page : 136-140

Headache presenting as cerebral venous thrombosis associated with heterozygous methylenetetrahydrofolate reductase gene mutation: A case report

Muhammed Jasim Abdul Jalal¹, Murali Krishna Menon²
¹ Department of Family Medicine, Lakeshore Hospital and Research Centre, Kochi, Kerala, India
² Department of Neurology, Lakeshore Hospital and Research Centre, Kochi, Kerala, India

Date of Web Publication

30-Jun-2016

Correspondence Address:
Muhammed Jasim Abdul Jalal
Department of Family Medicine, Lakeshore Hospital and Research Centre, P.O. Nettoor, Maradu, NH 47 - Bypass, Ernakulam - 682 040, Kochi, Kerala
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/0975-9727.185016

Abstract

Headache is among the most common pain problems encountered by the primary care physician. Cerebral venous thrombosis (CVT) is relatively rare in young adult males. Homocysteinemia is a significantly independent prothrombotic risk factor for atherogenic thrombotic cardiovascular, cerebrovascular, and peripheral vascular diseases. Methylenetetrahydrofolate reductase (MTHFR) gene mutation results in high serum homocysteine levels. Here, we report a 45-year-old male who presented with acute onset severe headache. Brain imaging showed thrombosis of superior sagittal sinus. The level of serum homocysteine was elevated and there was heterozygous CG677T polymorphism of the MTHFR gene.

Keywords: Cerebral venous thrombosis (CVT), hyperhomocysteinemia, methylenetetrahydrofolate reductase (MTHFR), gene mutation, secondary headache

How to cite this article:
Jalal MJ, Menon MK. Headache presenting as cerebral venous thrombosis associated with heterozygous methylenetetrahydrofolate reductase gene mutation: A case report. Muller J Med Sci Res 2016;7:136-40

How to cite this URL:
Jalal MJ, Menon MK. Headache presenting as cerebral venous thrombosis associated with heterozygous methylenetetrahydrofolate reductase gene mutation: A case report. Muller J Med Sci Res [serial online] 2016 [cited 2023 Jun 4];7:136-40. Available from: https://www.mjmsr.net/text.asp?2016/7/2/136/185016

Introduction

Headache or cephalalgia, is defined as diffuse pain in various parts of the head, with the pain not confined to the area of distribution of a nerve. Headache is among the most common pain problems encountered by the primary care physician. Approximately one-half of the adult population worldwide is affected by a headache disorder. The International Headache Society classification and diagnostic criteria differentiates primary headaches (e.g., tension, migraine, cluster) from secondary headaches (e.g., those caused by infection or vascular disease).

Cerebral venous thrombosis (CVT), which is a cause of secondary headache is relatively rare in young adult males. The incidence of CVT is estimated to be 4-8 cases per 100,000 people/year, with a mortality rate of between 10% and 20%. ^[1] The risk factors for CVT includes hereditary thrombophilia, postoperative state, and intracranial or local infections. Pregnancy, puerperium, and use of oral contraceptives are the common risk factors of CVT in females.

Homocysteinemia is a significantly independent prothrombotic risk factor for atherogenic thrombotic cardiovascular, cerebrovascular, and peripheral vascular diseases. Methylenetetrahydrofolate reductase (MTHFR) gene mutation results in high serum homocysteine levels. ^[2] Homozygous mutation in the MTHFR gene is associated with increased serum homocysteine levels and is a significant risk factor for ischemic stroke. ^[3] Here, we report a 45-year-old male who presented with acute onset severe headache.

Case Report

History

A 45-year-old nonalcoholic and nonsmoker Indian male presented with acute onset of severe headache of 3-day duration followed by one episode of generalized tonic-clonic seizures. The patient had severe holocranial headache with a visual analogue score of eight. The patient was otherwise normal without any significant past history.

Examination

General examination did not show pallor, icterus, cyanosis, clubbing, edema, and lymphadenopathy. The patient was afebrile with a pulse rate of 82/min and blood pressure of 130/80 mmHg. He was conscious and oriented with a Glasgow coma score of 15/15 (E4V5M6). Eye movements were equal in all directions. The pupils were equal and reactive to light. There was no nystagmus. Cranial nerve examinations were normal. Fundus examination was normal. There were no motor weaknesses/sensory loss. All the deep tendon refl exes were present. The plantar responses were flexor bilaterally. He did not have any cerebellar/meningeal signs. The patient did not have any focal neurological deficits. All other systems were within normal limits.

Investigations

Laboratory investigations revealed hemoglobin: 13.8 g%, white blood cells count: 6,600/mm ³ with 64% polymorphs, 32% lymphocytes, and 4% monocytes. Platelets were 3, 34,000/μL. Liver function revealed serum bilirubin 0.3 mg/dL (total) and 0.1 mg/dL (direct) with Aspartate aminotransferase (AST): 25U/L and Alanine aminotransferase (ALT): 55 U/L and alkaline phosphatase: 94 U/L. His blood urea was 45 mg/dL and serum creatinine was 0.8 mg/dL. The coagulation profile was normal (Prothrombin time: 14.2 s, International Normalised Ratio (INR): 1, Index: 100%, Activated Partial Thromboplastin Time (APTT): 32 s). He was seronegative for human immunodeficiency virus (HIV).

Imaging

Computed tomography (CT) of the brain [Figure 1] revealed hyperdensity in the right frontal and frontoparietal region with hyperdense superior sagittal sinus. Hence, the brain imaging was suggestive of hemorrhagic infarct. CT cerebral venogram [Figure 2] showed thrombosis of superior sagittal sinus, predominantly in the mid and anterior segment.

Figure 1: CT brain showing hyperdense blood in the right frontal and frontoparietal region with hyperdense superior sagittal sinus, suggestive of hemorrhagic venous infarct

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Figure 2: CT cerebral angiogram showing thrombosis of superior sagittal sinus, predominantly in mid and anterior segment

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Serology

The thrombophilic screening tests were negative for antinuclear antibodies, anti-double stranded deoxyribonucleic acid (DNA) antibodies and antiphospholipid immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies. There was no evidence of protein C and protein S deficiency. Antithrombin activity was also normal. No mutations were found for factor V Leiden and prothrombin gene (G20210A). But the level of serum homocysteine was elevated (17 micromol/L; normally 5-12 micromol/L) and there was heterozygous CG677T polymorphism of the MTHFR gene.

Management

The patient was anticoagulated simultaneously with low molecular weight heparin (40mg subcutaneously once daily) and oral anticoagulant warfarin. INR values were monitored regularly and warfarin dosage was titrated accordingly. He improved and was discharged without any sequelae. Neither recurrence of headache nor neurological deterioration was found during follow-up. The patient was advised family screening following detection of MTHFR gene mutation and genetic counseling was provided.

Discussion

CVT can occur de novo as the first manifestation or can overlap with other clinical etiologies. It has a highly variable symptomatology and clinical course. ^[4] Though headache is the most common presenting symptom, CVT can also present with seizures, impaired consciousness, papilledema, and focal neurological deficits. ^[5]

Diagnosis of CVT is often difficult in view of its heterogeneity in clinical presentation and etiology. High index of suspicion and awareness of its varied clinical manifestations is required for the early diagnosis of CVT. ^[6]

Disruption in the mechanism of hemostasis or decreased activity of the antithrombotic mechanisms or a combination of both causes the venous thrombosis in the body. The common contributory causes include: ^[6]

Diabetes.
Obesity.
Smoking.
Hormone replacement therapies: oral contraceptives-estrogen.
Dyslipidemia.
Surgery requiring immobilization.
Trauma.
Pregnancy.
Puerperium and.
Antiphospholipid antibody syndrome.

Hereditary thrombophilia like conditions, which are the rare etiologies of CVT include: ^[7]

Factor V Leiden mutation.
Prothrombin gene mutation.
Hereditary hyperhomocysteinemia.
Protein C deficiency.
Protein S deficiency.
Antithrombin deficiency.
Increased Factor VIII, and.
Dysfibrinogenemia.

Our patient had hyperhomocysteinemia and the heterozygous form of C677T mutation in the MTHFR gene. Homozygous and heterozygous mutation for MTHFR gene is associated with hyperhomocysteinemia, which is an independent risk factor for vascular diseases. ^[7]

In 1969, McCully's report showed widespread arterial thrombosis and atherosclerosis in the autopsy results of children with homocystinuria in which the plasma homocysteine levels were increased; since then, hyperhomocysteinemia has been shown in many studies to be an independent risk factor of several diseases. ^[8]

Homocysteine is produced during the metabolism of methionine, which is an essential amino acid, and it is metabolized by one of the two pathways:

Remethylation
Transsulfuration.

As 5-methyltetrahydrofolate functions as a methyl donor and vitamin B12 functions as a cofactor in the remethylation process, homocysteine is resynthesized to methionine by methionine synthase. 5-methyltetrahydrofolate is reduced from 5,10-methylenetetrahydrofolate by MTHFR, and the decreased enzymatic activity that results from the gene mutations is related to the increase in the serum homocysteine concentrations [Figure 3].

Figure 3: Schematic representation of homocysteine metabolism

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The MTHFR-expressing gene is located on chromosome 1p36.3, and the gene mutation occurs when cytosine (C) at the 677 ^th position is replaced by thymidine (T). The MTHFR polymorphisms are divided into a homozygous normal genotype (CC), a heterozygous genotype (CT), and a homozygous mutant genotype (TT), and several studies have reported that the TT genotype is associated with a marked increase in plasma homocysteine concentrations. ^{[9],[10],[11]}

When the plasma homocysteine concentration increases, oxidative stress increases, leading to inflammation of the vascular cells and thrombosis due to endothelial cell dysfunction. However, little is known about the effects of the association between MTHFR gene mutations and hyperhomocysteinemia on thrombosis.

Deficiencies in MTHFR, which is involved in the remethylation step in which methionine is resynthesized into homocysteine, causes severe hyperhomocysteinemia, and can result in severe clinical outcomes, such as coronary artery disease, deep vein thrombosis, peripheral arterial occlusive disease, and cerebral infarction. Among the common MTHFR mutations, the thermolabile variant C677T of MTHFR is a point mutation of the 667th C in the MTHFR coding sequence to T, which results in a change in the amino acid sequence from alanine to valine, leading to a decrease in enzymatic activity. ^[12]

It is uncertain whether the MTHFR gene mutation itself causes thrombosis. Even though there is clear evidence that the MTHFR gene mutation can cause hyperhomocysteinemia and hyperhomocysteinemia causes atherosclerosis and thrombosis, the MTHFR gene mutation cannot explain a direct cause of thrombosis. In 1998, Abbate et al. ^[13] reported that the TT genotype of the MTHFR gene mutation is not a risk factor of thrombosis or restenosis in patients with coronary artery disease. In 2007, a study by Bezemer et al. ^[14] on 4,375 patients with deep vein thrombosis and pulmonary thromboembolism and 4,856 normal controls, the MTHFR gene mutation was not a risk factor for venous thrombosis. Although, the MTHFR gene mutation has not been proven to have a direct association with the risk for arterial and venous thrombosis, we speculate that it plays an important indirect role by influencing the plasma homocysteine concentrations. In 2000, Morita et al. ^[15] reported that hyperhomocysteinemia in patients with ischemic heart disease is related to prognosis and is a risk factor for restenosis after percutaneous transluminal coronary angioplasty. In 2002, Kibbe et al. ^[16] reported that the TT genotype of the MTHFR gene mutation is a risk factor for low-graft patency rates and graft thrombosis after peripheral bypass surgery in patients with peripheral arterial occlusive disease. In 2004, Botto et al. ^[17] claimed that the TT genotype of the MTHFR gene mutation is a risk factor that is related to prognosis after coronary revascularization. Based on the results of these studies, although the MTHFR gene mutation is not a direct risk factor for atherosclerosis and thrombosis, it does have clinical significance with respect to prognosis.

Epidemiological studies have suggested that even mild hyperhomocysteinemia is associated with occlusive arterial vascular disease and venous thromboembolism. Histopathological hallmarks of homocysteine-induced vascular injury include:

Intimal thickening
Elastic lamina disruption
Smooth muscle hypertrophy
Marked platelet accumulation, and
Formation of platelet rich occlusive thrombi.

Conclusion

CVT should always be considered as a secondary cause for headache. Etiological investigations should be carried out immediately. Genetic counseling should be provided for the family members in order to prevent possible complications.

The cornerstone in the treatment of CVT lies in anticoagulation therapy. Even extensive hemorrhage in venous cerebral infarcts is not a contraindication for heparinization in CVT. ^[18] After the heparinization in the acute phase of CVT, the patient can be changed to oral anticoagulation therapy and followed up by titrating the dosage with INR values.

Financial support and sponsorship

The authors have no financial relationships relevant to this article to disclose.

Conflicts of interest

The authors have no conflicts of interest relevant to this article to disclose.

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