Khealani, Bhojo A.

Sheerani, Mughis

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Pakistan Journal ofNeurological Sciences (PJNS)Volume 1 | Issue 3 Article 412-2006Hyperhomocysteinemia and CerebralvenoussinusThrombosisMughis SheeraniAga Khan UniversityBhojo A. KhealaniAga Khan UniversityFollow this and additional works at: https://ecommons.aku.edu/pjnsPart of the Neurology CommonsRecommended CitationSheerani, Mughis and Khealani, Bhojo A. (2006) "Hyperhomocysteinemia and Cerebralvenoussinus Thrombosis," Pakistan Journal ofNeurological Sciences (PJNS): Vol. 1 : Iss. 3 , Article 4.Available at: https://ecommons.aku.edu/pjns/vol1/iss3/4Though cases of ischemic arterial thrombosis due tohypercoagulability caused by hyperhomocysteinemia (CVT)have been reported1 cerebral venous thrombosis due tohyperhomocysteinemia is a rarely reported cause ofvenous strokes.Elevated level of homocysteine is strongly associated withpremature arterial or venous thromboembolism. Factorsrelated with the pathogenesis of venous thrombosisinclude blood stasis, hypercoagulability, and vesseldamage. Increased thromboembolic risk has beenattributed to antithrombin III, protein C, or protein Sdeficiencies as well as factor V Leiden, prothrombinmutation G20210A, or hyperhomocysteinemia.2A more recent study demonstrated that elevation ofplasma factor V III leve l proved to be the mostprothrombotic risk factor for cerebral venous thrombosis(CVT).3We report two cases of young males, without anysignif icant identif iab le risk for hypercoagulabil ity,presenting with headaches, seizures and altered mentalstatus, who were found to have cortical venous sinusthrombosis. During workup of hypercoagulable state,these patients were found to have hyperhomocysteinemia,a rare cause of venous thrombosis.CASE 1A 23 year-old male developed symptoms of persistentdiffuse headaches for about a month. He took different'over-the-counter' medications. His symptoms improvedcompletely. About a week prior to his admission to thehospital, he developed double vision. CT scan of the headand lumbar puncture were normal. He was treated withoral steroids.His diplopia resolved. After 3 or 4 days, he developedvomiting, drowsiness and staggering gait.On the day of admission, the patient had a seizure forwhich he was brought to the hospital. Examination, exceptfor drowsiness, was unremarkable. MRI brain showed anischemic lesion in the right parietal cortex with gyriformenhancement suggestive of venous cortical infarction. MRvenogram showed irregular defect in the superior sagittalsinus suggestive of cerebral venous thrombosis and partialrecanalization.EEG, a repeat lumbar puncture, echocardiogram, routinechemist ries,  blood counts,  prote in C,  prote in S,antithrombin III, and Factor V Leiden were normal. Theblood cultures and antiphospholipid antibodies werenegative. Plasma homocysteine level was 20.52 µmol/l(normal reference value 4.45-12.42 µmol/l).The patient was treated with heparin infusion (intravenous)and a PTT was maintained around twice that of normal.He was also started on folic acid. His symptoms resolvedover a week and he was discharged on warfarin and folicacid.CASE 2A 37 year-old male with a history of diabetes mellituspresented to ER with new onset of headaches, seizuresand altered mental status.On initial examination, the patient was drowsy. An urgentplain CT scan of brain revealed left parieto-occipitalhemorrhage. An emergent cerebral angiogram showedthrombosis of the superior sagittal sinus, the confluence,the left transverse sinus and right transverse sinus.Further workup revealed normal protein C, protein S,antithrombin III and factor V Leiden. The antiphospholipidV O L .  1 ( 3 )   O C T - D E C  2 0 0 6P A K I S T A N  J O U R N A L  O F  N E U R O L O G I C A L  S C I E N C E S  136C A S E  R E P O R THYPERHOMOCYSTEINEMIA AND CEREBRALVENOUSSINUS THROMBOSISMughis Sheerani and Bhojo A. Khealani Section of Neurology, Aga Khan University Hospital, Karachi, PakistanCorrespondence to: Dr. Sheerani, Assistant Professor, Section of Neurology, Aga Khan University Hospital. P.O. Box 3500, Stadium Road, Karachi-74800. Tel: (92-21) 485-9467. Email: mughis.sheerani@aku.eduPak J Neurol Sci 2006; 1(3):136-7antibodies were also negative. However, the plasmahomocysteine levels were elevated i.e. 20.17 µmol/l(4.45-12.42 µmol/l). During hospital stay, the patient deteriorated and requiredcraniotomy and removal of the clot. After the surgery, heshowed dramatic improvement.DISSCUSIONCerebral venous thrombosis is a diagnostic challenge dueto its nonspecific symptoms and its relative infrequency.This is probably more common for underdevelopedcountries where investigations are not readily available.Even when diagnosed, the cause sometimes remainselusive.  McCully extensively studied children with homocysteinuriaand showed a relationship between homocysteinuria anddevelopment of premature coronary artery disease andstroke.4A correlation between hyperhomocysteinemia and arterialvascular disease is also well established. Several studieshave investigated the role of hyperhomocysteinemia inrecurrent vein peripheral thromboembolism.5 , 6 , 7 , 8 T h e r eare, however, very few reports of cort ical  venousthrombosis and hyperhomocysteinemia.Homocysteinuria primarily comes from methionine.Methionine is a by-product of protein catabolism. Thereare two distinct pathways whereby homocysteine ismetabolized:1. Transulfuration pathway requires cystathionine betasynthetase.  This coverts homocyteine to cystathionineand then to cysteine, which is excreted in the urine.Vitamin B6 is a required co- factor in this pathway.Deficiency causes homocysteinuria, an inborn error ofmetabolism.2. Remethylat ion pathway requires methylenetetrahydrofolate reductase (from folate metabolism) whichhelps methionine synthetase to convert homocysteineback to methionine. Vitamin B12 is a co-factor in thisreaction. Pathology in this pathway is responsible forhyperhomocysteinemia.High levels of auto-oxidation of homocysteine reacting withhighly reactive oxygen species cause lipid peroxidationwhich in turn leads to vascular matrix damage and smoothmuscle cell proliferation leading to atherogenesis. Thesame phenomenon also causes vascular endothelial injuryand is responsible for prothrombogenesis.CONCLUSIONThe two reported cases in our study had moderatelyelevated homocysteine level. These patients did not haveother risks for CVT. These cases had almost similarpresentations. Both showed good improvement withtreatment on long-term folate replacement. Furtherstudies are required to analyze the importance of checkinghomocysteine level in cases of CVT, especially where aclear risk factor has not been identified.REFERENCES1. Penix LP . Ischemic strokes secondary to vitamin B12 deficiency-induced hyperhomocystinemia. Neurology 1998; 51(2): 622-42. den Heijer M, Blom HJ, Gerrits WBJ, Rosendaal FR, Haak HL, Wijermans PW. Is hyperhomocysteinaemiaa risk factor for recurrent venous thrombosis? Lancet 1995; 345:882-8853. S.Cakmak; L. Derex; M. Berruyer; N. Nighoghossian,F. Philippeau, P. Adelenie, M.Hermier, J.C. Forment,P. Trouillas. Cerebral venous thrombosis: clinical outcome and systematic screening of prothrombotic factors. Neurology 2003; 60:1175-11784. Goodnight SH Jr., Hathaway WE. Disorders of Hemostasis & Thrombosis, 2nd ed. NewYork: McGrawHill, 2001 pp.397-4045. den Heijer M, Koster T, Blom HJ, Bos GMJ, Briët E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocystinemia as a risk factor for deep vein thrombosis. N Engl J Med. 1996; 334:759-7626. Simioni P, Prandoni P, Burlina A, Tormene D, Sardella C, Ferrari V, Benedetti L, Girolami A. Hyperhomocystinemia and deep vein thrombosis. Thromb Haemost. 1996; 76:883-8867. Brattström L, Tengborn L, Lagerstedt C, Israelsson B, Hultberg B. Plasma homocysteine in venous thromboembolism. Haemostasis 1991; 21:51-57 8. Amundsen T, Ueland PM, Waage A. Plasma homocysteine levels in patients with deep venous thrombosis. Arterioscler Thromb Vasc Biol. 1995;15:1321-1323V O L .  1 ( 3 )   O C T - D E C  2 0 0 6P A K I S T A N  J O U R N A L  O F  N E U R O L O G I C A L  S C I E N C E S  137

Hyperhomocysteinemia and Cerebralvenoussinus Thrombosis

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Hyperhomocysteinemia and Cerebralvenoussinus Thrombosis

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