Three young patients with unusual causes of stroke

Ischaemic stroke in the young may be associated with uncommon thrombophilic or atherogenic states. The rec­ ognition of such causes is important as they may require specific treatment. We report three young patients with ischaemic stroke associated with protein C deficiency (an inherited thrombophilia), paroxysmal nocturnal haemoglo­ binuria (an acquired thrombophilia) and hyperhomo­ cysteinaemia (an atherogenic and thrombophilic state). Case 1 A 29-year old man was seen with a sudden left hemiparesis. He had had three similar events previously with incomplete recovery. CT (computed tomography) scanning showed a right fronto-parietal infarct. Haematological and biochemical screening, vasculitic screening, echocardio­ graphy and carotid duplex scanning were normal. Throm­ bophilia testing performed 6 months after the stroke revealed protein C deficiency (33% of normal level). He was started on long term warfarin. Case 2 A 39-year of previously healthy man had right hom­ onymous hemianopia of sudden onset. CT scanning showed a left occipital infarct. Biochemical and vasculitic screening, echocardiography and carotid duplex scanning were nor­ mal. Blood counts showed leucopaenia and thrombocytopaenia, but bone marrow biopsy was normal. Urine was positive for haemosiderin even though a history of haemoglobinuria was not present. A positive Ham's test con­ firmed paroxysmal nocturnal haemoglobinuria. Warfarin was commenced. Case 3 A 31-year old man with an acute left cerebellar syn­ drome was noted to have hypertension at the age of 24, a myocardial infarction at 27, and a left cerebral infarct at 29 years. CT scanning showed a recent left cerebellar infarct and multiple old infarcts. Echocardiography showed hypokinetic segments with no intramural clots. Haematolo­ gical and biochemical screening and carotid duplex scan­ ning were normal. In view of the multiple vascular events, warfarin was commenced. He later developed an ischaemic right leg, and duplex scanning revealed multiple large artery occlusions in both lower limbs. The presence of ischaemic heart disease, multiple strokes and peripheral arterial dis­ ease all pointed to a premature atherosclerotic state. Urine homocysteine was positive and plasma homocysteine was elevated, confirming hyperhomocysteinaemia. He was treated with folic acid, pyridoxine and vitamin B12.


Introduction
Ischaemic stroke in the young may be associated with uncommon thrombophilic or atherogenic states.The rec ognition of such causes is important as they may require specific treatment.We report three young patients with ischaemic stroke associated with protein C deficiency (an inherited thrombophilia), paroxysmal nocturnal haemoglo binuria (an acquired thrombophilia) and hyperhomo cysteinaemia (an atherogenic and thrombophilic state).

Case 1
A 29-year old man was seen with a sudden left hemiparesis.He had had three similar events previously with incomplete recovery.CT (computed tomography) scanning showed a right fronto-parietal infarct.Haematological and biochemical screening, vasculitic screening, echocardio graphy and carotid duplex scanning were normal.Throm bophilia testing performed 6 months after the stroke revealed protein C deficiency (33% of normal level).He was started on long term warfarin.

Case 2
A 39-year of previously healthy man had right hom onymous hemianopia of sudden onset.CT scanning showed a left occipital infarct.Biochemical and vasculitic screening, echocardiography and carotid duplex scanning were nor mal.Blood counts showed leucopaenia and thrombocytopaenia, but bone marrow biopsy was normal.Urine was positive for haemosiderin even though a history of haemoglobinuria was not present.A positive Ham's test con firmed paroxysmal nocturnal haemoglobinuria.Warfarin was commenced.

Case 3
A 31-year old man with an acute left cerebellar syn drome was noted to have hypertension at the age of 24, a myocardial infarction at 27, and a left cerebral infarct at 29 years.CT scanning showed a recent left cerebellar infarct and multiple old infarcts.Echocardiography showed hypokinetic segments with no intramural clots.Haematolo gical and biochemical screening and carotid duplex scan ning were normal.In view of the multiple vascular events, warfarin was commenced.He later developed an ischaemic right leg, and duplex scanning revealed multiple large artery occlusions in both lower limbs.The presence of ischaemic heart disease, multiple strokes and peripheral arterial dis ease all pointed to a premature atherosclerotic state.Urine homocysteine was positive and plasma homocysteine was elevated, confirming hyperhomocysteinaemia.He was treated with folic acid, pyridoxine and vitamin B12.

Discussion
Stroke is a devastating illness.Its impact is even greater when it affects the young.12% of first ever strokes occur in 'young' patients (less than 45 years) (1).Unlike in older patients where causation is commonly related to hypertension, diabetes or heart disease, ischaemic stroke in the young are associated with unusual causes.Thrombo philic states and conditions predisposing to premature atherosclerosis are important among them.
Inherited thrombophilias result from deficiencies of naturally occurring anticoagulants (protein C, protein S, antithrombin III), or from functional resistance to them (activated protein C resistance) (2).Transmitted as an autosomal dominant trait, inherited protein C deficiency is not uncommon in heterozygote form, but symptomatic deficiency is rare (3).Protein C levels may be falsely low immediately after a thrombotic event, and it is important to perform testing after an interval of 3 to 6 months (3).Treatment is with lifelong anticoagulation.
Paroxysmal nocturnal haemoglobinuria (PNH) is an intriguing condition where an acquired mutation leads to a clonal haemopoietic disorder.Mutation of the PIG-A gene on the X-chromosome results in defective produc tion of a membrane protein, rendering the affected cells vulnerable to complement mediated lysis (4,5).Haematopoietic stem cells are affected, leading to excess haemolysis with haemoglobinuria, infections and throm bosis (6).PNH should be considered in all patients with thrombotic events and cytopaenias.Treatment is usually supportive, with anticoagulation after thrombotic events.PNH may undergo transformation to myeloproliferative or aplastic states (6), and the definitive treatment is bone marrow transplantation (4).
Hyperhomocysteinaemia is increasingly being recognised as an important risk factor for arterial disease (7).It is associated with both premature atherosclerosis and a prothrombotic state, acting via a number of mecha nisms involving the arterial wall smooth muscles, endot helial cells, natural antioxidants and circulating antico agulants (8,9).Fasting plasma homocysteine levels of more than 10.2 umol/1 are associated with a doubling of vascu lar risk (7).Dietary methionine is metabolised to homocys teine, and folate, pyridoxine and vitamin B12 act as cofactors in this metabolic pathway.Inherited deficiency of the regulating enzymes or acquired deficiency of the cofactors leads to hyperhomocysteinaemia.A combination of folic acid, pyridoxine and vitamin B12 is effective in re ducing the vascular risk (9,10).

Three young patients with unusual causes of stroke
Udaya K. Ranawaka 1 , A T Alibhoy 2 and Jagath C. Wijesekera 3 (Index words: Protein C deficiency, paroxysmal nocturnal haemoglobinuria, hyperhomocysteinaemia) Papers Young patients with stroke without an obvious un derlying cause should be evaluated for unusual and po tentially treatable causes.Failure to detect and treat them leads to recurrent vascular events, as seen in two of our patients.