STROKE IN THE STROKE IN THE YOUNGYOUNG

Chair : Prof. Dr. B. JayakumarChair : Prof. Dr. B. Jayakumar

INTRODUCTIONINTRODUCTION• Young stroke is stroke occurring

between 15 and 45 years of age• Differential diagnosis for potential

etiologies is broader• Even after extensive investigations,

the cause may remain elusive in 20-50% cases

• Prognosis depends on the underlying factor

• Responsible for about 5% of all cases of stroke

• Incidence is much higher in developing countries like India.

• Above the age of 30 years stroke is more common in males whereas below that female predominance is seen.

Etiology of young strokeEtiology of young strokeISCHEMIC• Large artery disease

– Premature atherosclerosis– Dissection (spontaneous or traumatic)– Inherited metabolic diseases (homocysteinuria,

Fabry’s disease, pseudoxanthoma elasticum, MELAS syndrome)

– Fibromuscular dysplasia– Vasculitis– Moyamoya disease– Radiation– Toxic (drug induced)

• Small vessel disease– Vasculopathy (infectious, non infectious,

microangiopathy)

• Cardioembolic disease– Rheumatic heart disease– Congenital heart disease– Arrhythmias– Bacterial and non-bacterial endocarditis– Mitral valve prolapse– Patent foramen ovale– Atrial myxoma– Cardiac surgeries and procedures

• Hematologic disease– Sickle cell disease– Leukemia– Hypercoagulable states (antiphospholipid

antibody syndromes, deficiency of antithrombin III or protein S or C, resistance to activated protein C, increased factor VIII)

– Disseminated intravascular coagulation– Thrombocytosis– Polycythemia vera– Thrombotic thrombocytopenic purpura– Venous occlusion

• Migraine

• HEMORRHAGIC• Subarachnoid hemorrhage

– Cerebral aneurysm

• Intraparenchymal hemorrhage– Arteriovenous malformation– Neoplasm (primary central nervous system,

metastatic, leukemia)– Hematological disorders (sickle cell disease,

neoplasm, thrombocytopenia)– Moyamoya disease– Drug use (warfarin, amphetamines, cocaine,

phenylpropanolamine)– Iatrogenic (peri-procedural)

Premature atherosclerosisPremature atherosclerosis

• Premature atherosclerosis is the single most important cause of stroke as age advances

• Incidence is 7-30% below the age of 50 years.

• It is presumed in all undiagnosed cases with more than two risk factors.

• Risk factors for atherosclerosis– Male sex– Systemic hypertension– Diabetes mellitus – Dyslipidemia (low HDL cholesterol,

hypertriglyceridemia)– Cigarette smoking– Alcohol abuse– Ischemic heart disease– Recent infection– Oestrogen related stroke including oral

contraceptives

NON ATHEROSCLEROTIC NON ATHEROSCLEROTIC VASCULOPATHIESVASCULOPATHIES

• Cervicocephalic arterial dissections• Traumatic cerebrovascular disease• Radiation-induced vasculopathy• Moyamoya disease• Fibromuscular dysplasia• Vasculitis• Migrainous infarction

Cerviocephalic arterial Cerviocephalic arterial dissectionsdissections

• Subintimal penetration of blood with subsequent longitudinal extension of the hematoma between its layers

• Common sites– Extracranial segment of internal carotid

artery– Extracranial vertebral arteries

• Recurrence rate is 1%, more in young and in those with positive family history

Causes• Spontaneous• Secondary

– Blunt or penetrating trauma– Fibromuscualar dysplasia– Ehlers’ Danlos syndrome type IV– Marfan’s syndrome– Pseudoxanthoma elasticum– Coarctation of aorta– Menke’s disease– α1-antitrypsin deficiency– Cystic medial degeneration– Osteogenesis imperfecta– Adult polycystic kidney disease– Homocystinuria– Luteic arteritis

• Dissection results in ischemic symptoms due to arterial occlusion or secondary embolism

• Diagnosis – Arteriography – Elongated, irregular,

narrow column of dye, ‘string sign’– High resolution MRI– MR angiography– CT angiography– Doppler ultrasound of the neck

especially for carotid diseection

Internal Internal carotid artery carotid artery

dissectiondissection

• Treatment– Anticoagulation with heparin should be

started followed by warfarin therapy for 3–6 months

– Antiplatelet therapy– Surgical therapy indicated in the

presence of pseudoaneurysms and if there is no response to medical treatment

– Anticoagulation should be withheld in intracranial dissection since there is a risk of subarachnoid haemorrhage

TraumaTrauma• Blunt or penetrating trauma can produce

arterial dissection, rupture, thrombosis, pseudoaneurysm formation and AV fistula.

• Can occur during sports, violent coughing, vigorous nose blowing, neck manipulation, anesthesia administration etc.

• Cervical rotation or extension compresses cervical carotid artery against transverse processes of upper cervical vertebra

• Angiography and surgical repair is the treatment.

Radiation vasculopathyRadiation vasculopathy• Accelerated atherosclerosis occurs

especially in those with dyslipidemia• Radiation results in damage to the

endothelial cells producing complications months to years later

• Lesions occur at unusual sites• The amount of damage depends on

– Radiation dose– Age at the time of therapy

Moyamoya diseaseMoyamoya disease• Moyamoya is a Japanese word meaning

‘puff of smoke’• It is a chronic progressive non-amyloid

non-atherosclerotic, non-inflammatory occlusive arteriopathy of unknown cause.

• Characterized by progressive bilateral stenosis of distal ICA extending to proximal ACA and MCA with involvement of circle of Willis and development of extensive collateral network (parenchymal, leptomeningeal or transdural) at the base of the brain like a puff of smoke. Intracranial aneurysms are seen, especially in posterior circulation.

• Pathology– Fibrocellular intimal thickening, smooth

muscle proliferation and increased elastin accumulation leading to stenosis of suprasellar intracranial ICA

– Thinning of media with tortuous and multilayered internal elastic lamina

• Clinical features– TIA, seizures, headache, movement

disorders, mental deterioration, cerebral infarction , intracranial hemorrhage

– TIAs are precipitated by crying, blowing and hyperventilation

• Bimodal age distribution is seen– First decade – ischemic events more common– Fourth decade – Hemorrhagic commoner

• Diagnosis is established by arteriography• Suzuki’s six arteriographic changes

– Stenosis of carotid fork– Initial appearance of moyamoya vessels at the

base of brain– Intensification of moyamoya vessels– Minimization of moyamoya vessels– Reduction of moyamoya vessels– Disappearance of the vessels

MCA block with multiple collateral MCA block with multiple collateral moyamoya vesselsmoyamoya vessels

Treatment• Ischemic Moyamoya

– Platelet antiaggregants, vasodilators, calcium channel blockers and corticosteroids have been tried.

– Anticoagulants are not useful– Surgical revascularization techniques

like superficial temporal to MCA anastamosis have produced good results.

• Hemorrhagic Moyamoya– No established therapy to prevent

rebleed

Fibromuscualar dysplasiaFibromuscualar dysplasia• Segmental, non-atheromatous, dysplastic,

non-inflammatory angiopathy • Commonly affects young and middle aged

women• White race more affected• Etiology

– Unknown– May be related to immunological mechanisms,

estrogenic effects, α1-antitrypsin deficiency– Familial association seen

• Renal arteries most commonly involved. Cervicocephalic involvement in less than 1%

• Most often extracranial carotids involved• Bilateral in two thirds• Four histologic types

– Intimal hyperplasia– Medial hyperplasia– Medial fibroplasia: Commonest– Perimedial dysplasia

• Most of the patients are asymptomatic

• Diagnosis– Cervical angiography– ‘String of beads’ appearance in medial

fibroplasia

• Treatment– Benign natural history– Platelet antiaggregants used– Surgical intervention seldom needed

Types of fibromuscular dysplasiaTypes of fibromuscular dysplasia

Cerebral autosomal dominant Cerebral autosomal dominant arteriopathy with subcortcal infarcts arteriopathy with subcortcal infarcts and leucoencephalopathy (CADASILand leucoencephalopathy (CADASIL))

• Familial nonarteriosclerotic, nonamyloid microangiopathy

• Characteristic features– Migraine with aura (CADASILM)– Recurrent subcortical ischemic strokes from

mid-adulthood– Pseudobulbar palsy, cognitive decline,

subcortical dementia– Early white matter hyperintensities in MRI

• Genetics – Missense mutations or small deletions

in Notch 3 gene on chromosome 19q12– Codes for transmembrane receptor

Notch 3

• Granular eosinophilic material deposited in arterial walls, including dermal arteries

Binswanger diseaseBinswanger disease• Widespread degeneration of cerebral

white matter of vascular causation• Associated with hypertension,

atherosclerosis of small blood vessels and multiple strokes.

• Radiological picture of leucoareosis – less intense appearance of periventricualar tissues in chronically hypertensive patients

Mitochondrial myopathy, lactic Mitochondrial myopathy, lactic acidosis and strokes (MELAS)acidosis and strokes (MELAS)

• Mitochondrial disorder which may manifest at any age,usually in childhood

• Clinical features– Proximal myopathy, exercise intolerance– Recurrent migraine-type headaches– Hemiparesis, hemianopsia or cortical blindness– Precipitated by exercise or infection

• Serum and CSF lactate concentrations are elevated

Migrainous infarctionMigrainous infarction• Migraine commonly affects women and

starts during childhood or adolescence• Rare association of migraine and ischemic

stroke seen in young women particularly below 35 years of age.

• Pathogenesis is not completely known• Migrainous infarctions are mostly cortical

and involve PCA territory• Usually there is gradual build up of

unilateral throbbing headaches with visual phenomena occurring in both visual fields simultaneously, in one of which the visual loss becomes permanent.

• Diagnostic critreria– Definite diagnosis of migraine with aura in the

past– One or more of the migrainous aura symptoms

must be present and not fully reversed within 7 days from the onset, with neuroimaging confirmation of ischemic infarction

– Clinical manifestations should be those typical of previous attacks

– Other causes of infarction should be excluded

• Definite migrainous infarction – all criteria satisfied

• Possible – only some criteria satisfied• Increases risk for recurrent stroke

CEREBRAL VASCULITIDESCEREBRAL VASCULITIDES

• Infectious vasculitis– Bacterial, fungal, parasitic, spirochetal, viral,

rickettsial, mycobacterial• Necrotising vasculitis

– Classic polyateritis nodosa, Wegener’s granulomatosis, allergic angitis and granulomatosis, lymphomatoid granulomatosis

• Vasculitis associated with collagen vascular disease– SLE, Rheumatoid arthritis, Scleroderma,

Sjogren’s syndrome• Giant cell arteritides

– Takayasu’s arteritis, temporal arteritis

• Vasculitis associated with other systemic diseases– Behcet’s disease, Ulcerative colitis,

Sarcoidosis, Relapsing polychondritis, Kohlmeier-Degos disease

• Hypersensitivity vasculitis– Henoch-Schonlein’s purpura, Drug-induced

vasculitis, Essential mixed cryoglobulinemia

• Miscellaneous– Vasculitis associated with neoplasia and

radiation, Cogan’s syndrome, Dermatomysoitis polymyositis, X-linked lymphoproliferative syndrome, TAO, Kawasaki’s syndrome, Primary central nervous system vasculitis

• Inflammatory vasculitis should be considered in– Young patients with stroke– Recurrent strokes– Stroke with encephalopathic features– Stroke with fever– Multifocal neurological events– Mononeuritis multiplex, palpable

purpura or abnormal urinary sediment• Diagnosis usually requires

confirmation with arteriography or biopsy

Meningovascular syphilisMeningovascular syphilis• Patients usually have prodromal

symptoms• Vasculitis can cause cerebral

infarctions, commonly in MCA territory or spinal cord infarction.

• May be associated with headache, meningismus, mental status abnormalities or cranial nerve abnormalities.

• Diagnosis– CSF study reveals lymphocytic

pleocytosis, elevated protein control and positive VDRL test

• Treatment– Aqueous Penicillin G x 10-14 days

• Luteic aneurysms of the ascending aorta can extend to the root of great vessels causing stroke

NeurotuberculosisNeurotuberculosis• Usually affects basilar meninges resulting

in basilar meningitis which traps 3, 4 and 6 cranial nerves causing their palsy. Basilar arteriolitis commonly involves the penetrating branches of ACA, MCA or PCA

• Risk factors include alcoholism, substance abuse, corticosteroid use or HIV

• CSF study shows increased protein and decreased glucose levels and lymphocytic and mononuclear pleocytosis. 10-20% of the CSF smears show AFB.

HIV/AIDSHIV/AIDS• Cerebral infarction on AIDS can result

from– Vasculitis, meningovascular syphilis,

varicella-zoster virus vasulitis, opportunistic infections, infective endocarditis, aneurysmal dilatation of major cerebral arteries, nonbacterial thrombotic endocarditis, aPL antibodies, or other hypercoagulable states, hyperlipidemia induced by protease inhibitors, HIV-1 related malignancy, cancer chemotherapy and TTP.

• Other infectious agents are varicella zoster, coxsackie 9 virus, California encephalitis, mumps paramyxovirus, hepatitis C virus, Mycoplasma pneumoniae, Borrelia burgdorferi, Rickettsia typhi, cat-scratch disease, Trichinella infection, cysticercus of Taenia solium and free living amoeba

Takayasu’s arteritisTakayasu’s arteritis• Chronic inflammatory arteriopathy of

aorta, its major branches and pulmonary artery

• More common in women• Probable immune mechanism• Slow progression of stenosis,

occlusion, aneurysmal dilatation and coarctation of the involved vessels

• Two phases– Acute or prepulseless phase – non-

specific systemic symptoms– Occlusive phase – multiple arterial

occlusions• Neurological symptoms usually result

from CNS or retinal ischemia due to stenosis or occlusion of the aortic arch and arch vessels, or arterial hypertension resulting from coarctation of aorta or renal artery stenosis

• Diagnosis– MR angiography– Aortogram

• Treatment– In active disease, treatment is with oral

glucocorticoids; cyclophosphamide, azathiprine or methotrexate used rarely

– Surgical treatment of severely stenotic vessels

Drug induced vasculitisDrug induced vasculitis• Drugs implicated

– Amphetamines, cocaine, phencyclidine, phenylpropanolamine, pentazocine with pyribenzamine, heroin, anabolic steroids and glue sniffing.

• Mechanisms– Foreign body embolization, vasculitis,

vasospasm, acute onset of arterial hypertension or hypotension, endothelial damage, accelerated atherosclerosis, hyper or hypocoagulability, cardiac arrhythmias, emboism from MI or AIDS.

CARDIOGENIC EMBOLISMCARDIOGENIC EMBOLISM• High embolic potential

– Rheumatic mitral valve – Acute myocardial infarction– Infective endocarditis– Mechanical prosthetic valves– Dilated cardiomyopathy– Cardiac tumours– Cardiac arrhythmias – Atrial fibrillation

• Other causes– Mitral valve prolapse– Mitral annulus calcification– Aortic valve calcification

– Non bacterial thrombotic endocarditis– Filamentous strands of mitral valve– Giant Lambl’s excresences– Aneurysms of Sinus of Valsalva– Intracardiac defects with paradoxical embolism

• Patent foramen ovale, atrial septal aneurysm, atrial septal defect

– Cyanotic congenital heart disease– Iatrogenic embolism

• Cavopulmonary anastamosis, coronary artery bypass grafting, pacing, heart transplantation, artificial hearts, cardioversion for atrial fibrillation, balloon angioplasty, ventricular support devices, extracorporeal membrane oxygenator

• Cardiac sources account for 15 to 20% of all ischemic strokes.

• The emboli usually consist of platelet, fibrin, platelet-fibrin, calcium, microorganisms, or neoplastic fragments.

• Cardioembolic cerebral infarcts – large, multiple, bilateral, wedge shaped

• Features of cardioembolic stroke– Worse at onset, fast recovery– Presence of Wernicke’s aphasia, homonymous

hemianopia, ideomotor apraxia– Involvement of posterior division of MCA, ACA or

cerebellar involvement– Involvement of multiple vascular territories– Hemorrhagic component of the infarction

• Acute myocardial infarction– 1% of patients with acute MI have

embolic stroke– LV thrombi are commonly associated

with recent anterior wall transmural MI– Usually embolism occurs within first 3

months, 85% within 4 weeks– Decreased ejection fraction –

independent predictor of risk of embolism

– There is more chance of embolism following thrombolysis with tpA

• Dilated cardiomyopathy– Akinesia of the chambers produces

stasis of blood and thrombus formation– Associated LV failure and atrial

fibrillation increase the risk– 18% of the non- anticoagulated patients

develop embolism• Mitral stenosis

– Rheumatic mitral stenosis associated with atrial fibrillation has high potential for embolisation. 9-14% have systemic emboli of which 60–75% have cerebral ischemia.

• Endocarditis– Infective endocarditis – vegetations may

cause systemic (left sided) or pulmonary (right sided) embolism. If vegetations are detectable by transthoracic echocardiogram, there is increased risk of embolism.

– Non bacterial thrombotic endocarditis – multiple small sterile thrombotic vegetations occur commonly involving the mitral and aortic valves

– Prosthetic valves – mechanical valves in mitral position are more prone. Filamentous strands attached to the mitral valve concede increased risk.

• Atrial fibrillation– More common in older adults– Risk for AF and embolism increases with

age– High risk for embolism exists with

rheumatic AF and AF in hyperthyroidism

• Sick sinus syndrome– Maximum risk is associated with

bradytachyarrhythmias, LA spontaneous echocardiographic contrast, and decreased atrial ejection force

• Intracardiac tumours– Atrial myxomas are the commonest tumours in

adults. Embolic complications are the presenting symptom in one-third of patients. Peripheral ad multiple cerebral arterial aneurysms are remote associations.

– Cardiac rhabdomyomas and mitral valve fibroelastomas are rarely associated with embolism.

• Congenital heart disease– Common cause of stroke in children. – Risk is increased with arterial hypertension,

atrial fibrillation, history of phlebotomy and microcytosis.

– Low Hb is associated with arterial stroke and high Hb with cerebral venous thrombosis.

• Paradoxical embolism– Higher rate of cerebral ischemia is reported in

persistent foramen ovale and atrial septal aneurysms.

– A demonstrable source of embolism should be present.

– Antiplatelet therapy, anticoagulant thearapy, transcatheter or surgical closure of PFO is the treatment.

• Spontaneous echo cardiographic contrast – Associated with elevated fibrinogen levels and

plasma viscosity and is a potential risk factor for stroke

• Post operative– Causes

• Hypoperfusion• Ventricular thrombi• Emboli

– Posterior circulation stroke is more common after cardiac catheterisation

INHERITED AND INHERITED AND MISCELLANEOUS DISORDERSMISCELLANEOUS DISORDERS

• Homocystinuria• Fabry’s disease• Marfan’s syndrome• Ehler-Danlos’ syndrome• Pseudoxanthoma elasticum• Sneddon’s syndrome• Rendu-Osler-Weber’s syndrome• Neoplastic angioendotheliomatoisis• Susac’s syndrome

• Eales’ disease• Reversible cerebral segmental

vasoconstriction• Hypereosinophilic syndrome• Cerebral amyloid angiopathy• Coils and kinks• Arterial dolichoectasia• Complications of coarctation of aorta• Air, fat, amniotic fluid, bone marrow, and

foreign particle embolism

HomocystinuriaHomocystinuria• Inborn error of amino acid metabolism.• Any of the three enzymes deficient

– Cystathionine β-synthetase– Homocysteine methyl transferase– Methylene tetrahydrofolate reductase

• This leads to accumulation of homocysteine in the blood – resulting in endothelial injury and premature atherosclerosis.

• Elevated levels of homocysteine is an independent risk factor for development of cerebrovascular disease, coronary and peripheral arterial occlusive disease.

Homocysteine metabolismHomocysteine metabolism

• Clinical features– Marfanoid habitus, malar flush, liveo reticularis,

ectopia lentis, myopia, glaucoma, optic atrophy, optic atrophy, psychiatric manifestations, mental retardation, spasticity, seizures, osteoporosis and a propensity for intracranial arterial or venous thrombosis

• Homocysteine levels may be reduced by administration of folic acid, with pyridoxine and vitamin B12, choline, betaine, estrogen and N-acetyl cysteine.

Fabry’s diseaseFabry’s disease• X-linked disorder of glycosphingolipid

metabolism• Deficient lysosomal α-galactosidase

activity• Ceramide trihexosidase accumulate in the

endothelial and smooth muscle cells• Clinical features

– Painful peripheral neuropathy, hypertension, cardiomegaly, renal dysfuction, autonomic dysfunction, corneal opacifications

– Angiokeratoma corporis diffusum

Marfan’s syndromeMarfan’s syndrome• Autosomal dominant• Quantitative and qualitative defects of

fibrillin• Variety of skeletal, ocular and

cardiovascular manifestations• Cystic medial necrosis of the aortic

segments occur• Dilatation of the aortic root dissection of

the ascending aorta ischemia of brain, spinal cord and peripheral nerves

• Saccular intracranial aneurysms or dissection of the carotid artery can occur

• Annual echocardiograms should be done

Ehler-Danlos’ syndromeEhler-Danlos’ syndrome• Inherited connective tissue disorder• Characterized by hyperextensibility of

skin, hypermobile joints and vascular fragility

• Arterial complications occur predominantly with type IV disease

• Complications include arterial dissections, arteriovenous fistulae and aneurysms.

• Arteriography should be avoided if possible.

Pseudoxanthoma elasticumPseudoxanthoma elasticum• Inherited disorder of elastic tissue• Clinical features

– Loose skin, orange-yellowish papules of intertriginous areas, arterial hypertension, angiod streaks, retinal hemorrhages, arterial occlusive disease and arterial dissection.

• High risk for arterial occlusion – coronary artery disease and stroke.

• Women should avoid estrogens

Sneddon’s syndromeSneddon’s syndrome• Unknown etiology• Frequent correlation with hypertension,

smoking and OCP• Occurs in young women• Charaterized by widespread livedo

reticularis and ischemic cerebrovascular infarcts in the carotid artery territory

• Histology reveals perivascular lymphocytic infiltration on the skin arteries with proliferation of smooth muscle fibres on the internal elastic lamina without inflammation.

Atheromatous emboliAtheromatous emboli• Cholesterol embolisation usually occurs

following manipulation of an atherosclerotic aorta during catheterisation or surgery.

• Patient may present with TIAs, strokes, retinal embolism, pancreatitis, renal failure, livedo reticualris and purple toes.

• Patients have eosinophilia, anemia, elevated ESR and elevated serum amylase.

• Anticoagulation should be avoided.

Air embolismAir embolism• Accidental introduction of air into systemic

circulation can occur during surgical procedures and scuba diving.

• Usually causes cerebral and retinal ischemia

• Symptoms include seizures and multifocal neurological findings such as cerebral edema, confusion, memory loss and coma.

• CT scan can visualize gaseous bubbles.• Treatment includes resuscitative

measures, placement in left lateral position, inotropic agents, anticonvulsants, anti-edema agents and hyperbaric agents.

HYPERCOAGULABLE HYPERCOAGULABLE DISORDERSDISORDERS

• Primary hypercoagulable states– Antithrombin III deficiency– Protein C deficiency– Protein S deficiency– Activated protein C resistance– Prothrombin G20210 mutation– Afibrinogenemia– Hypofibrinogenemia– Hypoplasminogenemia– Plasminogen activators deficiency– Lupus anticoagulant and anticardiolipin

antibodies

• Secondary hypercoagulable states– Malignancy– Pregnancy/Puerperium– Oral contraceptive use/ Other hormonal

treatments– Ovarian hyperstimulation syndrome– Nephrotic syndrome– Polycythemia vera– Essential thrombocythemia– Paroxysmal nocturnal hemoglobinuria– Diabetes mellitus– Heparin induced thrombocytopenia– Homocysteinuria– Sickle cell disease– Thrombotic thrombocytopenic purpura– Chemotherapeutic agents

• Inherited thrombophilias suspected if– Recurrent episodes of deep venous thrombosis– Recurrent pulmonary emboli– Family history of thrombotic events– Unusual sites of venous (mesenteric, portal or

cerebral) or arterial thrombosis– Thrombotic events in childhood, adolescence

or early adulthood

• More than half of the events occur spontaneously

• Risk is increased with additional risk factors like pregnancy, surgery, trauma or OCP

Coagulation cascadeCoagulation cascade

Antithrombin III deficiencyAntithrombin III deficiency• Autosomal dominant inheritance• Three classes of inherited deficiency

– Classic or type I – decreased immunological and biological activity of antithrombin III

– Type II – low biological activity, normal immunological activity

– Type III – normal activity in the absence of heparin, but reduced in heparin dependent assays

• Acquired deficiency can occur in acute thrombosis and DIC

• A normal level of AT-III during an acute event excludes primary deficiency.

• Treatment– In acute thrombosis – Heparin with or

without AT III concentrate– Recurrent thrombosis – Long term

warfarin therapy to keep INR at 2 - 3

Protein C deficiencyProtein C deficiency• Autosomal dominant inheritance

– Homozygous – Purpura fulminans neonatalis– Heterozygous – Recurrent thrombosis

especially venous

• Acquired form – Administration of L-aparaginase, warfarin, liver

disease, DIC, postoperatively, bone marrow transplantation and ARDS

• Assays should be done after discontinuing anticoagulation for at least a week.

• Initial treatment with heparin followed by incremental doses of warfarin ( to avoid skin necrosis)

Protein S deficiencyProtein S deficiency• Exists in free form (40%) and bound to

binding proteins• Autosomal dominant inheritance, patients

prone for recurrent thromboembolism• Acquired deficiency

– Pregnancy, acute thromboembolic episodes, DIC, nephrotic syndrome, SLE, OCP, anticoagulants and L-asparaginase

• Total and free protein S levels and functional assay of protein S is done after discontinuation of anticoagulants.

• Treatment with heparin; warfarin in case of recurrent thrombosis

Activated protein C resistanceActivated protein C resistance

• Commonest inherited thrombotic disorder

• Autosomal dominant, usually associated with a single point mutation in factor V gene (Arg to Gln at position 506)

• Prone for venous thrombosis• Assay is done after discontinuation of

the anticoagulants

Antiphospholipid Antiphospholipid antibody syndromeantibody syndrome

• Antiphospholipid antibodies may be IgG, IgA or IgM

• Different antibodies are – anticardiolipin– antiphosphatidyl ethanolamine– antiphospahtidyl serine – antiphosphatidyl choline.

• Characterized by– Recurrent arterial or venous thrombosis– Recurrent fetal loss– Livedo reticualris

Livedo reticularisLivedo reticularis

• β2 glycoprotein in plasma is needed to bind to cardiolipin.

• Occurs as– Secondary to SLE, other autoimmune diseases,

Sneddon’s syndrome, acute and chronic infections, neoplasias, IBD, drugs, severe pre eclampsia, liver transplantaion

– Primary APLA syndrome

• Treatment– High dose warfarin to keep INR above 3 with or

without aspirin– In pregnancy, low dose aspirin and prednisone

is given

Infarcts of Infarcts of undetermined causeundetermined cause(Cryptogenic stroke)(Cryptogenic stroke)

• In many cases the cause of the ischemic event is not identified even after after an extensive work up

• Occurs in 20 to 50% of people with young stroke

• Recurrence risk in such cases is less

INTRACEREBRAL INTRACEREBRAL HEMORRHAGEHEMORRHAGE

• Vascular malformations• Intracranial tumours• Bleeding disorders, anticoagulant and

fibrinolytic treatment• Cerebral amyloid angiopathy• Granulomatous angitis of the central

nervous system• Hemorrhagic infarction• Trauma

Vascular malformationsVascular malformations• The vascular malformation may be

– Saccular or mycotic aneurysms– Arteriovenous malformations– Cavernous angiomas

• Intracerebral hemorrhages caused by small lesions are characterized by– Located in the subcortical white matter– Hematoma is smaller– Symptoms develop slowly– Usually subarachnoid hemorrhage seen– Younger patients with female preponderance

• MRI or histological examination needed for diagnosis

• Aneurysms– On the basis of morphology, aneurysms

are classified as saccular, fusiform or dissecting.

– Saccular aneurysms are more often acquired than congenital

– They tend to occur at the branching points in the circle of Willis and proximal cerebral arteries (40% in anterior communicating artery).

– Usually presents as SAH; less commonly as ICH, space occupying lesion producing compression, seizures, embolism from thrombus, hydorocephalus

• Associations of intracranial saccular aneurysms– Polycystic kidney disease– Fibromuscular dysplasia– Cervical artery dissection– Coarctation of the aorta– Intracranial vascular malformations– Marfan’s syndrome– Ehler-Danlos syndrome– Pseudoxanthoma elasticum– Hereditary hemorrhagic telangiectasia– Moyamoya syndrome– Klinefelter’s syndrome– Progeria

Types of aneurysmsTypes of aneurysms

• Arteriovenous malformations– Abnormal fistulous connections between

one or more hypertrophied feeding arteries and dilated draining veins

– Diagnosis suspected in Ct scan. Non-enhanced scan shows calcification and non-specific hypo- or hyperdensity.

– Contrast CT scan shows dilated veins of large malformations.

– MRI or angiogram may be needed to confirm diagnosis.

• Cavernous hemangioma– Detected using MRI– Shows a central nidus of irregular bright

signal intensity mixed with mottled hypointensity, surrounded by a peripheral hypointense ring

– Hemosiderin deposits in periphery due to prior bleeding

– Usually single lesions– Predominantly supratentorial, presents

as seizures

Intracranial tumoursIntracranial tumours• Bleeding into tumour occurs with

– Glioblastoma multiforme– Metastasis from melanoma, bronchogenic

carcinoma, renal cell carcinoma, choriocarcinoma

• Relatively rare complication• If suspected, search for primary or

secondary brain tumour and systemic focus

• Cerebral angiography and craniotomy for biopsy of hematoma wall may be needed

• Extremely poor prognosis

• Suspicion of an underlying tumour should arise when– Presence of papilloedema at presentation– Rare location, e.g., corpus callosum– Presence of ICH in multiple sites– Ring of high density hemorrhage surrounding a

low density centre in non-enhanced CT scan– Disproportionate surrounding edema and mass

effect– Enhancing nodules adjacent to h’ages in

contrast CT scan– MRI showing heterogeneous signal lesions

within a mass lesion , surrounded by hemosiderin hypointense ring and bright signal edema at periphery in T2

Bleeding disordersBleeding disorders

• Hemophilia A• Immune mediated thrombocytopenia

– Platelet count < 10,000/μl

• Acute leukemia– Acute lymphocytic leukemia– Acute promyelocytic leukemia – due to

DIC

AnticoagulantsAnticoagulants• Risk factors for IC bleeding

– Advanced age– Hypertension– Preceding cerebral infarction– Head trauma– Excessive prolongation of prothrombin

time– Severe leukoareosis in CT scan

• Slowly progressive course, larger collections causing high mortality

Fibrinolytic agentsFibrinolytic agents• Thrombolysis with streptokinase or

t-PA for MI and use of intravenous t-PA or intraarterial prourokinase for ischemic stroke associated with ICH in 0.6% and 6.4% respectively.

• Complication more in those with pre-existing vasculopathies

• Risk factors for ICH in thrombolysis of cerebral infarct– Severe neurological deficit at

presentation– Documentation of hypodensity or mass

effect on CT before treatment– Hyperglycemia pretreatment– Microhemorrhages detected in gradient-

echo MRI sequences after thrombolysis• H’ages occur at the site of preceding

cerebral infarct• Dismal prognosis

Cerebral amyloid angiopathyCerebral amyloid angiopathy

• Occurs in the elderly• Selective deposition of amyloid in cerebral

vessels, primarily small and medium-sized arteries of cortex and leptomeninges

• Recurrent and multiple lobar hemorrhages• Associated with Alzheimer’s disease• Histology – congo red positive, birefringent

amyloid material in the media an dadventitia of arteries

Sympathomimetic agentsSympathomimetic agents• Cocaine, amphetamine and

phenylpropanolamine implicated • Risk increased with heavy alcohol

intake• Mechanism – Hypertension and drug

induced vasculitis

Conditions producing both Conditions producing both ischemic and h’agic strokesischemic and h’agic strokes

• Hypertension• Moyamoya disease• Vasculitis• Cocaine and other sypathomimetic

drugs

Causes of arterial and Causes of arterial and venous thrombosisvenous thrombosis

• Homocysteinemia• APLA syndrome• Protein S deficiency

APPROACH TO APPROACH TO A YOUNG PATEINTA YOUNG PATEINT

WITH STROKE WITH STROKE

• History– Presentation similar (R/o multiple

sclerosis and malignancy)– Presence of risk factors– H/o drug intake, hematologic disordrs,

cardiac disease, vasculitis, infections, radiation

Physical examination• Ocular findings

– Corneal arcus (hypercholesterolemia)– Corneal opacity (Fabry’s disease)– Lisch nodules, optic atrophy

(Neurofibromatosis)– Lens subluxation (Marfan’s, homocystinuria)– Retinal perivasculitis (sickle cell disease,

syphilis, connective tissue disease, IBD)– Retinal occlusions (emboli)– Retinal angioma (cavernous malformation)– Hamartoma (tuberous sclerosis)– Roth spots (infective endocarditis)

• Dermatologic examination– Splinter hemorrhages, Osler’s nodes,

Janeway lesions (endocarditis)– Xanthoma (hyperlipidemia)– Café-au-lait spots, neurofibromas

(neurfibromatosis)– Purpura (coagulopathy)– Capillary angiomata (cavernous

malformation)

• Cardiovascular examination

Approach to investigationsApproach to investigationsCT scan brain /MRI brain

Urine routineHb, TC, DC, ESR, Platelet count

PCV, Peripheral smearBlood sugar, renal function,

electrolytes

• Premature atherosclerosis– Blood sugar– Lipid profile– Urine homocysteine– Lipoprotein (a)– Serum fibrinogen level– Cystathionine synthetase level in

cultures of fibroblasts or liver biopsy

• Coagulation profile– PCV, platelet count– Red cell mass– PT, INR, aPTT– Antiphospholipid antibody– Protein C, protein S assay– Activated protein C resistance– Sickle cell preparation, Hemoglobin

electrophoresis– Serum viscosity, fibrinogen levels– Ham test, sucrose lysis test– Bone marrow study– Prothrombin mutation G20210A testing

• Cardiac study– ECG– Chest X ray– Transthoracic or transesophageal

echocardiography– 24 hour Holter monitoring– Coronary angiography– Gum or rectal biopsy for amyloid

(cardiomyopathy)

• Vasculitis– ESR– Autoantibody profile– VDRL, HIV, HBsAg– Mantoux test, sputum AFB– CSF study– Leptomeningeal biopsy

• Miscellaneous– Toxiclogical studies– Serum lactate

• Further imaging studies– MRI brain– MRI with diffusion weighted imaging and

perfusion imaging– Extracranial (carotid-vertebral) doppler

ultrasound– MR angiogram– Cerebral arteriography

TreatmentTreatment• The management in the acute stage

of stroke is similar to that of usual atherosclerotic CVD

• Further management depends upon the underlying cause

• Prognosis is usually much better than strokes in older individuals

• Chance of recurrence high if the primary cause is not corrected

SummarySummary• Stroke in young individuals is a

common phenomenon• The differential diagnosis of the

etiology is wider than for strokes in older individuals

• Patients should be judiciously investigated depending on other clinical features

• Prognosis is usually better

BibliographyBibliography• Neurology in clinical practice – Bradley, 4th

edition• Principles of neurology – Adams, 6th edition• Merrit’s textbook of neurology – 6th edition• Brain’s diseases of nervous system – 10th

edition• Harrison’s principles of internal medicine –

16th edition• Stroke – Journal of American Heart

Association