Stroke in the young



Ischemic stroke


Ischemic strokes occurring between 15 - 45 years of age account for approximately 1% of all strokes in the community and for 4 - 12% in specialized tertiary centers. Despite an extensive work-up the cause remains unclear in 15 - 40% of patients. The annual mortality rate is around 4.5% after the 1st year and 1.6% during the subsequent 2 years. CSF studies may show transient elevation in the IgG synthesis after ischemic injury in the nervous system.


Early atherosclerotic large vessel disease: There is usually a positive family history of early atherosclerosis (hyperlipidemia) or history of predisposing conditions such as diabetes and/or hypertension, homocystinuria or other metabolic disease (AFB and MELAS).


Nonatherosclerotic disease: Genetically determined: Connective tissue disorders: NF-1, Ehlers-Danlos type IV (hyperelasticity of the skin and hyperextensibility of the joints, epilepsy with cerebral cortical dysplasia) and Marfan syndrome. Vasculopathies: fibromuscular dysplasia and moyamoya disease. Cerebroretinal vasculopathy (CRV): The presence of a positive family history and generalized vasculopathy (abnormal liver function tests, abnormal Funduscopy and colon telangiectasia) are characteristic for CRV. The disease needs to be differentiated from CAA, CADASIL and vasculitis. CADASIL: Recurrent stroke (cerebral infarcts) (70-80%) and progressive cognitive impairment (subcortical dementia with pseudobulbar palsy and urinary incontinence) (30-50%) are the main clinical manifestations of CADASIL. Additional manifestations inlude migraine with aura (20-40%) and mood disturbance (30%). MRI reveals ‘leukoaraiosis’ consisting of extensive cerebral white matter lesions and subcortical infarcts. Temporal lobe and external capsula-insula hyperintensity is a radiologic marker of CADASIL. The disorder is autosomal dominant and is caused by mutations in the Notch3 gene on chromosome 19q13. The presence of a clear family history in the context of typical clinical and radiologic findings makes the diagnosis straigthforward. Skin biopsy with ultrastructural examination of small blood vessels may be diagnostic. Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS): Initial manifestations of this autosomal dominant multi-infarct syndrome with systemic involvement are visual impairment and renal insufficiency with proteinuria; neurologic deficits occurring in the 3rd or 4th decade of life. Symptoms included migraine-like headache, psychiatric disturbance, dysarthria, hemiparesis, and apraxia. Ophthalmologic evaluations may reveal macular edema with capillary dropout and perifoveal microangiopathic telangiectases, renal abnormalities (proteinuria and hematuria). Neuroimaging consistently demonstrates contrast-enhancing subcortical lesions with surrounding edema. CADASIL needs to be excluded in the differential diagnosis. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): This form is associated with osseous manifestations e.g. spinal deformities in addition to MRI findings of leukoencephalopathy and lacunar infarcts. Others: familial hemiplegic migraine. Non-genetically determined: Cerebral vasculitis: Vasculitis may be the initial manifestation of a systemic process, such as meningovascular syphilis, meningitis, mycoplasma infection, Takayasu disease, PACNS, SLE, Sjögren syndrome, PAN, Wegener granulomatosis, Churg-Strauss syndrome, Behçet disease, RA, drug abuse (particularly amphetamine and cocaine abuse), or MCTD. Focal CNS vasculitis, on the other hand, may be the sequela of a preceding viral infection (occurs in previously healthy children with no other identified risk factors), such as with EBV or VZV. The time elapsed from the primary varicella zoster infection to vasculitic symptoms may vary from weeks to months. Since the skin lesions resolve prior to the onset of vasculitic symptoms, varicella vasculitis may be underrecognized. Furthermore, postinfectious varicella vasculitis has been reported to cause focal angiitis at the M1 segment of the MCA near the origin of the lenticulostriate arteries. Acyclovir may be helpful in preventing further viral production, but its benefit in the resolution of vasculitis is unclear. Others: Henoch-Schönlein purpura, arterial dissection. Carotid artery dissection is often associated with ipsilateral Horner syndrome.


Cardioembolic stroke: Under the age of 30 the heart is the leading source of emboli (rheumatic valvular disease, bacterial endocarditis, atrial myxoma and congenital abormalities). Infective endocarditis causes neurologic deficits in 20% of cases. Risk factors for infective endocarditis include surgical or invasive diagnostic procedures, iv drug abuse, recent dental procedures, neoplasms and valve replacement procedures. Complications may be aseptic meningitis, brain abscess and encephalopathy. Brain hemorrhage occurs typically in iv drug users  (Staphylococcus aureus endocarditis). Transesophageal echocardiogram is more useful in the diagnostic work-up than tranthoracic echocardiogram. Complement and urinalysis are usually abnormal, together with increased ESR, and prominent weight loss, skin lesions and fever. Other causes are atrial fibrillation, right-left shunt with deep venous thrombosis and atrial myxoma.


Trousseau syndrome: Small strokes due to hypercoagulability or nonbacterial thrombotic endocarditis develop early in the course of cancer and need to be differentiated from vasculitis.


Hypercoagulable states: About 35% of patients with ischemic stroke of undetermined origin have coagulopathy. There is often a family history. Congenital coagulation deficiencies of AT III, protein C and S: Both the latter are autosomal dominant inherited disorders resulting in stroke or more often venous thrombosis (most often children). The defective gene is located at chromosome 2q13 (protein C) and 3p11 (protein S). Activated protein C resistance (factor V Leiden) may be another cause of stroke related to protein C. Antiphospholipid syndrome (APLS): This syndrome can masquerade vasculitis. The syndrome is part of the coagulopathies and results clinically in migraine, recurrent ischemic strokes or TIAs, livedo reticularis, acrocyanosis, ulceration, Raynaud's phenomenon, and purpuric macular lesions, thrombocytopenia, recurrent miscarriages (up to 30%), and thickening of the mitral valve. Age is significantly associated with coagulopathy with anticardiolipin IgG antibodies titer. The current diagnostic criteria for neurologic diagnosis of probable APLS are: (a) age < 55 years; (b) episodes of brain infarction, TIA, amaurosis fugax, retinal infarction, myelopathy, vascular dementia, or abnormal movements such as chorea; and (c) the presence of antiphospholipid antibodies of which there are at least two types: lupus anticoagulant and anticardiolipin antibody: high levels of IgG anticardiolipin antibodies (titer >16 on at least 2 occasions, 2 to 3 months apart), presence of lupus anticoagulant (abnormal aPTT, Kaolin clotting time test), or both. These antibodies are present in about 25% of patients with APLS and are associated with an increased risk for thrombosis; anticardiolipin antibodies resulting predominantly in venous thrombosis, while lupus anticoagulant is associated with both venous and arterial thrombosis (including coronary, cerebral, retinal and lower limbs). 8-10% of all patients with venous thrombosis have antiphospholipid antibodies. In patients with SLE these circulating procoagulant antibodies are found in 7-58% of patients. 23-58% of patients with lupus anticoagulant develop thrombosis, often recurrent. Sneddon syndrome (antiphospholipid antibodies, stroke and livedo reticularis in the absence of other systemic disease). Hematologic disorders: Anemia in general but in particular, sickle cell anemia: 17% of patients have cerebrovascular symptoms by early adulthood. Neuroradiologically, the disease may present with confluent white matter abnormalities, but often has gray matter accompaniment, and usually occurs in patients with established clinical disease. The transmission is autosomal recessive. Polycythemia vera and essential thrombocytosis.


Cryptogenic stroke: About half of the strokes in young patients are diagnosed as cryptogenic.


Non-traumatic Hemorrhagic stroke:


ICH is responsible for about 10% of all strokes, whereas 7% are attributed to SAH.


SAH: Ehlers-Danlos type IV, Marfan and polycystic kidney disease.


Vasculopathy: Moyamoya disease, eclampsia or postpartum vasculopathy


Hemorrhagic infarction: Venous infarcts are nearly always hemorrhagic. 




Cerebral venous thrombosis


Aneurysms, hemangiomas, AVM and cerebral cavernous malformations: The latter has a (multiple) popcorn-like lesions on T2 MRI images.


Vasculitis: PAN, PACNS.


Drug abuse: Sympathomimetic drugs, especially, cocaine and amphetamines.


Others: Coagulopathy and sickle cell disease