Stroke, Epilepsy, Sleep disorders, Coma, and Migraine

These three groups of disorders share tantalizingly common pathogenic mechanisms, even long before migraine was considered a vasospastic disorder with “aural” constriction and “algia” dilation. Chromosome 19 became the ultimate common denominator when its Notch3¹ and CACNL1A4² genes were found responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and familial hemiplegic migraine (FHM), respectively. Interestingly, the CACNL1A4 mutation in the P/Q type calcium channel was found in the recessive tottering mice,³ the animal model for human absence and motor seizures, as well as mild ataxia.

Migraine and epilepsy may have the same “positive phenomena” that “march” at the pace of the cortical spreading depression (CSD), the result of electrical changes and oligemia, which reciprocally appear to activate each other. Migraine, then, follows epilepsy as an electrical group of disorders in which excessive neuronal activation is mediated in part by serotonergic “pacemaker” raphe nuclei cells.

Migraine and stroke may share a reciprocal causal relationship by also leading to each other. Although migraine has established itself as a risk factor for cerebral infarction, at least in young women, the classic textbook “Wolff’s Headache” highlights the directional vagaries by stating that ischemia-induced migraine might even be more frequent than migraine-induced ischemia. Migrainous infarctions are the rare outcome of auras that overstay their welcome with severe hypoperfusion, especially in the territory of the posterior cerebral artery. If this example is followed partially (i.e., overstay is not permanent), before the third decade of life, FHM is a suspect. These migraine attacks with hemiparesis, aphasia, hemianopsia, and sometimes coma, leave no trail of evidence on their way out. Much unlike the way CADASIL declares itself. Once migraine with aura attacks begin to suggest transient ischemic attacks (TIAs), strokes, and dementia, a testimonial of widespread white matter abnormalities would have been secretly collecting for many years, as unveiled by T2W and FLAIR MRI sequences. The pathogenic highly stereotyped missense mutation in Notch3 allows for reliable diagnosis in about 75% of subjects. Other conditions linking migraine (usually with aura) and ischemic strokes are essential thrombocythemia, systemic lupus erythematosus, antiphospholipid antibody syndrome, and mitochondrial cytopathies (especially mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, or MELAS, which results from a point mitochondrial DNA mutation in the tRNA Leu gene). Finally, a polymorphism in the methylenetetrahydrofolate reductase gene (C677T) is overexpressed in migraine with aura patients.

Ischemic Stroke

Ischemic stroke applies to the sudden onset of focal neurological deficits localized to the distribution of an arterial or venous territory, which either resolve within minutes to hours (TIA) or persist (i.e., due to permanent tissue injury). It may be caused by atherothromboembolism, cardiogenic embolism, small-vessel ischemic disease, cervicocephalic arterial dissections, thrombophilia, or a combination thereof.

Independent risk factors for stroke include advanced age, prior TIA, atrial fibrillation (AF), chronic hypertension (systolic > diastolic), poor left ventricular function, diabetes mellitus, coronary artery disease, and dyslipidemia. AF affects 5% of the population over 65 years of age and is responsible for about 15% to 20% of all strokes in the United States.

Hyperthermia, hyperglycemia, and diastolic hypertension threaten full functional recovery. Early recurrence of stroke is around 2% within the first 14 days. Most brain infarctions are visible on head CT within 48 hours after symptom onset, become isodense in days 10 to 21, and achieve cerebrospinal fluid (CSF)-like density by 3 months.

Lacunar syndrome presents as a (1) pure motor stroke from an internal capsule, corona radiata, or basis pontis lacune, with hemiparesis or plegia involving the face, arm, and to a lesser extent the leg, accompanied by dysarthria; (2) pure sensory stroke due to a thalamic ventroposterolateral nucleus lacune, with unilateral hemisensory deficits involving the face, arm, trunk, and leg; (3) clumsy hand-dysarthria syndrome from a basis pontis or genu of the internal capsule lacune, causing supranuclear facial weakness, tongue deviation, dysphagia, dysarthria, and impaired hand fine motor control; or (4) ataxic hemiparesis from a capsular, thalamocapsular or pontine lacunar infarction, with ipsilateral ataxia and crural paresis. Lacunar infarctions are often correlated with diabetes and arterial hypertension.
Cardioembolic syndrome results in deficits from any vascular territory, especially due to AF, the most prevalent dysrrhythmia, which carries at least a fivefold increased risk of ischemic stroke in nonvalvular AF and 17-fold in valvular types of AF.
Intracerebral hemorrhage (ICH) may be caused by hypertension, oral anticoagulant use, arteriovenous malformations, and saccular aneurysms. ApolipoproteinE2 and E4 (APOE2 and E4) are associated with lobar ICH whereas hypertension is most often associated with nonlobar ICH. Lobar hematomas in the elderly are often caused by cerebral amyloid angiopathy (CAA).
Nontraumatic subarachnoid hemorrhage (SAH) is due to ruptured intracranial aneurysms, bleeding diatheses, brain tumors, vasculitis, and intracranial dissections. Less common causes include nonaneurysmal perimesencephalic SAH, CAA, cerebral venous sinus thrombosis (CVST), bacterial meningitis, spinal cord vascular malformations, and spinal cord tumors.
Cerebral venous sinus thrombosis (CVST) presents more gradually than arterial strokes. CVST usually occurs during pregnancy or puerperium and is suspected in someone with seizures, headaches, early papiledema, and family history of venous thromboembolism or thrombophilia.

Stroke of the young

Measurement of resistance to activated protein C in plasma is highly specific for FVL mutation but also sensitive for the presence of lupus anticoagulant, increased factor VIII levels, pregnancy, and the use of oral anticoagulant therapy.

Venous thrombosis is more common in patients homozygous for factor V Leiden (FVL) or the G20210A prothrombin gene mutations than in heterozygotes. Hyperhomocysteinemia has been associated with vitamins B₁₂, B₆, and folate deficiencies, renal failure, hypothyroidism, increasing age, menopause, smoking, and psoriasis. In addition, genetic disorders affecting the homocysteine pathway (5,10-methylenetetrahydrofolate reductase [MTHFR] gene mutation and cystathionine β-synthase deficiency).

Lifelong anticoagulation is recommended for:

Recurrent thrombosis

CVST due to any thrombophilia

Multiple thrombophilias

FVL homozygous mutation

Antithrombin deficiency

Antiphospholipid antibodies

The coexistence of both arterial and venous thrombosis have only been reported in patients with homocystinuria antiphospholipid antibody syndrome and heparin-induced thrombocytopenia thrombosis (HITT). Prophylaxis is initiated during high-risk situations (surgery, trauma, immobilization) and involves using unfractionated or low-molecular-weight heparin, avoidance of hormone replacement therapy, and maintenance of normal homocysteine level (vitamins B₁₂, B₆, and folate).

Anticoagulation: Nonvalvular atrial fibrillation (NVAF) refers to AF in the absence of a mechanical prosthetic heart valve and in the absence of rheumatic mitral valve stenosis. Primary prevention trials in patients with NVAF have shown that oral anticoagulants reduce the stroke risk by 60% to 70%. Adjusted-dose warfarin (INR 2.0-3.0) is better than aspirin in the secondary prevention of recurrent stroke and thromboembolism in high-risk NVAF (CHF, previous embolism, SBP >160, women >75 years). Direct oral anticoagulants (DOACs) which include direct thrombin inhibitors and factor Xa inhibitors are beneficial in patients with NVAF.

UHF: unfractionated heparin; LMWH: low-molecular-weight heparins. Neither offer significant benefit and are not used routinely in acute ischemic stroke management.

Thrombolytic drugs: Intravenous recombinant tissue plasminogen activator (rt-PA) or alteplase at a dose of 0.9 mg/kg (maximum 90 mg) given over 1 hour is the standard medical treatment for acute ischemic stroke within 4.5 hours after onset of symptoms. Intravenous alteplase improves functional outcome at 3 to 6 months when given within 4.5 hours of ischemic stroke onset; moreover, the benefit is greatest when therapy occurs early after stroke onset and decreases continuously over time. Ten percent of the total dose is given as an initial bolus, and the rest of the dose is infused over 60 minutes. The BP must be <185/110 mm Hg and should be kept <180/105 mm Hg during the infusion and for the next 24 hours. The risk of symptomatic intracerebral hemorrhage within 36 hours of intravenous alteplase infusion is 6%, half of which may be fatal. Hyperglycemia is associated with increased risk of ICH following intravenous alteplase. The mortality rate at 3 months after acute ischemic stroke is the same in those who receive intravenous alteplase versus those who do not.

Endovascular treatment with thrombectomy: Thrombectomy has become standard treatment for selected patients with acute ischemic stroke due to proximal large arterial occlusions of the anterior circulation. The benefit for patients with a documented proximal intracranial arterial occlusion of the anterior circulation treated mainly within a 6 hour time window has been shown in several randomized clinical trials. More recently, trials using advance neuroimaging showed the benefit of thrombectomy in patients with large artery occlusion of the anterior circulation treated in delayed therapeutic windows (6-24 hours). Thrombectomy within 6 hours yields a number-needed-to-treat (NNT) between 3 and 7.7; thrombectomy beyond 6 hours (DAWN and DEFUSE 3 studies) an NNT of 3 to 3.6 (at 90 days, the modified Rankin scale was between 0 and 2 for nearly 50% of those treated compared to controls).

Emergency Treatment of Acute Ischemic Stroke

Blood pressure control with labetalol, nicardipine, clevidipine, or other agents (hydralazine, enalaprilat) to ensure that systolic blood pressure (SBP) < 185 mm Hg and diastolic blood pressure (DBP) < 110 mm Hg. Below these thresholds, antihypertensive therapy is not indicated.

Blood pressure reduction yields a nearly 30% risk reduction in major strokes. However, there is a “Blood Pressure Paradox in Acute Ischemic Stroke” (INSPIRE Study Group, Ann Neurol. 2019): higher baseline BP in acute ischemic stroke patients with large vessel occlusion or stenosis was associated with better collateral flow and better clinical outcomes. However, for patients without reperfusion, higher baseline BP was associated with increased infarct growth, leading to unfavorable clinical outcomes. The relationship between BP and outcome is highly dependent on reperfusion.

Rule Out Exclusion Criteria

Potential Mimickers	Hemorrhagic Conditions
Glucose <50 mg/dL (<2.8 mmol/L), seizure at stroke onset (if residual impairments are postictal)	ICH or SAH, previous intracranial bleed, stroke, or head trauma within last 3 months, low platelets, high prothrombin time (PT), recent lumbar puncture (LP) or arterial puncture at a noncompressible site
Hypodensity on initial CT and severe stroke (NIH score > 22) may predict ICH but these patients still benefited in the overall analysis of the National Institute of Neurological Disorders and Stroke (NINDS) trial.

Administration of intravenous alteplase should occur within 4.5 hours from stroke onset. Neurologic status is monitored every 15 minutes for 2 hours, every 30 minutes for the next 6 hours, and hourly thereafter up to 24 hours. If ICH is suspected (neurologic deterioration, new headache, acute hypertension, nausea, vomiting), discontinue alteplase infusion, obtain STAT head CT scan and draw blood for prothrombin time (PT), activated partial thromboplastin time (aPTT), platelets and fibrinogen. Prepare 6 to 8 units of cryoprecipitate containing factor VIII and tranexamic acid (TXA) or epsilon-aminocaproic acid (EACA) if hemorrhage is confirmed. A neurosurgeon may need to be consulted for the potential need for hematoma evacuation. Consider a second CT scan to assess for size change. No antithrombotic agents should be given within 24 hours of IV alteplase administration.

Additional measures include the prevention of complications from cerebral edema (mannitol, or hypertonic saline), dehydration, aspiration pneumonia, DVT (SQ unfractionated heparin 5,000 U twice daily or SQ enoxaparin 40 mg daily), fever, hyperglycemia, infection, contractures, and decubitus ulcers.

Antiplatelet Drugs

Aspirin, a selective cyclo-oxygenase inhibitor, at low doses (50-325 mg), prevents early recurrence and reduces disability and death at 3 to 6 months after a stroke with a small risk of increased intracranial hemorrhage.
Aspirin plus modified release dipyridamole (Aggrenox) (200 mg twice daily) increases modestly the benefit of aspirin monotherapy. The phosphodiesterase inhibitor dipyridamole potentiates the antiadhesive effect of adenosine decreasing platelet aggregation. Headaches are a frequent side effect.
Clopidogrel (Plavix) (75 mg qd), an adenosine diphosphate (ADP) antagonist, can be initiated in patients with intolerance to aspirin or “aspirin failure.” Clopidogrel may cause polyarticular arthritis and thrombotic thrombocytopenic purpura (TTP) within 14 days after initiation of therapy.
Clopidogrel and aspirin (dual antiplatelet therapy [DAPT]) within 12 hours of minor ischemic stroke or high-risk TIA reduces the risk of recurrent strokes, but the combination also causes more bleeding than aspirin monotherapy. Duration of DAPT should be limited to 21 days from index ischemic event and then transitioned to monotherapy.
GPIIb/IIIa receptor antagonists such as abciximab, eptifibatide, and tirofiban block the activation of the specific platelet-aggregating membrane glycoprotein receptor GPIIb/IIIa. Despite their short-term efficacy, long-term use increases mortality by a partial agonist effect.
Direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban are as effective as warfarin in reducing the risk of stroke secondary to NVAF with a reduced risk of intracranial bleeding. Risk/benefit analysis of DOACs initiation can be assessed using the CHA₂DS₂VASc stroke risk score and the HAS-BLED score for hemorrhagic risk. Anticoagulation is recommended for people with a CHA₂DS₂VASc score of 2 or above (1 for men). Warfarin is preferred in patients with AF on hemodialysis or stage V CKD or with mechanical prosthetic heart valves. If anticoagulation is contraindicated or not tolerated in people with high thromboembolic risk, left atrial appendage occlusion is recommended.
Aspirin plus dipyridamole versus clopidogrel are similar in reducing the risk of recurrent stroke at 3 years and secondary prophylaxis of MI or vascular death. Risks of hemorrhagic events and headache are higher with the combination.

Antiplatelet Agents

Drug	Target and Action
Aspirin	COX-1 inhibitor
Clopidogrel Ticagrelor Prasugrel Cangrelor	P2Y12 purinergic receptor antagonist P2Y12 purinergic receptor antagonist P2Y12 purinergic receptor antagonist P2Y12 purinergic receptor antagonist
Dipyridamole + Aspirin	Platelet phosphodiesterase inhibitor
Abciximab Tirofiban Eptifibatide	GP IIb/IIIa receptor antagonist GP IIb/IIIa receptor antagonist GP IIb/IIIa receptor antagonist
Vorapaxar	PAR-1 receptor antagonist
COX, Cycloxygenase; GP, glycoprotein; PAR, protease-activated receptor.

HMG-CoA reductase inhibitors (“statins”) and the fibrate gemfibrozil reduce the risk of stroke. Cholesterol reduction not only lowers the risk of stroke, myocardial infarction, and death from vascular causes but also the need for vascular surgical procedures in patients with previous vascular diseases.

Antidislipidemic Agents, Indications, and Dosages

Classes of Agents	Classic Indications	Agents and Dosage Range
HMG-CoA Red inhibitor (statins): inhibit rate limiting enzyme in cholesterol synthesis	High LDL, familial hypercholesterolemia, diabetes or renal failure-related hyperlipidemia	Lovastatin 40-80 Pravastatin 40-80 Simvastatin 20-80 Fluvastatin 40-80 Atorvastatin 10-80 Rosuvastatin 5-80
Bile acid-binding sequestrants (resins): shifts cholesterol into bile acid	Hypercholesterolemia without high triglycerides (triglycerides < 300 mg/dL)	Cholestyramine 4-24 g/bid Colestipol 5-30 g/bid Colesevelam 1,250 bid-tid
Nicotinic acid (niacin): reduce use of FFA for synthesis of TG and VLDL	Low HDL, familial hypercholesterolemia or combined hyperlipidemia in combination with statins	Niacin 100-4,000 Niacin ER 500-2,000 Niacin SR 500-2,000
Fibric-acid derivatives (fibrates): activates FA uptake and LPL-induced VLDL catab.	Hypertriglyceridemia *Low HDL and* LDL** in patients with CAD	Gemfibrozil 300-600/bid Fenofibrate 67-200 Clofibrate (no longer used: high mortality, cholelithiasis)
Myositis is common in patients taking statins with gemfibrozil, niacin, erythromycin, and in patients with renal insufficiency. Aggressive medical therapy (as per SAMMPRIS study) include aspirin plus clopidogrel for the first 90 days, followed by aspirin alone; statin therapy to achieve an LDL <70 mg/dL; systolic BP <140 mm Hg in nondiabetics, <130 in diabetics; hemoglobin A1c <7%, and lifestyle risk factor control (tobacco avoidance, physical activity, dietary changes, and weight loss).

Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors alirocumab and evolocumab, recommended as adjunct to diet or in combination with other lipid lowering agents (statins, ezetimibe) for the treatment of hypercholesterolemia in patients with high risk clinical atherosclerotic vascular disease on maximally tolerated LDL lowering therapy.

Arterial hypertension and stroke. Arterial hypertension is the most modifiable risk factor for stroke and the most powerful risk factor for all forms of vascular neurocognitive impairment. Arterial hypertension increases the relative risk of stroke three to fourfold. Blood pressure reduction yields a nearly 30% risk reduction in major strokes. While no specific antihypertensive agent can be recommended, starting or restarting antihypertensive therapy during hospitalization in ischemic stroke patients with blood pressure >140/90 mm Hg, who are otherwise neurologically stable, is considered safe.

Although hyperhomocysteinemia is believed by some authors to be an independent risk factor for stroke, vitamin replacement using a combination of folic acid, pyridoxine (vitamin B6), and cobalamin (vitamin B12) remains controversial.

Carotid Endarterectomy and Other Surgical and Endovascular Techniques

Carotid endarterectomy (CEA) has been successfully used in the acute management of symptomatic ICA steno-occlusive disease. The severity of carotid artery stenosis is the best predictor of stroke recurrence. CEA offers the greatest risk reduction in recurrent ipsilateral ischemic stroke for those with symptomatic carotid stenosis > 70%, especially in elderly men and those with hemispheric rather than retinal ischemia. For symptomatic carotid artery stenosis of 50% to 69% (lower stroke risk) and perioperative risk of 6%, the number needed to treat (NNT) to prevent one stroke was 15 (by NASCET). The procedure’s benefit is greatest if performed within the first 2 weeks from the ischemic event, with a marked risk reduction by 12 weeks in those with at least 70% stenosis.

In asymptomatic carotid artery stenosis of 60% to 99% the absolute risk reduction for major stroke ranges between 5% and 6% at 5 years. This modest benefit favoring CEA assumes that operative complications are below 3%. Unlike trials in symptomatic patients, the benefit is not dependent on the severity of the carotid artery stenosis. Asymptomatic patients face only a 2% annual stroke rate, which falls below 1% after successful CEA. Hence, the NNT to prevent one stroke was found to be nearly 70. Although it has not been established that asymptomatic individuals at highest risk are those with the greatest severity of stenosis, the following are the American Heart Association’s guidelines for asymptomatic stenosis:

For patients with a surgical risk < 3% and life expectancy of at least 5 years, ipsilateral CEA is considered “proven indication” for asymptomatic stenotic lesions ≥ 60% regardless of contralateral carotid artery status
When the surgical risk is between 3% to 5%, ipsilateral CEA for stenosis ≥ 75% in the presence of contralateral ICA stenosis ranging from 75% to total occlusion is “acceptable but not proven.”

Carotid revascularization. Ischemic stroke is often caused by atherosclerotic lesions of the carotid artery bifurcation, particularly in areas of low vessel-wall shear stress. Carotid artery angioplasty/stenting (CAS) of the extracranial ICA is a less invasive alternative to CEA for the treatment of carotid artery stenosis, particularly among patients with high surgical risk.

The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) is an ongoing two-parallel multicentered randomized, observer-blinded trial whose aim is to assess the treatment differences between best medical management and CEA, and the treatment differences between best medical management and CAS, in patients with ≥70% asymptomatic carotid artery stenosis. Best medical management includes an antiplatelet agent, a statin, a blood pressure-modifying agent, healthy diet (olive oil, egg whites, whole grains, high vegetable, fruits and legumes, low sugars, low meat), smoking cessation, and increased physical activity.

Limiting the severity of ischemic injury (i.e., neuroprotection) to preserve the penumbral tissues and to extend the time window for revascularization remains aspirational.

Transient Ischemic Attack

TIAs are short-lived episodes of neurologic deficit attributed to focal cerebral or retinal ischemia of sudden onset and offset. Symptoms and signs usually last less than an hour, and in 90% of cases less than 10 minutes. Using the formal 24-hour time cutoff, up to 50% of patients have evidence of acute infarction by diffusion-weighted MRI. The incidence of TIA reaches 500,000 cases per year. The 90-day risk of stroke after a TIA is about 10%, with half occurring within 2 days. In TIA attributable to ICA 70% to 99% stenosis, the 90-day stroke risk exceeds 25%.

Evaluation of TIAs includes ruling out metabolic and hematologic causes of neurologic symptoms (hypoglycemia, hyponatremia). High ESR suggests temporal arteritis or infective endocarditis. Carotid stenosis should be explored by Doppler ultrasonography, magnetic resonance angiography (MRA), or computed tomography angiography (CTA). MRA and CTA have largely replaced angiography.

Aspirin (75-1,300 mg) provides a relative risk reduction of 22% for stroke and cardiovascular events after a TIA or stroke. The benefit is smaller (˜10%) during acute stroke partly due to the risk of intracranial hemorrhage. Clopidogrel is an alternative in patients who cannot tolerate aspirin or who were taking aspirin at the time of the event.

For patients with AF and a CHA₂DS₂-VASC of 2 or above, anticoagulation with warfarin or a DOAC is recommended. Subcutaneous low-molecular-weight heparin (LMWH) or intravenous unfractionated heparin (UFH) in full dose offers no benefit in these patients: the risk of hemorrhage is higher than the reduction in recurrent stroke.

For symptomatic patients with 70% to 99% carotid stenosis, the absolute risk reduction with CEA based on a 5-year risk of stroke is 15.65 (NNT = 6); in symptomatic patients with 50% to 69% stenosis, the absolute risk reduction is 7.8% (NNT = 13).

Antihypertensive drugs yield a long-term relative risk reduction of 25% to 30% after TIA or stroke even among those without hypertension. The blood pressure target is < 140/90 mm Hg in nondiabetics and < 130/80 mm Hg in diabetics. Blood pressure lowering should be achieved slowly. Home BP targets are lower than office BP targets.

Subarachnoid Hemorrhage

Nontraumatic SAH is a medical emergency most commonly caused by ruptured cerebral aneurysms (saccular or berry). There is an overall 51% mortality or significant morbidity after aneurysmal hemorrhage. Aneurysm rebleeding is greatest in the first 24 hours (2.6%-4%). A sentinel headache or warning leak may be the event preceding a major hemorrhage in 40% of the patients. The classic presentation consists of abrupt onset of the worst headache of one’s life followed by altered consciousness, meningismus, photophobia, nausea, and vomiting. They are all poorly localizing findings, except for:

Complete oculomotor palsy is often due to posterior communicating artery (PcomA) or basilar artery apex aneurysm
Crural-predominant hemiparesis results from anterior communicating artery (AcomA) aneurysm
Carotid-cavernous fistula may occur with a ruptured intracavernous ICA aneurysm

A noncontrast head CT shows blood filling the skull base cisterns until 6 to 10 days from the bleed (MRI yields delayed identification but blood changes persist longer than 30 days). Lumbar puncture (LP) is the next step if the HCT is normal. LP may be negative if done within 6 hours from onset of symptoms.

Four-vessel cerebral angiography or CTA confirms the presence and location of the aneurysm; additional ones may coexist in 10% to 15% of patients. Aneurysms <10 mm in diameter have a rupture risk of 0.05% per year.
Brain MRI ascertains angiographically occult AVMs, cavernous malformations, and dural AVMs.

Preoperative management is based on correction of any underlying physiologic derangements, discontinuation of antithrombotics, DVT prophylaxis, and the use of nimodipine 60 mg PO or NG every 4 hours for 21 days. The use of antiepileptic drugs for seizure prophylaxis and glucocorticoids is controversial. Cerebral vasospasm with delayed cerebral ischemia is the major cause of late neurologic deficits and correlates with the amount of blood collected in the basal cisterns. It typically occurs 3 days, and peaks between 7 to 8 days, after SAH. In the presence of hydrocephalus, ventriculostomy helps maintain the cerebral perfusion pressure (CPP) >60 torr and ICP <20 torr (other measures to decrease ICP are hyperventilation, elevation of the head of the bed, and hyperosmolar agents). Treatment of brain aneurysms can be accomplished either surgically (i.e., clipping) or endovascularly (i.e., coiling). Postoperative management is intended to treat ischemic deficits due to vasospasm with avoidance of hypovolemia.

Intracerebral Hemorrhage

ICH accounts for 10% of all strokes and is associated with a ˜60% mortality within the first year. Hypertension is the most common cause and accounts for the higher incidence of ICH among blacks (50 per 100,000), twice that of whites. Excessive alcohol use increases the risk by impairing coagulation. The most common sites of ICH are the putamen (lenticulostriate branches of the middle cerebral artery [MCA]), thalamus (thalamogeniculate branches of the PCA), cerebral lobes (penetrating cortical branches of the major brain vessels), pons (paramedian branches of the basilar artery), and the dentate nucleus region of the cerebellar hemisphere (branches of the superior cerebellar artery). CAA, presenting as lobar hemorrhages in the elderly, is caused by the deposition of β-amyloid protein (mostly in apolipoprotein [APO] allele E2 carriers) or fracture of the amyloid-laden vessel wall in cortical and leptomeningeal small- and medium-sized arteries. Hereditary CAA is caused by mutations in various genes, including APP, cystatin C, gelsolin, and transthyretin.

Primary ICH (˜80%)		Secondary ICH (˜20%)
Spontaneous rupture of small vessels	Annual risk of recurrence	Associated with vasculopathies, tumors, or coagulopathies	Annual risk of recurrence
Hypertension	2%	Arteriovenous malformations	18%
Cerebral amyloid angiopathy	10.5%	Intracranial aneurysms	50%-3%^a
Vasculitis	Variable	Cavernous malformations	4.5%
Hemorrhagic infarct	Variable	Developmental venous anomalies	0.15%
		Dural venous thrombosis	10%-1%^b
		Coagulopathies	Variable
^aThe risk of recurrent (usually subarachnoid) hemorrhage from a saccular aneurysm is 50% within the first 6 months, decreasing to 3% per year thereafter. Surgical clipping or placement of endovascular coils significantly reduces the risk. ^bThe risk of recurrent venous sinus thrombosis is 10% within the first year and less than 1% thereafter.

Neurologic deterioration is primarily due to hematoma expansion within the first 6 hours, but also to worsening cerebral edema 24 to 48 hours after the onset of hemorrhage. Poor predictive factors (leading to a mortality rate of 90% at 1 month) are a low Glasgow Coma Score (<9), large volume of hematoma (>60 mL), and presence of intraventricular blood on initial CT scan.

MRA or CTA are useful tools in detecting underlying structural abnormalities. Conventional angiography may be needed for selected individuals with no obvious cause for their hemorrhage. Surgical removal of supratentorial ICH remains unproven in the majority of patients. Selective patients with superficial lobar hemorrhages may require surgery. Surgery is indicated in most instances of cerebellar hemorrhages in an effort to prevent brainstem compression (Steiner T, Al-Shahi Salman R, Beer R, et al. European Stroke Organization (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. 2014 World Stroke Organization).

Increased Intracranial Pressure

Any process displacing the rigid cranial volume (a volume of about 1,500 cm³) increases the pressure in the intracranial compartment, which causes anatomical displacement on the parenchyma, impairs cerebral blood flow, and causes ischemia, neuronal death, and/or blood-brain barrier disruption with brain edema:

Vasogenic edema is caused by neoplasm and infections, accumulating extracellular water from primary cerebral vasculature damage. This variant of brain edema responds to corticosteroids.
Cytotoxic edema caused by hypoxia and ischemia that occurs in head injury and stroke consists of accumulation of intracellular water from primary neuronal dysfunction.
Ischemic edema is initially cytotoxic and later vasogenic, reaches its peak approximately 72 to 120 hours after stroke, and does not respond to corticosteroids.

Common causes of ICP are traumatic subdural, epidural, or intracerebral hematoma (ICH); spontaneous ICH; intraventricular hemorrhage; and subarachnoid hemorrhage. When occurring without significant brain injury and treated promptly before herniation, a full recovery can be expected.

Treatment of increased ICP may require removal of tumor or hematoma; CSF drainage, correction of hyperglycemia, and head elevation.

Mannitol 20% in acutely increased ICP is administered as 0.5 to 1 g/kg bolus infusion over 30 minutes followed by 0.25 to 0.5 g/kg every 4 to 6 hours thereafter for only a brief period to avoid rebound or paradoxical increased ICP. The serum osmolarity is allowed to increase to 310 to 320 mOsm/L.
Hypertonic saline solutions may decrease elevated ICP in stroke patients refractory to mannitol administration. Target serum sodium is 150 to 155 mEq/L.
Brief moderate hyperventilation (PaCO₂ = 30 − 34 mm Hg) leads to cerebral vasoconstriction and subsequent reduction in blood volume in the “vascular subdivision of the intracranial compartment,” reducing ICP. Best considered as a temporizing measure, aggressive hyperventilation (PaCO₂ = 25 mm Hg) may reduce CPP, cause secondary ischemia, and worsen neurologic outcome.
Barbiturates decrease cerebral metabolism and may inhibit free radical-mediated lipid peroxidation. High-dose pentobarbital (10 mg/kg over 30 minutes, followed by 1-1.5 mg/kg/h, keeping levels at ˜3 mg/dL), when other measures have failed, reduces ICP but may cause hypotension.
The benefit of induced hypothermia in acute ischemic stroke is uncertain.
In selective patients with malignant cerebral edema (e.g., malignant MCA syndrome) associated with hemispheric infarction, decompressive craniectomy with dural expansion is indicated.

Patent Foramen Ovale

About 30% of the population has a patent interatrial channel that normally closes soon after birth when pressure in the left atrium exceeds that in the right. A patent foramen ovale (PFO) provides a way through which right-to-left shunting takes place. Most people with a PFO remain asymptomatic throughout life. Stroke presumably results from paradoxical embolism of thrombotic material from the venous into the arterial circulation. The size of the foramen ranges from 1 to 19 mm (mean 4.9 mm).

The following conditions are believed to increase the risk of stroke among patients with PFO:

Coexistence with atrial septal aneurysms, lesions characterized by redundant hypermobile septal tissue causing turbulent flow and present in combination with PFO in about 20% of cases.
Large opening of the PFO correlates with a more severe right-to-left shunting at rest.

Diagnosis of PFO can be established through the following tests:

Transesophageal echocardiography (TEE) with intravenous injection of microbubble contrast agents is more sensitive than the transthoracic approach. Right-to-left shunt is indicated by the passage of microbubbles into the left atrium within three cardiac cycles after opacification of the right atrium. Testing is performed at rest and during Valsalva maneuvers.
Transcranial Doppler (TCD) ultrasound of the middle cerebral artery is highly sensitive and specific to detect arterial bubbles compared with TEE. Although TCD may avoid the need for transesophageal echocardiography, it does not provide any information about other potentially important cardiac embolic sources.
Documentation of deep venous thrombosis or pulmonary embolism is critical if the diagnosis of paradoxical embolism is entertained; however, when there is evidence for simultaneous pulmonary and systemic embolism, paradoxical embolism is not necessarily confirmed (venous thrombosis may be result rather than the cause of stroke).

Therapeutic options for PFO include antiplatelet drugs, oral anticoagulants (no difference between warfarin and aspirin; rivaroxaban is not superior to aspirin), and open heart or percutaneous closure.

PFO closure is supported by recent randomized clinical trials in patients younger than 60 years with large PFO and atrial septal aneurysms. Among patients with PFO who had a cryptogenic stroke, the risk of a recurrence of stroke is lower after PFO closure combined with antiplatelet therapy than with antiplatelet therapy alone. However, there were potential biases due to unblinded referral decisions for end point and adjudications. PFO closure was associated with an increased rate of AF. However, the majority of AF episodes after percutaneous PFO closure occur early, do not relapse, and are associated with a small number of stroke events.

Neurovascular Syndromes

Middle cerebral artery (MCA) syndromes

Stem occlusion causes contralateral hemiplegia, conjugate eye deviation toward the side of the infarct, hemianesthesia, and homonymous hemianopsia. Global aphasia lateralizes the lesion to the dominant hemisphere whereas hemineglect does to the nondominant.
Upper division MCA strokes are recognized by a gradient of face and arm greater than leg involvement and a greater tendency for aphasia of the Broca rather than Wernicke type (lower division MCA strokes).
Lenticulostriate branches may cause a lacunar infarction within the internal capsule expressed as a pure motor hemiparesis.

Amaurosis fugax and Horner syndrome (from oculosympathetic damage) are the only features that indicate a lesion proximal to the MCA, at the internal carotid level.

Anterior cerebral artery (ACA) syndrome produces a gradient of hemiparesis that affects the legs more than the arms, as well as abulia, akinetic mutism, sphincter incontinence, transcortical motor aphasia (dominant hemisphere), position greater than vibration sensory loss in the legs, and paratonia. An anterior disconnection syndrome (left arm apraxia) may be present.

Anterior choroidal artery (AChA) syndrome is characterized by the clinical triad of hemiparesis (posterior limb of the internal capsule), hemihypesthesia (posteroventrolateral thalamus) and hemianopsia sparing the horizontal meridian (lateral geniculate body).

Posterior inferior cerebellar artery (PICA) syndrome, often resulting from vertebral artery occlusion or dissection, leads to the Wallenberg or dorsolateral medullary syndrome. Its onset may be preceded by neck pain hours, days, or weeks in advance. The constellation of deficits include vertigo, nystagmus, Horner syndrome, dysphagia, dysarthria, ipsilateral facial hypesthesia to pain and temperature (trigeminal nucleus) with contralateral arm, and leg hypesthesia to the same sensory modalities (lateral spinothalamic tract).

Anterior inferior cerebellar artery (AICA) syndrome, or ventral cerebellar syndrome, is distinguished by the presence of Horner syndrome, ipsilateral facial and corneal hypesthesia to pain and temperature (trigeminal spinal nucleus and tract), and ipsilateral deafness and facial paralysis from lateral pontomedullary tegmentum involvement.

Superior cerebellar artery (SCA) syndrome, or dorsal cerebellar syndrome, is recognized by the presence of a cerebellar outflow tremor (Holmes tremor) in addition to Horner syndrome, nystagmus, and ipsilateral ataxia. A fourth nerve palsy may be seen contralaterally.

Midline Basilar Artery Syndromes of the Midbrain

Weber syndrome (cerebral peduncle; PCA penetrators): fascicular CN III and contralateral upper motor neuron deficit of the face, arm, and leg.
Benedikt syndrome (ventral mesencephalic tegmentum): Ipsilateral CN III and contralateral cerebellar outflow tremor, hemiathetosis, and chorea from red nucleus and brachium conjunctivum involvement.
Claude syndrome (dorsal mesencephalic tegmentum): Ipsilateral CN III and cerebellar deficits from dorsal red nucleus involvement.
Parinaud syndrome (mesencephalic tectum): Supranuclear vertical gaze palsy, light-near dissociation, convergence-retraction nystagmus, skew deviation, and lid retraction (Collier sign).
Top-of-the-basilar syndrome: midbrain, thalamus, and temporal and occipital lobes from thromboembolic disease of the rostral basilar artery.
- Behavioral abnormalities: peduncular hallucinosis, somnolence.
- Ocular findings: full Parinaud syndrome plus visual field deficits such as hemianopsia, cortical blindness, and Balint syndrome.

Midline Vertebrobasilar Syndromes of the Pons

Medial inferior pontine syndrome (paramedian basilar penetrators): Ipsilateral paralysis of conjugate gaze to the side of the lesion and ataxia with contralateral hemiparesis and hemihypesthesia.
Medial midpontine syndrome: above plus ipsilateral limb ataxia.
Bilateral ventral pontine syndrome (locked-in syndrome): impairment of horizontal eye movements and quadriplegia with intact wakefulness, blinking, and vertical gaze movements (intact supranuclear pathways).

Midline and Lateral Medullary Syndromes

Lateral medullary syndrome (Wallenberg syndrome): ipsilateral Horner syndrome, facial analgesia and thermoanesthesia, dysphagia, dysphonia, and cerebellar ataxia with contralateral hemihypesthesia due to intracranial vertebral artery and, less commonly, PICA occlusion.
Medial medullary syndrome: ipsilateral CN XII and contralateral hemiparesis-hemihypesthesia from distal vertebral artery steno-occlusive disease or atheromatous disease of penetrating branches (deep sensory modalities) of the anterior spinal artery.

Posterior cerebral artery (PCA) syndrome: Any combination of contralateral homonymous hemianopsia or quadrantanopsia with macular sparing, visual field neglect (nondominant lesion), visual and color agnosias, prosopagnosia, alexia without agraphia, transcortical sensory aphasia, and Dejerine-Roussy syndrome (thalamic pain, vasomotor disturbances, and choreoathetosis or hemiballism).

Spinal artery (SA) syndromes: Anterior—paraplegia, thermoanesthesia, and analgesia below the level of the lesion with preservation of proprioception, commonly occurring in the border zone segments between T1 and T4 and L1. Posterior—loss of proprioception and vibration below the lesion.

Thalamic Syndromes

Except for olfaction, most sensory modalities are somatotopically organized in the thalamus, from which projections are sent to the cortex. Only very fine discriminative sensory functions such as stereognosis, graphesthesia, two-point discrimination, and precise tactile localization require the cortex.

The internal medullary lamina divides the thalamus into the anterior, medial, and lateral nuclear groups. The centromedian nucleus, within the intralaminar nuclei of the internal medullary lamina, is the rostral extension of the brainstem reticular formation (arousal). The anterior nucleus, which lies between the Y-shaped arms of the internal medullary lamina, connects with the mammillary bodies and the cingulate gyrus (limbic system).The dorsomedial (DM) nucleus (cognition, affect, memory), is a target in Wernicke encephalopathy, as are the mammillary bodies. The ventral posterior lateral (VPL) and ventral posterior medial (VPM) nuclei are the major sensory relay nuclei for body (VPL) and face (VPM). They relay lemniscal (light touch, pressure, vibration, and position) and spinothalamic (pain and temperature) sensation to the somathesthetic cortex (Broadmann areas 1-3). Strokes affecting them may produce the syndrome of thalamic pain. The ventrolateral (VL) nucleus receives input from the globus pallidus and cerebellum and projects to the motor and premotor cortices.

Four specific stroke syndromes are recognized:

Anterior infarcts (occlusion of tuberothalamic or polar artery, arising from the posterior communicating artery or paramedian or thalamoperforating arteries) consist of perseverations, apathy, and amnesia.
Paramedian infarcts (occlusion of thalamoperforating arteries which originate from the first [P1] segment of the PCA) may lead to cyclical psychosis, manic delirium, personality changes, amnesia, vertical gaze paresis, and “thalamic dementia” in extensive lesions.

Inferolateral infarcts (occlusion of thalamogeniculate arteries, from the second [P2] segment of the PCA) may lead to hypesthesia and ataxia.

A 53-year-old man with acute onset of isolated, painless, left hemiataxia. Brain MRI shows restricted diffusion in the right thalamus. Acute isolated hemiataxia, most often due to infratentorial (cerebellar) stroke, may also occur with supratentorial (thalamic) lesions or damage to cerebellar pathways (dentatorubrothalamocortical or corticopontocerebellar).

Posterior infarcts (occlusion of medial and lateral branches of the posterior choroidal artery, which originates from the P2 segment of PCA) consists of hypesthesia, homonymous horizontal sectoranopsia (due to involvement of the lateral geniculate body), neglect, and aphasia.

Stroke Patterns (A)

Diffusion-weighted MRI shows restricted diffusion on the anterior right frontal region consistent with an acute infarct in the superior division of the right middle cerebral artery (MCA).

CT head without contrast shows a large parenchymal hemorrhage centered in the left temporal lobe measuring approximately 4.7 × 3.2 cm extending into the parietal region. There is slight rightward shift

Diffusion-weighted MRI shows restricted diffusion on the distribution of the posterior inferior cerebellar artery (PICA) consistent with an acute infarct.

Stroke Patterns (B)

Noncontrast CT of the head shows extensive amount of SAH with focal intraparenchymal hemorrhage in the left temporal lobe. There is also large amount of intraventricular hemorrhage extending caudally to the upper cervical spinal canal. The patient was found to have a ruptured left posterior communicating artery aneurysm.

CT head without contrast: Left—status post right frontal parietal craniectomy with decompression of hemorrhagic right MCA territory infarction in a patient with cervical right ICA occlusion; right (6 weeks later)—resolution of previously seen mass effect and edema in the right MCA territory infarct with no evidence of new ischemic change or hemorrhage.

Stroke Patterns (C)

CT head without contrast shows an acute hemorrhage in the left caudate nucleus dissecting into the ventricles.

DW MRI shows a focal area of restricted diffusion in the right posterolateral medulla (Wallenberg syndrome).

DW MRI shows signal changes with an acute infarction of the left temporal lobe in a patient with Wernicke aphasia.

Axial T1-weighted MRI of a left PCA arteriovenous malformation (AVM).

CT head without contrast shows remote right PCA distribution infarct.

DW MRI shows an acute lacunar infarction in the left periventricular white matter and posterior limb of the internal capsule.

Cerebral angiogram of a large left parietal AVM from a 51-year-old man with partial complex seizures.

Stroke Patterns (D)

CT brain demonstrates hypodensity with loss of gray-white matter differentiation involving the left frontal and parietal lobes compatible with infarcts involving the left anterior and middle cerebral artery territories.

DW MRI shows restricted diffusion involving the left anterior and middle cerebral artery territories with mild effacement of the sulci of the sulci overlying the left frontal and anterior parietal lobes.

Early CT signs of ischemic stroke include (1) hyperdense vessel, (2) loss of insular ribbon, (3) obscuration of the lenticular nucleus, (4) loss of gray-white matter differentiation, (5) sulcal effacement, and (6) focal hypoattenuation

CT (left) shows a hyperdense MCA, an early CT diagnostic feature of an acute ischemic stroke. DW MRI (right; same patient) demonstrates restricted diffusion on the superficial and deep left MCA territory. This patient subsequently developed brain edema and herniation consistent with a malignant left MCA infarction. The underlying mechanism of malignant MCA infarction is either a carotid artery terminus (carotid T) occlusion or a proximal MCA occlusion.

Hemorrhagic Neuroimaging Patterns

CT without contrast: Left and middle—hemorrhagic conversion of a PCA stroke. Right—intraparenchymal hemorrhage with surrounding edema, midline shift, and intraventricular extension with hydrocephalus in an 84-year-old man with a prior right temporal lobar hematoma suspected to have cerebral amyloid angiopathy.

CT without contrast: hemorrhagic conversion of metastatic breast cancer.

CT and T2W and postgadolinium T1 MRI: Hemorrhage in glioblastoma.

CADASIL

CADASIL is an inherited autosomal dominant condition characterized by migraine headaches, recurrent strokes, and frontal-predominant dementia. Classically, migraine occurs in the third to fourth decades, strokes in the fourth and fifth, dementia in the sixth and seventh, and death usually in the seventh decade. Psychiatric disturbances and epileptic seizures are part of the phenotypic spectrum. CADASIL is considered the most frequent cause of stroke of genetic origin. Although the clinical features are confined to the CNS, the pathology involves systemic arterioles, allowing “peripheral” tissue to be used for diagnostic purposes.

Point mutations in the Notch3 gene cause CADASIL. This gene codes for a transmembrane protein that participates in an intercellular signaling pathway essential for controlling cell fate during development. Thus far, all mutations reported in CADASIL occur in the extracellular portion of the protein, in the first 23 of its 33 exons. Since 60% to 70% of mutations cluster in exons 3 and 4, a limited screen can examine these exons alone. About a sixth of sporadic patients with MRI suggestive of CADASIL but negative family history carry the notch3 gene mutation in exons 10, 11, and 19.

If genetic testing is not available, diagnosis can be confirmed by the combination of suggestive brain MRI features and specific skin biopsy findings.

Brain MRI demonstrates confluent regions of high signal on T2W and FLAIR sequences in the periventricular and deep white matter (with U-fiber involvement), anterior temporal pole, external capsule, basal ganglia, and brainstem (see next page). Hemosiderin deposits due to microbleeds can be seen in the thalamus.
Skin biopsy shows PAS-positive granular deposits adjacent to the basement membrane of the smooth muscle cells of arterioles, which, on electron microscopy, consists of the pathognomonic granular osmiophilic material (GOM). Immunostaining the tissue specimen with a notch3 monoclonal antibody increases the sensitivity and reduced false negatives.

Patients with an autosomal dominant pattern of transmission of headache, stroke, and/or dementia, especially when the MRI findings are suggestive of leukoaraiosis, can be directly tested for Notch3 mutation status without first undergoing skin biopsy with electron microscopy. Other small vessel vasculopathies that need consideration in the differential include hereditary vasculopathies (Fabry disease, homocystinuria), arteriosclerosis (often associated with smoking, hyperlipidemia, and hypertension), vasculitis, and CAA. Nonvasculopathic leukoencephalopathic disorders mimicking CADASIL include cerebrotendinous xanthomatosis and hereditary leukoencephalopathy with axonal spheroids due to CSF1R (colony stimulating factor 1 receptor) mutations. This disorder leads to young-onset dementia, pyramidal dysfunction, parkinsonism, and ataxia, with progression to death within 10 years. Pathology shows demyelination with sparing of subcortical U fibers, axonal damage with neuroaxonal spheroids, and nonmetachromatic, sudanophilic lipopigment within macrophages and glia.

Classic Brain MRI Findings of CADASIL

The axial brain MRI shown here of a Notch3-positive patient, admitted for recurrent headaches, demonstrated confluent white matter abnormal signal on FLAIR (left column) and T2W (right column) sequences in, among others, two classic regions: (1) the anterior temporal pole (upper row; rarely affected in other leukoencephalopathies) and (2) the external capsule (lower row). Basal ganglia and pons are often affected. Cystic infarcts or enlarged perivascular spaces are also common.