Clinical manifestations

Presentation and course

• The clinical manifestations of drug-induced cerebrovascular disease are like those of cerebrovascular disease due to other causes.

• Prognosis varies according to the pathology of the drug-induced process.

The clinical manifestations of drug-induced cerebrovascular disease are no different from those of cerebrovascular disease due to other causes, except for the link to the suspected drug and possible added adverse effects caused by that drug.

Prognosis and complications

The prognosis varies according to the pathology of the drug-induced process. Most cases of vasculitis and vasospasm induced by drugs resolve when the offending medication is discontinued. The prognosis in cerebral infarction is somewhat better than in those patients who have serious underlying atherosclerotic cardiovascular disease. Withdrawal of the medication causing the cerebral ischemia prevents the recurrence of these episodes. In cases of intracerebral hemorrhage, the prognosis is worse and depends on the size and location of the hemorrhage.

Clinical vignette

A 56-year-old man without a previous history of stroke received intravenous recombinant tissue plasminogen activator for an evolving myocardial infarction and developed aphasia and right hemiparesis during the infusion. Possibility of an intracerebral hemorrhage was considered, but CT scan and MRI showed an ischemic stroke without evidence of hemorrhage. It is likely that in this case the infusion resulted in fragmentation of a cardiac thrombus, resulting in an ischemic cerebral stroke. Although hemorrhagic stroke is a more common complication of intravenous recombinant tissue plasminogen therapy, an ischemic stroke may also rarely occur.

Biological basis

• Cerebrovascular disease can occur as an adverse effect of several drugs and other substances.

• Pathomechanism varies according to the primary effect of the drug where the manifestations of cerebrovascular disease are secondary.

Etiology and pathogenesis

Table 2 lists various drugs associated with cerebrovascular disease. Several of these are from anecdotal case reports, whereas others have an established association.

Table 2. Drugs Associated with Cerebrovascular Disease

Therapeutic substances
	• Allopurinol • Androgens • Anticoagulants* • Antiplatelet aggregation agents: aspirin • Antineoplastic drugs* • Antipsychotics: risperidone • Beta-blockers • Calcium channel blockers • Decongestants containing pseudoephedrine • Doxazosin • Epsilon amino caproic acid • Ergot derivatives* • Erythropoietin • Ginseng • Hematopoietic stem cell transplantation • Isotretinoin • Nicotine • Nitrates • Nonsteroidal antiinflammatory drugs: cyclo-oxygenase-2 inhibitors • Oral contraceptives • Phentermine for weight loss • Phenylpropanolamine • Praziquantel for neurocysticercosis • Proton pump inhibitors • Quetiapine • Selective serotonin reuptake inhibitors • Triptans: nasal sumatriptan
Diagnostics
	• Cerebral angiography • Radiologic contrast media • Pharmacologic stress-testing using adenosine perfusion imaging
Substance abuse
	• Alcohol • Drug abuse*
* indicates an established association Updated from: (18)

Anticoagulant drugs. Both hemorrhagic and thromboembolic complications have been reported in patients on anticoagulant therapy for cardiac indications. A nonhemorrhagic cerebral infarct may convert to a hemorrhagic infarct after anticoagulant therapy. Preexisting vascular lesions (eg, intracranial aneurysms) may rupture during anticoagulant therapy. Risk factors for anticoagulant-induced intracerebral hemorrhage include anticoagulation intensity, hypertension, age, and previous stroke or cerebrovascular disease (39). Intracerebral hemorrhage is the most serious complication of oral anticoagulant therapy with mortality exceeding 50%. The excess of microbleeds in warfarin users with intracerebral hemorrhage compared to other groups suggests that microbleeds increase the risk of warfarin-associated intracerebral hemorrhage (26). Dabigatran is an oral replacement for warfarin for prevention of thromboembolic complications of atrial fibrillation. Intracranial bleeding can occur during dabigatran treatment, but the incidence is lower than during warfarin treatment. Hematomas that arise during dabigatran treatment are often small to moderate in size, do not expand, and are manageable, eg, by surgical evacuation with good prognosis (22). One of the problems with dabigatran is that plasma levels vary considerably following a single fixed dose. Dabigatran’s high variability is not considered to be a desirable characteristic for a drug where not enough anticoagulation means loss of benefit in stroke prevention and too much anticoagulation increases the risk of hemorrhage (28). Although not required by the FDA, the European Medicines Agency recommends therapeutic drug monitoring. A clinical trial is testing the hypothesis that the incidence of hemorrhagic stroke is lower in patients receiving new oral anticoagulants (NOACs) for nonvalvular atrial fibrillation such as dabigatran, rivaroxaban, apixaban, and edoxaban than in those receiving warfarin, and this is due to the difference in the effects of warfarin and NOACs on the progression of cerebral microbleeds (41).

Antiplatelet aggregation agents. The benefits of aspirin outweigh its hemorrhagic adverse effects in patients at high risk of vascular diseases. However, prolonged use of aspirin is associated with an increased risk of intracerebral hemorrhage. Aspirin-associated intracerebral hematoma tends to be lobar, suggesting that its pathology may be different from that of spontaneous intracerebral hemorrhage in nonaspirin users. Brain microbleeds are associated with antiplatelet-related intracerebral hemorrhage (14).

Thrombolytic therapy. Intracerebral hemorrhage as a complication of thrombolytic therapy is described in a separate article in MedLink Neurology.

Antineoplastic drugs. Antineoplastic agents have been associated with cerebral hemorrhage, infarction, and cerebral venous thrombosis. In some cases, it is difficult to determine whether stroke is caused by chemotherapy or by the cancer itself. Cancer patients are at increased risk for atrial fibrillation. Both are independent risk factors for ischemic stroke, and although chemotherapy exacerbates this risk, this association is observed even in the absence of any cancer-specific treatment (13).

The mechanisms by which antineoplastic agents may lead to stroke include endothelium toxicity and abnormalities of coagulation factors. Susceptibility to develop peripheral arterial disease, or stroke, or both reflects the complex interplay between patients’ baseline risk and pre-existing vascular disease, particularly hypertension and diabetes, while evidence for genetic predisposition is increasing (47). Proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), approved for use in multiple myeloma, carry a black box warning for an increased risk of stroke. Cerebrovascular events have been reported with the use of following chemotherapeutic agents:

	• Cisplatin
	• 5-fluorouracil
	• Carboplatin
	• Asparaginase, vincristine, daunorubicin
	• Vascular endothelial growth factor (VEGF) inhibitors, eg, prolonged low dose cyclophosphamide therapy reduces the concentration of circulating VEGF.
	• Anthracyclines can induce endothelial dysfunction and increase arterial stiffness.
	• Hormonal-chemotherapeutic regimens

Cerebral venous sinus thrombosis is an uncommon but recognized complication of treatment of leukemia with chemotherapeutic agents (34). Intracerebral hemorrhage following alemtuzumab (chemotherapeutic used off-label for treatment of multiple sclerosis) is likely due to hypertension that may occur during the infusion of the drug and rise of mean systolic blood pressure increases by 20 mmHg or more, or more than 20% throughout the infusion period, and is an indication for admission to the hospital for close observation (02). A 32-year-old man with testicular cancer presented with homonymous hemianopia secondary to acute stroke following 2 cycles of bleomycin/etoposide/cisplatin chemotherapy (20).

Antipsychotics. Risperidone, a dual 5-HT2 and dopamine receptor antagonist used for the treatment of schizophrenia, is associated with a possible increased risk of stroke among elderly patients. Risperidone is widely used to control behavioral disorders such as delusions, aggression, and anxiety in elderly patients with dementia. Stroke as an adverse event has not been reported with the other commonly used antipsychotic drug clozapine. Regulatory agencies have issued warnings about an increased risk of stroke in elderly patients with dementia receiving atypical antipsychotics, but a systematic review found conflicting findings. A population-based retrospective study has shown that use of second-generation antipsychotic agents is not associated with increased risk of cerebrovascular adverse events compared to first-generation agents in older adults, but long-term use of both second- and first-generation antipsychotic agents is associated with increased risk of cerebrovascular adverse events (27). A systematic review of clinical trials found that the highest risk of stroke is related to the first weeks of treatment with antipsychotic drugs and stroke is more likely to occur in patients with older age, cognitive impairment, and vascular illness (35). A systematic review and meta-analysis to evaluate increased risk of cerebrovascular accident associated with the use of antipsychotics suggests that the use of first-generation antipsychotics as opposed to second-generation antipsychotics significantly increased the risk of a cerebrovascular accident (15).

Androgens. Thromboembolic complications are not generally recognized as side effects of androgen therapy. However, some experimental evidence shows that testosterone stimulates thrombus formation by suppressing prostacyclin production in arterial smooth muscles cells. Isolated cases report of strokes in young men who have taken excessive testosterone for hypogonadism or anabolic androgenic steroids for athletic enhancement.

Beta-blockers. There are several case reports of beta-blockers administered to patients with migraine being related to the onset of a cerebrovascular ischemic event. Migraine itself is a risk factor for stroke. Nonselective beta-blockers, in addition to their vasoconstrictive effect, cause an increase in platelet activity by stimulation of the platelet alpha-2 receptors.

Ergot derivatives. Several ergot derivatives are used therapeutically. They have vasoconstrictor properties. The following have been reported to be associated with cerebrovascular disorders:

Dihydroergotamine. This is used in the treatment of migraine. There is a case report of a patient with migraine who developed superior sagittal sinus thrombosis after an intravenous injection and died due to cerebral infarction and increased intracranial pressure (12).

Ergonovine. This is an ergot alkaloid derivative used for control of postpartum hemorrhage. Several case reports of postpartum cerebral angiopathy due to ergonovine exist.

Bromocriptine. This ergot derivative has been reported to produce cerebral angiopathy. Cerebrovascular accidents have been reported in women who used bromocriptine for suppression of lactation during the postpartum period. Cases of stroke with seizures were reported following the use of bromocriptine for suppression of lactation, which led to a withdrawal of the drug for this purpose in the United States in 1994. There have also been reports of bromocriptine-induced cerebral vasculitis. This complication has been noted only in postpartum women, but not in patients with Parkinson disease treated with bromocriptine.

Erythropoietin. This is indicated for the treatment of chronic anemia associated with end-stage renal disease. It is considered to have a neuroprotective effect. Erythropoietin misuse by athletes for performance enhancement may lead to stroke due to erythrocytosis.

Estrogen and progestin. Several randomized, double-blind, placebo-controlled studies of estrogen plus progestin in postmenopausal women were stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group. A national cohort study in Denmark found increased risk of ischemic stroke with oral hormone therapies that was comparable to findings from randomized studies, a reduced risk with vaginal estrogen, and no risk of stroke with transdermal application (25). Results of a Swedish study suggest that the initiation of hormone therapy within 5 years after onset of menopause is associated with a decreased risk of stroke as compared to no use at all, whereas late initiation of therapy is associated with increased risk of stroke when conjugated equine estrogen is used as single therapy (09).

Hematopoietic stem cell transplantation. Neural stem cell and mesenchymal stem cell therapies have been safely used for the treatment of stroke in experimental studies. Neurologic complications of graft-versus-host disease following commonly used hematopoietic stem cell transplantation for hematological disorders and cancer include cerebrovascular events.

Immunoglobulin. Intravenous immunoglobulin therapy has been used for the treatment of Guillain-Barré syndrome and myasthenia gravis. Isolated cases of cerebral infarction have been reported following high-dose intravenous immunoglobulin therapy (08). Advanced age, atherosclerosis, increased serum gamma globulin level, and altered blood viscosity may be predisposing factors for thromboembolic events.

Nonsteroidal antiinflammatory drugs (NSAIDs). A systematic review of epidemiological studies indicates that the use of NSAIDs is significantly associated with a higher risk of developing hemorrhagic stroke (16).

Some cyclo-oxygenase-2 (COX-2) inhibitors, included in NSAIDs, were withdrawn from the market or restricted in use following concern with cardiovascular adverse effects. COX-2 inhibitors are considered contraindicated in elderly patients at risk for stroke.

A study has compared diclofenac use before and after implementation of European risk minimization measures in 2013, focusing on diclofenac initiators and prevalence of congestive heart failure (NYHA class II-IV), ischemic heart disease, peripheral arterial disease, and cerebrovascular disease (new contraindications) in these patients in Germany (37). The overall decline of about 30% in diclofenac initiation between 2011 and 2014 was largely independent of the presence or absence of new contraindications.

A multi-country European study found that highest significant risk of ischemic stroke was observed for ketorolac, but significantly increased risks (in decreasing order) were also found for diclofenac, indomethacin, rofecoxib, ibuprofen, nimesulide, diclofenac with misoprostol, and piroxicam (36). It is recommended that NSAIDs should be used judiciously, and their efficacy and safety should be monitored.

Oral contraceptives and cerebrovascular disorders. Considerable evidence can be found in the published literature of an association between oral contraceptives and cerebrovascular disease. The following types of cerebrovascular disease have been reported:

- Superior sagittal sinus thrombosis - Vasculitis - Dural arteriovenous fistula

Studies on the relation of oral contraceptives to stroke. Relation of oral contraceptives to stroke is controversial.

Stroke in young women should not be ascribed to oral contraceptives unless other possible causes are excluded. Risk factors for stroke in patients on oral contraceptives that have been identified in various studies are as follows:

	• Age over 35 years
	• Hypertension. Combined oral contraceptives can cause hypertension in about 4% to 5% of normotensive women and increase blood pressure in about 9% to 16% of women with existing hypertension. The start of oral contraceptives in a previously hypertensive woman can increase the risk of hemorrhagic stroke.
	• Insulin-dependent diabetes mellitus
	• Migraine. It is generally accepted that migraine is aggravated by oral contraceptives. Exposure to the effects of oral contraceptives may greatly increase the risk of ischemic stroke in some migraine subpopulations.
	• Previous history of thromboembolic disease
	• Smoking is clearly identified as increasing the risk in most studies.

Besides ischemic stroke, superior sagittal sinus thrombosis has also been reported in women taking oral contraceptives. In addition, the incidence of subarachnoid hemorrhage is increased in women taking oral contraceptives, and the mortality is higher.

The Women's Lifestyle and Health Cohort Study included 49,259 Swedish women, aged 30 to 49 years at baseline, to determine the risk of ischemic and hemorrhagic stroke with oral contraceptive use (46). There was no significant association of oral contraceptive use with ischemic or hemorrhagic stroke. Compared with nulliparous women, parous women had a statistically significant lower risk of hemorrhagic stroke, but similar association was not found for ischemic stroke.

Some gene polymorphisms may increase the risk of stroke with oral contraceptive use. A population-based case-control study in China showed that combined oral contraceptive users with rs10958409 GA/AA or rs1333040 CT/TT genotypes had an increased risk of overall stroke by 1.59-fold and 3.24-fold, respectively, as compared to nonusers with wild-type genotypes (44). A case-control study has shown that estrogen receptor 2 (ESR2) gene polymorphisms are associated with the risk of first-ever stroke in Chinese women, and the AA genotype of rs4986938 in those using combined oral contraceptives could significantly increase the risk of hemorrhagic stroke (45).

The American Heart Association/American Stroke Association summarized data on stroke risk factors that are unique to and more common in women to update prior stroke guidelines for women (06). In addition to other medical disorders, the statement includes oral contraceptives and hormone replacement as risk factors.

An analysis of risk factors of stroke and venous thromboembolism in females with oral contraceptives use showed that cigarette smoking was significantly more frequent in the group with stroke (50% vs. 25%), and the prevalence of cigarette smoking in the group with venous thromboembolism did not exceed the frequency in the general population (11). Women on oral contraceptive pills have higher risk of venous as well as arterial thrombosis and the risk of venous thrombosis is increased in females with inherited thrombophilia. A Danish cohort study of 15- to 49-year-old women has shown that although the absolute risks of thrombotic stroke associated with the use of hormonal contraception are low, the risk is increased by a factor of 1.3 to 2.3 with ethinyl estradiol at a dose of 30 to 40 μg (23).

A systematic review of observational studies has shown that the risk of myocardial infarction or ischemic stroke is only increased in women using combined oral contraceptives (COCs) containing greater than or equal to 50 µg of estrogen (32). After combining these data with the results of studies on the risk of venous thrombosis in COC users, the study concluded that a COC pill containing levonorgestrel and 30 µg of estrogen is the safest oral form of hormonal contraception.

Proton pump inhibitors. In a Danish study, use of proton pump inhibitors was associated with 29% greater absolute risk of first-time ischemic stroke, particularly amongst long-term users of high doses (38).

Quetiapine. It has been reported to cause immune-mediated thrombotic microangiopathy, although few cases have been reported thus far. An old man on maintenance renal dialysis suffered a hemorrhagic basal ganglia stroke and was treated with quetiapine for delirium; quetiapine-induced thrombotic microangiopathy was diagnosed (40). Due to persistent microbleeding, platelet transfusions were performed several times, but the platelet count recovered only after quetiapine was discontinued. Platelet activation predominantly by a drug-dependent antibody might be the cause of quetiapine-induced thrombotic microangiopathy.

Selective serotonin reuptake inhibitors. Selective serotonin reuptake inhibitors are widely used antidepressants and serotonin is a vasoactive amine, but cerebrovascular effects are uncommon according to available evidence. However, caution should be exercised in their use in patients at high risk for stroke. Several factors including pharmacogenetic and relation of depression to stroke may affect the outcome of treatment with this category of drugs.

Sympathomimetic agents. Several sympathomimetic agents have been linked to the development of hypertension leading to drug-induced cerebrovascular diseases. Stroke is associated with over-the-counter sympathomimetics, particularly pseudoephedrine. Phenylpropanolamine, an alpha-adrenergic agonist in diet aids, was linked to the risk of hemorrhagic stroke. The Food and Drug Administration requested the drug companies to stop marketing products that contain this substance; this includes prescription diet aids and cold medicines. Synephrine, a sympathomimetic amine related to ephedrine, may be associated with ischemic stroke. Phentermine, a sympathomimetic agent found commonly in weight loss products, has been linked to subarachnoid hemorrhage in a patient, which was likely secondary to drug-induced hypertension or vasculopathy (03).

Pathomechanism of drug-induced cerebrovascular disease. This will be considered according to various types.

Drug-induced cardiovascular disturbances. Cardiovascular disorders are a major cause of cerebrovascular disease. The same applies to drug-induced cardiovascular disorders.

Drug-induced hypertension is a major risk factor for stroke. Several drugs can induce hypertension; those that are well known for this effect are: nonsteroidal anti-inflammatory drugs, erythropoietin, cyclosporin, corticosteroids, and sympathomimetic drugs. Use of these drugs may result in intracerebral hemorrhage.

Drug-induced hypotension can be mediated by a fall in cardiac output or direct myocardial depression. Postural hypotension may result in syncope, and the patient may recover consciousness promptly with no cerebrovascular sequelae. A sudden major fall of blood pressure may cause localized necrosis of the gray as well as the white matter at the boundary zones ("water sheds") between major arterial territories. Elderly subjects with atherosclerotic disease of cerebral arteries are liable to suffer a major stroke during a sustained hypotensive episode. Moderate but sustained hypotension may lead to diffuse neuronal loss in the cerebral cortex. High mean blood pressure on admission, excessive drug-induced blood pressure reduction, and larger hemorrhage may be risk factors for development of asymptomatic acute ischemic lesions, which may be coincidentally found by brain MRI obtained during the acute phase, but their clinical significance has yet to be determined (21).

Although antihypertensive drugs protect the brain against harmful effects of prolonged hypertension, cerebral ischemia may occur during antihypertensive treatment under the following circumstances:

• Patients with malignant hypertension in the initial phase of treatment • Elderly hypertensive patients • Patients with acute stroke and high blood pressure • Patients with stenosis of functional cerebral arteries

Potent antihypertensive drugs (when used aggressively and given at bedtime) are emerging as risk factors for nocturnal hypotension, which is an important risk factor for the development and progression of silent strokes, particularly in persons dipping between episodes of high and low systolic blood pressure.

Drug-induced reduction of cerebral blood flow. Theophylline is known to reduce cerebral blood flow in patients with chronic obstructive pulmonary disease. Aminophylline decreases cerebral blood flow under hypoxic as well as normoxic conditions and, therefore, reduces oxygen delivery. Indomethacin has also been shown to decrease cerebral blood flow and cognitive function.

Drug-induced hemorheological disturbances. Hemorheological disturbances are an important cause of cerebrovascular disease. Several drug-induced hematological disturbances, particularly those involving the elements of the blood, can impair cerebral microcirculation. For example, drugs that produce a proliferation of leukocytes or increase platelet aggregation and increase number of leukocytes in drug-induced leukemias may affect cerebral microcirculation, or the leukemic blasts may compete for oxygen in the microcirculation and be invasive, thereby damaging the vessel wall. A critical factor is the deformability and size of the leukocytes. Total white blood counts higher than 400,000 µL can be tolerated in chronic lymphoid leukemia if the cells are small and easily deformable. No adverse effects of leukocytosis on cerebral circulation are usually noted in total white blood cell counts of less than 100,000 µL. However, a 2-fold increase is seen in incidence of strokes if biannual leukocyte counts are greater than 10,000 µL.

Platelets can be affected by several drugs. The usual adverse effect is thrombocytopenia, which tends to lead to complications such as cerebral hemorrhage and thromboembolism. Heparin-induced thrombocytopenia occurs in approximately 1% to 2% of patients treated with heparin and leads to thromboembolic complications, including stroke. These are known complications in cancer patients being treated with chemotherapy. Some of these patients are treated with granulocyte colony-stimulating factor to counteract the neutropenia resulting from chemotherapy. Strokes have been reported in these patients, but the relationship to granulocyte colony-stimulating factor is uncertain. However, it has been shown that granulocyte colony-stimulating factor increases the serum levels of granulocyte elastase, indicating highly activated leukocytes that can injure tissues. Thrombocytopenia is also known to occur in patients receiving granulocyte colony-stimulating factor, and platelet activation has been shown in human volunteers. Platelets possess granulocyte colony-stimulating factor receptors, and granulocyte colony-stimulating factor-augmented adenosine diphosphate induced platelet aggregation has been reported in human volunteers. This may occur in patients with severe chronic benign neutropenia who are on granulocyte colony-stimulating factor therapy and do not have concomitant chemotherapy to produce thrombocytopenia.

Drugs that activate platelets can lead to thrombosis. Even occasional cocaine exposure can cause platelet activation, alpha granule release, and platelet containing microaggregate formation. This may promote thrombosis and predispose healthy individuals to cerebral ischemic events.

Drug-induced cerebral vasculitis. The central nervous system may be involved secondary to systemic vasculitis. For example, subarachnoid hemorrhage and stroke have been reported in Henoch-Schönlein purpura. Cerebral vasculitis may occur without any other systemic manifestations, and it shares the histologic features of inflammation and necrosis of blood vessels with other vasculitides. Inflammatory process may be primary or secondary to other processes.

Vasculitis associated with drugs is usually "hypersensitivity vasculitis," but this is not an accurate description, as immune mechanisms are involved in the pathogenesis of the condition. Hypersensitivity vasculopathy can be considered an explanation of acute neurologic deficits resulting from the administration of drugs that normally do not affect the cerebral blood vessels, eg, allopurinol. Cerebral vasculitis and multifocal neurologic deficits have been reported as due to allopurinol-induced hypersensitivity syndrome (24).

The clinical effects of tissue ischemia in cerebral vasculature vary, but the symptoms may be transient or prolonged and strokes are a frequent complication. Vasculitis is a major pathology in patients who present with stroke due to drug abuse. Drugs associated with cerebral vasculitis are shown in Table 3.

Table 3. Drugs Associated with Cerebral Vasculitis

Therapeutic and diagnostic pharmaceuticals
	• Allopurinol • Amphetamine* • Ergot alkaloids • Ephedrine • Ginseng • Iopamidol as a contrast agent for myelography • Interleukin-2 • Methylphenidate, prolonged use • Oxymetazoline • Penicillin • Phenylpropanolamine • Pseudoephedrine • Sympathomimetic drugs • Tacrolimus • Vaccine: hepatitis B
Drug abuse
	• Cocaine • Heroin • Methylphenidate • Pentazocine • Phencyclidine • Sympathomimetic drugs*
*Used therapeutically but also abused.

Arterial hypertension has been considered as a factor in the etiology of cerebral vasoconstriction due to ergot alkaloids, but vasculitis appears to be a more likely mechanism. Cases of cerebral vasculitis have been reported in women after the start of bromocriptine to suppress lactation and all the patients recovered after discontinuation of the drug.

Multiple mechanisms may be involved in the pathogenesis of drug-induced stroke. Cocaine use is associated with ischemic stroke through mechanisms that include reversible vasospasm, drug-induced arteritis, enhanced platelet aggregation, cardioembolism, and hypertensive episodes (04). A case report indicates that heroin-induced hypereosinophilia, besides usual vasoconstriction, should be considered in pathomechanisms of drug-induced cerebral infarctions (05).

Drug-induced vasospasm. Vasospasm of cerebral arteries can be induced by cerebral angiography and may be accompanied by transient neurologic deficits. Hyperbaric oxygen at pressures of above 2 ATA may induce cerebral vasoconstriction but improves rather than impairs cerebral oxygenation (17). Nitric oxide synthase inhibitors also induce vasospasm by antagonizing the vasodilator effect of nitric oxide. Serotonergic drugs can also induce vasospasm. Cyclosporine-induced vasospasm has been reported to produce stroke-like episodes from which the patient recovered after the discontinuation of the drug (07). Vasospasm is a significant factor in cyclosporine-induced neurotoxicity.

Reversible cerebral vasoconstriction syndrome, which is usually a benign condition and resolves spontaneously, can be induced by drugs. A few cases with persistent neurologic deficits have been reports where drugs such as sumatriptan and cyclosporine were implicated (33).

Increased risk of acute myocardial infarction associated with the use of cyclooxygenase (COX) inhibitors as antiinflammatory agents is well recognized, but association of ischemic stroke with these drugs is not well documented even though sporadic cases of drug-induced reversible cerebral vasoconstriction syndrome have been reported. There is a case report of a patient who developed headache, hypertension, and cerebral ischemia due to reversible cerebral vasoconstriction following recent exposure to etoricoxib, a COX-2 inhibitor antiinflammatory drug with a favorable safety profile (10).

Drug-induced thromboembolic disease. Several drugs produce disturbances of blood coagulation as well as cerebral infarction by thromboembolism. Cerebral hemorrhage associated with anticoagulant therapy is well documented. Cerebral hemorrhage is the usual concern after thrombolytic therapy with tissue plasminogen activator, but ischemic cerebral infarction may also occur.

Pathophysiology of stroke in relation to oral contraceptives. Vascular lesions in the form of intimal hyperplasia with and without associated thrombus are found in the cerebral arteries of young women who developed strokes and died while taking oral contraceptives. Combined oral contraceptives increase the production of factor X, factor II, and plasminogen; they decrease the production of antithrombin and increase platelet aggregation by reducing the production of prostacyclin. Estrogens used in oral contraceptives have effects on the laboratory measures of clotting, such as fibrinogen, factor VII, and antithrombin III, but the effect is difficult to translate into clinical risk of vascular events.

Neonatal intracranial hemorrhage. Spontaneous hemorrhage into the cerebral ventricles is relatively common in premature infants. More than 50% of infants with a birth weight under 1500 g have periventricular-intraventricular hemorrhage detected by computerized tomography or echoencephalography. The exact cause of such hemorrhage is not known, but it is multifactorial. The role of drugs in the causation of neonatal hemorrhages will be described by using examples from maternal drug use as well as drugs given to the newborn. The following drugs used during pregnancy have been reported to be associated with bleeding disorders in the neonate: anticoagulant therapy (coumarins), aspirin, and antiepileptic drugs.

The following drugs have been reported to produce cerebral hemorrhage in the neonate:

Heparin. This is often used to maintain the patency of catheters for vascular access placed in the umbilical arteries of premature infants. Routine use of heparin in neonatal intensive care units is associated with a 4-fold increase in the risk of periventricular-intraventricular hemorrhage.

Benzyl alcohol. This is a bacteriostatic agent used to flush intravascular catheters. The volume of alcohol is significantly related to the development of kernicterus and intraventricular hemorrhage.

Sodium bicarbonate. This substance, when administered in excess to neonates with or without hypernatremia, may place them at greater risk of intracranial hemorrhage. Hypertonic loads of saline built up in the administration of sodium bicarbonate to correct acidosis in infants with respiratory distress syndrome can precipitate intraventricular hemorrhage.

Pathomechanism of cerebrovascular disease in chemotherapy for cancer. Possible mechanisms of cerebrovascular disturbances due to antineoplastic agents are as follows. More than 1 of these mechanisms may be operative in an individual patient.

• Drug-induced endovascular damage • Endothelium-independent vasoconstriction by action on vascular smooth muscle • Disturbances of clotting mechanism • Platelet activation • Abnormalities of thromboxane-prostacyclin homeostasis • Autonomic dysfunction • Vasculitis • Stimulation of fibroblasts

Epidemiology

The only epidemiological studies of a drug-related stroke are those of oral anticoagulants and oral contraceptives. The latter is important, because approximately 90 million women worldwide use oral contraceptives. The risk of stroke with use of oral contraceptives has already been discussed in an earlier section.

Cerebral hemorrhage as a complication of oral anticoagulation. Records of 20,347 outpatients who were receiving oral anticoagulants at 4 hospitals in Spain were searched for severe adverse events (30). Overall, 2369 hemorrhagic events were observed, 190 (8%) of which were severe, with 20 deaths. The highest probability of death (1 in 3) was associated with cerebral hemorrhage.

Two forms of direct oral anticoagulant are now available: direct thrombin inhibitors, such as dabigatran, and factor Xa inhibitors, such as rivaroxaban and apixaban. A comparative study of the safety and efficacy of the 2 forms in Japan showed that direct thrombin inhibitors were more effective in preventing intracerebral hemorrhage and atherothrombotic events (42).

Prevention

The only truly preventive measure is the avoidance of drugs suspected or known to be associated with cerebrovascular disease, particularly in patients with other risk factors.

It is difficult to predict the risk of cerebral hypoperfusion due to antihypertensive medications in an individual patient. Because of the increasing evidence that patients with severe hypertension are particularly liable to ischemic brain damage due to regional or global reduction in cerebral perfusion pressure, attempts should be made to lower the pressure gradually to allow the cerebral circulation to recover its normal reactivity.

In view of these reports, caution should be exercised when using intravenous immunoglobulin in patients with risk factors for cerebrovascular disease such as high serum viscosity and preexisting cerebrovascular disease.

The incidence of neonatal hemorrhages associated with the maternal use of antiepileptic drugs has been shown to be markedly reduced in those cases where oral vitamin K was given to the mother prior to delivery. Recommendations to reduce the incidence of neonatal cerebral hemorrhage are:

	• Vitamin K tablets should be given to the epileptic mother on antiepileptic drugs during the last month of pregnancy, and phytomenadione should be given intravenously to the infant immediately after birth.
	• Cord blood specimens should be submitted for clotting studies and if diminished vitamin K-dependent factors are found, fresh frozen plasma should be given to the infant.
	• Alternatively, the antiepileptic drug treatment of the pregnant epileptic women should be changed to a non-enzyme-inducing antiepileptic drug such as clonazepam.

Precautions in the use of oral contraceptives. Women with focal migraine (symptoms localized to 1 side of the head) associated with a major "aura" or hemiparesis should not use the combined pill because there is a risk of localized cerebrovascular occlusion. Use of oral contraceptives should be avoided in women over 35 with risk factors, and those over 44 even without risk factors. Strokes in women on oral contraceptives are sometimes preceded by transient neurologic symptoms such as paresthesias or weakness of limbs and the preparation should be stopped at once under these circumstances. The newest combined oral contraceptive formulations are generally well tolerated in migraine without aura without risk of stroke (01).

Differential diagnosis

Confusing conditions

The differential diagnosis is the same as that of any other cerebrovascular disease because the presenting feature may be similar. 5-FU may induce reversible encephalopathy that presents with acute stroke-like symptoms, but MRI in such a case does not show any cerebral infarction, and symptoms resolve after discontinuation of 5-FU (31).

Drug-induced vasculitis should be distinguished from primary central nervous system vasculitis as shown in Table 4.

Table 4. Differentiation Between Primary and Drug-Induced Vasculitis

Feature	Drug-induced	Primary
Vessels involved Predominant cellular infiltrate Giant cells Granulomas Necrosis Vessel wall involvement	Small arteries Polymorphonuclear leukocytes None None Marked Marked Intimal	Arteries and veins Lymphocytes, monocytes Characteristic Characteristic Moderate Moderate Adventitial

Diagnostic workup

• Basic diagnostics like other stroke patients.

• Drug history with drug screens.

• Brain imaging with cerebral angiography.

The diagnostic workup is the same as that of other patients with cerebrovascular disease. A thorough history should be taken of the use of drugs that are known to be associated with cerebrovascular disease. A thorough history focusing on the use of illicit substances and toxicological screening of urine and serum should be part of the evaluation of any young patient with a stroke. Drug-induced cerebral vasculitis should be considered as the most likely cause of recurrent ischemic strokes in the absence of any pathological findings during the diagnostic workup. Angiography should be part of the evaluation of most young patients with nontraumatic intracerebral hemorrhage, due to the likelihood of presence of an underlying angioma.

Management

• Therapeutic approach to drug-induced stroke depends on the pathology, which may differ from naturally occurring strokes.

The approach to management differs from that of cerebrovascular disease resulting from noniatrogenic causes. For example, a patient with sudden onset of hemiplegia due to a drug is unlikely to have a thrombus occluding 1 of the main cerebral arteries, and is, thus, unlikely to be a candidate for thrombolytic therapy. Vasculitis is usually treated with corticosteroids with good results. Patients with drug-induced subarachnoid hemorrhage who do not have a vascular lesion (such as an aneurysm) usually have a good prognosis, and the hemorrhage does not recur after discontinuation of the medication.

Morbidity and mortality of superior sagittal sinus thrombosis is high in intracerebral hemorrhage associated with anticoagulant therapy.

The following drugs have an adverse effect on recovery from stroke and should be avoided in all stroke patients, particularly in those patients whose stroke was drug-induced:

• Anticholinergics when given late after cerebral infarction • Antihypertensives: clonidine and prazosin • Anxiolytics acting through GABA/benzodiazepine receptor complex • Barbiturates such as phenobarbital • Dopamine receptor antagonists • Haloperidol

Special considerations

Pregnancy

Beta-sympathomimetic agents, commonly used to delay preterm delivery, are associated with an increase in the incidence of neonatal periventricular hemorrhage.

Beta-sympathomimetic tocolysis may exert several effects on the fetal cardiovascular system that may predispose the premature infant to periventricular and intraventricular hemorrhages. The immature preterm brain is not well protected by autoregulation against the fluctuations in blood pressure. An increase in mean arterial blood pressure and a redistribution of the fetal cardiac output in favor of the upper body may place a premature infant at risk of periventricular-intraventricular hemorrhage after initiation of beta-sympatholytic tocolysis. A historical cohort study concluded that a decrease in the given dose of tocolytic agents did not affect the timing of delivery and neonatal outcomes; therefore, long-term tocolysis in patients with threatened premature delivery should be restricted to prevent maternal and fetal adverse side effects (29).

Warfarin embryopathy has been described in women on anticoagulant therapy during pregnancy. Fetuses have the characteristic nasal hypoplasia, and various other malformations have been described. Cerebral hemorrhage is the major finding at autopsy indicating that bleeding is a significant factor in the pathogenesis of warfarin embryopathy (43).

Anesthesia

No agents used for anesthesia have been implicated in stroke, although stroke may occur during procedures performed under anesthesia. Hypotension may occur, and this is a predisposing factor for stroke in susceptible individuals.