Vascular Dementia - Treatment

From a public health perspective, the most effective measures for the treatment of vascular dementia are primary prevention measures.

Educational programs that explain the importance of risk factor control can reduce the incidence of stroke and its complications, including vascular dementia. Once vascular dementia has developed, targeting vascular risk factors and associated somatic diseases can reduce the rate of dementia progression. In some cases, the use of antiplatelet agents (aspirin, ticlopidine, clopidogrel) or indirect anticoagulants (warfarin) may be of some value.

Impact on risk factors. Reducing risk factors for stroke may reduce the likelihood of recurrent cerebral infarction. The use of antihypertensive agents to reduce arterial hypertension should be carefully monitored, since excessive drop in blood pressure may result in relative hypoperfusion, which may cause worsening of cerebral ischemia, general weakness, confusion, and deterioration of cognitive functions. Cerebral embolism is another treatable risk factor for stroke. Therefore, careful examination is necessary to detect episodic cardiac arrhythmias using Holter monitoring, as well as to establish the nature of cerebral embolism using CT and MR angiography, Doppler sonography, and echocardiography. Untreated atrial fibrillation may lead to decreased cardiac output, cerebral hypoperfusion, and the development of cerebral ischemia and even infarction.

Currently, the ability of aspirin (at a dose of 325 mg/day) and warfarin (at a dose maintaining the international normalized ratio at a level of 2-4.5) to reduce the risk of recurrent stroke has been proven. To reduce the risk of stroke (and, consequently, vascular dementia), patients with non-rheumatic atrial fibrillation should be prescribed warfarin or aspirin in the absence of contraindications (Stroke Prevention in Atrial Fibrillation Investigators, 1991). Anticoagulant therapy also reduces the risk of stroke after myocardial infarction. The most serious potential complication of anticoagulant therapy is intracranial hemorrhage, the likelihood of which can be reduced if the international normalized ratio is maintained at a level of no more than 4.

Men who develop myocardial infarction or ischemic stroke have elevated levels of the systemic inflammatory marker C-reactive protein. A decrease in C-reactive protein levels during aspirin treatment was associated with a decreased risk of stroke and myocardial infarction, suggesting the potential efficacy of anti-inflammatory drugs in preventing these diseases. Carotid endarterectomy is recommended in patients with hemodynamically significant carotid artery stenosis (North American Symptomatic Carotis Endarterectomy Trial Collaborators, 1991) and ulcerated carotid plaques. Poorly controlled diabetes mellitus and elevated blood lipids can reduce cerebral perfusion, causing microangiopathy, which can lead to the development of lacunar infarctions and ultimately to vascular dementia. Therefore, lowering triglyceride levels and controlling blood sugar levels may increase cerebral blood flow and reduce the risk of subsequent cerebral infarction.

Stopping smoking improves cerebral blood flow and cognitive function. All smokers should be advised to stop smoking, whether or not they have developed vascular dementia. Gradual detoxification with nicotine skin patches may help in some cases.

Data on the ability of estrogen replacement therapy to reduce the risk of vascular dementia are contradictory. Estrogen replacement therapy is currently used for osteoporosis, vasomotor menopausal symptoms, atrophic vaginitis, and hypoestrogenism. The effectiveness of estrogens in cardiovascular diseases, ischemic stroke, and vascular dementia can be explained by their ability to reduce platelet adhesion, lower blood lipid levels, and attenuate the thrombolytic and vasoconstrictor effects of thromboxane A2. However, there is evidence of the negative effects of estrogens.

Aspirin. Low-dose aspirin may reduce platelet aggregation and thus inhibit thrombosis. Aspirin also blocks the vasoconstrictor effect of thromboxane A2. Aspirin reduces the risk of recurrent stroke and cardiovascular complications. In one study, aspirin 325 mg/day in combination with interventions for stroke risk factors improved or stabilized cerebral perfusion and cognitive function in patients with mild to moderate multi-infarct dementia. Although these findings need to be confirmed in larger studies, low-dose aspirin (50-325 mg/day) is recommended for patients with vascular dementia unless contraindicated (eg, history of gastric or duodenal ulcer or gastric bleeding).

Ticlopidine.Ticlopidine inhibits platelet aggregation by inhibiting adenosine diphosphate-induced platelet binding to fibrinogen. The Ticlopidine Aspirin Stroke Study (TASS) found that ticlopidine (250 mg twice daily) was more effective than aspirin (650 mg twice daily) in preventing stroke, both fatal and nonfatal. Side effects of ticlopidine include diarrhea, rash, bleeding, and severe neutropenia. Skin and gastrointestinal side effects of ticlopidine usually resolve spontaneously. The possibility of neutropenia requires regular monitoring of white blood cell counts.

Clopidogrel reduces platelet aggregation by directly inhibiting adenosine diphosphate (ADP) receptor binding and inhibiting ADP-mediated activation of the glycoprotein IIb/IIIa complex. Several studies have shown the ability of clopidogrel (75 mg once daily) to reduce the incidence of stroke, myocardial infarction, and cardiovascular death in patients with a history of stroke, myocardial infarction, or peripheral arterial atherosclerosis. According to one study, clopidogrel reduced the risk of a recurrent vascular event by 8.7% more than aspirin. Clopidogrel was well tolerated. Unlike ticlopidine, it did not cause neutropenia, and the incidence of gastrointestinal bleeding and dyspepsia was lower than that of aspirin. At the same time, the incidence of diarrhea, rash, and itching in patients taking clopidogrel was higher than when taking aspirin.

Pentoxifylline. A 9-month, double-blind, placebo-controlled study showed that pentoxifylline produced some improvement in cognitive function, assessed using standardized scales, compared with placebo in patients with multi-infarct dementia diagnosed according to DSM-III criteria. The pentoxifylline dose was 400 mg 3 times daily (European Pentoxifylline Multi-Infarct Dementia Study, 1996).

Cholinesterase inhibitors. Double-blind, placebo-controlled studies have shown that galantamine and donepezil can improve cognitive function, daily activities, and reduce the severity of behavioral disorders in patients with vascular and mixed dementia.

Memantine: According to controlled studies, memantine at a dose of 20 mg/day reduced the severity of cognitive impairment in patients with mild to moderate vascular dementia, especially associated with damage to small cerebral vessels.

Noncognitive disorders. Most studies of this problem have been conducted in patients with the consequences of stroke. However, the general principles of pharmacological and nonpharmacological interventions outlined here are applicable to other forms of vascular dementia.

Post-stroke depression. Major depression is found in 10% of patients who have had a stroke. According to another study, 25% of patients hospitalized for stroke meet the criteria for major depression. If depressive symptoms are taken into account, regardless of whether they meet the criteria for major depression or not, their prevalence in patients who had a stroke no more than 2 years ago increases to 40%.

Major depression in patients with stroke often develops with damage to the frontal cortex of the left hemisphere and basal ganglia, and the closer the lesion is to the pole of the frontal lobe, the more pronounced the depressive symptoms.

Unrecognized and untreated depression has a negative impact on the patient's activity during rehabilitation, the effectiveness of rehabilitation measures and, ultimately, on the degree of restoration of lost functions. This remains true even after depression regresses. In cases of left hemisphere damage, depression is more often accompanied by cognitive impairment than in cases of right hemisphere damage.

During the examination, it is important to exclude other diseases that, in addition to stroke, can cause affective disorders. It has been proven that post-stroke depression can be treated with antidepressants. Thus, nortriptyline was more effective than placebo in a 6-week double-blind placebo-controlled study. However, this drug should be used with caution due to the high frequency of side effects, including delirium, syncope, dizziness, and increased sleepiness. A 6-week double-blind controlled study also demonstrated the effectiveness of the selective serotonin reuptake inhibitor citalopram. Moreover, the differences between citalopram and placebo were especially pronounced in patients with late onset of depression (7 weeks after the stroke). Many patients with early onset of depression experienced spontaneous recovery. In addition, fluoxetine was also effective in post-stroke depression in controlled trials.

Post-stroke anxiety. Anxiety in stroke patients is closely correlated with depression. In one study, 27% of stroke patients were diagnosed with generalized anxiety disorder, with 75% of them having concomitant symptoms of depression. This indicates the need to find and adequately treat depression in patients with post-stroke anxiety. It is also important to consider that anxiety may be a manifestation of a concomitant disease or a side effect of medications taken.

There are no systematic controlled studies of the efficacy of pharmacological agents for the treatment of anxiety in patients with stroke. Benzodiazepines are particularly often used to treat anxiety in patients without organic brain damage. These drugs can be used with caution in patients with stroke. In this case, it is recommended to prescribe short-acting drugs that do not form active metabolites (for example, lorazepam or oxazepam) in order to reduce the likelihood of side effects such as drowsiness, ataxia, confusion, or disinhibition. Buspirone can also be effective in post-stroke anxiety, but its effect occurs only after several weeks. At the same time, when using buspirone, dependence, drowsiness do not occur, and the risk of falls does not increase significantly. In generalized anxiety, an effect can be achieved using tricyclic antidepressants. In this case, careful titration of the dose and careful monitoring for the occurrence of possible anticholinergic effects are necessary. There are currently no controlled studies to guide drug selection and dosage. There is no risk of tolerance with SSRIs and a low risk of abuse. The drugs are particularly useful in treating comorbid depression, which often accompanies post-stroke anxiety.

Post-stroke psychosis. Psychosis in a patient with stroke may be triggered by a drug or a concomitant disease. Hallucinations are observed in less than 1% of patients with stroke. Post-stroke psychosis is more often observed in right-hemispheric lesions involving the parietotemporal cortex, as well as in patients with cerebral atrophy and epileptic seizures.

In a patient with delirium, the first step is to try to establish its cause and choose the right treatment. First, the clinician must rule out a somatic disease or a connection between psychosis and the intake of a particular substance. Accordingly, treatment may consist of correcting the primary disease, removing the toxic drug, and symptomatic therapy with antipsychotics (if psychotic symptoms pose a threat to the patient's life or prevent examination and treatment).

Neuroleptics. Only a few controlled studies have evaluated the efficacy of neuroleptics in psychosis in patients with stroke. The general principles of choosing an neuroleptic, determining the effective dose, and titrating it are the same as those used to treat psychotic disorders in patients with Alzheimer's disease. Neuroleptics should be prescribed after a thorough search for the cause of psychosis. If psychosis poses a threat to the patient's life or treatment, the benefits of neuroleptics outweigh the risks associated with their use. The choice of neuroleptic is based on the side effect profile rather than on its efficacy. If the patient has signs of parkinsonism, a moderately active drug (eg, perphenazine or loxitane) or a newer generation drug (risperidone, olanzapine, seroquel), which are less likely to cause extrapyramidal side effects, should be prescribed. Caution should be exercised when prescribing neuroleptics with a pronounced anticholinergic effect, especially in patients with prostatic hyperplasia, orthostatic hypotension, or a tendency to urinary retention. The anticholinergic effect of these agents may increase the cognitive deficit in such patients. In cases of agitation and swallowing disorders, parenteral administration of a neuroleptic may be necessary. Many traditional neuroleptics are available in a form for intramuscular administration, and some high-potency agents can also be administered intravenously. Caution should be exercised when administering haloperidol intravenously due to the risk of developing torsades de pointes. At the same time, many new-generation neuroleptics are not available in a form for parenteral administration. When prescribing neuroleptics to patients with a history of stroke, the risk of developing tardive dyskinesia or the rarer tardive akathisia should be taken into account. In this regard, attempts should be made from time to time to reduce the dose or discontinue the neuroleptic.

Post-stroke mania. Mania is very rare in stroke patients. In one study, its prevalence in this category of patients was less than 1%. As with other non-cognitive disorders associated with dementia, careful evaluation is necessary to exclude medical illness or a connection with the use of a particular drug, as these factors can cause or worsen mania. Pharmacotherapy for mania includes the use of valproic acid, carbamazepine, gabapentin, and lithium.

Lithium. The efficacy of lithium in post-stroke mania has not been studied in controlled trials. Several reports have noted low efficacy of lithium in secondary mania. Caution is required when treating post-stroke mania with lithium preparations due to the low therapeutic index. Patients with organic brain damage are especially sensitive to the side effects of lithium. Lithium intoxication can cause neurological symptoms such as tremor, ataxia, dysarthria, extrapyramidal and cerebellar symptoms, nystagmus, delirium and even mania. Before prescribing lithium, it is necessary to conduct an ECG, determination of TSH, electrolyte levels, a complete blood count, and to examine renal function. It is also necessary to consider the possibility of drug interactions - some diuretics and non-steroidal anti-inflammatory drugs increase lithium levels in the blood. During lithium treatment, it is necessary to regularly monitor the drug level in the blood, ECG, and concomitant treatment. Although there are no scientifically verified data on therapeutic drug concentrations for post-stroke mania, clinical experience shows that therapeutic concentrations may range from 0.5 to 0.7 mEq/L.

Carbamazepine.There are no controlled studies of the efficacy of carbamazepine in post-stroke mania. According to some data, patients with bipolar disorder arising from organic brain damage respond better to carbamazepine than to lithium. Before starting carbamazepine, it is necessary to conduct a clinical blood test to determine the platelet count, ECG, examine liver function, sodium content in the blood, and TSH level. It is also necessary to measure the blood levels of other drugs metabolized by the CYP3A4 enzyme. Carbamazepine is able to induce its own metabolism, therefore it is necessary to determine the carbamazepine content in the blood at least once every 6 months, as well as each time the dose is changed or drugs that can interact with carbamazepine are added. There are no scientifically developed recommendations regarding the therapeutic level of carbamazepine in post-stroke mania. Accordingly, the dose of the drug should be selected empirically, focusing on the clinical effect. Side effects of carbamazepine include hyponatremia, bradycardia, atrioventricular block, leukopenia, thrombocytopenia, ataxia, nystagmus, confusion, and drowsiness. Based on theoretical considerations, carbamazepine can be continued if the white blood cell count has decreased to no more than 3000/μl. In individuals sensitive to the side effects of carbamazepine, the initial dose should be less than 100 mg, and it is advisable to use a liquid dosage form of the drug. Dose titration is carried out slowly, since patients who have had a stroke are usually elderly, in whom liver clearance and the ability of plasma proteins to bind the drug are reduced, and therefore the concentration of the active substance is higher.

Valproic acid is another anticonvulsant used to treat post-stroke mania. However, there are no controlled studies to support its effectiveness in this condition. Blood and liver function should be assessed before and during treatment. Adverse effects include drowsiness, ataxia, cognitive impairment, thrombocytopenia, elevated liver transaminases, tremor, gastrointestinal disturbances, and hair loss. Drug interactions with other drugs that bind to plasma proteins are possible. Alopecia can be treated with a multivitamin containing zinc and selenium. The drug can be continued as long as the white blood cell count does not fall below 3,000/µL and liver function tests do not rise more than three times the upper limit of normal. Valproic acid can inhibit its own metabolism, and blood levels may increase while the drug is being taken at a stable dose. Therapeutic serum levels of the drug in post-stroke mania have not yet been determined. Treatment, especially in individuals sensitive to side effects, can be initiated with a dose of less than 100 mg using liquid dosage forms. With gradual dose increases, the likelihood of gastrointestinal side effects decreases.

Gabapentin. Gabapentin, which enhances GABAergic transmission, is used to enhance the effect of other anticonvulsants. Controlled studies of gabapentin in post-stroke mania have not been conducted. It is a relatively safe drug, its main side effect being drowsiness. Gabapentin does not interact with other drugs and does not form active metabolites.

Other medications. Benzodiazepines and antipsychotics may also be used in the treatment of post-stroke mania. These medications are discussed in detail in the sections on post-stroke anxiety and post-stroke psychosis.