AZ Guide u Stroke

APOLIPOPROTEIN E (Apo E)

Apo E is a polymorphic glycoprotein that plays a critical role in cholesterol homeostasis and in the catabolism of triglyceride-rich lipoproteins.
The association between apo E e 4 allele and

• high risk of cardiovascular ischemic events
• Alzheimer’s disease,

is now well established.
In contrast the association between e 4 and e 2 alleles and ischemic stoke is still debated.
M. Margaglione et al in their paper support the concept that apo E gene is a susceptibility locus for the risk of cerebrovascular ischemic disease.

(Stroke 1998; 29: 399-403).

ATHEROSCLEROSIS / INFECTION

u The concept that infections may be partly responsible for vascular occlusive disease is not new.
High levels of antibodies to Chlamydia pneumoniae have been reported in chronic coronary artery disease and in acute myocardial infarction.
Chlamydia pneumoniae DNA has been demonstrated in plaques by PCR.
"The West Birmingham Stroke Project" data support the association of cerebral vascular disease with previous Chlamydia pneumoniae infection and the association of stroke and transient cerebral ischemia with recrudescence of infection.

(P.J. Cook et al. Stroke 1998; 29: 404-410)

COGNITIVE DYSFUNCTION
AFTER STROKE

• Stroke frequently produces cognitive dysfunction.
• Tatemichi TK et al. (J Neurol Neurosurg Psychiatry 1994; 57: 202-207) found that 35.2% of a sample of 227 stroke patients examined 3 months after stroke failed 4 or more of the 17 neuropsychological tests vs 3.8% of control subjects.
• Severe cognitive impairment (dementia) was diagnosed in 16.3% of the 227 stroke patients.
  (Tatemichi TK et al, Neurology 1992; 42: 1185-1193).
• Long-term improvement in generalized cognitive function can occur after stroke in patients with left hemisphere infarction and severe hemispheral syndromes.
  Diabetes mellitus was associated with a failure to demonstrate improvement.
  (Desmond DW et al. Stroke 1996; 27: 1798-1803).
  Diabetes has been reported to be associated with microangiopathy, which may lead to lacunar infarction.
  The increased blood viscosity of diabetics may contribute to reduce cerebral blood flow (CBF).
  Disorders of CBF in diabetics could interfere with cerebral metabolic changes and thus compromise the recovery.

Dementia is a primary consequence of a number of neurological diseases, including stroke.

Dementia as a predictor of adverse outcomes following stroke.

Columbia University researchers have administered neuropsycological, neurological and functional examinations to 244 patients 3 months after ischemic stroke.
The results of the study suggest that dementia diagnosis based on neuropsychological assessment has superior predictive validity compared with other conventional methods.
It is able to identify patients at elevated risk of adverse outcomes following stroke.

[Desmond D.W. et al. Stroke 1998; 29: 69-74]

GLYCINE SITE ANTAGONIST: GV150526

The drug Gv150526 is a antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex.
Antagonism at this site specifically and selectively blocks activation of the NMDA receptor complex.
Preclinical models of stroke have shown that GV150526 reduces infarct volume and improves neurological outcome.
Half-life of GV150526 is about 19 hours.
A study, designed to test safety and tolerability, showed that GV150526 has not hemodynamic side effects, including hemorragic transformation or brain edema.
Abnormalities in liver function have been reported: small rise in bilirubin and increase in transaminases.

(Dyker AG et al, Stroke 1999; 30: 986:992).

Two phase III trials will evaluate the efficacy of GV150526 in acute stroke:

• GAIN-Americas (North America)
• GAIN-International (Europe, Africa, Australasia)

Optimal dose appears to be 800 mg as a loading infusion, follow by 200 mg maintenance infusion twice daily.

HEPARIN

• Large clinical trials of Heparin and Aspirin in acute stroke (IST, CAST, TOAST) have failed to show a net benefit from Heparin.
  The incidence of intracranical hemorrhage varies between 0 and 7.8% over 7 days of anticoagulation, while the incidence of other major bleeding complications varies from 2.9 to 12.3%.
  The decision to heparinize a patient after occurrence of stroke should be carefully taken.

[1999]

• Homocysteine is a sulfhydryl amino acid formed by the demethylation of methionine.
• Severe hyperhomocysteinemia (levels > 100 m mol/L) has been related to atherosclerosis and thromboembolic events including stroke.
• Moderate hyperhomocysteinemia (20 to 100 m mol/L) is a vascular risk factor.
• Several mechanisms have been suggested to explain how increased homocysteine concentrations may cause atherosclerosis and vascular disease:

1) endothelial cell damage in the vessel wall with a subsequent increase in platelet adhesiveness;
2) promotion of vascular smooth muscle cell growth and inhibitory effect on endothelial cell growth;3) modifying of blood clothing factors with a consequent increase in tendency to thrombosis;
4) adverse effects on lipid metabolism.

• Elevated homocysteine levels can be due to genetic disorders or deficiencies of folate, vitamin B₆ or vitamin B₁₂.
  Approximately two thirds of the cases of elevated homocysteine may be associated with low or moderate levels of folate, vitamin B₆ or vitamin B₁₂.

MINOR STROKE

Prognosis after a Minor Stroke

A cohort of 322 patients, admitted to the Neurological Department of the University of Rome between January 1977 and March 1986, with:

• first-ever minor ischemic strokes;
• minor (Rankin score = 2) or no disability (Rankin score < 2),

was followed for 10 years.
By the end of the follow-up period, there were 96 deaths for

• cardioversion events 41%
• recurrent strokes 25%
• other disease 32%

The 10-year mortality rate was 32% with a relative risk of 1.7 (95% CI, 1.4-2.1) compared with general population.
The 10-year recurrence rate of major strokes was 14%.

[Prencipe M. et al., Stroke 1998; 29: 126-132]

OBESITY

Obesity is an important cause of coronary heart disease and stroke.

Several studies have shown increased risk of stroke, especially ischemic stroke, with increasing adiposity in men.

• Honolulu Heart Program
  Stroke 1994; 25: 2370-2376

• Whitehall Study
  J Epidemiol Community Health 1991, 45: 138-142

A prospective study has examined the associations of body mass index (BMI) and weight change with risk of stroke in women.
The data indicate that both obesity and weight gain in women are important risk factors for ischemic and total stroke but not hemorrhagic stroke.

[Jama 1997; 277: 1539-1545]

TISSUE PLASMINOGEN ACTIVATOR (tPA)

NINDS trial demonstrated that T-PA (tissue Plasminogen Activator) was effective in the first 3 hours after acute ischemic stroke.

POSTMARKETING SURVEY OF t-PA FOR STROKE

30 patients, age 32 to 90 years, were treated with 0.9 mg/Kg of intravenous t-PA (maximum dose, 90 mg) within 3 hours of acute ischemic stroke.
The incidence of total intracerebral hemorrhage was 10% (3 pts):

• symptomatic intracerebral hemorrhage 2 (7%)
• fatal intracerebral hemorrhage 1 (3%)

[Chin D. et al., Stroke 1998, 29: 18-22]

AZ Guide Stroke
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