No increased risk of hemorrhagic stroke in patients adherent to high-dose statin therapy: SPARCL analysis

 

Results from a new post hoc on-treatment analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial presented at the World Congress of Cardiology, Barcelona, Spain, in September 2006 have shown that patients most adherent to atorvastatin demonstrated the greatest reductions in the risk of cardiovascular events, including a 31% reduction in the risk of stroke. In addition, the risk of hemorrhagic stroke, a finding observed when the study was first presented and published, was not increased in patients most adherent to high-dose statin therapy.

SPARCL was the first trial to specifically look at the effect of a statin, atorvastatin, in patients with a prior stroke or TIA but with no history of elevated cholesterol or coronary artery disease. Patients treated with atorvastatin 80 mg had a 16% reduction in the primary end point of nonfatal or fatal stroke over the five-year study. Despite the positive findings, investigators were unable to explain the slight increase in the risk of hemorrhagic stroke observed, with 2.3% of patients in the atorvastatin-treatment arm and 1.4% of patients in the placebo arm having a hemorrhagic stroke.

Taking advantage of the 55,000 LDL-cholesterol measurements taken during the study, investigators used LDL-cholesterol levels as a surrogate marker for adherence to statin therapy, with more than 11 measurements taken per patient. Of the 4731 patients included in SPARCL, 32.7% had no change or an increase in LDL levels, 39.4% had a less than 50% reduction in LDL, and 27.9% had a greater than 50% decrease in LDL cholesterol levels. Nearly all patients with LDL reductions >50% were taking atorvastatin 80 mg.

Investigators report that patients most adherent to atorvastatin- those with LDL reductions > 50% - had a significant 31% reduction in the risk of stroke, a significant 37% reduction in the risk of major coronary events, and a 47% reduction in the risk of revascularization. The risk of hemorrhagic stroke was not increased in patients with the largest reduction in LDL-cholesterol levels.

“Compared with patients who had no change in LDL-cholesterol levels, the group with more than a 50% reduction in LDL cholesterol had the largest stroke risk reduction, more than what was observed in overall SPARCL population. Further, among the group with the largest reduction in LDL there was no risk of hemorrhagic stroke. When the finding of increased hemorrhagic stroke first emerged, we believed it was chance, but that is why this on-treatment analysis was needed. Now I think we can convince clinicians that other factors were involved”, Dr. Pierre Amarenco, the lead investigator said. These findings support the initiation of high-dose statin therapy in patients with a stroke or TIA soon after the event.

Commenting on the results of the study, Dr Terje Pedersen, Ullevål University Hospital, Oslo, Norway, noted that the Apolipoprotein-Related Mortality Risk (AMORIS) study showed the risk of stroke to be related to the apoB/apoA-1 ratio, suggesting that stroke risk is related to dyslipidemia. He said the findings from SPARCL are likely to alter clinical practice, even among neurologists. "The benefit-to-risk ratio is favorable enough to justify high-dose statin therapy for most stroke patients," said Pedersen, but he added that further study is needed, especially as clinicians seek to fully understand the mechanisms of benefit in stroke patien

Presented at World Congress of Cardiology, Barcelona, Spain,
2-6 September 2006 (Abstract 130)

Transcranial Magnetic Stimulation Helps Stroke Patients Regain Motor Skill

 

By stimulating corticomotor excitability, high-frequency repetitive transcranial magnetic stimulation (rTMS) to the affected motor cortex helps stroke patients with chronic loss of hand function regain motor function, according to a report in the June 2006 issue of Stroke.

High-frequency rTMS provides a fast, effective, painless, noninvasive treatment for motor disorders during the rehabilitation of chronic stroke patients for whom there are currently few therapeutic options available.

In a crossover study, the researchers had 15 patients with chronic hemiparetic stroke practice a complex, sequential finger motor task using their paretic fingers after 20 pulses of 10 Hz or sham rTMS applied over the contralateral primary motor cortex.

Focal high-frequency rTMS induced corticomotor excitability (as evidenced by a significant increase in motor-evoked potential amplitude) correlated with a notable functional gain in finger motor skills. In contrast, cortical excitability and motor performance was unaffected by sham rTMS.

High-frequency rTMS was well tolerated; there were no adverse effects or seizures reported.

The researchers concluded that their findings support several prior studies in which motor performance was enhanced by magnetic or electrical cortical stimulation in healthy adults and stroke patients. Additional studies are needed to determine the clinical usefulness of high-frequency rTMS not only for stroke patients but also for other patients with neurological conditions that impair functional motor ability.

Stroke 2006;37:1471-6

Impaired Glucose Tolerance Raises Risk of Stroke in TIA Patients

 

Impaired glucose tolerance is independently linked to an elevated stroke risk in non-diabetic patients who have already experienced a TIA or minor stroke, as per the findings of a study published in the June 2006 issue of Stroke.

Impaired glucose tolerance, typically defined as a nonfasting glucose level between 7.8 and 11.0 mmol/L (140.4 - 198 mg/dL), has been linked to stroke in patients with coronary artery disease. However, it was unclear if this metabolic derangement increased the risk in patients with a prior TIA or minor stroke.

The researchers assessed the impact of glucose tolerance on stroke risk in 3127 patients with a prior TIA or minor stroke who participated in a trial comparing aspirin and atenolol with placebo. The average follow-up period was 2.6 years.

During follow-up, 272 patients developed a stroke and 200 patients experienced an MI or cardiac death. An 80% increased stroke risk was seen in patients with impaired glucose tolerance, but patients with excessively low glucose levels (< 4.6 mmol/L) also had a 50% greater risk than did those with normal glucose levels. The biggest risk of stroke-anearly threefold increased risk compared with normal glucose levels-was in patients with overt diabetes.

By contrast, the glucose levels seemed to have no bearing on the risk of MI or cardiac death. Intensive glucose control in both type 1 and type 2 diabetic patients seems to reduce stroke and other macrovascular events. The authors suggest that new secondary prevention trials should be initiated to investigate whether intensive glucose control reduces stroke incidence in these patients.

Stroke 2006;37:1413-7

Migraine and stroke : A complex relationship

 

  Introduction

Migraine is a common, primary, intermittent neurovascular headache disorder characterized by episodic severe headache accompanied by autonomic nervous system dysfunction. It is the most common headache in young adults, with an estimated prevalence of 4% before puberty and as high as 25% in women by their mid to late 30s. The prevalence of migraine is higher in women after puberty, with a lifetime prevalence of 25% as compared to 8% in men.

  Migraine and stroke

Migraine has been consistently associated with stroke in young women. Further, migraine with aura poses a higher risk than migraine without aura. In addition, migraine also acts as an acute precipitant of stroke, because some patients have a stroke during a migraine attack. However, the relationship between migraine and stroke is extremely complex, encompassing at least four aspects:

1.   Migraine as a cause of ischemic stroke (migrainous infarcts)
2.   Migraine and ischemic stroke sharing a common cause
      (symptomatic  migraine)
3.   Migraine attacks triggered by cerebral ischemia
4.   Migraine as a risk factor for ischemic stroke

There seems to be no sex difference regarding the first three issues, in contrast to the fourth issue, wherein migraine as a risk factor for ischemic stroke seems to apply mostly to young women.

  Migraine as a cause of ischemic stroke

Migrainous infarcts are said to be frequent causes of ischemic stroke in the young. However, true migrainous infarcts (i.e. infarcts due to an unusually severe hypoperfusion during the aura) are very rare and are vastly overdiagnosed. They occur in patients with migraine with aura, during an attack of migraine with aura, with symptoms that are those of the aura, with a documented infarct in the relevant area, and in the absence of other causes at an extensive workup. They most frequently affect the posterior cerebral artery territory. They are more frequent in women, but less so than expected from the female preponderance of migraine. It has been reported that up to 40% of strokes in migrainous women seem to develop directly out of a migraine attack.

  Migraine and ischemic stroke sharing a common cause

Numerous conditions can cause both ischemic stroke and migraine attacks, usually with aura. In these disorders, migraine is no longer a primary headache condition but a mere symptom of the underlying vascular disease, which can be a blood disorder, a cardiac disorder, a mitochondrial disorder, or, more frequently, a vessel wall abnormality, as illustrated by cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL), a small-artery disease of the brain affecting smooth muscle cells and due to Notch 3 mutations. This condition is characterized by small deep infarcts, dementia, mood disorders and, in one third of cases, migraine with aura. When migraine is present, it is the first symptom of the disease, occurring 10 to 15 years before the first stroke. Another example of chronic small-artery disease of the brain causing migraine with aura is the recently identified syndrome of autosomal dominant vascular retinopathy, migraine, and Raynaud's phenomenon. However, in all these conditions, there is no sex difference, so that estrogens are unlikely to play a major role in this variety of migraine-ischemic stroke connection.

  Migraine attacks triggered by cerebral ischemia

A number of observations show that cerebral ischemia, particularly when due to severe carotid stenosis related to dissections, can trigger a migrainous aura. A study suggested that such ischemia-induced migraine attacks were more frequent than migrainous infarctions. Whether this is related to the fact that migraine has been found to be a risk factor for cervical artery dissections remains unknown.

  Migraine as a risk factor for stroke

Numerous studies have been devoted to migraine as a risk factor for ischemic stroke. The odds ratio for migraine in stroke patients ranges from 1.48 in a study of working adults to 6.2 in young women who have migraine with aura. The risk of stroke is further increased by smoking with an odds ratio of 10 and even more by oral contraceptive use, odds ratio of 13.9 to 16.9. The triple combination of migraine, OC, and tobacco smoking is associated with the highest risk for stroke, having an odds ratio of 34-35.

A recent meta-analysis examined the association between migraine and risk of ischemic stroke by including 14 studies: 11 case-control studies and 3 cohort studies. Results showed that the risk for ischemic stroke in patients with any type of migraine headache was 2.16. Further, patients having migraine with aura had a 2.27-fold increased risk of stroke whereas for migraine without aura, the risk of stroke was 1.83-fold. In addition, users of oral contraceptives had an approximately eightfold increase in the risk of stroke compared to non-users.  The results of this meta-analysis are summarized in table1.

Patients with migraine may also be at increased risk of more diffuse subclinical lesions in the deep white matter or periventricular areas that are only detected on neuroimaging. A population-based MRI study investigated 435 individuals (134 patients with migraine without aura, 161 patients with migraine with aura, and 140 controls) to compare the prevalence of brain infarcts and white matter lesions and to identify migraine characteristics associated with these lesions. Results showed that the risk of posterior circulation territory (PCT) infarcts was 7.1 times higher in the patients with migraine compared with controls. The risk increased with increasing attack frequency and was 9.3 times higher in those with 1 attack or more per month as compared with controls. In addition, migraine with aura was associated with a significantly increased risk for PCT infarcts. The group with migraine with aura and 1 or more attack per month had the highest risk (15.8-fold) of PCT infarct. There was an increased risk for deep white matter lesions (DWMLs) only among women. Among women, migraine patients had a 2-fold significantly increased risk of high DWML load that was similar for patients with migraine without aura and patients with migraine with aura. This risk increased with increasing attack frequency; compared with controls, female migraine patients with less than 1 attack per month had an odds ratio of 1.6 and those with 1 or more attack per month had an odds ratio of 2.6.

Possible mechanisms for the association of migraine with stroke

The biological links by which migraine may be associated with ischemic vascular events are likely to be complex. Though the precise mechanisms are currently unknown, following are the possible mechanisms:

• Increased prothrombotic or vasoactive factors:  Migraine has been associated with increases in prothrombotic or vasoactive factors, including prothrombin factor 1.2, factor V Leiden, serotonin, von Willebrand factor, and endothelin. The release of vasoactive neuropeptides during migraine attacks that may stimulate inflammatory responses has also been implicated. Some of these have been specifically associated with migraine with aura. Furthermore, migraine, particularly migraine with aura, has been associated with the methylenetetrahydrofolate reductase C677T genotype, which is associated with increased homocysteine levels, a risk factor for vascular events. Thus, a synergistic effect between the vascular and endothelial dysfunction of migraine and factors that increase the risk of thrombotic events can be envisioned.
  
  
• Platelet-leukocyte interaction and platelet activation: In migraine, pro-inflammatory platelet adhesion to leukocyte occurs during headache free interval similar to that seen in acute coronary and cerebrovascular syndromes. Further, patients of migraine without aura have a higher baseline of platelet activation as compared to controls. This may suggest a link between migraine and stroke on a cellular level.
  
  
• Detrimental cardiovascular risk profile: Migraine with aura has been associated with a more detrimental cardiovascular risk profile, including elevated cholesterol levels, higher blood pressure, higher likelihood of hypertension, and increased Framingham risk score for coronary heart disease.  Thus, it is possible that migraine with aura may be a characteristic that identifies women at increased risk of progressive atherosclerosis  and subsequent vascular events.
  
  
• Use of oral contraceptives: The effect of ethinylestradiol in the combined contraceptive pill (COC) on ischemic stroke has been well established, with several studies confirming a dose-dependent increased risk.  One possible mechanism for increased ischemic stroke risk in healthy women with migraine using COC is the effect of ethinylestradiol on platelets. Platelet hyperaggregation is associated with the use of COCs but the degree to which it occurs is extremely variable.  This is due to the marked individual variation in plasma levels of ethinylestradiol in COC users.  It has been shown that women developed migraine after the onset of COC use in association with increased platelet aggregation to 5-hydroxytriptamine. Cessation of COCs led to a gradual reduction in the frequency of attacks that were associated with a significant reduction in the extent and rate of platelet aggregation in response to 5HT.
  
  
• Adverse hemodynamic features associated with migraine: Several hemodynamic features of migraine may contribute to the pathogenesis of both WMLs and infarcts in migraine. Repeated or prolonged reduced perfusion pressure, reduced blood flow, and oligemia in large and/or small arteries, combined with activation of the clotting system or vasoconstriction, possibly mediated or induced by endothelium perturbation (endothelin 1) could lead to arterial or venous (micro)embolism, thrombosis, or ischemia. Dehydration during migraine attacks might contribute to formation of local thromboses. It is also possible that local changes during migraine attacks, such as excessive neuronal activation, neurogenic inflammation, neuropeptide and cytokine release, or excitotoxity, directly lead to tissue damage. Damage to the white matter in migraine is hypothesized to be the result of ischemic complications of various microvascular processes, such as (even brief) ischemia, hypoglycemia, energy deprivation, oxidative stress, or platelet hyperaggregability.
  
  
• Genetic association: Since migraine with aura has been linked with silent brain infarctions and has been described as a consequence of a genetically determined arteriopathy, a genetic component with endothelial damage may also be a plausible explanation for the increased risk of vascular events.
  
  
  
• Patent foramen ovale (PFO): With regard to ischemic stroke, an association between migraine with aura and congenital heart defects, particularly PFO and mitral valve prolapse, have been proposed as another potential mechanism.

Management of migraine to reduce the risk of ischemic Stroke

 

Although migraine headache has been most consistently associated with stroke in young women, specific data showing that migraine prophylaxis decreases stroke risk is lacking. There are no proven primary prevention strategies for patients with migraine and/ or PFO. Also, there is no indication for a systematic antithrombotic treatment.

The 2006 American Heart Association/American Stroke Association guidelines for the primary prevention of ischemic stroke state that there are insufficient data to recommend a specific treatment approach that would reduce the risk of first stroke in women with migraine,  including migraine with aura.

However,  it is important to manage the two well known risk factors for stroke in migraine viz. smoking and oral contraceptives. Since smoking is associated with an increased risk of stroke, the first recommendation is to stop smoking. There is no systematic contraindication to COC use in the absence of migraine with aura or of other vascular risk factors, but the use of low-estrogen-content oral contraceptives or even of progestogen only is advised in those with migraine with aura.

Key points

• Migraine has been associated with stroke, particularly in young women
  
  
• The probable mechanisms by which migraine is associated with ishemic vascular events include increased prothrombotic or vasoactive factors, platelet activation and platelet-leukocyte  interaction, adverse cardiovascular profile and hemodynamic features,  oral contraceptives, genetic factors and congenital  heart defects
  
  
• The two established risk factors for stroke in migraine viz. Smoking and oral contraceptives, need to be managed. Use of low-estrogen-content oral contraceptives or progestogen only is advised in those with migraine with aura, and complete smoking cessation is recommended

References

 

1.  BMJ. 2005 Jan 8;330(7482):63. Epub 2004 Dec 13.
2.  Stroke 2004;35[supppl I]:2652-6
3.  BMJ 1999;318:13-8          
4.  JAMA 2004;291:427-34
5.  JAMA 2006;296:283-91               
6.  J Neurol Neurosurg Psychiatry 2004;75:984-7
7.  Vascular Medicine 2000;5:133-4                
8.  Stroke 2006;37:1583-633

New Approvals Internationally

  FDA approves Levetiracetam as adjunctive therapy in the treatment of Myoclonic Seizures in patients with  Juvenile  Myoclonic Epilepsy

The US FDA has approved the use of levetiracetam as an adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy.

The clinical trial supporting this new indication for levetiracetam was a phase III, double-blind, randomized, placebo-controlled study on the safety and efficacy of levetiracetam as an add-on therapy in patients with juvenile myoclonic epilepsy experiencing myoclonic seizures. Patients in this study included those with juvenile myoclonic epilepsy, juvenile absence epilepsy or with generalized tonic-clonic seizures on awakening. The majority were patients with juvenile myoclonic epilepsy.

The responder rate defined as > 50% reduction in myoclonic seizure days during the treatment period versus baseline was significantly greater in patients treated with levetiracetam as compared with placebo (60.4% with levetiracetam vs. 23.7% with placebo).  A total of 15.1% of patients in the levetiracetam group achieved freedom from myoclonic seizures during the treatment period compared with 3.4 % of placebo patients.

The most common adverse events seen with levetiracetam were somnolence,  neck pain,  and pharyngitis.

  Levetiracetam IV Approved by US FDA

The US FDA has approved an intravenous formulation of levetiracetam as an alternative treatment for epileptic seizures if the oral forms of the drug are not appropriate for patients.

The new formulation must be diluted prior to use and administered as a 15-minute intravenous infusion.

Levetiracetam is approved as an add-on therapy for the treatment of partial onset seizures in adults and children 4 years of age or older with epilepsy. The drug is currently available in tablet and in oral solution.

  FDA approves Rivastigmine for Parkinson's  Disease Dementia

FDA has approved rivastigmine tartrate, for the treatment of mild to moderate Parkinson's dementia, making it the first drug for the treatment of this condition. Rivastigmine is also indicated for the treatment of mild to moderate Alzheimer's disease.

The approval of rivastigmine for the treatment of Parkinson's disease dementia was based on results from the EXelon in PaRkinson's disease dementia Study (EXPRESS), which enrolled patients of Parkinson's disease with mild to moderately severe dementia. Results showed a statistically significant improvement in overall functioning in patients treated with rivastigmine relative to deterioration seen in those treated with placebo, in cognition and certain aspects of behavior. Patients treated with rivastigmine also had less deterioration in their ability to perform activities of daily living than those who received placebo.

The most frequent side effects associated with rivastigmine were nausea and vomiting, which were mild to moderate in nature. Although more patients treated with rivastigmine reported increased tremor than placebo, this rarely resulted in withdrawal from the study and nor did the rating scale used to measure motor function in Parkinson's disease show a significant deterioration relative to baseline or a significant increase in tremor between rivastigmine and placebo.

  FDA approves Lamotrigine for primary generalized tonic-clonic  seizures

The US Food and Drug Administration has approved a new use of lamotrigine for the treatment of Primary Generalized Tonic-Clonic (PGTC) seizures. With this new indication, lamotrigine can now be used as add-on therapy to treat PGTC seizures in children aged two and older as well as adults.

The approval of lamotrigine as add-on therapy in patients with PGTC seizures was based on a multicenter, placebo-controlled trial in pediatric (age 2) and adult patients (n=117). In the study, lamotrigine was given to patients whose seizures were not well controlled, even while taking one or two other anti-seizure medications.

Results showed that lamotrigine was highly effective in reducing the frequency of PGTC seizures. Over the entire treatment period, lamotrigine significantly reduced PGTC seizures by 66% compared to 34% for the placebo group. Similar effects were seen during the titration and maintenance phases of the study. Significantly more patients receiving lamotrigine as maintenance therapy experienced at least a 50% reduction compared to placebo (72 % vs. 49 %). Efficacy was similar across age groups. Overall, lamotrigine had a favorable tolerability profile.

The most common drug-related side effects observed in this clinical trial were dizziness,  drowsiness and nausea.

TICKLE YOUR BRAIN

Answers

1. ADIADOCHOKINSIS
2. GERSTMANNS
3. BINSWANGERS
4. WALLENBERG
5. JACOB-CREUTZFELDT
6. OPTIC CHIASM
7. KRABBE
8. LUMBAR PUNCTURE
9. DURA MATER
10. OPTIC NEURITIS

Final answer:

OLIGODENDROGLIA