Tuesday, June 17, 2008
hormones in young postmenopause
For Menopausal Hormone Therapy and Stroke Risk, Timing Makes a Difference
New NHS results corroborate previous findings about HT and stroke risk while providing reassurance for young menopausal women using HT for fewer than 5 years.
Previous results from the Nurses’ Health Study (NHS; Ann Intern Med 2000; 133:933) and the Women’s Health Initiative (WHI; JAMA 2003; 289:2673 and Circulation 2006; 113:2425) have shown that menopausal hormone therapy is associated with a 30% to 40% higher risk for stroke. In a new NHS analysis of data from questionnaires completed in 2004, investigators evaluated timing of HT initiation, duration of use, and estrogen dose as factors in determining risk for various types of stroke. Because vasomotor symptoms are most likely to be bothersome in young menopausal women and to diminish over time, for the analysis of HT duration, the authors focused on women who were within 4 years of menopause or were younger than 55.
Current use of estrogen-alone HT or combined HT was associated with age-adjusted relative risks for total stroke of 1.33 (95% confidence interval, 1.13–1.55) and 1.17 (95% CI, 0.96–1.42), respectively. RRs were generally similar for ischemic, hemorrhagic, nonfatal, and fatal strokes. Timing of HT with respect to onset of menopause did not change these risks appreciably. Despite a limited sample size for the analysis of HT duration, use of HT for fewer than 5 years was not associated with significant elevations in risk for stroke, particularly among women who were younger than 55. Estrogen dose correlated with stroke risk: For a 0.3-mg dose of conjugated equine estrogen, no excess risk was observed. In contrast, doses of 0.625 mg and 1.25 mg were associated with adjusted RRs of 1.54 and 1.62, respectively.
Comment: These results agree with prior NHS and WHI findings, which showed that HT use is associated with a small elevation in stroke risk regardless of age or time after onset of menopause. However, NHS and WHI researchers alike have found that HT use by young menopausal women is associated with a lower risk for heart disease. Among young menopausal women, excess risk for stroke (if any) seems particularly modest, especially when duration of HT use is limited and low estrogen doses are employed.
— Andrew M. Kaunitz, MD
Published in Journal Watch Women's Health June 5, 2008
Citation(s):
Grodstein F et al. Postmenopausal hormone therapy and stroke: Role of time since menopause and age at initiation of hormone therapy. Arch Intern Med 2008 Apr 28; 168:861.
Original article (Subscription may be required)
Medline abstract (Free)
Monday, May 12, 2008
Polyarterial clustered recurrence of cervical artery dissection appears to be the rule
Dittrich R, Nassenstein I, Bachmann R et al. Neurology 2007; 69: 180-186. Summary: Spontaneous cervical artery dissection is (wrongly ) thought to a monophasic disorder. The listed rate of recurrence 0-8 % over 8.6 years is low, WAYYY low. Serial MRI of 36 patients over six month showed the following: 6 % had polyarterial involvement on the first MRI. 25 % had recurrence in one or more (same or different ) arteries over the course of followup. Of the 25 %, most recurrences occurred within 4 weeks (19%), but 6 % were noted at six months. All but one of the recurrences were asymptomatic or mildly symptomatic. All patients (ie the ones with benign results) were treated with anticoagulation followed by ASA.
Tuesday, March 25, 2008
Fasting causes stroke
Saadatnia M et al. showed an fourfold increase in cerebral venous sinus thrombosis during Ramadan, a month during which Muslims fast. P02.007 AAN book 2008.
Misdiagnosis of Fabry disease
Po1.145 AAN book 2008 first author L Marchesoni. Argentina.
Fabry's disease is an x linked recessive lysosomal storage disease due to deficient alpha galactosidase A. Untreated males usually die by the end of the sixth decade. The initial presentation is usually acroparesthesias, not relieved by rubbing, but prevented with acetophenacetin and ingestion of large amounts of liquids. Subsequently, abdominal pain, angiokeratomas and anhidrosis occur. Most are diagnosed after 15 years or more. Misdiagnoses included cryptogenic/psychogenic pain, RF, flatfoot, gout, food intoxication, cholecystitis, "glandular block", petechiae, vascular fragility, and others. Angiokeratomas are seen first around the umbilicus, and on the extensor surfaces of the elbows and knees, and in body creases including the hips and the genital areas. Opthalmic signs include whirl like feathery opacities, dust like haziness on cornea, dilated and tortuous corneal vessels, and corneal dystrophy on slit lamp that does not affect vision(cornea vittilicata). The opthalmic abnormality is present in nearly 90 % including female carriers who can thus be diagnosed by slit lamp exam.
Features can include tinnitus and deafness, although that is not in many textbooks (Lou Caplan); also vertigo. Other features are heat intolerance, inability to sweat, with the skin turning beet red on heat exposure. Other factors are postprandial abdominal cramping, and diverticula that can rupture. Left ventricular hypertrophy is seen as is small fiber neuropathy with decreased TEMPERATURE sensation. A recent case was reported of a patient presenting with a mimic of TGA (The Neurologist 2012; 18:413-4).
Strokes occur in posterior circulation , large and small arteries.
Pathologically, thickened walls in smaller arterioles is noted and in the brain, a double refractile material is seen. Cardiac and renal disease predominate, and many strokes are subclinical. Treatment must begin very early. Misdiagnosis of MS is common especially with brainstem strokes. CRAO, optic atrophy, loss of nasal field, third nerve palsy, lateral medullary syndrome, TMB are all reported, as are various lacunar syndromes. Cardiac evaluation shows hypertrophic cardiomyopathy and MVP in more than half. Renal failure is due to the deposition of lipid in glomeruli and tubules. Proteinuria is a feature. Lymphedema is seen . Basilar artery is described as pathologically enlarged and at times dolichoectatic.
The gene for alpha galactosidase a is Xq22.1, and different mutations are known. Female heterozygotes still have early stroke and can have heart and kidney disease and elevated ceramide trihexoside in urine. Treatment is biochemical Fabrazyme made by Genzyme (see pubmed how to do). CBZ, PTN, ASA ticlid, Vit E can be used for various symptoms/problems.
Additional material:
Testai FD, Gorelick PB. Inherited metabolic disorders and stroke part I: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes. Arch Neurol; 2010: 67: 19-24.
More than 400 mutations of the alpha gal gene are identified, most being missense or nonsense substitutions. Absent family history does not rule out the diagnosis. The incidence is 1: 117,000 births and 1: 40,000 men. However, in cryptogenic stroke in the young, FD is responsible for 1.2 % (of age less than 55). Inn the database, women have more strokes than men, 2:1 with mean age 43 for women, and 28 for men. Basilar artery diameter is said to be a sensitive measure of FD (Neurology 2009).
Due to skewed organ specific X chromosome inactivation (nonrandom lionization), women may have atypical organ specific presentation, leading to challenges in diagnosis. These may include cardiac, renal and cerebrovascular manifestations. Diagnosis is made by alpha gal activity in leukocytes or plasma, but in women, gene sequencing and linkage studies may be needed, due to heterozygosity.
Acroparesthesias are associated with accumulation glycosphingolipids in DRG and Nerve conductions and EMG's are negative.
Measurement of leukocyte GAL activity is 100 percent sensitive in males but only five percent in women
MRI shows T2 hyperintense signal in frontal and parietal white matter and T1 hyperintensity in pulvinar as well as dolichoectasia. Treatment decreased LV mass and pain but unknown if it helps stroke.
Fabry's disease is an x linked recessive lysosomal storage disease due to deficient alpha galactosidase A. Untreated males usually die by the end of the sixth decade. The initial presentation is usually acroparesthesias, not relieved by rubbing, but prevented with acetophenacetin and ingestion of large amounts of liquids. Subsequently, abdominal pain, angiokeratomas and anhidrosis occur. Most are diagnosed after 15 years or more. Misdiagnoses included cryptogenic/psychogenic pain, RF, flatfoot, gout, food intoxication, cholecystitis, "glandular block", petechiae, vascular fragility, and others. Angiokeratomas are seen first around the umbilicus, and on the extensor surfaces of the elbows and knees, and in body creases including the hips and the genital areas. Opthalmic signs include whirl like feathery opacities, dust like haziness on cornea, dilated and tortuous corneal vessels, and corneal dystrophy on slit lamp that does not affect vision(cornea vittilicata). The opthalmic abnormality is present in nearly 90 % including female carriers who can thus be diagnosed by slit lamp exam.
Features can include tinnitus and deafness, although that is not in many textbooks (Lou Caplan); also vertigo. Other features are heat intolerance, inability to sweat, with the skin turning beet red on heat exposure. Other factors are postprandial abdominal cramping, and diverticula that can rupture. Left ventricular hypertrophy is seen as is small fiber neuropathy with decreased TEMPERATURE sensation. A recent case was reported of a patient presenting with a mimic of TGA (The Neurologist 2012; 18:413-4).
Strokes occur in posterior circulation , large and small arteries.
Pathologically, thickened walls in smaller arterioles is noted and in the brain, a double refractile material is seen. Cardiac and renal disease predominate, and many strokes are subclinical. Treatment must begin very early. Misdiagnosis of MS is common especially with brainstem strokes. CRAO, optic atrophy, loss of nasal field, third nerve palsy, lateral medullary syndrome, TMB are all reported, as are various lacunar syndromes. Cardiac evaluation shows hypertrophic cardiomyopathy and MVP in more than half. Renal failure is due to the deposition of lipid in glomeruli and tubules. Proteinuria is a feature. Lymphedema is seen . Basilar artery is described as pathologically enlarged and at times dolichoectatic.
The gene for alpha galactosidase a is Xq22.1, and different mutations are known. Female heterozygotes still have early stroke and can have heart and kidney disease and elevated ceramide trihexoside in urine. Treatment is biochemical Fabrazyme made by Genzyme (see pubmed how to do). CBZ, PTN, ASA ticlid, Vit E can be used for various symptoms/problems.
Additional material:
Testai FD, Gorelick PB. Inherited metabolic disorders and stroke part I: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes. Arch Neurol; 2010: 67: 19-24.
More than 400 mutations of the alpha gal gene are identified, most being missense or nonsense substitutions. Absent family history does not rule out the diagnosis. The incidence is 1: 117,000 births and 1: 40,000 men. However, in cryptogenic stroke in the young, FD is responsible for 1.2 % (of age less than 55). Inn the database, women have more strokes than men, 2:1 with mean age 43 for women, and 28 for men. Basilar artery diameter is said to be a sensitive measure of FD (Neurology 2009).
Due to skewed organ specific X chromosome inactivation (nonrandom lionization), women may have atypical organ specific presentation, leading to challenges in diagnosis. These may include cardiac, renal and cerebrovascular manifestations. Diagnosis is made by alpha gal activity in leukocytes or plasma, but in women, gene sequencing and linkage studies may be needed, due to heterozygosity.
Acroparesthesias are associated with accumulation glycosphingolipids in DRG and Nerve conductions and EMG's are negative.
Measurement of leukocyte GAL activity is 100 percent sensitive in males but only five percent in women
MRI shows T2 hyperintense signal in frontal and parietal white matter and T1 hyperintensity in pulvinar as well as dolichoectasia. Treatment decreased LV mass and pain but unknown if it helps stroke.
The varicella zoster virus vasculopathies: clinical, CSF, imaging and virologic features
Nagel MA, Cohrs RJ, Mahalingam R et al. Neurology 2008; 70:853-860.
Review article of 30 patients, the first large review in about 30 years, busts some myths about VZV stroke. Among them:
1. Rash occurred in only 63 %, often many months prior to the stroke (mean 4 months)
2. CSF pleocytosis occurred in only 67 %
3. Angiography was abnormal in only 70 %
4. Large arteries were involved with small arteries (50%) or small arteries were involved alone (37% ) whereas large arteries alone occurred in only 13 %.
5. VZV DNA was found in only 30 %
6. The best lab test, by far, was CSF anti VZV IgG antibody with reduced IgG index (serum : CSF) confirmed intrathecal synthesis. The only 2 negative cases out of 30 were children who developed vasculopathy after chickenpox.
7. Case series was not large enough to determine optimal treatment (acyclovir v. acyclovir + steroids); however, some cases relapsed and then improved when either acyclovir course was extended or steroids were addded to acyclovir. Overall in the small series, 2/3 improved with acyclovir alone, and 3/4 with acyclovir + steroids.
8. 11 patients out of 30 were immunocompromised (2 AIDS, 3 HIV +, 2 leukemia, 1 CREST s, 1 lymphoma, 1 low CD4 count, and 1 treatment for RA/SLE).
9
PRoFESS Trial
Diener HC , Sacco R, Yusud S et al. Rationale, design and baseline data of a randomized, double blind controlled trial comparing two antithromobotic regiments (a fixed dose combinations of ER dipyridamole and plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: the prevention regiment for effectively avoiding second strokes trial. Cereebrovasc Dis 2007; 23:368-380.
Blogger comment: The authors were obviously science and not English majors, and the lower case "O" is annoying. In sum this study compares aggrenox against plavix, and makes a side study of telmisartan.
There are 695 sites from 35 countries, involving patients over 50 with stroke within 120 days, with recurrent stroke as the primary outcome in a time to event analysis. The secondary outcome measure is the composite of stroke, MI or vascular death. The main study is non-inferiority, then superiority and the side study assesses suuperiority over placebo. Over 20,000 patients are randomized. The mean age was 66, 2:1 male, large and small vessel strokes are included. The deisgn is 2 x 2 factorial design.
The expected event rate in the clopidogrel group was 5.25 % per year, necessitating 15,500 subjects but the number was increased when the event rate turned out to be lower.
COL4A1 mutations and stroke
Vahedi et al. Neurology 2007; 69: 1564-8
and editorial
Meschia JF and Rosand J. Fragile vessels handle with care Neurology 2007; 69: 1560-1561
COL4A1 gives the brain resistance to minor head trauma. It encodes the gene for collagen alpha 1. Human conditions linked to a mutation include autosomal dominant porencephaly, retinal arteriolar tortuosities, and traumatic or antithrombotic associated symptomatic cerebral hemorrhages and otherwise undetected microhemorrhages on MRI. MRI can also show diffuse leukoencephalopathy and enlarged perivascular spaces. The report by Vahedi includes a patient who died of subarachnoid hemorrhage and another who died at age 40 of anticoagulation associated hemorrhage.
The editorial authors compare the condition to CADASIL insofar as many different mutations can cause the condition. The theme of trauma or injuries to vessels as triggers to hemorrhage recurs. Treatment of affected patients may including withholding antithrombotics or anticoagulants, avoiding contact sports, genetic screening in pregnancy, and of family members (including asking specifically about congenital hemiplegia rather than "porencephaly"), periodic screening with MRI's, further evaluating tortuous vessels seen on funduscopy and others.
Monday, March 24, 2008
Imaging Pearl for cerebral venous sinus thrombosis
Courtesy of David Lee Gordon, Chairman Oklahoma (the neurology department not the musical)
Look at the parenchymal MRI (not MRV) images, particularly the T1noncontrast sagittal images. If the noncontrast T1 sagittal images shownormal (hypointense = black) flow void in the left transverse sinus andlack of flow void (hyperintense = white) in the right transverse sinus,you have your answer without a venogram.The left transverse sinus is commonly hypoplastic, not the right (sinceuually the right transverse sinus drains the larger superior sagittalsinus and the left transverse sinus drains the smaller straight sinusand the confluence is usually not a confluence at all). Also a temporalhemorrhage is precisely what I would expect from an ipsilateraltransverse sinus thrombosis. If the patient does indeed have CVT,anticoagulation often leads to improve despite the presence ofhemorrhage.
Monday, February 11, 2008
SCA infarction and emotional facial paresis
SCA infarct classically produces ipsilateral limb and gait ataxia, static or intention tremor, Horner's syndrome, contralateral loss of pain and temperature and decreased masseter response. Other symptoms may include deafness, impaired sweating (with Horner's) and emotional facial paresis . This derives from dorsolateral pontine pathologyThis area is distinct from the corticobulbar tract mediating voluntary facial innervation (Neuroimages, Hopf HC, Fitzek C, Marx J et al., Emotional facial paresis of pontine origin, Neurology 2000; 54: 1217).
Blogger comment-- review brainstem anatomy including lateral st tract (crossed sensory), mes tract of V (masseter r), central sympathetic tract (Horners s), lateral lemniscus (responsible for deafness), MLF
Blogger comment-- review brainstem anatomy including lateral st tract (crossed sensory), mes tract of V (masseter r), central sympathetic tract (Horners s), lateral lemniscus (responsible for deafness), MLF
Subclavian artery dissection and triple infarction of the nervous system
Garewal M, Selhorst JB. Arch Neurol 2005; 62:1917-1919.
Background-- subclavian dissection is rare, and is usually associated with anomalies of the aortic arch, trauma or catheterization. The main clinical manifestations are chest and back pain preceding stroke, often with pain and weakness in the arm. This contrasts with vertebral artery dissection that is associated with headache and neck pain and arm pain/weakness.
In the case described, a 54 year old hypertensive developed crushing intrascapular pain and vertigo and vomiting and could not lift his arm over his head. His father had had an abdominal aortic aneurysm. He had decreased pinprick perception on his left lower jaw. He had weak deltoid, triceps, supraspinatus, and triceps. He had decreased left biceps and triceps jerks. He had dysmetria bilaterally and an ataxic gait. His radial arteries WERE SYMMETRIC!. DWI showed a left cerebellar stroke. On angio he had a subintimal thrombus in the subclavian artery. He improved over a month or two. The authors describe 3 strokes: cerebellar, spinal between C4 and C5, and multiple rootlet infarction with weak arms and denervation on EMG study.
The lit review describes a patient who developed subacute thoracic pain and bilateral arm pain.
Background-- subclavian dissection is rare, and is usually associated with anomalies of the aortic arch, trauma or catheterization. The main clinical manifestations are chest and back pain preceding stroke, often with pain and weakness in the arm. This contrasts with vertebral artery dissection that is associated with headache and neck pain and arm pain/weakness.
In the case described, a 54 year old hypertensive developed crushing intrascapular pain and vertigo and vomiting and could not lift his arm over his head. His father had had an abdominal aortic aneurysm. He had decreased pinprick perception on his left lower jaw. He had weak deltoid, triceps, supraspinatus, and triceps. He had decreased left biceps and triceps jerks. He had dysmetria bilaterally and an ataxic gait. His radial arteries WERE SYMMETRIC!. DWI showed a left cerebellar stroke. On angio he had a subintimal thrombus in the subclavian artery. He improved over a month or two. The authors describe 3 strokes: cerebellar, spinal between C4 and C5, and multiple rootlet infarction with weak arms and denervation on EMG study.
The lit review describes a patient who developed subacute thoracic pain and bilateral arm pain.
Saturday, February 09, 2008
Natural history of vertebrobasilar dolichoectasia
Passero SG, Rossi S. Neurology 2008; 70:66-72.
There is a high degree of variability in outcome ranging from benign to malignant. Clinical expression includes compression of cranial nerves or brainstem, obstructive hydrocephalus, ischemic and hemorrhagic stroke. This study of 156 patients followed an average of 11.7 years showed that 93 patients (60 % ) had at least one event; 59 ischemic strokes, 21 hemorrhagic strokes, 31 compressive symptoms, and 2 hydorcephalus. Risk stratification was based on the severity of , diameter, height of bifurcation, nad lateral displacement of the vertebral artery. Progression of VBD was associated with a worse outcome. 43 % of patients did progress.
Detail: the maximum diameter of the BA ranged from 4.6 to 13.4 mm (mean 6.8). 86 % invlved the VA's and 45 % the anterior circulation. Strokes were more likely among patients who were hypertensive and smokes. Of the strokes, 41 % were brainstem, 29 % superficial arterial territory of PCA, 24 % thalamus, 2 % cerebellum, 66 % lacunes, 34 % large artery.
Of 56 patients who presented with ischemic stroke, 50 received antiplatelet drugs and 6 anticoagulation. 54 % had recurent ischemic strokes, and 13 % recurrent hemorrhagic strokes. 73 % of recurrent strokes happened in first five years of followup.
Treatment initially was NOT related to risk of stroke. 42 % of treated patients (n=33) and 34 % of untreated patients (n=26) had one or more ischemic strokes during followup. Death from stroke (40 % of deaths) occurred among patients who first presented with stroke.
The ten year risk of recurrent stroke among patients presenting with stroke was 56 % which compares to the Rochester experience of 29 % (Meissner and Whisnant, Stroke, 1988).
There is a high degree of variability in outcome ranging from benign to malignant. Clinical expression includes compression of cranial nerves or brainstem, obstructive hydrocephalus, ischemic and hemorrhagic stroke. This study of 156 patients followed an average of 11.7 years showed that 93 patients (60 % ) had at least one event; 59 ischemic strokes, 21 hemorrhagic strokes, 31 compressive symptoms, and 2 hydorcephalus. Risk stratification was based on the severity of , diameter, height of bifurcation, nad lateral displacement of the vertebral artery. Progression of VBD was associated with a worse outcome. 43 % of patients did progress.
Detail: the maximum diameter of the BA ranged from 4.6 to 13.4 mm (mean 6.8). 86 % invlved the VA's and 45 % the anterior circulation. Strokes were more likely among patients who were hypertensive and smokes. Of the strokes, 41 % were brainstem, 29 % superficial arterial territory of PCA, 24 % thalamus, 2 % cerebellum, 66 % lacunes, 34 % large artery.
Of 56 patients who presented with ischemic stroke, 50 received antiplatelet drugs and 6 anticoagulation. 54 % had recurent ischemic strokes, and 13 % recurrent hemorrhagic strokes. 73 % of recurrent strokes happened in first five years of followup.
Treatment initially was NOT related to risk of stroke. 42 % of treated patients (n=33) and 34 % of untreated patients (n=26) had one or more ischemic strokes during followup. Death from stroke (40 % of deaths) occurred among patients who first presented with stroke.
The ten year risk of recurrent stroke among patients presenting with stroke was 56 % which compares to the Rochester experience of 29 % (Meissner and Whisnant, Stroke, 1988).
Wednesday, February 06, 2008
Aspirin for Primary prevention in women
Ridker PM, Cook NR, Lee I, et al. A randomized trial of low dose aspirin in the primary prevention of cardiovascular disease in women. NEJM 2005; 352:1293-1304. article with associated editorial by Levin RI The Puzzle of aspirin and sex NEJM 352:1366-1368.
Background: Low dose asa reduces the risk of a first MI in men, with little effect on risk of ischemic stroke. There are no similar data in women.
Article highlights: This large (39,876) trial of healthy women age 45 and older for primary prevention put them in a group of ASA 100 mg or placebo for ten years. ASA reduced the risk of stroke without affecting the risk of MI/death from cardiovascular causes, leading to a nonsignificant primary endpoint.
Editorial: the finding is the inverse in what they found in men. The author discusses that the studies were done in different decades (2 decades apart) and that the respective placebo groups had different risk profiles. The risk was 97/100000 person years in the Women's Health Study and 439 per 100,000 py's in the Physicians Health Initiiative (the male study). These were healthy women. The author reviews some of the pertinent differences in physiology by gender. Men usually have 2-3 times the number of MI's as women. Their coronary arteries are bigger and their carotid plaques "more aged." Women have 9 times the amount of stress cardiomyopathy . Their responses to drugs are different. Estrogen up-regulates prostacyclin by receptor mediated activation of cyclo-oxygenase 2. The study would seem to suggest that generally prescribing low dose aspirin to healthy women under 65 with a low risk score should be avoided. However, part of the book has yet to be written.
Background: Low dose asa reduces the risk of a first MI in men, with little effect on risk of ischemic stroke. There are no similar data in women.
Article highlights: This large (39,876) trial of healthy women age 45 and older for primary prevention put them in a group of ASA 100 mg or placebo for ten years. ASA reduced the risk of stroke without affecting the risk of MI/death from cardiovascular causes, leading to a nonsignificant primary endpoint.
Editorial: the finding is the inverse in what they found in men. The author discusses that the studies were done in different decades (2 decades apart) and that the respective placebo groups had different risk profiles. The risk was 97/100000 person years in the Women's Health Study and 439 per 100,000 py's in the Physicians Health Initiiative (the male study). These were healthy women. The author reviews some of the pertinent differences in physiology by gender. Men usually have 2-3 times the number of MI's as women. Their coronary arteries are bigger and their carotid plaques "more aged." Women have 9 times the amount of stress cardiomyopathy . Their responses to drugs are different. Estrogen up-regulates prostacyclin by receptor mediated activation of cyclo-oxygenase 2. The study would seem to suggest that generally prescribing low dose aspirin to healthy women under 65 with a low risk score should be avoided. However, part of the book has yet to be written.
Thoughts on the WASID trial
The warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial compared aspirin with warfarin and found no benefit from warfarin, but greater safety risks, leading the authors to conclude that there was no justification to use warfarin in this situation.
An editorial by Walter Koroshetz accompanying the landmark study (NEJM 2005;352:13)provides acceptance of the studies with enough included analysis of the detail to make a reasoned opinion about its limitations. Ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke occurred in 22 % of patients in either group. Recurrent stroke did not differ in the two groups (.2 in ASA, .17 in warfarin groups). In WASID, 73 % of recurrent stroke occurred in the index vessel.
Problems: 1) ASA dose of 1250 per day is nonstandard 2) the target INR of 2-3 was reached only about 63 % of the time and 3) 28 % of patients dropped out of the warfarin group. The rate of stroke related to IN mattered. It was 25 per 100 patient years with a subtherapeutic INR, 5.0 per 100 patient years with a therapeutic INR. Koroshetz notes that the "data suggest that anticoagulation within the therapeutic range is associated with a striking reduction in the risk of cerebrovacular and cadiovascular events." The problem, is achieving anticoagulation within the therapeutic range, either in a trial or in clinical practice. Koroshetz further notes that "the WASID data do not necessarily suggest that all patients with symptomatic intracranial stenosis should be treated with aspirin during all phases of their disease and be left to face a 22 % two year risk of ischemic stroke, brain hemorrhage or death from vascular causes other than stroke that the WASID trials predicts." There is a very high risk period right after enrollment, due to recurrent stroke, and Koroshetz suggests using Lovenox followed by anticoagulation rather than just warfarin.
Blogger comment: Recall that in most clinical trials of ASA (not for intracranial stenosis) the NTT for saving one person from a stroke is very high,, ranging from 79 to 129 in various aspirin trials, with the NTT for Plavix around 50 and for Aggrenox around 37. So for a disease with a 1/5 risk of stroke, aspirin may be better/safer than warfarin but still is not that good. So, a treatment, any treatment, that can improve those odds in a high risk group is desperately needed. If a new drug came forth that anticoagulated and could be kept in range reliably (unlike warfarin , which WASID proved can't be) another clinical trial for intrancranial stenosis would be indicated.
One last note-- it shold be noted that some of the initiators of the WASID and WARRS trials are Bostonians who have historically been dedicated warfarin users. These neurologists deserve our credit for designing and properly critiquing the studies here.
An editorial by Walter Koroshetz accompanying the landmark study (NEJM 2005;352:13)provides acceptance of the studies with enough included analysis of the detail to make a reasoned opinion about its limitations. Ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke occurred in 22 % of patients in either group. Recurrent stroke did not differ in the two groups (.2 in ASA, .17 in warfarin groups). In WASID, 73 % of recurrent stroke occurred in the index vessel.
Problems: 1) ASA dose of 1250 per day is nonstandard 2) the target INR of 2-3 was reached only about 63 % of the time and 3) 28 % of patients dropped out of the warfarin group. The rate of stroke related to IN mattered. It was 25 per 100 patient years with a subtherapeutic INR, 5.0 per 100 patient years with a therapeutic INR. Koroshetz notes that the "data suggest that anticoagulation within the therapeutic range is associated with a striking reduction in the risk of cerebrovacular and cadiovascular events." The problem, is achieving anticoagulation within the therapeutic range, either in a trial or in clinical practice. Koroshetz further notes that "the WASID data do not necessarily suggest that all patients with symptomatic intracranial stenosis should be treated with aspirin during all phases of their disease and be left to face a 22 % two year risk of ischemic stroke, brain hemorrhage or death from vascular causes other than stroke that the WASID trials predicts." There is a very high risk period right after enrollment, due to recurrent stroke, and Koroshetz suggests using Lovenox followed by anticoagulation rather than just warfarin.
Blogger comment: Recall that in most clinical trials of ASA (not for intracranial stenosis) the NTT for saving one person from a stroke is very high,, ranging from 79 to 129 in various aspirin trials, with the NTT for Plavix around 50 and for Aggrenox around 37. So for a disease with a 1/5 risk of stroke, aspirin may be better/safer than warfarin but still is not that good. So, a treatment, any treatment, that can improve those odds in a high risk group is desperately needed. If a new drug came forth that anticoagulated and could be kept in range reliably (unlike warfarin , which WASID proved can't be) another clinical trial for intrancranial stenosis would be indicated.
One last note-- it shold be noted that some of the initiators of the WASID and WARRS trials are Bostonians who have historically been dedicated warfarin users. These neurologists deserve our credit for designing and properly critiquing the studies here.
Statin therapy in stroke prevention: a metaanalysis involving 121,000 patients
O"Regan C, Wu P, Arora P, et al. Am J Med 2008; 121:24-33.
High points: the pooled relative risk of statin therapy for all cause mortality was 0.88 (95% CI .79-.91). Each unit increase in LDL results in a .3% increased RR of death. ONLY ONE TRIAL WAS FOR SECONDARY PREVENTION.
Details: RR of statin patients in all pooled trials, for cardiovascular death, .81, for nonhemorrhagic cerebrovscular death, .81, hemorrhagic stroke , 0.94, and fatal strokes .99. Be cautious of hemorrhagic strokes.
High points: the pooled relative risk of statin therapy for all cause mortality was 0.88 (95% CI .79-.91). Each unit increase in LDL results in a .3% increased RR of death. ONLY ONE TRIAL WAS FOR SECONDARY PREVENTION.
Details: RR of statin patients in all pooled trials, for cardiovascular death, .81, for nonhemorrhagic cerebrovscular death, .81, hemorrhagic stroke , 0.94, and fatal strokes .99. Be cautious of hemorrhagic strokes.
Sunday, February 03, 2008
Minocycline treatment for acute stroke
Lampl Y, Boaz M, Gilad R.Minocycline treatment in acute stroke. An open label, evaluator blinded study.
Patients received 200 mg minocycline orally for five days after stroke, and NIHSS was used. 152 patients were studied (74 received minocycline, 77 placebo). NIHSS and mRS were lower and BI higher in treated group. Deaths, MI, recurrent strokes, and hemorrhagic stroke transformations were no affected.
Study was based on "clear" neuroprotective effect seen in animal models of MS, PD, HD, and ALS. Pyramidal cell survival improved from 10 to 77 % due to "complete prevention of microglia ischemia induced activation." Minocycline prevents infarct volume expansion, inhibits IL 1B converting enzyme, cycklooxygenase 2, PGE 2 expression. Proposals suggests its antiinflammatory, reduces microglial activation, matrix metalloproteinase activation, nitric acid production, and inhibition of apoptosis. In spinal cord its an NMDA antagonist, and prevents activated caspace 3 formation.
Blogger note: The large multicenter phase III trial of minocycline in ALS reported that ALS was HARMED BY minocycline, details at the link below:
http://strokenotes.blogspot.com/2008/02/minocycline-treatment-for-acute-stroke.html
Patients received 200 mg minocycline orally for five days after stroke, and NIHSS was used. 152 patients were studied (74 received minocycline, 77 placebo). NIHSS and mRS were lower and BI higher in treated group. Deaths, MI, recurrent strokes, and hemorrhagic stroke transformations were no affected.
Study was based on "clear" neuroprotective effect seen in animal models of MS, PD, HD, and ALS. Pyramidal cell survival improved from 10 to 77 % due to "complete prevention of microglia ischemia induced activation." Minocycline prevents infarct volume expansion, inhibits IL 1B converting enzyme, cycklooxygenase 2, PGE 2 expression. Proposals suggests its antiinflammatory, reduces microglial activation, matrix metalloproteinase activation, nitric acid production, and inhibition of apoptosis. In spinal cord its an NMDA antagonist, and prevents activated caspace 3 formation.
Blogger note: The large multicenter phase III trial of minocycline in ALS reported that ALS was HARMED BY minocycline, details at the link below:
http://strokenotes.blogspot.com/2008/02/minocycline-treatment-for-acute-stroke.html
Friday, February 01, 2008
Predictors of stroke among patients with AF
1. Prior stroke/TIA is highest risk and confers > 5 % per year risk (6-9% per year)
2. Diabetes confers 2-3.5% risk
3. Age > 75 1.5-3 % per year
4. History of HTN 1.5-3 % per year
Source
Strokse Risk in AF Working Group. Independent predictors of stroke in patients with AF: A systematic review. Neurology 2007; 69:546-554.
2. Diabetes confers 2-3.5% risk
3. Age > 75 1.5-3 % per year
4. History of HTN 1.5-3 % per year
Source
Strokse Risk in AF Working Group. Independent predictors of stroke in patients with AF: A systematic review. Neurology 2007; 69:546-554.
Tuesday, January 29, 2008
Carotid endarterectomy pearls from zseemant Chaturvedi
The Neurologist 2002;8; 203-4.
1. NASCET showed in symptomatic patients with 70-99 % angiographic stenosis, there was a 2 year absolute benefit of 17%, which equate to a NNT of 6. In the 50-69 % group, there was a modest benefit of 1.3 % per year (NNT of 15 for ipsilateral stroke and NNT of 23 for disabling ipsilateral stroke. The author suggests CEA in the 50-69 % group only for those with 2 of the three following: male gender, ulcerated lesions, hemispheric ischemia. Blogger's note: the second suggested criteria is more subjective than thought at first read, and diabetes (absence of) also should be taken into account.
2. ACAS showed that in asymptomatic patients with 60-99 % stenosis, the benefit of 1.2 % per year has a NTT of 67.
3. Perioperative stroke in emergent CEA with progressive stroke of <24 20="" and="" as="" br="" day.="" definition="" does="" duration="" gray="" high="" hours="" is="" mean="" necessarily="" not="" of="" operating="" somewhat="" suggesting="" that="" the="" urgently="">
4. The elderly benefit from CEA, but also have higher perioperative complications.
5. The stroke / death rate in NASCET following CEA was 6.5 %. In ACE trial it was 4.6 %, higher than the benefit of the surgery.
Robert Brown's analysis:
Carotid stenosis >70 %, symptomatic, NASCET risk of ipsilateral stroke
*surgery 9 % over 2 years
*medical 26 % over 2 years
* abs rr 8.5 % per year NNT=12
50-70%
* surgery 16 %/5 years
*best medical 22 % over 5 years
* benefit 1.2 %/yr NNT-83
< 50 % no benefit
1. NASCET showed in symptomatic patients with 70-99 % angiographic stenosis, there was a 2 year absolute benefit of 17%, which equate to a NNT of 6. In the 50-69 % group, there was a modest benefit of 1.3 % per year (NNT of 15 for ipsilateral stroke and NNT of 23 for disabling ipsilateral stroke. The author suggests CEA in the 50-69 % group only for those with 2 of the three following: male gender, ulcerated lesions, hemispheric ischemia. Blogger's note: the second suggested criteria is more subjective than thought at first read, and diabetes (absence of) also should be taken into account.
2. ACAS showed that in asymptomatic patients with 60-99 % stenosis, the benefit of 1.2 % per year has a NTT of 67.
3. Perioperative stroke in emergent CEA with progressive stroke of <24 20="" and="" as="" br="" day.="" definition="" does="" duration="" gray="" high="" hours="" is="" mean="" necessarily="" not="" of="" operating="" somewhat="" suggesting="" that="" the="" urgently="">
4. The elderly benefit from CEA, but also have higher perioperative complications.
5. The stroke / death rate in NASCET following CEA was 6.5 %. In ACE trial it was 4.6 %, higher than the benefit of the surgery.
Robert Brown's analysis:
Carotid stenosis >70 %, symptomatic, NASCET risk of ipsilateral stroke
*surgery 9 % over 2 years
*medical 26 % over 2 years
* abs rr 8.5 % per year NNT=12
50-70%
* surgery 16 %/5 years
*best medical 22 % over 5 years
* benefit 1.2 %/yr NNT-83
< 50 % no benefit
Antiplatelet pearls from Harold P Adams
Adams HP. 10 most commonly askedquestions about which antiplatelet agent to prescribe
1. BMJ 2002 324: 71-86 published a meta-analysis including 100,000 patients with antiplatelet agents for prevention of death, MI and stroke in high risk patients. They showed a benefit of antiplatelet drugs in both men and women, in younger and older patients, diabetics and non-diabetics, patients with TIA or stroke.
2. No benefit of aspirin in primary prevention is proved.
3. Aspirin dosing studies favor low dose 81 mg or 325 mg as equal to or superior to higher doses. This was found in a study of patients undergoing endarterectomy in a study published in 1999(Lancet 353:2179-2184) and also in the meta-analysis cited above in (1).
4. The definition of aspirin "failure" is unclear but Adams favors switching to Plavix, Aggrenox, or Ticlid rather than increasing the dose based on the two studies cited above. Early failure is deemed more significant than if someone has an event after several years of aspirin therapy.
5. The relative benefits of newer antiplatelet agents over aspirin (irrespective of side effects) are: ticlid 12-18 % relative reduction, with most of that in the first year(NEJM 1989; 321:501-507). Clopidogrel had a modest benefit especially in patients with peripheral vascular disease (Caprie trial about 8.7 %). Aggrenox resulted in a risk reduction of approximately thirty percent.
6. Adverse effects of ticlodipine include: epigastric pain, diarrhea, allergic skin reactions. Less commonly, events include cholestatic hepatitis, interstitial pulmonary disease, nephritis, and arthritis. Potentially fatal AE's are neutropenia, aplastic anemia, TTP, and HUS (hemolytic -uremic syndrome). Most hematological AE's occur in the first 4 months and when patients begin therapy, blood monitoring should be done every two weeks. TTP occurs in first month, typically, and if platelet count drops not only should ticlid be stopped but plasma exchange can be considered. Clopidogrel also has caused cases of TTP requiring plasma exchange, as well as HUS.
7. Aggrenox and Plavix have never competed in a trial head to head. (old statement see more recent posts)
More pearls from other sources:
Nonwhites have more risk reduction and less AE's (Gorelick et al.) However, the marginal benefit of ticlid seen in prior pivotal study was not replicated in this somewhat smaller study.
TTP occurs in ticlid users at a rate of 1 in 2000-4000. Clopidogrel has a risk analysis similar "to aspirin."
Withdrawal of antiplatelet drugs for procedures remains a concern, especially in those who are older, have a history of stroke or HTN, hyperlipidemia or family history of stroke
Ticlid and Plavix are "thienopyridine derivatives." The be
1. BMJ 2002 324: 71-86 published a meta-analysis including 100,000 patients with antiplatelet agents for prevention of death, MI and stroke in high risk patients. They showed a benefit of antiplatelet drugs in both men and women, in younger and older patients, diabetics and non-diabetics, patients with TIA or stroke.
2. No benefit of aspirin in primary prevention is proved.
3. Aspirin dosing studies favor low dose 81 mg or 325 mg as equal to or superior to higher doses. This was found in a study of patients undergoing endarterectomy in a study published in 1999(Lancet 353:2179-2184) and also in the meta-analysis cited above in (1).
4. The definition of aspirin "failure" is unclear but Adams favors switching to Plavix, Aggrenox, or Ticlid rather than increasing the dose based on the two studies cited above. Early failure is deemed more significant than if someone has an event after several years of aspirin therapy.
5. The relative benefits of newer antiplatelet agents over aspirin (irrespective of side effects) are: ticlid 12-18 % relative reduction, with most of that in the first year(NEJM 1989; 321:501-507). Clopidogrel had a modest benefit especially in patients with peripheral vascular disease (Caprie trial about 8.7 %). Aggrenox resulted in a risk reduction of approximately thirty percent.
6. Adverse effects of ticlodipine include: epigastric pain, diarrhea, allergic skin reactions. Less commonly, events include cholestatic hepatitis, interstitial pulmonary disease, nephritis, and arthritis. Potentially fatal AE's are neutropenia, aplastic anemia, TTP, and HUS (hemolytic -uremic syndrome). Most hematological AE's occur in the first 4 months and when patients begin therapy, blood monitoring should be done every two weeks. TTP occurs in first month, typically, and if platelet count drops not only should ticlid be stopped but plasma exchange can be considered. Clopidogrel also has caused cases of TTP requiring plasma exchange, as well as HUS.
7. Aggrenox and Plavix have never competed in a trial head to head. (old statement see more recent posts)
More pearls from other sources:
Nonwhites have more risk reduction and less AE's (Gorelick et al.) However, the marginal benefit of ticlid seen in prior pivotal study was not replicated in this somewhat smaller study.
TTP occurs in ticlid users at a rate of 1 in 2000-4000. Clopidogrel has a risk analysis similar "to aspirin."
Withdrawal of antiplatelet drugs for procedures remains a concern, especially in those who are older, have a history of stroke or HTN, hyperlipidemia or family history of stroke
Ticlid and Plavix are "thienopyridine derivatives." The be
Sunday, December 02, 2007
T-PA: Beyond thrombolysis
Benarroch EE. Neurology 2007;69: 799-802.
Author discusses basic science oo t-PA. t-PA is serine protease that cleaves plassminogen into plasmin that digests fibrin. It is widely distributed in CNS and is involved in synaptic regulation, synaptic plasticity and neural injury. Clinically may wish to neutralize the extravascular neurotoxic effects of t-PA. Neuroserpin is a candidate that inhibits the actions of tPA in the CNS.
Mutations of the neuroserpin gene are linked to familial encephalopathy with neuroserpin inclusion bodies (degenerative disease).
t-PA is present in dense core granules in dendritic spines and axon terminals and is released via calcium dependent exocytosis in response to depolarization or activation of NMDA receptors. The gene encoding for t-PA is induced with neuronal activity involving translation of mRNA. It maybe released from injured blood vessels and microglia, suggesting a role for it in neuroplasticity.
Author discusses basic science oo t-PA. t-PA is serine protease that cleaves plassminogen into plasmin that digests fibrin. It is widely distributed in CNS and is involved in synaptic regulation, synaptic plasticity and neural injury. Clinically may wish to neutralize the extravascular neurotoxic effects of t-PA. Neuroserpin is a candidate that inhibits the actions of tPA in the CNS.
Mutations of the neuroserpin gene are linked to familial encephalopathy with neuroserpin inclusion bodies (degenerative disease).
t-PA is present in dense core granules in dendritic spines and axon terminals and is released via calcium dependent exocytosis in response to depolarization or activation of NMDA receptors. The gene encoding for t-PA is induced with neuronal activity involving translation of mRNA. It maybe released from injured blood vessels and microglia, suggesting a role for it in neuroplasticity.
Saturday, November 03, 2007
Stroke and amyloidosis
Zubkov AY et al. Primary systemic amyloidosis with ischemic stroke as a presenting sign.
Neurology 2007 69:1136-1141.
Widjicks most patients (37/49) had light chain disease rather than primary or secondary systemic amyloidosis. In AL (amyloid due to light chain) the amyloid sheets are made by clonal expansion of the bone marrow rather than the liver as in the other types. Most strokes were large vessel, single arterial territory. 2 patients had cardiac amyloid and recurrent strokes. Most patients had abnormal ECHO c/w amyloid. There was no gender preference and the average age was 70. The median time to death was 7 months. A few patients presented with stroke (or TIA). The average delay of diagnosis was over nine months, that could be shortened by discovering amyloid on ECHO. The cardiac disease is a constrictive cardiomyopathy with CHF. The classic finding with increased echogenicity, valvular infiltration, and biventricular thickening is seen only in cardiac amyloidosis. LVEF is normal but strain and strain rate imaging are abnormal with long axis dysfunction and disproportionate impairment of longitudinal contraction. 70 % had cardioembolic strokes. Amyloid is actually common in atrial appendage (40/259 in surgical specimens) and may be associated with Atrial fibrillation. Clues thickened valves and septum can lead to diagnostic myocardial biopsy or referral to hematologist for additional evaluation.
Neurology 2007 69:1136-1141.
Widjicks most patients (37/49) had light chain disease rather than primary or secondary systemic amyloidosis. In AL (amyloid due to light chain) the amyloid sheets are made by clonal expansion of the bone marrow rather than the liver as in the other types. Most strokes were large vessel, single arterial territory. 2 patients had cardiac amyloid and recurrent strokes. Most patients had abnormal ECHO c/w amyloid. There was no gender preference and the average age was 70. The median time to death was 7 months. A few patients presented with stroke (or TIA). The average delay of diagnosis was over nine months, that could be shortened by discovering amyloid on ECHO. The cardiac disease is a constrictive cardiomyopathy with CHF. The classic finding with increased echogenicity, valvular infiltration, and biventricular thickening is seen only in cardiac amyloidosis. LVEF is normal but strain and strain rate imaging are abnormal with long axis dysfunction and disproportionate impairment of longitudinal contraction. 70 % had cardioembolic strokes. Amyloid is actually common in atrial appendage (40/259 in surgical specimens) and may be associated with Atrial fibrillation. Clues thickened valves and septum can lead to diagnostic myocardial biopsy or referral to hematologist for additional evaluation.
Friday, July 06, 2007
Risk of bleeding with ASA-Plavix combination
MATCH trial Diener et al. Took 7599 high risk patients with TIA or stroke, on Plavix, and added ASA 75 mg. Followed patients for 18 months. The results wre highly statistically significant with more major and minor bleeding of all types among patients receiving combination therapy. However, in the combined group, the actual risk of symptomatic intracranial hemorrhage was 1 % in each group; major bleeding of all types combined two percent v. one percent; and minor bleeding of all types combined was 3 % v. 1 %. Thus the overall complication rate is relatively low. The trial was based on the previous CURE trial that showed an acceptable safety profile of combined therapy among patients with acute coronary syndrome.
By contrast, the vascular risk reduction from antiplatelet therapy after TIA or stroke (reduction in stroke, MI or vascular death) was, absolute. 0.72 percent (NTT about 100/.72 or 138) with a relative risk reduction of 5.9 %. Thus by comparison the 3 % risk of hemorrhage is large.
OTHER EVIDENCE
CHARISMA trial supported results of MATCH.
CARESS trial in symptomatic carotid stenosis showed less embolic signals, but not less clinical events in patients on dual therapy.
FASTER trial suggested a role for dual therapy after clopidogrel loading for brief trial (90 days) after TIA. Not conclusive.
By contrast, the vascular risk reduction from antiplatelet therapy after TIA or stroke (reduction in stroke, MI or vascular death) was, absolute. 0.72 percent (NTT about 100/.72 or 138) with a relative risk reduction of 5.9 %. Thus by comparison the 3 % risk of hemorrhage is large.
OTHER EVIDENCE
CHARISMA trial supported results of MATCH.
CARESS trial in symptomatic carotid stenosis showed less embolic signals, but not less clinical events in patients on dual therapy.
FASTER trial suggested a role for dual therapy after clopidogrel loading for brief trial (90 days) after TIA. Not conclusive.
intravenous v intrarterial (bridging) lysis therapy
data of IMS investigators, reported in Stroke 2004. The outcomes overtly appear the same. Percent with modified Rankin of 0-1 at 90 days was 30 % in IMS group, 32 % in iv tpa group. The respective percentages for NIHSS less than 1 at 90 days was 28 and 25 %; Barthel index 95 or 100 46 and 42 %; these data favor intravenous therapy. However patients in the IMS trial were not equivalent at baseline. They had persistent major vascular occlusions despite early iv tpa treatment and greater clot burden than those in the NINDS trial, and were treated later. This suggests greater benefit in selected patients.
Sunday, June 17, 2007
diabetes and stroke risk
Stroke Risk Doubles Within 5 Years After Diabetes Diagnosis
The risk for stroke is twice as high in patients with newly diagnosed diabetes as in the general population, according to a study in Stroke. Using health databases of a Canadian province, researchers identified some 12,200 adults aged 30 and older with recent diagnoses of type 2 diabetes. During a mean follow-up of about 5 years, 9.1% of the patients had hospital admissions with a stroke-related diagnosis. The rate ratio for stroke was 2.1 for diabetes patients, compared with the general population. The authors write that their results "will help to dispel the notion that macrovascular consequences of diabetes occur only in the long term" and may motivate "both patients and providers to aggressively control cardiovascular risk factors soon after diagnosis."
Stroke article (Free)
See what's free at AOL.com.
Thursday, May 24, 2007
Pillcam contraindicated in stroke alert
I have been asked twice this week regarding the safety and efficacy of the PillCam used to evaluate the esophagus and/or the intestinal track. These devices are highly contraindicated for any MRI procedure. Being within the vicinity of an MR system alters the operation, patient are at risk for RF burns if put inside an MR system. I have included information from the manufacturers website (contraindications in bold and underlined). I will be forwarding this information to all the techs corporately as well.
See what's free at AOL.com.
See what's free at AOL.com.
Saturday, May 19, 2007
Clinical Trials: DIAS
DIAS-- desmoteplase in acute ischemic stroke -- placebo controlled, double blind, dose-finding randomized Phase II trial designed to evaluate safety and efficacy of desmoteplase. Looked at patients presenting 3-9 hours, enrolled 2001-2003 104 patients with NIHSS of 4-20 and mismatch on perfusion/diffusion imaging. Doses were 25, 37.5, and 50 mg of drug given as an iv bolus over two minutes. Due to excess symptomatic ICH lower doses were investigated in part 2 (62.5, 90 and 125 ug/kg). Safety outcome was rate of sICH, efficacy outcome measures were rate of reperfusion after 4-8 hours and NIHSS, mRS and Barthel at 90 days. In part excess s ICH was seen (23-30 % all within 24 hours). In part 2, the rate of sICH was 2.2%. In part 2 rates of reperfusion UP TO 71.4 % were seen at 125 ug dose compared to 19.2 % with placebo. Good clinical outcome was seen in 22 % of placebo treated patients and 13.3-60 % of drug treated patients (proportional to higher dose) also corresponding with early reperfusion. Overall 52 % of patients with reperfusion had favorable outcome v 24.6 % without.
Conclusions-- DIAS showed iv lysis is safe at 3-9 hours in patients with mismatch on MRI and dose dependent reperfusion correlated with clinical outcome. Outcome at 6-9 hours was as good as 3-6 hours. A phase 3 trial comparing 90 and 125 ug / kg doses in ongoing.
Conclusions-- DIAS showed iv lysis is safe at 3-9 hours in patients with mismatch on MRI and dose dependent reperfusion correlated with clinical outcome. Outcome at 6-9 hours was as good as 3-6 hours. A phase 3 trial comparing 90 and 125 ug / kg doses in ongoing.
Clinical trials ECASS III and IST III
Background-- pooled data from earliir ATLANTIS ECASS AND NINDS trials, published in 2002 suggested good outcomes for subjects treated within 180 minutes, with a trend to improved outcomefrom 180-270 minutes, and little benefit beyond 270 minutes.
ECASS III (European Cooperative Acute Stroke Study) in an ongoing trial begun in 2003 of alteplase started from 3-4 hours after stroke onset. Leader Werner Hacke. Later changed to 3-4.5 hours to help recruitment. Primary endpoints are mRS, Barthel and NIHSS at 90 days. Will end in summer of 2007?
IST III (International Stroke Trial) plans to enroll 6000 patients to see if alteplase within six hours increases proportion of independent survivors at six months. It also wants to see which categories benefit most from treatment. Placebo controlled.
ECASS III (European Cooperative Acute Stroke Study) in an ongoing trial begun in 2003 of alteplase started from 3-4 hours after stroke onset. Leader Werner Hacke. Later changed to 3-4.5 hours to help recruitment. Primary endpoints are mRS, Barthel and NIHSS at 90 days. Will end in summer of 2007?
IST III (International Stroke Trial) plans to enroll 6000 patients to see if alteplase within six hours increases proportion of independent survivors at six months. It also wants to see which categories benefit most from treatment. Placebo controlled.
Stroke Trials CLOTBUST
Ultrasound enhanced thrombolysis-- u/s can help diagnose clot, monitor thrombolysis and increase t-Pa binding to thrombin. CLOTBUST-- combined lysis of thrombus in brain ischemia using transcranial ultrasound and systemic rt-PA. 2001-4 Texas-Houston, 126 patients enrolled. All patients received alteplase within guidelines and half got TCD monitoring, the other half placebo monitoring. Half (49 %) of treatment group reached endpoint of complete recanalization or dramatic clinical recovery (NIHSS of 3 or less) within 2 hours, compared to 30 % of controls. At 3 months 42-29 % favoring treatment had mRankins of 0 or 1. Three subjects in each group had ICH. Authors concluded that arterial recanalization was augmented by TCD.
Complications of Rx for Subclavian stenosis
( a benign disease)
transthoracic or extrathoracic bypass
Horner's s
phrenic palsy
pleural effusion
chylothorax
cervical lymph fistula
infection
hemorrhage
In a revie of 2496 patients, the surgical complication rate was 16 %, stroke rate 3 %, mortality rate of 2 %.
Angioplasty is better in this disease with major technical success and low rate of complications.
transthoracic or extrathoracic bypass
Horner's s
phrenic palsy
pleural effusion
chylothorax
cervical lymph fistula
infection
hemorrhage
In a revie of 2496 patients, the surgical complication rate was 16 %, stroke rate 3 %, mortality rate of 2 %.
Angioplasty is better in this disease with major technical success and low rate of complications.
Clinical trials for stenting: CAVATAS, SAPPHIRE
CAVATAS carotid and vertebral artery transluminal angioplasty study-- large prospective randomized trial oo CEA v. carotid angioplasty. Criteria-- symptommtic stenosis > 70 %. Surgical candidates were randomized to angioplasty or stent. Nonsurgical candidates were randomized to angioplasty v. best medical treatment. In first group, 504 patients were randomized and the differences were nonexistent. In both the surgical and angioplasty group, the rate of any stroke lasting more than a week or death in first 30 days was 10 % The rate of disabling stroke or death in first 30 days was 6 % for each. The rate of restenosis was twice as great in the endovascular cohort v. the surgical group, 18 v. 9 %.
SAPHIRE-- stenting and angioplasty with protection in patients at high risk for endarterectomy-- compared stenting with protection v. CEA in surgically high risk patients with comorbidities. Enrolled 747 patients with > 50 % symptomatic stenosis or > 80 % asymptomatic stenosis. Stenting with a dis: tal protection device was not inferior and narrowly missed superiority. The risk of stroke, death oo MI was 39 % lower with stenting at 30 days. The risk of ipsilateral stroke was 7.9 % lower at one year. Critiques: 1) a high number, 55 % were excluded due to "surgical risk." 2) 20 % had restenosis after prior CEA 3) Inclusion of MIi as an endpoint obscures cerebrovascular data.
Ongoing trials:
EVA 3S Endarterectomy v. angioplasty in severe carotid stenosis
ARCHeR-2 (Acculink)
ICSS= CAVATAS 2 compares stent v. CEA in high risk group
SPACE -Stent protected percutaneous angioplasty of the carotid v endarterectomy 1900 patients, German study
CREST
SAPHIRE-- stenting and angioplasty with protection in patients at high risk for endarterectomy-- compared stenting with protection v. CEA in surgically high risk patients with comorbidities. Enrolled 747 patients with > 50 % symptomatic stenosis or > 80 % asymptomatic stenosis. Stenting with a dis: tal protection device was not inferior and narrowly missed superiority. The risk of stroke, death oo MI was 39 % lower with stenting at 30 days. The risk of ipsilateral stroke was 7.9 % lower at one year. Critiques: 1) a high number, 55 % were excluded due to "surgical risk." 2) 20 % had restenosis after prior CEA 3) Inclusion of MIi as an endpoint obscures cerebrovascular data.
Ongoing trials:
EVA 3S Endarterectomy v. angioplasty in severe carotid stenosis
ARCHeR-2 (Acculink)
ICSS= CAVATAS 2 compares stent v. CEA in high risk group
SPACE -Stent protected percutaneous angioplasty of the carotid v endarterectomy 1900 patients, German study
CREST
Who is at risk for further stroke? MRI factors
Minor stroke or TIA with a lesion on DWI and and large artery stenosis had a 32 % chance of recurrence within 90 days (v. 11% with DWI alone and 4 % with neither finding) (Coutts SB et al. Ann Neurol 2005; 57:848-854)
Patients imaged within 24 hours who had DWi lesions with differing ADC values (implying different lesion ages) were more likely to develop recurrent stroke at 30 days v. those with DWIi lesions but nonvariable ADC (relative risk 3.6). Patients with cardioembolic source had a higher probability of having new DWI lesions on followup MRI (odds ratio 3.2). ( Sylaja et al. Neurology 2007; 68:415-419.
Patients imaged within 24 hours who had DWi lesions with differing ADC values (implying different lesion ages) were more likely to develop recurrent stroke at 30 days v. those with DWIi lesions but nonvariable ADC (relative risk 3.6). Patients with cardioembolic source had a higher probability of having new DWI lesions on followup MRI (odds ratio 3.2). ( Sylaja et al. Neurology 2007; 68:415-419.
Subarachnoid hemorrhage scales
Hunt Hess (Neurosurgery 1998)
Grade Clinical Condition
0 Unruptured
1 asymptomatic or minimal headache/nuchal rigidity
2 Mod/severe headache, nuchal rigidity, no neuro deficit except CN palsy
3 drowsy confused, mild focal deficit
4 stupor, moderate/severe hemiparesis, possible early decerebrate
5 deep coma
Fisher scale (based on CT) (Neurology 1980)
Score Description
1 No blood
2 diffuse deposition or vertical layers <1 mm thick, no clots
3 localized clot and/or vertical layers > 1 mm thick
4 intracerebral or intraventricular clots with diffuse or no blood
Ogilvy Carter System for prognosis (Neurosurgery 1998; 42:959-970)
Points Description
1 Hunt Hess grade > 3
1 Fisher score > 2
1 Aneurysm size > 10 mm
1 Age > 50
1 Giant (> 25 mm) posterior circulation location
Grade Clinical Condition
0 Unruptured
1 asymptomatic or minimal headache/nuchal rigidity
2 Mod/severe headache, nuchal rigidity, no neuro deficit except CN palsy
3 drowsy confused, mild focal deficit
4 stupor, moderate/severe hemiparesis, possible early decerebrate
5 deep coma
Fisher scale (based on CT) (Neurology 1980)
Score Description
1 No blood
2 diffuse deposition or vertical layers <1 mm thick, no clots
3 localized clot and/or vertical layers > 1 mm thick
4 intracerebral or intraventricular clots with diffuse or no blood
Ogilvy Carter System for prognosis (Neurosurgery 1998; 42:959-970)
Points Description
1 Hunt Hess grade > 3
1 Fisher score > 2
1 Aneurysm size > 10 mm
1 Age > 50
1 Giant (> 25 mm) posterior circulation location
Sunday, May 06, 2007
Stroke protocols per AAN meetings
Candidate selection for intervention level 2 evidence
1) Patients inelegible for iv tPA within 6 hours use lytics, within 8 hours, MERCI
2) Consider longer duration for posterior circulation disease
3) Use of DWI'PWI mismatch for patients beyond standard time windows.
Within 3 hours patients with ICA, MCA, BA occlusion, patients that fail to respond to IV tPA, or are excluded by NINDS iv exclusion criteria are candidates for intervention
3-6 hours patients with DWI/PWI mismatch are candidates for arterial
6-8 hours MERCI candidates
>8 hours for posterior circulation
Intervention
10 % vessels are open
first use 22-25 mg tPA inside clot
then go to stenting if reperfuse great
if don't reperfuse go to clot retrieval.
See what's free at AOL.com.
Recanalization after iv tpa-- MCA v. ICA
(Beth Israel, Boston) Lanfante et al, Stroke 2002.
This is not a summary of the article but presentation of a few facts pulled out from it. With initial NIHSS score of 16 or above most do not recanalize with iv tpa. At NIH of 14 or below, MCA strokes recanalize much better than ICA strokes.Outcome correlates closely with recanlization.
Christou et al showed that recanalization after iv tpa in 60 patients with TIMI 2 or 3, 80 % MCA recanalized, 25 % ICA, 19% MCA-ICA, 7 % BA recanalized.
Frequency of iv tpa use: national estimate is 1-2%. 30,000 ischemic strokes per month, 500 get iv tpa, 29,500 do not.
There are 3 categories of patients to consider. 1) Those excluded from iv tpa (time,recent stroke, 2 weeks surgery, trauma, coagulopathy or INR>1.7) 2) Nonresponders 3) Reooclusion after initial reperfusion.
Mechanical reperfusion-- no thrombolytics used to reduce chance of bleeding (MERCI 1st and 2d generation, angioplasty and stenting). "Requires a learning curve." Soft clots don't respond as well.
MultiMERCI
use of iv tPA allowed, newer device MERCI 1.5
mean age 66, baseline NIHSS 19, 34 %mRS <2 90 days, 30 % mortality at 90 days, 9 % SICH, 10 % procedure related SAE's (dissection, vessel perforation, distal embolization). Comment one third get better whereas they had been doomed to death or disability previously. Across trials all had about one third good outcome by mRS.
Patient selection:
How to select patients better.
MR rescue up to 8 hours
See what's free at AOL.com.
MERCI 1 notes
mean age 67 NIHSS 20, mean time stroke onset to groin puncture 4.3 hours, 38 % enrolled within 3 hours, mean procedure time 2 hours, device passes 2.9 7.8 % SICH, 11 device fractures, 2 contributing to mortality. Mortality was 43 %, partly due to perforation with device malfunction.
| MERCI I subgroup anal | Post circ n=14 | | Mca n=80 |
| Revasc | 50% | 53 | 45 |
| Favorable 90 day mRS | 36 | 24 | 29 |
| Favorable 90 day NIHSS | 50 | 33 | 29 |
| Mortality | 43 | 51 | 39 |
Clinical Trials Comparison
| | NINDS | Controls | PROACT 2 | Controls | IMS | MERCI |
| Patients | 168 | 165 | 121 | 59 | 80 | 141 |
| Window (hours) | 0-3 | 0-3 | 0-6 | 0-6 | 0-3 | 0-8 |
| BaseNIHSS | 14 | 15 | 17 | 17 | 18 | 20 |
| Timi 2-3 | | | 66 | 18 | 56 | 46 |
| sICH | 6 | 1 | 10 | 2 | 6 | 8 |
| mRS 0-1 | 31 | 26 | 26 | 7 | 30 | |
| mRS 0-2 | 39 | 28 | 40 | 25 | 43 | 23 |
| Death % | 21 | 24 | 25 | 27 | 16 | 43 |
| | | | | | | |
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Trials of interventional therapies for stroke (select)
Proact 2 ia prourokinase
474 screening angiograms, 180 randomized, mean age 64, NIHSS 17, all MCA occlusions 2:1 ratio placebo controlled,all patients received low dose heparin. MRS<=2 at 90 days was 40 % in pro UK group v. 25 % placebo, 15 % absolute benefit, mortality (pro UK) 25 % v. (placebo) 27 %. NTT for 1 benefit =7. Not approved due to high rate of ICH.
IMS Study Bridging therapy eg. .6 mg/kg iv tpa (15 % bolus) followed by ia tpa up to 22 mg over 2 hours, ages 18-80, NIHSS>=10 within 3 hours. Primary outcome safety SICH, clinical outcome mRS 0-1 at 3 months. 28/77 (36%) had major occlusion or high grade ICA stenosis, but 56 % were TIMI 2 or 3 at end of 2 hours of infusion.
IMS 2 - 3 ongoing multicenter randomized trial with similar design except that coull use iv tPA.endovascular (IA, MERCI, or ultrasound lysis) v. iv tPA alone.
See what's free at AOL.com.
Tuesday, April 24, 2007
New stroke reccomendations
In reviewing the new ASA guidelines regarding acute stroke treatment they basically say you should give IV rtPA to all eligible patients. They recommend IA thrombolysis only for patients with a significant MCA occlusion with a last time normal < 6 hours who are otherwise not candidates for IV rtPA. It appears that no IR procedures are recommended for posterior circulation strokes at this time. I have copy and pasted the specific recommendations below. For all other interventional approaches they recommend further evaluation within the context of clinical trials. Note the new language regarding the qualifications of interventionalists that has been added.
Class I Recommendations
Intra-arterial thrombolysis is an option for treatment of selected patients who have major stroke of <6 hours’ duration due to occlusions of the MCA and who are not otherwise candidates for intravenous rtPA (Class I, Level of Evidence B). This recommendation has not changed since previous guidelines.
Treatment requires the patient to be at an experienced stroke center with immediate access to cerebral angiography and qualified interventionalists. Facilities are encouraged to define criteria to credential individuals who can perform intra-arterial thrombolysis (Class I, Level of Evidence C). This recommendation has been added since previous guidelines.
Class II Recommendation
Intra-arterial thrombolysis is reasonable in patients who have contraindications to use of intravenous thrombolysis, such as recent surgery (Class IIa, Level of Evidence C). This recommendation was not included in the previous guideline.
Class III Recommendation
The availability of intra-arterial thrombolysis should generally not preclude the intravenous administration of rtPA in otherwise eligible patients (Class III, Level of Evidence C). This recommendation has not changed from previous guidelines.
Also, here are the new recommendations regarding imaging in acute stroke:
Class I Recommendations
Imaging of the brain is recommended before initiating any specific therapy to treat acute ischemic stroke (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.
In most instances, CT will provide the information to make decisions about emergency management (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.
The brain imaging study should be interpreted by a physician with expertise in reading CT or MRI studies of the brain (Class I, Level of Evidence C). This recommendation has been added since the previous guideline.
Some findings on CT, including the presence of a dense artery sign, are associated with poor outcomes after stroke (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.
Multimodal CT and MRI may provide additional information that will improve diagnosis of ischemic stroke (Class I, Level of Evidence A). This recommendation has been added since the previous guideline.
Class II Recommendations
Nevertheless, data are insufficient to state that, with the exception of hemorrhage, any specific CT finding (including evidence of ischemia affecting more than one third of a cerebral hemisphere) should preclude treatment with rtPA within 3 hours of onset of stroke (Class IIb, Level of Evidence A). This recommendation has not changed from the previous guideline.
Vascular imaging is necessary as a preliminary step for intra-arterial administration of pharmacological agents, surgical procedures, or endovascular interventions (Class IIa, Level of Evidence B). This recommendation has not changed from the previous guideline.
Class III Recommendations
Emergency treatment of stroke should not be delayed in order to obtain multimodal imaging studies (Class III, Level of Evidence C). This recommendation has been added since the previous guideline.
Vascular imaging should not delay treatment of patients whose symptoms started <3 hours ago and who have acute ischemic stroke (Class III, Level of Evidence B). This recommendation has been added since the previous guideline.
Class I Recommendations
Intra-arterial thrombolysis is an option for treatment of selected patients who have major stroke of <6 hours’ duration due to occlusions of the MCA and who are not otherwise candidates for intravenous rtPA (Class I, Level of Evidence B). This recommendation has not changed since previous guidelines.
Treatment requires the patient to be at an experienced stroke center with immediate access to cerebral angiography and qualified interventionalists. Facilities are encouraged to define criteria to credential individuals who can perform intra-arterial thrombolysis (Class I, Level of Evidence C). This recommendation has been added since previous guidelines.
Class II Recommendation
Intra-arterial thrombolysis is reasonable in patients who have contraindications to use of intravenous thrombolysis, such as recent surgery (Class IIa, Level of Evidence C). This recommendation was not included in the previous guideline.
Class III Recommendation
The availability of intra-arterial thrombolysis should generally not preclude the intravenous administration of rtPA in otherwise eligible patients (Class III, Level of Evidence C). This recommendation has not changed from previous guidelines.
Also, here are the new recommendations regarding imaging in acute stroke:
Class I Recommendations
Imaging of the brain is recommended before initiating any specific therapy to treat acute ischemic stroke (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.
In most instances, CT will provide the information to make decisions about emergency management (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.
The brain imaging study should be interpreted by a physician with expertise in reading CT or MRI studies of the brain (Class I, Level of Evidence C). This recommendation has been added since the previous guideline.
Some findings on CT, including the presence of a dense artery sign, are associated with poor outcomes after stroke (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.
Multimodal CT and MRI may provide additional information that will improve diagnosis of ischemic stroke (Class I, Level of Evidence A). This recommendation has been added since the previous guideline.
Class II Recommendations
Nevertheless, data are insufficient to state that, with the exception of hemorrhage, any specific CT finding (including evidence of ischemia affecting more than one third of a cerebral hemisphere) should preclude treatment with rtPA within 3 hours of onset of stroke (Class IIb, Level of Evidence A). This recommendation has not changed from the previous guideline.
Vascular imaging is necessary as a preliminary step for intra-arterial administration of pharmacological agents, surgical procedures, or endovascular interventions (Class IIa, Level of Evidence B). This recommendation has not changed from the previous guideline.
Class III Recommendations
Emergency treatment of stroke should not be delayed in order to obtain multimodal imaging studies (Class III, Level of Evidence C). This recommendation has been added since the previous guideline.
Vascular imaging should not delay treatment of patients whose symptoms started <3 hours ago and who have acute ischemic stroke (Class III, Level of Evidence B). This recommendation has been added since the previous guideline.
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