Category: Neurology

Taking First-Time Seizures Seriously

Last week, I covered a disastrous prevalence study that almost certainly over-estimates the frequency of pulmonary embolism in syncope. Today, something similar – the frequency of epilepsy in patients presenting to the Emergency Department with first-time seizure.

The most recent American College of Emergency Physicians position statement regarding first-time seizures is fairly clear: first-time seizures need not be started on anti-epileptic therapy. The thinking goes, of course, that few patients would be ultimately diagnosed with epilepsy, and most of those initiated on anti-epileptics would be exposed only to their adverse effects without any potential for benefit.

This small study tries to better clarify the frequency of an epilepsy diagnosis. At a single center, during convenience business hours Monday through Friday, consecutive patients with first-time seizure of uncertain etiology were screened for enrollment. During their enrollment period, they were able to capture 71 patients for whom they were able to complete an EEG in the Emergency Department. Of these, 15 (21%) patients were diagnosed with epilepsy based on their ED EEG. All of these patients were then initiated on an anti-epileptic, most commonly levetiracetam. Anti-epileptic therapy was additionally started on two patients with abnormal EEGs and structural brain disease on imaging, one of whom was able to be contacted in follow-up with a repeat EEG showing epilepsy. These authors use these data to suggest potential benefit for EEG performed in the ED.

This is a fairly reasonable conclusion, although the level of evidence from this single study is weak. This is probably another example of the ED filling a gap in outpatient follow-up; it would almost certainly be perfectly safe to discharge these patients without investigation or initiation of therapy if an ambulatory EEG could be arranged within a few days. Further, larger-scale evaluation of the value of an ED EEG would be needed to modify our current approach.

“The First-Time Seizure Emergency Department Electroencephalogram Study.”
https://www.ncbi.nlm.nih.gov/pubmed/27745763

Shaking Out Stroke Mimics

In a world of continued aggressive guideline- and pharmaceutical-sponsored expansion of stroke treatment with thrombolytics, this article fills and important need – better codifying the predictors of stroke mimics. While other editorials espouse the need to be fast without being sure, this is frankly irresponsible medicine – and, in resource-constrained environments, unsustainable.

These authors at two academic centers performed a retrospective clinical and imaging review of 784 patients evaluated for potential acute cerebral ischemia. Patients were excluded if they had signs of acute stroke on initial non-contrast imaging, and if they did not subsequently undergo MRI. Based on review of the totality of clinical information for each patient, 41% of this cohort were deemed stroke mimics. The authors scoring system, then derived 6 variables – and 3 or more were present, the chance of stroke mimic being cause of the current presentation was 87.2%. Their criteria:

  • Absence of facial droop
  • Age <50 y/o
  • Absence of atrial fibrillation
  • SBP <150 mm Hg
  • Presence of isolated sensory deficit
  • History of seizure disorder

When the rate of tPA administration to stroke mimics is ~15%, and 30-40% of patients evaluated for stroke are stroke mimics – there is a lot of waste and potential harm occurring here. These authors suggest the use of this score could potentially halve these errant administrations for 94% sensitivity, or cut errant administrations down to 2% with 90% sensitivity. Considering the patients for which stroke/stroke mimic is an ambiguous diagnosis, it is reasonably likely the symptoms are of lesser severity – and in the range for which tPA is of most tenuously “proven” value. While their rule has not been prospectively validated, some of these elements certainly have face validity, and can be incorporated into current practice at least as a reminder.

“FABS: An Intuitive Tool for Screening of Stroke Mimics in the Emergency Department”

http://stroke.ahajournals.org/content/early/2016/08/04/STROKEAHA.116.013842.abstract

Don’t Stop at the Headline

The verdict is in: “Aspiration Thrombectomy No Help for Large-Clot Strokes”, reports MedPage Today.

Except, they’re not precisely correct – in a way, you could even say they’re wrong.

This is THERAPY, an endovascular trial in acute stroke featuring the Penumbra aspiration device.  This is somewhat unique, as the technology differs from the otherwise popularized Solitaire retrieval system. This trial is also different from the most contemporary comparators, as its imaging criteria did not rely on perfusion imaging, but, rather, simply large-vessel occlusion with a clot length of 8mm or greater.

The results of the trial, as you might have picked up from the lay press headline, were negative – that is to say, they did not reach statistical significance. Their primary endpoint for modified Rankin Scale of 0-2 was achieved in 38% receiving endovascular treatment and 30% receiving intravenous thrombolysis alone, and this 8% absolute difference produced a p-value of only 0.52. However, the trial was initially scheduled to enroll 692 patients to be powered to detect a 10.6% difference, but stopped enrollment after 108 based on the publication of other positive endovascular trials.

So, simply put, this trial tells us hardly anything. Is the Penumbra system just as good as Solitare? Probably, but perhaps we’ll never know for certain. Does the 8% difference seen in this trial reflect the lower magnitude of effect of treatment relating to lack of perfusion imaging? Probably, as well, based on the the larger evidentiary context.

But, at the minimum, the medical reporting has simply gone off course with their headline.

“Aspiration Thrombectomy After Intravenous Alteplase Versus Intravenous Alteplase Alone”
http://www.ncbi.nlm.nih.gov/pubmed/27486173

The tPA Pushback Begins

It isn’t news to anyone in the Emergency Medicine community that tPA isn’t as effective as its efficacy trials suggested, and its overuse is driven by “quality” measures and medicolegal concerns more than any true belief in its usefulness.  However, it remains rare in the Neurology literature to challenge the primacy of tPA – it is much more frequent to see articles promoting and/or defending its expanded use.

This small retrospective series looks at a registry of stroke patients eligible for alteplase who received a CT perfusion study as part of their initial evaluation.  As criteria for review, the CT perfusion lesion needed to be <15mL in calculated volume.  Their final cohort included 366 patients with mostly mild-to-moderate strokes (NIHSS median 8 in each), and a little over half were treated with alteplase, while the remainder were not.  As a retrospective and confounded study, the level of evidence is weak, but the untreated population had significantly better outcomes (mRS 0-1 in 57% vs. 69%), and avoided such complications as parenchymal hemorrhage.

The authors conclude:

“we suggest that neither CTA nor standard clinical/NCCT assessment can appropriately define a relatively large sub-group of patients who are clinically eligible for alteplase, yet appear to have no benefit from treatment.”

Yes, if the volume of acutely injured tissue is quite small, the potential benefit of any therapy has an obvious ceiling – even before considering the viability of the affected tissue or the potential effectiveness of reperfusion.  But the key point here is one I’ve made, most recently at #smaccDUB: we can better individualize care, and avoid costs and risks, with more information.

Thanks to Robert Goulden for sending this in!

“Too good to treat? Ischemic stroke patients with small CT perfusion lesions may not benefit from thrombolysis”
http://onlinelibrary.wiley.com/doi/10.1002/ana.24714/abstract

You Can’t Spell “Insanity” Without tPA

When you think you’ve seen it all – a call to administer tPA to acute stroke patients without a prior non-contrast CT.

Indeed, in this “Views & Reviews” article, the authors ask explicitly the question: “Is the administration of alteplase to patients with primary ICH that harmful?”  After much stimulating confabulation, the authors bafflingly conclude: “we cannot argue with confidence that alteplase administration to patients with ICH is harmful”.

Perhaps they’ve never treated patients with alteplase personally, and they further mis-cite or misinterpret the evidence regarding the influence of cerebral microbleeds on symptomatic intracranial hemorrhage.  Despite the clear evidence from multiple meta-analyses that cerebral microbleed burden prior to alteplase administration leads to substantially increased risk of ICH and neurologic worsening, these authors sum up this evidence as “either no increased risk of symptomatic ICH or an increased risk that does not necessarily preclude an overall benefit from alteplase.”

Nonsense.

Even better, the entire purpose of their intellectual exercise boils down to discarding the inconvenience of pre-lytic CT so that alteplase can be delivered pre-hospital.  Yes, rather than clinically correlating the presentation with maximal vascular and perfusion information to consider the safest, most potentially effective (if any) reperfusion therapy – these authors are promoting administration of a $6000 medication in a pre-hospital setting with a paucity of diagnostic expertise or technology available.

Good plan.

“And why not thrombolysis in the ambulance (at least for some)?”
http://www.neurology.org/content/early/2016/06/15/WNL.0000000000002835.short

Futility, Thy Name is ATTACH-2

Intracranial hemorrhage tends to have a poor prognosis – the cascade of inflammation, vasospasm, and necrosis leaves the vast majority with some residual disability.  INTERACT-2 offered some glimpse of hope, at least, from a surrogate standpoint – finding that patients with “intensive” blood pressure control showed reduced hematoma growth.  It seems logical that reduced hematoma growth would directly correlate with improved clinical outcomes, and there was a reasonable suggestion this was present, as well.

And, so, ATTACH-2.

This trial randomized patients with ICH to “standard” 140-179 mmHg blood pressure control versus “intensive” 110-139 mmHg blood pressure control, with a primary outcome of modified Rankin scale of 4 to 6.  All patients were treated using nicardipine by continuous infusion, and generally achieved their blood pressure targets within 2 hours of randomization.  They included 500 in each arm of the trial before stopping prematurely when a pre-specified threshold for futility was crossed.

Since I’ve used the word “futility” twice so far, you’ve probably already discerned the result.  At 90 day follow-up, there were 38.7% with mRS 4-6 in the intensive group versus 37.7% in the standard group.  No other long-term clinical outcomes seemed to reflect an advantage to one arm or the other.  In both adjusted and unadjusted analyses, there were a few interesting tidbits.  Hematoma expansion was, indeed, attenuated by intensive control.  However, as a counterweight, the intensive treatment group was more likely to suffer neurologic deterioration within 24 hours (11.0% vs. 8.0%) and more likely to suffer a serious adverse event within 3 months (25.6% vs. 20.0%).

It certainly seemed plausible such intensive lowering might be of value – but, instead, we have an excellent example where patient-oriented outcomes trump surrogates, and the adverse effects from treatment seem to counterbalanced any benefit picked up along the way.

“Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage”
http://www.nejm.org/doi/full/10.1056/NEJMoa1603460

ENCHANTED – Positive or Negative?

I am probably the last person to comment on ENCHANTED, the trial testing low-dose vs. standard-dose tPA in “Asians”.  When it was released, to some fanfare in the New England Journal of Medicine, I had little to say – it is, frankly, a rather bland contribution to the science.  What has been fascinating, however, is the unusually divergent interpretation of the results.  To wit, the accompanying editorial in the NEJM states:

“ENCHANTED provides no compelling evidence for using low-dose alteplase for acute ischemic stroke in Asian or other populations on the basis of safety considerations or clinical outcomes.”

This is a relatively reasonable interpretation of the results – hinging on the word “compelling”.  No one’s hearts are to be set a-flutter over these results, but that does a disservice to the ultimate clinical question of which dose is appropriate.  The lay press, however, is here to clear things up – or is it?

“ENCHANTED: Low-Dose tPA Now a Viable Option in Stroke?” 
“ENCHANTED results challenge reduced alteplase dose in Asian stroke patients”
“Low-Dose tPA Not as Effective, Even for Asians”
“Lower Dose of Clot-Busting Drug Reduces Brain Bleeding”
“Low-dose alteplase fails to prove noninferiority to standard dose, shows some benefit in stroke”
“Low-Dose Alteplase Not as Effective as Standard-Dose in Acute Ischemic Stroke”

The question, simply, comes down to how easily one interprets “non-inferiority” – a point made nicely by Rory Spiegel in his post – and, further, how one interprets these findings in a Bayesian sense.  The prevailing opinion going into this trial was that low-dose tPA was safer and similarly efficacious in certain ethnic subpopulations on the Asian continent.  The nonsignificant difference (OR 1.09; 95% CI 0.95 to 1.25) in patients having excellent outcomes (mRS 0-1) and the even smaller difference (OR 1.03; 95% CI 0.89 to 1.19) in those having good outcomes (mRS 0-2) does nothing to move the needle on the prevailing clinical hypothesis.  If there is unlikely to be a profound difference in clinical outcomes, what of the safety outcomes?  Here, low-dose alteplase is obviously a winner – significant reductions in hemorrhage and a corresponding decrease in 90-day mortality (p=0.07).

If ECASS failed gloriously due to adverse effects at 1.1 mg/kg, subsequent trials found some favorable risk/benefit at 0.9 mg/kg, and the (supposed) clinical efficacy seems preserved with even greater safety at 0.6 mg/kg, it seems logical to expand interest in lower doses of tPA.  I disagree with those who would dismiss this trial as an unimportant “failure”.

“Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1515510

tPA – For Minor Strokes, With Many Caveats

It is well-established many patients with minor or rapidly improving stroke fail to thrive.  The NIHSS is a crude tool, and its correlation with infarct size and ultimate disability is limited.  It is not inconceivable some patients with minor stroke could be candidates for intervention.  However, these patients would need to fit our critical requirements: 1) there must be substantial at-risk territory preserved by collateral perfusion, and 2) the occluded vessel must be reliably opened at a greater rate and timelier fashion than the body’s natural recanalization process.

This brief report is an interesting stepping stone on the pathway towards the practical realization of some of these issues.  These authors present a retrospective review of patients with minor stroke (NIHSS ≤ 3) evaluated at their institution.  Their institution routinely performs CT imaging with perfusion (RAPID software) on most stroke evaluations.  They further trim out 73 of these patients for whom the CT perfusion demonstrated substantial volumetric deficits.  Generally, these were patients with small (<5 mL) core infarcts surrounded by 20-40 mL of delayed perfusion, as would be reasonably expected for patients with minimal clinical symptoms.

There were 34 patients in this cohort who received tPA and 39 who were admitted without.  Patients were generally similar, although the tPA cohort had twice the prevalence of prior stroke (29.4% vs. 16.7%) and – most importantly – double the area of delayed perfusion (41.3 mL vs. 25.1 mL with wide standard deviation).  Despite these poorer prognostic features, 90-day mRS 0-1 were 91.2% in the tPA cohort and 71.8% in the standard care.

This is hardly practice changing in its crude, non-randomized, retrospective form.  It does, however, have face validity for informing future study.  It also fits with the paradigm of stroke care I’ve been promoting on this blog for years – the inanity of unselected tPA – and the requirements as above – to maximize potential benefit by ensuring those offered tPA have salvageable tissue (read: small core, large mismatch) and likely to recanalize (read: small vessel).  There’s virtually no question CTP or its equivalent needs to become part of the treatment decision-making process, rather than simple non-contrast CT or even CTA without evaluation of collateral flow.

“Utility of Computed Tomographic Perfusion in Thrombolysis for Minor Stroke”
http://stroke.ahajournals.org/content/early/2016/05/19/STROKEAHA.116.013021.abstract

Put the Platelets Away in ICH

Sometimes, medical practice in the setting of uncertainty simply turns out to be futile and low-value.

This is one of those times where we’ve probably been at least futile, and possibly harmful.

Life-threatening or critical intracranial bleeding in the setting of concomitant antiplatelet therapy frequently offers a dire prognosis.  As part of our standard “don’t just stand there!” approach in Emergency Medicine, patients with ICH in this setting are frequently transfused platelets in an effort to provide untainted clotting substrate.  This practice, however, has never been reinforced by substantiated evidence, and the pharmacokinetics of the antiplatelet agents suggests this strategy is unlikely to be efficacious.

This is the PATCH trial, a randomized, open-label trial conducted at 60 hospitals between 2009 and 2015, investigating the utility of platelet transfusion in the setting of ICH.  Patients with normal baseline functional status and ICH while taking aspirin, clopidogrel, or dipyridamole were eligible for inclusion.  Specific excluded ICH were epidural or subdural hematomas, significant intraventricular blood, surgical intervention planned, or those in which death appeared imminent.  Treating clinicians could not be blinded to study arm allocation, but follow-up assessors and data analysis was masked.  The primary outcome is was functional outcome on the modified Rankin Scale, analyzed via ordinal shift analysis.

The authors do not present the number of patients screened for potential enrollment during the study period, but, ultimately, 190 participants were included from 41 centers.  The authors state patients were well-balanced on most demographics, although median ICH volumes were a little higher in the platelet-transfusion group, with 34% of patients having ICH >30mL versus only 21% in the standard-care group.  There were four patients in the platelet-transfusion group who did not receive transfusion, and two in the standard-care that did.

In the end, outcomes were universally dismal.  Only 15 patients in the entire study survived with minimal disability or better.  The vast majority of patients were at least moderately disabled or dead at follow-up.  And, while the confidence intervals for many of their comparisons cross unity, none of the trends favored platelet transfusion.  Generally speaking, there were more deaths, fewer patients with minimal disability, and additional adverse events in the transfusion group.

I tend to feel this is a small enough cohort the heterogeneity between individual patients is enough to effect the overall results – including the apparent harms relating to platelet-transfusion.  However, there is certainly no signal of benefit, and lacking a compelling indication to utilize a scarce resource, I believe this is enough to suggest this practice should be routinely avoided.

“Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30392-0/abstract

Triaging Large Artery Occlusions

Endovascular intervention for acute stroke can be quite useful – in appropriately selected patients.  However, few centers are capable of such interventions, and the technology to properly angiographically evaluated for large-artery occlusions is not available in all settings.  Thus, it is just as critical for patients to be clinically screened in some fashion to prevent over-utilization of scarce resources.

These authors retrospectively reviewed 1,004 acute stroke patients admitted to their facility since 2008, 328 of which had large-vessel occlusions: ICA, M1, or basilar artery.  They calculated the accuracy, sensitivity, and specificity of multiple different potential clinical scoring systems, cut-offs.  Unfortunately, every score made some trade-off – either in the rate of false-negative results excluding patients from potential intervention, or in the rate of false-positive results serving to simply subject every patient to advanced imaging.  The maximum accuracy of all their various scores topped around around 78%.

The authors’ conclusions are reasonable, if a little limited.  They feel every patient presenting with an acute stroke within 6 hours of symptom onset should undergo vascular imaging.  These are both reasonable, but ignore one of the major uses for simple clinical scoring systems: prehospital triage.  Admitting none of these are perfect, _something_ must be put to use – and, probably, given the current bandwidth for endovascular intervention, something with the highest specificity.

For what it’s worth, we use RACE to triage for CT perfusion, but CPSSS, ROSIER, or just NIHSS cut-offs around 10 would all be fair choices.

“Clinical Scales Do Not Reliably Identify Acute Ischemic Stroke Patients With Large-Artery Occlusion”
https://www.ncbi.nlm.nih.gov/pubmed/27125526