Category: Neurology

Endovascular for Stroke – Even Better than the Evidence

What happens when you let Medtronic, et al, author an article on endovascular therapy in The Lancet:  exactly what you’d expect.

We are, in principle, fans of endovascular therapy for acute stroke as presented in the major trials: ESCAPE, EXTEND-IA, and SWIFT-PRIME.  These trials carefully selected eligible patients by use of advanced perfusion imaging and demonstrated high rates of revascularization.  Viable brain plus restored flow has face validity for improved outcomes.

However, these sponsored authors use the meta-analysis for its most nefarious purpose: to obfuscate the important subtleties and eligibility criteria of its included trials.  These authors pool the aforementioned trials, along with MR CLEAN and REVASCAT to provide the following conclusion:

“Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location.”(emphasis mine)

The authors also provide a staggering number-needed-to-treat for endovascular therapy of 2.6.

But, of course, this was written to shock and awe the lay press and general medicine community, rather than edify the astute clinician.  Their NNT is not based on the typical dichotomous cut-off used in stroke trials of mRS 0-1 or 0-2 – but rather the hopelessly flawed ordinal shift analysis.  As the decades turn, apparently, we have forgotten why this approach was frowned upon from the start: it is not appropriate to equate the outcome value difference between mRS 5 and 4 with the difference between mRS 3 and 2, and the limitations in inter-rater reliability in the mRS introduce a vast additional amount of measurement error.  Then, by burying any mention of the strict imaging criteria responsible for the bulk of benefit seen in these trials, they mislead the reader into considering this therapy appropriate for all-comers.

Is there any value to these data as presented?  A little.  There is hypothesis generating evidence that tPA prior to endovascular therapy provides no additive benefit.  There is also evidence that increasingly distal sites of occlusion may not benefit from intervention.

Unfortunately, the flaws in this article outweigh the few potentially usable insights.  This is just yet another piece of direct-to-physician marketing masquerading as scientific evidence.

“Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials”
https://www.ncbi.nlm.nih.gov/pubmed/26898852

Try to Avoid tPA When Already Bleeding

Coming to us from the Department of Common Sense: don’t give tPA to stroke patients who already have intracranial hemorrhage.  There’s a little more subtlety here, of course, because in this instance, we’re dealing with cerebral microbleeds – tiny foci of angiographic damage visualized only on MRI.

These authors performed a pooled and individual-patient meta-analysis of those undergoing MRI prior to treatment with intravenous thrombolysis.  When stratified by CMB burden, arbitrarily divided into “none”, “1-10”, and “>10”, the obvious is … obvious: patients who are already bleeding are more likely to continue bleeding.  In the unadjusted raw numbers, patients with no CMB had a symptomatic intracranial hemorrhage rate of 4.3%, those with 1-10 CMB had 6.1%, and those with >10 had 40.0%.

There are many technical limitations inherent to the retrospective nature of their study, as well as likely other confounding variables – but, the basic gist: our current practice relying only on non-contrast CT likely misses an important safety indicator in the setting of tPA use.

“Risk of Symptomatic Intracerebral Hemorrhage After Intravenous Thrombolysis in Patients With Acute Ischemic Stroke and High Cerebral Microbleed Burden”
https://www.ncbi.nlm.nih.gov/pubmed/27088650

Hospitalization or Home After TIA

In the pursuit of “value-based care”, innovators are consistently looking for ways to deliver similar outcomes without the risks and resource utilization of inpatient hospitalization.  One of these realms is the evaluation of transient ischemic attack.  Most of the recommended follow-up tests are only relatively urgent in nature, and with medical management the typical mainstay of therapy.  As serious considerations go, it seems ripe a candidate for outpatient management.

This retrospective look at outcomes from Canada, however, suggests there may be pitfalls to such a strategy.  These authors reviewed the outcomes of 8,540 patients presenting with TIA or minor stroke, and compared those either admitted to the hospital at the index visit with those discharged, and among those discharged, referral to a specialized follow-up clinic or not.

Patients admitted to the hospital, by all measures, had more severe cerebrovascular disease – as evidenced by duration of symptoms, ABCD2 scores, diagnosis of minor stroke, and other comorbidities.  However, despite this, following hospitalization, these patients had the lowest risk or recurrent stroke or TIA within one year.  The benefit, presumably, comes from increased likelihood of undergoing risk stratification and treatment – carotid imaging, echocardiography, appropriate anticoagulation, appropriate antithrombotic therapy, and the like.  Then, among the discharged, various adjusted and propensity matched analysis demonstrated a protective effect of referral to specialty outpatient follow-up against death, but not for stroke or TIA.  These data do not have the granularity to fully describe whether the excess deaths were in some fashion related to cerebrovascular disease.

Most of the absolute differences in outcomes between groups are small – a few percentage points each, and smaller after adjustment.  That said, it’s probably clearly superior care, as configured in Ontario during this time frame, to have been admitted to the hospital.  As TIA evaluation, and other similar conditions, move to outpatient pathways rather than traditional hospitalization, this represents an important reminder of potential risks of degradation in thoroughness and quality.

“Association between hospitalization and care after transient ischemic attack or minor stroke”
https://www.ncbi.nlm.nih.gov/pubmed/27016521

Missed a Stroke? You’re Not Alone

It’s easy to fall prey to the quality assurance shaming associated with your hospital’s stroke team.  It’s nearly impossible to find the right balance between over-triage of any remotely neurologic complaint, and getting the inevitable nastygram follow-ups resulting from unexpected downstream stroke diagnoses.

Take heart: it’s not just you.

This retrospective review of evaluated patients discharged with a diagnosis of acute stroke at two hospitals – one an academic teaching institution, and one a non-teaching community hospital.  All patients discharged with such a diagnosis were reviewed manually by a neurologist, and charts were analyzed specifically to quantify the frequency with which an Emergency Physician did not initially document acute stroke as a possible diagnosis, or a consultant neurologist did not make a timely diagnosis of stroke when asked.

Out of 465 patients included in their one-year review period, 103 of strokes were missed – 22% of those at the academic institution and 26% of those at the community hospital.  And, again, take heart – 20 of 55 patients missed at the academic institution were neurology consults for acute stroke, but were initially misdiagnosed by our neurology consultants, as well.  Posterior strokes were twice as likely to be missed as anterior strokes, and symptoms such as dizziness and nausea and vomiting were more frequent in missed presentations.  Focal weakness, neglect, gaze preference, and vision changes were less frequently missed.

Entertainingly, these authors are mostly verklempt over the fact half of missed stroke diagnoses presented within time windows for tPA or endovascular intervention – although, no other accounting of potential eligibility is presented other than timeliness.

“Missed Ischemic Stroke Diagnosis in the Emergency Department by Emergency Medicine and Neurology Services”
http://www.ncbi.nlm.nih.gov/pubmed/26846858

Give More tPA, Pretty Please?

There’s been another scientific update from Genentech-by-proxy, this time lamenting the low utilization for tPA in ischemic stroke patients.  This guideline panel from the AHA notes administering tPA in a safe and timely fashion to stroke patients is a non-trivial organizational exercise, but, what really gets their goat are the various exclusion criteria.  These criteria – minor symptoms, elevated blood pressure, acute trauma, etc. – are aimed at reducing the overall harms of tPA use, but to “help” as many patients as possible, the stroke neurologists believe it is necessary to break all the eggs.

This document, most prominently, is an entertaining exercise in linguistic calisthenics.  Clearly, these authors would like to treat as many patients as possible with tPA.  In their pursuit of these justifications, absent evidence, they torture the English language into providing he most diverse possible assortment of non-committal positivity.  To wit:

  • “There should be no exclusion …”
  • “Intravenous alteplase treatment is reasonable …”
  • “Intravenous alteplase administration for ischemic stroke may be considered …”
  • “…  it is reasonable that urgent intravenous alteplase treatment not be delayed …”
  • “Intravenous alteplase may be considered on a case-by-case basis.”
  • “Intravenous alteplase may be reasonable …”
  • “Use of intravenous alteplase in carefully selected patients … may be considered …”
  • “In acute ischemic stroke patients … intravenous alteplase may be carefully considered …”
  • “… administration of intravenous alteplase is reasonable and probably recommended …
  • “Intravenous alteplase treatment is probably recommended …”
  • “Patients … may benefit from intravenous alteplase …”
  • “… intravenous alteplase treatment appears safe and may be beneficial …”
  • “… intravenous alteplase may be as effective … and may be a reasonable option …”
  • “Intravenous alteplase is probably indicated …”

I.e., this scientific update may be a reasonably probably carefully considered option.  Or, as I’ve heard Jerry Hoffman say, each instance of the word “may” should be paired with its logical partner – “may not” – for the appropriately even-handed reading.

Other gems:

The risk of symptomatic intracranial hemorrhage in the SM population is quite low; thus, starting intravenous alteplase is probably recommended in pref- erence over delaying treatment to pursue additional diagnostic studies (Class IIa; Level of Evidence B).

The authors devote half a page to overstating the safety margin of tPA in stroke mimics by focusing on a single 100-patient cohort.  The clinical anecdotes of the two patient suffering sICH, and being lucky enough to survive, in this cohort are provided as apparently definitive reassurance.

And:

For patients with mild but disabling stroke symptoms, intravenous alteplase is indicated within 3 hours from symptom onset of ischemic stroke. There should be no exclusion for patients with mild but nonetheless disabling stroke symptoms in the opinion of the treating physician from treatment with intravenous alteplase because there is proven clinical benefit for those patients (Class I; Level of Evidence A).

The pursuit of treating mild, but nonetheless disability symptoms is not new – and not specifically offensive.  However, they give this recommendation “Class I, Level of Evidence A”, which is the strongest level of support, based on, apparently, multiple randomized clinical trials or meta-analyses.  Except, however, their justification in the text for this recommendation is merely:

Alteplase may be beneficial for milder stroke cases judged as potentially disabling despite low NIHSS scores. The NINDS trialists explored 5 different definitions of minor stroke in a post hoc analysis and found benefit for alteplase across all definitions. However, data are not available on the effect of alteplase for milder stroke cases judged as not potentially disabling at presentation. Because nearly 3000 such cases of ischemic stroke were excluded from the 2 NINDS trials for mild symptoms, any analysis of mild symptoms within the 2 NINDS trials is difficult to interpret.

Why let the true level of evidence affect the final recommendation categorization?

If left to my own devices, this post could meander onward for an eternity.  I will, then, now step aside to allow the motivated reader to move along to source document itself.

“Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke”
http://stroke.ahajournals.org/content/early/2015/12/22/STR.0000000000000086.abstract

What’s the Big Deal About Meclizine?

When I was growing up, I used to go fishing with my Dad.  As we sat, in the dark and wet, freezing in Tillamook Bay in November, he would offer sage words of advice:  “Vertigo?  Meclizine, of course.”*

And, so, through residency and even as teaching faculty, the standard antihistamine treatment for vertigo has always been meclizine – until this past month, when all the meclizine was pulled from our Pyxis due to manufacturing contamination.  So, what would we use as an alternative?

I will not take credit for having performed the most exhaustive of possible literature searches, but, by far, the most fantastic piece of literature I found was from 1968.  This comes from the era of the Cold War and the Space Race, and the folks most interested in effect anti-motion sickness was NASA.  So, among other things, early aerospace medicine was interested in preventing astronauts from vomiting their brains out as they were spun and shaken under otherworldly conditions.  To do so:

“… subjects, male and female, were rotated using the step method to progressively increase the speed of rotation (+2 rpm) after every 40 head movements to a maximum of 35 rpm. The end point for motion sickness was the Graybiel Malaise III total of symptoms short of frank nausea.”

Awesome.

Regardless, what I found interesting – and potentially practice-changing, was that meclizine stunk.  It was, in fact, the worst performing antihistamine of their trial:

What worked best?  Scopolamine plus amphetamine was far superior to any other monotherapy or combination therapy.  However, this isn’t a realistic treatment option.  From these data, at least, probably the best option may actually be promethazine (Phenergan).  And, for what it’s worth, promethazine also comes in suppository form – meaning it can be used as a rescue when the vomiting has already taken hold.

Probably any other sedating antihistamine has some value in meclizine’s absence, but I’m going with promethazine.  In fact, I’m not entirely certain I’ll ever go back ….

“Evaluation of sixteen anti-motion sickness drugs under controlled laboratory conditions.”
http://www.ncbi.nlm.nih.gov/pubmed/4881887

* This never happened.

Hunting for Strokes in Vertigo

The vast majority of presentations for “dizziness” in the Emergency Department are benign diagnoses – various dysequilibrium syndromes, vestibulitis, neuritis, and other disorders of the otologic canalicular system.  But, then, some are strokes – and it’s quite challenging to balance diagnostic accuracy and MRI utilization.

This is an observational study performed at the University of Michigan evaluating patients presenting with complaint and exam findings consistent with acute dizziness – requiring either nystagmus or demonstrated gait instability.  Of these patients, all underwent a standardized neurologic examination, including HINTS examination, and subsequent MRI.  A stroke was the presumed diagnosis if an MRI was performed within 14 days and diagnostic of hemorrhage or acute infarction.

There were 320 patients enrolled, and 272 completed the clinical evaluation and an MRI.  Overall, 29 (10.7%) of patients had positive imaging – and, unfortunately, little was strongly predictive.  The few predictive features that shook out of their logistic regression model were the ABCD2 score, a positive HINTS exam, a central pattern to nystagmus, or the presence of other neurologic deficits.  Those individuals hitting all the risk factors ended up with ~20% risk of stroke, while those with none were <5%.  The remaining patients were simply in the intermediate risk group, reflecting the overall baseline level, and approximately one-third of the cohort fell into each category.

I do like their objective criteria for enrollment, based on a minimum of nystagmus or gait abnormality.  I tend to feel many patients receive MRI for similar complaints absent any of these features.  There is, unfortunately, no accounting of any general background rate of diagnosis of posterior circulation stroke at their institution, so there’s no way to estimate the miss rate or added value of their inclusion criteria.  I think their general observations are fair starting points for shared decision-making, although there’s still not quite enough information here to dramatically improve imaging yield.

“Stroke risk stratification in acute dizziness presentations: A prospective imaging-based study”
http://www.ncbi.nlm.nih.gov/pubmed/26511453

It’s Not Time, It’s Brain

The evidence continues to mount that, simply, we’re doing it wrong.

Part of this is an acceptable confusion: we didn’t have the computational power or acquisition resolution capable of evaluating the intracranial circulation or perfusion when treating stroke.  However, as the evidence continues to mount from advanced imaging, it seems clear the “time” aspect is not the best determinant of outcome in stroke.

This is a small review of patients from DUST and MR CLEAN with MCA stroke and CT perfusion imaging available.  CTA is frequently performed to evaluate intracranial vasculature and estimate collateral circulation, but CT perfusion provides a dynamic look at contrast flow throughout the brain.

Based on this small 70 patient cohort, the reliability of the observations is hardly bulletproof, with wide 95% confidence intervals.  However, there is a reasonable, linear decrease in good outcomes as poor perfusion characteristics proliferate.  The best perfused collateral circulation led to 15 of 26 patients recovering to mRS 0-2.  While the flow rate and quality of the collaterals degraded, those with good recovery dropped to 12 of 26, then 1 of 12, and finally to 0 of 6.

The horizon is not far now where, hopefully, we’ll look back at the “time is brain” mantra as the infantile scramblings of the dark ages of acute stroke treatment.  Better imaging technology continues to demonstrate some brain is unrecoverable, regardless of timeframe, while others are likely excellent candidates for preservation of some function.  We ought to have much better options for tailoring treatment to the individual in the near future – and as this technology spreads.

“Impact of Collateral Status Evaluated by Dynamic Computed Tomographic Angiography on Clinical Outcome in Patients With Ischemic Stroke”
http://www.ncbi.nlm.nih.gov/pubmed/26542691

What Have We Learned About Mobile Stroke Units?

To date, not much.  We’ve learned it’s physically possible to put a CT scanner in van.  It’s technically feasible to infuse an expensive medication into a vein.  A small amount of time is saved.

The presumption is, the few minutes saved, cumulatively, will outweigh any harms associated with the lack of evaluation in a comprehensive center by a fully-trained Emergency Physician.  And, this study – BEST-MSU – aims to measure this, comparing patient outcomes in a week-on/week-off fashion.

This is their initial report, covering a 10-week run-in phase.  During this time, the MSU was in service for 57 of those days – and there were 130 activations, or, approximately 2.7 per day.  Those activations resulted in 24 patients who were potentially eligible for the study.  Of those, 12 were treated with tPA pre-hospital.  And one of those had a non-stroke final diagnosis.

So, 130 activations for “appropriate” 11 administrations of tPA.

As the authors correctly report, very little can be concluded regarding the effectiveness of the therapy.  What does seem to be clear – this is a substantial resource expenditure associated with repeated deployments for the smallest handful of treatment eligible individuals.

“Benefits of Stroke Treatment Using a Mobile Stroke Unit Compared With Standard Management – The BEST-MSU Study Run-In Phase”
http://www.ncbi.nlm.nih.gov/pubmed/26508753

How Many LPs Does It Take to Find SAH?

In this observational series: 204.

This study describes the findings of 2,248 patients with “headache, suggestive of subarachnoid hemorrhage” who underwent computed tomography, followed by lumbar puncture.  CT is quite sensitive for aneurysmal hemorrhage in the few hours following onset, but fades with time.  Spectrophotometric analysis of CSF is the gold standard for diagnosis in the United Kingdom, and was used by these facilities to describe positive, negative, and indeterminate results on LP.

Of these 2,248 patients, LP were negative in 1,507, uninterpretable in 350, indeterminate in 299, and positive in 92.  All patients with positive LP had follow-up CTA or MRA, and there were 9 vascular abnormalities.  Then, a subset of the uninterpretable and indeterminate patients underwent CTA or MRA, as well, resulting in an additional two vascular abnormalities.

Thus, 204.

There are a few surprising bits regarding these data.  The ~4% rate of “SAH” detected in this study is lower than most other observational series.  Some of these, however, were neurosurgical referral centers, with much higher rates.  Then, of course, the incidence will further depend on various definitions of positivity and the rate at which patients with lower pre-test likelihood are evaluated for SAH.  Additionally, the rate of vascular abnormality in those with “SAH” was also quite low.  In such a small sample, the confidence intervals are quite wide, so it’s hard to estimate the generalizability of these findings.

Regardless of the precise numbers, their overall conclusion is reasonable: CT + LP is extremely low yield for true pathology.  There is a definite need for decision instruments with improved specificity to prevent such extensive resource utilization.

“An Observational Study of 2,248 Patients Presenting With Headache, Suggestive of Subarachnoid Hemorrhage, Who Received Lumbar Punctures Following Normal Computed Tomography of the Head”
http://www.ncbi.nlm.nih.gov/pubmed/26480290