Category: Neurology

When Peripheral Vertigo Isn’t

But, such misdiagnosis is rather rare.

These authors conduct a retrospective, administrative database study of patients discharged from an Ontario, Canada, Emergency Department between 2006 and 2011 with a diagnosis of peripheral vertigo.  They identify 41,794 patients with appropriate data and an explicit diagnosis of peripheral vertigo, and follow them for adverse outcomes.  Most importantly for this paper, looking at subsequent stroke diagnoses, they find 57 (0.14%) received a diagnosis of stroke within 7 days.  To these authors, this number represents a miss rate for actual cerebrovascular causes of vertigo on initial presentation.

It’s a little hard to put great confidence in this precise number, however, because there were actually 270,865 visits discharged with diagnoses of dizziness & vertigo.  The largest cohort of these, 71% of them, were discarded from analysis because their diagnosis was “Dizziness, giddiness, lightheadedness, vertigo NOS”, which was not specific enough for these authors’ purposes.  It would have been enlightening to have included this less-specific cohort in this analysis, at least as a parallel comparison group, for additional insight.

However, the authors do something I quite like in this paper, and something I think would improve the robustness of many other studies:  a propensity-matched analysis attempting to establish a baseline level of risk.  For these authors, they choose renal colic – a generally benign, yet frequent, condition, that ought confer no special additional risk of stroke.  These authors have no difficulty finding 34,872 of patients to pool into a cohort relatively well-matched on important risk factors.  These renal colic patients have very similar rates of falls and fractures in the short-term after discharge – but they have many fewer strokes.  Most of the difference between cohorts arises in the first 7 days, with 50 occurring in the vertigo cohort versus zero in renal colic.  Between day 7 and and 365, however, the rate difference narrows, with 74 strokes in the vertigo cohort and 49 in renal colic.

Despite the massive limitations of retrospective review and relying on diagnosis codes, I think the authors’ general observation is correct.  Dizziness can be a quite challenging diagnosis to evaluate in the Emergency Department, and clearly some patients are being erroneously given diagnoses of peripheral etiologies.  However, the rate of misdiagnosis in this cohort is likely somewhere better than 1 in 700, which I find generally clinically acceptable considering the impossibility of utilizing advanced imaging in such a vast population.

We can certainly endeavor to do better, but we have a lot of work cut out for ourselves in improving the specificity of our clinical evaluation first.

“Outcomes among patients discharged from the emergency department with a diagnosis of peripheral vertigo”

Tissue, Not Time, for Stroke

The new AHA guidelines for the use of endovascular therapy in acute ischemic stroke broadly include any patient within six hours of symptom onset.  These criteria are based, mostly, on MR-CLEAN – in spite of the follow-up EXTEND-IA, ESCAPE, and SWIFT-PRIME showing the highest yield patients are clearly those with salvageable tissue.  Treatment beyond six hours, however, is still considered reasonable – and this cohort from DEFUSE-2 seems to indicate as such.

Based on 78 patients with target mismatch volume on MRI prior to endovascular therapy, they found: time doesn’t matter, only reperfusion.  The reperfusion outcomes for intervention under six hours are, grossly, no different than the outcomes for those greater than six hours.  And, this makes sense – salvageable tissue is salvageable:

Frankly, this is probably the paradigm for which we should ultimately be moving for all stroke treatment.  Time should not be a limiting factor – and, vice versa, should not be the sole indicating factor.  Dead brain simply can’t benefit from revascularization – no matter how quickly it is provided, regardless of time window.  The traditional “non-contrast head CT” is no longer adequate to provide optimal stroke care – CT angiography with perfusion calculations, or a rapid MRI protocol, should probably form the basis of modern stroke care moving forward.

“Response to endovascular reperfusion is not time-dependent in patients with salvageable tissue”
http://www.ncbi.nlm.nih.gov/pubmed/26224727

It’s Time to Fix NIHSS

The purpose of the National Institute of Health Stroke Scale is to describe stroke severity.  Every point represents a deficit on exam, so, higher is worse – except it’s not that simple.

Every point on the scale is, unfortunately, clearly unequal.  Partial paralysis of the face is 2 points.  Profound hemi-inattention is also 2 points.  One of those patients – unless they’re Derek Zoolander – is not disabled.

This is a study, along with others in a similar vein, that translates that common sense directly into an indictment of the NIHSS as currently used.  These authors retrospectively evaluate six “profiles” of patients with discrete clinical manifestations of stroke, by basing their analysis on specific NIHSS item.  They use the NIHSS data from 6,843 patients in the SITS-MOST data, and, essentially, they find very different survival curves for patients with similar NIHSS when specifically categorized by clinical syndromes.

This leads to two main points:

  • We shouldn’t be using the NIHSS the way we’re used to using it.
  • The clinical variability of patients with similar NIHSS can vastly affect stroke trials with low sample sizes.

Time to fix the NIHSS!

“National Institutes of Health Stroke Scale Item Profiles as Predictor of Patient Outcome”

Endovascular Sans tPA in Bern

The first hints of a rollback in tPA use are starting to emerge – not unexpectedly, from those working to improve the outcomes of their endovascular programs.

This is a retrospective evaluation of patients from Bern, Switzerland, all treated with endovascular therapy.  Their registry includes 372 patients since 2004, all treated for MCA or ICA occlusions and with DWI measurements pre-treatment.  As with any data dredge, any findings are just hypotheticals – but, there’s a couple interesting tidbits:

  • Smaller lesions did much, much better – 54.5% achieved mRS 0-2 if lesion volume was <70mL, compared with 21.2% with lesion volume >70mL.
  • If you failed to reperfuse a lesion volume >70mL, mRS 0-2 outcomes sank to 8.6%.
  • Symptomatic intracranial hemorrhage jumped to 19.7% for lesion volume >70mL.
  • There were only 66 patients over >70mL lesion volume, but the best outcomes?  The 19 with mechanical therapy only – balancing 21.1% mRS 0-2 with only 5.3% SICH.

The authors ultimately conclude endovascular therapy for large lesion volumes might be best without any thrombolytic involved.

Wasn’t it lovely how fashionable tPA was – until endovascular therapy finally reached a tipping point in terms of efficacy?

“Younger Stroke Patients With Large Pretreatment Diffusion-Weighted Imaging Lesions May Benefit From Endovascular Treatment”
http://stroke.ahajournals.org/content/early/2015/08/06/STROKEAHA.115.010250.short

Better Less than More for tPA

Ah, but this is not one of those rants about the inefficacy of tPA.  This is just an amuse-bouche of a mention of an article from Stroke, regarding a line of investigation in Asian countries.

In these countries, particularly Korea and Japan, there is some substantial thought given to “low dose” tPA being just as effective, with a lower risk of intracranial hemorrhage.  Interestingly, approximately 40% of acute stroke patients in Asian countries is at this lower dose, 0.6 mg/kg compared with the typical 0.9 mg/kg.  This study is a retrospective evaluation of registry data from 13 academic stroke centers, comparing 3-month outcomes on the modified Rankin Scale.

There were, essentially, two entertaining bits from this article:

  • The rate of symptomatic ICH in centers contributing at least 100 patients during the study period ranges from 3.7% on the low side up to 13.0% on the high.
  • Given the constraints of the study, they were unable to demonstrate any reliable difference between the two doses.  In fact, as you can see from the figure below, retrospective data can be adjusted, propensity matched, or essentially tortured to show whatever advantage preferred:

Should we be using low-dose?  And why stop at 0.6 mg/kg – why not 0.3 mg/kg?  And, further down the rabbit hole, back to the ideal dose of … none.  Ah, but I kid, I kid ….

“Low-Versus Standard-Dose Alteplase for Ischemic Strokes Within 4.5 Hours: A Comparative Effectiveness and Safety Study”
http://www.ncbi.nlm.nih.gov/pubmed/26243232

Retinal Photography to Diagnose TIAs?

Our diagnostic approach to suspected cerebrovascular disease is quite simple.  Concerning neurologic findings or history?  Magnetic resonance imaging.

However, this approach is grossly inefficient – and, thus, the rise of various clinical scores such as the ABCD2 variants.  And, now, ocular fundus photography.  It generally makes sense – the retinal vessels travel through the optic nerve sheath.  They are, then, a unique window into the cerebrovascular circulation – and, accordingly, the degenerative diseases within.

It sort of works.

Looking at patients presenting to the ED with a report of focal neurologic deficits, the multivariate regression OR for cerebrovascular disease in patients with arterial narrowing in 2 segments is reported as 8.1 for stroke and 5.1 for TIA.  However, this finding was only present in 4 of 22 (18%) stroke patients and 6 of 59 (10%) TIA patients – compared with 5 of 176 (3%) patients who did not receive a diagnosis of cerebrovascular disease.

So, yes – it is probably true, as the authors claim, that finding arterial focal narrowing in the retinal vessels increases the likelihood of cerebrovascular disease (stroke and TIA).  But, clearly, the positive predictive value is still quite low, and the number of patients for whom this ocular photography adds substantially to the diagnosis is quite small.  At ~$25,000 a pop for the camera system, and the need for a specialist to screen the images for abnormalities, I do not share these authors’ enthusiasm for its eventual adoption into clinical practice.

“Ocular fundus photography of patients with focal neurologic deficits in an emergency department”
http://www.ncbi.nlm.nih.gov/pubmed/26109710

High-Dose Oral Steroids for Multiple Sclerosis Flare

I am always a fan of evidence supporting treatments that are safe, efficacious, and massively less expensive than conventional care.  Even if multiple sclerosis flares are infrequently seen in the Emergency Department setting compared with, say, sepsis or chest pain, their care is part of the spectrum of our purview.

We’ve known all along oral steroids are just as useful as intravenous steroids for asthma.  However, multiple sclerosis flares are typically treated with 1000mg of intravenous methylprednisolone.  When’s the last time you gave that dose – or equivalent with another steroid – orally?

So, this is the COPOUSEP trial, and it is a non-inferiority investigation comparing three days of high-dose oral administration of methylprednisolone with intravenous.  Enrolling 199, and reporting outcomes on 90 and 93 patients in the oral and IV groups, respectively, the authors find functional improvement in the most disabling aspect persisting at 28 days in 81% for oral and 80% of IV.  Adverse effects tended to favor the intravenous cohort, with agitation and insomnia troubling the oral cohort in greater fashion than IV.  Despite these adverse effects, given the costs and inconvenience of inpatient or infusion center treatment, it is certainly reasonable to encourage patients to pursue the oral option.

Oddly, the authors omit their intention-to-treat results from the paper, and provide only the per-protocol.  The ITT results, supposedly, are available in a supplementary appendix – not yet available, apparently –  and are similar to the per-protocol outcomes.  Thus, I see no particular reason to omit the ITT, as such better reflects the efficacy and safety profile of pragmatic use; the authors should either present both together, or defer the per-protocol analysis to the appendix.

Nearly all individuals involved in the study declared conflicts of interest with multiple pharmaceutical companies, although I do not see how any would have untoward effect on the work in question.

“Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial”
http://www.ncbi.nlm.nih.gov/pubmed/26135706

New AHA/ASA Endovascular Guidelines

How did I find out about the final publication of the new AHA/ASA Guidelines regarding endovascular intervention in acute ischemic stroke?  I received unsolicited e-mail spam from their representative at a public relations firm, gushing about the technology and offering to put me in touch with their generously available expert.

Before getting into the content, the standard housekeeping exercise regarding declared financial conflicts of interest:

  • Dr. Powers: None
  • Dr. Derdeyn: Microvention, Penumbra, SILK Road, Pulse Therapeutics
  • Dr. Biller: None
  • Dr. Coffey: None
  • Dr. Hoh: None
  • Dr. Jauch: Covidien, Genentech, Penumbra, Stryker
  • Dr. K. Johnston: Roche/Genentech
  • Dr. S. Johnston: None
  • Dr. Khalessi: Covidien, Microvention, Penumbra, Sequent, Codman, Stryker
  • Dr. Kidwell: None
  • Dr. Meschia: None
  • Dr. Ovbiagele: None
  • Dr. Yavagal: Covidien/Medtronic, Penumbra

Yes, Virginia, despite the worldwide availability of methodologists and clinicians to review evidence for guidelines, the AHA/ASA were unable to compose such content absent individuals with professional and financial relationships to the manufacturers of the products involved.  Another sad failure regarding the Institute of Medicine’s Guidelines We Can Trust.

So, what’s wrong with these guidelines?  I’ve written and published multiple times regarding endovascular intervention, and it’s a therapy I’m excited about.  For once, the theory and the practice seem to demonstrably align.  The new stent retrievers seem to substantially benefit patients with viable tissue behind a clot – whether because of collateral circulation, retrograde flow, or semi-permeable occlusion – and have the clot safely removed in a timely fashion.

But, that isn’t everyone.  The most successful trials – ESCAPE, EXTEND-IA, and SWIFT-PRIME – were all designed to intervene on a narrow population with salvageable tissue.  The less successful, but still positive, trials – REVASCAT and MR-CLEAN – generally intervened based only on broadly eligible angiographic occlusions.  Such a strategy will definitely catch the few patients with salvageable tissue, but also involves significant resource utilization and procedural risk conferred upon those without the possibility of benefit.

However, that’s what these guidelines suggest – to treat all-comers presenting within six hours, discarding the use of tissue-based criteria for intervention.  The benefit to the corporations involved is obvious, as routine angiography – let alone rapid perfusion calculation – is not widespread.  Without the broadest possible criteria, many centers might not refer patients for intervention.  Given the choice between maximizing yield of this intervention and generating profits for their financial and professional affiliates, the authors of this guideline have chosen the latter.

Not only that, these authors give this recommendation the strongest possible Class I and Level A qualifiers.  The body of the text states this is a result of the findings of the five aforementioned trials published at the time this was drafted.  Unfortunately, from just a simple methodologic standpoint, the authors have developed complete amnesia regarding the entire prior body of negative evidence regarding endovascular intervention – nor acknowledged the open-label nature of these trials stopped early, nor other threats to bias.

So, yet again – from the folks who gave us flawed tPA guidelines and “quality measures” – a guideline we can’t trust.  The Society for Academic Emergency Medicine was solicited to endorse this guideline several months ago, and I was involved in the review process at that time.  Unfortunately, none of the concerns expressed at that time appear to have been addressed – and as such, SAEM is not included among the professional societies endorsing this guideline.

Endovascular therapy is coming.  And, unfortunately, it is certainly going to be coming to many more than for whom appropriate.

“2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment”
http://m.stroke.ahajournals.org/content/early/2015/06/26/STR.0000000000000074.full.pdf

The New, Improved, ACEP Clinical Policy for tPA in Stroke

Released with minimal fanfare, approved by the ACEP Board of Directors on June 24th, the revised ACEP Clinical Policy regarding the use of TPA for acute ischemic stroke has gone final.

It is, of course, a vast improvement over the 2012 version – but has, unfortunately, changed for the worse since the draft was posted.

The highlights:

  • The Level A suggestion to consider the risk of ICH with tPA administration has been eliminated.  It has been moved, nonsensically into the Level B recommendations for offering tPA – when, frankly, it’s the only consistent finding across all the evidence.
  • The Level B recommendation in which tPA “may be given” within 3 hours has been strengthened to “should be offered and may be given”.  Obviously, a profound difference.
  • The Level B recommendation for 3-4.5 hours remains unchanged, based on only one flawed piece of Class II evidence (ECASS III), and conflicting Class III evidence (ATLANTIS, IST-3, meta-analyses).
  • The Level C recommendation to engage in shared decision-making now states “when feasible”, which is obviously open to interpretation.
  • No further clarification of “carefully selected patients” or “systems … in place to safely administer the medication” is provided.

Some wins, some losses.  Obviously, the shared decision-making supporting any “offer” of tPA can be very different, depending on an individual clinicians’ interpretation of the evidence – and it is nice to see the prior COI-infested husk of rotten guidelines finally, officially, tossed on the compost heap.  Let us hope (irrationally, of course) the efforts underway in the United Kingdom spur further, independent, investigation with which to better understand and individualize the risks and benefits of treatment with tPA.

“Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department”
http://www.acep.org/workarea/DownloadAsset.aspx?id=102373

DIAS-3 – Desmoteplase Fails in the Extended Time Window

It seems to be the stroke neurologists’ greatest lament – the restricted time windows for tPA, either 3 or 4.5 hours, excluding so many patients from receiving the blessing of thrombolysis.  There have been failed trials in the past in extended time windows, and, even, failed trials in the 3-5h time window.  But, this is desmoteplase, and it is more fibrin specific than alteplase – and this follows up DIAS-2, which seemed to suggest benefit in patients with demonstrated arterial conclusion on vascular imaging.

It is, sadly, negative by the primary outcome of 90-day Rankin score (mRS 0-2), adding another tick mark to the list of failed contemporary trials for systemic thrombolysis.  Safety outcomes, mercifully for the patients involved, were similar, with low rates of neurologic worsening associated with intracranial hemorrhage in each cohort.

The authors, as before, find and focus on a single positive subgroup: patients with ischemic injury volume of less than 25mL on MRI.  There was, interestingly, no positive effect noted for patients whose ischemic injury volume was less than 25mL on CT – and the authors had no specific explanation for the discrepancy.  However, given the recent successful endovascular trials, it is quite reasonable to suggest an imaging-based, tissue-salvage model is more appropriate than the simplistic time-based model suggested by NINDS.  Unfortunately, tissue salvage is dependent upon recanalization – and rates were not significantly different between cohorts, 49% with desmoteplase vs. 42% with placebo.  This is the persistent elephant neurologists fail to acknowledge – that systemic thrombolysis simply rarely works as advertised – greatly diminishing any possible beneficial effect.

The conflict-of-interest statement falls on what probably would have once been considered the extreme side, but now is tragically routine:

The funder was involved in the study design, data collection, data analysis, and data interpretation. Two employees of the funder provided medical writing assistance in the editing of the report. The corresponding author had full access to all study data; all other authors without funder affiliation had access to study data via the corresponding author and authors with funder affiliation had full access to all study data.

Interestingly, review of the ClinicalTrials.gov registration indicates the study was initially planned in 2008 to enroll 320 patients, with an end date in 2010.  In 2010, the planned enrollment was increased to 400, and the study ultimately enrolled 492.  Given the COI involved, it reasonable to suggest the funder was involved in ongoing analysis of the results with the intention of stopping the study at the precise moment a positive outcome – or ultimate futility – was detected.  Despite the best efforts of Jeff Drazen and the NEJM to downplay potential distortions secondary to funding sources, clearly, our vigilance for such likely scientific misconduct should not be diminished.

“Safety and efficacy of desmoteplase given 3–9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial”
http://www.ncbi.nlm.nih.gov/pubmed/25937443