Category: Neurology

Out of the Way!

The mobile stroke unit is the new, malignant, extravagant reaction to the “Time is Brain” mantra. However, not all locations are endowed with such an embarrassment of resources.

This very brief report details a systems approach in Mashhad, in Northeast Iran. In 2015, these authors reported only 1.2% of all strokes received treatment with IV tPA, and their analysis indicated prehospital delays were their primary issue. Rather than take the CT to the patient, their far more entertaining solution was simply to clear a path. To relieve delays from chronic traffic congestion and gridlock, they designed an online control system for all traffic lights to be activated based on the severity of the emergency medical condition. Green lights in a continuous path from the incident location to the medical facility help activate traffic flow to allow ambulances room to maneuver. These authors report their successful implementation reduced prehospital transfer time by 50%, although absolute measures are not reported.

Now, they do mention their next step is to report on improvements in patient-oriented outcomes. However, unless the traffic is truly catastrophic, I expect improvements in anything but process surrogates will be difficult to detect.

“Time is brain: An online controlling of traffic lights can save lives”
http://emj.bmj.com/content/early/2017/11/24/emermed-2017-206888

“DAWN” of the Mismatch Era

It wasn’t truly so long ago the treatment for an acute stroke was virtually nonexistent. Then, it progressed, with patients eligible for treatment within 3 hours … then 4.5 hours … then 6 … and, now, 24 hours. Whatever happened to “time is brain”? How can we possibly be treating patients out to a day after onset of symptoms?

This is the DAWN trial, randomizing patients with acute ischemic stroke to endovascular intervention or medical management within 6 or 24 hours of symptom onset. Eligibility criteria included occlusion of the internal carotid or proximal middle cerebral artery paired with one of three different clinical syndrome/infarct core mismatches based on CT or MRI perfusion imaging: three cohorts with NIHSS of 10 or 20, with differing sizes of infarct cores. The underlying theory here stems from observations of the viability of cerebral tissue as dependent upon collateral circulation, rather than simply the linear passage of time.

This is, as you might already have gathered from the press releases, a positive study. Unfortunately, it was so positive it was stopped early for benefit based on a primary outcome these authors almost certainly created uniquely to support early termination of these sorts of trials: the “utility-weighted modified Rankin scale”. Rather than use the traditional mRS as in all other stroke trials, or, even, the statistically flawed “ordinal shift analysis”, these authors assigned point values to the various mRS categories, those with the least disability receiving the most points. This resulted in the potential enrollment of 500 patients being stopped at the earliest possible pre-specified interim analysis with a mere 200 patients enrolled.

Tossing out their nonsensical fake outcome measure for the more easily approachable mRS categories, 52 of 107 (49%) of thrombectomy patients were functionally independent (mRS 0-2) at 90 days versus 13 of 99 (13%) of those in the control group. These results were roughly consistent across their various subgroup analyses, although, with such a small trial, the confidence intervals get awfully wide, awfully quickly. That said, despite all the other associated trial shenanigans, it is fairly obvious this sort of treatment is helpful to patients. I’ve been preaching tissue-based approaches to therapy for a couple years now, and despite this trial’s individual issues, in a Bayesian sense these results are consistent with prior evidence.

Of course, this does not actually indicate the window for screening ought to be 24 hours as will likely be justified from these data – the bounds of eligibility for the study do not simply translate subsequently to clinical policy recommendations. The study design does explicitly stratify patients to 6 to 12 hour and 12 to 24 hour cohorts, but the IQR range for “time from symptom onset” for the entire cohort is 10.2 to 16.3 hours, implying approximately half the 12 to 24 hour cohort was actually randomized between 12 and 16 hours. This leaves a paucity – approximately 25 patients in each arm – of data to inform treatment in the 16 to 24 hour window. Contrariwise, these data also do not explicitly exclude patients beyond 24 hours as potential candidates for intervention, as this is a tissue-based, not time-based, paradigm. Further prospective study will be needed to determine the precise time window at which perfusion screening for large vessel occlusions ultimately becomes so low-yield there is no value in the pursuit.

These authors also do not provide useful information regarding the number of patients screened for possible inclusion. Much will be made of these results, with a likely profound impact on our approach to stroke. To properly design stroke systems of care and project resource utilization, physicians and policy makers need data regarding the clinical characteristics of all patients evaluated and those features best identifying those who ought be triaged or transferred to specialized centers.

Finally, of course, there is the perpetual elephant in the room – heavy involvement from the sponsor in the conduct of the study, along with multiple authors on the payroll. These financial conflicts of interest always threaten internal and external validity by limiting generalizability and amplifying apparent effect sizes. All this said, however, this is probably an important step forward in the evolution in our approach to stroke.

“Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct”
http://www.nejm.org/doi/full/10.1056/NEJMoa1706442

It’s SAH Silly Season Again!

A blustery, relentless wind is blowing the last brittle teeth from the trees here in late November – which must mean it’s time to descend, yet again, into decision-instrument madness. Today’s candidate/culprit:

The Ottawa Subarachnoid Rule, once-derived, now-validated in this most recent publication highlighting their prospective, observational, multi-center follow-up to the original. The components are as you see above, and the cohort eligible for inclusion were neurologically intact “adult patients with nontraumatic headache that had reached maximal intensity within 1 hour of onset”. Over four years, six Canadian hospitals, and a combined annual census of 365,000, these authors identified 1,743 eligible patients with headache, 1,153 of whom consented to study inclusion and follow-up. Of these, there were 67 patients ultimately diagnosed with SAH, and the Rule picked up all of them for a sensitivity of 100% (95% CI 94.6% to 100%) – and a specificity of 13.6% (95 CI 13.1% to 15.8%).

Unfortunately, take the infographic above and burn it, because, frankly, their route to 100% sensitivity is, essentially: everyone needs evaluation.  This can be reasonable when the disease is life-threatening, such as this, but the specificity is so poor in a population with such a low prevalence the rate of evaluation becomes absurd.

If their rule had been followed in this cohort, the rate of investigation would have been 84.3% – or, 972 patients evaluated in order to pick up the 67 positives. Then, in the context of usual practice in this cohort, the investigation rate was 89.0%. That means, over the course of 4 years in these six hospitals, use of this decision instrument would have saved 1 fewer patient from an investigation for SAH every six months. However, the hospitals included for this validation were also the same ones who assisted in the derivation, meaning their practice was likely already based around the rule. I expect, in most settings, this decision instrument will increase the rate of investigation – and do so without substantially improving sensitivity.

Furthermore, their definition also includes patients with a diagnosis of non-aneurysmal SAH who did not undergo intervention, a cohort in whom the diagnosis is of uncertain clinical significance.  If only those with aneurysms and morbidity/mortality-preventing interventions were included, the prevalence of disease would be even lower.  We would then be looking at even fewer true positives  for all this resource expenditure.

The other issue with a rule in which ~85% of patients undergo investigation for headache is the indication creep that may occur when physicians apply the rule outside the inclusion criteria for this study. The prevalence of SAH here is very high compared with the typical ED population presenting with headache. If less strict inclusion criteria are used, the net effect willy likely be to increase low-value investigations in the overall population. Dissemination of this decision instrument and the downstream application to other severe headaches in the ED will likely further degrade the overall appropriateness of care.

Finally, just as a matter of principle, the information graphic is inappropriate because it implies a mandated course of medical practice. No decision instrument should ever promote itself as a replacement for clinical judgment.

“Validation of the Ottawa Subarachnoid Hemorrhage Rule in patients with acute headache”

http://www.cmaj.ca/content/189/45/E1379.abstract

Why Are Children Dizzy?

Vertigo presentations in adults are nearly always benign – with cerebral ischemia generally the most worrisome diagnosis in the differential. But, what about children? With a much lower risk for stroke, but also spared the other decay and decrepitude of aging, ought we be more or less concerned?

The short answer: mostly no. However, the etiologies of pediatric vertigo are almost certainly different.

In this short systematic review comprised of 24 studies and 2,726 children, the vast majority of cases resulted from generally benign etiologies. The most common diagnosis was ascribed to “vestibular migraine”, at about a quarter of the cases, followed by a smattering of peripheral vertigo and labyrinthitis-spectrum disorders. Not until diagnostic prevalence approached ~1% of cases did the most serious underlying etiologies begin to manifest, with central nervous system tumors, demyleninating disease, and ototoxic medication effects at the top of the lists of infrequent findings.

The limitations of this analysis include lack of generalizability to the Emergency Department, as several of the included articles are drawn from outpatient subspecialty case series review. A reasonable takeaway from these data, at least, as in adults, is serious underlying etiologies are very infrequently, and isolated vertigo need not be particularly worrisome absent other important neurologic findings.

“The Differential Diagnosis of Vertigo in Children: A Systematic Review of 2726 Cases”
https://www.ncbi.nlm.nih.gov/pubmed/29095392

Don’t Dilaudid for Headaches

What’s the most common Emergency Department treatment for “migraine” in U.S. Emergency Departments? If you guessed one of our respected go-to medications – metoclopramide, prochlorperazine, ketorolac, or such ilk – you’re be wrong. It’s friggin’ hydromorphone (Dilaudid). Ask for it by name. It starts with a “D”, and your doctor will know what you’re talking about.

For what it’s worth (hopefully), these data are out of date – coming from the 2010 National Hospital Ambulatory Medical Care Survey in an article published in 2014.  In their report, over half of patients treated for headache in the Emergency Department received opiate therapy, and hydromorphone led the pack. But, if hydromorphone is so widely used, are the rest of us responsible adults missing something?

No.

This is a randomized, double-blind trial in which patients with migraneous headache in the Emergency Department were treated with either hydromorphone or prochlorperazine intravenously. The dose for hydromorphone was 1mg and the prochlorperazine 10mg, with those receiving prochlorperazine concurrently given diphenhydramine 25mg. The primary outcome was headache relief at 2 hours, as measured by patient reported symptoms and by any use of rescue medications, and patients could receive a second dose of the active study medication at the 1 hour mark.

These authors enrolled 127 patients, and at one hour, 15% of the prochlorperazine cohort still had severe or moderate headache, while 48% of the hydromorphone cohort reported the same. Similar absolute magnitudes of patients in the hydromorphone cohort requested a second dose of medication or required use of an off-protocol rescue medication. Then, the study was stopped – they expected to enroll 208, but a pre-planned analysis after 120 required the study be terminated with respect to the observed treatment difference.

And, that’s what I’d suggest be done in this case to hydromorphone use for headache – terminated. I hope the next time a report is published regarding the medications used for acute headache in the Emergency Department, hydromorphone has virtually disappeared from the list.

“Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine”

https://www.ncbi.nlm.nih.gov/pubmed/29046364

CT (Almost) Never Before LP

The guidelines describing the patients with suspected bacterial meningitis for whom neuroimaging is indicated prior to lumbar puncture are quite broad. The Infectious Disease Society of America includes virtually every imaginable mental status or immune system impairment, and guidelines in Europe are similar. The anachronistic concern: cerebral herniation in the setting of increased intracranial pressure leading to an otherwise potentially avoidable death. But, guidelines in Sweden are different. In Sweden, their neuroimaging guidelines suggest only those virtually comatose or with focal neurologic signs should undergo CT prior to LP.

In this review of patients with acute bacterial meningitis from a Swedish registry, the authors attempt to parse out whether a decision to perform CT is not only unnecessary – but also potentially harmful. They analyze 815 patients ultimately diagnosed with bacterial meningitis and stratify them by those who received LP without CT, LP before CT, and CT before LP. Presenting features and comorbid medical conditions were abstracted retrospectively, and the results were analyzed with respect to the varying guideline recommendations, mortality, and functional outcomes.

The clear winner: CT rarely before LP, as in Sweden. By their guidelines, only ~7% of those ultimately diagnosed with bacterial meningitis had indication for CT prior to LP – but, unfortunately, 52% of patients underwent imaging anyway. The reason for “winning” if adherent to the Swedish strategy, however, was not just reduced resource utilization – it was mortality and functional outcomes. Mortality was almost halved in those for whom Swedish guidelines were followed, only rarely CT prior to LP. The authors attribute the signals for the underlying mortality difference to a greater percentage of patients receiving antibiotics within 1 hour or 2 hours when no CT was performed.

This probably overstates the magnitude of harm relating to CT use, as delays in antibiotics are probably more accurately delays in diagnosis, rather than logistics impacting timely delivery of antibiotics. After all, even in those with LP prior to CT, only 41% received steroids plus adequate antibiotics, so I expect the magnitude of effect seen here likely ties more reliably to confounding individual patient factors not easily adjusted for in a retrospective analysis.

That said, I do think the Swedes are doing the right thing – the vast majority of CTs were unhelpful. Their guidelines for neuroimaging – deep coma and/or lateralizing neurologic signs – will probably pick up any relevant findings (like the subdural empyema in this series), and reduce waste while obviating any possible delays in care.

“Lumbar puncture performed promptly or after neuroimaging in adult bacterial meningitis: A prospective national cohort study evaluating different guidelines”
https://academic.oup.com/cid/article-abstract/doi/10.1093/cid/cix806/4110207/Lumbar-puncture-performed-promptly-or-after

Nothing But Advantages to Treating Stroke Mimics!

What is the acceptable rate of treatment of stroke mimics with tPA? Zero? A few percent?  No limit?  It’s mostly harmless, after all – with only a ~1% rate of intracerebral hemorrhage. And, thanks to the free-market forces of comparison shopping and collective bargaining power of individual stroke patients, the cost of alteplase has increased >100% in the past decade to ~$6400 per dose. With all this going for it, it’s no wonder the American Heart Association gives a Class II recommendation for empirically treating, rather than pursuing additional diagnostic tests.

The added bonus – the more mimics you treat, the better your stroke outcomes appear!

This retrospective review of 725 tPA-treated patients at three hospitals evaluated the difference in rate of treatment of stroke mimics at an MRI-based “hub” hospital and CT-based “spokes”. Of 514 patients treated at the hub, only 3 (0.3%) were ultimately given a non-stroke diagnosis. Of 211 treated at the spokes, 33 (16%) were stroke mimics. The authors also noted, splitting their review period into 2005-09 and 2010-14, the rate of treatment of stroke mimics at spokes had increased from 9% to 20%.

To no great surprise, clinical outcomes – as measured both by mRS ≤1 five days after discharge and hemorrhagic transformation – significantly favored the spoke hospitals. Outcomes also improved between the time periods compared – hand-in-hand with the increase in treatment of stroke mimics.

These authors go on to mention treatment of stroke mimics has real financial cost to the health system and to individual patients, the misdiagnosis of stroke notwithstanding – growing ever more important as our health system lurches back towards penalties for pre-existing conditions. The authors acknowledge the luxury of having rapid MRI available for stroke, but go on to implicate aggressive efforts to improve door-to-needle times as contributing to misdiagnosis and harmful waste.

But, none of that matters when you can get a shiny promotional merit badge for your stroke center!

“Effects of increasing IV tPA-treated stroke mimic rates at CT-based centers on clinical outcomes”
http://www.neurology.org/content/early/2017/06/28/WNL.0000000000004149.abstract

PCCs for Non-Warfarin ICH?

This quick post comes to you from the EMedHome weekly clinical pearl, which was forwarded along to me with a “Good stuff?” open-ended question.

The “good stuff” referred to a series of articles discussing the “CTA spot sign”, referring to a radiologic marker of ongoing extravasation of blood following an intracranial hemorrhage. As logically follows, ongoing bleeding into a closed space has been associated with relatively increased hematoma growth and poorer clinical outcomes.

However, the post also highlighted – more in an informational sense – an article highlighting potential use of prothrombin concentrate complexes for treatment of bleeding, regardless of anticoagulation status. We are all obviously familiar with their use in warfarin-related and factor Xa-associated ICH, but this article endeavors to promote a hypothesis for PCC use in the presence of any ICH with ongoing radiologically apparent bleeding.

The evidence produced to support their hypothesis? A retrospective 8 patient cohort of patients with ICH and CTA spot sign, half of whom received PCCs and half who did not. Given the obvious limitations regarding this level of evidence, along with problems of face validity, there is no reason to revisit their results. The EMedHome pearl seemed to suggest we ought to be aware of this therapy in case a specialist consultant requested it. Now, you are aware – expensive, unproven, and not indicated without a substantially greater level of evidence to support its use.

“Role of prothrombin complex concentrate (PCC) in Acute Intracerebral Hemorrhage with Positive CTA spot sign: An institutional experience at a regional and state designated stroke center”
https://www.ncbi.nlm.nih.gov/pubmed/27915393

Stem Cells for Stroke Redux

A few months ago, folks at Stanford were claiming miraculous recoveries after implanting stem cells directly into patients’ brains at the site of injury. An interesting concept, to be certain.

Now we have “stem cells lite”, or, at least, the slightly-fewer-holes-in-the-skull version – and it’s apparently just as miraculous.

This is a Phase 2 double-blinded dose-escalation study evaluating treatment with intravenous multipotent adult progenitor cells, with treatment initiated between 24 and 48 hours. Their trial design reflects the nature of a Phase 2 trial, with three cohorts, unbalanced allocation, and dosing differences between groups, but is otherwise fairly straightforward. Until you get to the primary outcome:

“The primary efficacy outcome was the multivariate global stroke recovery at day 90, which assesses global disability, neurological deficit, and activities of daily living and consists of mRS 2 or less; NIHSS total score improvement of 75% or more from baseline; and Barthel index of 95 or more in the multipotent adult progenitor cells treatment group, compared with the placebo treatment.”

Which is to say, they’ve conjured up their own unique black-box composite primary outcome – an outcome they changed midway through the trial.

Why would you need to change the primary efficacy outcome in 2014 for a study that started in 2011? The obvious implication is the results were unfavorable – and, the cursory review of their results table suggests this is a reasonable stance to take.

These authors screened 160 patients at several different sites for eligibility and ultimately randomized 129. Of these, three did not receive the allocated intervention – leaving the remainder for analysis. Patients in each group were generally similar based on NIHSS, time until infusion, and stroke interventions. Sticking to traditional outcomes measured by stroke trials, there was no difference between groups: mRS ≤2 in 37% of the intervention group and 36% of the placebo.  However:

“exploratory analyses suggested an increase in excellent outcome in the multipotent adult progenitor cells arms in the ITT population, and a beneficial clinical effect on long-term 1 year disability.“

This “excellent” outcome is the product of the midstream outcome change combined with their post-hoc data dredging for a feasible positive finding – a combination of patients with mRS ≤1, a NIHSS ≤1, and a Barthel Index ≥95. Then, the bulk of their analysis is further restricted to one year outcomes of those who received their stem cells within 36 hours from stroke onset. With such an obvious “beneficial clinical effect”, is there any question regarding the role of the funding source?

“The funder of the study was involved in study design and in data interpretation. All data collection and analysis were overseen by Medpace. One employee of the funder (RWM) was represented on the writing committee.“

and:

“DCH received grants from Athersys, payments to his university from Medpace for patient enrolment, has a patent on the MultiStem cells through his university and has received licensing revenue through his university. LRW received grants from SanBio and Athersys, and personal fees from SanBio. GAF is a consultant for Athersys; received personal fees from Medpace; and payment from Medpace to his institution for study costs. SS received grants from Athersys. SIS received grants from Athersys, and consulting fees that were paid to the institution from Mesoblast, Aldagen, and Celgene. CAS received grants from Athersys. DC received grants from Athersys.”

The likelihood these results are valid, reproducible, and have a clinically meaningful effect size is nearly zero – but that certainly won’t stop them from throwing good money after bad.

“Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial”
https://www.ncbi.nlm.nih.gov/pubmed/28320635

All Aboard the tPA Hype Bus

Indiscriminate use of tPA in those with undifferentiated stroke is a low-value proposition – even if you find the evidence reliable. The utility of tPA for stroke depends on anatomy, time, and tissue status – information the traditional non-contrast head CT does not usually provide. Unfortunately, one of the latest “innovations” in stroke care is simply to do this useless test faster – in a bus, down by the river.

This is the PHAST project out of Cleveland, which, like similar efforts in Berlin, Chattanooga, and Houston, puts a CT scan machine in an oversized ambulance. Many of the initial phases of these projects included a stroke physician physically in the vehicle – but this, as you would expect, takes advantage of telemedicine technology to provide consultation from afar.

The stated hypothesis of this project is “that the MSTU will allow significant reductions in time to evaluation and treatment of patients when compared to a traditional ambulance model in an American urban environment”, which is just mind-numbingly infantile. Of course, pre-hospital administration will be faster than in-house thrombolysis – the interesting data would be with regard to safety and misdiagnosis.

This report is of the first 100 patients evaluated – generated by 317 system alerts. Of these, 33 were given a preliminary diagnosis of probable stroke, 30 possible stroke, 4 transient ischemic attacks, 5 intracerebral hemorrhages, and 28 non-cerebrovascular. Of the 33 probable strokes, 16 received thrombolysis – and, by most of their various metrics, care was accelerated by 20-40 minutes. And, then, no outcomes, safety, or follow-up data is presented – apparently we are simply supposed to operate under the assumption this resource outlay and rush to provide the substrate for potential tPA administration is obviously prudent and effective care.

Probably the only interesting tidbit from this paper was with regard to one of the cases of ICH diagnosed by CT in the prehospital setting. One patient was identified as taking anticoagulation, and prothrombin concentrate complexes were initiated in the pre-hospital setting. The timeliness of anticoagulation reversal is almost certainly beneficial, although the magnitude of effect for the few minutes saved is uncertain.

“Reduction in time to treatment in prehospital telemedicine evaluation and thrombolysis”

http://www.neurology.org/content/early/2017/03/08/WNL.0000000000003786.abstract