Category: Neurology

Add Clopidogrel to Aspirin, Temporarily

In the Emergency Department, we’re not necessarily spending a lot of our time sending home patients with minor stroke or high-risk transient ischemic attack – or, even if we are, we’re usually not doing it independently. That said, our scope of practice always seems to be expanding, observation units are frequently run by emergency physicians, and hospitals are looking to take advantage of opportunities to discharge patients rather than admit.

Regardless, this is a meta-analysis supporting the findings of CHANCE, looking specifically at the short-term use of aspirin and clopidogrel after a minor stroke or high-risk TIA. CHANCE enrolled 5,170 patients, while this meta-analysis effectively combines these with POINT, while also tossing in the patients from FASTER.

The main takeaway here is the combination of the evidence from the long-term treatment observing it was effectively a wash between stroke prevention and bleeding complications, and the observation that stroke risk was highest immediately following the index event. A reasonable interpretation, as highlighted by the guidelines, is to use dual-antiplatelet therapy short-term after the index event. The evidence does not specifically describe the optimal duration, but anywhere between 10 and 21 days seems reasonable.

Just wanted to toss this one out there with a little more prominence, as this isn’t particularly new, but I also wouldn’t want it to be overlooked.

“Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high risk transient ischaemic attack: systematic review and meta-analysis”
https://www.bmj.com/content/363/bmj.k5108

“Guideline: Starting dual antiplatelet therapy ≤ 24 h after high-risk TIA or minor ischemic stroke is recommended.”
https://www.ncbi.nlm.nih.gov/pubmed/30986828

Levetiracetam vs. Phenytoin

The epic, classic showdown from time immemorial: new vs. old.

But, more specifically, these are two trials set to determine relative utility of each in pediatric seizures, vying for the coveted “second-line” therapy recommendation once benzodiazepines have failed. The thought and hope is, of course, the newer agent – levetiracetam – is at least as efficatious, if not moreso, as it can be infused more quickly. The authors then propose levetiracetam is associated with fewer long-term adverse effects and medication interactions during oral maintenance, and, as such, allows for convenient continuation after intravenous initiation.

Generally speaking, these two trials are very similar – both open-label trials randomizing pediatric patients with ongoing seizures, both analyzing about 250 patients … and both demonstrating effectively similar results by different routes. EcLiPSE, interestingly, was designed as a superiority trial, with a primary outcome of time from randomization to seizure cessation. Median time to seizure cessation not statistically different at 35 minutes for fosphenytoin and 45 minutes for levetiracetam, with similar numbers of treatment failures for additional anticonvulsants or intubation. In ConSEPT, the primary outcome was cessation of seizure activity within 5 minutes of the end of the infusion, and here results favored phenytoin at 60% versus 50% for levetiracetam.

Effectively, however, the sample sizes are small enough, the types of patients heterogenous enough, and the differences small enough, the Bayesian interpretation is probably a wash. These are both fine second-line options, but these trials do not provide any data supporting levetiracetam as a superior option.

“Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30724-X/fulltext

“Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial”
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30722-6/fulltext

Lacunar Infarcts & Thrombolysis

For some period of time, folks have debated the utility of thrombolysis in lacunar infarcts. The underlying concern is with regard to their underlying suspected pathology relating to non-thrombotic occlusion of small perforating arteries, in contrast to the process seen in small- or large-vessel stroke. This little subgroup analysis of WAKE-UP – the MRI-driven tissue-based trial of alteplase for ischemic stroke – tries to shed further light on this specific concern.

Of the 503 patients included in WAKE-UP (out of 1,362 patients screened), 108 had imaging-defined lacunar infarcts. The median NIHSS of these patients was 4 to 5, and about half were randomized to alteplase and half to placebo. Overall, this subgroup – underpowered for any definitive conclusion – demonstrated similar outcomes as those whose stroke subtype was not lacunar.

The issue is not so much the finding observed here, but the effort in the Discussion and accompanying editorial to generalize WAKE-UP to all strokes. There is only a loose association between DWI and FLAIR findings and predicting time of stroke onset in their cited reference. A little fewer than 2/3rds of strokes of ≤4.5h age seem to have positive DWI and negative FLAIR, and this study enrolled only a tiny fraction of patients with potential lacunar infarcts.

Long story short, a treatment effect observed in this tissue-based enrollment cohort cannot reliably predict treatment response for lacunar strokes screened and treated based on routine non-contrast imaging. Most patients screened for WAKE-UP were excluded based on not meeting imaging criteria, potentially around half of whom were otherwise within 4.5 hour stroke onset (based on their citation above). Thrombolysis does benefit the patients in WAKE-UP, overall, but this almost certainly represents the ceiling for a positive effect size – and in routine practice, effectiveness is likely much lower.

Related aside: when we start routinely screening strokes with MRI in that happy future time, do we exclude DWI+/FLAIR+ from thrombolysis, even if within the “treatment window”? I would think so.

“Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial”
https://jamanetwork.com/journals/jamaneurology/fullarticle/2729091

Emergencies in Medicine

Just a quick note to follow-up this splendid little conference in Park City, UT, where I featured in a debate regarding the utility of tPA for stroke. We had a generally respectful discussion about the state of stroke care and our vision for the future.

Unfortunately, it – as you might expect – looks a lot like a future where tPA flows like water.

The overall gist of the presentation by Chris Lewandowski, one of the original NINDS investigators: pool the trial data, and the benefit is clear. My gripes, well-chronicled on this site: benefit is not uniformly distributed, we should tailor its use, rather than expand it.

Interesting tidbits from the follow-up discussion:

  • No one is going to re-do NINDS in this country. They couldn’t even complete PRISMS because too many mild, non-disabling strokes were already being treated.
  • Treating vast numbers of stroke mimics is not troublesome to them – Lewandowski claims to have never heard of one ever having a bleed.
  • The expected benefit to mobile stroke units relates to “fresh” clot being more likely to lyse, as much as the brief time savings.
  • Studies like TIMELESS and other tissue-based thrombolytic studies will likely extend the treatment window, just like WAKE-UP.
  • No qualms about treating NIHSS scores of 1 causing only mild disability (say, unilateral leg weakness). They’ve seen that some NIHSS 1 deteriorate, and believe tPA will prevent it.
  • They are utterly comfortable with forever using NINDS as their default NNT/NNH consent – and no problem using the same numbers now matter what the NIHSS. Except, they just reduce their risk number for harm, as ICH is generally related to infarct size/NIHSS. This drives me mad.
  • They feel strongly tPA has been proven “cost-effective”, while I would note those analyses are based on assumptions and models not matching current practice and treatment population.
  • Treating cervical artery dissection with tPA is favored to them because they expect the clot that showers distally will benefit from lysis, though they agree there is no evidence to support their claims.
  • They agreed that, overall, the recommendations issued by the AHA overstate the strength of the evidence.

Would be fun to do again – even if it is effectively just shouting into the wind!

Who Recanalizes with Just tPA?

The original argument: tPA helps all strokes, we must give it to everyone as quickly as possible!
The updated argument: tPA doesn’t not help all strokes, so it should still be given!

Specifically, as applies to the cohort of patients with large vessel occlusions being considered for mechanical thrombectomy. This small, pooled registry sample looked at cases from four centers, evaluating the rate and predictive characteristics for recanalization prior to cerebral angiography. The stated purpose of their study was to develop a predictive score, with the reasonable goal of reducing unnecessary tPA exposures prior to thrombectomy.

The numbers, in their score derivation and validation cohorts:

  • ICA: 6.4%/1.0%
  • M1 proximal: 16.1%/13.7%
  • M1 distal: 30.3%/30.7%
  • M2: 33.7%/34.0%

But, an even more powerful a predictor was thrombus length, as measured by T2 MRI susceptibility vessel sign. Recanalization was seen at over 80% for clots <5mm, 30% for 6-10mm, and below 10% for clots longer than 10mm, with particular futility for >20mm.

Interesting data – and a nice look at how not all sites of occlusion and clots are created equal. Whether, and how, we ought to treat them differently remains uncertain until the results of a prospective trial.

“Post-Thrombolysis Recanalization in Stroke Referrals for Thrombectomy”
https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.118.022335

Tenecteplase vs. Alteplase For … Stroke Mimics?

Bless their little hearts.

It’s almost as though this is a submission fo the IgNobel Prize, rather than a serious scientific manuscript. “How well does a medicine work when the patient doesn’t have the disease?” is basically a joke, right?

Not in the magical world of stroke neurology, replete with its array of meretricious interventions.

This is a secondary analysis of NOR-TEST, a phase III trial comparing alteplase with tenecteplase. A few folks believe tenecteplase has superior fibrinolysis to alteplase, and therefore ought to be potentially favored in acute ischemic stroke. NOR-TEST, for what it’s worth, could not detect any statistically significant difference between the two.

What is notable in this trial, of course, is the 17% rate of stroke mimics. And, this is a Very Important publication comparing the safety of these two medications when given to patients inappropriately. And, of course, there is no difference. There were three cases of intracerebral hemorrhage and three cases of extracranial bleeding, none of whom – you know – died, but were clearly all unnecessary iatrogenic injury.

Some more interesting notes, at least, from their analysis of stroke mimics. The average NIHSS in this entire study was 4, with the IQR for mimics 2-6 and for acute ischemia 2-8. There’s no useful evidence to suggest thrombolysis is superior to placebo in this sort of mild stroke cohort, but, here we are. Absent this evidence, some neurologists make an argument based on the Get With the Guidelines-Stroke registry, observing many patients with mild stroke are ultimately unable to be discharged to home due to persistent disability. In the NOR-TEST cohort of mimics, however, only 79% were assessed to have mRS 0-1 at 3 months, while their treated stroke cohort achieved mRS 0-1 only 60% of the time.  It would seem the base rate of mimic- or mild-stroke disability is effectively as observed in the GWTG-Stroke registry, regardless of treatment.

In sum, these authors have basically provided us with an unwitting glimpse into how acute stroke treatment has gone utterly off the rails in Norway.  Now, I wonder if they’re related to the group trying to push tPA in less than 20 minutes ….

“Safety and predictors of stroke mimics in The Norwegian Tenecteplase Stroke Trial (NOR-TEST)”

https://www.ncbi.nlm.nih.gov/pubmed/30019629

Starting Treatment on First-Time Seizures

We see a fair bit of ostensibly “first-time” seizure in the Emergency Department. With some room for nuance and debate, general practice is typically still to defer initiation of anti-epileptic therapy.

This decision analysis in the neurology literature ultimately comes to the alternative conclusion – initiation of AEDs is reasonable even absent a clear or likely diagnosis of epilepsy. Based on their cases and parameters regarding seizure recurrence, the degradation of quality-of-life relating to seizure recurrence, and the features of modern AEDs, these authors find in favor of initiation of AEDs. Specifically, they find the previous threshold of ≥60% or greater chance of seizure recurrence after a first seizure is likely too high, and 30-40% may be more reasonable.

These conclusions are appropriate, considering the decision analysis model parameters – but, of course, by definition they also depend on the validity of these parameters. Then, whether this decision analysis can be applied clinically in the Emergency Department is another question, considering the challenges with regard to determine whether a seizure is truly unprovoked. Regardless, as AEDs evolve, have fewer adverse effects, and reach generic status, more liberal strategies of AED initiation in the Emergency Department may be in our future.

“Antiepileptic drug treatment after an unprovoked first seizure: A decision analysis”
http://n.neurology.org/content/early/2018/09/12/WNL.0000000000006319

“Autoimmune Encephalitis”? Eh?

Despite its rarity, this is an interesting topic to cover for a couple of reasons. First, in one of my health system administrative roles, I’ve noticed a large uptick in evaluation for this entity. And, then, second, it was picked up by the NEJM Emergency Medicine Journal Watch. So, paradoxically, the purpose here is both to heighten awareness of this disease process while at the same time throwing cold water on it.

The hullabaloo is all about autoimmune encephalitis – and the subset involved in this study concerns the typical onset after herpes simplex encephalitis. A non-trivial number of patients recover from an initial HSV encephalitis only to have recurrence of seizures and/or cognitive decline. Some of these cases can be attributed to reactivation of latent virus, while the others were of uncertain etiology. It now seems clear there is a significant autoimmune link, with increasing reports of antibodies against synaptic receptors detected in CSF.

In part of this very small, prospective study out of Spain, they identified 51 index cases of HSV encephalitis. None of these patients had neuronal antibiodies present at the index presentation.  However, within one year follow-up, a quarter developed new onset encephalitis with neuronal antibodies detectable in the CSF, primarily NMDA-receptor type. The typical presenting features of these patients differed between young children and adults, but most notably included seizures, behavior changes, and psychosis.

Recognition of this disorder is important because patients can have profound improvement with treatment and immunosuppression. That said, this is still an uncommon complication of a fairly rare disease – it took these authors 3 years to prospectively enroll their 51 patients, and even their retrospective case review across 6 years only managed to pick up 48 patients. These antibody responses are extremely rare, and recency bias should not dramatically change your practice. However, in the context of new-onset psychosis, an LP may be reasonable – and, if the remainder of the clinical evaluation supports it, antibody testing could dramatically alter treatment in a small cohort of patients.

“Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis”
https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30244-8/fulltext

So Many Strokes, Oddly

There a fairly steady stream of occasional articles describing the evolution of stroke care in the U.S. These are typically pieces praising improvements tied to “Get With The Guidlines-Stroke”, describing decreases in overall stroke mortality, and the like. “Never better!” would probably be how most neurologists describe the current state of stroke care.

These impressions might be a bit of a rose-colored view of the elephant. This is just a simple descriptive analysis in trends for stroke, TIA, and ICH care in U.S. emergency departments and hospitals from 2006 until 2014.  A couple things of curiosity and/or concern stand out:

  • Annual in-hospital mortality from stroke has declined from ~5.8% to ~4.4%. This looks good until it’s noted annual total stroke admissions increased from 353,000 to 415,000. So, in an absolute sense, mortality hasn’t changed much – we’ve probably just been adding additional cases that wouldn’t otherwise have been diagnosed as stroke.
  • Costs of hospitalization for all diagnoses have almost doubled. For stroke, hospitalization charges have risen from a mean of $27,000 to $48,000. I’d love to chalk up the cost increase solely to the accompany increased frequency of use of our favorite clot-buster, but the relative cost increases are similar for TIA, as well.

The overall gist I get from these data is the value, overall, of our care for acute neurologic emergencies is diminishing. I’m certain we’re doing a much better job of post-stroke care these days for those who would truly benefit, but clearly we’re also sinking a lot more money into an expanding population where the average benefit is probably lower.  It’s shaping up to be an interesting race to see which aspect of healthcare can bankrupt our economy first.

“National trends in stroke and TIA care in U.S. emergency departments and inpatient hospitalizations”

https://www.ajemjournal.com/article/S0735-6757(18)30648-X/fulltext

The Futility of Repeat Imaging in Seizure

In the adult patient with new-onset seizure, it can be reasonable to pursue emergency neuroimaging in many cases. However, the vast majority of presentations to the Emergency Department for seizure are for those with known seizure disorders. In this population, the calculus is different.

This is a retrospective review of 822 presentations for non-index seizures from two hospitals, examining the rate of neuroimaging and incidence of clinically important new findings. Of these, neuroimaging was obtained in about half. Of these 381, only 8 had true positive, clinically important findings on imaging. All of these cases had persistent altered level of consciousness, head trauma, or a focal finding on examination. Absent these factors, there were no cases of true positive imaging findings related to the acute presentation. If imaging were deferred in those cases absent any of those three factors, approximately half of scans could have been obviated.

This is a small sample at two academic institutions and a retrospective evaluation, so it is hardly definitive. However, the authors’ conclusion is reasonable there is certainly an opportunity to further reduce unnecessary imaging in non-index seizures.

“Emergency department neuroimaging for epileptic seizures”

https://www.ncbi.nlm.nih.gov/pubmed/30019464