This entertaining brief communication refers to Chvostek sign – the twitching of the facial muscles after tapping the facial nerve purportedly associated with hypocalcemia.
This neurologist notes, after one of his residents presented with bilateral Chvostek sign, he convenience sampled other residents and medical students on the wards – and 6 out of 11 exhibited Chvostek sign. He otherwise notes 25-43% of healthy individuals exhibit this sign and 29% of patients with hypocalcemia do not. He bluntly states Chvostek sign should simply be retired as a clinically relevant entity.
Stick with the Trousseau sign!
“Chvostek sign, frequently found in healthy subjects, is not a useful clinical sign”
http://www.neurology.org/content/80/11/1067.full
Category: Neurology
Mechanical Embolectomy Kills People
Interestingly, it especially killed people who were going to have a favorable outcome with standard care.
This is MR-RESCUE, a trial evaluating the efficacy of endovascular mechanical thrombectomy for acute ischemic stroke. Patients were eligible for this trial up to 8 hours from stroke onset, and most were enrolled because they were outside the window for tPA – or received tPA but failed to recanalize. One of the special features of this study was using emergent MRI to identify a patient subgroup that had a potentially viable “penumbra” of brain tissue surrounding the original infarct. The imaging hypothesis in this study was that patients would particularly benefit from mechanical intervention in the presence of a penumbra such as this.
However, they were wrong. Oddly, the authors reported their primary outcome differences in mean mRS. As discussed on the last blog post, mean and median mRS aren’t used in stroke trials because the profound disability/living death/death numbers at the bottom of the scale don’t represent the clinically relevant treatment effects. Regardless, they failed to show benefit of mechanical embolectomy.
Overall, patients simply did poorly. This is a fine example of the exquisite relationship between NIHSS and outcomes, as the median NIHSS in this trial was 17, less than 20% of the patients had good outcomes (mRS 0-2), and 21% died with in 90 days. Looking at Figure 2, it’s clear the penumbra was an excellent prognostic feature – until the mechanical embolectomy occurred. Then, mortality jumps from 9% to 16%, and the favorable mRS drops from 23% to 15%.
These authors used the MERCI and Penumbra systems. You might already be familiar with the MERCI retriever from earlier, negative trials with significant device complications. Someday we might see the last of it – but, I’m guessing, where there’s already money sunk into a device, there’s more patient harms to come.
“A Trial of Imaging Selection and Endovascular Treatment for Ischemic Stroke”
Statistics For tPA & Profit
IST-3 broke new ground for misleading statistics in stroke trials with its secondary ordinal analysis, demonstrating “benefit” in the presence of an overall negative, open-label, randomized trial of over 3,000 patients. Now, who here can decipher the Cochran-Mantel-Haenszel test? Team Genentech/Boehringer Ingelheim is hoping you can’t.
This is a retrospective, observational cohort from the Virtual International Stroke Trials Registry looking for a way around the pesky “contraindications” to tPA treatment that currently prevent large groups of patients from receiving treatment. These authors pulled non-treated “controls” from the cohort along with tPA-treated patients who had at least one contraindication or warning to tPA use and compared mRS outcomes at 90 days. The control group was significantly older and sicker – though their strokes were milder (NIHSS 12 [SD 9] vs. NIHSS 14 [SD 8]) – but the authors adjusted only for age and NIHSS. Their conclusion?
“Many of the warnings and contraindications of alteplase may not be justified and licences, guidelines, and protocols should be adjusted to accommodate recent data from registries and real-world experience.”
As the authors correctly note earlier in the paper, observational data combined from heterogenous trials spread over many years is likely rife with differences in care and selection bias. This alone renders their results invalid as anything but hypothesis-generating, rather than practice-changing.
The other issue is their primary outcome and statistical tool of choice:
“The primary outcome measure was the mRS at 90 days, analyzed across the whole distribution of scores with the use of the Cochran–Mantel–Haenszel test,”
Here’s an example of an unadjusted mRS distribution “favoring” alteplase:
Just at first glance, looks pretty much the same – perhaps even favors placebo (top bar). How the heck is this significantly positive towards tPA? Well, the CMH takes into all ordinal levels – even the perturbations between disability/living death/death at the bottom of the scale – as opposed to just the clinically relevant mRS 0-1 or mRS 0-2 that were primary outcomes in other stroke trials. So, the statistical significance in this test has nothing to do with the clinical efficacy of the treatment in question. Then, the adjusted OR of 1.29 (95% CI 1.00 – 1.66) is somehow based on a mélange of “dichotomized outcomes at 90 days (mRS 0–1, mRS 0–2, NIHSS 0–1, and mortality)”.
I’m afraid this simply looks like the authors dragged the VISTA data through every permutation of statistical tools possible until they found a test and a combined endpoint for logistic regression that came out in favor of tPA. And, then, sold it as practice-altering.
Disheartening.
Here’s the disclosures, for your reading pleasure:
BF has received modest honoraria for participation in clinical trials (Sanofi-Aventis). AVA has served as PI of CLOTBUST trial partially funded by Genentech, and currently serves as PI of CLOTBUSTER funded by Cerevast Therapeutics and consultant to Genentech. EB is an employee of Boehringer Ingelheim. JCG, CW, PL, and NKM have no relevant conflicts of interest. AM has served as a consultant for Boehringer Ingelheim, received speaker’s honoraria from Boehringer Ingelheim, and congress expenses from Lundbeck. NW has received expenses from Boehringer Ingelheim for his role as member of the steering committee in relation to the ECASS III trial with alteplase and served as a consultant to Thrombogenics as chairman of the DSMB. SITS International (chaired by NW) received a grant from Boehringer Ingelheim and from Ferrer for the SITS-MOST/SITS- ISTR. His institution has also received grant support toward administrative expenses for coordination of the ECASS III trial. NW has also received lecture fees from Boehringer Ingelheim and from Ferrer. AS and KRL have received research grants, modest honoraria for participation in clinical trials, and have a consultancy or advisory board relationship with manufacturers from drugs (including Boehringer Ingelheim). KRL administered the grant from Genentech for support of this study.
“Thrombolysis in Stroke Despite Contraindications or Warnings?”
stroke.ahajournals.org/…/STROKEAHA.112.674622.abstract
The Latest Prognostication for Stroke
We have a fairly robust vascular neurology program at my institution, and – unsurprisingly – they’re rather pro-thrombolysis. While our disagreements over the efficacy of thrombolysis for acute strokes are generally set aside in a truce stemming from academic and research interests, the main philosophical difference between our services remains this: the difference between eligible and indicated.
Vascular neurology tends to treat these terms as synonymous regarding thrombolysis and acute stroke, while it’s clear from the literature that not every patient benefits from thrombolysis. The most recent issue of Neurology features another prognostic tool, the SPAN-100, which is the simplest by far: NIHSS + age. If this score is >100, fewer patients will benefit from tPA than will be harmed. There’s a quality-of-life discussion to be had regarding individualized treatment decisions in SPAN-positive patients, and this is derived from a very small cohort, but it’s consistent with the remaining literature.
The accompanying editorial is also pro-thrombolysis, but does recognize these scoring systems are important clinical tools in educating patients and families regarding the potential for benefits and harms. Most importantly, this table from the editorial summarizes the growing body of literature available to assist the decision-making process:
Vascular neurology tends to treat these terms as synonymous regarding thrombolysis and acute stroke, while it’s clear from the literature that not every patient benefits from thrombolysis. The most recent issue of Neurology features another prognostic tool, the SPAN-100, which is the simplest by far: NIHSS + age. If this score is >100, fewer patients will benefit from tPA than will be harmed. There’s a quality-of-life discussion to be had regarding individualized treatment decisions in SPAN-positive patients, and this is derived from a very small cohort, but it’s consistent with the remaining literature.
The accompanying editorial is also pro-thrombolysis, but does recognize these scoring systems are important clinical tools in educating patients and families regarding the potential for benefits and harms. Most importantly, this table from the editorial summarizes the growing body of literature available to assist the decision-making process:
I look forward to seeing these develop such that clinicians have better tools with which to separate eligible from indicated.
“Stroke Prognostication using Age and NIH Stroke Scale: SPAN-100″
www.ncbi.nlm.nih.gov/pubmed/23175723
www.ncbi.nlm.nih.gov/pubmed/23175723
Evidence Summary for Bell’s Palsy
Although the incidence of stroke in young people is rising, some of these “strokes” can still be clinically diagnosed with Bell’s Palsy.
However, once the diagnosis is made, the practice variation is extensive. In light of this, the American Academy of Neurology has published an update to their evidence-based guidelines for the treatment of Bell’s Palsy.
Short answer:
– Steroids are good, with a 12 to 15% increased chance of functional recovery.
– Antivirals have no consistent evidence of benefit.
Long answer:
– Only ~4% of Bell’s Palsy sufferers are left with severe residual deficits, with the remainder fully recovering or with slight/mild deficits. Some folks would pose the question whether any of these treatments are necessary, considering the minimal absolute benefits, even if relative benefits are consistent.
Another risk/benefit decision to discuss with patients.
“Evidence-based guideline update: Steroids and antivirals for Bell palsy : Report of the Guideline Development Subcommittee of the American Academy of Neurology”
Predicting Immediate Improvement After tPA
tPA for stroke remains controversial, to say the least. The reasons behind the Emergency Medicine/Neurology disconnect are complex and covered elsewhere. Regardless, thrombolysis is here to stay – and probably helps some patients. The hard part is finding those patients with the most favorable risk/benefit ratio.
This is a study that looked at diffusion-weighted imaging to try and predict which patients were most likely to rapidly improve with tPA. These authors enrolled sixty-six patients with acute stroke eligible for tPA under the Japanese license and performed diffusion-weighted MRI on each of them. Previous studies had suggested an ASPECTS score > 7 predicted response to tPA – and this study confirmed it. Essentially, this translates as larger vascular territories showing greater improvement in NIHSS after tPA than smaller vascular territories.
There’s a bit of a bias in this study, since smaller vascular territories may have produced smaller initial NIHSS. The population was quite old for a stroke study – median age 79. And, truly, the more interesting data presented is the breakdown demonstrating the massively favorable impact of early (within 1 hour) recanalization after tPA administration.
But, mildly interesting paper, important as part of a slow, gradual trend of attempts to delineate which patients have the best potential to benefit from tPA.
“DWI-ASPECTS as a Predictor of Dramatic Recovery After Intravenous Recombinant Tissue Plasminogen Activator Administration in Patients With Middle Cerebral Artery Occlusion”
www.ncbi.nlm.nih.gov/pubmed/23212169
The Hazards of Love
“Sexual activity is mechanically dangerous, potentially infectious and stressful for the cardiovascular system.”
Indeed!
According to this retrospective review of 11 years of electronic health records from University Hospital Bern, Switzerland, they identified 445 patients seeking emergency care secondary to sexual intercourse. The majority of emergency department visits were secondary to suspected infectious etiologies (62%), but neurologic complaints, trauma, and cardiovascular incidents comprised the remaining portion.
The trauma portion probably speaks for itself without need for additional detail. There was one myocardial infarction and one aortic dissection. Among the “various complaints”, two patients were diagnosed with “eczema”. However, among the neurologic emergencies, there were 12 cases of subarachnoid hemorrhage and 11 cases of – ah – “transient global amnesia”.
All things being equal, at least, sexual activity was only associated with 0.1% of emergency department visits – hardly the most dangerous of potential choices of recreation.
“Sexual activity-related emergency department admissions: eleven years of experience at a Swiss university hospital”
http://www.ncbi.nlm.nih.gov/pubmed/23100321
What To Do With The “Dizzy” Patient?
As the authors in this retrospective review state, “Vertigo/dizziness is a common and challenging problem faced by the ER physician.” And, this is obviously true. Is it dysequilibrium? Is it true vertigo? Is it central or peripheral? And, finally, “now what”?
This is a clearly pro-MRI and con-CT study which, unfortunately, leads to a massive disconnect with reality. For most institutions, CT might be feasible, but MRI comes to town once a week for scheduled studies only. But, in this review of 448 head CTs for dizziness, the CT picked up essentially 10 interesting findings – but 16% of the subset of follow-up MRIs performed changed the initial diagnosis. Mostly, the missed diagnoses on CT were posterior circulation strokes and intracranial masses.
So, essentially what they observed was more false negatives than true positives for CT. This implies – at least in a retrospective fashion – that if your pretest probability is high enough for an intracranial process causing dizziness, the intention ought to be to conclude your investigations only with a negative MRI. I think most folks – given infinite resources – would agree. Otherwise, you’ll need to base imaging (if any) on clinical findings and risk factors for cerebrovascular disease in an attempt to develop an estimate for their true probability.
“Utility of head CT in the evaluation of vertigo/dizziness in the emergency department”
www.ncbi.nlm.nih.gov/pubmed/22940762
November Annals of EM Journal Club
Our EM Journal Club group down here at UT-Houston collaborated to write the Annals of Emergency Medicine monthly Journal Club installment, published in the November issue.
You get the questions now – at least, they’re available online starting today – but you’ll have to wait in suspense for months to hear our “answers”.
I don’t know if it was an editorial decision to put our thinly veiled IST-3 critique on page 666 of this year’s volume, but I can’t imagine it’s just a coincidence….
“rt-PA and Stroke: Does IST-3 Make It All Clear or Muddy the Waters?”
http://www.ncbi.nlm.nih.gov/pubmed/23089093
tPA of The Future
“The potential benefits associated with this approach are faster reperfusion, lower risk of hemorrhage, and earlier initiation of fibrinolytic therapy, possibly by first responders.”
Sounds lovely, yes? This is the pie-in-the-sky version of tPA, complete with flying cars and hoverbuses. It’s a “Clinical Implications of Basic Research” article from NEJM covering a Science article about shear-activated nanoparticles.
Essentially, in a mouse model of acute arterial thrombosis and pulmonary embolism, researchers bound tPA to aggregated nanoparticles. In normal vasculature, these aggregates remain unaffected. However, in regions of turbulence and shear associated with stenosis, the aggregates break apart, exposing the biochemically active tPA in greater quantities. The authors, taking cue from the current political season, promise potential 100-fold reductions in dosing of tPA associated with this serendipitously targeted approach rather than standard systemic therapy.
So, someday, instead of taking an aspirin and calling 911 – home thrombolytics?
“The Shear Stress of Busting Blood Clots”
www.ncbi.nlm.nih.gov/pubmed/23034026