When I was a resident, we normally started someone on aspirin if they weren't on it when they had a stroke. If they were, we might consider switching to a different drug, such as clopidogrel. We almost never used the two together, as the thought was that this would increase the risk of bleeding without reducing the chance of someone getting stroke in the future.
Then came the recent CHANCE Trial. This large trial involved 5170 people with transient ischemic attacks (TIA) or small strokes, who were given either aspirin or both aspirin and clopidogrel. The outcome was better in the group treated with both drugs together.
Interestingly, despite being a well-designed trial, results have not been replicated outside of China. For example, a recently published trial in Neurology found no such benefit to combined therapy with aspirin and clopidogrel after small strokes.
Perhaps there is something unique about the population that was studied--can the results be generalized to people elsewhere? A subsequent trial, the POINT trial, is currently underway to clarify that question.
Wang Y, Johnston SC, Wang Y. Clopidogrel with aspirin in minor stroke or transient ischemic attack. N Engl J Med. 2013 Oct 3;369(14):1376-7. doi: 10.1056/NEJMc1309713.
I've already touched on one negative trial in stroke--on to another. While using catheters to do endovascular thrombus retrieval or lysis in acute stroke can effectively open up the vessel, several trials have not shown any benefit overall to patient outcome. This holds true even if neuroimaging techniques are being used to try to triage people to endovascular treatment. The severity of the stroke doesn't seem to matter. Whether someone uses a MERCI device, Penumbra device, Solitaire, or intraarterial tissue plasminogen activator (tPA), there seems to be no benefit over the current standard of giving IV tPA alone.
So when will be abandon all hope for catheter-based stroke treatment? Not yet. Some of these treatments are very time dependent--for example, 90 minutes is the cutoff to do a catheterization for the heart after a heart attack. Maybe we're just getting people to the catheter too late to be useful? Endovascular therapy vs. best medical therapy in people triaged by image selection is still also an open question, being evaluated in the SWIFT PRIME and DAWN trials.
In the meantime, though, there doesn't seem to be much use to catheterization that we've found in acute stroke. While the question is certainly still worth exploring, it would be probably be ill-advised, for example, to transfer from one hospital to another just so someone could get a catheter treatment for an acute stroke.
"Time is brain." Such is the stroke neurologist's mantra, reflecting the loss of millions of neurons every minute part of the brain goes without blood trapped behind a clot. The strongest medication to help people with stroke, tissue plasminogen activator (tPA), can only be given within a few hours of the first symptoms, and the sooner the better. The FDA still only approves use of the medication within 3 hours, though research suggests that there may be benefits in some people out to 4.5 hours.
One of the contributors to the time delay between symptoms and tPA is the need to obtain a CT scan first to ensure that the patient's symptoms are not in fact due to a bleed. The same clot busting drug that can be so useful in ischemic stroke would be disasterous in the setting of an intracerebral hemorrhage. But a CT takes precious time, as does waiting for a neurological evaluation.
The city of Berlin is pioneering a novel approach to this dilemma. STEMO involves an ambulance equipped with a neurologist, a CT scanner, and a technician. A hemorrhage can thereby ruled out and an appropriate examination done before the patient ever reaches the hospital. People are much more likely to be sooner with this technique--in fact, the time from the first phone call to being given tPA is only 58 minutes. That's better than many hospitals have once the patient enters their doors.
The results are impressive. 25% more patients are discharged home with this treatment than without the in-ambulance evaluation. I wonder what it would take to establish something like this in the States?
Hot on the heels of my post about "negative" trials not getting enough press, here's something about a very well designed, impressive trial. The goal of the FAST-MAG trial was to see if magnesium could improve neurological outcomes following stroke if given relatively quickly after the person first noticed symptoms.
Dr. Jeffrey Saver in Los Angeles arranged a double-blind, placebo controlled trial of IV magnesium given even before the patient reached the hospital. This took 8 years, and involved over 1700 participants, as well as over 95 study coordinators and research associates. This was a huge and laudable effort.
At three months, magnesium has no beneficial effect on recovery from stroke. We won't give magnesium--that's one thing that has been learned. But this study also had a very high number of patients treated within two hours of stroke--using similar methods with agents known to work, such as tPA, could have major implications for stroke victims.
JL Saver, S Starkman, M Eckstein, S Stratton, F Pratt et al. Methodology of the Field Administration of Stroke Therapy - Magnesium (FAST-MAG) phase 3 trial: Part 1 - rationale and general methods. International Journal of Stroke. Volume 9, Issue 2, pages 215-219, February 2014
Science is something like the game 20 questions--to approach a big question, we ask a series of smaller questions that are often only answered in "yes" or "no." Based off this, we hone in on the truth.
There has been a traditional bias in the scientific community to predominantly publish research in which the answer was "yes." Of course in the big picture, "no" is just as important in getting to the big answers--but because it's not deemed as exciting, "no" doesn't get published.
The publication bias against so-called "negative" studies also contributes to lack of overall efficiency in scientific progress. How many times have people repeated the same thing that won't work, because no one published that it doesn't work? We'll never know--it wasn't published. That's something like playing 20 questions in a team in which "no" answers can only be given to one team member at a time, and they aren't allowed to tell anyone else about it.
The trend is changing in science, though certainly not in the general media, where "positive" results are published quickly and even exaggerated. I'll keep trying to publish "negative" trial results when I think they are interesting--certainly these can sometimes have major effects on how patients with neurological issues are treated by physicians.
Most people come to the doctor wanting a clear answer. Unfortunately, the truth is that few things in life are certain, and medicine, perhaps especially neurology, is actually full of controversies.
For example, consider vascular diseases like stroke. The idea seems simple-- a clot in an artery blocks blood flow to the brain. Get rid of the clot, prevent more from forming... how hard could it be?
The truth is, well, quite hard. For example, you'd think that simply removing the clot would help people get better, but many studies exploring endovascular clot retrieval show no benefit. You'd think that better blood pressure control could lead to better outcomes, but there's a lot of disagreement about what constitutes optimal blood control in both hemorrhagic and ischemic stroke.
Arguments expand beyond simple stroke. For example, what do you do with an unruptured arteriovenous malformation? The counter-intuitive answer may be "not much."
Expect more controversies to come, I'm afraid...
Lennox-Gastaut syndrome (LGS) involves seizures, developmental delay, and a typical electroencephalogram (EEG) pattern. It can be very difficult to treat, though this may in fact be due to our trying to treat several different diseases, all causing the same syndrome. Why should one medication treat such a variety?
For this reason, it may be worth testing genetics in patients with LGS. Even if there is no family history, epileptic encephalopathies sometimes result from a new mutation. Of 264 patients in one study, about 11 to 12% of patients had an explanation offered by genetics.
Genetic testing is not for everyone, but for some it may allow consideration of different medications. For example, if a mutation is similar to that found in Dravet syndrome, you would avoid the drugs lamictal or carbamazepine, and consider valproate, keppra, clonazepam or stiripentol. Furthermore, for some genetic counseling may offer a degree of closure as an explanation is offered.
However, genetic testing can also raise concerns about the risk of other family members having epilepsy. Genetic counseling is recommended even before results are obtained to ensure that the significance of any results is understood.
Daniel Lowenstein: Epilepsy an Update, Recent Advances in Neurology Conference, San Francisco Ritz-Carlton, February 13, 2014
The word dysplasia means an abnormal cellular development. Immature cells may replace more mature cells, for example.
Dysplasia is sometimes, but not always, the first sign of a cancerous process. This is one reason why gynecologists search for cervical dysplasia during routine examinations. Cervical dysplasia may progress to cancer, and it is best to catch it early. Now that cervical dysplasia has been associated with human papilloma virus (HPV) infection and now that we have a vaccine for that virus, hopefully we will see a decrease in cervical cancer.
The cortex of the brain can also have dysplasia. Dysplastic areas of the cortex can serve as a seizure focus, thereby leading to epilepsy. In 2013, researchers realized that dysplastic areas of cortex resembled cervical dysplasia. A shared protein abnormality was noted between the two types of dysplasias, both of which are coded for by HPV. This suggests that HPV not only causes cervical dysplasia, but may contribute to some types of cortical dysplasia and thereby seizures as well. The timing of exposure and potential for treatment is unknown, but it will be interesting to see if cortical dysplasia is reduced as HPV vaccines become more common.
Chen J, Tsai V, Parker WE, Aronica E, Baybis M, Crino PB. Detection of human papillomavirus in human focal cortical dysplasia type IIB. Ann Neurol. 2012;72:881-892.
Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010. J Infect Dis. 2013 Jun 19. [Epub ahead of print]
Sudden Unexplained Death in Epilepsy (SUDEP) may be one step closer to being explained.
SUDEP risk is higher in Dravet syndrome, a seizure disorder that impacts children and causes developmental delays and severe seizures.
In a recent study, stem cells were derived from patients with Dravet syndrome and transformed into nerve cells. Perhaps unsurprisingly, though still impressively, the derived nerve cells had abnormal electrical activity, simulating seizures in a dish.
The next step, though, was even more intriguing. The stem cells were transformed into heart cells, which again had abnormal electrical activity--an arrhythmia.
Dravet syndrome is known to cause problems with a particular ion channel, most commonly a sodium channel (NaV1.1) encoded by SCN1A. This ion channel mutation may also result in arrhythmias of the heart, predisposing children with Dravet to SUDEP.
Time will tell how or if this understanding will translate into better safety for children with SUDEP. One can imagine a cardiac monitoring system at night, for example, or some more creative approach. For those with Dravet syndrome and their families, relief cannot come soon enough.
Liu, Y., Lopez-Santiago, L. F., Yuan, Y., Jones, J. M., Zhang, H., O'Malley, H. A., Patino, G. A., O'Brien, J. E., Rusconi, R., Gupta, A., Thompson, R. C., Natowicz, M. R., Meisler, M. H., Isom, L. L. and Parent, J. M. (2013), Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism. Ann Neurol., 74: 128-139.
It used to be thought that most seizures spread predominantly along the cortex, the surface of the brain. While involvement of deep structures like the thalamus were known to become involved in major seizures, it's becoming apparent that the connection between the thalamus and cortex is involved in less serious seizures as well.
Scientists have found that focal seizures stemming from lesions in rats can be reduced using a technique called optogenetics. A special molecule was implanted in the thalamus, which would inhibit activity when stimulated by light. A fiberoptic device was then implanted to trigger the molecule. The result was that seizure was less common when the light was turned on.
While not used in humans at this time, this could represent a new technique to reduce seizures in the future.
D Lowenstein: Epilepsy an Update, Recent Advances in Neurology Conference, San Francisco Ritz-Carlton, February 13, 2014
JT Paz, TJ Davidson, ES Frechette, B Delord, I Parada et al. Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury.Nat Neurosci. 2013 Jan;16(1):64-70.