In the process of writing a blog post on the research findings altering neurological practice, my sight fell on the drug, Masitinib. I was completely unaware of this tyrosine kinase inhibitor, one of the promising drugs in the fight against multiple sclerosis (MS). We are likely to hear a lot more about Masitinib in MS in the coming months.
Masitinib is however not flexing its muscles just in neuro-inflammation. On the contrary, it is seeking laurels far afield, in the realm of neuro-degeneration. I was indeed pleasantly surprised to find that researchers are studying the impact of Masitinib on two other horrible scourges of neurology. The first report I came across is the favourable outcome of a phase 3 trial of Masitinib in motor neurone disease (MND) or amyotrophic lateral sclerosis (ALS). The drug reportedly ‘reached its primary objectives‘ of efficacy and safety. In this trial, Masitinib was used as an add-on to Riluzole, the established MND drug. It’s all jolly collaborative at this stage, but who knows what threat Masitinib will pose to Riluzole in future! You may read a bit more on Masitinib and MND in this piece from Journal of Neuroinflammation.
The second report I came across is the potential of Masitinib in the treatment of Alzheimer’s disease (AD). This is at the phase 2 trial stage, and already showing very good outcomes in people with mild to moderate AD. Masitinib was used as an add-on drug to the conventional AD medications Memantine, Donepezil, Galantamine and Rivastigmine. These drugs can therefore rest comfortably on their thrones…at least for now! You can read a bit more on Masitinib and AD in this article from Expert Review of Neurotherapeutics.
The question however remains, why should one drug work well on such disparate diseases? I know, this feels like deja vu coming shortly after my last blog post titled Alzheimers disease and its promising links with diabetes. In that post I looked at the promise of the diabetes drug, Liraglutide, in the treatment of Alzheimers disease. I have however also reviewed this type of cross-boundary activity of drugs in my older posts, Will riluzole really be good for cerebellar ataxia? and old drugs, new roles?Perhaps Masitinib is another pointer that, as we precisely define the cause of diseases, they will turn out to be merely different manifestations of the same pathology. Food for thought.
As I said, this wasn’t the post I set out to write. So watch out for my next blog post, the major research outcomes altering neurological practice.
In the excellent book, The Innovators Prescription, the authors predict that precisionmedicinewill replace intuitive medicine, and diseases will be defined by their underlying metabolic mechanisms, and not by the organs they affect, or the symptoms they produce. Clayton Christensen and colleagues argue that this precise definition of diseases will lead to more effective treatments. But they also show that precision medicine will show that many different diseases actually share the same underlying metabolic derangements. Many disparate diseases will therefore turn out to be just mere manifestations of the same metabolic disease.
Why should Liraglutide work so well in both diabetes and Alzheimer’s, diseases with apparently different pathologies? The answer lies in insulin resistance, the underlying mechanism of type 2 of diabetes; there is now evidence that insulin resistance contributes to dementia. If this is the case, Liraglutide, by improving glucose metabolism, could potentially treat both diabetes and Alzheimer’s disease.
To explore this potential further, there is now a large multicentre trial exploring the real benefit of Liraglutide in Alzheimer’s disease. Titled Evaluating Liraglutide in Alzheimer’s Disease or ELAD, it is recruiting people with mild disease, aged between 50-85 years old, and who do not have diabetes. As they say, watch this space!
Dystonia is probably the most nebulous of neurological terms. Neurologists use the term for a vast array of neurological diseases. Dystonia also crops up as part of many complex neurological syndromes. Worse still, neurologists also use the name dystonia as a symptom. All quite confusing and perplexing for the lay observer.
The abnormal postures that typify dystonia are observable, and the neurologist can describe and define the disorder (or disorders!). This is not the case with many neurological disorders such as migraine, which rely entirely on a history, or epilepsy, which rely heavily on eyewitness accounts. The abnormal postures in dystonia are often very dramatic, and sometimes literally defy description. To help ‘decode’ complex dystonia, neurologists often make video recordings of their patients and send to dystonia experts. And dystonia experts present their own video recordings at neurology conferences, to teach the less initiated of course, but also to flaunt their well-earned expertise.
2. Dystonia is both hereditary and acquired
Many types of dystonia are hereditary. Myoclonus-dystonia and dopa-responsive dystonia (DRD) for example are caused by well-defined genetic mutations. Dystonia is however also frequently acquired, for example as an adverse effect of antidepressant, antipsychotic, and anti-epileptic drugs. Neurologists go to great lengths to sort out what type of dystonia their patients have, bristling with anticipation that the next genetic blood test they send off will clinch the diagnosis. It doesn’t seem to matter that this is often hope trumping experience.
Unlike some neurological specialities that are stuck with age-old diseases, dystonia experts regularly describe new dystonia syndromes and genetic mutations, filling up an already crowded taxonomy. An example is the ever-expanding genetic mutations that cause primary dystonia, starting from DYT 1 to DYT 21, and still counting. The field of non-genetic dystonia is also expanding with new disorders such as Watchmaker’s dystonia. Well-established dystonia syndromes also surprise neurologists by manifesting in completely unexpected ways. Recent examples of these new phenotypes are foot drop dystonia resulting from parkin (PARK2) mutation. Neurologists alsoget excited when they come across known, but rare, presentations of dystonic syndromes such as this recent report on feeding dystonia in chorea-acanthocytosis.
But why is a neurologist talking about seahorses. It’s all in the name. The Latin name for seahorse is hippocampus , derived from hippos for horse, and kampos for sea monster. Where biologists saw fish, the ancients saw monsters. And you really can’t blame them…take a closer look
It is no mystery why neuroanatomists name this important part of the brain after the seahorse, the resemblance is eerily striking.
Neurologists are passionate about the hippocampus for various reasons. In people with memory complaints, for example, hippocampal atrophy may predict the development of Alzheimer’s disease . A shrunken hippocampus is also seen in some forms of epilepsy. Neurologists thereforeendlessly harangue their neuroradiology colleagues to look closely at their patients’ brain MRI scans, and to tell them that the hippocampus is shrunken…even if it’s just a little bit smaller. Unfortunately for the neuroradiologists, the MRI scans do not come colour-coded as in the illustrative scan below.
This blog post is however about major depression, and not about epilepsy or dementia. Depression, that bad feeling we all feel every now and then is frustrating, but major depression is devastating. And we now know that it is accompanied by major alterations in the structure of the brain. And, yes, the changes are in the hippocampus. I got interested in this subject when I came across a piece in Neurology News reporting that people with depression have a smaller hippocampus.
The association of depression with hippocampal atrophy is however an old one. Proceedings of the National Academy of Science (PNAS) reviewed the relationship in an editorial from 2011 titledDepression, antidepressants, and the shrinking hippocampus. The author addressed the unresolved puzzle…which of the two came first. Reminiscent of the chicken and egg scenario, it is not clear if the hippocampal atrophy causes depression, or vice versa. To add to the puzzle, the paper conjectured the possibility of a third, unknown agent, causing both the depression and the small hippocampus.
This question was the focus of a meta-analysis published in Molecular Psychiatry this year. It reviewed the brain imaging data of 15 studies, involving about 1700 people with major depression. Titled Subcortical brain alterations in major depressive disorder, the authors confirmed the link between depression and hippocampal atrophy, and also showed that the shrinkage is worse in those who developed depression at an early age, and in those who have had frequent episodes of depression.
Does depression lead to hippocampal atrophy? The meta-analyses hinted so, but there were too many caveats for the authors to arrive at a definitive conclusion. They admit that more needs to be done to unravel depression….leaving the mystery of the shrinking seahorses to continue to another day.
Zika virus exploded into the news with striking images of children born with small heads in Brazil. This was at a time the country was struggling to plan for the Rio Olympics, and also embroiled in political turmoil. These all helped to embed the virus firmly in the public’s mind.
Events have unfolded very rapidly, with shifting certainties and swirling speculations. The storm is however now settling, and a clearer picture emerging. And neurology is right at the centre of this viral catastrophe. What is the current state of play? Here are 20 things we now know about the Zika virus.