Masitinib, a breakthrough drug shattering neurology boundaries

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.

By Zeldj - Own work, CC BY-SA 4.0, Link
By ZeldjOwn work, CC BY-SA 4.0, Link

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.

By Capilano1 - Own work, CC BY-SA 4.0, Link
By Capilano1Own work, CC BY-SA 4.0, Link

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.

Alzheimer's Disease. Hamza Butt on Flikr. https://www.flickr.com/photos/141735806@N08/28007367952
Alzheimer’s Disease. Hamza Butt on Flikr. https://www.flickr.com/photos/141735806@N08/28007367952

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.

Benjah-bmm27 assumed. Own work assumed (based on copyright claims). Public Domain, Link
Benjah-bmm27 assumed. Own work assumed (based on copyright claims). Public Domain, Link

 

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.

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Alzheimers disease and its promising links with diabetes

In the excellent book, The Innovators Prescription, the authors predict that precision medicine will 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.

Precision Medicine Conference at Harvard. Isaac Kohane on Flikr. https://www.flickr.com/photos/52786697@N00/16892093678
Precision Medicine Conference at Harvard. Isaac Kohane on Flikr. https://www.flickr.com/photos/52786697@N00/16892093678

A clear indication that precision medicine will blur the boundaries between diseases is the recent suggestion that the anti-diabetes drug Liraglutide may help to treat Alzheimer’s disease (AD). Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist which is effective in type 2 diabetes, a condition which is worlds apart from Alzheimer’s disease. So far removed from each other, it would be easy to dismiss any links as tenuous. But the headlines were emphatic: Drug used to treat diabetes could cure Alzheimer’s, and Diabetes drug could influence brain activity in Alzheimer’s. 

diabetes-1326964_1280

It is however no hype: there is evidence that Liraglutide may benefit people with Alzheimer’s disease. Trials in animal have shown that Liraglutide promotes neuronal survival, learning and memory, and reduces neuroinflammation and amyloid plaque formation. One such study is titled Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Beyond animals, small human trials have shown that Liraglutide improves brain glucose metabolism in Alzheimer’s disease.

beta-amyloid-plaques. vestque on Flikr. https://www.flickr.com/photos/35049835@N00/16867428955
beta-amyloid-plaques. vestque on Flikr. https://www.flickr.com/photos/35049835@N00/16867428955

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.

Sugar Cubes. David Pace on Flikr. https://www.flickr.com/photos/63723146@N08/7164573186
Sugar Cubes. David Pace on Flikr. https://www.flickr.com/photos/63723146@N08/7164573186

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!

Brain Aging. Kalvicio de las Nieves on Flikr. https://www.flickr.com/photos/118316968@N08/19444505382
Brain Aging. Kalvicio de las Nieves on Flikr. https://www.flickr.com/photos/118316968@N08/19444505382

Going back to the subject of precision medicine, why not visit my other blog, The Doctors Bookshelf where I will soon be reviewing The Innovators Prescription

Why does dystonia fascinate and challenge neurology?

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.

Public Domain, Link
Public Domain, Link

No wonder dystonia defies simple definitions. Take the National Institute of Neurological Disorders and Stroke (NINDS) definition which labels dystonia as “a disorder characterized by involuntary muscle contractions that cause slow repetitive movements or abnormal postures“. Then compare it with the NHS Choices definition which sees dystonia as “a medical term for a range of movement disorders that cause muscle spasms and contractions“. We must accept the flexibility of dystonia as both a disorder, and a range of disorders. The defining feature of dystonia however is simple enough-abnormal muscle postures and contractions.

By Katomin at the English language Wikipedia, CC BY-SA 3.0, Link
By Katomin at the English language Wikipedia, CC BY-SA 3.0, Link

The complexity in the definition is just a tip of the iceberg of the things that neurologists find fascinating about dystonia. Here are 5 big reasons why dystonia excites and challenges neurologists.

1. Dystonia is a very visible disorder

Rogers Hartmann at TEDxSMU from tedxsmu on Vimeo.

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

Von James Heilman, MD - Eigenes Werk, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9445214
Von James Heilman, MDEigenes Werk, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9445214

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.

3. Dystonia manifests in a multitude of ways

By Henry Vandyke Carter - Henry Gray (1918) Anatomy of the Human Body (See "Book" section below)Bartleby.com: Gray's Anatomy, Plate 1194, Public Domain, Link
By Henry Vandyke CarterHenry Gray (1918) Anatomy of the Human Body (See “Book” section below)Bartleby.com: Gray’s Anatomy, Plate 1194, Public Domain, Link

Dystonia may be localised such as with blepharospasm (excessive eyelid twitching), hemifacial spasm, Meige’s syndrome, and cervical dystonia (torticollis). At the same time, dystonia may be generalised as in Wilson’s disease, neuroferritinopathy, and neuroacanthocytosis. Dystonic symptoms often manifest spontaneously, but they may only be task-specific such as in writers cramp and musician’s dystonia. A further way dystonia crops up is as an ally of other movement disorders, as we see with dystonic tremor.

4. Dystonia is a rapidly evolving field

Bootstrap DNA by Charles Jencks, 2003. Mira66 on Flikr. https://www.flickr.com/photos/21804434@N02/3707633630
Bootstrap DNA by Charles Jencks, 2003. Mira66 on Flikr. https://www.flickr.com/photos/21804434@N02/3707633630

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 also get excited when they come across known, but rare, presentations of dystonic syndromes such as this recent report on feeding dystonia in chorea-acanthocytosis. 

5. Treatments of dystonia are proliferating

Drugs. Daniel Foster on Flikr. https://www.flickr.com/photos/danielfoster/15097483625
Drugs. Daniel Foster on Flikr. https://www.flickr.com/photos/danielfoster/15097483625

Just as the types of dystonia are burgeoning, so are the treatments. Some interventions are novel, and some have a feel of ‘back to the future’. A few recent examples are treatment of isolated dystonia with zolpidem and selective peripheral denervation for cervical dystonia. Enough to keep the dystonia researchers busy, and to keep their patients feeling valued. Old school treatment such as botulinum toxin however maintain their pride of place. 

Human Genome. Richard Ricciardi on Flikr. https://www.flickr.com/photos/ricricciardi/11622986115
Human Genome. Richard Ricciardi on Flikr. https://www.flickr.com/photos/ricricciardi/11622986115

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For more on dystonia syndromes and treatment, check out:

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Dystonia is a hydra; why not get a concise handle by exploring the dystonia topics in neurochecklists  

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Depression and the shrinking seahorses in the brain

Seahorses are beautiful creatures. The biologists convince us that seahorses are fish, even if they don’t look anything like fish. They also tell us, intriguingly, that seahorses are monogamous and the males do the childbearing.

By © Hans Hillewaert, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=22106851
By © Hans Hillewaert, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=22106851

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

By Gervais et Boulart - Les poissons Gervais, H., Public Domain, https://commons.wikimedia.org/w/index.php?curid=19157222
By Gervais et Boulart – Les poissons Gervais, H., Public Domain, https://commons.wikimedia.org/w/index.php?curid=19157222

Deep in the brain is a structure also called the hippocampus, one on each side. The hippocampus plays a central role in memory, and it is considered by some to be the brain’s emotional centre.

By Images are generated by Life Science Databases(LSDB). - from Anatomography, website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, https://commons.wikimedia.org/w/index.php?curid=7887124
By Images are generated by Life Science Databases(LSDB). – from Anatomography, website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, https://commons.wikimedia.org/w/index.php?curid=7887124

It is no mystery why neuroanatomists name this important part of the brain after the seahorse, the resemblance is eerily striking.

By Hippocampus_and_seahorse.JPG: Professor Laszlo Seressderivative work: Anthonyhcole (talk) - Hippocampus_and_seahorse.JPG, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9451294
By Hippocampus_and_seahorse.JPG: Professor Laszlo Seressderivative work: Anthonyhcole (talk) – Hippocampus_and_seahorse.JPG, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9451294

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 therefore endlessly 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.

By Amber Rieder, Jenna Traynor - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=16393748
By Amber Rieder, Jenna Traynor – Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=16393748

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. 

depression-242024_1280

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 titled Depression, 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.

Depression. Shattered.art66 on Flikr. https://www.flickr.com/photos/shattered_art/3369289879
Depression. Shattered.art66 on Flikr. https://www.flickr.com/photos/shattered_art/3369289879

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.

5 stages of grief (Depression) #4. COCOMARIPOSA on Flikr. https://www.flickr.com/photos/8463160@N08/1790592784
5 stages of grief (Depression) #4. COCOMARIPOSA on Flikr. https://www.flickr.com/photos/8463160@N08/1790592784

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.

 

20 things we now know for certain about the Zika virus

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.

rio-1512643_1920

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.

1. Zika is an arbovirus of the family Flaviviridae

By Manuel Almagro Rivas - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=47941048
By Manuel Almagro RivasOwn work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=47941048

2. Zika was first identified in Uganda in 1947

 

By User TShilo12 on en.wikipedia, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1155428
By User TShilo12 on en.wikipedia, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1155428

3. Zika was first isolated from a Rhesus macaque monkey

Rhesus Macaque. Robert Martinez on Flikr. https://www.flickr.com/photos/madrerik/16328787935
Rhesus Macaque. Robert Martinez on Flikr. https://www.flickr.com/photos/madrerik/16328787935

4. The first human cases were reported from Nigeria

Nigeria flag. Global Panorama on Flikr. https://www.flickr.com/photos/121483302@N02/13777960823
Nigeria flag. Global Panorama on Flikr. https://www.flickr.com/photos/121483302@N02/13777960823

5. Outbreaks of Zika have ocurred in BrazilMicronesia, and French Polynesia

French Polynesia Grunge Flag. Nicholas Raymond on Flikr. https://www.flickr.com/photos/80497449@N04/7384286938
French Polynesia Grunge Flag. Nicholas Raymond on Flikr. https://www.flickr.com/photos/80497449@N04/7384286938

 

6. Zika is mainly transmitted by Aedes mosquitoes

By Rafaelgilo - Praca własna, Domena publiczna, https://commons.wikimedia.org/w/index.php?curid=40189440
By RafaelgiloPraca własna, Domena publiczna, https://commons.wikimedia.org/w/index.php?curid=40189440

7. Zika virus is transmitted perinatally

By Øyvind Holmstad - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34796811
By Øyvind HolmstadOwn work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34796811

The Centre for Disease Control (CDC) recommendations for pregnant women are

  • To avoid travel to affected countries
  • To be tested if they travel to affected countries
  • To have 3–4 weekly foetal ultrasound if they test positive for the virus
  • To have their babies tested at birth if they were infected

8. Zika virus is also sexually transmitted 

gender-23777

9. Zika virus is most likely transmissible through the skin

223 [Pocari Sweat]. Evan Blaser on Flikr. https://www.flickr.com/photos/evanblaser/6032270876
223 [Pocari Sweat]. Evan Blaser on Flikr. https://www.flickr.com/photos/evanblaser/6032270876
  • fatal case report of Zika infection from the New England Journal of Medicine strongly suggests Zika may be transmitted through sweat or tears

10. Zika virus primarily infects neural stem cells

Adult neural stem cells. California Institute for Regenerative Medicine on Flikr. https://www.flickr.com/photos/cirm/3289062760
Adult neural stem cells. California Institute for Regenerative Medicine on Flikr. https://www.flickr.com/photos/cirm/3289062760

11. Zika infection usually only causes mild and self-limiting symptoms

By Beth.herlin - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=46867814
By Beth.herlinOwn work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=46867814

The typical symptoms of Zika virus infection are

  • Fever
  • Skin rash
  • Conjunctivitis
  • Joint pains
  • Muscle aches
  • Headache

12. Microcephaly is the striking feature of congenital Zika

By Centers for Disease Control and Prevention - http://www.cdc.gov/ncbddd/birthdefects/images/microcephaly-comparison-500px.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=46674502
By Centers for Disease Control and Prevention – http://www.cdc.gov/ncbddd/birthdefects/images/microcephaly-comparison-500px.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=46674502

 

13. Zika infection causes several other brain abnormalities

By Ralphelg - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16057859
By RalphelgOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16057859

Brain abnormalities with congenital Zika infection include:

  • Calcification of the brain’s white matter
  • Cerebellar dysgenesis: abnormal development of the cerebellum
  • Craniosynostosis: premature closure of the bones of the brain
  • Lissencephaly: an abnormal shape of the brain 
  • Ventriculomegaly: enlargement of the brain’s fluid-containing spaces

These abnormalities may be seen on brain imaging

14. Adult Zika infection causes Guillain Barre syndrome (GBS)

 

By Doctor Jana - http://docjana.com/#/gbs; http://www.patreon.com/posts/guillain-barre-4374004, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=46847816
By Doctor Jana – http://docjana.com/#/gbs; http://www.patreon.com/posts/guillain-barre-4374004, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=46847816

15. Zika virus infection causes other neurological diseases

Knitted Neurology. estonia76 on Flikr. https://www.flickr.com/photos/estonia76/6453525355
Knitted Neurology. estonia76 on Flikr. https://www.flickr.com/photos/estonia76/6453525355

There are other neurological diseases associated with Zika virus such as

 

16. Zika virus infection causes many eye abnormalities

By JDrewes - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3117810
By JDrewesOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3117810

Eye abnormalities reported with Zika virus infection include

  • Mottling and atrophy of the retina
  • Abnormalities of the optic nerve
  • Coloboma (defects) of the iris
  • Subluxation (dislocation) of the lens

 

17. Zika virus may cause impairments in other organ systems

By Mikael Häggström - Image:Respiratory system complete numbered.svg (Public domain licence), Public Domain, https://commons.wikimedia.org/w/index.php?curid=5806243
By Mikael HäggströmImage:Respiratory system complete numbered.svg (Public domain licence), Public Domain, https://commons.wikimedia.org/w/index.php?curid=5806243

Other organs affected by Zika virus lead to disorders such as

  • Pulmonary hypoplasia, or underdeveloped lungs
  • Severe thrombocytopaenia, or low platelet counts
  • Urinary and genital symptoms

18. Zika virus infection is confirmed by laboratory tests

CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=340018
CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=340018
  • rRT-PCR (real time reverse transcriptase polymerase chain reaction) is the best test for the Zika virus
  • This is done on urine and blood samples collected within 2 weeks of infection

19. There is an experimental human vaccine trial for the Zika virus

 

 

 

20. There are promising antiviral treatments for Zika virus

syringe-417786_1920

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Want to explore more? You may check out the following: