Will Riluzole really be good for cerebellar ataxia?

This is just a quick post on a recent paper in Lancet Neurology which looked at the potential benefit of Riluzole in the treatment of cerebellar ataxia.

By Kamil9243 (Own work) [GFDL or CC BY 3.0], via Wikimedia Commons
By Kamil9243 (Own work) [GFDL or CC BY 3.0], via Wikimedia Commons
Neurologist know Riluzole very well. It is the only drug that has even the slightest hint of slowing down the dreadful motor neurone disease (MND). It is however fraught with side effects and demands a strict regime of regular blood tests to monitor for liver toxicity; this puts many people off it. Many neurologists are also sceptical of its reported benefits (in whispering tones of course).

By Images are generated by Life Science Databases(LSDB). - from Anatomography[1] 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=7768824
By Images are generated by Life Science Databases(LSDB). – from Anatomography[1] 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=7768824

It is therefore with some surprise for me to see a trial of Riluzole in another disease at all. Why Riluzole I wondered? The paper is titled Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. And it answers my question in the introduction- Riluzole just happened to be one of a bunch of drugs the authors had previously tried at random, and somehow the one that showed any hint of a benefit. Sounds strangely familiar, or is it just déjà vu?

Cerebellum: the brain's locomotion control center. ZEISS Microscopy on Flikr. https://www.flickr.com/photos/zeissmicro/14441559904
Cerebellum: the brain’s locomotion control center. ZEISS Microscopy on Flikr. https://www.flickr.com/photos/zeissmicro/14441559904

 

The authors studied subjects with the genetic conditions spinocerebellar ataxia (SCA) and Friedreich’s ataxia (FA). They used the SARA scoring system to monitor for improvement in the study subjects. And their faith was rewarded; 50% of the subjects on Riluzole improved compared to only 11% of the subjects on placebo. The authors suggest further trials to confirm the benefit. The academically minded will pick apart the methodology and statistical significance; the neurologist on the coal face will hold on to any hope.

 

13 unexpected and unusual reports about Parkinson’s disease

Parkinson’s disease (PD) looms large in neurology. As I try to make sense of developments in this field, I am struck by the large number of curious reports emerging all around it. I thought I had covered this comprehensively in my previous blogs, PD-a few curious things and Bee venom acupuncture for PD. On the contrary it looks like I opened a can of worms. I will therefore give the peculiar and the curious one last heave before proceeding to some conventional blogs I have in the pipeline on PD.  Here then are 13 unusual things about PD.

Appendicectomy may delay the onset of PD

Appendectomy. msafari2425 on Flikr. https://www.flickr.com/photos/msafari/6020024188
Appendectomy. msafari2425 on Flikr. https://www.flickr.com/photos/msafari/6020024188

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People with melanoma may have early PD signs

By Unknown - National Cancer Institute (AV Number: AV-8500-3850; Date Created: 1985; Date Entered: 1/1/2001), http://visualsonline.cancer.gov/details.cfm?imageid=2184, Public Domain, https://commons.wikimedia.org/w/index.php?curid=859342
By Unknown – National Cancer Institute (AV Number: AV-8500-3850; Date Created: 1985; Date Entered: 1/1/2001), http://visualsonline.cancer.gov/details.cfm?imageid=2184, Public Domain, https://commons.wikimedia.org/w/index.php?curid=859342

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PD gives rise to cerebellar atrophy

Cerebellum: the brain's locomotion control center. ZEISS microscopy on Flikr. https://www.flickr.com/photos/zeissmicro/14441559904
Cerebellum: the brain’s locomotion control center. ZEISS microscopy on Flikr. https://www.flickr.com/photos/zeissmicro/14441559904

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PD may give rise to a drunk-like state 

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A light skin pigmentation may increase the risk of PD

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People with red hair may run a higher risk of PD

Feuerrotes Haar. Markus Lütkemeyer on Flikr. https://www.flickr.com/photos/helico/363729534
Feuerrotes Haar. Markus Lütkemeyer on Flikr. https://www.flickr.com/photos/helico/363729534

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Coffee consumption may reduce the risk of dyskinesia in PD 

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Hepatitis C virus is a risk factor for PD

By BruceBlaus - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=44967236
By BruceBlausOwn work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=44967236

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A high cholesterol diet may reduce risk of PD in men 

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Milk intake in midlife may predispose to PD

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Drumming classes improve the quality of life of people with PD

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The GyroGlove reduces tremors in PD

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Focal muscle vibration improves gait in PD

Muscles of the forearm and hand, posterior view. Rob Swatski on Flikr. https://www.flickr.com/photos/rswatski/4769875140
Muscles of the forearm and hand, posterior view. Rob Swatski on Flikr. https://www.flickr.com/photos/rswatski/4769875140

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Do you have any unusual reports about PD? Please leave a comment

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neurochecklists-image

Minocycline-induced vasculitic neuropathy

This is a quick post to highlight the association of minocycline and neuropathy.

By Elbreapoly (Own work) [Public domain], via Wikimedia Commons
By Elbreapoly (Own work) [Public domain], via Wikimedia Commons

This comes from an article in Neurology titled Vasculitic neuropathy following exposure to minocycline. Minocycline is an antibiotic commonly used in the treatment of acne. Vasculitic neuropathy on the other hand is as bad as neuropathies come-in the cases reported here, one developed stroke, and another severe systemic symptoms.

By Ben Mills - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=6051872
By Ben MillsOwn work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=6051872

 

Worse still, stopping the treatment doesn’t resolve the problem, the patients requiring long-term immunosuppression.What a hero-to-zero move by minocycline, a fall from grace to infamy.

acne

The learning point however: ask your next patient with severe neuropathy if they have been treated for acne!

Migraine and its strange and surprising associations

By Sasha Wolff from Grand Rapids - Can't Concentrate: 14/365, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=11343038
By Sasha Wolff from Grand Rapids – Can’t Concentrate: 14/365, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=11343038

I am casting my sight on the scourge of millions around the world-migraine. This post is a prelude to a piece I am working on titled How is migraine research soothing the pain of neurology? In doing this, I came across a few curiosities which I thought would do nicely as a separate post. Therefore, before the real stuff, here are 8 strange and surprising migraine associations.

α. Migraine and the weather

Texture: Thunder Clouds. Virginia Moerenhout on Flikr. https://www.flickr.com/photos/yndra/4784553320
Texture: Thunder Clouds. Virginia Moerenhout on Flikr. https://www.flickr.com/photos/yndra/4784553320

Some migraineurs know that their migraine attacks are related to changes in the weather. For them therefore, the science is just catching up. This piece from the American Migraine Foundation summarises some recent articles which discuss the weather alterations that may trigger migraine headaches. The fingers are pointing at low barometric pressure, high environmental temperature, strong winds, and…wait for it…> 3hours of sunshine!

β. Migraine and irritable bowel syndrome (IBS)

This is not even officially out yet, but a press release announcing the American Academy of Neurology’s April 2016 meeting whets our appetites. The findings of a study to be unveiled in Vancouver reports that migraine is probably genetically linked to irritable bowel syndrome (IBS). Not only that, the two may also share genetic markers with tension type headache (TTH). And the link is thought to be the serotonin transporter, and the serotonin receptor 2A, gene. The association of migraine and IBS will really put the cat among the pigeons; dealing with migraine alone is hard enough but combine the two and…

γ. Migraine and Parkinson’s disease (PD)

By Marvin 101 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7533521
By Marvin 101Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7533521

Migraine sufferers will really balk at the scary report of migraine as a risk factor for Parkinson’s disease (PD). This is the conclusion of a research work published in the journal Cephalalgia (really just a fancy word for headache). The authors followed up >40,000 people to see if those with migraine are more likely to develop PD than those without. Curious indeed! I have to confess, whatever the hazard ratios say, that I was not impressed by the difference in numbers developing PD of 148 versus 101.

δ. Migraine and radiotherapy

Varian radiation therapy machine. Dina-Roberts Wakulczyk on Flikr. https://www.flickr.com/photos/littlesister/490643515
Varian radiation therapy machine. Dina-Roberts Wakulczyk on Flikr. https://www.flickr.com/photos/littlesister/490643515

I’m not trying to be smart, but SMART syndrome is real. It is an acronym for Stroke-like migraine attacks after radiation therapy. It is easy for neurologists to miss this condition because it sets in years after the radiation treatment. There is however a clue in the MRI of people with SMART syndrome: cortical thickening and gadolinium enhancement in the area of brain treated with radiation. It’s simple really!

ε. Migraine and raised intracranial pressure

By Jonathan Trobe, M.D. - University of Michigan Kellogg Eye Center - The Eyes Have It, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=16115920
By Jonathan Trobe, M.D. – University of Michigan Kellogg Eye Center – The Eyes Have It, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=16115920

An article in Journal of Neurology reports that many people with unrelenting migraine have raised pressure in the brain (raised intracranial pressure or ICP). The article, titled association of unresponsive chronic migraine and raised intracranial pressure, showed that reducing the pressure by a spinal tap (lumbar puncture) leads to sustained remission of migraine. Neurologists diagnose raised ICP by look into the back of the eye for a sign called papilledema. This article however throws a spanner in the works because >75% of the people with migraine and raised ICP in the study did not have papilledema. What do the headache gurus have to say about this, I wonder?

ζ. Migraine and stroke

Neurologists really haven’t sorted this one out yet. We struggle to give our patients a straightforward answer to their simple question, ‘does migraine cause stroke?‘ This is because the literature on this is all smoke and mirrors, and recent papers do little to clear the air. Take this paper in a recent issue of Neurology titled Age-specific association of migraine with cryptogenic TIA and stroke. The authors could only conclude that there is probably a causal or shared risk, and this only in older people. The accompanying editorial, titled Migraine and cryptogenic stroke: the clot thickens, concludes that there may be a higher risk of stroke in migraineurs, but this is in those with other traditional stroke risk factors in the first place. A shaky association I say, but one not to be dismissed too hastily.

η. Migraine and teeth-grinding

By Mik81 - Photography of author, original description page was here., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2478383
By Mik81 – Photography of author, original description page was here., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2478383

I did say these are strange links. Teeth grinding or bruxism is not something neurologists would give a second thought to, but a review article in Practical Neurology says we should think again. Titled Bruxism in the Neurology Clinic, the review says bruxism is closely linked to migraine, and sleep bruxism is only associated with migraine. There is much more to bruxism and neurology; the authors suggests that bruxism may be a form of oromandibular dystonia, and it may arise from dysregulation in the basal ganglia. Quite a lot to chew! Dentists out there should be very worried-the neurologists are out to expand their territory.

θ. Migraine and hiccups

Try this Flikr. Bart on Flikr. https://www.flickr.com/photos/cayusa/3029282000
Try this Flikr. Bart on Flikr. https://www.flickr.com/photos/cayusa/3029282000

And finally a report which links migraine and hiccups. Again from Cephalalgia, this is a case series of people with migraine who report hiccups as aura of migraine. Strange and surprising indeed!

migraine aura 2 - when it's light and shimmery. Joanna Roja on Flikr. https://www.flickr.com/photos/cats_mom/2758240218
migraine aura 2 – when it’s light and shimmery. Joanna Roja on Flikr. https://www.flickr.com/photos/cats_mom/2758240218

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screen-shot-2016-12-19-at-18-32-39

The emerging progress from the world of MS

Multiple sclerosis (MS) takes a large chunk of neurological practice. This is not only because it is common, but also because of its devastating impact. It predominantly affects the young, and deals a blow that reverberates through the wider family and society. This is why it is a top priority in neurology.

A lot however remains uncertain and controversial in MS. The cause of MS for instance remains unknown although the list of risk factors is a mile long (see my previous blog listing the top 6 MS risk factors). MS is a well-known condition but it features prominently in the most controversial questions in neurology. The pathology and subtypes of MS are subjects of intense debate, and the best tests and treatments are still being worked out.

By Marvin 101 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2846763
By Marvin 101Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2846763

The uncertainties in MS are quite fundamental. Take these two recent publications in high impact journals arguing opposites sides of an MS risk factor. One says there is no association of multiple sclerosis activity and progression with EBV or tobacco use, and the other says smoking cessation improves prognosis of multiple sclerosis. Another research article in the JNNP published this year suggests that we are still not sure what constitutes pathological brain atrophy in MS.

By Monthly_multiple_sclerosis_anim.gif: Waglionederivative work: Garrondo - This file was derived from  Monthly multiple sclerosis anim.gif: , Public Domain, https://commons.wikimedia.org/w/index.php?curid=26444219
By Monthly_multiple_sclerosis_anim.gif: Waglionederivative work: Garrondo – This file was derived from  Monthly multiple sclerosis anim.gif: , Public Domain, https://commons.wikimedia.org/w/index.php?curid=26444219

But it’s not all controversy and conflict in the world of MS. There is real progress shining a light to a brighter future in MS ,and here are a 11 I have found.

1. Interferons, with twists

Interferons have been the mainstay of MS treatment for decades. They are still standing their grounds despite inconclusive evidence of their effectiveness, their side effects, and the challenge from newer treatments. One way they hope to carry on into the future is by joining forces with oral contraceptives. This is according to a paper published in Neurology last year titled Oral contraceptives combined with interferon β in multiple sclerosis. The authors report that ethinylstradiol and desogestrel aid interferon-ß to reduce the number of new lesions in women with relapsing remitting multiple sclerosis.

We are also learning a little bit more about the types of patients who do worse on interferons. The Journal of Neuroimmunology reports that MS subjects with obesity do less well on interferons, and never achieve the valued status of NEDA, no evidence of disease activity. Another paper in JAMA Neurology, on the other hand, suggests that MS subjects with low Vitamin D levels have poorer disease control when treated with interferon.

2. Vitamin D

There is a lot of uncertainty about the significance of Vitamin D deficiency in MS. A big question is if vitamin D should be given routinely to prevent and treat MS. The potential benefit of Vitamin D was recently the subject of an article published in Journal of Cell Biology titled Vitamin D receptor–retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. The University of Cambridge researchers who carried out the study showed that Vitamin D activates a protein receptor, retinoid X receptor γ (RXR-γ), and this plays a role in the repair of myelin, the fatty nerve sheathing that is damaged in multiple sclerosis. The University of Cambridge statement announcing the finding makes for a simpler read: Vitamin D could repair nerve damage in multiple sclerosis.

3. Melatonin

An article in Scientific Americanfirst highlighted an association between seasonal MS relapses and melatonin. The science is rather complex, but the idea is based on the recognition that people with MS have fewer relapses in the darker months of the year, and this is when production of the hormone, melatonin, peaks. The research paper itself is published in Cell under the title Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses. The researchers proved their hypothesis by demonstrating that melatonin levels are lowest during an MS relapse than at other times. Furthermore, the pathology of the disease improves in MS mice treated with melatonin. For a simplified read, try this, perhaps over-enthusiastic, take from MD titled Melatonin Could One Day Treat MS.

4. Helicobacter pylori

Helicobacter pylori. AJ Cann on Flikr. https://www.flickr.com/photos/ajc1/6946417103
Helicobacter pylori. AJ Cann on Flikr. https://www.flickr.com/photos/ajc1/6946417103

In what may be an attempt at rehabilitation, H pylori is attempting to make a good name for itself. Notorius for causing stomach ulcers, it now wants to be known as the patron saint of MS. It is a tenuous link I have to say, but I can’t argue against the research paper published in the prestigious Journal of Neurology, Neurosurgery and Psychiatry (JNNP). The article has a refreshingly self-explanatory title Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females. The authors show that people with MS are less likely to be infected with H. pylori than control subjects. But I will not rush to swim in that dirty-looking pool yet, the margin is thin; 16% versus 21% in control subjects. It however raises the intriguing relationship between infections and autoimmunity, a subject explored brilliantly in the accompanying editorial, the hygiene hypothesis of multiple sclerosis.

5. Phenytoin

Phenytoin is very familiar to neurologists because it was a leading epilepsy medication for decades. Although it still has pride of place in the treatment of status epilepsy, it has largely fallen out of favour-mainly for its cosmetic and cognitive side effects. It is therefore surprising to see phenytoin resurrecting in the world of multiple sclerosis. In a large trial published in Lancet Neurology this year, researchers showed a neuroprotective effect of phenytoin on optic neuritis, a common symptom of MS. Neuroprotection, if you must know, is the holy grail of neurology. The article is titled Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. But you might as well read the distilled, and not over-sensational title, in The TelegraphCheap epilepsy drug could prevent nerve damage in Multiple Sclerosis. I think the findings require a long stretch of the imagination, but I am happy to do this to remain positive.

6. Pramipexole

Modelling the molecular basis of Parkinson's disease. Argonne National Laboratory on Flikr. https://www.flickr.com/photos/argonne/4192798573
Modelling the molecular basis of Parkinson’s disease. Argonne National Laboratory on Flikr. https://www.flickr.com/photos/argonne/4192798573

Pramipexole is a dopamine agonist, a group of drugs used in the treatment of Parkinson’s disease. They are not as popular as they once were, partly again due to side effects. They may however take on an important role in MS. I first came across this in the Barts MS Blog titled Dopamine modulation – a novel target for MS. This refers to an article published in Molecular Neurobiology, Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice. I fail to understand why our ivory towers love these long-winded titles! The bottom line however is that Pramipexole can modulate the immune system thereby limiting the damage it inflicts on the nervous system. Don’t ask me how it does this-I dare you to go read the abstract!

7. Ozanimod

Ozanimod is a sphingosine-1-phosphate receptor modulator, and it has shown promise in trials of relapsing remitting MS. This was the conclusion of a recent randomised, placebo-controlled, phase 2 trial of Ozanimod in MS published in Lancet Neurology. Heart-warmingly called the RADIANCE study, the authors demonstrated the effectiveness of Ozanimod in subjects across 55 centres spread over 13 countries. This feat was rewarded with demonstrable reduction in MRI lesion load in the treated subjects. The phase 3 trial therefore promises a lot…but will it deliver?

8. Anoctamin 2 (ANO2)

By Unknown photographer/artist (False color modifications made by myself--DO11.10) - Dr. Triche National Cancer Institute, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1243806
By Unknown photographer/artist (False color modifications made by myself–DO11.10) – Dr. Triche National Cancer Institute, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1243806

Researchers are veritable hunters, looking for weak spots in their prey, diseases. They then hone in on their victims vulnerabilities, and pounce. In this way they develop treatment strategies. One such weak spot, recently reported in Proceedings of the National Academy of Sciences (PNAS), is connected to the  chloride channel protein Anoctamin 2 (ANO2). The paper, Anoctamin 2 identified as an autoimmune target in multiple sclerosis, reports that subjects with MS have high antibody activity against ANO2. It’s rather complex biochemistry, and for a digested read see the version in Multiple Sclerosis News Today titled New Protein, Anoctamin 2, Identified as a Target of Autoantibody Production in MS. If ANO2 has anything to do with causing MS, you can be sure treatment strategies will follow. If this turns out to be an important pathway in MS, the armoury of MSologists will soon contain stronger firepower.

9. Intrathecal CD20

By Gray (Gray's Anatomy) [Public domain], via Wikimedia Commons
By Gray (Gray’s Anatomy) [Public domain], via Wikimedia Commons
I know, getting into unfamiliar territory now, but the future always feels that way. In a study titled Intrathecal anti-CD20 efficiently depletes meningeal B cells in CNS autoimmunity, researchers injected CD20 into the spinal fluid of mice. They then showed that this depletes the B cells that cause the inflammation in MS. The article is published in Annals of Clinical and Translational Neurology, (I know, I haven’t heard of it before now myself). It is a significant enough step for JAMA Neurology to ask, Is intrathecal anti-CD20 a therapeutic option in treating MS relapse? Whether this would translate into clinical benefit is not clear from the article, but it is promising.

10. Haematopoietic cell transplant (HCT)

There have been reports in the lay press of subjects with MS getting up and walking, almost miraculously. There is however actually some science behind it all, for a change. An article in JAMA Neurology titled, rather clumsily, High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS), illustrated the benefits of haematopoietic cell transplant in MS. The 3 year interim analysis shows that HCT successfully induces sustained remission in MS-what more can we expect from an emerging treatment!

11. FLAIR2

© Nevit Dilmen [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
© Nevit Dilmen [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
MS is as much a neurological, as it is a radiological, condition. The diagnosis of MS is heavily reliant on what is, or is not, a lesion on MRI scans; what is new and what is old; and what is getting bigger or smaller. Believe me, this is hardly ever straightforward. It is therefore gratifying to read an article (OK, I admit it, an abstract) in the American Journal of Neuroradiology titled FLAIR2: A Combination of FLAIR and T2 for Improved MS Lesion Detection. The authors report that they greatly improved the detection of MS lesions by combining two standard magnetic resonance imaging (MRI) techniques called T2 and FLAIR. This technique, FLAIR2, the authors say, is ‘a simple approach of obtaining CSF suppression with an improved contrast-to-noise ratio’, whatever that means! It does make one worry- how much we are actually missing now? FLAIR2 to the rescue.

12. Developing prospect

I know I said 11, but for those who like things to be even I will take you out of your misery and make it an even dozen. Look out for the Amiloride Clinical Trial In Optic Neuritis (ACTION). Something for the future!

Is neurology research finally breaking the resolve of MND?

Motor neurone disease (MND) is, to say the least, dreadful. It also doesn’t help that the terminology neurologists use adds to the distress. West of the Atlantic, amyotrophic lateral sclerosis (ALS) means MND but goes eastwards and it is only a subtype of MND. Thankfully, for most Americans at least, there is no confusion; it is simply Lou Gehrig disease.

By Goudey [Public domain], via Wikimedia Commons
By Goudey [Public domain], via Wikimedia Commons

MND however remains a conundrum for neurologists who are struggling to solve its puzzling riddles. MND researchers continue to toil and sweat, but their efforts are bearing fruits. Take for example the great strides that established the link between MND and the C9ORF72 gene. What are the promising prospects in the world of MND? Here are some.

Associations: Thiamine deficiency and Diabetes 

By Jynto [CC0], via Wikimedia Commons
By Jynto [CC0], via Wikimedia Commons
Should we be on the lookout for thiamine deficiency in patients with MND? This question is prompted by an article in the JNNP which shows an unexpectedly high frequency of laboratory, but not clinical, thiamine deficiency. Titled Thiamine deficiency in amyotrophic lateral sclerosis, the paper reported thiamine deficiency in about 28% of subjects with MND. The authors did not impute any causal association, and there is nothing to suggest that replenishing the thiamine improved outcomes. It is still worth thinking about because people with MND, as the paper emphasised, are at risk of thiamine deficiency.

Another reported association, more difficult to fathom, is the one between MND and diabetes mellitus. The report in the European Journal of Neurology is titled Association between diabetes and amyotrophic lateral sclerosis in Sweden. Why am I sceptical?

Risk factor: Human endogenous retrovirus K (HERV K) 

Retrovirus capsid. A J Cann on Flikr. https://www.flickr.com/photos/ajc1/3269017701/in/photostream/
Retrovirus capsid. A J Cann on Flikr. https://www.flickr.com/photos/ajc1/3269017701/in/photostream/

The cause for MND remains unknown. Risk factors however abound such as smoking and other environmental risk factors. You may now add human endogenous retrovirus K (HERV K) to that list. This is according to a recent paper in Science Translational Medicine titled Human endogenous retrovirus-K contributes to motor neuron disease. The authors report that HERV K is activated in some people with MND, and it is the envelope proteins that cause damage to tissues. The US National Institutes of Health (NIH) think this is an important development, and it released a press statement titled Dormant viral genes may awaken to cause ALS. Scary! Is this important, or just another risk factor? Only time will tell.

Pathology: Neuromuscular junction inflammation 

By Elliejellybelly13 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=40798702
By Elliejellybelly13Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=40798702

This sounds almost sacrilegious- the thought that inflammation may really play a role in MND. And at the neuromuscular junction (NMJ), not the anterior horn cells. Well, some researchers are ready to commit blasphemy; publishing in Experimental Neurology, the authors showed evidence of inflammation in the muscles and NMJs of rat models of MND. They went further to show that injecting a growth factor called GDNF reduced this inflammation. Do I perceive a potential treatment pathway? Read all about it if you dare, its titled Macrophage-mediated inflammation and glial response in the skeletal muscle of a rat model of familial amyotrophic lateral sclerosis (ALS).

Treatment target: TDP-43 protein 

By Emw (Own work) [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
By Emw (Own work) [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
Will MND ever be a curable disease? A big question, but this is the vision of all the hard-working researchers in this field. What are the prospects for a cure? One group of researchers believe the answer is in preventing misfolding of TDP-43, the protein that plays an important role in MND. They set out their case in an article published in Neurotherapeutics titled TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets. And don’t worry, its free access. The bold abstract says it all: “we present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS”. The proof of the pudding….

Diagnostic test: Nerve ultrasound

By Oleg Alexandrov - self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844
By Oleg Alexandrov – self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844

Making the diagnosis of MND is not always (make that is hardly ever) straightforward. In the early stages, symptoms are vague, and clinical signs are non-specific. MND also has many mimics. One of such mimics is multifocal motor neuropathy (MMN). To distinguish this and other mimics from MND, neurologist rely on a test called nerve conduction study (NCS). Even this however is not always helpful.

Researchers have now reported that ultrasound may be more sensitive in distinguishing MND from MMN. Another sacrilegious thought! They published their paper in Journal of Neurology with a rather long title: Nerve ultrasound in the differentiation of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis with predominant lower motor neuron disease (ALS/LMND). Could the diagnosis of MND really be this simple? I am concerned that there were only 16 subjects with MND in the study, all from one centre. Perhaps a randomised, multi-centre, trial will come to the rescue?

Diagnostic biomarker: Brain iron deposition 

By Oleg Alexandrov - self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844
By Oleg Alexandrov – self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844

Brain magnetic resonance imaging (MRI) is not a test neurologist rely upon to make the diagnosis of MND. Not anymore it seems, going by an article in American Journal of Neuroradiology. The paper is titled A Potential Biomarker in Amyotrophic Lateral Sclerosis. In the article, the authors assessed the amount of iron deposition in the brains of people with MND using the MRI techniques called SWI and DTI. Their findings suggest that the amount of iron in the motor cortex and motor tracts of the brain is a good guide to the presence of MND. If confirmed, this technique will help to reduce the long time it often takes before neurologists confirm their suspicions of MND to patients and their families.

Prognostic biomarker: Neurofilament light chain (NfL) 

Neurofilament and MBP. Dan O'Shea on Flikr. https://www.flickr.com/photos/dan_oshea/4079086197
Neurofilament and MBP. Dan O’Shea on Flikr. https://www.flickr.com/photos/dan_oshea/4079086197

The outcome of MND, poor as it often is, varies quite widely. This is influenced by several factors such as the type of MND, use of the medicine riluzole, and multidisciplinary care. New research suggests that neurofilament light chain (NfL) may be a more sensitive marker of prognosis. This is reported in an article published in Neurology titled Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. The authors demonstrated that patients with MND have much higher levels of NfL than those without the disease. Furthermore, subjects with MND who had the highest levels at the onset had a higher mortality hazard ratio. I think I know what that means.

Prognostic scale: ALS-MITOS predictive system

A paper in the JNNP has proposed a new predictive system for MND called ALS-MITOS, reportedly better than the more familiar ALSFRS-R. The report is titled The MITOS system predicts long-term survival in amyotrophic lateral sclerosis. Most practicing neurologists wouldn’t know the difference because they don’t to use such predictive systems. But MND researchers would be licking their lips at the prospect of a better measure of disease progression; it will make it much easier for them to show that their interventions really do work!

Treatment: Copper 

By Native_Copper_Macro_Digon3.jpg: “Jonathan Zander (Digon3)"derivative work: Materialscientist (talk) - Native_Copper_Macro_Digon3.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7223304
By Native_Copper_Macro_Digon3.jpg: “Jonathan Zander (Digon3)”derivative work: Materialscientist (talk) – Native_Copper_Macro_Digon3.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7223304

There are >100 mutations in the superoxide dismutase 1 (SOD-1), a gene known to cause MND. SOD-1 is an enzyme that binds both copper and zinc, and when defective it results in mutant copper (don’t worry, I’m just finding this out myself). Acting on this hypothesis, researchers came up with a crafty way of delivering normal copper into the central nervous system of  mice modelled with SOD-1 MND. Publishing in Neurobiology of Disease, the authors showed how they achieved this with CuATSM, a chemical that contains copper and currently used for PET scans. CuATSM is readily transported into the nervous system, delivering its copper as it does so.

The paper has a rather cumbersome title: Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD. The result is however anything but. The technique extended the lives of the mice by an average of 18 months. Unbelievable it seems. Any doubts however vanished when, on stopping the treatment, the mice died within 3 months. The finding is exciting enough for Eureka Alert to run the story with the headline New therapy halts progression of Lou Gehrig’s disease in mice. ‘Halt’ sounds very much like ‘cure’, but lets put the brakes on and wait for confirmation in human trials .

Treatment: Gene therapy

Gene_therapy. 1Droid JamLos on Flikr. https://www.flickr.com/photos/jamlos/2734418031
Gene_therapy. 1Droid JamLos on Flikr. https://www.flickr.com/photos/jamlos/2734418031

Every recalcitrant disease is today threatened with gene therapy. Considering it has a long list of genetic risk factors, why should MND be any different? Research taking steps in this direction is therefore long overdue. One such step was published in Gene Therapy and is titled Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex. The authors report that they successfully transduced motor nerves of mice models of MND. In doing so they have set the stage for gene therapy in MND. I don’t claim to understand it all, but it sounds very much like they have set the ball rolling. Promising.

Treatment: Stem cell therapy

By Ryddragyn at English Wikipedia - Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2148036
By Ryddragyn at English Wikipedia – Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2148036

Where gene therapy goes, stem cell therapy seems to follow. And this comes from JAMA Neurology with a classic unwieldy academic title: Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis. The content isn’t any easier to interpret, and I will not pretend I get it at all. I comfort myself that it’s all at the ‘open-label, proof of concept‘ stage, and only the very brainy brains need to delve further. But it seems to offer hope.

By Jim Campbell/Aero-News Network - http://www.flickr.com/photos/39735679@N00/475109138/ / http://mediaarchive.ksc.nasa.gov/detail.cfm?mediaid=31873, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3655144
By Jim Campbell/Aero-News Network – http://www.flickr.com/photos/39735679@N00/475109138/ / http://mediaarchive.ksc.nasa.gov/detail.cfm?mediaid=31873, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3655144

 

The sky is surely the limit. Here are a couple of other headlines if you wish to explore further:

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neurochecklists-image

 

Why is neuromyelitis optica (NMO) endlessly surprising neurology?

Neuromyelitis optica (NMO) may be seen as the rarer and more mysterious cousin of multiple sclerosis (MS). It is characterised by a long segment of inflammation in the spinal cord, and this occurs almost simultaneously with inflammation of the optic nerves. Unlike MS, there is usually no involvement of the brain. NMO is also  known as Devic disease, after the French neurologist Eugène Devic.

Optic Nerve Side View. Francisco Bengoa on Flikr. https://www.flickr.com/photos/frecuenciamedicafb/7404373800
Optic Nerve Side View. Francisco Bengoa on Flikr. https://www.flickr.com/photos/frecuenciamedicafb/7404373800

 

NMO has had a very chequered history, refusing to be tied down, and defying all attempts at pigeon-holing. It has thrown up surprises over the decades, from its humble beginnings as a possible variant of multiple sclerosis, to its current complex status as an independent entity. It marks its territory by sprinkling anti aquaporin 4, its presumed causative antibody. We however now know that NMO doesn’t respect any of its defining features, even the presence of  aquaporin 4. The International consensus diagnostic criteria for neuromyelitis optica spectrum disorders confirms this. The experts struggled to pin it down … couldn’t…gave in… and took the easy way out: they developed a wider construct to accommodate it all, calling this neuromyelitis spectrum disorders (NMOSD).

Optic Nerve Front View. Francisco Bengoa on Flikr. https://www.flickr.com/photos/frecuenciamedicafb/7404373518/in/photostream/
Optic Nerve Front View. Francisco Bengoa on Flikr. https://www.flickr.com/photos/frecuenciamedicafb/7404373518/in/photostream/

 

Why is NMO such an enigma? Because neurologists are never satisfied with the superficial. We like digging deeper, unearthing the hidden. And the longer neurologist study NMO, the more unusual the syndrome turns out to be. No wonder NMO now also encompasses patients with cerebral, diencephalic, and brainstem lesions. How more intriguing can it get? Here are 6 surprising reports about NMO.

1. Spinal movement disorders

Spinal movement disorders are not run-of-the-mill in neurology. Myoclonus is probably the closest we get to see. A recent report in Movement Disorders (where else) enlightens us that spinal movement disorders in NMO are not infrequent (pardon the double negative, but it’s so convenient sometimes). The authors classify these disorders into five: tonic spasmsfocal dystonia; spinal myoclonus, spontaneous clonus, and tremors. The paper cautions that NMO may present first with spinal movement disorders, and these are often ‘overlooked, mislabeled, or under-treated’.

2. Impaired sense of smell

Just when you thought only neurodegenerative diseases present with an impaired sense of smell, an article turns up in Journal of Neurology titled Olfactory dysfunction in neuromyelitis optica spectrum disorders. The authors of the paper found that slightly more than half of the 49 subjects with NMO had olfactory dysfunction. Bring out the UPSIT.

3. Abortions

It appears that women who get pregnant after they are diagnosed with NMO are at a higher risk of abortions. This is from a piece in Neurology, a poster rather than a paper, titled Pregnancy outcome in aquaporin-4 positive neuromyelitis optica spectrum disorder. To complicate things, the women run the risk of pre-eclampsia if they also have other autoimmune diseases.

BIO 120 Lab Spinal Cord 031. djneight on Flikr. http://bit.ly/1p7S6pe
BIO 120 Lab Spinal Cord 031. djneight on Flikr. http://bit.ly/1p7S6pe

4. Unusual NMO differential diagnoses

The hallmark of NMO is the longitudinally extensive transverse myelitis (LETM), inflammation of the spinal cord at least 3 vertebral segments long. There are however many other diseases that present with LETM-see this review article in Nature Reviews Neurology which lists diseases that may manifest with LETM. Spoiler alert-it’s not open access! A recent piece in Neurology further extended the list (pardon the puns) with a case of MELAS presenting with LETM. MELAS is a mitochondrial disease that is more notorious for being a stroke mimic. Not to be outdone, JAMA Neurology had a case of nitrous oxide myelopathy with LETM.  Last word however to Neurology, LETM may be seen in CLIPPERS.

By Simon Caulton - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=29451273
By Simon CaultonOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=29451273

5. Genetic pointer to relapse after treatment

It is no news that the monoclonal antibody, Rituximab, is an effective treatment for NMO. What is news is the report of a genetic marker of poor responsiveness to treatment with Rituximab. Researchers publishing in JAMA Neurology report that the fragment c gamma receptor 3A (FCGR3A) polymorphism increases the risk of relapse on treatment. Why on earth did they check for that specific polymorphism? I didn’t have access to the full article to find out…if you have the answer please let us know.

6. Escalation of treatment improves outcome

Sadly the outcome of NMO is not as good as one would hope. Relapses are common after remission, and these are not always amenable to treatment. A recent article however raised the spirits by showing that recalcitrant relapses may respond to escalation of the treatment level. The authors carried out a large scale trial published in Annals of Neurology titled Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. With escalation of treatment, raising the bar a notch higher, remission is achieved in many cases. There is therefore no place for pulling any punches when it comes to NMO.

The phenotype of neuromyelitis optica will no doubt evolve further. Please leave a comment on any unusual sightings.