mTORopathy: an emerging buzzword for neurology

I was recently perplexed with my first case of tuberous sclerosis complex (TSC). I had no idea what treatment, monitoring and surveillance I needed to institute. I quickly checked things up in neurochecklists; I found excellent checklists on the pathology and clinical features, but was disappointed that there were no treatment or monitoring checklists. I quickly hunted down TSC diagnostic criteria and TSC surveillance recommendations and updated neurochecklists. Phew!

By Herbert L. Fred, MD and Hendrik A. van Dijk - http://cnx.org/content/m14895/latest/, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11892420
By Herbert L. Fred, MD and Hendrik A. van Dijk – http://cnx.org/content/m14895/latest/, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11892420

In the process I discovered that TSC features may improve on treatment with a class of drugs called mTOR inhibitors. Highfalutin stuff I said to myself, and thought nothing more of it. I had to reassess my opinion very shortly afterwards when I came across the Association of British Neurologists (ABN) SoundCloud page with ABN President Phil Smith interviewing Ingrid Scheffer on epilepsy genetics.

We have all experienced that disquieting feeling of just learning something new, and then seeing it crop up all over the place. This is what I felt when Ingrid Scheffer casually stated that Tuberous Sclerosis is an mTORopathy. mTOR is big enough to be an ‘opathy‘, and I was completely ignorant of it! And how come I haven’t heard of Ingrid Scheffer before now-serves me right for missing the last ABN conference in Brighton.

I decided to dig a bit deeper and here are 9 things about mTOR I discovered:

1

mTOR stands for mammalian (or mechanistic) target of rapamycin

2

mTOR is a kinase

3

The mTOR pathway is important in regulating cell growth and cell death

4

mTOR has an important role in many disorders (mTORopathies). These include tuberous sclerosis, epilepsy, autism, traumatic brain injury, brain tumours, and dementia

5

Mutations in TSC1 or TSC2 genes cause hyperactivation of the mTOR pathway

6

mTOR inhibitors are under investigation for the treatment of these diverse diseases

7

Sirolimus is the major mTOR inhibitor

By Fvasconcellos - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1549073
By FvasconcellosOwn work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1549073

8

The DEPDC5 gene regulates mTOR inhibition.

9

The DEPDC5 gene is mutated in many neurological disorders such as familial focal epilepsies, focal cortical dysplasia, and epileptic spasms. These constitute DEPDC5 motoropathies.

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Enough information to tickle the little grey cells but if you want to dig deeper than you may follow these links:

What are the obstacles to creating reliable neurology checklists?

This is a follow up to my previous blog post on the value of checklists in medical practice. That post explored how checklists improve clinical practice and promote patient safety. It also cited Atul Gawande‘s call to Medicine to “seize the opportunity” and produce checklists for all aspects of clinical practice.

Neurology. MV Maverick. https://www.flickr.com/photos/themvmaverick/11396461045
Neurology. MV Maverick. https://www.flickr.com/photos/themvmaverick/11396461045

 

Picking up this gauntlet for neurology comes with peculiar challenges. Here are the 7 hurdles to overcome.

1. The challenge of a diverse specialty

Legume diversity. Global Crop Diversity Trust on Flikr. https://www.flickr.com/photos/croptrust/3594324633
Legume diversity. Global Crop Diversity Trust on Flikr. https://www.flickr.com/photos/croptrust/3594324633

Neurology consists of an astonishing diversity of sub-specialities. Any neurology checklist must exhaustively cover the major neurological categories such as stroke, epilepsy, movement disorders, headache, dementia, neuromuscular diseases, sleep disorders, neuro-inflammation, nervous system tumours, and neurological infections. These topics must be thoroughly covered with emphasis on their clinical features, investigations, and treatments. A useful database must also include rare neurological diseases, of which neurology has quite a few. This is reflected in my previous blog on the most perplexing diseases that excite neurologists.

2. The challenge of multiple associated specialties

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Neurological disorders cut across many diverse allied neurological specialties. Any dependable checklist database must cover these specialised fields which include neurosurgery, neuroradiology, neuroophthalmology, neuropsychiatry, neuropaediatrics, and pain management. It must also include important diseases which straddle neurology and general medicine. These include a long list of cardiovascular, nutritional, endocrine and gastrointestinal disorders. Furthermore, neurologists often have to deal with surgical complications especially in orthopaedics and following transplant surgery. Neurologists are also frequently called upon to attend to neurological problems that are unique to pregnancy. Any practical checklist application must therefore thoroughly address these areas.

Brain Cells Created From Skin Cells in Landmark Study. Day Donaldson on Flikr. https://www.flickr.com/photos/thespeakernews/15656329862
Brain Cells Created From Skin Cells in Landmark Study. Day Donaldson on Flikr. https://www.flickr.com/photos/thespeakernews/15656329862

3. The challenge of reliable content

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It goes without saying that the most important feature of any database is reliable content which alone will engender trust and confidence. A reliable checklist must obtain its material from dependable sources. Neurology is replete with reliable textbooks and reference websites, . Neurology is also bursting at the seams with journals such as Neurology, Brain, the JNNP, and Journal of Neurology, each churning out a bewildering array of neurology guidelines, review articles, ground-breaking studies, and fascinating case reports. The challenge is to keep a regular handle on these sources, sifting through for practical and established material. As important for the user is that any checklist must be fully referenced and hyperlinked to the source material.

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4. The challenge of practical functionality

Any practical checklist database must be available on the move, easily accessible and searchable. In other words, it must be in the form of a mobile application. The app must have a reliable search functionality. More importantly for users is the requirement that the application must serves as a prompt to remember important points across the breadth of neurological practice: history taking, investigations, differential diagnosis, and treatment. For the administrator, the technology must make it easy to update and edit content, keeping the content consistently up-to-date.

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5. The challenge of varied target groups

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In developing any form of medical resource, it is a challenge to define the target audience. The primary aim of a neurology checklist application is to ease the challenges medical professionals face in accessing relevant and practical information about neurology in a timely way. This may be on a busy ward round or clinic, but also when researching a topic or preparing a presentation. The core users of a neurology application will therefore clearly be neurologists and neurology trainees.

By SpinningSpark real life identity: SHA-1 commitment ba62ca25da3fee2f8f36c101994f571c151abee7 - Created with Superliminal's Magic Cube 4D, CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=17492843
By SpinningSpark real life identity: SHA-1 commitment ba62ca25da3fee2f8f36c101994f571c151abee7 – Created with Superliminal’s Magic Cube 4D, CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=17492843

In many places however other cadres of medicine cater for people with neurological diseases. Psychiatrists, neurosurgeons, paediatriciansgeneral physicians, obstetricians, ophthalmologists, specialist and general nurses, would likely access the database. Other health care professionals may also find areas of interest such as speech therapists, physiotherapists and occupational therapistsMedical students and researchers also require vast amounts of neurological information, often within restricted time frames.

A Tangle of Different Colours 001. Christina Quinn on Flikr. https://www.flickr.com/photos/chrisser/7909899736
A Tangle of Different Colours 001. Christina Quinn on Flikr. https://www.flickr.com/photos/chrisser/7909899736

6. The challenge of public access

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Specialised medical application are never aimed at non-medically trained people. The reality however is that the general public are closely involved in their care today, seeking reliable information to address their medical concerns. It is inevitable that patients and their families will access the checklist database. For this reason the language must be simple and clear, avoiding any sort of ambiguity.

7. The challenge of resources and pricing

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A checklist application, to be most beneficial, should ideally be free to use. A Wikipedia model would be a model to adapt. But creating a checklist database, with all the features mentioned above, would surely stretch resources in terms of time and funding. There will also be great demands on resources to maintain and enhance it. A balance must be struck between beneficence and realism. Such a balance should have, as with most applications, a free version with sufficient access of some sort, and a premium version with unlimited access. The developer must also be aware that potential users have limited resources to spread round their conflicting demands. Any premium account should be affordable, perhaps not more than the equivalent cost of a cup of coffee and a cake a month.

Muffin and coffee. Phil Gyford on Flikr. https://www.flickr.com/photos/philgyford/6534958441
Muffin and coffee. Phil Gyford on Flikr. https://www.flickr.com/photos/philgyford/6534958441 

 

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Is there any neurology checklist application that has taken the above challenges into consideration? This will be revealed in my next blog post, How simple checklists unlock excellent neurological practice?

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What precisely is the driver for essential tremor?

Neurologists do not break into a sweat when they make the diagnosis of essential tremor (ET). Theoretically, at least, they shouldn’t. Essential tremor presents with an obvious shaking of the hands when performing tasks; this is unlike the tremor of Parkinson’s disease which is typically at rest. Neurologists also have handy evidence-based treatment guidelines which recommend medications such as Propranolol and Primidone.

tremors. Daniel Chong Kah Fui דניאל 張家輝 on Flikr. https://www.flickr.com/photos/dckf/281301724/in/photolist-qRKcJ
tremors. Daniel Chong Kah Fui דניאל 張家輝 on Flikr. https://www.flickr.com/photos/dckf/281301724/in/photolist-qRKcJ

 

Essential tremor is however anything but straightforward. Tremor is a feature of many other medical and neurological diseases. Neurologists also know that essential tremor may mimic Parkinson’s disease and dystonic tremor. To muddy the waters further, essential tremor also has non-motor symptoms such as cognitive difficulties. And to add to the frustration, the touted evidence-based treatments, when tolerated, rarely work well enough. These twists and turns that accompany essential tremor are the reasons a review article in Practical Neurology labelled it ‘deceptively simple‘. This deception extends to the core puzzle in essential tremor-what causes it? Here are two tantalising suggestions which attempt to answer this question.

Is essential tremor a neurodegenerative disease?

L1070037. haemin kim on Flikr. https://www.flickr.com/photos/kimhaemin/1347409143/in/photolist-344PN8
L1070037. haemin kim on Flikr. https://www.flickr.com/photos/kimhaemin/1347409143/in/photolist-344PN8

 

Neurodegeneration is the usual suspect when neurologists are looking for ‘a cause’. With essential tremor the focus has been on the cerebellum, the part of the brain that co-ordinates movements. This is logical because tremor is a classical symptom of diseases of the cerebellum. This link, circumstantial as it is, has led researchers to interrogate the cerebellum in essential tremor. In doing this they also wondered if the problem is neurodegenerative. The logic behind this line of thinking is explained in a paper published in JAMA Neurology in 2009 titled, Essential tremors: a family of neurodegenerative disorders? 

B0006224 Purkinje cells in the cerebellum. Ludovic Collin / Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/6880271296
B0006224 Purkinje cells in the cerebellum. Ludovic Collin / Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/6880271296

 

Pursuing this lead, some researchers have tried to hone down on which of the different types of cerebellar cells is involved in essential tremor. Writing in the journal Movement Disorders, the authors are convinced that the seat of neurodegeneration in essential tremor is the Purkinje cell. Purkinje cells are unique cerebellar cells which are vulnerable to all sorts of insults. The researchers in this case demonstrated significantly fewer Purkinje cells in the brains of people with essential tremor than in control subjects without the disease. And they attributed this pathology to neurodegeneration (what else?). The answer to a long-standing riddle, or a hasty conclusion?

Purkinje cell Saguaro. Anita Gould on Flikr. https://www.flickr.com/photos/anitagould/3427285447
Purkinje cell Saguaro. Anita Gould on Flikr. https://www.flickr.com/photos/anitagould/3427285447

 

Is essential tremor a channelopathy?

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Neurologists have known for a long time that essential tremor has a strong genetic element. The diagnosis always feels more certain when there is another family member with tremor. The exact nature of this genetic link is however uncertain. Into this void comes a research paper suggesting that people with essential tremor may have abnormal cellular channels. Channels are proteins in the cell wall that let electrolytes like sodium and potassium in and out, and channelopathies are diseases that affect these channels. The authors of this paper studied a large essential tremor family who also suffer with epilepsy, a typical channel disorder. And the genetic tests they carried out revealed an abnormality in the SCN4A sodium channel. Correlation or causation? The mystery only deepens, I think.

tremor. Rufus Gefangenen on Flikr. https://www.flickr.com/photos/rufo_83/330164755/in/photolist-vbbtM
tremor. Rufus Gefangenen on Flikr. https://www.flickr.com/photos/rufo_83/330164755/in/photolist-vbbtM

 

As researchers dig deeper, they will have to decide if it’s neurodegeneration or channelopathy. Or perhaps both. This may then open the doors to better treatments for the disease, confining Propranolol and Primidone to the history books.

 

 

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!

What are the most controversial questions in neurology?

Uncertainty and doubt abound in Neurology. There are many evidence-free areas where experts rub each other the wrong way. These controversies are big and occur in all neurology subspecialties. Controversy-busters have tried for about a decade to iron out these wrinkles on neurology’s face, but the unanswered questions remain. This is why there is a 10th World Congress of Controversies in Neurology (CONy) holding in Lisbon this year.

I want to assure you I have no conflict of interest to declare in this blog. My interest is to explore  which questions have plagued this conference over the last 10 years to pick out the most controversial topics in neurology. To do this I reviewed all previous conference programs and focused on the items that were slated for debate. I looked for practical topics that have remained unresolved, or are just emerging. Here are my top controversial neurological questions:

Raccoon argument II. Tambako The Jaguar on Flikr. https://www.flickr.com/photos/tambako/7460999402
Raccoon argument II. Tambako The Jaguar on Flikr. https://www.flickr.com/photos/tambako/7460999402

 

1st CONy 2007 (Berlin, Germany)

  • Clinically isolated syndromes (CIS): To treat or not to treat
  • Is stem cell therapy an imminent treatment in advanced multiple sclerosis (MS)?
  • Vascular cognitive impairment is a misleading concept?
  • Is mild cognitive impairment a misleading concept?

 

2nd CONy 2008 (Athens, Greece)

  • Can physical trauma precipitate multiple sclerosis?
  • Should patients with Parkinson’s disease (PD) be treated in the pre-motor phase?
  • What is the first line therapy for chronic inflammatory demyelinating polyneuropathy (CIDP)?
  • Is intravenous immunoglobulin (IVIg) effective in chronic myasthenia gravis (MG)?
  • Tau or ß-amyloid immunotherapy in Alzheimer’s disease (AD)?
  • Chronic fatigue syndrome is an organic disease and should be treated by neurologists?

 

3rd CONy 2009 (Prague, Czech Republic)

  • Should cerebrospinal fluid (CSF) be tested in every clinically isolated syndrome?
  • Can we prevent multiple sclerosis (MS) by early vitamin D supplementation and EBV vaccination?
  • Does Parkinson’s disease (PD) have a prion-like pathogenesis?
  • Patients with medication overuse headache should be treated only after analgesic withdrawal?

 

 

4th CONy 2010 (Barcelona, Spain)

  • Camptocormia in parkinson’s disease (PD): Is this dystonia or myopathy?
  • Does chronic venous insufficiency play a role in the pathogenesis of multiple sclerosis (MS)?
  • IVIg or immunosuppression for long-term treatment of CIDP?

 

5th CONy 2011 (Beijing, China)

  • Is sporadic Parkinson’s disease etiology predominantly environmental or genetic?
  • Is multiple sclerosis (MS) an inflammatory or a primarily neurodegenerative disease?
  • Are the new multiple sclerosis oral medications superior to conventional therapies?
  • Is bilateral transverse venous sinus stenosis a critical finding in idiopathic intracranial hypertension (IIH)?

 

6th CONy 2012 (Vienna, Austria)

  • Will there ever be a valid biomarker for Alzheimer’s disease (AD)?
  • Is amyloid imaging clinically useful in Alzheimer’s disease (AD)?
  • Do functional syndromes have a neurological substrate?
  • Should blood pressure be lowered immediately after stroke?
  • Migraine is primarily a vascular disorder?

 

 

7th CONy 2013 (Istanbul, Turkey)

  • Is intravenous thrombolysis the definitive treatment for acute large artery stroke?
  • Atrial fibrillation related stroke should be treated only with the new anticoagulants?
  • Is the best treatment for chronic migraine botulinum toxin?
  • IS CGRP the key molecule in migraine?
  • Is chronic cluster headache best treated with sphenopalatine ganglion (SPG) stimulation?
  • When should deep brain stimulation (DBS) be initiated for Parkinson’s disease?
  • Do interferons prevent secondary progressive multiple sclerosis (SPMS)?
  • Is deep brain stimulation (DBS) better than botulinum toxin in primary dystonia?
  • Are present outcome measures relevant for assessing efficacy of disease modifying therapies in multiple sclerosis (MS)?
  • Should radiologically isolated syndromes (RIS) be treated?
  • Does genetic testing have a role in epilepsy management?
  • Should cortical strokes be treated prophylactically against seizures?
  • Should enzyme-inducing antiepileptic drugs (AEDs) be avoided?
  • EEG is usually necessary when diagnosing epilepsy

 

8th CONy 2014 (Berlin, Germany)

  • Is late-onset depression prodromal neurodegeneration?
  • Does Parkinson’s disease begin in the peripheral nervous system?
  • What is the best treatment in advanced Parkinson’s disease?
  • Are most cryptogenic epilepsies immune mediated?
  • Should epilepsy be diagnosed after the first unprovoked seizure?
  • Do anti-epileptic drugs (AEDs) contribute to suicide risk?
  • Should the ketogenic diet be prescribed in adults with epilepsy?
  • Do patients with idiopathic generalized epilepsies require lifelong treatment?
  • Cryptogenic stroke: Immediate anticoagulation or long-term ECG recording?
Southern Chivalry: Argument Vs Clubs. elycefeliz on Flikr. https://www.flickr.com/photos/elycefeliz/6271932825
Southern Chivalry: Argument Vs Clubs. elycefeliz on Flikr. https://www.flickr.com/photos/elycefeliz/6271932825

 

9th CONy 2015 (Budapest, Hungary)

  • Is discontinuation of disease-modifying therapies safe in  long-term stable multiple sclerosis?
  • Is behavioral therapy necessary for the treatment of migraine?
  • Which is the first-line therapy in cases of IIH with bilateral papilledema?
  • Should patients with unruptured arterio-venous malformations (AVM) be referred for intervention?
  • Should survivors of hemorrhagic strokes be restarted on oral anticoagulants?
  • Will stem cell therapy become important in stroke rehabilitation?
  • Do statins cause cognitive impairment?

 

10th CONy 2016 (Lisbon, Portugal)

  • Which should be the first-line therapy for CIDP? Steroids vs. IVIg
  • Should disease-modifying treatment be changed if only imaging findings worsen in multiple sclerosis?
  • Should disease-modifying therapies be stopped when secondary progressive MS develops?
  • Should non-convulsive status epilepsy be treated aggressively?
  • Does traumatic chronic encephalopathy (CTE) exist?
  • Does corticobasal degeneration (CBD) exist as a clinico-pathological entity?
  • Is ß-amyloid still a relevant target in AD therapy?
  • Will electrical stimulation replace medications for the treatment of cluster headache?
  • Carotid dissection: Should anticoagulants be used?
  • Is the ABCD2 grading useful for clinical management of TIA patients?
  • Do COMT inhibitors have a future in treatment of Parkinson’s disease?

 

Debate Energetico. Jumanji Solar on Flikr. https://www.flickr.com/photos/jumanjisolar/5371921203
Debate Energetico. Jumanji Solar on Flikr. https://www.flickr.com/photos/jumanjisolar/5371921203

 

Going through this list, I feel reassured that the experts differ in their answers to these questions? The acknowledgement of uncertainty allows us novices to avoid searching for non-existent black and white answers. It is however also unsettling that I thought some of these questions had been settled long ago. It goes to show that apparently established assumptions are not unshakable?

Do you have the definitive answers to resolve these controversies? Are there important controversies that are missing here? Please leave a comment

 

12 fascinating advances in epilepsy: big data to pacemakers

I recently posted on the role of vagus nerve stimulation (VNS) in epilepsy. Exciting as it is, there are several cutting edge developments in epilepsy that are making VNS ‘old school’. Here is a round-up of 12 such developments

1. Big data to improve epilepsy care

"Scatter plot" by UCRL - Visualizations that have been created with VisIt. at wci.llnl.gov. Licensed under Public Domain via Commons - https://commons.wikimedia.org/wiki/File:Scatter_plot.jpg#/media/File:Scatter_plot.jpg
“Scatter plot” by UCRL – Visualizations that have been created with VisIt. at wci.llnl.gov. Licensed under Public Domain via Commons – https://commons.wikimedia.org/wiki/File:Scatter_plot.jpg#/media/File:Scatter_plot.jpg

Big Data is spreading its tentacles everywhere and epilepsy is no exception. Take this review in Lancet Neurology for example; titled ‘Epilepsy in 2015: the year of collaborations for big data’, it reviews the impact of big data in five key epilepsy areas such as surgery, effect of epilepsy on pregnancy, and risks if anti-epileptic drugs (AEDs). I was however more impressed by the paper in Neurology titled Predicting frequent ED use by people with epilepsy with health information exchange data‘ which shows how big data may be used to identify frequent emergency department attenders. The authors showed how big data achieves this; the whole aim is to pick out those patients may benefit most from targeted-interventions. The article itself doesn’t mention big data, but the accompanying editorial fortunately does.

2. Better epilepsy monitoring devices

"EEG Recording Cap" by Chris Hope - http://www.flickr.com/photos/tim_uk/8135755109/. Licensed under CC BY 2.0 via Commons - https://commons.wikimedia.org/wiki/File:EEG_Recording_Cap.jpg#/media/File:EEG_Recording_Cap.jpg
“EEG Recording Cap” by Chris Hope – http://www.flickr.com/photos/tim_uk/8135755109/. Licensed under CC BY 2.0 via Commons – https://commons.wikimedia.org/wiki/File:EEG_Recording_Cap.jpg#/media/File:EEG_Recording_Cap.jpg

 

The management of epilepsy is very dependent on the accurate assessment of each patient’s day-to-day event pattern. In the simplest form, this is by a seizure diary. Seizures, the abnormal electrical brain activity that result in epilepsy, do not always manifest as recognisable events. Furthermore, many abnormal movements and behaviours do not necessarily arise from seizures. The neurologist therefore often recommends some form of prolonged brain activity monitoring to sort out what is actually happening. This is often done with procedures such as ambulatory electroencephalogram (EEG) and video EEG telemetry. These are all inconvenient and may only be used for a limited period. It is therefore reassuring that there are better techniques on the way. This press release from the World Federation of Neurology titled New epilepsy monitoring devices offer alternatives to inpatient video EEG lists ‘an array’ of devices such as the Brain Sentinel® System and the EEG PatchTM. These go further than just identifying the seizure activity; they allow patients to monitor clinical and subclinical seizure activity in the everyday home environment and get advance warning before a seizure strikes‘. What could be better for people with epilepsy?

3. Precision medicines for epilepsy

 

Drug firms 'creating ills for every pill' by Publik15 on Flikr. https://www.flickr.com/photos/publik15/3415531899
Drug firms ‘creating ills for every pill’ by Publik15 on Flikr. https://www.flickr.com/photos/publik15/3415531899

Epilepsy is a disease with several types and subtypes, and many genetic forms. Treating epilepsy therefore requires a close fit (no pun intended) of the disease type to its treatment. This is however a difficult task because many epilepsies are poorly defined, and the activity of anti-epileptic drugs (AEDs) are poorly understood. Whilst there are general principles of action of AEDs, these may not apply to individual patients. Herein then lies the promise of precision medicines which, making use of the patient’s genetic makeup or genome, offer a better match of AEDs to individuals. It is still early days but the course is being charted; the EpiPM Consortium recently published ‘A roadmap to precision medicines in the epilepsies‘ in Lancet Neurology.

4. Better prediction of SUDEP

"Ventricular fibrillation" by Jer5150 - Own work. Licensed under CC BY-SA 3.0 via Commons - https://commons.wikimedia.org/wiki/File:Ventricular_fibrillation.png#/media/File:Ventricular_fibrillation.png
“Ventricular fibrillation” by Jer5150 – Own work. Licensed under CC BY-SA 3.0 via Commons – https://commons.wikimedia.org/wiki/File:Ventricular_fibrillation.png#/media/File:Ventricular_fibrillation.png

 

Sudden unexpected death in epilepsy (SUDEP) is a nightmare. It strikes out of the blues, shocking families and neurologists alike. How to predict and prevent this phenomenon is a holy grail in epilepsy care. It is therefore gratifying news in a recent article in the journal Brain that there is a potential SUDEP imaging biomarker. The authors of the paper, titled Structural imaging biomarkers of sudden unexpected death in epilepsyreport that the magnetic resonance imaging (MRI) scans of people at risk of SUDEP show characteristic signs. The main feature is a larger grey matter volume in the right hippocampus and amygdala. The rest of the story is more tricky to understand and involves impaired oxygen regulation leading to the abnormal heart rhythms that presumably cause SUDEP. OK, just take it that this is a potential biomarker to risk-stratify patients for SUDEP!

5. Out-of-hospital status epilepsy injections

 

By AngelHM (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons
By AngelHM (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)%5D, via Wikimedia Commons

A generalised tonic-clonic (or grand mal) seizure often self-terminates within 5 minutes. It may however be prolonged, or occur repeatedly, and this is called status epilepsy or status epilepticus. Out-of-hospital care to terminate status epilepticus often involves the use of buccal Midazolam or, thankfully fading into history, rectal Diazepam. The most effective short-term treatment is however intravenous Lorazepam, but this may only be administered in hospital. Is there something as effective as intravenous Lorazepam which could be administered by paramedics in the community? You guessed it, there probably is. A recent trial published in the New England Journal of Medicine (NEJM) shows that pre-hospital intramuscular Midazolam delivered by paramedics is effective. There are safety issues to sort out but this development promises to avert brain damage that may result from prolonged convulsions. Neuroscience News offers a simplified version of this study.

6. Optogenetics to improve arousal during a seizure

Optogenetics is the use of light to control cell activity in living tissues. I previously listed this in my previous post as one of 10 remarkable breakthroughs that will change neurology. A recent paper in the journal Epilepsia showed how optogenetics may improve epilepsy. Published under the rather unwieldy title Optogenetic stimulation of cholinergic brainstem neurons during focal limbic seizures…., the authors report the application of optogenetics to stimulate subcortical brainstem cells during a focal epileptic seizure. The story is rather complicated but this technique somehow causes inhibition of the cortical cells that generate seizures. A lot of the physiology remains to be sorted, but hey, its shining a light on a difficult problem!

7. 3D electroencephalography (3D-EEG)

 

"Spike-waves". Licensed under CC BY-SA 2.0 via Commons - https://commons.wikimedia.org/wiki/File:Spike-waves.png#/media/File:Spike-waves.png
“Spike-waves”. Licensed under CC BY-SA 2.0 via Commons – https://commons.wikimedia.org/wiki/File:Spike-waves.png#/media/File:Spike-waves.png

The electroencephalogram (EEG) is an indispensable tool in the diagnosis of epilepsy. It helps, amongst other things, to localise the site of a seizure discharge, and to classify the epilepsy type. It is however a rather insensitive tool for planning epilepsy surgery compared to imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) scans which are far better. 3D EEG is however set to make its mark in this area if a recent paper in Epilepsia fulfils its promise. Titled ‘The diagnostic utility of 3D electroencephalography source imaging in pediatric epilepsy surgery‘, the authors show that 3-D EEG is comparable to PET and SPECT in planning epilepsy surgery; and it is also cheaper and less risky.

8. Neurotransmitter imaging of epilepsy

By courtesy of Massachusetts General Hospital and Draper Labs [Public domain], via Wikimedia Commons
By courtesy of Massachusetts General Hospital and Draper Labs [Public domain], via Wikimedia Commons

Epilepsy surgery relies on accurate mapping of the seizure focus. Current techniques are however still suboptimal and scientists are exploring better ways of doing this. One promising field is neurotransmitter-based imaging, and the main neurotransmitter here is glutamate. This MRI technique called glutamate chemical exchange saturation transfer (GluCEST) promises to identify seizure foci that are otherwise difficult to detect. You may read the technical aspects in the original paper in Science Translational Medicine, or go for the layman’s version in Neuroscience News.

An extension of glutamate imaging uses PET scans and relies on imaging NMDA, one type of glutamate receptor. This technique is reported in the Journal of Neurology, Neurosurgery and Psychiatry (JNNP) in an article titled NMDA receptor binding in focal epilepsies. The principle behind NMDA imaging is the knowledge that NMDA receptor ion channels are overactive in epilepsy. Isn’t it nice when science follows first principles!

9. Better mapping of seizure focus

"MRI Location Hippocampus up." by Amber Rieder, Jenna Traynor - Own work. Licensed under CC0 via Commons - https://commons.wikimedia.org/wiki/File:MRI_Location_Hippocampus_up..png#/media/File:MRI_Location_Hippocampus_up..png
“MRI Location Hippocampus up.” by Amber Rieder, Jenna Traynor – Own work. Licensed under CC0 via Commons – https://commons.wikimedia.org/wiki/File:MRI_Location_Hippocampus_up..png#/media/File:MRI_Location_Hippocampus_up..png

Surgery is a very useful tool in treatment of drug-resistant epilepsy. Epilepsy surgery is however not universally successful because localisation of the seizure focus is often imprecise. One promising way to improve the localisation of the seizure focus is to map the changes in oxygen levels that occur in the brain during an epileptic seizure. A paper in the JNNP reports that this is feasible with the use of simultaneous EEG (electroencephalography) and fMRI (functional magnetic resonance imaging). It’s all rather complicated stuff and I recommend this version from the Epilepsy Society which offers an excellently simplified summary. 

10. Personalised epilepsy surgery

"White Matter Connections Obtained with MRI Tractography" by Xavier Gigandet et. al. - Gigandet X, Hagmann P, Kurant M, Cammoun L, Meuli R, et al. (2008) Estimating the Confidence Level of White Matter Connections Obtained with MRI Tractography. PLoS ONE 3(12): e4006. doi:10.1371/journal.pone.0004006. Licensed under CC BY 2.5 via Commons.
White Matter Connections Obtained with MRI Tractography” by Xavier Gigandet et. al. – Gigandet X, Hagmann P, Kurant M, Cammoun L, Meuli R, et al. (2008) Estimating the Confidence Level of White Matter Connections Obtained with MRI Tractography. PLoS ONE 3(12): e4006. doi:10.1371/journal.pone.0004006. Licensed under CC BY 2.5 via Commons.

 

A holy grail of epilepsy (OK, there are many holy grails) is to individualise all types of epilepsy treatment, including surgery. Personalised epilepsy surgery is guided by a simulated model of a patient’s brain neural connections or connectome. This technique is reported in PLOS Computational Biology  under the title Predicting surgery targets in temporal lobe epilepsy through structural connectome based simulations. Why scientists love long windy titles baffles me. Anyway, the authors first acquired a map of their subject’s brain connectivity using an MRI technique called diffusion tensor imaging (DTI). They then applied a computerised model of how a seizure propagates to the connectivity map. In this way they are able to establish a more accurate surgical target. The area that is resected at surgery using this technique produced better outcomes than resection using a standard procedure. Makes sense to me.

11. Endoscopic epilepsy surgery

"Flexibles Endoskop" by de:Benutzer:Kalumet - Own work. Licensed under CC BY-SA 3.0 via Commons - https://commons.wikimedia.org/wiki/File:Flexibles_Endoskop.jpg#/media/File:Flexibles_Endoskop.jpg
“Flexibles Endoskop” by de:Benutzer:Kalumet – Own work. Licensed under CC BY-SA 3.0 via Commons – https://commons.wikimedia.org/wiki/File:Flexibles_Endoskop.jpg#/media/File:Flexibles_Endoskop.jpg

 

Although surgery is a good technique for epilepsy, it is an invasive procedure with attendant risks. Endoscopy, using minimal access to perform great feats, reduces this risk significantly. It is widely practiced in medicine and indeed neurosurgeons use it to relieve raised intracranial pressure in some cases. It is therefore a relief to learn that major epilepsy operations may be performed endoscopically. A recent article in the Journal of Neuroscience titled ‘Endoscopic corpus callosotomy and hemispherectomy reports the effectiveness of endoscopy in epilepsy operations such as corpus callosotomy; a procedure that interrupts the large bundle of nerve fibers that connect the two brain hemispheres. You may read the easy version in Mental Floss.

12. Deep brain stimulation for epilepsy

 

By Shamir R, Noecker A and McIntyre C [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons
By Shamir R, Noecker A and McIntyre C [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)%5D, via Wikimedia Commons

Deep brain stimulation (DBS) is now routine in many neurological diseases such as Parkinson’s disease (PD). Epilepsy has been slow to catch on but this is changing. A recent piece on the Mayo Clinic website peered into the future treatment options for epilepsy and referred to pacemaker-like devices to control the seizure focus. There are many studies showing the feasibility and effectiveness of implantable devices which directly stimulate an epileptic focus to abort a seizure. One such system is Responsive Brain Neurostimulator (RNS® System)It may be counterintuitive but stimulation rather than suppression is the key. A review of Responsive neurostimulation in epilepsy says ‘the strategy is to interfere as early as possible with the accumulation of seizure activity to prematurely abort or even prevent an upcoming seizure’.

"Hippocampus small" 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.. Licensed under CC BY-SA 2.1 jp via Commons - https://commons.wikimedia.org/wiki/File:Hippocampus_small.gif#/media/File:Hippocampus_small.gif
“Hippocampus small” 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.. Licensed under CC BY-SA 2.1 jp via Commons – https://commons.wikimedia.org/wiki/File:Hippocampus_small.gif#/media/File:Hippocampus_small.gif

The future is bright for epilepsy care-and it can’t come soon enough for the millions of people whose lives are restricted and compromised by this disease.

Vagus nerve stimulation: from neurology and beyond!

The vagus nerve is one of 12 pairs of nerves that come off the lower part of the brain called the brainstem. It is the tenth in line and therefore also called the tenth cranial (or X) nerve.

 

By Brain_human_normal_inferior_view_with_labels_en.svg: *Brain_human_normal_inferior_view.svg: Patrick J. Lynch, medical illustrator derivative work: Beao derivative work: Dwstultz [CC BY 2.5 (http://creativecommons.org/licenses/by/2.5)], via Wikimedia Commons
By Brain_human_normal_inferior_view_with_labels_en.svg: *Brain_human_normal_inferior_view.svg: Patrick J. Lynch, medical illustrator derivative work: Beao derivative work: Dwstultz [CC BY 2.5 (http://creativecommons.org/licenses/by/2.5)%5D, via Wikimedia Commons

It is an interesting nerve for various reasons. Unlike other cranial nerves, it travels way beyond the head and neck. It has a very long course through the neck to the chest and abdomen. Furthermore it regulates a wide variety of organ functions such as heart, respiratory and gut activities. An important branch of the vagus nerve is the recurrent laryngeal nerve which innervates the larynx (voice box). 

Due to a quirk of the embryonic development of the aorta, this nerve gets pulled down into the chest before it makes a U-turn back to the neck. It is therefore easily damaged in operations of the neck or chest, and therefore the bane of surgeons.

 

By Truth-seeker2004 (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons
By Truth-seeker2004 (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)%5D, via Wikimedia Commons

Scientists have recognised this characteristic feature of the vagus nerve and have tried to manipulate it for therapeutic reasons. The most well-recognised is the stimulation of the vagus nerve to control epileptic seizures. This vagus nerve stimulation (VNS) requires implanting a stimulator under the skin on the chest, and this is connected to the vagus nerve with wires. Somehow or the other, this stimulation modulates seizures. The Epilepsy Society has detailed information on the technical aspects of VNS, and below is a video showing how VNS works.

The American Academy of Neurology guidelines on VNS, published in the journal Neurology, help Neurologists decide when to use VNS. Below are the main indications for VNS in epilepsy:

  • Refractory partial onset seizures in adults >12 years not suitable for surgery
  • Partial or generalised seizures in children
  • Lennox-Gastaut syndrome (LGS)
  • Mood improvement in adult epilepsy

VNS has other neurological indications  which are coming online and top of these is Cluster headache. And now, just off the press, is a possible role for VNS in migraine.

Headache by openDemocracy on Flikr. https://www.flickr.com/photos/opendemocracy/1482020719
Headache by openDemocracy on Flikr. https://www.flickr.com/photos/opendemocracy/1482020719

 

There are however several non-neurological diseases that may benefit from VNS including arthritis, diabetes, hiccups and heart failure. Science News explores these indications further in an article interestingly titled Viva Vagus: Wandering Nerve Could Lead to Range of TherapiesLike opening a can of worms, VNS may extend it’s tentacles far and wide; imagine for example that there is a study looking at the benefit of VNS in bulimia.

"Bulimiav bvjkfhdnijf" by Merlymeleanrossana - Treball propi. Licensed under CC BY-SA 3.0 via Wikimedia Commons - https://commons.wikimedia.org/wiki/File:Bulimiav_bvjkfhdnijf.jpg#/media/File:Bulimiav_bvjkfhdnijf.jpg
“Bulimiav bvjkfhdnijf” by Merlymeleanrossana – Treball propi. Licensed under CC BY-SA 3.0 via Wikimedia Commons – https://commons.wikimedia.org/wiki/File:Bulimiav_bvjkfhdnijf.jpg#/media/File:Bulimiav_bvjkfhdnijf.jpg

 

Whatever next?

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