What are the new diseases emerging in neurology?

Medical futurists predict that scientific advances will lead to more precise definition of diseases. This will inevitably result in the emergence of more diseases and fewer syndromes. This case is made very eloquently in the book, The Innovators Prescription. Many neurological disorders currently wallow at the intuitive end of medical practice, and their journey towards precision medicine is painfully too slow. Neurology therefore has a great potential for the emergence of new disorders.

https://pixabay.com/en/pie-chart-diagram-statistics-parts-149727/
https://pixabay.com/en/pie-chart-diagram-statistics-parts-149727/

In the ‘good old days’, many diseases were discovered by individual observers working alone, and the diseases were named after them. In this way, famous diseases were named after people such as James Parkinson, Alois Alzheimer, and George Huntington. For diseases discovered by two or three people, it didn’t take a great stretch of the imagination to come up with double-barrelled names such as Guillain-Barre syndrome (GBS) or Lambert-Eaton myasthenic syndrome (LEMS).

By uncredited - Images from the History of Medicine (NLM) [1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=11648572
By uncredited – Images from the History of Medicine (NLM) [1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=11648572
Today, however, new diseases emerge as a result of advances made by large collaborations, working across continents. These new diseases are named after the pathological appearance or metabolic pathways involved (as it will require an act of genius to create eponymous syndromes to cater for all the scientists and clinicians involved in these multi-centre trials). This is unfortunately why new disorders now have very complex names and acronyms. Take, for examples, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) and chronic relapsing inflammatory optic neuropathy (CRION). It is a sign that we should expect new neurological diseases to be baptised with more descriptive, but tongue-twisting, names.

 

https://pixabay.com/en/letters-a-abc-alphabet-literacy-67046/
https://pixabay.com/en/letters-a-abc-alphabet-literacy-67046/

New disease categories emerge in different ways. One is the emergence of a new disorder from scratch, with no antecedents whatsoever. Such was the case with autoimmune encephalitis, a category which has come from relative obscurity to occupy the centre stage of eminently treatable diseases. I have posted on this previously as What’s evolving at the cutting edge of autoimmune neurology and What are the dreadful autoimmune disorders that plague neurology? Other disease categories form when different diseases merge into a completely new disease category, or when a previously minor diseases mature and stand on their own feet. These are the stuff of my top 8 emerging neurological disorders.

 

By Photo (c)2007 Derek Ramsey (Ram-Man) - Self-photographed, CC BY-SA 2.5, Link
By Photo (c)2007 Derek Ramsey (Ram-Man) – Self-photographed, CC BY-SA 2.5, Link

1. mTORopathy

This huge monster is ‘threatening’ to bring together, under one roof, diverse disorders such as tuberous sclerosis complex, epilepsy, autism, traumatic brain injury, brain tumours, and dementia. You may explore this further in my previous blog post titled mTORopathy: an emerging buzzword for neurology.

Merging bubbles. Charlie Reece on Flikr. https://www.flickr.com/photos/charliereece/777487250
Merging bubbles. Charlie Reece on Flikr. https://www.flickr.com/photos/charliereece/777487250

2. IgG4-related autoimmune diseases

This new group of neurological diseases is threatening to disrupt the easy distinction between several neurological disorders such as myasthenia gravis (MG), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and Guillain Barre syndrome (GBS). It even includes the newly described IgLON 5 antibody disorder, something I blogged about as IgLON5: a new antibody disorder for neurologists. You may explore IgG4-related disorders in this paper titled The expanding field of IgG4-mediated neurological autoimmune disorders. 

By Aida Pitarch - Own work, CC BY-SA 4.0, Link
By Aida PitarchOwn work, CC BY-SA 4.0, Link

3. Anti-MOG antibody disorders

Now, neurologists have always known about MOG, mostly as a minor bit player, an extra, so to say. No more, it is now all grown up and matured. And the growth is fast and involves many inflammatory demyelinating disease of the CNS such as fulminant demyelinating encephalomyelitis and multiphasic disseminated encephalomyelitis. How far will it go?

http://thebluediamondgallery.com/a/autoimmune.html
http://thebluediamondgallery.com/a/autoimmune.html

4. Hepatitis E virus related neurological disorders

A field which is spurning new neurological disorders is neurological infections, and Hepatitis E virus (HEV) is in the forefront. We are now increasingly recognising diverse Hepatitis E related neurological disorders. HEV has now been linked to diseases such as Guillain Barre syndrome (GBS) and brachial neuritis. And the foremost researcher in this area is Harry Dalton, a hepatologist working from Cornwall, not far from me! And Harry will be presenting at the next WESAN conference in Exeter in November 2017.

By Transferred from en.wikipedia to Commons.This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #5605.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−, Public Domain, Link
By Transferred from en.wikipedia to Commons.This media comes from the Centers for Disease Control and Prevention‘s Public Health Image Library (PHIL), with identification number #5605.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−, Public Domain, Link

5. Zika virus

Zika virus is another novel infection with prominent neurological manifestations. We are learning more about it every day, and you may check my previous blog post on this, titled 20 things we now know for certain about the Zika virus.

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

6. Multisystem proteinopathy

Multisystem proteinopathy is a genetic disorder which affects muscles and bone, in addition to the nervous system. It is associated with Paget’s disease of the bone and inclusion body myositis, with implications for motor neurone disease (MND) and frontotemporal dementia (FTD). Quite a hydra-headed monster it seems, all quite complex, and perhaps one strictly for the experts.

Hydra. Andrew Jian on Flikr. https://www.flickr.com/photos/andrew_jian/475479747
Hydra. Andrew Jian on Flikr. https://www.flickr.com/photos/andrew_jian/475479747

7. GLUT-1 deficiency syndromes

GLUT-1 stands for glucose transporter type 1. Deficiency of GLUT-1 results in impaired transportation of glucose into the brainGLUT-1 deficiency syndrome presents with a variety of neurological features such as dystonia, epilepsy, ataxia, chorea, and a host of epilepsy types. It starts in infancy and is characterised by a low level of glucose and lactic acid in the cerebrospinal fluid. Expect to hear more on this in the near future.

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

8. Progressive Solitary Sclerosis

And this is my favourite paradigm shifter. Neurologists often see people with brain inflammatory lesions and struggle to decide if they fulfil the criteria for multiple sclerosis (MS). The current threshold for concern is when there have been two clinical events consistent with inflammation of the nervous system, or their MRI scan shows involvement of at least two different sites of the nervous system. Well, dot counting may soon be over, going by this paper in Neurology titled Progressive solitary sclerosis: gradual motor impairment from a single CNS demyelinating lesion. The authors identified 30 people with progressive clinical impairment arising from a single inflammatory nervous system lesion. The authors were convinced enough to recommend the inclusion of this new entity, progressive solitary sclerosis, in future classifications of inflammatory disorders of the central nervous system. Move over progressive MS, here comes progressive SS. Neurologists will surely have their job cut out for them.

Solitary tree at Sunset. epcp on Flikr. https://www.flickr.com/photos/epcprince/3418260382
Solitary tree at Sunset. epcp on Flikr. https://www.flickr.com/photos/epcprince/3418260382

Do you have any suggestions of emerging neurological disorders? Please leave a comment

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PS. These disorders are all covered in neurochecklists

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What are the prospects of stamping out Huntington’s disease?

Huntington’s disease (HD) is, without doubt, one of the most dreaded neurological disorders. It is named after George Huntington, but the first description is probably by Charles Oscar Waters in 1842. It is dominantly inherited, each child carrying a 50% chance of acquiring the faulty gene. The genetics is slightly tricky because HD is also a tricnucleotide repeat expansion disorder, similar to some other neurological diseases such as Friedreich’s ataxia (FA), Kennedy disease, myotonic dystrophyspinocerebellar ataxia (SCA), and oculopharyngeal muscular dystrophy (OPMD). In these diseases, a section of the genetic code duplicates itself repeatedly, producing abnormally long segments; worse still, these segments get longer which each transmission down the family line. This is called genetic anticipation, and it leads to later generations of the family developing the disease at an earlier age, and manifesting it more severely.

By Zephyris from en.wikipedia.org, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2118354
By Zephyris from en.wikipedia.org, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2118354

HD is not a nice disease. It is accompanied by chorea, probably the most distressing abnormal movement to torment the human body. This is a continuous, writhing muscle activity which involves all the body, and generating very grotesque and painful postures. As if this wasn’t enough, dementia eventually sets in, as does almost every other neurological symptom one could imagine. HD is a problem neurology needs to solve. And thankfully there is some activity in that direction. Here are 4 recent hope-raising developments.

1. Gene silencing with ISIS-HTTRx

RNA molecules. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/24148252722
RNA molecules. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/24148252722

The manufacturers of ISIS-HTTRx must surely be rueing the unfortunate choice of name for their gene silencing drug. But they will take comfort in its promise to crush HD. It is the first trial of a new drug for HD, and it is touted as probably ‘one of the most important developments since the gene for Huntington’s disease was discovered‘. ISIS-HTTRx neutralises huntingtin, the toxic product which accumulates in, and damages, the nerves of people with HD. The only snag…it has to be delivered directly into the spinal fluid. I’m sure an oral tablet will eventually follow, but ISIS-HTTRx is still a long way off; it has to be tested in human volunteers first. One eye then on Sarah Tabrizi, the trial lead, and the other eye on the drug’s name; ISIS pharmaceuticals is now IONIS.

2. Suppressing Huntingtin by enhancing PPAR-δ

By Emw - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8820973
By EmwOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8820973

PPAR-δ stands for peroxisome proliferator-activated receptor delta, and it is a good guy. Researchers have shown that enhancing the activity of PPAR-δ in mouse models of HD has a beneficial effect on mitochondrial function, motor activity, neurodegeneration, and survivalHuntingtin, the infamous bad protein in HD, suppresses PPAR-δ activity. But the wily researchers found a way to reverse this suppression by using an agent called KD3010. They announced their findings in Nature Medicine under the refreshingly self-explanatory title, PPAR-δ is repressed in Huntington’s disease, is required for normal neuronal function and can be targeted therapeutically. (OK, it could be a little shorter). The question now is whether this can be translated to humans. We don’t have too long to wait to find out because the Food and Drug Administration (FDA) has just approved KD3010 human trials

3. Removing cholesterol by boosting CYP46A1

By Jynto (talk) - Own workThis chemical image was created with Discovery Studio Visualizer., CC0, https://commons.wikimedia.org/w/index.php?curid=37702275
By Jynto (talk) – Own workThis chemical image was created with Discovery Studio Visualizer., CC0, https://commons.wikimedia.org/w/index.php?curid=37702275

CYP46A1 is an enzyme which regulates the breakdown of cholesterol. And what has cholesterol got to do with HD? Well…wait for this…cholesterol accumulates in the nerve cells of people with HD, and may contribute to nerve damage. The good news is that CYP46A1 helps to get rid of cholesterol, and some researchers postulate that medicines which enhance the activity of CYP46A1 will improve HD. This all comes from a paper in the journal Brain titled CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease. We are still at the proof of concept stages, but it will help if the CYP46A1-enhancing drugs come as handy pills! 

4. Controlling chorea with deutetrabenazine

By (bencbartlett (talk)) - I (bencbartlett (talk)) created this work entirely by myself., CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=27611647
By (bencbartlett (talk)) – I (bencbartlett (talk)) created this work entirely by myself., CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=27611647

Neurologists are familiar with tetrabenazine, the best treatment for chorea. And Star Trek fans are familiar with the heavy hydrogen atom, deuterium. Put the two together and, voila, you get deutetrabenazine (SD809). The heavy hydrogen of deuterium makes deutetrabenazine a more stable drug. This should make it last longer in the body, and also cause less side effects. Considering that the adverse effects of tetrabenazine include depression and parkinsonism, this is not an insignificant advantage (pardon the double negative…I couldn’t help it).

How well does deutetrabenazine translate to clinical practice? Sufficiently well enough it seems, going by the trial published in JAMA Neurology titled Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease. The authors compared the drug to placebo and showed that deutetrabenazine effectively improved chorea at 12 weeks. It is not surprising that the trial compared deutetrabenazine to placebo rather than the existing alternative; head-to-head drug trials are as rare as hen’s teeth in medicine (I wonder why that is). Anyway, deutetrabenazine may be coming to a pharmacy near you soon…we hope. 

Hope. Sign pointing to the village of Hope, Derbyshire UK. Paul Sifter on Flikr. https://www.flickr.com/photos/polsifter/4047982682
Hope. Sign pointing to the village of Hope, Derbyshire UK. Paul Sifter on Flikr. https://www.flickr.com/photos/polsifter/4047982682

There is still a long way to go yet, but each  small step is a glimmer of hope for a neurodegenerative disease such as HD.

Remember, you can have everything HD at your fingertips with neurochecklists (and pardon the shameless pitch).

Addendum

Shortly after posting this blog I came across these articles on HD prospects

  • From Huntington’s Disease News comes Pridopidine. One more to add to the hope for neuroprotection against HD.
  • From the Hazard Gazette comes SIRT2 as a future treatment target for HD

Are these the all-time most influential Neurologists?

Who are the most influential neurologists in history? Not an easy task as the starting field is rather wide. Creating a ‘top list‘ of anything is potentially controversial because there are often no clear inclusion criteria, and justifications are often subjective.

 

"Alois Alzheimer 003" by uncredited - http://neurophilosophy.wordpress.com/2006/11/03/100-years-of-alzheimers-disease/. Licensed under Public Domain via Commons - https://commons.wikimedia.org/wiki/File:Alois_Alzheimer_003.jpg#/media/File:Alois_Alzheimer_003.jpg
“Alois Alzheimer 003” by uncredited – http://neurophilosophy.wordpress.com/2006/11/03/100-years-of-alzheimers-disease/. Licensed under Public Domain via Commons – https://commons.wikimedia.org/wiki/File:Alois_Alzheimer_003.jpg#/media/File:Alois_Alzheimer_003.jpg

 

I was initially swayed by the length of Wikipedia entries but cautioned myself when I noticed that the piece on Raymond Adams was very brief. Furthermore, there was no entry at all for C David Marsden! Sacrilege, I thought. I felt strongly enough about this that I registered as a Wikipedia editor, and now there is a Wikipedia page for David Marsden.

By Joaquín Sorolla (1863 - 1923) ([1]) [Public domain or Public domain], via Wikimedia Commons
Santiago Ramon y Cajal by Joaquín Sorolla (1863 – 1923) ([1]) [Public domain or Public domain], via Wikimedia Commons

Fame and celebrity are also significant influences on ‘top lists’. The debate that followed Gerald Stern‘s article, the world’s best known neurologist, shows the justifiable importance of fame, but I tried hard to discount ‘mere’ celebrity. By the way, Stern’s lecture on this subject is worth viewing.

Eponymous syndromes also tug at the heart, and I discovered that there is a book titled Neurological Eponyms. I have not read it, so I am unbiased in this regard. It is however difficult to avoid the influence of JMS Pearce who seems to have written on every neurology great!

To compose a credible list, I thought a set of criteria was essential and I guided myself with these:

  • Volume, significance, and variety of contribution to neurology
  • Influence on clinical practice
  • Longevity of contribution
  • Breaking new grounds
  • Influence on other Neurology greats
  • Receipt of a Nobel prize
  • Lasting legacy in terms of books 
Jean Marie Charcot by André Brouillet (see below) [Public domain], via Wikimedia Commons
Jean Marie Charcot by André Brouillet (see below) [Public domain], via Wikimedia Commons

I have been liberal with the term ‘neurologist’ in the context of making this list. I have considered any specialist who has made a significant contribution to neurological knowledge and practice (how else would Alois Alzheimer get on the list?) Did I forget to mention-each name on the list is not living!

George Huntington (c. 1908)
George Huntington (c. 1908)

 

Here then is my list of The Top 30 Most Influential Neurologists with links to their Wikipedia entries:

  1. Raymond ADAMS
  2. Alois ALZHEIMER
  3. Joseph BABINSKI
  4. Charles BELL
  5. Paul BROCA
  6. Santiago Ramón y CAJAL
  7. Jean-Martin CHARCOT
  8. Macdonald CRITCHLEY
  9. Guillaume DUCHENNE
  10. Charles Miller FISHER
  11. Nikolaus FRIEDREICH
  12. Norman GESCHWIND
  13. William Richard GOWERS
  14. Anita HARDING
  15. Gordon Morgan HOLMES
  16. George HUNTINGTON
  17. John Hughlings JACKSON
  18. Gheorghe MARINESCU
  19. Rita LEVI-MONTALCINI
  20. Pierre MARIE
  21. C David MARSDEN
  22. H Houston MERRITT
  23. Antonio Egas MONIZ
  24. James PARKINSON
  25. Arnold PICK
  26. Heinrich Irenaeus QUINCKE
  27. Charles Scott SHERRINGTON
  28. Charles Putnam SYMONDS
  29. Thomas WILLIS
  30. Samuel Alexander Kinnier WILSON

 

"An unidentified man" by Unknown - http://www.tecnologiahechapalabra.com/img_noticias/@old/%7B6E28BB2F-B004-4354-865D-F275131FBEB2%7D_James_Parkinson.jpg. Licensed under Public Domain via Wikimedia Commons - https://commons.wikimedia.org/wiki/File:An_unidentified_man.jpg#/media/File:An_unidentified_man.jpg
“An unidentified man” by Unknown – http://www.tecnologiahechapalabra.com/img_noticias/@old/%7B6E28BB2F-B004-4354-865D-F275131FBEB2%7D_James_Parkinson.jpg. Licensed under Public Domain via Wikimedia Commons – https://commons.wikimedia.org/wiki/File:An_unidentified_man.jpg#/media/File:An_unidentified_man.jpg

 

There are however too many influential neurologists, and to do justice to more of them, here is The Neurology Lounge Top 100 Neurology Greats.

If you think there is a name that is not on this list, and you strongly feel that it should be, please let me know (but you must suggest which name on the list should be replaced!) And by the way, do you have a photo of C David Marsden for his Wikipedia entry?

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