When Shakespeare meets neurology: Hamlet, Ophelia and autoimmune encephalitis

Neurology can’t seem to get away from autoimmune disorders of the central nervous system. This blog has visited this topic several times before such as with the posts titled What are the dreadful autoimmune disorders that plague neurology? and What’s evolving at the cutting-edge of autoimmune neurology? The attraction of autoimmune neurological diseases lies in part in the ever-expanding spectrum of the antibodies and the challenging symptoms and syndromes they produce.

By Gentaur – Gentaur, Public Domain, Link

The fairly well-recognised ‘conventional’ antibodies are those against VGKC (Caspr 2 and LGI1), NMDA, and AMPA. There is however an almost endless list of less familiar antibodies such as those against glycine, adenylate kinase 5, thyroid, GABA-A receptors, α-enolase, neurexin-3α, dipeptidyl-peptidase-like protein 6 (DPPX), and myelin oligodendrocyte glycoprotein (MOG). I am however fascinated by the group of disorders caused by antibodies to metabotropic receptors. The main antibody in this group targets the metabotropic glutamate receptor 5 (mGluR5). The clinical picture with this antibody is a form of encephalitis which may manifest with prosopagnosia (difficulty recognising faces), and with the curious Ophelia syndrome.

By Benjamin WestOwn work, Public Domain, Link

Yes, you read it correctly. Ophelia syndrome is named after Shakespeare’s unfortunate Danish maiden, and it was first described by Dr. Ian Carr whose daughter, at the age of 15, developed progressive loss of memory, depression, hallucinations, and bizarre behaviour. These symptoms aptly describe Ophelia’s deluded and obsessional attraction to the equally deluded and murderous Hamlet. Ophelia syndrome is almost always associated with Hodgkins lymphoma and affects young people.

By V from Coventry, UK – Hamlet, CC BY 2.0, Link

Thankfully Ophelia syndrome is a relatively mild disease without the Shakespearean tragic ending because it has a good outcome if recognised and treated.

Why not explore all the autoimmune neurological disorders on neurochecklists.

What are the drugs promising neuroprotection in PD?

This is a follow up to my previous blog post titled The emerging research boosting Parkinson’s disease treatment. That post reviewed breakthroughs in the treatment of Parkinson’s disease (PD). But what are the advances in preventing the dreaded disease? What is the state of neuroprotection in PD? What are the hopes for attaining this elusive holy grail of neurology, the lodestone of neuroscientists?

shield-33957

Previous claims to neuroprotection have unfortunately fallen flat on their faces. For example, those with long memories will remember the unfulfilled hopes of selegiline. It is therefore not surprising that neurologists entertain all reports of neuroprotection with a heavy dose of scepticism. But this has not deterred the flow of drugs which aim to achieve the seemingly improbable. After scanning the neuroprotection horizon, I came up with this list of 7 potential neuroprotective drugs for PD.

LB-3627

Lab Mouse chekin out the camera. Rick Eh? on Flikr. https://www.flickr.com/photos/rick-in-rio/2593063816
Lab Mouse chekin out the camera. Rick Eh? on Flikr. https://www.flickr.com/photos/rick-in-rio/2593063816

LB-3627 is a drug which is reported to protect dopamine-producing cells in experimental animals. The wary neurologist will surely ignore the hype in the headlines such as New drug that protects dopamine cells raises treatment hope for Parkinson’s, or Pioneering Neuroprotective Results Achieved in Parkinson’s Disease Preclinical Studies. The neurologists will prefer to forensically interrogate the study directly, and it is published in Journal of Neuroscience as Selective VIP Receptor Agonists Facilitate Immune Transformation for Dopaminergic Neuroprotection in MPTP-Intoxicated Mice. The researchers theorise that the damage to dopamine producing cells in the brain is a result of some sort of inflammation, and this damage can be prevented if vasoactive intestinal peptide (VIP) receptors on the cells are ‘tuned’ correctly. LB-3627, by acting as a VIP-like substance, seems to do this tuning quite well. By doing this, it protects up to 80% of the cells in PD mice. The dubious, but curious, neurologists will await the results of human trials.

Phenylbutyrate

By Marvin 101 - Own work, CC BY-SA 3.0, Link
By Marvin 101Own work, CC BY-SA 3.0, Link

α-synuclein is the abnormal protein which accumulates in brain cells, thereby causing the damage which results in PD. α-synuclein is removed from the brain by another protein named DJ-1. Researchers have shown that the gene which regulates the production of DJ-1 is abnormal in a hereditary form of PD called PARK-7. This is where phenylbutyrate steps into the picture; studies have shown that phenylbutyrate ‘up-regulates‘ the DJ-1 gene, thereby enhancing its activity, which is to efficiently flush α-synuclein out of the brain. As phenylbutyrate seems to do this trick in mice, human trials are now under way. All is explained in the paper published in the Journal of Biological Chemistry titled Phenylbutyrate upregulates DJ-1 and protects neurons in cell culture and in animal models of Parkinson’s disease.

Rapamycin

mTOR-FKBP12-RAPAMYCIN. Enzymlogic on Flikr. https://www.flickr.com/photos/101755654@N08/9735128265
mTOR-FKBP12-RAPAMYCIN. Enzymlogic on Flikr. https://www.flickr.com/photos/101755654@N08/9735128265

What we need is a drug which stops PD from taking its first step. And this is what Rapamycin seems to have done in mice. I first read this in an article in PsyPost brilliantly titled Rapamycin prevents Parkinson’s in mouse model of incurable neurodegenerative disease. I followed the link to the research paper published in Journal of Neuroscience, irritatingly titled Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin. I tried to decipher what the abstract was saying but read like a foreign language to me. I therefore recommend the PsyPost article for the sake of sanity. Again, we have to wait and see what rapamycin does in humans.

Safinamide

Microglia. Servier Medical Art on Flikr. https://www.flickr.com/photos/serviermedicalart/9731764084
Microglia. Servier Medical Art on Flikr. https://www.flickr.com/photos/serviermedicalart/9731764084

PD researchers are also exploring the neuroprotective potential of safinamide. This is a monoamine oxidase inhibitor (MAOI) which reduces the breakdown of levodopa, the key drug treatment of PD. Safinamide is already licensed as an add-on drug in the treatment of PD. Its neuroprotective effect has been linked to its ability to suppress the activation of microglia, the brain cells which mediate inflammatory cellular damage. Only time will tell.

Miscellaneous

The last three potentially  neuroprotective PD drugs are:

Simvastatin

Ambroxol

Exenatide

 

face-89346_1280

Portents of great things to come, I’m sure. Want to explore more on PD? Have a look at these older posts, and do leave a comment

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neurochecklists-image

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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Masitinib, a breakthrough drug shattering neurology boundaries

In the process of writing a blog post on the research findings altering neurological practice, my sight fell on the drug, Masitinib. I was completely unaware of this tyrosine kinase inhibitor, one of the promising drugs in the fight against multiple sclerosis (MS). We are likely to hear a lot more about Masitinib in MS in the coming months.

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

Masitinib is however not flexing its muscles just in neuro-inflammation. On the contrary, it is seeking laurels far afield, in the realm of neuro-degeneration. I was indeed pleasantly surprised to find that researchers are studying the impact of Masitinib on two other horrible scourges of neurology. The first report I came across is the favourable outcome of a phase 3 trial of Masitinib in motor neurone disease (MND) or amyotrophic lateral sclerosis (ALS). The drug reportedly ‘reached its primary objectives‘ of efficacy and safety. In this trial, Masitinib was used as an add-on to Riluzole, the established MND drug. It’s all jolly collaborative at this stage, but who knows what threat Masitinib will pose to Riluzole in future! You may read a bit more on Masitinib and MND in this piece from Journal of Neuroinflammation.

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

The second report I came across is the potential of Masitinib in the treatment of Alzheimer’s disease (AD). This is at the phase 2 trial stage, and already showing very good outcomes in people with mild to moderate AD. Masitinib was used as an add-on drug to the conventional AD medications Memantine, Donepezil, Galantamine and Rivastigmine. These drugs can therefore rest comfortably on their thrones…at least for now! You can read a bit more on Masitinib and AD in this article from Expert Review of Neurotherapeutics.

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

The question however remains, why should one drug work well on such disparate diseases? I know, this feels like deja vu coming shortly after my last blog post titled Alzheimers disease and its promising links with diabetes. In that post I looked at the promise of the diabetes drug, Liraglutide, in the treatment of Alzheimers disease. I have however also reviewed this type of cross-boundary activity of drugs in my older posts, Will riluzole really be good for cerebellar ataxia? and old drugs, new roles? Perhaps Masitinib is another pointer that, as we precisely define the cause of diseases, they will turn out to be merely different manifestations of the same pathology. Food for thought.

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

 

As I said, this wasn’t the post I set out to write. So watch out for my next blog post, the major research outcomes altering neurological practice.

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Neurochecklists image

20 things we now know for certain about the Zika virus

Zika virus exploded into the news with striking images of children born with small heads in Brazil. This was at a time the country was struggling to plan for the Rio Olympics, and also embroiled in political turmoil. These all helped to embed the virus firmly in the public’s mind.

rio-1512643_1920

Events have unfolded very rapidly, with shifting certainties and swirling speculations. The storm is however now settling, and a clearer picture emerging. And neurology is right at the centre of this viral catastrophe. What is the current state of play? Here are 20 things we now know about the Zika virus.

1. Zika is an arbovirus of the family Flaviviridae

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

2. Zika was first identified in Uganda in 1947

 

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

3. Zika was first isolated from a Rhesus macaque monkey

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

4. The first human cases were reported from Nigeria

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

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

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

 

6. Zika is mainly transmitted by Aedes mosquitoes

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

7. Zika virus is transmitted perinatally

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

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

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

8. Zika virus is also sexually transmitted 

gender-23777

9. Zika virus is most likely transmissible through the skin

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

10. Zika virus primarily infects neural stem cells

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

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

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

The typical symptoms of Zika virus infection are

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

12. Microcephaly is the striking feature of congenital Zika

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

 

13. Zika infection causes several other brain abnormalities

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

Brain abnormalities with congenital Zika infection include:

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

These abnormalities may be seen on brain imaging

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

 

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

15. Zika virus infection causes other neurological diseases

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

There are other neurological diseases associated with Zika virus such as

 

16. Zika virus infection causes many eye abnormalities

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

Eye abnormalities reported with Zika virus infection include

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

 

17. Zika virus may cause impairments in other organ systems

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

Other organs affected by Zika virus lead to disorders such as

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

18. Zika virus infection is confirmed by laboratory tests

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

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

 

 

 

20. There are promising antiviral treatments for Zika virus

syringe-417786_1920

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

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

Advances in the management of giant cell arteritis

Giant cell arteritis (GCA), or temporal arteritis, is an affliction of older people. It results in headache and, more worryingly, blindness and stroke.

By Henry Vandyke Carter - Henry Gray (1918) Anatomy of the Human Body (See "Book" section below)Bartleby.com: Gray's Anatomy, Plate 508, Public Domain, https://commons.wikimedia.org/w/index.php?curid=541352
By Henry Vandyke CarterHenry Gray (1918) Anatomy of the Human Body (See “Book” section below)Bartleby.com: Gray’s Anatomy, Plate 508, Public Domain, https://commons.wikimedia.org/w/index.php?curid=541352

 

The diagnosis of GCA is a clinical one. GCA diagnostic criteria stipulate, amongst other things, onset over the age of 50 years, and inflammation in the blood. A temporal artery biopsy may help to firm up the diagnosis. This is however not always readily available, and often falsely negative. Treatment with steroids is imperative to prevent sudden and irreversible visual loss.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=37300811
By NephronOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=37300811

 

Not much has changed in the world of giant cell arteritis since I was in medical school. Or so I thought. I couldn’t be more wrong. Here are 3 advances challenging the old order in the management of GCA.

 

1. Antiviral treatment

Varicella zoster virus. NIAID on Flikr. https://www.flickr.com/photos/niaid/5614251360
Varicella zoster virus. NIAID on Flikr. https://www.flickr.com/photos/niaid/5614251360

The cause of GCA is a mystery. One suspect is varicella zoster virus (VZV), of shingles fame. As shingles is also a disease of older people, it is no surprise that some researchers suspected a link between VZV and GCA. Writing in the Journal of Infectious Diseases in a paper titled Varicella Zoster Virus in Temporal Arteries of Patients With Giant Cell Arteritis, the authors detected VZV in the arteries of people with GCA, but did not pick up even a scent of VZV in control subjects who did not have GCA.

Another paper which strengthened the bond between GCA and VZV is in JAMA Neurology titled Analysis of Varicella-Zoster Virus in Temporal Arteries Biopsy Positive and Negative for Giant Cell Arteritis. The authors of this study found VZV in the temporal arteries of 119 subjects with GCA. On the strength of this finding, the authors suggest GCA should be treated with anti-viral drugs. I am picking up the scent of a guideline on the way.

2. Monoclonal antibodies

B0007277 Monoclonal antibodies Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814713820
B0007277 Monoclonal antibodies
Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814713820

 

Some researchers, obviously uncomfortable with antiviral drugs, have looked elsewhere for ways to improve the treatment of GCA. And they found a champion in the monoclonal antibody Toclizumab. They published their findings in the Lancet under the title Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. The authors showed that adding Toclizumab to steroids in people with GCA led to sustained remission in 85% of cases; only 40% of the people on placebo achieved remission. I didn’t smell a rat here; the evidence seems quite convincing.

3. PET scan imaging

By Hg6996 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18889860
By Hg6996Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18889860

 

Temporal artery biopsy is hit and miss because GCA is a patchy process. Furthermore, biopsy is invasive and despised by doctor and patient equally. Ever keen to make things painless, doctors have looked at imaging of the artery as a substitute to biopsy. The imaging modalities on the cards include duplex ultrasound and magnetic resonance imaging (MRI). The prize must, however, go to positron emission tomography (PET) which has great potential as indicated in this review of PET scan in GCA. This suggests that PET scan aids the diagnosis, grading, and follow-up of GCA. Additionally, PET scan also identifies inflammation in other blood vessels. I perceive the end of the days of temporal artery biopsy!