Chronic inflammatory demyelinating polyneuropathy (CIDP) is a neurological disorder which causes loss of the fatty myelin covering of large nerves (demyelination). This slows down the speed at which the nerves can transmit electrical impulses. People with CIDP develop weakness and sensory disturbances, but not always in equal measure. CIDP is a pain for the afflicted, and a veritable nightmare for the neurologist.
The diagnostic process for CIDP includes some rather uncomfortable tests such as nerve conduction studies and lumbar puncture (spinal tap). CIDP is however a most rewarding disease to treat because many people respond to immune treatments such as steroids, intravenous immunoglobulins (IVIG), or plasma exchange (PE).
The diagnosis of CIDP is however not straightforward. The results of the tests are not always clearcut, and a lot of sifting and sorting goes into nailing the diagnosis. And even when the diagnosis is eventually made, there is a very long list of potential causes of CIDP which often require treatment on their own merit. Worryingly, some of these conditions make the treatment of CIDP difficult. And this is where IgG antibodies play a nasty role in CIDP.
Neurologists are now recognising that a subset of people with CIDP have IgG4 antibodies which greatly influence the clinical presentation and the treatment of CIDP. Anti-contactin antibody is one such antibody, but by far the most important is anti-neurofascin 155 (NF155). What do we know about this antibody? How does it influence the course of CIDP? To answer these questions, below are 10 important things we now know about CIDP associated with anti-NF155.
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?
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.
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.
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.
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 JamesParkinson, Alois Alzheimer, and GeorgeHuntington. 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).
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.
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.
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.
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.
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.
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 brain. GLUT-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.
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.
Do you have any suggestions of emerging neurological disorders? Please leave a comment
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.
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.
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.
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.
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.
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.
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.
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 dystrophy, spinocerebellar 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.
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
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.
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
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.
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).
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 SIRT2as a future treatment target for HD