At first, it seemed like a single drop, but it is quickly turning into a trickle. The first inkling was a study of >1,700 people with motor neurone disease (MND) which was published in the journal Neurology titled Depression in amyotrophic lateral sclerosis. The authors found that depression is a very frequent diagnosis shortly before people are diagnosed with MND.
Surely a coincidence, I thought. A rogue finding, or even an understandable response to illness. My excuses were however debunked by another paper published soon after in the Annals of Neurology. Titled Psychiatric disorders prior to amyotrophic lateral sclerosis, the study found that depression may precede the diagnosis of MND by more than 5 years. The authors also report a high frequency of other psychiatric conditions preceding the diagnosis of MND, such as anxiety and psychosis.
And just off the press is this report from Nature Communications titled Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. What do we make of this? Is this just the tip of the iceberg? Surely more studies are needed before any firm conclusions. Perhaps this may lead to some early biomarker that enables neurologists to stop the process of progression to full blown MND. Perhaps.
Prophetic it seems, as I am here forced to revisit the topic because I came across a few recent interesting reports on the neurology of gluten.
Take this case report from Nutrients titled gluten psychosis: confirmation of a new clinical entity. The article comes with some good references that suggest it will do no harm to check anti-gliadin antibodies in people with unexplained psychosis. I do wonder how one case report would confirm an entity such as gluten psychosis, but there you are.
Gluten-induced visual impairment
The second item is another case report published in Journal of Neurology titled severe, persistent visual impairment associated with occipital calcification and coeliac disease. The subject of the case report has long-standing coeliac disease and visual impairment. Her brain MRI scan showed calcifications in the visual area, evidence the authors claim, of celiac disease causing brain calcifications …..and thereby causing the patients visual loss. Is it just a case of correlation rather than causation? But there you are.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is as complicated to articulate, as it is to manage. CIDP is the result of an inflammatory attack against myelin, the fatty layer that encases large nerves. The damage to the myelin sheath considerably slows down the speed at which nerves transmit electrical impulses. This leads to limb weakness, sensory impairment, and a host of other symptoms.
The diagnosis of CIDP is made on the basis of a clinical examination, nerve conduction studies (NCS), spinal fluid analysis, and countless blood tests. If this convoluted diagnostic process is hair-tearing, the treatment is even more perplexing.
There are 2 major CIDP treatment conundrums. The first is whether to start the treatment with steroids, or with intravenous immunoglobulins (IVIg). The second conundrum is what to do when the patient fails to respond to both of these first line CIDP treatments. Two recent papers have now come to the rescue, and they hope to settle, once and for all, these two major neurological puzzles.
1. Choosing steroids or IVIg as 1st line treatment
The first line treatment for CIDP is usually a toss-up between steroids and intravenousimmunoglobulins (IVIg). This is because neurologists had no way of telling who will do well on steroids, and who will respond to IVIg. Until now, that is. A recent report in the Journal of Neurology, Neurosurgery and Psychiatry (JNNP) set out to understand what patient characteristics predict response to IVIg. The authors studied >200 people with CIDP treated with IVIg, and reported that 1/4 did not respond. These IVIg non-responders had the following features:
The presence of pain
Association with other autoimmune diseases
A difference in the severity of weakness between the arms and the legs
The absence of anti-myelin associated glycoprotein (anti-MAG)
The authors conclude that people with CIDP who have the features above should start their treatment with steroids rather than IVIg. This surely beats tossing a coin.
2. Choosing rituximab as 1st line treatment
Choosing the 2nd line treatment of CIDP is comparatively easy; swap between IVIG and steroids, or go for plasma exchange (PE). Rituximab, a monoclonal antibody, is now also recognised as an effective treatment for CIDP. Conventional practice is to use this expensive treatment only when both IVIg and steroids fail. A recent paper however suggests that people with CIDP who also have IgG4 antibodies do not respond to either IVIg or steroids. On the bright side however, they do well when treated with Rituximab. The paper in the journal Neurology is titled Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins. The authors studied only 4 patients, but the number was enough for them to suggest that patients with CIDP, who also have IgG4 antibodies, should be treated with Rituximab. Makes sense to me, if the alternative is predictable failure.
Now that some light has been shone on the treatment of CIDP, the next stage is to see how things work at the coal face. Do you have any feedback on CIDP treatment? Please leave a comment.
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
Restless legs syndrome (RLS) does what it says on the can. Victims need to only sit or lie down for a few seconds before creepy-crawly sensations literally drive them up the wall. The discomfort is as insatiable as the urge to move is uncontrollable. It is, literally again, a nightmare; a frantic evening quickly followed by a frenetic night.
Neurologists rarely struggle to make the diagnosis of RLS. And with the efforts of support groups such as the RLS foundation, patients are now well-informed about the diagnosis. To the chagrin of the neurologists, patients often come with a list of medications they have tried, and failed.
The list of RLS risk factors is quite long. Some of these are modifiable, and the ‘must-exclude’ condition here, iron deficiency, requires checking the level of ferritin in blood. Other modifiable risk factors are quite diverse such as obesity, migraine, and even, surprisingly, myasthenia gravis (MG). Most RLS risk factors, such as peripheral neuropathy and Parkinson’s disease (PD), are unfortunately irreversible; in these cases some form of treatment is required.
Multiple sclerosis (MS) is a common and blighting neurological disease. It frequently targets young people, often with disabling effects. It may affect any part of the central nervous system, and it manifests with relapsing or steadily progressive clinical features.
Research is improving our understanding of MS at a breathtaking pace. Just as one is getting comfortable with the status quo, a sudden paradigm shift occurs. This is the work of the men and women in white coats, labouring in dingy labs, peering down powerful microscopes, and scrutinising imaging scans-all in the drive to improve the care of people who suffer from this defiant disease. To avoid becoming dinosaurs, neurologists have to keep up with the rapid developments at the cutting-edge of multiple sclerosis.
It seems a long time ago now when the treatment of Multiple Sclerosis (MS) revolved just around interferons and steroids. Since then the monoclonal antibodies have changed the field radically. Drugs such as natalizumab and alemtuzumab are now mainstream, and many other ‘mabs’ have followed fast on their heels. Daclizumab is about to come into clinical practice soon, and ocrelizumab is full of promise for progressive MS, as discussed in this article in Medscape. With the floodgates now fully opened, other ‘mabs’ such as ofatumumab are trooping in fast. Unfortunately not all monoclonal antibodies are making the grade; an example is Opicinumab (anti LINGO-1), touted as a drug that boosts nerve signals, but which latest reports indicate failed to meet up to its high expectations.
Fingolimod is the leader in the pack of sphingosine-1-phosphate receptor modulators. It has led the way and has the advantage that it is taken by mouth rather than by injection. It is limited by its risks on heart activity, and must be initiated under close cardiac monitoring. Beyond MS, it may have a wider impact on neurological practice as it is under consideration in the treatment of motor neurone disease (MND). Following quickly behind fingolimod, still in trial stages, are laquinimod, ozanimod, ponesimod, siponimod, and amiselimod. It is still not clear if these drugs will have a similar impact as the monoclonal antibodies, in which case we may end up with the war of the ‘Mabs’ versus the ‘Mods’.
Terifluonomide is another oral drug developed for the treatment of MS. It is a pyrimidine synthesis inhibitor. Unlike dimethyl fumarate, a recent Cochrane database review for terifluonomide found only low-quality evidence from 5 clinical trials. The review says ‘all studies had a high risk of detection bias for relapse assessment, and a high risk of bias due to conflicts of interest‘. Not very glowing tributes, but in its favour is the low frequency of significant side effects.
Cluster headaches are nasty, excruciatingly severe, headaches. They are not called suicide headaches without good reason. Cluster headaches are typically one-sided, localised around the orbit. The eye on the affected side classically turns red and waters. The nostril follows suit by either running or blocking up. The episodes last between 45 minutes to 3 hours during which the hapless victims pace up and down, feeling like smashing their heads against a concrete wall. Relief is short-lasting because the headache cycle repeats itself several times a day, for weeks and months on end. People with episodic cluster headaches may go several months without headaches, but those with the chronic form are not afforded this luxury.
Treatment of cluster headache is typically three-pronged: acute treatment with triptans; intermediate prevention with oralsteroids; and prevention with verapamil. OK, I over simplify. Each of these strategies has 2nd, 3rd, and 4th line options. Verapamil, the cornerstone of treatment, comes with significant risks to the heart. And in extreme cases, invasive measures are called upon to save the day.
Unfortunately all these treatments fail miserably more often than we like to admit. Even invasive treatments are not always successful in cluster headaches. Neurologists and patients alike are therefore always on the lookout for developments which will improve the understanding and management of cluster headaches. And, thankfully, there are a few.
A. Abnormal tyrosine metabolism and cluster headache
The sad fact about cluster headache is, nobody knows what causes it. We know it is due to some malfunction of the autonomic nervous system, and to the trigeminal, or fifth, cranial nerve. This is why it is called a trigeminal autonomic cephalalgia. We know that it favours men who smoke. Beyond this we are rather clueless. It is therefore with high hopes that I read about abnormal tyrosine metabolism in chronic cluster headache, in the journal Cephalalgia. The authors report that people with cluster headaches have high levels of the products of tyrosine metabolism in their blood, such as dopamine, noradrenaline, and tyramine. If this turns out to be confirmed, it may open the way to the development of newer and more effective treatments for this painful condition.
B. Heart monitoring on verapamil
The heart is at risk whenever people are put on verapamil. This is because it may induce abnormal and dangerous heart rhythms. It is therefore important to check the electrocardiogram (ECG) of people on verapamil. Guidelines suggest checking the ECG before starting, 10 days after starting, and before each dose increment. It was therefore disconcerting that a recent study, published in the journal Neurology, found that 40% of people on verapamil never had any form of heart monitoring. The paper, titled electrocardiographic abnormalities in patients with cluster headache on verapamil therapy, is an audit of >200 people with cluster headaches on high dose verapamil. In those who had cardiac monitoring, the authors found ECG abnormalities in more than 50%, some very significant and life threatening. A similar finding was reported in an older study published in the Journal of Headache and Pain, titled cardiac safety in cluster headache patients using the very high dose of verapamil (≥720 mg/day). Worrying!Time to take ECG monitoring more seriously in people on verapamil.
C. New preventative drug options
Besides verapamil, there are many other options for cluster headache prevention. The list is quite long, and this is the case whenever we are uncertain of what else really works. That is why I was relieved to see a recent guideline on treatment of cluster headaches touting new evidence to guide neurologists. Published in the journal Headache, it is titled Treatment of Cluster Headache: The American Headache Society Evidence-Based Guidelines. This guideline establishes that lithium is effective in preventing cluster headache, but valproate is probably ineffective. More importantly, the guidelines introduce new effective preventative agents such as civamide nasal spray, melatonin, and warfarin. For transitional prevention, occipital nerve injection comes through with glowing tributes. Progress, surely!
D. Neurostimulation for cluster headache
It is no longer surprising to find neurostimulation cropping up in the treatment of any neurological disorder. And cluster headache is no exception. The most effective agent, according to the latest guidelines, is sphenopalatine ganglion stimulation. It now ranks very high in the acute treatment of cluster headache, even if less effective than the good old, conventional acute treatments which are subcutaneous sumatriptan, intransal zolmitriptan, and 100% oxygen. Neurostimulation is also likely to play a future preventative role in cluster headaches, and the candidates here are invasive and non-invasivevagus nerve stimulation. We are waiting with bated breaths!