This is just a quick post on a recent paper in Lancet Neurology which looked at the potential benefit of Riluzole in the treatment of cerebellar ataxia.
Neurologist know Riluzole very well. It is the only drug that has even the slightest hint of slowing down the dreadful motor neurone disease (MND). It is however fraught with side effects and demands a strict regime of regular blood tests to monitor for liver toxicity; this puts many people off it. Many neurologists are also sceptical of its reported benefits (in whispering tones of course).
The authors studied subjects with the genetic conditions spinocerebellar ataxia (SCA) and Friedreich’s ataxia (FA). They used the SARA scoring system to monitor for improvement in the study subjects. And their faith was rewarded; 50% of the subjects on Riluzole improved compared to only 11% of the subjects on placebo. The authors suggest further trials to confirm the benefit. The academically minded will pick apart the methodology and statistical significance; the neurologist on the coal face will hold on to any hope.
Parkinson’s disease (PD) looms large in neurology. As I try to make sense of developments in this field, I am struck by the large number of curious reports emerging all around it. I thought I had covered this comprehensively in my previous blogs, PD-a few curious things and Bee venom acupuncture for PD. On the contrary it looks like I opened a can of worms. I will therefore give the peculiar and the curious one last heave before proceeding to some conventional blogs I have in the pipeline on PD. Here then are 13 unusual things about PD.
This is a quick post to highlight the association of minocycline and neuropathy.
This comes from an article in Neurology titled Vasculitic neuropathy following exposure to minocycline. Minocycline is an antibiotic commonly used in the treatment of acne. Vasculitic neuropathy on the other hand is as bad as neuropathies come-in the cases reported here, one developed stroke, and another severe systemic symptoms.
Worse still, stopping the treatment doesn’t resolve the problem, the patients requiring long-term immunosuppression.What a hero-to-zero move by minocycline, a fall from grace to infamy.
The learning point however: ask your next patient with severe neuropathy if they have been treated for acne!
I am casting my sight on the scourge of millions around the world-migraine. This post is a prelude to a piece I am working on titled How is migraine research soothing the pain of neurology? In doing this, I came across a few curiosities which I thought would do nicely as a separate post. Therefore, before the real stuff, here are 8 strange and surprising migraine associations.
α. Migraine and the weather
Some migraineurs know that their migraine attacks are related to changes in the weather. For them therefore, the science is just catching up. This piece from the American Migraine Foundationsummarises some recent articles which discuss the weather alterations that may trigger migraine headaches. The fingers are pointing at low barometric pressure, high environmental temperature, strong winds, and…wait for it…> 3hours of sunshine!
Migraine sufferers will really balk at the scary report of migraine as a risk factor for Parkinson’s disease (PD). This is the conclusion of a research work published in the journal Cephalalgia (really just a fancy word for headache). The authors followed up >40,000 people to see if those with migraine are more likely to develop PD than those without. Curious indeed! I have to confess, whatever the hazard ratios say, that I was not impressed by the difference in numbers developing PD of 148 versus 101.
δ. Migraine and radiotherapy
I’m not trying to be smart, but SMART syndrome is real. It is an acronym for Stroke-like migraine attacks after radiation therapy. It is easy for neurologists to miss this condition because it sets in years after the radiation treatment. There is however a clue in the MRI of people with SMART syndrome: cortical thickening and gadolinium enhancement in the area of brain treated with radiation. It’s simple really!
ε. Migraine and raised intracranial pressure
An article in Journal of Neurology reports that many people with unrelenting migraine have raised pressure in the brain (raised intracranial pressure or ICP). The article, titled association of unresponsive chronic migraine and raised intracranial pressure, showed that reducing the pressure by a spinal tap (lumbar puncture) leads to sustained remission of migraine. Neurologists diagnose raised ICP by look into the back of the eye for a sign called papilledema. This article however throws a spanner in the works because >75% of the people with migraine and raised ICP in the study did not have papilledema. What do the headache gurus have to say about this, I wonder?
ζ. Migraine and stroke
Neurologists really haven’t sorted this one out yet. We struggle to give our patients a straightforward answer to their simple question, ‘does migraine cause stroke?‘ This is because the literature on this is all smoke and mirrors, and recent papers do little to clear the air. Take this paper in a recent issue of Neurology titled Age-specific association of migraine with cryptogenic TIA and stroke. The authors could only conclude that there is probably a causal or shared risk, and this only in older people. The accompanying editorial, titled Migraine and cryptogenic stroke: the clot thickens, concludes that there may be a higher risk of stroke in migraineurs, but this is in those with other traditional stroke risk factors in the first place. A shaky association I say, but one not to be dismissed too hastily.
η. Migraine and teeth-grinding
I did say these are strange links. Teeth grinding or bruxism is not something neurologists would give a second thought to, but a review article in Practical Neurology says we should think again. Titled Bruxism in the Neurology Clinic, the review says bruxism is closely linked to migraine, and sleep bruxism is only associated with migraine. There is much more to bruxism and neurology; the authors suggests that bruxism may be a form of oromandibular dystonia, and it may arise from dysregulation in the basal ganglia. Quite a lot to chew! Dentists out there should be very worried-the neurologists are out to expand their territory.
θ. Migraine and hiccups
And finally a report which links migraine and hiccups. Again from Cephalalgia, this is a case series of people with migraine who report hiccups as aura of migraine. Strange and surprising indeed!
Multiple sclerosis (MS) takes a large chunk of neurological practice. This is not only because it is common, but also because of its devastating impact. It predominantly affects the young, and deals a blow that reverberates through the wider family and society. This is why it is a top priority in neurology.
A lot however remains uncertain and controversial in MS. The cause of MS for instance remains unknown although the list of risk factors is a mile long (see my previous blog listing the top 6 MS risk factors). MS is a well-known condition but it features prominently in the most controversial questions in neurology. The pathology and subtypes of MS are subjects of intense debate, and the best tests and treatments are still being worked out.
But it’s not all controversy and conflict in the world of MS. There is real progress shining a light to a brighter future in MS ,and here are a 11 I have found.
1. Interferons, with twists
Interferons have been the mainstay of MS treatment for decades. They are still standing their grounds despite inconclusive evidence of their effectiveness, their side effects, and the challenge from newer treatments. One way they hope to carry on into the future is by joining forces with oral contraceptives. This is according to a paper published in Neurology last year titled Oral contraceptives combined with interferon β in multiple sclerosis. The authors report that ethinylstradiol and desogestrel aid interferon-ß to reduce the number of new lesions in women with relapsing remitting multiple sclerosis.
In what may be an attempt at rehabilitation, H pyloriis attempting to make a good name for itself. Notorius for causing stomach ulcers, it now wants to be known as the patron saint of MS. It is a tenuous link I have to say, but I can’t argue against the research paper published in the prestigious Journal of Neurology, Neurosurgery and Psychiatry (JNNP). The article has a refreshingly self-explanatory title Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females. The authors show that people with MS are less likely to be infected with H. pylori than control subjects. But I will not rush to swim in that dirty-looking pool yet, the margin is thin; 16% versus 21% in control subjects. It however raises the intriguing relationship between infections and autoimmunity, a subject explored brilliantly in the accompanying editorial, the hygiene hypothesis of multiple sclerosis.
Phenytoin is very familiar to neurologists because it was a leading epilepsy medication for decades. Although it still has pride of place in the treatment of status epilepsy, it has largely fallen out of favour-mainly for its cosmetic and cognitive side effects. It is therefore surprising to see phenytoin resurrecting in the world of multiple sclerosis. In a large trial published in Lancet Neurology this year, researchers showed a neuroprotective effect of phenytoin on optic neuritis, a common symptom of MS. Neuroprotection, if you must know, is the holy grail of neurology. The article is titled Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. But you might as well read the distilled, and not over-sensational title, in The Telegraph, Cheap epilepsy drug could prevent nerve damage in Multiple Sclerosis. I think the findings require a long stretch of the imagination, but I am happy to do this to remain positive.
Ozanimod is a sphingosine-1-phosphate receptor modulator, and it has shown promise in trials of relapsing remitting MS. This was the conclusion of a recent randomised, placebo-controlled, phase 2 trial of Ozanimod in MS published in Lancet Neurology. Heart-warmingly called the RADIANCE study, the authors demonstrated the effectiveness of Ozanimod in subjects across 55 centres spread over 13 countries. This feat was rewarded with demonstrable reduction in MRI lesion load in the treated subjects. The phase 3 trial therefore promises a lot…but will it deliver?
8. Anoctamin 2 (ANO2)
Researchers are veritable hunters, looking for weak spots in their prey, diseases. They then hone in on their victims vulnerabilities, and pounce. In this way they develop treatment strategies. One such weak spot, recently reported in Proceedings of the National Academy of Sciences (PNAS), is connected to the chloride channel protein Anoctamin 2 (ANO2). The paper, Anoctamin 2 identified as an autoimmune target in multiple sclerosis, reports that subjects with MS have high antibody activity against ANO2. It’s rather complex biochemistry, and for a digested read see the version in Multiple Sclerosis News Today titled New Protein, Anoctamin 2, Identified as a Target of Autoantibody Production in MS. If ANO2 has anything to do with causing MS, you can be sure treatment strategies will follow. If this turns out to be an important pathway in MS, the armoury of MSologists will soon contain stronger firepower.
MS is as much a neurological, as it is a radiological, condition. The diagnosis of MS is heavily reliant on what is, or is not, a lesion on MRI scans; what is new and what is old; and what is getting bigger or smaller. Believe me, this is hardly ever straightforward. It is therefore gratifying to read an article (OK, I admit it, an abstract) in the American Journal of Neuroradiology titled FLAIR2: A Combination of FLAIR and T2 for Improved MS Lesion Detection. The authors report that they greatly improved the detection of MS lesions by combining two standard magnetic resonance imaging (MRI) techniques called T2 and FLAIR. This technique, FLAIR2, the authors say, is ‘a simple approach of obtaining CSF suppression with an improved contrast-to-noise ratio’, whatever that means! It does make one worry- how much we are actually missing now? FLAIR2 to the rescue.
Motor neurone disease (MND) is, to say the least, dreadful. It also doesn’t help that the terminology neurologists use adds to the distress. West of the Atlantic, amyotrophic lateral sclerosis (ALS) means MND but goes eastwards and it is only a subtype of MND. Thankfully, for most Americans at least, there is no confusion; it is simply Lou Gehrigdisease.
MND however remains a conundrum for neurologists who are struggling to solve its puzzling riddles. MND researchers continue to toil and sweat, but their efforts are bearing fruits. Take for example the great strides that established the link between MND and the C9ORF72 gene. What are the promising prospects in the world of MND? Here are some.
Associations: Thiamine deficiency and Diabetes
Should we be on the lookout for thiamine deficiency in patients with MND? This question is prompted by an article in the JNNP which shows an unexpectedly high frequency of laboratory, but not clinical, thiamine deficiency. Titled Thiamine deficiency in amyotrophic lateral sclerosis, the paper reported thiamine deficiency in about 28% of subjects with MND. The authors did not impute any causal association, and there is nothing to suggest that replenishing the thiamine improved outcomes. It is still worth thinking about because people with MND, as the paper emphasised, are at risk of thiamine deficiency.
Will MND ever be a curable disease? A big question, but this is the vision of all the hard-working researchers in this field. What are the prospects for a cure? One group of researchers believe the answer is in preventing misfolding of TDP-43, the protein that plays an important role in MND. They set out their case in an article published in Neurotherapeutics titled TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets. And don’t worry, its free access. The bold abstract says it all: “we present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS”. The proof of the pudding….
Diagnostic test: Nerve ultrasound
Making the diagnosis of MND is not always (make that is hardly ever) straightforward. In the early stages, symptoms are vague, and clinical signs are non-specific. MND also has many mimics. One of such mimics is multifocal motor neuropathy (MMN). To distinguish this and other mimics from MND, neurologist rely on a test called nerve conduction study (NCS). Even this however is not always helpful.
Brain magnetic resonance imaging (MRI) is not a test neurologist rely upon to make the diagnosis of MND. Not anymore it seems, going by an article in American Journal of Neuroradiology. The paper is titled A Potential Biomarker in Amyotrophic Lateral Sclerosis. In the article, the authors assessed the amount of iron deposition in the brains of people with MND using the MRI techniques called SWI and DTI. Their findings suggest that the amount of iron in the motor cortex and motor tracts of the brain is a good guide to the presence of MND. If confirmed, this technique will help to reduce the long time it often takes before neurologists confirm their suspicions of MND to patients and their families.
The outcome of MND, poor as it often is, varies quite widely. This is influenced by several factors such as the type of MND, use of the medicine riluzole, and multidisciplinary care. New research suggests that neurofilament light chain (NfL) may be a more sensitive marker of prognosis. This is reported in an article published in Neurology titled Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. The authors demonstrated that patients with MND have much higher levels of NfL than those without the disease. Furthermore, subjects with MND who had the highest levels at the onset had a higher mortality hazard ratio. I think I know what that means.
Prognostic scale: ALS-MITOS predictive system
A paper in the JNNP has proposed a new predictive system for MND called ALS-MITOS, reportedly better than the more familiar ALSFRS-R. The report is titled The MITOS system predicts long-term survival in amyotrophic lateral sclerosis. Most practicing neurologists wouldn’t know the difference because they don’t to use such predictive systems. But MND researchers would be licking their lips at the prospect of a better measure of disease progression; it will make it much easier for them to show that their interventions really do work!
There are >100 mutations in the superoxide dismutase 1 (SOD-1), a gene known to cause MND. SOD-1 is an enzyme that binds both copper and zinc, and when defective it results in mutant copper (don’t worry, I’m just finding this out myself). Acting on this hypothesis, researchers came up with a crafty way of delivering normal copper into the central nervous system of mice modelled with SOD-1 MND. Publishing in Neurobiology of Disease, the authors showed how they achieved this with CuATSM, a chemical that contains copper and currently used for PET scans. CuATSM is readily transported into the nervous system, delivering its copper as it does so.
Every recalcitrant disease is today threatened with gene therapy. Considering it has a long list of genetic risk factors, why should MND be any different? Research taking steps in this direction is therefore long overdue. One such step was published in Gene Therapy and is titled Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex.The authors report that they successfully transduced motor nerves of mice models of MND. In doing so they have set the stage for gene therapy in MND. I don’t claim to understand it all, but it sounds very much like they have set the ball rolling. Promising.
Neuromyelitis optica (NMO) may be seen as the rarer and more mysterious cousin of multiple sclerosis (MS). It is characterised by a long segment of inflammation in the spinal cord, and this occurs almost simultaneously with inflammation of the optic nerves. Unlike MS, there is usually no involvement of the brain. NMO is also known as Devic disease, after the French neurologist Eugène Devic.
NMO has had a very chequered history, refusing to be tied down, and defying all attempts at pigeon-holing. It has thrown up surprises over the decades, from its humble beginnings as a possible variant of multiple sclerosis, to its current complex status as an independent entity. It marks its territory by sprinkling anti aquaporin 4, its presumed causative antibody. We however now know that NMO doesn’t respect any of its defining features, even the presence of aquaporin 4. The International consensus diagnostic criteria for neuromyelitis optica spectrum disordersconfirms this.The experts struggled to pin it down … couldn’t…gave in… and took the easy way out: they developed awider construct to accommodate it all, calling this neuromyelitis spectrum disorders (NMOSD).
Why is NMO such an enigma? Because neurologists are never satisfied with the superficial. We like digging deeper, unearthing the hidden. And the longer neurologist study NMO, the more unusual the syndrome turns out to be. No wonder NMO now also encompasses patients with cerebral, diencephalic, and brainstem lesions. How more intriguing can it get? Here are 6 surprisingreports about NMO.
1. Spinal movement disorders
Spinal movement disorders are not run-of-the-mill in neurology. Myoclonus is probably the closest we get to see. A recent report in Movement Disorders (where else) enlightens us that spinal movement disorders in NMOare not infrequent (pardon the double negative, but it’s so convenient sometimes). The authors classify these disorders into five: tonic spasms, focal dystonia; spinal myoclonus,spontaneous clonus, and tremors.The paper cautions that NMO may present first with spinal movement disorders, and these are often ‘overlooked, mislabeled, or under-treated’.
2. Impaired sense of smell
Just when you thought only neurodegenerative diseases present with an impaired sense of smell, an article turns up in Journal of Neurology titled Olfactory dysfunction in neuromyelitis optica spectrum disorders. The authors of the paper found that slightly more than half of the 49 subjects with NMO had olfactory dysfunction. Bring out the UPSIT.
The hallmark of NMO is the longitudinally extensive transverse myelitis (LETM), inflammation of the spinal cord at least 3 vertebral segments long. There are however many other diseases that present with LETM-see this review article in Nature Reviews Neurology which listsdiseases that may manifest with LETM.Spoiler alert-it’s not open access! A recent piece in Neurology further extended the list (pardon the puns) with a case of MELAS presenting with LETM. MELAS is a mitochondrial disease that is more notorious for being a stroke mimic. Not to be outdone, JAMA Neurology had a case of nitrous oxide myelopathy with LETM. Last word however to Neurology, LETM may be seen in CLIPPERS.
5. Genetic pointer to relapse after treatment
It is no news that the monoclonal antibody, Rituximab, is an effective treatment for NMO. What is news is the report of a genetic marker of poor responsiveness to treatment with Rituximab. Researchers publishing in JAMA Neurology report that the fragment c gamma receptor 3A (FCGR3A) polymorphism increases the risk of relapseon treatment. Why on earth did they check for that specific polymorphism? I didn’t have access to the full article to find out…if you have the answer please let us know.
6. Escalation of treatment improves outcome
Sadly the outcome of NMO is not as good as one would hope. Relapses are common after remission, and these are not always amenable to treatment. A recent article however raised the spirits by showing that recalcitrant relapses may respond to escalation of the treatment level. The authors carried out a large scale trial published in Annals of Neurology titled Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. With escalation of treatment, raising the bar a notch higher, remission is achieved in many cases. There is therefore no place for pulling any punches when it comes to NMO.
The phenotype of neuromyelitis optica will no doubt evolve further. Please leave a comment on any unusual sightings.