As we have done for the last five years, I am taking stock of my neurology blogging activities over last 12 months. A sort of reckoning, it enables me to list the blog posts that have attracted the most attention, and to quietly reflect on why some did not blaze a trail.
With almost 40,000 visitors, and more than 50,000 views, 2020 has been the busiest so far in the Lounge, outstripping every year since 2015 when I launched the blog. Whilst a lot of the footfall has been to blogs I posted in 2020, I must admit that the golden oldies are attracting more visits than the newbies, making up the top 7 most viewed posts this year. Talk about blossoming with age!
2020 was characterised by horror of epidemic proportions. Spawned in 2019, COVID did not attain plague status until 2020. Unfurling its envelope, and baring its spikes, it struck with ruthless efficiency. But the chillingterror it unleashed was not enough to freeze the ink of neurologists. With flowing prose and radiant captions, neurological penmanship flourished in defiance of SARS-CoV-2. So, as we say goodbye to a year we can’t wait to forget, let us take a moment to marvel at the outstanding neurology titles of the last 12 months. Here then are 12 catchy neurology headlines to cast out a year of infamy.
This just happens to be the first ever COVID-related catchy title we will feature in this blog, and we surely hope it will be the last! It is however appropriate that we begin our 2020 run down with a COVID title, and our first choice is apt, literally and metaphorically. Published in the journal Headache, the paper is a brilliant review of the different headaches which follow in the trail of COVID 19, complete with prevalence, pathophysiology, and clinical characteristics. It is also full to the brim with scary facts, such as up to 10% of people with COVID19 will first manifest with a headache, and, more worryingly, we should expect some COVID headaches to linger long after the pandemic is over. Ominous!
Linking weight and obesity in a title doesn’t sound like creativity, but add evidence to the mix and what you see is inventiveness. The authors of this editorial, published in Multiple Sclerosis Journalargue that for a dreadful disease such as multiple sclerosis (MS), where the real cause remains elusive, it is critical to explore all its potentially modifiable risk factors and, well, weigh the evidence for them. The editorial was commenting on a study that did exactly this for obesity and found that a few pounds here, and a few inches there, do increase the odds of developing MS. Ingeniously, their marker for MS was atrophy of the prepapillary retinal nerve fibre layer thickness as measured during optical coherence tomography (OCT). And the evidence for this appears to be, well, somewhat weighty.
A cautionary title if ever there was one. This paper, full title being Cavernous malformations with DVA: hold those knives, is an editorial published in the journal Neurology. The authors were commenting on a paper in the same journal which investigated the risk of bleeding from cavernomas when they are associated with developmental venous anomalies (DVAs). The editorial is very enlightening, pointing out that DVAs are only associated with sporadic, and not with familial, cavernomas, and a whopping 25% of sporadic cavernomas are associated with DVAs. Even more surprising was the study finding that the risk of bleeding from a cavernoma is reduced if the cavernoma is associated with a DVA. Quite counterintuitive, but then this is the brain we are talking about. So the next time your eager-beaver neurosurgeon embarks on a knife-edge mission to chop out a cavernoma, flag this paper, and tell them to sheathe their scalpels.
By <a href=”//commons.wikimedia.org/wiki/User:Daderot” title=”User:Daderot”>Daderot</a> – <span class=”int-own-work” lang=”en”>Own work</span>, CC0, Link
This paper in the journal Epilepsia is all about seizures that occur in the setting of autoimmune encephalitis. ‘Fire’ and ‘kindling’ are entirely appropriate in this regard when one considers that autoimmune encephalitis has been symbolically depicted as Brain on Fire. The paper, full title Seizures in autoimmune encephalitis: kindling the fire, reviews the complex pathogenic mechanisms by which autoimmune encephalitis develops. And the picture the authors paint is of pyromaniac antibodies igniting neuro-inflammatory flames and stoking hyper-excitability blazes, one consequence of which is recalcitrant epilepsy. The question for neuroscience is therefore clear: how do we quench this inferno?
That is the full title, honest. And this is as short and catchy as a title can possibly be. Published in the journal Practical Neurology, the piece is not about how to detect fasciculations, but about how the etymology of the word ‘fasciculation‘ tells us that many clinicians are wielding it inappropriately. And this all stems from a tenuous battle of ideas that is raging in Newcastle neurology because some fussy older neurologists become very ‘twitchy’ when their presumably younger colleagues misuse and abuse the word. It appears, for example, that it is sacrilege to use the word in a plural form. In a detailed analysis of the word, the authors traced its fitful and flickering history, making allusions to, amongst other things, fascism! You will be very nervy at the end of the short article, but what a brilliant title!
The yellow brick road, in case you need reminding, is a fictional path in the famous children’s novel The Wonderful Wizard of Oz. If, like me, you never actually ever read the book, you would surely have watched one or the other incarnation of its screen version; there is therefore no excuse not to be familiar with the really oddball characters created by L. Frank Baum (I bet you thought it was Lewis Carroll!). I digress. The authors of our catchy headline, clearly fans of Baum, got their inspiration from his classical farcical adventure, from which they extracted differential diagnostic lessons to help neurologists distinguish between Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The paper, full title Diagnosing the frontal variant of Alzheimer’s disease: a clinician’s yellow brick road, is a report of three patients who presented with typical features of behavioural variant FTD (bvFTD), but eventually turned out to be suffering from the frontal variant AD (fvAD). The authors characterise their differential diagnostic clues as the yellow brick road, an allusion to the road that leads to success in Oz. They metaphorically refer to bvAD as “the irritable, paranoid, and tremulousScarecrow“, and bvFTD as “the heartless, ritualistic, and rigid Tin Man“. As for Lion, he probably lost his way on the yellow brick road…surely a metaphor for some other cognitive disorder.
The full title of this short article in the journal Neurology is Intracranial extramedullary hematopoiesis: blood disorders on the mind. The authors presented the case of a woman whose clinical presentation and striking brain MRI features are typical of a primary brain tumour…but for the fact that she has an underlying complex blood disorder: polycythemia vera and myelodysplastic/myeloproliferative overlap. The histology of her dural lesions revealed extramedullary hematopoiesis (EMH). You must mind the blood…even if you are in the brain!
This really insightful editorial, also from the journal Neurology, is a commentary on a paper in the same issue which explored the relationship between apathy and impulse control disorders (ICDs) in people with Parkinson’s disease (PD). Admitting that apathy is more a psychiatric than neurological concept, the editorial makes the strong case that neurologists need to shake off their indifference for the word that evokes disinterest. The editorial underscored the key lesson from the paper in question, that as contrasting as their manifestations are, apathy and ICDs are travelling companions in PD. And what strange bedfellows they make, a veritable parkinsonian Jekyll and Hyde! (Let’s not get started on another classic of literature).
If Agatha Christie had written a neurological murder mystery, this might well have been the title. Imagine a geneticmutation which alters the conformation of a chromosome from linear to circular, thereby unleashing indescribable havoc. That, in a nutshell, is ring 14 syndrome. But for the neurologist, it spells a trigger for drug-resistant epilepsy and a host of congenital anomalies. The intriguing paper that explores this is published in the journal Epilepsia, and its full title is Chromosome 14 deletions, rings, and epilepsy genes: a riddle wrapped in a mystery inside an enigma. The authors, just like Miss Marple or Hercule Poirot would have done, set out to solve the enigma of how the deletion could produce such a remarkable chromosomal metamorphosis, and why this should turn out to be so devastating. The only spoiler…the striking quotation is adapted from Winston Churchill, who was, in turn, referring to Russia. The plot thickens, you might say.
I admit that it doesn’t take genius to see the obvious link between the small vessel disease CADASIL, and its causative mutation on the NOTCH3 gene. But ‘NOTCHing‘ is what clinched it for me as a truly catchy title. This paper is an editorial, again in the journal Neurology, which reviews the studies that are steadily increasing our understanding of a disease that manifests with no less than three major neurological disorders: migraine, stroke, and dementia. The author was specifically commenting on a paper in the same journal which studied the diverse manifestations of ‘cysteine-altering NOTCH3 variants‘. What is remarkable is the range of manifestations of these variants, from an overwhelming burden of small vessel disease, to no clinical features whatsoever. We clearly need to do more than notch towards understanding…we need some speed!
I have always wondered when James Bond would burst into a neurology headline, and when he eventually did, it was was characteristic flair in the Annals of the Indian Academy of Neurology. The full title of the paper, Shaken not stirred: a pilot study testing a gyroscopic spoon stabilization device in Parkinson’s disease and tremor, is rather long-winded, but the question at its heart was quite straight-forward – to test the effectiveness of devices that claim to relieve the tremor of Parkinson’s disease. And the device the skeptical authors assessed is a gyroscopic stabilisation device (me too, never heard of it). Expectedly perhaps, the authors discovered that this “tremor cancellation technology” failed to meet up to its advertised billing; the shaken patients were not stirred one bit by the gyroscope: on the contrary, some of the patients even shook more vigorously after the device was switched on. Talk of licence to shake! Ian Fleming must be turning under his pillar.
As we come to the last goodbye to 2020, it is important that we make a triumphant exit, and this victorious editorial in the Lancet Neurology perfectly fits the bill. The author of the editorial was commenting on the truly ambitious, and aptly titled, CONQUER trial, which ticked all the boxes to make Archie Cochrane smile from his grave: it was a “multicentre, randomised, double-blind, placebo-controlled, phase 3b” study which was carried out over 64 sites across 12 countries. The CONQUERERS examined the effectiveness of Galcanezumab, a calcitonin gene related peptide (CGRP) monoclonal antibody (mab), in the prevention of migraine. And the editorialist concluded that Galcanezumab, along with the related Erenumab and Fremanezumab, “are safe, tolerable, and efficacious in many patients with frequent migraines, even in those with several non-successful preventive treatment attempts”. The emergence of the CGRP mabs is surely one bright spot in what has been a dark year. So let us bid farewell to 2020 on a positive note…and welcome 2021 with good cheer and virus-free expectations!
It is the season again for reflecting over the most important neurology papers published in the year. Because we keep a keen eye on the relevant journals and neurology headlines, we are well-placed at Neurochecklists to pinpoint those papers which asked the most pressing neurological questions, and either answered them, or pointed to where the wind […]
Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Mohr JP, Overbey JR, Hartmann A, et al. Lancet Neurol 2020; 19:573-581. Abstract Background In A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), randomisation was halted at a mean follow-up […]
Radiologically isolated syndrome: 10-year risk estimate of a clinical event. Lebrun-Frenay C, Kantarci O, Siva A, et al. Ann Neurol 2020 (Online ahead of print). Abstract Objective We have previously identified male sex, younger age, and the presence of spinal cord lesions as independent factors that increase the 5-year risk for evolution from radiologically isolated […]
The brain-gut axis has become a well-recognised cliche, and for very good reasons. Possessing an almost independent and complex nervous system, the gut is considered to be the ‘second brain‘. The gut of course coordinates things hand-in-hand with the brain with which it communicates via the vagus nerve; through this it not only determines our body balance or homeostasis, but also rules our emotions and guides our decision-making. But some scientists are beginning to think that the brain-gut axis, or more appropriately the gut-brain axis, has a dark side, and this is the simple idea that ‘very bad things‘ in the gut can smuggle their way into the brain by latching on to the vagus nerve. The gut-brain axis may therefore be the seditious agent of neurological ruin by acting as a Trojan horse which surreptitiously jumps over the brain’s elaborate defensive big wall.
Parkinson’s disease (PD) is perhaps the most illustrative example of the consequence of the treacherous behaviour of the gut-brain axis. Some researchers are now convinced that PD actually starts in the gut and, like an undesirable hitchhiker, fastens itself on the vagus nerve as it meanders its way up to the brain. This migration hypothesis is not a fanciful notion but an idea founded on sound facts. For example, take the observation that the guts of people with PD are riddled with α-synuclein, the misfoldedprotein that is thought to cause PD by disabling the basal ganglia. The story, according to researchers, is that α-synuclein first accumulates in the gut and, feeling cramped, seeks greener pastures. It therefore propagates up the vagus nerve, in ‘prion-like‘ fashion, to get to the brain. Further support for this theory is the observation that people who have had their vagus nerves resected (that’s another story) have a much lower risk of developing PD.
That’s just as well you may say, but where does the appendix come into all this? I admit the so-called vermiform or worm-like appendix is not a structure that readily comes to mind when one thinks of the gut-brain axis. Apart from being the seat of the dreaded appendicitis, it was considered to be just a useless appendage, nature’s trick on anatomists and physiologists. As diminutive as it may be however, it is part of the gut, and as it turns out, it is heavily laden with α-synuclein in people with PD. Furthermore, it has been shown that people who have had an appendicectomy, or appendectomy if you prefer, have a much lower risk of developing PD. We know this because of researchers such as Bryan Killinger and colleagues who, in their paper titled The vermiform appendix impacts the risk of developing Parkinson’s disease, published in the journal Science Translational Medicine in 2018, found that “early removal of the appendix is associated with a reduced risk of developing PD”. And it all comes down to the powerful immune surveillance function of the appendix which, it seems, mops up all sorts of threats that find their way into our guts. You may say that the appendix is punching way beyond its weight class.
As happens to all beautiful theories, they often come up against some immovable objections….and there are quite a few raised eyebrows at the appendix-PD hypothesis. For one, many studies have just not been able to confirm it. For example, take this paper published in the journal Movement Disorders in 2018, titled Appendectomy and risk of Parkinson’s disease in two large prospective cohorts of men and women; the authors disappointingly found little or no evidence for the association between having an appendectomy and the risk of developing Parkinson’s disease. Another paper published in the same journal in 2016, titled Appendectomy and risk of Parkinson’s disease: A nationwide cohort study with more than 10 years of follow‐up, further upturned the applecart because the authors found that having an appendectomy actually increased the risk of developing PD. Another paper from a 2017 issue of the Journal of Parkinson’s Disease was succinctly brutal in shooting down the appendix-PD connection with its title: Appendectomy history is not related to Parkinson’s disease. Even more damning to the “appendectomy is good against PD” theory is this 2019 study whose blazing headline is Parkinson’s disease is more prevalent in patients with appendectomies. Just when you were beginning to feel good about having your appendix removed all those year ago!
So, is the appendix a hero or a villain in the PD saga? Does it defend the brain from PD by mopping up α-synuclein, or is it the source of all the problems that α-synuclein presumably causes? Or are both the appendix and α-synuclein just innocent by-standers, ring-side onlookers, collateral damage in a disease process that defies all explanations? There will surely be more to come on this topic but, in the meantime, why not explore our previous PD blog posts:
This is just a quick blog post to let you know of some of our recently revised checklists Alemtuzumab neurological complications Anti MOG antibody disease treatment Cavernomas clinical features Cenobamate Cerebral amyloid angiopathy related inflammation (CAA-ri) *** CIDP clinical features Cluster headache acute treatment Dravet syndrome management Duchenne muscular dystrophy genetic treatments Functional neurological disorders […]
Magnesium is a rather understated metal which however plays such a significant role in health. This should not be surprising as it is the eighth most common metal in the Earth’s crust, and the fourth most abundant mineral in the human body. Explaining why magnesium is so central to health, Uwe Gröber and colleagues, in their paper titled Magnesium in prevention and therapy, point out that this underrated element is a cofactor in more than 300 enzyme systems which regulate such diverse biochemical reactions ranging from protein synthesis to neuromuscular transmission.
With such an important physiological function, it is alarming that the body can very easily run out of magnesium. But this is exactly what Gröber and colleagues demonstrated in their paper, which was incidentally published in the journal, Nutrients, in 2015; they showed that magnesium deficiency can result from a myriad of medical disorders such as alcoholism, malabsorption, endocrine disorders, chronic kidney diseases, and dialysis, or from the use of drugs such as antibiotics, chemotherapeutic agents, diuretics, and proton pump inhibitors.
Because of its diverse and important role, magnesium deficiency doesn’t lie down quietly in the corner and mope; rather it screams out in many tongues. Low magnesium therefore presents with symptoms such as lethargy, vomiting, fatigue, cramps, tremor, carpopedal spasm, tetany, seizures, and cardiac arrhythmias. Even more astonishing is the list of disorders that may be triggered by magnesium deficiency, from asthma, diabetes, hypertension, and osteoporosis, to stroke, attention deficit hyperactivity disorder (ADHD), Alzheimer’s disease, of all things, and of course migraine. Obstetricians will of course remind us of the indispensability of magnesium for eclampsia.
With the foregoing in the background, it is easy to understand why researchers have thoroughly investigated the possible place of magnesium in the treatment of migraine. Exploring its prophylactic role, for example, Hsiao-Yean Chiu and colleagues touted the virtues of magnesium in their paper titled Effects of intravenous and oral magnesium on reducing migraine: a meta-analysis of randomized controlled trials. Publishing in the journal Pain Physician in 2016, the authors reviewed 10 key studies, with a combined number of 789 subjects, which assessed the ability of magnesium to prevent migraine, and they concluded that “oral magnesium significantly alleviated the frequency and intensity of migraine“. The authors felt confident enough in their findings to recommend oral magnesium as a part of a “multimodal approach to reduce migraine”.
Even more authoritative about the role of magnesium in migraine prophylaxis is the conclusion of the systematic reviewpublished in the journal Headache in 2017 titledMagnesium in migraine prophylaxis-is there an evidence-based rationale? a systematic review. The authors, Alexander von Luckner and Franz Riederer, found grade C, or possibly effective, evidence in support of the preventative role of magnesium in migraine. Going further, Charly Gaul and colleagues, publishing in the Journal of Headache and Pain in 2015, reported that adding riboflavin and coenzyme Q10 significantly increased the beneficial effect of magnesium.
There is however a dampener to the celebrity status of magnesium in the migraine prophylaxis saga: some reports simply found insufficient evidence for it. One such paper, published in the journal Cephalalgia in 2014 is titled An evidence-based review of oral magnesium supplementation in the preventive treatment of migraine. The authors, Levi Teigen and Christopher Boesy, reviewed 16 relevant studies and concluded that “the strength of evidence supporting oral magnesium supplementation is limited at this time“. But even then, they appreciate that absence of evidence is not the evidence of absence. They therefore did not dismiss the potential benefit of magnesium in migraine, and had no objection to migraineurs supplementing their dietary magnesium intake. As this paper was published in 2014, a lot has clearly passed under the bridge since then.
Magnesium in the acute treatment of migraine has also been under scrutiny, and one such searchlight was shone by Hsiao-Yean Chiu and colleagues in their paper cited above. After reviewing 11 relevant studies comprising 948 subjects, they found that “intravenous magnesium significantly relieved acute migraine“. It is reassuring that two older papers also came to the same conclusion; the first, by ME Bigal and colleagues, was published in the journal Cephalalgia in 2002, and the second, by Şeref Demirkaya and colleagues, is reported in the journal Headache in 2004. Both papers revealed that 1000mg of magnesium sulfate intravenously was effective in aborting acute migraine attacks, especially if the attacks are associated with auras. Furthermore, writing in the journal Clinical Neurology and Neurosurgery in 2019,Fanny Xu and colleagues found that magnesium is effective even in status migrainosus, the most pernicious form of acute migraine.
But, as you guessed, the verdict on the benefit of magnesium in acute migraine is far from unanimous. For example, Y Ceteand colleagues, publishing their case series of emergency department patients in the journal Cephalagia in 2005, reported that magnesium is no better than placebo for acute migraine. Furthermore, Hyun Choi and Nandita Parmar in their meta-analysis, published in the European Journal of Emergency Medicine in 2014, said intravenous magnesium “failed to demonstrate a beneficial effect”in acute migraine. Arpad Pardutz and Laszlo Vecsei, commenting in the Journal of Neural Transmission in 2012, even discouraged the use of magnesiumbecause there are more effective treatment options.
Why are there such conflicting conclusions about the value of magnesium in acute migraine? One answer may lie in the almost prehistoric observation by Alexander Mauksop and colleagues; writing way back in 1996, in the journal Headache, they suggested that only a subset of migraine sufferers are susceptible to low magnesium levels. The authors go further to argue that low magnesium may be a trigger, not just for migraine, but for tension type headaches and cluster headaches; they therefore recommended that magnesium levels should be assessed in patients presenting with significant headaches, whatever the cause.
In conclusion, the evidence for the use of oral magnesium in migraine prophylaxis justifies its clinical use. The evidence for the use of intravenous magnesium for acute migraine is however less clear-cut, and future studies may help to clarify the ambiguity. In the meantime, it may be worth checking magnesium levels when a migraine attack defies conventional treatment: a top-up might just make the difference. And for the researchers, it may be time to look more closely at precision migraine medicine – it might just help to define those migraine sufferers who will benefit from that magic shot of magnesium.
In her most catchily titled book, The Angel and the Assassin, Donna Jackson Nakazawa highlighed nerve cells which have hitherto been very little acknowledged – microglia. Long ignored as bit players in the big league of the nervous system, Nakazawa colourfully illustrated what many neuroscientists are beginning to realise: the small size of microglia belies theirhuge influence; microglia are, after all, the defence force of the nervous system, protecting the brain from microbial invaders. In keeping with their small size, their role is to surreptitiously present the antigens of invading bugs to T cells, the toffs who actually carry out the final hatchet job. It is therefore not surprising that any dysfunction of microglia will come with significant clinical consequences.
The most important clinical fallout of dysfunctional microglia appears to be the emergence of dementia. It is indeed speculated that microglia may hold the key to stopping the notorious Alzheimer’s disease (AD). This is because microglia seem to play a role in eliminating the amyloid plaques which are thought to contribute to the disease process. Experiments suggest that there is excessive microglial activation in AD, and these supercharged microglia destructively ‘eat up’ synapses, the all-important junctions where nerve cells communicate with each other. It is also relevant that microglial activation is particularly prominent in the hippocampus, a structure critical for memory formation. Because synaptic loss is such a key feature of AD, it is hoped that a better understanding of microglial function may lead to therapeutic tools that modulate AD microglial activation.
Microglial activation also seems to play a role in another prominent neurodegenerative disease, Parkinson’s disease (PD). It is also speculated that microglia are activated in PD as a response to environmental triggers, and the activated microglia cause neuronal damage by producing toxic substances. Because this is presumably an inflammatory process, there is the hope that a better understanding of the process will open up new therapeutic possibilities.
Another disorder in which microglia may play a pathogenetic role is frontotemporal dementia (FTD) in whichchronic microglial activation has been reported. It is significant that the microglial activation is most evident in the frontal cortex as this correlates with the behavioural and speech disorders which characterise FTD. More intriguingly, the activated microglia seem to express the progranulin (PGRN) gene mutations that are known to be associated with FTD. Enough clues one might say.
Mitigating alemtuzumab-associated autoimmunity in MS: a “whack-a-mole” B-cell depletion strategy Meltzer E, Campbell S, Ehrenfeld B, et al. Neurol Neuroimmunol Neuroinflamm 2020; 7:e868. Abstract Objective To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19+ B cells approximates 40%-50% of baseline levels as measured before alemtuzumab […]
