Medicine is as much defined by diseases as by the people who named them. Neurology particularly has a proud history of eponymous disorders which I discussed in my other neurology blog, Neurochecklists Updates, with the title 45 neurological disorders with unusual EPONYMS in neurochecklists. In many cases, it is a no brainer that Benjamin Duchenne described Duchenne muscular dystrophy, Charle’s Bell is linked to Bell’s palsy, Guido Werdnig and Johann Hoffmann have Werdnig-Hoffmann disease named after them. Similarly, Sergei Korsakoff described Korsakoff’s psychosis, Adolf Wellenberg defined Wellenberg’s syndrome, and it is Augusta Dejerine Klumpke who discerned Klumpke’s paralysis. The same applies to neurological clinical signs, with Moritz Romberg and Romberg’s sign, Henreich Rinne and Rinne’s test, Jules Babinski and Babinski sign, and Joseph Brudzinski with Brudzinki’s sign.
Yes, it could become rather tiresome. But not when it comes to diseases which, for some reason, never had any names attached to them. Whilst we can celebrate Huntington, Alzheimer, Parkinson, and Friedreich, who defined narcolepsy and delirium tremens? This blog is therefore a chance to celebrate the lesser known history of neurology, and to inject some fairness into the name game. Here then are 25 non-eponymous neurological diseases and the people who discovered, fully described, or named them.
This post continues our long tradition of highlighting the catchiest neurology titles out there in the universe of the neurological literature. Looking back, I have done quite a few posts on this topic, but the fountain of catchy neurology titles is yet to dry up. But before going on, you may want to catch up with our previous posts on this theme:
This is the title of a 2019 editorial in the journal Epilepsy Currents, and FIRES here refers to febrile infection related epilepsy syndrome (FIRES). FIRES is itself a form of new onset refractory status epilepticus (NORSE) in which there is associated fever. NORSE and FIRES are notoriously resistant to treatment, and the editorial points out the abject failures of steroids, IVIg, and plasma exchange, and the limited benefit of ketogenic diet and anakinra. This is where the hose comes in: it is the interleukin‐6 receptor inhibitor tocilizumab; the original research paper, published in the journal Annals of Neurology in 2018, reported that seven patients treated with Tocilizumab had very good outcomes. Take home messages: perhaps Tocilizumab is the right fire-extinguisher for this blazing inferno, and there must be an acronym-generating machine in the epilepsy universe!
The full title of this paper is “Dosing interval of natalizumab in MS: do good things come to those who wait?” It comes from a 2019 issue of the journal Neurology, and it is itself an editorial on a paper in the same journal which touted the benefits of extended dosing interval of natalizumab in multiple sclerosis. That paper showed that the risk of progressive multifocal leukoencephalopathy (PML) can be reduced by reducing the frequency of Natalizumab infusions. The authors used a 6 weekly, rather than the conventional 4 weekly, dosing interval of Natalizumab, and their gamble had paid off; they reported a “remarkable” risk reduction of developing PML by 88-99%. Enough justification for a catchy title, and proof that procrastination pays off…sometimes.
The full, more intriguing, title of this paper is “Looking for Mr(s) Right: Decision bias can prevent us from finding the most attractive face”. Something for incurable romantics. Published in the journal Cognitive Psychology in 2019, the paper revealed that, when it comes to picking partners, we stick at it much longer than we do when we make other decisions, somehow believing that the best has been saved for the last. The participants in the study kept looking out for “rare, highly-attractive faces“, so much so that many of them couldn’t make any choice at all. Proof that Mr and Mrs Right are hard to find…if they exist at all!
The full title of this paper is “Don’t fear the reefer-evidence mounts for plant-based cannabidiol as treatment for epilepsy”. Published in Epilepsy Currents in 2019, it set out to reassure clinicians that cannabis is OK…sort of. The paper reports the findings of a double-blind study of 225 people with Lennox-Gastaut syndrome (LGS), the severe epilepsy disorder which manifests with dangerous drop attacks. The study subjects were randomised to receive one of two two doses of cannabidiol, and their response was compared to a matched control group who were treated with placebo. The good news is that both doses of cannabidiol produced “greater reductions in the frequency of drop seizures than placebo”. Dispel the fear…and embrace the reefer!
This paper has nothing to do with why you can’t get that musical note out of your head, as revealed by the full title which is “Can’t get it off my brain: meta-analysis of neuroimaging studies on perseverative cognition”. But do not panic, at least not yet: perseverative cognition, it turns out, is just a fancy term for worrying or rumination. Published in the journal Psychiatry Research: Neuroimaging in 2020, the paper is a meta-analysis of 43 imaging studies of pathological worriers, those of us who have “intrusive, uncontrollable, repetitive thoughts”. To cut to the chase, and to avoid going round in circles, the centre of our rumination is a part of the brain called the anterior cingulate cortex (ACC). This structure, the authors said, is “critical for the pathological expression of rumination and worry”. You can now panic: you have the ACC to add to your list of things to worry about!
Visual snow syndrome is a relatively new thing for neurologists who are very much in the dark about it. From being a manifestation of migraine, it has climbed up the slippery disease classification ladder and is now a full-fledged syndrome of its own. It is therefore time for neurologists to see the light of visual snow, and what better way to show it than by such a catchy title. The paper, published in the journal Neurology in 2019, calls attention to this enigmatic phenomenon by providing a detailed review of the syndrome. But is the light bright enough for the neurologist?
Things that go twist in neurology are almost always dystonic, and this paper is no exception. Published in the journal Neurology Clinical Practice in 2019, the full title of the paper is “Sternocleidomastoid muscle hypertrophy in cervical dystonia: an unexpected twist”. It is a rather convoluted tale of a patient with Parkinson’s disease (PD) who developed cervical dystonia 10 days after he was treated with quetiapine. However, his sternocleidomastoid muscle was massively enlarged or hypertrophied, an impossible thing to happen within 10 days. You are beginning to get the twist. With their curiosity piqued, and their Sherlock Holmes hat on, the authors discovered that the patient has a previous history of dystonia, and the hypertrophy is really not as new as it first appeared. One surely for Agatha Christie fans, a tale with many unexpected twists. But the catchy title belies an important lesson- Occam’s razor doesn’t always cut sharply.
The idea that multiple sclerosis (MS), the quintessential white matter brain disease, is also a grey matter disease, is a bit of a shock to the traditional neurologist. The grave implication is that MS, the ultimate neuroinflammatory disease, is also a neurodegenerative disorder. This paradigm shift has all to do with the much better imaging tools available which show the grey matter changes in MS. And this editorial, published in the journal Nature in 2019, sums up the situation aptly, and catchily. The paper on which the editorial is based discusses how T cells interact with β-synuclein to cause the grey matter pathology in Lewis rats (rodents susceptible to experimental inflammatory diseases). Catchy editorials like this are doing a good job of taking us into the grey zone, and enabling us to see MS as much more than just relapses and progression.
If this headline doesn’t stop you in your tracks, then nothing ever will. The full title of this editorial is “Don’t just stand there: do something! The case for peri-ictal intervention”, and it comes from the journal Epilepsy Currents published in 2019. The paper it comments on, published in the journal Neurology in 2019, investigated the risk factors and best treatment for post-ictal hypoxaemia, that is low oxygen levels after generalised convulsions. It is not clear that the paper adds any new insights apart from stating the rather obvious fact that generalised convulsions lead to low blood oxygen levels. They however point out that the earlier oxygen is administered, the better the outcome. Not exactly groundbreaking research, but it resulted in an excellent catchy editorial.
This editorial, full title being “Heartbreakers-cardiac stress after uncomplicated generalized convulsive seizures”, is from the journal Epilepsy Currents published in 2019. And it is all about the risk of potentially fatal cardiac complications of epilepsy. The author was commenting on a paper published in the journal Epilepsia in 2019, which investigated the biomarkers of cardiac stress after a generalised convulsion. In essence, they were on the hunt for any red flags of fatal arrythmias, and of Takotsubo cardiomyopathy. And (you may insert drum roll here) the leading heartbreaker turned out to be… high‐sensitive troponin T (hsTNT). A catchy title to remind us that the heart is at risk in epilepsy.
Catchy titles help make the point. And there are more in the pipeline; the next in the series will look at catchy titles from the neurology archives. Watch this space, as they say.
I am yet to request serum neurofilament light protein (NfL) in my practice. I am not sure yet why I should, but until now I confess I really haven’t looked for a reason to do so. I however know that some MSologists now tick it, along with other blood tests, when they investigate people they suspect may have multiple sclerosis (MS). NfL are proteins that are released by damaged neurones. Should I be requesting NfL in my clinical practice? I sniffed around to find the case for testing serum NfL, and below is what I found.
Many studies have looked at the value of NfL in MS. One such very well-planned study that addresses many of my questions is that by Guili Disanto and colleagues, published in the journal Annals of Neurology in 2017. In the paper, titled Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis, the authors studied >380 people with MS and >150 healthy controls, and report four important findings.
The levels of NfL in serum strongly correlate with the levels in cerebrospinal fluid (CSF) of people with MS.
People with more active and more severe MS had higher levels of NfL.
People with MS on disease modifying treatment (DMT) had lower NfL levels than those who were not on treatment.
In people with MS who had their serum NfL tested serially over time, the level of NfL predicted those who will develop frequent relapses or progressive MS.
The authors concluded, with enough justification I think, that serum NfL is a “sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS“.
As for long term outcome, the 10 year follow up study by Alok Bahn and colleagues, published in the Multiple Sclerosis Journal in 2018, is most informative. In their paper titled Neurofilaments and 10-year follow-up in multiple sclerosis, the authors noted that “CSF levels of NfL at the time of diagnosis seems to be an early predictive biomarker of long-term clinical outcome and conversion from RRMS to SPMS”. Further support for the long term prognostic value of serum NfL comes from a paper published in 2018 in the journal Brain titled Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. The authors, Christian Barro and colleagues, studied more than 250 people with MS and concluded that “the higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss“.
In medicine, microbes are notorious for causing disease. In neurology particularly, infection is the direct cause of serious diseases such as meningitis and encephalitis. Infections may also act as catalysts for neurological disorders, for example when they trigger Guillain Barre syndrome (GBS). Infection is therefore a villain, a scoundrel to be apprehended and disarmed whenever it rears its head. But this picture may not hold true when it comes to multiple sclerosis (MS) where a contrary story is emerging, a narrative which holds infection as the hero, the daredevil that will save the day. The premise is simple: MS has very little presence in the regions of the world where infections reign supreme. Just look at any world prevalence map of MS to be convinced.
How strong is this inverse relationship between infection and MS? It all boils down to the so-called hygeine hypothesis of autoimmune diseases. This suggests that the human immune system becomes dysregulated when it is not primed by infections, and this dysregulation results in autoimmune disorders. This point was strongly argued by Aakanksha Dixitand colleagues in their paper published in the International Journal of Molecular Science, titled Novel Therapeutics for Multiple Sclerosis Designed by Parasitic Worms. They contend that the relationship between parasitic infections and autoimmune diseases is “most compelling“, going on to assert that helminthic infections “may be the protective environmental factor against the development of MS”.
To support the hygiene theory of MS, that helminthic infections play a role in banishing MS, three levels of evidence are offered.
Neurologists are however very cynical people, and they never believe what single trials tell them. After all, many microbes, such as Ebstein Barr virus (EBV), are touted as MS risk factors. For the sceptical neurologist, only systematic reviews and meta-analyses will do; these are the stuff of our dreams, the essence of our daily existence. So it is with a huge cheer that neurologists welcomed a 2018 systematic review and meta-analysis published in the Journal of Neuroimmunology and titled Is toxoplasma gondii playing a positive role in multiple sclerosis risk? The paper poured verycold water on the beautiful hygiene hypothesis. Whilst the authors, Reza Saberi and colleagues, confirmed that MS subjects had a lower risk of exposure to T. gondii, they found no relationship between this parasite and the development of MS. Wither a theory when it hits the reality of cold statistical analysis.
Notwithstanding the systematic review, the helminth hypothesis marches on. It has even reached the stage of therapeutic trials where, as distasteful as it sounds, subjects ingest parasites by mouth! And the fancied parasite is not Toxoplasma gondii but Trichuris suis ova (TSO). It all began with a small observational trialin 10 people which proved that TSO is safe and well-tolerated (phew), but it had no value whatsoever in treating MS. Not discouraged, the hypothesis entered the slightly larger HINT 2 trial; this again confirmed good tolerability in 16 subjects, but any benefit in reversing MS was questionable. Undeterred, the hypothesis has gone for a bigger study in the form of the TRIOMS trial. This is a randomized, placebo-controlled study of 50 people with MS or clinically isolated syndrome (CIS) in which subjects will be ingesting 2,500 Trichuris suis eggs every two weeks. We wait with bated breaths for the results.
Autoimmunedisorders are probably the most proliferative field of neurology. It seems like there is a blazing headline every week announcing a new antibody disease. Many of these antibodies are esoteric, but some shake the foundations of medical practice. Anti-MOGantibody is one of those which requires you to stop and pay attention, and it has significantly affected neurological practice in a very big way.
Perhaps the most important thing about anti-MOG antibody disease is that, like the chameleon, it presents in many guises. For the neurologist therefore, the first thing is to recognise these varied manifestations. Here then is a quick list of the 9 manifestations of anti MOG antibody disorder.
This is not something neurologists often come across, but it comes close enough to the specialty. Oral-facial-digital-syndrome is typified by facial deformities, but more importantly, the title makes it clear that it is a syndrome with diverse subtypes. A catchy title for a rare disorder, and this paper reveals all.
Not all catchy titles are convoluted. This one is simple but yet very inspired. It refers to the 2016 Consensus Statement on Concussion in Sport. As for all guidelines, it is all well and good to develop them, but a herculean task to get anyone to take notice. It is therefore very ingenious to use a catchy editorial to do the job.
Another one on amnesia, and what a great title. It is a report of 13 cases of focal retrograde amnesia, all typified by loss of autobiographical memory. The amnesia is severe enough in some cases “to erase the knowledge of their own identity”.
This inspired title clearly took some thinking to conjure. It is on the subject of transthyretin-related amyloidosis (ATTR), a hereditary disorder that equally maims the heart and the brain. Typical features are small fiber neuropathy, autonomic neuropathy, and ventricular hypertrophy. And the treatment, incidentally, requires transplanting a third organ, the liver.
Now here is a title to pique anyone’s neurological curiosity. It is about a peculiar disorder, parakinesia brachialis oscitans. There is really no cat to be let out of the bag here; the paper’s abstract reveals all. In some cases of hemiplegia, the abstract says, “yawning is associated with involuntary raising of the paralysed arm”. Read all about it!
This simple but catchy title is an excellent play on words. It is clearly about the contrariness of the acts of sleep and waking in one headline. This editorial is more than just a catchy title; it is a strong call to action!
It takes great imagination to come up with a title that contains burnout, embers and kindling. And the result is catchy. Burnout is a serious issue that threatens neurological practice, and this editorial flags the concern very forcefully: “the message for all is clear: medicine must identify the root causes of burnout, and more importantly, put the joy back in medicine“. It is time to see the light!
Probably not the catchiest title one could come up with, but it is catchy enough to attract attention. The title refers to fingolimod, the multiple sclerosis drug which predisposes to treatment-resistant warts. Simple verruca is bad enough, but the human papilloma virus (HPV) which causes it happens to trigger more sinister diseases: cervical and anogenital cancer. Therefore, with fingolimod, we must pay attention to warts and all!
Do you have any catchy titles up your sleeves? Do leave a comment.
Regular visitors to this blog know that we love catchy article titles. It is always heartwarming to see how some authors create imaginative and inventive headlines. This skill involves the ability to play with words, and the capacity to be double-edged. This is why this blog keeps a lookout for fascinating neurology titles. And in line with this tradition, and in no particular order of inventiveness, here are 15more catchy neurology titles!
This paper, for some unfathomable reason, set out to ask if the public knows the difference between what psychiatrists and psychologists actually do. And the authors discovered that “there is a lack of clarity in the public mind about our roles”. More worryingly, or reassuringly (depending on your perspective), they also found out that “psychologists were perceived as friendlier and having a better rapport“. Not earth-shattering discoveries, but what a great title!
Optical coherence tomography (OCT) is a cool tool which measures the thickness of the retinal fiber layer (RFL). And it has the habit of popping its head up in many neurological specialties. In this case, the specialty is multiple sclerosis, and the subject is how OCT influences its diagnosis and surveillance. Surely a window into the brain is easier to achieve than one into the soul.
The homonculus is the grotesque representation of the body on the surface or cortex of the brain. This paper reviews how formidable neurosurgeons such as Wilder Penfield worked out the disproportionate dimensions of this diminutive but influential man. He (always a man for some reason) has giant hands, a super-sized mouth, very small legs, and a miniature trunk. The clever brain doesn’t readily allocate its resources to large body parts that perform no complex functions! But be warned, this article is no light-weight reading!
This title is a play on words around MR-guided focussed ultrasound surgery (MRgFUS), an emerging technique for treating disorders such as essential tremor and Parkinson’s disease (PD). This review looks at the controversial fuss that this technique has evoked.
This paper explores the interesting subject of delusional misidentification syndromes (DMSs). The authors argue that few concepts in psychiatry can be as confusing as DMSs. And they did an excellent job of clearing our befuddlement around delusions such as Capgras and Fregoli. Very apt title, very interesting read.
This title belongs to a review of trypanosomiasis, aka sleeping sickness. It is a superb play on words, one that evokes several levels of meaning. It is simple and yet complex at the same time. Great imagination.
This paper discusses two parts of nervous system that are affected by toxoplasmosis. Playing on the symbolic contradiction between intellect and strength, the authors show how toxoplasmosis is an ecumenical abuser: it metes out the same fate to both brain and brawn.
Nitrous oxide, or laughing gas, is now “the seventh most commonly used recreational drug”. But those who pop it do so oblivious of the risk of subacute combined degeneration. This damage to the upper spinal cord results from nitrous oxide-induced depletion of Vitamin B1 (thiamine). Not a laughing matter at all!
Dopamine transport (DaT)scan is a useful brain imaging tests that helps to support the diagnosis of Parkinson’s disease and other disorders which disrupt the dopamine pathways in the brain. It is particularly helpful in ruling out mimics of Parkinson’s disease such as essential tremor. When to request a DaT scan is however a tricky question in practice. This paper, with its Shakespearean twist, looks at the reliability of DaT scans.
It should be no surprise if Shakespeare rears his head more than once in this blog post. Not when the wordsmith is such a veritable source of inspiration for those struggling to invent catchy titles. This paper looks at taupathy, a neurodegeneration as tragic as Hamlet. It particularly comments on an unusual taupathy, one induced by traumatic brain injury. Curious.
What better way to call attention to a serious complication than a catchy title like this one. This paper highlights the neurological complications of coarctation of the aorta, a serious congenital cardiovascular disease. And the key concerns here are the risks of stroke and cerebral aneurysms. Cardiologists, mind the brain!
This paper reviews the unexpected biochemical links between diabetes and Parkinson’s disease. And this relationship is assuming a rather large dimension. Why, for example, are there so many insulin receptors in the power house of Parkinson’s disease, the substantia nigra? A sweet curiosity.
The foraman ovale is a physiological hole-in-the-heart which should close up once a baby is born. A patent foramen ovale (PFO) results when this hole refuses to shut up. PFOs enable leg clots to traverse the heart and cause strokes in the brain. This paper reviews the evidence that surgically closing PFOs prevents stroke. Common sense says it should, but science demands proof. And the authors assert that they have it all nicely tied up. Hmmm.
When it comes to imaging the nervous system, nothing but an MRI will do for the fastidious neurologist. CT has its uses, such as in detecting acute intracranial bleeding, but it lacks the sophistication to detect or differentiate between less glaring abnormalities. It also comes with a hefty radiation dose. MRI on the other hand, relying on powerful magnetic fields, is a ‘cleaner’ technology.
MRI scans on their own are however often insufficient to sate the craving of the neurologist for precision. A plain MRI scan, for example, will not tell if a multiple sclerosis lesion is old or new, and it may fail to detect subtle but significant lesions such as low grade brain tumours or lymphoma. Many lesions on routine MRI scan are also ill-defined and non-specific, and could pass for abscesses, vasculitis, inflammation or just small vessel disease (wear and tear) changes.
To silence the niggling doubts, the neurologist often requests an MRI scan with contrast. The idea is to use a dye to separate the wheat from the chaff, the active lesions from the silent ones. This works because sinister lesions have a bad and dangerous habit of disrupting the blood brain barrier. All such insurgencies across the hallowed BBB is sacrilege, a sign that something serious is afoot, (or is it underfoot?). Contrast dyes, on the other hand, are adept at detecting these breaches, traversing them, and staining the sinister lesion in the process. This stain appears on the MRI scan as contrast enhancement. MRI with contrast is therefore invaluable, and a positive study is a call to arms.
Without any doubt, gadolinium is the favoured dye for contrast MRI scans. Gadolinium (Gd) is a lanthanide rare earth metal and it is one of the heavier elements of the periodic table with atomic number 64. It is named after the thrice-knighted Finnish chemist Johan Gadolin, who also discovered the first rare earth metal, yttrium.
We know a lot about some of the risks of injecting gadolinium into the body, such as its tendency to accumulate in people with kidney impairment (who cannot excrete it efficiently). We also know that it may cross the placenta to damage the developing baby. These are however hazards with simple and straight-forward solutions: avoid gadolinium in pregnancy, and don’t use it in people with poor renal function.
Much more challenging is the problem of gadolinium deposition in the brain of people with normal renal function. This is concerning because it is unpredictable, and because it has the potential to compromise brain structure and function. This blog has previously asked the question, “Is gadolinium toxic?“. The question remains unanswered, andregulatory agencies are still studying the data to provide guidance to doctors. Patient groups on the other hand have been up in arms, as one would expect, impatiently waiting for answers. What then is the state of play with gadolinium? Should neurologists and their patients really be worried? Below are 8 things we now know about gadolinium and its potential brain toxicity.
1. Gadolinium deposition is related to its insolubility at physiological pH
The toxic potential of gadolinium is thought to be the result of its insolubility at physiological pH. Furthermore, gadolinium competes against calcium, an element fundamental to cellular existence. This competition is obviously detrimental to the body.
2. The less stable gadolinium agents are the most toxic
There are two forms of gadolinium based contrast agents (GBCAs): the less stable linear GBCAs, and the more stable macrocyclic GBCAs. The linear GBCAs are more toxic, of which Gadodiamide (Omniscan)stands out. Other linear agents are gadobenate dimeglumine (MultiHance), gadopentetate dimeglumine (Magnevist), gadoversetamide (OptiMARK), gadoxetate (Eovist), and gadofosveset (Ablavar). The macrocyclic GBCAs, even though safer, are not entirely blameless. They include gadobuterol (Gadavist), gadoterate meglumine (Dotarem), and gadoteridol (ProHance). Therefore, choose your ‘gad’ wisely.
3. Gadolinium deposits in favoured sites in the brain
It is now established that gadolinium deposits in three main brain areas. The most favoured site is the dentate nucleus of the cerebellum. Other popular regions are the globus pallidus and the pulvinar. This deposition is, paradoxically, visible on plainT1-weighted MRI scans where it shows as high signal intensity.
4. The risk of deposition depends on the number of injections
The risk of gadolinium deposition in the brain is higher with multiple administrations. Stated another way, and to stretch this paragraph out a bit longer, the more frequently contrast injections are given, the higher the chances gadolinium will stick to the brain. The possible risk threshold is 4 injections of gadolinium. The fewer the better…obviously!
5. Gadolinium also deposits outside the brain
The favoured site of gadolinium deposition outside the brain is the kidney, where it causes nephrogenic systemic fibrosis, a scleroderma-like disorder. This however occurs mostly in people with renal impairment. Gadolinium also deposits in other organs outside the brain including bone, skin, and liver. (Strictly speaking, this item has nothing to do with the brain, but it helped to tot up the number to 8 in the title of this blog post, avoiding the use of the more sinister se7en).
6. Harm from gadolinium brain deposition has not been established
8. There are emerging ways to avoid gadolinium toxicity
The safest use of gadolinium is not to use it at all. There are some developments in the pipeline to achieve this, although probably not in the very near future. Such developments include manganese based contrast agents such as Mn-PyC3A. A less definitive option is to mitigate the effects of gadolinium by using chelating agents; two such potential agents are nanoparticlesand 3,4,3-LI(1,2-HOPO).
Why not get the snapshot view of gadolinium toxicity in the neurochecklist:
The Neurology Lounge strives hard to keep to the straight and narrow path of clinical neurology. But every now and then it takes a peek at what is happening at the cutting edge of neuroscience. And what can be more cutting edge then biomarkers, with their promise of simplifying disease identification, making prompt and accurate diagnosis an effortless task.
The quintessential biomarker however remains as elusive as quicksilver. Not that one could tell, going by the rate biomarkers are being spun from the neuroscience mills. Biomarkers are the buzz in many neurological fields, from brain tumours to multiple sclerosis (MS), from Alzheimer’s disease (AD) to Huntington’s disease (HD).
The proliferation of contending biomarkers is however probably highest in the field of motor neurone disease (MND). Is there a holy grail out there to enable the rapid and accurate diagnosis of this relentlessly progressive disease? There is clearly no dearth of substances jostling for prime position in the promised land of MND biomarkers. Below is a shortlist of potential MND CSF biomarkers; just click on any to go to the source!
Biomarkers elevated in the cerebrospinal fluid (CSF)
Some general neurologists get away with not having to think too much about multiple sclerosis (MS). This is because they have an ‘MSologist‘ at hand to refer all their patients with ‘demyelination‘. Many general neurologists however care for people with MS because they do not have a ‘fallback guy‘ to do the heavy lifting for them. This therefore makes it imperative for neurologists to keep up with everything about this often disabling and distressing disorder.
The management of MS is however very tricky, and it is challenging to get a grip of it all. This is partly because the clinical course is varied, and the diagnostic process tortuous. The patient first goes through an onerous retinue of tests which include an MRI, a lumbar puncture, evoked potentials, and a shedload of blood tests. This is all in a bid to secure the diagnosis and to exclude all possible MS mimics.
Then comes the head-scratching phase of determining if the patient actually fulfils the diagnostic criteria for MS, or if they just have clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS). To secure the diagnosis of MS, the neurologist turns to the McDonald criteria which stipulate dissemination in time and place of inflammatory events. As simple as this should be, this is no easy task at all. This is because, at different times, the criteria have meant different things to different people. The guidelines have also gone through several painful, and often confusing, iterations. Indeed the McDonald criteria have only recently been re-revised-to the delight of MSologists but the chagrin of the general neurologist!
Once the diagnosis of relapsing remitting MS (RRMS) is reasonably established, the patient is taken through a guided tour of the ever-expanding available treatment options. These are typically to prevent relapses, but more recently to prevent disease progression as well. People with mild to moderate MS are nudged towards interferons, glatiramer acetate, dimethylfumarate, or terifluonamide. Those with more aggressive disease, on the other hand, are offered a menu of fingolimod, natalizumab, or alemtuzumab. Other newer agents include daclizumab and cladribine. And, just stepping into the arena, there is ocrelizumab for primary progressive (PPMS). Whichever option is chosen, the course of treatment is long, and it is fraught with risks such as infections and immune suppression.
Once the bigger questions have been settled, the neurologist then braces for the ‘minor’ questions her enlightened patients will ask. The easier questions relate to the treatment of symptoms, and some of the most vexing concern the role of Vitamin D deficiency. Such questions include, ‘Is vitamin D deficiency a cause of MS?‘, ‘Do people who are vitamin D deficient experience a worseoutcome?‘, and ‘Should patients with MS be on Vitamin D supplementation?‘.
To attempt to resolve these questions I plunged into some of the literature on Vitamin D and MS. And this is like opening Pandora’s box. Here are some of the things I found.
It therefore appears that there is an association of vitamin D deficiency with MS, but it is far from certain that this is a causative relationship. One hypothesis is that vitamin D deficiency is the outcome, rather than the cause, of MS. The deficiency presumably results becuase the very active immune system in people with MS mops up the body’s Vitamin D. This so-calledreverse causation hypothesis asserts thatvitamin D deficiency is a consumptive vitaminopathy.
Even if Vitamin D deficiency doesn’t cause MS, the evidence suggests that it negatively influences the course of the disease.
What to do?
This is the million dollar question eloquently posed by a recent editorial in the journal Neurology titled Preventing multiple sclerosis: to (take) vitamin D or not to (take) vitamin D?The reasonable consensus is to encourage vitamin D replenishment to prevent MS, starting from preconception. It is also generally agreed that people with MS should be on vitamin D supplementation in the expectation that it will slow the disease activity.
A practical approach to Vitamin D replacement is the Barts MS team vitamin D supplementation recommendation. This is to start with 5,000IU/day vitamin D, and aim for a plasma level of 100-250 nmol/L. Depending on the level, the dose is then adjusted, up or down, to between 2-10,000IU/day. They also advise against giving calcium supplementation unless there is associated osteoporosis.
What is a general neurologist to do? To follow the prevailing trend, and hope it doesn’t change direction too soon!