The long-term treatment of myasthenia gravis (MG) relies on drugs which suppress the immune system. I listed some of these in my previous post titled How is innovative neurology research energising myasthenia? Steroids are the established first line immune suppressing treatment for MG but because of their many nasty side effects, they cannot be used at effective doses for long periods. This is why neurologists treating MG use so-called steroid-sparing agents to reduce, or eliminate, the need for steroids.
Azathioprine has the best evidence of effectiveness as a steroid-sparing drug, and it is the acknowledged favourite of neurologists. Azathioprine may however fail or cause unacceptable side effects. It is also unsuitable for people who lack TPMT, the enzyme that breaks it down. It is in these situations that things become slightly tricky for the neurologist.
In theory, neurologists are spoilt for choice when they can’t use Azathioprine. Methotrexate is my favourite option in such cases because it has an easy weekly dosing regime and it is fairly well-tolerated. Alas, a recent paper in Neurology titled A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis has unsettled me by suggesting that methotrexate is not living up to its top billing. The authors of the paper studied 50 people with myasthenia gravis who were already taking steroids. They put some of them on methotrexate, and the others on placebo. The outcome was surprising; methotrexate did very little to reduce the requirement for steroids, and it did nothing to improve the symptoms of MG.
This is clearly disappointing. Whilst waiting for further studies to confirm or refute this finding, I wonder how reliable the other steroid-sparing MG drugs are. How good are mycophenolate, ciclosporin, cyclophosphamide, tacrolimus, and rituximab? What really works in MG? To the rescue comes the International consensus guidance for management of myasthenia gravis, just hot off the press! Alas, the experts who drafted this guidance only compounded my woes. They made many treatment recommendations, but these came with as many caveats. They said the evidence for mycophenolate and tacrolimus in MG is rather thin, and the evidence-based ciclosporine and cyclophosphamide have potentially serious side effects. And they couldn’t agree on how promising rituximab, the new kid on the block, really is.
We are therefore back to the question, what to do when Azathioprine fails? The experts tell us to stick to the usual suspects, but they urge caution. Perhaps what we need are newer and safer alternatives such as Lefluonamide, so new to the MG arena that it did not get a mention in the expert guidance.
I was recently perplexed with my first case of tuberous sclerosis complex (TSC). I had no idea what treatment, monitoring and surveillance I needed to institute. I quickly checked things up in neurochecklists; I found excellent checklists on the pathology and clinical features, but was disappointed that there were no treatment or monitoring checklists. I quickly hunted down TSC diagnostic criteriaand TSC surveillance recommendations and updated neurochecklists. Phew!
In the process I discovered that TSC features may improve on treatment with a class of drugs called mTOR inhibitors. Highfalutin stuff I said to myself, and thought nothing more of it. I had to reassess my opinion very shortly afterwards when I came across the Association of British Neurologists (ABN)SoundCloud page with ABN President Phil Smith interviewing Ingrid Scheffer on epilepsy genetics.
We have all experienced that disquieting feeling of just learning something new, and then seeing it crop up all over the place. This is what I felt when Ingrid Scheffer casually stated that Tuberous Sclerosis is an mTORopathy. mTOR is big enough to be an ‘opathy‘, and I was completely ignorant of it! And how come I haven’t heard of Ingrid Scheffer before now-serves me right for missing the last ABN conference in Brighton.
I decided to dig a bit deeper and here are 9 things about mTOR I discovered:
mTOR stands for mammalian (or mechanistic) target of rapamycin
Neurologists breathe guidelines. And they churn them out at a breathtaking pace. It is extremely difficult keeping up with what’s in, what’s out, and what’s back in again! Often the new guidelines add nothing new, or the important points are buried in sheafs of text justifying the guidelines.
But we can’t get away from them. How then do neurologists keep up, short of becoming paranoid? By becoming obsessive! In developing neurochecklists I had no idea keeping up with the guidelines would be a challenging task because they are released in quick succession. I have looked back to see which are the latest practical guidelines, released in the last 12 months or so. Here they are by disease… but be quick before the guideline-masters revise them…again!
The American Academy of Neurology (AAN) and the American Epilepsy Society published their 1st seizure management guidelines in Neurology. Among the key recommendations are to inform patients of a 2-year recurrence risk of 21-45%, and that a nocturnal seizure is among the usual culprits that increase the risk. The vexing question of whether to treat a 1st unprovoked seizure remains that-vexing.
Not to be outdone, the International League Against Epilepsy (ILAE) released it’s evidence-based guidelines and recommendations for the management of infantile seizures. Published in Epilepsia in late 2015, it shows that Levetiracetam is tops for both focal and generalised seizures. It also confirmed the hard-earned place of Stiripentol alongside Valproate and Clobazam for Dravet syndrome. It is open access so well-worth a detailed look.
Duchenne muscular dystrophy (DMD)
Steroids are now standard treatment in Duchenne’s muscular dystrophy (DMD). A recent practice guideline update on corticosteroids in Duchenne’s highlights this, and it also indicates the strength of evidence for the different benefits. There is Level B evidence that steroids improve strength and lung function, and Level C for delaying scoliosis and cardiomyopathy. Enough to encourage any doubters out there.
Facio-scapulo-humeral muscular dystrophy (FSHD)
Not one I thought had guidelines, but this FSHD diagnosis and management guidelines turned out to be quite useful. The guidelines address four key areas-diagnosis, predictors of severity, surveillance for complications, and treatment. And if you like flow charts, there is an excellent one here. A lot of helpful tips here for example, subjects with large D4Z4 gene deletions are more prone to earlier and more severe disability, and these patients should be reviewed by a retinal specialist.
Multiple sclerosis (MS)
Multiple sclerosis (MS) is one of the most shifty conditions when it comes to guidelines, both diagnostic and management. Take the latest NICE MS guidelines, 39 pages long. All sensible stuff mind you, with time-restricted targets such as 6 weeks for a post-diagnosis follow-up, and 2 weeks to treat a relapse. Mind you, just to keep neurologists on their toes!
MS diagnosis and follow up is often the game of countinglesions on MRI scans. The question of what to count, and when to do so, is addressed in the recent MAGNIMS MS consensus guidelines. More recommendations than guidelines, these did not challenge the sacrosanct MacDonald criteria for dissemination in time, but tinker with dissemination in place. They suggest, for example, that optic nerve lesions be counted. The MAGNIMS consensus guidelines on the use of MRI goes on to stipulate when and how to count lesions throughout the course of MS. Not an easy bedtime read.
Finally, Neurology published guidelines on rehabilitation in MS. Unfortunately there are quite a few qualifying ‘possibles‘ and ‘probables‘ which water down the strength of most of the recommendations. But what else do we have to go by?
The Journal of Neurology, Neurosurgery and Psychiatry (JNNP) published a review of CIDP in February 2015. It covers everything ”from bench to bedside”, but heavily skewed towards the former. It confirms that CIDP is a “spectrum of related conditions”, great news for splitters, and disappointing for lumpers. I personally struggle with the concepts of sensory and focal CIDP, have never diagnosed CANOMAD, but never tire of listening to Michael Lunn on VEGF, or be fascinated by the links between CIDP and POEMSsyndrome. The review, an editors choice, is open access, and is backed by the authority of Richard Hughes; you really have no choice but to read it!
Unruptured intracranial aneurysms
The America Stroke Association (ASA) published new guidelines on management of unruptured aneurysms in a June 2015 issue of Stroke. It gives a comprehensive review of cerebral aneurysms, addressing the “presentation, natural history, epidemiology, risk factors, screening, diagnosis, imaging and outcomes from surgical and endovascular treatment“. It also suffices for a review article. Some recommendations are easily overlooked such as counsel against smoking and monitor for hypertension (evidence level B). Some important recommendations however have weak evidence, for example surveillance imaging after endovascular treatment (evidence level C).
The guidelines still advocate screening if there are 2 or more affected first degree family members. (I confess my threshold is lower than this). The extensive list of at-risk conditions for aneurysms include the usual suspects such as adult polycystic kidney disease and fibromuscular dysplasia. New culprits (at least to me) are microcephalic osteodysplastic primordial dwarfism, Noonan syndrome, and α-glucosidase deficiency.
The American Stroke Association (ASA), along with the American Heart Association (AHA), released their guidelines for the management of spontaneous intracerebral haemorrhage in 2015. There are several additional recommendations to the previous guidelines; these include the recommendation to control hypertension immediately from onset to prevent recurrent haemorrhage.
The ASA/AHA also published their updated guidelines on endovascular stroke therapy in 2015. To to show how important this treatment has become, the debate now is whether to use thrombectomy alone, or after thrombolysis. And the winner is…to use thrombectomy after thrombolysis. The eligibility checklist for endovascular therapy with a stent retriever is thankfully quite short.
OK, I confess these guideline are from 2014, a bit dated. But how often does one think ‘guidelines’ in the context of Friedreich’s ataxia. Furthermore, this Consensus clinical management guidelines for Friedreich ataxia is open access! Published in Orphanet Journal of Rare Diseases, they are the product of 39 experts, and consist of 146 recommendations! They cover everything from sleep, spasticity, and scoliosis to diabetes, dysphagia, and dysarthria. I bet you don’t enquire about restless legssyndrome (RLS) in your patients with FA!
Motor neurone disease (MND)
And hot off the press are the NICE guidelines on motor neurone disease (MND). One thing to mention is its sheer volume- 319 pages long, and containing 123 recommendations! The guidelines targets every aspect of MND care, and it’s futile trying to master it all. Each specialist can really only pick and choose which aspect is relevant to them. There is a lot of balancing of clinical and economic benefits, and this is reflected by questions such as “what are the most clinically- and cost-effective methods of maintaining nutrition…?” The guidelines address several long-standing issues such as the clinically appropriate timing for placing PEG tubes. Whether they add anything really new is however debatable.
Do you have a recent guideline or update to share? Please leave a comment.
Every now and then neurologists come across patients with what appears to be ‘straightforward’ viral encephalitis but who do not respond to conventional treatment. These treatments are usually according to established guidelines such as the ABN/BIAN guidelines, theIDS Guidelines. What to do when the patient isn’t responding is however very challenging.
Journal of Neuroinfectious Diseases (ssshh…the JNNP declined it) has just published our case report of such a patient who turned out to have H1N1 influenza encephalopathy. This experience suggests we should consider an autoimmune cause in such cases, especially if the spinal fluid does not show any viruses.
It’s only a single patient but with an excellent outcome and valuable insights (I would say so wouldn’t I!). It was rather fortuitous as her treatment with IVIg was on the assumption she had anti NMDA antibody encephalitis. Its not always in the science as the viral serology subsequently showed!
Is your interest piqued enough? OK, here is the link (and its open access):
Neurology is huge. It consists of diverse subspecialties, each covering several distinct diseases. Neurology is also a rapidly advancing field with cutting-edge diagnostic processes and novel therapeutic approaches. Neurological practice, therefore, depends on reliable and up-to-date resources.
The NINDS Disorder Index is a library of all neurological disorders listed alphabetically. All sections have information on current research, and provide links to involved organisations. It is an extensive resource, but you would expect this from the world-renown National Association of Neurological Disorders and Stroke.
MedLink Neurologyis an extensive resource for a wide variety of neurological diseases. Content requires paid registration. Articles cite references linked to PubMed and indicate the date they were last updated.
General medical sites with neurology sections
Uptodatehas a neurology section with a good search function but needs a subscription. It is text intensive.
Medscape has a very good and extensive neurology section listed alphabetically, and it is free!
The Neurology Lounge will be incomplete without guidelines-what can we do without them? To come up with a list I took the easy path and searched a database of neurology checklists I am working on for an app. Guess how many guidelines there are? I found 120! 120 guidelines neurologists should know about! This surprised me. As the lounge doesn’t have a bookshelf large enough to accommodate them all, I scaled the number down to my most important 30.
Here then are my top 30 neurology guidelines-all linked.