What is the startling research unsettling the treatment of myasthenia gravis?

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.

Little red pills. Jon nagl on Flikr. https://www.flickr.com/photos/jonnagl/2470078845
Little red pills. Jon nagl on Flikr. https://www.flickr.com/photos/jonnagl/2470078845

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.

By NLM - NLM Pillbox, http://pillbox.nlm.nih.gov/assets/large/000040lg.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=14666931
By NLM – NLM Pillbox, http://pillbox.nlm.nih.gov/assets/large/000040lg.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=14666931

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.

By Fdardel - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15465576
By Fdardel – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15465576

 

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.

By Oguenther at de.wikipedia - Own work mit Jmol auf Basis RCSB PDB 2OSL., Public Domain, https://commons.wikimedia.org/w/index.php?curid=15482243
By Oguenther at de.wikipedia – Own work mit Jmol auf Basis RCSB PDB 2OSL., Public Domain, https://commons.wikimedia.org/w/index.php?curid=15482243

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.

 

 

mTORopathy: an emerging buzzword for neurology

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 criteria and TSC surveillance recommendations and updated neurochecklists. Phew!

By Herbert L. Fred, MD and Hendrik A. van Dijk - http://cnx.org/content/m14895/latest/, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11892420
By Herbert L. Fred, MD and Hendrik A. van Dijk – http://cnx.org/content/m14895/latest/, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11892420

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:

1

mTOR stands for mammalian (or mechanistic) target of rapamycin

2

mTOR is a kinase

3

The mTOR pathway is important in regulating cell growth and cell death

4

mTOR has an important role in many disorders (mTORopathies). These include tuberous sclerosis, epilepsy, autism, traumatic brain injury, brain tumours, and dementia

5

Mutations in TSC1 or TSC2 genes cause hyperactivation of the mTOR pathway

6

mTOR inhibitors are under investigation for the treatment of these diverse diseases

7

Sirolimus is the major mTOR inhibitor

By Fvasconcellos - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1549073
By FvasconcellosOwn work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1549073

8

The DEPDC5 gene regulates mTOR inhibition.

9

The DEPDC5 gene is mutated in many neurological disorders such as familial focal epilepsies, focal cortical dysplasia, and epileptic spasms. These constitute DEPDC5 motoropathies.

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Enough information to tickle the little grey cells but if you want to dig deeper than you may follow these links:

Keeping up with the latest practical guidelines in neurology

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!

Epilepsy

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 counting lesions 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.

Not far behind MAGNIMS, the Association of British Neurologists (ABN) released their revised 2015 guidelines for prescribing disease-modifying treatments in MS. The guidelines classify DMT’s by efficacyAlemtuzumab and Natalizumab triumphing here. We also learn which DMTs to use in different patient groups.

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?

Chronic inflammatory demyelinating polyneuropathy (CIDP)

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 POEMS syndrome. 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.

 

CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=36822177
CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=36822177
Stroke 

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.

Concussion and traumatic brain injury (TBI)

Concussion is a very topical issue, what with Will Smith as Bennett Omalu in the recent movie aptly titled… Concussion. I have previously posted on the effect of celebrities on neurology, but this here is the serious stuff.  Unlike most guidelines, these clinical practice guidelines for concussion/mild traumatic brain injury and persistent symptoms is not open access. Published in Brain Injury, I could only peruse the abstract, and this mentions 93 recommendations! Tempting however is it’s breadth, addressing everything from post-traumatic headache to sleep disturbance; from vestibular to visual dysfunction.

Friedreich's ataxia (FA)

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 legs syndrome (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.

Should neurologists be thinking of Influenza H1N1?

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, the IDS 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.

3D model of influenza virus
3D model of influenza virus

 

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):

H1N1 Associated Encephalopathy in an Adult: Response to Intravenous Immunoglobulin Supporting an Autoimmune Pathogenesis

Which are the most reliable neurology reference sources?

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.

"Interior view of Stockholm Public Library" by Marcus Hansson from Göteborg, Sweden - The best days are not planned. Licensed under CC BY 2.0 via Wikimedia Commons.
Interior view of Stockholm Public Library” by Marcus Hansson from Göteborg, Sweden – The best days are not planned. Licensed under CC BY 2.0 via Wikimedia Commons.

 

I have previously posted on the proven all-time outstanding neurology textbooks, the most helpful and practical neurology guidelines, and the top all-time neurology review articles. These are all very useful, but all struggle keep up with the rapidly evolving progress in neurology; these resources become obsolete very quickly, and updates often go through laborious and slow processes. Neurologists therefore need reliable sources that keep up with new knowledge, and make sense of all the information ‘out there’. What are these dependable neurology reference sites?  Here is a selection.

Neurology-specific reference sites

  1. 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.
  2. MedLink Neurology is 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

  1. Uptodate has a neurology section with a good search function but needs a subscription. It is text intensive.
  2. Medscape has a very good and extensive neurology section listed alphabetically, and it is free!
  3. BMJ Best Practice also lists neurology topics alphabetically but requires access
  4. BMJ Neurology resources page has a few important neurology links
  5. The Cochrane Library is searchable using neurology as search terms; as far as I can see, most if not all, contents are free
  6. Scholarpedia appears to be a growing site with a helpful neuroscience section worth keeping an eye on.
  7. Medline is the go-to resource for current articles on everything medical. It is however difficult to confirm which articles are relevant or reliable
  8. Trip Database is another huge searchable resource including neurology

Specialty-specific neurology reference sites

  1. The Neuromuscular Disease Centre of Washington University has a detailed database of neuromuscular diseases
  2. Brain Infections UK is a useful site for updates on neurological infections but has a research-focus
  3. Radiopaedia is, as expected, an image-intensive site. It is useful because neurologists need to keep on top of the subtle neuro-radiological features of the diseases they treat. And its free.
  4. PsychCentral is a useful resource for mental health diseases, but you should go straight to the resources directory.

Neurology Guidelines resources

  1. American Academy of Neurology (AAN) guidelines is a reliable site for guidelines covering the broad range of neurology
  2. NICE guidelines are the authoritative benchmark for medical practice in the UK and there is extensive coverage of the major neurological conditions
  3. SIGN guidelines are the equivalent of the NICE guidelines in Scotland
  4. Guidelines Central has an extensive library of guidelines and this link is to neurology section

 

Neurochecklists

For the future, neurochecklists is now live. Learn more about it in my blog post What is the secret of neurochecklists?  Check it out and leave some feedback:

Neurochecklists web-Banner

Looking for more? The Queen Square Library resources page of University College London (UCL) Queen Square Library has several helpful links.

 

Any thoughts or suggestions? Please leave a comment.

The most helpful and practical neurology guidelines

 

 

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.

The list is on the blogs sidebar for easy reference.

Do you agree with my top 30? Do you have any suggestions or updates? Feel free to comment.

Here is a pdf of my top 120 Neurology guidelines.

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