In neurology, the word ‘refractory‘ is almost exclusively used in relation seizures. It may apply to drug-resistant epilepsy(DRE), or to rampaging status epilepticus.’Refractory’ doesn’t sound good in whatever context it is used, typically connoting a situation beyond redemption. But this is not the case with epilepsy. Rather than a bell tolling in despair, refractory is used in epilepsy as a bugle calling to arms.
If anyone was asked to imagine refractory epilepsy, they would surely picture a case that has failed to respond to the heavy arsenal of anti-epileptic drugs (AEDs). They would visualise a patient who has failed Lamotrigine, Carbamazepine, Valproate, and Levetiracetam. They would envisage subsequent failures with Zonisamide, Eslicarbazepine, Oxcarbazepine, and Lacosamide. They would clearly see a neurologist desperately hoping that the seizures would respond to the new AEDs on the block such as Perampanel, Brivaracetam or Retigabine.
They would be very wrong. Rather than a failure of all AEDs, refractory epilepsy is defined by the International League Against Epilepsy (ILEA) as the failure of two well-chosen and tolerated AEDs. The chances of achieving seizure freedom in this situation are slim, and the sooner non-drug interventions are considered, the better. ‘Refractory’, in the context of epilepsy, is therefore a red flag for the neurologist to prevent years of juggling partially effective drugs. It is an early warning system to consider non-drug interventions such as surgery and neuromodulation. This point was strongly made in an article in European Neurological Review titledTreating Drug-resistant Epilepsy – Why are we Waiting? Well worth a read!
Refractory status epilepticus
Refractory is also used in the context of status epilepticus where it describes the failure of two different anti-status medications. In this case, ‘refractory’ tells us that it’s time to use anaesthetic agents to put the patient to sleep, and essentially wait for things to settle. The real challenge comes when this strategy fails. What name do we give this conundrum that goes beyond refractory, and is there anything we can do about it?
The experts ingeniously named this scenario super-refractory status epilepticus! And this super duper name doesn’t scare them from trying to treat it. In their enlightening and hope-raising critical review of super refractory status epilepticus, published in the journal Brain, epilepsy experts Simon Shorvon and Monica Ferlisi offer a surprisingly long list of interventions for super refractory status epilepticus. These include magnesium, steroids, IVIg, plasma exchange, hypothermia, the ketogenic diet, and Rufinamide. The review is a must-read for anyone who manages status epilepticus (or they could look up the condensed version in neurochecklists!)
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.