How is migraine research soothing the pain of neurology?

Migraine is a very common medical disorder. 15% of the world’s population have migraine, and 2% have chronic migraine. Most migranuers never need to see a neurologist because they have learnt how to manage their headaches. Neurologists are called in only when the usual treatments fail, often a euphemism for ‘inadequate doses and duration of treatment’.

Migraine. Quinn Dumbrowski on Flikr. https://www.flickr.com/photos/quinnanya/3820597553/in/photostream/
Migraine. Quinn Dumbrowski on Flikr. https://www.flickr.com/photos/quinnanya/3820597553/in/photostream/

Many people with difficult to control migraine however really have just that…difficult to control migraine. And it is the most avid neurologist who doesn’t silently sigh and grunt at referrals which say the patient has tried every migraine treatment, to no avail. And with good reason: the journey for people with chronic migraine is hardly ever smooth-sailing.

By User:S. JähnichenBrain_bulbar_region.svg: Image:Brain human sagittal section.svg by Patrick J. Lynch; Image:Brain bulbar region.PNG by DO11.10; present image by Fvasconcellos. - Brain_bulbar_region.svg, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=6049291
By User:S. JähnichenBrain_bulbar_region.svg: Image:Brain human sagittal section.svg by Patrick J. Lynch; Image:Brain bulbar region.PNG by DO11.10; present image by Fvasconcellos. – Brain_bulbar_region.svg, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=6049291

Why does migraine remain such a pain, and what hope is there to relieve the headache for patients and their neurologists? Here are 8 prospective candidates jostling to soothe the pain.

 

1. The hypoxia hypothesis for migraine triggers

There are probably as many migraine triggers as there are migraine hypotheses. Some of the triggers are curious, as discussed in my previous blog Migraine and its strange and surprising associations. Some researchers think the common link to migraine triggers is low oxygen or hypoxia. Writing in the prestigious journal Brain, they report on Migraine induced by hypoxia: an MRI spectroscopy and angiography study. Sorry, the full paper is locked to non-subscribers, but the abstract is unequivocal: hypoxia induces migraine-like attacks. And the accompanying editorial is agog with the prospects this study opens up with its headline, Hypoxia, a turning point in migraine pathogenesis? Who doesn’t love turning points, especially as the previous turning points can then be conveniently forgotten?

2. Migraine with cranial autonomic symptoms-clarified

Alison Smith on Flikr. https://www.flickr.com/photos/polygrams/232755351/in/photostream/
Alison Smith on Flikr. https://www.flickr.com/photos/polygrams/232755351/in/photostream/

Migraine with unilateral cranial autonomic symptoms is a new construct for most jobbing neurologists (OK I may just be speaking for myself here). Unilateral cranial autonomic symptoms (UAS) refer to one-sided symptoms such as reddening of the eye, blockage or running of the nose, a droopy eyelid, and a small pupil. These features are however classically seen in conditions called trigeminal autonomic cephalalgias (TACS), the main one being cluster headache.

Neurologists often see people with classical migraine but who, in addition, have UAS. The cognitive dissonance this causes the neurologist is relieved by making a diagnosis of cluster migraine. It is therefore important to know that unilateral cranial autonomic symptoms are common in migraine. The authors studied >750 migraine sufferers who also had UAS, and report that it is a severe, one-sided headache. Worse still, it goes on for more than the 72 hours which headache experts have ‘specified’ as the maximum duration for migraine. Naughty, naughty. Hopefully this study will put the final nail in the coffin of cluster migraine-it is Migraine with UAS from now on.

3. Persistent migraine aura or visual snow?

By Googleaseerch at the English language Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3359664
By Googleaseerch at the English language Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3359664

I admit I didn’t know persistent migraine aura (PMA) even existed before now. It is migraine aura lasting more than a week, and it has two subtypes-persistent primary visual disturbance (PPVD) and typical aura (TA). Digging deeper, I found that PMA could easily be confused with something called visual snow. Another new one for me. An article in Brain titled ‘Visual snow’ – a disorder distinct from persistent migraine aura makes the differences clear. With its co-author no less than the headache authority Peter Goadsby, go on and read all about it-its open access after all. For a simplified read, try this piece in About Health titled Why Visual Snow Syndrome is Not a Migraine Variant. Another small step to making the right diagnosis.

4. Monoclonal antibodies for migraine

monoclonal-antibody-services.jpg. 元永利 on Flikr. https://www.flickr.com/photos/linsc/4628425031/in/dateposted/
monoclonal-antibody-services.jpg. 元永利 on Flikr. https://www.flickr.com/photos/linsc/4628425031/in/dateposted/

Neurologists have a long list of interventions for migraine. The treatments range from Triptans to Topiramate, from Propranolol to Pizotifen. But the long list of interventions is no comfort for the equally long list of dissatisfied chronic migraine sufferers. Perhaps what we need are newer and better drugs. And monoclonal antibodies are in the frontline here. Take TEV-48125 and AMG 334  both reported in Lancet Neurology. These are monoclonal antibodies against the calcitonin gene receptor peptide (CGRP) receptor. The articles are classical illustrations of bench-to-bedside neurology, treatment following where the hypothesis leads. The hypothesis in this case stipulates that the CGRP system is central to the pathology in migraine, and CGRP may be a migraine biomarker. TEV-48125 and AMG 334 are entering phase 3 trial stages. And we can’t wait, what with both treatments having a unique 4-weekly subcutaneous injection regime! AMG 334, also known as erenumab, has passed phase 3 trials with good results.

5. Statins and Vitamin D: new tricks for old dogs

Statins are very old dogs in medicine, and their classical trick is to lower cholesterol levels. They are however very adaptive, these statins. They have edged into secondary stroke prevention, and they are now trying to muscle into migraine prevention. But for migraine they are planning a double act with Vitamin D. The cat was let out of the bag by Annals of Neurology in an article titled Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial. There were only 57 study subjects but the results are encouraging; >25% of the study subjects reported a >50% reduction in migraine days; only 3% of those not on the magic combination showed this type of improvement. Note here that neurologists never promise you 100% reduction in your migraine days. Clever, clever.

6. Memantine-another old dog

Another old dog looking for new tricks is Memantine. This is a drug which usually gets its accolades in the fields of dementia and eye movement disorders. It is however not getting the appreciation it thinks it rightly deserves, and it is seeking a wider audience. And is there a wider audience than in the migraine arena? Memantine made its grand migraine debut through the journal Headache in an article titled  Memantine for Prophylactic Treatment of Migraine Without Aura. It may turn out to be a damp squid because the researchers only compared it to placebo. But guess its unique selling point… its potential safety in pregnancy. We have to wait and see what the migraine arena masters think of this.

7. Transcranial magnetic stimulation (TMS):old tricks for a new dog 

Away with old dogs, and welcome back more new dogs. One is transcranial electrical stimulation (TMS) which now has the blessing of the UK National Institute of Clinical and Health Excellence (NICE) for migraine treatment and prevention. See my previous blog, Are magnets transforming neurological practice, for more on TMS.

8. Peripheral nerve stimulation

Another new dog is reported in Neurology with the self-explanatory title: Migraine prevention with a supraorbital transcutaneous stimulator. Nerve stimulation is of course an old trick in migraine, but the supraorbital nerve is a new target. This article from Pain Physician gives a detailed review of peripheral nerve stimulation and migraine.

 

Migraine Aura Kaleidoscope. Joana Roja on Flikr. https://www.flickr.com/photos/cats_mom/2988669345/in/photostream/
Migraine Aura Kaleidoscope. Joana Roja on Flikr. https://www.flickr.com/photos/cats_mom/2988669345/in/photostream/

 

Migraine remains challenging to neurologists and distressing for their patients. Perhaps we can now dispense hope along with prescriptions.

=========================================================================

screen-shot-2016-12-19-at-18-32-39

What are the most controversial questions in neurology?

Uncertainty and doubt abound in Neurology. There are many evidence-free areas where experts rub each other the wrong way. These controversies are big and occur in all neurology subspecialties. Controversy-busters have tried for about a decade to iron out these wrinkles on neurology’s face, but the unanswered questions remain. This is why there is a 10th World Congress of Controversies in Neurology (CONy) holding in Lisbon this year.

I want to assure you I have no conflict of interest to declare in this blog. My interest is to explore  which questions have plagued this conference over the last 10 years to pick out the most controversial topics in neurology. To do this I reviewed all previous conference programs and focused on the items that were slated for debate. I looked for practical topics that have remained unresolved, or are just emerging. Here are my top controversial neurological questions:

Raccoon argument II. Tambako The Jaguar on Flikr. https://www.flickr.com/photos/tambako/7460999402
Raccoon argument II. Tambako The Jaguar on Flikr. https://www.flickr.com/photos/tambako/7460999402

 

1st CONy 2007 (Berlin, Germany)

  • Clinically isolated syndromes (CIS): To treat or not to treat
  • Is stem cell therapy an imminent treatment in advanced multiple sclerosis (MS)?
  • Vascular cognitive impairment is a misleading concept?
  • Is mild cognitive impairment a misleading concept?

 

2nd CONy 2008 (Athens, Greece)

  • Can physical trauma precipitate multiple sclerosis?
  • Should patients with Parkinson’s disease (PD) be treated in the pre-motor phase?
  • What is the first line therapy for chronic inflammatory demyelinating polyneuropathy (CIDP)?
  • Is intravenous immunoglobulin (IVIg) effective in chronic myasthenia gravis (MG)?
  • Tau or ß-amyloid immunotherapy in Alzheimer’s disease (AD)?
  • Chronic fatigue syndrome is an organic disease and should be treated by neurologists?

 

3rd CONy 2009 (Prague, Czech Republic)

  • Should cerebrospinal fluid (CSF) be tested in every clinically isolated syndrome?
  • Can we prevent multiple sclerosis (MS) by early vitamin D supplementation and EBV vaccination?
  • Does Parkinson’s disease (PD) have a prion-like pathogenesis?
  • Patients with medication overuse headache should be treated only after analgesic withdrawal?

 

 

4th CONy 2010 (Barcelona, Spain)

  • Camptocormia in parkinson’s disease (PD): Is this dystonia or myopathy?
  • Does chronic venous insufficiency play a role in the pathogenesis of multiple sclerosis (MS)?
  • IVIg or immunosuppression for long-term treatment of CIDP?

 

5th CONy 2011 (Beijing, China)

  • Is sporadic Parkinson’s disease etiology predominantly environmental or genetic?
  • Is multiple sclerosis (MS) an inflammatory or a primarily neurodegenerative disease?
  • Are the new multiple sclerosis oral medications superior to conventional therapies?
  • Is bilateral transverse venous sinus stenosis a critical finding in idiopathic intracranial hypertension (IIH)?

 

6th CONy 2012 (Vienna, Austria)

  • Will there ever be a valid biomarker for Alzheimer’s disease (AD)?
  • Is amyloid imaging clinically useful in Alzheimer’s disease (AD)?
  • Do functional syndromes have a neurological substrate?
  • Should blood pressure be lowered immediately after stroke?
  • Migraine is primarily a vascular disorder?

 

 

7th CONy 2013 (Istanbul, Turkey)

  • Is intravenous thrombolysis the definitive treatment for acute large artery stroke?
  • Atrial fibrillation related stroke should be treated only with the new anticoagulants?
  • Is the best treatment for chronic migraine botulinum toxin?
  • IS CGRP the key molecule in migraine?
  • Is chronic cluster headache best treated with sphenopalatine ganglion (SPG) stimulation?
  • When should deep brain stimulation (DBS) be initiated for Parkinson’s disease?
  • Do interferons prevent secondary progressive multiple sclerosis (SPMS)?
  • Is deep brain stimulation (DBS) better than botulinum toxin in primary dystonia?
  • Are present outcome measures relevant for assessing efficacy of disease modifying therapies in multiple sclerosis (MS)?
  • Should radiologically isolated syndromes (RIS) be treated?
  • Does genetic testing have a role in epilepsy management?
  • Should cortical strokes be treated prophylactically against seizures?
  • Should enzyme-inducing antiepileptic drugs (AEDs) be avoided?
  • EEG is usually necessary when diagnosing epilepsy

 

8th CONy 2014 (Berlin, Germany)

  • Is late-onset depression prodromal neurodegeneration?
  • Does Parkinson’s disease begin in the peripheral nervous system?
  • What is the best treatment in advanced Parkinson’s disease?
  • Are most cryptogenic epilepsies immune mediated?
  • Should epilepsy be diagnosed after the first unprovoked seizure?
  • Do anti-epileptic drugs (AEDs) contribute to suicide risk?
  • Should the ketogenic diet be prescribed in adults with epilepsy?
  • Do patients with idiopathic generalized epilepsies require lifelong treatment?
  • Cryptogenic stroke: Immediate anticoagulation or long-term ECG recording?
Southern Chivalry: Argument Vs Clubs. elycefeliz on Flikr. https://www.flickr.com/photos/elycefeliz/6271932825
Southern Chivalry: Argument Vs Clubs. elycefeliz on Flikr. https://www.flickr.com/photos/elycefeliz/6271932825

 

9th CONy 2015 (Budapest, Hungary)

  • Is discontinuation of disease-modifying therapies safe in  long-term stable multiple sclerosis?
  • Is behavioral therapy necessary for the treatment of migraine?
  • Which is the first-line therapy in cases of IIH with bilateral papilledema?
  • Should patients with unruptured arterio-venous malformations (AVM) be referred for intervention?
  • Should survivors of hemorrhagic strokes be restarted on oral anticoagulants?
  • Will stem cell therapy become important in stroke rehabilitation?
  • Do statins cause cognitive impairment?

 

10th CONy 2016 (Lisbon, Portugal)

  • Which should be the first-line therapy for CIDP? Steroids vs. IVIg
  • Should disease-modifying treatment be changed if only imaging findings worsen in multiple sclerosis?
  • Should disease-modifying therapies be stopped when secondary progressive MS develops?
  • Should non-convulsive status epilepsy be treated aggressively?
  • Does traumatic chronic encephalopathy (CTE) exist?
  • Does corticobasal degeneration (CBD) exist as a clinico-pathological entity?
  • Is ß-amyloid still a relevant target in AD therapy?
  • Will electrical stimulation replace medications for the treatment of cluster headache?
  • Carotid dissection: Should anticoagulants be used?
  • Is the ABCD2 grading useful for clinical management of TIA patients?
  • Do COMT inhibitors have a future in treatment of Parkinson’s disease?

 

Debate Energetico. Jumanji Solar on Flikr. https://www.flickr.com/photos/jumanjisolar/5371921203
Debate Energetico. Jumanji Solar on Flikr. https://www.flickr.com/photos/jumanjisolar/5371921203

 

Going through this list, I feel reassured that the experts differ in their answers to these questions? The acknowledgement of uncertainty allows us novices to avoid searching for non-existent black and white answers. It is however also unsettling that I thought some of these questions had been settled long ago. It goes to show that apparently established assumptions are not unshakable?

Do you have the definitive answers to resolve these controversies? Are there important controversies that are missing here? Please leave a comment