What unconventional stroke risk factors are out there?

Stroke is a terrible disease. It comes unexpectedly out of the blue, strikes quickly, and leaves devastation in its wake.

Ischemic stroke. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/24964721940
Ischemic stroke. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/24964721940

 

Stroke treatment is advancing in leaps and bounds, but the best approach remains preventative. We are all aware of the need to guard against the conventional harbingers of stroke: hypertension, high cholesterol, diabetes mellitus, and smoking. We are also aware of the benefits of a healthy diet and exercise.

There are of course stroke risk factors we can do nothing about: age is one, and there is of course a long list of genetic stroke risk factors.

DNA rendering. ynse on Flikr. https://www.flickr.com/photos/ynse/542370154
DNA rendering. ynse on Flikr. https://www.flickr.com/photos/ynse/542370154

 

Just as we are getting used to monitoring our blood pressures and heading to the park, some neurologists are bent on making our task a little bit harder. It’s no longer enough to flex those biceps or stamp out that stub; we now have to take notice of unconventional stoke risk factors. The first of these is infection.

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

This paper in Neurology titled Infection, vaccination, and childhood arterial ischemic stroke establishes the association between infection and stroke. The authors showed that 18% of children with stroke had an infection in the preceding week, compared to only 3% of those that did not have a stroke. Adults should not count themselves lucky going by another paper in the journal Vaccine titled Influenza vaccination and risk of stroke: Self-controlled case-series study. Both papers reassure us that immunisation helps to counter the stroke hazard of infections- one strong reason not to skip the next round of flu vaccinations.

By LaurMG. - Cropped from "File:Frustrated man at a desk.jpg"., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=20367001
By LaurMG. – Cropped from “File:Frustrated man at a desk.jpg“., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=20367001

 

Beyond infection come more bizarre unconventional stroke risk factors. We have always known that stress is no good; now we have some evidence to back this up. Just take the following factors now linked to stroke:

Add depression to this and you have a dangerous trio.

 

By BruceBlaus - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=44968538
By BruceBlaus – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=44968538

 

Some medical risk factors are difficult to relate with stroke. Take for example

By M. Adiputra - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11602220
By M. AdiputraOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11602220

 

Another risk factor to watch out for is air pollution. And to cap it off, being bilingual improves the chances of recovery from stroke. How unconventional is that!

Addendum

And straight off the press, you can now add sleep apnoea and insomnia to the list of stroke risk factors.

What’s looming at the frontline of peripheral neuropathy?

Peripheral neuropathy is a very old and often straightforward problem for neurologists. Its presentation is well-defined, and neurologists are at their theatrical best when they map out the classical glove-and-stocking distribution of impaired temperature and touch sensation. They proficiently demonstrate distal muscle weakness and wasting, and masterfully elicit absent reflexes or areflexia.

Stripped hand on a stick. Tysone Moore on Flikr. https://www.flickr.com/photos/tymora42/302709271/in/photostream/
Stripped hand on a stick. Tysone Moore on Flikr. https://www.flickr.com/photos/tymora42/302709271/in/photostream/

 

Below the surface however, peripheral neuropathy is anything but straightforward. It has a wide variety of subtypes and causes, and its classification now has subclassifications of subclassifications. Research is continually demonstrating how complex peripheral neuropathy really is, and here are 4 concepts to illustrate this complexity.

1. IgG4-related peripheral neuropathy
Cold Spring Harbor 012. Vik Nanda on Flikr. https://www.flickr.com/photos/viknanda/315753219
Cold Spring Harbor 012. Vik Nanda on Flikr. https://www.flickr.com/photos/viknanda/315753219

 

As soon as neurologists make the clinical diagnosis of peripheral neuropathy, they reach for the blood request form. They almost mindlessly tick off tests which include immunoglobulins, the building block of antibodies. The nerve damage arising from excessive amounts of immunoglobulins is called paraproteinaemic neuropathy. This simple paradigm, high immunoglobulins equalling paraproteinaemic neuropathy, is however set to change. And this is going by a paper in Neurology titled Immunoglobulin G4-related pathologic features in inflammatory neuropathies. The article showed that IgG4 levels are elevated in a subgroup of people with neuropathy, but these people have vasculitic neuropathy rather than straightforward paraproteinaemic neuropathy. Because the treatment of vasculitis differs from that of paraproteinaemia, this finding is completely changing the rules of the game.

 2. More genes please, we're neurologists
Framed Embroidery Chromosome Art. Hey Paul Studios on Flikr. By Database Center for Life Science (DBCLS), CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=27942321
Framed Embroidery Chromosome Art. Hey Paul Studios on Flikr. By Database Center for Life Science (DBCLS), CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=27942321

 

Hereditary neuropathy is a quagmire for neurologists, but it hasn’t always been that way. In the good old days, (and I have enough grey hairs to say this), a neurologist just needed to have a smattering knowledge of one or two genetic mutations that cause Charcot Marie Tooth disease (CMT), and a vague familiarity with CMT’s genetic cousin, hereditary neuropathy with liability to pressure palsy (HNPP). It used to be a few minutes of counselling, an aliquot of blood, and a confirmatory blood test 6 months later. Not anymore this life of luxury; CMT alone is now classified into multiple subtypes, each subtype caused by a multitude of genetic mutations. And the genetic neuropathists are not done yet; the articles below show the broadening scope of genetic neuropathies we have to contend with. Your neurologist really deserves your sympathies!

 

3. Nodopathies
By Dr. Jana - http://docjana.com/#/saltatory ; https://www.patreon.com/posts/4374048, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=46818964
By Dr. Jana – http://docjana.com/#/saltatory ; https://www.patreon.com/posts/4374048, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=46818964

 

Still in nostalgic mood, there was a time when a neurologist just needed to know if a neuropathy was axonal (affecting the main nerve fiber), or demyelinating (involving the nerve ensheathing layer called myelin). Confine that classification to the history books because nodopathy is toppling the prevailing order. This is from a paper titled Nodopathies of the peripheral nerve: an emerging concept, in the Journal of Neurology, Neurosurgery and Psychiatry (JNNP). The authors of the paper are scathing of the traditional classification which, they say, is ‘inadequate or even misleading’. Why? Because many cases of typical demyelinating neuropathy demonstrate clear axonal changes. The authors explain this paradox by describing the anatomy of myelinated nerves which are made up of domains: node, paranode, juxta-paranode and inter-node. And it is the node which bucks the trend because it resolutely refuses to be ensheathed by myelin. And this singular act of defiance will be the source of anguish for generations of medical students and doctors, not to mention neurophysiologists.

4. Growth factor receptor antibodies

When requesting immunoglobulins and other blood tests, neurologists only needed to tick boxes in standard blood request forms. This life of ease and luxury has been on the way out because the standard blood request form no longer accommodates the ever-expanding causes of peripheral neuropathy. What was previously the almost mindless ticking of B12 and folate is fast becoming anxiety-provoking for the neurologist. It is one thing to remember the test to request, it is another to justify this to your friendly biochemist that this test is worth the cost. But what could a neurologist do when researchers keep coming up with more causes of neuropathy. Take anti-FGFR3 antibodies for example, again from a paper in the JNNP titled antifibroblast growth factor receptor 3 antibodies in sensory neuropathy. The authors have no idea how their findings threaten a cosy B12-and-folate relationship between neurologist and biochemist!

Teased Myelinated Medullated Nerve 2. Green Flames 09 on Flikr. https://www.flickr.com/photos/greenflames09/100294772
Teased Myelinated Medullated Nerve 2. Green Flames 09 on Flikr. https://www.flickr.com/photos/greenflames09/100294772

 

Looking for a comprehensive approach to the management of peripheral neuropathy? I haven’t come across anything better than Clinical Approach to Peripheral Neuropathy in  Continuum…but you need to have access. For a hands-on take on genetic neuropathies, A Practical Approach to the Genetic Neuropathies is the place to start. Thankfully, this is open access.

 

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.

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