What should we really know about cerebral aneurysms?

Cerebral aneurysms are scary things. It is alarming enough that they exist, but it is more spine-chilling that they enlarge with time. The most infamous aneurysm arises from the posterior communicating artery, the so-called PCOM aneurysm. And it signifies its sinister intent when it gradually enlarges and compresses its vascular neighbour, the third cranial nerve, otherwise known as the oculomotor nerve. A dysfunctional third nerve manifests with a droopy eyelid (ptosis) and double vision (diplopia). The reason for the double vision becomes obvious when the neurologist examines the eyes; one eyeball is out of kilter and is deviated downwards and outwards; it is indeed down and out! The pupil is also very widely dilated (mydriasis). These are among the most worrying red flags in medicine, and a very loud call to arms. Cerebral aneurysms however often wave no flags, red or otherwise. Indeed the most malevolent of them will expand quietly until they reach horrendous proportions, and then, without much ado, just rupture. They are therefore veritable time bombs…just waiting to go off.

By Tiago Etiene Queiroz – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=24418848

Cerebral aneurysm however do not need to reach large proportions to rupture; some just rupture when they feel like. Aneurysms under 7mm in diameter however are less prone to rupture. A rupturing aneurysm presents with very startling symptoms. The most ominous is a sudden onset thunderclap headache (TCH), subjects reporting feeling as if they have been hit on the back of the head with a baseball or cricket bat. It is not quite known what non-sporting patients experience-for some reason they never get aneurysms in neurology textbooks! More universally appropriate, a ruptured aneurysm may manifest as sudden loss of consciousness. Both symptoms result from leakage of blood into the cerebrospinal fluid (CSF) space, a condition known as a subarachnoid haemorrhage (SAH).

By Lipothymia – Anonymised CT scan from my own practice, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=787177

You may breath a small sigh of relief here because the vast majority of people with thunderclap headaches do not have subarachnoid haemorrhage. Unfortunately, every person who presents with a thunderclap headache must be investigated- to exclude (hopefully), or confirm (ruefully), this catastrophic emergency. The first test is a CT head scan which identifies most head bleeds. The relief of a normal scan is however short-lived because some bleeds do not show on the CT. The definitive test to prove the presence or absence of a bleed is less high tech, but more invasive: the humble spinal tap or lumbar puncture (LP). This must however wait for least 12 hours after the onset of headache or blackout. This is the time it takes for the haemoglobin released by the red blood cells to be broken down into bilirubin and oxyhaemoglobin. These breakdown products are readily identified in the biochemistry lab, and they also impart on the spinal fluid a yellow tinge called xanthochromia. The test may be positive up to 2 weeks after the bleed, but the sensitivity declines after this time. A positive xanthochromia test is startling and sets off an aggressive manhunt for an aneurysm-the culprit in most cases. 

By Ben Mills – Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=13051957

Many people with cerebral aneurysms have a family history of these, or of subarachnoid haemorrhage. Some others may have connective tissue diseases such as Ehler’s Danlos syndrome (EDS), adult polycystic kidney disease (APCKD), or the rare Loeys-Dietz syndrome. This family history is a window of opportunity to screen family members for aneurysms. The screening is usually carried out with a CT angiogram (CTA) or MR angiogram (MRA). People are often not born with aneurysms, but tend to develop them after the age of 20 years. Aneurysm surveillance therefore starts shortly after this age, and many experts advocate repeating the screening test every 5-7 years until the age of 70-80 years.

By Nicholas Zaorsky, M.D. – Nicholas Zaorsky, M.D., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15533196

How are aneurysms treated? This will be the subject of a future blog post so watch this space!

 

Migraine and the challenge of white matter lesions in the brain

Neurologists often refer their patients with headache for a brain MRI scan. Quite often the reason for this is to reassure their patients who are worried about a sinister cause for their headache…and the anxiety provoking culprit is usually a brain tumour. The headache is often a migraine which has recently changed in character, or which is defying conventional treatment.

The neurologist is often ambivalent when requesting such scans. On the one hand, she expects the scan to be normal. On the other hand, she can not be certain there is indeed no sinister cause for the headaches. Another thing also bothers the neurologist, beyond the chance of detecting a brain tumour. And this is the ‘risk’ that the brain scan detects ‘incidental’ findings called white matter lesions (WML). Alas, these reassurograms frequently pick up these less sinister, but nevertheless unexplained, findings.

By Xavier Gigandet et. al. - Gigandet X, Hagmann P, Kurant M, Cammoun L, Meuli R, et al. (2008) Estimating the Confidence Level of White Matter Connections Obtained with MRI Tractography. PLoS ONE 3(12): e4006. doi:10.1371/journal.pone.0004006, CC BY 2.5, Link
By Xavier Gigandet et. al. – Gigandet X, Hagmann P, Kurant M, Cammoun L, Meuli R, et al. (2008) Estimating the Confidence Level of White Matter Connections Obtained with MRI Tractography. PLoS ONE 3(12): e4006. doi:10.1371/journal.pone.0004006, CC BY 2.5, Link

White matter lesions are often just age-related, ‘wear and tear’ changes, and they are more common in people with vascular risk factors such as hypertension, smoking and raised cholesterol levels. Neurologists generally believe migraine is also a risk factor for white matter lesions. And there are several studies to support this belief.

An example is a paper by the headache gurus Marcelo Bigal and Richard Lipton, published in the journal Cephalalgia, titled migraine as a risk factor for deep brain lesions and cardiovascular disease. Another is a paper by Kruit and colleagues in the Journal of the American Medical Association (JAMA) titled migraine as a risk factor for subclinical brain lesions. If you are still not convinced, try this article in the Archives of Neurology by Swartz and colleagues, with the unequivocal title-migraine is associated with magnetic resonance imaging white matter abnormalities.

MIGRAINE. aka TMan on Flikr. https://www.flickr.com/photos/rundwolf/331545021
MIGRAINE. aka TMan on Flikr. https://www.flickr.com/photos/rundwolf/331545021

With this strong evidence, neurologists are able to convince themselves there is nothing to these MRI high signal changes in their patients with migraine. No ‘chicken and egg’ philosophical equivocation is entertained. The scans are sometimes discussed at neuroradiology meetings where everybody murmurs ‘migraine white matter lesions’. All doubt dispelled, the neurologist reassures the patient, and hurriedly closes the chapter.

https://pixabay.com/en/book-closed-bookmark-close-section-2159519/

It is therefore with a strong jolt that neurologists read a recent article in the prestigious journal, Brain, greatly upsetting this cosy neurological consensus. In the paper titled migraine with aura and risk of silent brain infarcts and white matter hyperintensities, the authors found no association between migraine and brain white matter lesions. Shocking!

Shocked girl. Bixendro on Flikr. https://www.flickr.com/photos/bixentro/6360922151
Shocked girl. Bixendro on Flikr. https://www.flickr.com/photos/bixentro/6360922151

The authors studied female twin pairs aged between 30–60 years. The twins were  identified through the population-based Danish Twin Registry. The authors compared the MRI scans of the subjects with and without migraine, and found no difference in the frequency of white matter changes between the two groups. They proudly, and disconcertingly, declare that ‘we found no evidence of an association between silent brain infarcts, white matter hyperintensities, and migraine with aura‘.

Migraine with aura. Joana Roja on Flikr. https://www.flickr.com/photos/cats_mom/2761999058
Migraine with aura. Joana Roja on Flikr. https://www.flickr.com/photos/cats_mom/2761999058

Oh dear-what do neurologists tell their patients now? I shudder to think!

_________________________________________________________________________

 

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.

The emerging progress from the world of MS

Multiple sclerosis (MS) takes a large chunk of neurological practice. This is not only because it is common, but also because of its devastating impact. It predominantly affects the young, and deals a blow that reverberates through the wider family and society. This is why it is a top priority in neurology.

A lot however remains uncertain and controversial in MS. The cause of MS for instance remains unknown although the list of risk factors is a mile long (see my previous blog listing the top 6 MS risk factors). MS is a well-known condition but it features prominently in the most controversial questions in neurology. The pathology and subtypes of MS are subjects of intense debate, and the best tests and treatments are still being worked out.

By Marvin 101 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2846763
By Marvin 101Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2846763

The uncertainties in MS are quite fundamental. Take these two recent publications in high impact journals arguing opposites sides of an MS risk factor. One says there is no association of multiple sclerosis activity and progression with EBV or tobacco use, and the other says smoking cessation improves prognosis of multiple sclerosis. Another research article in the JNNP published this year suggests that we are still not sure what constitutes pathological brain atrophy in MS.

By Monthly_multiple_sclerosis_anim.gif: Waglionederivative work: Garrondo - This file was derived from  Monthly multiple sclerosis anim.gif: , Public Domain, https://commons.wikimedia.org/w/index.php?curid=26444219
By Monthly_multiple_sclerosis_anim.gif: Waglionederivative work: Garrondo – This file was derived from  Monthly multiple sclerosis anim.gif: , Public Domain, https://commons.wikimedia.org/w/index.php?curid=26444219

But it’s not all controversy and conflict in the world of MS. There is real progress shining a light to a brighter future in MS ,and here are a 11 I have found.

1. Interferons, with twists

Interferons have been the mainstay of MS treatment for decades. They are still standing their grounds despite inconclusive evidence of their effectiveness, their side effects, and the challenge from newer treatments. One way they hope to carry on into the future is by joining forces with oral contraceptives. This is according to a paper published in Neurology last year titled Oral contraceptives combined with interferon β in multiple sclerosis. The authors report that ethinylstradiol and desogestrel aid interferon-ß to reduce the number of new lesions in women with relapsing remitting multiple sclerosis.

We are also learning a little bit more about the types of patients who do worse on interferons. The Journal of Neuroimmunology reports that MS subjects with obesity do less well on interferons, and never achieve the valued status of NEDA, no evidence of disease activity. Another paper in JAMA Neurology, on the other hand, suggests that MS subjects with low Vitamin D levels have poorer disease control when treated with interferon.

2. Vitamin D

There is a lot of uncertainty about the significance of Vitamin D deficiency in MS. A big question is if vitamin D should be given routinely to prevent and treat MS. The potential benefit of Vitamin D was recently the subject of an article published in Journal of Cell Biology titled Vitamin D receptor–retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. The University of Cambridge researchers who carried out the study showed that Vitamin D activates a protein receptor, retinoid X receptor γ (RXR-γ), and this plays a role in the repair of myelin, the fatty nerve sheathing that is damaged in multiple sclerosis. The University of Cambridge statement announcing the finding makes for a simpler read: Vitamin D could repair nerve damage in multiple sclerosis.

3. Melatonin

An article in Scientific Americanfirst highlighted an association between seasonal MS relapses and melatonin. The science is rather complex, but the idea is based on the recognition that people with MS have fewer relapses in the darker months of the year, and this is when production of the hormone, melatonin, peaks. The research paper itself is published in Cell under the title Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses. The researchers proved their hypothesis by demonstrating that melatonin levels are lowest during an MS relapse than at other times. Furthermore, the pathology of the disease improves in MS mice treated with melatonin. For a simplified read, try this, perhaps over-enthusiastic, take from MD titled Melatonin Could One Day Treat MS.

4. Helicobacter pylori

Helicobacter pylori. AJ Cann on Flikr. https://www.flickr.com/photos/ajc1/6946417103
Helicobacter pylori. AJ Cann on Flikr. https://www.flickr.com/photos/ajc1/6946417103

In what may be an attempt at rehabilitation, H pylori is attempting to make a good name for itself. Notorius for causing stomach ulcers, it now wants to be known as the patron saint of MS. It is a tenuous link I have to say, but I can’t argue against the research paper published in the prestigious Journal of Neurology, Neurosurgery and Psychiatry (JNNP). The article has a refreshingly self-explanatory title Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females. The authors show that people with MS are less likely to be infected with H. pylori than control subjects. But I will not rush to swim in that dirty-looking pool yet, the margin is thin; 16% versus 21% in control subjects. It however raises the intriguing relationship between infections and autoimmunity, a subject explored brilliantly in the accompanying editorial, the hygiene hypothesis of multiple sclerosis.

5. Phenytoin

Phenytoin is very familiar to neurologists because it was a leading epilepsy medication for decades. Although it still has pride of place in the treatment of status epilepsy, it has largely fallen out of favour-mainly for its cosmetic and cognitive side effects. It is therefore surprising to see phenytoin resurrecting in the world of multiple sclerosis. In a large trial published in Lancet Neurology this year, researchers showed a neuroprotective effect of phenytoin on optic neuritis, a common symptom of MS. Neuroprotection, if you must know, is the holy grail of neurology. The article is titled Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. But you might as well read the distilled, and not over-sensational title, in The TelegraphCheap epilepsy drug could prevent nerve damage in Multiple Sclerosis. I think the findings require a long stretch of the imagination, but I am happy to do this to remain positive.

6. Pramipexole

Modelling the molecular basis of Parkinson's disease. Argonne National Laboratory on Flikr. https://www.flickr.com/photos/argonne/4192798573
Modelling the molecular basis of Parkinson’s disease. Argonne National Laboratory on Flikr. https://www.flickr.com/photos/argonne/4192798573

Pramipexole is a dopamine agonist, a group of drugs used in the treatment of Parkinson’s disease. They are not as popular as they once were, partly again due to side effects. They may however take on an important role in MS. I first came across this in the Barts MS Blog titled Dopamine modulation – a novel target for MS. This refers to an article published in Molecular Neurobiology, Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice. I fail to understand why our ivory towers love these long-winded titles! The bottom line however is that Pramipexole can modulate the immune system thereby limiting the damage it inflicts on the nervous system. Don’t ask me how it does this-I dare you to go read the abstract!

7. Ozanimod

Ozanimod is a sphingosine-1-phosphate receptor modulator, and it has shown promise in trials of relapsing remitting MS. This was the conclusion of a recent randomised, placebo-controlled, phase 2 trial of Ozanimod in MS published in Lancet Neurology. Heart-warmingly called the RADIANCE study, the authors demonstrated the effectiveness of Ozanimod in subjects across 55 centres spread over 13 countries. This feat was rewarded with demonstrable reduction in MRI lesion load in the treated subjects. The phase 3 trial therefore promises a lot…but will it deliver?

8. Anoctamin 2 (ANO2)

By Unknown photographer/artist (False color modifications made by myself--DO11.10) - Dr. Triche National Cancer Institute, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1243806
By Unknown photographer/artist (False color modifications made by myself–DO11.10) – Dr. Triche National Cancer Institute, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1243806

Researchers are veritable hunters, looking for weak spots in their prey, diseases. They then hone in on their victims vulnerabilities, and pounce. In this way they develop treatment strategies. One such weak spot, recently reported in Proceedings of the National Academy of Sciences (PNAS), is connected to the  chloride channel protein Anoctamin 2 (ANO2). The paper, Anoctamin 2 identified as an autoimmune target in multiple sclerosis, reports that subjects with MS have high antibody activity against ANO2. It’s rather complex biochemistry, and for a digested read see the version in Multiple Sclerosis News Today titled New Protein, Anoctamin 2, Identified as a Target of Autoantibody Production in MS. If ANO2 has anything to do with causing MS, you can be sure treatment strategies will follow. If this turns out to be an important pathway in MS, the armoury of MSologists will soon contain stronger firepower.

9. Intrathecal CD20

By Gray (Gray's Anatomy) [Public domain], via Wikimedia Commons
By Gray (Gray’s Anatomy) [Public domain], via Wikimedia Commons
I know, getting into unfamiliar territory now, but the future always feels that way. In a study titled Intrathecal anti-CD20 efficiently depletes meningeal B cells in CNS autoimmunity, researchers injected CD20 into the spinal fluid of mice. They then showed that this depletes the B cells that cause the inflammation in MS. The article is published in Annals of Clinical and Translational Neurology, (I know, I haven’t heard of it before now myself). It is a significant enough step for JAMA Neurology to ask, Is intrathecal anti-CD20 a therapeutic option in treating MS relapse? Whether this would translate into clinical benefit is not clear from the article, but it is promising.

10. Haematopoietic cell transplant (HCT)

There have been reports in the lay press of subjects with MS getting up and walking, almost miraculously. There is however actually some science behind it all, for a change. An article in JAMA Neurology titled, rather clumsily, High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS), illustrated the benefits of haematopoietic cell transplant in MS. The 3 year interim analysis shows that HCT successfully induces sustained remission in MS-what more can we expect from an emerging treatment!

11. FLAIR2

© Nevit Dilmen [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
© Nevit Dilmen [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
MS is as much a neurological, as it is a radiological, condition. The diagnosis of MS is heavily reliant on what is, or is not, a lesion on MRI scans; what is new and what is old; and what is getting bigger or smaller. Believe me, this is hardly ever straightforward. It is therefore gratifying to read an article (OK, I admit it, an abstract) in the American Journal of Neuroradiology titled FLAIR2: A Combination of FLAIR and T2 for Improved MS Lesion Detection. The authors report that they greatly improved the detection of MS lesions by combining two standard magnetic resonance imaging (MRI) techniques called T2 and FLAIR. This technique, FLAIR2, the authors say, is ‘a simple approach of obtaining CSF suppression with an improved contrast-to-noise ratio’, whatever that means! It does make one worry- how much we are actually missing now? FLAIR2 to the rescue.

12. Developing prospect

I know I said 11, but for those who like things to be even I will take you out of your misery and make it an even dozen. Look out for the Amiloride Clinical Trial In Optic Neuritis (ACTION). Something for the future!

MS risk factors: the top 6

Before day 2 commences, a quick word on a wonderful symposium on Multiple Sclerosis (MS).

 

"Journal.pone.0057573.g005" by Veela Mehta, Wei Pei, Grant Yang, Suyang Li, Eashwar Swamy, Aaron Boster, Petra Schmalbrock, David Pitt - Mehta V, Pei W, Yang G, Li S, Swamy E, et al. (2013) Iron Is a Sensitive Biomarker for Inflammation in Multiple Sclerosis Lesions. PLoS ONE 8(3): e57573. doi:10.1371/journal.pone.0057573. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057573#pone-0057573-g005. Licensed under CC BY 2.5 via Wikimedia Commons.
Journal.pone.0057573.g005” by Veela Mehta, Wei Pei, Grant Yang, Suyang Li, Eashwar Swamy, Aaron Boster, Petra Schmalbrock, David Pitt – Mehta V, Pei W, Yang G, Li S, Swamy E, et al. (2013) Iron Is a Sensitive Biomarker for Inflammation in Multiple Sclerosis Lesions. PLoS ONE 8(3): e57573. doi:10.1371/journal.pone.0057573. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057573#pone-0057573-g005. Licensed under CC BY 2.5 via Wikimedia Commons.

 

MS epidemiologists and researchers dissected the topic Causes/Triggers of MS. Speakers were David Hafler, Alberto Aschiero, Lisa Barcellos and Larry Steinman. And the top 6 are

  • Genetics
  • Tobacco smoking

 

smoking

  • Vitamin D deficiency

 

milk-33603_1280

 

  • EBV infection
  • Overweight in early age
  • High salt intake

 

salt-653072_1280

 

 

I suggested to David we should only be looking for correlation rather than causation (an idea I picked up from a great book Big Data).


He strongly disagreed! He believes genome wide association studies (GAS) have confirmed the cause for MS. I think the search for a definite cause is probably futile but we define cause flexibly. Alberto made the point that even if all the known risk factors were eliminated, MS will still be very prevalent