9 promising advances in the management of traumatic brain injury

Traumatic brain injury (TBI) is simply disheartening. It is particularly devastating because it usually affects young people in their prime, with the consequent personal, social, and economic consequences. This blog has previously touched a little on TBI with the post titled Will Smith and chronic traumatic encephalopathy? This was a light-hearted take on concussion in sports, but traumatic brain injury is nothing but a serious burden. So what are the big brains in white coats doing to take down this colossus? Quite a lot it seems. Here, for a taster, are 9 promising advances in the management of traumatic brain injury.

brain 22. Affen Ajlfe on Flickr. https://www.flickr.com/photos/142299342@N06/32794072623

Better understanding of pathology

An amyloid PET imaging study by Gregory Scott and colleagues, published in the journal Neurology, reported a rather surprising link between the pathology seen in long-term survivors of traumatic brain injury, with the pathology seen in Alzheimers disease (AD). In both conditions, there is an increased burden of β-amyloid () in the brain, produced by damage to the nerve axons. The paper, titled Amyloid pathology and axonal injury after brain trauma, however notes that the pattern of deposition in TBI can be distinguished from the one seen in AD. The big question this finding raises is, does TBI eventually result in AD? The answer remains unclear, and this is discussed in the accompanying editorial titled Amyloid plaques in TBI.

By National Institute on Aging – http://nihseniorhealth.gov/alzheimersdisease/whatisalzheimersdisease/01.html, Public Domain, https://commons.wikimedia.org/w/index.php?curid=25038029

Blood tests to detect concussion

The ideal biomarker for any disorder is one which is easy to detect, such as a simple blood test. A headline that screams Blood test may offer new way to detect concussions is therefore bound to attract attention. The benefits of such a test would be legion, especially if the test can reduce the requirement for CT scans which carry the risks of radiation exposure. This is where glial fibrillary acidic protein (GFAP) may be promising. The research is published in the journal, Academic Research Medicine, with a rather convoluted title, Performance of Glial Fibrillary Acidic Protein in Detecting Traumatic Intracranial Lesions on Computed Tomography in Children and Youth With Mild Head Trauma. The premise of the paper is the fact that GFAP is released into the blood stream from the glial cells of the brain soon after brain injury. What the authors therefore did was to take blood samples within 6 hours of TBI in children. And they demonstrated that GFAP levels are significantly higher following head injury, compared to injuries elsewhere in the body. This sounds exciting, but we have to wait and see where it takes us.

Diabetes test. Victor on Flickr. https://www.flickr.com/photos/v1ctor/10871254373

Advanced imaging

Brain Scars Detected in Concussions is the attention-grabbing headline for this one, published in MIT Technology Review. Follow the trail and it leads to the actual scientific paper in the journal Radiology, with a fairly straight-forward title, Findings from Structural MR Imaging in Military Traumatic Brain Injury The authors studied >800 subjects in what is the largest trial of traumatic brain injury in the military. Using high resolution 3T brain magnetic resonance imaging (MRI), they demonstrated that even what is reported as mild brain injury leaves its marks on the brain, usually in the form of white matter hyperintense lesions and pituitary abnormalities. It simply goes to show that nothing is mild when it comes to the brain, the most complex entity in the universe.

Volume rendering of structural MRI scan. Proxy Design on Flickr. https://www.flickr.com/photos/proxyarch/5920559323

Implanted monitoring sensors

Current technologies which monitor patients with traumatic brain injury are, to say the least, cumbersome and very invasive. Imagine if all the tubes and wires could be replaced with microsensors, smaller than grains of rice, implanted in the brain. These would enable close monitoring of critical indices such as temperature and intracranial pressure. And imagine that these tiny sensors just dissolve away when they have done their job, leaving no damage. Now imagine that all this is reality. I came across this one from a CBS News piece titled Tiny implanted sensors monitor brain injuries, then dissolve away. Don’t scoff yet, it is grounded in a scientific paper published in the prestigious journal, Nature, under the title Bioresorbable silicon electronic sensors for the brain. But don’t get too exited yet, this is currently only being trialled in mice.

Public Domain, https://commons.wikimedia.org/w/index.php?curid=190358

Drugs to reduce brain inflammation

What if the inflammation that is set off following traumatic brain injury could be stopped in its tracks? Then a lot of the damage from brain injury could be avoided. Is there a drug that could do this? Well, it seems there is, and it is the humble blood pressure drug Telmisartan. This one came to my attention in Medical News Today, in a piece titled Hypertension drug reduces inflammation from traumatic brain injury. Telmisartan seemingly blocks the production of a pro-inflammatory protein in the liver. By doing this, Telmisartan may effectively mitigate brain damage, but only if it is administered very early after traumatic brain injury. The original paper is published in the prestigious journal, Brain, and it is titled Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Again, don’t get too warm and fuzzy about this yet; so far, only mice have seen the benefits.

Neural pathways in the brain. NICHD on Flickr. https://www.flickr.com/photos/nichd/16672073333

Treatment of fatigue

Fatigue is a major long-term consequence of traumatic brain injury, impairing the quality of life of affected subjects in a very frustrating way. It therefore goes without saying, (even if it actually has to be said), that any intervention that alleviates the lethargy of TBI will be energising news. And an intervention seems to be looming in the horizon! Researchers writing in the journal, Acta Neurologica Scandinavica, have reported that Methylphenidate significantly improved fatigue in the 20 subjects they studied. Published under the title Long-term treatment with methylphenidate for fatigue after traumatic brain injury, the study is rather small, not enough to make us start dancing the jig yet. The authors have rightly called for larger randomized trials to corroborate their findings, and we are all waiting with bated breaths.

Ritalin. Ian Brown on Flickr. https://www.flickr.com/photos/igb/15713970479

Treatment of behavioural abnormalities

Many survivors of traumatic brain injury are left with behavioural disturbances which are baffling to the victim, and challenging to their families. Unfortunately, many of the drugs used to treat these behaviours are not effective. This is where some brilliant minds come in, with the idea of stimulating blood stem cell production to enhance behavioural recovery. I am not clear what inspired this idea, but the idea has inspired the paper titled Granulocyte colony-stimulating factor promotes behavioral recovery in a mouse model of traumatic brain injury. The authors report that the administration of G‐CSF for 3 days after mild TBI improved the performance of mice in a water maze…within 2 weeks. As the water maze is a test of learning and memory, and not of behaviour, I can only imagine the authors thought-surely only well-behaved mice will bother to take the test. It is however fascinating that G‐CSF treatment actually seems to fix brain damage in TBI, and it does so by stimulating astrocytosis and microgliosis, increasing the expression of neurotrophic factors, and generating new neurons in the hippocampus“. The promise, if translated to humans, should therefore go way beyond water mazes, but we have to wait and see.

By Ryddragyn at English Wikipedia – Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2148036

Drugs to accelerate recovery

The idea behind using Etanercept to promote recovery from brain injury sound logical. A paper published in the journal, Clinical Drug Investigation, explains that brain injury sets off a chronic lingering inflammation which is driven by tumour necrosis factor (TNF). A TNF inhibitor will therefore be aptly placed to stop the inflammation. What better TNF inhibitor than Eternacept to try out, and what better way to deliver it than directly into the nervous system. And this is what the authors of the paper, titled Immediate neurological recovery following perispinal etanercept years after brain injury, did. And based on their findings, they made some very powerful claims: “a single dose of perispinal etanercept produced an immediate, profound, and sustained improvement in expressive aphasia, speech apraxia, and left hemiparesis in a patient with chronic, intractable, debilitating neurological dysfunction present for more than 3 years after acute brain injury”. A single patient, mind you. Not that I am sceptical by nature, but a larger study confirming this will be very reassuring.

By Doxepine – Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=6796200

Neuroprotection

And finally, that elusive holy grail of neurological therapeutics, neuroprotection. Well, does it exist? A review of the subject published in the journal, International Journal of Molecular Sciences, paints a rather gloomy picture of the current state of play. Titled Neuroprotective Strategies After Traumatic Brain Injury, it said “despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed“. But all is not lost. The authors promise that “recent changes in experimental approach and advances in clinical trial methodology have raised the potential for successful clinical translation”. Another review article, this time in the journal Critical Care, doesn’t offer any more cheery news about the current state of affairs when it says that the “use of these potential interventions in human randomized controlled studies has generally given disappointing results”. But the review, titled Neuroprotection in acute brain injury: an up-to-date review, goes through promising new strategies for neuroprotection following brain injury: these include hyperbaric oxygen, sex hormones, volatile anaesthetic agents, and mesenchymal stromal cells. The authors conclude on a positive note: “despite all the disappointments, there are many new therapeutic possibilities still to be explored and tested”.

brain 59. Affen Ajlfe on Flickr. https://www.flickr.com/photos/142299342@N06/32794069243/

What an optimistic way to end! We are not quite there yet, but these are encouraging steps.

What is the impact of Vitamin D on the complicated course of MS?

Some general neurologists get away with not having to think too much about multiple sclerosis (MS). This is because they have an ‘MSologist‘ at hand to refer all their patients with ‘demyelination‘. Many general neurologists however care for people with MS because they do not have a ‘fallback guy‘ to do the heavy lifting for them. This therefore makes it imperative for neurologists to keep up with everything about this often disabling and distressing disorder.

MS prevalence map. By AdertOwn work and [1], CC BY-SA 3.0, Link
The management of MS is however very tricky, and it is challenging to get a grip of it all. This is partly because the clinical course is varied, and the diagnostic process tortuous. The patient first goes through an onerous retinue of tests which include an MRI, a lumbar puncture, evoked potentials, and a shedload of blood tests. This is all in a bid to secure the diagnosis and to exclude all possible MS mimics.

MRI scan. NIH Image Galley on Flikr. https://www.flickr.com/photos/nihgov/30805879596

Then comes the head-scratching phase of determining if the patient actually fulfils the diagnostic criteria for MS, or if they just have clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS). To secure the diagnosis of MS, the neurologist turns to the McDonald criteria which stipulate dissemination in time and place of inflammatory events. As simple as this should be, this is no easy task at all. This is because, at different times, the criteria have meant different things to different people. The guidelines have also gone through several painful, and often confusing, iterations. Indeed the McDonald criteria have only recently been re-revised-to the delight of MSologists but the chagrin of the general neurologist!

Steampunk Time and Space Machine. Don Urban on Flikr. https://www.flickr.com/photos/donpezzano/3230179951

Once the diagnosis of relapsing remitting MS (RRMS) is reasonably established, the patient is taken through a guided tour of the ever-expanding available treatment options. These are typically to prevent relapses, but more recently to prevent disease progression as well. People with mild to moderate MS are nudged towards interferons, glatiramer acetate, dimethylfumarate, or terifluonamide. Those with more aggressive disease, on the other hand, are offered a menu of fingolimod, natalizumab, or alemtuzumab. Other newer agents include daclizumab and cladribine. And, just stepping into the arena, there is ocrelizumab for primary progressive (PPMS). Whichever option is chosen, the course of treatment is long, and it is fraught with risks such as infections and immune suppression.

https://pixabay.com/en/syringe-pill-bottle-morphine-small-1884784/

Once the bigger questions have been settled, the neurologist then braces for the ‘minor’ questions her enlightened patients will ask. The easier questions relate to the treatment of symptoms, and some of the most vexing concern the role of Vitamin D deficiency. Such questions include, ‘Is vitamin D deficiency a cause of MS?‘, ‘Do people who are vitamin D deficient experience a worse outcome?‘, and ‘Should patients with MS be on Vitamin D supplementation?‘.

Pandora’s box. Michael Hensman on Flikr. https://www.flickr.com/photos/mycael/3664900435

To attempt to resolve these questions I plunged into some of the literature on Vitamin D and MS. And this is like opening Pandora’s box. Here are some of the things I found.

***

Is MS associated with Vitamin D deficiency?

It therefore appears that there is an association of vitamin D deficiency with MS, but it is far from certain that this is a causative relationship. One hypothesis is that vitamin D deficiency is the outcome, rather than the cause, of MS. The deficiency presumably results becuase the very active immune system in people with MS mops up the body’s Vitamin D. This so-called reverse causation hypothesis asserts that vitamin D deficiency is a consumptive vitaminopathy

Sunshine Falls. Dawn Ellner on Flikr. https://www.flickr.com/photos/naturesdawn/4299041739

Does Vitamin D deficiency worsen MS progression?

There is therefore no single answer to this question, but the emerging consensus is that Vitamin D deficiency adversely affects the course of MS. 

Milk splash experiment. Endre majoros on Flikr. https://www.flickr.com/photos/boneball/24597145866

Should people with MS be on Vitamin D supplementation?

Even if Vitamin D deficiency doesn’t cause MS, the evidence suggests that it negatively influences the course of the disease.

Salmon salad nicoise. Keith McDuffee on Flikr. https://www.flickr.com/photos/gudlyf/3609052894

What to do?

This is the million dollar question eloquently posed by a recent editorial in the journal Neurology titled Preventing multiple sclerosis: to (takevitamin D or not to (takevitamin D? The reasonable consensus is to encourage vitamin D replenishment to prevent MS, starting from preconception. It is also generally agreed that people with MS should be on vitamin D supplementation in the expectation that it will slow the disease activity.

A practical approach to Vitamin D replacement is the Barts MS team vitamin D supplementation recommendation. This is to start with 5,000IU/day vitamin D, and aim for a plasma level of 100-250 nmol/L. Depending on the level, the dose is then adjusted, up or down, to between 2-10,000IU/day. They also advise against giving calcium supplementation unless there is associated osteoporosis.

What is a general neurologist to do? To follow the prevailing trend, and hope it doesn’t change direction too soon!

Vitamin D Pills. Essgee51 on Flikr. https://www.flickr.com/photos/sg51/5224823967

 

Is neurology research finally breaking the resolve of MND?

Motor neurone disease (MND) is, to say the least, dreadful. It also doesn’t help that the terminology neurologists use adds to the distress. West of the Atlantic, amyotrophic lateral sclerosis (ALS) means MND but goes eastwards and it is only a subtype of MND. Thankfully, for most Americans at least, there is no confusion; it is simply Lou Gehrig disease.

By Goudey [Public domain], via Wikimedia Commons
By Goudey [Public domain], via Wikimedia Commons

MND however remains a conundrum for neurologists who are struggling to solve its puzzling riddles. MND researchers continue to toil and sweat, but their efforts are bearing fruits. Take for example the great strides that established the link between MND and the C9ORF72 gene. What are the promising prospects in the world of MND? Here are some.

Associations: Thiamine deficiency and Diabetes 

By Jynto [CC0], via Wikimedia Commons
By Jynto [CC0], via Wikimedia Commons
Should we be on the lookout for thiamine deficiency in patients with MND? This question is prompted by an article in the JNNP which shows an unexpectedly high frequency of laboratory, but not clinical, thiamine deficiency. Titled Thiamine deficiency in amyotrophic lateral sclerosis, the paper reported thiamine deficiency in about 28% of subjects with MND. The authors did not impute any causal association, and there is nothing to suggest that replenishing the thiamine improved outcomes. It is still worth thinking about because people with MND, as the paper emphasised, are at risk of thiamine deficiency.

Another reported association, more difficult to fathom, is the one between MND and diabetes mellitus. The report in the European Journal of Neurology is titled Association between diabetes and amyotrophic lateral sclerosis in Sweden. Why am I sceptical?

Risk factor: Human endogenous retrovirus K (HERV K) 

Retrovirus capsid. A J Cann on Flikr. https://www.flickr.com/photos/ajc1/3269017701/in/photostream/
Retrovirus capsid. A J Cann on Flikr. https://www.flickr.com/photos/ajc1/3269017701/in/photostream/

The cause for MND remains unknown. Risk factors however abound such as smoking and other environmental risk factors. You may now add human endogenous retrovirus K (HERV K) to that list. This is according to a recent paper in Science Translational Medicine titled Human endogenous retrovirus-K contributes to motor neuron disease. The authors report that HERV K is activated in some people with MND, and it is the envelope proteins that cause damage to tissues. The US National Institutes of Health (NIH) think this is an important development, and it released a press statement titled Dormant viral genes may awaken to cause ALS. Scary! Is this important, or just another risk factor? Only time will tell.

Pathology: Neuromuscular junction inflammation 

By Elliejellybelly13 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=40798702
By Elliejellybelly13Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=40798702

This sounds almost sacrilegious- the thought that inflammation may really play a role in MND. And at the neuromuscular junction (NMJ), not the anterior horn cells. Well, some researchers are ready to commit blasphemy; publishing in Experimental Neurology, the authors showed evidence of inflammation in the muscles and NMJs of rat models of MND. They went further to show that injecting a growth factor called GDNF reduced this inflammation. Do I perceive a potential treatment pathway? Read all about it if you dare, its titled Macrophage-mediated inflammation and glial response in the skeletal muscle of a rat model of familial amyotrophic lateral sclerosis (ALS).

Treatment target: TDP-43 protein 

By Emw (Own work) [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
By Emw (Own work) [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
Will MND ever be a curable disease? A big question, but this is the vision of all the hard-working researchers in this field. What are the prospects for a cure? One group of researchers believe the answer is in preventing misfolding of TDP-43, the protein that plays an important role in MND. They set out their case in an article published in Neurotherapeutics titled TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets. And don’t worry, its free access. The bold abstract says it all: “we present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS”. The proof of the pudding….

Diagnostic test: Nerve ultrasound

By Oleg Alexandrov - self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844
By Oleg Alexandrov – self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844

Making the diagnosis of MND is not always (make that is hardly ever) straightforward. In the early stages, symptoms are vague, and clinical signs are non-specific. MND also has many mimics. One of such mimics is multifocal motor neuropathy (MMN). To distinguish this and other mimics from MND, neurologist rely on a test called nerve conduction study (NCS). Even this however is not always helpful.

Researchers have now reported that ultrasound may be more sensitive in distinguishing MND from MMN. Another sacrilegious thought! They published their paper in Journal of Neurology with a rather long title: Nerve ultrasound in the differentiation of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis with predominant lower motor neuron disease (ALS/LMND). Could the diagnosis of MND really be this simple? I am concerned that there were only 16 subjects with MND in the study, all from one centre. Perhaps a randomised, multi-centre, trial will come to the rescue?

Diagnostic biomarker: Brain iron deposition 

By Oleg Alexandrov - self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844
By Oleg Alexandrov – self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844

Brain magnetic resonance imaging (MRI) is not a test neurologist rely upon to make the diagnosis of MND. Not anymore it seems, going by an article in American Journal of Neuroradiology. The paper is titled A Potential Biomarker in Amyotrophic Lateral Sclerosis. In the article, the authors assessed the amount of iron deposition in the brains of people with MND using the MRI techniques called SWI and DTI. Their findings suggest that the amount of iron in the motor cortex and motor tracts of the brain is a good guide to the presence of MND. If confirmed, this technique will help to reduce the long time it often takes before neurologists confirm their suspicions of MND to patients and their families.

Prognostic biomarker: Neurofilament light chain (NfL) 

Neurofilament and MBP. Dan O'Shea on Flikr. https://www.flickr.com/photos/dan_oshea/4079086197
Neurofilament and MBP. Dan O’Shea on Flikr. https://www.flickr.com/photos/dan_oshea/4079086197

The outcome of MND, poor as it often is, varies quite widely. This is influenced by several factors such as the type of MND, use of the medicine riluzole, and multidisciplinary care. New research suggests that neurofilament light chain (NfL) may be a more sensitive marker of prognosis. This is reported in an article published in Neurology titled Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. The authors demonstrated that patients with MND have much higher levels of NfL than those without the disease. Furthermore, subjects with MND who had the highest levels at the onset had a higher mortality hazard ratio. I think I know what that means.

Prognostic scale: ALS-MITOS predictive system

A paper in the JNNP has proposed a new predictive system for MND called ALS-MITOS, reportedly better than the more familiar ALSFRS-R. The report is titled The MITOS system predicts long-term survival in amyotrophic lateral sclerosis. Most practicing neurologists wouldn’t know the difference because they don’t to use such predictive systems. But MND researchers would be licking their lips at the prospect of a better measure of disease progression; it will make it much easier for them to show that their interventions really do work!

Treatment: Copper 

By Native_Copper_Macro_Digon3.jpg: “Jonathan Zander (Digon3)"derivative work: Materialscientist (talk) - Native_Copper_Macro_Digon3.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7223304
By Native_Copper_Macro_Digon3.jpg: “Jonathan Zander (Digon3)”derivative work: Materialscientist (talk) – Native_Copper_Macro_Digon3.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7223304

There are >100 mutations in the superoxide dismutase 1 (SOD-1), a gene known to cause MND. SOD-1 is an enzyme that binds both copper and zinc, and when defective it results in mutant copper (don’t worry, I’m just finding this out myself). Acting on this hypothesis, researchers came up with a crafty way of delivering normal copper into the central nervous system of  mice modelled with SOD-1 MND. Publishing in Neurobiology of Disease, the authors showed how they achieved this with CuATSM, a chemical that contains copper and currently used for PET scans. CuATSM is readily transported into the nervous system, delivering its copper as it does so.

The paper has a rather cumbersome title: Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD. The result is however anything but. The technique extended the lives of the mice by an average of 18 months. Unbelievable it seems. Any doubts however vanished when, on stopping the treatment, the mice died within 3 months. The finding is exciting enough for Eureka Alert to run the story with the headline New therapy halts progression of Lou Gehrig’s disease in mice. ‘Halt’ sounds very much like ‘cure’, but lets put the brakes on and wait for confirmation in human trials .

Treatment: Gene therapy

Gene_therapy. 1Droid JamLos on Flikr. https://www.flickr.com/photos/jamlos/2734418031
Gene_therapy. 1Droid JamLos on Flikr. https://www.flickr.com/photos/jamlos/2734418031

Every recalcitrant disease is today threatened with gene therapy. Considering it has a long list of genetic risk factors, why should MND be any different? Research taking steps in this direction is therefore long overdue. One such step was published in Gene Therapy and is titled Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex. The authors report that they successfully transduced motor nerves of mice models of MND. In doing so they have set the stage for gene therapy in MND. I don’t claim to understand it all, but it sounds very much like they have set the ball rolling. Promising.

Treatment: Stem cell therapy

By Ryddragyn at English Wikipedia - Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2148036
By Ryddragyn at English Wikipedia – Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2148036

Where gene therapy goes, stem cell therapy seems to follow. And this comes from JAMA Neurology with a classic unwieldy academic title: Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis. The content isn’t any easier to interpret, and I will not pretend I get it at all. I comfort myself that it’s all at the ‘open-label, proof of concept‘ stage, and only the very brainy brains need to delve further. But it seems to offer hope.

By Jim Campbell/Aero-News Network - http://www.flickr.com/photos/39735679@N00/475109138/ / http://mediaarchive.ksc.nasa.gov/detail.cfm?mediaid=31873, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3655144
By Jim Campbell/Aero-News Network – http://www.flickr.com/photos/39735679@N00/475109138/ / http://mediaarchive.ksc.nasa.gov/detail.cfm?mediaid=31873, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3655144

 

The sky is surely the limit. Here are a couple of other headlines if you wish to explore further:

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neurochecklists-image

 

12 fascinating advances in epilepsy: big data to pacemakers

I recently posted on the role of vagus nerve stimulation (VNS) in epilepsy. Exciting as it is, there are several cutting edge developments in epilepsy that are making VNS ‘old school’. Here is a round-up of 12 such developments

1. Big data to improve epilepsy care

"Scatter plot" by UCRL - Visualizations that have been created with VisIt. at wci.llnl.gov. Licensed under Public Domain via Commons - https://commons.wikimedia.org/wiki/File:Scatter_plot.jpg#/media/File:Scatter_plot.jpg
“Scatter plot” by UCRL – Visualizations that have been created with VisIt. at wci.llnl.gov. Licensed under Public Domain via Commons – https://commons.wikimedia.org/wiki/File:Scatter_plot.jpg#/media/File:Scatter_plot.jpg

Big Data is spreading its tentacles everywhere and epilepsy is no exception. Take this review in Lancet Neurology for example; titled ‘Epilepsy in 2015: the year of collaborations for big data’, it reviews the impact of big data in five key epilepsy areas such as surgery, effect of epilepsy on pregnancy, and risks if anti-epileptic drugs (AEDs). I was however more impressed by the paper in Neurology titled Predicting frequent ED use by people with epilepsy with health information exchange data‘ which shows how big data may be used to identify frequent emergency department attenders. The authors showed how big data achieves this; the whole aim is to pick out those patients may benefit most from targeted-interventions. The article itself doesn’t mention big data, but the accompanying editorial fortunately does.

2. Better epilepsy monitoring devices

"EEG Recording Cap" by Chris Hope - http://www.flickr.com/photos/tim_uk/8135755109/. Licensed under CC BY 2.0 via Commons - https://commons.wikimedia.org/wiki/File:EEG_Recording_Cap.jpg#/media/File:EEG_Recording_Cap.jpg
“EEG Recording Cap” by Chris Hope – http://www.flickr.com/photos/tim_uk/8135755109/. Licensed under CC BY 2.0 via Commons – https://commons.wikimedia.org/wiki/File:EEG_Recording_Cap.jpg#/media/File:EEG_Recording_Cap.jpg

 

The management of epilepsy is very dependent on the accurate assessment of each patient’s day-to-day event pattern. In the simplest form, this is by a seizure diary. Seizures, the abnormal electrical brain activity that result in epilepsy, do not always manifest as recognisable events. Furthermore, many abnormal movements and behaviours do not necessarily arise from seizures. The neurologist therefore often recommends some form of prolonged brain activity monitoring to sort out what is actually happening. This is often done with procedures such as ambulatory electroencephalogram (EEG) and video EEG telemetry. These are all inconvenient and may only be used for a limited period. It is therefore reassuring that there are better techniques on the way. This press release from the World Federation of Neurology titled New epilepsy monitoring devices offer alternatives to inpatient video EEG lists ‘an array’ of devices such as the Brain Sentinel® System and the EEG PatchTM. These go further than just identifying the seizure activity; they allow patients to monitor clinical and subclinical seizure activity in the everyday home environment and get advance warning before a seizure strikes‘. What could be better for people with epilepsy?

3. Precision medicines for epilepsy

 

Drug firms 'creating ills for every pill' by Publik15 on Flikr. https://www.flickr.com/photos/publik15/3415531899
Drug firms ‘creating ills for every pill’ by Publik15 on Flikr. https://www.flickr.com/photos/publik15/3415531899

Epilepsy is a disease with several types and subtypes, and many genetic forms. Treating epilepsy therefore requires a close fit (no pun intended) of the disease type to its treatment. This is however a difficult task because many epilepsies are poorly defined, and the activity of anti-epileptic drugs (AEDs) are poorly understood. Whilst there are general principles of action of AEDs, these may not apply to individual patients. Herein then lies the promise of precision medicines which, making use of the patient’s genetic makeup or genome, offer a better match of AEDs to individuals. It is still early days but the course is being charted; the EpiPM Consortium recently published ‘A roadmap to precision medicines in the epilepsies‘ in Lancet Neurology.

4. Better prediction of SUDEP

"Ventricular fibrillation" by Jer5150 - Own work. Licensed under CC BY-SA 3.0 via Commons - https://commons.wikimedia.org/wiki/File:Ventricular_fibrillation.png#/media/File:Ventricular_fibrillation.png
“Ventricular fibrillation” by Jer5150 – Own work. Licensed under CC BY-SA 3.0 via Commons – https://commons.wikimedia.org/wiki/File:Ventricular_fibrillation.png#/media/File:Ventricular_fibrillation.png

 

Sudden unexpected death in epilepsy (SUDEP) is a nightmare. It strikes out of the blues, shocking families and neurologists alike. How to predict and prevent this phenomenon is a holy grail in epilepsy care. It is therefore gratifying news in a recent article in the journal Brain that there is a potential SUDEP imaging biomarker. The authors of the paper, titled Structural imaging biomarkers of sudden unexpected death in epilepsyreport that the magnetic resonance imaging (MRI) scans of people at risk of SUDEP show characteristic signs. The main feature is a larger grey matter volume in the right hippocampus and amygdala. The rest of the story is more tricky to understand and involves impaired oxygen regulation leading to the abnormal heart rhythms that presumably cause SUDEP. OK, just take it that this is a potential biomarker to risk-stratify patients for SUDEP!

5. Out-of-hospital status epilepsy injections

 

By AngelHM (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons
By AngelHM (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)%5D, via Wikimedia Commons

A generalised tonic-clonic (or grand mal) seizure often self-terminates within 5 minutes. It may however be prolonged, or occur repeatedly, and this is called status epilepsy or status epilepticus. Out-of-hospital care to terminate status epilepticus often involves the use of buccal Midazolam or, thankfully fading into history, rectal Diazepam. The most effective short-term treatment is however intravenous Lorazepam, but this may only be administered in hospital. Is there something as effective as intravenous Lorazepam which could be administered by paramedics in the community? You guessed it, there probably is. A recent trial published in the New England Journal of Medicine (NEJM) shows that pre-hospital intramuscular Midazolam delivered by paramedics is effective. There are safety issues to sort out but this development promises to avert brain damage that may result from prolonged convulsions. Neuroscience News offers a simplified version of this study.

6. Optogenetics to improve arousal during a seizure

Optogenetics is the use of light to control cell activity in living tissues. I previously listed this in my previous post as one of 10 remarkable breakthroughs that will change neurology. A recent paper in the journal Epilepsia showed how optogenetics may improve epilepsy. Published under the rather unwieldy title Optogenetic stimulation of cholinergic brainstem neurons during focal limbic seizures…., the authors report the application of optogenetics to stimulate subcortical brainstem cells during a focal epileptic seizure. The story is rather complicated but this technique somehow causes inhibition of the cortical cells that generate seizures. A lot of the physiology remains to be sorted, but hey, its shining a light on a difficult problem!

7. 3D electroencephalography (3D-EEG)

 

"Spike-waves". Licensed under CC BY-SA 2.0 via Commons - https://commons.wikimedia.org/wiki/File:Spike-waves.png#/media/File:Spike-waves.png
“Spike-waves”. Licensed under CC BY-SA 2.0 via Commons – https://commons.wikimedia.org/wiki/File:Spike-waves.png#/media/File:Spike-waves.png

The electroencephalogram (EEG) is an indispensable tool in the diagnosis of epilepsy. It helps, amongst other things, to localise the site of a seizure discharge, and to classify the epilepsy type. It is however a rather insensitive tool for planning epilepsy surgery compared to imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) scans which are far better. 3D EEG is however set to make its mark in this area if a recent paper in Epilepsia fulfils its promise. Titled ‘The diagnostic utility of 3D electroencephalography source imaging in pediatric epilepsy surgery‘, the authors show that 3-D EEG is comparable to PET and SPECT in planning epilepsy surgery; and it is also cheaper and less risky.

8. Neurotransmitter imaging of epilepsy

By courtesy of Massachusetts General Hospital and Draper Labs [Public domain], via Wikimedia Commons
By courtesy of Massachusetts General Hospital and Draper Labs [Public domain], via Wikimedia Commons

Epilepsy surgery relies on accurate mapping of the seizure focus. Current techniques are however still suboptimal and scientists are exploring better ways of doing this. One promising field is neurotransmitter-based imaging, and the main neurotransmitter here is glutamate. This MRI technique called glutamate chemical exchange saturation transfer (GluCEST) promises to identify seizure foci that are otherwise difficult to detect. You may read the technical aspects in the original paper in Science Translational Medicine, or go for the layman’s version in Neuroscience News.

An extension of glutamate imaging uses PET scans and relies on imaging NMDA, one type of glutamate receptor. This technique is reported in the Journal of Neurology, Neurosurgery and Psychiatry (JNNP) in an article titled NMDA receptor binding in focal epilepsies. The principle behind NMDA imaging is the knowledge that NMDA receptor ion channels are overactive in epilepsy. Isn’t it nice when science follows first principles!

9. Better mapping of seizure focus

"MRI Location Hippocampus up." by Amber Rieder, Jenna Traynor - Own work. Licensed under CC0 via Commons - https://commons.wikimedia.org/wiki/File:MRI_Location_Hippocampus_up..png#/media/File:MRI_Location_Hippocampus_up..png
“MRI Location Hippocampus up.” by Amber Rieder, Jenna Traynor – Own work. Licensed under CC0 via Commons – https://commons.wikimedia.org/wiki/File:MRI_Location_Hippocampus_up..png#/media/File:MRI_Location_Hippocampus_up..png

Surgery is a very useful tool in treatment of drug-resistant epilepsy. Epilepsy surgery is however not universally successful because localisation of the seizure focus is often imprecise. One promising way to improve the localisation of the seizure focus is to map the changes in oxygen levels that occur in the brain during an epileptic seizure. A paper in the JNNP reports that this is feasible with the use of simultaneous EEG (electroencephalography) and fMRI (functional magnetic resonance imaging). It’s all rather complicated stuff and I recommend this version from the Epilepsy Society which offers an excellently simplified summary. 

10. Personalised epilepsy surgery

"White Matter Connections Obtained with MRI Tractography" 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. Licensed under CC BY 2.5 via Commons.
White Matter Connections Obtained with MRI Tractography” 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. Licensed under CC BY 2.5 via Commons.

 

A holy grail of epilepsy (OK, there are many holy grails) is to individualise all types of epilepsy treatment, including surgery. Personalised epilepsy surgery is guided by a simulated model of a patient’s brain neural connections or connectome. This technique is reported in PLOS Computational Biology  under the title Predicting surgery targets in temporal lobe epilepsy through structural connectome based simulations. Why scientists love long windy titles baffles me. Anyway, the authors first acquired a map of their subject’s brain connectivity using an MRI technique called diffusion tensor imaging (DTI). They then applied a computerised model of how a seizure propagates to the connectivity map. In this way they are able to establish a more accurate surgical target. The area that is resected at surgery using this technique produced better outcomes than resection using a standard procedure. Makes sense to me.

11. Endoscopic epilepsy surgery

"Flexibles Endoskop" by de:Benutzer:Kalumet - Own work. Licensed under CC BY-SA 3.0 via Commons - https://commons.wikimedia.org/wiki/File:Flexibles_Endoskop.jpg#/media/File:Flexibles_Endoskop.jpg
“Flexibles Endoskop” by de:Benutzer:Kalumet – Own work. Licensed under CC BY-SA 3.0 via Commons – https://commons.wikimedia.org/wiki/File:Flexibles_Endoskop.jpg#/media/File:Flexibles_Endoskop.jpg

 

Although surgery is a good technique for epilepsy, it is an invasive procedure with attendant risks. Endoscopy, using minimal access to perform great feats, reduces this risk significantly. It is widely practiced in medicine and indeed neurosurgeons use it to relieve raised intracranial pressure in some cases. It is therefore a relief to learn that major epilepsy operations may be performed endoscopically. A recent article in the Journal of Neuroscience titled ‘Endoscopic corpus callosotomy and hemispherectomy reports the effectiveness of endoscopy in epilepsy operations such as corpus callosotomy; a procedure that interrupts the large bundle of nerve fibers that connect the two brain hemispheres. You may read the easy version in Mental Floss.

12. Deep brain stimulation for epilepsy

 

By Shamir R, Noecker A and McIntyre C [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons
By Shamir R, Noecker A and McIntyre C [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)%5D, via Wikimedia Commons

Deep brain stimulation (DBS) is now routine in many neurological diseases such as Parkinson’s disease (PD). Epilepsy has been slow to catch on but this is changing. A recent piece on the Mayo Clinic website peered into the future treatment options for epilepsy and referred to pacemaker-like devices to control the seizure focus. There are many studies showing the feasibility and effectiveness of implantable devices which directly stimulate an epileptic focus to abort a seizure. One such system is Responsive Brain Neurostimulator (RNS® System)It may be counterintuitive but stimulation rather than suppression is the key. A review of Responsive neurostimulation in epilepsy says ‘the strategy is to interfere as early as possible with the accumulation of seizure activity to prematurely abort or even prevent an upcoming seizure’.

"Hippocampus small" by Images are generated by Life Science Databases(LSDB). - from Anatomography, website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL.. Licensed under CC BY-SA 2.1 jp via Commons - https://commons.wikimedia.org/wiki/File:Hippocampus_small.gif#/media/File:Hippocampus_small.gif
“Hippocampus small” by Images are generated by Life Science Databases(LSDB). – from Anatomography, website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL.. Licensed under CC BY-SA 2.1 jp via Commons – https://commons.wikimedia.org/wiki/File:Hippocampus_small.gif#/media/File:Hippocampus_small.gif

The future is bright for epilepsy care-and it can’t come soon enough for the millions of people whose lives are restricted and compromised by this disease.

Is gadolinium toxic?

The US Food and Drug Administration (FDA) has set up an investigation into the risk of brain deposits from repeated contrast-enhanced MRI scans. This follows case reports of brain deposits from gadolinium-based contrast agents (GBCA’s). The risk seems to start from 4 exposures.

By W. Oelen - http://woelen.homescience.net/science/index.html, CC BY-SA 3.0, Link
By W. Oelen – http://woelen.homescience.net/science/index.html, CC BY-SA 3.0, Link

Gadolinium is very important in ‘lighting up‘ lesions which would otherwise be missed on plain MRI scans. There is no doubt of the importance of gadolinium to neurologists, but it is also the case that it is requested more often than is absolutely necessary. There is no conclusive evidence yet, but this report should make neurologists, and patients, think twice before proceeding with the next contrast MRI. These MRI’s are often done ‘just to be sure we’re not missing anything’. We are most probably not!

By زرشک - Own work, CC BY-SA 3.0, Link
By زرشکOwn work, CC BY-SA 3.0, Link

Want to explore this further?

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