I was recently perplexed with my first case of tuberous sclerosis complex (TSC). I had no idea what treatment, monitoring and surveillance I needed to institute. I quickly checked things up in neurochecklists; I found excellent checklists on the pathology and clinical features, but was disappointed that there were no treatment or monitoring checklists. I quickly hunted down TSC diagnostic criteriaand TSC surveillance recommendations and updated neurochecklists. Phew!
In the process I discovered that TSC features may improve on treatment with a class of drugs called mTOR inhibitors. Highfalutin stuff I said to myself, and thought nothing more of it. I had to reassess my opinion very shortly afterwards when I came across the Association of British Neurologists (ABN)SoundCloud page with ABN President Phil Smith interviewing Ingrid Scheffer on epilepsy genetics.
We have all experienced that disquieting feeling of just learning something new, and then seeing it crop up all over the place. This is what I felt when Ingrid Scheffer casually stated that Tuberous Sclerosis is an mTORopathy. mTOR is big enough to be an ‘opathy‘, and I was completely ignorant of it! And how come I haven’t heard of Ingrid Scheffer before now-serves me right for missing the last ABN conference in Brighton.
I decided to dig a bit deeper and here are 9 things about mTOR I discovered:
mTOR stands for mammalian (or mechanistic) target of rapamycin
This is a follow up to my previous blog post on the value of checklists in medical practice. That post explored how checklists improve clinical practice and promotepatient safety. It also cited Atul Gawande‘s call to Medicine to “seize the opportunity” and produce checklists for all aspects of clinical practice.
Picking up this gauntlet for neurology comes with peculiar challenges. Here are the 7 hurdles to overcome.
1. The challenge of a diverse specialty
Neurology consists of an astonishing diversity of sub-specialities. Any neurology checklist must exhaustively cover the major neurological categories such as stroke, epilepsy, movement disorders, headache, dementia, neuromuscular diseases, sleep disorders, neuro-inflammation, nervous system tumours, and neurological infections. These topics must be thoroughly covered with emphasis on their clinical features, investigations, and treatments. A useful database must also include rare neurological diseases, of which neurology has quite a few. This is reflected in my previous blog on the most perplexing diseases that excite neurologists.
2. The challenge of multiple associated specialties
Neurological disorders cut across many diverse allied neurological specialties. Any dependable checklist database must cover these specialised fields which include neurosurgery, neuroradiology, neuroophthalmology, neuropsychiatry, neuropaediatrics, and pain management. It must also include important diseases which straddle neurology and general medicine. These include a long list of cardiovascular, nutritional, endocrine and gastrointestinal disorders. Furthermore, neurologists often have to deal with surgical complications especially in orthopaedics and following transplant surgery. Neurologists are also frequently called upon to attend to neurological problems that are unique to pregnancy. Any practical checklist application must therefore thoroughly address these areas.
3. The challenge of reliable content
It goes without saying that the most important feature of any database is reliable content which alone will engender trust and confidence. A reliable checklist must obtain its material from dependable sources. Neurology is replete with reliable textbooks and reference websites, . Neurology is also bursting at the seams with journals such as Neurology, Brain, the JNNP, and Journal of Neurology, each churning out a bewildering array of neurology guidelines, review articles, ground-breaking studies, and fascinating case reports. The challenge is to keep a regular handle on these sources, sifting through for practical and established material. As important for the user is that any checklist must be fully referenced and hyperlinked to the source material.
4. The challenge of practical functionality
Any practical checklist database must be available on the move, easily accessible and searchable. In other words, it must be in the form of a mobile application. The app must have a reliable search functionality. More importantly for users is the requirement that the application must serves as a prompt to remember important points across the breadth of neurological practice: history taking, investigations, differential diagnosis, and treatment. For the administrator, the technology must make it easy to update and edit content, keeping the content consistently up-to-date.
5. The challenge of varied target groups
In developing any form of medical resource, it is a challenge to define the target audience. The primary aim of a neurology checklist application is to ease the challenges medical professionals face in accessing relevant and practical information about neurology in a timely way. This may be on a busy ward round or clinic, but also when researching a topic or preparing a presentation. The core users of a neurology application will therefore clearly be neurologists and neurology trainees.
In many places however other cadres of medicine cater for people with neurological diseases. Psychiatrists, neurosurgeons, paediatricians, general physicians, obstetricians, ophthalmologists, specialist and general nurses, would likely access the database. Other health care professionals may also find areas of interest such as speech therapists, physiotherapists and occupational therapists. Medical students and researchers also require vast amounts of neurological information, often within restricted time frames.
6. The challenge of public access
Specialised medical application are never aimed at non-medically trained people. The reality however is that the general public are closely involved in their care today, seeking reliable information to address their medical concerns. It is inevitable that patients and their families will access the checklist database. For this reason the language must be simple and clear, avoiding any sort of ambiguity.
7. The challenge of resources and pricing
A checklist application, to be most beneficial, should ideally be free to use. A Wikipedia model would be a model to adapt. But creating a checklist database, with all the features mentioned above, would surely stretch resources in terms of time and funding. There will also be great demands on resources to maintain and enhance it. A balance must be struck between beneficence and realism. Such a balance should have, as with most applications, a free version with sufficient access of some sort, and a premium version with unlimited access. The developer must also be aware that potential users have limited resources to spread round their conflicting demands. Any premium account should be affordable, perhaps not more than the equivalent cost of a cup of coffee and a cake a month.
Is there any neurology checklist application that has taken the above challenges into consideration? This will be revealed in my next blog post, How simple checklists unlock excellent neurological practice?
Neurologists do not break into a sweat when they make the diagnosis of essential tremor (ET). Theoretically, at least, they shouldn’t. Essential tremor presents with an obvious shaking of the hands when performing tasks; this is unlike the tremor of Parkinson’s disease which is typically at rest. Neurologists also have handy evidence-based treatment guidelines which recommend medications such as Propranolol and Primidone.
Essential tremor is however anything but straightforward. Tremor is a feature of many other medical and neurological diseases. Neurologists also know that essential tremor may mimic Parkinson’s disease and dystonic tremor. To muddy the waters further, essential tremor also has non-motor symptoms such as cognitivedifficulties. And to add to the frustration, the touted evidence-based treatments, when tolerated, rarely work well enough. These twists and turns that accompany essential tremor are the reasons a review article in Practical Neurology labelled it ‘deceptively simple‘. This deception extends to the core puzzle in essential tremor-what causes it? Here are two tantalising suggestions which attempt to answer this question.
Is essential tremor a neurodegenerative disease?
Neurodegeneration is the usual suspect when neurologists are looking for ‘a cause’. With essential tremor the focus has been on the cerebellum, the part of the brain that co-ordinates movements. This is logical because tremor is a classical symptom of diseases of the cerebellum. This link, circumstantial as it is, has led researchers to interrogate the cerebellum in essential tremor. In doing this they also wondered if the problem is neurodegenerative. The logic behind this line of thinking is explained in a paper published in JAMA Neurology in 2009 titled, Essential tremors: a family of neurodegenerative disorders?
Pursuing this lead, some researchers have tried to hone down on which of the different types of cerebellar cells is involved in essential tremor. Writing in the journal Movement Disorders, the authors are convinced that the seat of neurodegeneration in essential tremor is the Purkinje cell. Purkinje cells are unique cerebellar cells which are vulnerable to all sorts of insults. The researchers in this case demonstrated significantly fewer Purkinje cells in the brains of people with essential tremor than in control subjects without the disease. And they attributed this pathology to neurodegeneration (what else?). The answer to a long-standing riddle, or a hasty conclusion?
Is essential tremor a channelopathy?
Neurologists have known for a long time that essential tremor has a strong genetic element. The diagnosis always feels more certain when there is another family member with tremor. The exact nature of this genetic link is however uncertain. Into this void comes a research paper suggesting that people with essential tremor may have abnormal cellular channels. Channels are proteins in the cell wall that let electrolytes like sodium and potassium in and out, and channelopathies are diseases that affect these channels. The authors of this paper studied a large essential tremor family who also suffer with epilepsy, a typical channel disorder. And the genetic tests they carried out revealed an abnormality in the SCN4A sodium channel. Correlation or causation? The mystery only deepens, I think.
As researchers dig deeper, they will have to decide if it’s neurodegeneration or channelopathy. Or perhaps both. This may then open the doors to better treatments for the disease, confining Propranolol and Primidone to the history books.
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.
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.
In what may be an attempt at rehabilitation, H pyloriis 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.
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 Telegraph, Cheap 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.
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)
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.
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.
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:
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?
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
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
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
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 aholy 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, titledStructural imaging biomarkers of sudden unexpected death in epilepsy, report 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
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 versionof this study.
6. Optogenetics to improve arousal during a seizure
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
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 paperin Science Translational Medicine, or go for the layman’s versionin 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
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 Societywhich offers an excellently simplified summary.
10. Personalised epilepsy surgery
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
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 hemispherectomyreports 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 versionin Mental Floss.
12. Deep brain stimulation for epilepsy
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 epilepsyand referred to pacemaker-like devicesto 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’.
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.
The vagus nerve is one of 12 pairs of nerves that come off the lower part of the brain called the brainstem. It is the tenth in line and therefore also called the tenth cranial (or X) nerve.
It is an interesting nerve for various reasons. Unlike other cranial nerves, it travels way beyond the head and neck. It has a very long course through the neck to the chest and abdomen. Furthermore it regulates a wide variety of organ functions such as heart, respiratory and gut activities. An important branch of the vagus nerve is the recurrent laryngeal nerve which innervates the larynx (voice box).
Due to a quirk of the embryonic development of the aorta, this nerve gets pulled down into the chest before it makes a U-turn back to the neck. It is therefore easily damaged in operations of the neck or chest, and therefore the bane of surgeons.
Scientists have recognised this characteristic feature of the vagus nerve and have tried to manipulate it for therapeutic reasons. The most well-recognised is the stimulation of the vagus nerve to control epileptic seizures. This vagus nerve stimulation (VNS) requires implanting a stimulator under the skin on the chest, and this is connected to the vagus nerve with wires. Somehow or the other, this stimulation modulates seizures. The Epilepsy Society has detailed information on the technical aspects of VNS, and below is a video showing how VNS works.