Adult attention deficit hyperactivity disorder (ADHD) is a key psychiatric disorder. It is characterised by some core clinical featureswhich are hyperactivity, inattention, impulsivity, disorganisation, and low stress tolerance. People with ADHD have several life impediments that characterise their day-to-day lives; these include difficulty starting tasks, struggling to prioritise, and failing to pay attention to details. Enduring chaotic lifestyles, they struggle to keep up with their academic, employment, and relationship commitments.
For the public and for most physicians, ADHD is recognised only as a childhood disorder. But 10-60% of childhood onset ADHD persist into adulthood. Furthermore, about 4.5% of adults have ADHD. The failure to recognise ADHD as an adult problem therefore means it is easily missed in adult psychiatry and neurology clinics. Referring to this in a review published in the journal Psychiatry (Edgmont), David Feifel labelled adult ADHD as the invisible rhinoceros (you must read the article to understand why it is not the elephant in the room). Concerned that many adults with ADHD are misdiagnosed as suffering with anxiety or depression, he urged psychiatrists to routinely screen for adult ADHD in every adult presenting with these disorders.
The scale of the failure to diagnose adult ADHD was emphasised by Laurence Jerome in a letter to the Canadian Journal of Psychiatry. Titled Adult attention-deficit hyperactivity disorder is hard to diagnose and is undertreated, his letter highlighted the finding of the US ADHD National Comorbidity Survey which concluded that most adults with ADHD have ‘never been assessed or treated’. He argued that this oversight places heavy lifetime burdens on adults with ADHD such as impaired activities of daily living, academic underachievement, poor work record, marital breakdown, and dysfunctional parenting. A great burden indeed, but a preventable and treatable one!
How is all this psychiatry relevant to the general neurologist? Well, many manifestations of ADHD are the stuff of the neurology clinic. Cognitive dysfunction for example is prevalent in adult ADHD, and it may present to the neurologist as impaired short term memory, executive dysfunction, impaired verbal learning, and, of course, impaired attention. Sleep related disordersare also frequent in adult ADHD, and these include excessive daytime sleepiness (EDS), restless legs syndrome (RLS), periodic leg movements of sleep (PLMS), and cataplexy. There are also several other neurological co-morbidities of adult ADHD such as epilepsy and learning disability.
Alice’s Adventures in Wonderland is a fairy tale that is beyond comparison in its implausible scenarios and outlandish characters. It intrigues and fascinates in equal measure, and it has held generations of children and adults spellbound since its publication in 1865. The fantasy is as fanciful as Lewis Carroll, the pseudonym of the author Charles Lutwidge Dodgson.
As outrageous and as preposterous as it is, the book actually confirms the truism that most works of fiction are grounded in hard reality. In their excellent article, Alice in Wonderland Syndrome: A Historical and Medical Review, Osman Farooq and Edward Fine demonstrated that Alice’s adventures are not a figment of the author’s imagination, but the depiction of his real-life illusory experiences. Lewis Carroll suffered from migraine, and Alice was a perfect incarnation of the visual distortions that accompany this very common and debilitating disorder. Therefore, when lay people read that Alice’s body “had grown too tall or too small”, the stoney-eyed neuroscientists only see macropsia and micropsia, objects appearing larger or smaller than they actually are. When ordinary folks read that “parts of her body were changing shape, size, or relationship to the rest of her body”, the neurologist just sighs and yawns…migraineauras again! What spoilsports they are!
Large and small of course bring to mind another great work of fantastic fiction, Gulliver’s Travels by Jonathan Swift. His Lilliputian and Brobdingnagian hallucinations are in another scale altogether, but did Swift also suffer from migraine? He probably did because the list of artists with probable migraine is fairy long (please don’t miss the intended pun). Some neuroscientist will however pour cold water on the idea that migraineurs are blessed with any creative impulses. Indeed it is not universally accepted that Lewis Crroll suffered from migraine auras. And just when you thought your migraines were worth the suffering! You may read more about art-disease relationships in this excellent article titled Alice in Wonderland Syndrome: A Clinical and Pathophysiological Review.
But we mustn’t be distracted or derailed from the theme of today, Alice in Wonderland syndrome (AIWS). This fascinating disorder, and a disorder it is according to neurologists, puts us in a circular situation: fiction first mimicked fact to produce Alice, and fact then imitated fiction to produce a real ailment. I know, it all sounds absurd. But what did you expect with this theme!
What then is the cause of these illusory experiences that literally blow the mind? Yung-Ting Kuo and colleagues attribute it all to reduction in blood flow to the visual centers in the brain. And how many disorders may do this? Because this is neurology we are talking about…almost anything. The common culprits however are migraine, epilepsy, LSD, an assortment of intoxicants, and a menagerie of braininfections. The syndrome has also been reported in a host of psychiatric and organic brain disorders such as Cotard syndrome, Capgras syndrome, depression, and schizophrenia. More worrying however is the association of the syndrome with prescription medications. One such drug is Topiramate, a medicine neurologists prescribe to prevent, among other conditions, migraine! And another, Aripiprazole, is paradoxically an excellent treatment for…hallucinations!
By Polygon data were generated by Database Center for Life Science(DBCLS)[2]. – Polygon data are from BodyParts3D[1]., CC BY-SA 2.1 jp, Link
As bizarre as Alice’s adventures are, Alice in Wonderland syndrome goes much farther: people with the syndrome experience a wider variety of even more grotesque illusory experiences than Lewis Carroll ever imagined. A recent paper in the journal, Neurology Clinical Practice, shows just how grotesque. Titled Clinical Characteristics of Alice in Wonderland Syndrome in a Cohort with Vestibular Migraine, the authors provide an almost endless list of unusual clinical manifestations of AIWS. The prize must however go the illusion that thebrain is coming out of the head! There you go Lewis Carroll, you may eat your mad hat: fact will always be stranger than fiction!
Yes, you read it correctly. Ophelia syndrome is named after Shakespeare’sunfortunate Danish maiden, and it was first described by Dr. Ian Carr whose daughter, at the age of 15, developed progressive loss of memory, depression, hallucinations, and bizarrebehaviour.These symptoms aptly describe Ophelia’s deluded and obsessional attraction to the equally deluded and murderous Hamlet. Ophelia syndrome is almost always associated with Hodgkins lymphoma and affects young people.
Thankfully Ophelia syndrome is a relatively mild disease without the Shakespearean tragic ending because it has a good outcome if recognised and treated.
Why not explore all the autoimmune neurological disorders on neurochecklists.
At first, it seemed like a single drop, but it is quickly turning into a trickle. The first inkling was a study of >1,700 people with motor neurone disease (MND) which was published in the journal Neurology titled Depression in amyotrophic lateral sclerosis. The authors found that depression is a very frequent diagnosis shortly before people are diagnosed with MND.
Surely a coincidence, I thought. A rogue finding, or even an understandable response to illness. My excuses were however debunked by another paper published soon after in the Annals of Neurology. Titled Psychiatric disorders prior to amyotrophic lateral sclerosis, the study found that depression may precede the diagnosis of MND by more than 5 years. The authors also report a high frequency of other psychiatric conditions preceding the diagnosis of MND, such as anxiety and psychosis.
And just off the press is this report from Nature Communications titled Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. What do we make of this? Is this just the tip of the iceberg? Surely more studies are needed before any firm conclusions. Perhaps this may lead to some early biomarker that enables neurologists to stop the process of progression to full blown MND. Perhaps.
But why is a neurologist talking about seahorses. It’s all in the name. The Latin name for seahorse is hippocampus , derived from hippos for horse, and kampos for sea monster. Where biologists saw fish, the ancients saw monsters. And you really can’t blame them…take a closer look
Neurologists are passionate about the hippocampus for various reasons. In people with memory complaints, for example, hippocampal atrophy may predict the development of Alzheimer’s disease . A shrunken hippocampus is also seen in some forms of epilepsy. Neurologists thereforeendlessly harangue their neuroradiology colleagues to look closely at their patients’ brain MRI scans, and to tell them that the hippocampus is shrunken…even if it’s just a little bit smaller. Unfortunately for the neuroradiologists, the MRI scans do not come colour-coded as in the illustrative scan below.
This blog post is however about major depression, and not about epilepsy or dementia. Depression, that bad feeling we all feel every now and then is frustrating, but major depression is devastating. And we now know that it is accompanied by major alterations in the structure of the brain. And, yes, the changes are in the hippocampus. I got interested in this subject when I came across a piece in Neurology News reporting that people with depression have a smaller hippocampus.
The association of depression with hippocampal atrophy is however an old one. Proceedings of the National Academy of Science (PNAS) reviewed the relationship in an editorial from 2011 titledDepression, antidepressants, and the shrinking hippocampus. The author addressed the unresolved puzzle…which of the two came first. Reminiscent of the chicken and egg scenario, it is not clear if the hippocampal atrophy causes depression, or vice versa. To add to the puzzle, the paper conjectured the possibility of a third, unknown agent, causing both the depression and the small hippocampus.
This question was the focus of a meta-analysis published in Molecular Psychiatry this year. It reviewed the brain imaging data of 15 studies, involving about 1700 people with major depression. Titled Subcortical brain alterations in major depressive disorder, the authors confirmed the link between depression and hippocampal atrophy, and also showed that the shrinkage is worse in those who developed depression at an early age, and in those who have had frequent episodes of depression.
Does depression lead to hippocampal atrophy? The meta-analyses hinted so, but there were too many caveats for the authors to arrive at a definitive conclusion. They admit that more needs to be done to unravel depression….leaving the mystery of the shrinking seahorses to continue to another day.
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 healthydiet 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.
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
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.
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:
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:
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 brain is a mystery and that is why neurologists find it fascinating. The more we know, the more it tantalises us with its hidden gems. Great neurologists have waxed lyrical about the ability of the brain to elude all efforts to fully understand it. Santiago Ramon y Cajal for instance says:
“The brain is a world
consisting of a number of unexplored continents
and great stretches of unknown territory”
Non-neurologists are similarly awed by the brain. Emerson M. Pugh for example says:
“If the human brain were so simple that we could understand it,
we would be so simple that we couldn’t”
Neuroscience and neuroanatomy are at the forefront of exploring this great unknown; the research output from these fields is mind-boggling (pardon the intended pun). But which recent findings are most likely to change neurological practice in the near future? Here are my top 6.
The finding however raises hope of better treatments for some neurological diseases. Because the lymphatic system is closely linked to the immune system, multiple sclerosis (MS) is one potential beneficiary of this discovery. Because lymphatics also act as drainage systems, there are implications for conditions such as Alzheimer’s Disease (AD). Hopefully this brain lymphatic system could be manipulated to clear the accumulated abnormal proteins that cause AD and other neurodegenerative diseases.
The brain’s extensive connections is one of its enduring and fascinating mysteries. The winding fibers and tracts, meandering and looping around each other, demonstrate the brain’s complexity. As soon as we think we have grasped it all, along comes a discovery that causes a paradigm shift. This is illustrated by the report of the discovery of a new brain network involved in memory processing. This Parietal Memory Network (PMN), in the brain’s left hemisphere, responds differentially to new and to old information. This may have relevance for cognitive disorders such as Alzheimer’s Disease (AD). For the more technical details of the network, the paper is published in the journal Trends in Cognitive Neuroscience.
In a similar vein is the discovery of previously unknown brain fiber tractscalled the vertical occipital fasciculus (VOF). This new ‘brain corridor‘ is involved in visual processing. The research paper, published in the Proceedings of the National Academy of Science (PNAS), says the VOF is important in the perception of words and faces, amongst other things, and is ‘involved in the control of eye movements, attention, and motion perception‘. The main benefit of this finding is the improvement of our understanding of how the brain learns to read.
The common assumption that the electrical activity of the comatose brain flatlines on the electroencephalogram (EEG) now appears to be a misconception. This is according to a report of the discovery of a previously unknown electrical brain activity in deep comasuggests. One journal reported this as the discovery oflife after brain death!
These electrical waves, seen in deep coma, are called Nu complexes. They are well-described in the original paper in PLoS One. This finding will alter our definition of brain death which relies very much on the absence of organised brain electrical activity. Another implication is for patients whose medical conditions require that they are put into a coma; this finding will potentially guide the anaesthetist to apply the best form of induced coma.
5. Newly discovered brain cell type
I thought I learnt all the different types brain cells or neurones that exist when I was in medical school. The mysterious brain however has a joker at every corner. The report of the discovery of a new type of neuroneshould come as a surprise, but by now we have learnt not to be shocked by new brain discoveries. The strange thing about these cells, found in the hippocampus of the the brains of mice, is that they have direct connections between their axons (the single long tail) and their dendrites (the smaller hair like projections). This connection by-passes the nerve body; this direct connection enhances the strength of the signals the cell generates. The reason for this peculiarity is not clear but, because the hippocampus is the seat of memory, I guess there are implications for cognitive disorders.
6. Newly discovered brain repair enhancers
We know that the brain repairs itself (neuroplasticity), and that brain fibers make new connections even if this occurs very slowly. What is new is that these processes can be enhanced or accelerated by external agents. Two interesting substances recently reported are psilocybin and curry. Yes, healing mushrooms and spices!
It appears that Psilocybin (psychedelic mushrooms) can establish stable connections between parts of the brain which do not normally communicate well. The research on this is published under the title ‘Homological Scaffolds of Brain Functional Networks‘. The paper describes how psilocybin helps in nerve re-wiring with the potential implications for the treatment of depression and addiction. A bit paradoxical, using an addictive substance to treat addiction; but hey, this is the brain we are talking about!
Curry on the other hand contains tumeric which contains tumerone. Tumerone has now been shown to help with nerve growth repair, and it does this by causing proliferation of brain nerve cells. The research itself is titled ‘Aromatic-tumerone induces neural stem cell proliferation in vitro and in vivo‘. It is a study in rats, but are human brains very different? Potential beneficiaries are all the neurodegenerative diseases which neurologists have singularly failed to reverse.
This is the age of rapidly advancing technology. Blink, and the scene changes unrecognisably. It would be unbelievable if we weren’t actually living it. What technological advances will impact Neurology in the near future? Here are my top 10 neurology-impacting technologies.
Clot-busting or thrombolysis is life saving treatment following stroke. This however requires getting to hospital within 4.5 hours of the event, and is given by intravenous injections. How much better if it would be if thrombolysis could be delivered by mouth, and at the point of contact with paramedics. Indeed this is the idea behind clot-busting nanocapsules. Nanoparticles may also have future applications in prevention of MS relapses.
2. Disease-monitoring wearables
What if people with epilepsy could predict their next seizure? Or if someone with multiple sclerosis (MS) could predict an impending relapse? Well, wearable technology promises to do just that. This goes beyond the fitbit which measures basic biological processes; these technologies will monitor realtime data such as a watch that measures skin moisture for seizure-prediction, or an iPad strapped to the back to monitor walking speed of patients with MS. I predict this technology will rapidly spread to many other chronic neurological diseases.
3. Nanoscale-resolution brain imaging
From the humble X-ray to the CT scan, brain imaging has progressed in leaps and bounds to a proliferation of MRI modalities with ever-increasing resolution or power. But nanoscale resolution imagingpromises to make things more SciFi than healthcare. With the ability to look at ‘every nook and cranny‘ of the brain, this technology will visualise brain connections with incredible detail. Imagine how this will enhance diagnostic accuracy (and diagnostic conundrums in equal measure). This work is still in mice butI’m sure human application will follow shortly.
4. High-resolution eye selfies
Mobile phones are ubiquitous and the camera function seems to be more valuable than the talk mode. What with the number of selfies proliferating like a rah over social media. This may however be of advantage to healthcare. As the camera resolution increases exponentially, eye-selfies may come to the aid of neurologists and ophthalmologists who treat patients with a condition called idiopathic intracranial hypertension (IIH). In this condition the pressure of the fluid around the brain is elevated. This shows as a blurring of the margins of an area called the disc and this is seen in the back of the eye using an ophthalmoscope. With advanced mobile phone cameras patients with IIH could make an eye-selfie diagnosis or assist in monitoring their eyes themselves.
The electroencephalogram (EEG) is an invaluable tool for making the diagnosis of epilepsy. The process requires a time-consuming application of several electrodes to specific points on the scalp. The electrodes are then connected by wires or leads to a machine which records the brains electrical activity. This cumbersome process is time consuming especially for patients that need to keep the wires on for days. To the rescue is the wireless brain helmet. This will not only make the recording easier, it will send the recording wirelessly to the physiologist who will interpret the test. More interestingly, it will allow receive signals sent by the physiologist which will be targeted to treat epilepsy or other conditions like depression. The NeuroPace’s RNS system is one such device leading the way.
6.Wireless drug delivery
This is another wireless technologywhich facilitates thedirect delivery of drugs into the brain. The device, not thicker than a human hair, is implanted into the brain and wirelessly controlled to deliver the required dose of drug, at specified times. The likely beneficiary diseases are epilepsy and depression (again). It is still in the stage of trials in mice but coming to your neighbourhood hospital very soon. If you want the complicated details then see the journal Cell for the research paper titled Wireless Optofluidic Systems for Programmable In-vivo Pharmacology and Optogenetics. What a mouthful!
A blood test to warn of the risk of impending suicide? Wouldn’t that be great? It is not a far-fetched dream if reports that a blood test for RNA biomarkers of suicidal thoughts fulfils its potential. This will have psychiatrists whooping for joy-or out of a job!
8. Optogenetics
Optogenetics is the use of light to control cells. This has the potential to alter nervous system function with exciting prospects for disease treatment. Again epilepsy appears to be a prime beneficiary if this takes off. Imagine programming a brain cell or neurone to glow red when calcium flows into it. This glow then dampens the activity of neighbouring cells thereby inhibiting any rouge electrical impulse that may result in an epileptic seizure. The process requires the injection of a genetically engineered virus which infects the brain cells. This ability to modify brain cell behaviour also has implications for the treatment of Parkinson’s disease (PD) and depression among other things. More SciFi you say.
9. Gene therapy for muscular dystrophy
Genetic therapy is an old dog that is still barking. This is just as well because it remains the only hope for many genetic conditions. Genetic therapy has had its ups and downs and a very recent high is the positive outcome in leukaemia. Neurology is however not too far behind if this report that muscular dystrophy gene therapy has been successful in dogsis translated to humans.The research is rather complex but the academically minded may be interested in details of the trial.
10. Molecular spies for early cancer detection
A molecular spy is an antibody probe that is directed at the brain to detect and destroy ‘rogue’ cells. The leading researcher for this is Sam Gembhir who is based at the Canary Center at Stanford for Cancer Early Detection. Best to hear it from the horse’s mouth- speaking here at a TED talk.
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