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…migraine auras 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 brain infections. 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!
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 the brain is coming out of the head! There you go Lewis Carroll, you may eat your mad hat: fact will always be stranger than fiction!
Neurology can’t seem to get away from autoimmune disorders of the central nervous system. This blog has visited this topic several times before such as with the posts titled What are the dreadful autoimmune disorders that plague neurology? and What’s evolving at the cutting-edge of autoimmune neurology? The attraction of autoimmune neurological diseases lies in part in the ever-expanding spectrum of the antibodies and the challenging symptoms and syndromes they produce.
The fairly well-recognised ‘conventional’ antibodies are those against VGKC (Caspr 2 and LGI1), NMDA, and AMPA. There is however an almost endless list of less familiar antibodies such as those against glycine, adenylate kinase 5, thyroid, GABA-A receptors, α-enolase, neurexin-3α, dipeptidyl-peptidase-like protein 6 (DPPX), and myelin oligodendrocyte glycoprotein (MOG). I am however fascinated by the group of disorders caused by antibodies to metabotropic receptors. The main antibody in this group targets the metabotropic glutamate receptor 5 (mGluR5). The clinical picture with this antibody is a form of encephalitis which may manifest with prosopagnosia (difficulty recognising faces), and with the curious Ophelia syndrome.
Yes, you read it correctly. Ophelia syndrome is named after Shakespeare’s unfortunate 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 bizarre behaviour. 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.
Seahorses are beautiful creatures. The biologists convince us that seahorses are fish, even if they don’t look anything like fish. They also tell us, intriguingly, that seahorses are monogamous and the males do the childbearing.
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
It is no mystery why neuroanatomists name this important part of the brain after the seahorse, the resemblance is eerily striking.
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 therefore endlessly 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 titled Depression, 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 is a terrible disease. It comes unexpectedly out of the blue, strikes quickly, and leaves devastation in its wake.
Stroke treatment is advancing in leaps and bounds, but the best approach remains preventative. We are all aware of the need to guard against the conventional harbingers of stroke: hypertension, high cholesterol, diabetes mellitus, and smoking. We are also aware of the benefits of a healthy diet and exercise.
There are of course stroke risk factors we can do nothing about: age is one, and there is of course a long list of genetic stroke risk factors.
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.
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:
Add depression to this and you have a dangerous trio.
Some medical risk factors are difficult to relate with stroke. Take for example
Another risk factor to watch out for is air pollution. And to cap it off, being bilingual improves the chances of recovery from stroke. How unconventional is that!
And straight off the press, you can now add sleep apnoea and insomnia to the list of stroke risk factors.
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:
- Clinically isolated syndromes (CIS): To treat or not to treat
- Is stem cell therapy an imminent treatment in advanced multiple sclerosis (MS)?
- Vascular cognitive impairment is a misleading concept?
- Is mild cognitive impairment a misleading concept?
- Can physical trauma precipitate multiple sclerosis?
- Should patients with Parkinson’s disease (PD) be treated in the pre-motor phase?
- What is the first line therapy for chronic inflammatory demyelinating polyneuropathy (CIDP)?
- Is intravenous immunoglobulin (IVIg) effective in chronic myasthenia gravis (MG)?
- Tau or ß-amyloid immunotherapy in Alzheimer’s disease (AD)?
- Chronic fatigue syndrome is an organic disease and should be treated by neurologists?
- Should cerebrospinal fluid (CSF) be tested in every clinically isolated syndrome?
- Can we prevent multiple sclerosis (MS) by early vitamin D supplementation and EBV vaccination?
- Does Parkinson’s disease (PD) have a prion-like pathogenesis?
- Patients with medication overuse headache should be treated only after analgesic withdrawal?
- Camptocormia in parkinson’s disease (PD): Is this dystonia or myopathy?
- Does chronic venous insufficiency play a role in the pathogenesis of multiple sclerosis (MS)?
- IVIg or immunosuppression for long-term treatment of CIDP?
- Is sporadic Parkinson’s disease etiology predominantly environmental or genetic?
- Is multiple sclerosis (MS) an inflammatory or a primarily neurodegenerative disease?
- Are the new multiple sclerosis oral medications superior to conventional therapies?
- Is bilateral transverse venous sinus stenosis a critical finding in idiopathic intracranial hypertension (IIH)?
- Will there ever be a valid biomarker for Alzheimer’s disease (AD)?
- Is amyloid imaging clinically useful in Alzheimer’s disease (AD)?
- Do functional syndromes have a neurological substrate?
- Should blood pressure be lowered immediately after stroke?
- Migraine is primarily a vascular disorder?
- Is intravenous thrombolysis the definitive treatment for acute large artery stroke?
- Atrial fibrillation related stroke should be treated only with the new anticoagulants?
- Is the best treatment for chronic migraine botulinum toxin?
- IS CGRP the key molecule in migraine?
- Is chronic cluster headache best treated with sphenopalatine ganglion (SPG) stimulation?
- When should deep brain stimulation (DBS) be initiated for Parkinson’s disease?
- Do interferons prevent secondary progressive multiple sclerosis (SPMS)?
- Is deep brain stimulation (DBS) better than botulinum toxin in primary dystonia?
- Are present outcome measures relevant for assessing efficacy of disease modifying therapies in multiple sclerosis (MS)?
- Should radiologically isolated syndromes (RIS) be treated?
- Does genetic testing have a role in epilepsy management?
- Should cortical strokes be treated prophylactically against seizures?
- Should enzyme-inducing antiepileptic drugs (AEDs) be avoided?
- EEG is usually necessary when diagnosing epilepsy
- Is late-onset depression prodromal neurodegeneration?
- Does Parkinson’s disease begin in the peripheral nervous system?
- What is the best treatment in advanced Parkinson’s disease?
- Are most cryptogenic epilepsies immune mediated?
- Should epilepsy be diagnosed after the first unprovoked seizure?
- Do anti-epileptic drugs (AEDs) contribute to suicide risk?
- Should the ketogenic diet be prescribed in adults with epilepsy?
- Do patients with idiopathic generalized epilepsies require lifelong treatment?
- Cryptogenic stroke: Immediate anticoagulation or long-term ECG recording?
- Is discontinuation of disease-modifying therapies safe in long-term stable multiple sclerosis?
Is behavioral therapy necessary for the treatment of migraine?
- Which is the first-line therapy in cases of IIH with bilateral papilledema?
- Should patients with unruptured arterio-venous malformations (AVM) be referred for intervention?
- Should survivors of hemorrhagic strokes be restarted on oral anticoagulants?
- Will stem cell therapy become important in stroke rehabilitation?
- Do statins cause cognitive impairment?
- 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