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!
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!
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!
Many people with difficult to control migraine however really have just that…difficult to control migraine. And it is the most avid neurologist who doesn’t silently sigh and grunt at referrals which say the patient has tried every migraine treatment, to no avail. And with good reason: the journey for people with chronic migraine is hardly ever smooth-sailing.
Why does migraine remain such a pain, and what hope is there to relieve the headache for patients and their neurologists? Here are 8 prospective candidates jostling to soothe the pain.
2. Migraine with cranial autonomic symptoms-clarified
Migraine with unilateral cranial autonomic symptomsis a new construct for most jobbing neurologists (OK I may just be speaking for myself here). Unilateral cranial autonomic symptoms (UAS) refer to one-sided symptoms such as reddening of the eye, blockage or running of the nose, a droopy eyelid, and a small pupil. These features are however classically seen in conditions called trigeminal autonomic cephalalgias (TACS), the main one being cluster headache.
Neurologists often see people with classical migraine but who, in addition, have UAS. The cognitive dissonance this causes the neurologist is relieved by making a diagnosis of cluster migraine. It is therefore important to know that unilateral cranial autonomic symptoms are common in migraine. The authors studied >750 migraine sufferers who also had UAS, and report that it is a severe, one-sided headache. Worse still, it goes on for more than the 72 hours which headache experts have ‘specified’ as the maximum duration for migraine. Naughty, naughty. Hopefully this study will put the final nail in the coffin of cluster migraine-it is Migraine with UAS from now on.
Neurologists have a long list of interventions for migraine. The treatments range from Triptans to Topiramate, from Propranolol to Pizotifen. But the long list of interventions is no comfort for the equally long list of dissatisfied chronic migraine sufferers. Perhaps what we need are newer and better drugs. And monoclonal antibodies are in the frontline here. Take TEV-48125and AMG 334 both reported in Lancet Neurology. These are monoclonal antibodies against the calcitonin gene receptor peptide (CGRP) receptor. The articles are classical illustrations of bench-to-bedside neurology, treatment following where the hypothesis leads. The hypothesis in this case stipulates that the CGRP system is central to the pathology in migraine, and CGRP may be a migraine biomarker. TEV-48125 and AMG 334 are entering phase 3 trial stages. And we can’t wait, what with both treatments having a unique 4-weekly subcutaneous injection regime! AMG 334, also known as erenumab, has passed phase 3 trials with good results.
5. Statins and Vitamin D: new tricks for old dogs
Statins are very old dogs in medicine, and their classical trick is to lower cholesterol levels. They are however very adaptive, these statins. They have edged into secondary stroke prevention, and they are now trying to muscle into migraine prevention. But for migraine they are planning a double act with Vitamin D. The cat was let out of the bag by Annals of Neurology in an article titled Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial. There were only 57 study subjects but the results are encouraging; >25% of the study subjects reported a >50% reduction in migraine days; only 3% of those not on the magic combination showed this type of improvement. Note here that neurologists never promise you 100% reduction in your migraine days. Clever, clever.
6. Memantine-another old dog
Another old dog looking for new tricks is Memantine. This is a drug which usually gets its accolades in the fields of dementia and eye movement disorders. It is however not getting the appreciation it thinks it rightly deserves, and it is seeking a wider audience. And is there a wider audience than in the migraine arena? Memantine made its grand migraine debut through the journal Headache in an article titled Memantine for Prophylactic Treatment of Migraine Without Aura. It may turn out to be a damp squid because the researchers only compared it to placebo. But guess its unique selling point… its potential safety in pregnancy. We have to wait and see what the migraine arena masters think of this.
7. Transcranial magnetic stimulation (TMS):old tricks for a new dog