In our continuing zeal to maintain a grip on all of neurology, We regularly add to our already exhaustive database of checklists. As a taster of what we have recently done, Below are 15 brand new checklists expanding our horizon. *** Acute amnestic syndromes Alzheimer’s disease preventative measures Antiplatelet resistance: causes Antiplatelet resistance: management Encephalocraniocutaneous […]A few more helpful and practical neurology checklists — Neurochecklists Blog
It is difficult to really say when neuroscience began, but most sources trace the first account of the nervous system to what is now known as the Edwin Smith papyrus; this is an Egyptian text written around 1700 B.C which documents surgical procedures for brain trauma. Since then, neuroscience breakthroughs have come at breakneck speed. The sources I have consulted for this blog post, referenced at the end, name innumerable discoveries made by countless innovators. To attempt to put a number to the most important breakthroughs will therefore be a well-nigh impossible task. So I came up with the idea of chunking key discoveries under distinct sections or systems of the nervous system.
But even this plan to chunk key breakthroughs came with strong challenges. For example, it is not always clear when a discovery was first made, or who crossed the finishing line first. This is because there are often several contenders in a tight race to the finish, and only a few discoveries were definite one-man paradigm-changing works. On the contrary, most discoveries were made by two or three pioneers working in a creative partnership, or by larger groups of people working in innovative collaborations. A further challenge was establishing what or where the finishing line was, as this is not always well-defined; this is understandable because most scientific advances were made over centuries, in small incremental steps, in a gradual progression from basic observation to complex synthesis.
To overcome these challenges, I have avoided too much emphasis on the ‘who first‘ conundrum that drives, and sometimes mires, science. I have also side-stepped the ‘when first‘ problem by noting only a few dates just to maintain some sense of chronology. I did a lot of picking and choosing for this post, and it is inevitable that somebody’s favourite discovery, or discoverer, would be missing; take heart and exult in the collective effort that has gone into these monumental breakthroughs in the history of neuroscience.
Cerebrospinal fluid (CSF)
It is difficult to pinpoint who first described the cerebrospinal fluid (CSF) circulation but Nicolo Massa, Lewis Weed, Gustav Retzius, Francois Magendie and Albrecht von Haller have all been cited. The names associated with accurately describing the constituents of CSF are William Halliburton and William Mestrezat. Franciscus de la Boe Sylvius is credited with describing the aqueduct of Sylvius, and Alexander Monro for describing the foramen of Monro. Antonio Pacchioni discovered arachnoid granulations, whilst Guilio Cesare and Thomas Willis are credited for describing the anatomy and function of the choroid plexus. The accurate description of the blood brain barrier has been attributed to both Max Lewandowsky and Paul Erlich.
Cerebral localisation of functions has always been, and continues to be, a key neuroscience task. As brain functions become increasingly recognised as network-based, rather than region-based, cerebral localisation is taking more of a back seat in neuroscience. But it is still worthwhile to acknowledge the pioneers who identified key brain areas. Paul Broca is credited with the first description of the cortical speech area, whilst motor function localisation is traced to the works of Eduard Hitzig, Gustav Fritsch, David Ferrier, and Victor Horsley. The classification of cerebral areas into 52 parts was done by Korbinian Brodmann, whilst it was neurosurgeon Wilder Penfield who defined the cortical maps of the motor and sensory homunculus.
Both Rudolph Virchow and Heinrich Müller are credited with describing neuroglia. The credit for classifying these into microglia and oligodendroglia goes to Pio del Rio Hortega, whilst that for describing dendrites and axons goes to Otto Friedrich Karl Deiters. Camillo Golgi introduced the critical silver nitrate method of staining nerve cells, a technique advanced by Santiago Ramon y Cajal, who developed the gold chloride-mercury method for staining astrocytes. The description of the synapse is attributed to the truly great Charles Scott Sherrington. W. Bevan Lewis, Vladimir Betz and Johannes Purkinje have all been credited with describing the giant motor nerves of the cortex.
Rufus of Ephesus is named as the first person to describe and name the optic chiasma. Other cranial nerve achievements are the discovery of the tenth cranial nerve by Marinus, and the description of seven cranial nerves by Rhazes. The trochlear and abducens nerves were described by Gabriele Falloppio, and it was Samuel Thomas von Soemmerring who introduced the current classification of the twelve cranial nerves.
The credit for distinguishing between myelinated and unmyelinated nerves goes to Robert Remak, whilst the credit for describing myelin formation goes to Theordor Schwann. It was Louis-Antoine Ranvier who described the gaps between myelin sheaths called the nodes of Ranvier. The different types of sensory nerves were described by Herbert Gasser, and it was Friedreich Merkel who described the sensory receptors now known as Merkel corpuscles. Credit for describing the cutaneous distribution of sensory nerves goes to Henry Head, and it was Francois Magendie who recognised the different functions subserved by the dorsal and ventral nerve roots of the spinal cord.
The early understanding of how nerves function has a lot to do with the description by Hermann Helmholtz of the electrical nerve impulse velocity. The resting membrane potential was described by Julius Bernstein and Walter Nernst, whilst Keith Lucas and Edgar Adrian measured peripheral nerve impulses, Adrian going on to confirm that nerve impulses are all or none. Alan Hodgkin and Andrew Huxley are credited with describing the mechanisms of action potentials, whilst Joseph Erlanger and Herbert Spencer Gasser described the function of single nerve fibers.
Whilst nerve function is electrical, it is chemicals that bridge the gap between nerves. The chemical neurotransmitters of peripheral nerves, norepinephrine and acetylcholine, were isolated by George Barger and Henry Dale. The credit for establishing chemical neurotransmission between nerves and muscles, at the neuromuscular junction, goes to Otto Loewi‘s dream-inspired work on Vagusstoff. The discovery of the central nervous system neurotransmitter GABA is credited to Eugene Roberts and Jorge Awapara. Most of the later work on neurotransmitters were made by Julius Axelrod, Bernard Katz and Ulf Svante von Euler, and the credit for elucidating the function of ion channels goes to Erwin Neher and Bert Sakmann.
The visual system is fundamental to neuroscience, and credit for describing its mechanism goes to Ragnar Granit, Halden Hartline and George Wald. The merit for elucidating the details of visual processing goes to David Hubel and Torsten Wiesel. The sense of smell is similarly important, and initial work on this was made by David Ferrier, but it is to Linda Buck and Richard Axel that kudos go for discovering odour receptors, and for describing the configuration of the olfactory system.
Memory, pain, and prions
The acclaim for establishing the anatomical foundations of memory goes to Brenda Milner for her work on Patient HM. It is however Eric Kandel who has the honour of working out the functional process of memory formation. The gate control theory of pain was established by Ronald Melzack and Patrick Wall, whilst credits for establishing the nature of prion diseases go to the lively Daniel Carleton Gajdusek, and the indefatigable Stanley Prussiner.
Navigation, mirror neurones, and growth factors
The brain’s positioning system was discovered by John O’Keefe, Edvard Moser, and May-Britt Moser. Cedit for discovering mirror neurones goes to Giacomo Rizzolatti, whilst Rita Levi-Montalcini and Stanley Cohen were the first to isolate nerve growth factor.
Brain circulation and brain waves
Thomas Willis, Henry Duret and Johann Heubner first described the arterial circulation of the brain, whilst the electrical brain wave activity of the brain was first recorded by Hans Berger, incidentally when he was investigating telepathy.
And so ends this rapid whizz through the annals of neuroscience. This is just the condensed tip of the iceberg; to learn more about the fascinating giants who defined the glorious history of neuroscience, you may wish to slowly digest the following sources:
Like something from a futuristic medical thriller, you have mice diagnosing bladder tumours, and dogs detecting prostate cancer, just by sniffing the urine of patients. And like a plot from a Sci-Fi film, dogs are also trained to smell-out malaria. But we are not forward to the future – we are still in the here and now. And it is not just cats, dogs, and mice; pouched rats and nematodes have staked their claim as well. And the number of diseases that pets can presumably detect grows longer by the day (OK perhaps by the year), and these range from diabetic hypoglycaemia, colorectal cancer and migraine, to infections such as Clostridium difficile and tuberculosis. And whilst there are many animals in on the act, they are just bit players on this set – dogs are by far the superstars of the show.
As weird as it may sound, many of the reports being anecdotal, there are actually grains of truth and crumbs of evidence supporting the claim that pets are not just for Christmas. For example, there is a trail of research studies confirming the effectiveness of seizure detecting dogs; one paper specifically reports that they enabled 90% of subjects to reduce their seizure frequency by 34-50%. Although the time from seizure-detection to the actually seizure varies wildly, from 10 seconds to 5 hours before the epileptic attack, there seems to be enough time in most cases for the subject to take preventative measures.
But not all dogs are as skilled in the act as others, and your best bet is on alerting dogs which have a stronger bond with their owners. And if you want to pick a dog for its seizure-detecting skills, go for one that scores high in motivation…and low in neuroticism. This is important because the ability of dogs to detect seizures is not always benign; they are known to respond by attacking the subject or their helpers as part of an untrained fight or flight reaction. It is important therefore that seizure-alerting dogs are trained not to be stressed, and to respond appropriately.
But what are dogs actually detecting when they detect seizures? The conventional theory is that they are responding to subtle changes in behaviour; this may therefore explain why dogs can also warn of impending non-epileptic attacks, an observation that has been duplicated in another paper. The other possibility however is that the dogs are detecting disease-specific odours. This concept should not be surprising because, for example with infections, it has been shown that endotoxins induce a detectable aversive body odour. Similarly with liver disease, exhaled breath is already being considered in sorting out differential diagnoses. One premise behind the disease-odour hypothesis is the existence of disease-specific volatile organic compounds (VOCs). It feels all so exciting-no wonder there is now a well-developed scientific field of exhaled air analytics.
But as with all things in life, and particularly in science, here are always the naysayers, the gatecrashers to the party. And so it is that, with the case of seizures, there are those who are not convinced that pets possess the guile to pick up seizures. For example, in a small study of 3 subjects in an epilepsy monitoring unit, Rafael Ortiz and Joyce Liporace, reporting in the journal Epilepsy and Behaviour, found that seizure alert dogs were not effective in predicting seizures. In another paper published in the journal Epilepsy Research, titled Can seizure-alert dogs predict seizures?, Stephen Brown and Laura Goldstein observed that there is “no rigorous data” to support the assertion that seizure alert dogs accurately predict seizures. Another detailed review in Plos One in 2018, by Amélie Catala and colleagues, concluded that appropriate empirical evidence that dogs can alert or respond to epileptic seizures is still missing.
But as the overused cliché goes, absence of evidence is not the evidence of absence. So how can we prove that dogs are indeed detecting seizure-specific odours? This is the task Amélie Catala and her colleagues also set out to accomplish when they made 5 dogs to sniff the odours obtained from 5 people with epilepsy. They tasked the dogs to tell apart the odours obtained around the time of the subjects’ seizures, from the odours obtained at other times when there were no proximate seizures. Reporting their findings in Science Report in 2019, under the title Dogs demonstrate the existence of an epileptic seizure odour in humans, they found that all the 5 dogs easily distinguished the seizure-related odours from the non-seizure related odours. But the small scale of the trial (were there just not enough dogs to go round?) justifies the authors’ call for larger trials to confirm their findings.
This is clearly still a grey area in epilepsy management, but one with a high potential if explored further. Are there any pet-loving neurologists willing to get in on the act? Do come along with your pets!
Medicine is as much defined by diseases as by the people who named them. Neurology particularly has a proud history of eponymous disorders which I discussed in my other neurology blog, Neurochecklists Updates, with the title 45 neurological disorders with unusual EPONYMS in neurochecklists. In many cases, it is a no brainer that Benjamin Duchenne described Duchenne muscular dystrophy, Charle’s Bell is linked to Bell’s palsy, Guido Werdnig and Johann Hoffmann have Werdnig-Hoffmann disease named after them. Similarly, Sergei Korsakoff described Korsakoff’s psychosis, Adolf Wellenberg defined Wellenberg’s syndrome, and it is Augusta Dejerine Klumpke who discerned Klumpke’s paralysis. The same applies to neurological clinical signs, with Moritz Romberg and Romberg’s sign, Henreich Rinne and Rinne’s test, Jules Babinski and Babinski sign, and Joseph Brudzinski with Brudzinki’s sign.
Yes, it could become rather tiresome. But not when it comes to diseases which, for some reason, never had any names attached to them. Whilst we can celebrate Huntington, Alzheimer, Parkinson, and Friedreich, who defined narcolepsy and delirium tremens? This blog is therefore a chance to celebrate the lesser known history of neurology, and to inject some fairness into the name game. Here then are 25 non-eponymous neurological diseases and the people who discovered, fully described, or named them.
Amyotrophic lateral sclerosis (ALS)
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Corticobasal degeneration (CBD)
Frontotemporal dementia (FTD)
Inclusion body myositis (IBM)
Multiple sclerosis (MS)
Multiple system atrophy (MSA)
Myasthenia gravis (MG)
Progressive supranuclear palsy (PSP)
Restless legs syndrome (RLS)
Stiff person syndrome (SPS)
Let us then celebrate the pioneers…
Eponymous and anonymous alike
It is no exaggeration to say that most progress in medicine has been achieved one unfortunate patient after another. Either by accident, or by misguided design, our understanding of human physiology and pathology have frequently come at the expense of the misfortune of countless patients, and it continues to do so. Whilst large trials teach us a lot about the characteristics of diseases, it is however the single case study that often reveals the most defining insights. For example, it was the accidental gunshot injury sustained by Alexis St Martin that led to our understanding that the gastric phase of digestion depends on the acid produced by the stomach. The gory injury resulted in a permanent fistula between St Martin’s stomach and his skin, a veritable window through which the army doctor, William Beaumont, peered to see nature at work.
But enough of other organs; our interest is of course the nervous system. Who then were the tragic heroes of neuroscience, the valiant who submitted their bodies in life, and their brains in death, for the advancement of science? Who are the famous, and the infamous, in the annals of the brain? Here is our run down of 7 remarkable patients who defined the history of neuroscience.
7. Patient SM
Patient SM is one of the lesser known figures in neuroscience, but her contribution to the science of emotions is immense. As someone who simply did not know what it was to experience fear, she provided the clues to the anatomical foundations of our passions. It turned out that the source of her fearlessness were lesions in her amygdala. It is little wonder that her life was characterised by risky ventures and perilous experiences, as she was incapable of detecting and avoiding danger. The amygdala is now established as the command and control centre for the emotions. One could argue, albeit unoriginally, that to lose one amygdala may be an accident, but to lose both will have to be termed a disaster. And in the case of Patient SM, her catastrophe is a result of Urbach–Wiethe disease, a disorder which destroys both amygdalas…but mercifully spares the hippocampus.
6. Anna ‘O’
Bertha Pappenheim, better known by her nickname ‘Anna O‘, was the seminal hysterical patient reported by Josef Breuer and Sigmund Freud. It is probably to her singular credit that the concept of hysteria became a neuroscience curiosity, even if this was on the fringes. Her constellation of symptoms will however be familiar to every neurologist: limb paralysis, speech difficulties, visual impairment, hallucinations, and episodes of loss of consciousness. It is clear that this disorder lives on, and after several iterations, now comes under the remit of functional neurological disorders (FND). It is interesting that Freud had the largely correct insight that behind many cases of hysteria lies some form of trauma.
5. Blanche Wittman
The great French neurologist Jean-Martin Charcot is not a person to be outdone by other neuroscientists, and this applies to his one-time protege, Sigmund Freud. It is therefore not surprising that in studying hysteria, he outdid Freud by finding a more remarkable subject called Blanche Wittman. She became his star attraction in the demonstrations he held at the Pitié-Salpêtrière Hospital where she performed for the great and the good of French neurology. It is in this way that she achieved abiding fame in the iconic painting of Pierre Aristide André Brouillet. Her dramatic hysterical attacks earned her the sobriquet ‘The Queen of Hysterics‘, but her contribution to the actual science of the brain is rather underwhelming. There is however no denying that she is a lasting landmark in the history neuroscience.
4. Auguste Deter
Whilst the name Alois Alzheimer has gone down in history for describing the fearsome dementia that bears his name, the name of the patient who made it all possible is not a household one at all. Auguste Deter was the first person to be diagnosed with the horrendous disease which still ravages mankind, and without any cure in sight. After studying her illness in life, Alzheimer had the fortune of examining her brain after her death. It is his detailed examination that revealed what we now know as the hallmarks of the disease, senile plaques and neurofibrillary tangles. It is remarkable that a recent analysis of Alzheimer’s preserved histopathological slides revealed that Auguste Deter carried the classical presenilin 1 (PSEN1) gene mutation that is associated with the disease. Can neuroscience ever be any more satisfying than that!
3. Louis Victor Leborgne
Yet another watershed neuroscience patient whose name doesn’t often ring any bells, or flow easily off the tongue. Leborgne’s misfortune was to develop a curious inability to speak, now recognised as expressive aphasia. He was only able to communicate with a single word, tan, and this explains his nickname, Patient Tan. Paul Broca’s fortune, on the other hand, was to study Leborgne in life, and to examine his brain after death. This singular patient made Broca a household name because this type of speech difficulty is also known as Broca’s aphasia. Broca also localised the lesion responsible for Leborgne’s aphasia, and it was in a part of the dominant hemisphere now known as Broca’s area. Two eponyms for the price of one you may say. Leborgne is also probably the turning point for the contentious concept of cerebral localisation, resurrecting it from the ashes of phrenology.
2. Phineas Gage
Phineas Gage is remarkable for achieving what few other neuroscience patient have, entry into popular folklore. The victim of a work-related accident, Gage sustained a unique form of brain injury when he was impaled by a tamping rod whilst trying to set explosions as part of his work as a rail construction worker. The explosion was accidentally set off prematurely, and the rod was propelled through Gage’s left cheek bone, through his left eye socket, and it then penetrated both frontal lobes. It was remarkable that Gage was not physically inconvenienced immediately following the accident, but surviving the whole affair was just the beginning of his real misfortune; his personality, previously calm and dedicated, became volatile and disinhibited. In relating the story of Gage, there is no getting away from a famous quotation; those who knew him before his accident pithily remarked that Gage ‘was no longer Gage‘. It is to his misfortune that we owe our understanding of the important role the frontal lobes play in regulating personality and behaviour.
1. Henry Molaison
Known only as Patient HM throughout his life, Henry Gustav Molaison is perhaps the most important patient to ever cross the path of neuroscience. He earned this distinction on account of the profound amnesia he developed after he underwent brain surgery to control his severe epilepsy. Very bravely, his neurosurgeon, William Beecher Scoville, removed large chunks of his temporal lobes on both sides, a previously unheard of procedure. His epilepsy became largely controlled, but the aftermath was a disaster; he lost the ability to form new memories. As it has become a familiar refrain by now, Henry’s misfortune became a boon for neuroscience. He became probably the most extensively studied patient in the history of brain science; he spent the rest of his life undergoing one neuropsychological test or the other until neuroscientists obtained a thorough understanding of the anatomical and functional foundations of memory formation. Whilst the key lesson from his case is the important role of the hippocampus in memory formation, there is so much more he contributed to brain science in life. And even after death, his brain is an object of fascination for neuroscientists; they opened up his skull as soon as he died, took out his brain, and cut it up into tiny slices for further study. Henry is therefore the ultimate neuroscience patient who keeps giving even after departing this mortal coil.
Over the next few weeks I will be reviewing three excellent books on Henry Molaison in my book review blog, The Doctors Bookshelf. Why not follow me there to find out more about the remarkable man.
Do you want to explore more interesting neuroscience patients?
Here are 9 to satisfy your urge!
I am yet to request serum neurofilament light protein (NfL) in my practice. I am not sure yet why I should, but until now I confess I really haven’t looked for a reason to do so. I however know that some MSologists now tick it, along with other blood tests, when they investigate people they suspect may have multiple sclerosis (MS). NfL are proteins that are released by damaged neurones. Should I be requesting NfL in my clinical practice? I sniffed around to find the case for testing serum NfL, and below is what I found.
Many studies have looked at the value of NfL in MS. One such very well-planned study that addresses many of my questions is that by Guili Disanto and colleagues, published in the journal Annals of Neurology in 2017. In the paper, titled Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis, the authors studied >380 people with MS and >150 healthy controls, and report four important findings.
- The levels of NfL in serum strongly correlate with the levels in cerebrospinal fluid (CSF) of people with MS.
- People with more active and more severe MS had higher levels of NfL.
- People with MS on disease modifying treatment (DMT) had lower NfL levels than those who were not on treatment.
- In people with MS who had their serum NfL tested serially over time, the level of NfL predicted those who will develop frequent relapses or progressive MS.
The authors concluded, with enough justification I think, that serum NfL is a “sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS“.
The strong correlation between cerebrospinal fluid (CSF) and serum NfL was also confirmed by a study published in the journal Neurology, by Lenka Novakova and colleagues titled Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. As the title indicates, they discovered that serum NfL is as good as CSF NfL in monitoring the progression of MS.
The observation that NfL predicts the course of MS is supported by many other studies, such as the one by Kristin Varhaug and colleagues in the journal Neurology Neuroimmunology and Neuroinflammation whose title is also self-explanatory: Neurofilament light chain predicts disease activity in relapsing-remitting MS. A more recent paper, also published in Neurology, further reinforces the benefit of serum NfL in disease course prediction. It is titled Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. In this paper, Jehns Kuhle and colleagues practically confirm all the above stated benefits of NfL, concluding that “our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response”.
As for long term outcome, the 10 year follow up study by Alok Bahn and colleagues, published in the Multiple Sclerosis Journal in 2018, is most informative. In their paper titled Neurofilaments and 10-year follow-up in multiple sclerosis, the authors noted that “CSF levels of NfL at the time of diagnosis seems to be an early predictive biomarker of long-term clinical outcome and conversion from RRMS to SPMS”. Further support for the long term prognostic value of serum NfL comes from a paper published in 2018 in the journal Brain titled Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. The authors, Christian Barro and colleagues, studied more than 250 people with MS and concluded that “the higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss“.
It is pertinent to note that the MS sphere is not the only one in which NfL is making waves. It has been found to be elevated in many other disorders such as motor neurone disease (MND), multiple system atrophy (MSA), hereditary spastic paraplegia (HSP), stroke, active small vessel disease, and peripheral neuropathy (PN). With these disclaimers in place, it may just be time to start ticking that NfL box.
The role of ultrasound in treatment is reviewed in the excellent paper in Nature Neurology titled Ultrasound treatment of neurological diseases-current and emerging applications. And the emphasis is on trans-cranial MR-guided focused ultrasound (tcMRgFUS). tcMRgFUS is making waves in the treatment of essential tremor (ET), Parkinson’s disease (PD), and central pain. The benefit for PD is already filtering out into the popular press such as this article in STAT titled New treatment offers some hope for an unshakable tremor. Ultrasound is also rapidly emerging as an option in the ablation of brain tumours, and in the treatment of stroke (sonothrombolysis).
Drug delivery into the brain
The blood brain barrier is a rigidly selective barricade against most things that venture to approach the brain-even if their intentions are noble. This is a huge impediment to getting drugs to reach the brain where they are badly needed. It is therefore humbling that it is the simple ultrasound that is promising to smuggle benevolent drugs across the blockade to aid afflicted brains. This was reported in the journal Science Translational Medicine, and the article is titled Clinical trial of blood-brain barrier disruption by pulsed ultrasound. The trial subjects were people with the notorious brain tumour, glioblastoma. They were injected with their conventional chemotherapy drugs, delivered along with microbubbles. The blood brain barrier was then repeatedly ‘pelted’ with pulsed ultrasound waves; this seem to leapfrog the drugs into the brain in greater than usual concentrations, enough to do a much better job. This surely makes films such as Fantastic Voyage and Inner Space not far-off pipe-dreams.
Treatment of coma
Some of the emerging neurological applications of ultrasound are even more Sci-Fi than pulsed ultrasound. And a sign of this Sci-Neuro world is this report titled UCLA scientists use ultrasound to jump-start a man’s brain after coma. One is tempted to dismiss this as ‘fake news’ but it is a proper case report, in a proper scientific journal, Brain Stimulation, and with a proper scientific title, Non-Invasive Ultrasonic Thalamic Stimulation in Disorders of Consciousness after Severe Brain Injury: A First-in-Man Report. By targeting ultrasounds to the subject’s thalamus, the authors assert, the subject just woke up (and presumably asked for a hot cup of tea!). A word of caution is however needed; the authors rightly point out that it may have all been…coincidental!
Ultrasound is clearly humble no more.
Big ambition trumps humble beginnings.
Neurofibromatosis (NF) is one of the major neurocutaneous disorders neurologists see. These are disorders which primarily affect the nervous system and have prominent skin manifestations. Also known as phakomatoses, they are typified by abnormal growths and a variety of cancers. They include well-defined conditions such as tuberous sclerosis complex (TSC), Sturge-Weber syndrome (SWS), von Hipple Lindau disease (VHL), schwannomatosis, and the various PTEN hamartoma tumour syndromes. There are two types of neurofibromatosis, NF1 and NF2. NF2 is characterised by vestibular schwannomas, tumours arising from the sheath that encases the nerve that control balance, and by meningiomas, tumours of the covering of the brain.
NF1, also known as von Recklinghausen disease is, by far, the commoner form of neurofibromatosis. It is readily recognised on the skin by the frequently multiple and disfiguring nerve tumours called neurofibromas. Other benign skin lesions include the coffee-coloured skin lesions aptly called cafe-au-lait spots, armpit lesions called axillary freckles, and small lesions on the iris of the eyes called Lisch nodules. More sinister skin lesions called malignant peripheral nerve sheath tumours (MPNST) are, as the name implies, capable of spreading to other organs such as the lungs. Other sinister tumours in NF1 include gliomas of the brain and optic nerve, gastrointestinal stromal tumours (GIST) of the gut, and rhabdomyosarcomas of bone.
What can neurologists do for people with neurofibromatosis? Traditionally, nothing much apart from watchful waiting. We would monitor for the development of tumours by regular surveillance MRI scans of the brain and spine, and refer people with painful, compressive, or malignant lesions to the plastic surgeons or neurosurgeons to do what they do best, taking things out. Surgery may work fine for simple neurofibromas, but it is less practical for the complex or plexiform type. Thankfully, many neuroscientists are working hard, looking at different approaches to managing neurofibromas. To illustrate, below are 5 emerging treatments for neurofibromatosis.
In a 2016 paper in the New England Journal of Medicine, Eva Dombi and colleagues investigated the effect of selumetinib, an oral inhibitor of an enzyme called MAPK kinase (MEK) in 24 children with NF1. The paper, titled Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas, showed that selumetinib reduced the size of neurofibromas, and there was evidence that it improved pain and reduced disfigurement.
In a 2012 paper published in Lancet Oncology, Kent Robertson and colleagues, investigated the potential benefit of Imitanib, an inhibitor of the enzyme tyrosine kinase, in 36 people with NF1. The paper, titled Imitatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial, showed at least a 20% reduction in one or more plexiform neurofibromas.
Brian Weiss and colleagues investigated the effect of sirolimus, an inhibitor of mTOR complex 1, in 46 people with NF1 and published their findings in the journal Neuro-Onclology. The paper, titled Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas, demonstrated that sirolimus prolonged the time to progression (TTP) of plexiform neurofibromas by about 4 months. A modest effect they admit, but nevertheless, a hope-raising effect.
Everolimus is already making waves in the treatment of various lesions in tuberous sclerosis complex, and it is not surprising that it has turned up here. In their paper titled Treatment of disfiguring cutaneous lesions in neurofibromatosis-1 with everolimus, published in the journal Drugs in R&D, John Slopis and colleagues reported that everolimus significantly reduced the surface volume of NF1 lesions, including plexiform neurofibromas. The authors were however cautious, calling for future studies to confirm these results. Unfortunately, one such study in the Journal of Investigational Dermatology poured cold water on the reported benefit of everolimus. The paper was titled Absence of Efficacy of Everolimus in Neurofibromatosis 1-Related Plexiform Neurofibromas: Results from a Phase 2a Trial. Hopefully future studies will be more favourable!
Pegylated interferon alfa-2b
Regina Jakacki and colleagues looked at the effect of pegylated interferon alfa-2b on plexiform neurofibromas and found a greater than doubling of their time to progression (TTP). Their paper is published in Neuro-Oncology, and it is titled Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas. As the authors studied a reasonable number of subjects, 84, and as the trial was placebo-controlled trial, this result is unlikely to be overturned by future trials…but only time will tell.
Therefore is clearly enough justification for hope in the search for a cure for neurofibromatosis.
First, some basic science to lay the groundwork for this blog post. Parkinson’s disease (PD) is all about dopamine, the chemical neurotransmitter that makes our movements smooth. It is produced by cells in the substantia nigra, a structure in the midbrain. The substantia nigra nerves project to the putamen, one of the structures that make up the basal ganglia, somewhere deep in the brain. The substantia nigra nerves are also called the nigrostriatal nerves because the putamen, along with the caudate nucleus and the nucleus accumbens, form a body called the corpus striatum. The work of these so-called nigrostriatal nerves is to produce and deliver dopamine to the putamen. In summary, the putamen is the playpen of dopamine; it is here that it does its work of smoothening our movements.
In Parkinson’s disease, the nogrostriatal system slowly degenerates, therefore becoming unable to supply enough dopamine to the putamen. The obvious solution is to find an alternative supply of dopamine for the putamen. The obvious way again would be to deliver dopamine orally as a tablet, but dopamine unfortunately does not cross the blood brain barrier. However, the similar but more pliant levodopa is able to do so. Once in the brain, levodopa is then converted to the active dopamine by an enzyme called aromatic L‐amino acid decarboxylase (AADC). Because this strategy is reasonably efficient, levodopa has become the foundation of PD treatment. But this strategy is totally dependent on the presence of enough AADC to convert levodopa to dopamine. And this is a vulnerability that PD explores to the full.
Levodopa treatment is usually effective in the early stages of PD. But as the disease progresses, the degenerating nigrostriatal nerves increasingly struggle to produce enough AADC. Remember, AADC is essential for converting levodopa to the active dopamine. Without AADC, in other words, levodopa is useless. The declining ability to produce AADC is therefore the Achille’s heel of levodopa treatment. It is the reason people with advanced PD require increasingly higher doses of levodopa. It is the reason they get unpredictable treatment fluctuations. It is the reason they get abnormal movements called dyskinesias. To remedy this big flaw in the levodopa treatment strategy, and increase AADC levels in the putamen, neuroscientists have investigated the potential role of gene therapy. To unravel this topic, not a ride in the park by any means, I have relied on this excellent 2019 paper titled Magnetic resonance imaging–guided phase 1 trial of putaminal AADC gene therapy for Parkinson’s disease.
If one group of cells becomes unable, or unwilling, to do its job, why not get another group of cells to take over the task? Indeed this simple concept lies at the heart of gene therapy for PD. And neuroscientists have identified the right type of cells to take over the job of producing AADC. These are the medium spiny neurones of the putamen which do not degenerate in PD. The brilliant strategy is to embed the gene for producing AADC into the DNA of the medium spiny neurones. A viral vector is required to carry the gene into the nerves, and the vector of choice here is adenovirus-associated virus (AAV). The vector ‘invades’ the medium spiny neurones and embeds the AADC gene into their DNA. The cells then start producing dopamine from levodopa. It is as simple as that in theory. It is easier said than done in reality.
The intricate steps involved in this strategy are outlined by Chadwick Christine and colleagues who carried out the phase 1 trial of AADC gene therapy. They infused the AAV viral vector directly into the putamen during neurosurgery, and they used magnetic resonance imaging to confirm that the injected material is delivered to the correct target. The detailed protocol refers to technical terms such as bilateral frontal burr holes, intraoperative delivery, neuro‐navigational systems, and the like. The whole affair however appears to be well-tolerated and reasonably successful; the authors reported a dose-dependent increase in AADC enzyme production, and their 15 subjects had more ‘on-time’, less troublesome treatment fluctuations, and required less levodopa. It is interesting that a similar benefit was demonstrated by Karin Kojima and colleagues when they used the same procedure in a genetic disorder called aromatic l-amino acid decarboxylase deficiency. In their paper titled Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency, the authors reported ‘remarkable’ motor improvement in all the six subjects they treated.
An alternative approach to PD gene therapy is to use the AAV viral vector to deliver, not the gene for producing AADC this time, but the gene for producing glial cell line‐derived neurotrophic factor (GDNF). The idea behind this is, not to replace, but to flog the dying horse. The theory is that GDNF, a growth factor, should rejuvenate the flagging nigrostriatal nerves, thereby increasing their ability to produce dopamine. This approach was described by John Heiss and colleagues in their paper titled Trial of magnetic resonance–guided putaminal gene therapy for advanced Parkinson’s disease. The authors indeed demonstrated that GDNF-carrying adenovirus vectors can be safely infused into the putamen, and that the process is well-tolerated. They also demonstrated increased dopamine levels in the putamen in 12 of their 13 subjects.
It is clearly early days, but there have been small successes along the way so far. Future trials, already underway, will tell us whether the hope is sustained or dashed. We must wait and see. In the meantime, you can read more about PD gene therapy in this update.