The Neurology Lounge strives hard to keep to the straight and narrow path of clinical neurology. But every now and then it takes a peek at what is happening at the cutting edge of neuroscience. And what can be more cutting edge then biomarkers, with their promise of simplifying disease identification, making prompt and accurate diagnosis an effortless task.
The quintessential biomarker however remains as elusive as quicksilver. Not that one could tell, going by the rate biomarkers are being spun from the neuroscience mills. Biomarkers are the buzz in many neurological fields, from brain tumours to multiple sclerosis (MS), from Alzheimer’s disease (AD) to Huntington’s disease (HD).
The proliferation of contending biomarkers is however probably highest in the field of motor neurone disease (MND). Is there a holy grail out there to enable the rapid and accurate diagnosis of this relentlessly progressive disease? There is clearly no dearth of substances jostling for prime position in the promised land of MND biomarkers. Below is a shortlist of potential MND CSF biomarkers; just click on any to go to the source!
Medical futurists predict that scientific advances will lead to more precise definition of diseases. This will inevitably result in the emergence of more diseases and fewer syndromes. This case is made very eloquently in the book, The Innovators Prescription. Many neurological disorders currently wallow at the intuitive end of medical practice, and their journey towards precision medicine is painfully too slow. Neurology therefore has a great potential for the emergence of new disorders.
In the ‘good old days’, many diseases were discovered by individual observers working alone, and the diseases were named after them. In this way, famous diseases were named after people such as JamesParkinson, Alois Alzheimer, and GeorgeHuntington. For diseases discovered by two or three people, it didn’t take a great stretch of the imagination to come up with double-barrelled names such as Guillain-Barre syndrome (GBS) or Lambert-Eaton myasthenic syndrome (LEMS).
By uncredited – Images from the History of Medicine (NLM) [1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=11648572Today, however, new diseases emerge as a result of advances made by large collaborations, working across continents. These new diseases are named after the pathological appearance or metabolic pathways involved (as it will require an act of genius to create eponymous syndromes to cater for all the scientists and clinicians involved in these multi-centre trials). This is unfortunately why new disorders now have very complex names and acronyms. Take, for examples, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) and chronic relapsing inflammatory optic neuropathy (CRION). It is a sign that we should expect new neurological diseases to be baptised with more descriptive, but tongue-twisting, names.
New disease categories emerge in different ways. One is the emergence of a new disorder from scratch, with no antecedents whatsoever. Such was the case with autoimmune encephalitis, a category which has come from relative obscurity to occupy the centre stage of eminently treatable diseases. I have posted on this previously as What’s evolving at the cutting edge of autoimmune neurology and What are the dreadful autoimmune disorders that plague neurology?Other disease categories form when different diseases merge into a completely new disease category, or when a previously minor diseases mature and stand on their own feet. These are the stuff of my top 8 emerging neurological disorders.
This huge monster is ‘threatening’ to bring together, under one roof, diverse disorders such as tuberous sclerosis complex, epilepsy, autism, traumatic brain injury, brain tumours, and dementia. You may explore this further in my previous blog post titled mTORopathy: an emerging buzzword for neurology.
This new group of neurological diseases is threatening to disrupt the easy distinction between several neurological disorders such as myasthenia gravis (MG), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and Guillain Barre syndrome (GBS). It even includes the newly described IgLON 5 antibody disorder, something I blogged about asIgLON5: a new antibody disorder for neurologists. You may explore IgG4-related disorders in this paper titled The expanding field of IgG4-mediated neurological autoimmune disorders.
4. Hepatitis E virus related neurological disorders
A field which is spurning new neurological disorders is neurological infections, and Hepatitis E virus (HEV) is in the forefront. We are now increasingly recognising diverse Hepatitis E related neurological disorders. HEV has now been linked to diseases such as Guillain Barre syndrome (GBS) and brachial neuritis. And the foremost researcher in this area is Harry Dalton, a hepatologist working from Cornwall, not far from me! And Harry will be presenting at the next WESAN conference in Exeter in November 2017.
Zika virus is another novel infection with prominent neurological manifestations. We are learning more about it every day, and you may check my previous blog post on this, titled 20 things we now know for certain about the Zika virus.
Multisystem proteinopathy is a genetic disorder which affects muscles and bone, in addition to the nervous system. It is associated with Paget’s disease of the bone and inclusion body myositis, with implications for motor neurone disease (MND) and frontotemporal dementia (FTD). Quite a hydra-headed monster it seems, all quite complex, and perhaps one strictly for the experts.
GLUT-1 stands for glucose transporter type 1. Deficiency of GLUT-1 results in impaired transportation of glucose into the brain. GLUT-1 deficiency syndrome presents with a variety of neurological features such as dystonia, epilepsy, ataxia, chorea, and a host of epilepsy types. It starts in infancy and is characterised by a low level of glucose and lactic acid in the cerebrospinal fluid. Expect to hear more on this in the near future.
And this is my favourite paradigm shifter. Neurologists often see people with brain inflammatory lesions and struggle to decide if they fulfil the criteria for multiple sclerosis (MS). The current threshold for concern is when there have been two clinical events consistent with inflammation of the nervous system, or their MRI scan shows involvement of at least two different sites of the nervous system. Well, dot counting may soon be over, going by this paper in Neurology titled Progressive solitary sclerosis: gradual motor impairment from a single CNS demyelinating lesion. The authors identified 30 people with progressive clinical impairment arising from a single inflammatory nervous system lesion. The authors were convinced enough to recommend the inclusion of this new entity, progressive solitary sclerosis, in future classifications of inflammatory disorders of the central nervous system. Move over progressive MS, here comes progressive SS. Neurologists will surely have their job cut out for them.
Neurology is a broad specialty covering a staggering variety of diseases. Some neurological disorders are vanishingly rare, but many are household names, or at least vaguely familiar to most people. These are the diseases which define neurology. Here, in alphabetical order, is my list of the top 60 iconic neurological diseases, with links to previous blog posts where available.
The Neurology Lounge has a way to go to address all these diseases, but they are all fully covered in neurochecklists. In a future post, I will look at the rare end of the neurological spectrum and list the 75 strangest and most exotic neurological disorders.
As I update neurochecklists I come across some papers which make me go, ‘really!’ Such studies challenge established theories and threaten conventional practice. Such is the case with a recent paper in Brain titled, unequivocally, Corticosteroids compromise survival in glioblastoma.
Glioblastoma is the worst form of primary brain tumour, and survival is already poor. Treatment is usually palliative with debulking surgery and radiotherapy. Dexamethasone, a corticosteroid, effectively reduces the swelling or oedema that the tumour evokes around it. Corticosteroids are therefore often the first treatment for glioblastoma because they almost immediately improve symptoms such as reduced consciousness, headache, and visual blurring.
It is, therefore, surprising when a study suggests that corticosteroids cause harm. But this is no ordinary study; it is a classic bench-to-bedside research which looked at patients with glioblastoma, and then devised a mouse model to study the real impact of steroids on the tumour.
The authors show that a ‘ dexamethasone-associated gene expression signature correlated with shorter survival’. They pass the verdict that corticosteroids are detrimental to survival and urge caution when prescribing dexamethasone.
Brain cancer is a horrible disease even among cancers. Apart from benign tumours such as meningioma, very few brain tumours have happy endings. It is however not all doom and gloom- there are many advances raising hope for the future of brain cancer. Here are 10 hope-raisers.
Nanotechnology is promising a lot for neurology, and I discussed this in my previous post on 10 remarkable breakthroughs that will change neurology. It is heart-warming to learn that nanotechnology is stepping into brain cancer treatment. Their role is in reducing the damage that normal tissues sustain when brain cancer is treated with conventional radiation. Scientists hope to minimise this damage by delivering the radiation treatment through nanomolecules; because of their small size it is presumed this approach should cause less harm. In this article in Neuro-Oncology titled Rhenium-186 liposomes as convection-enhanced nanoparticle brachytherapy for treatment of glioblastoma, the authors report the efficacy of liposomally encapsulated radionuclides in rat models of glioblastoma. It is complicated stuff but Science Daily’s headline says it all: Treating deadly brain tumors by delivering big radiation with tiny tools.
The challenge for every drug cancer treatment is to deliver the drug as close as possible to the tumour cells. This is particularly difficult for brain cancer because of the protective brain blood barrier (BBB). This shield is composed of the walls of the blood vessels, and the triple-layered sheath covering the brain called the dura.
What if the drugs could be sent across this barrier without breaching it? More Dr. Who than neuroscience, but this is what the ultrasonic screwdriver recently achieved to wide acclaim. Using ultrasound, the scientists successfully delivered chemotherapy drugs across the BBB. This press release from Sunnybrook Health Sciences Centre explains it further. The neurosurgeons used an MRI-guided focused low-intensity ultrasound to force drug microbubbles in the bloodstream across the blood-brain barrier. “The waves repeatedly compress and expand the microbubbles, causing them to vibrate and loosen tight junctions of the cells comprising the BBB. Once the barrier was opened, the chemotherapy flowed through and deposited into the targeted regions”. Very exciting SciFi stuff. Here is a simplified version from IFL Science titled Scientists Have Breached The Blood-Brain Barrier For The First Time And Treated A Brain Tumor Using An “Ultrasonic Screwdriver”.
Electromagnetic field therapy is a new area of brain tumour treatment and not conventional in any way. It however promises to improve survival of patients with glioblastoma who have received conventional radiotherapy and chemotherapy. I came across this in MNT under the title Use of type of electromagnetic field therapy improves survival for patients with brain tumor. This treatment is a form of tumor-treating fields (TTFields), “a treatment that selectively disrupts the division of cells by delivering low-intensity, intermediate-frequency alternating electric fields via transducer arrays applied to the shaved scalp”. The evidence for this is a trial reported in the Journal of the American Medical Association (JAMA) titled Alternating electric fields for the treatment of glioblastoma. It is not a panacea but any light at the end of the dreadful tunnel of brain cancer is worth exploring. It is a good sign that the FDA has approved this technology.
Another technique that is under investigation for treatment of brain cancer is pulsed electric field (PEF). This was the focus of a recent paper in Scientific Reports titled Targeted cellular ablation based on the morphology of malignant cells. PEFpreferentially targets and destroys malignant cells relatively sparing normal cells. The mechanism, if you are curious to know, is called high frequency irreversible electroporation (HFIRE). Or, in plain English, electric disruption of cells. This has reportedly been effective in dogs, and the challenge is to translate the benefits to humans.
Touted as the drug that makes cancer cells explode, Vacquinols are experimental agents which have shown remarkable efficacy in rat models of glioblastoma. The research reported in the journal Cell is titled Vulnerability of glioblastoma cells to catastrophic vacuolization and death induced by a small molecule. The article is quite ‘scientific’ as reflected by the tortuous title, but the whole idea is that vacquinols target some cellular processes and cause the cell membranes of glioblastoma cells to rupture . There is some way to go but imagine this advance translating into clinical practice!
Temozolomide is a conventional treatment for glioblastoma but unfortunately some patients become resistant to this useful drug. Scientist have observed that glioblastoma cells achieve temozolomide-resistance via a protein called connexin 43 (Cx43). Working on this knowledge, they have developed a Cx43 inhibitor called aCT1. I came across this agent in a piece in EurekaAlert titled Scientists find way to make resistant brain cancer cells sensitive to treatment. The scientific paper, published in Cancer Research, is titled Connexin 43 inhibition sensitizes chemoresistant glioblastoma cells to temozolomide. A lucid title for a scientific paper for a change!
4. Propentofylline
“Glioblastoma (1)” by No machine-readable author provided. KGH assumed (based on copyright claims). – No machine-readable source provided. Own work assumed (based on copyright claims).. Licensed under CC BY-SA 3.0 via Commons.
I came across propentofylline in the blog brainmysteries.com under the title Drug that could limit spread of deadly brain tumours. Propentofylline seems to enhance the effects oftemozolomide and radiotherapy, the conventional treatments of brain cancer. In this way propentofylline may slow the spread of the brain tumour cells. It seems to work by inhibiting TROY, the protein that enables glioblastomas to spread to healthy brain cells. For the small print you may read the paper published in Journal of Neuro-oncology titled Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway.
Two recent papers have reported on cellular proteins which brain tumours depend on. These are therefore potential targets for future therapeutic interventions. The first is hypoxia inducible factor-1 (HIF-1) whichcancer cells produce when their oxygen supply is threatened. HIF-1 enables the cancer cells to produce new blood vessels (angiogenesis) thereby maintaining their supply of nourishing oxygen. This process is under investigation by researchers at Emory University.
The second property is related to proteins called sterol regulatory element-binding proteins (SREBPs). SREBP’s control the metabolism of glucose and fat in all cells, and researchers at Ohio State University are looking at ways to inhibit these proteins. This would potentially impair the ability of cancer cells to build their cell walls (membranes). Yes, only in mice again but still, hope. Here is a review of SREBP’s and cancer.
The news that Jimmy Carter has melanoma, and this had spread or metastasised to his brain, came as a shock to many of his admirers. It was therefore a relief when they learnt later that Carter’s cancer has all but cleared away. Very unusual to say the least, especially with a cancer as dreadful as melanoma. This remarkable achievement is attributable to an immunotherapy drug called Pembrolizumab, one of several types of drugs called humanised monoclonal antibodies.
Pembrolizumab has demonstrated effectiveness in melanoma and there are now NICE Guidelines for Pembrolizumab in melanoma. But how good is it in primary brain cancers?A trial is currently in progress to assess the efficacy of Pembromizumab in glioblastoma, the most dreaded of brain cancers. There are several other immune therapies that may be effective in brain metastases, and these are reviewed in an article in Current Treatment Options in Neurology titled Targeted therapies in brain metastases.
Brain tumours rage on, but the science is hopefully catching up. Victory beckons over this dreaded disease.
This is a follow-up to my previous blog post, So what is remarkable about neurology anyway? That post reviewed the challenging tasks neurologists face everyday. How do they go about it? How do they evaluate their patients with suspected neurological disorders?
For the uninitiated, the process of the neurological assessment must seem like an outlandish ritual. Unlike cardiologists who approach patients with the familiar stethoscope, neurologists come armed to the hilt with an arsenal of threatening equipment. Patients are often bewildered, and occasionally irritated, with the neurological exam. Admitted, they sometimes, they sometimes emerge from the assessment feeling battered and bruised-all for a good cause of course!
So what are these bizarre deeds that marks the neurological consultation?
1. Neurologists welcome you with an overly firm handshake
The handshake is a valuable neurological tool. It tells the neurologist right from the beginning if there is any weakness or if there is a form of muscle stiffness called myotonia. Therefore avoid the neurologist’s handshake if you suffer with arthritis or other painful hand conditions.
2. Neurologists make you do the catwalk
The way you walk, the gait, may show the neurologist a variety of clues or signs. There are a variety of abnormal gaits that often point to a diagnosis even before the consultation actually begins. Examples include the shuffling gait in Parkinson’s disease, the hemiparetic gait in Stroke, and the waddling gait in diseases that give rise to hip girdle weakness. More embarrassing for some patients is that the neurologist may actually ask them to do a catwalk, all for the sake of making a diagnosis you must understand!
Other bizarre associated tests are walking an imaginary tightrope, standing on one leg, standing on tip toes and then on the heels, and marching in one spot with eyes shut
The face often give the neurologist the clue to many diagnoses. Conditions such as Bell’s palsy and Stroke are evident from the face as are Parkinson’s disease, myotonic dystrophy and facio-scapulo-humeral muscular dystrophy (FSHD). There’s no need to blush therefore when the intent gaze seems to go on endlessly.
4. Neurologists come up very close- to peer into your soul
If the eyes are the windows to the soul, then neurologists are second only to ophthalmologists in recognising this nebulous entity. The back of the eye, or retina, holds a variety of valuable clues for many neurological diseases. The neurologist typically looks for signs of increased pressure in the head and this may occur with brain tumours, meningitis, encephalitis, This may also occur without any obvious cause in a condition called idiopathic intracranial hypertension (IIH). Other eye signssuch as cataracts and pigmented retina seen with disorders for example mitochondrial diseases.
To peer into the soul, the neurologist may come very uncomfortably close, (hoping the aftershave isn’t too strong and that the morning deodorant has lasted till then). Don’t hold your breath however, as this gazing into the soul may take longer than you anticipate.
5. Neurologists ask you to roll your eyes-in all sorts of directions
Abnormal eye movements are key pointers to many neurological disorders. There are six muscles that move each eyeball, and these are under the control of three pairs of cranial nerves-the oculomotor, the trochlear, and the abducens nerves. These nerves in turn are coordinated by complex nerve cell bodies or nuclei in the brain stem.The eyelids and pupils are also muscles under control of nerves.
These cranial nuclei coordinate a symphony of unparalleled and unimaginable complexity. This allows us to focus on moving objects without any hinderance. Things may go wrong with this symphony, and this typically results in double vision (diplopia) and droopy eyelids (ptosis). Diseases that cause these symptoms include brain aneurysms,myasthenia gravis (MG), and brainstem stroke. Some diseases may cause the eyeballs to move in uncontrollable and chaotic ways called nystagmus, oscillopsia, and opsoclonus(neurologists love these names!)
Don’t be shocked therefore when your neurologist asks you to look up, look down, look to the right and left; to follow this or the other hand; to look at this fist then at these fingers…. It’s all a helpful game-honest!
6. Neurologists ask you to pretend to brush your teeth
Your neurologist may request you to brush your teeth or hair with an imaginary brush, or ask you to do victory sign or the thumbs-up sign (never thumbs-down mind you). Almost verging on the comedic, this is a serious test because these simple tasks are impaired in many diseases. The difficulty in performing tasks one has previously been proficient at is called dyspraxia, or apraxia if the ability is completely lost. Without any weakness or numbness, people with dyspraxia are unable to use common tools and equipment, reporting that they have no idea how to manipulate them. This could be seen in some forms of stroke and some dementias. Do decline however if she asks you to mimic the great mime Marcel Marceau.
7. Neurologists ask you to wiggle your tongue and poke it out
The tongue is a very important muscle and holds countless clues for the neurologist. It is innervated by the last of the 12 cranial nerves, the hypoglossal nerve. which may be paralysed by a very localised stroke and this is often in the context of a condition called cervical artery dissection. This is a tear in one of the big arteries in the neck which take blood to the brain. The tear may arise from trivial neck movements and manipulations such as look up for a long time or staying too long on the hairdressers couch. A clot then forms at the site of the tear, and this then migrates to block a smaller blood vessel supplying the brainstem where the hypoglossal nerve sets off from…phew! Anyway, when this kind of stroke occurs, the tongue deviates to the the weaker side when it is poked out.
The more general weakness of the tongue is seen in conditions such as motor neurone disease (MND),in which the tongue also quivers at rest-something neurologists call fasciculations. The cheeky neurologist (pun intended) will ask you to push against her finger through your cheek to test its full strength.
Another problem that may affect the tongue is myotonia, a condition in which he tongue and other muscles are stiff and relax very slowly after they are activated. To test this, your neurologist may actually tap on your tongue, and then watches in fascination as it stiffens and then relaxes very slowly. Strong but slow moving tongues may be seen in Parkinson’s disease (PD). So, when next your neurologist says ‘open up’, he really means business.
OK, she will not literally wrestle you to the ground but it may appear so at times. Pushing against your head, pressing down against your elbows, leaning hard against your leg-she will do everything to show she is stronger than you. Only if she fails will she score your power as grade 5/5-the best you can get. If you do not score full marks however you place the neurologist in a bit of a quagmire; a score between 0-5 is not always easy to allocate, and the obsessive neurologist may get in a bind and may give you marks such as 3+ or 4-. Just for fun let her win, and see her consternation!
9. Neurologists hit you with a hammer-in all sorts of places
The reflex hammer is perhaps the most well-recognised tool of the neurologist. These hammers come in all shapes and sizes, and some are really quite scary. People expect to have their knees tapped and look forward to what they have seen many times on TV-the leg kicking out. Most patients find this amusing. They are however often surprised when the neurologist proceeds to use the hammer on their jaw, elbow, wrist and ankles. The then often bristle at having the soles of their feet stroked by the end of the hammer’s handle, a sharp uncomfortable end it is. All the hammer does is to stretch the tendons of muscles, and this elicits a reflex that causes the muscle to contract or tighten up. This response may be exaggerated (hypereflexia) if there is any problem in the central nervous system. Conversely the reflex response may be diminished (hyporeflexia) with problems of the peripheral nervous system. Stroking the foot is called the Babinski response and gives a similar form of information to the neurologist. But beware the neurologist who then proceeds to stroke the side of your foot or squeeze your shins, all in an effort to get the same information-it is really an unnecessary and uncomfortable duplication of tests.
10. Neurologists prick and prod you with a sharp pin
Now this must take the cake, and quite rightly often comes at the end of the neurological examination. As threatening as this tests appears, this is probably the neurologist at his most acute. Using a sterile pin, the neurologist asks you to respond ‘yes’ if the sensation you perceive is sharp, and ‘no’ if it is dull. He then carefully proceeds to map out areas of reduced sensation or feeling, frowning as he struggles to keep track of your responses in his mind. He tries to establish if you have a glove and stocking pattern of sensory loss seen in peripheral neuropathy (nerve end damage). It may also be a dermatomal pattern seen with radiculopathy (trapped nerve in the spine). Unfortunately for the neurologist however many patients do not understand the rules of the game and give all sorts of unimaginable responses; not surprising when one is under the threat of a sharp pointy object!
These are but a few of the bizarre doings of neurologists. Seeing a neurologist soon? Be prepared-you have been warned!
PS. Images used in this blog post are for illustration purposes only and do not necessary depict the actual equipment used by neurologists. The examination steps described are however a good reflection of actual neurological practice.
![By uncredited - Images from the History of Medicine (NLM) [1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=11648572](https://theneurologylounge.files.wordpress.com/2016/07/alois_alzheimer_002.jpg)
![By Carl Vandyk (1851–1931) - [No authors listed] (July 1937). "S. A. Kinnier Wilson". Br J Ophthalmol 21 (7): 396–97. PMC: 1142821., Public Domain, https://commons.wikimedia.org/w/index.php?curid=11384670](https://theneurologylounge.files.wordpress.com/2016/07/samuel_alexander_kinnier_wilson.jpg)
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