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!
Neurology embodies some of the most dreadful diseases known to man. Every neurological disorder is disheartening, each characterised by unique frustrations for patients and their families. It is difficult to quantify the distress and misery these afflictions impose on their victims, and even harder to appreciate the despair and anguish they evoke in those who care for them.
It is clearly hard to compare the impact of different neurological diseases. Some neurological disorders however stand out because of the consternation their names evoke, and the terror that follows in their wake. These diseases come with unimaginable physical and psychological burdens, and crushing demands on human and material resources. They impose either a debilitating morbidity, or a hasty mortality.
The nervous system ailments in the list below pose exacting therapeutic challenges, resistant as they are to all attempts at treatment or cure. This list sets out to emphasise the urgency for neuroscience to find a remedy for each of them, but it does not intend to belittle the horror of the disorders omitted from it. The choice of the number 13 is, sadly, self-evident. Here then are the top 13 most dreadful neurological disorders…all with gold links to the associations helping to defeat them.
Ataxia, in lay terms, is incoordination. This typically manifests as an unsteady gait and clumsiness. Ataxia converts all activities of daily living into burdensome chores. Whilst many types of ataxia are preventable or reversible, primary ataxias are progressive and carry a dismal outlook. In this category are Spinocerebellar ataxia (SCA), Friedreich’s ataxia, and Ataxia telangiectasia. You may read more about ataxia in these previous blog posts:
Brain cancers hardly need any description. They are either primary, arising from the brain cells, or metastatic, spreading to the brain from other organs. Some primary brain cancers, such as meningiomas and pituitary tumours, are, relatively, treatable. Many others are unfortunately ominously malignant. The most dreadful in this category is surely the spine-chilling glioblastoma multiforme. You may check out these previous blog posts for more on these tumuors:
Peripheralneuropathy is ubiquitous in the neurology clinic. Neuropathy may result from reversible situations such as overindulgence in alcohol, uncontrolled diabetes, or Vitamin B12 deficiency. Neuropathy is often just a minor inconvenience when it manifests with sensory symptoms such as tingling and numbness. It may however be debilitating when it presents as limb paralysis, or complicated by major skeletal deformities. At the severe end of the spectrum of neuropathy are the hereditary forms such as CharcotMarie Tooth disease (CMT) and Familialamyloid polyneuropathy. Read more in these blog posts:
CJD is the most iconic of the prion diseases. These disorders are as horrendous as they are enigmatic, defying categorisation as either infections or neurodegenerative diseases. More puzzling is their ability to be either hereditary and acquired. CJD exists in the classic or variant form, but both share a relentlessly rapid course, and a uniformly fatal end. You may read more in these previous blog posts titled:
Dystonia marks its presence by distressing movements and painful postures. At its most benign, dystonia is only a twitch of the eyelid (blepharospasm) or a flicker of one side of the face (hemifacial spasm). At the extreme end, it produces continuous twisting and swirling motions, often defying all treatments. The causes of dystonia are legion, but the primary dystonias stand out by their hereditary transmission and marked severity. Read more on dystonia in these blog posts:
Huntington’sdisease is an iconic eponymous neurological disorder which is marked by the vicious triumvirate of chorea, dementia, and a positive family history. It is an awful condition, often driving its victims to suicide. It is a so-called trinucleotide repeat expansion disorder, implying that successive generations manifest the disease at an earlier age, and in more severe forms (genetic anticipation). You may read more on HD in the previous blog post titled:
Also known as Amyotrophiclateral sclerosis (ALS), MND is simply devastating. Recognising no anatomical boundaries, it ravages the central and peripheral nervous systems equally. MND creeps up on the neurones and causes early muscle twitching (fasciculations) and cramps. It then gradually devours the nerves resulting in muscle wasting, loss of speech, ineffectual breathing, and impaired swallowing. Our previous blog posts on MND are:
Multiple sclerosis is a very common disease, and gets more common the further away you get from the equator. It is the subject of intense research because of the devastation it foists on predominantly young people. Many drugs now ameliorate, and even seem to halt the progression of, relapsing remitting MS (RRMS). This is however not the case with primary progressive MS (PPMS) which, until the introduction of ocrelizumab, defied all treatments. There are many contenders vying for the cause of MS, but the reason nerves in the central nervous system inexplicably lose their myelin sheaths remains elusive. You may read more on MS in these blog posts:
Rabies, a rhabdovirus, is a zoonosis-it is transmitted to man by a wide range of animals such as dogs, bats, racoons, and skunks. It is the quintessential deadly neurological disease, popularised by the Steven King book and film, Cujo. Rabies manifests either as the encephalitic (furious) or the paralytic (dumb) forms. It wreaks havoc by causing irritability, hydrophobia (fear of water), excessive sweating, altered consciousness, and inevitably death. Whilst there are vaccines to protect against rabies, a cure has eluded neuroscientists. This blog is yet to do justice to rabies but it is, at least, listed in the post titled What are the most iconic neurologicaldisorders? But you could better by checking neurochecklists for details of the clinicalfeatures and management of rabies.
Nothing is quite as heart-wrenching as the sudden loss of body function that results from spinal cord trauma. This often causes paralysis of both legs (paraplegia), or all four limbs (quadriplegia). This life-changing disorder is often accompanied by loss of control over bowel and bladder functions, and complications such as bed sores and painful spasms. You may read about the heroic efforts to treat spinal cord injury in the blog posts titled:
Tetanus is an eminently preventable disease, now almost wiped out in developed countries by simple immunisation. It however continues its pillage and plunder in the developing world. It strikes young and old alike, often invading the body through innocuous wounds. Tetanus is caused by tetanospasmin and tetanolysin, the deadly toxins of the bacterium Clostridium tetani. The disease is classified as generalised, localised, cephalic, or neonatal tetanus. It is characterised by painful spasms which manifest as lockjaw (trismus), facial contortions (risus sardonicus), trunkal rigidity (opisthotonus), and vocal cord spasms (laryngospasm). The disease is awfully distressing and, when advanced, untreatable. It is a stain on the world that this avoidable disorder continuous to threaten a large number of its inhabitants. Check neurochecklists for more on the pathology,clinicalfeatures, and management of tetanus.
Huntington’s disease (HD) is, without doubt, one of the most dreaded neurological disorders. It is named after George Huntington, but the first description is probably by Charles Oscar Waters in 1842. It is dominantly inherited, each child carrying a 50% chance of acquiring the faulty gene. The genetics is slightly tricky because HD is also a tricnucleotide repeat expansion disorder, similar to some other neurological diseases such as Friedreich’s ataxia (FA), Kennedy disease, myotonic dystrophy, spinocerebellar ataxia (SCA), and oculopharyngeal muscular dystrophy (OPMD). In these diseases, a section of the genetic code duplicates itself repeatedly, producing abnormally long segments; worse still, these segments get longer which each transmission down the family line. This is called genetic anticipation, and it leads to later generations of the family developing the disease at an earlier age, and manifesting it more severely.
HD is not a nice disease. It is accompanied by chorea, probably the most distressing abnormal movement to torment the human body. This is a continuous, writhing muscle activity which involves all the body, and generating very grotesque and painful postures. As if this wasn’t enough, dementia eventually sets in, as does almost every other neurological symptom one could imagine. HD is a problem neurology needs to solve. And thankfully there is some activity in that direction. Here are 4 recent hope-raising developments.
The manufacturers of ISIS-HTTRx must surely be rueing the unfortunate choice of name for their gene silencing drug. But they will take comfort in its promise to crush HD. It is the first trial of a new drug for HD, and it is touted as probably ‘one of the most important developments since the gene for Huntington’s disease was discovered‘. ISIS-HTTRx neutralises huntingtin, the toxic product which accumulates in, and damages, the nerves of people with HD. The only snag…it has to be delivered directly into the spinal fluid. I’m sure an oral tablet will eventually follow, but ISIS-HTTRx is still a long way off; it has to be tested in human volunteers first. One eye then on Sarah Tabrizi, the trial lead, and the other eye on the drug’s name; ISIS pharmaceuticals is now IONIS.
PPAR-δ stands for peroxisome proliferator-activated receptor delta, and it is a good guy. Researchers have shown that enhancing the activity of PPAR-δ in mouse models of HD has a beneficial effect on mitochondrial function, motor activity, neurodegeneration, and survival. Huntingtin, the infamous bad protein in HD, suppresses PPAR-δ activity. But the wily researchers found a way to reverse this suppression by using an agent called KD3010. They announced their findings in Nature Medicine under the refreshingly self-explanatory title, PPAR-δ is repressed in Huntington’s disease, is required for normal neuronal function and can be targeted therapeutically. (OK, it could be a little shorter). The question now is whether this can be translated to humans. We don’t have too long to wait to find out because the Food and Drug Administration (FDA) has just approved KD3010 human trials.
CYP46A1 is an enzyme which regulates the breakdown of cholesterol. And what has cholesterol got to do with HD? Well…wait for this…cholesterol accumulates in the nerve cells of people with HD, and may contribute to nerve damage. The good news is that CYP46A1 helps to get rid of cholesterol, and some researchers postulate that medicines which enhance the activity of CYP46A1 will improve HD. This all comes from a paper in the journal Brain titled CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease. We are still at the proof of concept stages, but it will help if the CYP46A1-enhancing drugs come as handy pills!
Neurologists are familiar with tetrabenazine, the best treatment for chorea. And Star Trek fans are familiar with the heavy hydrogen atom, deuterium. Put the two together and, voila, you get deutetrabenazine (SD809). The heavy hydrogen of deuterium makes deutetrabenazine a more stable drug. This should make it last longer in the body, and also cause less side effects. Considering that the adverse effects of tetrabenazine include depression and parkinsonism, this is not an insignificant advantage (pardon the double negative…I couldn’t help it).
How well does deutetrabenazine translate to clinical practice? Sufficiently well enough it seems, going by the trial published in JAMA Neurology titled Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease. The authors compared the drug to placebo and showed that deutetrabenazine effectively improved chorea at 12 weeks. It is not surprising that the trial compared deutetrabenazine to placebo rather than the existing alternative; head-to-head drug trials are as rare as hen’s teeth in medicine (I wonder why that is). Anyway, deutetrabenazine may be coming to a pharmacy near you soon…we hope.
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.
![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)
