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, Joseph 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.
Myasthenia gravis (MG) is an iconic neurological disorder. It is classical in its presentation, weakness setting in with exertion and improving with rest. This fatigability is demonstrable in the laboratory when repetitive nerve stimulation (RNS) of the muscles results in a progressively decrementalresponse. Clinically, myasthenia gravis is often a benign disorder which restricts itself to the muscles of the eyes: this ocular MG manifests just with droopy eyelids (ptosis) and double vision (diplopia). At the extreme however is generalised MG, a severe and life-threatening condition that justifies its grave appellation.
Myasthenia gravis depletes the energy reserve of muscles, something which is entirely dependent on acetylcholine (ACh), a chemical released at nerve endings. After release, ACh traverses the neuromuscular junction (NMJ) to attach itself to the acetylcholine receptor (AChR), which is comfortably nestled on the surface of the muscle. This binding of chemical to receptor is a significant event, setting sparks flying, and muscles contracting. In myasthenia gravis, this fundamental process is rudely disrupted by the onslaught of acetylcholine receptor antibodies. These aggressive AChR antibodies, produced by the thymus gland in the chest, vent their rage by competitively binding to the receptor, leaving acetylcholine high and dry. Eventually, the rampaging antibodies destroy the receptor in an act of unjustified savagery.
In tackling myasthenia gravis, it is no wonder that neurologists first have to hunt down the ferocious AChR antibodies. They whisk off an aliquot of serum to a specialist laboratory, but waste no time in planning a counteroffensive, confident that the test will return as positive. The strategy is to boost the level of acetylcholine in the NMJ, tilting the balance in favour of ACh against the antibodies. The tactic is to zealously despatch a prescription for a drug that will block acetylcholine esterase inhibitor, the enzyme which breaks down acetylcholine. The neurologist then closely observes the often dramatic response, one of the most gratifying in clinical medicine; one minute as weak as a kitten, the next minute as strong as an ox. MG is therefore one disorder which debunks the wicked jibe that neurologists know so much…but do so little to make their patients better!
Unfortunately for the neurologist, every now and then, the AChR antibody test result comes back as negative. In the past, the dumbfounded and befuddled, but nevertheless undaunted neurologist, will march on, battling a diagnosis of antibody-negative MG. Nowadays however, this not a comfortable diagnosis to make because AChR antibody is no longer the only game in town. We now know that there are many other antibodies that are jostling for commanding positions in the anti-myasthenia coalition. These include anti LRP4,cotarctin, titin,agrin,netrin1, VGKC, andryanodine. However, the clear frontrunner in this melee is anti-MUSK antibody, responsible for 30-50% of MG in which there are no AChR antibodies.
Anti MUSK syndrome has many distinguishing featuresthat set it apart from the run-of-the-mill myasthenia gravis. Below are five distinctive markers of anti-MUSK syndrome:
Subjects with anti-MUSK syndrome are typically middle-aged women in their 3rd or 4th decades. This is younger than the usual age of people with AChR MG. Indeed neurologists now recognise typical myasthenia as a disease of older people.
Single fiber electromyogram (sfEMG), a specific and reliable neurophysiological test of MG, is often normal in anti-MUSK syndrome. This is partly because the limb muscles are usually spared in anti MUSK syndrome.
People with anti-MUSK myasthenia often do not benefit from, nor do they tolerate, the acetylcholinesterase inhibitors which are used to treat MG. Indeed, these drugs may worsen anti-MUSK syndrome.
Thymectomy, removal of the thymus gland, is not beneficial in people with anti-MUSK syndrome, unlike its usefulness in AChR MG.
All this is just the tip of the evolving myasthenia gravis iceberg. You may explore more of myasthenia in our previous blog posts:
Neurologists spend most of their time diagnosing benign conditions which are curable or treatable, or at least people learn to live with. Every now and then we see people with startling symptoms such as coma, convulsions, neck stiffness, or paralysis. These are obviously concerning to patients and their families who have a foreboding of diseases such as meningitis, epilepsy, and stroke. Serious as these disorders are, they at least announce themselves and show their hands. Many other neurological symptoms unfortunately give no hint of the serious diseases that follow in their trail. That is when things get a bit tricky.
What are these seemingly benign symptoms which jolt neurologists out of their blissful complacency? What are these red flag symptoms that pretend they are grey? Here are my 7 deceptively ominous neurological signs everyone should know about.
7. A numb chin
This must be the most deceptive sinister symptom in neurology. Not many people will rush to their doctors to complain about a numb chin, but it is a symptom that makes neurologists very nervous. This is because the chin gets its sensory supply from the mandibular branch of the fifth cranial nerve, also called the trigeminal nerve because it has three branches. And neurologists know that, for some bizarre reason, cancers from other parts of the body occasionally send deposits to this nerve. The numb chin syndrome is therefore not to be treated lightly.
6. Muscle twitching
OK, don’t panic yet. We have all experienced this; a flickering of an overused and tired muscle; a twitching of the odd finger; the quivering of the calf muscles in older people. Neurologists call these fasciculations, and they are only a concern if they are persistent, progressive, and widespread. And also usually only if the affected muscles are weak. In such cases neurologists worry that fasciculations are the harbingers of sinister diseases, particularly motor neurone disease (MND), better known in America as amyotrophic lateral sclerosis (ALS) or Lou Gehrig disease. Many people with muscle twitching will however have nothing seriously wrong with them, and many will be shooed out of the consulting room with the label of benign fasciculations syndrome (we love our syndromes, especially when they are benign). There are many other causes of fasciculations, but MND is clearly the most sinister of them all.
5. Transient visual loss
Neurologists often ask people with headache if their vision blurs or disappears for brief periods of time. These visual obscurations are not as dramatic as the visual loss that accompanies minor strokes or transient ischaemic attacks (TIAs). Visual obscurations affect both eyes and last only a few seconds. They are the result of sudden but brief increases in an already elevated pressure in the head. This may occur with relatively benign conditions such as idiopathic intracranial hypertension (IIH), but it may also portend a serious disorder such as a brain tumour.
4. Sudden loss of bowel or bladder control
Loss of control down there would surely concern many people, but often not with the urgency it deserves. There are many non-neurological causes of bowel or bladder incontinence, but a sudden onset suggests that it is arising from the nervous system. The worrying diagnoses here are spinal cord compression and spinal cord inflammation (transverse myelitis). These disorders are often associated with other symptoms such as leg stiffness and weakness, but I really wouldn’t wait until these set in before I ask to see a neurologist.
3. Saddle anaesthesia
Whilst we are on the topic of things down there, a related sinister symptom is loss of sensation around the genitals and buttocks, something your doctor will prudently call saddle anaesthesia. This arises when the nerves coming off the lower end of the spinal cord, collectively called the cauda equina, are compressed. The unpalatable condition, cauda equina syndrome (CES), worries neurologists because the compression may be due to a tumour in the spinal canal.
PS: The bicycle saddle is an apt analogy, but if you prefer horseriding, below is an alternative image to soothe your hurt feelings.
2. A painful droopy eyelid
A droopy eyelid is a deceptively benign symptom which worries neurologists. This symptom, which neurologist prefer to call ptosis, is particularly concerning if it is accompanied by double vision. One worrying disorder which causes ptosis is myasthenia gravis (MG), and this presents with ptosis on both sides. More sinister is ptosis which is present only on one side, particularly if it is painful. This may be caused by brain aneurysms, especially those arising from a weakness of the posterior communicating artery (PCOM) artery. As the aneurysm grows, it presses on the third cranial or oculomotor nerve, one of three nerves that controls the eyeballs and keeps the eyelids open. An aneurysm is literally a time-bomb in the brain as they wield the threat of bursting and causing a catastrophic bleeding around the brain. This makes ptosis an ominous, but also a helpful, neurological symptom.
There are many other causes of ptosis including Horner’s syndrome, so don’t panic yet but get that eyelid checked out if it refuses to straighten out.
1. Thunderclap headache
A thunderclap headache is a symptom that means exactly what it says on the label! Neurologists will ask if the onset felt as if one was hit by a cricket bat. Even though most people have never been so assaulted, almost everyone with thunderclap headache readily agree this is what it feels like. It is such a distressing symptom that it doesn’t strike the afflicted person (pun intended) that their doctors are more concerned about investigating them, then they are in curing their headache. They patient is rushed to the CT scanner, and then subjected to a lumbar puncture. The doctors then heave a huge sigh of relief when the spinal fluid shows no blood or blood products, reassured that the patient has not suffered a subarachnoid haemorrhage (SAH) from a ruptured a brain aneurysm. The patient, who now has just another headache, is left to get to grips with their now, suddenly, very uninteresting symptom. There are many other causes of a thunderclap headache, but a ruptured aneurysm is the most sinister. If you develop a thunderclap headache, don’t wait to see a neurologist…just get to the nearest hospital!
PS: Don’t feel aggrieved if you are across the Pacific; it is also a thunderclap headache if it felt like being hit by a baseball bat!
The long-term treatment of myasthenia gravis (MG) relies on drugs which suppress the immune system. I listed some of these in my previous post titled How is innovative neurology research energising myasthenia? Steroids are the established first line immune suppressing treatment for MG but because of their many nasty side effects, they cannot be used at effective doses for long periods. This is why neurologists treating MG use so-called steroid-sparing agents to reduce, or eliminate, the need for steroids.
Azathioprine has the best evidence of effectiveness as a steroid-sparing drug, and it is the acknowledged favourite of neurologists. Azathioprine may however fail or cause unacceptable side effects. It is also unsuitable for people who lack TPMT, the enzyme that breaks it down. It is in these situations that things become slightly tricky for the neurologist.
In theory, neurologists are spoilt for choice when they can’t use Azathioprine. Methotrexate is my favourite option in such cases because it has an easy weekly dosing regime and it is fairly well-tolerated. Alas, a recent paper in Neurology titled A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis has unsettled me by suggesting that methotrexate is not living up to its top billing. The authors of the paper studied 50 people with myasthenia gravis who were already taking steroids. They put some of them on methotrexate, and the others on placebo. The outcome was surprising; methotrexate did very little to reduce the requirement for steroids, and it did nothing to improve the symptoms of MG.
This is clearly disappointing. Whilst waiting for further studies to confirm or refute this finding, I wonder how reliable the other steroid-sparing MG drugs are. How good are mycophenolate, ciclosporin, cyclophosphamide, tacrolimus, and rituximab? What really works in MG? To the rescue comes the International consensus guidance for management of myasthenia gravis, just hot off the press! Alas, the experts who drafted this guidance only compounded my woes. They made many treatment recommendations, but these came with as many caveats. They said the evidence for mycophenolate and tacrolimus in MG is rather thin, and the evidence-based ciclosporine and cyclophosphamide have potentially serious side effects. And they couldn’t agree on how promising rituximab, the new kid on the block, really is.
We are therefore back to the question, what to do when Azathioprine fails? The experts tell us to stick to the usual suspects, but they urge caution. Perhaps what we need are newer and safer alternatives such as Lefluonamide, so new to the MG arena that it did not get a mention in the expert guidance.
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.
Anti VGKC antibody encephalitis is caused by two different antibodies called LGI1 and Caspr2. The immunology laboratory would however only test for these two if the ‘generic’ VGKC test is positive. Neurologists are understandably left scratching their heads when both tests turn out to be negative. Not any more, going by a report in Neurology titled The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. The judgment is out: a positive VGCK antibody test is not significant if both LGI1 and Caspr2 are negative. What a relief.
Many acquired neurological disorders have a way of dragging genetics into their fold. Such is the case it seems with anti NMDA receptor encephalitis. This is the case with the GRIN-1 gene which codes for an NMDA receptor subunit. Mutations in this gene results in visual impairment, intellectual disability, and eye movement disorders. This is reported in Neurology by Josep Dalmauand colleagues in a paper titled Delineating the GRIN1 phenotypic spectrum. It is appropriate that the authors call this the genetic sibling of NMDA receptor encephalitis.
4. ECT for anti-NMDA receptor encephalitis
The typical treatment of autoimmune encephalitis revolves around steroids, intravenous immunoglobulins (IVIg), and plasma exchange. Neurologists, when pushed to the wall, may use heavy duty agents such as Rituximab and Cyclophosphamide. Because anti-NMDA receptor encephalitis may be associated with ovarian teratomas, neurologists may make the difficult trip across the border to consult their gynaecology colleagues. I thought these were all the treatment options for anti NMDA receptor encephalitis until I read this case report, again in Neurology, which reported an excellent response to Electroconvulsive therapy in anti-NMDA receptor encephalitis. A no-brainer then if you see neurologists exchanging pleasantries with psychiatrists: they are the ECT experts. It is just a case report for now, but well-worth thinking about when all else fails.
Neurologists have always known that autoimmunity accounts for many nervous system disorders. A classical example is Sydenham’s chorea or St Vitus dance. This movement disorder develops after rheumatic fever, and is caused by antibodies to the bacterium called Streptocccus. The modern-day resurrection of this condition is called paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. I know, too long, but just call it PANDAS. A great acronym I must say, quite unlike ABGA which stands for anti basal ganglia antibody syndrome, an umbrella term for many movement disorders provoked by external agents.
A third group of neurological diseases are more sinister because the antibodies are generated by cancer cells. These paraneoplastic neurological syndromes are legion and protean, requiring a high index of suspicion to diagnose. Most frustrating for neurologists is that the cancer itself may not emerge for several years after the diagnosis of a paraneoplastic syndrome. Notorious for this cloak and dagger behaviour is small cell lung cancer (SCLC). Because of the potential consequences, neurologists deploy their heavy duty imaging scans such as positron emission tomography (PET) scans. They then lie low, year after year, waiting to nab the devious cancer as soon as it shows up.
In recent years, a completely different class of disorders has attained notoriety and infamy in the form of autoimmune encephalitis. These disorders often pretend to be infectious diseases, but they totally disregard the antibiotics and antiviral agents the neurologist attacks them with. By subterfuge and subversion they disable ion channels and receptors to cause havoc in the brain. And nobody has described such havoc better than Susannah Cahalan in her book Brain on Fire: My Month of Madness.
Autoimmune encephalitis may fester for weeks, years or decades, evading detection by its duplicitous behaviour, and by the increasing number of antibodies that may be responsible. There are however three main culprit antibodies which neurologists are now getting a grip on:
These conditions are all potentially fatal but eminently curable; this underlies the importance of recognising and treating them very early. A recent paper in Lancet Neurology summarises the clinical approach to autoimmune encephalitis(pdf).
Autoimmune neurology is a rapidly evolving field. I will review recent developments in this area in a second post to follow shortly titled What’s breaking at the cutting edge-of autoimmune neurology?
Myasthenia gravis (MG) is one of the best characterised neurological disorders. The hallmark of MG is fatigable weakness. This manifests as intermittent ptosis (droopy eyelids), diplopia (double vision), and limb weakness. There are two main types-ocular MG affects just the eyes and eyelids, and generalised MG affects the body, including the bulbar functions of breathing and swallowing.
The problem in MG is straightforward lack of communication; the nerves and muscles aren’t talking to each other. The two meet up at the neuromuscular junction (NMJ) where the nerves send packages of acetylcholine to bind with acetylcholine receptors (AChR) on the surface of the muscles. The muscles usually acknowledge this by contracting and producing action, but in MG this response is blocked by antibodies to the acetylcholine receptor (AChR antibodies). Like all culprits, it has wily accomplices such as anti-muscle specific kinase (anti-MUSK) antibody.
AChR antibodies are produced by a gland in the chest called the thymus. Disturbingly, this rather shabby-looking tissue may become enlarged (thymichyperplasia), or cancerous (thymoma). The neurologist is therefore quick to request a CT chest scan as soon as MG is confirmed. Alas, the thymus is often normal or even shrivelled, to the delight of the patient who escapes the cardiothoracic surgeon. The neurologist is however ambivalent because surgery often gives a one-off cure, and saves the neurologist from a life-long commitment to monitor toxic treatments. The life of a Neurologist!
With so much known about MG, one would think there is very little on the horizon to put a smile on the faces of people with MG. But this old dog still has a few new tricks, and here are 4 energising reports I came across.
1. Predicting generalisation of ocular MG
Neurologists are aware that ocular MG could transform to generalised MG, they just don’t know who is at risk. Generalised MG is obviously a worse condition and requires more heavy-duty treatments. After much speculation, a report in JAMA Neurology has found the predictor of MG generalisation. Titled Clinical Utility of Acetylcholine Receptor Antibody Testing in Ocular Myasthenia Gravis, the authors confirmed, for the first time ever, that the risk of generalisation is linked to higher AChR antibody levels. I know, you were expecting some new, cutting-edge test or technology: sorry for the dampener, but sometimes it’s the little things that count.
2. Linking MG to muscular dystrophy
Congenital myasthenia is a slightly different kettle of fish from conventional MG. For one, the diversity of genetic mutations that cause congenital myasthenia is mind-boggling; there are >20 genetic forms of MG such as DOK 7, RAPSYN, LAMB 2, and AGRIN. And these all differ in their presentation and response to treatment. An addition to this long list of congenital myasthenic syndromes should therefore normally not be exciting news. But there is something different in the recent report in the journal Brain about GMPPB (you really don’t want to know what this stands for). The paper, titled Mutations in GMPPB cause congenital myasthenic syndrome, opens up a can of worms because GMPPB also plays a role in causing muscular dystrophy. The authors see this as a bridge between myasthenia and muscular dystrophy. All rather complicated stuff, not quite sure what the implications are, but that’s the reason neurologists exist!
3. Leflunomide for drug-resistant MG
Immunosuppression is the ultimate treatment for MG because it reduces the production of the MG-causing antibodies. And the neurologist has a list, an arm length, of immunosuppressive agents to try. This variety of options is helpful because earlier choices may be ineffective, intolerable, or impractical. Azathioprine, methotrexate, mycophenolate …these roll out easily from the neurologist’s pen. Leflunomide would however sound very strange in neurological circles; it is more familiar to rheumatologists who use it to treat rheumatoid arthritis. Neurologists, ever peeping into the rheumatology recipe book, thought why not try Leflunomide in MG. They reported their findings in Journal of Neurology as Leflunomide treatment in corticosteroid-dependent myasthenia gravis: an open-label pilot study. And the recipe worked; 9 of 15 people with severe, steroid-dependent, MG improved on Leflunomide. Great news for when the going gets tough.
3, 4 Diaminopyridine for anti-MUSK MG
Thankfully not all MG treatment involves immunosuppression. One approach is to prevent the break down of the enzyme (esterase) that breaks down acetylcholine-got it? In this way there will be more acetylcholine available to counter the effect of AChR antibodies. Medications that work in this way are called acetylcoline esterase inhibitors (ACEI). It’s OK to re-read all this before proceeding!
Pyridostigmine is the quintessential ACEI. But this is not effective in the more severe anti-MUSK MG where typical MG treatments don’t work so well. Neurologists have tried all sorts, including Rituximab, to varying success. What to do when all fails? A paper in the journal Neurology offers some hope that anti-MUSK MG may respond to 3,4 Diaminopyridine. This will be heart-warming news to all neurologists, if they ignore the fact that it is a single case report! But hey, from little acorns grow giant oak trees.