What are the promising CSF biomarkers of MND?

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.

Darts. Richard Matthews on Flickr. https://www.flickr.com/photos/richardofengland/6788829651

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).

By Muffinator – Own work, CC0, Link

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!

By Horia Varlan from Bucharest, Romania – Graduated cylinders and beaker filled with chemical compounds, CC BY 2.0, Link

Biomarkers elevated in the cerebrospinal fluid (CSF) 

Ferritin heavy chain (FHC)

Ferritin light chain (FLC)

Interferon g (IFN-g)

MIP 1a

Interleukin 12

Interleukin 15

Interleukin 17

Interleukin 23

Chromogranin A (CgA)

Basic fibroblast growth factor (bFGF)


Green Coral brain. Sarah Spaulding on Flickr. https://www.flickr.com/photos/visionwithin/61464453/


Vascular endothelial growth factor (VEGF)

Chitotriosidase 1 (CHIT 1)

Insulin-like growth factor 1 (IGF 1)

Matric metaloproteinases (MMPs)


Cystacin C

Monocyte chemotactic protein 1 (MCP 1)

Flt3 ligand

Prostaglandin E2 (PGE2)


Anti-ganglioside antibodies

By Nevit Dilmen (talk) – Own work, CC BY-SA 3.0, Link

Biomarkers reduced in the cerebrospinal fluid (CSF) 

Alpha 1 antitrypsin



Angiotensin II

Cytochrome C

Cyclic GMP (cGMP)

Acetylcholine esterase (AChE) activity


Why not check out more about MND in Neurochecklists

By © Nevit Dilmen, CC BY-SA 3.0, Link

What is the impact of Vitamin D on the complicated course of MS?

Some general neurologists get away with not having to think too much about multiple sclerosis (MS). This is because they have an ‘MSologist‘ at hand to refer all their patients with ‘demyelination‘. Many general neurologists however care for people with MS because they do not have a ‘fallback guy‘ to do the heavy lifting for them. This therefore makes it imperative for neurologists to keep up with everything about this often disabling and distressing disorder.

MS prevalence map. By AdertOwn work and [1], CC BY-SA 3.0, Link
The management of MS is however very tricky, and it is challenging to get a grip of it all. This is partly because the clinical course is varied, and the diagnostic process tortuous. The patient first goes through an onerous retinue of tests which include an MRI, a lumbar puncture, evoked potentials, and a shedload of blood tests. This is all in a bid to secure the diagnosis and to exclude all possible MS mimics.

MRI scan. NIH Image Galley on Flikr. https://www.flickr.com/photos/nihgov/30805879596

Then comes the head-scratching phase of determining if the patient actually fulfils the diagnostic criteria for MS, or if they just have clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS). To secure the diagnosis of MS, the neurologist turns to the McDonald criteria which stipulate dissemination in time and place of inflammatory events. As simple as this should be, this is no easy task at all. This is because, at different times, the criteria have meant different things to different people. The guidelines have also gone through several painful, and often confusing, iterations. Indeed the McDonald criteria have only recently been re-revised-to the delight of MSologists but the chagrin of the general neurologist!

Steampunk Time and Space Machine. Don Urban on Flikr. https://www.flickr.com/photos/donpezzano/3230179951

Once the diagnosis of relapsing remitting MS (RRMS) is reasonably established, the patient is taken through a guided tour of the ever-expanding available treatment options. These are typically to prevent relapses, but more recently to prevent disease progression as well. People with mild to moderate MS are nudged towards interferons, glatiramer acetate, dimethylfumarate, or terifluonamide. Those with more aggressive disease, on the other hand, are offered a menu of fingolimod, natalizumab, or alemtuzumab. Other newer agents include daclizumab and cladribine. And, just stepping into the arena, there is ocrelizumab for primary progressive (PPMS). Whichever option is chosen, the course of treatment is long, and it is fraught with risks such as infections and immune suppression.


Once the bigger questions have been settled, the neurologist then braces for the ‘minor’ questions her enlightened patients will ask. The easier questions relate to the treatment of symptoms, and some of the most vexing concern the role of Vitamin D deficiency. Such questions include, ‘Is vitamin D deficiency a cause of MS?‘, ‘Do people who are vitamin D deficient experience a worse outcome?‘, and ‘Should patients with MS be on Vitamin D supplementation?‘.

Pandora’s box. Michael Hensman on Flikr. https://www.flickr.com/photos/mycael/3664900435

To attempt to resolve these questions I plunged into some of the literature on Vitamin D and MS. And this is like opening Pandora’s box. Here are some of the things I found.


Is MS associated with Vitamin D deficiency?

It therefore appears that there is an association of vitamin D deficiency with MS, but it is far from certain that this is a causative relationship. One hypothesis is that vitamin D deficiency is the outcome, rather than the cause, of MS. The deficiency presumably results becuase the very active immune system in people with MS mops up the body’s Vitamin D. This so-called reverse causation hypothesis asserts that vitamin D deficiency is a consumptive vitaminopathy

Sunshine Falls. Dawn Ellner on Flikr. https://www.flickr.com/photos/naturesdawn/4299041739

Does Vitamin D deficiency worsen MS progression?

There is therefore no single answer to this question, but the emerging consensus is that Vitamin D deficiency adversely affects the course of MS. 

Milk splash experiment. Endre majoros on Flikr. https://www.flickr.com/photos/boneball/24597145866

Should people with MS be on Vitamin D supplementation?

Even if Vitamin D deficiency doesn’t cause MS, the evidence suggests that it negatively influences the course of the disease.

Salmon salad nicoise. Keith McDuffee on Flikr. https://www.flickr.com/photos/gudlyf/3609052894

What to do?

This is the million dollar question eloquently posed by a recent editorial in the journal Neurology titled Preventing multiple sclerosis: to (takevitamin D or not to (takevitamin D? The reasonable consensus is to encourage vitamin D replenishment to prevent MS, starting from preconception. It is also generally agreed that people with MS should be on vitamin D supplementation in the expectation that it will slow the disease activity.

A practical approach to Vitamin D replacement is the Barts MS team vitamin D supplementation recommendation. This is to start with 5,000IU/day vitamin D, and aim for a plasma level of 100-250 nmol/L. Depending on the level, the dose is then adjusted, up or down, to between 2-10,000IU/day. They also advise against giving calcium supplementation unless there is associated osteoporosis.

What is a general neurologist to do? To follow the prevailing trend, and hope it doesn’t change direction too soon!

Vitamin D Pills. Essgee51 on Flikr. https://www.flickr.com/photos/sg51/5224823967


The 13 most dreadful neurological disorders…and the groups standing up to them

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.

Brain Art. Ars Electronica on Flikr. https://www.flickr.com/photos/arselectronica/7773544158

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.

Neural pathways in the brain. NICHD on Flikr. https://www.flickr.com/photos/nichd/16672073333

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.

Working Brain. Gontzal García del Caño on Flikr. https://www.flickr.com/photos/euskalanato/2052487054


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: The 43 spinocerebellar ataxias: the complete checklistsOld drugs, new roles?, and Will Riluzole really be good for cerebellar ataxia?

Brain tumours

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: Calming the rage of brain tumours: hope for a dreaded cancerMaggots, viruses and lasers: some innovations for brain tumoursand Are steroids detrimental to survival in brain tumours?

Peripheral neuropathy

Peripheral neuropathy 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 Charcot Marie Tooth disease (CMT) and Familial amyloid polyneuropathy. Read more in these blog posts: The 52 variants of CMT… and their practical checklistsWhat’s looming at the frontline of peripheral neuropathy? and Will a pill really hold the cure for CMT?

Creutzfeldt Jakob disease (CJD)

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 Final day of ANA 2015- Prions center stage, and What are the links between Prion diseases and Parkinsonian disorders?


Dementia is the scourge of longevity. Its name strikes terror because it insidiously colonises the cells that make us who we are. The most prominent dementia is Alzheimer’s disease, but it has equally dreadful companions such as Frontotemporal dementia (FTD) and Dementia with Lewy bodies (DLB). Read more on dementia in these blog posts: How bright is the future for Alzheimer’s disease?Alzheimer’s disease: a few curious things, and Alzheimers disease and its promising links with diabetes.


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: Why does dystonia fascinate and challenge neurology? and Making sense of the dystonias: the practical checklists.

Huntington’s disease (HD)

Huntington’s disease 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 What are the prospects of stamping out Huntington’s disease? 

Motor neurone disease (MND) 

Also known as Amyotrophic lateral 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. It is no wonder that one of the most read post on this blog is titled Is neurology research finally breaking the resolve of MND? Other previous blog posts on MND are The emerging links between depression and MNDWhat is the relationship of MND and cancer?Does diabetes protect from MND?, and MND and funeral directors-really?

Multiple sclerosis (MS)

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: The emerging progress from the world of MS , What are the remarkable drugs which have transformed the treatment of MS?, and Is low vitamin D a cause of multiple sclerosis?

Muscular dystrophy 

Muscular dystrophy is an umbrella term that covers a diverse range of inherited muscle diseases. The most devastating, on account of its early onset and unrelenting progression, is Duchenne muscular dystrophy (DMD). Adult neurologists will be more familiar with late onset muscular dystrophies such as Myotonic dystrophy and Facioscapulohumeral muscular dystrophy (FSHD). Read more on muscular dystrophy in these previous blog posts: How is neurology stamping out the anguish of Duchenne? and The A–Z of limb girdle muscular dystrophy (LGMD).


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 neurological disorders? But you could better by checking neurochecklists for details of the clinical features and management of rabies.

Spinal cord injury

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 6 innovations in the treatment of spinal cord injury and Head transplant, anyone?


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, clinical features, and management of tetanus.


Light brain. Mario D’Amore on Flikr. https://www.flickr.com/photos/kidpixo/3470448888

As for all lists, this will surely be subject to debate, or perhaps some healthy controversy. Please leave a comment.

Why is CLIPPERS breaking its shackles to the pons?

CLIPPERS is unusual enough you would think. Nothing to do with barbing and shearing I assure you. CLIPPERS stands for Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. The striking feature of CLIPPERS is inflammation in the pons, the chunky middle part of the brainstem. This distinguishes it from other neurological inflammatory disorders such as multiple sclerosis (MS) and neuromyelitis optica (NMO).

By Images are generated by Life Science Databases(LSDB). - from Anatomography[1] website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, Link
By Images are generated by Life Science Databases(LSDB). – from Anatomography[1] website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, Link

CLIPPERS has however now broken loose from its shackles to the pons, and is spreading down into the spinal cord. Sacrilege you might say.

By BruceBlaus - Own work, CC BY 3.0, Link
By BruceBlausOwn work, CC BY 3.0, Link

This disruptive and subvertive action was reported in two prestigious neurology journals. The first paper in the journal, Neurology, is titled CLIPPERS with diffuse white matter and longitudinally extensive spinal cord involvement. The second is reported in the journal, Brain, as CLIPPERS with lesions distributed predominantly in spinal cord.

"What's in a name?" Jack Dorsey on Flikr. https://www.flickr.com/photos/jackdorsey/170257936
“What’s in a name?” Jack Dorsey on Flikr. https://www.flickr.com/photos/jackdorsey/170257936

What is it about neurological inflammatory disorders that makes them so rebellious? Why do they defy convention and disregard their defining features. I discussed a similar phenomenon in my previous blog post titled Why is neuromyelitis optica (NMO) endlessly surprising neurology? NMO refused to play by the rules and was punished by having it’s named changed to NMOSD. Perhaps it’s time for CLIPPERS to suffer the same fate….starting with a shorter acronym perhaps?


Check out more on CLIPPERS in Neurochecklists



What are the new diseases emerging in neurology?

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 James Parkinson, Alois Alzheimer, and George Huntington. 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=11648572
By uncredited – Images from the History of Medicine (NLM) [1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=11648572
Today, 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.


By Photo (c)2007 Derek Ramsey (Ram-Man) - Self-photographed, CC BY-SA 2.5, Link
By Photo (c)2007 Derek Ramsey (Ram-Man) – Self-photographed, CC BY-SA 2.5, Link

1. mTORopathy

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.

Merging bubbles. Charlie Reece on Flikr. https://www.flickr.com/photos/charliereece/777487250
Merging bubbles. Charlie Reece on Flikr. https://www.flickr.com/photos/charliereece/777487250

2. IgG4-related autoimmune diseases

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 as IgLON5: 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. 

By Aida Pitarch - Own work, CC BY-SA 4.0, Link
By Aida PitarchOwn work, CC BY-SA 4.0, Link

3. Anti-MOG antibody disorders

Now, neurologists have always known about MOG, mostly as a minor bit player, an extra, so to say. No more, it is now all grown up and matured. And the growth is fast and involves many inflammatory demyelinating disease of the CNS such as fulminant demyelinating encephalomyelitis and multiphasic disseminated encephalomyelitis. How far will it go?


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.

By Transferred from en.wikipedia to Commons.This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #5605.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−, Public Domain, Link
By Transferred from en.wikipedia to Commons.This media comes from the Centers for Disease Control and Prevention‘s Public Health Image Library (PHIL), with identification number #5605.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−, Public Domain, Link

5. Zika virus

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.

By Manuel Almagro Rivas - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=47941048
By Manuel Almagro RivasOwn work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=47941048

6. Multisystem proteinopathy

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.

Hydra. Andrew Jian on Flikr. https://www.flickr.com/photos/andrew_jian/475479747
Hydra. Andrew Jian on Flikr. https://www.flickr.com/photos/andrew_jian/475479747

7. GLUT-1 deficiency syndromes

GLUT-1 stands for glucose transporter type 1. Deficiency of GLUT-1 results in impaired transportation of glucose into the brainGLUT-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.

Sugar Cubes. David pacey on Flikr. https://www.flickr.com/photos/63723146@N08/7164573186
Sugar Cubes. David pacey on Flikr. https://www.flickr.com/photos/63723146@N08/7164573186

8. Progressive Solitary Sclerosis

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.

Solitary tree at Sunset. epcp on Flikr. https://www.flickr.com/photos/epcprince/3418260382
Solitary tree at Sunset. epcp on Flikr. https://www.flickr.com/photos/epcprince/3418260382

Do you have any suggestions of emerging neurological disorders? Please leave a comment


PS. These disorders are all covered in neurochecklists


What are the remarkable drugs which have transformed the treatment of MS?

Multiple sclerosis (MS) is a common and blighting neurological disease. It frequently targets young people, often with disabling effects. It may affect any part of the central nervous system, and it manifests with relapsing or steadily progressive clinical features.

"Carswell-Multiple Sclerosis2" by derivative work: Garrondo (talk)Carswell-Multiple_Sclerosis.jpg: Robert Carswell (1793–1857) - Carswell-Multiple_Sclerosis.jpg. Licensed under Public Domain via Commons.
Carswell-Multiple Sclerosis2” by derivative work: Garrondo (talk)Carswell-Multiple_Sclerosis.jpg: Robert Carswell (1793–1857) – Carswell-Multiple_Sclerosis.jpg. Licensed under Public Domain via Commons.

Research is improving our understanding of MS at a breathtaking pace. Just as one is getting comfortable with the status quo, a sudden paradigm shift occurs. This is the work of the men and women in white coats, labouring in dingy labs, peering down powerful microscopes, and scrutinising imaging scans-all in the drive to improve the care of people who suffer from this defiant disease. To avoid becoming dinosaurs, neurologists have to keep up with the rapid developments at the cutting-edge of multiple sclerosis.

Blade end of 'Cutting Edge', Sheaf Square. Robin Stott http://www.geograph.org.uk/photo/2894285
Blade end of ‘Cutting Edge’, Sheaf Square. Robin Stott http://www.geograph.org.uk/photo/2894285

MS research has enhanced our knowledge of all aspects of the disease. For example, we know a lot more about MS risk factors, as discussed in my previous post titled MS risk factors: the top 6. There is also a lot going on with drug development, as I addressed in my previous blog posts, The emerging progress from the world of MS, and Masitinib, a breakthrough drug shattering neurology boundaries. More importantly, there are many drugs, already in use, which have radically changed neurological practice in a very short time. In this blog post I will review 5 treatments which have already transformed the management of MS.

1. Monoclonal antibodies 

B0007277 Monoclonal antibodies. Anna Tanczos. Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814713820
B0007277 Monoclonal antibodies. Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814713820

It seems a long time ago now when the treatment of Multiple Sclerosis (MS) revolved just around interferons and steroids. Since then the monoclonal antibodies have changed the field radically. Drugs such as natalizumab and alemtuzumab are now mainstream, and many other ‘mabs’ have followed fast on their heels. Daclizumab is about to come into clinical practice soon, and ocrelizumab is full of promise for progressive MS, as discussed in this article in Medscape. With the floodgates now fully opened, other ‘mabs’ such as ofatumumab are trooping in fast. Unfortunately not all monoclonal antibodies are making the grade; an example is Opicinumab (anti LINGO-1), touted as a drug that boosts nerve signals, but which latest reports indicate failed to meet up to its high expectations.

2. Fingolimod

By Williamseanohlinger - Created with Spartan'10 softwareon my personal PC, Public Domain, Link
By Williamseanohlinger – Created with Spartan’10 softwareon my personal PC, Public Domain, Link

Fingolimod is the leader in the pack of sphingosine-1-phosphate receptor modulators. It has led the way and has the advantage that it is taken by mouth rather than by injection. It is limited by its risks on heart activity, and must be initiated under close cardiac monitoring. Beyond MS, it may have a wider impact on neurological practice as it is under consideration in the treatment of motor neurone disease (MND). Following quickly behind fingolimod, still in trial stages, are laquinimod, ozanimod, ponesimodsiponimod, and amiselimod. It is still not clear if these drugs will have a similar impact as the monoclonal antibodies, in which case we may end up with the war of the ‘Mabs’ versus the ‘Mods’.

3. Dimethyl fumarate

By Ben Mills - Own work, Public Domain, Link
By Ben MillsOwn work, Public Domain, Link

Dimethyl fumarate is an oral MS drug which works by activating the erythroid-derived 2-like transcriptional pathway. It has the stamp of approval of a Cochrane Database review on account of moderate quality evidence from two randomized clinical trials. It is fairly well-tolerated, mild flushing being the commonest reported side effect. 

4. Terifluonomide

By Jynto (talk) - Own workThis chemical image was created with Discovery Studio Visualizer., CC0, Link
By Jynto (talk) – Own workThis chemical image was created with Discovery Studio Visualizer., CC0, Link

Terifluonomide is another oral drug developed for the treatment of MS. It is a pyrimidine synthesis inhibitor. Unlike dimethyl fumarate, a recent Cochrane database review for terifluonomide found only low-quality evidence from 5 clinical trials. The review says ‘all studies had a high risk of detection bias for relapse assessment, and a high risk of bias due to conflicts of interest‘. Not very glowing tributes, but in its favour is the low frequency of significant side effects.

5. PEGylated interferon

Von Anypodetos - Eigenes Werk, CC0, Link
Von AnypodetosEigenes Werk, CC0, Link

PEG-interferon is an enhancement to good interferons of old (which, by the way, are still on active duty in MS). It was developed to reduce the high frequency of injections associated with Interferon beta-1a. Pegylation is the attachment of polyethylene glycol (PEG), and this process increases the half life of drugs. It is not clear that pegylation offers any other advantage over ‘ordinary’ interferon, but surely the 2 weekly injection is a significant advance. 

Breakthrough VSCO Monochrome Black & White KitCam at Carnegie Museum Of Art. Spiro Bolos on Flikr. https://www.flickr.com/photos/spirobolos/15879318128
Breakthrough VSCO Monochrome Black & White KitCam at Carnegie Museum Of Art. Spiro Bolos on Flikr. https://www.flickr.com/photos/spirobolos/15879318128


For the future direction of MS treatment, I recommend Gavin Giovannoni‘s BartsMS Blog.

You may also  check out this recent review in American Health and Drug Benefits titled The Latest Innovations in the Drug Pipeline for Multiple Sclerosis



Masitinib, a breakthrough drug shattering neurology boundaries

In the process of writing a blog post on the research findings altering neurological practice, my sight fell on the drug, Masitinib. I was completely unaware of this tyrosine kinase inhibitor, one of the promising drugs in the fight against multiple sclerosis (MS). We are likely to hear a lot more about Masitinib in MS in the coming months.

By Zeldj - Own work, CC BY-SA 4.0, Link
By ZeldjOwn work, CC BY-SA 4.0, Link

Masitinib is however not flexing its muscles just in neuro-inflammation. On the contrary, it is seeking laurels far afield, in the realm of neuro-degeneration. I was indeed pleasantly surprised to find that researchers are studying the impact of Masitinib on two other horrible scourges of neurology. The first report I came across is the favourable outcome of a phase 3 trial of Masitinib in motor neurone disease (MND) or amyotrophic lateral sclerosis (ALS). The drug reportedly ‘reached its primary objectives‘ of efficacy and safety. In this trial, Masitinib was used as an add-on to Riluzole, the established MND drug. It’s all jolly collaborative at this stage, but who knows what threat Masitinib will pose to Riluzole in future! You may read a bit more on Masitinib and MND in this piece from Journal of Neuroinflammation.

By Capilano1 - Own work, CC BY-SA 4.0, Link
By Capilano1Own work, CC BY-SA 4.0, Link

The second report I came across is the potential of Masitinib in the treatment of Alzheimer’s disease (AD). This is at the phase 2 trial stage, and already showing very good outcomes in people with mild to moderate AD. Masitinib was used as an add-on drug to the conventional AD medications Memantine, Donepezil, Galantamine and Rivastigmine. These drugs can therefore rest comfortably on their thrones…at least for now! You can read a bit more on Masitinib and AD in this article from Expert Review of Neurotherapeutics.

Alzheimer's Disease. Hamza Butt on Flikr. https://www.flickr.com/photos/141735806@N08/28007367952
Alzheimer’s Disease. Hamza Butt on Flikr. https://www.flickr.com/photos/141735806@N08/28007367952

The question however remains, why should one drug work well on such disparate diseases? I know, this feels like deja vu coming shortly after my last blog post titled Alzheimers disease and its promising links with diabetes. In that post I looked at the promise of the diabetes drug, Liraglutide, in the treatment of Alzheimers disease. I have however also reviewed this type of cross-boundary activity of drugs in my older posts, Will riluzole really be good for cerebellar ataxia? and old drugs, new roles? Perhaps Masitinib is another pointer that, as we precisely define the cause of diseases, they will turn out to be merely different manifestations of the same pathology. Food for thought.

Benjah-bmm27 assumed. Own work assumed (based on copyright claims). Public Domain, Link
Benjah-bmm27 assumed. Own work assumed (based on copyright claims). Public Domain, Link


As I said, this wasn’t the post I set out to write. So watch out for my next blog post, the major research outcomes altering neurological practice.


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