10 things we now know about CIDP associated with anti NF155 antibodies

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a neurological disorder which causes loss of the fatty myelin covering of large nerves (demyelination). This slows down the speed at which the nerves can transmit electrical impulses. People with CIDP develop weakness and sensory disturbances, but not always in equal measure. CIDP is a pain for the afflicted, and a veritable nightmare for the neurologist.

 

By AjimonthomasOwn work, CC BY-SA 4.0, Link

The diagnostic process for CIDP includes some rather uncomfortable tests such as nerve conduction studies and lumbar puncture (spinal tap). CIDP is however a most rewarding disease to treat because many people respond to immune treatments such as steroids, intravenous immunoglobulins (IVIG), or plasma exchange (PE).

PRED SOV 5. Leo Reynolds on Flikr. https://www.flickr.com/photos/lwr/3300474346

The diagnosis of CIDP is however not straightforward. The results of the tests are not always clearcut, and a lot of sifting and sorting goes into nailing the diagnosis. And even when the diagnosis is eventually made, there is a very long list of potential causes of CIDP which often require treatment on their own merit. Worryingly, some of these conditions make the treatment of CIDP difficult. And this is where IgG antibodies play a nasty role in CIDP.

By Database Center for Life Science (DBCLS), CC BY 3.0, Link

Neurologists are now recognising that a subset of people with CIDP have IgG4 antibodies which greatly influence the clinical presentation and the treatment of CIDP. Anti-contactin antibody is one such antibody, but by far the most important is anti-neurofascin 155 (NF155). What do we know about this antibody? How does it influence the course of CIDP? To answer these questions, below are 10 important things we now know about CIDP associated with anti-NF155.

By BruceBlausOwn work, CC BY-SA 4.0, Link

1. Anti-NF155 is an antibody to paranodal structures

2. The antibody is present in 7-14% of people with CIDP

3. CIDP with anti-NF155 usually affects young subjects

4. Anti NF155 antibody CIDP is usually severe

5. Anti NF155 may cause central nervous system inflammation 

6. It causes a very high protein level in the spinal fluid

7. It causes very severe changes on nerve conduction studies

8. It responds poorly to intravenous immunoglobulins (IVIg)

9. It may respond to steroids and plasma exchange

10. Treatment-resistant cases may respond to Rituximab
By Oguenther at de.wikipediaOwn work mit Jmol auf Basis RCSB PDB: 2OSL​., Public Domain, Link

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Why not check out everything CIDP on Neurochecklists:

When Shakespeare meets neurology: Hamlet, Ophelia and autoimmune encephalitis

Neurology can’t seem to get away from autoimmune disorders of the central nervous system. This blog has visited this topic several times before such as with the posts titled What are the dreadful autoimmune disorders that plague neurology? and What’s evolving at the cutting-edge of autoimmune neurology? The attraction of autoimmune neurological diseases lies in part in the ever-expanding spectrum of the antibodies and the challenging symptoms and syndromes they produce.

By Gentaur – Gentaur, Public Domain, Link

The fairly well-recognised ‘conventional’ antibodies are those against VGKC (Caspr 2 and LGI1), NMDA, and AMPA. There is however an almost endless list of less familiar antibodies such as those against glycine, adenylate kinase 5, thyroid, GABA-A receptors, α-enolase, neurexin-3α, dipeptidyl-peptidase-like protein 6 (DPPX), and myelin oligodendrocyte glycoprotein (MOG). I am however fascinated by the group of disorders caused by antibodies to metabotropic receptors. The main antibody in this group targets the metabotropic glutamate receptor 5 (mGluR5). The clinical picture with this antibody is a form of encephalitis which may manifest with prosopagnosia (difficulty recognising faces), and with the curious Ophelia syndrome.

By Benjamin WestOwn work, Public Domain, Link

Yes, you read it correctly. Ophelia syndrome is named after Shakespeare’s unfortunate Danish maiden, and it was first described by Dr. Ian Carr whose daughter, at the age of 15, developed progressive loss of memory, depression, hallucinations, and bizarre behaviour. These symptoms aptly describe Ophelia’s deluded and obsessional attraction to the equally deluded and murderous Hamlet. Ophelia syndrome is almost always associated with Hodgkins lymphoma and affects young people.

By V from Coventry, UK – Hamlet, CC BY 2.0, Link

Thankfully Ophelia syndrome is a relatively mild disease without the Shakespearean tragic ending because it has a good outcome if recognised and treated.

Why not explore all the autoimmune neurological disorders on 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.

https://pixabay.com/en/pie-chart-diagram-statistics-parts-149727/
https://pixabay.com/en/pie-chart-diagram-statistics-parts-149727/

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.

 

https://pixabay.com/en/letters-a-abc-alphabet-literacy-67046/
https://pixabay.com/en/letters-a-abc-alphabet-literacy-67046/

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?

http://thebluediamondgallery.com/a/autoimmune.html
http://thebluediamondgallery.com/a/autoimmune.html

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

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PS. These disorders are all covered in neurochecklists

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Terminological exactitude: changing the names of established neurological disorders

This is a quick post to highlight changes and proposed changes to some neurological terms. It is not unusual for such changes to occur every now and then. We have, for example, seen benign intracranial hypertension (BIH) changed to idiopathic intracranial hypertension (IIH), and Hallavorden Spatz disease transformed into pantethonate kinase associated neurodegeneration (PKAN).

Names scratched into a wall. Evelyn Simak on Geograph. http://www.geograph.org.uk/photo/4681807
Names scratched into a wall. Evelyn Simak on Geograph. http://www.geograph.org.uk/photo/4681807

One recent important change in neurological terminology, starting tentatively but beginning to take hold, is of nocturnal frontal lobe epilepsy (NFLE) to sleep-related hypermotor epilepsy.

The second is the suggested change from exploding head syndrome to episodic cranial sensory shock. I am not quite sure it will take off, but time will tell!

The third, not too new but surprising non-the-less, is the change from primary dystonia to focal isolated dystonia

Are you aware of any other issues of terminological exactitude? Please leave a comment.

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What’s evolving at the cutting-edge of autoimmune neurology?

This is a follow up to my previous blog titled What are the dreadful autoimmune disorders that plague neurology. Autoimmune neurology is a rapidly evolving field; blink and you will miss important developments. So what’s evolving in autoimmune neurology? Below are my top 4.

 

1. Insignificance of isolated VGKC positivity

By The original uploader was Iantresman at English Wikipedia - Transferred from en.wikipedia to Commons., CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=1821346
By The original uploader was Iantresman at English Wikipedia – Transferred from en.wikipedia to Commons., CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=1821346

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.

2. IgG4-mediated autoimmune disorders

By Swharden - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=4752456
By SwhardenOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=4752456

This is a fairly new group of autoimmune disorders consisting of at least 13 different types. They are bad news because they cause many neurological disorders and also ravage other organs. I have previously discussed IgG4 peripheral neuropathy in my post titled What’s looming at the frontline of peripheral neuropathy. The other neurological diseases associated with IgG4 include, surprisingly, myasthenia gravis (MG), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and neuromyotonia. Less familiar IgG4 disorders are encephalopathyhypertrophic pachymeningitis and  sleep disorders with antibody to Iglon5. Trust the researchers to keep the clinicians ever on their toes.

3. GRIN-1 NMDA receptor encephalitis

DNA strand. Mehmet Pinarci on Flikr. https://www.flickr.com/photos/99843102@N05/14002600832
DNA strand. Mehmet Pinarci on Flikr. https://www.flickr.com/photos/99843102@N05/14002600832

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 impairmentintellectual disability, and eye movement disorders. This is reported in Neurology by Josep Dalmau and 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 

Medcraft B-24 MarkII ECT. Niall Williams on Flikr. https://www.flickr.com/photos/niftyniall/17654690751
Medcraft B-24 MarkII ECT. Niall Williams on Flikr. https://www.flickr.com/photos/niftyniall/17654690751

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.

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You may check out The Anti NMDA Receptor Encephalitis Foundation which is raising awareness of autoimmune encephalitis.

And here is a recent practical and comprehensive review of anti NMDA encephalitis by Eric Lancaster in the Journal of Clinical Neurology

And indulge me to make another shameless pitch here for neurochecklists which, after all, covers   autoimmune neurology comprehensively!

What are the dreadful autoimmune disorders that plague neurology?

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.

Prague. Pedro Szekely on Flikr. https://www.flickr.com/photos/pedrosz/3806301921
Prague. Pedro Szekely on Flikr. https://www.flickr.com/photos/pedrosz/3806301921

Neurologists are also comfortable with the knowledge that primary autoimmune disorders affect the nervous system. Prominent here are the neuropsychiatric features of systemic lupus erythematosus (SLE). SLE also presents with movement disorders such as chorea, amongst many other features. Similarly, there are diverse neurological manifestations of the anti-phospholipid antibody syndrome.

By Gentaur - Gentaur, Public Domain, https://commons.wikimedia.org/w/index.php?curid=7222221
By Gentaur – Gentaur, Public Domain, https://commons.wikimedia.org/w/index.php?curid=7222221

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.

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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:

  • Voltage gated potassium channel (VGKC)
  • N-methyl-d-aspartase (NMDA)
  • α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)

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).

 

B0007683 Ion channels. Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814248573
B0007683 Ion channels. Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814248573

 

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?

IgLON5: a new antibody disorder for neurologists

IgLON5 antibody syndrome first came to my attention in a paper from Lancet Neurology titled A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5. A passing phenomenon I thought, but added it to neurochecklists anyway.

Antibody by Gentaur (Gentaur) [Public domain], via Wikimedia Commons
Antibody by Gentaur (Gentaur) [Public domain], via Wikimedia Commons

I then came across another paper in Neurology 2015 expanding the phenotype titled Sleep disorder, chorea, and dementia associated with IgLON5 antibodies. And another paper from Journal of Immunology practically established this as a real, and not a phantom, phenomenon. The paper is titled Chorea and parkinsonism associated with autoantibodies to IgLON5 and responsive to immunotherapy.

polar-bear-614721_1280

So what is IgLON5? Well its a neuronal cell adhesion protein. Naturally. The key features of the syndrome are:

  • Parasomnia
  • Sleep-related breathing problems
  • Rapid eye movement (REM) sleep behaviour disorder
  • Chorea
  • Dementia
  • Parkinsonism

We are surely going to hear more of this antibody syndrome. Watch this space!

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