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?