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:

Resolving the treatment conundrums of CIDP

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is as complicated to articulate, as it is to manage. CIDP is the result of an inflammatory attack against myelin, the fatty layer that encases large nerves. The damage to the myelin sheath considerably slows down the speed at which nerves transmit electrical impulses. This leads to limb weakness, sensory impairment, and a host of other symptoms.

By Dr. Jana - http://docjana.com/#/saltatory ; https://www.patreon.com/posts/4374048, CC BY 4.0, Link
By Dr. Jana – http://docjana.com/#/saltatory ; https://www.patreon.com/posts/4374048, CC BY 4.0, Link

The diagnosis of CIDP is made on the basis of a clinical examination, nerve conduction studies (NCS), spinal fluid analysis, and countless blood tests. If this convoluted diagnostic process is hair-tearing, the treatment is even more perplexing.

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

There are 2 major CIDP treatment conundrums. The first is whether to start the treatment with steroids, or with intravenous immunoglobulins (IVIg). The second conundrum is what to do when the patient fails to respond to both of these first line CIDP treatments. Two recent papers have now come to the rescue, and they hope to settle, once and for all, these two major neurological puzzles.

1. Choosing steroids or IVIg as 1st line treatment

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

The first line treatment for CIDP is usually a toss-up between steroids and intravenous  immunoglobulins (IVIg). This is because neurologists had no way of telling who will do well on steroids, and who will respond to IVIg. Until now, that is. A recent report in the Journal of Neurology, Neurosurgery and Psychiatry (JNNP) set out to understand what patient characteristics predict response to IVIg. The authors studied >200 people with CIDP treated with IVIg, and reported that 1/4 did not respond. These IVIg non-responders had the following features:

  • The presence of pain
  • Association with other autoimmune diseases
  • A difference in the severity of weakness between the arms and the legs
  • The absence of anti-myelin associated glycoprotein (anti-MAG)

The authors conclude that people with CIDP who have the features above should start their treatment with steroids rather than IVIg. This surely beats tossing a coin.

2. Choosing rituximab as 1st line treatment

By Oguenther at de.wikipedia - Own work mit Jmol auf Basis RCSB PDB: 2OSL., Public Domain, Link
By Oguenther at de.wikipediaOwn work mit Jmol auf Basis RCSB PDB: 2OSL., Public Domain, Link

Choosing the 2nd line treatment of CIDP is comparatively easy; swap between IVIG and steroids, or go for plasma exchange (PE). Rituximab, a monoclonal antibody, is now also recognised as an effective treatment for CIDP. Conventional practice is to use this expensive treatment only when both IVIg and steroids fail. A recent paper however suggests that people with CIDP who also have IgG4 antibodies do not respond to either IVIg or steroids. On the bright side however, they do well when treated with Rituximab. The paper in the journal Neurology is titled Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins. The authors studied only 4 patients, but the number was enough for them to suggest that patients with CIDP, who also have IgG4 antibodies, should be treated with Rituximab. Makes sense to me, if the alternative is predictable failure.

Flash light. Steve Johnson on Flikr. https://www.flickr.com/photos/artbystevejohnson/5202597852
Flash light. Steve Johnson on Flikr. https://www.flickr.com/photos/artbystevejohnson/5202597852

Now that some light has been shone on the treatment of CIDP, the next stage is to see how things work at the coal face. Do you have any feedback on CIDP treatment? Please leave a comment.

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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

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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

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What are the advances in the management of cluster headache?

Cluster headaches are nasty, excruciatingly severe, headaches. They are not called suicide headaches without good reason. Cluster headaches are typically one-sided, localised around the orbit. The eye on the affected side classically turns red and waters. The nostril follows suit by either running or blocking up. The episodes last between 45 minutes to 3 hours during which the hapless victims pace up and down, feeling like smashing their heads against a concrete wall. Relief is short-lasting because the headache cycle repeats itself several times a day, for weeks and months on end. People with episodic cluster headaches may go several months without headaches, but those with the chronic form are not afforded this luxury.

Lego splitting headache. Matt Brown on Flikr. https://www.flickr.com/photos/londonmatt/15191073177
Lego splitting headache. Matt Brown on Flikr. https://www.flickr.com/photos/londonmatt/15191073177

Treatment of cluster headache is typically three-pronged: acute treatment with triptansintermediate prevention with oral steroids; and prevention with verapamil. OK, I over simplify. Each of these strategies has 2nd, 3rd, and 4th line options. Verapamil, the cornerstone of treatment, comes with significant risks to the heart. And in extreme cases, invasive measures are called upon to save the day.

By Hansjorn - το :Αρχείο:Poseidon sculpture Copenhagen 2005.jpg, CC BY-SA 3.0, Link
By Hansjorn – το :Αρχείο:Poseidon sculpture Copenhagen 2005.jpg, CC BY-SA 3.0, Link

Unfortunately all these treatments fail miserably more often than we like to admit. Even invasive treatments are not always successful in cluster headaches. Neurologists and patients alike are therefore always on the lookout for developments which will improve the understanding and management of cluster headaches. And, thankfully, there are a few.

A. Abnormal tyrosine metabolism and cluster headache

By No machine-readable author provided. Benjah-bmm27 assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims)., Public Domain, Link
By No machine-readable author provided. Benjah-bmm27 assumed (based on copyright claims). – No machine-readable source provided. Own work assumed (based on copyright claims)., Public Domain, Link

The sad fact about cluster headache is, nobody knows what causes it. We know it is due to some malfunction of the autonomic nervous system, and to the trigeminal, or fifth, cranial nerve. This is why it is called a trigeminal autonomic cephalalgia. We know that it favours men who smoke. Beyond this we are rather clueless. It is therefore with high hopes that I read about abnormal tyrosine metabolism in chronic cluster headache, in the journal Cephalalgia. The authors report that people with cluster headaches have high levels of the products of tyrosine metabolism in their blood, such as dopamine, noradrenaline, and tyramine. If this turns out to be confirmed, it may open the way to the development of newer and more effective treatments for this painful condition.

B. Heart monitoring on verapamil

https://pixabay.com/en/pulse-trace-healthcare-medicine-163708/
https://pixabay.com/en/pulse-trace-healthcare-medicine-163708/

The heart is at risk whenever people are put on verapamil. This is because it may induce abnormal and dangerous heart rhythms. It is therefore important to check the electrocardiogram (ECG) of people on verapamil. Guidelines suggest checking the ECG before starting, 10 days after starting, and before each dose increment. It was therefore disconcerting that a recent study, published in the journal Neurology, found that 40% of people on verapamil never had any form of heart monitoring. The paper, titled electrocardiographic abnormalities in patients with cluster headache on verapamil therapy, is an audit of >200 people with cluster headaches on high dose verapamil. In those who had cardiac monitoring, the authors found ECG abnormalities in more than 50%, some very significant and life threatening. A similar finding was reported in an older study published in the Journal of Headache and Pain, titled cardiac safety in cluster headache patients using the very high dose of verapamil (≥720 mg/day). Worrying! Time to take ECG monitoring more seriously in people on verapamil. 

C. New preventative drug options

By Stomac - Own work, CC BY-SA 2.0 fr, Link
By StomacOwn work, CC BY-SA 2.0 fr, Link

Besides verapamil, there are many other options for cluster headache prevention. The list is quite long, and this is the case whenever we are uncertain of what else really works. That is why I was relieved to see a recent guideline on treatment of cluster headaches touting new evidence to guide neurologists. Published in the journal Headache, it is titled Treatment of Cluster Headache: The American Headache Society Evidence-Based Guidelines. This guideline establishes that lithium is effective in preventing cluster headache, but valproate is probably ineffective. More importantly, the guidelines introduce new effective preventative agents such as civamide nasal spray, melatonin, and warfarin. For transitional prevention, occipital nerve injection comes through with glowing tributes. Progress, surely!

D. Neurostimulation for cluster headache

By C. Clark - NOAA Photo Library (direct), NOAA Central Library; OAR/ERL/National Severe Storms Laboratory (NSSL), Image ID: nssl0010, Public Domain, Link
By C. Clark – NOAA Photo Library (direct), NOAA Central Library; OAR/ERL/National Severe Storms Laboratory (NSSL), Image ID: nssl0010, Public Domain, Link

It is no longer surprising to find neurostimulation cropping up in the treatment of any neurological disorder. And cluster headache is no exception. The most effective agent, according to the latest guidelines, is sphenopalatine ganglion stimulation. It now ranks very high in the acute treatment of cluster headache, even if less effective than the good old, conventional acute treatments which are subcutaneous sumatriptan, intransal zolmitriptan, and 100% oxygen. Neurostimulation is also likely to play a future preventative role in cluster headaches, and the candidates here are invasive and non-invasive vagus nerve stimulation. We are waiting with bated breaths!

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For more on vagus nerve stimulation, you may check out my previous post titled Vagus nerve stimulation: from neurology and beyond!

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What is the startling research unsettling the treatment of myasthenia gravis?

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.

Little red pills. Jon nagl on Flikr. https://www.flickr.com/photos/jonnagl/2470078845
Little red pills. Jon nagl on Flikr. https://www.flickr.com/photos/jonnagl/2470078845

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.

By NLM - NLM Pillbox, http://pillbox.nlm.nih.gov/assets/large/000040lg.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=14666931
By NLM – NLM Pillbox, http://pillbox.nlm.nih.gov/assets/large/000040lg.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=14666931

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.

By Fdardel - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15465576
By Fdardel – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15465576

 

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.

By Oguenther at de.wikipedia - Own work mit Jmol auf Basis RCSB PDB 2OSL., Public Domain, https://commons.wikimedia.org/w/index.php?curid=15482243
By Oguenther at de.wikipedia – Own work mit Jmol auf Basis RCSB PDB 2OSL., Public Domain, https://commons.wikimedia.org/w/index.php?curid=15482243

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.

 

 

Advances in the management of giant cell arteritis

Giant cell arteritis (GCA), or temporal arteritis, is an affliction of older people. It results in headache and, more worryingly, blindness and stroke.

By Henry Vandyke Carter - Henry Gray (1918) Anatomy of the Human Body (See "Book" section below)Bartleby.com: Gray's Anatomy, Plate 508, Public Domain, https://commons.wikimedia.org/w/index.php?curid=541352
By Henry Vandyke CarterHenry Gray (1918) Anatomy of the Human Body (See “Book” section below)Bartleby.com: Gray’s Anatomy, Plate 508, Public Domain, https://commons.wikimedia.org/w/index.php?curid=541352

 

The diagnosis of GCA is a clinical one. GCA diagnostic criteria stipulate, amongst other things, onset over the age of 50 years, and inflammation in the blood. A temporal artery biopsy may help to firm up the diagnosis. This is however not always readily available, and often falsely negative. Treatment with steroids is imperative to prevent sudden and irreversible visual loss.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=37300811
By NephronOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=37300811

 

Not much has changed in the world of giant cell arteritis since I was in medical school. Or so I thought. I couldn’t be more wrong. Here are 3 advances challenging the old order in the management of GCA.

 

1. Antiviral treatment

Varicella zoster virus. NIAID on Flikr. https://www.flickr.com/photos/niaid/5614251360
Varicella zoster virus. NIAID on Flikr. https://www.flickr.com/photos/niaid/5614251360

The cause of GCA is a mystery. One suspect is varicella zoster virus (VZV), of shingles fame. As shingles is also a disease of older people, it is no surprise that some researchers suspected a link between VZV and GCA. Writing in the Journal of Infectious Diseases in a paper titled Varicella Zoster Virus in Temporal Arteries of Patients With Giant Cell Arteritis, the authors detected VZV in the arteries of people with GCA, but did not pick up even a scent of VZV in control subjects who did not have GCA.

Another paper which strengthened the bond between GCA and VZV is in JAMA Neurology titled Analysis of Varicella-Zoster Virus in Temporal Arteries Biopsy Positive and Negative for Giant Cell Arteritis. The authors of this study found VZV in the temporal arteries of 119 subjects with GCA. On the strength of this finding, the authors suggest GCA should be treated with anti-viral drugs. I am picking up the scent of a guideline on the way.

2. Monoclonal antibodies

B0007277 Monoclonal antibodies 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

 

Some researchers, obviously uncomfortable with antiviral drugs, have looked elsewhere for ways to improve the treatment of GCA. And they found a champion in the monoclonal antibody Toclizumab. They published their findings in the Lancet under the title Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. The authors showed that adding Toclizumab to steroids in people with GCA led to sustained remission in 85% of cases; only 40% of the people on placebo achieved remission. I didn’t smell a rat here; the evidence seems quite convincing.

3. PET scan imaging

By Hg6996 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18889860
By Hg6996Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18889860

 

Temporal artery biopsy is hit and miss because GCA is a patchy process. Furthermore, biopsy is invasive and despised by doctor and patient equally. Ever keen to make things painless, doctors have looked at imaging of the artery as a substitute to biopsy. The imaging modalities on the cards include duplex ultrasound and magnetic resonance imaging (MRI). The prize must, however, go to positron emission tomography (PET) which has great potential as indicated in this review of PET scan in GCA. This suggests that PET scan aids the diagnosis, grading, and follow-up of GCA. Additionally, PET scan also identifies inflammation in other blood vessels. I perceive the end of the days of temporal artery biopsy!

 

Are steroids detrimental to survival in brain tumours?

As I update neurochecklists I come across some papers which make me go, ‘really!’ Such studies challenge established theories and threaten conventional practice. Such is the case with a recent paper in Brain titled, unequivocally, Corticosteroids compromise survival in glioblastoma.

By Christaras A - Created myself from anonymized patient MR, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=1247035
By Christaras A – Created myself from anonymized patient MR, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=1247035

Glioblastoma is the worst form of primary brain tumour, and survival is already poor. Treatment is usually palliative with debulking surgery and radiotherapy. Dexamethasone, a corticosteroid, effectively reduces the swelling or oedema that the tumour evokes around it. Corticosteroids are therefore often the first treatment for glioblastoma because they  almost immediately improve symptoms such as reduced consciousness, headache, and visual blurring.

By LHcheM - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18648311
By LHcheMOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18648311

It is, therefore, surprising when a study suggests that corticosteroids cause harm. But this is no ordinary study; it is a classic bench-to-bedside research which looked at patients with glioblastoma, and then devised a mouse model to study the real impact of steroids on the tumour.

By Jensflorian - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11814552
By JensflorianOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11814552

 

The authors show that a ‘ dexamethasone-associated gene expression signature correlated with shorter survival’. They pass the verdict that corticosteroids are detrimental to survival and urge caution when prescribing dexamethasone.

hope-1220981_1920

You may be feeling a bit low after reading. You may, however, lift your spirits by reading my previous posts titled maggots, viruses and lasers: some innovations for brain tumours and calming the rage of brain tumours.

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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 strange things about IBM leave neurologists puzzled?

Inclusion body myositis (IBM) is classified as an inflammatory muscle disease. It however stands out from all other muscle diseases, inflammatory or not. IBM has quite unique, and often unexplained, characteristics. These features mark it out as an enigma, and the mystery deepens the more neurologists research it.

Puzzled. andy.brandon50 on Flikr. https://www.flickr.com/photos/54027476@N07/4999919941
Puzzled. andy.brandon50 on Flikr. https://www.flickr.com/photos/54027476@N07/4999919941

IBM continues to throw up new and challenging riddles for neurologists, and here are my 6 puzzling things about IBM.

6. Unique muscle distribution

Muscle diseases in adults almost always start in the upper or proximal parts of the limbs. IBM however bucks the trend with a specific predilection for muscles of the middle part of the limbs, the knee extensors in the legs, and the long finger flexors in the arms. This unique pattern of muscle involvement results in a characteristic or pathognomonic clinical picture of IBM: marked wasting of the muscles of the forearms, and of the quadriceps. People with IBM therefore complain of a weak grip, and a tendency to fall. The reason for this unique muscle specificity has me dumbfounded.

5. Unusual muscle biopsy features

By Jensflorian - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11763608
By JensflorianOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11763608

 

The classical inflammatory muscle diseases are polymyositis (PM) and dermatomyositis (DM), and the inflammation in these conditions is easily detected on muscle biopsy. This is however not the case with IBM which shows very little inflammation, and this paucity of inflammation underlies IBM’s unresponsiveness to anti-inflammatory treatment with steroids. IBM muscle biopsy specimens however show typical eosinophilic cytoplasmic inclusions and rimmed vacuoles. The unwary neuropathologist however easily misses these specific but elusive landmarks, making IBM notoriously difficult to diagnose, or worse still, easily misdiagnosed as PM or DM.

4. Association with strange bedfellows

IBM is typically an isolated disease, preferring to roam in solitude. Or so I thought until I came across a paper in Neurology which introduced me to the concept of multisystem proteinopathy. This is the association of IBM with Paget’s disease of the bone (PDP), motor neurone disease (MND), or frontotemporal dementia (FTD). Why IBM should associate with these strange and unrelated diseases leaves me totally baffled.

3. Genetic underpinnings

jeans for genes. susan on Flikr. https://www.flickr.com/photos/certified_su/3803103894
jeans for genes. susan on Flikr. https://www.flickr.com/photos/certified_su/3803103894

 

Neurologists like to keep the geneticists busy with every disease they study, and IBM is no exception. It is not clear exactly when, how or why neurologists went gene-hunting in a condition that is typically sporadic. But hunt they did, and their perseverance paid off; we now know that IBM may also be hereditary or familial. And the genetic spectrum of IBM continues to grow. Take this paper in Neurology Genetics which reports two families with abnormalities in the hnRNPA1 gene. Another genetic association of IBM is GNE. To muddy things up a bit more, IBM has been linked to HLA-DRB1*03. Why any disease should decide to have sporadic and genetic forms leaves me very befuddled.

2. Association with hepatitis C virus (HCV)

By HCV_pictures.png: Maria Teresa Catanese, Martina Kopp, Kunihiro Uryu , and Charles Ricederivative work: TimVickers (talk) - HCV_pictures.png, Public Domain, https://commons.wikimedia.org/w/index.php?curid=10903740
By HCV_pictures.png: Maria Teresa Catanese, Martina Kopp, Kunihiro Uryu , and Charles Ricederivative work: TimVickers (talk) – HCV_pictures.png, Public Domain, https://commons.wikimedia.org/w/index.php?curid=10903740

 

Just when you start adjusting your mindset to a disease that may be genetic, sporadic and inflammatory, the neurologists do it again. This time in cahoots with the infectious disease specialists. They ask you once more to adjust your mindset, and see IBM as a possible fallout of a viral invasion, the culprit here being hepatitis C virus (HCV). Writing in Neurology, the authors boldly suggest a possible pathomechanistic link between the 2 conditions. Mindset tuning in progress.

1. Autoimmune pathogenesis

Immune cell detects disease. Welcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/16233121363/in/photolist-qJsZqP
Immune cell detects disease. Welcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/16233121363/in/photolist-qJsZqP

 

Just before you lose it all, the neurologists take you gently back to familiar territory, autoimmunity. But even here there are strange undertones. The autoimmune antibody associated with IBM is rather unique, as you have now learnt to expect. The reported association of anti cN-1A and IBM comes from the Annals of the Rheumatic Diseases, letting the neurologist off this time. The authors looked at autoantibodies to cytosolic 5′-nucleotidase 1A in sporadic IBM. The significance of the association is still not clear. One thing is however obvious-neurologists need to start working on the reasons they will give to their immunologists to justify sending off that blood sample for anti cN-1A. I foresee a drawn-out battle!

1_________0____________1____________0___________1___________0

These and many other things go to show why IBM is such a conundrum for neurologists. It has the neurologists vigorously scratching their heads, wishing for an enigma cipher machine. In the meantime all they can do is assure their patients of the therapeutic advances in IBM. As with all mysteries however, it shall all be revealed in time… and neurologists and their patients will be all smiles!

smiley. susan on Flikr. https://www.flickr.com/photos/certified_su/3802633000/in/photostream/
smiley. susan on Flikr. https://www.flickr.com/photos/certified_su/3802633000/in/photostream/

 

How is neurology stamping out the anguish of Duchenne?

Duchenne muscular dystrophy (DMD) is the most familiar of the inherited muscle diseases called muscular dystrophies. DMD is life limiting, but advances in care are enabling children born with this disease to survive well into adulthood. The disease is named after the French neurologist Guillaume Duchenne.

See page for author [CC BY 4.0], via Wikimedia Commons
See page for author [CC BY 4.0], via Wikimedia Commons

The foundation of long survival in DMD is close supervision of breathing and heart functions. DMD however affects much more than these vital functions, and it remains a challenging disease for families and management teams. Thankfully researchers are not resting on their laurels, working ever hard on heart-warming advances. Here are three.

STEROIDS

By Ring0 (Own work) [Public domain], via Wikimedia Commons
By Ring0 (Own work) [Public domain], via Wikimedia Commons
Steroids are now well-established in the treatment of Duchenne muscular dystrophy. What is new however is a better understanding of their benefits in DMD, together with clearer guidance on their use. This is contained in the recent practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy.

Published in the journal Neurology, this document shows how steroids help to improve muscle strength, maintain breathing functions, stabilise ambulation, prevent spinal deterioration (scoliosis), and delay onset of heart disease.

Is there more one could hope for? Yes, a lot more when it comes to genetic diseases.

IDEBENONE

Mitokondria. 140264jd on Flikr. https://www.flickr.com/photos/140264jd/6286783453/in/photostream/
Mitokondria. 140264jd on Flikr. https://www.flickr.com/photos/140264jd/6286783453/in/photostream/

 

Idebenone is not new to neurologists. Researchers at Newcastle have been investigating its vision-preserving effect in the mitochondrial disease called Leber’s hereditary optic neuropathy (LHON). Idebenone is thought to improve the activity of mitochondria, the energy-producing component of all cells. Idebenone has also been investigated in other neurological disorders such as Friedreich’s ataxia.

Perhaps as an indication of its growing importance, researchers have now looked at the effect of Idebenone in people with DMD, and they did this in two separate trials. DELPHI is published in the journal Neuromuscular Disorders as Idebenone as a novel, therapeutic approach for Duchenne muscular dystrophy. The authors reported benefit in both cardiac and respiratory function.

DELOS, the second trial, is published in Lancet Neurology and titled Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids. The authors again reported similar benefits. For a synthesised take, see this useful review in Touch Neurology.

But is this enough for ambitious researchers? Of course not…not when you see the promise of gene editing.

GENE EDITING

Jazz Mouse. Richard Scott on Flikr. https://www.flickr.com/photos/richardmscott/2091183925
Jazz Mouse. Richard Scott on Flikr. https://www.flickr.com/photos/richardmscott/2091183925

 

I first came across this in Eureka Alert which proclaimed: Gene-editing technique successfully stops progression of Duchenne muscular dystrophy. The gene editing, or gene splicing, technique is called CRISPR. The research itself is published in the journal Science as In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy.

The researchers used CRISPR technology to delete exon 23 from the Duchenne gene on the X chromosome. Exon 23 is the site of the fault that makes DMD patients unable to produce the muscle protein called dystrophin. By splicing this exon out, the researchers demonstrated an increase in the production of dystrophin. And this increase was significant enough to lead to an improvement in muscle strength.

OK, its only the humble mouse at the moment, but exon skipping therapy is clearly beckoning.

B0007267 Muscle Fibers. Welcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814145089
B0007267 Muscle Fibers. Welcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814145089