What are the emerging treatments for neurofibromatosis?

Neurofibromatosis (NF) is one of the major neurocutaneous disorders neurologists see. These are disorders which primarily affect the nervous system and have prominent skin manifestations. Also known as phakomatoses, they are typified by abnormal growths and a variety of cancers. They include well-defined conditions such as tuberous sclerosis complex (TSC), Sturge-Weber syndrome (SWS), von Hipple Lindau disease (VHL), schwannomatosis, and the various PTEN hamartoma tumour syndromes. There are two types of neurofibromatosis, NF1 and NF2. NF2 is characterised by vestibular schwannomas, tumours arising from the sheath that encases the nerve that control balance, and by meningiomas, tumours of the covering of the brain.

By RadsWiki – RadsWiki, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3520114

NF1, also known as von Recklinghausen disease is, by far, the commoner form of neurofibromatosis. It is readily recognised on the skin by the frequently multiple and disfiguring nerve tumours called neurofibromas. Other benign skin lesions include the coffee-coloured skin lesions aptly called cafe-au-lait spots, armpit lesions called axillary freckles, and small lesions on the iris of the eyes called Lisch nodules. More sinister skin lesions called malignant peripheral nerve sheath tumours (MPNST) are, as the name implies, capable of spreading to other organs such as the lungs. Other sinister tumours in NF1 include gliomas of the brain and optic nerve, gastrointestinal stromal tumours (GIST) of the gut, and rhabdomyosarcomas of bone.

By Seiradcruz at English Wikipedia, CC BY-SA 3.0, Link

What can neurologists do for people with neurofibromatosis? Traditionally, nothing much apart from watchful waiting. We would monitor for the development of tumours by regular surveillance MRI scans of the brain and spine, and refer people with painful, compressive, or malignant lesions to the plastic surgeons or neurosurgeons to do what they do best, taking things out. Surgery may work fine for simple neurofibromas, but it is less practical for the complex or plexiform type. Thankfully, many neuroscientists are working hard, looking at different approaches to managing neurofibromas. To illustrate, below are 5 emerging treatments for neurofibromatosis. 

Bởi Klaus D. Peter, Gummersbach, GermanySelf-photographed, CC BY 3.0 de, Liên kết



In a 2016 paper in the New England Journal of Medicine, Eva Dombi and colleagues investigated the effect of selumetinib, an oral inhibitor of an enzyme called MAPK kinase (MEK) in 24 children with NF1. The paper, titled Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas, showed that selumetinib reduced the size of neurofibromas, and there was evidence that it improved pain and reduced disfigurement.

By Dimitrios MalamosOwn work, CC BY 4.0, Link


In a 2012 paper published in Lancet Oncology, Kent Robertson and colleagues, investigated the potential benefit of Imitanib, an inhibitor of the enzyme tyrosine kinase, in 36 people with NF1. The paper, titled Imitatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial, showed at least a 20% reduction in one or more plexiform neurofibromas.

By Department of Pathology, Calicut Medical College – Calicut Medical College, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=36652650


Brian Weiss and colleagues investigated the effect of sirolimus, an inhibitor of mTOR complex 1, in 46 people with NF1 and published their findings in the journal Neuro-Onclology. The paper, titled Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas, demonstrated that sirolimus prolonged the time to progression (TTP) of plexiform neurofibromas by about 4 months. A modest effect they admit, but nevertheless, a hope-raising effect.

By ajc3527 – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=59202851


Everolimus is already making waves in the treatment of various lesions in tuberous sclerosis complex, and it is not surprising that it has turned up here. In their paper titled Treatment of disfiguring cutaneous lesions in neurofibromatosis-1 with everolimus, published in the journal Drugs in R&D, John Slopis and colleagues reported that everolimus significantly reduced the surface volume of NF1 lesions, including plexiform neurofibromas. The authors were however cautious, calling for future studies to confirm these results. Unfortunately, one such study in the Journal of Investigational Dermatology poured cold water on the reported benefit of everolimus. The paper was titled Absence of Efficacy of Everolimus in Neurofibromatosis 1-Related Plexiform Neurofibromas: Results from a Phase 2a Trial. Hopefully future studies will be more favourable!

By MarinaVladivostokOwn work, CC0, Link

Pegylated interferon alfa-2b

Regina Jakacki and colleagues looked at the effect of pegylated interferon alfa-2b on plexiform neurofibromas and found a greater than doubling of their time to progression (TTP). Their paper is published in Neuro-Oncology, and it is titled Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas. As the authors studied a reasonable number of subjects, 84, and as the trial was placebo-controlled trial, this result is unlikely to be overturned by future trials…but only time will tell.

By Nevit Dilmen – Self created from PDB entry with Cn3D Data Source: https://www.ncbi.nlm.nih.gov/Structure/, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1308980


Therefore is clearly enough justification for hope in the search for a cure for neurofibromatosis.

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