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

 

Selumetinib

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

Imatinib

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

Sirolimus

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

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.

Revealing the invisible rhinoceros: paying attention to adult ADHD

Adult attention deficit hyperactivity disorder (ADHD) is a key psychiatric disorder. It is characterised by some core clinical features which are hyperactivity, inattention, impulsivity, disorganisation, and low stress tolerance. People with ADHD have several life impediments that characterise their day-to-day lives; these include difficulty starting tasks, struggling to prioritise, and failing to pay attention to details. Enduring chaotic lifestyles, they struggle to keep up with their academic, employment, and relationship commitments.

ADHD. Practical Cures on Flickr. https://www.flickr.com/photos/practicalcures/23280349432

For the public and for most physicians, ADHD is recognised only as a childhood disorder. But 10-60% of childhood onset ADHD persist into adulthood. Furthermore, about 4.5% of adults have ADHD. The failure to recognise ADHD as an adult problem therefore means it is easily missed in adult psychiatry and neurology clinics. Referring to this in a review published in the journal Psychiatry (Edgmont), David Feifel labelled adult ADHD as the invisible rhinoceros (you must read the article to understand why it is not the elephant in the room). Concerned that many adults with ADHD are misdiagnosed as suffering with anxiety or depression, he urged psychiatrists to routinely screen for adult ADHD in every adult presenting with these disorders.

Southern White Rhino. William Murphy on flickr. https://www.flickr.com/photos/infomatique/34467891470

The scale of the failure to diagnose adult ADHD was emphasised by Laurence Jerome in a letter to the Canadian Journal of Psychiatry. Titled Adult attention-deficit hyperactivity disorder is hard to diagnose and is undertreated, his letter highlighted the finding of the US ADHD National Comorbidity Survey which concluded that most adults with ADHD have ‘never been assessed or treated’. He argued that this oversight places heavy lifetime burdens on adults with ADHD such as impaired activities of daily living, academic underachievement, poor work record, marital breakdown, and dysfunctional parenting. A great burden indeed, but a preventable and treatable one!

ADHD. Bob on Flickr. https://www.flickr.com/photos/contortyourself/5016270276

How is all this psychiatry relevant to the general neurologist? Well, many manifestations of ADHD are the stuff of the neurology clinic. Cognitive dysfunction for example is prevalent in adult ADHD, and it may present to the neurologist as impaired short term memory, executive dysfunction, impaired verbal learning, and, of course, impaired attention. Sleep related disorders are also frequent in adult ADHD, and these include excessive daytime sleepiness (EDS), restless legs syndrome (RLS), periodic leg movements of sleep (PLMS), and cataplexy. There are also several other neurological co-morbidities of adult ADHD such as epilepsy and learning disability.

ADHD. Jesper Sehested on Flickr. https://www.flickr.com/photos/153278281@N07/38447999522

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It is therefore high time for neurologists and psychiatrists to reveal the invisible rhinoceros!

Putting cerebral malaria in the powerful spotlight

The blogosphere is a crowded place. To stand out from the pack, a lot of bustling and hustling takes place. Medical blogging is not exempt from this melee. However, in the zeal to put blog posts in the limelight, the blogger may inadvertently fixate on high profile diseases, the ones that seem to readily covet the headlines. In this way, deadlier but less ‘celebrity’ maladies are left to simmer and fester below the radar. To avoid falling into this trap, this blog endeavours, (every now and then), to shine a light on these clandestine infirmities. These are the plagues which profit by virtue of their anonymity. It is no surprise that many of these disorders are tropical diseases, and there is no sweltering equatorial beast more sinister than the ague. It is therefore in the interest of fairness and balance that we are putting cerebral malaria in the powerful spotlight.

Malaria in peripheral blood. Ed Uthman on Flickr. https://www.flickr.com/photos/euthman/6289093848

Malaria is a beast because it is endemic in many developing countries. The epidemiological map below gives a flavour of which countries receive the brunt of the miasm.

Von S. Jähnichenhttp://rbm.who.int/wmr2005/html/map1.htm and http://www.dtg.org/uploads/media/Malariakarte-DTG-2005_04.pdf, CC BY-SA 3.0, Link

Just like other parasitic infections, malaria undertakes a tortuous life cycle. It appears that it is in the nature of these scroungers to beguile and hoodwink their way to the human bloodstream. Scurrying and scampering, they transit from mosquito to man. It is to the credit of malaria-busters such as Ronald Ross that their deceptive course, pictured below, was revealed.

Life cycle of the malaria parasite. NIAID on Flickr. https://www.flickr.com/photos/niaid/20771605491

And a nasty monster is malaria. The different malaria species are transmitted by the female Anopheles mosquito (please don’t ask why). Finding warm veins irresistible, she sates her bloodthirsty cravings whilst  unknowingly transmitting the malaria buggers called sporozoites. Once they get to the liver, these transform into insatiable merozoites which are tasked with one hatchet job: detect, invade and destroy innocent hardworking red blood cells. OK, I admit that’s three hatchet jobs.

By NIAID – Malaria Parasite Connecting to Human Red Blood Cell, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=62117171

The plasmodium species vivax, ovale, and malariae can all wreak atrocious havoc, but it is falciparum that poses the greatest threat to the nervous system. This is partly because falciparum can make its host cells sticky, and in the brain, these sticky cells adhere tightly to the walls of blood vessels. This is how falciparum evades detection by the immune system, and how it escapes destruction by drugs. The sticky cells eventually clog up the cerebral circulation, resulting in the infamous malarial vasculopathy. Left untreated, cerebral malaria is sadly invariably fatal.

By Content Providers(s): CDC/James GathanyProvider Email: jdg1@cdc.govPhoto Credit: James Gathany – CDC http://phil.cdc.gov/PHIL_Images/09262002/00008/A.gambiae.1354.p_lores.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=745600

Cerebral malaria has diverse manifestations, and the most devastating include retinopathy, rigidity, ataxia (poor balance), subarachnoid haemorrhage, psychosis, hemiparesis, epilepsy, behavioural abnormalities, and coma. And this is over and above what malaria does to the other organs. The run down is very scary indeed; from anaemia to pulmonary edema, from hypoglycaemia (low glucose) to hyponatraemia (low sodium); from metabolic acidosis to hyperpyrexia (high fever), from disseminated intravascular coagulation (DIC) to adult respiratory distress syndrome (ARDS). Heartbreaking.

Malaria-infected red blood cell. NIH Image Gallery on Flickr. https://www.flickr.com/photos/nihgov/26834372607

The investigations of cerebral malaria range from the humble blood film to brain imagingTreatments include artemisinin derivatives and cinchona alkaloids. A malaria vaccine remains a dream, but not a far-off one; the RTS,S/AS01 vaccine is a promising candidate. Until this aspiration is achieved, the best hope against cerebral malaria remains prevention. The solutions are simple: basic sanitation, public education, and poverty alleviation. But the implementation seems to defy the wits of the great and the good. A lot of work remains to be done.

By Rick Fairhurst and Jordan Zuspann, National Institute of Allergy and Infectious Diseases, National Institutes of Health – https://www.flickr.com/photos/nihgov/25534997493/in/photolist-EUrx8t-CvR53a-B3Ad52-ydGygr-wZzPff-C5BN5H, Public Domain, https://commons.wikimedia.org/w/index.php?curid=49182050

Why not check out the following related posts in our other blog, Neurochecklists Updates:

The 8 most parasitic infestations of the nervous system

 

The 7 most ruthless bacterial infections of the nervous system

 

The 7 most devastating viral neurological infections

 

Standing up to the challenge of refractory epilepsy

In neurology, the word ‘refractory‘ is almost exclusively used in relation seizures. It may apply to drug-resistant epilepsy (DRE), or to rampaging status epilepticus.’Refractory’ doesn’t sound good in whatever context it is used, typically connoting a situation beyond redemption. But this is not the case with epilepsy. Rather than a bell tolling in despair, refractory is used in epilepsy as a bugle calling to arms.

Ask Not For Whom the Bell Tolls...Vicky Vinch ON/OFF on FLikr https://www.flickr.com/photos/91593630@N08/28095933065
Ask Not For Whom the Bell Tolls…Vicky Vinch ON/OFF on Flikr https://www.flickr.com/photos/91593630@N08/28095933065
 

Refractory epilepsy

If anyone was asked to imagine refractory epilepsy, they would surely picture a case that has failed to respond to the heavy arsenal of anti-epileptic drugs (AEDs). They would visualise a patient who has failed Lamotrigine, Carbamazepine, Valproate, and Levetiracetam. They would envisage subsequent failures with Zonisamide, Eslicarbazepine, Oxcarbazepine, and Lacosamide. They would clearly see a neurologist desperately hoping that the seizures would respond to the new AEDs on the block such as PerampanelBrivaracetam or Retigabine.

Hands of Desperation. Chris Kueh on Flikr. https://www.flickr.com/photos/chriskueh/2377817173
Hands of Desperation. Chris Kueh on Flikr. https://www.flickr.com/photos/chriskueh/2377817173

They would be very wrong. Rather than a failure of all AEDs, refractory epilepsy is defined by the International League Against Epilepsy (ILEA) as the failure of two well-chosen and tolerated AEDs. The chances of achieving seizure freedom in this situation are slim, and the sooner non-drug interventions are considered, the better. ‘Refractory’, in the context of epilepsy, is therefore a red flag for the neurologist to prevent years of juggling partially effective drugs. It is an early warning system to consider non-drug interventions such as surgery and neuromodulation. This point was strongly made in an article in European Neurological Review titled Treating Drug-resistant Epilepsy – Why are we Waiting? Well worth a read!

Red Flags on the Railway Line. Evelyn Simak on geograph. http://www.geograph.org.uk/photo/1572393
Red Flags on the Railway Line. Evelyn Simak on Geograph. http://www.geograph.org.uk/photo/1572393

Refractory status epilepticus

Refractory is also used in the context of status epilepticus where it describes the failure of two different anti-status medications. In this case, ‘refractory’ tells us that it’s time to use anaesthetic agents to put the patient to sleep, and essentially wait for things to settle. The real challenge comes when this strategy fails. What name do we give this conundrum that goes beyond refractory, and is there anything we can do about it?

By Vaikoovery - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=18416242
By Vaikoovery – Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=18416242

The experts ingeniously named this scenario super-refractory status epilepticus! And this super duper name doesn’t scare them from trying to treat it. In their enlightening and hope-raising critical review of super refractory status epilepticus, published in the journal Brain, epilepsy experts Simon Shorvon and Monica Ferlisi offer a surprisingly long list of interventions for super refractory status epilepticus. These include magnesium, steroids, IVIg, plasma exchange, hypothermia, the ketogenic diet, and Rufinamide. The review is a must-read for anyone who manages status epilepticus (or they could look up the condensed version in neurochecklists!)

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Wish to explore more? Why not check out

Should neurologists be thinking of Influenza H1N1?

Every now and then neurologists come across patients with what appears to be ‘straightforward’ viral encephalitis but who do not respond to conventional treatment. These treatments are usually according to established guidelines such as the ABN/BIAN guidelines, the IDS Guidelines. What to do when the patient isn’t responding is however very challenging.

Journal of Neuroinfectious Diseases (ssshh…the JNNP declined it) has just published our case report of such a patient who turned out to have H1N1 influenza encephalopathy. This experience suggests we should consider an autoimmune cause in such cases, especially if the spinal fluid does not show any viruses.

3D model of influenza virus
3D model of influenza virus

 

It’s only a single patient but with an excellent outcome and valuable insights (I would say so wouldn’t I!). It was rather fortuitous as her treatment with IVIg was on the assumption she had anti NMDA antibody encephalitis. Its not always in the science as the viral serology subsequently showed!

Is your interest piqued enough? OK, here is the link (and its open access):

H1N1 Associated Encephalopathy in an Adult: Response to Intravenous Immunoglobulin Supporting an Autoimmune Pathogenesis