5 exciting developments in the management of Wilson’s disease

In all fairness, neurologists only very rarely come across patients with Wilson’s disease. This disorder of excessive copper deposition in tissues is however not vanishingly rare. And because it is one of the few curable neurological disorders, it is drummed into the brain of every neurologist to consider Wilson’s disease in any person, at any age, with any movement disorder. Dystonia is probably the most characteristic movement disorder in Wilson’s disease, and one of its classical signs is rhisus sardonicus, a fixed vacuous smile (which, by the way, may also be seen in tetanus). Other movement disorders of Wilson’s disease include parkinsonism, wing-beating tremor, ataxia, myoclonus, chorea, athetosis, stereotypies, tics, and restless legs syndrome. It is therefore not surprising that the disorder is named after one of neurology’s greats, Samuel Alexander Kinnier Wilson.

By Carl Vandyk – Carl Vandyk, Public Domain, https://commons.wikimedia.org/w/index.php?curid=11384670

The other name for Wilson’s disease is hepatolenticular degeneration. ‘Lenticular’ in this context refers to the favoured brain targets of Wilson’s disease, the lentiform nuclei. These are the putamen and globus pallidus, which, along with the caudate nucleus, make up the basal ganglia. The basal ganglia are very important in the coordination of movement, and are also dysfunctional in disorders such as Huntington’s disease and Parkinson’s disease.

By Niubrad at the English Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19495297

Wilson’s disease is however more than a brain disorder because it is, quintessentially, multi-systemic. The monicker hepatolenticular, for example, hints at the prominent and varied involvement of the liver in Wilson’s disease. Liver dysfunction here ranges from mild elevation of liver enzymes, to frank hepatic failure requiring liver transplantation. The eye is another important organ targeted by Wilson’s disease, and the neurologist is ever searching for the tell-tale but elusive Kayser-Fleischer ring. This is a brownish tinge seen around the iris caused by copper deposition, and named after the German ophthalmologists Bernhard Kayser and Bruno Fleischer. Another distinctive eye sign in Wilson’s disease is the sunflower cataract. The long reach of Wilson’s disease however extends to almost every organ system.

By Herbert L. Fred, MD, Hendrik A. van Dijk – http://cnx.org/content/m15007/latest/, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=2746925

Wilson’s disease is all about the ‘C’ words. The first ‘C’, Copper, is of course the essential element recognised as Cu, with atomic number 29, and snugly occupying group 4 in the periodic table. An autosomal recessive genetic mutation in ATP7B, the copper transporter gene, means some people are unable to move copper around the body. It therefore accumulates, and is eventually deposited, in almost every organ. Oh, and it also overflows in high amounts in urine.

Copper crystals. James St John on Flickr. https://www.flickr.com/photos/jsjgeology/17127538489

The other ‘C’ word is Ceruloplasmin, the blood protein that binds up the dangerous free-floating copper in the blood. The blood level of ceruloplasmin is low in Wilson’s disease because it is overwhelmed by the massive amounts of copper. The classical laboratory features of Wilson’s disease are therefore raised blood copper, low blood ceruloplasmin, and elevated 24 hour urinary copper excretion. The diagnosis of Wilson’s disease may also involve a liver biopsy to confirm copper accumulation, but this is rarely required. Long-term treatment depends on one of several therapeutic options for chelating or binding copper. Surveillance requires a tight monitoring regime to monitor the metabolic profile of the disease, and the complications its treatment.

By own work – adapted from http://www.pdb.org/pdb/files/1kcw.pdb using PyMOL, Public Domain, https://commons.wikimedia.org/w/index.php?curid=4982229

Is it however not all and dusted for Wilson’s disease. Not at all. There are advances being made to simplify the diagnosis and monitoring of this devastating disease, and below are 5 exciting developments in the management of Wilson’s disease.

Exchangeable copper

I learnt of this from a paper published in the European Journal of Neurology titled Exchangeable copper: a reflection of the neurological severity in Wilson’s disease. The authors, Aurelia Poujois and colleagues, investigated this new technique of measuring exchangeable copper (CuEXC) as an aid to the diagnosis of Wilson’s disease, and as an indicator of the severity of extra-hepatic damage. They studied 48 newly diagnosed subjects and found that CuEXC is a reliable test for making the diagnosis, and a cut-off value of >2.08 μmol/l is a marker of severe organ damage. Other papers have confirmed the value of exchangeable copper, even if they call it relative exchangeable copper.

By Alchemist-hp (pse-mendelejew.de) – Own work, CC BY-SA 3.0 de, https://commons.wikimedia.org/w/index.php?curid=6958463

X-ray fluorescence

Slávka Kaščáková and colleagues, in their paper published in the journal Pathology, touted X-ray fluorescence as a rapid way to quantify copper in tissues, thereby facilitating the diagnosis of Wilson’s disease. The rather technical paper, titled Rapid and reliable diagnosis of Wilson disease using X-ray fluorescence, describes the technique as ‘high‐resolution mapping of tissue sections’ which enables the measurement of ‘the intensity and the distribution of copper, iron and zinc while preserving the morphology’. This technique can, we have to accept, reliably distinguish Wilson’s disease from other diseases such as haemochromatosis and alcoholic cirrhosis. Not a bad deal, but the squeamish neurologist must realise it requires a liver biopsy!

X-ray Fluorescence Analyzer. IAEA Imagebank on Flickr. https://www.flickr.com/photos/iaea_imagebank/30483472557

Quantitative transcranial ultrasound

The typical method of ‘seeing’ the brain abnormalities of Wilson’s disease is by magnetic resonance imaging (MRI). Ultrasound is however much cheaper and easier, and would be a preferable option if it can be shown to be sensitive and specific. And this is what Gotthard Tribl and colleagues demonstrated in their paper published in the Journal of Neurological Sciences titled Quantitative transcranial sonography in Wilson’s disease and healthy controls: cut-off values and functional correlates. They reported that in Wilson’s disease, the lenticular nuclei (we are familiar with this now) and substantia nigra (literally a black substance in the midbrain) are hyperechogenic compared to normal control subjects. They also came up with reliable cut-off for normality. To make things better, the thalami and midbrain are also hyperechogenic. And to add the cherry on top, the third ventricle is enlarged. More than expected from a rather simple technology.

CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=19500021

Optical coherence tomography (OCT)

Hardly a day goes by that one doesn’t read a report on the applicability of optical coherence tomography (OCT) in one neurological disorder or the other. And Wilson’s disease is clearly not going to be the exception. OCT simply assesses the thickness or density of the retinal nerve fiber layer (RNFL), and this is reduced in many neurodegenerative diseases. In their paper titled Optical coherence tomography as a marker of neurodegeneration in patients with Wilson’s diseaseEwa Langwińska-Wośko and colleagues studied 58 subjects with Wilson’s disease. They reported that OCT can reliably measure the severity of Wilson’s disease, and it may reliably monitor disease progression. Another simple and non-invasive tool with big potential. 

Optical coherence tomography of my retina. Brewbooks on Flickr. https://www.flickr.com/photos/brewbooks/8463332137

Bis-choline tetrathiomolybdate

The treatment of Wilson’s disease centres on chelation or binding of copper. And the three major players here are  Penicillamine, Trientine, and Zinc, each with its own unique advantages and serious complications. They are however all rather cumbersome and inconvenient to administer and monitor. Into this unsatisfactory situation enters a study which promises to ease the burden for neurologist and patient. The trial is titled Bis-choline tetrathiomolybdate in patients with Wilson’s disease: an open-label, multicentre, phase 2 study, and it is published in the journal Lancet Gastroenterology and Hepatology. The authors, Karl Heinz Weiss and colleagues, investigated bis-choline tetrathiomolybdate (nicknamed WTX101), which they described as ‘an oral first-in-class copper-protein-binding molecule’. It binds up copper that is either stuck in the liver or swimming freely in blood. 70% of the 28 subjects they treated met the criteria for treatment success, and they were not unduly bothered by any nasty side effects. To add to this favourable profile, WTX101 has the convenience of a once daily dosing regime.

By I, Jonathan Zander, CC BY-SA 3.0, Link

 

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It is reassuring that so much as happening at the cutting edge of Wilson’s disease, and neurologists can’t wait to see when these will form part of their armamentarium.

Do statins really increase the risk of Parkinson’s disease?

Statins are famous, and their fame lies in their ability to bust cholesterol, the villain in many medical disorders such as heart attack (myocardial infarction) and stroke. Some may add that statins are infamous, and this is partly because of their side effects such as muscle pain. Love them or hate them, we can’t get away from statins…even as the debate rages about their benefits and downsides.

By ChiltepinsterOwn work, CC BY-SA 3.0, Link

It is not surprising therefore that the statin debate will filter into neurology. The sticking point here however has nothing to do with cholesterol busting, but all to do with whether statins increase or reduce the risk of developing Parkinson’s disease (PD). Strange as it may seem, statins and PD have a long history. And a positive one generally, I hasten to add. There is a large body of evidence to suggest a protective effect of statins on PD as reflected in the following studies:

  1. Confounding of the association between statins and Parkinson disease: systematic review and meta-analysis 
  2. Statin therapy prevents the onset of Parkinson disease in patients with diabetes
  3. Statin use and risk of Parkinson’s disease: A meta-analysis 
  4. Statin use and its association with essential tremor and Parkinson’s disease
  5. Statin use and the risk of Parkinson’s disease: an updated meta-analysis
  6. Long-term statin use and the risk of Parkinson’s disease
  7. Discontinuation of statin therapy associated with Parkinson’s disease
Modeling the Molecular Basis of Parkinson’s Disease. Argonne National Laboratory on Flikr https://www.flickr.com/photos/argonne/4192798573

It was therefore with some consternation that a recent study, published in the journal Movement Disorders, really put the cat among the pigeons. The paper is titled:

Statins may facilitate Parkinson’s disease: insight gained from a large, national claims database,

The authors of this paper set out to investigate ‘the controversy surrounding the role of statins in Parkinson’s disease’. In this retrospective analysis of over 2,000 people with PD, and a similar number of control subjects, the authors found that statins significantly increased the risk of developing PD. This is clearly a conclusion looking for a fight!

By Col. Albert S. Evans – internet archives, Public Domain, Link

I must admit I was totally unaware there was any controversy about statins and PD. I was therefore curious to find out what studies are out there fuelling it. Which other trials have bucked the trend and reported an increased risk of PD from statins? And where best to find the answers but in PubMed, the repository of all human knowledge! And I found that there were only a few studies that did not report a protective effect of statins on PD, and these studies concluded, quite reasonably, that they found no relationship between PD and statins. Here are a few of the studies:

  1. Statin adherence and the risk of Parkinson’s disease: A population-based cohort study. 
  2. Use of statins and the risk of Parkinson’s disease: a retrospective case-control study in the UK. 
  3. Statin use and the risk of Parkinson disease: a nested case control study. 

These papers reporting the absence of evidence seem happy to engage in an amicable debate to resolve the question.

By DavidKF1949Own work, CC BY-SA 3.0, Link

One study however stood out like a sore thumb because it positively reported a negative effect of statins on PD (try and work that out!). This 2015 study, also published in Movement Disorders, is titled Statins, plasma cholesterol, and risk of Parkinson’s disease: a prospective study. The paper concludes that “statin use may be associated with a higher PD risk, whereas higher total cholesterol may be associated with lower risk“. Not only are the authors arguing that statins are bad for PD, they are also suggesting that cholesterol is good! This is a paper that was itching for fisticuffs.

By Jan SteenWeb Gallery of Art:   Image  Info about artwork, Public Domain, Link

What is a jobbing neurologist to do? What are the millions of people on statins to do? Whilst awaiting further studies, I will say stay put. Go with the bulk of the evidence! And keep track of The Simvastatin Trial, funded by The Cure Parkinson’s Trust. This trial is looking at the benefit of statins in slowing down PD. And surely, very soon, the science will lead to a resolution of the argument-all you need to do is keep track of everything PD in Neurochecklists.

By Léon Augustin Lhermittehttp://wellcomeimages.org/indexplus/obf_images/fc/7f/643258ab30237374aaea5ac15757.jpgGallery: http://wellcomeimages.org/indexplus/image/L0006244.html, CC BY 4.0, Link

 

What are the obstacles to creating reliable neurology checklists?

This is a follow up to my previous blog post on the value of checklists in medical practice. That post explored how checklists improve clinical practice and promote patient safety. It also cited Atul Gawande‘s call to Medicine to “seize the opportunity” and produce checklists for all aspects of clinical practice.

Neurology. MV Maverick. https://www.flickr.com/photos/themvmaverick/11396461045
Neurology. MV Maverick. https://www.flickr.com/photos/themvmaverick/11396461045

 

Picking up this gauntlet for neurology comes with peculiar challenges. Here are the 7 hurdles to overcome.

1. The challenge of a diverse specialty

Legume diversity. Global Crop Diversity Trust on Flikr. https://www.flickr.com/photos/croptrust/3594324633
Legume diversity. Global Crop Diversity Trust on Flikr. https://www.flickr.com/photos/croptrust/3594324633

Neurology consists of an astonishing diversity of sub-specialities. Any neurology checklist must exhaustively cover the major neurological categories such as stroke, epilepsy, movement disorders, headache, dementia, neuromuscular diseases, sleep disorders, neuro-inflammation, nervous system tumours, and neurological infections. These topics must be thoroughly covered with emphasis on their clinical features, investigations, and treatments. A useful database must also include rare neurological diseases, of which neurology has quite a few. This is reflected in my previous blog on the most perplexing diseases that excite neurologists.

2. The challenge of multiple associated specialties

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Neurological disorders cut across many diverse allied neurological specialties. Any dependable checklist database must cover these specialised fields which include neurosurgery, neuroradiology, neuroophthalmology, neuropsychiatry, neuropaediatrics, and pain management. It must also include important diseases which straddle neurology and general medicine. These include a long list of cardiovascular, nutritional, endocrine and gastrointestinal disorders. Furthermore, neurologists often have to deal with surgical complications especially in orthopaedics and following transplant surgery. Neurologists are also frequently called upon to attend to neurological problems that are unique to pregnancy. Any practical checklist application must therefore thoroughly address these areas.

Brain Cells Created From Skin Cells in Landmark Study. Day Donaldson on Flikr. https://www.flickr.com/photos/thespeakernews/15656329862
Brain Cells Created From Skin Cells in Landmark Study. Day Donaldson on Flikr. https://www.flickr.com/photos/thespeakernews/15656329862

3. The challenge of reliable content

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It goes without saying that the most important feature of any database is reliable content which alone will engender trust and confidence. A reliable checklist must obtain its material from dependable sources. Neurology is replete with reliable textbooks and reference websites, . Neurology is also bursting at the seams with journals such as Neurology, Brain, the JNNP, and Journal of Neurology, each churning out a bewildering array of neurology guidelines, review articles, ground-breaking studies, and fascinating case reports. The challenge is to keep a regular handle on these sources, sifting through for practical and established material. As important for the user is that any checklist must be fully referenced and hyperlinked to the source material.

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4. The challenge of practical functionality

Any practical checklist database must be available on the move, easily accessible and searchable. In other words, it must be in the form of a mobile application. The app must have a reliable search functionality. More importantly for users is the requirement that the application must serves as a prompt to remember important points across the breadth of neurological practice: history taking, investigations, differential diagnosis, and treatment. For the administrator, the technology must make it easy to update and edit content, keeping the content consistently up-to-date.

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5. The challenge of varied target groups

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In developing any form of medical resource, it is a challenge to define the target audience. The primary aim of a neurology checklist application is to ease the challenges medical professionals face in accessing relevant and practical information about neurology in a timely way. This may be on a busy ward round or clinic, but also when researching a topic or preparing a presentation. The core users of a neurology application will therefore clearly be neurologists and neurology trainees.

By SpinningSpark real life identity: SHA-1 commitment ba62ca25da3fee2f8f36c101994f571c151abee7 - Created with Superliminal's Magic Cube 4D, CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=17492843
By SpinningSpark real life identity: SHA-1 commitment ba62ca25da3fee2f8f36c101994f571c151abee7 – Created with Superliminal’s Magic Cube 4D, CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=17492843

In many places however other cadres of medicine cater for people with neurological diseases. Psychiatrists, neurosurgeons, paediatriciansgeneral physicians, obstetricians, ophthalmologists, specialist and general nurses, would likely access the database. Other health care professionals may also find areas of interest such as speech therapists, physiotherapists and occupational therapistsMedical students and researchers also require vast amounts of neurological information, often within restricted time frames.

A Tangle of Different Colours 001. Christina Quinn on Flikr. https://www.flickr.com/photos/chrisser/7909899736
A Tangle of Different Colours 001. Christina Quinn on Flikr. https://www.flickr.com/photos/chrisser/7909899736

6. The challenge of public access

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Specialised medical application are never aimed at non-medically trained people. The reality however is that the general public are closely involved in their care today, seeking reliable information to address their medical concerns. It is inevitable that patients and their families will access the checklist database. For this reason the language must be simple and clear, avoiding any sort of ambiguity.

7. The challenge of resources and pricing

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A checklist application, to be most beneficial, should ideally be free to use. A Wikipedia model would be a model to adapt. But creating a checklist database, with all the features mentioned above, would surely stretch resources in terms of time and funding. There will also be great demands on resources to maintain and enhance it. A balance must be struck between beneficence and realism. Such a balance should have, as with most applications, a free version with sufficient access of some sort, and a premium version with unlimited access. The developer must also be aware that potential users have limited resources to spread round their conflicting demands. Any premium account should be affordable, perhaps not more than the equivalent cost of a cup of coffee and a cake a month.

Muffin and coffee. Phil Gyford on Flikr. https://www.flickr.com/photos/philgyford/6534958441
Muffin and coffee. Phil Gyford on Flikr. https://www.flickr.com/photos/philgyford/6534958441 

 

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Is there any neurology checklist application that has taken the above challenges into consideration? This will be revealed in my next blog post, How simple checklists unlock excellent neurological practice?

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