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.

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3 exciting emerging interventional treatments for Parkinson’s disease

Parkinson’s disease (PD) is one of the bedrock disorders of neurology. It is common, universal, well-defined, usually easily diagnosed, and eminently treatable, even if not curable. PD is so important that I have visited it so many times on this blog. My previous blog posts on this topic include:

What are the drugs promising neuroprotection in PD?

What is the state of Parkinson’s disease biomarkers? 

The emerging research boosting Parkinson’s disease treatment.

PD is debilitating even when treated. This is because of the staggering number of motor and non-motor symptoms it provokes. And there is the long list of side effects the treatments induce, such as abnormal movements called dyskinesias. There is therefore a never-ending need for more effective and less agonising treatments for PD. And this blog has kept a keen eye on any advances that will make this disorder more bearable for the sufferers and their families, and less nerve-racking for the treating neurologist. It is therefore gratifying to know that there are many developments in the management of PD, and here I focus on 3 emerging interventional treatments.

By Marvin 101 – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7533521

 

Magnetic resonance-guided focused ultrasound (MRgFUS)

MRgFUS is a technique that uses thermal heat to create lesions in the brain. This is a much less invasive approach than the current interventional treatments for PD which are surgery and deep brain stimulation (DBS). Surgical interventions for PD work by making therapeutic lesions in the globus pallidus (pallidotomy). In a first of its kind, Young Cheol Na and colleagues used MRgFUS to create similar pallidal lesions. They published their finding in 2015 in the journal Neurology under the title Unilateral magnetic resonance-guided focused ultrasound pallidotomy for Parkinson disease. They reported improvement in the motor symptoms of PD, and in drug-induced dyskinesias. But before MRgFUS pallidotomy will take off, it has to be as good as surgical pallidotomy which reduces dyskinesias for as long as 12 years!

Blue sonar. Gisela Giardino on Flickr. https://www.flickr.com/photos/gi/192984384

Repetitive transcranial magnetic stimulation (rTMS) 

In a reasonably large randomized trial published in 2016 in the journal Neurology, Miroslaw Brys and colleagues reported that rTMS improves motor symptoms in PD. Titled Multifocal repetitive TMS for motor and mood symptoms of Parkinson disease, the study reports that the benefit was significant. Indeed a systematic review and meta-analysis by Ying-hui Chou and colleagues in the journal JAMA Neurology, published just the year before, had established the benefit of rTMS in PD. The review, titled Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease, concluded with the hope that their findings “may guide treatment decisions and inform future research“. Hopefully it has, because a 2018 paper, published in the Journal of Clinical Neuroscience, has gone on to establish that the best results for rTMS are obtained with stimulation of the primary and supplementary motor cortex. That’s scientific progress.

Magnetic Fields-15. Windell Oskay on Flickr. https://www.flickr.com/photos/oskay/4581194252

Spinal cord stimulation 

It appears counterintuitive to think of the spinal cord in the context of PD, which is after all a disease of the brain. That is until you remember that walking impairment is a major problem in PD, and the spinal cord is the gateway for gait. Inspired by this insight, Carolina Pinto de Souza and colleagues stimulated the spinal cords of people with PD who have already undergone deep brain stimulation surgery. They published their findings in the journal Movement Disorders with the title Spinal cord stimulation improves gait in patients with Parkinson’s disease previously treated with deep brain stimulation. A clear title like this leaves little room for commentary. The authors however studied only four subjects, a number clearly missing from the paper’s title, but the benefit is an encouraging 50-65% improvement in gait. The omission is forgiven.

Spinal cord 8. GreenFlames09 on Flickr. https://www.flickr.com/photos/greenflames09/116396804

Taking things a step further, Reon Kobayashi and colleagues, writing in the journal Parkinsonism and Related Disorders, reported that a new mode of spinal cord stimulation called BurstDR, does a much better job than conventional stimulation. Again, the title of the paper is self-explanatory: New mode of burst spinal cord stimulation improved mental status as well as motor function in a patient with Parkinson’s disease.

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Surely the future must be bright with all these developments in the field of PD.

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