I am a UK Neurologist keen on general neurology, but with an interest in neuromuscular diseases. I maintain the neurology searchable database, www.neurochecklists.com. I also blog at www.theneurologylounge.com. I share and discuss current issues around clinical neurology. I hope you find my blogs enlightening, practical, and even entertaining.
A large case-control study on vaccination as risk factor for multiple sclerosis. Hapfelmeier A, Gasperi C, Donnachie E, Hemmer B. Neurology 2019; 93:e908-e916. Abstract OBJECTIVE: To investigate the hypothesis that vaccination is a risk factor for multiple sclerosis (MS) by use of German ambulatory claims data in a case-control study. METHODS: Using the ambulatory claims data of the Bavarian Association of Statutory […]
The practice of medicine is a finely balanced art. Clinical features are often very subtle, and the ground is littered with booby traps. You could say medicine is a minefield, strewn with mimics and chameleons. This explains why diagnostic error is rife in medicine, and this is perhaps more so in neurology. Admittedly, some misdiagnoses only […]
First, some basic science to lay the groundwork for this blog post. Parkinson’s disease (PD) is all about dopamine, the chemical neurotransmitter that makes our movements smooth. It is produced by cells in the substantia nigra, a structure in the midbrain. The substantia nigra nerves project to the putamen, one of the structures that make up the basal ganglia, somewhere deep in the brain. The substantia nigra nerves are also called the nigrostriatal nerves because the putamen, along with the caudate nucleus and the nucleus accumbens, form a body called the corpus striatum. The work of these so-called nigrostriatal nerves is to produce and deliver dopamine to the putamen. In summary, the putamen is the playpen of dopamine; it is here that it does its work of smoothening our movements.
In Parkinson’s disease, the nogrostriatal system slowly degenerates, therefore becoming unable to supply enough dopamine to the putamen. The obvious solution is to find an alternative supply of dopamine for the putamen. The obvious way again would be to deliver dopamine orally as a tablet, but dopamine unfortunately does not cross the blood brain barrier. However, the similar but more pliant levodopa is able to do so. Once in the brain, levodopa is then converted to the active dopamine by an enzyme called aromatic L‐amino acid decarboxylase (AADC). Because this strategy is reasonably efficient, levodopa has become the foundation of PD treatment. But this strategy is totally dependent on the presence of enough AADC to convert levodopa to dopamine. And this is a vulnerability that PD explores to the full.
Levodopa treatment is usually effective in the early stages of PD. But as the disease progresses, the degenerating nigrostriatal nerves increasingly struggle to produce enough AADC. Remember, AADC is essential for converting levodopa to the active dopamine. Without AADC, in other words, levodopa is useless. The declining ability to produce AADC is therefore the Achille’s heel of levodopa treatment. It is the reason people with advanced PD require increasingly higher doses of levodopa. It is the reason they get unpredictable treatment fluctuations. It is the reason they get abnormal movements called dyskinesias. To remedy this big flaw in the levodopa treatment strategy, and increase AADC levels in the putamen, neuroscientists have investigated the potential role of gene therapy. To unravel this topic, not a ride in the park by any means, I have relied on this excellent 2019 paper titled Magnetic resonance imaging–guided phase 1 trial of putaminal AADC gene therapy for Parkinson’s disease.
If one group of cells becomes unable, or unwilling, to do its job, why not get another group of cells to take over the task? Indeed this simple concept lies at the heart of gene therapy for PD. And neuroscientists have identified the right type of cells to take over the job of producing AADC. These are the medium spiny neurones of the putamen which do not degenerate in PD. The brilliant strategy is to embed the gene for producing AADC into the DNA of the medium spiny neurones. A viral vector is required to carry the gene into the nerves, and the vector of choice here is adenovirus-associated virus (AAV). The vector ‘invades’ the medium spiny neurones and embeds the AADC gene into their DNA. The cells then start producing dopamine from levodopa. It is as simple as that in theory. It is easier said than done in reality.
The intricate steps involved in this strategy are outlined by Chadwick Christine and colleagues who carried out the phase 1 trial of AADC gene therapy. They infused the AAV viral vector directly into the putamen during neurosurgery, and they used magnetic resonance imaging to confirm that the injected material is delivered to the correct target. The detailed protocol refers to technical terms such as bilateral frontal burr holes, intraoperative delivery, neuro‐navigational systems, and the like. The whole affair however appears to be well-tolerated and reasonably successful; the authors reported a dose-dependent increase in AADC enzyme production, and their 15 subjects had more ‘on-time’, less troublesome treatment fluctuations, and required less levodopa. It is interesting that a similar benefit was demonstrated by Karin Kojima and colleagues when they used the same procedure in a genetic disorder called aromatic l-amino acid decarboxylase deficiency. In their paper titled Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency, the authors reported ‘remarkable’ motor improvement in all the six subjects they treated.
An alternative approach to PD gene therapy is to use the AAV viral vector to deliver, not the gene for producing AADC this time, but the gene for producing glial cell line‐derived neurotrophic factor (GDNF). The idea behind this is, not to replace, but to flog the dying horse. The theory is that GDNF, a growth factor, should rejuvenate the flagging nigrostriatal nerves, thereby increasing their ability to produce dopamine. This approach was described by John Heiss and colleagues in their paper titled Trial of magnetic resonance–guided putaminal gene therapy for advanced Parkinson’s disease. The authors indeed demonstrated that GDNF-carrying adenovirus vectors can be safely infused into the putamen, and that the process is well-tolerated. They also demonstrated increased dopamine levels in the putamen in 12 of their 13 subjects.
It is clearly early days, but there have been small successes along the way so far. Future trials, already underway, will tell us whether the hope is sustained or dashed. We must wait and see. In the meantime, you can read more about PD gene therapy in this update.
By Images are generated by Life Science Databases(LSDB). – from Anatomography, website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, Link
Risk for major hemorrhages in patients receiving clopidogrel and aspirin compared with aspirin alone after transient ischemic attack or minor ischemic stroke: a secondary analysis of the POINT randomized clinical trial. Tillman H, Johnston SC, Farrant M, et al. JAMA Neurol 2019; 76:774-782. Abstract IMPORTANCE: Results show the short-term risk of hemorrhage in treating patients with acute transient ischemic attack (TIA) or minor acute ischemic stroke (AIS) with clopidogrel plus aspirin or aspirin alone. […]
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.
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.
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.
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, thecopper 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.
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.
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.
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 alcoholiccirrhosis. Not a bad deal, but the squeamish neurologist must realise it requires a liver biopsy!
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.
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 disease, Ewa 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.
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 dailydosing regime.
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.
Predictors of atrial fibrillation in patients with cryptogenic stroke Renati S, Stone DK, Almeida L, Wilson CA. Neurohospitalist 2019; 9:127-132. Abstract BACKGROUND: Many patients diagnosed with cryptogenic stroke or transient ischemic attack are subsequently found to have atrial fibrillation (AF) on outpatient cardiac telemetry monitoring. Identification of predictive factors for the detection of AF could […]
Neurochecklists is a comprehensive and practical neurology database Handy and fully referenced, it is in a constant state of review and renewal Below are just 21 of our recently updated neurology checklists *** Cervical artery dissection: clinical features Epilepsy: blood and CSF features Huntington’s disease: clinical features Leber hereditary optic neuropathy: management Parkinson’s disease tremor […]
