Imaging is central to neurological practice. It doesn’t take much to tempt a neurologist to ‘order’ or ‘request’ an MRI or a CT. In appropriate circumstances the imaging is a DAT scan, and with a bit more savvy, exciting imaging modalities such as amyloid scans and tau PET scans. In the playpen of the neurologist, the more ‘high tech’ the imaging technology, the more cutting-edge it feels-even if it doesn’t make much of a difference to the patient. Ultrasound on the other hand is the mongrel of imaging technologies. Too simple, too cheap, too available, too unsophisticated-not better than good old X-rays. It is safe to assume that the pen of the neurologist hardly ever ticks the ultrasound box. What for?
And yet, ultrasound has an established, even if poorly appreciated, place in neurological imaging. It is perhaps best known for its usefulness in assessing carpal tunnel syndrome at the wrist. But, for the neurologist, CTS is sorted out by wrist splints, steroid injections, and decompression surgery-forgetting that there may just be a ganglion, a cyst, or a lipoma lurking in there. Ultrasound also has a place in the assessment of muscle disorders, picking up anomalies and detecting distinctive muscle disease patterns. The only problem is that, even when radiologists and neurologists put their heads together, they struggle to understand what the patterns actually mean. And since the first pass of this blog post, I was reminded of the place of ultrasound-guided lumbar puncture in improving the safety and accuracy of this otherwise blind procedure. And there are even guidelines to help takers. My guess is that most neurologists prefer the thrill of hit-and-miss that goes with conventional LP. For many reasons therefore, the ultrasound box remains un-ticked.
Despite these limitations, the place of ultrasound remains entrenched in neurological practice. Indeed, ultrasound has been spreading its wings to exotic places, broadening its range, and asserting its presence. Perhaps it is time to reconsider the humble ultrasound, and to catch up with what it has been up to. Here then are 3 emerging roles of ultrasound in neurology
Therapeutic ultrasound
The role of ultrasound in treatment is reviewed in the excellent paper in Nature Neurology titled Ultrasound treatment of neurological diseases-current and emerging applications. And the emphasis is on trans-cranial MR-guided focused ultrasound (tcMRgFUS). tcMRgFUS is making waves in the treatment of essential tremor (ET), Parkinson’s disease (PD), and central pain. The benefit for PD is already filtering out into the popular press such as this article in STAT titled New treatment offers some hope for an unshakable tremor. Ultrasound is also rapidly emerging as an option in the ablation of brain tumours, and in the treatment of stroke (sonothrombolysis).
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Drug delivery into the brain
The blood brain barrier is a rigidly selective barricade against most things that venture to approach the brain-even if their intentions are noble. This is a huge impediment to getting drugs to reach the brain where they are badly needed. It is therefore humbling that it is the simple ultrasound that is promising to smuggle benevolent drugs across the blockade to aid afflicted brains. This was reported in the journal Science Translational Medicine, and the article is titled Clinical trial of blood-brain barrier disruption by pulsed ultrasound. The trial subjects were people with the notorious brain tumour, glioblastoma. They were injected with their conventional chemotherapy drugs, delivered along with microbubbles. The blood brain barrier was then repeatedly ‘pelted’ with pulsed ultrasound waves; this seem to leapfrog the drugs into the brain in greater than usual concentrations, enough to do a much better job. This surely makes films such as Fantastic Voyage and Inner Space not far-off pipe-dreams.
Some of the emerging neurological applications of ultrasound are even more Sci-Fi than pulsed ultrasound. And a sign of this Sci-Neuro world is this report titled UCLA scientists use ultrasound to jump-start a man’s brain after coma. One is tempted to dismiss this as ‘fake news’ but it is a proper case report, in a proper scientific journal, Brain Stimulation, and with a proper scientific title, Non-Invasive Ultrasonic Thalamic Stimulation in Disorders of Consciousness after Severe Brain Injury: A First-in-Man Report. By targeting ultrasounds to the subject’s thalamus, the authors assert, the subject just woke up (and presumably asked for a hot cup of tea!). A word of caution is however needed; the authors rightly point out that it may have all been…coincidental!
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.
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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.
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:
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.
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!
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.
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Surely the future must be bright with all these developments in the field of PD.
I can’t seem to get away from the theme of Mozart and epilepsy. When I first looked at this, in a blog post titled Mozart and seizures? The links between epilepsy and music, I took the topic rather lightly, more a subscript than a headline you may say. But I have since learnt to take the links between epilepsy and music more seriously.
The major trigger for my ‘road to Damascus’ conversion is a 2018 paper titled Study of the Mozart effect in children with epileptic electroencephalograms, published in the journal Seizure. The paper was an eye-opener because it gave a very helpful comprehensive context to the broader beneficial effect of music…not just in epilepsy, but in other neurological disorders such as Parkinson’s disease, dementia and sleep disorders. The authors, Elyza Grylls and colleagues, started on the established premise that Mozart’s music has a beneficial effect on epilepsy. What they wanted to know was if other forms of music have a similar settling effect on epilepsy, or if only Mozart’s music carries the magic touch. The authors therefore played Mozart’s Sonata for two pianos in D major (K448) to 40 children with epilepsy who were undergoing an EEG (electroencephalogram, or electrical brain wave test). They then compared this with the effect of playing other types of music. Remarkably, they found that only Mozart’s Sonata led to a significant reduction in EEG epileptic discharges.
The authors concluded that there was indeed an anti-epileptic effect of Mozart’s music, the so-called ‘Mozart therapy’. But what is so special about K448? They speculate that it has to do with the structure of Mozart’s music, containing as it does, long periodicities. Interestingly, the music of Yanni, which is similarly structured, has somewhat a similar effect on brain wave activity. On the contrary, and sorry to Beethoven fans, Fur Elisedoesn’t have this effect.
By Bionerd – MRI at Charite Mitte, Berlin (used with permission), CC BY 3.0, Link
You have surely wondered by now whether K448 is the only one of Mozart’s compositions to have an anti-epileptic effect. It doesn’t matter if you haven’t, because the authors of another interesting paper have. They titled their study, published in 2018, Mozart’s music in children with drug-refractory epileptic encephalopathies: comparison of two protocols. Published in the journal Epilepsy and Behaviour, the authors,Giangennaro Coppola and colleagues, compared the effect of K448 with a set of his other compositions. Intriguingly they found that the composition set actually had a greater effect in epilepsy than K448…by a wide margin of 70% to 20%! Furthermore, the set was better tolerated by the children; they were less irritable and had a better nighttime sleep quality.
So, is it all rosy in the garden of music and the brain? No, it’s not! As every rose grows on a thorny tree, so do some forms of music trigger epileptic seizures. This so-called musicogenic epilepsy is well-recognised, and two recent culprits are the music of Sean Paul, discussed in the journal Scientific American , and the music of Ne Yo, explored by NME. Therefore you should craft your playlist wisely.
Regular visitors to this blog know that we love catchy article titles. It is always heartwarming to see how some authors create imaginative and inventive headlines. This skill involves the ability to play with words, and the capacity to be double-edged. This is why this blog keeps a lookout for fascinating neurology titles. And in line with this tradition, and in no particular order of inventiveness, here are 15more catchy neurology titles!
This paper, for some unfathomable reason, set out to ask if the public knows the difference between what psychiatrists and psychologists actually do. And the authors discovered that “there is a lack of clarity in the public mind about our roles”. More worryingly, or reassuringly (depending on your perspective), they also found out that “psychologists were perceived as friendlier and having a better rapport“. Not earth-shattering discoveries, but what a great title!
Optical coherence tomography (OCT) is a cool tool which measures the thickness of the retinal fiber layer (RFL). And it has the habit of popping its head up in many neurological specialties. In this case, the specialty is multiple sclerosis, and the subject is how OCT influences its diagnosis and surveillance. Surely a window into the brain is easier to achieve than one into the soul.
The homonculus is the grotesque representation of the body on the surface or cortex of the brain. This paper reviews how formidable neurosurgeons such as Wilder Penfield worked out the disproportionate dimensions of this diminutive but influential man. He (always a man for some reason) has giant hands, a super-sized mouth, very small legs, and a miniature trunk. The clever brain doesn’t readily allocate its resources to large body parts that perform no complex functions! But be warned, this article is no light-weight reading!
This title is a play on words around MR-guided focussed ultrasound surgery (MRgFUS), an emerging technique for treating disorders such as essential tremor and Parkinson’s disease (PD). This review looks at the controversial fuss that this technique has evoked.
This paper explores the interesting subject of delusional misidentification syndromes (DMSs). The authors argue that few concepts in psychiatry can be as confusing as DMSs. And they did an excellent job of clearing our befuddlement around delusions such as Capgras and Fregoli. Very apt title, very interesting read.
This title belongs to a review of trypanosomiasis, aka sleeping sickness. It is a superb play on words, one that evokes several levels of meaning. It is simple and yet complex at the same time. Great imagination.
This paper discusses two parts of nervous system that are affected by toxoplasmosis. Playing on the symbolic contradiction between intellect and strength, the authors show how toxoplasmosis is an ecumenical abuser: it metes out the same fate to both brain and brawn.
A slightly paradoxical title this one. Ponder on it just a little more! And then explore the excellent paper shedding light on a condition that is averse to light.
Nitrous oxide, or laughing gas, is now “the seventh most commonly used recreational drug”. But those who pop it do so oblivious of the risk of subacute combined degeneration. This damage to the upper spinal cord results from nitrous oxide-induced depletion of Vitamin B1 (thiamine). Not a laughing matter at all!
Dopamine transport (DaT)scan is a useful brain imaging tests that helps to support the diagnosis of Parkinson’s disease and other disorders which disrupt the dopamine pathways in the brain. It is particularly helpful in ruling out mimics of Parkinson’s disease such as essential tremor. When to request a DaT scan is however a tricky question in practice. This paper, with its Shakespearean twist, looks at the reliability of DaT scans.
It should be no surprise if Shakespeare rears his head more than once in this blog post. Not when the wordsmith is such a veritable source of inspiration for those struggling to invent catchy titles. This paper looks at taupathy, a neurodegeneration as tragic as Hamlet. It particularly comments on an unusual taupathy, one induced by traumatic brain injury. Curious.
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What better way to call attention to a serious complication than a catchy title like this one. This paper highlights the neurological complications of coarctation of the aorta, a serious congenital cardiovascular disease. And the key concerns here are the risks of stroke and cerebral aneurysms. Cardiologists, mind the brain!
This paper reviews the unexpected biochemical links between diabetes and Parkinson’s disease. And this relationship is assuming a rather large dimension. Why, for example, are there so many insulin receptors in the power house of Parkinson’s disease, the substantia nigra? A sweet curiosity.
The foraman ovale is a physiological hole-in-the-heart which should close up once a baby is born. A patent foramen ovale (PFO) results when this hole refuses to shut up. PFOs enable leg clots to traverse the heart and cause strokes in the brain. This paper reviews the evidence that surgically closing PFOs prevents stroke. Common sense says it should, but science demands proof. And the authors assert that they have it all nicely tied up. Hmmm.
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.
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:
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:
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, theauthors 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:
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,plasmacholesterol, 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.
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 TheSimvastatin Trial, funded by TheCure 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.
Restless legs syndrome (RLS) does what it says on the can. Victims need to only sit or lie down for a few seconds before creepy-crawly sensations literally drive them up the wall. The discomfort is as insatiable as the urge to move is uncontrollable. It is, literally again, a nightmare; a frantic evening quickly followed by a frenetic night.
Neurologists rarely struggle to make the diagnosis of RLS. And with the efforts of support groups such as the RLS foundation, patients are now well-informed about the diagnosis. To the chagrin of the neurologists, patients often come with a list of medications they have tried, and failed.
The list of RLS risk factors is quite long. Some of these are modifiable, and the ‘must-exclude’ condition here, iron deficiency, requires checking the level of ferritin in blood. Other modifiable risk factors are quite diverse such as obesity, migraine, and even, surprisingly, myasthenia gravis (MG). Most RLS risk factors, such as peripheral neuropathy and Parkinson’s disease (PD), are unfortunately irreversible; in these cases some form of treatment is required.
Parkinson’s disease (PD) is probably the most iconic neurological disorder. It has diverse manifestations, typical of many neurological diseases. PD is a result of brain dopamine deficiency, and its clinical picture is dominated by motor symptoms- tremor, rigidity and bradykinesia (slowing of movements). It however also manifests with a variety of non-motor symptomswhich rival the motor symptoms in their impact. PD is responsive to treatment with several oral medications such as levodopa, infusions such as apomorphine, and interventions such as deep brain stimulation (DBS).
Regardless of the intervention used, PD is a neurodegenerative disorder that grinds, slowly and steadily, along a chronic progressive course. This often manifests with disabling features such as freezing, hallucinations, and dyskinesias (drug-induced writhing movements). These symptoms creep or barge in unannounced, challenging the wits of the neurologist, and pushing the resolve of patients and their families to the limit. What hope does research offer to smooth the journey for people with PD? Here are my top 7.
1. Increasing evidence for the benefit of exercise
OK, not every advance has to be groundbreaking. It is self-evident that exercise is beneficial for many chronic disorders, but proving this has been difficult…until now that is. Researchers, publishing in the journal Movement Disorders, looked at the benefits of exercise on cognitive function in PD, and their verdict is-yes, it works! The study, titled Exercise improves cognition in Parkinson’s disease: The PRET-PD randomized, clinical trial, comes with strings attached- you have to keep at the exercise for 2 years! A review in the same journal indicates that exercise also improves mood and sleep in PD.
Dyskinesias are abnormal, fidgety movements that develop as side effects of the drugs used to treat PD. Most people with dyskinesias are not overly concerned about the movements because the alternative, disabling freezing and immobility, is worse. Dyskinesias are however energy-sapping, and are distressing for family members. Amantadine is one drug neurologists add-on to improve dyskinesias, but many people do not tolerate or benefit from this. The suggestion that lithium may help dyskinesias is therefore welcome news. The report comes from a study in mice reported in the journal Brain Research titled The combination of lithium and l-Dopa/Carbidopa reduces MPTP-induced abnormal involuntary movements (AIMs). A long way to go yet, but hope.
Transcranial magnetic stimulation (TMS) is playing an increasing role in neurology as I discussed in a previous post titled Are magnets transforming neurology? It is almost inevitable therefore that TMS will crop up in attempts to treat PD. And so it has, going by a meta-analysis and systematic review published in JAMA Neurology. The paper is titled Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease. The reviewers passed the judgement that repetitive TMS improves motor symptoms in PD. Perhaps time to invest in TMS!
What a great thing, the blood-brain barrier, protecting the brain from all the bugs and toxins running amok in the bloodstream. This iron-clad fence unfortunately also effectively keeps out, or limits the entrance of, many beneficial drugs which need to get to the brain to act. As with all borders however, there are always people ready to break through, without leaving any tracks behind. And the people in this case are neurosurgeons who have successfully bypassed the blood brain barrier, and safely ‘transported’ PD drugs in to the brain. They did this by removing a portion of the blood brain barrier of mice, and replaced it with a piece of the tissue which lines the inside of the nose, a procedure called nasal mucosal grafting. They then delivered glial derived neurotrophic factor (GDNF), a protein that treats PD in mice, across the graft. The neurosurgeons explained all this in their paper titled Heterotopic mucosal grafting enables the delivery of therapeutic neuropeptides across the blood brain barrier. You may however prefer the simpler version from the Boston Business Journal (can you believe it!) titled A new way to treat Parkinson’s disease may be through your nose.It will however take time before human trials of nasal mucosal grafting…this is science after all, not science fiction!
It doesn’t seem too long ago when all ethical hell broke loose because some scientists were transplanting fetal tissue into human brains. I thought the clamour had put this procedure into the locker, never to be resurrected. Apparently not; fetalstem cell transplantation (SCT) is back, reminiscent of Arnold Schwarzenegger in the Terminator films. Learn more of this comeback in this piece from New Scientist titled Fetal cells injected into a man’s brain to cure his Parkinson’s. The work is from Roger Barker‘s team at the University of Cambridge, and they are planning a big study into this named TRANSNEURO. Watch this space
The future of stem cell transplantation probably lies with pluripotent, rather than fetal cells. The idea is to induce skin cells, called fibroblasts, to transform into dopamine-producing cells. Fibroblasts can do this because they are pluripotent cells; that is they are capable of becoming whatever type of cells you want, so long as you know the magic words. In this case, the words are likely to be the transcription factors Mash1, Nurr1 and Lmx1a. Beats ‘open sesame‘, and surely less controversial than fetal cells. Researchers are taking this procedure very seriously indeed, setting out ground rules in articles such as Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. This was publishedin the journal Nature, but you may prefer the easier read in New Scientist titled Brain cells made from skin could treat Parkinson’s. But don’t get too excited…pluripotent stem cell transplantation is barely at the starting line yet.
There is so much more going on in the field of Parkinson’s disease to cover in one blog post. I will review neuroprotection in Parkinson’s disease in a coming post. In the meantime, here are links to 12 interesting articles and reviews on the future of PD:
Neurology is a broad specialty covering a staggering variety of diseases. Some neurological disorders are vanishingly rare, but many are household names, or at least vaguely familiar to most people. These are the diseases which define neurology. Here, in alphabetical order, is my list of the top 60 iconic neurological diseases, with links to previous blog posts where available.
The Neurology Lounge has a way to go to address all these diseases, but they are all fully covered in neurochecklists. In a future post, I will look at the rare end of the neurological spectrum and list the 75 strangest and most exotic neurological disorders.
![By uncredited - Images from the History of Medicine (NLM) [1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=11648572](https://theneurologylounge.files.wordpress.com/2016/07/alois_alzheimer_002.jpg)
![By Carl Vandyk (1851–1931) - [No authors listed] (July 1937). "S. A. Kinnier Wilson". Br J Ophthalmol 21 (7): 396–97. PMC: 1142821., Public Domain, https://commons.wikimedia.org/w/index.php?curid=11384670](https://theneurologylounge.files.wordpress.com/2016/07/samuel_alexander_kinnier_wilson.jpg)
