What is the place of magnesium in the treatment of migraine?

Magnesium is a rather understated metal which however plays such a significant role in health. This should not be surprising as it is the eighth most common metal in the Earth’s crust, and the fourth most abundant mineral in the human body. Explaining why magnesium is so central to health, Uwe Gröber and colleagues, in their paper titled Magnesium in prevention and therapy, point out that this underrated element is a cofactor in more than 300 enzyme systems which regulate such diverse biochemical reactions ranging from protein synthesis to neuromuscular transmission.

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With such an important physiological function, it is alarming that the body can very easily run out of magnesium. But this is exactly what Gröber and colleagues demonstrated in their paper, which was incidentally published in the journal, Nutrients, in 2015; they showed that magnesium deficiency can result from a myriad of medical disorders such as alcoholism, malabsorption, endocrine disorders, chronic kidney diseases, and dialysis, or from the use of drugs such as antibiotics, chemotherapeutic agents, diuretics, and proton pump inhibitors.

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Because of its diverse and important role, magnesium deficiency doesn’t lie down quietly in the corner and mope; rather it screams out in many tongues. Low magnesium therefore presents with symptoms such as lethargy, vomiting, fatigue, cramps, tremor, carpopedal spasm, tetany, seizures, and cardiac arrhythmias. Even more astonishing is the list of disorders that may be triggered by magnesium deficiency, from asthma, diabetes, hypertension, and osteoporosis, to stroke, attention deficit hyperactivity disorder (ADHD), Alzheimer’s disease, of all things, and of course migraine. Obstetricians will of course remind us of the indispensability of magnesium for eclampsia.

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With the foregoing in the background, it is easy to understand why researchers have thoroughly investigated the possible place of magnesium in the treatment of migraine. Exploring its prophylactic role, for example, Hsiao-Yean Chiu and colleagues touted the virtues of magnesium in their paper titled Effects of intravenous and oral magnesium on reducing migraine: a meta-analysis of randomized controlled trials. Publishing in the journal Pain Physician in 2016, the authors reviewed 10 key studies, with a combined number of 789 subjects, which assessed the ability of magnesium to prevent migraine, and they concluded that “oral magnesium significantly alleviated the frequency and intensity of migraine“. The authors felt confident enough in their findings to recommend oral magnesium as a part of a “multimodal approach to reduce migraine”.

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Even more authoritative about the role of magnesium in migraine prophylaxis is the conclusion of the systematic review published in the journal Headache in 2017 titled Magnesium in migraine prophylaxis-is there an evidence-based rationale? a systematic review. The authors, Alexander von Luckner and Franz Riederer, found grade C, or possibly effective, evidence in support of the preventative role of magnesium in migraine. Going further, Charly Gaul and colleagues, publishing in the Journal of Headache and Pain in 2015, reported that adding riboflavin and coenzyme Q10 significantly increased the beneficial effect of magnesium.

Magnesium. fdecomite on Flickr. https://www.flickr.com/photos/fdecomite/6257573610

There is however a dampener to the celebrity status of magnesium in the migraine prophylaxis saga:  some reports simply found insufficient evidence for it. One such paper, published in the journal Cephalalgia in 2014 is titled An evidence-based review of oral magnesium supplementation in the preventive treatment of migraine. The authors, Levi Teigen and Christopher Boesy, reviewed 16 relevant studies and concluded that “the strength of evidence supporting oral magnesium supplementation is limited at this time“. But even then, they appreciate that absence of evidence is not the evidence of absence. They therefore did not dismiss the potential benefit of magnesium in migraine, and had no objection to migraineurs supplementing their dietary magnesium intake. As this paper was published in 2014, a lot has clearly passed under the bridge since then.

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Magnesium in the acute treatment of migraine has also been under scrutiny, and one such searchlight was shone by Hsiao-Yean Chiu and colleagues in their paper cited above. After reviewing 11 relevant studies comprising 948 subjects, they found that “intravenous magnesium significantly relieved acute migraine“. It is reassuring that two older papers also came to the same conclusion; the first, by ME Bigal and colleagues, was published in the journal Cephalalgia in 2002, and the second, by Şeref Demirkaya and colleagues, is reported in the journal Headache in 2004. Both papers revealed that 1000mg of magnesium sulfate intravenously was effective in aborting acute migraine attacks, especially if the attacks are associated with auras. Furthermore, writing in the journal Clinical Neurology and Neurosurgery in 2019, Fanny Xu and colleagues found that magnesium is effective even in status migrainosus, the most pernicious form of acute migraine.
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But, as you guessed, the verdict on the benefit of magnesium in acute migraine is far from unanimous. For example, Y Cete and colleagues, publishing their case series of emergency department patients in the journal Cephalagia in 2005, reported that magnesium is no better than placebo for acute migraine. Furthermore, Hyun Choi and Nandita Parmar in their meta-analysis, published in the European Journal of Emergency Medicine in 2014, said intravenous magnesium “failed to demonstrate a beneficial effect” in acute migraine. Arpad Pardutz and Laszlo Vecsei, commenting in the Journal of Neural Transmission in 2012, even discouraged the use of magnesium because there are more effective treatment options.

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Why are there such conflicting conclusions about the value of magnesium in acute migraine? One answer may lie in the almost prehistoric observation by Alexander Mauksop and colleagues; writing way back in 1996, in the journal Headache, they suggested that only a subset of migraine sufferers are susceptible to low magnesium levels. The authors go further to argue that low magnesium may be a trigger, not just for migraine, but for tension type headaches and cluster headaches; they therefore recommended that magnesium levels should be assessed in patients presenting with significant headaches, whatever the cause.

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In conclusion, the evidence for the use of oral magnesium in migraine prophylaxis justifies its clinical use. The evidence for the use of intravenous magnesium for acute migraine is however less clear-cut, and future studies may help to clarify the ambiguity. In the meantime, it may be worth checking magnesium levels when a migraine attack defies conventional treatment: a top-up might just make the difference. And for the researchers, it may be time to look more closely at precision migraine medicine – it might just help to define those migraine sufferers who will benefit from that magic shot of magnesium.

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The case for testing serum neurofilament light protein in MS

I am yet to request serum neurofilament light protein (NfL) in my practice. I am not sure yet why I should, but until now I confess I really haven’t looked for a reason to do so. I however know that some MSologists now tick it, along with other blood tests, when they investigate people they suspect may have multiple sclerosis (MS). NfL are proteins that are released by damaged neurones. Should I be requesting NfL in my clinical practice? I sniffed around to find the case for testing serum NfL, and below is what I found.

By GerryShaw – Standard tissue culture and immunofluorescencePreviously published: Unpublished, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=26518273

Many studies have looked at the value of NfL in MS. One such very well-planned study that addresses many of my questions is that by Guili Disanto and colleagues, published in the journal Annals of Neurology in 2017. In the paper, titled Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis, the authors studied >380 people with MS and >150 healthy controls, and report four important findings.

By GerryShaw – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17500647
  1. The levels of NfL in serum strongly correlate with the levels in cerebrospinal fluid (CSF) of people with MS.
  2. People with more active and more severe MS had higher levels of NfL.
  3. People with MS on disease modifying treatment (DMT) had lower NfL levels than those who were not on treatment.
  4. In people with MS who had their serum NfL tested serially over time, the level of NfL predicted those who will develop frequent relapses or progressive MS.

The authors concluded, with enough justification I think, that serum NfL is a “sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS“.

Culture rat hippocampal neuron. ZEISS Microscopy on Flickr. https://www.flickr.com/photos/zeissmicro/24327909026

The strong correlation between cerebrospinal fluid (CSF) and serum NfL was also confirmed by a study published in the journal Neurology, by Lenka Novakova and colleagues titled Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. As the title indicates, they discovered that serum NfL is as good as CSF NfL in monitoring the progression of MS.

Neuron. NICHD on Flickr. https://www.flickr.com/photos/nichd/21086076575

The observation that NfL predicts the course of MS is supported by many other studies, such as the one by Kristin Varhaug and colleagues in the journal Neurology Neuroimmunology and  Neuroinflammation whose title is also self-explanatory: Neurofilament light chain predicts disease activity in relapsing-remitting MS. A more recent paper, also published in Neurology, further reinforces the benefit of serum NfL in disease course prediction. It is titled Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. In this paper, Jehns Kuhle and colleagues practically confirm all the above stated benefits of NfL, concluding that “our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response”.

“Neuron” by Roxy Paine. Christopher Neugebauer on Flickr. https://www.flickr.com/photos/chrisjrn/4745660322

As for long term outcome, the 10 year follow up study by Alok Bahn and colleagues, published in the Multiple Sclerosis Journal in 2018, is most informative. In their paper titled Neurofilaments and 10-year follow-up in multiple sclerosis, the authors noted that “CSF levels of NfL at the time of diagnosis seems to be an early predictive biomarker of long-term clinical outcome and conversion from RRMS to SPMS”. Further support for the long term prognostic value of serum NfL comes from a paper published in 2018 in the journal Brain titled Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. The authors, Christian Barro and colleagues, studied more than 250 people with MS and concluded that “the higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss“.

Nervous Tissue: Spinal Cord Motor Neuron. Berkshire Community College on Flickr. https://www.flickr.com/photos/146824358@N03/41850849912/in/album-72157666241437517/

It is pertinent to note that the MS sphere is not the only one in which NfL is making waves. It has been found to be elevated in many other disorders such as motor neurone disease (MND), multiple system atrophy (MSA), hereditary spastic paraplegia (HSP), stroke, active small vessel disease, and peripheral neuropathy (PN). With these disclaimers in place, it may just be time to start ticking that NfL box.


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What are the emerging treatments for neurofibromatosis?

Neurofibromatosis (NF) is one of the major neurocutaneous disorders neurologists see. These are disorders which primarily affect the nervous system and have prominent skin manifestations. Also known as phakomatoses, they are typified by abnormal growths and a variety of cancers. They include well-defined conditions such as tuberous sclerosis complex (TSC), Sturge-Weber syndrome (SWS), von Hipple Lindau disease (VHL), schwannomatosis, and the various PTEN hamartoma tumour syndromes. There are two types of neurofibromatosis, NF1 and NF2. NF2 is characterised by vestibular schwannomas, tumours arising from the sheath that encases the nerve that control balance, and by meningiomas, tumours of the covering of the brain.

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NF1, also known as von Recklinghausen disease is, by far, the commoner form of neurofibromatosis. It is readily recognised on the skin by the frequently multiple and disfiguring nerve tumours called neurofibromas. Other benign skin lesions include the coffee-coloured skin lesions aptly called cafe-au-lait spots, armpit lesions called axillary freckles, and small lesions on the iris of the eyes called Lisch nodules. More sinister skin lesions called malignant peripheral nerve sheath tumours (MPNST) are, as the name implies, capable of spreading to other organs such as the lungs. Other sinister tumours in NF1 include gliomas of the brain and optic nerve, gastrointestinal stromal tumours (GIST) of the gut, and rhabdomyosarcomas of bone.

By Seiradcruz at English Wikipedia, CC BY-SA 3.0, Link

What can neurologists do for people with neurofibromatosis? Traditionally, nothing much apart from watchful waiting. We would monitor for the development of tumours by regular surveillance MRI scans of the brain and spine, and refer people with painful, compressive, or malignant lesions to the plastic surgeons or neurosurgeons to do what they do best, taking things out. Surgery may work fine for simple neurofibromas, but it is less practical for the complex or plexiform type. Thankfully, many neuroscientists are working hard, looking at different approaches to managing neurofibromas. To illustrate, below are 5 emerging treatments for neurofibromatosis. 

Bởi Klaus D. Peter, Gummersbach, GermanySelf-photographed, CC BY 3.0 de, Liên kết



In a 2016 paper in the New England Journal of Medicine, Eva Dombi and colleagues investigated the effect of selumetinib, an oral inhibitor of an enzyme called MAPK kinase (MEK) in 24 children with NF1. The paper, titled Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas, showed that selumetinib reduced the size of neurofibromas, and there was evidence that it improved pain and reduced disfigurement.

By Dimitrios MalamosOwn work, CC BY 4.0, Link


In a 2012 paper published in Lancet Oncology, Kent Robertson and colleagues, investigated the potential benefit of Imitanib, an inhibitor of the enzyme tyrosine kinase, in 36 people with NF1. The paper, titled Imitatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial, showed at least a 20% reduction in one or more plexiform neurofibromas.

By Department of Pathology, Calicut Medical College – Calicut Medical College, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=36652650


Brian Weiss and colleagues investigated the effect of sirolimus, an inhibitor of mTOR complex 1, in 46 people with NF1 and published their findings in the journal Neuro-Onclology. The paper, titled Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas, demonstrated that sirolimus prolonged the time to progression (TTP) of plexiform neurofibromas by about 4 months. A modest effect they admit, but nevertheless, a hope-raising effect.

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Everolimus is already making waves in the treatment of various lesions in tuberous sclerosis complex, and it is not surprising that it has turned up here. In their paper titled Treatment of disfiguring cutaneous lesions in neurofibromatosis-1 with everolimus, published in the journal Drugs in R&D, John Slopis and colleagues reported that everolimus significantly reduced the surface volume of NF1 lesions, including plexiform neurofibromas. The authors were however cautious, calling for future studies to confirm these results. Unfortunately, one such study in the Journal of Investigational Dermatology poured cold water on the reported benefit of everolimus. The paper was titled Absence of Efficacy of Everolimus in Neurofibromatosis 1-Related Plexiform Neurofibromas: Results from a Phase 2a Trial. Hopefully future studies will be more favourable!

By MarinaVladivostokOwn work, CC0, Link

Pegylated interferon alfa-2b

Regina Jakacki and colleagues looked at the effect of pegylated interferon alfa-2b on plexiform neurofibromas and found a greater than doubling of their time to progression (TTP). Their paper is published in Neuro-Oncology, and it is titled Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas. As the authors studied a reasonable number of subjects, 84, and as the trial was placebo-controlled trial, this result is unlikely to be overturned by future trials…but only time will tell.

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Therefore is clearly enough justification for hope in the search for a cure for neurofibromatosis.

What is the state of gene therapy for Parkinson’s disease?

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.

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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.

By Jynto (talk) – Own workThis image was created with Discovery Studio Visualizer., CC0, Link

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.

By Jynto (talk) – Own workThis image was created with Discovery Studio Visualizer., CC0, Link

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.

By Thomas Splettstoesser (www.scistyle.com) – Own work, CC BY-SA 4.0, Link

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.

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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.

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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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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.

Are parasites the simple solution to the problem of MS?

In medicine, microbes are notorious for causing disease. In neurology particularly, infection is the direct cause of serious diseases such as meningitis and encephalitis. Infections may also act as  catalysts for neurological disorders, for example when they trigger Guillain Barre syndrome (GBS). Infection is therefore a villain, a scoundrel to be apprehended and disarmed whenever it rears its head. But this picture may not hold true when it comes to multiple sclerosis (MS) where a contrary story is emerging, a narrative which holds infection as the hero, the daredevil that will save the day. The premise is simple: MS has very little presence in the regions of the world where infections reign supreme. Just look at any world prevalence map of MS to be convinced.

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How strong is this inverse relationship between infection and MS? It all boils down to the so-called hygeine hypothesis of autoimmune diseases. This suggests that the human immune system becomes dysregulated when it is not primed by infections, and this dysregulation results in autoimmune disorders. This point was strongly argued by Aakanksha Dixit and colleagues in their paper published in the International Journal of Molecular Science, titled Novel Therapeutics for Multiple Sclerosis Designed by Parasitic Worms. They contend that the relationship between parasitic infections and autoimmune diseases is “most compelling“, going on to assert that helminthic infections “may be the protective environmental factor against the development of MS”.

By Doc. RNDr. Josef Reischig, CSc. – Archiv autora, CC BY 3.0, Link

To support the hygiene theory of MS, that helminthic infections play a role in banishing MS, three levels of evidence are offered.

  1. The prevalence of MS steadily increases when the frequency of infections in a community is reduces.
  2. People with MS who also have helminthic infections have fewer relapses and slower disease progression.
  3. MS patients who are treated for their helminthic infections develop more relapses and have a more active disease course
Diversity and prevalence of gastrointestinal parasites in seven non-human primates of the Taï National Park, Côte d’Ivoire. Parasite, 2015, 22, 1.doi:10.1051/parasite/2015001, CC BY 4.0, Link

Toxoplasma gondii, the cause of toxoplasmosis, is perhaps the major parasite investigated in relation to MS. Asli Koskderelioglu and colleagues, for example, reported that exposure to T.gondii is less frequent in people with MS than in healthy control subjects. In their 2017 paper titled Is Toxoplasma gondii infection protective against multiple sclerosis risk?, published in Multiple Sclerosis and Related Disorders, they found that MS subjects who have higher toxoplasma antibody levels experience fewer relapses and less severe disease courses. This finding is corroborated by a 2015 paper in the Journal of Neuroimmunology titled Toxoplasma gondii seropositivity is negatively associated with multiple sclerosis.

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Neurologists are however very cynical people, and they never believe what single trials tell them. After all, many microbes, such as Ebstein Barr virus (EBV), are touted as MS risk factors. For the sceptical neurologist, only systematic reviews and meta-analyses will do; these are the stuff of our dreams, the essence of our daily existence. So it is with a huge cheer that neurologists welcomed a 2018 systematic review and meta-analysis published in the Journal of Neuroimmunology and titled Is toxoplasma gondii playing a positive role in multiple sclerosis risk? The paper poured very cold water on the beautiful hygiene hypothesis. Whilst the authors, Reza Saberi and colleagues, confirmed that MS subjects had a lower risk of exposure to T. gondii, they found no relationship between this parasite and the development of MS. Wither a theory when it hits the reality of cold statistical analysis.

Cloudburst. Liz West on Flickr. https://www.flickr.com/photos/calliope/28825267500

Notwithstanding the systematic review, the helminth hypothesis marches on. It has even reached the stage of therapeutic trials where, as distasteful as it sounds, subjects ingest parasites by mouth! And the fancied parasite is not Toxoplasma gondii but Trichuris suis ova (TSO). It all began with a small observational trial in 10 people which proved that TSO is safe and well-tolerated (phew), but it had no value whatsoever in treating MS. Not discouraged, the hypothesis entered the slightly larger HINT 2 trial; this again confirmed good tolerability in 16 subjects, but any benefit in reversing MS was questionable. Undeterred, the hypothesis has gone for a bigger study in the form of the TRIOMS trial. This is a randomized, placebo-controlled study of 50 people with MS or clinically isolated syndrome (CIS) in which subjects will be ingesting 2,500 Trichuris suis eggs every two weeks. We wait with bated breaths for the results.

By Universidad de Córdoba – http://www.uco.es/dptos/zoologia/zoolobiolo_archivos/practicas/practica_4/practica4_botton.htm, Public Domain, Link

Before leaving this subject, we must know that helminths are not the only game in town; they have strong competition from their cousins, bacteria. And the standout character in this arena is Helicobacter pylori. We learnt this from a study published in 2015 in the Journal of Neurology Neurosurgery and Psychiatry. Titled Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females, the paper reported that people with MS were less likely than controls to have been exposed to H. pylori. Two meta-analyses have also reviewed the relationship of H. pylori and MS, arguing strongly that, in Western countries, there is an inverse relationship between H pylori and MS. And they assert that H. pylori may be protective against MS. If it feels like déjà vu, it is.

Helicobacter pylori. AJC21 on Flickr. https://www.flickr.com/photos/ajc1/6946417103

We have surely not heard the last of bugs and MS. However, for now, the foundations of the hygiene theory are a bit shaky, and the future rather hazy.

By Doc. RNDr. Josef Reischig, CSc. – Archiv autora, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=17268274


What are the promising CSF biomarkers of MND?

The Neurology Lounge strives hard to keep to the straight and narrow path of clinical neurology. But every now and then it takes a peek at what is happening at the cutting edge of neuroscience. And what can be more cutting edge then biomarkers, with their promise of simplifying disease identification, making prompt and accurate diagnosis an effortless task.

Darts. Richard Matthews on Flickr. https://www.flickr.com/photos/richardofengland/6788829651

The quintessential biomarker however remains as elusive as quicksilver. Not that one could tell, going by the rate biomarkers are being spun from the neuroscience mills. Biomarkers are the buzz in many neurological fields, from brain tumours to multiple sclerosis (MS), from Alzheimer’s disease (AD) to Huntington’s disease (HD).

By Muffinator – Own work, CC0, Link

The proliferation of contending biomarkers is however probably highest in the field of motor neurone disease (MND). Is there a holy grail out there to enable the rapid and accurate diagnosis of this relentlessly progressive disease? There is clearly no dearth of substances jostling for prime position in the promised land of MND biomarkers. Below is a shortlist of potential MND CSF biomarkers; just click on any to go to the source!

By Horia Varlan from Bucharest, Romania – Graduated cylinders and beaker filled with chemical compounds, CC BY 2.0, Link

Biomarkers elevated in the cerebrospinal fluid (CSF) 

Ferritin heavy chain (FHC)

Ferritin light chain (FLC)

Interferon g (IFN-g)

MIP 1a

Interleukin 12

Interleukin 15

Interleukin 17

Interleukin 23

Chromogranin A (CgA)

Basic fibroblast growth factor (bFGF)


Green Coral brain. Sarah Spaulding on Flickr. https://www.flickr.com/photos/visionwithin/61464453/


Vascular endothelial growth factor (VEGF)

Chitotriosidase 1 (CHIT 1)

Insulin-like growth factor 1 (IGF 1)

Matric metaloproteinases (MMPs)


Cystacin C

Monocyte chemotactic protein 1 (MCP 1)

Flt3 ligand

Prostaglandin E2 (PGE2)


Anti-ganglioside antibodies

By Nevit Dilmen (talk) – Own work, CC BY-SA 3.0, Link

Biomarkers reduced in the cerebrospinal fluid (CSF) 

Alpha 1 antitrypsin



Angiotensin II

Cytochrome C

Cyclic GMP (cGMP)

Acetylcholine esterase (AChE) activity


Why not check out more about MND in Neurochecklists

By © Nevit Dilmen, CC BY-SA 3.0, Link

10 things we now know about CIDP associated with anti NF155 antibodies

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a neurological disorder which causes loss of the fatty myelin covering of large nerves (demyelination). This slows down the speed at which the nerves can transmit electrical impulses. People with CIDP develop weakness and sensory disturbances, but not always in equal measure. CIDP is a pain for the afflicted, and a veritable nightmare for the neurologist.


By AjimonthomasOwn work, CC BY-SA 4.0, Link

The diagnostic process for CIDP includes some rather uncomfortable tests such as nerve conduction studies and lumbar puncture (spinal tap). CIDP is however a most rewarding disease to treat because many people respond to immune treatments such as steroids, intravenous immunoglobulins (IVIG), or plasma exchange (PE).

PRED SOV 5. Leo Reynolds on Flikr. https://www.flickr.com/photos/lwr/3300474346

The diagnosis of CIDP is however not straightforward. The results of the tests are not always clearcut, and a lot of sifting and sorting goes into nailing the diagnosis. And even when the diagnosis is eventually made, there is a very long list of potential causes of CIDP which often require treatment on their own merit. Worryingly, some of these conditions make the treatment of CIDP difficult. And this is where IgG antibodies play a nasty role in CIDP.

By Database Center for Life Science (DBCLS), CC BY 3.0, Link

Neurologists are now recognising that a subset of people with CIDP have IgG4 antibodies which greatly influence the clinical presentation and the treatment of CIDP. Anti-contactin antibody is one such antibody, but by far the most important is anti-neurofascin 155 (NF155). What do we know about this antibody? How does it influence the course of CIDP? To answer these questions, below are 10 important things we now know about CIDP associated with anti-NF155.

By BruceBlausOwn work, CC BY-SA 4.0, Link

1. Anti-NF155 is an antibody to paranodal structures

2. The antibody is present in 7-14% of people with CIDP

3. CIDP with anti-NF155 usually affects young subjects

4. Anti NF155 antibody CIDP is usually severe

5. Anti NF155 may cause central nervous system inflammation 

6. It causes a very high protein level in the spinal fluid

7. It causes very severe changes on nerve conduction studies

8. It responds poorly to intravenous immunoglobulins (IVIg)

9. It may respond to steroids and plasma exchange

10. Treatment-resistant cases may respond to Rituximab
By Oguenther at de.wikipediaOwn work mit Jmol auf Basis RCSB PDB: 2OSL​., Public Domain, Link


Why not check out everything CIDP on Neurochecklists:

When Shakespeare meets neurology: Hamlet, Ophelia and autoimmune encephalitis

Neurology can’t seem to get away from autoimmune disorders of the central nervous system. This blog has visited this topic several times before such as with the posts titled What are the dreadful autoimmune disorders that plague neurology? and What’s evolving at the cutting-edge of autoimmune neurology? The attraction of autoimmune neurological diseases lies in part in the ever-expanding spectrum of the antibodies and the challenging symptoms and syndromes they produce.

By Gentaur – Gentaur, Public Domain, Link

The fairly well-recognised ‘conventional’ antibodies are those against VGKC (Caspr 2 and LGI1), NMDA, and AMPA. There is however an almost endless list of less familiar antibodies such as those against glycine, adenylate kinase 5, thyroid, GABA-A receptors, α-enolase, neurexin-3α, dipeptidyl-peptidase-like protein 6 (DPPX), and myelin oligodendrocyte glycoprotein (MOG). I am however fascinated by the group of disorders caused by antibodies to metabotropic receptors. The main antibody in this group targets the metabotropic glutamate receptor 5 (mGluR5). The clinical picture with this antibody is a form of encephalitis which may manifest with prosopagnosia (difficulty recognising faces), and with the curious Ophelia syndrome.

By Benjamin WestOwn work, Public Domain, Link

Yes, you read it correctly. Ophelia syndrome is named after Shakespeare’s unfortunate Danish maiden, and it was first described by Dr. Ian Carr whose daughter, at the age of 15, developed progressive loss of memory, depression, hallucinations, and bizarre behaviour. These symptoms aptly describe Ophelia’s deluded and obsessional attraction to the equally deluded and murderous Hamlet. Ophelia syndrome is almost always associated with Hodgkins lymphoma and affects young people.

By V from Coventry, UK – Hamlet, CC BY 2.0, Link

Thankfully Ophelia syndrome is a relatively mild disease without the Shakespearean tragic ending because it has a good outcome if recognised and treated.

Why not explore all the autoimmune neurological disorders on neurochecklists.

What are the drugs promising neuroprotection in PD?

This is a follow up to my previous blog post titled The emerging research boosting Parkinson’s disease treatment. That post reviewed breakthroughs in the treatment of Parkinson’s disease (PD). But what are the advances in preventing the dreaded disease? What is the state of neuroprotection in PD? What are the hopes for attaining this elusive holy grail of neurology, the lodestone of neuroscientists?


Previous claims to neuroprotection have unfortunately fallen flat on their faces. For example, those with long memories will remember the unfulfilled hopes of selegiline. It is therefore not surprising that neurologists entertain all reports of neuroprotection with a heavy dose of scepticism. But this has not deterred the flow of drugs which aim to achieve the seemingly improbable. After scanning the neuroprotection horizon, I came up with this list of 7 potential neuroprotective drugs for PD.


Lab Mouse chekin out the camera. Rick Eh? on Flikr. https://www.flickr.com/photos/rick-in-rio/2593063816
Lab Mouse chekin out the camera. Rick Eh? on Flikr. https://www.flickr.com/photos/rick-in-rio/2593063816

LB-3627 is a drug which is reported to protect dopamine-producing cells in experimental animals. The wary neurologist will surely ignore the hype in the headlines such as New drug that protects dopamine cells raises treatment hope for Parkinson’s, or Pioneering Neuroprotective Results Achieved in Parkinson’s Disease Preclinical Studies. The neurologists will prefer to forensically interrogate the study directly, and it is published in Journal of Neuroscience as Selective VIP Receptor Agonists Facilitate Immune Transformation for Dopaminergic Neuroprotection in MPTP-Intoxicated Mice. The researchers theorise that the damage to dopamine producing cells in the brain is a result of some sort of inflammation, and this damage can be prevented if vasoactive intestinal peptide (VIP) receptors on the cells are ‘tuned’ correctly. LB-3627, by acting as a VIP-like substance, seems to do this tuning quite well. By doing this, it protects up to 80% of the cells in PD mice. The dubious, but curious, neurologists will await the results of human trials.


By Marvin 101 - Own work, CC BY-SA 3.0, Link
By Marvin 101Own work, CC BY-SA 3.0, Link

α-synuclein is the abnormal protein which accumulates in brain cells, thereby causing the damage which results in PD. α-synuclein is removed from the brain by another protein named DJ-1. Researchers have shown that the gene which regulates the production of DJ-1 is abnormal in a hereditary form of PD called PARK-7. This is where phenylbutyrate steps into the picture; studies have shown that phenylbutyrate ‘up-regulates‘ the DJ-1 gene, thereby enhancing its activity, which is to efficiently flush α-synuclein out of the brain. As phenylbutyrate seems to do this trick in mice, human trials are now under way. All is explained in the paper published in the Journal of Biological Chemistry titled Phenylbutyrate upregulates DJ-1 and protects neurons in cell culture and in animal models of Parkinson’s disease.


mTOR-FKBP12-RAPAMYCIN. Enzymlogic on Flikr. https://www.flickr.com/photos/101755654@N08/9735128265
mTOR-FKBP12-RAPAMYCIN. Enzymlogic on Flikr. https://www.flickr.com/photos/101755654@N08/9735128265

What we need is a drug which stops PD from taking its first step. And this is what Rapamycin seems to have done in mice. I first read this in an article in PsyPost brilliantly titled Rapamycin prevents Parkinson’s in mouse model of incurable neurodegenerative disease. I followed the link to the research paper published in Journal of Neuroscience, irritatingly titled Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin. I tried to decipher what the abstract was saying but read like a foreign language to me. I therefore recommend the PsyPost article for the sake of sanity. Again, we have to wait and see what rapamycin does in humans.


Microglia. Servier Medical Art on Flikr. https://www.flickr.com/photos/serviermedicalart/9731764084
Microglia. Servier Medical Art on Flikr. https://www.flickr.com/photos/serviermedicalart/9731764084

PD researchers are also exploring the neuroprotective potential of safinamide. This is a monoamine oxidase inhibitor (MAOI) which reduces the breakdown of levodopa, the key drug treatment of PD. Safinamide is already licensed as an add-on drug in the treatment of PD. Its neuroprotective effect has been linked to its ability to suppress the activation of microglia, the brain cells which mediate inflammatory cellular damage. Only time will tell.


The last three potentially  neuroprotective PD drugs are:






Portents of great things to come, I’m sure. Want to explore more on PD? Have a look at these older posts, and do leave a comment