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:
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!
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:
These papers reporting the absence of evidence seem happy to engage in an amicable debate to resolve the question.
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
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.
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!
6. Fetal stem cell transplantation
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
7. Pluripotent stem cell transplantation
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.
Multiple system atrophy (MSA) is a mimic of Parkinson’s disease (PD). Neurologists suspect MSA in people with apparent PD who, in addition, have other defining features. In many people with MSA their prominent symptoms are cerebellar dysfunction (MSA-C), and these have unsteadiness and incoordination of movements. In other people with MSA the predominant symptoms are of Parkinsonism, and this type is called MSA-P.
Making a diagnosis of MSA is gratifying, but treating it is frustrating. Only about a third of people with MSA respond to the standard PD medication, Levodopa. Furthermore, MSA confers a shortened life expectancy. It is therefore important that neurologists resolve the mystery of MSA, and they are indeed hacking away at its cutting-edge.
The general assumption is that MSA is acquired rather than inherited. This assumption did not dissuade neurologists from looking for MSA genetic risk factors, and their quest has led to the discovery of a candidate MSA gene. This is called coenzyme Q2 4-hydroxybenzoate polyprenyltransferase, or simply the COQ2 gene. This gene was first touted in a 2013 paper in the New England Journal of Medicine titled Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy. Using whole genome sequencing, the authors identified COQ2 gene mutations in both sporadic and familial cases of MSA. Another paper in Neurology in 2016, titled New susceptible variant of COQ2 gene in Japanese patients with sporadic multiple system atrophy, reported that the COQ2 gene mutation is more likely in MSA-C than in other types of MSA.
When neurologists are considering the diagnosis of MSA, they come up against many disorders jostling to confuse them. There are of course PD and related conditions such as progressive supranuclear palsy (PSP). There is also the endless list of conditions which cause either cerebellar or autonomic dysfunction. The neurologist is usually cautious to exclude these known differential diagnoses of MSA. But what happens when they come across a mimic that isn’t in the textbooks? Such is the situation with this case report published in Movement Disorders of Concomitant Facioscapulohumeral Muscular Dystrophy and Parkinsonism Mimicking Multiple System Atrophy.
This case defies the law of parsimony, Occam’s razor. To paraphrase, this law states that a single diagnosis is the most likely cause for a patient’s clinical features. Clearly in some cases such as this, the neurologist must disregard William of Occam,and make multiple diagnoses.
Neurologists often request some tests to confirm their suspicion of MSA. The usual investigation is the painless but claustrophobic magnetic resonance imaging (MRI). In MSA, this shows shrinking or atrophy of the cerebellum. It may alsoshow the hot cross bun sign, a characteristic pattern of shrinking of the chunky middle section of the brainstem, the pons.
Some neurologists are not satisfied with this culinary sign and have explored other radiological indicators of MSA. They studied an MRI technique called diffusion tensor imaging tractography (DTI tractography) and reported their findings in the Journal of Neurology. Their paper titled Characteristic diffusion tensor tractography in multiple system atrophy reports that DTI tractography appears to distinguish MSA-C from other causes of cerebellar dysfunction.
Biomarkers again, so soon after my previous blog post, What is the state of parkinson’s disease biomarkers. The whole idea behind biomarkers is their potential to make for an easier and earlier diagnosis. They are all the rage in neurodegenerative diseases, and MSA can’t be an exception. The first potential MSA biomarker is α-synuclein, the abnormal protein that is found in the brains of people with PD, MSA and Lewy body disease (LBD), the so-called synucleopathies. Researchers have now discovered that α-synuclein also resides in the skin. They carried out skin biopsies in people with PD and MSA and found skin deposits of α-synuclein in both. Writing in the journal Movement Disorders, they showed that in PD, the deposits were mainly in autonomic nerve fibers, whilst in MSA they were in the larger somatic nerves. Time to brush up those skin biopsy skills!
The second potential biomarker is optical coherence tomography (OCT). This is reported in Movement Disorders in a paper titled Progressive retinal structure abnormalities in multiple system atrophy. The authors used OCT to measure the thickness of the retina of the eye. They demonstrated that the retina is thin in both PD and MSA, but the thinning advances more rapidly in MSA than in PD. If confirmed, this would be a handy, and painless, biomarker.
The objective of all research is to arrive at effective treatments. There is unfortunately no bright treatment looming in the MSA horizon because the research so far have produced disappointing results. Such failures include Rifampicin, Fluoxetine and Lithium. There is however no scarcity of potential therapeutic candidates. The most exciting is a vaccine against MSA. For this and other research efforts read this excellent review in Advances in Clinical Neurology and Rehabilitation (ACNR) titled Updates on potential therapeutic targets in MSA.
Parkinson’s disease (PD) looms large in neurology. As I try to make sense of developments in this field, I am struck by the large number of curious reports emerging all around it. I thought I had covered this comprehensively in my previous blogs, PD-a few curious things and Bee venom acupuncture for PD. On the contrary it looks like I opened a can of worms. I will therefore give the peculiar and the curious one last heave before proceeding to some conventional blogs I have in the pipeline on PD. Here then are 13 unusual things about PD.
Uncertainty and doubt abound in Neurology. There are many evidence-free areas where experts rub each other the wrong way. These controversies are big and occur in all neurology subspecialties. Controversy-busters have tried for about a decade to iron out these wrinkles on neurology’s face, but the unanswered questions remain. This is why there is a 10th World Congress of Controversies in Neurology (CONy) holding in Lisbon this year.
I want to assure you I have no conflict of interest to declare in this blog. My interest is to explore which questions have plagued this conference over the last 10 years to pick out the most controversial topics in neurology. To do this I reviewed all previous conference programs and focused on the items that were slated for debate. I looked for practical topics that have remained unresolved, or are just emerging. Here are my top controversial neurological questions:
Which should be the first-line therapy for CIDP? Steroids vs. IVIg
Should disease-modifying treatment be changed if only imaging findings worsen in multiple sclerosis?
Should disease-modifying therapies be stopped when secondary progressive MS develops?
Should non-convulsive status epilepsy be treated aggressively?
Does traumatic chronic encephalopathy (CTE) exist?
Does corticobasal degeneration (CBD) exist as a clinico-pathological entity?
Is ß-amyloid still a relevant target in AD therapy?
Will electrical stimulation replace medications for the treatment of cluster headache?
Carotid dissection: Should anticoagulants be used?
Is the ABCD2 grading useful for clinical management of TIA patients?
Do COMT inhibitors have a future in treatment of Parkinson’s disease?
Going through this list, I feel reassured that the experts differ in their answers to these questions? The acknowledgement of uncertainty allows us novices to avoid searching for non-existent black and white answers. It is however also unsettling that I thought some of these questions had been settled long ago. It goes to show that apparently established assumptions are not unshakable?
Do you have the definitive answers to resolve these controversies? Are there important controversies that are missing here? Please leave a comment