I am a UK Neurologist keen on general neurology, but with an interest in neuromuscular diseases. I maintain the neurology searchable database, www.neurochecklists.com. I share and discuss current issues around clinical neurology. I hope you find this blog enlightening, practical, and even entertaining.
White matter abnormalities in the corpus callosum with cognitive impairment in Parkinson disease. Bledsoe IO, Stebbins GT, Merkitch D, Goldman JG. Neurology 2018 (Epub ahead of print) Abstract OBJECTIVE: To evaluate microstructural characteristics of the corpus callosum using diffusion tensor imaging (DTI) and their relationships to cognitive impairment in Parkinson disease (PD). METHODS: Seventy-five participants […]
Ever wondered what Neurochecklists subscribers most frequently search? Below are the 10 most popular topics on Neurochecklists: Drug-induced encephalopathy: causes Seizure history Seizures: classification Antiepileptic drugs (AEDs): choice with medical conditions Sleep disorders: classification Exploding head syndrome (EHS) Anti DPPX autoimmune encephalitis Lumbar puncture (LP): indications and precautions Transient ischaemic attacks (TIA): clinical features Cervical […]
Alzheimer’s disease (AD) is one of the most fearsome and recalcitrant scourges of neurology. We think we know a lot about it; after all it has been a quite a while since Alois Alzheimer described amyloid plaques and neurofibrillary tangles in his index patient, Frau Deter. But the more neuroscientists study the disease, the murkier the field looks. For example, we are still not quite sure what the plaques and tangles really signify; for all we know, they may just be innocent bystanders, powerless by-products of a neurodegenerative process that defies understanding. We have accumulated an endlessly long list of AD risk factors, but we have singularly been unable to point a finger at the cause of AD.
This elusive void may however be a void no longer, if what superficially appears to be an outlandish theory turns out to be correct. And the theory is that AD is caused by infection! Just take a deep breathe, and allow yourself the space to make a giant leap of imagination. My attention was first drawn to the infective hypothesis of AD by a headline in Scientific American screaming Controversial New Push to Tie Microbes to Alzheimer’s Disease. The obvious key word here of course is controversial: is it possible that AD, this quintessential neurodegenerative disease, is…just another chronic infection?
To find the original source of the story, the trail of bread crumbs led to an editorial published in the Journal of Alzheimer’s Disease in 2016, plainly titled Microbes and Alzheimer’s Disease. But this is not a run-of-the-mill editorial at all because it was written by 33 senior scientists and clinicians from a dozen countries. And their reason for an alternative theory of AD is simple: amyloid, the long-suspected culprit for decades, has failed to live up to its billing. They point out that amyloid exists harmlessly in the brains of many older people who never go on to develop dementia. They also cite studies which demonstrate that treating amyloid, by immunological means, does not improve the state of people suffering from AD. Amyloid, in other words, is not such a bad guy after all. But all the while we have been setting traps to ensnare it, the microbial villains have been running amok, having a field day.
But why should microbes succeed where amyloid, the ubiquitous protein, has woefully failed? The editorial gave 8 good reasons to argue that the infection theory is better than the amyloid hypothesis. One reason is that the brains of people with AD are often riddled with inflammation, a characteristic feature of infections. Another reason is the observation that AD can be transferred to primates when they are inoculated with the brain tissue of someone with AD.
And the culprit with the most number of index fingers pointing at it is herpes simplex virus type 1 (HSV1). The editorial tells us that there have been about 100 publications, by different groups, demonstrating that HSV1 is a ‘major factor‘ in the causation of AD. Some of these studies have shown that people with AD have immunological signs of significant HSV infection in their blood. The editorial goes further to review the possible mechanisms by which HSV1 may cause AD; one of these is the possibility that the virus lowers the risk of AD in people who possess the APOE ɛ4 allele genetic liability.
Just when you are getting your head round the idea, the infection theory takes a very sinister turn. And this relates to the perversemodus operandi of the microbes. The authors tell us that the microbes first gain access to the brains of their victims when they (the victims) were much younger. Like sleeper cells in their ghoulish crypts, the microbes hibernate, biding their time until their victims get older, and their immunity declines. The microbes then awaken, and like malevolent zombies, set out to wreak gory mayhem and cataclysmic destruction. And they do this either by causing direct damage to the brain, or indirectly by inducing inflammation.
You can now descend form your giant imaginative leap and start to wonder: if AD is indeed caused by microbes, what can we do about it? ‘Tis time for some down-to-earth deep thinking.
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Traumatic brain injury (TBI) is simply disheartening. It is particularly devastating because it usually affects young people in their prime, with the consequent personal, social, and economic consequences. This blog has previously touched a little on TBI with the post titled Will Smith and chronic traumatic encephalopathy?This was a light-hearted take on concussion in sports, but traumatic brain injury is nothing but a serious burden. So what are the big brains in white coats doing to take down this colossus? Quite a lot it seems. Here, for a taster, are 9 promising advances in the management of traumatic brain injury.
An amyloid PET imaging study by Gregory Scott and colleagues, published in the journal Neurology, reported a rather surprising link between the pathology seen in long-term survivors of traumatic brain injury, with the pathology seen in Alzheimers disease (AD). In both conditions, there is an increased burden of β-amyloid (Aβ) in the brain, produced by damage to the nerve axons. The paper, titled Amyloid pathology and axonal injury after brain trauma, however notes that the pattern of Aβ deposition in TBI can be distinguished from the one seen in AD. The big question this finding raises is, does TBI eventually result in AD? The answer remains unclear, and this is discussed in the accompanying editorial titled Amyloid plaques in TBI.
The ideal biomarker for any disorder is one which is easy to detect, such as a simple blood test. A headline that screams Blood test may offer new way to detect concussionsis therefore bound to attract attention. The benefits of such a test would be legion, especially if the test can reduce the requirement for CT scans which carry the risks of radiation exposure. This is where glial fibrillary acidic protein (GFAP) may be promising. The research is published in the journal, Academic Research Medicine, with a rather convoluted title, Performance of Glial Fibrillary Acidic Protein in Detecting Traumatic Intracranial Lesions on Computed Tomography in Children and Youth With Mild Head Trauma. The premise of the paper is the fact that GFAP is released into the blood stream from the glial cells of the brain soon after brain injury. What the authors therefore did was to take blood samples within 6 hours of TBI in children. And they demonstrated that GFAP levels are significantly higher following head injury, compared to injuries elsewhere in the body. This sounds exciting, but we have to wait and see where it takes us.
Brain Scars Detected in Concussionsis the attention-grabbing headline for this one, published in MIT Technology Review. Follow the trail and it leads to the actual scientific paper in the journal Radiology, with a fairly straight-forward title, Findings from Structural MR Imaging in Military Traumatic Brain InjuryThe authors studied >800 subjects in what is the largest trial of traumatic brain injury in the military. Using high resolution 3T brain magnetic resonance imaging (MRI), they demonstrated that even what is reported as mild brain injury leaves its marks on the brain, usually in the form of white matter hyperintense lesions and pituitary abnormalities. It simply goes to show that nothing is mild when it comes to the brain, the most complex entity in the universe.
Current technologies which monitor patients with traumatic brain injury are, to say the least, cumbersome and very invasive. Imagine if all the tubes and wires could be replaced with microsensors, smaller than grains of rice, implanted in the brain. These would enable close monitoring of critical indices such as temperature and intracranialpressure. And imagine that these tiny sensors just dissolve away when they have done their job, leaving no damage. Now imagine that all this is reality. I came across this one from a CBS News piece titled Tiny implanted sensors monitor brain injuries, then dissolve away. Don’t scoff yet, it is grounded in a scientific paper published in the prestigious journal, Nature, under the title Bioresorbable silicon electronic sensors for the brain. But don’t get too exited yet, this is currently only being trialled in mice.
What if the inflammation that is set off following traumatic brain injury could be stopped in its tracks? Then a lot of the damage from brain injury could be avoided. Is there a drug that could do this? Well, it seems there is, and it is the humble blood pressure drug Telmisartan. This one came to my attention in Medical News Today, in a piece titled Hypertension drug reduces inflammation from traumatic brain injury. Telmisartan seemingly blocks the production of a pro-inflammatory protein in the liver. By doing this, Telmisartan may effectively mitigate brain damage, but only if it is administered very early after traumatic brain injury. The original paper is published in the prestigious journal, Brain, and it is titled Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Again, don’t get too warm and fuzzy about this yet; so far, only mice have seen the benefits.
Fatigue is a major long-term consequence of traumatic brain injury, impairing the quality of life of affected subjects in a very frustrating way. It therefore goes without saying, (even if it actually has to be said), that any intervention that alleviates the lethargy of TBI will be energising news. And an intervention seems to be looming in the horizon! Researchers writing in the journal, Acta Neurologica Scandinavica, have reported that Methylphenidate significantly improved fatigue in the 20 subjects they studied. Published under the title Long-term treatment with methylphenidate for fatigue after traumatic brain injury, the study is rather small, not enough to make us start dancing the jig yet. The authors have rightly called for larger randomized trials to corroborate their findings, and we are all waiting with bated breaths.
Many survivors of traumatic brain injury are left with behavioural disturbances which are baffling to the victim, and challenging to their families. Unfortunately, many of the drugs used to treat these behaviours are not effective. This is where some brilliant minds come in, with the idea of stimulating blood stem cell production to enhance behavioural recovery. I am not clear what inspired this idea, but the idea has inspired the paper titled Granulocyte colony-stimulating factor promotes behavioral recovery in a mouse model of traumatic brain injury. The authors report that the administration of G‐CSF for 3 days after mild TBI improved the performance of mice in a water maze…within 2 weeks. As the water maze is a test of learning and memory, and not of behaviour, I can only imagine the authors thought-surely only well-behaved mice will bother to take the test. It is however fascinating that G‐CSF treatment actually seems to fix brain damage in TBI, and it does so by stimulating astrocytosis and microgliosis, increasing the expression of neurotrophic factors, and generating new neurons in the hippocampus“. The promise, if translated to humans, should therefore go way beyond water mazes, but we have to wait and see.
The idea behind using Etanercept to promote recovery from brain injury sound logical. A paper published in the journal, Clinical Drug Investigation, explains that brain injury sets off a chronic lingering inflammation which is driven by tumour necrosis factor (TNF). A TNF inhibitor will therefore be aptly placed to stop the inflammation. What better TNF inhibitor than Eternacept to try out, and what better way to deliver it than directly into the nervous system. And this is what the authors of the paper, titled Immediate neurological recovery following perispinal etanercept years after brain injury, did. And based on their findings, they made some very powerful claims: “a single dose of perispinal etanercept produced an immediate, profound, and sustained improvement in expressive aphasia, speech apraxia, and left hemiparesis in a patient with chronic, intractable, debilitating neurological dysfunction present for more than 3 years after acute brain injury”. A single patient, mind you. Not that I am sceptical by nature, but a larger study confirming this will be very reassuring.
And finally, that elusive holy grail of neurological therapeutics, neuroprotection. Well, does it exist? A review of the subject published in the journal, International Journal of Molecular Sciences, paints a rather gloomy picture of the current state of play. Titled Neuroprotective Strategies After Traumatic Brain Injury, it said “despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed“. But all is not lost. The authors promise that “recent changes in experimental approach and advances in clinical trial methodology have raised the potential for successful clinical translation”. Another review article, this time in the journal Critical Care, doesn’t offer any more cheery news about the current state of affairs when it says that the “use of these potential interventions in human randomized controlled studies has generally given disappointing results”. But the review, titled Neuroprotection in acute brain injury: an up-to-date review, goes through promising new strategies for neuroprotection following brain injury: these include hyperbaric oxygen, sex hormones, volatile anaesthetic agents, and mesenchymal stromal cells. The authors conclude on a positive note: “despite all the disappointments, there are many new therapeutic possibilities still to be explored and tested”.
The blogosphere is a crowded place. To stand out from the pack, a lot of bustling and hustling takes place. Medical blogging is not exempt from this melee. However, in the zeal to put blog posts in the limelight, the blogger may inadvertently fixate on high profile diseases, the ones that seem to readily covet the headlines. In this way, deadlier but less ‘celebrity’ maladies are left to simmer and fester below the radar. To avoid falling into this trap, this blog endeavours, (every now and then), to shine a light on these clandestine infirmities. These are the plagues which profit by virtue of their anonymity. It is no surprise that many of these disorders aretropical diseases, and there is no sweltering equatorial beast more sinister than the ague. It is therefore in the interest of fairness and balance that we are putting cerebral malaria in the powerful spotlight.
Malaria is a beast because it is endemic in many developing countries. The epidemiological map below gives a flavour of which countries receive the brunt of the miasm.
Just like other parasitic infections, malaria undertakes a tortuous life cycle. It appears that it is in the nature of these scroungers to beguile and hoodwink their way to the human bloodstream. Scurrying and scampering, they transit from mosquito to man. It is to the credit of malaria-busters such as Ronald Ross that their deceptive course, pictured below, was revealed.
And a nasty monster is malaria. The different malaria species are transmitted by the female Anopheles mosquito (please don’t ask why). Finding warm veins irresistible, she sates her bloodthirsty cravings whilst unknowingly transmitting the malaria buggers called sporozoites. Once they get to the liver, these transform into insatiable merozoites which are tasked with one hatchet job: detect, invade and destroy innocent hardworking red blood cells. OK, I admit that’s three hatchet jobs.
The plasmodium species vivax, ovale, and malariae can all wreak atrocious havoc, but it is falciparum that poses the greatest threat to the nervous system. This is partly because falciparum can make its host cells sticky, and in the brain, these sticky cells adhere tightly to the walls of blood vessels. This is how falciparum evades detection by the immune system, and how it escapes destruction by drugs. The sticky cells eventually clogup the cerebral circulation, resulting in the infamous malarial vasculopathy. Left untreated, cerebral malaria is sadly invariably fatal.
Cerebral malaria has diverse manifestations, and the most devastating includeretinopathy, rigidity, ataxia (poor balance), subarachnoid haemorrhage, psychosis, hemiparesis, epilepsy, behavioural abnormalities, and coma. And this is over and above what malaria does to the other organs. The run down is very scary indeed; from anaemia to pulmonary edema, from hypoglycaemia (low glucose) tohyponatraemia (low sodium); from metabolic acidosis to hyperpyrexia (high fever), from disseminated intravascular coagulation (DIC) to adult respiratory distress syndrome (ARDS). Heartbreaking.
The investigations of cerebral malaria range from the humble blood film to brain imaging. Treatments include artemisinin derivatives and cinchona alkaloids. A malaria vaccine remains a dream, but not a far-off one; the RTS,S/AS01 vaccine is a promising candidate. Until this aspiration is achieved, the best hope against cerebral malaria remains prevention. The solutions are simple: basic sanitation, public education, and poverty alleviation. But the implementation seems to defy the wits of the great and the good. A lot of work remains to be done.
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: CDC/James GathanyProvider Email:jdg1@cdc.govPhoto Credit: James Gathany - CDC http://phil.cdc.gov/PHIL_Images/09262002/00008/A.gambiae.1354.p_lores.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=745600)
