Putting cerebral malaria in the powerful spotlight

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 are tropical 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 in peripheral blood. Ed Uthman on Flickr. https://www.flickr.com/photos/euthman/6289093848

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.

Von S. Jähnichenhttp://rbm.who.int/wmr2005/html/map1.htm and http://www.dtg.org/uploads/media/Malariakarte-DTG-2005_04.pdf, CC BY-SA 3.0, Link

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.

Life cycle of the malaria parasite. NIAID on Flickr. https://www.flickr.com/photos/niaid/20771605491

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.

By NIAID – Malaria Parasite Connecting to Human Red Blood Cell, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=62117171

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 clog up the cerebral circulation, resulting in the infamous malarial vasculopathy. Left untreated, cerebral malaria is sadly invariably fatal.

By Content Providers(s): 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

Cerebral malaria has diverse manifestations, and the most devastating include retinopathy, 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) to hyponatraemia (low sodium); from metabolic acidosis to hyperpyrexia (high fever), from disseminated intravascular coagulation (DIC) to adult respiratory distress syndrome (ARDS). Heartbreaking.

Malaria-infected red blood cell. NIH Image Gallery on Flickr. https://www.flickr.com/photos/nihgov/26834372607

The investigations of cerebral malaria range from the humble blood film to brain imagingTreatments 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.

By Rick Fairhurst and Jordan Zuspann, National Institute of Allergy and Infectious Diseases, National Institutes of Health – https://www.flickr.com/photos/nihgov/25534997493/in/photolist-EUrx8t-CvR53a-B3Ad52-ydGygr-wZzPff-C5BN5H, Public Domain, https://commons.wikimedia.org/w/index.php?curid=49182050

Why not check out the following related posts in our other blog, Neurochecklists Updates:

The 8 most parasitic infestations of the nervous system

 

The 7 most ruthless bacterial infections of the nervous system

 

The 7 most devastating viral neurological infections

 

Standing up to the challenge of refractory epilepsy

In neurology, the word ‘refractory‘ is almost exclusively used in relation seizures. It may apply to drug-resistant epilepsy (DRE), or to rampaging status epilepticus.’Refractory’ doesn’t sound good in whatever context it is used, typically connoting a situation beyond redemption. But this is not the case with epilepsy. Rather than a bell tolling in despair, refractory is used in epilepsy as a bugle calling to arms.

Ask Not For Whom the Bell Tolls...Vicky Vinch ON/OFF on FLikr https://www.flickr.com/photos/91593630@N08/28095933065
Ask Not For Whom the Bell Tolls…Vicky Vinch ON/OFF on Flikr https://www.flickr.com/photos/91593630@N08/28095933065
 

Refractory epilepsy

If anyone was asked to imagine refractory epilepsy, they would surely picture a case that has failed to respond to the heavy arsenal of anti-epileptic drugs (AEDs). They would visualise a patient who has failed Lamotrigine, Carbamazepine, Valproate, and Levetiracetam. They would envisage subsequent failures with Zonisamide, Eslicarbazepine, Oxcarbazepine, and Lacosamide. They would clearly see a neurologist desperately hoping that the seizures would respond to the new AEDs on the block such as PerampanelBrivaracetam or Retigabine.

Hands of Desperation. Chris Kueh on Flikr. https://www.flickr.com/photos/chriskueh/2377817173
Hands of Desperation. Chris Kueh on Flikr. https://www.flickr.com/photos/chriskueh/2377817173

They would be very wrong. Rather than a failure of all AEDs, refractory epilepsy is defined by the International League Against Epilepsy (ILEA) as the failure of two well-chosen and tolerated AEDs. The chances of achieving seizure freedom in this situation are slim, and the sooner non-drug interventions are considered, the better. ‘Refractory’, in the context of epilepsy, is therefore a red flag for the neurologist to prevent years of juggling partially effective drugs. It is an early warning system to consider non-drug interventions such as surgery and neuromodulation. This point was strongly made in an article in European Neurological Review titled Treating Drug-resistant Epilepsy – Why are we Waiting? Well worth a read!

Red Flags on the Railway Line. Evelyn Simak on geograph. http://www.geograph.org.uk/photo/1572393
Red Flags on the Railway Line. Evelyn Simak on Geograph. http://www.geograph.org.uk/photo/1572393

Refractory status epilepticus

Refractory is also used in the context of status epilepticus where it describes the failure of two different anti-status medications. In this case, ‘refractory’ tells us that it’s time to use anaesthetic agents to put the patient to sleep, and essentially wait for things to settle. The real challenge comes when this strategy fails. What name do we give this conundrum that goes beyond refractory, and is there anything we can do about it?

By Vaikoovery - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=18416242
By Vaikoovery – Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=18416242

The experts ingeniously named this scenario super-refractory status epilepticus! And this super duper name doesn’t scare them from trying to treat it. In their enlightening and hope-raising critical review of super refractory status epilepticus, published in the journal Brain, epilepsy experts Simon Shorvon and Monica Ferlisi offer a surprisingly long list of interventions for super refractory status epilepticus. These include magnesium, steroids, IVIg, plasma exchange, hypothermia, the ketogenic diet, and Rufinamide. The review is a must-read for anyone who manages status epilepticus (or they could look up the condensed version in neurochecklists!)

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Wish to explore more? Why not check out

Should neurologists be thinking of Influenza H1N1?

Every now and then neurologists come across patients with what appears to be ‘straightforward’ viral encephalitis but who do not respond to conventional treatment. These treatments are usually according to established guidelines such as the ABN/BIAN guidelines, the IDS Guidelines. What to do when the patient isn’t responding is however very challenging.

Journal of Neuroinfectious Diseases (ssshh…the JNNP declined it) has just published our case report of such a patient who turned out to have H1N1 influenza encephalopathy. This experience suggests we should consider an autoimmune cause in such cases, especially if the spinal fluid does not show any viruses.

3D model of influenza virus
3D model of influenza virus

 

It’s only a single patient but with an excellent outcome and valuable insights (I would say so wouldn’t I!). It was rather fortuitous as her treatment with IVIg was on the assumption she had anti NMDA antibody encephalitis. Its not always in the science as the viral serology subsequently showed!

Is your interest piqued enough? OK, here is the link (and its open access):

H1N1 Associated Encephalopathy in an Adult: Response to Intravenous Immunoglobulin Supporting an Autoimmune Pathogenesis