Thursday, 8 August 2013

Sunday, 9 June 2013

Neuroprotection in stroke; a slow burner

Neuroprotection in stroke; a slow burner.

One of the real surprises of medical school is coming to terms with the protracted nature of medical research.  Developing a robust drug which passes appropriate quality and safety standards is increasingly likely to tip-toe over the decade mark onwards.

Within Neurology, arguably the most troublesome of clinic trials has revolved around finding a group of neuroprotective agents which tick all the boxes. Neuroprotection works on the principal that neuronal tissue may be salvaged from an ischaemic event by endowing it with a greater resilience to the effects of hypoxia.

While neuroprotective agents offer a tantalizing holy grail of a lower risk, lower resource alternative to thrombolytics, the development process has been dogged by setbacks..... To the tune of over 1000 unsuccessful potential treatments.  Most of which have been nipped in the bud by the jump from cellular and rodent models to human trials by an unwanted side effects profile or ineffectiveness. 

NA-1, is a neuroprotective agent that has previously been shown to be efficacious in a primate model of stroke.  It works by disrupting the neurotoxic pathways of NMDA glutamate receptors and imbuing cells with a greater tolerance to hypoxia. A recent Lancet Neurology paper followed a phase II trial of individuals undergoing endovascular intracranial aneurysm repair.  Participants were randomized to receive either intraoperative NA-1 or a saline control. Up to 90% of individuals undergoing this procedure show evidence of small embolic iatrogenic stroke on diffusion weighted MRI.  So the study group was a very appropriate target to put it mildly.

Individuals receiving NA-1 were significantly less likely to have experienced new brain infarctions (OR 0.53 CL 0.38-74) on DW MRI then controls.  More so, rather conspicuously, the authors reported no serious adverse effects of the study drug, a promising finding that if genuine warrants a larger trial.  However the drug's administration soley to individuals who were anaesthetised may limit its study in the near future to invasive treatments carrying a risk of brain injury rather than community admitted patients with ischaemic stroke. 

For the moment the clock keeps ticking…

Friday, 24 May 2013

Hitting the sweet spot

In his landmark work The Structure of Scientific Revolutions Thomas Kuhn argued that far from being a well ordered and timely process, scientific advancement occurs in an erratic, opportunistic and even irrational manner often with no overt overarching dialogue.    The scientific community is just that, a community.  Ideas continuously flourish, grow and are put to the mill to make room for better fitting (or perhaps just better sounding) paradigms. So it may be worth asking, in the age of the meme driven global village, what hope is there for mere individuals to make ripples in a sea of convolution and hyperspecialisation?
Well, perhaps more than we think.  Contributing to scientific progress as a whole, far from becoming more unreachable for individuals or indeed small groups of interested individuals, may actually be becoming more attainable.  This is thanks to the widening array of easily accessible and evolving technologies which have, at present, outstripped our capacity to come up with innovative uses for them.
Echoing this idea, the BMJ, recently published a meta-analysis of several trials looking at the use of ultrasound as a guidance technique for lumbar puncture.  With the advent of portable ultrasound probes, novel uses are in abundance.  Screening for parkinsons disease, the management of shoulder dislocation and joint reduction to name a few.  One of the advantages of metaanalyses is that they clump together groups of similar studies to look at outcomes which may not be obvious in small studies or have the statistical power to be significant.  Through grouping the studies the authors were able to show that ultrasound guided lumbar puncture has a significantly lower failure rate and risk of trauma than unguided procedures.   A relatively simple finding which may forever change the way we perform this essential diagnostic investigation.
It seems that the chance of having a idea that is ripe for the times has never been better...

Sunday, 19 May 2013

Niblet by Andrew Cummings

Getting into minutiae in a big way….

You can know the name of a bird in all the languages of the world, but when you're finished, you'll know absolutely nothing whatever about the bird...”
 Richard Feynman

In our investigation centric age you are likely someday to find yourself nodding blandly at an MRI head report with the words “age related changes with SVD only” hanging loosely in the opening sentence.  For all our sense of familiarity with small vessel disease (SVD) its apparent unobtrusiveness disguises a world of complexity. 

The putative role for SVD in neurological, psychiatric and cognitive disease burden is huge.  It is responsible for around a fifth of all strokes, doubles the overall risk and contributes to around half of all dementias. In this months Lancet Neurology, Joanna Wardlaw produced a well thought out review which goes into detail about the who’s who of this disease.

But lets go back a step.  What actually is SVD?  On pathological sections, typical T1-, T2-weighted imaging and FLAIR scans, SVD appears as a combination of small subcortical hemorrhages and infarctions, their resultant lacunes (CSF filled cavities) and brain atrophy.  With the advent of more advanced forms of imaging such as diffusion tensor imaging and magnetization ratio, the more indolent effects of SVD; altered myelination, focal thinning of cortical grey matter and even disruption to axonal transport have been observed.  This is all well and good, but the key question is what is the actual cause of these phenomenon?

At a histopathological level SVD appears as a diffuse, intrinsic disease of small arterioles with a characteristic appearance of damage from inflammatory cell infiltration into the vessel wall and perivasculature.  Hypertension, vasospasm and microatheroma have all been put forward as possible mechanisms for this. 

But there’s a difficulty…

The bare bones of it is that while SVD and cortical strokes are globally associated with vascular risk factors, in studies of normotensive patients with SVD verified at autopsy a majority showed limited vascular risk factors.  While hypertension is known associated with the development of white matter hyperintensities (another radiological sign of SVD) the mechanism by which these lead to vascular damage is convoluted at best.  There is a suggestion, that part of the observed association we see between SVD and hypertension may actually be due in part to co-localisation of genetic loci for susceptibility to both these conditions.

So if hypertension isn’t the only answer, what else might be?    Wardlaw and colleagues noticed that in many pathological specimens of lacunar infarcts, a central perforating arteriole with a thickened wall runs through the centre of the infarct rather than proximal to it.  This suggests that rather than occlusion and resultant hypoxia occurring downstream of an atheromatous lesions (as we are familiar with), something else is happening directly around the affected vessel that leads to the eventual infarction.  That something, the authors suggest, is endothelial dysfunction. 

The cells of the cerebrovascular endothelium are most closely “packed” at the level of capillaries with widening gap junctions in arterioles and venules.  With advancing age, inflammation and oxidative stress this barrier becomes more permeable.  Interestingly, in animal models of SVD, short exposure to salt (a known risk factor) is enough to cause a worsened degree of the latter two of these alongside small vessel pathology.  The authors suggest that in areas of the brain which have impaired endothelial function, a leakage of plasma contents and migration of inflammatory cells ensues.  This leads to distortion of the arteriolar lumen eventually leading to thrombosis. Perivascular tissue damage also takes place, resulting in the white matter demyelination and dilatation of perivascular spaces observed as hyperintensities on MRI. 

By Andrew Cummings (Academic F2, Barts Health)

Wednesday, 3 April 2013

Case study: apnoea post cardiac arrest

You are called to see a patient who has had a cardiac arrest and was successfully resuscitated and is the intensive care unit in a "coma". The patient is not on a ventilator and is breathing spontaneously. You notice that the patient has periods of apnoea. The following is a trace of the patient's breathing pattern:


Level 1:

How do you define apnoea?

Level 2:

What is this pattern or breathing called?

What is the prognostic significance of this breathing pattern?

How does it differ from Cheyne-Stokes respiration?


Saturday, 19 January 2013

The Neurological Exam

Level 1: the neurological examination

I found a very good site that is well indexed with embedded videos of the neurological examination. You may want to use this as a refresher. 


Knowing how to perform the neurological examination and knowing the relevant functional neuroanatomy that underpins the examination is vital if you want to graduate from medical school a neurophile. The alternative is neurophobia and a life of professional hell every time you have to see a patient with a neurological complaint. 

Sunday, 13 January 2013

Blink reflex or optical reflex

Level 1: optical reflex & Level 3: blindsight

Optical reflex: In addition to the corneal or sensory blink reflex, blinking can be elicited by visual or auditory input; i.e. bright lights, central and peripheral stimuli and loud noises. The evolutionary purpose of this reflex is again to protect the eyes from foreign bodies and bright lights. Blinking in response to a threatening visual stimulus is known as the optical reflex. 

Neuroanatomy and neurophysiology: The optical reflex is subcortical and is controlled via a pathway that bypasses the lateral geniculate body, optic radiations and visual cortex and goes directly to the superior colliculi. This pathway then relays to several brain stem and spinal nuclei via the tectobulbar and tectospinal pathways that initiate the motor response; i.e. blinking, flexing your arms upwards to protect your eyes, flexion and lateral rotation of the head away from the stimulus and finally flexion of the trunk and lower limbs to duck under the stimulus. Most of us will have experienced this reflex, for example when an insect flies suddenly into our field of vision, or when we duck or dive to prevent being hit in the face by a tennis or football, or the reflex ducking of the head to prevent hitting an overhanging branch when walking. This neuronal pathway is responsible for reflex movements in response to visual stimuli and is the pathway that allows us to play ball sports that require very rapid movements, for example tennis, cricket, baseball etc. A cricketer or tennis player hits the ball before they become consciously aware of the ball. 

Clinical Utility: The optical reflexes can be used to test visual function in patients who are semi-concious or unconscious and indicate that the retina and brain stem are functioning. This reflex is particularly useful in young children. It is also used in patient who present with blindness; if present it indicates that the lesion is very posterior, i.e. cortical, or the patient has functional or hysterical blindness. In these situations the pupillary reflexes are also present , but not the optokinetic response or reflex that is a more complex visual reflex that relies cortical functioning to activate it. 

The optical reflex is usually tested creating  a threatening lateral visual stimulus, typically your finger or hand that is brought into the lateral visual field very rapidly. There is one caveat to the so called hand method is that it may cause a gust of air over the cornea that can stimulate the corneal reflex. To prevent this from happening it can be done from behind a glass screen. This is rarely necessary in a clinical situation. 

This science experiment shows the optical blink reflex very well!

The optical reflex is responsible for the clinical phenomenon of blindsight, i.e. patients responding to visual stimuli without being of aware of it. The majority of these patients are conciously awarr of being blind, but rarely  they may deny being blind. The latter is referred to as the Anton-Babinski syndrome

The following is a short clip from the two-part documentary "Phantoms in the Brain" in which neurologist V S Ramachandran describes how the study of patients with certain types of brain damage can give us clues about the nature of consicousness and perception. For those of you who are interested in this can see both documentaries for free online. 

"Phantoms in the Brain" V S Ramachandran 

For those of you who are interested you may find this case study of interest: 

Hamm et al. Affective blindsight: intact fear conditioning to a visual cue in a cortically blind patient. Brain. 2003 Feb;126(Pt 2):267-75.

Blindsight refers to remarkable residual visual abilities of patients with damage to the primary visual cortex (V1). Recent studies revealed that such residual abilities do not apply only to relatively simple object discriminations, but that these patients can also differentially categorize and respond to emotionally salient stimuli. The current study reports on a case of intact fear conditioning to a visual cue in a male patient with complete bilateral cortical blindness. The patient was admitted to the stroke unit of the neurological department because of complete loss of vision. Both CT and structural MRI scans confirmed lesions in both territories of the posterior cerebral artery. No visual evoked potentials could be detected confirming complete cortical blindness. During fear conditioning, a visual cue predicted the occurrence of an aversive electric shock. Acoustic startle probes were presented during and between the conditioned stimuli. Relative to the control condition, startle reflexes were substantially potentiated when elicited in the presence of the conditioned stimuli. No such potentiation was observed prior to conditioning. These data suggest that fear learning to visual cues does not require a cortical representation of the conditioned stimulus in the primary sensory cortex and that subcortical pathways are sufficient to activate the fear module in humans.

Further reading: blindsight

Friday, 11 January 2013

Multiple sclerosis lecture - Brain and Behaviour 2

Level 1:  Year-2 Brain & Behaviour Lecture on 17th Jan 2013

Saltatory axonal conduction!

Conduction via a demyelinated axonal segment!

The corneal or blink reflex

Level 1

Description: The corneal is one of the blink reflexes, is an involuntary blinking of the eyelids elicited by stimulation of the cornea. Stimulation should elicit both a direct and indirect or consensual response (opposite eye). The reflex consumes a rapid rate of 0.1 second. The evolutionary purpose of this reflex is to protect the eyes from foreign bodies. 

Neuroanatomy: As will all reflexes it has an afferent (sensory) and efferent (motor) arm. The reflex is mediated by the nasociliary branch of the ophthalmic branch (Vi) of the trigeminal or 5th cranial nerve that senses the stimulus on the cornea, lid, or conjunctiva. The temporal and zygomatic branches of the facial or 7th cranial nerve initiates the motor response. The reflex is driven via interneurones in the medulla. 

Interpretation: An absent corneal reflex can be due to sensory loss in Vi (e.g. neuropathy or ganglionpathy), weakness or paralysis of the facial muscles (myopathy) or facial nerve (facial palsy, for example Bell's palsy) or brain stem disease. For a myopathy to cause a loss of the blink reflex the weakness has to be very severe, for example a chronic progressive external ophthalmoplegia (CPEO)

Contact lenses may diminish or abolish the testing of this reflex; therefore an absent corneal reflex is not necessarily abnormal. The examination of the corneal reflex is useful in unconscious patients and if present indicates that the lower brain stem is functioning. It is used as part of the assessment for determining if someone is brain dead; if the corneal reflex is present the person can't be diagnosed with brain death.

Clinical demonstration: The following YouTube video shows you how to do a corneal reflex:

Neurophysiology: The blink reflex can be tested electrophysiologically by stimulating the supra-orbital nerve and measuring the blink in both eyes. The ipsilateral blink occurs quicker (R1 component) compared to the contralateral blink that occurs a few milliseconds later with the R2 component. In the figure below you will notice that the R2 component affects both eyes, i.e. the ipsilateral eye has a double input. The figure below demonstrates the hypothesized wiring diagram of the blink reflex. 

James Parkinson's London

Level 1

It should be compulsory for all medical students at Barts and The London to watch this video:

"Professor Gerald Stern, Emeritus Professor of Neurology UCL, who narrates this short documentary is an alumnus of The London Medical School. He also grew up in Whitechapel; his grandfather ran a general store on the Whitechapel Road next to the Whitechapel Bell Foundry on the site that is now the East London Mosque! Professor Stern is one of my mentors and a great neurologist." 

Friday, 4 January 2013

4th-yr lecture notes on multiple sclerosis

Level 1: the following are my lecture notes and presentation from my lecture on the 17th December 2012. These can be downloaded.