Safinamide in Parkinson’s Disease

 

safinamideBackground

The rather specific dopaminergic deficit in Parkinson’s disease (PD) has meant that dopaminergic replacement medications have proven to be an effective mainstay of treatment of the condition. However, later on in the course of the disease, such treatment may have increasing limitations resulting from decreasing efficacy and increasing complications such as dyskinesia, postural hypotension and hallucinations or other psychological manifestations.

Most recent developments in pharmacotherapy have therefore consisted of different formulations of or delivery systems for dopamine agonists or levodopa, as well as agents that promote the effects of dopamine.  It is rare that a new class of agent arrives on the scene for treatment of Parkinson’s disease and such an agent is therefore worthy of close attention.

Safinamide is one such agent, an alpha- aminoamide that, as well as having monoamine oxidase B inhibitory action also has a non-dopaminergic action in the form of glutamate modulation. This modulation is probably achieved by blocking N type Ca channel mobilisation and therefore reducing presynaptic glutamate vesicle release.  An action to stabilise Na channels by promoting the inactive state may also be relevant.

The MAO-B action is therefore akin to that of selegeline and rasagiline, though safinamide is reversible and more selective for MAO-B, perhaps reducing the tendency to side effects such as tyramine reactions and obviating the need for dietary restriction of cheese, etc. The action on glutamate is more akin to that of amantadine, a drug that has useful antidyskinetic properties in PD.

A number of studies on safinamide were conducted prior to its recent licence acquisition. First, as drug companies tend to do, the focus was on initiation therapy in early disease. Presumably a greater market share would be gained, and many patients would start on the drug early and remain on it longer during the long course of their disease.

There does not appear to be a major effect of safinamide when used de novo in early disease. When used in early disease as an adjunct to dopamine agonists, one trial (Stocci et al, 2012) in 270 patients found over 6 months that 100 mg had a significant UPDRS benefit versus placebo (-6 vs. -3.6). The dose of agonist was to remain stable, yet an increase was allowed if worsening symptoms! On blood analysis, drug was found in the placebo group in 26% of patients!! Someone had mixed up the bottles… Despite this, the study was published, presumably because these flaws might have negated rather than enhanced perceived benefit. An extension study in some patients failed to reach the primary end point of delay in requiring additional treatment. Another trial (Barone et al., 2013) in 679 patients failed its primary end point of change in UPDRS, but the 100mg (rather than 50mg) dose subgroup may have improved.

In more advanced disease, a study (Schapira et al., 2013) on 549 patients on any medications except MAO B inhibitors and with at least 1 ½ hours “off” time in a day showed improved “on” time without dyskinesia when safinamide was added to their regime in comparison with the addition of placebo.

The study discussed in this journal club, “Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations” by Borgohain et al., (2014) similarly looks at 699 patients with more advanced disease. Please refer to the Parkinson’s Disease primer for more general background information.

 

Study Design

This multicentre study first stabilised patients on their levodopa and then continued for 6 months, with a 18 month placebo-controlled extension study in those who had not experienced side effects or whose disease had worsened over the initial 6 months.

Enrolled patients had to have had PD lat least 3 years, be on levodopa with or without other therapies and they had to have at least 1 ½ hours of “off” time a day. Patients with severe dyskinesia or severe dose fluctuations were excluded!

Two doses of safinamide were chosen because of previous evidence that 50 mg may be sufficient for MAO–B action but 100 mg is necessary for gluatamate inhibition.

Assessments included 30 minute interval diary scores of “on” versus “off” and dyskinesia, UPDRS, clinical global impression of change, dyskinesia rating scale when “on”, % change in levodopa (the intention was to keep levodopa unchanged but it could be increased if patients deteriorated) and the PDQ-39 questionnaire. If PD therapy had to increase by 20%, their evaluation was done at this point rather than at 6 months.

A mixed model co-variate statistical analysis was used, comparing versus baseline. The 100 mg dose was analysed first and only if significant was the 50 mg dose versus placebo analysed.

The primary end point, total “on” time without troublesome dyskinesia, was a 1.36 hour improvement after 6 months on 100 mg safinamide, 1.37 hours on 50 mg safinamide and 0.97 hours for placebo. These were both significant versus placebo. There was likewise an improvement in “off” time. The disability measures, PDQ-39 and UPDRS II showed significant improvement only for 100 mg doses. In the extension study there was overall maintenance of benefits and a non significant reduction in dyskinesia. There was no significant increase in side effects.

Authors’ Conclusions

The authors concluded that the drug was successful when used as add-on therapy in improving “on” and “off” time without increasing troublesome dyskinesia, which would be a risk if increasing other types of anti PD medications. This correlates with MPTP treated monkey studies, which showed an improvement in dyskinesia as well as “off” symptoms. However, dyskinesia when reported as a side effect by patients was more common that with placebo in this study, but not more likely with 100 mg doses than with 50 mg doses.

Journal Club Comments

The study numbers were sufficiently powered to produce a meaningful result and the statistical analysis was good, making the main conclusion convincing. The issues of being allowed to change levodopa dose during the study, and then escape the study but still record the outcome if the change was 20%, were discussed. While one suspects that levodopa has stronger anti-PD action and may mask the effect of safinamide, in effect “rescuing” both placebo and safinamide groups, it would tend to decrease the observed benefit of  safinamide versus placebo. One can understand inclusion of this study design element on the grounds of ethics, and also it provides a more real-world setting.

What was strange was the exclusion of more severely dyskinetic patients from the study, given that the main novel pharmacological benefit may be in helping dyskinesia and the paper’s emphasis on measuring dyskinesia, though it was not the primary end point. It is not as if there have not been any other studies already conducted on the drug’s basic action. Perhaps it was felt another study could be got out of addressing this variable, but from the point of view of clinician prescribing, current evidence would not support its use as an antidyskinetic drug (since it was actually a side effect of the drug as reported by patients directly rather than recorded on the diary). Instead it may be a modestly beneficial drug for PD with relatively little action in provoking dyskinesia.

As is always the case, we are hampered by lack of direct comparison with a real life alternative. We would never consider offering a placebo to patients in real life. What we would like to know is does the drug work better in direct comparison with addition of rasagiline or of a dopamine agonist or entacapone. We have a clue that it may be better then simply increasing levodopa dose, but this was not really the primary comparison in the study, merely a possibility allowed by the study design.

The Queens Hospital Journal Club meeting upon which this article is based was perpared and presented  by Dr Stevan Wing, SpR in Neurology.

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Anti K+ Channel Antibodies in Neuromyotonia

neuromyotoniaBackground

At this Journal Club it was decided to review a historical paper on the pathophysiology underlying autoimmune neuromyotonia. The paper, “Autoantibodies Detected to Expressed K+ Channels Are Implicated in Neuromyotonia”, from Annals of Neurology (1997, 41:238-246), used a novel technique that depended on knowing the gene for the suspected antibody target protein, in this case a potassium channel. The purpose of choosing this paper was partly to highlight how the known range of antibody mediated neurological disease has grown hugely over the subsequent twenty years, and partly to illustrate how positive findings can sometimes be seen in retrospect to have arisen through a degree of serendipity.

Acquired neuromyotonia is now known to be one of a number of neurological conditions that arise through auto-antibodies interfering with voltage gated potassium (KV) channel function. Interference with resting potentials and membrane recovery after action potentials in peripheral nerve results in continual high frequency discharges and continuous muscle activation as cramp, fasciculations and neuromyotonia. Sometimes this can be precipitated by cold, exercise or voluntary muscle activation. Other features included in the spectrum of KV channel auto-immunity include autonomic dysfunction, seizures, psychiatric disturbance and limbic encephalitis. When resulting in a neuropathy  and neuromyotonia, the term Isaac’s syndrome is often used, while a presentation of neuromyotonia with autonomic or CNS involvement is described as Morvan’s syndrome.

Study Design

The techniques used by Hart et al inferred that there would be an affinity of patients’ antibodies for the Kv channel, as it was already known that acquired myotonia results from disturbances of Kv channel function. If there was a known toxin for this channel, as with bungarotoxin for nicotinic acetyl choline receptors, this could be used as a labelled high affinity ligand and form the basis for a radioimmunoassay for detection of circulating antibodies against the channel. Dendrotoxin is a highly specific and high affinity toxin, but binds only a cohort of potassium subunits (Kv 1.1, 1.2 and 1.6).

The first type of assay used in this paper relied upon dendrotoxin; brains containing solubilised Kv channels were treated with radiolabelled dendrotoxin, and then with serum from neuromyotonia patients. An anti-human IgG was used to immunoprecipitate all human antibodies from this solution, which would include any Kv complex-dendrotoxin bound antibodies. When neuromyotonia patient serum was used, the resulting precipitant (which contains any antibody that has bound to its antigen) contained the radiolabel, indicating that the patient antibodies had become coupled to material containing the dendrotoxin and, by inference, become bound to the Kv channel. This result was found in some – but not all – patients (6/12) and reassuringly in none of the control samples (myasthenia gravis, Lambert-Eaton and healthy controls)

Verification that the Kv channel rather than other dendrotoxin-bound material from solubilised brain was provided by demonstrating binding of neuromyotonia patient antibodies to dendrotoxin-bound Kv1 subunits expressed in Xenopus toad oocytes via cRNA after complementary RNA expression. Knowing the gene for Kv1 enabled production of the complementary RNA. Expression of this in the toad oocyte meant that the KV1 protein would now be present in pure form. In this experiment,  4/12 samples were positive of the neuromyotonia cohort (and again, 0/18 controls). This positivity rate was felt to be consistent with the fact that human disease antibodies might be to subunits other than Kv1. The authors offered no information on the correlation between titres on the human brain assay and Xenopus expression system.

The authors then turned to immunohistochemical staining instead of immunoprecipitation. In this assay, antibodies labelled with horseradish peroxidase stain are created that bind to immune complexes. Thus any patient serum anti-Kv channel antibody that has bound to Kv1 channels expressed on the toad oocytes will in turn be bound to by the staining antibody-binding antibodies. The oocytes are then looked at under a microscope. They found positive staining of serum added to different Kv subtypes but not to a number of controls. However, since the oocytes had been fixed, permeabilised and sectioned prior to incubation with patient antibody, one could not confirm that the KV1 channel had actually been expressed on the membrane surface as it would naturally in human neurones. They suggested the technique could be applied to many other putative antigens for pathogenic circulating antibodies, provided the genes for the antigens were known, which is the case for most proteins now.

In another experiment to check for antibody binding to potassium channel subtypes for which dendrotoxin is not a ligand, these Xenopus cells were incubated with sulphur labelled methionine at the time that they were injected with one of three different Kv complementary RNAs, so that when they expressed the channel protein, it would be radiolabelled by the incorporated methionine amino acid, and detectable with autoradiography. The serum of neuromyotonia patients and controls was applied to these preparations and anti-human IgG was used to determine patient antibody-bound Kv material. However, this precipitant did not reveal any labelling with either patient or control serum. The authors suggested that this may be because the antibody binding is conformationally dependent, a feature that somehow did not apply when dendrotoxin had already bound in the other assay. Alternatively, it could also reflect that Kv channels are not really the antigenic target in neuromyotonia – an explanation which has subsequently been confirmed in more recent data.

Historical Context and Journal Club Discussion

Since this paper was published, as mentioned in the background, a more extensive spectrum of disorders associated with potassium channel antibodies has been described, but unfortunately there appears to be no specificity linking disease phenotype to antibodies to particular Kv subunit combinations.

More recently still, the antigenic targets of these antibodies have been clarified to be proteins associated with the potassium channel rather than the channel itself. So the antibodies were not what they were purported by the paper to be after all! It is not surprising therefore that the experiment with directly methionine-labelled subunits yielded negative results. It is not clear why the authors thought the naturally occurring pathological antibodies would bind to a channel better when it had toxin attached to it. But it is also now not clear why the immuno-histochemistry labelling of Kv1 expressing oocytes was positive in some cases, as the actual antigen in most cases was absent. Only in a small minority of neuromyotonia cases have the newer assays demonstrated that the Kv channel proper (and not an associated protein) is the true antigen.

In fact, since 1997, the radioimmunoprecipitation assay by which these antibodies are detected remains largely unchanged from that used before the advance that the paper was supposed to introduce: rodent brain is used as the substrate of Kv channels and still labelled with dendrotoxin. So, since the toxin binds only a small proportion of all Kv channels, there are likely to be many cases of antibodies against other Kv or Kv-associated antigens that are currently undetected by current methods. There is significant scope for improvement in these assays, in terms of range of antigens tested, cross-assay standardisation and, importantly, timescales of test to result.  It was discussed in the journal club how this currently significantly limits appreciation of the potential scope of antibody mediated neurological diseases.

This case was presented and summarised by Dr Sian Alexander, Specialist Registrar in Neurology at Queens Hospital, Romford.

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Comparison of New Oral Anticoagulants (NOACs) with Warfarin

comparison of NOACSBackground

Ischaemic stroke is typically either thrombotic (clotting within a cerebral vessel) or embolic (passage of clot material from a more proximal vessel to become lodged in a cerebral vessel). A proportion of embolic stroke events will arise from arterial vessels such as the carotid in the neck, while others will arise from the heart. In atrial fibrillation, the chamber wall does not contract properly and this “stagnant” blood is more inclined to development of thrombus (clot), which may embolise up the arterial tree to the brain (or indeed anywhere else in the body).

While embolisation from high flow vessels may be reduced by antiplatelet agents, such as aspirin, that from low flow vessels (veins and the atria) may be reduced by anticoagulant agents, such as warfarin.

It can be seen, therefore, that some causes of stroke may be reduced by anticoagulant therapy. It will also be readily seen that such therapy is not going to make any difference at all to the statistical majority of causes of stroke, and in fact by its very nature may increase the likelihood of non-ischaemic stroke, namely brain haemorrhage. Nevertheless, there is a rather long-held view that on balance anticoagulation statistically reduces the risk of stroke in many patients who have atrial fibrillation (AF). In fact, this applies not only to patients who have already had a stroke or transient ischaemic attack, or who have structural heart disease making them even more susceptible to thrombus formation, but to patients who have AF as an isolated finding – so-called lone atrial fibrillation.

Two factors have made the issue of anticoagulation for AF topical:

  • Recent evidence has emphasised the view that lone AF is worth treating, as demonstrated in the UK by a recent National Institute of Clinical Evidence (NICE) Guidance document (CG 180).
  • As well as warfarin, there are four (at the time of writing) new anticoagulant agents to choose from and these do not require tedious weekly to monthly blood monitoring.

However, two factors have made the issue of anticoagulation for AF controversial:

  • The new drugs are much more expensive than warfarin
  • Anticoagulation will kill some people and harm others. The very nature of anticoagulants means that they will increase haemorrhage from the bowel or at the time of trauma or emergency surgery and, since some strokes are in fact the result of brain haemorrhage rather than ischaemia, they will even increase the risk of  this type of stroke!

It is not surprising therefore that a meta-analysis of the major studies comparing risks and benefits of warfarin versus novel oral anticoagulants (NOACs) was published recently and has become the subject of much debate. This study, “Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials (Lancet 2014)” by Ruff et al., looks at the four major trials on this subject, all run by the drug companies manufacturing the NOACs.

Before describing the paper, it is worth mentioning wider controversies surrounding these studies.

First, as reported by the British Medical Journal, one of the studies (Rocket-AF) used a defective device to record the clotting effectiveness (INR) of the patients in the warfarin arm. Therefore, the patients using warfarin may have had an artificially bad outcome, not only potentially harming them but compromising the study’s findings. There is debate over when the drug company first knew about this fact.

Second, there was an issue where it was found that blood monitoring of NOACs improves outcome in terms of efficacy and reduction in bleeding complications. Obviously, there is not the same level of risk associated with not monitoring NOACs versus not monitoring warfarin, but there is an argument that some patients statistically might come to avoidable harm through not monitoring. Nevertheless, because the US Food and Drug Administration (FDA) approved the drugs before this was known about, the prescribing recommendation, and the major selling point of the new drugs, need not be changed.

 

Study Design and Findings

The meta-analysis looked at four studies

RE-LY, comparing dabigatran in two doses versus warfarin

ROCKET-AF, comparing rivaroxaban and warfarin

ARISTOTLE, comparing apixaban and warfarin

ENGAGE AF-TIMI 48, comparing edoxaban and warfarin.

A meta-analysis was felt to be justified on the basis that the class effect of the NOACs is similar; they all have a direct antithrombotic effect, while warfarin acts via inhibition of vitamin K, a precursor for different components of the thrombotic pathway. This results in similar shared benefits of faster onset and offset of action,  more predictable action and fewer drug interactions. Any intra-class differences would therefore be outweighed by differences between subgroup populations. Pooling the data would increase the chance of finding subgroup differences in the balance between efficacy and safety, the main stated purpose of the meta-analysis. In all there were around 72,000 non-valvular AF participants!

Median follow up ranged from 1.8 to 2.8 years and the outcome measures were occurrences of ischaemic stroke, haemorrhagic stroke, myocardial infarction, all cause mortality, intracranial haemorrhage, gastrointestinal bleeding and other major bleeding events.

Some studies had higher baseline risks than others, as expected because they had different CHADS2 scores ( a scale measuring risk of ischaemic stroke from AF).

The headline finding of the meta-analysis was that NOACS had a significantly (19%) reduced stroke risk (i.e. better efficacy) and a significantly  (48%) reduced intracranial haemorrhage risk (i.e. better safety). There was reduced all-cause mortality (10%) but increased gastrointestinal bleeding (25%). The relative efficacy and safety was consistent across a wide range of patients.

 

Opinion

Some of the cautionary notes on this study have already been publicised.

First, the study uses one parameter both as a measure of efficacy and safety – intracranial haemorrhage is counted twice! The study does say that the effects of stroke reduction were largely because of reduced haemorrhage; If we are looking at the effects of anticoagulation on stroke, we should be looking at its specific biological action, namely to reduce embolic stroke from the heart in comparison to warfarin, not at reduction in all-cause stroke.

Second, the way data are publicised can shift emphasis, especially for patients. The 0.48 relative risk reduction means a clinician could say that there is less than half the chance of a brain haemorrhage on NOACs compared to warfarin. But this actually equates to a 0.58% risk versus 1.24% risk. The actual risk reduction is therefore 0.66%.  (The absolute rise in gastrointestinal bleed was almost as much at 0.5%, but the latter would still be preferable on balance to intracranial bleed.)

The absolute risks are not annualised risks so they illustrate a point rather than being something useful to quote to patients. In its guidance to UK clinicians, NICE recommends that patients have a choice whether or not to receive anticoagulation. They provide a chart for clinicians so that they can explain the particular annual risk of a stroke based on the CHADS2 score versus a bleeding complication based on the VASC score. These risks are described in terms of “out of 1000 patients, x would be saved from having a stroke each year by taking anticoagulation”.  Converting the figures of this meta-analysis into an annualised form using the same language, about 5 patients per year would have a brain haemorrhage on warfarin, and 3 on NOACs.

In a rationed health economy, we have also to look at costs. In the UK, annual costs per patient for Rivaroxaban and Apixaban are around £700 to £800, and that for warfarin including the clinics for regular monitoring are£283 (NICE CG180).

NICE did a costing exercise (June 2014) based on the CG180 guidance and based on the increased uptake of anticoagulation for AF in general but they assumed that warfarin and NOAC use would increase in parallel (warfarin from 34% to 47% use in AF, and NOACs each from 4.7% to 11.7%). NICE stipulates that patient and clinician choice should determine whether patients go on warfarin or NOAC. But if the figure of 50% reduction in brain haemorrhage is quoted, and it is explained that patients do not have to attend a clinic for a blood test every fortnight, we can all guess what patients who are not paying for their medication will choose!

However, health providers might choose differently. In the UK, some have taken the view that since the excess risk of warfarin was more in a subgroup who had brittle control, warfarin should be given first line in patients for whom vitamin K antagonists are not contraindicated, and switched to a NOAC only if they prove to have brittle control.

Some may find all these economic arguments  laboured and somewhat distasteful – can one put a price on human life? But, again in a rationed economy, some person (or unwieldy committee) has to decide whether a limited amount of money goes on NOACs, or on life-prolonging cancer treatment, or on running blades for childhood amputees. The way these decisions are (supposed to be) made is on the basis of quality adjusted life years (QALYs). The UK Department of Health might have a guide of, for sake of argument, maximum £50,000 cost per QALY gained. The QALY loss of a brain haemorrhage might be 0.5 per year for 5 years, i.e. 2.5. (Some will be trivial, some will be fatal while factoring in a certain life expectancy, some will recover over time, some will die after a finite time.) The prevalence of AF is 1.6% and for 100,000 population, around 1000 should be on anticoagulation, so NOACS would save 2 brain haemorrhages per year in that population. The excess annual cost per 1000 patients is about £500,000. So a rough estimate of cost per QALY is £100,000. One could argue about additional increased efficacy and reduced mortality of NOACs, but perhaps that is subsumed by the haemorrhage reduction anyway, and there would be nearly as many increased GI bleeds as reduced intracranial bleeds.

The other reason why this topic is an emotive issue, and why it has received considerable attention with NICE invoking “patient choice”, is a controversy not related to NOACs versus warfarin as such, but to the knowledge that in a few patients we will be doing potentially terminal harm by starting either treatment. This goes against the physician’s mantra, “First do no harm” and follows the alternative mantra, “The needs of the many outweigh those of the few”. Statistically we know anticoagulation will help more AF patients than it harms, but no-one wants to be one of the few who suffer the brain haemorrhage, or to be the physician who gave them the drug that caused it.

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Varicella Zoster is the Cause of Giant Cell Arteritis

vzv and gcaBackground

Giant cell arteritis is an inflammatory condition of certain blood vessels that presents in the elderly. Those vessels affected include the:

  • temporal artery resulting in headache and scalp tenderness over the inflamed artery,
  • ciliary artery resulting in ischaemic optic neuropathy,
  • retinal artery resulting in central retinal artery occlusion,
  • arteries to various muscles resulting in jaw claudication and polymyalgia rheumatica.

There may be systemic symptoms of weight loss and fever, and a raised eosinophil sedimentation rate is typical. The main clinical urgency relates to the visual loss, as this may be permanent without prompt treatment with high dose steroids.

Varicella zoster reactivation later in life following initial infection with chicken pox typically results in shingles, but a recognised complication of shingles is an arteritis of large vessels such as the carotid artery. This may result in emboli and consequently present as stroke.

Since both arteritides occur in similar populations, it was natural to speculate that there might be some pathogenic link. However different pathological studies on temporal arteries have yielded different results. Some revealed no VZV on Polymerase chain reaction (PCR) or immunohistochemistry (IHC), while other series have revealed around 25% occurrence in GCA positive biopsy samples , and 0% in GCA negative samples.

This paper, Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis in Neurology (2015) by Gilden and a large number of co-authors from all the different centres that contributed temporal arteries, addresses this question with a rigorous examination for the correlation of CGA findings and VZV presence in alternating contiguous temporal artery slices and uses temporal arteries of cadavers as controls.

Study Design and Findings

All investigators took formalin fixed temporal arteries and made 100 5-micron sections. Every other section was examined by IHC for VZV antigen and, in one case, electron microscopy (EM) for virions. If the antigen test was positive, PCR was performed for viral DNA. The remaining sections were examined for GCA inflammation changes. To validate the sensitivity, positive controls were obtained by infecting cadaveric temporal arteries and testing after 14 days in vitro.

A total of 86 histologically confirmed GCA positive temporal arteries were examined, and 16 negative post-mortem controls (i.e. randomly selected, not the ones that were deliberately infected) . All subjects had to be over 50 years. There were no other clinical inclusion or exclusion criteria, but if they were having biopsies presumably the patients had clinical features leading to suspicion of GCA. There was disagreement over the blinded light microscopy findings for GCA in 4 of the presumed positive cases and 3 of the negative controls, so these were removed from analysis. (The findings in these should really have been included in the results; if three additional negative controls out of sixteen all had GCA changes and then analysed and found to have VZV, this would have changed the results in a major way! Presumably at least one pathologist thought they had GCA changes; is this a common coincidental finding?)

VZV was present in 74% of the GCA cases and in one of the cadaveric negative controls. The VZV was present usually in multiple slices with intervening negative areas (skip lesions). Across all 61 VZV positive samples, there were 347 VZV positive skip lesions. The virus tended to be present more in the adventitia than in the intima, and was sometimes present in adjoining skeletal muscle.

In one positive case, VZV virions were found on EM in the artery adventitia.

Only in some cases was PCR positive, perhaps due to the formalin fixation technique.

In 89% of cases where there was VZV antigen, there were light microscopy changes of GCA in adjacent sections. (Presumably, in the remaining cases the light microscopy changes were only in distant sections. If they were not positive somewhere they would not have been included in the study.) In the only post mortem sample out of 13 that had positive VZV there were no GCA changes.

The authors conclude a causative relationship on the basis of:

  • The pattern of VZV presence is patchy (ie skip lesions) in the same way that the typical GCA pattern is patchy.
  • The pattern of VZV was such that there were often GCA changes in nearby sections.
  • The VZV was present in adjoining skeletal muscles, the increased incidence in the adventitia and presence of virions in one case indicating a spread starting outside the artery wall from the cranial nerve ganglia (presumably via the nerve supply to the vessels).
  • The authors never find in other diseases, e.g. meningitis, that inflammation per se is responsible for VZV activation.
  • The pathology and distribution of VZV in these samples is similar to that in other cases of VZV vasculopathy not considered to be GCA.

The authors consider that the variable findings in the literature reflect the fact that the other studies did not take enough sections – the skip lesion problem. Relying on PCR might also result in negative findings. They predict that if they took hundreds of sections per biopsy they would have found VZV in all GCA positive cases, in other words VZV reactivation is the sole cause of GCA.

The obvious implication is that while steroids may suppress the inflammatory response of GCA, such treatment often needs to be maintained for a long time and some cases are refractory. Possibly the steroids are also prolonging the viral activation. Hence aciclivor should be added to the treatment regime.

Opinion

The journal club were persuaded by the main finding and will be prescribing iv acyclovir in future. Consideration might be given to gancyclovir since the effectiveness of acyclovir is less against VZV than against HSV. Hence we would not rely on oral acyclovir.

Points that were noted included the fact that the authors could have made more of the presence or absence of section-by-section concordance vs discordance regarding VZV and GCA pathology. It is one thing to say that the GCA changes were more likely in sections near VZV presence, but perhaps as important to find a concordant absence of both changes between the skip lesions. This could be tested statistically.

Comment was made about the post-mortem specimens. Might the VZV antigen degrade after death? What was the time between death and fixing the temporal artery?

The reason for choosing post mortem controls is obvious. If there was a negative living control, it would be wondered why they were having the biopsy in the first place. Did they really indeed have mild GCA? However, in our experience there are plenty of TA negative biopsies because the disease is over-diagnosed clinically. If the same rigour of analysing multiple sections was employed, the negative presence of VZV in living tissue in a GCA susceptible population would have been persuasive.

Clearly a study comparing these pathological findings with clinical features and outcome is the next step. However, after reading this study, we would be a little worried ethically about not adding antiviral treatment in a placebo arm of a future controlled trial. The level of evidence ends up being inversely correlated with the likely effectiveness of an intervention!

This paper was presented to our Journal Club by Dr Tim Ham, Specialist Registrar in Neurology, Queens Hospital, Romford, UK.

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Myasthenia Gravis: Subgroup Classification and Therapeutic Strategies

myastheniaBackground

Myasthenia gravis (MG) is a neurological condition characterised by a fatiguing weakness of certain muscle groups, particularly those that control eye opening, eye movements, speech and swallowing When severe the proximal muscles of the limbs and respiratory muscles may be involved. Acquired myasthenia is an autoimmune disease, where antibodies are directed against the post synaptic nicotinic acetyl choline receptors (AChR) of neuromuscular junctions or against other proteins that affect AChR function.

Diagnosis and appropriate management of MG is particularly important because at any time it can transform suddenly from a relatively benign condition of ptosis and diplopia to a crisis with potentially fatal bulbar dysfunction and respiratory failure. These latter symptoms may in turn reverse with prompt emergency supportive care and immunomodulatory treatment.

The discussed review in Lancet Neurology by Gilhus & Vershuuren seeks to provide an insight into the usefulness of the latest antibody assays in predicting in individual patients the clinical course of MG and response to therapy. Evidence was gathered from the literature on the basis of appropriate searches on Medline and the Cochrane library for English language publications from 1995 to 2015.

Content

The review first describes the pathophysiology of the different associated antibodies. AChR antibodies cross link receptors, accelerating their breakdown. Muscle specific kinase (MUSK) and lipoprotein related protein 4 (LRP4) exist as a complex on the post-synaptic membrane. When activated by agrin protein, this complex affects the aggregation of AchR and the morphology of the terminal. Antibodies to MUSK, LRP4 and agrin influence this process and are therefore are likely to be directly pathogenic. Titin and ryanodine receptor antibodies occur in some patients with thymoma related MG, but may be markers of severe disease rather than directly pathogenic.

Comorbidities may be present in MG, and awareness of these is important. Younger onset patients may have other organ specific autoimmune disease , including polymyositis. Thymoma associated MG is associated with increased risk of haematological malignancies and with a severe autoimmune cardiomyopathy.

Classical subtypes include:

  • Early onset MG with ACh antibodies. This often has ocular involvement and has a female preponderance. Thymic hyperplasia may be present and in these cases the condition responds to thymectomy.
  • Late onset MG with AChR antibodies.  This is also often ocular, but there is only rarely thymic hyperplasia.
  • Thymoma-associated MG. These patients usually have generalised disease and AChR antibodies. There are also other paraneoplastic associations, such as pure red cell aplasia and neuromyotonia.
  • MUSK associated MG. These antibodies are present in 1-4% of MG cases. The condition is usually bulbar or generalised rather than ocular and there is no thymic involvement.
  • LRP4 associated MG. This can be ocular or generalised in presentation.
  • Antibody negative MG occurs in 5% and is heterogenous, probably reflecting different undiscovered causative factors.
  • Ocular MG is defined as being restricted to the ocular muscles; if this remains the case for 2 years, 90% of the time it will remain so. Half of such cases have AChR antibodies, but only very rarely do they have MUSK antibodies.

When symptoms are typical, the review considers neurophysiological testing unnecessary in all cases bar those that are seronegative.

Finally the review discusses treatment options. Immunosuppressive treatment is recommended when symptomatic treatments (anticholinesterases such as pyridostigmine) fail alone to control symptoms. (MUSK antibody associated disease often has a poor response to such treatment.) An extensive review of clinical trials reveals disappointing results in many cases when compared with placebo. Nevertheless a clear treatment plan of steroids combined with immunosuppressive drugs is recommended. Other treatment plans may vary from this. The only information regarding treatment in relation to antibody serology is that rituximab in uncontrolled studies may be particularly effective in MUSK associated MG.

The review concludes with a discussion of new treatments, such as other monoclonal antibody therapies targeting autoantibodies, or antigen specific treatments that encourage the development of immune tolerance.

 

Opinion

The review provides a welcome revision of management in an important therapeutic area. However it was felt that there was little specific information on serological-clinical correlations that practically affect management. This was the presumed main hypothesis of the review. The lack of ocular and thymic involvement in MUSK associated disease, and its poor symptomatic response to anticholinesterases, were interesting points.

Other points that arose out of the discussion were:

  • The lack of evidence base for treatment compared to the clear benefits observed in practice does point to the limitation of relying solely on evidence based medicine. It was conjectured that in some cases this may reflect patient selection. If for example, all ocular myasthenic patients are started on immunosuppression, in many cases it may be unnecessary and so demonstrating an improved response compared with placebo may prove difficult. Perhaps clinical focus is understandably upon patients with myasthenic crises or who have recently had myasthenic crises, where the response to treatment is more dramatic and clearly in some cases life-saving.
  • The indication in the review that neurophysiology was only necessary in seronegative patients was surprising. In our practice, we often have neurophysiology results before serology becomes available. In patients with ocular symptoms only, the differential includes cranial nerve palsy, sympathetic lesions, myopathic processes and even muscle tension related symptoms. Identification by neurophysiology alerts clinicians to the fact that the patient is at risk of life-threatening myasthenic crisis. Patients with bulbar involvement may have motor neurone disease or myopathy. Finally, there is a significant false positive AChR occurrence; in patients with low positive AChR  titre in whom we feel that myasthenia is actually unlikely, normal neurophysiology on single fibre EMG jitter study helps to confirm this. While not 100% sensitive and specific, neurophysiology does lend valuable diagnostic support.

This paper was presented to our Journal Club by Dr Salman Haider, Specialist Registrar in Neurology, Queens Hospital, Romford, UK.

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Clinical Features and Pathology of “Parkinson’s Plus” Syndromes

msa jounral clubBackground

It has long been known that there exist variants of Parkinson’s disease (PD), loosely and perhaps inaccurately described as PD plus syndromes, that may carry features of Parkinsonism but which also have other clinical features. Such conditions have distinct pathology at autopsy.

However, it has also long been known that clinicopathological correlations of these conditions are not perfect; in other words, a patient in life may have clinical features indicating one PD plus syndrome but may be found subsequently to bear the pathology of another.

The subject of this journal club, When Dementia with Lewy Bodies, Parkinson’s Disease and Progressive Supranuclear Palsy Masquerade as Multiple Systems Atrophy by Koga et al. (2015) in Neurology, is a retrospective review of Mayo Clinic brain bank cases labelled as having Multiple Systems Atrophy (MSA) in life.

MSA is a neurodegenerative condition that may have one or both of parkinsonism and ataxia features, and may also have autonomic features, pyramidal features and even features of anterior horn cell disease. According to the Second Consensus Statement (2008), the criteria for probable MSA are:

A sporadic neurodegenerative condition of onset >30 with:

  • Urinary incontinence (plus erectile dysfunction in males) or measuredorthostatic hypotension within 3 min of 30mmHg systolic or 15mmHg diastolic and at least one of:
    • Poorly levodopa responsive Parkinsonism (bradykinesia with rigidity, tremor or postural instability)
    • Cerebellar syndrome

However some patients will have pathologically proven MSA without satisfying these criteria, while in others the clinical picture will be confused by coexisting conditions in this age group, such as Alzheimer’s disease (AD) or cerebrovascular disease.

 

Study Design

The study reviewed the autopsy results of 134 cases that had consecutively been submitted to the brain bank with a clinical label of MSA. Patients came from 37 US states. The pathological assessments were done using a standard protocol. In 125 patients there were useful clinical records, and in some cases further information was gained by questionnaires sent to living relatives.

 

Study Findings

A pathological diagnosis of MSA was confirmed in 62% of cases. Of the remaining 38% of cases, 37% had Dementia with Lewy body (DLB) pathology, 29% had PSP, and 15% had PD. Two of the 134 total had Corticobasa Degeneration (CBD), two had cerebrovascular disease and five were “miscellaneous”.

On retrospective assessment of clinical features according to the above criteria, only 49 patients had probable MSA and 35 possible. (But incomplete records do not mean that patients did not have particular clinical features). Once this had been done, 71% of probable MSA patients had pathological MSA, and 60% possible MSA patients had MSA pathology.

The paper describes pathological changes in some detail. In the same way that there are, according to Braak, “stages” or at least grades of neurofibrillary tangle involvement in Lewy body disease, there have been described five phases of A beta amyloid deposition in Alzheimer-type disease. These range from phase 1 where deposition is exclusively in neocortex, to phase 5 where there is widespread involvement even in the cerebellum.

In pathological MSA, 8% also had Lewy body pathology. Overall the median Braak stage was I (not 0). A quarter of the MSA brains had phase 1 or worse A beta phase of Alzheimer’s.

With pathological diagnosis as the reference point, the features that were more common in MSA than in DLB were urinary continence, ataxia, nystagmus and pyramidal signs. Cognitive impairment and visual hallucinations were more common in the latter.

Comparing MSA vs PD, incontinence was more frequent and visual hallucinations less frequent.

Comparing MSA vs PSP, urinary incontinence, constipation, orthostatic hypotension and REM sleep behaviour disorder were more frequent, and vertical gaze palsy less frequent.

Levodopa responsiveness and mini-mental state score actually did not distinguish these diagnoses.

The main errors related to assuming that orthostatic hypotension automatically resulted in an MSA diagnosis instead of DLB or PD, and assuming that ataxia resulted in an MSA diagnosis instead of PSP. Severe dysautonomia early in the course of PD should not be considered an exclusion criterion for that diagnosis.

Imaging has poor sensitivity. Only 38% of pathological MSA had imaging changes. The hot-cross bun sign was rare. There were similar rates of abnormality in PSP.

 

Opinion

As suggested by the authors, a limitation of the study is that retrospective post mortem analysis suffers from clinical signs being recorded at different stages of disease advancement and there is a selection bias in those that come to autopsy (such as atypical cases).

Our feelings were that for the above reasons the study cannot be used to determine real diagnostic accuracy. The “improvement” in diagnosis from 62% to 71% when a movement disorders specialist applies probable diagnostic criteria carries little meaning, given the limited data available from those who examined the patient in life. A “brain bank” is only as good as the accuracy and detail of clinical label attached to the specimens.

It was pointed out, though, that the very wide geographical distribution of specimens, which included those not from academic centres, does reperesent a cross-section of patients in the US labelled as having MSA.

We wondered if the difference between PD and DLB is essentially quantitative. DLB is rather arbitrarily defined according to dementia changes manifesting before extrapyramidal changes, otherwise it is considered PD dementia. Perhaps “diffuse” Lewy body disease is a better clinical label. Pathologically there is likely to be a borderline state between the localised involvement of PD and the diffuse involvement of DLB, and indeed if the Braak hypothesis is correct, this overlap may apply to all patients at certain stages of disease progression.

Our final point was a philosophical one about what is the gold standard of diagnosis. Is it necessarily always pathology, which presumably accurately reflects the pathophysiological process that led to the observed pathology? What if there is dual pathology, as reflected in a number of specimens in this study? Which supercedes the other? Is it simply relative severity? If one set of clinical features can reflect either one or both of two different pathological appearances, what is actually more important for the patient and clinician? Would we deny a patient a trial of cholinesterase inhibitor for their dementia and hallucinations if we somehow knew that their pathology was MSA or if their Lewy bodies were localised to the brainstem? Would we not treat their autonomic symptoms if their pathology was PD? Would we fail to check a clinical MSA patient for sleep apnoea if their pathology instead revealed Lewy bodies?

While pathology might be the gold standard when conducting clinical trials, in normal clinical practice it is the clinical features guiding practical management and prognostication that are of primary importance. The broad clinical labels of system involvement still help to classify patients according to their present and future clinical needs.

This paper was presented to our Journal Club by Dr Gemma Cummins, Specialist Registrar in Neurology, Queens Hospital, Romford, UK.

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Acute Flaccid Myelitis and Enterovirus D68

enterovirus 1Background

Enteroviruses, which may cause gastroenteritis or upper respiratory tract infections, are well-known to have neurotropism – a predilection in a proportion of individuals to spread to certain types of neurones, thereby resulting in characteristic neurological syndromes that occur after initial infection. The most well-known example is of course poliomyelitis which results in acute flaccid paralysis from anterior horn cell involvement. More recently, enterovirus A71, causing hand foot and mouth disease, has resulted in epidemiological clusters of brainstem encephalitis and acute flaccid paralysis.

Enteroviruses may also be responsible for acute viral meningoencephalitis, presenting classically with fever, meningism and obtundation, and perhaps with focal cerebral neurological signs or seizures. In fact, in our experience,  enteroviruses, along with herpes simplex virus, are the most commonly identified organisms responsible for sporadic viral meningoencephalitis.

This paper, by Messacar et al. in the Lancet (2015), reports cases of the latest enterovirus identified to have possible neurotropism, namely enterovirus D68. Localised outbreaks occurred between 2008 and 2010, and a large outbreak occurred in the USA in the Autumn of 2014. A cluster of cases of acute flaccid paralysis in children were identified at the same time (Autumn 2014); they presented with weakness in proximal limb, facial and bulbar muscles and radiological changes of either longitudinal grey matter spinal cord lesions and/or brainstem hyperintensities were identified.

Study Design and Findings

Cases were retrospectively identified from records of children admitted to a hospital in Colorado in the Autumn of 2014. Inclusion criteria were acute flaccid paralysis with mainly grey matter spinal cord involvement on imaging and/or acute cranial nerve dysfunction with brainstem lesions on imaging.

In the acquisition period twelve children satisfied the neurological inclusion criteria. All but one had fever and preceding upper respiratory tract symptoms. Ten had meningism. The limb weakness, present in ten cases, was proximal with hyporeflexia and preserved sensation. A similar proportion of children had symmetrical and asymmetrical weakness. Ten had cranial nerve dysfunction, bulbar weakness, diplopia or facial weakness. None had encephalopathy or seizures.

The spinal cord lesions, present in eleven children, always affected the central grey matter, especially the anterior horn cells. The longitudinal spread was from 4 to 20 vertebral levels (we commented that there were only 19 levels from C1 to T12, but younger children’s spinal cords extend a little lower). Brainstem lesions were present in nine children, mainly in the dorsal pontine tegmentum.

Some children had EMG, which showed variable motor denervation, presumably indicating either anterior horn cell or ventral nerve root involvement.

Spinal fluid analysis typically showed a pleocytosis (unlike typical cases of acute motor axonal neuropathy subtype of Guillain Barre syndrome) and normal or mildly elevated protein in all but one case.

In five of eleven cases, nasopharynx specimens were positive for enterovirus D68. Blood and spinal fluid PCR was negative, as is commonly the case in polio and other enterovirus neurotropic infections. Polio also has a delay between initial and neurological symptoms and yet is due to direct viral spread to the anterior horn cells, so the delay after respiratory symptoms and the lack of spinal fluid virus observed in these cases does not necessarily indicate that the condition is post-infectious rather than infectious.

Many of the children were treated with intravenous immunoglobulins or steroids. Some had plasmapheresis. There was no clear benefit from these therapies. Many children had lengthy admissions and significant residual neurological deficits despite treatment.

The paper compared the number of these neurological cases in 2014 with average numbers of similar presentations (from ICD 9 code discharge database) between 2010 and 2014. In any previous 3 month period the maximum number of cases was 4 (significantly lower). One was positive for D68.

enterovirus2

The background epidemiological context in the paper describes a 77% increase in children with acute respiratory admissions in 2014 compared with equivalent months in previous years.  It is not clear if all such cases were tested for viruses but a number were tested with a screening nasopharyngeal swab PCR array that does not distinguish enteroviruses from rhinoviruses. There was a “substantial increase” in positive results on this test during the acquisition period. Only 25 cases were actually tested for D68, and these were cases admitted to ITU with severe respiratory disease. These were positive for D68 in 76%.

Opinion

The paper presents a persuasive argument for a defined neurological syndrome, with the flaccid paralysis, exclusive motor involvement, pleocytosis and rather characteristic neuroimaging features.

Less persuasive is the causative role of enterovirus D68. It was identified in less than half of the neurological cohort during a presumptive D68 outbreak. The background level of enterovirus D68 positive asymptomatic children during the acquisition period is unknown. The increase in neurological cases during that Autumn epidemic compared to baseline levels could be skewed by ascertainment bias and, given the sample size, a coincidental increase is always possible.

Neurological D68 infection is not new. In fact a previous paper (Ayscue et al., 2014) (which this paper mentions at the end of the discussion) reported 23 cases of acute flaccid myelitis in California from 2012 to 2014, two of which were positive for D68. The lower rate of D68 identification could have reflected testing late during the illness, whereas earlier testing as in this paper is more likely to yield positive results.

Nevertheless the paper does contribute to a body of evidence suggesting that enterovirus D68 is one of a group of viruses that have accounted for recent outbreaks of upper respiratory tract infections and may have particular patterns of neurotropism resulting in acute infectious or post-infectious complications. Unfortunately, as the paper identifies, there are as yet no specific and effective preventative or treatment strategies for these neurotropisms.

This paper was presented to our Journal Club by Dr Sian Alexander, Specialist Registrar in Neurology, Queens Hospital, Romford, UK.

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Journal Club Review: “Cerebral Amyloid Angiopathy with and without Haemorrhage

BackgroundCAA 1

Sporadic cerebral amyloid angiopathy (CAA) is the most common cause of lobar intracranial haemorrhage, which in itself accounts for about 5-10% of all strokes. Amyloid deposition in small arteries of the cerebrum leads to friability and haemorrhage. There are also rare familial forms of amyloidosis affecting the nervous system that more typically result in early onset dementia or peripheral neuropathy, and amyloid deposition in general constitutes part of the pathological process of other neurological conditions such as Alzheimer’s disease.

There is no specific treatment for CAA other than blood pressure control, as hypertension may be an association. It might nevertheless be useful to identify markers of the condition before major symptomatic haemorrhage occurs, so that one can avoid anticoagulants and perhaps antiplatelets in such susceptible individuals.

Potential markers include the apolipoprotein (APO) E ε2 genotype and imaging markers such as superficial siderosis and centrum semiovale white matter perivascular spaces. Superficial siderosis is not specific to CAA, being the result of any cause of chronic cerebral or spinal subarachnoid leakage of blood. Enlarged perivascular spaces could relate to small haemorrhages in the more distant past.

This paper, by Chridimou et al. (2015)  in Neurology, looks at these associations retrospectively by a database review of brain biopsies or of evacuated haemorrhage material. These are correlated with MRI findings and APO E ε genotype in patients with positive pathological findings.

Study Design and Findings

The brain biopsy and haemorrhage specimen database review found around 100 cases of pathological cerebral amyloid angiopathy (CAA). Roughly half had had a symptomatic lobar intracranial haemorrhage (ICH). The others were presumably identified coincidentally.

There was no difference in pathological CAA severity between those with or without ICH, but neuritic plaques without neurofibrillary tangles were more likely to be found in ICH cases (53% vs 13%); this is because, as is already known, neurofibrillary tangles are associated with a more Alzheimer type amyloid deposition process. Again as expected, the ε2 allele was more associated with ICH cases and the ε4 allele (a risk factor for Alzheimer’s disease) more likely in the others.

Imaging features of white matter changes, enlarged perivascular spaces and microbleeds were the same in both groups but superficial siderosis was more common in ICH cases (52% vs 20 %).

caa2Follow up of the non ICH patients 3 years after brain biopsy revealed that 2 of 51 subsequently had lobar ICH; one of these had superficial siderosis changes.

The study’s main conclusion is that the ICH subgroup of CAA is more likely to have superficial siderosis on imaging.

Strengths and Weaknesses of Study

It is already known that different APO genotypes are associated with Alzheimer’s disease or with ICH, and despite the fact that pathological changes were not worse in the ICH patients it is not surprising that ICH patients are statistically more likely to have the “haemorrhage” genotype than the “dementia” genotype. The presence pathologically of CAA appears to be less specific for ICH as opposed to Alzheimer’s disease than the presence of an APOE ε2 allele or superficial siderosis on imaging.

However, the degree of specificity and sensitivity of these markers is not diagnostically helpful.

The association with superficial siderosis is not surprising as it is a direct marker of haemorrhage more specifically than general markers of small vessel disease that could also reflect atherosclerosis. At least the paper confirms this and raises awareness of superficial siderosis, but anticoagulation would not be given to such patients anyway, even without awareness of the strength of association with ICH. A patient with superficial siderosis would typically be investigated on imaging for a cause of chronic subarachnoid haemorrhage. If no such cause was found, and the patient was relatively elderly, possibly it could be concluded that they were susceptible to CAA and in particular to ICH from such pathology.

Our Journal Club wondered in passing if homozygotes for either ε2 or ε4 had extra susceptibility to haemorrhage or dementia respectively. Certainly, homozygous ε4 carries increased risk of dementia; compared to being homozygous for the “neutral” ε3 allelle, ε4ε4 carries a x15 risk of developing AD, while ε3ε4 carries a x3.2 risk. APOE transports cholesterol and lipoproteins to the neurones by binding to neuronal APOE receptors. Mutations may lead to atherosclerosis because of hyperlipoproteinaemia. The ε2 allele is less efficient at binding so homozygotes may be more susceptible to atherosclerosis. On the other hand one ε2 allele is protective versus the e4 allele in relation to various neurodegenerative conditions including ischaemic stroke!

It is not immediately clear why these polymorphisms of a lipoprotein transporter would influence amyloid deposition into vessels and how friable this would make the vessels become.

A limitation of the study is the selection of patients; it would be heavily skewed to ICH patients because there would be pathology available in many of these. Patients would rarely have a biopsy if superficial siderosis was found on MRI, given its many other causes, and there would presumably have been some other major brain pathology, such as early onset dementia, in the remainder of non ICH cases that would have prompted such an invasive investigation. Hence the increased occurrence of ε4 allele is not surprising.

The true specificity and sensitivity of these markers remains unknown because the biopsy reflects a single snap-shot in time; there may be two subgroups of ICH negative patients, one who have amyloid deposition in blood vessels as part of some other amyloid process, possibly a by-product of dementia-related pathology, and the other who are susceptible to ICH but who simply have not had their haemorrhage yet. Unfortunately 3 years follow up, to see if it is specifically those who also have superficial siderosis who are in the susceptible group, is probably too short to answer this question.

This paper was presented to our Journal Club by Dr Sam Nightingale, Specialist Registrar in Neurology, Queens Hospital, Romford, UK.

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Journal Club Review “Certainty of Stroke Diagnosis: Incremental Benefit with CT Perfusion over Non-Contrast CT and CT Angiography”

BackgroundCT Perfusion Journal Review

The accompanying primer,  Thrombolysis for Stroke and role of CT perfusion Imaging, describes the difficulties and potential shortcomings of thrombolysis for acute stroke and the way that CT perfusion may improve patient selection for thrombolysis. This paper, by Hopyat et al. (Radiology 2010) describes a related problem: the risks of thrombolysis, mainly constituting secondary haemorrhage, are greater when reperfusing a large area of infarcted brain. In the second European Cooperative Acute Stroke Study (ECASS II), failure to recognise involvement of more than one-third of the middle cerebral artery territory resulted in a high risk of haemorrhage when such patients received thrombolysis. CT perfusion may allow better identification of this situation and avoidance of thrombolysis. In addition, CT perfusion may aid in identifying the baseline stroke size for prognostication and research purposes, in positive confirmation of ischaemia during a TIA and, as discussed in the primer, in identification of stroke mimics. The study uses an incremental protocol with up to date CT perfusion technology to assess its use in positive identification of stroke.

Study Design

The study took 191 consecutive patients with presumed stroke/ unresolved TIA who were admitted within 3 hours of symptom onset. Unenhanced CT, CT angiogram and CT perfusion were assessed in that order by non-expert reviewers. A final diagnosis of stroke was established about a month later by an experienced clinician with the aid of a subsequently-performed MRI with diffusion weighted imaging (DWI).

Results

According to the final diagnosis made retrospectively, 64% of the patients had stroke, 18% had TIA and 17% were stroke mimics.

The sensitivity, averaged over all patients and within and across image reviewers, of correct identification of stroke by unenhanced CT was 52.5%, by unenhanced CT and CT angiography was 58.3% and by unenhanced CT, CT angiography and CT perfusion all together was 70.7%; using all three was significantly better than using one or two modalities (p=0.0003 and p=0.013 respectively).

This was not at the cost of reduced specificity (i.e. false positive errors), which was around 85% for all three conditions. Rather than give an all or none answer, the reviewers scored their confidence levels for diagnosis of stroke, and this allowed calculation of receiver operating characteristic (ROC) curves for unenhanced CT alone, unenhanced CT and CT angiography and all three together.

Receiver operating characteristics plotting sensitivity against false positive rate (i.e. 100-specificity) determined by reviewers scoring their confidence level in diagnosing stroke in various different patients. Unenhanced CT alone is blue, unenhanced CT plus CT angiography is red, and unenhanced CT plus CT angiography plus CT perfusion is orange.

Receiver operating characteristics plotting sensitivity against false positive rate (i.e. 100-specificity) determined by reviewers scoring their confidence level in diagnosing stroke in various different patients. Unenhanced CT alone is the blue trace, unenhanced CT plus CT angiography is in brown, and unenhanced CT plus CT angiography plus CT perfusion is in orange.

For example a reviewer at a very conservative level, requiring a high confidence level for positive diagnosis, may rarely identify stroke; he will have high specificity when he does label a case as having a stroke, but very low sensitivity. A good diagnostic tool will be one where there is a larger area under the curve of sensitivity versus 100% minus specificity. In other words, accepting just slightly less than 100% specificity makes the sensitivity rise very dramatically. It is seen that using all three modalities together improves sensitivity over unenhanced CT alone at all levels of specificity, but at very high levels of specificity, CT perfusion does not improve performance over CT angiography.

Inter-observer agreement (Cohen kappa) was only between 0.28 and 0.44 for unenhanced CT alone, and between 0.68 and 0.78 for all three modalities together. Intra-observer agreement was similarly better using all three modalities together.

Strengths and Weaknesses of Study

The authors attempted a “real-life” situation analysis using an incremental protocol, a realistically early time of imaging, inexperienced reviewers and a range of stroke severities that included mild stroke and TIAs. They demonstrate clear superiority in these circumstances. The circumstances also explain why absolute performance may have been lower than in other studies.

The authors cite the advantages of CT perfusion, namely being done just after standard CT and taking just 1-2 minutes extra to perform and about 5 minutes extra to process. In their hands the radiation dose was only that of another unenhanced CT head. The disadvantages they cited are the confounding effects of chronic internal carotid artery occlusion and chronic ischaemic changes making it hard to determine what is new and what is old.

They consider the addition of CT perfusion well adapted to triage of stroke patients but are cautious about the benefits of identifying penumbra because of the absence of actual evidence that reperfusing penumbra improves outcome.

However, the “real-life” analysis situation might not be without shortcomings in interpretation because real life may be different in different units. Certainly in many stroke units there will be individuals on hand to assess imaging in real-time who may have several years’ experience rather than the one year’s experience of the study’s reviewers. Their lack of skill may have overestimated the extra sensitivity of CT perfusion.

While it is also laudable that they have not selected for their study only patients whose stroke was clinically obvious on admission, it does seem strange that there were so many TIAs when most TIAs do not usually last more than an hour. The mean delay was 117 minutes +/- 59 minutes, so generally there was a 1 to 3 hour window. Some clinicians might delay imaging a little if the patient attended within an hour with as yet not improving symptoms. It would not be a fault of imaging, as such, if a TIA was identified as stroke simply because the scan was performed early enough to detect the ischaemia. A more experienced radiologist might better distinguish ischaemia from established infarction on CT perfusion by the lack of reduction of cerebral blood volume, but this was not specifically examined in this study.

As a tool for ruling out stroke mimics, CT perfusion is clearly and unsurprisingly better than unenhanced CT (which was never intended for this purpose). But with sensitivities around 75% and specificities around 85%, it can hardly be considered a gold standard. Should we thrombolyse on that basis, given the 6% risk of causing harm from intracranial haemorrhage (though the harm engendered on thrombolysing the normal brain of some stroke mimics is likely to be low compared to thrombolysing an extensive established infarct)?

The performance of CT perfusion in positive diagnosis might in fact come up short compared with that of an experienced clinician examining the patient shortly after initial triage, and then one wonders whether that clinician ought not then to rely on his clinical judgement alone or upon an early MRI with DWI, accepting that this might not be universally feasible.

The introduction in the paper started by describing early major middle cerebral artery infarction as a relative contraindication for thrombolysis and how CT perfusion may help identify this. I cannot help but wish this is what the study actually investigated rather than detection of stroke mimics, but it does at least provide a good guide as to how to go about conducting such an investigation rigorously.

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Primer on Thrombolysis for Stroke and Role of CT Perfusion Imaging

Stroke-Header_FASTStroke, defined as a sudden vascular event resulting in localised brain damage (World Health Organisation, 1978), is without doubt a major challenge in health care, being the third most common cause of mortality in developed countries and the single greatest cause of lasting disability (Mant et al., 2004). In the UK, stroke patients occupy 2.6 million days in hospital beds a year, equivalent to one in five total acute hospital beds and one in four long-term beds (National Audit Office, 2005). Over the last decade, there have been increasing efforts to organise acute stroke care into dedicated stroke units and to raise public awareness that stroke is a medical emergency to be managed in a timely fashion (e.g. the FAST campaign).

The development of thrombolysis has been one of the drivers for management of stroke as an emergency. This “clot buster” treatment may be given intravenously to dissolve the thrombus or embolus in a cerebral artery and allow reperfusion of the territory supplied by the artery before those areas of the brain become irreversibly infarcted. Timing is critical for such treatment to be effective; if given too soon after symptom onset, the thrombolysing agent (tissue plasminogen activator (TPA)) may be unnecessary as the patient may in fact be suffering a transient event that would reverse spontaneously, and if given too late the brain tissue will already be dead.

alteplase-actilyse-for-ischaemic-stroke-500x500The standard European criteria for thrombolysis, developed from the major multicentre study (Safe Implementation of Thrombolysis in Stroke Monitoring Study, abbreviated to SITS-MOST (Lancet. 2007)) that validated its use, originally stipulated a time window of 3 hours after symptom onset and excluded patients whose symptoms were rapidly resolving. In practice, giving the treatment too early is not a major concern as most self-resolving events, called transient ischaemic attacks (TIAs) last less than an hour and it is very rare to be ready logistically to thrombolyse within an hour of symptom onset.

Outcome following Thrombolysis

Unfortunately, thrombolysis is not a panacea even within this narrow time window. A fair comparison is achieved with a randomised double-blind study against placebo, but because of widespread use such studies have not recently been performed. The original positive trial (National Institute of Neurological Disorders (NINDS) Stroke Study Group, 1995) showed no clear clinical differences after 24 hours but what was described as “at least 30% better outcome” at 3 months (global odds ratio 1.7 (95% confidence interval 1.2 to 2.6). By way of example, the percentage of patients achieving 0-1 on the modified Rankin score (meaning no or minimal disability) was 39% vs 26%, in other words 13% more patients had  excellent outcome after thrombolysis than after placebo. There was no improvement in mortality.

However, there have been concerns over the fact that in this study the placebo patients had a worse severity stroke at onset, that other studies have shown unclear benefit, and that some studies have relied upon open label self-reporting by patients to measure outcome.

Underpinning these concerns is the risk of haemorrhage associated with intravenous thrombolysis. Thrombolysis was originally developed for coronary thrombosis in myocardial infarction; the brain is an organ far more sensitive to insult and reperfusing infarcted brain may make it particularly susceptible to haemorrhage, with far worse consequences than a haemorrhage into myocardium. In the NINDS study, 7% of patients had a symptomatic intracerebral haemorrhage (meaning neurological deterioration or other clinical suspicion in presence of haemorrhage on CT not seen pre-treatment) within 36 hours after thrombolysis, versus 1% of patients given placebo. In 3% of thrombolysed patients, the haemorrhage was fatal.

The SITS-MOST study was designed to look at safety of thrombolysis given according to the same protocol and collected data on 6483 patients and found a similar figure of 7.3% patients significantly worsened (<=4 points higher on NIHSS score) within the first 7 days by intracranial haemorrhage.

So when counselling patients on giving thrombolysis, we should say that within the 3 hour window, out of 100 treated patients, around 12 will have a better outcome (more likely to be disability free or minimal disability), 4 will be made worse because of brain haemorrhage, 2 will die from brain haemorrhage and 82 will be unchanged. It does not sound as good as quoting 30% better outcome (taken as the increased proportional percentage gain rather than absolute percentage gain over placebo).

Recent Changes to Prescribing Guidelines

More recent studies have explored widening the window of thrombolysis to 4.5 hours, or even longer in certain circumstances. The third European Cooperative Acute Stroke Study (ECASS III, 2008) randomised patients at 3 to 4.5 hours after stroke onset to thrombolysis or placebo, and found a 52.4% versus 45.2% good outcome; the significance level for this 7% improvement was only 0.04 – the lower 95% CI for the odds ratio of better outcome (according to their chosen criterion on Rankin) was 1.02! If other Rankin criteria were chosen, e.g. 0-2 versus 3-6 instead of 0-1 versus 2-6), no significant improvement would be demonstrated. In fact the chance of being dead or severely disabled at 3 months (modified Rankin scores 5-6) was non-significantly higher if thrombolysed (14.8% versus 13.4%). Concern has also been voiced that, despite randomisation, the placebo group had on average a more severe stroke before thrombolysis (one point worse on NIHSS), and were more likely to have had a previous stroke. The risks of intracerebral haemorrhage were comparable to data from patients thrombolysed within 3 hours.

In counselling a patient within this time window, we would therefore have to add that because the time is more than 3 hours after thrombolysis, the chance of improvement to the state of no or minimal disability increases by around 7% instead of 12%.

Cost effectiveness analysis of patients thrombolysed in this time window show limited favourability but are based on limited evidence; of course fatalities reduce cost compared to disability so I find such analysis morally inappropriate.

In the UK, the National Institute of Clinical Excellence (NICE) guidelines for stroke were updated in 2013 to increase the thrombolysis window from 3 hours to 4.5 hours. There is also now no exclusion of posterior territory infarction and debate over excluding patients over 80 years. I personally have reservations about this, and consider it a situation where we have permission under licence to give it if we feel in our judgement it is clinically appropriate. Despite the trumpeting of trial data, there are ethical reservations about giving a treatment that will help a modest proportion of patients but harm a significant proportion too. The haemorrhage risk is more than those surgeons and anaesthetists typically quote for surgery.

Unsurprisingly, this situation polarises medical opinion. Outcome data on thrombolysis have come under intense scrutiny and been subjected to endless meta-analysis and debate. What is really needed is less spin on statistics and more information on predicting a good outcome of thrombolysis in an individual patient who has just had a stroke.

Current guidelines for selecting patients for thrombolysis depend on a clinical diagnosis of ischaemic stroke, a clinical scale of stroke severity, various exclusion criteria and a CT scan of the head. This CT scan will not demonstrate the stroke; the changes of stroke after 3 hours are too early to be detected on CT, which is simply showing the reduced density of infarcted brain. Instead, the CT excludes a haemorrhagic stroke where thrombolysis would be pointless and dangerous, or an established large stroke where thrombolysis may be too late and also associated with increased risk.

An alternative investigation that positively diagnosed stroke within the thrombolysis time window would be very useful to exclude “stroke mimics”, such as patients with acute unilateral muscular weakness from spondylosis or patients who are imagining that they are having a stroke and reproducing its clinical features (functional stroke). What would be even more useful is an investigation that could positively identify ischaemic but potentially retrievable brain from brain that was already infarcted and might only result in haemorrhage if suddenly reperfused by thrombolysis. This retrievable brain is known as the “penumbra”, alluding to the surrounding region of partial rather than complete shadow cast by an object in front of a non-point light source .

CT Perfusion Imaging

Of such investigations, the most promising may be CT perfusion. This requires only the hardware for standard CT, with an intravenous iodinated contrast injection, and may be performed more rapidly and be more easily tolerated than MRI. The limiting factor is likely to be user dependence and the quality of the analysis software.

Technique of CT Perfusion Imaging

After a bolus injection of contrast, a sequence of images are taken that measure the rise and subsequent fall in contrast density as the bolus travels through the cerebral vasculature. Two reference time plots are normally taken; that for the input transit time is the A2 segment of the anterior cerebral artery as it passes perpendicular to the axial plane of imaging, and that for the output transit time is the superior sagittal sinus. For each region of interest voxel, four parameters are then calculated:

  • cerebral blood flow (CBF)
  • cerebral blood volume (CBV)
  • mean transit time (MTT)
  • time to peak contrast enhancement (TTP).

These are then mapped onto an axial slice of the brain to convey visually how the different parameters vary across brain regions, with high values represented as red and low values represented as blue.

Flow dynamics tells us that three of these parameters are interdependent:

  • MTT = CBV / CBF

So if there is a thrombus reducing flow to a region of brain, as the CBF is lowered, the MTT increases in parallel if the CBV stays the same.

Normal grey matter has a higher CBF and CBV, so cortical areas of gyri tend to look more red on both CBF and CBV. Because the increases are similar, the changes cancel out on MTT so the MTT tends to look more blended between white and grey matter. The venous sinuses also look very red on CBF and CBV and similar to background on MTT, presumably because these voxels are purely blood so have relatively high blood volume as well as flow. (One might expect arteries to have higher flow, and therefore blue on MTT, but the resolution of CT perfusion may not be great enough to identify arteries in cross-section.)

In the early hours after an acute stroke, it is considered that an “umbra” of infarcted brain may be surrounded by a “penumbra” of ischaemic brain that will shortly become infarcted but is potentially salvageable on reperfusion. CT perfusion may allow differentiation of the two because the CBV reduces more in infarcted brain. So:

Infarcted Brain ↓↓↓ CBF ↓↓ CBV ↑↑ MTT
Ischaemic Brain ↓↓ CBF slight ↓ CBV ↑↑ MTT
CT perfusion

In a patient 70 minutes after stroke onset (NIHSS score 10), the unenhanced CT, not shown, is normal. The cerebral blood flow (top left) and cerebral blood volume (top right) show reductions in the arrowed area. There is a corresponding increase in mean transit time (bottom left) and a DWI weighted high signal area several days later on MRI (bottom right). (Figures taken from Hopyan et al., 2010.)

 

Cerebral blood flow is obviously reduced if there is a proximal thrombus, and in infarction there is reduction in cerebral blood volume. This could be because of tissue swelling raising local intracranial pressure and constricting capacitance vessels, because there is a certain elasticity in vessels so that constriction will follow from reduced flow, or because of reflex vasoconstriction of capacitance vessels in damaged brain. The reduced CBV is still less than the dramatically reduced flow, so that MTT is significantly prolonged. The infarcted area appears more blue on CBF and CBV and more red on MTT.

In ischaemic brain, the CBV is relatively preserved, perhaps because the affected brain area is not as swollen or perhaps because of preserved reflex capacitance vessel dilatation in an attempt to improve perfusion of these areas. Cerebral blood flow is reduced (blue), but there is now a mismatch between CBV (relatively normal) and MTT (clearly red).

Problems in interpreting CT perfusion

  • Image processing is complex and user dependent. There may be poor selection of the anterior cerebral artery and superior sagittal sinus reference points
  • If the protocol is poorly designed, the radiation dose may be massive
  • Many protocols do not analyse the whole brain, so clinical knowledge is required to determine if the area of interest is middle cerebral artery territory. Brainstem areas cannot easily be assessed.
  • The resolution of CT perfusion is such that small strokes may not be visualised
  • If there is extracranial vessel occlusion, e.g. carotid artery, the hypoperfused area may give a false impression of acute infarction. The same applies to areas of leukoaraiosis. Thus CT perfusion must be interpreted in the context of unenhanced CT appearances and preferably with CT angiography.

Practical Uses of CT Perfusion

  • Identification of penumbra. If a patient was outside the 3-hour time window for thrombolysis, or the time of onset was unknown, but was otherwise a good candidate, a CT perfusion scan revealing a relatively large penumbra with normal CBV and prolonged MTT would indicate salvageable brain that might benefit from thrombolysis.
  • Positive identification of stroke. CT perfusion reveals changes very early after stroke onset, but there may be poor sensitivity because of lack of clarity over the territory of interest, the possibility of posterior circulation stroke and poor resolution of a small stroke, e.g. lacunar infarction.
  • Measuring cerebrovascular reserve. In the non acute setting, CT perfusion before and after administration of intravenous acetazolamide can help to identify brain areas that are chronically ischaemic. Acetazolamide is a vasodilator, but will have less effect on ischaemic areas because such areas already have ongoing maximal compensatory vasodilation. Thus, after acetazolamide, there will be less increase in CBF in ischaemic areas compared to normal neighbouring areas, less increase in CBV (though this is generally increased throughout the brain), and most clearly an extra prolongation of MTT (more red) in areas that may already have somewhat prolonged times compared to normal areas.
  • Identifying vasospasm. In the situation of subarachnoid haemorrhage, areas of brain suffering reactive vasospasm react like the penumbra of a stroke and indicate that measures taken to reduce vasospasm may reduce the risk of lasting focal neurological deficit after subarachnoid haemorrhage.

An accompanying Journal Club Review looks at a study that investigates the use of CT perfusion in acute stroke primarily in terms of stroke diagnosis.

stroke-act-fast

 

 

 

 

 

 

 

 

 

 

Posted in Primer Posts for General Readers, Stroke | Tagged , , , , | 1 Comment