Thursday, 27 October 2016

Stop Smoking

O'Gorman CM, Broadley SA. Smoking increases the risk of progression in multiple sclerosis: A cohort study in Queensland, Australia. J Neurol Sci. 2016 ;370:219-223.

BACKGROUND:Cigarette smoking has been associated with increased risk of progressive multiple sclerosis (MS). The effect of smoking status on risk and timing of disease progression in patients with MS in Queensland, Australia has not been established.
METHODS:A clinical cohort of 646 cases (531 females, 115 males) were followed from first clinic attendance to onset of clinically determined progressive disease. Progression risk was analysed with gender, age, age of onset, exposure to disease modifying therapy, and smoking status as covariates
RESULTS: There were significantly higher risks of secondary progressive disease in males (Hazard Ratio, HR 1.83, 95% CI: 1.3-2.7) and in ever smokers (HR 1.4, 95% CI: 1.0-2.0). Progressive disease occurred approximately 4years earlier in ever smokers. Smoking did not affect age of onset of primary progressive disease.
CONCLUSIONS: Cigarette smoking was associated with earlier onset of progressive disease in this large clinical cohort. For patients with relapsing-remitting disease, smoking cessation should be encouraged.

You know this... but if you can stop the ciggies.

To stop you have to want to do it

Yes there are many people who have never smoked who have progressive MS, this suggests that you are more likely to progress if you have smoked.

Wednesday, 26 October 2016

#ClinicSpeak: what's in a name?

Why have we turned MS into two diseases instead of one? #ClinicSpeak #MSBlog

I was a meeting this weekend and presented a talk in which I discussed MS being a length-dependent axonopathy. I made the case why progressive MS is modifiable and presented the positive results of the oral low dose methotrexate and ASCEND (natalizumab) trials and said that we had thrown the baby out with the bathwater. If we had interpreted the results of the oral low-dose methotrexate progressive trial from over 20 years ago correctly we would have had licensed therapies for progressive MS decades ago. 

I was then told by one of the participants at the meeting that the parcelling up of MS into relapsing and non-relapsing forms, and of chronic progressive MS into primary and secondary progressive MS, was driven by money. When the interferon trials started it was important to make MS an orphan disease, i.e. to having fewer than 200,000 patients classified as having the disease. Being an orphan disease allowed Pharma to access the market with one pivotal trial, gave them market exclusivity and allowed them to charge much more for their drugs. The consequences of this is that we have divided MS into being many diseases, which is to the detriment of people with MS. The consequences of this are not trivial. Being diagnosed as having MS is bad enough, but then being diagnosed as having secondary progressive disease is worse. The latter is interpreted by most people that their disease is not modifiable and that they are not eligible for DMTs. This is incorrect; remember #ThinkHand. In England we are meant to stop DMTs in the SPMS phase. There are also many other reasons to avoid the diagnosis of SPMS. 

An analogy to the RRMS vs. SPMS dichotomy is being diagnosed with a low-grade tumour, that on average is quite indolent and slow growing, however, after time the tumour mutates to become highly-malignant and terminal. Just as people fear their tumour mutating, and becoming 'terminal', people with relapsing MS live in fear of developing progressive MS. 

Two diseases-in-one.

Our PROXIMUS trial, which is now over a year behind in recruitment, has been a victim of MS being two and not one disease. We made the mistake of calling it a secondary progressive trial. Very few of my colleagues have referred patients for this trial simply because it means diagnosing their patients as having early SPMS. Almost every neurologist I know avoids making a diagnosis of SPMS as long as possible because of the repercussions it has for their patients. 

I think we need to turn the clock back and get rid of arbitrary, non-science, based definitions of MS. They don't help us clinically. I recently wrote a short commentary for MSARDs arguing the MS begins long before the first clinical attack, I plan to write a piece on the observations that progressive MS is present from the start of the disease. There is simply no magic point in time when you become SPMS. Dividing MS into relapsing and progressive phases may have helped Pharma get interferons licensed under the orphan-drug act, made them lots of money, but it has done the field of MS a major disservice

Cannabis controling spasticity

Squintani G, Donato F, Turri M, Deotto L, Teatini F, Moretto G, Erro R. Cortical and spinal excitability in patients with multiple sclerosis and spasticity after oromucosal cannabinoid spray. J Neurol Sci. 2016;370:263-268. doi: 10.1016/j.jns.2016.09.054.

BACKGROUND: Delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex®) has been recently approved for the management of treatment-resistant multiple sclerosis (MS) spasticity. Although the symptomatic relief of Sativex® on MS-spasticity has been consistently demonstrated, the pathogenetic implications remain unclear and the few electrophysiological studies performed to address this topic yielded controversial results. We therefore aimed to investigate the mechanisms underpinning the modulation of spastic hypertonia by Sativex®, at both central and spinal levels, through an extensive neurophysiological battery in patients with MS.
METHODS: Nineteen MS patients with treatment-resistant spasticity were recruited. Before and after 4weeks of treatment with Sativex® patients were clinically assessed with the Modified Ashworth Scale (MAS) and underwent a large neurophysiological protocol targeting measures of excitability and inhibition at both cortical [e.g., intracortical facilitation (ICF), short (SICI) and long (LICI) intracortical inhibition, cortical silent period (CSP)] and spinal level [e.g., H-reflex, H/M ratio and recovery curve of the H-reflex (HRC)]. A group of 19 healthy subjects served as controls.
RESULTS: A significant reduction of the MAS score after 4weeks of Sativex® treatment was detected. Before treatment, an increase in the late facilitatory phase of HRC was recorded in patients compared to the control group, that normalised post treatment. At central level, SICI and LICI were significantly higher in patients compared to healthy subjects. After therapy, a significant strengthening of inhibition (e.g. reduced LICI) and a non-significant facilitation (e.g. marginally increased ICF) occurred, suggesting a modulatory effect of Sativex® on different pathways, predominantly of inhibitory type. Sativex® treatment was well tolerated, with only 3 patients complaining about dizziness and bitter taste in their mouth.
DISCUSSION:Our results confirm the clinical benefit of Sativex® on spastic hypertonia and demonstrate that it might modulate both cortical and spinal circuits, arguably in terms of both excitation and inhibition. We suggest that the clinical benefit was likely related to a net increase of inhibition at cortical level that, in turn, might have influenced spinal excitability.

During the MS trials it was impossible for them to find an effect on the Ashworth scale of spasticity and this is one of the reasons why sativex is not available in the USA, because the FDA want to see an effect on the Ashworth, but here we are seeing an effect with just 38 people 19 on drug and 19 not on drug.

Here they look at electrophysiology (movement of nerve impulses) in the brain and the spinal cord.

Cortical (cortex outside of the brain) output depends on the balance between different inhibitory and facilitatory circuits. Transcranial magnetic stimulation (TMS) is a widely used technique to examine motor cortical physiology in humans. 

Depending on the stimulus parameters, TMS can be used to test different inhibitory and facilitatory circuits in the motor cortex (M1). 

With a subthreshold (below threshold) conditioning stimulus (CS) followed by a suprathreshold (above threshold) test stimulus (S1) at interstimulus interval (ISI) of 1–6 ms, the motor (movement) evoked potential (nerve signal) (MEP) generated by the S1 is inhibited and this is known as short interval intracortical inhibition (SICI). 

On the other hand, the MEP generated by S1 is facilitated at ISI of 8–30 ms and this is termed intracortical facilitation (ICF). 

If the S1 is followed by a second pulse (S2) at threshold intensity, another type of facilitation, known as short interval intracortical facilitation (SICF) or indirect (I) wave facilitation, can be elicited

Following electrical stimulation of M1 two waves are noted. The first wave was the direct (D) wave due to direct activation of the axon of corticospinal neurons and the subsequent I waves were due to trans-synaptic activation of these output neurons. I waves appeared at regular clocklike intervals of 1.5 ms. Since the three peaks of SICF also occur at about 1.5 ms intervals, it has been suggested that SICF is due to interaction of I waves generated by the two stimuli (S1 and S2) 

SICF originates in the cortical level because there was no facilitation if electrical stimulation was used to elicit S2 and it is associated with increased amplitudes (height) of the I waves generated by the S1. SICF-1 is likely to be due to I2 waves from S1 interacting with I1 waves from S2; SICF-2 is likely to be due to I3 waves from S1 interacting with I1 waves from S2; and SICF-3 is likely to be related to I4 waves from S1 interacting with I1 waves from S2. Additionally, anterior–posterior (AP) directed current in the M1 preferentially induces I3 waves whereas the usual posterior–anterior (PA) directed currents induce I1 waves. SICF-1 elicited by S1 and S2 in the AP direction is likely to be due to I3 waves from S1 interacting with I2 waves from S2 .

LICI results in attenuation of the MEP when a suprathreshold CS is paired with a suprathreshold TS at long ISIs (50-200 ms) 

Don't worry I dont understand it either:-)

The H-reflex (or Hoffmann's reflex) is a reflectory reaction of muscles after electrical stimulation of sensory fibers (Ia afferents stemming from muscle spindles) in their innervating nerves. 

The H-reflex test is performed using an electric stimulator and an EMG set to record the muscle response. An M-wave, an early response, occurs 3-6 ms after the onset of stimulation travels down the motor/movement nerve. There is a response that moves up the sensory nerves into the spinal cord and then travels down the motor nerve to the muscle. The H-wave occurs 28-35 ms after the stimulus, in mice because they are small the H wave arrives 7 ms (a thousandth of a second)

H-reflex is analogous to the mechanically induced spinal stretch reflex (for example, knee jerk reflex). "The primary difference between the H-reflex and the spinal stretch reflex is that the H-reflex bypasses the muscle spindle, and, therefore, is a valuable tool in assessing modulation of monosynaptic (single synapse) reflex activity in the spinal cord.

H-reflex amplitudes measured by EMG, increases in spasticity because the inhibitory circuits are reduced and amplifying the nerve signal as it travels through the damaged spinal cord. 

Hypertonia is a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by injury to motor pathways in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle tone, and reflexes.

There was too much excitation in the spinal cord which will mean that muscles are contracted. 

Cannabis inhibited this

The Dizziness is because the people in the study were "stoned/high"

So in short more evidence for cannabis controlling spasticity. But we need ways to control this without the dizziness

CoI This what we are trying to do.

Tuesday, 25 October 2016

#PoliticalSpeak: NHS in crisis

NHS in crisis will innovation be sufficient to change the way we manage MS?  #PoliticalSpeak #MSBlog

The editorial in this week's BMJ (below) says it all. Our attempts to try and improve productivity within Barts-MS may be simply a sticking plaster. It is clear the NHS needs more money. I suspect innovation won't be enough, but is that a reason not to try? 

Our proposal to set-up a Barts-MS Expert Patient Course may be an act of folly. During the course we propose teaching you everything you need to know about MS, the management of MS and how to monitor and manage your own disease. You will then provide you with the tools to get on with it. The system we propose setting-up will allow you to contact us if you run into problems and/or need help, for example with a specialist referral. We will hopefully allow you to self-refer for essential services, for example continence advise and therapy. We also will identify expert patients with MS who can help us run the teaching course and our service on a voluntary basis. If you haven't responded already we would appreciate it if you could complete the survey below. We need the data to make the case to our managers and to Barts Health for crowd funding. 

Andy Cowper. Feature NHS Performance: A view to a plan? BMJ 2016;355:i5583

For almost all the wrong reasons, NHS performance is scarcely out of national news headlines. The State of Care report just published by the Care Quality Commission (CQC) outlines a system having to deal with a record 23 million emergency department attendances and six million hospital admissions in 2015-16.

The CQC chief executive, David Behan, identifies falling and failing social care provision and pressures in primary care as key contributors to problems with NHS performance. “[They] are now beginning to impact both on the people who rely on these services and on the performance of secondary care. The evidence suggests we may be approaching a tipping point,” he said.

The cause is obvious. Despite a 33% rise people aged 85 and over the past decade, the proportion receiving care funded by local authorities has fallen. A National Audit Office review found that local authority income, including council tax, fell by 25.2% in real terms from 2010-11 to 2015-16.

This hits on the same day that NHS England’s latest figures for August 2016 reveal that overall referral-to-treatment performance deteriorated. The total waiting list rose to 3 691 739, and the proportion of people referred for elective care being treated within 18 weeks fell further below target to 90.9% (this is not including providers who, for various reasons, are not reporting their waiting times).

There were 1 931 981 emergency department attendances in August 2016 (3.6% more than in August 2015). Attendances over the past 12 months are 4.2% higher than in the preceding 12 months. The number of days of delayed care rose to 188 000—the highest since monthly data were first collected.

Financial arguments

Yet August 2016 wasn’t all bad news. The financial and performance regulator, NHS Improvement, announced that overall, the NHS provider sector had hit its financial target in the first quarter of the 2016-17 financial year, reversing a three year trend of missing it.

The Treasury is understood to be pressuring NHS leaders to achieve quarterly financial balance at almost any cost and has no appetite to revisit the 2015 comprehensive spending review financial settlement.

The government repeatedly trumpets its £10bn extra for the NHS, saying it only asked for £8bn. This isn’t really true: as financial expert Sally Gainsbury of the Nuffield Trust think tank points out, the “extra” £2bn was allocated before the comprehensive spending review in 2014, to mop up deficits.

In addition, the House of Commons health select committee calculates that the actual increase will be just £4.5bn from 2015-6 to 2020-21.

And Gainsbury adds that once healthcare specific inflation is taken into account, that figure dwindles to £0.8bn.

Pressure on the NHS and social care seems unrelenting. The latest QualityWatch report from the Nuffield Trust and the Health Foundation highlights how what was once considered “winter pressure” is now almost year round. Winter is the new normal.

A sustainable future

It can be hard to remember that when NHS system leaders collaborated to publish the Five Year Forward View two years ago, there was general buy-in to its vision of a more networked system, away from being a heavily acute focused series of organisational silos.

One problem was the lack of a means of delivering the Forward View’s desired change in providers.

One answer emerged in the 44 geographically based sustainability and transformation plans (STPs), announced last December and currently being negotiated and finalised. These bodies, crucially, have £2.1bn of STP funding in 2016-17, which can be withheld from providers and STP “footprints” who do not deliver financial balance.

So STPs are the change delivery vehicle? Politicians may hope so. At Prime Minister’s questions on 12 October, six of the 29 questions were asked on health and NHS issues. The latest parliamentary health questions heard numerous concerns about provider issues and STP processes and results, including from Conservative MPs.

NHS Providers (whose name describes its constituency) expressed the sector’s serious doubts to the health select committee last week. Chief executive, Chris Hopson, called many STPs “vastly overambitious,” adding that their authors “are now looking at a set of figures that to be frank just look completely undeliverable. Our members are spending quite a lot of time creating plans that in their view are not deliverable, and usually involve major structural service changes because that’s the only way they can create a balanced plan.”

It bodes ill if the authors of the only game in town don’t believe in their STPs. In a recent interview, Simon Stevens reflected at length on the funding question. His concluding remarks offer politicians a lightly veiled warning of a change that is going to come: “Since we’re now facing a tougher challenge than set out in the Five Year Forward View, there will inevitably be pressures, choices, and controversies as the NHS copes with these constraints. Frontline staff, clinicians, and local NHS leaders need full national backing and support in doing so.”

The political and public reaction to STPs is about to get interesting.

JCV are we in safer times?

Acta Neurol Scand. 2016 Oct 20. doi: 10.1111/ane.12699. [Epub ahead of print]

JCV serology in time: 3 years of follow-up.

Cambron M, Hadhoum N, Duhin E, Lacour A, Chouraki A, Vermersch P.



Although many neurologists are reluctant to use natalizumab in MS (multiple sclerosis) given the increased risk for PML (progressive multifocal leukoencephalopathy), trust was regained with the introduction of JCV antibody titres as a potent disease-modifying therapy. Literature shows that in patients with a negative JCV serology, the risk of PML is virtually non-existent. Unfortunately, seroconversion causes concern amongst many neurologists. Furthermore, when patients seroconvert, it is still unclear what the risk is of passing the important threshold of 1.5.


JCV serology data of 161 patients were analysed, upon treatment with natalizumab at the University Hospital in Lille, France, between May 2012 and November 2014.


Of the 81 patients who tested negative for JCV antibody at baseline, 23 (28.3%) seroconverted but only seven (8.6%) passed the threshold of 1.5. Of the 80 patients testing positive for JCV antibody at baseline, eight had an initial JCV antibody titre of 0.9 or lower of which only one of eight (12.5%) patients passed the threshold of 1.5 in the following 3 years. Eight of 15 (53.3%) patients passed this threshold if the initial serology was higher than 0.9.


JCV-negative patients and JCV-positive patients with antibody levels below or equal to 0.9 both have a low risk of surpassing the 1.5 threshold.

Figure: Google trends for interest in natalizumab from 2004 - current. The peak in 2005 corresponds to suspension of marketing authorization of natalizumab (Tysabri) by the FDA.

The John Cunningham virus causes a serious demyelinating CNS disorder called progressive multifocal leukoencephalopathy (PML). Although, 33-91% of the general population is positive for the virus, only half of PwMS are positive for the antibody (the seroconverted). PML risk is at the heart of natalizumab therapy; public and professional concerns over this have not yet been convincingly allayed. In addition, there is the added concern of seroconversion on therapy; with some researchers (most recently N Schwab's group at ECTRIMS 2016) suggesting that those on natalizumab seroconvert at higher rates than expected by aging.

A lot of sweat has therefore gone into a developing an antibody test (STRATIFY) that can be used to risk stratify PML development in natalizumab users. An index threshold of 1.5 is used by many as the cut-off. In this study, Cambron et al. wanted to investigate the risk of an initially negative antibody test person passing the threshold of 1.5. They found that 28.3% seroconverted with 8.6% passing the threshold of 1.5. They found that the likelihood of seropositivity increased in those receiving a higher number of infusions. But they also then suggest that the ones with an index of =/<0.9 had a lower risk of passing the 1.5 threshold (an oxymoron possibly).

I'm not sure how this allays my fears. The authors conclude: "Patients who have a positive response to natalizumab and a positive JCV index values below 0.9 can be reassured and safely continue their natalizumab treatment, obviously with an accurate clinical and radiological follow-up". And therein lies the problem, a negative baseline test is not fool-proof or protective against PML development (see Abstract P1259 below), and where cases of diagnosed PML are concerned, their defining characteristics are being JCV positive and receiving natalizumab for >2 years (see Abstract P1111 below)!

Maybe, we need to stop worrying our heads over this one; there is only so many ways you can cut a cake.

Abstract: P1259, ECTRIMS 2016
Progressive multifocal leukoencephalopathy in a JCV seronegative patient treated by natalizumab : a new case report
Author(s):N Hadhoum ,V Neuville ,P Vermersch
Background: the prediction of the risk of progressive multifocal leukoencephalopathy (PML) is crucial to guide natalizumab (NTZ) prescription and ensure a higher safety use. The JCV index (a corollary to antibody titer) is a predictive factor of PML.

Case presentation: here we report a case of a 55-year-old female diagnosed with multiple sclerosis in 1996. Because of a continued clinical disease activity despite interferon, she was switched to NTZ. A total of 84 infusions were administered between 2011 and 2016. She never received any prior immunosuppressor and has been tested negative for anti-JCV antibodies: index at 0.22 in 06/2014 and 0.11 in 06/2015 and 10/2015. The annual MRI were strictly stable. During a routine follow-up, the patient complained of a right-sided lower limb paresis. NTZ was immediately stopped. Brain magnetic resonance imaging revealed a sub-cortical white matter lesion, hypoT1, hyperT2 in the left parietal lobe invading the U-fibers in DIR sequence. PML was suspected then confirmed by detection of JCV-DNA in the CSF (2 analyses: 11 then 68 copies/ml). The peripheral CD4+ T-cell count was 1149/mm3, CD8+ at 395/mm3. Note that the JCV index was still negative at the diagnosis and 15 days later. We investigate the lymphopenia and found a probable common variable immune deficiency (CVID) with severe hypogammaglobulinemia (3g/dL), surprisingly asymptomatic until now. A JCV seroconversion was noted at 3 months (index at 3.48).

Discussion: it is well-known that PML risk is influenced by NTZ duration, prior use of immunosuppressors and seropositivity for the JCV. The JCV seronegativity status does not allow to exclude any risk of PML. Indeed, de novo infection with seroconversion is theoretically possible and underestimate rate of infection appears likely (in case of low viremia). One recent publication reports a NTZ-related PML diagnosed 2 weeks after negative anti-JCV antibody assay and 2 others PML due to NTZ were tested negative (prior to diagnostic) among the 541 reported cases. In our case, we can hypothesize that the JCV index were false negative results as the asymptomatic CVID imply a fail in humoral responses.

Conclusion: this case must not undermine the central role of the JCV index in predicting the risk of PML. However, it seems wise to regularly control the blood lymphocyte phenotype and immunoglobulins. CVID is the one of the most common causes of adult immunodeficiency.

Abstract: P1111, ECTRIMS 2015
JCV (John Cunningham virus) index: follow-up of a French cohort
Author(s):S. Mathais ,A. Gayou ,X. Moisset ,J.C. Ouallet ,B. Pereira ,A. Ruet ,F. Taithe ,K.-K. Kounkou ,E. Dumont ,B. Brochet ,P. Clavelou

Objectives: Patients receiving natalizumab (NTZ) are at risk of PML (Progressive Multifocal Leukoencephalopathy) due to JCV reactivation. In order to predict that risk we currently use the JCV index. Recently, cut-off values for the JCV index have been published. The risk of PML seems to be very low under 0.9, low between 0.9 and 1.5 and high above 1.5.

We wanted to better characterize the JCV index and its evolution and check whether the suggested thresholds were applicable to our cohort.

Methods: This study was conducted in two French University Hospitals (Bordeaux and Clermont-Ferrand) until the 31/12/2014. We included 352 patients over 18 years with a relapsing-remitting multiple sclerosis and at least one JCV index. We got 908 samples. Three subjects developed a PML. We evaluated the seropositivity for JCV, the potential modifying factors of JCV index (before and under NTZ), its evolution under NTZ and particularly in case of PML.

Results: 63.2% of NTZ-naïve patients were positive for JCV. At this stage the JCV index is statistically related with the age but independent from sex, disease duration or anterior exposure to immunosuppressive agents. Among the patients finally treated with NTZ 39.7% were positive for JCV at baseline and 55% at the last JCV index. On NTZ only the treatment duration was statistically related to the evolution of the JCV index. 84.5% of subjects remained stable during the follow-up specially if they were initially positive for JCV (45.4%). 6.7% seroconverted and 1.5% seroreverted. Our three cases of PML presented two risk factors (over 2 years of NTZ and seropositivity for JCV). Their indexes were above 1.5 for at least 3 months prior PML.

Conclusions: JCV index seems to remain fairly constant over time and the published threshold for high PML risk (1.5) was confirmed in our cohort.