Thursday, 27 October 2016

#ClinicSpeak: What about PPMS?

Do you have PPMS? This post is for you. #MSBlog #ClinicSpeak

Primary progressive MS (PPMS) = relapse-onset MS = MS 

A lot of assumptions about PPMS have crept into the field and have become entrenched; we call these dogmas. We need to challenge the dogma; in particular that (1) PPMS in non-inflammatory, (2) PPMSers don't have relapses and (3) PPMS is a different disease to relapse-onset MS.

Dogma 1: PPMS in non-inflammatory - WRONG!

This pathology study done at Queen Square from the early 1990s clearly shows that PPMS is inflammatory, albeit at a slightly lower level than relapse-onset MS. The dogma has crept in because PPMSers have fewer focal lesions on MRI. This however does not mean that there is no inflammation; focal inflammation is simply occurring below the threshold of the MRI. What MRI sees in relation to focal lesions is simply the tip of the iceberg. The PPMS iceberg simply looks different with less above the surface. The positive ocrelizumab PPMS, or Oratorio, study supports PPMS as being inflammatory. 

Revesz et al. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain. 1994 Aug;117 ( Pt 4):759-65.

Background: The dynamics of primary progressive multiple sclerosis differ from those of the more common secondary progressive form. The observation by MRI that the frequency of enhancement with gadolinium-DTPA, a marker for blood-brain barrier dysfunction, is significantly less in the primary progressive form, has led to the hypothesis that inflammation is less intense in this group. 

Aims: To test this, we have studied postmortem material from 9 cases judged from a retrospective analysis of case notes to show clear clinical evidence of either primary progressive or secondary progressive disease. 

Methods: 578 lesions were analysed. 

Results: There was significantly more inflammation in secondary progressive multiple sclerosis (as judged by the frequency of perivascular cuffing and cellularity of the parenchyma) than in primary progressive disease. 

Conclusions: These observations have implications for therapeutic strategies in progressive multiple sclerosis.

Dogma 2: PPMSers don't have relapses WRONG!

In almost all PPMS trials done to date a proportion, albeit a small proportion, of PPMSers go onto have relapses. For example in the Rituximab trial in PPMS (Olympus Trial), 11 out of 439 (2.5%) of study subjects had a relapse during the 96 weeks of the trial.

Hawker et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009 Oct;66(4):460-71.

Similarly, about 5% of study subjects in the glatiramer acetate PPMS, or PROMISE, trial had relapses. Unfortunately, the exact number of relapses is not reported in the main manuscript. What is reported is MRI activity; 14% of 938 study subjects had Gd-enhancing lesions on MRI during the study. The latter is the MRI equivalent of relapses. Can we say therefore make the claim that PPMS is non-relapsing? 

Wolinsky et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol. 2007 Jan;61(1):14-24.

Dogma 3: PPMS is a different disease to SPMS WRONG!

Did you know that it is not that uncommon in siblings pairs with MS for one to have relapse-onset disease and the other to have PPMS? The figure from the UK sibling study is in fact 23% (please see article and table below). This indicates to me that relapse onset and PPMS are the same disease.

Chataway et al. Multiple sclerosis in sibling pairs: an analysis of 250 families. J Neurol Neurosurg Psychiatry. 2001 Dec;71(6):757-61.
(33.7+27) / (84+68.3+33.7+39.3+27+9.7) x 100 = 23%

Other arguments in favour of PPMS and relapse-onset MS being the same disease relates to genetic and natural history studies. PPMSers and relapse-onset MSers have the same genetic background. Once relapse-onset MSers enter the clinical apparent phase of SPMS they progress at exactly the same rate as PPMSers.

It is for the reasons above that there is a strong argument for doing trials on combined populations of progressive MSers. In other words we should combine PPMS and SPMS populations into one study. The latter will simply be going back to chronic progressive MS classification that existed before we split MS in different subtypes. I am aware that  this is a controversial topic but it needs debate. If we don't do this then treatments will only be licensed for one subtype of progressive MS, and not the other clinical subtype, until additional trials are done. Additional trials cost money and time. Time is not a something people with progressive MS have on their side. 5-years in the life of someone with clinically-apparent progressive MSers may be the difference between using a walking-stick and being bed-ridden.

In short, pwPPMS have unfortunately missed out in the relapsing phase of the disease. They are simply unlucky that a new lesion did not occur in a clinically-eloquent site to cause a relapse and bring them to the attention of a neurologist earlier in the course of their disease. They only present when they have lost their reserve capacity. The good news is we now have a positive trial of ocrelizumab. Let's hope the regulators and payer allow pwPPMS access to ocrelizumab. 

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.