Monday, 24 April 2017

Adenosine deaminase elevation in MS


Multiple sclerosis showing elevation of adenosine deaminase levels in the cerebrospinal fluid.Samuraki M, Sakai K, Odake Y, Yoshita M, Misaki K, Nakada M, Yamada M.Mult Scler Relat Disord. 2017 Apr;13:44-46.

An 80-year-old man developed dysarthria, quadriplegia, sensory disturbance and ataxia in all limbs. Brain and spinal magnetic resonance imaging (MRI) revealed multiple enhanced lesions. Cerebrospinal fluid (CSF) levels of adenosine deaminase (ADA) remarkably elevated. Tuberculosis DNA was not detected, and tuberculosis was not cultured either in the CSF. Brain biopsy revealed the inflammatory demyelinating lesions. With the diagnosis of multiple sclerosis, corticosteroid therapy resulted in rapid improvement of his symptoms and MRI abnormalities. CSF levels of ADA also decreased. Multiple sclerosis should be included in differential diagnosis of disorders with ADA elevation in the CSF.


Adenosine deaminase is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues. 

A function in humans is the development and maintenance of the immune system. If you don't make it you have reduced B cells and can also have reduce T cells, If you make it does it mean you can make more lymphocytes? 

Increased adenosine deaminase has been seen before

Alterations in the cholinesterase and adenosine deaminase activities and inflammation biomarker levels in patients with multiple sclerosis.


Cladribine is a adenosine deaminase inhibitor and it depletes T cells and particularly B cells and MS

CoI: None

#AAN2017: Teaching Course Progressive MS

Did you know that progressive MS is a tractable problem? #AAN2017 #MSBlog 

As promised my slides from my AAN teaching course this year. I think my talk went down reasonably well. As I had quite a few slides I tended to rush through the presentation, but overall I think I got several important messages across including a punt for our #ThinkHand campaign. I spent at least 30 minutes after my presentation dealing with questions. If anything I at least stimulated discussion around the topic of progressive MS.



CoI: multiple

Sunday, 23 April 2017

Detecting myelin

Myelin Detection Using Rapid Quantitative MR Imaging Correlated to Macroscopically Registered Luxol Fast Blue-Stained Brain Specimens.Warntjes JBM, Persson A, Berge J, Zech W.
AJNR Am J Neuroradiol. 2017 . doi: 10.3174/ajnr.A5168. [Epub ahead of print]

BACKGROUND AND PURPOSE: Myelin detection is of great value in monitoring diseases such as multiple sclerosis and dementia. However, most MR imaging methods to measure myelin are challenging for routine clinical use. Recently, a novel method was published, in which the presence of myelin is inferred by using its effect on the intra- and extracellular water relaxation rates and proton density, observable by rapid quantitative MR imaging. The purpose of this work was to validate this method further on the brains of 12 fresh, intact cadavers.
MATERIALS AND METHODS: The 12 brains were scanned with a quantification sequence to determine the longitudinal and transverse relaxation rates and proton density as input for the myelin estimations. Subsequently, the brains were excised at postmortem examination, and brain slices were stained with Luxol fast blue to verify the presence of myelin. The optical density values of photographs of the stained brain slices were registered with the MR images and correlated with the myelin estimation performed by quantitative MR imaging.
RESULTS: A correlation was found between the 2 methods with a mean Spearman ρ for all subjects of 0.74 ± 0.11. Linear regression showed a mean intercept of 1.50% ± 2.84% and a mean slope of 4.37% ± 1.73%/%. A lower correlation was found for the separate longitudinal relaxation rates and proton density (ρ = 0.63 ± 0.12 and -0.73 ± 0.09, respectively). For transverse relaxation rates, the ρ was very low (0.11 ± 0.28).
CONCLUSIONS: The observed correlation supports the validity of myelin measurement by using the MR imaging quantification method.

If true this should be an advance in this study they imaged dead people and then did the histology to suggest whats seen is myelination, so more easy validation steps. Too often we see MR parameter this or MR parameter that described to be this or that, based on unconfirmed presumptions. Eg Gadolium is alway presumed to be cell infiltration, when it is probably just fluid movement and therefore is more extensive than cellular movement.

Not in my Name again

Zakaria MMA, Mikhael SY, Hussein AKA, El-Din RAS, El-Malak HWA, Hewedi IH, Nadim HS.Failure of the vascular hypothesis of multiple sclerosis in a rat model of chronic cerebrospinal venous insufficiency. Folia Neuropathol. 2017;55(1):49-59

Chronic cerebrospinal venous insufficiency (CCSVI) is a series of stenotic malformations in the cerebrospinal venous outflow routes, which is postulated to cause multiple sclerosis (MS). The hypotheses assumed that CCSVI leads to iron deposition which triggers inflammation and demyelination in MS. Invasive endovascular treatment of CCSVI was initiated based on the previous theory. The present study was designed to validate this hypothesis using a rat model of CCSVI. Bilateral jugular vein ligation (JVL) was performed on female albino rats (n = 15), and sham-operated rats (n = 15) were used as a control group. The rats were followed clinically for eight months and neurological examination detected no weakness or paralysis in the operated rats. At the end of the experiment, the rats were sacrificed and the brains were processed for histopathological examination of tissue sections stained by haematoxylin and eosin, myelin stain, silver impregnation, iron stain and immunohistochemical preparations for GFAP, CD68 and CD45. Semithin sections stained with toluidine blue were also examined. In the JVL group, increased iron deposition in the white matter was detected. An increase in the size and number of astrocytes along with increased GFAP immunoreactivity denoting reactive gliosis was also noted in the JVL group. However, no signs of demyelination, inflammation or axonopathy were detected. This study revealed that iron deposition in the JVL group as a model for CCSVI was not associated with cardinal histopathological findings of MS. It is therefore recommended that the invasive endovascular treatment of CCSVI should be reconsidered and further controlled clinical studies be carried out to provide a better understanding of the pathogeneses of MS.
I said I wasn't going to report on this subject, but really I need to say...why?

As part of openess we have been asked to speak about animal experimentation, which I do on this blog.

In relation to the above post, the human studies have already questioned the existence of CCSVI as for animal studies.

We have been here before, 5 years ago in fact 


It was a waste of time then also.

Saturday, 22 April 2017

#ThinkSpeak: blinkered

What do you do when your neurologist knows best and says no? #ThinkSpeak #MSBlog

The other day an esteemed colleague, who is based in the US, contacted me as a co-author on the ocrelizumab in PPMS (Oratorio) study, to ask me 'how could I support the study's claim that ocrelizumab was effective in PPMS?'. He said the study was only positive because it was loaded with relapsing patients. The latter is based on the observation that approximately a quarter of subjects had Gd-enhancing lesions on their baseline scan.

I informed him that he was wrong for several reasons:

1. Firstly, the subjects in this study had PPMS. Anyone with a history of relapses was excluded.

2. It is not uncommon for pwPPMS to have Gd-enhancing lesions on MRI, particularly early in the course of their disease. I pointed out that the reason why a quarter of subjects had active baseline scans was that this was an early, and relatively young, population of PPMSers. The latter didn't occur by chance but by design. The study design was informed by the rituximab in PPMS trial, which showed that younger people with active MRIs were more likely to respond to treatment in a short period of time. To ignore this insight would have been folly.

3. I mentioned to him that the study was also positive across numerous secondary and tertiary endpoints, including objective MRI outcomes. Surely this meant the drug was working?

4. I explained to him my length-dependent axonopathy hypothesis and sent him our recent publication, which goes a long way to explaining the ORATORIO results. He said very interesting, but this didn't change his position.

5. I pointed out to him that although the treatment effect on EDSS and timed-25ft walk was relatively modest (~25% slowing of progression), the impact on upper limb function (9-HPT) was almost double (~45%). Wasn't ocrelizumab indicated on this observation alone? This particular individual is fully aware about how important hand function is for pwMS.

6. I also said that ocrelizumab worked in both cohorts of subjects, those with and without Gd-enhancing lesions at baseline. Although the results in these two subgroups were not statistically significant, the positive trends were obvious. It is important to realise the study was not powered to test a treatment effect in these two cohorts therefore we have to accept the overall results at face value. 

Despite my protestations he informed me that although all my points were interesting and valid he was not convinced by the science and therefore would not be offering ocrelizumab to his patients with PPMS. How do I respond to this? As I said last weekend neurologists are never wrong they can always justify their position from their own perspective. All I that I can hope is that pwPPMS under his care are informed and active. They need to arm themselves with knowledge and ask the right questions. If you aren't satisfied with the answers challenge them and ask some more questions. If you are still not satisfied you can always vote with your feet. 

This episode is deja vu. Almost the exact scenario played out in the UK when the interferons were launched for treating RRMS. Many neurologists would not accept that this class of drug was effective and hence were not offering them to their patients. Gradually things changed and most neurologists now accept that DMTs do modify the course of RRMS. I can only expect the same thing to happen with the treatment of more advanced MS (formerly know as progressive MS). Let's hope so for the sake of the thousands of PPMSers out there. 


Montalban et al. Ocrelizumab versus Placebo in Primary Progressive Multiple SclerosisN Engl J Med. 2017 Jan 19;376(3):209-220.

Background: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primaryprogressive form of the disease. 

Methods: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. 

Results: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. 

Conclusions: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).

CoI: multiple

MS news maybe you will get access to fampridine

I was speaking to a pwMS and they told me that the company Acorda developing fampridine with Biogen has lost its patents in a court case, meaning that from 2018, generic fampridine may become available.

At present it has not got the NICE seal of approval and is not considered cost effective and so in many place you get no access.
Although there are surely a few more court battles to be had.

The price should drop and create greater access, but whilst checking this out, it seems the company has shed 20% of its staff.

So it is a business and a brutal business at that.
So it is about the bottom line

Potassium Channels as a major autoimmune target in MS, it ain't Kir 4.1

Zhong R1, Liang JTao AWu LYang XXu HHuang QZhuang SLong YGao C.
Anti-KIR4.1 Antibodies in Chinese Patients with Central Nervous System Inflammatory Demyelinating Disorders.

OBJECTIVES: The aim of this study was to explore the frequency of KIR4.1 antibodies in patients with multiple sclerosis (MS) and in control groups using a cell-based assay.
MATERIALS AND METHODS: A transfected HEK-293A cell line expressing KIR4.1 was established to test for the presence of KIR4.1 antibodies in blood serum. We tested 904 subjects, including 188 patients with MS, 264 patients with neuromyelitis optica spectrum disorders (NMOSD), 209 patients with other inflammatory neurologic disease (OIND), 203 patients with other noninflammatory neurological disease (OND), and 40 healthy controls.
RESULTS: KIR4.1 antibodies were present in 23 of the 188 (12.2%) MS patients, 42 of the 264 (15.9%) NMOSD patients, 32 of the 209 (15.3%) OIND patients, 24 of the 203 (11.8%) OND patients, and 2 of the 40 (5%) healthy controls. There were no significant differences among the MS and control groups (p = 0.279).
CONCLUSIONS:Anti-KIR4.1 antibody, as determined by a cell-based assay, is not a specific biomarker for MS


However we also have

Navas-Madroñal M, Valero-Mut A, Martínez-Zapata MJ, Simón-Talero MJ, Figueroa S, Vidal-Fernández N, López-Góngora M, Escartín A, Querol L. Absence of antibodies against KIR4.1 in multiple sclerosis: A three-technique approach and systematic review. PLoS One. 2017;12(4):e0175538.

INTRODUCTION: Antibodies targeting the inward-rectifying potassium channel KIR4.1 have been associated with multiple sclerosis (MS) but studies using diverse techniques have failed to replicate this association. The detection of these antibodies is challenging; KIR4.1 glycosylation patterns and the use of diverse technical approaches may account for the disparity of results. We aimed to replicate the association using three different approaches to overcome the technical limitations of a single technique. We also performed a systematic review to examine the association of anti-KIR4.1 antibodies with MS.
METHODS:Serum samples from patients with MS (n = 108) and controls (n = 77) were tested for the presence of anti-KIR4.1 antibodies using three methods: 1) by ELISA with the low-glycosylated fraction of recombinant KIR4.1 purified from transfected HEK293 cells according to original protocols; 2) by immunocytochemistry using KIR4.1-transfected HEK293 cells; and 3) by immunocytochemistry using the KIR4.1.-transfected MO3.13 oligodendrocyte cell line. We developed a systematic review and meta-analysis of the association of anti-KIR4.1 antibodies with MS according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
RESULTS: We did not detect anti-KIR4.1 antibodies in the MS patients or in controls using ELISA. Neither did we detect any significant reactivity against the antigen on the cell surface using the KIR4.1-transfected HEK293 cells or the KIR4.1-transfected MO3.13 cells. We included 13 prospective controlled studies in the systematic review. Only three studies showed a positive association between anti-KIR4.1 and MS. Clinical and statistical heterogeneity between studies precluded meta-analysis of their results.
CONCLUSION:We found no association between anti-KIR4.1 antibody positivity and MS. Although this lack of replication may be due to technical limitations, evidence from our study and others is mounting against the role of KIR4.1 as a relevant MS autoantigen.


So one arguably paper in  a high impact factor journal spawned 15+ papers of which the majority (12 show the original claim  was incorrect that the majority of people do not have antibodies to channel. The is a common problem.

                                                                                   source Brain RNAseq

We have previously posted on the the relevance of potassium (K) channels to MS


ATP-sensitive inward rectifier potassium channel 10 is a protein that in humans is encoded by the KCNJ10 gene.

This has as a greater tendency to allow potassium to flow into, rather than out of, a cell. Kir4.1, may form a channel with other potassium channel protein and may be responsible for controlling potassium levels by glial cells in the brain. 

Humans with mutations in the KCNJ10 gene that cause loss of function in related K+ channels can display EpilepsyAtaxia, sensorineural deafness and tubulopathy of the kidney

A channel that is "inwardly-rectifying" is one that passes current (positive charge) more easily in the inward direction (into the cell) than in the outward direction (out of the cell). It is thought that this current may play an important role in regulating neuronal activity, by helping to stabilize the resting membrane potential of the cell.

At membrane potentials negative to potassium's reversal potential/Nernst potential (at the point when there is no ions moving across the membrane) inwardly rectifying K+ channels support the flow of positively charged K+ ions into the cell, pushing the membrane potential back to the resting potential, which is about -70mv. 


However, when the membrane potential is set positive to the channel's resting potential (e.g. +60 mV), these channels pass very little current. Simply put, this channel passes much more current in the inward direction than the outward one, at its operating voltage range. 

These channels are not perfect rectifiers, as they can pass some outward current in the voltage range up to about 30 mV above resting potential, which would occur when marked depolarisation happens.

Kir.4.1 was implicated as a target for autoantibodies antibodies in MS,  but as so often occurs these things are never replicated and indeed these studies, supports other studies and says the original idea that Potassium channels were a major cause of autoimmunity is clearly wrong. As reported previously.


Could antibodies directed to Kir4.1 cause problems? 
Absolutely as they react with astrocytes and oligodendrocytes, and so could block function or kill the cells


Neusch C, Rozengurt N, Jacobs RE, Lester HA, Kofuji P.
Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci. 2001 ;21(15):5429-38. Kir4.1 forms the major K(+) conductance of oligodendrocytes and is therefore crucial for myelination. 


Potassium ions may therefore critical in myelination.

Bezine M, Debbabi M, Nury T, Ben-Khalifa R, Samadi M, Cherkaoui-Malki M, Vejux A, Raas Q, de Sèze J, Moreau T, El-Ayeb M, Lizard G. Evidence of K+ homeostasis disruption in cellular dysfunction triggered by 7-ketocholesterol, 24S-hydroxycholesterol, and tetracosanoic acid (C24:0) in 158N murine oligodendrocytes. Chem Phys Lipids. 2017. pii: S0009-3084(17)30011-7.

Imbalance in the homeostasis of K+ ions has been reported to contribute to the pathogenesis of neurodegenerative diseases. 7-ketocholesterol (7KC), 24S-hydroxycholesterol (24S-OHC) (this is oxidised cholesterol=oxysterols), and tetracosanoic acid (C24:0), often found at increased levels in patients with Multiple Sclerosis, are able to trigger numerous nerve cell dysfunctions......They induced [K+]i (potassium ion concentrations within the cell) and changes in lipid content and polarization of the cytoplasmic membrane. These events were associated with increased potassium ion concentrations...(and oligodendrocyte death). Blocking K channels with 4-AP (active ingredient of fampridine) exacerbated oligodenrocyte killing.

So lowering cholesterol should be good. Is this how statins work in progressive MS, by blocking oxysterols?
Too much potassium accumulating in a oligodendrocyte causes it to die. Interestingly 4-AP makes this worse.

Therefore, does fampridine kill off oligodendrocytes and block remyelination?

Bacia A, Wollmann R, Soliven B. K+ channel blockade impairs remyelination in the cuprizone model. Glia. 2004; 48(2):156-65.
We found that treatment with 4-aminopyridine (4-AP), a broad-spectrum K(+) channel antagonist, results in: (1) decreased number of oligodendroglial progenitors (OP) and OLGs; (2) diminished astrogliosis; and (3) decreased remyelination in the corpus callosum based on the immunoreactivity to myelin basic protein (MBP), Rip monoclonal antibody, and by electron microscopy.

However to counter that data in peripheral nerves indicate

Tseng KC, Li H, Clark A, Sundem L, Zuscik M, Noble M, Elfar J. 4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury. EMBO Mol Med. 2016 ;8(12):1409-1420.


We know Fampridine allows nerves to work harder, improving walking speeds, but is this good news in the long term? 

Maybe it is time, that we saw data on slow release 4-AP improving remyelination in animal models and protecting nerves. 

Friday, 21 April 2017

#ResearchSpeak: why is there an increasing number of people with benign MS?

Do you have benign MS? If yes, why? #ResearchSpeak #MSBlog

The restrospective study below suggests the prevalence of benign MS is going up. This is good news and I suspect is due to many factors:

1. Ascertainment bias; diagnosing more people with MS who would not have been diagnosed in the past. This is driven by greater access to neurologists and imaging technology. Another factor is the 'Dr Google' effect. When you search online using a lot of non-specific symptoms MS often comes up on the list of possible causes prompting people to seek a neurological opinion. This is not a bad thing as it should lead to an earlier diagnosis.

2. Change in diagnostic criteria, which allows one to diagnosis MS earlier. This causes the so called Will Rogers phenomenon. "Will" Rogers (November 4, 1879 – August 15, 1935) was an American cowboy, performer, humorist, social commentator and motion picture actor. He was one of the world's best-known celebrities in the 1920s and 1930s. The Will Rogers phenomenon is obtained when moving an element from one set to another set raises the average values of both sets. It is based on the following quote, attributed (perhaps incorrectly) to Will Rogers: "When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states." The effect will occur when both of these conditions are met: (i) The element being moved is below average for its current set. Removing it will, by definition, raise the average of the remaining elements; (ii) the element being moved is above the current average of the set it is entering. Adding it to the new set will, by definition, raise the average.The paper by Sormani and colleagues has shown this very elegantly in the case of MS (Sormani et al. Will Rogers phenomenon in multiple sclerosis. Ann Neurol. 2008 Oct;64(4):428-33.).



The Will Rogers Phenomenon has occurred as the more active CISers are taken out of the CIS group and added to the MS group. This improves the outcome of both groups because the CISers left behind in the CIS group are more benign and it improves the MS group as the CISers that have been moved from CIS to MS are less active than the old MS group.


As a result of the Will Rogers Phenomenon we cannot use historical controls for MS trials. Each change in the diagnosis of MS alters the prognosis. Therefore in clinical trials we need contemporary placebo of control groups.

3. The effect of DMTs. Could it be that the treatment of MS is increasing the proportion of pwMS who fulfill the current definition of benign MS?


Sartori A, Abdoli M, Freedman MS. Can we predict benign multiple sclerosis? Results of a 20-year long-term follow-up study. J Neurol. 2017 Apr 17. doi: 10.1007/s00415-017-8487-y.

Background: Benign multiple sclerosis (MS) is a discussed clinical entity, with variable reported prevalence (6-64%) requiring at least 5-10 years of clinical observation. Moreover, many benign patients progress with time becoming no longer benign (NLB).

Objectives: The objective of this study is to compare benign MS patients (EDSS ≤3, 10 years from disease onset) who still fulfilled the definition at 20 years to those NLB.

Results: In our retrospective study based on Ottawa Hospital MS Clinic database, 175 benign patients fulfilled the inclusion criteria (clinically definite MS, EDSS ≤3 at 10 years, disease onset from 1983 to 1993, and clinical assessments performed at 10 ± 1 and 20 ± 1 years from onset). Out of the identified patients, 66.3% remained benign at 20 years; however, by changing the definition for benign to EDSS ≤2 or ≤1 at 10 years, they increased to 71.9 and 81.6%, respectively. Female sex, EDSS ≤1 at 10 years, and a pure sensory onset were associated with a benign course, while a pure motor onset with an NLB condition.

Conclusion: According to multivariate analysis, an EDSS ≤2 at 10 years predicted a long-term benign course. Our study questions the current definition of "benign" MS, suggesting a more stringent EDSS cutoff at 10 years to predict long-term benign prognosis.

MS and EBV

If EBV is the driver of MS, then there must surely be evidence that something related to EBV that associates with disease activity.

Does the Black Swan get it?

Gieß RM, Pfuhl C, Behrens JR, Rasche L, Freitag E, Khalighy N, Otto C, Wuerfel J, Brandt AU, Hofmann J, Eberspächer B, Bellmann-Strobl J, Paul F, Ruprecht K. Epstein-Barr virus antibodies in serum and DNA load in saliva are not associated with radiological or clinical disease activity in patients with early multiple sclerosis. PLoS One. 7;12(4):e0175279.

OBJECTIVE:

To investigate the association of Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) and viral capsid antigen (VCA) immunoglobulin (Ig)G antibodies in serum as well as EBV DNA load in saliva with radiological and clinical disease activity in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS).

METHODS:

EBNA-1 and VCA immunoglobulin (Ig)G antibodies were determined in serum of 100 patients with CIS/early RRMS and 60 healthy controls. EBV DNA load was measured in saliva of 48 patients and 50 controls. Patients underwent clinical assessment with the Expanded Disability Status Scale (EDSS) and 3 Tesla magnetic resonance imaging at baseline and after a median of 20 months of follow-up (n = 63 for MRI, n = 71 for EDSS). The association of EBV parameters with occurrence of a second relapse, indicating conversion to clinically definite MS (CDMS), was evaluated over a median of 35 months of follow-up after the first clinical event (n = 89).

RESULTS:

EBNA-1 IgG antibody frequency (p = 0.00005) and EBNA-1 and VCA IgG antibody levels (p<0.0001 for both) were higher in patients than in controls. EBV DNA load in saliva did not differ between groups. Neither EBV antibody levels nor DNA load in saliva were associated with baseline or follow-up number or volume of T2-weighted (T2w) or contrast enhancing lesions, number of Barkhof criteria or the EDSS, or with the number of new T2w lesions, T2w lesion volume change or EDSS change on follow-up. Likewise, levels of EBV IgG antibodies in serum and DNA load in saliva were not associated with conversion to CDMS.

CONCLUSIONS:

While these findings confirm the association of EBV infection with early MS, neither EBNA-1 nor VCA IgG antibodies in serum nor EBV DNA load in saliva were associated with radiological or clinical disease activity in patients with CIS/early RRMS. These data are compatible with the concept that EBV may be a trigger for MS acting very early during the development of the disease.

Sisay S, Lopez-Lozano L, Mickunas M, Quiroga-Fernández A, Palace J, Warnes G, Lafuente RA, Dua P, Meier UC. Untreated relapsing remitting multiple sclerosis patients show antibody production against latent Epstein Barr Virus (EBV) antigens mainly in the periphery and innate immune IL-8 responses preferentially in the CNS. J Neuroimmunol. 2017 May 15;306:40-45.

BACKGROUND:Multiple sclerosis (MS) is an inflammatory and neurodegenerative disorder of the central nervous system (CNS). Reliable biomarkers are urgently needed for its diagnosis and management, and as clues to its pathogenesis, in which EBV is implicated.
OBJECTIVE:To measure IgG antibodies against EBV nuclear antigen-1 (EBNA-1) and innate inflammation status in paired serum and cerebrospinal fluid (CSF) samples from untreated relapsing-remitting MS (RRMS) patients.
MATERIALS AND METHODS:Anti-EBNA-1 IgG titres and IL-8, IL-1β, IL-6, IL-10, TNF-α and IL-12p70 cytokine levels were measured in 20 untreated RRMS-patients and 17 healthy controls.
RESULTS:We found higher serum anti-EBNA-1 IgG and IL-8 levels in RRMS-patients than in healthy controls. Interestingly, levels of IL-8 - relative to total protein - were much higher in the CSF, whereas the anti-EBNA-1 antibodies were significantly higher in the sera. More detailed analysis showed that anti-EBNA-1 antibodies relative to total IgG were also higher in the serum in the majority of RRMS patients compared to CSF. Levels of anti-EBNA-1 IgG and IL-8 showed a strong correlation between serum and CSF.
CONCLUSION:These findings in newly diagnosed RRMS-patients imply anti-EBNA-1 antibody production mainly in the periphery and innate immune responses preferentially in the CNS. Both their potential as disease biomarkers and their implications for the pathogenesis of MS warrant further investigation.

So both studies agree that there is evidence of EBV infection in people diagnosed with MS. So the Black swan lives. 

However, no evidence of viral shedding in saliva and clinical activity was found, but not sure why this would be the casse even if EBV was the driver for attacks.

Thursday, 20 April 2017

Wonderdrug...To protect nerves

The BBC news was awash with the new "wonderdrug" and was hailed as the saviour of Alzheimers and Parkinsons disease. Quite rightly you are asking is this the saviour for MS?


Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Halliday et al. Brain


I was thinking of gearing up for a post, but I'm not sure I can be bothered to do a proper post. As ever there is a lot of media hype

This work stems from earlier work where the authors found that a drug that blocked protein folding shutdown seemed to help prion infected mice survive. Prion disease is caused by protein misfolding and this occurs in Alzheimer's disease and we showed that this occurs in MS too.

Abnormally phosphorylated tau is associated with neuronal and axonal loss in experimental autoimmune encephalomyelitis and multiple sclerosis. Anderson JM, Hampton DW, Patani R, Pryce G, Crowther RA, Reynolds R, Franklin RJ, Giovannoni G, Compston DA, Baker D, Spillantini MG, Chandran S. Brain. 2008;131(Pt 7):1736-48


They screened a library and found two drugs that stopped the misfolding issue and it saved mice from two different diseases. 

It is hailed as a "wonderdrug" and a turning point and this has been has been splashed over the news. 

Let's hope so. As I said I am too busy to spend a lot of time on this mouse study, but Let's just look at the wondercure in the two models and let's see what it does!



On the left we can see that mice survive a whole extra ten days before they die from the problem...Wondercure..Yeah.

It says in the media stuff that the drugs arrest...I take this to mean stop...not delay by ten days. This type of delay we see in Motor neuron mice with riluzole and this hasn't been a cure, so don't get your hopes up.

On the right, are mice that accumulate Tau protein and lose news in the hippocampus... they loose 50% rather than 75% of their nerves....Wondercure....Yeah

So there will be a clamour to do a human study, which will take years to do. Will this ultimately go anywhere?  I guess it depends on whether there is a patent. However, it may show something.

However, it is said that people talk trazodone to treat depression. Has this stopped Alzheimer's....obviously not otherwise it would have been known by now....Can it change the trajectory? I don't know. 

So more irresponsible reporting by the BBC and the media 

Trazodone  is an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) class. Trazodone also has anti-anxiety (anxiolytic) and sleep-inducing (hypnotic) effects. However, a side effect of trazodone, orthostatic hypotension, which may cause dizziness and increase the risk of falling. 

#ClinicSpeak & #ResearchSpeak: Are you a faller?

If you are at risk of falls does increasing the number of steps walked each day reduce the number of falls you have? #ResearchSpeak #ClinicSpeak

The study below suggest that pwMS who fall, or at increased risk of falling, are less mobile and active than those who don't fall. The correlation between reduce activity/mobility (steps per day) was independent of disability (EDSS). The investigators' imply in the conclusion that the link between reduced mobility/activity is causal and that if you increase the number of steps pwMS take this would reduce their risk of falling. I am not sure if this is correct. The association could be reverse causation, i.e. pwMS who have problems with balance and postural righting reflexes, as defined using the Activities-Balance Confidence scale in this study, may reduce mobility (loss of confidence) as well as putting pwMS at risk of falling. If this is the case then increasing the number of steps you take, i.e. exposure time, might increase your risk of falling. This is why we need to test the hypothesis in a randomised trial. 

Question underpinning the hypothesis: In pwMS at increased risk of falling does increasing their mobility/activity reduce their risk of falling compared to a control population?  

It is a common mistake in research to assume that an association is causative. Implementing an intervention based on causation may give you the wrong outcome. PwMS clearly benefit from exercise, but rather than using walking it may be better to design an exercise programme that doesn't expose these people to falling, e.g. swimming. 



Sebastião et al. Lower Physical Activity in Persons with Multiple Sclerosis at Increased Fall Risk: A Cross-sectional Study. Am J Phys Med Rehabil. 2017 May;96(5):357-361.

Background: Persons with multiple sclerosis (MS) often report being afraid of falling, and this may have effects on physical activity (PA) engagement. 

Objective: This study investigated PA levels in persons with MS as a function of fall risk categories. 

Methods: Forty-seven persons with MS participated in the study and were categorized into either increased fall risk (IFR; n = 21; 55.5 ± 9.0 years) or normal fall risk (NFR; n = 26; 51.2 ± 12.9 years) groups based on scores from the Activities-Balance Confidence scale. PA was measured by accelerometer and expressed as average steps per day, and time spent in sedentary behavior, light PA, and moderate to vigorous physical activity over the course of 7 consecutive days. Univariate and covariate analyses were used to compare the differences in PA between fall risk groups. 

Results: The average steps per day of the NFR group was significant higher compared with the IFR group (6024 ± 2533.1 vs. 2599 ± 1622.7 steps; P < 0.001), and the difference remained after controlling for disability level (5351 ± 2298.6 vs. 3432 ± 2363.6 steps; P = 0.016). There were no differences in light PA and moderate to vigorous physical activity between groups after controlling for disability level. Persons with MS at IFR accumulate fewer steps per day compared with those at NFR. 

Conclusion: This underscores the need for well-designed interventions targeting walking in this population who are far from the recommended 10,000 steps, particularly those with IFR.

Measuring Brain Loss

Carassiti D, Altmann DR, Petrova N, Pakkenberg B, Scaravilli F, Schmierer K.Neuronal loss, demyelination and volume change in the multiple sclerosis neocortex.Neuropathol Appl Neurobiol. 2017 doi: 10.1111/nan.12405. [Epub ahead of print]
A IMS:Indices of brain volume (grey matter, white matter, lesions) are being used as outcomes in clinical trials of patients with multiple sclerosis (MS). We investigated the relationship between cortical volume, the number of neocortical neurons estimated using stereology, and demyelination.
METHODS:Nine MS and seven control hemispheres were dissected into coronal slices. On sections stained for Giemsa (a Dye), the cortex was outlined and optical disectors applied using systematic uniform random sampling. Neurons were counted using an oil immersion objective (x60) following stereological principles. Grey and white matter demyelination was outlined on myelin basic protein immuno-stained sections, and expressed as percentages of cortex and white matter, respectively.
RESULTS: In MS, the mean number of neurons was 14.9 ± 1.9 billion versus 24.4 ± 2.4 billion in controls (p < 0.011), a 39% difference. The density of neurons was smaller by 28% (p < 0.001), and cortical volume by 26% (p= 0.1). Strong association was detected between number of neurons and cortical volume (p < 0.0001). Demyelination affected 40 ± 13% of the MS neocortex and 9 ± 12% of the white matter, however neither correlated with neuronal loss. Only weak association was detected between number of neurons and white matter volume.
CONCLUSION:Neocortical neuronal loss in MS is massive and strongly predicted by cortical volume. Cortical volume decline detected in vivo may be similarly indicative of neuronal loss. Lack of association between neuronal density and demyelination suggests these features are partially independent, at least in chronic MS.

Yesterday we got the other half of the story that there was massive loss of spinal cord axons in the people tested in this study, but that the spinal cord was not shrinking. 


Now DrK and crew not happy with counting thousands of nerves want to count billions of nerves in the brain. In the individuals in this study they had lost 10,000,000,000 nerves.  But I suspect it 

I wonder what this would have been if highly effective treatments were available and used.

In this cases there was a better correlation with nerve content and the vloume of the cortex and perhaps supports the notion that Grey Matter Volume changes are a better biomarker for MRI studies.

This level of nerve loss did not correlate with demyelination however I think it shows that with time the nerve damage eleswhere eventually leads to loss of the whole nerve.

Wednesday, 19 April 2017

Measuring Nerve Loss in MS

Petrova N, Carassiti D, Altmann DR, Baker D, Schmierer K.
Axonal loss in the multiple sclerosis spinal cord revisited.
Brain Pathol. 2017 Apr 12. doi: 10.1111/bpa.12516. [Epub ahead of print]



Preventing chronic disease deterioration is an unmet need in people with multiple sclerosis, where axonal loss is considered a key substrate of disability. Clinically, chronic multiple sclerosis often presents as progressive myelopathy. Spinal cord cross-sectional area assessed using MRI predicts increasing disability and has, by inference, been proposed as an indirect index of axonal degeneration. However, the association between cross-sectional area and axonal loss, and their correlation with demyelination, have never been systematically investigated using human post mortem tissue. We extensively sampled spinal cords of seven women and six men with multiple sclerosis (mean disease duration= 29 years) and five healthy controls to quantify axonal density and its association with demyelination and cross-sectional area. 396 tissue blocks were embedded in paraffin and immuno-stained for myelin basic protein and phosphorylated neurofilaments. Measurements included total cross-sectional area, areas of (i) lateral cortico-spinal tracts, (ii) grey matter, (iii) white matter, (iv) demyelination, and the number of axons within the lateral cortico-spinal tracts. Linear mixed models were used to analyse relationships. In multiple sclerosis cross-sectional area reduction at cervical, thoracic and lumbar levels ranged between 19 and 24% with white (19-24%) and grey (17-21%) matter atrophy contributing equally across levels. Axonal density in multiple sclerosis was lower by 57-62% across all levels and affected all fibres regardless of diameter. Demyelination affected 24-48% of the grey matter, most extensively at the thoracic level, and 11-13% of the white matter, with no significant differences across levels. Disease duration was associated with reduced axonal density, however not with any area index. Significant association was detected between focal demyelination and decreased axonal density. In conclusion, over nearly 30 years multiple sclerosis reduces axonal density by 60% throughout the spinal cord. Spinal cord cross sectional area, reduced by about 20%, appears to be a poor predictor of axonal density.

In this study we looked at the amount of nerve content in the spinal cord and found signfcant loss in people with long standing MS. They people were in wheelchairs at the time they passed and they had lost 60% of their nerve content. 

However when we measured the spinal cord area it did not shrink by that much despite a large amount of nerve loss. 

As this is a central measure, detected by MRI used to suggest nerve loss, it suggests that MRI measures of atrophy are missing an awful lot. 

Whilst there may be alot of nerve loss the space can be filled by other cells or fluid. This may be why we see pseudoatrophy with drugs that block inflammation, this removes swelling and so the nerve looks like it shrinks. Therefore, one of the central measures of progression is probably flawed.

CoI: This work of TeamG & S

#ResearchSpeak: survival in people with MS is improving

Good news people with MS are living longer and catching-up with their peers. #ResearchSpeak #MSBlog

We have posted several times in the past on MS and mortality. 

The latest data to published from Norway, with 60 years of follow-up, confirms what we already know that MS reduces life expectancy. Importantly the so called standardised mortality ratio (SMR) of pwMS is higher than the general population and puts MS high-up the SMR league tables. In short MS is a bad disease, but has it changed its spots?

The SMR, is a quantity, expressed as a ratio quantifying the increase, or decrease, in mortality of a study cohort with respect to the general population. The SMR is simply the ratio of observed deaths in the study group to expected deaths in the general population. Hence a SMR of 2.7 amongst MSers means that 2.7 people died to every one person in the general population. A SMR of 2.7 is high. Of interest the SMR is higher for women with MS (2.9) than men with MS (2.5); this is because in the general population men are more likely to die young than women, hence a larger number of male deaths is the denominator. Life expectancy for pwRRMS was longer (77.8 years) than for pwPPMS (71.4 years). 

Mortality decreased over the course of the study, as pwMS with onset from 1997 to 2012 showed lower rates than those who fell sick from 1953 to 1974. In comparison, pwMS younger than 20 years of age at disease onset or diagnosis showed greater mortality than those above 60 years.
Interestingly, despite the high SMR the life expectancy of someone with MS is only shown to be ~7 years lower than the general population; this is a lower figure than previous studies. What this means is that pwMS in Norway tend to live a relatively long life. With an average age of MS onset of 30 years it means that the average MS must expect to live the majority of their lives with disabilities. 

As usual this is not necessarily a pleasant narrative, or is it? Overall survival from MS disease onset was more than twice as long as reported in the first study from 1969. The increase in survival over time is almost certainly the result of better MS treatments, improved diagnosis, socioeconomic factors, better treatment of co-morbidities and other lifestyle changes. 

Do you think this is a good news story?


Bøe Lunde et al. Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study. JNNP April 2017.

Objective: Survival and causes of death (COD) in multiple sclerosis (MS) provide ultimate endpoints. We aimed to investigate survival and COD in a 60-year population-based MS cohort compared with the general population.

Methods: All patients with incident multiple sclerosis (MS) (N=1388) with onset during 1953–2012 in Hordaland County, Western Norway, were included. Data were obtained from patient records at Haukeland University Hospital and linked to the Norwegian COD registry. Survival adjusted for sex, age and disease course were estimated by Kaplan-Meier analyses from birth and from disease onset. Mortality and COD in MS relative to the general population were examined by standardised mortality ratio (SMR).

Results: Of 1388 patients, 291 had deceased, mainly of MS (56.4%). Median life expectancy was 74.7 years for MS and 81.8 years for the general population (p<0.001); 77.2 years for women with MS and 72.2 years for men with MS (p<0.001). Life expectancy for patients with relapsing remitting MS (RRMS) was 77.8 years and 71.4 years for primary progressive MS (PPMS) (p<0.001). Overall SMR was 2.7 (p>0.0001); 2.9 in women and 2.5 in men (p=0.0009). SMR was 2.4 in RRMS and 3.9 in PPMS (p<0.0001). SMR from disease onset during 1953–1974 was 3.1; 2.6 during 1975–1996 and 0.7 during 1997–2012 (p<0.0083). No difference in cause-specific deaths were found (p=0.0871).

Conclusion: We found a 7-year shorter life expectancy and almost threefold higher mortality in MS compared with the general population. A rise in survival in MS was observed during the entire observation period.

Tuesday, 18 April 2017

#GuestPost: Hannah Laycock

Has MS impacted on your life in a positive way? #GuestPost #MSBlog

In an effort to make the blog 'more interesting' we are trying to encourage more guest posters including pwMS doing amazing things  with their hands and arms (#ThinkHand). Please let us know what you think of including pwMS as guest bloggers? 


BARTS MS BLOG: HANNAH LAYCOCK

It was 2009 that photography became my saving grace. That was the year my father was diagnosed with Motor Neuron Disease (MND).

Towards the end of my 2nd and into my 3rd year of my photography degree I created two volumes of work; ‘Railing At The Enthrallment to The Failing of The light’, part I and II, which documented my family’s life as they and I came to terms with the pronouncement of my father’s MND.

After graduating, my creative practice lapsed between 2011 and 2014. I had focused my energy on capturing and presenting my father’s diagnosis in both a truthful and loving way, but the process dulled my creativity. It wasn’t until I was dealt with my own diagnosis of Multiple Sclerosis (MS) in 2013, aged 31, that my creativity began, ironically, to flourish and bounce back again.

A few months after diagnosis my MS Specialist Mental Health nurse introduced me to George Pepper, Co-founder of Shiftms, a social network for people with MS. I became closely connected with the Shiftms team and in August 2014 I was invited to create a new body of work in response to their #GoodOutofBad (#GOOB) commission, as part of their MS Energy initiative. With this, ‘Perceiving Identity’ was created, which launched my photography back into the public domain with the #GOOB exhibition in London, February 2015.



After relocating from London back to Scotland, April 2015, and in May of the same year, I won an Artist in Residence in Glasgow at Six Foot Gallery and sponsorship from Street Level Photoworks, for the month of July. It was during this time that I created ‘Awakenings’; inspired by Oliver Sacks book, of the same title, that illuminates the relationship between body and self. The project launched as a solo exhibition at the end of the residency.

July 2015 was a month that tore me apart physically and mentally. So many transitions had taken place in my life in such a short space of time. My body and mind were bearing the brunt of all those changes. There was nothing I could do to escape its overwhelming presence, but to turn to my camera. It was a passage to forget, to gain clarity, resilience; to break free from the numbness of living with MS.

MS always changes. It never stays the same. I'm not trying to document it. It's impossible to do that with MS. It’s an intangible disease for those without the experience of it and to try and help them understand. I have to engage with what I'm feeling to portray the experience of having the condition.

‘Perceiving Identity’ and ‘Awakenings’ are photographic journeys that explore my feelings of uncertainty, fear, loss and liberation, intuitively delving into and questioning the notion of neurological ‘lack’.

For me, photography is painting with light. I was never really skilled at painting in the traditional sense, nor was I skilled at other creative mediums. Photography has enabled me to skillfully explore my creativity. Providing me with a tool to better understand and work through such events in my life. It has been a means of artistic expression and catharsis.

‘Perceiving Identity’ and ‘Awakenings’ correlate to my earlier art and portrait photography; Fragility and Primacy Subject, which deal with fragility, image and desire, and power relations between subject and observer.

Using photography, I aim is to reach out and help the general population, patients and health professionals to tell and engage with complex and unique stories of illness through the use of visual language. With this, I hope that people will better understand such conditions as MND or MS on a person centered level.


BIOGRAPHY

Hannah Laycock was born in Forres, Scotland. She Lived in London and Brighton for 10 years and returned to the Highlands of Scotland in Spring 2015.

Hannah studied photography at the University of Brighton. Her latest project, ‘Awakenings’, documents her diagnosis and subsequent experiences of living with multiple sclerosis; select images are currently showing at Glasgow Women’s Library as part of the women’s photography collective WildFires. Her work has been recognised in international competitions such as International Talent Support, Italy, and has appeared as the cover piece, including an extended essay written about her work, in the BMJ’s Medical Humanities journal in February of this year. She has also been interviewed about her work, multiple sclerosis and motor neuron disease for BBC Radio Scotland.

LINKS

More Than An Image’ campaign feature about the power of photography for Wex Photographic. Alongside Humanitarian photographer, Giles Duley.

BMJ Medical Humanities feature: ‘Capturing the worlds of multiple sclerosis: Hannah Laycock’s photography’, by Dr Stella Bolaki, School of English, University of Kent, Rutherford College Extension, The Spires, Canterbury, Kent CT2 7NX, UK; S.Bolaki@kent.ac.uk

WildFires: Women photographers network in Scotland

Link to my Hannah Laycock's website: http://www.hannahlaycock.com


CoI: Genzyme sponsored the #GoodOutofBad (#GOOB) Shiftms commission, for which ‘Perceiving Identity’ was created.

Alternative medicine anyone? Acupuncture in MS

J Altern Complement Med. 2017 Apr 14. doi: 10.1089/acm.2016.0355. [Epub ahead of print]

Effects of Acupuncture on Gait of Patients with Multiple Sclerosis.

Criado MB, Santos MJ, Machado J, Gonçalves AM, Greten HJ.

Abstract


Multiple sclerosis is considered a complex and heterogeneous disease. Approximately 85% of patients with multiple sclerosis indicate impaired gait as one of the major limitations in their daily life. Acupuncture studies found a reduction of spasticity and improvement of fatigue and imbalance in patients with multiple sclerosis, but there is a lack of studies regarding gait. We designed a study of acupuncture treatment, according to the Heidelberg model of Traditional Chinese Medicine (TCM), to investigate if acupuncture can be a useful therapeutic strategy in patients with gait impairment in multiple sclerosis of relapsing-remitting type. The sample consisted of 20 individuals with diagnosis of multiple sclerosis of relapsing-remitting type. Gait impairment was evaluated by the 25-foot walk test. The results showed differences in time to walk 25 feet following true acupuncture. In contrast, there was no difference in time to walk 25 feet following sham acupuncture. When using true acupuncture, 95% of cases showed an improvement in 25-foot walk test, compared with 45% when sham acupuncture was done. Our study protocol provides evidence that acupuncture treatment can be an attractive option for patients with multiple sclerosis, with gait impairment.


Science and logic are my great escapes. Alternative medicine is the antithesis of this, a world stuck in the past. Much to my chagrin, alternative medical practitioners also display a certain arrogance in their practice, and have no desire to explain their practice beyond that of sensationalism and soothsaying! The difference between success and failure in this day and age, as the world faces seismic changes due to globalisation, is adaptation.

So, why am I bothering to post on this?

Simple really. If I had control over one thing in life, it would be to banish cynicism as an entitlement of the educated. I hope you'd agree when I say cynicism is unworthy of a liberal mind, and leads to passive aggression that triggers a rejoinder of equal malice.

The author, Maria Criado, in a paper which makes up her thesis has designed a cross-over, randomized control trial (i.e. has a sham arm and both arms either get the treatment or sham in different orders) of acupuncture in a small cohort (20) of relapsing-remitting MS subjects. She uses timed 25-foot walk (as well as tandem walking times over the same length), which is an objective measure of walking ability in MS.

With acupuncture she reports a 95% improvement in walking times compared to 45% in the sham group (placebo effect). I might add that this is better than that of fampridine (of course, fampridine has been tested in larger sample sizes than this). This doesn't require statistics, a change of >20% is considered to represent reliable change.

The Heidelberg model used in this study unifies traditional Chinese medicine with contemporary medical-scientific knowledge (for example, microcirculation, neural pathways etc). Acupuncture (see Figure 1) forms part of this. The conduits in acupuncture are the information pathways that connect the body (top/bottom, left/right, interior/exterior, and all of them together). When a tissue, or organ is imbalanced, information of the abnormality is passed through specific areas of the body, called reflex points (acupoint) or information zones. There are 324 acupoints, of which 323 have innervation of cranial and spinal nerves. The anatomic localization of the acupoints used in the study are shown in Figure 2. Sham acupuncture used points outside of the conduit points.

Figure 1: Mode of action of acupuncture (1: energetic; 2: neural; 3: humoural mechanisms).



Figure 2: Acupuncture points taken from the Heidelberg model.

These findings needs to be replicated in a much larger sample size. By demonstrating an improvement in an accepted measures of disability, acupuncture enters as a true contender in the MS therapeutics arena. Potential confounders, such as day-to-day variability in walking ability, impact of fatigue, pain symptoms and male:female differences also need to be considered in future studies. However, by undertaking a randomized controlled trial, Maria Criado demonstrates that it is possible to put alternative medicine through the same rigors as a conventional drug trial.

Monday, 17 April 2017

#ClinicSpeak & #SocialMedicine: social medicine the next healthcare revolution

Are you engaging in social medicine? #ClinicSpeak #SocialMedicine #MSBlog

The current big topic in the study of evolution is 'cultural evolution' and how the human brain is wired to be social. We are social animals and like to be connected. This is why we are tribal and flock to cities in our billions. The real success of the internet, or the web, is the 'social web'. The most successful tech products are social products. Facebook, Whats-app, Instragram, Google+, Pinterest, Waze, etc. Why have we not picked-up on this in healthcare and run with it? I think it is because healthcare, similar to education, as a field is slow to adopt new technologies and ways of doing things. 


The perspective article below in a recent NEJM makes the case for shared clinics. or as I now prefer to call them 'social clinics'. The concept is not new; we have posted on the topic several times before under the term 'group clinics'. The current healthcare model in relation to MS diagnosis and management is based on a synchronous model of one-to-one consultations typically in specialised centres. This requires pwMS to travel long-distances, to get a cursory examination and very short amount of time with their HCP. Both the HCP and the user, you a pwMS, are more often than not dissatisfied with the consultation. There must be a better way of doing things.   

At Barts-MS we plan to change the options available to our patients and have been successful in getting a grant to test several new initiatives to make our service more responsive. We plan to expand our on-line offering; essentially a better curated and easier to navigate information portal. At present this is text-based, but we will need it to make it multimedia and include video and podcasts (see below). We now offer telephone and Skype clinics. We have tested a 'Falls and Bone Health' group clinic and are now in he process of testing a few more topics. Our annual MS Research Day needs to become a more frequent event, perhaps smaller and more focused. We envisage running these using a similar format to our MS Roadshows to the regional hospitals in our local network. If successful we hope to be able to make all these offerings a permanent feature at Barts Health. 

Most practice of medicine, including MS, is not rocket science and getting pwMS to self-manage and to help others self-manage is potentially a game-changer. Importantly, we are certain that if implemented well we can get better outcomes, whilst saving the NHS money. 

My family gave me a Google Home Assistant for my birthday last week. Although I am still learning and teaching the assistant it has already revolutionised my life. I simply speak to it to do tasks that used to take me minutes to complete. Already the device has killed our Sonos music system in the kitchen; over the weekend we have played all our music through Google Home. Can you imaging using the Google Home Assistant to deliver healthcare? For example, you simply say 'Hey Google, I have MS please tell me how to manage my MS fatigue'. The Google Assistant will then offer a selection of formats and you could, for example, choose a podcast to listen to on MS fatigue self-management. As the use of assistant is hands-free it will revolutionise how disabled pwMS communicate with their families, carers, HCPs and other pwMS. The potential applications for this technology are endless. 

If anybody from Google is reading this post, or if you have a contact within Google who can help, I would love to discuss implementing a MS self-management system using the Google Home Assistant. We live in exciting times; the potential that technology offers to change how we practice medicine is endless, but when we design these services/systems they need to be social.

If you are engaging in social medicine please let us know. Similarly, if you have any ideas around social medicine please share them. Thanks. 


Ramdas & Darzi. Adopting Innovations in Care Delivery — The Case of Shared Medical Appointments. N Engl J Med 2017; 376:1105-1107. 

Excerpts:

...... Transformative innovations in care delivery often fail to spread. Consider shared medical appointments, in which patients receive one-on-one physician consultations in the presence of others with similar conditions. Shared appointments are used for routine care of chronic conditions, patient education, and even physical exams. Providers find that they can improve outcomes and patient satisfaction while dramatically reducing waiting times and costs.....

........ Patients benefit from interacting with their peers and hearing answers to questions that may be relevant to them. Doctors avoid repeating common advice, which improves their productivity and enables higher-quality interactions with individual patients. Increased system capacity reduces waiting times even for patients who opt for traditional one-on-one appointments. Shared appointments have been used successfully for over 15 years at the Cleveland Clinic, in the Kaiser Permanente system, and elsewhere......

...... Shared service delivery isn’t a new concept. Group interventions are common for primary prevention (e.g., encouraging smokers to quit) and secondary prevention (e.g., helping patients with chronic obstructive pulmonary disease to avoid complications). Group-based programs such as Alcoholics Anonymous and Weight Watchers allow people to acknowledge that they have a problem and start working toward solutions......

....... Given the effectiveness of group interventions, why aren’t doctors routinely using them to treat physical and mental conditions? We believe four crucial components are missing: rigorous scientific evidence supporting the value of shared appointments, easy ways to pilot and refine shared-appointment models before applying them in particular care settings, regulatory changes or incentives that support the use of such models, and relevant patient and clinician education. Such enablers are necessary for any highly innovative service-delivery model to become standard......

..... Shared medical appointments change the boundaries of health care services because fellow patients, rather than only the doctor, can provide information and support......

..... With any new delivery model, regulation and participation incentives influence uptake.....

...... Finally, patient education could stimulate interest in shared appointments.....

....... When altering an interaction as unstructured and personal as a doctor visit, patient education is critical. Many patients may hesitate to participate in a shared appointment for their annual physical, imagining that they would meet fellow patients in their underwear. In fact, in a typical shared physical for female patients at the Cleveland Clinic, the doctor performs pelvic and breast exams and discusses test results with each patient in private. The remainder of the appointment is conducted as a shared appointment. By sitting in on shared appointments as unbilled observers, patients can experience for themselves the less tangible benefits of peer interaction.....

...... Doctors also need education. Large health care organizations could experiment with new care models and invite doctors within their system to observe and learn......

....... Indeed, these needs apply to all new delivery models: to accelerate their adoption, we will need to embrace new strategies for collecting evidence on their outcomes; find safe, quick, and cheap ways to experiment; offer incentives to providers; and educate stakeholders....