Wednesday, 31 July 2013

Progressive MS trials

Koch MW, Cutter G, Stys PK, Yong VW, Metz LM. Treatment trials in progressive MS-current challenges and future directions. Nat Rev Neurol. 2013 Jul 30. doi: 10.1038/nrneurol.2013

The introduction of immunomodulatory treatments has transformed the management of patients with relapsing-remitting multiple sclerosis (MS), but has had no consistent benefit in progressive MS. Patients with primary or secondary progressive MS, therefore, are faced with relentless functional decline that remains without treatment. Clinical trials in progressive MS are clearly needed, but their design and conduct is challenging, and different from that of trials in relapsing-remitting MS. Challenges to reliable measurement of clinical progression, uncertainties about the natural history of progressive MS, and the unclear role of imaging outcomes all impede optimal trial design. Clinical trials in progressive MS have used time to a predefined change on the Expanded Disability Status Scale as their main outcome measure, which has had important consequences for trial duration and has led to inclusion of only a highly selected minority of patients. Here, we review the current approach to clinical trial design in progressive MS, outline key ongoing challenges, and suggest strategies to overcome such hurdles.

It is time to think outside the box.

Phase IV Tysabri data

#MS Research # MSBlog Effect of Tysabri

Outteryck O, Ongagna JC, Brochet B, Rumbach L, Lebrun-Frenay C, Debouverie M, Zéphir H, Ouallet JC, Berger E, Cohen M, Pittion S, Laplaud D, Wiertlewski S, Cabre P, Pelletier J, Rico A, Defer G, Derache N, Camu W, Thouvenot E, Moreau T, Fromont A, Tourbah A, Labauge P, Castelnovo G, Clavelou P, Casez O, Hautecoeur P, Papeix C, Lubetzki C, Fontaine B, Couturier N, Bohossian N, Clanet M, Vermersch P, de Sèze J, Brassat D; BIONAT network, and CFSEP. A prospective observational post-marketing study of natalizumab-treated multiple sclerosispatients: clinical, radiological and biological features and adverse events. The BIONAT cohort. Eur J Neurol. 2013 Jun 12. doi: 10.1111/ene.12204. [Epub ahead of print]


BIONAT is a French multicentric phase IV study of natalizumab (NTZ)-treated relapsing-remitting multiple sclerosis(MS) patients. The purpose of this study was to collect clinical, radiological and biological data on 1204 patients starting NTZ, and to evaluate the clinical/radiological response to NTZ after 2 years of treatment.
METHODS:Patients starting NTZ at 18 French MS centres since June 2007 were included. Good response to NTZ was defined by the absence of clinical and radiological activity. Data analysed in this first report on the BIONAT study focus on patients who started NTZ at least 2 years ago (n = 793; BIONAT2Y ).
RESULTS:NTZ was discontinued in 17.78% of BIONAT2Y . The proportion of patients without combined disease activity was 45.59% during the first two successive years of treatment. Systematic dosage of anti-NTZ ntibodies (Abs) detected only two supplementary patients with anti-NTZ Abs compared with strict application of recommendations. A significant decrease of IgG,M concentrations at 2 years of treatment was found.
CONCLUSIONS: The efficacy of NTZ therapy on relapsing-remitting MS in a real life setting is confirmed in the BIONAT cohort. The next step will be the identification of biomarkers predicting response to NTZ therapy and adverse events.
Phase IV is the post-licensing phase of drug development, when people start to take drug in a less constrained fashion than in clinical trials. This is where rare adverse events begin to crop up.

This study shows that tysabri is efficacious...the question is the risk benefit ratio. So keep checking profGs risk update so you can make more informed choices

First case of PML that may be attributable to fingolimod

#MS Research # MSBlog PML after Gilenya

Reuters: Patient taking Novartis MS pill developed rare disease. Tue Jul 30, 2013 2:48pm IST

... A patient taking Novartis' multiple sclerosis pill Gilenya developed a rare and potentially fatal viral disease, the Swiss drugmaker said on Tuesday, an unexpected setback as it faces growing competition from new oral treatments....

.... Novartis said it had been informed of a case of progressive multifocal leukoencephalopathy (PML) in a patient who had been taking Gilenya for MS for seven months....

.... It said it was working with the reporting physician to understand all possible contributing factors, including those beyond treatment, given several atypical features of the case....

.... "The course of the underlying neurological disease was rapid with some atypical findings for MS on the MRI scans of the brain and spinal cord, as well as some unusual clinical features," Novartis said in a statement....

.... Novartis said all previously reported cases of PML among the approximately 71,000 patients treated with Gilenya thus far had been attributed to prior treatment with Biogen Idec's Tysabri, which bears a known risk of PML....

Click here for full article


Rivera VM, Jeffery DR, Weinstock-Guttman B, Bock D, Dangond F. Results from the 5-year, phase IV RENEW (Registry to Evaluate Novantrone Effects in WorseningMultiple Sclerosis) study. BMC Neurol. 2013;13(1):80. [Epub ahead of print]

BACKGROUND:Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis (RENEW) was a 5-year, phase IV study in which the safety of Mitoxantrone was monitored in a patient cohort from the United States (US). The objective of the study was to evaluate the long-term safety profile of Mitoxantrone in patients with secondary progressive multiple sclerosis (SPMS), progressive relapsing multiple sclerosis (PRMS), and worsening relapsing-remitting multiple sclerosis (RRMS).
METHODS:Overall, 509 patients (395 SPMS, 81 worsening RRMS, 33 PRMS) were enrolled and treated at 46 multiple sclerosis (MS) treatment centres located in the US. Patients received Mitoxantrone in accordance with the package insert every 3 months. During the treatment phase, patients received laboratory workups and cardiac monitoring every 3 months and then annually for a total of 5 years.
RESULTS: Five hundred and nine subjects were enrolled in this trial and received at least one infusion of Mitoxantrone. Overall, 172 (33.8%) completed the 5-year trial (i.e., participated for 5 years +/- 3 months [treatment + follow-up]); 337 (66.2%) did not complete the 5-year trial. Annual follow-up data were available for 250 of 509 enrolled patients. Left ventricular ejection fraction reduction under 50% was reported in 27 (5.3%) patients during the treatment phase (n = 509) and 14 (5.6%) patients during the annual follow-up phase (n = 250). Signs and symptoms of congestive heart failure were observed in 10 (2.0%) patients (six during treatment phase and four during the annual follow-up phase). Post-hoc analyses of the risk for cardiotoxicity outcomes revealed that cumulative dose exposure is the primary risk factor associated with the risk of cardiac toxicity with Mitoxantrone. Therapy-related leukaemia was reported in three (0.6%) patients who received total cumulative Mitoxantrone doses of 73.5 mg/m2, 107.3 mg/m2, and 97.1 mg/m2 respectively. During the treatment phase, persistent amenorrhea (no menstrual cycle) developed in 22% (28/128) of women with regular menses (Period) and 51% (25/49) of women with irregular menses at baseline. During the annual follow-up phase, persistent amenorrhea developed in 5% (4/73) of women with regular menses at baseline.
CONCLUSION: RENEW results are consistent with the known safety profile of Mitoxantrone, and provide additional long-term safety data for Mitoxantrone in MS patients.

FYI. Maybe ProfG will comment on this...Its not my Job to do this

CoI: None

Too much brain Iron may be bad for the nerves

Hametner S, Wimmer I, Haider L, Pfeifenbring S, Brück W, Lassmann H. Iron and neurodegeneration in the multiple sclerosis brain.Ann Neurol. 2013 Jul 19. doi: 10.1002/ana.23974. [Epub ahead of print]
Objective: Iron (pronounced eye-urn) may contribute to the pathogenesis and progression of multiple sclerosis (MS) due to its accumulation in the human brain with age. Our study focused on non-heme iron distribution and the expression of the iron-related proteins ferritin, hephaestin and ceruloplasmin in relation to oxidative damage in the brain tissue of 33 MS and 30 control cases. 
Methods: We performed (1) whole-genome microarrays including 4 MS and 3 control cases in order to analyze the expression of iron-related genes, (2) non-heme iron histochemistry, (3) immunohistochemistry for proteins of iron metabolism and (4) quantitative analysis by digital densitometry and cell counting in regions representing different stages of lesion maturation. 
Results: We found an age-related increase of iron in the white matter of controls as well as in patients with short disease duration. In chronic MS, however, there was a significant decrease of iron in the normal appearing white matter (NAWM) with disease duration, when corrected for age. This decrease of iron in oligodendrocytes and myelin was associated with an up-regulation of iron-exporting ferroxidases. In active MS lesions, iron was apparently released from dying oligodendrocytes, resulting in extracellular accumulation of iron and uptake into microglia and macrophages. Iron-containing microglia showed signs of cell degeneration. At lesion edges and within centers of lesions, iron accumulated in astrocytes and axons. 
Interpretation: Iron decreases in the NAWM of MS patients with increasing disease duration. Cellular degeneration in MS lesions leads to waves of iron liberation, which may propagate neurodegeneration together with inflammatory oxidative burst. 
It is well known that there are changes in iron deposition in the brains of MSers and iron is important to brain health as the blood vessels have transporters to get iron into the brain. This study shows that too much may be bad for glial cells in a complexway which you can read above.

Vitamin E analogue has remyelinating potential

Tocopherol Derivative TFA-12 Promotes Myelin Repair in Experimental Models of Multiple Sclerosis. Blanchard B, Heurtaux T, Garcia C, Moll NM, Caillava C, Grandbarbe L, Klosptein A, Kerninon C, Frah M, Coowar D, Baron-Van Evercooren A, Morga E, Heuschling P, Nait Oumesmar B. J Neurosci. 2013 ;33:11633-11642.

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is associated with demyelination and axonal loss, resulting in severe neurological handicap. Current MS therapies mostly target neuroinflammation but have only a little impact on CNS myelin repair. Progress toward treatments that enhance remyelination would therefore represent major advances in MS treatment. Here, we examined the ability of TFA-12, a new synthetic compound belonging to tocopherol long-chain fatty alcohols, to promote oligodendrocyte regeneration and remyelination in experimental models of MS. We showed that TFA-12 significantly ameliorates neurological deficit and severity of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) in mice. Histological evaluation of mouse EAE spinal cords showed that TFA-12 treatment reduces inflammation, astrogliosis, and myelin loss. Additionally, we demonstrated that TFA-12 accelerates remyelination of focal demyelinated lesions induced by lysolecithin injections. We also found that this compound induces the differentiation of oligodendrocyte precursor cells into mature oligodendrocytes through the inhibition of the Notch/Jagged1 signalling pathway. Altogether, our data provide important proof of principle indicating that TFA-12 could be a potential therapeutic compound for myelin repair in MS.

We are are all interested in remyelination. This study reports on a new drug TFA-12. It appears to augment remyelination in a chemical model of demyelination and in the EAE it has anti-inflammatory effects. Tocopherols (or TCP) are a class of chemical compounds of which many have vitamin E activityWill this of related compounds make it in the drug development process..along time will tell.

Tuesday, 30 July 2013

Aubagio affects relapsing MS without stopping vaccination to Flu

Bar-Or A, Freedman MS, Kremenchutzky M, Menguy-Vacheron F, Bauer D, Jodl S, Truffinet P, Benamor M, Chambers S, O'Connor PW.Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis. Neurology. 2013 Jul  [Epub ahead of print]

OBJECTIVE: To investigate the effect of teriflunomide on the efficacy and safety of seasonal influenza vaccine.
METHODS: The 2011/2012 seasonal influenza vaccine (containing H1N1, H3N2, and B strains) was administered to patients with relapsing forms of multiple sclerosis (RMS) treated for ≥6 months with teriflunomide 7 mg (n = 41) or 14 mg (n = 41), or interferon-β-1 (IFN-β-1; n = 46). The primary endpoint was the proportion of patients with influenza strain-specific antibody titers ≥40, 28 days postvaccination.
RESULTS:More than 90% of patients achieved postvaccination antibody titers ≥40 for H1N1 and B in all groups. For H3N2, titers ≥40 were achieved in ≥90% of patients in the 7 mg and IFN-β-1 groups, and in 77% of the 14-mg group, respectively. A high proportion of patients already had detectable antibodies for each influenza strain at baseline. Geometric mean titer ratios (post/prevaccination) were ≥2.5 for all groups and strains, except for H1N1 in the 14-mg group (2.3). The proportion of patients with a prevaccination titer <40 achieving seroprotection was ≥61% across the 3 treatment groups and 3 influenza strains. However, fewer patients in the 14-mg than the 7-mg or IFN-β-1 groups exhibited seroprotection to H3N2 (61% vs 78% and 82%, respectively).
CONCLUSION: Teriflunomide-treated patients generally mounted effective immune responses to seasonal influenza vaccination, consistent with preservation of protective immune responses.

As an immunosuppressant there is a concern that you may be more liable to infections. This study indicates that Aubagio did not stop the development to immunity to Flu, which is a good thing, So what happens to disease, well as seen below  there is an inhibitory effect.

O'Connor PW, Lublin FD, Wolinsky JS, Confavreux C, Comi G, Freedman MS, Olsson TP, Miller AE, Dive-Pouletty C, Bégo-Le-Bagousse G, Kappos L.Teriflunomide reduces relapse-related neurological sequelae, hospitalizations and steroid use. J Neurol. 2013 Jul 14. [Epub ahead of print]

 Multiple sclerosis (MS) relapses impose a substantial clinical and economic burden. Teriflunomide is a new oral disease-modifying therapy approved for the treatment of relapsing MS. We evaluated the effects of teriflunomide treatment on relapse-related neurological sequelae and healthcare resource use in a post hoc analysis of the Phase III TEMSO study. Confirmed relapses associated with neurological sequelae [defined by an increase in Expanded Disability Status Scale/Functional System (sequelae-EDSS/FS) ≥30 days post relapse or by the investigator (sequelae-investigator)] were analyzed in the modified intention-to-treat population (n = 1086). Relapses requiring hospitalization or intravenous (IV) corticosteroids, all hospitalizations, emergency medical facility visits (EMFV), and hospitalized nights for relapse were also assessed. Annualized rates were derived using a Poisson model with treatment, baseline EDSS strata, and region as covariates. Risks of sequelae and hospitalization per relapse were calculated as percentages and groups were compared with a χ2 test. Compared with placebo, teriflunomide reduced annualized rates of relapses with sequelae-EDSS/FS [7 mg by 32 % (p = 0.0019); 14 mg by 36 % (p = 0.0011)] and sequelae-investigator [25 % (p = 0.071); 53 % (p < 0.0001)], relapses leading to hospitalization [36 % (p = 0.015); 59 % (p < 0.0001)], and relapses requiring IV corticosteroids [29 % (p = 0.001); 34 % (p = 0.0003)]. Teriflunomide-treated patients spent fewer nights in hospital for relapse (p < 0.01). Teriflunomide 14 mg also decreased annualized rates of all hospitalizations (p = 0.01) and EMFV (p = 0.004). The impact of teriflunomide on relapse-related neurological sequelae and relapses requiring healthcare resources may translate into reduced healthcare costs.

 So it has some activity on relapsing MS
CoI  The lab has received research support from the makers of Aubagio

Radiologically Isolated Syndrome..Real or a Red Herring

Gabelic T, Ramasamy DP, Weinstock-Guttman B, Hagemeier J, Kennedy C, Melia R, Hojnacki D, Ramanathan M, Zivadinov R. Prevalence of Radiologically Isolated Syndrome and White Matter Signal Abnormalities in Healthy Relatives of Multiple Sclerosis Patients.AJNR Am J Neuroradiol. 2013 Jul 25. [Epub ahead of print]

BACKGROUND AND PURPOSE:The exact prevalence of WM signal abnormalities in healthy relatives of MS patients and their impact on disease development has not been fully elucidated. The purpose of this study was to compare WM signal abnormality characteristics and the prevalence of radiologically isolated syndrome in healthy control subjects selected randomly from the population with the healthy relatives of patients with MS.
MATERIALS AND METHODS:Healthy control subjects (n = 150) underwent physical and 3T MR imaging examinations. Healthy control subjects were classified as non-familial healthy control subjects (n = 82) if they had no family history of MS or as healthy relatives of patients with MS (n = 68) if they had ≥1 relative affected with MS. The presence of radiologically isolated syndrome was evaluated according to the Okuda criteria; dissemination in space on MR imaging and fulfillment of radiologically isolated syndrome criteria were also evaluated according to Swanton criteria.
RESULTS: There was a significantly higher total volume of WM signal abnormality in the healthy relatives of patients with MS compared with the non-familial healthy control subjects (P = .024 for signal abnormality ≥3 mm in size and P = .025 for all sizes). Periventricular localization and the number of lesions in all groups (P = .034 and P = .043) were significantly higher in the healthy relatives of patients with MS; 8.8% of the healthy relatives of patients with MS and 4.9% of non-familial healthy control subjects showed ≥9 WM signal abnormalities; 2.9% of subjects in the healthy relatives of patients with MS group and 2.4% of non-familial healthy control subjects fulfilled radiologically isolated syndrome according to the Okuda criteria, whereas 10.3% and 3.7% of subjects fulfilled radiologically isolated syndrome according to the Swanton criteria. In the healthy relatives of patients with MS, smoking was associated with the presence of WM signal abnormalities, whereas obesity was related to the presence of ≥9 WM signal abnormalities and to fulfillment of radiologically isolated syndrome according to the Swanton criteria.
CONCLUSIONS:The frequency of WM signal abnormalities and radiologically isolated syndrome is higher in the healthy relatives of patients with multiple sclerosis patients compared with non-familial healthy control subjects.

3% of healthy sample had radiological abnormalities, but only 0.1% of the population get MS. Therefore what does it say about what the MRI is really detecting. Maybe time to revisit radiologically isolated syndrome criteria as 3% of this sample may now be worried and could mean that people could be getting unnecessary treatment if one was to start treating at RIS.

Thiamine for Fatigue

Costantini A, Nappo A, Pala MI, Zappone A High dose thiamine improves fatigue in multiple sclerosis. BMJ Case Rep. 2013 Jul 16;2013.

The majority of the patients with multiple sclerosis (MS) experience fatigue. Some observations indicate that fatigue and related manifestations concomitant with MS could be associated with an intracellular mild thiamine deficiency. We recruited 15 patients with MS who also experience fatigue and assessed the severity of the fatigue using the Fatigue Severity Scale. Although blood thiamine and thiamine pyrophosphate levels were within normal limit in all the patients, high-dose thiamine therapy administered orally or parenterally led to an appreciable improvement of the fatigue. The absence of apparent decrease in blood thiamine despite the presence of symptoms referable to a mild thiamine deficiency suggests that these patients may have a dysfunction of the mechanisms of intracellular transport or structural enzymatic abnormalities. The administration of large quantities of thiamine was effective in reversing the fatigue in MS, suggesting that the abnormalities in thiamine-dependent processes could be overcome by diffusion-mediated transport at supranormal thiamine concentrations.

Prof G is not here to comment on this, so I will not except to say that it is a small study, and probably needs replicating

Rituximab review

Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One. 2013 Jul 2;8(7):e66308

BACKGROUND:Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS.
OBJECTIVES:To evaluate the efficacy and safety of rituximab for MS treatment.
DATA COLLECTION:Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies.
MAIN RESULTS:Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MS while the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-label rituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events. AUTHOR’S CONCLUSION: Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal.

Anti-CD20 antibodies inhibit relapsing disease but does not appear to inhibit non-relapsing progressive MS

ClinicSpeak: should I start glatiramer acetate?

Question: Relapsing/remitting MS for 7 years; 4.5 years on interferon-beta (Rebif) until pregnancy, no medication for 2.5 years, mild symptoms once a year. I have been offered Copaxone by my consultant. Should I start Copaxone?

Answer: There is no one line answer to this question, I need a lot more information and have numerous questions myself that will need answering before being able to give advice. Please note the emphasis is to give advice; I strongly believe that the person who has the disease should make the final decision about what treatment to start. They're the person who has to live with the disease, with all its uncertainties and disabilities, and its treatments, with their side effects and potential risks, not me. My role, or more accurately the role of the MS team, is to make this process easier for them.

This clinical scenario is not atypical. I am often asked to see MSers for a 2nd or 3rd opinions usually to give advice around disease modifying therapies (DMTs).

In reality, I would need to meet this MSer to get an understanding of what she is like as a person and ascertain how much she understands about MS, its prognosis and the various treatment options. During the consultation I would review the diagnosis of MS. Yes, I always ask does this person have MS? The MS misdiagnosis rate is somewhere between 2-5%; in other words 1 in 20 to 1 in 50 MSers don't actually have MS. One of my hardest tasks as an MSologist is undiagnosing MS; telling someone they don't have MS is not easy.

For arguments sake let's say this woman has a history, examination, MRI, spinal fluid analysis, evoked potentials, other blood tests and clinical course typical of RRMS. Importantly, there are no red flags to make me doubt the diagnosis of MS. Believe it or not the most important job we do as neurologists is make a correct diagnosis; get this wrong and everything downstream of the diagnosis is wrong. This is why I always take a step backwards and question the diagnosis. I hope you realise by the end of this post, which will be longer than usual, that you can't do this via an email or a blog The clinical consultation is too complex to be relegated to an asynchronous communication tool.

Back to the question about giving advice about treatment. This does not occur in a vacuum. Firstly, I would need to ascertain what prognostic category did this lady fall into at baseline when she initially presented with MS? In general I have three prognostic categories:
  1. Inactive MS - a favourable baseline prognostic profile 
  2. Active MS - baseline prognostic profile may be good or bad, but will become better defined over time; this could be on or off a DMT. 
  3. Highly-active MS - baseline prognostic profile is poor. 

Did she respond to interferon-beta (Rebif) that she was on for 4 years prior to her pregnancy? In other words was she rendered disease-activity free (DAF) on Rebif? Was she actively monitored during this 4 year period, both clinically and with annual MRIs? Did she tolerate the subcutaneous interferon-beta (Rebif) injections and were there any other side effects or adverse events? Did she develop neutralizing antibodies (NABs) to interferon-beta?

These questions will allow me to ascertain whether or not she was a interferon-beta responder, sub-optimal responder or a non-responder. If she was a responder and tolerated the injections without side effects she may want to restart interferon-beta. Interferon-beta has been shown to work very well in a minority of MSers and is safe in the long-term. If she didn't tolerate the subcutaneous injections she could always switch to the intramuscular interferon-beta formulation (Avonex). I personally don't think there is much difference between the interferon-beta formulations in terms of their long-term efficacy; they are all part of the same class of drug and work in the same way. Although there is weak evidence that the dosing schedule may be important when it comes to the impact of interferons on brain atrophy; the less frequent weekly administration seems to have a more favourable impact on slowing brain atrophy when compared to the more frequently administered formulations (thrice weekly Rebif or the every other day Betaseron/Betaferon/Extavia) that have no impact on slowing brain atrophy. The interferon-beta preparations also differ when it comes to inducing NABs; more on NABs another time.

Poor tolerability of the injectables will be addressed by the emergence of oral treatments. Fingolimod (Gilenya) already has a license for RRMS in the UK, but can only be used as a second-line agent in MSers falling interferon-beta. Teriflunomide (Aubagio) recently got given the green light by the EMA and should be available in the UK in the next 3-6 months. Another option is BG12 or dimethyl fumarate (Tecfidera), which also got give a green light by the EMA for RRMS. However, Biogen-Idec may not launch this drug in Europe unless they are given the necessary data exclusivity on their trials to prevent the early entry of generics. MSers in the US already have access to both teriflunomide (Aubagio) and BG12 (Tecfidera). If I was a practicing neurology in the US this consultation would almost certainly include a detailed discussion about these new entrants.

This lady describes mild symptoms once a year. I assume these symptoms are due to relapses. I would need to make sure of this on history; the symptoms need to be compatible with involvement of one or more of the nerve pathways in either the brain and spinal cord. To define a relapse the symptoms should last more than 24 hours and should not occur in association with a current infection and fever.

It is important to document relapses, which is why I encourage you to contact your nurse to arrange an appointment so that you can be examined. If this can't be done you should start a diary and document the symptoms of your relapse in writing; you will be surprised how difficult it is to remember specific details of past relapses months or years later.

Relapses indicate that her MS is active, i.e. that an inflammatory lesion is affecting a particular part of her nervous system. This is not good for her as active lesions cause damage; they strip nerves of myelin and can damage nerve processes (axons). Please remember the shredder analogy. You have to remember that for every clinical attack you have there may be 10 or more lesions on MRI that come and go and many more that are beyond the detection threshold of the MRI. This is why most MSologists are now doing regular MRI studies to monitor MS and we are beginning to incorporate additional measures into clinical practice to monitor the activity of MS.

In addition to the number of relapses, it is important to find out if these relapse were disabling or not. I define a relapse as being disabling if affected her ability to function normally; it may simply being unable to walk the dog the usual 2 miles because of a dragging leg or the fatigue associated with the relapse prevented her from going to work. Documenting the frequency and severity of relapse are very important for deciding whether or not MSers can receive certain DMTs under the NHS. I am not sure what country this lady lives in, but access to DMTs vary depending in local guidelines.

I would then examine this lady to assess her baseline neurological function. If I had time I would complete and EDSS, this is not always possible due to time constraints. The EDSS will give me an idea of how disabled she is; remember disability begets disability. MSers who have acquired disability over a short period of time are more likely to become disabled in the future. Knowing your EDSS is important for assessing your prognosis. At the lower end of the EDSS you may not be aware of any problems that the neurologist detects on his or her clinical examination. Therefore you must ask if your examination is normal or not, and if abnormal what part of your nervous system is affected. You will be surprised how you adapt to the deficits of subtle neurological dysfunction; for example not being able to walk heel-to-toe is often ascribed to aging rather than MS. The truth is many MSers hide and/or adapt to their deficits; this is part of having MS. Some call it denial; in reality you cope.

As part of my holistic approach to managing MSers I would actively enquire about hidden symptoms; anxiety, depression, fatigue, cognition, poor sleep, bladder, bowel and sexual dysfunction etc. Although I will address these issues in more detail in future clinic speak postings these hidden symptoms are an indication of whether or not MS is active and causing damage below the clinical threshold. Is MS using up your reserve capacity? 

To complete my assessment I would then request that this lady have a gadolinium-enhanced or contrast-enhanced MRI study of the brain. I would like this MRI to be compared to her last MRI study if that was available. I am particularly interested to see if her MS is active, i.e. does she have enhancing lesions and to see if her lesion load has increased compared to her previous scan. In addition to the lesion load, I would also look for other signs on the MRI that are linked to a poorer prognosis; i.e. black holes on the T1-weighted images, lesions in the the so called posterior fossa or back of the brain and brain atrophy. Atrophy simply means shrinkage of the brain that is greater than is expected for age. Brain atrophy is the hardest thing to look for on MRI with the naked eye; in reality we need to measure brain atrophy using specialised computer software. This software is not available in routine clinical practice; this is something we are trying to address at the Royal London Hospital.

Having poor clinical and MRI prognostic features may swing this lady's decision towards currently licensed highly effective therapies, i.e. fingolimod (Gilenya) or natalizumab (Tysabri). This would then trigger a detailed discussion with regard to risks and benefits of the treatments including a discussion about the PML (Progressive Multifocal Leukoencephalopathy). To complete the latter discussion we would have to arrange for her to have her JC virus serology checked to see if she has been infected with the virus in the past. The risks of PML in seronegative, or low titre positive, MSers is low. If fingolimod is a serious consideration we would need to check her varicella-zoster virus (VZV) status and make sure she does not have latent tuberculosis (TB). MSers who are VZV seronegative - who don't have antibodies to the virus need to be vaccinated before starting fingolimod. TB screening requires a specialised blood test or a skin test. In MSers exposed to people with active TB in the past, so called high-risk MSers, also get a chest x-ray at our hospital. The chest x-ray is not mandatory, some neurologists feel it is unnecessary. All MSers considering fingolimod have to have their hearts examined and an ECG performed. I am confident enough to do these two things myself, however, some MSologists prefer MSers to see a cardiologist before starting fingolimod.

When discussing highly-effective therapies it is important to balance the risks of this strategy with the risks of MS. I would therefore enquire if she knew about the prognosis of MS; its impact on physical and cognitive functioning, survival, employment status, relationships and quality of life. I tend to layer this information depending on the level of knowledge the MSer has already and their emotional state. How much information I give and how I give this information is a judgement call. This is why medicine is still an art and not a science. How we communicate with MSers is very important; it is critical that you understand your disease and why we are treating it and what the aims of treatment are.

Most MSers who come and see me for a second or third opinion already know that I am aggressive treater. In other words I favour the hit hard and early strategy over the safe and smooth one. Despite this I have constraints that prevent me from prescribing highly-effective therapies as first-line treatments. I have to explain this to MSers if they don't meet our NHS guidelines for treatment with the more effective treatments.

Another aspect that will affect this MSer's decision about treatment is family planning. Have her and her partner completed their family? If not she may well want to choose glatiramer acetate (Copaxone) as a treatment. Although none of the current licensed DMTs should be prescribed during pregnancy glatiramer acetate (Copaxone) has a good safety record in pregnancy and a large number of MSologists are allowing MSers under their care to fall pregnant on the drug and to continue taking it throughout pregnancy.

Although alemtuzumab is not officially licensed yet it will be an appealing drug for woman wanting to start or extend their families. Alemtuzumab works as an induction agent and once you have completed your two course and you have no evidence of disease activity (NEDA) you could fall pregnant. Alemtuzumab is not administered continuously therefore it does not stay in your body and hence is not associated with any effects on the developing baby. However, to be eligible for alemtuzumab this MSer would have to have active MS. I suspect she has active disease as she is having relapses and she therefore may be eligible for the drug if it gets it European license as recently suggested by the EMA.

I note this woman has already had a baby. I will enquire whether or not she is aware of the familial clustering of MS. If she has a daughter her daughter's risk of getting MS is approximately 2.5% or 1 in 40 and if it is a boy his risk is less; approximately 1.25% or 1 in 80. Please note that these figures are rough estimates and relate to the Canadian data that is not too dissimilar to the UK. The closer you live to the equator the lower your risk. 

The discussion of familial risk rarely goes down well in a consultation; the typical response from most MSers is 'I thought MS was not genetic'. MS is not typical of Mendelian genetic disorders in that it is not linked to a single gene. However, there is clearly a genetic component to MS. Several genes linked to MS increase your chances of getting the disease by interacting with environmental risk factors that trigger MS. I would discuss these risk factors; i.e. vitamin D, sunshine, latitude, EBV and smoking. I would explain to her that we believe that if you keep yourself vitamin replete throughout life you will drastically lower your chances of getting MS; Prof. George Ebers thinks this may reduce your chances by up to 85%. 

I would explain that the current RDA (recommended daily allowance) of vD is woefully too low and give her advice on what is appropriate for her and her family to take. If her child was older (6 or older) we would enrol them onto our new 'Digesting Science' course to teach them about MS. One of the aims of this course is to get the message across that 'vD supplementation may prevent MS'. I am hoping that this message will get through to children of MSers so they don't forget to take their daily vD supplements. This last comment is speculative, we need to research this aspect of the 'Digesting Science' course; there is little point in preaching the virtues of evidence-based practice without being able to demonstrate that what we are trying to do actually works. We are in the process of putting together a grant application so that we can get a PhD student to study this formally. However, more on this another time.

Finally, I always give MSers I see the option of participating in clinical trials. Clinical trials are part of the MS service we provide. I would estimate that about half of my new MS referrals are for possible inclusion in clinical trials. If MSers did not volunteer themselves for clinical trials we would never move the field forward. The fact that we have so many DMTs available today is a testament to all the MSers out there who volunteered for trials in the past. At the present time we are recruiting MSers with active disease for our raltegravir (INSPIRE) trial and for a study of a new monoclonal antibody targeting B cells via the CD19 receptor.

So in conclusion you can see this simple yes no question has generated more questions than answers. So should this lady go onto glatiramer acetate (Copaxone)? Maybe.

When writing this post, which has taken me longer than I anticipated, it has become clear to me how specialised MS has become and that we are truly in the age of personalised medicine. No algorithm will be able to answer this woman's question. In reality, what this lady need is a face-to-face consultation with her MSologist, which I think she has already had. He/She has recommended glatiramer acetate (Copaxone).

CoI: multiple

Monday, 29 July 2013

Tysabri and Endogenous Retro virus.

Arru G, Leoni S, Pugliatti M, Mei A, Serra C, Delogu LG, Manetti R, Dolei A, Sotgiu S, Mameli G.Natalizumab inhibits the expression of human endogenous retroviruses of the W family in multiple sclerosis patients: a longitudinal cohort study. Mult Scler. 2013 Jul 22. [Epub ahead of print]

BACKGROUND: Several viruses were reported as co-factors triggering the pathogenesis of multiple sclerosis (MS), including the endogenous retroviruses of the HERV-W family, that were also proposed as biomarkers of disease progression and therapy outcome.

OBJECTIVE:The objective of this article is to clarify whether in MS patients treatment with natalizumab has effects on MSRV/syncytin-1/HERV-W expression and the possible relationship with disease outcome.
METHODS:Peripheral blood mononuclear cells were collected from 22 patients with relapsing-remitting disease, at entry and after three, six and 12 months of treatment with natalizumab. The cell subpopulations and the expression of MSRVenv/syncytin-1/HERV-Wenv were analyzed by flow cytometry and by discriminatory env-specific RT-PCR assays.

RESULTS: By flow cytometry the relative amounts of T, NK and monocyte subpopulations were shown to remain fairly constant. A relative increase of B lymphocytes was observed at three to six months (p = 0.033). The MSRVenv and syncitin-1 transcripts were reduced at six to 12 months of therapy (p = 0.0001). Accordingly, at month 12, the plasma-membrane levels of the HERV-Wenv protein were reduced (p = 0.0001). B cells, NK and monocytes but not T cells expressed the HERV-Wenv protein. None of the patients relapsed during therapy.
CONCLUSION: Effective therapy with natalizumab downregulates MSRV/syncytin-1/HERV-W expression.

The ProfGs think that viruses are a central problem in MS and have put their necks on the block and started the Charcot Project..recruiting now. 

Human endogenous retrovirus or HERV have been implicated. 

They are present in your DNA, in every cell, and can become reactivated to make viral particles. In this study people getting tysabri made less HERV and had no relapses. Is this the reason why tysabri works?..

I doubt works because it stops white cells getting in the brain. 

However, maybe it is inflammation that triggers HERV expression, get rid of inflammation and the HERV go. Therefore could HERV expression by the consequence rather than the cause of MS. If so is the Charcot Project treating the chicken and not the egg.

CoI: None

Risk of MS and children

Hedström A, Hillert J, Olsson T, Alfredsson L. Reverse causality behind the association between reproductive history and MS. Mult Scler. 2013 Jul 25. [Epub ahead of print]

BACKGROUND:Possible associations between childbearing patterns and multiple sclerosis (MS) risk have been studied for a long time, with conflicting results. We aimed to investigate the influence of reproductive history on MS risk.
METHODS:Using a Swedish population-based case-control study involving incident cases of MS (1798 cases, 3907 controls), we calculated odds ratios (OR) for MS comparing parents with childless subjects together with 95% confidence intervals (CI) employing logistic regression.
RESULTS: Overall, there was an association between having children and reduced MS risk among both sexes. Subjects who had become parents within five years prior to the index year had a substantially reduced risk of developing MS (OR 0.6, 95% CI 0.5-0.8 for women, and OR 0.4, 95% CI 0.3-0.6 for men). No association between having children and MS risk was observed when more than 10 years had passed since the birth of the last child. We found no association between increasing offspring number and MS risk.
CONCLUSIONS: The observed association between reproductive history and MS risk is restricted to a limited time period preceding the index year, with similar findings in both sexes, which contradicts biologic impact of pregnancy on MS risk and argues in favor of reverse causality, i.e. that fecundity is affected by yet-undiagnosed MS.
This study indicates that people with children have lower risk of MS, but argue that yet undiagnosed MS, reduces you chance of having children and this is where the risk lies

Prognostic value of MRI

Zhang WY, Hou YL. Prognostic value of magnetic resonance imaging in patients with clinically isolated syndrome conversion to multiple sclerosis: A meta-analysis.Neurol India. 2013;61(3):231-8

Background: Numerous studies have investigated the associations of brain or spinal cord MRI with the risk of developing Multiple Sclerosis (MS) in people with Clinically Isolated Syndrome (CIS), however, the findings are uncertain. Therefore, we performed a meta-analysis based on 24 publications to comprehensively evaluate such associations. 

Materials and Methods: The databases of EMBASE and MEDLINE (January 1980-August 2011) were searched electronically for all relevant studies. Data were extracted from each study independently by both reviewers using a predefined structured spreadsheet. The quality of each study was assessed independently by two reviewers according to Newcastle-Ottawa Scale for reading cohort study proposed by Deeks et al. The meta-analysis including 24 qualified studies was performed by using the Cochrane Collaborations RevMan5.0 software. 
Results: Twenty-four identified studies met the inclusion criteria and minimum quality threshold. A meta-analysis of cohort studies indicated that the CISs having MRI lesions did have significantly increased risk for MS (risk ratio [RR] = 3.71, 95% confidence interval [CI], 3.27-4.21, P < 0.00001). In the subgroup analysis (according to the number of T2 lesions at baseline), the risk of developing MS in CIS patients with the medium MRI burden (4-9 lesions) was higher than with the low MRI burden (1-3 lesions) (RR = 0.66,95% CI, 0.45-0.95, P < 0.00001). While, no correlation was found in group between the medium MRI burden and the high MRI burden(>9 lesions) (RR = 0.97, 95% CI, 0.82-1.15, P = 0.72). Meanwhile, the CIS patients with abnormal baseline MRI, especially with infratentorial lesions, had a high risk of conversion to MS compared to patients without the such infratentorial lesions (RR = 1.37, % CI, 1.09-1.73, P = 0.0008). 
Conclusions: Despite some limitations, this meta-analysis established solid statistical evidence for an association between the presence or absence of MRI lesions within the brain or spinal cord MRI and the risk of developing MS, particularly for studies with large sample size. The CIS patients with abnormal baseline MRI, especially with infratentorial lesions, had a high risk of conversion to MS. However, this association warrants additional validation in larger and well designed studies.

Despite years of claims for prognostic predictions of MRI and trends in the direction of detecting something. It is not clear what is being detected and is a loose correlation so the prognostic value is less clear,

Pregnancy- Epidurals and MS

Lu E, Zhao Y, Dahlgren L, Preston R, van der Kop M, Synnes A, Sadovnick AD, Traboulsee A, Tremlett H. Obstetrical epidural and spinal anesthesia in multiple sclerosis. J Neurol. 2013  [Epub ahead of print]
To examine obstetrical epidural and spinal anesthesia use in women with multiple sclerosis (MS) and the relationship with MS clinical factors. This was a retrospective (Already done and looking through the records) cohort study, linking clinical data from women with MS in the British Columbia (BC) MS database to obstetrical data (1998-2009) from the BC Perinatal Database Registry. We compared epidural use in 431 deliveries to women with MS and 2,959 deliveries from the general population, as well as spinal use in cesarean deliveries (128 to women with MS and 846 in the general population). We also examined the association between epidural or spinal anesthesia and MS clinical factors-disease duration and disability [Expanded Disability Status Scale (EDSS) score]. Of 431 deliveries to women with MS, 116 were exposed to epidural anesthesia and of 128 cesarean deliveries, 82 were exposed to spinal anesthesia. The use of epidural anesthesia was similar in nullipara (adjusted OR = 0.86, 95 % CI = 0.63-1.18, p = 0.36), but more likely in multipara with MS (adjusted OR = 1.75, 95 % CI = 1.20-2.54, p = 0.004). Spinal anesthesia use in cesarean deliveries was comparable between the MS and general population cohorts (adjusted OR = 0.84, 95 % CI = 0.55-1.31, p = 0.45). Women who delivered 5 to <10 years after MS onset were less likely to have an epidural (adjusted OR = 0.57, 95 % CI = 0.34-0.95, p = 0.03) vs. those delivering within 5 years. EDSS was not associated with use of either type of anesthesia (adjusted p > 0.1). Contrary to previous studies, epidural anesthesia use differed between women with MS and the general population and was influenced by parity and MS disease duration.
Come on Dr. Helen (blog reader) you know this is the stuff that women MSers of child bearing age may like to know so start writing these abstracts in Ingrish/Canadian:-) 

Epidural anaesthesia. The epidural route is frequently employed to administer analgesic and local anaesthetic agents through a catheter placed into the epidural space.Spinal anaesthesia is a technique whereby a local anaesthetic drug is injected into the cerebrospinal fluid. This technique has some similarity to epidural anaesthesia important differences include:
  • To achieve epidural analgesia, a larger dose of drug is typically necessary than with spinal analgesia.
  • The onset of analgesia is slower with epidural analgesia than with spinal analgesia.
  • An epidural injection may be performed anywhere along the vertebral column (cervical, thoracic, lumbar, or sacral), while spinal injections are typically performed below the second lumbar vertebral body to avoid piercing and consequently damaging the spinal cord.
  • It is easier to achieve segmental analgesia or anaesthesia using the epidural route than using the spinal route.
  • An indwelling catheter is more commonly placed in the setting of epidural analgesia or anaesthesia than with spinal analgesia or anaesthesia.
Nullipara is a woman who has never given birth is not someone from the parachute regiment, multipara is a woman who has had two or more pregnancies not loads of paratroopers. In those having multiple births you are more likely to use epidurals than non MSers. In you were older you less likely use epidurals.

What does this me not a lot as it is not my thing, but it says whatever your choice..pain or no pain, you are not alone. Maybe MSers are more accepting of using drugs as a person who gets back pain...why suffer when you don't need to. However this study does not say negative stuff about pregnancy and this is important to know.

Degrading antibodies

Challa DK, Bussmeyer U, Khan T, Montoyo HP, Bansal P, Ober RJ, Ward ES. Autoantibody depletion ameliorates disease in murine experimental autoimmune encephalomyelitis.MAbs. 2013 19;5. [Epub ahead of print]

Much data support a role for central nervous system antigen-specific antibodies in the pathogenesis of multiple sclerosis (MS). The effects of inducing a decrease in (auto)antibody levels on MS or experimental autoimmune encephalomyelitis (EAE) through specific blockade of FcRn, however, remain unexplored. We recently developed engineered antibodies that lower endogenous IgG levels by competing for binding to FcRn. These Abdegs ("antibodies that enhance IgG degradation") can be used to directly assess the effect of decreased antibody levels in inflammatory diseases. In the current study, we show that Abdeg delivery ameliorates disease in an EAE model that is antibody dependent. Abdegs could therefore have promise as therapeutic agents for MS.

Maybe more useful for NMO where an antibody has been implicated as beneficial and respond to plasma exchange.

Sunday, 28 July 2013

Next time they have a moan

Next time your partner has a moan...suggest they get some weights and go for a walk.

As part of our Public Engagement we have been spending our weekends talking to Children of MSers.

There are lots of fun tasks and running round a track with weights on your legs is a way of explaining why mum or dad can't walk as freely as they would like. 

Sometimes Dads will have a go too.

Are you ensuring your Kids have enough Vitamin D!

Macrophages nick target for daclizumab from T cells

Zhang Y, McClellan M, Efros L, Shi D, Bielekova B, Tang M, Vexler V, Sheridan J. Daclizumab reduces CD25 levels on T cells through monocyte-mediated trogocytosis.  Mult Scler. 2013 Jul  [Epub ahead of print]

Daclizumab is a humanized monoclonal antibody that prevents interleukin-2 (IL-2) binding to CD25, blocking IL-2 signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling. The phase 2a CHOICE study evaluating daclizumab as a treatment for multiple sclerosis (MS) included longitudinal analysis of activated T cell counts. Whereas an exposure-dependent relationship was observed between daclizumab and reductions in HLA-DR+-activated T cells, a similar relationship was not observed for reductions in CD25 levels. The objective of this report is to determine the mechanism by which daclizumab reduces CD25 levels on peripheral blood mononuclear cells (PBMCs) using cytometric techniques. Daclizumab reduced T cell CD25 levels through a mechanism that required the daclizumab-Fc domain interaction with Fc receptors (FcR) on monocytes, but not on natural killer (NK) cells, and was unrelated to internalization or cell killing. Activated CD4+ T cells and FoxP3+ Treg cells showed evidence of trogocytosis of the CD25 antigen in the presence of monocytes. A daclizumab variant that retained affinity for CD25 but lacked FcR binding did not induce trogocytosis and was significantly less potent as an inhibitor of IL-2-induced proliferation of PBMCs. In conclusion, Daclizumab-induced monocyte-mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to daclizumab inhibition of IL-2 signalling.

Daclizumab blocks a T cell growth factor and affects natural killer cell function. How does it work, well in this study binding of the antibody to the target stimulates blood macrophage to bind to the antibody and pull the target for daculizumab off the T cell. This is a process known as Trogocytosis.  If T cells loose this marker they can not respond to the cell growth factor. 

Saturday, 27 July 2013

Clinic speak: personal consultations

"Whilst lying on the beach and getting my vD levels up I have been thinking about MS and our blog and how it should evolve. My beach think has become an annual ritual; but more on this later when I highlight our research priorities for the new academic year that begins in September."

"As a result of the blog I get a lot or personal emails asking for advice about treatment and personal issues. Legally I am not allowed to respond to these emails. I had plans to start to a private e-medicine portal to deal with this issue, but I have had to shelve this idea as I simply don't have the time and resources to launch this service at this point in my career. In fact when I did due diligence on the idea I realised that it would probably be a full-time job and I would need to set-up a start-up company to raise finance to get the project off the ground. Another option was to give the idea away, but then I would not have control over its implementation. I need to have control over its design and implementation to make sure it achieves what I want it to achieve for MSers."

"A simpler solution will be to anonymise the email consultations and to respond to them generically on the blog under a sub-heading 'Clinic Speak'. I have used this sub-heading in the past when discussing clinical issues. Clinic speak postings will not directly report research, but will demonstrate how a practising neurologist, or MSologist, uses evidence to aid clinical practice and decision making. Before expanding the brief of this blog into the adoption and clinical translation of evidence, or research, I would appreciate your thoughts about this proposal?"

06 May 2013
Clinic speak: poor sleep due to bladder overactivity. Do you have night-time bladder problems? This post is for you. #MSBlog #MSResearch "Recently I have focused on sleep problems in MS. One particular problem is ...
14 Feb 2013
Clinic speak: DABDA or DABDAA. #MSBlog MS is emotionally exhausting! "Being a neurologist, who sees MSers, a clinical scientist, who studies the disease, and one who puts his head above the parapet, it is getting ...

Placebo Effect

Mechanisms and therapeutic implications of the placebo effect in neurological and psychiatric conditions.Murray D, Stoessl AJ. Pharmacol Ther. 2013. doi:pii: S0163-7258(13)00155-1. 10.1016/j.pharmthera.2013.07.009. [Epub ahead of print]

The power of a placebo to effect clinically meaningful neurobiological change comparable to pharmacological therapies has been demonstrated, although the mechanisms are not fully understood. Predicting placebo responsiveness has only recently received more attention, but psychological disposition, contextual and biological factors are now known to dramatically affect a person's susceptibility to the placebo effect. The placebo effect depends upon expectancies that can be modified in a number of ways, including conditioning through explicit or implicit learned associations. Based on the dopaminergic response to anticipation of benefit in Parkinson's disease, it was suggested that the placebo effect can be seen as analogous to the expectation of reward. Dopaminergic pathways have since been implicated in the placebo response in pain and depression. Additionally, endogenous opioid release is known to mediate many forms of placebo analgesia. We provide an overview of the mechanisms and the therapeutic implications of the placebo effect in neurological and psychiatric conditions. We include evidence for detrimental effects arising from seemingly inert interventions, termed the 'nocebo effect.' Neuroimaging has critically advanced the study of the placebo effect and provides some of the strongest evidence for the mechanisms of this phenomenon prevalent across an array of human health-related circumstances. This review specifically focuses on mechanisms of the placebo effect in the three conditions that have most significantly demonstrated this effect and for which a plausible physiological basis can be identified: pain, PD and depression. Other neurological and psychiatric diseases reviewed include multiple sclerosis, Huntington's disease, Alzheimer's disease, schizophrenia and epilepsy.

Thought I would post this before ProfG got his teeth into this on. The placebo effect is a very real entity and therefore it is important that this is factored into the reported treatment effects of any intervention, whether it is a pharmaceutical and nutriceutical or a fad. This paper examines how the nerve transmitter dopamine is involved. This transmitter stimulates the "reward" centres in the brain.

The placebo control has become an ethical issue for RRMS as there are drugs available a placebo is not really ethical. However, this makes it difficult as some treatments unblind themselves. we need to wait for results of controlled studies of CCSVI before we can conclusively say anything.

Factors in the spinal fluid that can stimulate nerve growth and myelin formation

Cristofanilli M, Cymring B, Lu A, Rosenthal H, Sadiq SA. Cerebrospinal fluid derived from progressive multiple sclerosis patients promotes neuronal and oligodendroglial differentiation of human neural precursor cells in vitro. Neuroscience. 2013 Jul  doi:pii: S0306-4522(13)00604-0.10.1016/j.neuroscience. 2013.07.022. [Epub ahead of print]

In the adult central nervous system (CNS), tissue-specific germinal niches, such as the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus, contain multipotent neural precursor cells (NPCs) with the capacity to self-renew and differentiate into functional brain cells (i.e. neurons, astrocytes or oligodendrocytes). Due to their intrinsic plasticity, NPCs can be considered an essential part of the cellular mechanism(s) by which the CNS tries to repair itself after an injury. In inflammatory CNS disorders, such as multiple sclerosis (MS), neurogenesis and gliogenesis occur as part of an 'intrinsic' self-repair process. However, full and long-lasting repair in progressive MS is not achieved. 

Recent data suggest that endogenous NPCs, while trying to repair the damaged CNS in MS, may become the target of the disease itself. It is possible that factors produced during MS, like CNS-infiltrating blood-borne inflammatory mononuclear cells, reactive CNS-resident cells, and humoral mediators, can alter the physiological properties of NPCs, ultimately impairing their ability to promote neural regeneration. Here, we investigate the effect of cerebrospinal fluid derived from primary progressive (PPMS) and secondary progressive (SPMS) MS patients (CSF-MS) on the survival, proliferation, and differentiation of commercially available human embryonic-derived NPCs named ENStem-A. We found that PPMS derived CSF markedly reduced the proliferation of ENStem-A (Stem cell line) and increased their differentiation toward neuronal and oligodendroglial cells, compared to control CSF. Similar but less striking results were seen when ENstem-A were treated with SPMS derived CSF. Our findings suggest that in both SPMS and PPMS the CNS milieu, as determined by extrapolation from CSF findings, may stimulate the endogenous pool of NPCs to differentiate into neurons and oligodendrocytes.

Inflammation is about getting rid of infection and then repairing the damage. There seems to be a problem in MS that the nerve tissue is treated like an infection. There is repair in MS (red arrows in picture above) this can be seen histologically and recovery of function and there are soluble factors that promote this repair, we have named quit a few. This study shows that there are repair factors produced in progressive MSers

CCSVI July..Its CCSVI super saturday...

#MSResearch #MSblog CCVSI is not causal in MS

Dolic K, Siddiqui AH, Karmon Y, Marr K, Zivadinov R. The role of noninvasive and invasive diagnostic imaging techniques for detection of extra-cranial venous system anomalies and developmental variants. BMC Med. 2013 Jun 27;11(1):155. [Epub ahead of print]

The extra-cranial venous system is complex and not well studied in comparison to the peripheral venous system. A newly proposed vascular condition, named chronic cerebrospinal venous insufficiency (CCSVI), described initially in patients with multiple sclerosis (MS) has triggered intense interest in better understanding of the role of extra-cranial venous anomalies and developmental variants. So far, there is no established diagnostic imaging modality, non-invasive or invasive, that can serve as the "gold standard" for detection of these venous anomalies. However, consensus guidelines and standardized imaging protocols are emerging. Most likely, a multimodal imaging approach will ultimately be the most comprehensive means for screening, diagnostic and monitoring purposes. Further research is needed to determine the spectrum of extra-cranial venous pathology and to compare the imaging findings with pathological examinations. The ability to define and reliably detect noninvasively these anomalies is an essential step toward establishing their incidence and prevalence. The role for these anomalies in causing significant haemodynamic consequences for the intra-cranial venous drainage in MS patients and other neurologic disorders, and in aging, remains unproven.

Was this paper written before or after the clinical study done by this group? The use of "further research is needed" should be banned from abstracts or maybe people need to do the further work before publishing as it says this work does not say much concrete.

Luo J, Yablonskiy DA, Hildebolt CF, Lancia S, Cross AH. Gradient echo magnetic resonance imaging correlates with clinical measures and allows visualization of veins within multiple sclerosis lesions.

Mult Scler. 2013 Jul 8. [Epub ahead of print]

BACKGROUND:Conventional magnetic resonance imaging (MRI) methods do not quantify the severity of multiple sclerosis (MS) white matter lesions or measure pathology within normal-appearing white matter (NAWM).

OBJECTIVE: Gradient Echo Plural Contrast Imaging (GEPCI), a fast MRI technique producing inherently co-registered images for qualitative and quantitative assessment of MS, was used to 1) correlate with disability; 2) distinguish clinical MS subtypes; 3) determine prevalence of veins co-localized within lesions in WM.

METHODS:Thirty subjects representing relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS) subtypes were scanned with clinical and GEPCI protocols. Standard measures of physical disability and cognition were correlated with magnetic resonance metrics. Lesions with central veins were counted for RRMS subjects.

RESULTS:Tissue damage load (TDL-GEPCI) and lesion load (LL-GEPCI) derived with GEPCI correlated better with MS functional composite (MSFC) measures and most other neurologic measures than lesion load derived with FLAIR (LL-FLAIR). GEPCI correctly classified clinical subtypes in 70% subjects. A central vein could be identified in 76% of WM lesions in RRMS subjects on GEPCI T2*-SWI images.

CONCLUSION: GEPCI lesion metrics correlated better with neurologic disability than lesion load derived using FLAIR imaging, and showed promise in classifying clinical subtypes of MS. These improvements are likely attributable to the ability of GEPCI to quantify tissue damage.

So white matter lesions centre around veins. I guess we knew this

Fankhauser GT, Stone WM, Fu R, Money SR. Spiral vein graft for internal jugular bypass in a patient with multiple sclerosis and suspected chronic cerebrospinal venous insufficiency. Ann Vasc Surg. 2013;27(5):673.e5-8.
Chronic cerebrospinal venous insufficiency (CCSVI) has been implicated as a contributing factor to multiple sclerosis (MS). This theory is strongly debated within the neurology and radiology communities. This report presents the case of a 45-year-old man with known MS and suspected CCSVI who had undergone previous internal jugular angioplasty and stenting. The patient reported dramatic improvement of symptoms after intervention. The stent thrombosed despite anti-thrombotic medication, and several endovascular interventions failed to restore long-term patency. Open venous reconstruction of the internal jugular vein was performed with a spiral graft from the saphenous vein. The patient's symptoms improved for several weeks until the venous reconstruction occluded. This case is the first reported open venous reconstruction for suspected CCSVI.

It had to happen, obviously once people realise that the effect of CCSVI wears off then it has to be repeated to unblock the vein so more money for the scammers. They may put in a stent but the obvious next stage of the scam is to by-pass the vein. The sapenous vein is used by surgeons in by-pass surgery. Why not let dodgy surgeons in on the act.

In this case it was a failure be warned. There is no class I evidence that these procedures provides benefit.  You should not do this unless being part of a clinical trial so it canbe really assessed whether benefit is being seen.

I see it now.....the Canadian government shelling out another $8,000,000 for a trial

I wonder how many people have had this procedure done?. 

Diehn FE, Schwartz KM, Hunt CH, Eckel LJ, Campeau NG, Carter RE, Allred JB, Kallmes DF. Prevalence of Incidental Narrowing of the Superior Segment of the Internal Jugular Vein in Patients Without Multiple Sclerosis. Clin Neuroradiol. 2013 Jul 2. [Epub ahead of print]

PURPOSE:Internal jugular vein (IJV) narrowing superiorly is likely relatively frequent. IJV narrowing has been proposed as a potential pathophysiologic component for multiple sclerosis (MS). Our purpose was to investigate the prevalence of incidental superior IJV narrowing in patients imaged with neck computed tomography angiography (CTA) for reasons unrelated to IJV pathology or MS.

METHODS:We retrospectively identified 164 consecutive adult patients who had undergone neck CTA in which at least one IJV superior segment was opacified (158 right, 155 left IJVs). At the narrowest point of the upper IJV, each IJV was assessed for dominance, graded (shape and narrowing), measured (diameter and area), and located (axially and craniocaudally). Associations were analyzed using Spearman rank correlations (p < 0.05 significant). Medical records were reviewed for MS.

RESULTS: Among 164 patients, at least one IJV was: absent/pinpoint in 15 % (25/164), occluded/nearly occluded in 26 % (43/164). Shape, narrowing, and the three measurements all correlated with each other (all p < 0.01). Lateral location with respect to C1 transverse foramen correlated with subjectively and objectively smaller IJVs (p < 0.01). The most common craniocaudal location was at the C1 transverse process (79 % (125/158) of right and 81 % (126/155) of left IJVs). No patient had a diagnosis of MS.

CONCLUSIONS: The appearance of the superior IJV is variable, with an occlusive/near-occlusive appearance present in approximately one-quarter of patients without known MS undergoing CTA. Radiologists should be aware of and cautious to report or ascribe clinical significance to this frequent anatomic variant.

Yet more evidence that a causal link of narrowing veins to MS is lacking

Brod SA, Kramer LA, Cohen AM, Barreto AD, Bui TT, Jemelka JR, Ton K, Lindsey JW, Nelson F, Narayana PA, Wolinsky JS. Chronic cerebrospinal venous insufficiency: masked multimodal imaging assessment. Mult Scler. 2013 Jul. [Epub ahead of print]

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) was implicated in the pathophysiology of multiple sclerosis (MS).

OBJECTIVE: We evaluated neurosonography (NS), magnetic resonance venography (MRV), and transluminal venography (TLV) in subsets of MS patients drawn from a single-center, prospective, case-control study of 206 MS and 70 non-MS volunteers.

METHODS: As previously reported, findings on high-resolution B-mode NS imaging with color and spectral Doppler of the extracranial and intracranial venous drainage consistent with CCSVI were similar among MS and non-MS volunteers (3.88% vs 7.14%; p = 0.266). Ninety-nine MS participants consented to intravascular contrast-enhanced 3D MRV to assess their major systemic and intracranial venous circulation, and 40 advanced to TLV that included pressure measurements of the superior vena cava, internal jugular, brachiocephalic, and azygous veins.

RESULTS: NS findings and MRV patterns were discrepant for 26/98 evaluable subjects, including four with abnormal findings on NS that had normal venous anatomy by MRV. In no instance were TLV pressure gradients indicative of clinically significant functional stenosis encountered. The three imaging approaches provided generally consistent data with discrepancies referable to inherent technique properties.

CONCLUSIONS: Our findings lend no support for altered venous outflow dynamics as common among MS patients, nor do they likely contribute to the disease process.

Somebody gloated "there is no evidence that EAE and MS are the same right"...I guess the response is "There is no compelling evidence for  a venous abnormality as a causal link of MS  right!"

Simka M, Ludyga T, Latacz P, Kazibudzki M, Majewski E, Zaniewski M Chronic cerebrospinal venous insufficiency is unlikely to be a direct trigger of multiple sclerosisMultiple Sclerosis and Related Disorders Volume 2, Issue 4 , Pages 334-339, 

Background Chronic cerebrospinal venous insufficiency, a vascular pathology affecting the veins draining the central nervous system can accompany multiple sclerosis and is suspected to be involved in its pathogenesis.
Objective.This study was aimed at exploring a potential role for chronic cerebrospinal venous insufficiency in triggering multiple sclerosis. If it were venous abnormalities responsible for neurological pathology, one should expect negative correlation, i.e. more severe vascular lesions in the patients with early onset of multiple sclerosis.
Methods Localization and degree of venous blockages in 350 multiple sclerosis patients were assessed using catheter venography. Statistical analysis comprised evaluation of the correlations between severity of venous lesions and patients' age at onset of the disease.
Results We found weak, yet statistically significant positive correlations between patients' age at onset of multiple sclerosis and accumulated and maximal scores of venous lesions. The patients, also those with duration of multiple sclerosis not longer than 5 years, who had their first attack of the disease at younger age, presented with less severe vascular lesions.
Positive correlation suggests that venous lesions are not directly triggering multiple sclerosis. There should be another factor that initiates pathological processes in the central nervous system.

Somebody gloated "there is no evidence that EAE and MS are the same right"...I guess the response is "There is no compelling evidence for  a venous abnormality as a causal link of MS  right!"
Am I just repeating myself? Well we have heard this over and over again, the weight of evidence I think is overwhelming.

 Rahman MT, Sethi SK, Utriainen DT, Hewett JJ, Haacke EM. A comparative study of magnetic resonance venography techniques for the evaluation of the internal jugular veins in multiple sclerosis patients. Magn Reson Imaging. 2013 Jul 11. doi:pii: S0730-725X(13)00211-7

BACKGROUND AND PURPOSE: The use of magnetic resonance imaging (MRI) to assess the vascular nature of diseases such as multiple sclerosis (MS) is a growing field of research. This work reports on the application of MR angiographic (MRA) and venographic (MRV) techniques in assessing the extracranial vasculature in MS patients. 
MATERIALS AND METHODS: A standardized MRI protocol containing 2D TOF-MRV and dynamic 3D contrast-enhanced (CE) MRAV was run for 170 MS patients and 40 healthy controls (HC). The cross-sectional area (CSA) of the internal jugular veins (IJVs) was measured at three neck levels in all subjects for both MRV techniques to determine the presence of venous stenoses. All data were analyzed retrospectively. 
RESULTS: For the values where both methods showed signal, the 3D method showed larger CSA measurement values compared to 2D methods in both IJVs, in both MS and HC subjects which was confirmed with student paired t-tests. Of the 170 MS patients, 93 (55%) in CE-MRAV and 103 (61%) in TOF-MRV showed stenosis in at least one IJV. The corresponding numbers for the 40 HC subjects were 2 (5%) and 4 (10%), respectively. Carotid ectasias with IJV stenosis were seen in 26 cases (15%) with 3D CE-MRAV and were not observable with 2D TOF-MRV. Carotid ectasias were not seen in the HC group. In the 2D TOF-MRV data, banding of the IJVs related to slow flow was seen in 58 (34%) MS cases and in no HC cases. MS patients showed lower average CSAs than the HC subjects. 
CONCLUSION: The 3D CE MRAV depicted the vascular anatomy more completely than the 2D TOF-MRV. However, the 3D CE MRAV does not provide any information about the flow characteristics which are indirectly available in the 2D TOF-MRV in those cases where there is slow flow.

Not much to say here, stenois in controls and more MSers...sound familiar ......nothing causal.

Juenemann M, Yeniguen M, Stolz E, Berghoff M. No evidence for CCVSI in relapsing-remitting multiple sclerosis patients with moderate disability. J Neurol. 2013 Jul 14. [Epub ahead of print]

Didn't get to read this one, but the title is rather damming

Benedict RH, Weinstock-Guttmam B, Marr K, Valnarov V, Kennedy C, Carl E, Brooks C, Hojnacki D, Zivadinov R.Chronic cerebrospinal venous insufficiency is not associated with cognitive impairment in multiple sclerosis. BMC Med. 2013 Jul 18;11(1):167. [Epub ahead of print]
BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) has been reported in multiple sclerosis (MS) yet its significance in relation to cognitive function is undetermined.This study measured the association between the presence and severity of CCSVI and cognitive impairment in patients with MS.
METHODS: CCSVI was assessed using extra-cranial and trans-cranial Doppler sonography in 109 MS patients (79 with relapsing-remitting, 23 with secondary-progressive and 7 with primary-progressive disease subtype). A subject was considered CCSVI-positive if >=2 venous haemodynamic criteria were fulfilled. The Minimal Assessment of Cognitive Function in MS (MACFIMS) battery was administered assessing the full spectrum of cognitive domains known to be affected by MS. Depression was quantified using the Beck Depression Inventory Fast Screen (BDIFS). Partial correlations, analysis of variance (or covariance) and linear regression were used to examine the hypothesis that CCSVI status is related to cognition or depression after controlling for education and gender.
RESULTS: There were 64 (58.7%) patients who were considered CCSVI-positive. The regression models predicting venous haemodynamic insufficiency severity score were not statistically significant for any of the MACFIMS predictor variables. The analysis of variance tests showed a significant effect of CCSVI-positive diagnosis on cognitive ability in only one of the 10 MACFIMS outcomes, and that one was in the opposite direction of the tested hypothesis. There was no correspondence between CCSVI diagnosis and depression, as measured by the BDIFS.
CONCLUSIONS: We find no evidence of an association between the presence and severity of CCSVI with cognitive impairment and depression in patients with MS.

There is no correlation between CCSVI and cognitive impairment. some, not me, may say why would you expect correlations with something that does not exist....

In MS, I would say that MRI does show correlations with cognitive impairments......I would not say MRI causes MS, would you?

However something that MRI detects is involved in/the consequence of the problem

Krsmanovi E, Ivkovi M, Lepi T, Stankovi A, Rai Evi R, Din I E. Small internal jugular veins with restricted outflow are associated with severe multiple sclerosis: a sonographer-blinded, case--control ultrasound study. BMC Neurol. 2013 ;13(1):90. [Epub ahead of print]
BACKGROUND: Recent evidence has indicated an association between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis. Small internal jugular veins (IJVs) (with a cross-sectional area of less than 0.4 cm2) have been previously described as difficult to catheterize, and their presence may potentially affect cerebrospinal venous drainage. In this blinded extracranial color-Doppler study we had two principal aims: first, to assess prevalence of CCSVI among Serbian MS patients compared to healthy controls; and second, to assess prevalence of small IJVs (with a CSA <= 0.4 cm2) among MS patients and controls.
METHODS: The sixty seven unrelated patients with clinical isolated syndrome (CIS), relapsing-remitting (RR), secondary progressive (SP) and primary progressive (PP) multiple sclerosis and 21 healthy controls were examined by high-resolution color-Doppler.
RESULTS: The ultrasonographic criteria of CCSVI (according to Zamboni) were positive in 11.9% of the patients and in none of the control subjects. The CCSVI-positive patients had significantly longer disease durations and were significantly more disabled (measured by their Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) scores), but after adjustment for gender and disease duration, CCSVI was not an independent risk factor for multiple sclerosis severity. The small IJVs were found in 28.4% of the patients and 28.6% of the controls. The patients with small IJVs were associated with decreased venous outflow from the brain and presented with longer disease durations and significantly higher EDSS and MSSS scores compared to patients without small IJVs. Analysis adjusted for gender and disease duration showed that small IJV is an independent factor associated with multiple sclerosis severity (EDSS >=6) (adjusted OR = 8.9, 95% CI: 1.8-45.6, p = 0.007). Among patients with small IJVs the 36.84% were also CCSVI positive.
CONCLUSIONS: Both, CCSVI and small IJVs seem to influence or follow MS severity, but only small IJVs turned out to be an independent factor in this study. Thus, small IJVs with restricted outflow, which might be aspects of CCSVI different from the criteria originally described by Zamboni, emerge as a cofactor in the multifactorial pathophysiology of multiple sclerosis.

Canada, Italy and Serbia have been CCSVI hotspots. This study from Serbia reports yet another study showing CCSVI is not causal to MS. The answer to this in pretty clear the original Zamboni concept is not correct...100% Msers with CCSVI and 0% controls. 

Laughlin S, Macgowan CK, Traubici J, Chan K, Khan S, Arnold DL, Marrie RA, Banwell B.

No Evidence for Impairment of Venous Hemodynamics in Children or Young Adults with Pediatric-Onset Multiple Sclerosis. AJNR Am J Neuroradiol. 2013 Jul. [Epub ahead of print]

BACKGROUND AND PURPOSE:Chronic cerebrospinal venous insufficiency is a postulated etiologic factor for multiple sclerosis, but the higher frequency with longer disease duration and progressive disability suggests that chronic cerebrospinal venous insufficiency is secondary to chronic disease. We evaluated the presence of chronic cerebrospinal venous insufficiency in pediatric-onset MS.
MATERIALS AND METHODS:Twenty-six pediatric patients with MS (18 years of age or younger), 26 age-matched healthy controls, and 13 young adults with pediatric-onset MS underwent sonography of the internal jugular, vertebral, and deep cerebral veins. Five venous hemodynamic criteria were assessed, with 2 criteria required for chronic cerebrospinal venous insufficiency. MR imaging studies, performed in the pediatric patients with MS and healthy control groups, included intracranial 2D time-of-flight MR venography and velocity-sensitive phase-contrast sequences. Contrast-enhanced brain MR images were obtained in pediatric patients with MS to further evaluate venous patency. We used paired t tests, Wilcoxon matched pairs, McNemar tests, and exact conditional logistic regression to estimate the association of chronic cerebrospinal venous insufficiency with MS.
RESULTS:Fifty participants (73.5%) had normal ultrasound findings, 15 (23.1%) met 1 venous hemodynamic criterion, and 2 pediatric patients with MS and 1 young adult with pediatric-onset MS met chronic cerebrospinal venous insufficiency criteria. Chronic cerebrospinal venous insufficiency was not associated with MS (odds ratio, 2.41; 95% CI, 0.19-infinity). Demographic and disease characteristics did not differ between the patients with MS meeting chronic cerebrospinal venous insufficiency criteria (n = 3) and those who did not (n = 36; all, P > .05). The mean (SD) MR imaging measures of intracerebral flow did not differ between the 2 pediatric patients with MS meeting chronic cerebrospinal venous insufficiency criteria (0.85 ± 0.11) and healthy controls (0.87 ± 0.16, P = .50); no child demonstrated venous obstruction.
CONCLUSIONS:Chronic cerebrospinal venous insufficiency is rarely observed in children or young adults with pediatric-onset MS. Venous anatomy and flow rates indicate that venous outflow is intact in pediatric patients with MS. Our findings argue against chronic cerebrospinal venous insufficiency as a component of MS aetiology.
Enough already many times do you want to hear the same thing, CCSVI is not causal to MS!, if is not observed in early MS so if present is an secondary age/disease-related event.

CCSVI also continues its downward trend.