Saturday, 30 June 2012

Research: childhood-onset vs. adult-onset MS

EpubPichler et al. Differences and similarities in the evolution of morphologic brain abnormalities between paediatric and adult-onset multiple sclerosis. Mult Scler. 2012 Jun 19.

Background: Paediatric-onset multiple sclerosis (pMS) is MS occurring before the age of 18 years and may present and develop differently from adult-onset MS (aMS). Whether there are also differences regarding the accrual of brain changes is largely unknown.

Methods: This study compared the evolution of the T2- and T1-lesion load (LL), the black hole ratio (BHR), and annualised brain volume change (aBVC) between 21 pMS patients (age at onset: 14.4±2.3 years) and 21 aMS patients (age at onset: 29.4±6.5 years) matched for disease duration (pMS: 1.0±1.8 years; aMS: 1.6±1.7 years, p=0.27). Follow-up was for 4.2±3.7 years in pMS and 3.1±0.6 years in aMS. Clinical comparisons included the course of disability assessed with the Expanded Disability Status Scale (EDSS) score and annualised relapse rate (ARR).

Results: At baseline, pMS and aMS had similar EDSS, T1-LL, BHR, whereas T2-LL was higher in aMS (aMS: 9.2±11.6 ccm; pMS: 4.1±6.2 ccm, p=0.02). The change of T2-LL and T1-LL during the observation period was similar in both groups. At follow-up, disability was lower in pMS (EDSS score in pMS: 0.9±0.9; aMS: 1.7±1.3, p=0.04), despite a significantly higher accrual of destructive brain lesions (BHR in pMS: 23.7±23.7%; aMS: 5.9±4.0%, p=0.02) and a similar rate of brain volume loss.

Conclusion: This study observed a more aggressive disease evolution paralleled by less disability in pMS than in aMS (defined using EDSS) suggests a higher compensatory capacity in pMS. This fact may obscure the need for treatment of pMS patients with disease modifying treatments (DMTs) based solely on clinical observation.


"Not surprising; the younger you are the more likely you are to recover from an insult. The corollary being the older you are the worse you are likely to do due to poor recovery mechanisms. This one of the reasons why we believe progressive MS may be driven by the ageing process."

Research Progression Onset

Tuntuncu M et al. Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis.
Mult Scler. 2012 Jun 26. [Epub ahead of print]

Background:It is unclear if all patients with relapsing-remitting multiple sclerosis (RRMS) ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration-dependent. Some forms of progressive MS (e.g. primary progressive MS (PPMS)) are uncommon in population-based studies. Ascertainment of patients with PPMS from clinic-based populations can facilitate a powerful comparison of age at progression onset between secondary progressive MS (SPMS) and PPMS but may introduce unclear biases.

Objective:Our aim was to confirm that onset of progressive disease course is more relevant to the patient's age than the presence or duration of a pre-progression relapsing disease course in MS.

Methods:We studied a population-based MS cohort (n=210, RRMS n=109, progressive MS n=101) and a clinic-based progressive MS cohort (n=754). Progressive course was classified as primary (PPMS; n=322), single attack (SAPMS; n=112) and secondary progressive (SPMS; n=421). We studied demographics, age-of-progression-onset and time to Expanded Disability Status Scale of 6 (EDSS6). 

Results: Sex ratio (p=0.58), age at progression onset (p=0.37) and time to EDSS6 (p=0.16) did not differ between the cohorts. Progression had developed before age 75 in 99% of patients with known progressive disease course; 38% with RRMS did not develop progression by age 75. Age at progression onset did not differ between SPMS (44.9±9.6), SAPMS (45.5±9.6) and PPMS (45.7±10.8). In either cohort, only 2% of patients had reached EDSS6 before onset of progression.

Conclusions:  Some MSers with RRMS do not inevitably develop a progressive disease course. Onset of progression is more dependent on age than the presence or duration of a pre-progression symptomatic disease course. Moderate disability is sustained predominantly after the onset of a progressive disease course in MS.

Prof G was talking about childhood MS and saying that Young MSers can show better recovery and the flip side was that be he thought that as you get older, you probably get worse at recovery. This study suggests that progression in MS more relates to your age than disease duration so younger people are more likely to start with RRMS prior to SPMS, whereas as if you are older at onset then the risk that disease is PPMS will increase, but this work shows that sometimes progressive MS does not occur. This may relate to the repair process and as we get older we do not repair evvery thing as well as we were younger. We have reported previously that this could related to immune effects and how well macrophages can clear up myelin damage or how we produce growth factors that facilitate recovery of nerve contacts and nerve pathways. This provides us some clues for treatments.

I was looking at some brain tissues of Progressive MSers with DoctorLove and ProfPaul over the last few days and it is easy to see why Immune therapies directed at lymphoid cells may not be that great at treating progressive MS, as the lesions are predominated by microglia and macrophages.

An holistic approach to MS


"I have put this map together to illustrate an holistic approach to MS; i.e. what we need to think about it when considering the services we provide MSers. Have I left anything out? Thanks"

CCSVI Monthly June

Below are this months offerings

Yes. beside the couple of offerings that Prof G has served up there is nothing to report this month. Maybe people just want to see what the clinical studies show. Maybe the scientific interest is waning.
Maybe it is time to kick this last saturday of the month slot into touch. Let's see what July brings.

Friday, 29 June 2012

New blog initiative: grand challenges in MS

After my talk last week, to the MSers at the East London branch of the MS Society, I have been contemplating "life the universe and everything"; that is "life the universe and everything to do with MS". 


It is clear that despite researchers engaging with MSers at several levels there is still a disconnect between MSers and MS Researchers in what their aims, objectives and expectations are. 


It also apparent from an MSer perspective that your aims, objectives and expectations change over time. For example, early in the course of the disease you may want more emphasis placed on relapse prevention and wellness and later in the course of the disease on slowing progression and improving symptoms. Is this correct?


Reconciling these under one umbrella can be difficult. 


I am haunted by the experience of meeting a recently diagnosed young woman at the meeting who did not want to know about the prognosis and course of MS; she was still in denial and clearly was not prepared for bad news. I hope she is okay and getting the support she needs. Information should be drip fed and done at pace  and in an environment determined by you. 


In response to my experience last week I propose posting a series of "Grand Challenges" to MS Researchers; these will be what we consider the most important questions to be answered in the field. I suggest using a MSer-centric perspective and using the phases of the MS as a template: 


Phases of MS

Prevention
Diagnostic phase
Minimal impairment phase
Moderate impairment phase
Severe impairment phase
Terminal phase


I would appreciate proposals around these phases before setting-out our stall. Thanks. 


Survey results: life expectancy




"The results are interesting; I need to contemplate them."


"It is clear that life expectancy is an important issue and that neurologists should choose the correct moment to discuss this information with MSers. It could be viewed as bad news are simply stating the obvious. The important message is that most of the data on reduced life expectancy in MS comes from the pre-DMT era and that we now have data showing that DMTs impact on survival is very good and should make it easier to put this information into context. What do you think?"


"I wonder if NICE will consider this information when it reassesses the cost-effectiveness of interferon-beta in the future? I sincerely hope so."


Previous post of interestECTRIMS 2011: IFNbeta and 21-yr survival - Multiple Sclerosis ...18 Feb 2012; ECTRIMS 2011: IFNbeta and 21-yr survival. Goodin et al. Predictive value of baseline and short-term outcomes on mortality in multiple sclerosis: data from the Interferon Beta-1b 21-Year Long-Term Follow-Up Study.

Research: MS and stroke

EpubZöller et al. Risk of subsequent ischemic and haemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden. BMC Neurol. 2012;12(1):41.

Background: Certain immune immune-mediated diseases (IMD) have been associated with increased risk for cardiovascular disorders. 

Aim: The aim of this study was to examine whether there is an association between 32 different IMD and first hospitalization for ischemic or hemorrhagic stroke. 

Methods: All individuals in Sweden hospitalized with a main diagnosis of IMD (without previous or coexisting stroke), between January 1, 1987 and December 31, 2008 (n=216,291), were followed for first hospitalization for ischemic or hemorrhagic stroke. The reference population was the total population of Sweden. Adjusted standardized incidence ratios (SIRs) for ischemic and hemorrhagic stroke were calculated.

Results: Totally 20 and 15 of the 32 IMD studied, respectively were associated with an increased risk of ischemic or hemorrhagic stroke during follow-up. Overall risk of ischemic and hemorrhagic stroke during the first year after hospitalization for IMD was 2.02 (95% CI 1.90-2.14) and 2.65 (95% CI 2.27-3.08), respectively. The overall risk of ischemic or hemorrhagic stroke decreased over time, from 1.50 (95% CI 1.46-1.55) and 1.83 (95% CI 1.69-1.98), respectively, after 1-5 years, to 1.29 (95% CI 1.23-1.35) and 1.47 (95% CI 1.31-1.65), respectively, after 10+ years. Risk of hemorrhagic stroke was [greater than or equal to] 2 during the first year after hospitalization for seven IMD: ankylosing spondylitis (SIR=8.11), immune thrombocytopenic purpura (SIR=8.60), polymyalgia rheumatica (SIR=2.06), psoriasis (SIR=2.88), rheumatoid arthritis (SIR=3.27), systemic lupus erythematosus (SIR=8.65), and Wegener's granulomatosis (SIR=5.83). Risk of ischemic stroke was [greater than or equal to] 2 during the first year after hospitalization for twelve IMD: Addison's disease (SIR=2.71), Crohn's disease (SIR=2.15), Grave's disease (SIR=2.15), Hashimoto's thyroiditis (SIR=2.99), immune thrombocytopenic purpura (SIR=2.35), multiple sclerosis (SIR=3.05), polymyositis/dermatomyositis (SIR=3.46), rheumatic fever (SIR=3.91), rheumatoid arthritis (SIR=2.08), Sjogren's syndrome (SIR=2.57), systemic lupus erythematosus (SIR=2.21), and ulcerative colitis (SIR=2.15).

Conclusions: Hospitalization for many IMD is associated with increased risk of ischaemic or haemorrhagic stroke. The findings suggest that several hospitalized IMD are linked to cererobrovascular disease.



EpubChristiansen CF. Risk of vascular disease in patients with multiple sclerosis: a review. Neurol Res. 2012 Jun 16.

BACKGROUND: Vascular dysfunction and shared risk factors may lead to an increased risk of arterial and venous vascular disease in MSers. 

AIM: The aim of this review was to describe studies examining the risk of vascular diseases in MSers.

METHODS: A PubMed search combined with review of reference lists and table of contents revealed eight relevant studies describing the occurrence or risk of one or more vascular diseases.

RESULTS: One cohort study and three cross-sectional studies described stroke occurrence in 898 to 13 963 MSers. MS was associated with an increased risk of stroke and cerebrovascular diseases compared with the general population and other hospitalized patients, particularly within the first years after MS diagnosis and in young and middle-aged MSers. In contrast, data are conflicting with regard to the association between MS and coronary artery disease including myocardial infarction. Cross-sectional studies found a lower prevalence of coronary artery disease in MSers, while the only cohort study found an increased risk within the first year after MS diagnosis only. MS was, however, associated with an increased risk of venous thromboembolism, including deep venous thromboembolism and pulmonary embolism, in particular within the first years after MS diagnosis.

DISCUSSION: MS is associated with an increased risk of vascular diseases within the first years after a firs time MS diagnosis compared with the general population. The risk declines thereafter, but remains elevated for stroke and venous thromboembolism. Shared risk factors, linked pathogenesis, and bias may contribute to the association.

"I learn something new about MS everyday of the week; the information about MSers being at increased risk of stroke is new. I wonder why? Could it be due to inflammation increasing the ability of the blood to clot. i.e. being pro-coagulant? This much be telling us something about the pathogenesis of MS. What?"

"It makes sense why MSers are at increased risk of having deep vein thromboses and pulmonary emboli (clots to the lungs); being less mobile puts you at increased risk of this complication."

Thursday, 28 June 2012

Research: skin reactions to glatiramer acetate

Mayorga et al. Immunological mechanisms underlying delayed-type hypersensitivity reactions to glatiramer acetate. Ann Allergy Asthma Immunol. 2012;109(1):47-51.

BACKGROUNDDelayed-type hypersensitivity (skin allergy reaction) to glatiramer acetate is rare, and the underlying immunological mechanisms are not completely understood.

OBJECTIVE: To study the immunologic response in 2 patients with multiple sclerosis who developed maculopapular exanthema (skin rash, with bumps) related with the administration of glatiramer acetate.

METHODS: The allergologic study included general blood tests, viral serologic tests, and skin tests (patch and intradermal tests). The immunologic study was performed in skin biopsy specimens by immunohistochemistry and in the peripheral blood by flow cytometry and the lymphocyte transformation test.

RESULTS: Skin test results were negative in both patients, and the diagnosis was confirmed by a drug provocation test. The evaluation of the acute phase showed an increase in the percentage of CD8 T lymphocytes (>50%) and the percentage of cells expressing skin-homing receptor (cutaneous lymphocyte-associated antigen) (>70%) and chemokine receptors (CCR4 and CXCR3) at T1. A positive proliferative response was observed in T lymphocytes (stimulation index [SI] = 3.5 in patient 1 and 3.59 in patient 2), especially the CD8(+) subpopulation (SI = 5.5 and 4.6 in patients 1 and 2, respectively), and NK lymphocytes (SI = 3.9 and 8.5 in patients 1 and 2, respectively) after glatiramer acetate stimulation.

CONCLUSION: This study demonstrates the important role of T(H)1 cells expressing skin-homing receptors in delayed-type hypersensitivity reactions to glatiramer acetate. A lymphocyte transformation test revealed a specific glatiramer acetate recognition by T lymphocytes and NK lymphocytes.


Skin tests for allergies are usually immediate reactions within minutes and causes itching and swelling and reddening, which is a type I allergic reaction a type IV reaction is delayed taking 24-48 hours to manifest itself. This causes swelling and reddening.

Glaterimer acetate is a random copolymer of 4 amino acids. The original idea was that the four amino acids were selected as they were present in myelin basic protein (MBP) and it was thought that autoimmunity to myelin basic protein was the problem in MS. Glaterimer acetate somehow mimicked MBP and switched off the immune response.

The problem with this, is the logic. In my mind even if MS is an autoimmune disease, MBP is not a very good candidate to be an autoimmune target. Why? It is found in both CNS and peripheral nerve and MS is essentially a disease of the CNS. When you look not many cells react with MBP. If they do you can get a poly neuropathy (that affect peripheral nerves). I think the reason why it was studied so much in the 1970s was because it was the only myelin sheath protein that could be purified and made as it was water soluble and so could be used in cell culture. The CNS -specific proteins were either only fat soluble and so could not easily be purified or was present in only very minor amounts and so difficult to study until the 1980s and 1990s when these molecules could be syntheitically made.

What this study shows that some times glaterimer acetate can cause an allergic reaction. This is manifest by skin reactions in the injection site. It this concoction was so similar to MBP, as was claimed originally, you would expect these individuals to get some form of encephalitis (Brain swelling). They didn't so this not likely to be how it work. 

However since the 1970s when glaterimer acetate was first made, it has been reported to work via so many mechanisms. These follow the flavour of the month/year with regard to mechanism of control og the immune response, that we will probably not know how it works. My guess is it just swamps the antigen presenting cells with peptide that can not function properly.

CoI: None

Research: lower risk of cancer in MS

Epub: Kingwell E et al. Cancer risk in multiple sclerosis: findings from British Columbia, Canada.
Brain. 2012 Jun 21.

Background: Findings regarding cancer risk in MSers have been inconsistent and few studies have explored the possibility of diagnostic neglect. The influence of a relapsing-onset versus primary progressive course on cancer risk is unknown. 

Objective: This study examined cancer risk and tumour size at diagnosis in a cohort of MSers compared to the general population and we explored the influence of disease course. 

Methods: Clinical data of patients with MS residing in British Columbia, Canada who visited a British Columbia MS clinic from 1980 to 2004 were linked to provincial cancer registry, vital statistics and health registration data. MSers were followed for incident cancers between onset of MS, and the earlier of emigration, death or study end (31 December 2007). Cancer incidence was compared with that in the age-, sex- and calendar year-matched population of British Columbia. Tumour size at diagnosis of breast, prostate, colorectal and lung cancers were compared with population controls, matched for cancer site, sex, age and calendar year at cancer diagnosis. 

Results: There were 6820 MSers included, with 110 666 person-years of follow-up. The standardized incidence ratio for all cancers was 0.86 (95% confidence interval: 0.78-0.94). Colorectal cancer risk was also significantly reduced (standardized incidence ratio: 0.56; 95% confidence interval: 0.37-0.81). Risk reductions were similar by sex and for relapsing-onset and primary progressive MS. Tumour size was larger than expected in the cohort (P = 0.04). 

Conclusions: Overall cancer risk was lower in MSers with multiple sclerosis than in the age-, sex- and calendar year matched general population. The larger tumour sizes at cancer diagnosis suggested diagnostic neglect; this could have major implications for the health, well-being and longevity of MSers.

Cancer cells
"This study is important for several respects. MS differs from other systemic autoimmune diseases, such as rheumatoid arthritis, that is associated with a higher risk of cancer than the general population. The thinking is that inflammation is one of the drivers of cancer development, by its effect on DNA. More importantly is the implications this data has for pharmocovigilance, i.e. monitroing whether or not DMTs are associated with higher risks of cancer. A lot of the studies compare MSers to the general population; this is clearly not the correct comparator. We would have to do formal studies to assess cancer risk from the newer DMTs; the studies will have to compared exposed MSers with a control group of non-exposed MSers, for example those on IFNbeta or GA or not on any treatment."


Wednesday, 27 June 2012

Research: can eye movements determine fatigue

EpubFinke et al. Dynamics of saccade parameters in multiple sclerosis patients with fatigue. J Neurol. 2012 Jun.

Background: Fatigue is one of the most frequent and disabling symptoms in MS. The mechanisms underlying fatigue remain poorly understood and objective measures to quantify fatigue are unavailable to date. 


Objective: To investigate whether analysis of ocular motor movements can provide diagnostic information in MSers with fatigue, 37 MSers (21 female, age 44 ± 9 years) and 20 age- and gender-matched healthy controls were prospectively recruited. Fatigue was assessed with the fatigue severity scale (FSS). 25 MSers were fatigued (defined as FSS ≥4) and 12 MSers were not. Subjects performed a saccadic fatigue task that required execution of uniform saccades over a period of 10 min. 

"Saccadic eye movements are rapid movements from side-to-side or up-and-down; the type of movements that are used to watch tennis. In contrast pursuit movements are slow eye movements to  track an object. The following video demonstrates how we measure saccadic eye movements."


Saccadic amplitude (size), latency (time from stimulus) and peak velocities (speed) during the task were analysed and selected parameters analysed. 

Results: Fatigued MSers showed a significantly larger decrease of saccadic peak velocity and amplitude when compared to MSers without fatigue and healthy controls. Furthermore, fatigued MSers showed significantly longer latencies compared to non-fatigued MSers and healthy controls. Peak velocity change over time and latencies correlated with FSS scores. The best parameter to discriminate between fatigued and non-fatigued patients was peak velocity change over time. 

Conclusions: Assessment of peak velocity, amplitude and latency in a saccade fatigue task is a promising approach for quantifying fatigue in MSers.

"This study is important as it may allow us  to use eye movements to test drugs that target fatigue. I wonder what fampridine will do to eye movements. Below are two YouTube videos on the affect of fampridine on walking speed; imagine these videos being replaced by eye movement ones. Exciting? I think so!"

Fampridine responder 1

Fampridine responder 2

Research: anxiety, depression and fatigue are common in PwMS and tend to cluster together.

Epub: Wood B et al. Prevalence and concurrence of anxiety, depression and fatigue over time in multiple sclerosis. Mult Scler. 2012 Jun 22.


Background: Anxiety, depression and fatigue are commonly reported by persons with multiple sclerosis (PwMS).

Objectives: We estimated the prevalence of each factor in a representative sample of PwMS, and in subgroups defined by age, sex and disease duration, at cohort entry and over time. We further examined whether and how these factors clustered together.

Methods: A population-based longitudinal cohort of 198 PwMS was followed 6-monthly for 2.5 years. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety (cut-point >7) and depression (>7) and the Fatigue Severity Scale (FSS) to measure fatigue (≥5).

Results: At cohort entry, prevalence of anxiety was 44.5% (95%CI 37-51%), depression 18.5% (95%CI 12.6-23.4%), and fatigue 53.7% (95%CI 47-61%). Fatigue was more common in males than females (RR 1.29, p=0.01), with attenuation of the effect after adjustment for Expanded Disability Status Scale (adjusted RR 1.18, p=0.13). Prevalence of anxiety (but not depression or fatigue) decreased by 8.1% per year of cohort observation (RR 0.92, 95%CI 0.86-0.98, p=0.009), with the effect more pronounced in women (14.6%, RR 0.85, 95%CI 0.79-0.93, -<0.001) than men (2.6%, RR 1.03, 95%CI 0.90-1.17, p=0.77). There was no apparent seasonal variation in the prevalence of any of the three factors (p>0.05). All three factors occurred contemporaneously at cohort entry in a higher proportion of the cohort than expected by chance (p<0.001).

Conclusions: Anxiety, depression and fatigue are common in PwMS and tend to cluster together. The findings are important for clinical management of PwMS and to the exploration of possible shared causal biological pathways.




The conclusions say it all!

Tuesday, 26 June 2012

Trial (TEMSO) of Teriflunomide


Background:The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients.
Objective:The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups.
Methods:RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately.
Results:Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance.
Conclusion:The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.

The TEMSO study was reported as a news flash where it was claimed that teriflunomide was benefical in most MSers and the full trial has been published and showed that both 7 mg and 14 mg once-daily oral doses of teriflunomide significantly reduced the annualized relapse rate (ARR) (relative risk reductions: 31.2% (p=0.0002) and 31.5% (p=0.0005)) and 12-week confirmed disability progression (hazard ratio reductions: 23.7% (p=0.0835) and 29.8% (p=0.0279)) compared with placebo .

We have reported on the TOWER teriflunomide study and other studies involving teriflunomide. In TOWER, a double-blind, multi-center trial enrolled 1,169 MSers and compared once-daily treatment with either 7 mg (There was a 22% reduction in relapse) or 14 mg (there was about a 35% reduction in relapse) oral teriflunomide against placebo, with a modest reduction of relapses at the 14mg dose.

The objective of current report was to determine whether the effects of both doses of teriflunomide on ARR and disability progression were demonstrated consistently in a range of pre-specified patient subgroups from the TEMSO study related to demographic and disease characteristics at baseline.

                                   Teriflunomide structure


Although there was no difference in relapse rate between placebo and secondary progressive MSers this would be expected as the number of relapses in SPMS is reduced. However there was some influence in the rate of progression in this group.


This study shows there is not one group of MSers (based on sex, age, EDSS status, Location, number of relapses etc.) who benefit over another group it works as well, or not, in all groups.

This drug is being positioned to compete against beta interferons and glaterimer acetate as it as about as safe and effective as the compounds mentioned but has the advantage of been oral.


CoI: None. Prof G multiple

Case Report: Loss of leg fat through bad injection technique

EpubWeise et al. Lobular panniculitis and lipoatrophy of the thighs with interferon-ß1a for intramuscular injection in a patient with multiple sclerosis. J Clin Neurosci. 2012 Jun 19.

Background: MSers may experience severe local inflammatory skin reactions during disease-modifying therapy with subcutaneously injected interferon-β (IFN-β). It is common clinical practice to switch those patients to an intramuscularly administered formulation, where severe local skin reactions have not been described. 

Case report: This is a case report of a 42-year-old woman with stable relapsing-remitting MS, who was switched from subcutaneously to intramuscularly injected IFN-β1a due to abdominal skin necroses and slight multifocal lipoatrophy (loss of fatty tissue under the skin). After two years of complication-free therapy with intramuscular IFN-β1a, the MSer slowly developed painful lobular panniculitis (inflamed nodules of fat under the skin) and severe lipoatrophy of both lateral thighs. A careful diagnostic workup identified misguided subcutaneous injections due to a wrong injection angle as the most plausible cause. Upon correction of her injection technique, pain and skin reddening resolved, while her disfiguring lipoatrophy was irreversible. 

Severe lipoatrophy post interferon-beta injection
Severe skin necrosis post interferon-beta injection
Conclusion: This report should enhance awareness that severe skin adverse effects may also occur, although rarely, with IFN-β for intramuscular injection. Early recognition and correction of the injection technique may help to prevent severe complications.

"Fortunately these severe skin (ulcers or necrosis) and subcutaneous (lipoatrophy) complications of interferon-beta injections are seldom seen these days. Improved injection technique, smaller needles and better education have made complications very rare. Nevertheless minor reactions are still a problem and MSers don't like them. Hopefully the emergence of oral treatments will allow MSers to switch to better tolerated drugs."

Research: SWI venography

EpubBeggs et al. Sensitivity and specificity of SWI venography for detection of cerebral venous alterations in multiple sclerosis.Neurol Res. 2012 Jun 16.

OBJECTIVES: To determine the sensitivity and specificity of decreased venous vasculature visibility (VVV) on susceptibility-weighted imaging (SWI) venography in MSers versus controls, and to compare this with assessment of whole brain atrophy.

METHODS: Forty MSers and 22 controls without known central nervous system (CNS) disease who had non-specific white-matter (WM) lesions were imaged on a 3T GE scanner using SWI venography. Apparent total venous volume (ATVV) and increased average distance from vein (DFV) were calculated for various vein mean diameter categories: <0.3, 0.3-0.6, 0.6-0.9, and >0.9 mm. Data was analysed using quite complex statistical techniques.

RESULTS: Analysis identified 0.3-0.6 mm venous relative fraction (VRF) and  distance from vein as useful metrics. ROC analysis results in initial sample of 40 MS patients and 22 controls were (sensitivity, specificity): 0.3-0.6 mm VRF (95.0%, 100.0%); DFV (100.0%, 100.0%); and NBV (82.5%, 68.2%). The results in validation sample were: 0.3-0.6 mm VRF (92.9%, 75.0%); DFV (100.0%, 100.0%); and NBV (78.6%, 75.0%).

DISCUSSION: Altered VVV indices on SWI venography showed high sensitivity and specificity for MS. The value of SWI venography for diagnosis of MS has to be further tested at early disease stages and against patients with other neurologic diseases.




"This study suggests that detecting decreased venous vasculature visibility (smaller veins) can distinguish MSers from healthy controls. It is interesting that MSers have a reduced venous volume; if there was an obstruction to flow, as proposed with the CSSVI hypothesis, you would expect an increased volume due to distension of the veins."

"Blood volume and flow is proportional to the tissue requirements of oxygen and glucose; i.e. reduced brain volume less blood flow hence reduced venous volume. As MS is associated with brain atrophy, from nerve cell and axonal loss, you would expect MSers to have reduced blood flow and venous volumes. Therefore the correct comparator for this study would be another disease control group, of a similar age, that has a similar degree of brain atrophy. Normal controls are a poor comparator group. Finally, this is a small study and hence will need to be reproduced."

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Anonymous said...
Not a comment but an important question, foremost to the research team in relation to the article posted on http://teachneuro.blogspot.de/2012/05/spurious-elevations-of-vitamin-b12-with.html

It is VERY likely that I am one of those people with thrice as high Vit B 12 levels than normal (blood tests for over 3 years). Nobody can explain why. From my own research I strongly suspect pernicious anemia because I've got 2 disorders linked to that (I also have iron deficiency which coincided with the onset of RRMS).

So my question is: which tests should I suggest to my GP next time I see him in order to know what's going on for sure? Since I've got more than one autoimmune disorder it is imperative to tackle a faulty Vit B metabolism, methinks.

Your thoughts on this would be GREATLY appreciated - I've hit a brick wall so far with my doctors.
Gavin Giovannoni said...
Re: "So my question is: which tests should I suggest to my GP next time I see him in order to know what's going on for sure? Since I've got more than one autoimmune disorder it is imperative to tackle a faulty Vit B metabolism, methinks."

I suggest you make your GP aware of the article in the NEJM and he/she should screen you for auto-antibodies associated with pernicious anaemia and/or do a Schilling's test. The latter is a specialised test done by haematologists to assess the absorption of vB12.

Please note this blog is not the forum for personal medical advice. So I can't give you anything more specific.
Anonymous said...
Dear Prof

thanks a lot, that's exactly what I needed to know - helps a lot. I apologize for this very me-centred question but I had no choice in this specific case.
Tony Fonda said...
Dear Gavin, Mouse,

I have a quick question that has been puzzling me lately.

I am trying to understand Pharma's marketing material.

When Company X says that its DMD Y cuts down on relapses by 50% per annum:

Does it mean that:

if 2 people with MS are taking this drug (1 relapse per person per year), one will relapse as usual and the other will not.

OR

the same 2 people (1 relapse per person per year), will have 0.5 relapse per year after taking the drug (i.e. a relapse every 2 years)?

In other words, I am wondering if the 50% relapse reduction rate is an average (or median) or a sum or positive/negative obs ?

Tony
MouseDoctor said...
Dear Tony

You personally can not have half a relapse (0.5) so in this case it would be one relapse every two years as you say

In terms of the 50% reduction in relapse rate, this means that you have half as many relapses as would occur if you were not having the drug.

So if the Annual relapse rate on drug was 0.25 compared to 0.5 on placebo. It means that on average people on placebo have one relapse every two years and the person on the drug had on average on relapse every 4 years. As you say this is an average so the middle mark and within any trial some people to better than the average and some people to worse.
Tony Fonda said...
Thanks Mouse.

But I must say that this does not really address my question.(probably because I didn't phrase it properly).

If you have 4 balls in a box, and you take 2 balls: you are left with 50% of the balls.

If you cut each of the 4 balls in half, you are left with 50% as well?

so what does 70% reduction on Tysabry mean? NO RELAPSE for some and full relapse for the rest, or reduction for all on an equal basis?

I logged a formal question to Biogen Idec (both USA and UK) this afternoon. Awaiting their replies (ought to come from the statisticians who analysed the data of the clinical trials...)
MouseDoctor said...
so what does 70% reduction on Tysabry mean? NO RELAPSE for some and full relapse for the rest, or reduction for all on an equal basis?

Yes, no relapse of full relapse there is nothing in between in this context. You have a relpse or you do not. There is nothing about a mild or severe relapse in this context

If you have a 70% reduction of relapse it means you are 70 percent less likely to have a relapse that would occur if you took nothing=placebo

So if 100 people were taking tysabri only 30 would relapse compared to a 100 taking placebo.

The beneficial effect is statisitical and not impirical and not on an equal basis

However if you relapsed does this means the drugs failed... well not necessarily as you may have been destined to have two or more relapese as the drug got rid of one or two etc. of them. Likewise it could be less severe than it would have been
Tony Fonda said...
Thanks again Mouse you're the best.

Let's wrap-up: I did not mean that you could have a partial (or light) relapse as it is an indivisible event. Either it happens or not.

But as you know, MS is a long term experiment.
You are answering me as if our horizon is 1-2 years. but how about 5-6 years? then no need to talk about decimals any more .

"If you have a 70% reduction of relapse it means you are 70 percent less likely to have a relapse that would occur if you took nothing=placebo

So if 100 people were taking tysabri only 30 would relapse compared to a 100 taking placebo."

Over a time frame of 5 years, does the above means that:

I) all tysabri takers will have a total reduction in relapses over 5 years of 70% - on an equal basis.

OR

II) some people will have a reduction of 100% and the others will relapse as frequently as needed to get to a population average of 70%?

This second scenario clearly excludes NABs, SPMS, drug holidays... as those extreme observations will render the average irrelevant.

again, I appreciate the technicalities of this question and will post if I ever hear back from the manufacturer.
MouseDoctor said...
The information comes from clinical trials these last no more than 3 years so there is no real answer for 5 years.
Tony Fonda said...
Can I conclude that 70% were relapse free during the 3 year time frame?

Any post-marketing study on these guys with a longer horizon?
Anonymous said...
i've always understood the relapse reduction to be an aggregate for all patients:

When there is a 70% relapse reduction with a drug
-some patients may have 0 relapses
-some may have fewer relapses
-a few may stay the same
-and a few may even get worse

The 70% is for the group as a whole. We need to know many were in each of the above categories. Perhaps half the patients fell in the 0 relapses category and 5% of the patients got worse
Tony Fonda said...
Precisely!

Neither you nor me are averages.

An average may work for a regulator, a manager or an investor.

But as we know, I am an individual and not an average.

The "look through" data analysis should be published if it has not already.... I wonder if there are statistical tables out there?
Tony Fonda said...
Biogen-Idec return to me after 48 hours with this answer:

"We investigated this situation for you and can tell you that Tysabri has cut ARR by 68%".

Then I called to understand more and was outraged by their reply:
"We can not and will not disclose any more information"

I calmly explained to them that this information is needed in my decision making as it is a matter of life or death - and asked them to provide me the info within the next 10 days or I will file a claim in the UK courts.

And I will. I am not playing poker games.

To be continued....
Roshni said...
Good! We should have complete information clearly laid out and I think treating neurologists need to have it. An average is not enough
MouseDoctor said...
You can read the actual figures in phase III trial the paper by Polman et al. As you will read it was based on a two year study.

http://www.nejm.org/doi/full/10.1056/NEJMoa044397

"After one year of treatment, natalizumab reduced the annualized rate of relapse to 0.26 relapse per year, as compared with 0.81 relapse per year in the placebo group (P<0.001) (Table 2). The 68 percent relative reduction in the annualized rate of relapse produced by natalizumab was maintained at two years (P<0.001)".

"The proportion of relapse-free patients was significantly higher in the natalizumab group than in the placebo group at one year (77 percent vs. 56 percent, P<0.001) and at two years (67 percent vs. 41 percent, P<0.001)".

If you are considering Tysabri please read the posts on PML.
MouseDoctor said...
The problem with post-marketing data is that there is no placebo arm and generally no natural history data.

Remember if you are thinking about Tysabri you need to know your JC virus status so taht you can asses the risks of taking the drug, which increase alot if you go past the 24 month period.

If you look at the Polman paper you can see the neurological landscape changing over time.
Roshni said...
That NEJM paper has all the figures
So the Biogen person who said 'we cannot and will not disclose ...' was very uninformed
Tony Fonda said...
Dear Mouse,

I have done good progress on this.

Caroline Wilding (head of the medical information distribution dept) reached out and agreed to share the post marketing data.

I am potentially looking at 6 years of history for up to 80,000 users.

That should allow us to cluster in subgroups to understand more how Tysabri affects different patient-types.

One hick: I am not a medical professional and not allowed to received the data directly.
Can you kindly reach out to Caroline requesting the tape? She agreed to provide it : caroline.wilding@biogenidec.com

I will happily run the stats in Matlab once I get the tape.

Thanks for your help.

Tony
Anonymous said...
Well done Tony!

We are the 99 percent!!!
MouseDoctor said...
Dear Tony
I suspect that I am not considered a medical professional either.

Write to Prof G
(g.giovannoni@qmul.ac.uk) with details of the conversation that you have had with Caroline including what she said she would supply and the details of what you have requested and a contact email.

I don't understand what you mean by tape and in terms of looking at subtypes. Tysabri is licenced for treatement of RRMS there is a study in progressive MS ongoing.