Sunday, 30 June 2013

EBV infection precedes to onset of MS: articles of Interest (16)

Is EBV the cause of MS? #MSBlog #MSResearch

"Having been here from the beginning I incorrectly assume that all our readers would have gone back and read all our previous posts. How could they have there are now over 2600 to read. This paper has been covered before, but it is a very important paper. It shows that in EBV-negative people who go onto to develop MS, 100% of MSers EBV positive prior to the onset of MS compared to only 36% of control subjects. Why is this important? To claim that EBV causes MS you have to show a clear temporal pattern, i.e. of being exposed to the virus before the onset of  the disease. I have also covered causation theory on this blog and this is one of the criteria you need to fulfill to claim that X causes Y, in this case EBV causes MS."

"I personally think there is enough evidence to claim that EBV causes MS. To prove this we need to show that if you prevent people being infected with the virus we prevent MS. This is easier said than done and can only really be done with an EBV vaccination study at a population level. Another option is to target EBV, with anti-viral drugs, and if this reduces MS disease activity it will support EBV as the cause of MS. This is the primary aim of the Charcot Project."

Levin et al. Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol. 2010 Jun;67(6):824-30.

Objective: To determine whether MS risk increases following primary infection with the Epstein-Barr virus (EBV): 

Methods: A nested case-control study, was conducted, including 305 individuals who developed MS and 610 matched controls selected among the >8 million active-duty military personnel whose serum has been stored in the Department of Defense Serum Repository. Time of EBV infection was determined by measuring antibody titers in serial serum samples collected before MS onset among cases, and on matched dates among controls. 

Results: Ten (3.3%) cases and 32 (5.2%) controls were initially EBV negative. All of the 10 EBV-negative cases became EBV positive before MS onset; in contrast, only 35.7% (n = 10) of the 28 controls with follow-up samples seroconverted (exact p value = 0.0008). 

Conclusions: The investigators' concluded that MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection.

"Did you know that almost all highly-effective DMTs target B-cells the cells where EBV resides? I have been trying for years to get EBV biomarkers added into clinical trials to test the hypothesis that these drugs are working via an anti-EBV mechanism. Unfortunately, it seems as if Pharma are not interested in proving their drugs work in this way. Why would they? This would simply lower the hurdle and open the door for anti-viral studies.Why would we want to kill the goose that is laying the golden eggs?"

Remyelinating fish

Epub: Chung et al. Generation of demyelination models by targeted ablation of oligodendrocytes in the zebrafish CNS. Mol Cells. 2013 Jun 25.

Demyelination is the pathological process by which myelin sheaths are lost from around axons, and is usually caused by a direct insult targeted at the oligodendrocytes in the vertebrate central nervous system (CNS). A demyelinated CNS is usually remyelinated by a population of oligodendrocyte progenitor cells, which are widely distributed throughout the adult CNS. However, myelin disruption and remyelination failure affect the normal function of the nervous system, causing human diseases such as multiple sclerosis. In spite of numerous studies aimed at understanding the remyelination process, many questions still remain unanswered. Therefore, to study remyelination mechanisms in vivo, a demyelination animal model was generated using a transgenic zebrafish system in which oligodendrocytes are conditionally ablated in the larval and adult CNS. In this transgenic system, bacterial nitroreductase enzyme (NTR), which converts the prodrug metronidazole (Mtz) into a cytotoxic DNA cross-linking agent, is expressed in oligodendrocyte lineage cells under the control of the mbp and sox10 promoter. Exposure of transgenic zebrafish to Mtz-containing media resulted in rapid ablation of oligodendrocytes and CNS demyelination within 48 h, but removal of Mtz medium led to efficient remyelination of the demyelinated CNS within 7 days. In addition, the demyelination and remyelination processes could be easily observed in living transgenic zebrafish by detecting the fluorescent protein, mCherry, indicating that this transgenic system can be used as a valuable animal model to study the remyelination process in vivo, and to conduct high-throughput primary screens for new drugs that facilitate remyelination.

Zebrafish as increasing being used as it means use of less animals in research. The larval forms are transparent so you see things you can label structures with green fluorescence protein from Jellyfish or mCherry a monomeric red fluorescent protein from disc coral.

This study has devised a novel way to demyelinate axons by having an oligodendrocyte toxin that can be switched on and off. As is common in mammals the default pathway is rapid repair. This system may be used to study repair. 

It is a shame that many drugs that get into the brain are like brick dust when it comes to dissolving in water, but maybe there is space for a new FishDoctor on the blog?

Gilenya affecting the processes driving progression?

Alzheimer's disease (AD) as a neurodegenerative brain disorder is the most common cause of dementia. To date, there is no causative treatment for AD and there are few preventive treatments either. The sphingosine-1-phosphate receptor modulator FTY720 (fingolimod) prevents lymphocytes from contributing to an autoimmune reaction and has been approved for multiple sclerosis treatment. In concert with other studies showing the anti-inflammatory and protective effect of FTY720 in some neurodegenerative disorders like ischemia, we have recently shown that FTY720 chronic administration prevents from impairment of spatial learning and memory in AD rats. Here FTY720 was examined on AD rats in comparison to the only clinically approved NMDA receptor antagonist, Memantine. Passive avoidance task showed significant memory restoration in AD animals received FTY720 comparable to Memantine. Upon gene profiling by QuantiGeneplex, this behavioral outcomes was concurrent with considerable alterations in some genes transcripts like that of Mitogen Activated Protein Kinases (MAPKs) and some inflammatory markers that may particularly account for the detected decline in hippocampal neural damage or memory impairment associated with AD. From a therapeutic standpoint, our findings conclude that FTY720 may suggest new opportunities for AD management probably based on several modulatory effects on genes involved in cell death or survival.

Whilst this may seem inherently uninteresting to MSers as this is about studies in animals related to Alzheimer's disease, the interesting thing is that it appears to be influencing a degenerative condition which is not typically associated with autoimmunity. So does this mean that fingolimod and or siponimod may be useful for progressive MS. The studies are ongoing.

Saturday, 29 June 2013

Alemtuzumab and uncertainty: are you ready for it?

Uncertainty: how used to it are you? It may get worse before it gets better. #MSBlog #MSResearch

"Some of you will be asking, after the euphoria of yesterday,how will Alemtuzumab play out in the field? This will depend on a risk benefit assessment; the risks of the drug, the benefits of the drug and the risk of having MS. The problem with risks and benefits is that at an individual level they are difficult to define; we talk in probabilities. The following perspective in this week's NEJM captures the issue of uncertainty very well. The paradox is that alemtuzumab offers more certainty about MS, but creates uncertainty about the potential complications. Despite this I think the field is ready to adopt a game-changer. Do you?"

Alexander et al. Uncertainty — The Other Side of Prognosis N Engl J Med 2013; 368:2448-2450.


..... has been a resurgence of interest in prognosis. This interest has been driven by a recognition that prognosis plays a central role in medical decision making, from counseling outpatients about stopping cancer screening to making decisions with patients' surrogates about withdrawal of life support in intensive care units....

.... Patients say that understanding prognosis is important for making life choices, such as engaging in financial planning, arranging custodial care, and deciding when it's important for long-distance family members to visit....

.... Despite a proliferation of data about prognosis and life expectancy, our best estimates still carry a high degree of uncertainty.....

.... no matter what we do, there will always be some uncertainty in prognosis.....
.... uncertainty is difficult for patients and their families to deal with. For patients, not knowing what the future will bring is psychologically difficult. Worrying about the future may impede their ability to enjoy the present. They may be consumed by trying to figure out whether things are getting better and therefore become hyperaware of any physical changes that occur. Families may spend a great deal of time acquiring information in an effort to learn more about what the future will bring and may focus excessively on the medical details. For both patients and family members, anxiety may increase.....

.... The first task is to normalize the uncertainty of prognosis. We believe this step is important because it seeks to reset expectations. Patients are bombarded in the lay media with the notion that high-tech advances in imaging and genomics have resulted in definitive answers to clinical questions such as prognosis. Clinicians should be honest with patients about the boundaries of knowledge, saying, for example, “I understand that you want more accurate information about the future. The reality is that it's like predicting the weather — we can never be absolutely certain about the future. I wish I could be more certain.”....

..... The second task is to address patients' and surrogates' emotions about uncertainty, acknowledging how difficult it may be for them not to know. Responding to emotional distress is an important goal in itself, but it may also have important consequences for medical decision making. Studies suggest that patients make poor decisions when they are anxious or experiencing strong emotions. Clinicians can invite patients to discuss these emotional reactions, saying for example, “It is tough not knowing what the future is going to bring.”....

..... The third task is to help patients and families manage the effect of uncertainty on their ability to live in the here and now. The search for certainty may impede the ability of patients and family caregivers to live in the present. They may believe that if they only knew what the future would bring, their decision making would be easier — they wouldn't make mistakes or have to worry about regret. Patients and families may feel trapped ruminating about a future they cannot predict with complete accuracy or control. Continually asking and worrying about that future inhibits their ability to enjoy the time they have now. Rather than view uncertainty as part of the human condition, they view it — and therefore their life — as terrifying.....

.... Clinicians may be complicit in encouraging patients and families to dwell on an uncertain future rather than the here and now. Clinicians often say, “We need more time to be sure.” Although more time brings greater prognostic certainty in some cases, in other cases the hoped-for clarity never emerges and decisions are pushed off to an ever-more-distant future. The time spent waiting may be dear to patients and their families. Patients may miss important opportunities to spend time with family because they're focused on the future and unable to enjoy the present. To help a patient refocus on the here and now, the clinician might ask, “What can we do to help you now, given that we are unsure of exactly what the future will bring?”......

..... To be sure, the present may not be a comfortable place for some. Living with anxiety, pain, or the support of a mechanical ventilator are reasons to focus on the future. Uncertainty may thus represent hope for some, an escape from the present for others.....

..... Prognosis, and prognostic uncertainty, have a profound influence on physicians, as well as on patients and families. Physicians' generally optimistic bias is well documented.....

CCSVI or Alemtuzumab/Campath: which has the longest tail?

"An interesting comparison between CCSVI and Alemtuzumab/Campath. Some of you,as I may find studying search volumes interesting."

Icebreaker for the Iceberg Arriving!

Good News for MSers in Europe as Alemtuzumab/Lemtrada gets a first line Licence

It is all about choice, I suspect we will see more of it in the future

Time to break the Iceberg


OBJECTIVE. The purpose of this study is to report the 30-day morbidity and mortality associated with the endovascular diagnosis and management of chronic cerebrospinal venous insufficiency. MATERIALS AND METHODS. The medical records of 95 consecutive patients (60 women and 35 men) with a mean age of 48 years (age range, 25-66 years) who underwent diagnostic endovascular evaluation and intervention for chronic cerebrospinal venous insufficiency between June 2010 and September 2011 were reviewed retrospectively. All patients had a diagnosis of multiple sclerosis by McDonald criteria. Endovascular evaluation of the internal jugular and azygos veins was performed with digital subtraction venography and intravascular ultrasound. Indications for percutaneous transluminal angioplasty (PTA) were venographic findings of a greater than 50% diameter stenosis, the presence of reflux on digital subtraction venography, greater than 50% cross-sectional area stenosis by intravascular ultra-sound, or a finding of abnormal thick valves or webs by either method. The primary endpoint of this study was the 30-day mortality, and the secondary endpoint was the presence of major complications. Results are presented as means and percentages. 
RESULTS. A total of 107 procedures were performed in 95 patients. Endovascular evaluation showed venous lesions requiring intervention in 90 of 95 patients (94.7%) and was negative in five of 95 patients (5.3%). A total of 193 venous lesions were treated; angioplasty was technically successful in 188 of 193 (97.4%) lesions. Internal jugular vein thrombosis after PTA was identified in three of 95 (3.2%) of the treated patients. Bleeding at the puncture site not requiring transfusion occurred in four of 95 patients (4.2%). There were no reported procedure-related deaths. 
CONCLUSION. The results of the current study suggest that endovascular evaluation and management of chronic cerebrospinal venous insufficiency is safe, with low morbidity and no procedure-related mortality

CCSVI treatment has low frequency of side-effects in this study 

Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear.

The last line says it all. This open source so you can read and agree/disagree if you want.

Djordje R, Nenad I, Jovo K, Dragan S, Zelimir A, Slobodan T, Nikola A, Srdjan B, Petar O Incidence and distribution of extravascular compression of extracranial venous pathway in patients with chronic cerebrospinal venous insufficiency and multiple sclerosis. Phlebology. 2013 May. [Epub ahead of print]

OBJECTIVE:To examine the incidence and distribution of extravascular compression of the extracranial venous pathway (the jugular and/or azygous veins) in multiple sclerosis patients with chronic cerebrospinal venous insufficiency evaluated by mulitislice computer tomographic angiography.
METHODS AND RESULTS: Study group consisted of 51 consecutive patients with multiple sclerosis in whom chronic cerebrospinal venous insufficiency was diagnosed by colour Doppler sonography (CDS). Mulitislice computer tomographic angiography was performed in all patients, and it revealed significant extravascular compression (>70%) of extracranial venous pathway in 26 patients (51%), while in 25 patients (49%) no significant extravascular compression was seen. Extracranial compression due to transverse processus of cervical vertebrae was seen in 23 patients, carotid bulb compression was seen in two patients, and in one case, compression presented as a thoracic outlet syndrome.
CONCLUSION: Our data indicate that extravascular compression of the extracranial venous pathway is frequent in multiple sclerosis patients with chronic cerebrospinal venous insufficiency, and that it is mainly due to compression caused by transverse process of cervical vertebrae. Further studies are needed to evaluate potential clinical implications of this phenomenon.

Yet further evidence that the vascular problems are not causal otherwise it would be 100%. What is going on?

Mezei Z, Olah L, Kardos L, Kovacs RK, Csiba L, Csepany T. Cerebrovascular hemodynamic changes in multiple sclerosis patients during head-up tilt table test: effect of high-dose intravenous steroid treatment. J Neurol. 2013 Jun 12. [Epub ahead of print] 
Demyelination in multiple sclerosis (MS) may cause damage to the vegetative nervous system. Our objective was to examine cerebral autoregulation assessed via blood pressure and cerebral blood flow velocity fluctuations during head-up tilt table testing. We also investigated the effects of high-dose intravenous corticosteroid treatment. Transcranial Doppler registration of middle cerebral artery blood flow velocity and continuous blood pressure and heart rate monitoring were performed at rest and during tilt table testing in 30 MS patients. Ten age-matched healthy subjects were also examined as controls. Correlations between mean arterial blood pressure (MBP) and cerebral blood flow velocity (CBF) fluctuations were averaged, yielding the correlation coefficient index Mx. For a subgroup of 11 patients with acute exacerbations, results were also evaluated before and after methylprednisolone treatment (1 g/day intravenously for 5 days). No significant differences in the autoregulatory indices were seen between patients and controls, or between pre- and post-steroid results. Modeling CBF velocity changes associated with a 1-mmHg increase in MBP, significant differences (p < 0.05) were detected in patients vs. controls, and also after vs. before steroid administration. We conclude that cerebrovascular autoregulation impairments are detectable in early phase MS. Corticosteroid treatment has a significant effect on haemodynamic changes in acute exacerbations.

van Zuuren EJ, Fedorowicz Z, Pucci E, Jagannath V, Robak EW.
BACKGROUND: It has been recently hypothesised that chronic cerebrospinal venous insufficiency (CCSVI) may be an important factor in the pathogenesis of multiple sclerosis (MS). The proposed treatment for CCSVI is percutaneous transluminal angioplasty, also known as the 'liberation procedure', which is claimed to improve the blood flow in the brain, thereby alleviating some of the symptoms of MS. Our objective was to determine the effects of percutaneous transluminal angioplasty used for the treatment of CCSVI in people with MS.
METHODS:We searched the following databases up to June 2012 for randomised controlled trials: The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register, CENTRAL, in The Cochrane Library 2012, Issue 5, MEDLINE (from 1946), EMBASE (from 1974) and reference lists of articles. We also searched several online trials registries for ongoing trials.
RESULTS:Our searches retrieved 159 references, six of which were related to ongoing trials. No randomised controlled trials met our inclusion criteria.
CONCLUSIONS:There is currently no high level evidence to support or refute the efficacy or safety of percutaneous transluminal angioplasty for treatment of CCSVI in people with MS. Clinical practice should be guided by evidence supported by well-designed randomised controlled trials: closure of some of the gaps in the evidence may be feasible at completion of the six ongoing clinical trials. 

Systematic review of the literature says the stuff in the literature on CCSVI is weak so what’s new. 

Elsankari S, Balédent O, van Pesch V, Sindic C, de Broqueville Q, Duprez T. Concomitant analysis of arterial, venous, and CSF flows using phase-contrast MRI: a quantitative comparison between MS patients and healthy controls. J Cereb Blood Flow Metab. 2013 Jun 19. doi: 10.1038/jcbfm.2013.95. [Epub ahead of print]

Venous dysfunction has recently been hypothesized to contribute to the pathophysiology of multiple sclerosis (MS). 2D phase-contrast (PC) magnetic resonance imaging (MRI) is a non-invasive and innocuous technique enabling reliable quantification of cerebrospinal fluid (CSF) and blood flows in the same imaging session. We compared PC-MRI measurements of CSF, arterial and venous flows in MS patients to those from a normative cohort of healthy controls (HC). Nineteen MS patients underwent a standardized MR protocol for cerebral examination on a 3T system including Fast cine PC-MRI sequences with peripheral gating in four acquisition planes. Quantitative data were processed using a homemade software to extract CSF and blood flow regions of interest, animate flows, and calculate cervical and intracranial vascular flow curves during the cardiac cycle (CC). Results were compared with values obtained in 21 HC using multivariate analysis. Venous flow patterns were comparable in both groups without signs of reflux. Arterial flows (P=0.02) and cervical CSF dynamic oscillations (P=0.01) were decreased in MS patients. No significant differences in venous cerebral and cervical outflows were observed between groups, thereby contradicting the recently proposed theory of venous insufficiency. Unexpected decrease in arterial perfusion in MS patients warrants further correlation to volumetric measurements of the brain.

So another study not finding a difference. The CCSVI hypothesis is fuelling a lot of negative data. Is it time to call a halt to these futile studies?

Friday, 28 June 2013

Good news: alemtuzumab gets a first-line license in Europe

Today is a historic day for people with MS living in Europe. #MSBlog #MSResearch

"Somebody asked for some good news. It doesn't come much better than this."

Press release:  Genzyme, a Sanofi company, announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion for approval of Aalemtuzumab for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features.

"What does this mean? It means that we will have the option of using Alemtuzumab in MSers with relapsing disease who are active. This means it can be used as a first line agent and it won't only be limited to MSers with highly active MS. This means the EMA have shifted their position and realised that MSers and neurologists need the option of choosing an early highly-effective therapy early in the disease. The question now is will NICE and other payers adopt this strategy."

"We were in the process of setting up a pan-European petition and protest to lobby against Alemtuzumab getting a second or third-line license. This means we can hold back on the protest for the time being; however, we may need this campaign to lobby Genzyme to price the drug at a price European countries can afford and to encourage local or regional payers to allow wide access to the drug."

"This means flat-lining may become a reality for those MSers willing to take the risk of early effective treatment."

"This ruling will also set off a chain of events in the industry. If alemtuzumab can get a relatively broad license why not natalizumab and fingolimod? Yes, why not? I suspect we will see the EMA push back on these drugs as well and maybe European neurologists can join our colleagues in the USA who will surely have the luxury of using all highly-effective treatments early in relapsing MS"

"Several of my colleagues in the US have stopped using first-line injectables; I can't argue with them. Why waste time on an ineffective drug when you can receive a highly-effective drug with a good chance of flat-lining or improving your condition?"

"This is also a time to reflect on the alemtuzumab programme and thank all the MSers for taking the risks of being in the trials, the trial team at Barts and The London, for their hard work and dedication, Genzyme for investing in such a high-risk programme, Professor Compston for being a such brave pioneer and to Dr Coles for devoting his academic life to Alemtuzumab. I have particular respect for Dr Coles' role in the programme; his commitment and dedication to Alemtuzumab has been truly outstanding."

"Are you prepared to wait 15-20 years for the results of early highly-effective treatment strategy to read out? Will alemtuzumab treatment early in the course of MS prevent secondary progressive MS? Will alemtuzumab treatment early in the course of MS cure MS? It won't in all of you, but it may in some."

CoI: multiple

Other relevant posts of interest:

25 Jun 2013
Flatlining MS disease activity; what do we need to do to make it a reality? #MSBlog #MSResearch "In the last few weeks we have been discussing the paradigm of early effective treatment as an emerging treatment strategy to ...

20 Jun 2013
Survey results on MS as a dementing illness. #MSBlog #MSResearch "Next to my posts on CCSVI the 'Rebranding MS a Dementia' post caused quite a stir in the blogosphere. It is clear from the comments in relation to this ...
12 Jun 2013
"For me the best thing about going to conferences is that it allows you thinking time, and time to interact with like minded colleagues. After my platform presentation on early aggressive treatment several European neurologists ...
17 Jun 2013
Rebranding MS a dementia (3): Cognitive impairment in asymptomatic MS (or RIS). Cognitive impairment may begin before the first attack of MS. #MSBlog #MSResearch "This is an old post that needs more air time. It shows ...
14 Jun 2013
Rebranding MS as a Dementia: part 2. "What do you think of this of short animation? It tries to explain the impact of MS on the brain; in the other words the early phases of MS Dementia." ...

Is MS a whole brain disease?

MS is a iceberg within and iceberg within an iceberg. #MSBlog #MSResearch

"I am at a specialist MRI meeting in London. More thinking time; a precious resource. The meeting is focusing on MS as a whole brain disease. It is clear that MS is not only on iceberg, but an iceberg within an iceberg within an iceberg. What happens clinically is a fraction of what is seen on MRI and what is seen on MRI is a fraction what is seen under the microscope."

Abnormal brain sodium in MS

Brain sodium is abnormal in MSers. #MSBlog #MSResearch

"This is work done by our UCL partners (UCLP) at UCL and describes a new MRI technique that can quantify sodium. MSers have increased brain sodium content and it appears to correlates with disability. Exactly what this means is subject to debate and it may suggest a new therapeutic target. We are very active in this field and testing various sodium channel blockers as neuroprotective agents in MS. Our optic neuritis and PROXIMUS study are testing two established sodium channel blockers in MS; i.e. phenytoin and oxcarbazepine. We plan to include sodium imaging in the PROXIMUS study. We will get an answer on whether or not we can modify this process with oxcarbazepine."

Paling et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain. 2013 Jul;136(Pt 7):2305-2317.

Background: Neuroaxonal loss is a major substrate of irreversible disability in multiple sclerosis, however, its cause is not understood. In multiple sclerosis there may be intracellular sodium accumulation due to neuroaxonal metabolic dysfunction, and increased extracellular sodium due to expansion of the extracellular space secondary to neuroaxonal loss. Sodium magnetic resonance imaging measures total sodium concentration in the brain, and could investigate this neuroaxonal dysfunction and loss in vivo. Sodium magnetic resonance imaging has been examined in small cohorts with relapsing-remitting multiple sclerosis, but has not been investigated in patients with a progressive course and high levels of disability. 

Methods: They performed sodium magnetic resonance imaging in 27 healthy control subjects, 27 RRMSer, 23 with SPMSers and 20 with PPMSer. Cortical sodium concentrations were significantly higher in all subgroups of multiple sclerosis compared with controls, and deep grey and normal appearing white matter sodium concentrations were higher in primary and secondary-progressive multiple sclerosis. 

Results: Sodium concentrations were higher in secondary-progressive compared with relapsing-remitting multiple sclerosis in cortical grey matter (41.3 ± 4.2 mM versus 38.5 ± 2.8 mM, P = 0.008), normal appearing white matter (36.1 ± 3.5 mM versus 33.6 ± 2.5 mM, P = 0.018) and deep grey matter (38.1 ± 3.1 mM versus 35.7 ± 2.4 mM, P = 0.02). Higher sodium concentrations were seen in T1 isointense (44.6 ± 7.2 mM) and T1 hypointense lesions (46.8 ± 8.3 mM) compared with normal appearing white matter (34.9 ± 3.3 mM, P < 0.001 for both comparisons). Higher sodium concentration was observed in T1 hypointense lesions in secondary-progressive (49.0 ± 7.0 mM) and primary-progressive (49.3 ± 8.0 mM) compared with relapsing-remitting multiple sclerosis (43.0 ± 8.5 mM, P = 0.029 for both comparisons). Independent association was seen of deep grey matter sodium concentration with expanded disability status score (coefficient = 0.24, P = 0.003) and timed 25 ft walk speed (coefficient = -0.24, P = 0.01), and of T1 lesion sodium concentration with the z-scores of the nine hole peg test (coefficient = -0.12, P < 0.001) and paced auditory serial addition test (coefficient = -0.081, P < 0.001). 

Conclusions: Sodium concentration is increased within lesions, normal appearing white matter and cortical and deep grey matter in multiple sclerosis, with higher concentrations seen in secondary-progressive multiple sclerosis and in patients with greater disability. Increased total sodium concentration is likely to reflect neuroaxonal pathophysiology leading to clinical progression and increased disability.

Sodium accumulation in nerves is not good for you

                                  Did people take their drugs

Too much sodium is not good for you and I am not talking about salt intake here...but suggests that blocking sodium accumulation in nerves and microglia could be a good idea. So the PROXiMuS trial may not be a bad idea.....The trial is going through the ethics process..Yes this is slow......we did not make the rules.

"The lamotrigine trial failed I hear you say".......well I say "not surprising because there were a lot of naughty MSers throwing away their drugs (maybe not surprising if they make you feel like crap) how can a drug work if you don't take it!"

No drugs in the blood doesn't lie....empty drug wrappers can..Naughty Naughty!!

But what happens if you do take it?............well you will have to watch this space for the lastest results from Team G...coming soon.

Different Skin Colour but Same MS Genes

Epub: Isobe  et al. Genetic risk variants in African Americans with multiple sclerosis. Neurology. 2013 Jun 14.

OBJECTIVES: To assess the association of established multiple sclerosis (MS) risk variants in 3,254 African Americans (1,162 cases and 2,092 controls).

METHODS: Human leucocyte antigen (HLA)-DRB1, HLA-DQB1, and HLA-A alleles were typed by molecular techniques. Single nucleotide polymorphism (SNP) genotyping was conducted for 76 MS-associated SNPs and 52 ancestry informative marker SNPs selected throughout the genome. Self-declared ancestry was refined by principal component analysis of the ancestry informative marker SNPs. An ancestry-adjusted multivariate model was applied to assess genetic associations.

RESULTS: The following major histocompatibility complex risk alleles were replicated: HLA-DRB1*15:01 (odds ratio [OR] = 2.02 [95% confidence interval: 1.54-2.63], p = 2.50e-07), HLA-DRB1*03:01 (OR = 1.58 [1.29-1.94], p = 1.11e-05), as well as HLA-DRB1*04:05 (OR = 2.35 [1.26-4.37], p = 0.007) and the African-specific risk allele of HLA-DRB1*15:03 (OR = 1.26 [1.05-1.51], p = 0.012). The protective association of HLA-A*02:01 was confirmed (OR = 0.72 [0.55-0.93], p = 0.013). None of the HLA-DQB1 alleles were associated with MS. Using a significance threshold of p < 0.01, outside the major histocompatibility complex region, 8 MS SNPs were also found to be associated with MS in African Americans.

CONCLUSION: MS genetic risk in African Americans only partially overlaps with that of Europeans and could explain the difference of MS prevalence between populations.

Thursday, 27 June 2013

Mitoxantrone is very effective DMT

Mitoxantrone is a very effective DMT. So why aren't we using it more? #MSBlog #MSResearch

Martinelli Boneschi et al. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2013 May 31;5:CD002127.

BACKGROUND: This is an updated Cochrane review of the previous published version. Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in MSers.

OBJECTIVES: The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing-remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants. 

SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (June 2012) and reference lists of articles. We also undertook handsearching and contacted trialists and pharmaceutical companies.

DATA COLLECTION AND ANALYSIS: The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed-effect model was used.

MAIN RESULTS: Three trials were selected and 221 participants were included in the analyses. MX reduced the progression of disability at two years follow-up (proportion of participants with six months confirmed progression of disability (OR 0.30, 95% CI 0.09 to 0.99 and MD -0.36, 95% CI- 0.70 to -0.02; P = 0.04)). Significant results were found regarding the reduction in annualised relapse rate (MD -0.85, 95% CI -1.47 to -0.23; P = 0.007), the proportion of patients free from relapses at one year (OR 7.13, 95% CI 2.06 to 24.61; P = 0.002) and two years (OR 2.82, 95% CI 1.54 to 5.19; P = 0.0008), and the number of MSers with active MRI lesions at six months or one year only (OR 0.24, 95% CI 0.10 to 0.57; P = 0.001). Side effects reported in the trials (amenorrhoea, nausea and vomiting, alopecia and urinary tract infections) were more frequent in treated patients than in controls, while no major adverse events have been reported. These results should be considered with caution because of the heterogeneous characteristics of included trials in term of drug dosage, inclusion criteria and quality of included trials. Moreover, it was not possible to estimate the long-term efficacy and safety of MX.

Oncologists call mitoxantrone the 'Blue Devil'.

AUTHORS' CONCLUSIONS: MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in MSers affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic cardiac dysfunction (~12%) and therapy-related acute leukaemias (~0.8%), which are increasingly reported in the literature. MX should be limited to treating MSers with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual MSers' risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.

"Someone recently asked about the effectiveness of mitoxantrone. This review is therefore very timely. These are impressive results and places mitoxantrone high the list on relative efficacy. It is one of the highly effective DMTs."

"Mitoxantrone is another agent that brutally exposes the therapeutic window of opportunity. If you use it early it stops and often reverses disability, but if you use it late MSers continue to progress, but at a slower rate. The slower rate of progression is a win for us, but if you have MS it is an unimpressive outcome. We have previously addressed this issue in a survey on our blog; MSers with progressive disease want to stabilise their disease or improve."

"Mitoxantrone is not without side effects. It is all about risk and benefits. The cardiotoxicity is dose limiting therefore you can only receive the drug for a maximum of 2 years. What happens after the 2 years? In some centres it is used as an induction agent and the mitoxantrone is followed up with either interferon-beta or glatiramer acetate. The main risks relate to its effect in woman on fertility; this is age related and the risk of delayed treatment-related leukaemia. The latter is a very characteristic leukemia and has a genetic finger print that is characteristic of mitoxantrone. The type of leukemia is called promyelocytic leukemia and is associated with a 50% mortality. In other words 50% of individuals who get this leukemia die from it. I most point out that this complication is dose related so the more mitoxantrone you receive the greater your chances. It is interesting that mitoxantrone has a license for the treatment of MS in many countries despite these risks. So why then did the regulators say no to oral cladribine? Some food for thought."

Multiple Sclerosis Research: Survey results: neuroprotection - 27 Apr 2012. Survey results: neuroprotection ... Neuroprotection in progressive MS in unlikely to result in recovery of function as progressive MSers have usually exhausted the nervous system's ability to recover.......

Autoimmunity occurs in MS

The pathogenic role of antibodies in multiple sclerosis (MS) is still controversial. We transferred to mice with experimental autoimmune encephalomyelitis (EAE), animal model of MS, IgG antibodies purified from a MS patient presenting a dramatic clinical improvement during relapse after selective IgG removal with immunoadsorption. Passive transfer of patient's IgG exacerbated motor paralysis and increased mouse central nervous system (CNS) inflammation and demyelination. Binding of patient's IgG was demonstrated in mouse CNS, with a diffuse staining of white matter oligodendrocytes. These data support a growing body of evidence that antibodies can play an important role in the pathobiology of MS.

As I have been saying for sometime, MSers blood contains antibodies against brain tissues and that these are not good for you. In this study they removed antibodies from an MSer and then injected them into an animal with EAE so that the antibodies could get in the brain and this made EAE worse. This clearly demonstrates that there is an autoimmune component that is ongoing in some MSers. What is does not answer is whether this is a primary or secondary problem? What is clear is that it is a problem in MS.

Phase 4 trials ECTRIMS Summer School, Bari 2013

ECTRIMS Summer School presentation available for down load. #MSBlog #MSResearch

"As promised my presentation from yesterday for download. I hope it makes sense."

Wednesday, 26 June 2013

Cognitive decline in early MS

Cognitive impairment in early MS. Time is brain. #MSBlog #MSResearch

: Hankomäki et al. The progress of cognitive decline in newly diagnosed MS patients. Acta Neurol Scand. 2013 Jun 15.

OBJECTIVES: Cognitive impairment occurs in multiple sclerosis already in the early stages of the disease. Less is known about the evolution of cognitive decline, especially in newly diagnosed MSers. The results of existing studies are contradictory in that both cognitive preservation and progressive deterioration have been reported. The purpose of this study was to examine how cognitive impairment evolves over time in the early stages of MS.

MATERIAL AND METHODS: At baseline, the participants were 36 newly diagnosed MSers and 37 controls. A group of 30 MSers were followed longitudinally at a mean test-retest interval of 6.1 years. The test battery covered attention, information processing, memory and learning, verbal and motor functions and reasoning.

RESULTS: There was a significant decline in divided attention (dual task) and information-processing speed (SDMT) at follow-up, but no significant deterioration in overall cognitive performance.

CONCLUSIONS: Overall cognitive functioning remained quite stable during the 6-year follow-up, whereas divided attention and processing speed deteriorated. However, deterioration in performance on the SDMT and the dual task does not seem to indicate more extensive cognitive deterioration. Given the impact of cognitive impairment on MSers' quality of life, early detection of its occurrence in MS is extremely important.

"This small study reiterates that cognitive impairment is there early and that if you institute early treatment you can delay the onset of progressive cognitive impairment. Fortunately Finland does not have a problem with access to DMTs early in the course of the disease and most MSers with CIS get offered treatment. Unlike the UK where you have to have at least 2 clinical attacks or relapses in a 2 year period before accessing first-line treatments. Current Department of Health guidance does not allow us to take into account sub-clinical disease activity on MRI. This is a great pity as we know that this activity is associated with a poor outcome. Time is Brain."

CoI: multiple

MS Registry MSers in UK

Jones KH, Ford DV, Jones PA, John A, Middleton RM, Lockhart-Jones H, Peng J, Osborne LA, Noble JG How People with Multiple Sclerosis Rate Their Quality of Life: An EQ-5D Survey via the UK MS Register. PLoS One. 2013 Jun 11;8(6):e65640. doi: 10.1371/journal.pone.0065640. Print 2013.

The EQ-5D is a widely-used, standardised, quality of life measure producing health profiles, indices and states. The aims of this study were to assess the role of various factors in how people with Multiple Sclerosis rate their quality of life, based on responses to the EQ-5D received via the web portal of the UK MS Register.
METHODS: The 4516 responses to the EQ-5D (between May 2011 and April 2012) were collated with basic demographic and descriptive MS data and the resulting dataset was analysed in SPSS (v.20).
RESULTS:The mean health state for people with MS was 59.73 (SD 22.4, median 61), compared to the UK population mean of 82.48 (which is approximately 1SD above the cohort mean). The characteristics of respondents with high health states (at or above +1SD) were: better health profiles (most predictive dimension: Usual Activities), higher health indices, younger age, shorter durations of MS, female gender, relapsing-remitting MS, higher educational attainment and being in paid employment (all p-values<0.001). Conversely, the characteristics of respondents with low health states (at or below -1SD) were: poorer health profiles (most predictive dimension: Mobility), lower health indices, older age, longer durations of MS, male gender, progressive MS, lower educational attainment and having an employment status of sick/disabled (p = 0.0014 for age, all other p-values<0.001). Particular living arrangements were not associated with either the high or low health status groups.
CONCLUSIONS: This large-scale study has enabled in-depth analyses on how people with MS rate their quality of life, and it provides new knowledge on the various factors that contribute to their self-assessed health status. These findings demonstrate the impact of MS on quality of life, and they can be used to inform care provision and further research, to work towards enhancing the quality of life of people with MS.

This is open source soyou can readit.Have you considered joining the MS register

Alemtuzumab in mice

Turner MJ, Lamorte MJ, Chretien N, Havari E, Roberts BL, Kaplan JM, Siders WM.Immune status following alemtuzumab treatment in human CD52 transgenic mice. J Neuroimmunol. 2013 Jun 4. doi:pii: S0165-5728(13)00115-X. 10.1016/j.jneuroim.2013.04.018. [Epub ahead of print]
Alemtuzumab is a monoclonal antibody against the CD52 antigen present at high levels on the surface of lymphocytes. While treatment of multiple sclerosis patients with alemtuzumab results in marked depletion of lymphocytes from the circulation, it has not been associated with a high incidence of serious infections. In a human CD52 transgenic mouse, alemtuzumab treatment showed minimal impact on the number and function of innate immune cells. A transient decrease in primary adaptive immune responses was observed post-alemtuzumab but there was little effect on memory responses. These results potentially help explain the level of immunocompetence observed in alemtuzumab-treated MS patients.

This study looks at the effect of lemtrada in mice, which have the target. In mice it has not much effect on the innate system and it had a transient effect on the immune arm and no much effect on memory cells. This just shows us the difference between mice and man. You give alemtuzumab to people and their T cells are gone for a few years but in mice they cells are replaced within a few weeks.

However not keeping your subject under constant immunosuppressing conditions will of course allow immune cells to expand and get rid of infections. Rather than tell us what happens in mice it is easier to see how the body responds to infection after vaccination

Time to Lobby?

This is a repost....

There needs to be a political response to help get people access to highly effective DMT. 

This needs co-ordination......who are the champions?

Not this lot? But can they help?

All Party Parlimentary Group for Multiple Sclerosis

Minster for Health; Jeremy Hunt (Constiuency-South West Surrey) 

Did you know that there is the All-Party Parliamentary Group for Multiple Sclerosis who aim To promote the interests of people affected by MS.  Now we know who to lobby

Chair               Lord Dubs
Vice-Chairs     Stephen Lloyd, David Amess
Treasurer         Pamela Nash


James Gray – Con
David Amess – Con
Bernard Jenkin – Con
Chris White – Con
Lord Bowness - Con
John Hemming – LD
Stephen Lloyd – LD
Annette Brooke – LD
Lord Jones of Cheltenham – LD
Graham Brady - Con

Catherine McKinnell
Joe Benton
Paul Blomfield
Tom Blenkinsop
Richard Burden
Michael Dugher
Pat Glass
Clive Efford
Pamela Nash
Lord Dubs

For Non-UK readers. Con does not mean criminal/convict but Conservative party and LD is Liberal Democrats and not Linkage disequalibrium and labour is not something that happens in pregnancy :-)
I wrote to my MP about this via fax your MP, who responded within 24 hours (so they keep their response rate up) and she wrote to the Health Minister who responded sadly with a cut and paste response that could have been done by a robot and was totally inadequate...It was frankly patronizing. 

Lord Dubs never responded so we can ask what is this lot of Parliamentarians doing for MS? 

I will go back to them but need to get something for them to read first

Attitudes to pregnancy in MSers living in North America

Pregnancy and MS; to start a family or not? #MSBlog #MSResearch

Alwan et al. Multiple Sclerosis and Pregnancy: A Comparison Study. Can J Neurol Sci. 2013 Jul;40:590-596.

Objective: To determine whether different healthcare systems may affect reproductive decision-making among MSers, we describe the reproductive practices and attitudes of Canadian MSers ascertained from the multidisciplinary MS Clinic at Hôpital Notre-Dame in Montreal, Quebec (NDMSC), in comparison to those of matched American self registrants from the database of the North American Research Committee on Multiple Sclerosis (NARCOMS). 

Methods: A total of 665 self-administered questionnaires on reproductive practices were sent out to eligible attendees attending the NDMSC. The short questionnaires were completed and returned to the authors in an anonymous format for analysis. 

Results: A total of 459 completed questionnaires were returned. The majority of NDMSC respondents (72.5%) and NARCOMS subset (75.2% females), did not encounter a pregnancy following diagnosis of MS. The most common MS-related reason for this decision was "symptoms interfering with parenting" (75.0% for the NDMSC, 72.6% for the NARCOMS). The most commonly reported non-MS-related reason was "a completed family" by the time of diagnosis in both the NDMSC and NARCOMS subset (58.0%, 40.4%, respectively). Concerns about financial issues both related and unrelated to MS were also commonly reported by males and females in both cohorts but significantly more so among the NARCOMS participants. 

Conclusion: These results indicate that reproductive decisions of MSers are highly affected by their illness and its associated disability, regardless of the available health care program. Health care providers should discuss their patients' reproductive needs and perceptions to help them make more informed decisions.

"This study compared differences between Canadian and American MSers about their decisions to start, or not start, a family. Pregnancy and MS is a difficult subject. Decisions about whether to start or extend a family is not an easy one. Typically questions that are asked include the following: 1) What will pregnancy do to my MS?; 2) Will I be able to continue my treatments during pregnancy; 3) Will I be able to breastfeed?; 4) Will I be able to be cope with being a parent if I become disabled?; 5) What if become unemployed due to MS, will I be able to afford having a family; 6) What are the risks of my children getting MS?; 7) Can I do anything to reduce the chances of my children getting MS?; 8) What happens if my partner leaves me; will I be able to cope with MS and being a single parent?'; 9) I am already fatigued, will I be able to cope with the sleep deprivation of having a baby?"

"If you have any other questions please ask them. I will try and collate them and run a 'Clinic Speak' session on pregnancy to answer them."

"To get an idea of issues related to pregnancy it would be helpful if you could complete the survey below. Thanks."

Other relevant post on pregnancy on this blog:

02 Jun 2013
Objective: The analysis of perinatal results in pregnant women with multiple sclerosis (MS) and the assessment of the influence of pregnancy on this chronic disease in the population of pregnant women in our hospital in the ...
02 May 2013
OBJECTIVES: The objectives of this research are to prospectively evaluate the prevalence of thyroid autoimmunity among MSers in relation to pregnancy, and to investigate its impact on pregnancy outcome, postpartum ...
09 Mar 2013
"I am often asked what topics are neglected in MS research, that are very important for MSers? Pregnancy is one of these areas. Therefore it is very appropriate that ECTRIMS has just sponsored a focused workshop on this ...
11 Mar 2013
"As you are aware pregnancy affects the natural history of MS; what are the mechanisms that underlie these effects? If we can define them we may be able to mimic a state of pregnancy, i.e. pseudopregnancy, and use this to ...

12 Jan 2013
Pregnancy & MS: birth hospitalisation for MSers is no different to anybody else. #MSBlog: For female MSers; MS affect on the outcome of birth for both you and your baby. Epub: Lu et al. On behalf of the British Columbia ...
25 Oct 2012
METHODS: They recruited MSers, prospectively followed-up in 21 Italian MS Centres, for whom a pregnancy was recorded in the period 2002--2008. MSers were divided into 2 groups: drug-exposed pregnancies (EP: ...
14 Apr 2012
The investigators reviewed medical records and used a structured questionnaire to investigate gravidity (number of pregnancies), parity (number of births), and the number of relapses during the 2 years before pregnancy, ...
14 Aug 2012
Conclusion: Although the course of MS was deteriorated 3 months after delivery, it was not statistically significant comparing annual relapsing rates during the years prior to pregnancy. Moreover, the rate of disease ...

15 Nov 2012
This has been hypothesised to be related to maternal vitamin D levels during pregnancy, although conclusive evidence to support this is lacking. To date, no large studies of latitudinal variation in the month of birth effect have ...
16 Jul 2011
"Because of this study, and the fact that pregnancy itself reduces the attack rate, researcher's have been trying to find out what it is about pregnancy that is so beneficial for MS'ers." "We assume that the profound changes that ...
28 Jul 2011
Methods: In 2001, 35,794 mothers of participants of the Nurses' Health Study II completed a questionnaire inquiring about their experiences and diet during pregnancy with their nurse daughters. This allowed these ...
31 May 2011
Of the women exposed to natalizumab during pregnancy, 29 women gave birth to 28 healthy children; one child was born with hexadactyly (an extra finger), 5 pregnancies ended in an early miscarriage and one woman ...

15 Jul 2011
The average or mean rate of relapse was 0.7 per year in the year before pregnancy, 0.5 during the first trimester, 0.6 during the second trimester and 0.2 during the third. The rate increased to 1.2 during the first three months ...
16 Sep 2011
21/101 (21%) of births to MS women treated with DMD prior to pregnancy were exposed to a DMD. In all cases, exposure was documented as unintentional and DMD treatment was stopped within 2 months of gestation.
05 Jun 2012
RESULTS: From the total group of patients, 89 pregnancies occurred without any exposure to MS drugs, while 61 pregnancies occurred with at least eight weeks of exposure to MS immunomodulatory drugs. The rate of ...
20 Dec 2010
A report on 88 pregnancies in Italian woman that were exposed to interferon-beta (average exposure 4 to 5 weeks) has demonstrated that exposure to interferon-beta was not associated with an increased risk of spontaneous ...

06 Jan 2013
METHODS: In the context of an Italian prospective study on the safety of immunomodulators in pregnancy, we included pregnancies occurred between 2002 and 2008 in women MSers regularly followed-up in 21 Italian MS ...
27 May 2012
Objective: Pregnancy has a well documented effect on relapse risk in MS. Prospective studies have reported a significant decline by two-thirds in the rate of relapses during the third trimester of pregnancy and a significant ...
19 Sep 2011
Natalizumab did not affect the ability of treated males to produce pregnancies in untreated females. In female guinea pigs, no treatment-related changes were seen in uterine weights or ovary weights. Pregnancy rates were ...
05 Aug 2011
"Why does MS go away during pregnancy?". Your baby is made up of features from Mum and Dad. The bits from dad should be rejected by the mum's immune system, just as a organ transplant would be, as they are foreign to ...

16 Jul 2012
Of the 20.9% of participants who decided to become pregnant (or father a pregnancy) following a diagnosis of MS, 49.5% had two or more pregnancies. Conclusion:This study indicates that an MS diagnosis does not ...
13 Jul 2011
The only significant predictor of having a relapse after childbirth was an increased number of relapses in the year before pregnancy and during the pregnancy itself. Therefore, the reported association between breastfeeding ...
28 Oct 2012
However, the topic is important and if we want to provide holistic care for woman with MS we need to address how we handle the issue of pregnancy and the advice we give. Misinformation or inconsistent information is one ...
11 Oct 2012
To investigate if women with multiple sclerosis (MS) experience changes in MS symptoms related to pregnancy, the postpartum period, menopause or use of oral contraception (OC) or postmenopausal hormone therapy (HT).