Wednesday, 22 October 2014

Multiple Sclerosis Management - update on the NICE guideline 2014

Multiple sclerosis: management of multiple sclerosis in primary and secondary care - published Oct 2014

This guideline replaces the clinical guideline published in 2003 (i.e. NICE or the National Insitute for Health and Care Excellence that also advices on MS treatments has not updated their thinking on the care and treatment of MS patients in over 10 years!). Having said this, here is an overview of their suggestions (see figure); some which I have no comment on or prefer to keep my own counsel.

Advance warning: this is a large blog!


1) When to refer to a consultant neurologist
Refer people suspected of having MS to a consultant neurologist. Speak to the consultant neurologist if you think a person needs to be seen urgently. If a person has an episode of isolated optic neuritis, confirmed by an ophthalmologist, refer them to a consultant neurologist for further assessment.

This should be standard practice, I would go one step further and say that MSers should be under the care of  MS specialists.

2) Initial investigations
Before referring a person suspected of having MS to a neurologist, exclude alternative diagnoses by performing blood tests including:
full blood count, inflammatory markers for example erythrocyte sedimentation rate, C-reactive protein, liver function tests, renal function tests, calcium, glucose, thyroid function tests, vitamin B12, HIV serology.

This is normally performed by your GP's and covers the MS mimics. Why HIV? HIV can mimic any neurological disorder (so can Syphilis, but is less common nowadays) - the National AIDS trust quotes a figure of 98,400 people living with HIV in the UK alone, 22% of whom are unaware of their infection).

3) Information at the time of diagnosis
The consultant neurologist should ensure that people with MS and, with their agreement their family members or carers, are offered oral and written information at the time of diagnosis. This should include, but not be limited to, information about: what MS is
treatments, including disease-modifying therapies symptom management, how support groups, local services, social services and national charities are organised and how to get in touch with them, legal requirements such as notifying the Driver and Vehicle Licensing Agency (DVLA) and legal rights including social care, employment rights and benefits.

This admittedly is a lot to cover at the first visit and is often a shared venture between the neurologist and your MS nurse. Previously the MS societies used to provide a folder which would cover at least the first bit about what is MS? However this appears to have disappeared into the ether as more of us now rely on the internet for our information.The final bit about DVLA is very important and not readily highlighted at the first visit but is a requirement.

4) Provide information and support
Ensure people with MS and their family members or carers have a management plan that includes who to contact if their symptoms change significantly. Explain to people with MS that the possible causes of symptom changes include: another illness such as an infection, further relapse, change of disease status (for example progression).
Vaccinations: Be aware that live vaccinations may be contraindicated in people with MS who are being treated with disease-modifying therapies. Discuss with the person with MS:
the possible benefits of flu vaccination and the possible risk of relapse after flu vaccination if they have relapsing–remitting MS.

Pregnancy: Explain to women of childbearing age with MS that:
relapse rates may reduce during pregnancy and may increase 3–6 months after childbirth before returning to pre-pregnancy rates
pregnancy does not increase the risk of progression of disease.
If a person with MS is thinking about pregnancy, give them the opportunity to talk with a healthcare professional with knowledge of MS about: fertility, the risk of the child developing MS
use of vitamin D before conception and during pregnancy
medication use in pregnancy, pain relief during delivery (including epidurals), care of the child, breastfeeding.

I'm somewhat baffled by the comment on vaccines precipitating a relapse - does that mean NICE believes in the molecular mimicry hypothesis?! Reading between the lines they're probably trying to say don't have the flu vaccine.

5) Lifestyle advice
Exercise: Encourage people with MS to exercise. Advise them that regular exercise may have beneficial effects on their MS and does not have any harmful effects on their MS. For mobility problems and fatigue related to MS, consider supervised exercise programmes involving moderate progressive resistance training and aerobic exercise.

Smoking: Advise people with MS not to smoke and explain that it may increase the progression of disability.

I agree with both points, with exercise, but do this at regular intervals (any runner will agree with this); this would release endorphins and provide positive feedback for the brain for remodelling (cf. stroke patients where brain training is the norm in rehabilitation). And smoking, unless you have fixation with not developing Parkinson's disease, I would strongly discourage.6) Disease-modifying therapies
Beta interferon and glatiramer acetate
On the balance of their clinical and cost effectiveness neither beta interferon or glatiramer acetate is recommended for the treatment of multiple sclerosis (MS) in the NHS in England and Wales.

It is likely that patients currently receiving beta interferon or glatiramer acetate for MS, whether as routine therapy or part of a clinical trial, could suffer loss of well being if their treatment is discontinued at a time they did not anticipate. Because of this, all NHS patients who are on therapy at the date of publication of this guidance should have the option to continue treatment until they and their consultant consider it is appropriate to stop, having regard to the criteria established for withdrawal from treatment in the Guidelines of the Association of British Neurologists published in January 2001.

Dimethyl fumarate
Dimethyl fumarate is recommended as an option for treating adults with active relapsing-remitting multiple sclerosis (normally defined as 2 clinically significant relapses in the previous 2 years), only if:
they do not have highly active or rapidly evolving severe relapsing-remitting multiple sclerosis and the manufacturer provides dimethyl fumarate with the discount agreed in the patient access scheme.
People currently receiving treatment initiated within the NHS with dimethyl fumarate that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.

Alemtuzumab is recommended as an option, within its marketing authorisation, for treating adults with active relapsing–remitting multiple sclerosis.

Teriflunomide is recommended as an option for treating adults with active relapsing–remitting multiple sclerosis (normally defined as 2 clinically significant relapses in the previous 2 years), only if they do not have highly active or rapidly evolving severe relapsing–remitting multiple sclerosis and the manufacturer provides teriflunomide with the discount agreed in the patient access scheme.

Fingolimod is recommended as an option for the treatment of highly active relapsing–remitting multiple sclerosis in adults, only if: they have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon, and the manufacturer provides fingolimod with the discount agreed as part of the patient access scheme.

The decision on the first line DMTs is a bit a bombshell!!! NHS England is a lapdog to NICE recommendations, so I predict a mad rush to the sales!! I wonder if pharma are aware of this subtle change in the NICE recommendations and are NICE blatantly ignoring the latest findings from the risk-sharing scheme. So it would seem that its oral therapies all the way.

7) Managing multiple sclerosis symptoms
Cognition including memory
Be aware that the symptoms of MS can include cognitive problems, including memory problems that the person may not immediately recognise or associate with their MS. Be aware that anxiety, depression, difficulty in sleeping and fatigue can impact on cognitive problems. If a person with MS experiences these symptoms and has problems with memory and cognition, offer them an assessment and treatment.

Mobility and fatigue
Consider supervised exercise programmes involving moderate progressive resistance training and aerobic exercise to treat people with MS who have mobility problems and/or fatigue.
Mobility and/or fatigue with balance problems:
Consider vestibular rehabilitation for people with MS who have fatigue or mobility problems associated with limited standing balance.
Treatment programmes for mobility and/or fatigue:
Encourage people with MS to keep exercising after treatment programmes end for longer term benefits (see the NICE pathway on behaviour change).
Help the person with MS continue to exercise, for example by referring them to exercise referral schemes.
If more than one of the interventions recommended for mobility or fatigue are suitable, offer treatment based on which the person prefers and whether they can continue the activity after the treatment programme ends.

Ensure people with MS and mobility problems have access to an assessment to establish individual goals and discuss ways in which to achieve them. This would usually involve rehabilitation specialists and physiotherapists with expertise in MS.
Do not use fampridine to treat lack of mobility in people with MS because it is not a cost effective treatment.

Assess and offer treatment to people with MS who have fatigue for anxiety, depression, difficulty in sleeping, and any potential medical problems such as anaemia or thyroid disease. For more information see the NICE pathways on generalised anxiety disorder and depression.
Explain that MS-related fatigue may be precipitated by heat, overexertion and stress or may be related to the time of day.
Offer amantadine to treat fatigue in people with MS.
Consider mindfulness-based training, cognitive behavioural therapy or fatigue management for treating MS-related fatigue.
Advise people that aerobic, balance and stretching exercises including yoga may be helpful in treating MS-related fatigue.
Do not use vitamin B12 injections to treat fatigue in people with MS.
Consider a comprehensive programme of aerobic and moderate progressive resistance activity combined with cognitive behavioural techniques for fatigue in people with MS with moderately impaired mobility (an EDSS score of greater than or equal to 4).

In people with MS assess and offer treatment for factors that may aggravate spasticity such as constipation, urinary tract or other infections, inappropriately fitted mobility aids, pressure ulcers, posture and pain.
Encourage people with MS to manage their own spasticity symptoms by explaining how doses of drugs can be adjusted within agreed limits.
Ensure that the person with MS:
has tried the drug at an optimal dose, or the maximum dose they can tolerate stops the drug if there is no benefit at the maximum tolerated dose has their drug treatment reviewed at least annually once the optimal dose has been reached.
Consider baclofen or gabapentin as a first-line drug to treat spasticity in MS depending on contraindications and the person's comorbidities and preferences. If the person with MS cannot tolerate one of these drugs consider switching to the other.
Consider a combination of baclofen and gabapentin for people with MS if: individual drugs do not provide adequate relief or
side effects from individual drugs prevent the dose being increased.
Consider tizanidine or dantrolene as a second-line option to treat spasticity in people with MS.
Consider benzodiazepines as a third-line option to treat spasticity in MS and be aware of their potential benefit in treating nocturnal spasms.
Do not offer Sativex to treat spasticity in people with MS because it is not a cost effective treatment.
If spasticity cannot be managed with any of the above pharmacological treatments, refer the person to specialist spasticity services.

Most of this is self-explanatory. I'd like to focus your attention again on exercise and mindfulness programmes not only for mobility and fatigue but also pain management. 
It goes without saying that the 'mouse doctor' will not be impressed on their take on Sativex! And fampridine seriously? It's the only thing us clinicians have to offer for our progressive patients.

8) Treatments that should not be used
Vitamin D
Do not offer vitamin D solely for the purpose of treating MS.
Omega fatty acids compounds
Do not offer omega-3 or omega-6 fatty acid compounds to treat MS. Explain that there is no evidence that they affect relapse frequency or progression of MS.
Interventional procedure for use only in the context of research
NICE has published guidance on percutaneous venoplasty for chronic cerebrospinal venous insufficiency for multiple sclerosis (NICE interventional procedure guidance 420), which should be used only in the context of research.

I declare that I take 'A-Z multivitamins and Omega 3 - no Vitamin D - only because my levels are normal'. One of my colleagues takes the following: 'A-Z multivitamins, minerals, omega 3, primrose oil, zinc, selenium, vitamin C (only in winter months!), and folic acid' - and I declare she can provide an excuse for all of them!

Why do I think the fingolimod primary progressive trial will be positive?

Will the fingolimod PPMS trial disprove my hypothesis about progressive MS? #MSBlog #MSResearch

Have you heard about asynchronous progressive MS hypothesis? #MSBlog #MSResearch

"You may recall the post I did on a study of interferon-beta treatment in PPMS. After 2-years of treatment there was no difference between PPMSers who had been treated with IFNbeta or placebo. The investigators' concluded that interferon-beta was ineffective in PPMS. However, when these patients were reassessed at 5-years there were clear clinical and MRI features favouring interferon treatment. I suggested that in progressive MS there was a lag in the onset of action of interferon-beta. I proposed that the impact of anti-inflammatory medications in progressive MS may take several years to play out. In other words progression over the next 2 years is primed by inflammation occurring in the past. Therefore, suppressing inflammation today will have not have an impact over the next 2-years as the damage that has primed progression over the next 2 years has already occurred. In other words all anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS."

"This diagram illustrates the concept of the therapeutic lag. The good news is that the fingolimod PPMS or INFORMS trial is a long study with most study subjects having been followed longer than 3 years with some over 5 years. This is partly due to the design of the study, i.e. it is event driven study and the study will only be completed when enough events, or confirmed progressions occurr, to give a definitive result. This is unlike the natalizumab in SPMS, or ASCEND, trial that is only being run over 96 weeks; I personally don't think this is a long enough period of time to overcome the therapeutic lag."

"The other reason why I think the fingolimod trial in PPMS will be positive is that PPMS affects different functional systems asynchronously; i.e. my so called asynchronous progressive MS hypothesis."

"What is the asynchronous progressive hypothesis? I have made the argument in the past that the neurological systems to be affected first by progressive MS are those that have the longest, or most, wiring and hence more likely to be hit by multiple lesions; this is why the motor system to the legs, bladder and the cerebellar or balance system are typically affected first when progressive disease starts. The other systems (vision, motor system to the upper arms and face, sensory system, cognition, etc.) tend to be affected later by 'overt' progressive disease. I say overt because there is now good MRI evidence that the progressive component of MS is present from the start of the disease. The only reason we don't see it clinically is because the nervous system can compensate. However, once the compensatory systems fail progressive MS ensues. This does mean that we may have different windows of opportunity to impact on these different systems. In other words there are multiple windows of therapeutic opportunity to act and we should therefore shift our focus in PPMSers on trying to delay the onset of progression in systems that are still not clinically affected. It the fingolimod PPMS trial the the primary endpoint is the effect of fingolimod relative to placebo on delaying sustained disability progression, defined by 3 month sustained increase (>=20%) from baseline in the 25-foot timed walk test, or 9-hole peg test, or sustained increase in EDSS (0.5 or 1). The inclusion of an upper limb outcome measure makes it much more likely that this trial will be positive. In addition, the 25-foot timed walk test is also more sensitive to change than the EDSS. All these factors greatly increase the chances of the INFORMS trial being positive."

"If the INFORMS study is positive it will have halo effect and increase the use of fingolimod in SPMS as well. The other good news for MSers across the world is that fingolimod's patent expires in 2019 and as the first small molecule to come off patent will have a dramatic impact on  the MS market. It means that MSers in resource poor healthcare environments will get access to a cheap licensed drug; when small molecule drugs come off-patent the price typically drops by up to 90%."

"The news on the block is that Novartis will make an announcement before the end of the year regarding the outcome of the INFORMS study. My money is on the trial being positive. This would be the best news ever for PPMSers."

CoI: multiple

Walking Again

Vaccination and Risks of MS

Langer-Gould A, Qian L, Tartof SY, Brara SM, Jacobsen SJ, Beaber BE, Sy LS, Chao C, Hechter R, Tseng HF. Vaccines and the Risk of Multiple Sclerosis and Other Central Nervous System Demyelinating Diseases. JAMA Neurol. 2014. doi: 10.1001/jamaneurol.2014.2633. [Epub ahead of print]

IMPORTANCE: Because vaccinations are common, even a small increased risk of multiple sclerosis (MS) or other acquired central nervous system demyelinating syndromes (CNS ADS) could have a significant effect on public health.
OBJECTIVE: To determine whether vaccines, particularly those for hepatitis B (HepB) and human papillomavirus (HPV), increase the risk of MS or other CNS ADS.
DESIGN, SETTING, AND PARTICIPANTS: A nested case-control study was conducted using data obtained from the complete electronic health records of Kaiser Permanente Southern California (KPSC) members. Cases were identified through the KPSC CNS ADS cohort between 2008 and 2011, which included extensive review of medical records by an MS specialist. Five controls per case were matched on age, sex, and zip code.
EXPOSURES: Vaccination of any type (particularly HepB and HPV) identified through the electronic vaccination records system.
MAIN OUTCOMES AND MEASURES: All forms of CNS ADS were analyzed using conditional logistic regression adjusted for race/ethnicity, health care utilization, comorbid diseases, and infectious illnesses before symptom onset.
RESULTS: We identified 780 incident cases of CNS ADS and 3885 controls; 92 cases and 459 controls were females aged 9 to 26 years, which is the indicated age range for HPV vaccination. There were no associations between HepB vaccination (odds ratio [OR], 1.12; 95% CI, 0.72-1.73), HPV vaccination (OR, 1.05; 95% CI, 0.62-1.78), or any vaccination (OR, 1.03; 95% CI, 0.86-1.22) and the risk of CNS ADS up to 3 years later. Vaccination of any type was associated with an increased risk of CNS ADS onset within the first 30 days after vaccination only in younger (<50 years) individuals (OR, 2.32; 95% CI, 1.18-4.57).
CONCLUSIONS AND RELEVANCE: We found no longer-term association of vaccines with MS or any other CNS ADS, which argues against a causal association. The short-term increase in risk suggests that vaccines may accelerate the transition from subclinical to overt autoimmunity in patients with existing disease. Our findings support clinical anecdotes of CNS ADS symptom onset shortly after vaccination but do not suggest a need for a change in vaccine policy
You can read the conclusions