Turkeys voting for Christmas

Barts-MS rose-tinted-odometer: ★★★ (dollar color Monday hex #6B8068)

Did you know that the effectiveness of high-dose steroids to treat a relapse is small? In reality, there is no difference in outcome at 6 months between relapses treated with steroids and those managed without steroids. In reality, high-dose steroids simply speed up recovery of function by about 2 weeks. So if you are not disabled by your relapse and it has not affected your day-to-day functioning it is better not to have them.

High-dose steroids don’t come without risks, i.e. psychosis, insomnia, depression, avascular necrosis of the hip, hypertension, diabetes, infections, blunted vaccine responses, higher risk of severe COVID-19, etc. So then why do we prescribe them so frequently? Money, money, money!

In many fee-for-service healthcare systems, neurologists and healthcare institutions make money out of admissions and intravenous infusions, which acts as a perverse incentive to prescribe steroids. The good news is that high-dose oral steroids for relapses, taken as an outpatient, work as well. 

The French study below shows how much money could be saved from shifting from inpatient intravenous to outpatient oral steroid use (25 million euros per year in France). I doubt this will change behaviour when there is money to be earned. As the saying goes ‘turkeys voting for Christmas’; not on your life. 

So the next time you are offered inpatient-intravenous steroids for a relapse you should ask for home-oral steroids instead and see what response you get from your HCP.

Michel et al. Cost-utility of oral methylprednisolone in the treatment of multiple sclerosis relapses: Results from the COPOUSEP trial. Rev Neurol (Paris). 2021 Sep 28;S0035-3787(21)00664-0. 

Background: Studies have shown that oral high-dose methylprednisolone (MP) is non-inferior to intravenous MP in treating multiple sclerosis relapses in terms of effectiveness and tolerance. In order to assist with resource allocation and decision-making, its cost-effectiveness must also be assessed. Our objective was to evaluate the cost-utility of per os high-dose MP as well as the cost-savings associated with implementing the strategy.

Methods: A cost-utility analysis at 28 days was carried out using data from the French COPOUSEP multicenter, double-blind randomized controlled non-inferiority trial and the statutory health insurance reimbursement database. Costs were calculated using a societal perspective, including both direct and indirect costs. An incremental cost-effectiveness ratio was calculated and bootstrapping methods assessed the uncertainty surrounding the results. An alternative scenario analysis in which MP was administered at home was also carried out. A budgetary impact analysis was carried at five years.

Results: In the conditions of the trial (hospitalized patients), there was no significant difference in utilities and costs at 28 days. The incremental cost-effectiveness ratio was €15,360 per quality-adjusted life-year gained. If multiple sclerosis relapses were treated at home, oral MP would be more effective, less costly and associated with annual savings up to 25 million euros for the French healthcare system.

Conclusions: Oral MP is cost-effective in the treatment of multiple sclerosis relapses and associated with major savings.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

Twitter   /  LinkedIn  /  Medium

General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

#MSCOVID19 – a pyrrhic victory

Some of you may have read and being appalled by the following piece in this morning’s Guardian.

Robert Booth. Coronavirus: real care home death toll double official figure, study says. 13th May 2020

Excerpt: “More than 22,000 care home residents in England and Wales may have died as a direct or indirect result of Covid-19, academics have calculated – more than double the number stated as passing away from the disease in official figures.”

The hidden burden of COVID-19 goes way and beyond care homes. I was on a Zoom video conference with my UK colleagues last week and each person was asked about their centre’s COVID-19 experience. Almost everyone had had a COVID-19 related MS death. The tragedy was the deaths tended to be in older people with MS who were more disabled and with comorbidities. I am aware of two MS deaths in our patch, both bed-bound with end-stage MS. Whether or not these patients died from COVID-19 related problems is unknown. Both deaths have been ascribed to complications of MS. 

Forget about the deaths what about MS disease activity? Before COVID-19 it was very unusual to have patients on established DMTs have severe relapses. Severe attacks were typically seen in patients presenting with their first attack or in patients who were non-adherent to their DMTs. 

Since the lockdown, I have had three patients who have had severe relapses waiting to be initiated on treatment. One who has been furloughed and decided to be locked-down in her parents home far away from London. One waiting to start a DMT, but had delays in relation to baseline screening bloods and making a decision about treatment. As she has now had a severe and disabling brainstem or cerebellar relapse this shifts her into the high-disease activity group so she is now eligible for natalizumab. The latter could be viewed as some kind of “COVID-19 pyrrhic victory” as she now gets to be put on a high efficacy therapy. Fortunately, she is young so she should make a reasonable recovery from the relapse, but the damage has been done and some of her precious brain reserves has been shredded and lost forever. 

The final patient is a bit of a procrastinator and he decided to delay starting his treatment until after the peak of the COVID-19 epidemic. If there was no COVID-19 he would have almost certainly be treated two months ago, which would have potentially prevented the relapse. 

I would be interested to hear if any of you have had similar experiences, i.e. poor outcomes due to a delay in your treatment or untoward events due to your MS service being mothballed during the COVID-19 crisis.

I have little doubt that people with MS will be paying the price for COVID-19 for years to come. I suspect many will have been started on lower efficacy DMTs, some will have had their DMTs stopped or switched to lower efficacy or supposedly safer DMTs, others would have had their treatment initiation delayed and other would have had repeat dosing postponed to some yet to be determined date in the future. In addition, many people with very active MS who were lined-up to undergo HSCT have had their procedure delayed indefinitely. 

I wonder what the true cost of the above will be for people with MS?

CoI: multiple

#MSCOVID19: assessing and managing relapses remotely

Can we assess MS relapses remotely? 

Yes, I think we can. Most neurological assessments are based on history and examination. You definitely can take a history of new-onset neurological symptoms by telephone, or preferably using video consultation. I am currently using accuRx the most widely adopted NHS platform for remote consultations. It is remarkably easy to use and satisfaction levels are very high for both clinicians and patients. In addition, you can also do a brief or truncated neurological examination using a video link. I am beginning to ask some of my patients to complete a battery of online assessments (webEDSS, 9PHPT, T25W) and PROMS (MSIS-29) to document the impact of the relapse on their physical functioning.

Once you have documented a relapse the question arises should you treat the relapse with steroids? 

At the moment I am trying to avoid steroids for relapses. Why? In general, the benefits of steroids in the treatment of relapses are quite small. They essentially speed-up the recovery by about 2 weeks. At 6-months the level of recovery from a relapse, as assessed by EDSS, is the same whether or not you have steroids. When you tell patients this they often agree not to be treated, particularly when you mention the potential side effects of high-dose steroids, i.e. avascular necrosis of the hip, steroid psychosis, diabetes, hypertension, insomnia and infections.

Despite this, some patients still prefer to be treated. This raises the question of IV (intravenous) versus oral. There have been several studies showing that there is no difference between high-dose IV or oral steroids in terms of relapse outcome. Therefore, in the current COVID-19 environment, when we are trying to avoid patients having to travel and come to the hospital, oral steroids are the prefered route. The steroids can be dispensed via your general practitioner or through our pharmacy with courier delivery if you live locally (within London or in the home counties).

Before starting steroids it is good to get some basic things done to try and de-risk the adverse events. This includes a recent blood pressure; we don’t want to prescribe high-dose steroids to someone with uncontrolled hypertension. Nowadays most people have access to some form of home BP measurement device. 

If you have a history of recurrent urinary tract infections it is always advisable to have a urine dipstick done to make sure you don’t have an asymptomatic infection. Five days of steroids are sufficient to blunt your innate immune response, which has the potential to allow a bacterial urinary tract infection to become a systemic infection and to cause septicaemia. I learned a hard lesson early my MS career when I agreed for a patient to have his relapse treated by his GP without considering a UTI. The patient was admitted to ITU on day 4 of his course of oral steroids in septic shock and nearly died.  A lesson to take UTIs seriously.

It is also important to make sure the relapse is not a pseudo-relapse, which are often triggered by a UTIs in patients with more advanced MS. 

Not all patients have urine dipsticks at home, which is why you may have to attend your local GP practice or come to the hospital to get this done. Another solution is to purchase urine dipsticks online and do the test yourself. The latter is an example of taking control and self-managing your MS or UTI. 

Please be aware in the context of a UTI the dipsticks assess two main things; (1) urine nitrite levels and (2) the presence of esterase and enzyme that is produced by white blood cells or leukocytes. Please be aware that about a third of UTIs are caused by bacteria that don’t produce nitrate reductase, the enzyme that converts nitrates to nitrite, so your urine, even if you have a UTI, maybe negative for nitrites, however, it should be positive for white cell esterase if you have a significant infection.

In summary, to diagnose a probable UTI you need white cells and possibly nitrites to be positive on the dipstick. Other abnormalities that can be found with UTIs are a raised protein and red blood cells, which are also detected on most commercial dipsticks. However, positive protein and red blood cells in the absence of the white cells and nitrites are not indicative of a UTI and can be caused by other pathologies.

If you have doubt about interpreting the dipstick you can always take a photograph of it and send it to your MS nurse, GP or neurologist for interpretation. If you have a UTI it is advisable to get your urine cultured in a laboratory and to start a course of antibiotics. The antibiotics can be changed if the culture grows a bacteria that is resistant to the antibiotic you are on. To get a culture done you need to drop-off fresh urine to your GP that needs to be sent to the laboratory within two hours. Please note you will have to collect a prescription for antibiotics from your GP. I personally like you to start your antibiotics for at least 24 hours before starting steroids.

If you are overweight or obese and have a family history of diabetes it is also worthwhile getting your blood glucose checked. We don’t want to give high-dose steroids to someone who has uncontrolled diabetes. Blood glucose is checked using a finger prick test that can be done by your GP or anyone who has a glucose home testing kit. 

Will high-dose oral steroid put you at risk of COVID-19 or severe COVID-19? 

I don’t know the answer to this question. However, significant immunosuppression is only considered to occur with a prolonged course of steroids, i.e. longer than 3 weeks at a dose of greater than 20mg of prednisone per day or equivalent.  Therefore the level of immunosuppression with a short 5-day course of high-dose 500mg/day of methylprednisolone is relatively low. Although this is medical dogma there is good scientific evidence that high-dose steroids blunt innate immune responses, i.e. neutrophil and monocyte/macrophage responses to infection, which is why short-term steroids can cause UTIs to become systemic. The blunting of the innate immune response may be important in the early stages of COVID-19. Because of this, I am telling my patients who opt for steroid treatment to self-isolate for a period of 14 days after completing the 5-day course. The logic of this is simple; with a lack of evidence, it is better to be safe than sorry. 

In addition to 500mg/day of methylprednisolone for 5-days, I also prescribe lansoprazole 30mg daily for 14 days to protect you from steroid-induced gastritis. I am aware that not all neurologists prescribe gastric protection with high-dose steroids. Steroid-induced gastritis is not an uncommon problem and the last thing you need is an upper GI bleed that needs hospitalisation.

If you have diabetes and/or hypertension it is important to monitor your blood sugars levels and blood pressure whilst you are on steroids in case your medications need to be adjusted. 

The one side effect that worries me the most is steroid-induced hypomania, psychosis and depression. I have a handful of patients in my career that have had to be sectioned because of psychosis. It is important to be mindful of the mood-altering effects of steroids and if necessary seek help. I always warn partners or family members of the possibility of hypomania, psychosis and depression and that it is better to address these as soon as possible if they occur. The good news is that steroid-induced psychosis tends to respond to treatment relatively quickly.

Another side effect that is common is steroid-induced insomnia. If you have a history of this please ask for a short course of sedatives to help you sleep. The sedatives are only needed for 4 to 5 days and shouldn’t be taken for longer than this.

As you can see assessing and treating relapses remotely is possible, but on balance we should try and avoid using steroids.

If you any queries I will happy to ask them. I will also post this information to MS-Selfie, my COVID-19 and MS microsite.

Temperature Sensitivity

Are you temperature sensitive? 

In my experience the vast majority of pwMS are affected by changes in temperature; typically it is hot or cold temperature that triggers changes in central nerve conduction velocity that brings on old symptoms. One of my patients reports becoming paralysed if sits outdoors in the sunshine for as little as 30 minutes in the middle of summer. Other report worsening of their cognitive fatigue with relatively minor changes in temperature.  Women post-ovulation raise their body temperatures by about 0.5C; in some woman this enough to incapacitate them. I call this catamenial temperature-related fatigue and it often responds to non-steroidal anti-inflammatories and maybe the reason why aspirin has been shown to improve MS-related fatigue. 

This Korean study below is fascinating. They show that short-term exposure to wide diurnal temperature ranges (DTRs), which have become increasingly common as a result of climate change, is associated with an increased risk of visits to A&E (emergency departments). The was an ~9% change in the odds ratio per 1 °C increase in the diurnal temperature range. If this data is reproduced then it will have a major impact on how we manage patients with MS as global warming ramps up. I suspect the many exacerbations triggered by hot weather may prove to be pseudo-relapses. I suspect this may be the ideal use of serum neurofilament levels; to differentiate relapses from pseudorelapses. Sorting out this old problem may prevent unnecessary MRI scans and more importantly reduce the use of corticosteroids use for possible relapse.

Please be aware that it is not only the ambient temperature that is important, fever can also result in worsening of symptoms. With the COVID-10 pandemic in full swing, I suspect many more pwMS will be monitoring their temperatures as an indicator of infection. I wonder how many of you are doing this? And if yes was it advised by any HCP?  

Byun et al. Association between diurnal temperature range and emergency department visits for multiple sclerosis: A time-stratified case-crossover study. Sci Total Environ. 2020 Feb 25;720:137565. doi: 10.1016/j.scitotenv.2020.137565.

Although multiple sclerosis (MS) has been the leading cause of neurologically-induced disability in young adults, risk factors for the relapse and acute aggravation of MS remain unclear. A few studies have suggested a possible role of temperature changes on the relapse and acute aggravation of MS. We investigated the association between short-term exposure to wide diurnal temperature ranges (DTRs) and acute exacerbation of MS requiring an emergency department (ED) visit. A total of 1265 patients visited EDs for acute aggravation of MS as the primary disease in Seoul between 2008 and 2014 from the national emergency database. We conducted a conditional logistic regression analysis of the time-stratified case-crossover design to compare DTRs on the ED visit days for MS and those on control days matched according to the day of the week, month, and year. We examined possible associations with other temperature-related variables (ambient temperature, between-day temperature change, and sunlight hours). Short-term exposure to wide DTRs immediately increased the risk of ED visits for MS. Especially, 2-day average (lag0-1) DTR levels on the day of and one day prior to ED visits exhibited the strongest association (an 8.81% [95% CI: 3.46%-14.44%] change in the odds ratio per 1 °C increase in the DTR). Other temperature-related variables were not associated with MS aggravation. Our results suggest that exposure to wider DTR may increase the risk of acute exacerbation of MS. Given the increasing societal burden of MS and the increasing temperature variability due to climate change, further studies are required.

CoI: multiple