Seizures, epilepsy, and MS

Any type of injury to the brain - whether focal or diffuse - can increase your risk of developing epileptic seizures. pwMS who have lots of lesions or significant atrophy are probably more at risk of developing epilepsy. The exact risk of epilepsy in MS has been a bit variable in reported studies. Because the absolute numbers of pwMS who also develop epilepsy is quite low, you need a really big cohort to see if there is any increased risk compared to people without MS. 

Another (I know I am obsessed) amazing Swedish registry study has looked into the risk of epilepsy in pwMS. They looked at all of their pwMS (14,545) and matched each person to 3 controls. Over the study period - it's just abstract at the mo so I can't see how long - the rate of epilepsy was 3.5% in the MS group vs 1.4% in the control group. Looking at subgroups of the pwMS, they found that the epilepsy rate was much higher (5.5%) in pwProgressiveMS vs 2.2% in pwRelapsingMS. Longer disease duration and higher EDSS were both associated with an increased risk of epilepsy.

There are a couple of caveats and confounders. There may be a diagnostic bias - pwMS may be over or under-diagnosed with seizures. DMTs themselves might increase the risk of having systemic and CNS infections which increase your risk of seizures. There are lots of other possible explanations for why this association might not be causal. I actually find it quite convincing because it makes biological sense and there is a clear dose-response relationship: the longer and the more active the disease, the higher the risk of epilepsy. 

This study shows clearly that pwMS are at a higher risk of epilepsy than age and sex-matched controls. The strong association between risk of epilepsy and both disease duration and EDSS implies that the effect is related to disease activity. I imagine that atrophy and focal lesions both drive the increased risk of seizures. Additionally, chronic inflammation itself may lead to alterations in brain networks which predispose to seizures independently of causing degeneration of focal lesions. 

This work is really important because epilepsy is another chronic disease which can impact substantially on your life and often necessitates long-term medications, many of which have nasty side effects and complex interactions with other drugs. 

These data are all retrospective and so - without full access to the paper yet - I am not sure how many of these people will have been treated in the pre-DMT era. They mention some people who have had MS for over 34 years, so clearly some of their cohort will have been treated initially with no, or low-efficacy, DMTs. If epilepsy risk is directly related to cumulative disease activity and neurodegeneration, I will be very interested to see how these figures change in the next 20 years. I imagine that with the advent of the big hitters - alemtuzumab, natalizumab, fingolimod, and now cladribine - and the move to targeting 'No Evident Disease Activity', the rate of epilepsy will drop towards the normal population rate. 

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Abstract

OBJECTIVE:

To determine the cumulative incidence of epilepsy in a population-based cohort of patients with multiple sclerosis (MS) and to investigate the association between epilepsy and clinical features of MS.

METHODS:

All available patients in the Swedish MS register (n = 14,545) and 3 age- and sex-matched controls per patient randomly selected from the population register (n = 43,635) were included. Data on clinical features of MS were retrieved from the Swedish MS register, and data on epilepsy and death were retrieved from comprehensive patient registers.

RESULTS:

The cumulative incidence of epilepsy was 3.5% (95% confidence interval [CI] 3.17-3.76) in patients with MS and 1.4% (95% CI 1.30-1.52) in controls (risk ratio 2.5, 95% CI 2.19-2.76). In a Cox proportional model, MS increased the risk of epilepsy (hazard ratio 3.2, 95% CI 2.64-3.94). Patients with relapsing-remitting MS had a cumulative incidence of epilepsy of 2.2% (95% CI 1.88-2.50), whereas patients with progressive disease had a cumulative incidence of 5.5% (95% CI 4.89-6.09). The cumulative incidence rose continuously with increasing disease duration to 5.9% (95% CI 4.90-7.20) in patients with disease duration ≥34 years. Patients with an Expanded Disability Status Scale (EDSS) score ≥7 had a cumulative incidence of epilepsy of 5.3% (95% CI 3.95-7.00). Disease duration and EDSS score were associated with epilepsy after multiple logistic regression (odds ratio [OR] 1.03, 95% CI 1.01-1.04 per year, p = 0.001; and OR 1.2, 95% CI 1.09-1.26 per EDSS step, p < 0.0001).

CONCLUSIONS:

Epilepsy is more common among patients with MS than in the general population, and a diagnosis of MS increases the risk of epilepsy. Our data suggest a direct link between severity of MS and epilepsy.

Are you what you eat?

Circumstantial evidence has suggested an association between diet and MS, but hard evidence proving a causal link has been lacking. 

A new multicentre, prospective, longitudinal cohort study from the USA tried to crack this problem. They recruited children with MS from 11 centres. 


People were included if they met the following criteria:

•           ‘high risk’ CIS or RRMS
•           Disease onset < 18
•           >= 2 silent MRI lesions
•           Disease duration < 4 years

Dietary intake was assessed using a special questionnaire completed by the participant or a caregiver. The main outcome of interest was the time to the first relapse.

219 people were included in the final analysis. Over about 2 years of follow-up, (median 1.8 years), 42.5% experienced at least one relapse.

They adjusted for age, gender, race, ethnicity, disease duration, BMI, total energy intake and use of DMT. After all of these adjustments, they found a significantly increased hazard ratio for each 10% increase in the proportion of the diet made up by fat (overall) and saturated fats. Conversely, the hazard ratio was significantly decreased for each extra 10% of the diet made up by vegetables.

A brief note on hazard ratios…

Hazard ratios are used to compare the time taken to some kind of adverse event between two groups. Examples of adverse events used in MS studies include relapse and disability progression. The ‘hazard’ is the probability of the adverse event occurring at any given time point. You can work this out as the number of people who experience the event at that time divided by the number of people who are left in the study. The hazard ratio is equal to the hazard in one group divided by the hazard in the other. A hazard ratio of less than 1 implies a protective effect.

So in this study it appears that getting a higher proportion of daily calories from fats in general, and saturated fats in particular, increased the risk of having another relapse in paediatric MS. Vegetable calories, on the other hand, appear to decrease the risk of further relapse. This is biologically plausible as there is some data suggesting that contents of the diet can lead to alterations in gut bacteria which may promote inflammation in the CNS.

I do not think these data show that saturated fats cause more active MS. While there is a clear correlation between dietary saturated fat content and the hazard of relapse, I am doubtful that this supports a causal relationship between diet and MS activity. 

First, as the authors acknowledge, dietary data were collected as a one-off at baseline, often reported by the patients themselves. This not only carries the risk of recall bias, but as a snapshot is unlikely to capture accurately what the participants’ ‘average’ diet looked like over time. 

Second, there are lots of possible confounding factors that might explain the increased correlation between relapse risk and increased fat intake. Increased fat intake might be associated with, for example, increased smoking and decreased physical activity, which may be independently associated with disease activity. 

Third, there is the possibility of reverse causation; that the fact of having more active MS changes people’s behaviour and predisposes them to eat more saturated fat and fewer vegetables. It is plausible, for instance, that the parents or guardians of children with more active MS are more likely to let them eat more sweets. There is no evidence to suggest whether this is the case or not from this study. The point is that there are lots of plausible reasons for why dietary contents might be associated with MS activity while not having any causal bearing on the disease.

All in all this is a good paper that, to be fair to the authors, does not make any outlandish claims and merely makes some interesting observations about the link between diet and MS activity. While there is very little harm in recommending a healthy lifestyle with a well-balanced diet and regular exercise, there is not enough here to conclude that saturated fats influence the course of MS.

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Abstract

Objective The role of diet in multiple sclerosis (MS) course remains largely unknown. Children with MS have a higher relapse rate compared with MS in adults. Thus, studying the effect of diet on relapse rate in this age group is likely to provide more robust answers.

Methods This is a multicentre study done at 11 paediatric MS centres in the USA. Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) with disease onset before 18 years of age and duration of less than 4 years were included in this study. Dietary intake during the week before enrolment was assessed with the validated Block Kids Food Screener. The outcome of the study was time from enrolment to the next relapse. 219 patients with paediatric RRMS or CIS were enrolled. Each 10% increase in energy intake from fat increased the hazard of relapse by 56% (adjusted HR 1.56, 95% CI 1.05 to 2.31, p=0.027), and in particular each 10% increase in saturated fat tripled this hazard (adjusted HR: 3.37, 95% CI 1.34 to 8.43, p=0.009). In contrast, each additional one cup equivalent of vegetable decreased the hazard of relapse by 50% (adjusted HR: 0.50, 95% CI 0.27 to 0.91, p=0.024). These associations remained with mutual adjustment and persisted when adjusting for baseline 25(OH) vitamin D serum level. Other studied nutrients were not associated with relapse.

Conclusions This study suggests that in children with MS, high energy intake from fat, especially saturated fat, may increase the hazard to relapse, while vegetable intake may be independently protective.