#T4TD – Prof G's MS Blog Archive

#T4TD: pneumonia

Barts-MS rose-tinted-odometer: zero-stars

#T4TD (thought for the day)

How bad is your breathing and lung function?

Every year a few of our patients with advanced MS die. During the first COVID-19 lockdown I received an email from the husband of one of my patients I had been looking after for over a decade. Thankfully she died peacefully in her sleep. Her MS had affected her swallowing to such an extent that she had to have a feeding tube inserted into her stomach for feeding. Prior to the feeding tube, she was getting recurrent chest infections. Her speech was also very poor and at times I couldn’t really understand what she was saying. Her other complications included intermittent pressure sores and frequent bladder infections.

A common cause of unscheduled hospital admissions and sadly death is aspiration pneumonia. This is when people with MS have poor coordination of their swallowing mechanism and instead of swallowing saliva and/or food properly some of it travels down the trachea or windpipe into their lungs and causes pneumonia.

At the same time, people with swallowing difficulties may have weakness of their muscles of respiration, in particular, the diaphragm. The cause of diaphragmatic weakness is usually lesions in the upper cervical spine. However, it is often made worse by poor posture. For the diaphragm to work properly it needs to be able to move downwards into the abdominal cavity without being impeded; sitting upright and not hunched over help. Seeing a physiotherapist is important to correct your posture and to make sure your wheelchair if you are using a wheelchair, has the correct postural supports. There has been a lot of wheelchair innovation recently with the production of bespoke moulded body supports to keep you sitting straight and upright.

When the diaphragm is weak the so-called accessory muscles of respiration help a person breath. The accessory muscles lift the thorax or chest as the weak diaphragm pushes downwards. The accessory muscles actually work as a pulley and then rely on gravity to lower the chest. So for the accessory muscles to work well you need to be sitting upright; as soon as you lean back or lay down you reduce the effect of gravity and the accessory muscles’ ability to function as a pulley.

When we look at how well your breathing capacity is we often measure your so-called vital capacity, i.e. how much air you can move in and out of your lungs. A normal vital capacity is around 60-70 mL/kg; so a 70kg person has a vital capacity of about 4.5-5.0 litres. When the vital capacity drops below about 20-30ml/kg it is associate with a reduced ability to cough and move mucus plugs out of your lungs. When your cough reflex is weak it puts you at risk of segments of the lung collapsing (atelectasis) and becoming infected.

When your vital capacity drops below 15mL/kg you are in serious trouble and are likely to be in or close to respiratory failure and your blood gases (oxygen and carbon dioxide) may be affected.

When I was a trainee neurologist in South Africa we used to carry around a vital capacity flow metre on our ward consult rounds. This was to assess respiratory function in patients admitted with paralysis from nerve or muscle disease. These vital capacity meters were expensive and in short supply and we didn’t own them and some hospitals didn’t have them. Nowadays you can purchase relatively cheap vital capacity meters that connect to a smartphone.

At Baragwanath hospital, now called the Chris Hani hospital, in Soweto (South Western Township) outside Johannesburg, we used to use low tech clinical signs. The first was how many numbers could someone count at a rate of one number per second on a single breath-hold, whilst sitting-up. If the person couldn’t get to 12 they needed to be seen by the respiratory intensive care team. The other test was whether or not the patient could blow out a lit match or candle held 30cm from their face. The use of a lit match or candle was not really allowed on the wards because of the fire risk, particularly if patients were on oxygen therapy, but the Baragwanath consultants ignored health and safety and used the test anyway. It is important to realise that if someone can’t blow out a lit match or candle at 30cm then their ability to cough is likely to be compromised and they are therefore likely to at risk of collapsing part of their lung and getting a serious lung infection.

Another important clinical sign is simply to listen to a person speak. If their speech is not smooth, but soft and broken up with frequent pauses to take a breath, also indicates a problem with their breathing. You can also ask the person to cough; if the quality of the cough is poor and weak that can also be taken as a sign of weak respiratory muscles.

A mistake that many people make is to use a so-called peak flow meter and pulse oximeter to monitor lung function. These two devices are not suitable for pwMS. The peak flow is really best for people with asthma and bronchospasm and the peripheral blood oxygenation as measured with a pulse oximeter only becomes abnormal very late. Although a pulse oximeter is good to monitor lung function when you have an infection, such as COVID-19 pneumonia, or when someone has a pulmonary embolus (blood clot in the arteries to the lung) it is not a good measure of your respiratory reserve.

If you have advanced MS with swallowing or breathing problems you may want to self-monitor yourself. You need to see a speech therapist to have your swallowing assessed. If your swallowing is compromised you may need to change your diet; for example, if you are choking or coughing when drinking liquids you may need to use thickened liquids. It is also important to have regular home chest physiotherapy to prevent sections of your lung collapsing and to lung muscle exercises. The physiotherapists use so-called incentive spirometers to make the lung exercises fun. I know all about these devices; I had to do incentive spirometry four times a day in the first few weeks after my accident to prevent lung atelectasis.

It is also important that your family and carers have basic first aid training and can do a pharyngeal sweep and/or Heimlich manoeuvre to dislodge food stuck in your throat. Portable pharyngeal suction or vacuum devices can also be purchased and kept at home to clear the throat. If you go this route then your carers and family will need to be trained in how to use them.

If this post is relevant to you because you have advanced MS or you have a family member or patient with advanced MS it is important to ask them if they have an advanced directive. An advanced directive is a legally binding document setting-out how you want to be managed if you ever end up with life-threatening medical complications of having MS. For example, do you want advanced life support or not? It is important that your family doctor, hospital team, family members and carers have a copy of this directive so that they can ensure your wishes are carried out if ever the need arises.

Finally, please make sure you have had your vaccine requirements reviewed. You need your annual flu vaccine, the pneumococcal vaccine if you have not had one on the last 5 years and a COVID-19 vaccine.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#T4TD Anticholinergics

Are you taking anticholinergics?

It is clear that centrally acting anticholinergic drugs, which block so-called muscarinic receptors, are being used by many people with multiple sclerosis as DIY agents to promote remyelination. The scientific rationale for this practice is based on preclinical work in cell culture systems and animal models and one proof-of-concept study of clemastine in pwMS with previous optic neuropathy.

Is this practice wise? I say no. We need properly controlled large studies to confirm the results and show that clemastine and other drugs in this class are remyelinating, have a clinical effect that is meaningful and improve quality of life.

Why am I being so pessimistic? The problem is centrally-acting anticholinergic affect cognition. Oxybutynin, a first-generation CNS-penetrant anticholinergic, which is commonly prescribed for urinary frequency, reduces the average IQ of someone with MS by 7 points or half a standard deviation. This is a massive drop in cognitive function particularly if you already have cognitive impairment, which may be overt or hidden and is very common in pwMS.

I have been waging a war with many continence services who look after my patients who still use oxybutynin because it is cheap. There are many alternative newer anticholinergic agents that don’t penetrate the CNS or work on a different mechanism. So if you are on oxybutynin you need to switch drugs.

Lessons from the opicinumab phase 2 remyelination trial suggests that only a subset of pwMS are likely to benefit from a remyelinating agent. This is because not everyone with MS has demyelinated axons or nerve fibres that need remyelination. The estimate is that in pwMS with moderate disability (EDSS 2.0-5.5) only a third will benefit from a remyelinating agent. So if you are taking clemastine you may be taking a hit on your cognition when you don’t even know if you are one of those people who has a population of nerve fibres that are ready to be remyelinated.

For how long do you have to take a remyelination drug to achieve maximum benefit? Provided your MS is under control with an anti-inflammatory DMT and you are not demyelinating new axons you may only need a remyelination agent for a few weeks or months. Once you have stimulated remyelination and all the naked axons are remyelinated there is no need to continue taking the remyelination agent.

Please note these concepts about remyelination are based on animal models and early trials and are mostly hypothetical when it comes to pwMS.

Another worrying observation about anticholinergic drugs is that the impact on cognition may be irreversible and reduce your brain reserve. Several epidemiological studies have shown that in the general population 2-3 years of continuous anticholinergic exposure increases your risk of getting dementia by ~30%. Whether this is applicable to pwMS is at present unknown, but I can’t think of any reason why the MS brain would be less susceptible to anticholinergics; in fact, I suspect the MS brain may be more susceptible as pwMS have reduced brain and cognitive reserve.

So if you are taking off-label clemastine for its unconfirmed benefits in MS or another anticholinergic that is CNS penetrant my advice would be to stop taking them and to seek alternative cognition-friendly medication.

Please be aware that there are many drugs that have anticholinergic effects; the following website lists them. In addition, apart from blunting cognition the list of side effects attributable to anticholinergics includes the following:

Dry mouth
Difficulty in swallowing
Constipation
Paralytic ileus (paralysis of the bowl)
Nausea or vomiting
Increased heart rate
Urinary retention
Difficulty in urinating
Blurred vision
Dry eyes
Exacerbation or precipitation of acute angle-closure glaucoma
Decreased sweating
Drowsiness or sedation
Dizziness
Hallucinations
Deliriums
Restlessness
Irritability
Nervousness
Slurred speech
Impaired concentration
Confusion
Memory impairment

Postscript 1: I have been asked which of the anticholinergics used for MS-related bladder dysfunction are the safest. The table below indicates that Trospium is by far the least CNS penetrant; is the least lipid-soluble and the most positively charged. It is clear that oxybutynin is the worst. Tolterodine, darifenacin and solifenacin are in between.

Source: Chancellor M, Boone T. Anticholinergics for overactive bladder therapy: central nervous system effects. CNS Neurosci Ther. 2012;18(2):167-174. doi:10.1111/j.1755-5949.2011.00248.x

Postscript 2: I have also been asked about what dose of drug X or drug Y is sufficient to cause anticholinergic cognitive effects. A good example on this list is Amitriptyline; just 10mg of Amitriptyline per day is sufficient.

Source: Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175(3):401-407. doi:10.1001/jamainternmed.2014.7663

#T4TD = Thought for the Day

CoI: nil in relation to this post

#T4TD onychogryphosis

When last did you cut your toenails?

In patients who I think are vulnerable, I always try to take the time to look at their feet. Unfortunately, because of COVID-19-induced NHS service changes, this is very difficult using telemedicine.

Poor foot hygiene and uncut toenails are in my experience an integrator of neglect. As the feet are generally hidden from view people with MS often neglect their foot hygiene more than other aspects of their grooming. Poor foot hygiene is not intentional, but simply represents the reality of living with a disability. Poor eyesight, double vision, oscillopsia, weakness, tremor, loss of feeling in the hands, slow movement, incoordination, obesity, etc. are all more common in pwMS and make cutting your own toenails difficult.

During COVID-19 lockdown nail bars have been closed and podiatrists have not been seeing patients; therefore, I suspect general foot hygiene may have deteriorated in many people with more advanced MS.

There is little doubt that MS or physical disability is a risk factor for onychogryphosis; in plain English overgrown and neglected toenails. Onychogryphosis makes it difficult to wear shoes, causes pain and may even put mobile patients at risk of falls. So if you can’t manage to look after your own feet I suggest post-lockdown setting-up regular appointments to have your toenails cut and your feet examined by a podiatrist. Please note in the UK podiatry is an NHS service.

Marginal gains, i.e. focusing on small differences which add up can make big differences to the quality of life and health outcome for people with MS, and this should include foot hygiene and taking care of your toenails. This is just another factor that HCPs need to consider if they want to manage MS holistically.

#T4TD = Thought for the Day

CoI: nil in relation to this post

#T4TD Infected

Did you know that a third of relapses are triggered by infections, typically non-specific viral infections?

The observation that a relapse is more likely to occur in the so-called ‘at risk’ period, typically 5-6 weeks after infection than at other times predates the disease-modifying therapy era of MS. The mechanism is thought to be that infection boosts the immune system non-specifically, which then trigger relapses. This observation was extrapolated to vaccinations, but most vaccine studies now show that vaccines in general, with the possible exception of the yellow fever vaccine*, are safe and are not associated with an increased risk of relapses nor MRI activity.

* Please note recent data on the live yellow fever vaccine shows that it doesn’t trigger MS relapses.

Once people are on an effective DMT the link between infections and relapses is not observed. This is another, albeit minor, reason to be on a DMT. However, there is an emerging field in basic science and clinical evidence to support it that recurrent infections drive some of the pathological processes that are responsible for smouldering MS. Systemic inflammation activates CNS microglia that then produce cytokines and inflammatory mediators that have a negative effect on neuronal function. This is why people with MS handle infections so poorly and often don’t get back to baseline after a severe systemic infection.

Therefore as part of the holistic management of MS, it is a good idea to prevent chronic or recurrent infections. So if you have recurrent or chronic bladder infections, periodontitis (gum disease), chronic sinusitis or recurrent chest infections you need to do something about it. Don’t just accept recurrent infections as your lot in life ask your MS team for advice and help.

#T4TD = Thought for the Day

CoI: nil in relation to this post

#T4TD when it comes to Anti-CD20 therapy body size counts

Did you know that if you are a large person standard dose ocrelizumab is not as effective as it is in a small person?

When looking at the efficacy of anti-CD20 therapies such as ocrelizumab you shouldn’t bother looking at relapses and focal MRI activity (Gd-enhancing lesions or new T2 lesions) when comparing effectiveness between doses and competing products. Relapses and MRI lesions are ultrasensitive to the effects of anti-CD20 therapies and are suppressed, to almost zero, at relatively low doses. In scientific measurement-speak we refer to this as a floor effect; in other words, you can’t go lower than zero or near-zero.

However, when you look at disability progression (the real MS) there is clearly a dose effect, i.e. the higher the dose of ocrelizumab relative to body size, the greater the B-cell depletion and the less likely you are to progress. Most commentators miss this insight and are lulled into a false sense of security by seeing the relapse and MRI data when the real MS may be smouldering away and shredding your brain unabated.

For this reason, we really need to do studies with higher doses of ocrelizumab and almost certainly higher doses of rituximab and ofatumumab. The observation that rituximab, at relatively low doses, doesn’t prevent the majority of pwMS becoming secondary progress is not surprising when it seems we need more intensive and not less intensive B-cell depletion.

There are two hypotheses that could explain the dose-effect of ocrelizumab: (1) CNS penetration and the need to scrub the brain free of B-cells, or (2) really deep tissue B-cell depletion. Higher doses of ocrelizumab may achieve both of these. The real question is what is it about B-cells that is driving MS?

Those of you who are up to speed with safety and vaccine readiness data will argue that higher dose ocrelizumab will come with a price. Yes and no. Until we do the studies we won’t know. In relation to vaccine responses, I suspect there will be little difference between low and high dose ocrelizumab as both will almost certainly ablate germinal centre function.

In terms of long-term safety, I suspect we may not need to use high-dose or very high-dose anti-CD20 therapy long term; we may get away with using it as an induction therapy followed by a maintenance therapy.

Does this have implications for you as an individual? Yes, don’t accept your neurologist saying your disease is under control simply because you are relapse and MRI activity free; remember smouldering MS is the real disease. There are now compelling reasons why we need to do the double-dose ocrelizumab trial or DODO study and other add-on studies to target smouldering MS. Do you agree?

#T4TD = Thought for the Day

CoI: multiple

#T4TD falls and fractures

Did you know that people with MS have a six times higher risk than age-matched controls of having a long bone fracture of the lower limb?

The reason for this is that pwMS often have balance problems, unsteadiness of gait (ataxia), lower limb weakness (dropped foot) and are maybe excessively sedated from their medications. All these factors increase your chances of falling. In addition, pwMS are at high risk of poor bone health (osteopaenia or osteoporosis) due to inactivity, reduced outdoor activity, low vitamin D levels, steroid treatment and comorbidities such as smoking.

falls + poor bone health = increased long bone fractures

Why is this so important? A lower limb long bone fracture is one of the events that can tip someone with MS from being independent into becoming dependent and is often the trigger for needing a wheelchair. In addition, people with advanced MS don’t rehabilitate very well because they have reduced reserve and are usually quite disabled.

How do you know if you are at risk of falls and fractures? We have shown that the best predictor of falls is the need for a walking aid (splint, stick, crutch, frame, functional electrical stimulator, etc.). If you are using a walking aid and are having falls, or near falls, you need to see a physiotherapist to be enrolled in a falls prevention programme and you will also need to have your bone density checked. This latter can be assessed via several methods, but the commonest is called a DEXA scan (dual-energy X-ray absorptiometry scan). If you are found to be osteopaenic or osteoporotic you may need treatment.

Falls and fracture prevention is another self-management task; please don’t ignore it!

Prevention is better than treating the consequences of falls and fractures. For example, one of my patients with MS tragically fell going to the toilet at night. She crashed into a mirror that shattered and lacerated her arm and severed her brachial artery. She tragically bled to death as she lived alone, did not have an alert dongle around her neck and was unable to get herself up off the floor. Ever since she died I have taken falls prevention very seriously. Can you please do the same? You never know it may even save your life.

Long bones of the lower limbs = femur, tibia and fibula

#T4TD = Thought for the Day

CoI: none for this post

#T4TD vascular comorbidities

Did you know if you have MS and vascular comorbidity you are likely to need a walking stick approximately 6 years earlier than if you did not have vascular comorbidity? Importantly this 6-year difference in reaching EDSS 6.0 (requiring a walking stick) is larger than the treatment effect of a platform DMT.

As vascular comorbidities are largely preventable are you doing anything to prevent or optimally treat your own comorbidities? If not, you need to ask yourself why not? Self-management and taking responsibility for your own health is the order of the day; this has become the new normal.

Vascular comorbidities = diabetes, hypertension, heart disease, hypercholesterolemia, peripheral vascular disease and smoking.

#T4TD = Thought for the Day

CoI: none for this post

#T4TD menstruation

Women with MS may notice increased fatigue and intermittent symptoms in the second half of their menstrual cycle and during menstruation. Why?

After ovulation, a woman’s body temperature rises by ~0.4℃ (range = 0.3 to 0.6℃) which in someone with MS is enough to cause temperature-dependent conduction block. In addition, the process of menstruation involves a mild systemic inflammatory reaction that may exacerbate fatigue. I refer to this as catamenial fatigue.

Catamenial = relating to or associated with menstruation

Over the years I have had several female patients with MS who have reported using aspirin or non-steroidal anti-inflammatories or paracetamol (acetaminophen) to self-manage these two periods of their cycle. Interesting?

If you suffer from catamenial fatigue you may want to try one of these agents that almost certainly work by lowering body temperature.

#T4TD = Thought for the Day

CoI: none in relation to this post

#T4TD Intermittent diarrhoea?

Did you know constipation with intermittent diarrhoea may mean you have faecal impaction?

The majority of people with MS who have bowel problems suffer from constipation. This occurs because the MS bowel is sluggish due to reduced motility. This can be made worse by anticholinergic drugs that are used for treating urinary frequency and urgency. Over time pwMS may impact their bowels with faeces, which can form a faecolith (faecal stone). Above the hard and impacted faeces or faecolith, the gut bacteria overgrow and liquefy the stool, which is then able to bypass the impaction and cause diarrhoea.

So if you suffer from chronic constipation and intermittent diarrhoea you need to contact your HCP for help.

Please note another cause of this problem is cyclical use of laxatives, i.e. you get constipated and then you use laxatives to treat your constipation. The laxatives then cause diarrhoea so you stop taking them. You then become constipated again and the cycle repeats itself.

To manage MS-related constipation you really need to:

Optimise your diet by eating lots of fibre.
Don’t dehydrate yourself. Drink plenty of water and don’t equate caffeine and alcoholic beverages as hydrating. Both caffeine and alcohol cause the kidney to make more urine (diuresis) and are in fact dehydrating.
Try and eliminate concomitant medication that exacerbates constipation (anticholinergics and opioids).
Exercise regularly; the anticipation of exercise and exercise stimulates a defaecation reflex.
If you need to use laxatives start with a prokinetic agent that stimulates the bowel to move, for example, senna, and then add-in bulking (e.g. psyllium husks or other fibre substitutes) followed by liquifying agents (lactulose or polyethylene glycol).
Don’t suppress the need to go to the toilet; a lot of people with chronic constipation have learnt bad habits, for example, they don’t like using toilets that are unfamiliar to them.

#T4TD = Thought for the Day

CoI: none

#T4TD Feeling tired this morning?

Did you know that as many as 1 in 5 people with MS suffer from obstructive sleep apnoea?

Obstructive sleep apnoea occurs when your breathing stops and starts while you sleep. It typically occurs due to a collapse in the tone of the muscles in your throat. The main symptoms of sleep apnoea include making gasping or choking noises while you sleep, snoring loudly, waking unrefreshed with a muggy feeling as if you have a hangover, feeling very tired during the day and frequently falling asleep in the day.

Sleep apnoea is usually treated with a CPAP (continuous positive airway pressure) mask that you wear while you are asleep. Although sleep apnoea is associated with obesity and getting older it can occur in people who are thin with a normal BMI (body mass index). It is very common in MS and is likely to be due to MS lesions affecting the function of the brainstem.

If you identify with any of these symptoms you need to raise the issue with your HCP so that you can be investigated. Sleep studies to diagnose sleep apnoea can even be done at home using portable devices.

#T4TD = Thought for the Day

CoI: none