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.
In response to a comment from one of our readers, I am starting a series of posts called #MS-Selfie, which is derived from the term self-management. These posts are a long read but will help you manage your own MS.
Over the last few weeks, many of my posts have focused on MS-specific mechanisms underlying why pwMS become disabled and how DMTs can delay, or prevent, this damage from occurring. The message as always is to treat early and effectively, and if you want the best chance of doing well over your lifetime you need to consider flipping the pyramid and going for high-efficacy DMTs. I have also highlighted subtle, but potentially important differences, between the non-selective immune reconstitution therapies (NIRTs) and the more selective immune reconstitution therapies (SIRTs) and maintenance therapies in terms of their impact on end-organ damage markers and disability improvement. These two will almost certainly become more important as a treatment target in the next decade.
You may or may not know about Sir Dave Brailsford and his philosophy of marginal gains. Sir Dave applied a theory of marginal gains to cycling; he proposed that if the British team broke down everything they could think of that goes into competing on a bike, and then improved each element by 1%, they would achieve a significant aggregated increase in performance. He got the British Cycling to adopt this and the rest is history. Britain dominates the World Championships, Olympic Games, Paralympics and now the Tour de France with Team Sky. So what this got to do with MS?
If we approached the management of MS in the same way, we will almost certainly improve the outcome of British people living with MS. To optimise your outcome it is not good enough just to focus on MS DMTs, but all the factors that could worsen or improve your MS.
This is post is about one of these factors infections and bladder dysfunction.
Relapses and infections
Infections, in particular, viral infections, are a known trigger of relapse. You are more than twice as likely to have a relapse in the week prior to, or the 5 weeks after, an infection. In the study below infections in this paper were mainly symptomatic upper respiratory infections due to viruses, so the risk may be much higher if we could also count hidden or asymptomatic infections.
What do I mean by asymptomatic infections? We are continuously being exposed to new viruses that infect us but don’t necessarily cause symptoms. An example of this is the JC virus that causes PML (progressive multifocal leukoencephalopathy). When we initially become infected with the JC virus it does not cause any symptoms; it simply gets into our body and persists. It persists as an asymptomatic lytic infection. In the majority of us, persistent JC virus infection doesn’t cause any problems. Only if we become immunocompromised do we have a chance of this virus mutating and causing PML. Similarly, for the majority of us when we get infected with Epstein-Barr virus (EBV) it does not cause symptoms; only the minority of us get glandular fever or infectious mononucleosis. The same applies to another herpes virus called CMV or cytomegalovirus; asymptomatic infection is the rule. What is interesting about the herpes viruses is that they become latent in the body and reactivate every now and then. These reactivations of latent viruses are usually asymptomatic but are strong enough to stimulate the immune system and may trigger relapses. In fact, there is some evidence that this may actually be the case.
When I did my PhD I studied a marker of immune activation on a daily basis in pwMS over many months. I found that immune activation usually preceded the occurrence of new MRI lesions by a few weeks. Please remember new MRI lesions are the equivalent of subclinical relapses. I, therefore, proposed in my thesis that latent viral reactivations may be the factor responsible for this immune activation, which then triggers MS disease activity. This is one of the reasons why I am so interested in the viral MS hypothesis. Virus-induced MS exacerbations don’t have to apply to exogenous viruses only, i.e. viruses that come from outside the body but could also apply to endogenous viruses, i.e. viruses that reside in our bodies or genome. The latter refers to human endogenous retroviruses (HERVs). This is one of the hypotheses that underpins our Charcot Project. Can we treat MS by reducing endogenous viral reactivation (HERVs)? Can we treat MS by preventing reactivation of latent herpes viruses, in particular, EBV? This is why we are exploring add-on antiviral studies to see if we can prevent MS disease reactivation.
It is very difficult to avoid viral infections. The one thing you can do is have your annual flu vaccine and try to avoid coming into contact with people who are clearly ill and potentially shedding virus.
Please, note that the observation of infections triggering relapses is not limited to viral infections, but also applies to bacterial infections, in particular, urinary tract infections. This is why we have to improve the management of bladder problems in pwMS with the aim of preventing or reducing urinary tract infections (UTIs). PwMS with recurrent UTIs do worse than pwMS without UTIs. However, to prevent or reduce the frequency of UTIs you have to know how MS causes bladder problems and to deal with them.
Bladder dysfunction
Bladder dysfunction is the most common symptomatic problem I have to deal with in the clinic. More than 50% of pwMS have bladder problems. Bladder dysfunction in pwMS is one of the integrators of early damage, particularly spinal cord damage, and an early read-out of a poor prognosis. I, therefore, take symptoms of bladder problems seriously as it has implications around MS prognosis and its treatment. For example, if you have early bladder symptoms may choose a more effective therapy early on rather than take chance on a lower efficacy DMT waiting to see if you are a responder or not.
Why do pwMS who develop bladder dysfunction do worse than those who don’t have bladder symptoms? The bladder is a complicated organ with several neurological components that can be affected by MS and hence is sensitive to damage. The descending nerve fibres that travel from the brain to the lower spinal segments are very long and hence have a greater chance of being affected by MS lesions in their path to the bladder centre in the lower spinal cord. The same is true for motor fibres that control movement in the lower legs. The bladder, unlike the motor fibres to the leg, is more complicated because of the need to coordinate the different muscles. Therefore any progressive MS damage is more likely to manifest with bladder dysfunction early on. This is why I now include bladder problems in my list of poor prognostic factors in MS.
The bladder has two muscles that need to be coordinated in their action for the bladder to function normally. The detrusor or balloon muscle and the sphincter or valve muscles When the bladder is filling up the detrusor muscle has to relax to allow the bladder to expand with urine and the sphincter has to contract to keep the urine in the bladder. The opposite occurs when you pass urine; the sphincter or valve opens and the detrusor contracts to empty the bladder.
Hesitancy
What happens if the two muscles are not coordinated? This causes the symptom of hesitancy, i.e. when you try and pass urine the sphincter won’t open and you have to wait for the bladder to open; pwMS find this very frustrating. The sphincter can also close as you passing urine, which breaks up the urine stream or prevents you from emptying your bladder completely. The latter also causes dribbling. The medical term for incoordination of the bladder muscles is dyssynergia or more correctly detrusor-sphincter-dyssynergia (DSD). The drug treatment for DSD includes the so-called alpha-blockers ( prazosin, indoramin, tamsulosin, alfuzosin, doxazosin and terazosin). Other strategies include small bladder stimulators or vibrators; these are placed over the pubic area and work by blocking signals that inhibit the sphincters. The vibrators work in some pwMS and may help relax the sphincter. It is also important to try and relax when passing urine; this often helps improve hesitancy. The sound of running water, for example from a tap, may trigger the relaxation of the sphincter. This can be a problem in public toilets when opening a nearby tap may not be possible or inappropriate. Some pwMS find pressing on the lower abdomen helps. If all else fails regarding hesitancy intermittent self-catheterisation (ISC) may be the only option.
Frequency
In MS the commonest bladder problem is spasticity, or irritability, of the detrusor muscle. The detrusor can’t relax and this prevents the bladder filling to its maximum capacity. Frequent spasms of the detrusor muscle tell the brain that it is full and you need to go to the toilet. This causes frequency; i.e. the need to go to the toilet many times during the day and night. Frequency often goes with the symptom of urgency, the need to get to the toilet as quickly as possible to prevent yourself from being incontinent. Incontinence occurs as you often lose the ability to suppress or ignore the signals from the detrusor muscle and the sphincter relaxes or opens as part of spinal cord reflex. We typically treat this problem with the so-called anti-cholinergic drugs, for example, oxybutynin, solifenacin or tolterodine. The older generation anticholinergics such as oxybutynin cross the blood-brain-barrier and enter the brain where they can exacerbate cognitive problems in pwMS. This is why I avoid using them. The commonest side-effect of anticholinergics is dryness of the mouth and they can make constipation worse. There is also a risk that they will relax the bladder too much and precipitate urinary retention. All pwMS must be warned about this problem when starting anticholinergics; I have several pwMS under my care go into retention on starting anticholinergics.
The good news is that we now have a new muscle relaxant mirabegron (Betmiga), which works by activating the β3 adrenergic receptor in the detrusor muscle. I increasingly using it to avoid the side effects associated with the anticholinergics.
Urgency
When urgency is a problem try some distraction techniques such as breathing exercises and mental tricks (for example, counting) to take your mind off the bladder may be helpful. If urinary frequency is your main problem you may want to try and retrain your bladder by holding on for as long as you can each time before passing urine. The aim is to train the detrusor muscle to expand more so that it can hold on for longer when you need to go to the toilet. In my experience these behavioural techniques rarely work for long; MS is a relapsing and/or progressive disease and in all likelihood, the bladder pathways will be affected more due to the development of new lesions or the expansion of old lesions.
If you fail to respond to anticholinergics and/or mirabegron and behavioural techniques you need to have your bladder scanned to see if you have a raised residual volume. The residual volume is the amount of urine left behind after you have emptied your bladder. If the residual volume is greater than 80-100mL you may need to consider intermittent self-catheterisation or ISC. ISC serves two purposes; it increases your so-called functional residual bladder volume allowing more storage space for urine in the bladder; this reduces frequency and urgency. This is can help you if you have to take a long trip or to get through a social activity without having to pass urine. It also helps reduce nocturia or having to get up frequently at night to pass urine. You will be surprised how much better you feel if you get a good nights sleep. Reducing nocturia and improving sleep and improves daytime fatigue.
Another treatment that is becoming increasingly common is botox of the detrusor muscle. This paralyses the muscle turning it into a flaccid bag for urine storage. Almost all pwMS who have detrusor botox are using ISC. In the past, before botox was available, there were surgical techniques that could be used to denervate or remove the nerve supply to the bladder that had the same effect; these techniques are rarely used nowadays.
ISC also removes urine from the bladder. This is important if you are having recurrent bladder infections. The residual urine acts as a culture medium for bacteria and by clearing your bladder you can prevent bladder infections. The opposite can occur. If you are don’t get the ISC technique correct you can introduce bacteria into the bladder that then cause infections.
UTIs and disease progression
The more infections you have, in particular, severe infections, the more likely it is your MS will progress. Therefore if you have recurrent bladder infections you should try and prevent them occurring. How do you do this? Drink lots of liquids; flushing the bladder reduces infection rates. Also alkalinizing your urine by drinking citric acid (citrasoda or lemonade) also helps. Cranberry extract contains proanthocyanidins substance that reduces bacteria from colonising the bladder may help. Please note you need to use the extract and not the juice as the proanthocyanidin concentration in the juice is too low to have an effect.
An infrequently used option is bladder installation with a liquid containing sodium hyaluronate (Cystistat), which replaces the glycosaminoglycan (GAG) layer or glycocalyx of the bladder wall. This makes it difficult for bacteria to stick to the wall to cause infections and is one way of preventing bacterial biofilms, or slime, from forming. Biofilms are increasingly being recognised as a major problem as they prevent antibiotics reaching the bacteria to kill them and act as a nidus for recurrent infections. I have a few patients who have used Cystistat with dramatic results.
Increasing the frequency of ISC may also help reduce recurrent UTIs. Finally using urinary antiseptics may help reduce infection rates. Urinary antiseptics are antibiotics that are concentrated in the urine; they are given in low concentrations so they have little impact on the rest of the body. I tend to cycle their use, every 3-4 months, to prevent the bacteria in the bladder becoming resistant to a specific antibacterial. The agents I use currently are trimethoprim, cephalexin, nalidixic acid and nitrofurantoin.
Nocturia
If nocturia is your main problem using agents to concentrate the urine at night might help. There is a hormone called DDAVP that works on the kidney to reduce it making urine. You can take DDAVP as a nasal spray or tablets. DDAVP can only be taken once a day; if you use it continuously your kidneys will retain water and that can be very dangerous. The latter is called water intoxication; it presents as swelling of the feet and reduces the salt or sodium levels in your blood. If blood sodium level becomes too low it can cause problems. This is why when you start using DDAVP you need to have your sodium levels checked about 4-6 weeks after starting therapy. I am not sure why, but some neurologists are reluctant to prescribe DDAVP. This is a shame as it is a very good drug and can make the difference between getting a good nights sleep or waking feeling tired. You can use DDAVP intermittently and you can use it the day, for example when you need to go on a long trip or for social occasions, e.g. going to the movies or theatre. You can only use DDAVP once a day. The most common side effect is swelling of the feet; it happens in approximately a third of pwMS and is more common in pwMS who are less mobile.
Other advice I give to pwMS is that if you are a smoker then stopping smoking may significantly improve your bladder symptoms; nicotine irritates the bladder. Similarly, reducing alcohol and caffeine consumption may also help; both these agents affect the kidneys and cause them to make more urine. Medically this is referred to as diuresis; both nicotine and caffeine are diuretics. Try to anticipate times when urinary frequency and urgency are likely to be most inconvenient; reducing the amount that you drink beforehand may help. For example, when you go out, don’t drink much for 2-3 hours before you go out. However, do not reduce your total fluid intake to less than 1.5 litres each day. After you have finished passing urine, go back to the toilet again after a few minutes to try to pass some more urine. This is called the double micturition technique, which aims to make sure the bladder is emptied completely.
Conclusion
Finally, if all else fails some pwMS may need to be permanently catheterised. This can be done via the urethra or the lower abdominal wall. The latter is called a suprapubic catheter. Being permanently catheterised sounds awful, but in some pwMS, this drastically improves their quality of life. I have several pwMS who have let bladder dysfunction control their lives and as a result they have become socially isolated. They are typically anxious about being incontinent in public. To avoid this possibility they choose to stay at home. This is clearly unnecessary and with the strategies highlighted above adequate bladder control should be the norm in MS.
In my experience, the biggest hurdle to achieving adequate bladder control is pwMS accepting their bladder symptoms as being part of the disease and living with them.
If you have problems tell your nurse or neurologist; they will be able to help you.
