What is your ACB?

ACB = anticholinergic burden

Barts-MS rose-tinted-odometer: ★

“I had no idea oxybutynin and other anticholinergics affected cognition to such an extent” is the standard response I get when I discuss the impact of the most commonly prescribed drugs for MS-related bladder problems (urgency and frequency). The older the bladder drug the more likely it is to cross the blood-brain barrier and affect cognition. Oxybutynin, for example, reduces IQ or cognition by a half a standard deviation, or approximately 7 points on the standardised IQ scale. Although I stopped prescribing oxybutynin decades ago it is often still prescribed.

And it is not only common bladder medications that have anticholinergic effects the list, which is long, also includes tricyclic antidepressants and over the counter anti-histamines. Tricyclic antidepressants are often prescribed to help pwMS with pain and are used as sedatives. It is remarkable how often neurologists and pain doctors reach from the prescription pad to prescribe amitriptyline to their patients. I think it is time for us to step back from this practice as we now have other options or better medication with less off-target anticholinergic effects. 

It is also worth noting that exposure to anticholinergics increases your risk of developing dementia. There have been several population case-control studies showing this. As MS affects cognition I suspect the MS brain is more vulnerable to the effects of anticholinergics and hence we may have inadvertently been exacerbating MS dementia. It is time for us to reevaluate how we manage bladder dysfunction and other symptomatic problems in MS and avoid prescribing drugs with anticholinergic effects. 

The study below compared a relatively new class of drug represented by mirabegron that works on the so-called beta-3 adrenergic receptor and showed it was as effective as anticholinergic drugs in controlling bladder symptoms in MS. However, as it is a newer drug it is more expensive than the commonly prescribed anticholinergics and GPs, therefore, are often reluctant to prescribe mirabegron. The question I ask is if they had MS and bladder dysfunction, which agent would they like to be on. I bet mirabegron would be their choice. ‘Prescribe for your patients what you would want to be prescribed to you’ is a maxim that should be commonly used by doctors.

Anticholinergics also make MS-related constipation worse and cause dryness of the mouth that is often the most common adverse effect that causes patients to stop taking their medication. 

Another trend has been the off-label prescribing of anticholinergic agents to promote remyelination, in particular, the drug clemastine. The clinical data on clemastine is at present rather weak and we need to wait for further trials to try and confirm preliminary results in pwMS. In addition, you may not need to take clemastine for prolonged periods of time to promote remyelination as once the demyelinated areas are remyelinated the drug could theoretically be stopped. So I don’t advocate the off-label use of clemastine or benztropine, another remyelinating anticholinergic, in pwMS because of the downside of cognitive impairment for questionable benefits in relation to remyelination. 

Can I suggest you review your symptomatic medications and ask yourself what your anticholinergic burden (ABC) is and if it is high you should review your medication with your MS team to see if anything can be done to reduce the burden on your brain? There is an online ACB (anticholinergic burden calculator)  that makes this task relatively easy and provides you with a risk score. Although this calculator was created for confusion, falls and death in the elderly it is still useful to give you an idea of your anticholinergic burden. Any score of 3 or higher is undesirable. 

I would be interested to know if any of you have stopped taking and anticholinergic and noticed an improvement in your cognition? 

Glykas et al. B3 agonists or anticholinergics in the treatment of the lower urinary tract dysfunction in patients with multiple sclerosis?-A randomized study. World J Urol. 2021 Jan 2. doi: 10.1007/s00345-020-03555-8. 

Introduction and objective: Multiple sclerosis (MS) is the most frequent autoimmune demyelinating disease of the central nervous system. MS patients usually present with lower urinary tract dysfunction (LUTD). Objective of this study is to evaluate and compare the efficacy and safety of treating MS patients with LUTD with either a b3 agonist (mirabegron) or anticholinergics. The study’s primary outcome is the LUTD symptom improvement.

Material and methods: This is a multi-center, single-blinded, comparative study including 91 MS patients with LUTD. At baseline, patients underwent thorough clinical examination, urine cultivation and abdominal ultrasound and completed urination diaries and specific, validated questionnaires (NBSS, MusiQoL). At second visit, patients were administered either mirabegron or anticholinergics. Treatment was always carried out alongside with MS treatment. Reevaluation was performed 3 months after first visit. Patients underwent the same clinical and imaging tests that were carried out at first visit.

Results: We compared several clinical and imaging parameters between the two groups at first visit and month 3 after treatment. Νo statistical difference was noted between the mirabegron group and the anticholinergic group in terms of LUTD improvement. In both groups, improvement from baseline regarding LUTD was recorded. Statistical analysis was performed using the paired and unpaired t test method. No patient discontinued either medication due to side effects.

Conclusions: MS patients receiving either mirabegron or anticholinergic therapy for LUTD showed improvement. Nevertheless, no statistical difference was noted between the two cohorts at 3 months in terms of drug efficacy in all the statistically significant parameters.

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 effectsCNS 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 studyJAMA 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

Zombie

Are you an anticholinergic zombie? 

A few months ago a 63-year-old MSer was admitted to hospital because of faecal impaction and overflow diarrhoea. She had had worsening constipation for years and was having intermittent diarrhoea due to liquification of stool from an overgrowth of bacteria in her colon, above a massive faecolith (a faecal rock). Her neurologist had her on a long-acting formulation of solifenacin for her neurogenic bladder and 50mg of amitriptyline to help her sleep at night. She had restless legs due to myelopathic pain and spasticity, which was helped by the amitriptyline. Could this be you? Or if you are an HCP do you recognise this patient? 

Faecolith and severe constipation

Her daughter had noticed that she had become increasingly forgetful over the last few months and had missed appointments and had started to repeat herself during casual conversation; often asking the same question during a short conversation. She also could not recall the name of her granddaughter, which was out of character and quite worrying. Her family had started to worry about whether, or not, she was developing dementia. 

During her admission to hospital, her solifenacin was replaced with mirabegron, a new class of drugs that work by stimulating the beta-3 receptor in the bladder wall, that is not associated with CNS side effects. Her amitriptyline was also stopped. Both of these were done to reduce the anticholinergic effects of these drugs on her bowels, which is constipation and on rare occasions faecal impaction. A day or two after these changes to her medication and the clear out of her bowels she woke up cognitively; she became animated and began to interact with her daughter and family members in a way that she had not done for years. She also stopped repeating herself. I identify this syndrome as the ‘Anticholinergic Zombie Syndrome’. Centrally acting anticholinergics have major cognitive side effects and in people with MS, who have reduced reserve, these can be severe. 

I have been developing the argument over the last few months that we should approach the management of MS holistically using the marginal gains philosophy developed by Sir Dave Brailsford when he initially started to manage the Team GB cycling team. 

“The whole principle came from the idea that if you broke down everything you could think of that goes into riding a bike, and then improved it by 1%, you will get a significant increase when you put them all together.” Dave Brailsford.

If you apply this to MS, i.e. break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together. This also means avoiding things that make MS worse. 

One particular factor that we know makes MS worse is exposure to anticholinergics. We use this class of drug mainly for bladder dysfunction, i.e. to reduce bladder irritability. The older the bladder drug the more likely it is to cross the blood-brain barrier and affect cognition. Oxybutynin, for example, reduces IQ or cognition by a half a standard deviation or 7 points. This is enough to make someone with MS-related cognitive impairment demented. 

However, many of the other drugs we prescribe to help MSers have anticholinergic effects off-target. These include the tricyclic antidepressants. As a class, these are used to help MSers with myelopathic pains and as sedatives. It is quite remarkable how often neurologists reach from the prescription pad to prescribe amitriptyline for their patients. I think it is time for us to step back from this practice. We now have other options. 

The remarkable thing is that in the general population exposure to anticholinergics increases your risk of developing dementia. The most recent population case-control study confirming this has just been published in JAMA. I suspect the MS brain is more vulnerable to the effects of anticholinergics and hence we may have inadvertently been exacerbating MS dementia. It is time for us to rethink how we manage the MS bladder and other symptomatic problems and avoid drugs with anticholinergic effects? 

Dare I suggest we should have zero-tolerance for anticholinergics and try and avoid them altogether? 

Coupland et al Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. JAMA Intern Med. Published online June 24, 2019. doi:10.1001/jamainternmed.2019.0677

Question: Is the risk of dementia among persons 55 years or older associated with the use of different types of anticholinergic medication?

Findings: In this nested case-control study of 58 769 patients with a diagnosis of dementia and 225 574 matched controls, there were statistically significant associations of dementia risk with exposure to anticholinergic antidepressants, antiparkinson drugs, antipsychotic drugs, bladder antimuscarinics, and antiepileptic drugs after adjusting for confounding variables.

Meaning: The associations observed for specific types of anticholinergic medication suggest that these drugs should be prescribed with caution in middle-aged and older adults.

Importance: Anticholinergic medicines have short-term cognitive adverse effects, but it is uncertain whether long-term use of these drugs is associated with an increased risk of dementia.

Objective:  To assess associations between anticholinergic drug treatments and risk of dementia in persons 55 years or older.

Design, Setting, and Participants:  This nested case-control study took place in general practices in England that contributed to the QResearch primary care database. The study evaluated whether exposure to anticholinergic drugs was associated with dementia risk in 58 769 patients with a diagnosis of dementia and 225 574 controls 55 years or older matched by age, sex, general practice, and calendar time. Information on prescriptions for 56 drugs with strong anticholinergic properties was used to calculate measures of cumulative anticholinergic drug exposure. Data were analyzed from May 2016 to June 2018.

Exposures:  The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls (index date).

Main Outcomes and Measures  Odds ratios (ORs) for dementia associated with cumulative exposure to anticholinergic drugs, adjusted for confounding variables.

Results:  Of the entire study population (284 343 case patients and matched controls), 179 365 (63.1%) were women, and the mean (SD) age of the entire population was 82.2 (6.8) years. The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. Results were similar when exposures were restricted to exposure windows of 3 to 13 years (AOR, 1.46; 95% CI, 1.41-1.52) and 5 to 20 years (AOR, 1.44; 95% CI, 1.32-1.57) before the index date for more than 1095 TSDDs. Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%.

Conclusions and Relevance:  Exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.

CoI: multiple

#MS-Selfie: infections and how to self-manage your bladder

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.

What can I do about my bladder?

Prof G, I was incontinent last week on the train and was very embarrassed. Can you help me please?

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Clinical problem: I am 36 years of age and I have developed urinary frequency and urgency. Apart from this, I am well and active. I was incontinent last week on the train and was very embarrassed. It also happened several weeks ago on the way home from the pub. I had been out with friends and had had several glasses of wine. I had emptied my bladder before leaving the pub, but clearly, this was not enough to prevent wetting myself. What can I do?

Bladder dysfunction is the most common symptomatic problem I have to deal with in my MS clinic. More than half of MSers have bladder problems.

The following generic advice is what I would give MSers with different sorts of bladder symptoms:

I view bladder dysfunction in MSers as an integrator of damage and an early read-out of a poor prognosis. I would, therefore, take this symptom in any of patients very seriously. I would have a frank discussion with her about her prognosis and treatment and would assess her to see if she has possibly had a relapse and has other signs to localise the lesion causing her bladder problems. Most often it is due to spinal cord lesions and you may find other signs, for example, subtle weakness in the legs.

Over the years I have observed that MSers who develop bladder dysfunction tend to do worse than MSers who don’t have bladder symptoms. Why? The bladder is a complicated organ with several neurological components that can be affected by MS and hence is more sensitive to early damage.

Why is the bladder an integrator of MS 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 main 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 high up on my list of poor prognostic factors in MS.

The bladder has two muscles that need to be coordinated. The (1) detrusor muscle, or balloon, and the (2) sphincter, or valve, muscle. 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. Simple?

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; MSers 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 MSers 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 MSers find pressing on the lower abdomen helps. If all else fails regarding hesitancy intermittent self-catheterisation (ISC) may be the only option.

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 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 MSers. 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 MSers must be warned about this problem when starting anticholinergics; I have several MSers under my care go into retention on starting anticholinergics.

There is a new class of drug that works on the so-called β₃ adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity.  Mirabegron (Betmiga) is the first drug in this class and has the advantage over the other bladder drugs in that it does not have anticholinergic side effects. I am increasingly using mirabegron to prevent the unwanted anticholinergic side effects.

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; some MSers find this helpful. When 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 very long. As MS may be a progressive disease the bladder pathways may be affected by new MS lesions and hence get worse with time.

If you fail to respond to anticholinergics 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 reduces daytime fatigue.

Another treatment that is becoming more common is botox of the detrusor muscle. This paralyses the muscle turning it into a flaccid bag for urine storage. Almost all MSers who have detrusor botox will have to use ISC as well. 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 flushing your bladder with urine you can prevent bladder infections. However, the opposite can occur. If you are don’t get the ISC technique correct you can introduce bacteria into the bladder that can then cause recurrent infections.

There is a potential link between bladder infections 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? By drinking lots of liquids; flushing the bladder reduces infection rates. Also alkalinising your urine by drinking cranberry juice or citric acid (citrasoda or lemonade) also helps. Increasing the frequency of ISC may also help. 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 which are meant to limit the 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. The agents I use currently are trimethoprim, cephalexin, nalidixic acid and nitrofurantoin.

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 slay level become too low it can cause problems. This is why when you start using DDAVP you need to have your blood 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 up feeling awful. You can also use DDAVP intermittently. If you use it the day, for example, when you need to go on a trip or to go out, you mustn’t use it again.

WARNING: You can only use DDAVP once a day.  The most common side effect of DDAVP is swelling of the feet; it happens in approximately a third of MSers and is more common in MSers who are less mobile.

Other advice I give to MSers is that if you are a smoker you may want to consider stopping. Stopping smoking may significantly improve your bladder symptoms, as nicotine irritates the bladder. Similarly, reducing alcohol and caffeine consumption may also help; both these agents affect the kidney and cause it to make more urine. Medically this is referred to as diuresis and these agents are mild 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 2.0 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.

Finally, if all else fails some MSers may need to be 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 MSers, this drastically improves their quality of life. I have several MSers who have let bladder dysfunction control their lives; 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 MSers accepting their bladder symptoms as being part of the disease and living with them.

If you have bladder problems tell your nurse or neurologist; they will be able to help you. Don’t suffer in silence.