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? 

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