Stimulation of the Tibial nerve Repetitively to Improve Incontinence in Parkinson’s Electronically
Bladder symptoms are common in Parkinson’s disease and have significant impact on quality of life as well as implications for morbidity, contributing to falls and hospital admission. However, the treatment of bladder symptoms can be complicated and better treatments are required. STRIPE was a phase II randomised control trial that aimed to determine whether electrical stimulation of the tibial nerve improves overactive bladder symptoms. We aimed to recruit 220 individuals with Parkinson’s disease who had symptoms of urgency, nocturia or both in combination and were able to travel to the RICE research centre near Bath.
email: stripe-trial@bristol.ac.uk
Recap – why we did this trial
The reason for undertaking the STRIPE trial was to explore whether repurposing the Geko device might help with people’s bladder symptoms in Parkinson’s. This was originally designed to prevent blood clots in people’s legs after surgery by putting it on the knee.
For many years, a little used technique where a small electric current is applied to one of the main nerves in the ankle (Tibial nerve stimulation) has been used by urology doctors in general patients (not specifically Parkinson’s) in a small selection of hospitals. This potentially could overcome the problem that many of the medications used for bladder symptoms often cause side-effects, particularly for people with Parkinson’s. The potential for a non-medication way of helping these symptoms is of great interest. Tibial nerve stimulation has historically required people to go to hospital and use a machine in the clinic, but the promise of Geko was a small device that could be taken and used at home. We therefore hoped to explore if using Geko on the ankle, rather than the knee, could replicate the benefits of normal hospital tibial nerve stimulation.
To answer this question, we needed to compare the genuine version of the stimulation with Geko, against a “placebo” version of stimulation. This is incredibly important, as the placebo effect is hugely strong and people can have marked changes in their health purely due to something new happening. Because of this, testing against placebo is the only way we can know if something genuinely works.
What did the results show?
To test whether it worked, the main thing we used was the response to a questionnaire called “ICIQ-OAB” – this is the one that was repeated every two weeks in the diary. The higher the score, the worse someone’s symptoms are. Of greatest interest was the score for this questionnaire at week 12, which was after 3 months of using Geko. One reason for choosing this point was that it allowed the effect to work, any novelty factor to wear off, and is also the point that has been used in past research for tibial nerve stimulation, so that we could compare to this.
Many people noticed an improvement with the Geko device. However, this was experienced in both the active and placebo groups.
Below is a graph which is used in the scientific publication. One line is the average score showing the questionnaire totals for active (solid blue) and placebo (a.k.a. sham, green dashed). This travels over each two-week time point between start (week 0) and the end (week 12).
Remembering that a lower score is better, we can see that between the point before people started using Geko (week 0) and the end of the trial (week 12), both groups follow the same pattern. They both start at roughly the same start score (around 11) and end with the same score (just under 10).
Therefore, both active and placebo groups improved on average by one point. This was confirmed by using statistical tests, suggesting that this really was a significant difference compared to the start and not just due to chance. Unfortunately, the key issue is that both groups were the same at week 12.
Although a one-point change seems only quite a small difference, previous research has shown that a one-point difference is the level of change that needs to happen to suggest a meaningful improvement in symptoms for patients.
Importantly, because the score is averaged over everyone in each group, this adds together the people who had a really big response with those who had little or no response. To try and make sure that we were not missing an effect where a small selection of people had a great response, and that this was just cancelled out by the people who didn’t, we ran another analysis that classified people as either “responders” or “non-responders”. We worked this out by classifying people as responders if they experienced over a certain level of improvement between the start and end. This showed that 21.2% were responders in the active group, and 21.3% in placebo group – nearly identical.
How do we make sense of this?
The results show that using Geko either in the genuine way that delivers tibial nerve stimulation, or in the placebo way, leads to a small but meaningful improvement in both groups. Roughly a fifth in each group also experienced a marked improvement, regardless of which group they were in. This suggests that Geko does not have a genuine effect on bladder symptoms.
The simplest way of interpreting this is that this is probably all a placebo effect. This is generally the accepted interpretation when you get a result of active versus placebo treatments that show the same outcome.
As mentioned earlier, the placebo effect is really strong but is well known to be particularly an issue in research trials affecting people’s bladder symptoms. One theory behind this is that symptoms such as urgency (having to rush suddenly to the toilet) are partly driven by wiring in our brains, which can be affected by things going on in the outside world.
As part of STRIPE, for the latter 58 people who took part, we collected whether you experienced any specific trigger of urgency symptoms (something that has never been looked at in Parkinson’s). It appears that there is a huge effect of outside cues and triggers, with 83% having at least one trigger. By far the most common was running water, followed by symptoms being triggered by arriving home (eg. coming through the front door).
This further backs up how easily bladder symptoms can be influenced by external things going on, even if this is an apparently “positive” thing to make symptoms better. Probably, this is even more likely to happen because of the nature of how some of the brain pathways work differently in people with Parkinson’s.
There is another consideration, and that is whether the “placebo” treatment was still delivering some form of stimulation despite not being fully fledged tibial nerve stimulation. The placebo treatment still gave stimulation at an incredibly low level, however not at the site of any major nerve, nor at any accepted level thought to be able to influence the bladder. However, many in the placebo group could feel a low level of stimulation, particularly after wearing the device for some time. This was intentional to help ensure the placebo was believable. Could it be that this very low level of stimulation, just through the skin, is enough to cause a positive effect on the bladder?
It is well known that it is incredibly hard to design placebo treatments in research trials that use a device or some other form of treatment that is not a medicine. For a drug trial, it is very easy to make a tablet that looks identical but just contains sugar. Unfortunately from the data we have alone, we will never be able to determine this for STRIPE.
What else did we find?
Although disappointingly the main trial was probably negative, we did learn some other important results from the study.
From the bladder diaries that people so carefully did, we found out that an unexpectedly high amount of urine was made by people in the night time. Normally this should be less than a third (33%) of the day’s urine, but in some people this was as high as almost two thirds (64%). There was also a very clear link showing that as the number of visits to the toilet went up at night, so did the amount produced.
Previous work has shown that going to the toilet during the nighttime is the most common bladder symptom in Parkinson’s. This result is therefore important to have found out, because it explains that this common symptom is probably due to simply too much urine being made at night, rather than bladder being “overactive”. If this was just because of the bladder being overactive, the same amount of urine should be made over the night, just with less coming out at each visit. Physically finding a bigger amount tells us this is being over-produced, probably coming from the kidneys. Helpfully, this can help us target new treatments, as current medications look to only “calm” the bladder, but don’t do anything to address over-production of urine.
Not only did we find out that producing too much urine at night was really common, but also it seemed to be linked to having problems with low blood pressure. We found that the more urine people made at night, the more likely they were to have a problem with their blood pressure dropping when they stood up. This may help us explain why this is happening, possibly with blood pressure variations leading to too much blood going through the kidneys on lying down to sleep at night. However, we can only speculate based on this and need much more in-depth data to prove this link.
What is the next direction for the research?
Sadly, the results mean that is very unlikely that Geko will become available on the NHS for treating bladder symptoms. There is still some possibility that tibial nerve stimulation might be helpful for bladder symptoms, as the Geko device works slightly differently to the older fashioned machines used in hospital. Potentially developing a new device that works even closer to how these work could be an option for a future trial.
We are very interested in exploring further how to improve night-time symptoms, based on the finding of people making an unexpectedly large amount of urine at night. We are currently looking into funding to run a medicine trial that will look at reducing the amount of urine produced at night. This is at a very early stage at the moment but would hopefully be run from multiple sites across the UK, making this easier to access for people.
As part of this, we would explore much more rigorous blood pressure monitoring (including wearable home monitors) to try and explore the link to changes in blood pressure and explain why the excess urine is produced.