Not managing expectations in someone with PPMS

Not managing expectations results in angry patients. How not to get it right? 

Please note that the details of this case has been fictionalised, but illustrate a real-life scenario.

Yesterday one of my new patients with primary progressive MS came back for a follow-up visit after undergoing investigations to assess whether, or not, he was eligible for our compassionate use programme of off-label cladribine. He had been specifically referred to me by his consultant neurologist for cladribine therapy. He had rapidly progressive MS and gone from diagnosis to EDSS 6.5 (bilateral support) in approximately 8 years, with an 18-month history of a prodrome, i.e. he had noticed mild foot drop on exercise and this had been dismissed by his GP as a possible trapped nerve. Please note that 18 months from symptom onset to diagnosis of PPMS is actually quite quick. 

MS had already taken its toll, he was single having split-up with his long-term partner and had already had to give up work because of MS. He had sexual dysfunction, bladder and bowel symptoms, fatigue and spasticity. The spasticity was causing nighttime leg jerks, or spasms, that were waking him up in the early hours of the morning. As a result, he had interrupted sleep and never woke feeling refreshed. He managed his own activities of daily living but was very slow at doing manual tasks. He was unable to do domestic chores but was still able to drive. He was using a light-weight electric scooter for outdoor mobility. The scooter had been purchased for him by his family. As a result of leg weakness and a dropped foot on the right, he had had several falls. He had previously had physiotherapy for his walking difficulties and had been prescribed a foot-up device, which he was not using, and a lightweight walker. Other issues were social isolation, he rarely got out to meet family and friends, he had a poor diet, a current smoking history of 15-20 roll-up cigarettes per day and he did no exercise. He was also depressed and very anxious about the future.

After assessing him I ordered an MRI of his brain and spinal cord with gadolinium enhancement as well as a lumbar puncture to measure his spinal fluid neurofilament light chain (NFL) levels. His MRI showed a moderate brain lesion load, several spinal cord lesions with cord atrophy. None of the lesions enhanced after the administration of contrast or gadolinium. His spinal fluid showed locally synthesised oligoclonal IgG bands, compatible with his diagnosis of PPMS, and the NFL levels were well within the normal range for his age.

In summary, we have a middle-aged man with rapidly worsening PPMS with no signs of active focal inflammation on MRI or on spinal fluid analysis (NFL levels), i.e. his PPMS was inactive. I told him that based on our current treatment guidelines he would not be eligible for treatment with off-label cladribine. He was furious and wanted to know why. I tried to explain to him that we have no hard evidence at present on whether or not cladribine is effective in people with inactive PPMS. I said to him that his worsening disability may be due to damage from the past and/or early ageing in neuronal pathways in the spinal cord with no reserve capacity. He didn’t buy this explanation and wanted cladribine regardless of the potential consequences to his health. I was not prepared to give in and tried to give him hope. He may become eligible for ocrelizumab if NICE gives it a green light for use on the NHS in PPMS. However, the NICE single technology appraisal of ocrelizumab for the treatment of PPMS is unlikely to happen for many months, possibly years. He isn't prepared to wait. Another option I offered him was the possibility of volunteering for an upcoming treatment trial. I explained that both alemtuzumab (EDSS <=6.5) and ocrelizumab (EDSS <=8.0) PPMS trials will be recruiting patients later on this year. He asked if they were placebo-controlled and I said yes. He was adamant that he is not prepared to go into a placebo-controlled trial. The consultation ended with him telling me that he will have to make plans to travel abroad for HSCT. I explained to him why I thought the latter was not a good idea, but he was not in the right frame of mind to accept any further advice from me. In short, I had let him down.

On leaving my consulting room he accused me of not caring and that I should have given him treatment despite having no evidence. Therein lies the rub; people with PPMS are so desperate to try anything to halt, or slow down, their worsening disability that they are prepared to take risks without necessarily the evidence of any potential benefit. We the healthcare professionals are trying our best to practice evidence-based medicine and where we don’t have evidence to at least apply some basic scientific principles. In an ideal world, I would be treating this patient with ocrelizumab and in a less than ideal world with off-label rituximab. Unfortunately, the NHS does not cover the costs of rituximab for PPMS. Cladribine may become an option in the future when we have data that could support some efficacy in worsening, but inactive, PPMS. This is why it is so important that DrK’s proposed Chariot-MS study is funded. As for HSCT, I am not aware of any evidence to support its use in worsening, inactive, PPMS. In fact with an EDSS of 6.5, I suspect the myeloablative chemotherapy, which is potentially neurotoxic, may actually make things worse. This why our London HSCT treatment criteria exclude patients who have more advanced MS. 

We seem to be caught between a rock and a hard place. We are trying to give PPMSers hope, but are we selling them false hope? In future, I am going to spell out more clearly how we define active PPMS so that when patients come for follow-up assessments they are forewarned and prepared for a possible decision of no treatment. Would you agree?

MSers also need to be made aware of therapeutic lag and reserve capacity. What does this mean for this patient? Even if we could initiate ocrelizumab next week we may not be able to prevent further deterioration in his lower limb function, i.e. progression today is driven by inflammatory damage in the past and by switching off inflammation now this may not be noticeable to him. In other words, progressive MSers may not be able to notice a slowing down in worsening of their progression. To expect flat-lining and improvement in functioning we probably need add-on neuroprotective and remyelination therapies and possibly even neurorestorative therapies. Please note add-on therapies targeting recovery of function will only work long-term if they are given on top of anti-inflammatory DMTs. What is the point of repairing and protecting the damaged nervous system to leave MS untreated? 

Do you agree all MSers with advanced MS and worsening disability should be informed of this information?

Another component that needs to be tackled is this man's lifestyle. He is smoking that is almost certainly making him progress faster. In addition, there is a lot of symptomatic therapies that could be tried to help him. He needs an anti-spastic agent and possible treatments for his bladder, bowel and sexual function. He may also be eligible for a trial of fampridine. A graded exercise programme may help with his mood and improve his long-term outcome. It is important to remember that treating MS, in particular, advanced MS, is a partnership between the patient and the team of HCPs looking after them. This patient was expecting a quick and easy pharmacological solution to his advanced MS and was not addressing lifestyle issues that are just as important as any DMT. 


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