Two minutes

MSer: ‘What do you mean I don’t have active secondary progressive MS? I am getting worse! Compared to this time last year it now takes me almost two minutes longer to walk to the newsagent at the end of my road to buy the daily newspaper.’

Neurologist: ‘I doubt your worsening last August was a relapse as it coincided with the summer heatwave. We had many people, like you, calling up saying they were having a relapse, but they were pseudo-relapses due to the heat. Your MRIs of your brain and spinal cord show no new lesions. We classify active SPMS as having relapses or new lesions on MRI. Therefore you have inactive-worsening secondary progressive MS.’

MSer: ‘Does that mean I am not eligible for treatment with siponimod?’

Neurologist: ‘Yes, you don’t fulfil our national guidelines for treatment. In addition, as you are now over 60 and are in an age group that is unlikely to benefit from siponimod. When the subgroups based on age were analysed in the siponimod trial it showed that participants over the age of 60 did not benefit from the drug.’

MSer: ‘Is there anything you can offer me then?’

Neurologist: ‘Unfortunately, not!’

MSer: ‘In other words, I am unsalvageable!’

Several weeks later after some online research and reading several posts on the Barts-MS blog this MSer requested a referral to me for a second opinion.

He is a 63-year-old medically retired lawyer and has had MS for 20 years. His diagnose had been delayed by 8 years; his initial episode of vertigo had been put down to labyrinthitis. By the time he got to see the ENT surgeon, his symptoms were resolving so no MRI was performed. His second MS-related symptoms were a hot buzzing sensation in his left leg. His GP said it was likely to be ‘mild sciatica’ and that it would settle down in a few weeks, which it duly did. Similarly, a single episode of urinary incontinence was ascribed to the diuretic effects of a few pints of larger and not investigated. It was only when his leg had started dragging on long walks, which prompted a referral for a neurological opinion. MRI of the brain and spinal cord showed multiple spinal cord and brain lesions compatible with MS. Within four years of diagnosis his walking distance was down to less than a mile, by 9 years he was needing a foot splint and now 20 years later he is using a walking stick.

Other problems include urinary frequency, urgency and urgency incontinence, which had resulted in him starting intermittent self-catheterisation. He suffers from severe constipation and has to use a rectal irrigation system to have a daily bowel action. He has been impotent for several years despite having occasional erections. His main problems from a work perspective have been cognitive problems with mental fatigue and forgetfulness. He was forced to stopping working because of these problems 5 years ago.

He suffers from severe anxiety: ‘I want to avoid the inevitable; I will do anything to prevent going into a wheelchair. I want to walk down the aisle with my daughter at her wedding. I want to be able to continue to buy my newspaper at the newsagent each morning and I want to be able to potter around my garden. Is there anything you can do for me?’ he asked.

I explained to him that we have new evidence that raised neurofilament levels in the spinal fluid are another indicator of active MS and if he was prepared to have a lumbar puncture we may be able to interrogate his disease at a more granular or microscopic level. I explained that neurofilament levels can remain elevated for months after a relapse and that I have many examples of patients who have not had objective relapses or new lesions on MRI that have had raised CSF neurofilament levels.

‘How come the MRI does not show up all lesions?’ he asked. I explained to him that MS is like an iceberg and that for every release there are 10 or more lesions that can be seen on MRI. Similarly, for every visible MRI lesion, there are many more lesions that are too small for an MRI to detect, or are located in the grey matter an area that is not easy to see MS lesions using standard MRI.

‘Wow, this beast called MS is a medusa. It has so many different heads’, was his reply.

He was reluctant to have a lumbar puncture because of all the scare stories he had heard about on the web. I explained to him that we had derisked lumbar punctures by using atraumatic or non-cutting needles and that post-LP headaches were now much less common. In addition, if the anatomy of his back was difficult we would do his LP using ultrasound or X-ray guidance. After hearing this he agreed and had his LP several weeks later.

Not unexpectedly his neurofilament light chain levels came back raised at a level of 60% above his age cutoff.

When he came back to see me in clinic I explained that he almost certainly had active SPMS, but because the NHS did not accept raised CSF neurofilament levels as a sign of disease activity we could offer him off-label subcutaneous cladribine, mitoxantrone or another one of the generic, but less effective DMTs, namely leflunomide or methotrexate. He had been reading our blog and was prepared for the news and gladly accepted being treated with generic cladribine.

‘Doing something about my MS is better than doing nothing’, was his response.

At the end of the consultation, he asked me what would I have offered him if his neurofilament levels had been normal? I said nothing at the moment; watchful waiting to see if his disease became active in the future or the option of being screened for a trial of a new S1P modulator in chronic progressive MS. The latter trial had not yet started but would be starting in the next 6 months and would be enrolling patients with either primary or secondary progressive MS.

‘But what if I wanted to be treated regardless of having a normal CSF neurofilament level as an insurance policy against me having another attack that would leave me wheelchair bound?’ he implored.

I tried to explain to him that I am trying not to be a cowboy and that I have to try and practice evidence-based medicine. I am aware that some neurologists treat all-comers. I recall sitting next to an American KoL at a dinner several years ago and him telling me that he treats all his patients with MS, because they come to him to be treated. He told me an anecdote of a 75-year woman with longstanding MS who recently come to him for an opinion. She had quite indolent SPMS, but he had started her on low-dose weekly methotrexate. Is this the correct way to manage MS?

We have no evidence to back-up using off-label subcutaneous cladribine in patients with inactive worsening SPMS. We would be exposing them to the risks of cladribine, but not necessarily any of the benefits from its anti-inflammatory effect. The latter is a hard concept to grasp. Many MSers are of the opinion that ‘As I have the disease I should be the one taking the risks’. Yes and no. If everything went well and the patient had no adverse events it would be fine. However, if something went wrong and say the patient got a severe infection and died the treating neurologist could be accused of malpractice, i.e. using an off-label drug in someone with inactive MS. The medicolegal system would ask whether or not he neurologist was practising in line with the common practice of his/her peers. The answer, given the evidence-base, would in all likelihood be no. This is why we take our role of educator so seriously. It is fine to be an innovator or early adopter of a new treatment paradigm, but you can do it alone. You need to generate evidence to change the practice of your colleagues. This is why we have started generating circumstantial evidence about the utility of off-label cladribine in more advanced MS, which has been essential in getting our Chariot-MS trial funded.

The response to our off-label efficacy data presented at the AAN was quite amazing. It is clear that some Pharma executives, particularly in middle- and low-income countries were worried about the potential impact the use of off-label cladribine could have. It is cheap, it is backed by phase 3 data of the oral formulation and cladribine is relatively easy to monitor. Could off-label cladribine do to more advanced MS what rituximab has done to relapsing MS?

I sincerely hope off-label cladribine is the game-changer it promises to be. One of the biggest warts on the face of MS is the poor access to treatment in resource-poor settings. We have always held the position that off-label subcutaneous, or even intravenous, cladribine is a potential solution to the problem of undertreated MS in the world. Just maybe enough neurologists will have gotten home from the AAN with a small light turned on in their heads and will now start using off-label cladribine to treat untreated, or under-treated, active MS. Whether or not cladribine should be used in inactive MS will depend on the outcome of our Chariot-MS and other studies.

CoI: multiple