Help! How do I manage progressive brain atrophy in a patient who is NEDA-3?
End-organ damage is a catch-all phrase for the degeneration of the brain; it occurs as part of the ageing process that some consider pathological and others as a normal fact of life. I have hinted that I consider it both because end-organ damage is potentially modifiable via lifestyle modifications and pharmacological interventions. If it was a normal process it should not be modifiable. How can you be more normal than normal? Making ageing a disease also has political ramifications, for example, it will almost certainly incentivise Pharma to develop treatments for ageing.
In MS end-organ damage is massively accelerated by the MS disease process itself, i.e. inflammation and demyelination, and from delayed downstream processes triggered by inflammation, for example, energy failure, microglial activation, ongoing inflammation driven by antibodies, possible slow viral infection and its consequences and comorbidities. It is clear that all people with MS will have end-organ damage, but what can we do about it? To be honest, apart from early treatment to prevent damage, we haven’t got an evidence base about how to manage this problem in MS.
As an example, I saw a patient earlier this week. He has relapsing-remitting MS diagnosed in the mid-2000s and started on interferon-beta (Avonex). He also has type 1 diabetes which he developed when he was 14 years of age, 8 years before he was diagnosed with MS. His diabetes was poorly controlled initially but is now well controlled on an insulin pump. He has renal (proteinuria), eye (retinopathy) and hypertension as complications of his diabetes. His hypertension is controlled on medication. He has been relapse-free and his MRI has not shown any obvious new lesions over the last 6 years; i.e. he is NEDA-3. He does not smoke, but he drinks between 3 and 4 units of alcohol per day. He was referred to me because he is sick and tired of injecting himself with interferon and he has heard of a new drug called ocrelizumab. He wants to be switched to it because is more efficacious and only give every 6 months. His treating neurologist said no, hence his referral to me for a second opinion.
When I went through his history it is clear he has had no relapses in the last 6 years and is fully functional and working full-time. I reviewed his MRIs and I agree he has no new lesions over the last 6 years, but he has developed quite profound and progressive brain atrophy over this timeframe; he is definitely not NEDA-4. What do I do?
Do I switch him from interferon-beta to ocrelizumab? Or do I leave him on Avonex, which is doing its job and rendering him NEDA-3?
If I do switch him to ocrelizumab, will it normalise his brain volume loss? Will he become NEDA-4?
What is causing his brain volume loss? MS, hypertension, diabetes, alcohol or something else?
Do I tell him about his gross brain atrophy, which he is blissfully unaware of?
Do I offer him a formal cognitive assessment to see if he has cognitive impairments? If he has a cognitive assessment and they come back abnormal, which they are likely to, how do I tell him? Will knowing he cognitively impaired affect his management?
Do I offer him a lumbar puncture to measure his spinal fluid neurofilament levels?
Do I recommend any add-on off-label treatments that may help?
Or do I just take the easy option and send him back to his neurologist with a recommendation to leave things as is?
Can I suggest we debate these issues over the next few days and I can then potentially do a live webinar on the issue of end-organ damage and how to handle the problem of progressive brain volume loss on DMTs when you are NEDA-3.