When to start a DMT if you have CIS? #ClinicSpeak #MSBlog #MSResearch
"I received an email query from a young woman who has had a clinically-isolated syndrome (CIS) and had difficulty getting onto an injectable 1st-line therapy because of confusion around the guidance from NHS England regarding eligibility for treatment. The guidance simply states that 'Patients are eligible for treatment within 12 months of a clinically significant clinically isolated syndrome when MRI evidence predicts a high likelihood of recurrent episodes'. The question proposed is what is a high likelihood of recurrent episodes? This guidance refers back to the Association of British Neurology (ABN) 2009 guidelines and is deliberately loosely-defined to leave it up to the neurologist to make a judgement call. In the past we had to make sure all patients with CIS fulfilled MacDonald criteria for having multiple sclerosis, i.e. dissemination in time and space, and had a high lesion load (>9 T2 lesions) and/or an active lesion(s) (Gd-enhancing lesion) on their baseline scan. This guidance is based on the Queen Square and other data sets demonstrating that baseline lesion load, and baseline activity (Gd-enhancement), predicts a poorer prognosis and more rapid conversion time to clinically definite MS or the next clinical attack."
"The figure above shows that CISers with 1-3 lesions take longer to become disabled than those with 4-10 baseline lesion and both these groups have a better short-term prognosis than CISers presenting with 10 or more lesions. Are you surprised? CISers with 10 or more lesions have had MS longer and therefore they tend to hit disability milestones earlier. I agree that there will always be a small number of patients who will end up with benign MS, but the proportion of people with benign MS shrinks with time, so that by the time you have MS for 40 or more years the proportion of patients with benign MS, in hospital-based practice, is less than 5%. Please note that this figure refers to natural history data and in the era of DMTs this figure will be much higher. DMTs should increase the proportion of MSers with benign MS."
"I personally think the prescribing guidance, based on baseline lesion load and/or presence of Gd-enhancing lesions, is outdated and is not in keeping with our current understanding of multiple sclerosis. It is clear that MS has a relatively long asymptomatic period and what determines when you present with your first clinical attack is whether, or not, a new lesion happens to occur in a clinically eloquent site. Therefore baseline MRI is an indicator of how long you have had the disease; the higher the lesion load the longer you have had the disease the and the more likely you have underlying end-organ damage. If our aim is to prevent damage with DMTs the lower you lesion load the earlier you are in the course of the disease the more there is to protect. According this logic you are lucky if you present with a low lesion load as you are earlier on in the course of the disease and hence more likely to benefit from DMTs. Please remember that the aim of DMTs is to prevent damage not repair damage; to maximise this prevention strategy you have to start treatment early."
"Please remember that what we see on MRI in terms of lesions is only the tip of the MS iceberg; the majority of disease is not visible on MRI. All the CIS trials included patients with abnormal MRI scans and they have all shown that patients started early do better. So why wait? When you interrogate CISers at baseline you find a significant proportion (30-50%) have cognitive impairment, fatigue and depression. These hidden symptoms are probably due to gray matter involvement that is not visible on routine diagnostic MRI scans. If you apply specialised data analysis tools to the MRI scans in CISers you find a large proportion of them have baseline gray matter atrophy indicating that their disease has been active (shredding the cortex) prior to their CIS presentation."
"The exception to the above or those CISers presenting with no lesions; these CISers do very well with only 1 in 5 going on to develop a second attack, or MS, over the next 20 years. This would indicate that a large proportion of CISers with normal baseline MRI scans do not have MS. Therefore it is entirely appropriate to wait, watch and see what happens with these patients."
"In addition, to the lesion load which is an integrator of activity over the course of the disease the presence of active gadolinium-enhancing lesions provides a temporal metric and tells us that those enhancing-lesions are actively inflamed. As the duration of enhancement is about 3-4 weeks you can infer that these lesions probably appeared within the last month. This is why we have a greater tendency to treat CISers with active scans.”
"What is not frequently communicated to patients is that those CISers who access injectable therapies early, compared to those who have to wait until their second attack or were only started treatment as part of the open-label extension studies (typically 18-24 months later), do better. This has been elegantly shown with regard to cognitive outcomes in the BENEFIT study. The EDSS data is relatively weak in relation to disability, but that is not unexpected as the EDSS a very poor outcome measure for tracking disability early in the course of MS; in statistical jargon the EDSS has a floor effect and this was seen in the BENEFIT study."
"What I can say is that in general UK neurologists are the outliers when it comes to prescribing DMTs for CISers. In almost every country in the world CISers with an abnormal scan will be offered the option of going onto a treatment. Most UK neurologists would rather wait for the second attack, during which time irreversible damage could potentially accumulate. What you have to remember is that when you present with CIS some CISers are not ready for DMTs. They go often in denial and are not interested in knowing about the link between CIS and MS, and their future prognosis. It is not wise to push the issue with these patients, but to support them and be there if and when they are ready to make a decision. Poor adherence to DMTs are a problem and if you are not ready for treatment you are unlikely to adhere to your treatment. Therefore we really need to adapt and personalise decision making; doing things relatively slowly may result in the best long-term outcomes."
"What I haven’t discussed in this post in detail are the other prognostic factors that we tend to take into account when profiling CISers at baseline; these include whether or not there are lesions at the back of the brain in the so called posterior fossa, is there obvious baseline brain atrophy, which is a very poor prognostic sign, the type of clinical attack (motor/cerebellar vs. sensory), was the first attack mono or polysymptomatic (polysymptomatic attacks have been linked to worse outcomes in some studies), the degree of recovery from the attack (poor recovery poor prognosis), sex (males do worse), ethnicity (Asians and Africans do worse) and whether or not the spinal fluid analysis was abnormal (CISers with CSF OCBs do worse). In addition, to the disease profile personal factors come into the decision including psychological state, level of background knowledge and if you are a female whether or not you are planning to have children. Outside the UK and other countries with socialist healthcare systems, medical insurance coverage and being able to afford DMTs, are sadly a crucial factor deciding access to DMTs.”
“What do you do if your neurologist refuses to offer you DMTs for CIS? I suggest you have a frank discussion about why and ask him/her to justify their reasons. If the latter are unacceptable to you, you can always ask for a second independent opinion; the NHS Charter allows this. A reasonable compromise is to ask for a monitoring follow-up scan at say 3, 6 or 12 months on the condition that if your disease has been active (increased lesion load or active lesions) you can be started on treatment. This would indicate you have developed definite MS.”
"To the person who asked the question, please let me know if this post has answered your question?"