Saturday, December 14, 2013

What type of MS do you have?

Fact 1"Current licensed DMTs are only effective in relapsing-forms of MS." 

Fact 2"There are no DMTs licensed for treating non-relapsing progressive MS." 

Fact 3: "Primary progressive MS and relapse-onset MS are the same disease." 

There are two main clinically-defined types of MS; (1) relapse-onset MS and (2) primary progressive MS. 

Relapse-onset disease is the most common type of MS and occurs in approximately 85% of MSers. Typically relapse-onset disease presents with an initial clinical attack and is referred to as a clinically isolated syndrome (CIS) compatible with demyelination. 80% of CISers go onto to have a second attack and develop clinically-definite MS (CDMS). CDMS in the latter context is referred to as relapsing-remitting MS (RRMS), which in the majority of subjects (i.e. in the order of 80%), who are not treated with DMTs, go onto develop secondary progressive MS (SPMS). Please note I say not on DMTs; we don't know exactly what DMTs are doing to the natural history of MS. There is emerging evidence that DMTs are delaying, and possibly preventing, the onset of SPMS. This latter is one of the strongest arguments for using DMTs, in particular early treatment with the target of no evident disease activity (NEDA). 

The transition from the relapsing to the SP phase does not happen suddenly, there is a gradual transition period. As a result of this overlap between the relapsing and SP phases of the disease, SPMSers can still have an occasional relapse. I therefore subclassify the SPMS into relapsing-SPMS and non-relapsing SPMS. 

Approximately 15% of MSers present with a form of MS that is progressive from the outset; we refer to this as being primary progressive MS (PPMS). Interestingly, about 10-15% of PPMSers go onto to have relapses and these MSers are refered to as having progressive-relapsing disease. 

Another rare subtype of MS is the individual who has CIS and then presents with progressive MS many years later; some people refer to this as single attack progressive MS (SAP) or transitional MS. Most of us however simply classify these MSers as having SPMS.  

These clinical classifications can be very confusing for MSers. 

What is important? At present only relapsing MS responds to DMTs. Progressive MS without relapses has not been shown to respond to any of the DMTs that are currently licensed for relapsing-forms of MS. This is why the FDA and other regulators license DMTs to treat relapsing-forms of MS. The corrollary is non-relapsing forms of MS, i.e. non-relapsing SPMS and PPMS, should not be treated with DMTs at present unless as part of a clinical trial. This simplified classification of relapsing vs. non-relapsing forms of MS is the most pragmatic one for clinical practice to guide treatment. 

People often ask the question whether PPMS is a different disease to relapse-onset disease. In short it is not. All the evidence suggests there is no differences between the subtypes of MS to suggest they are different diseases. Both subtypes are inflammatory at postmortem and have demyelination and nerve cell loss. The onset of PPMS is on average 10 years later than relapse-onset MS; however, this age is very similar to the age of onset of the SPMS. In twins who both have MS, if one has RRMS the other twin is as likely to have PPMS. The rate of progression of SPMS and PPMS are exactly the same. There are no differences in the genetic profile of PPMSers and relapse-onset MS. In short, most of us in the field accept that PPMS is the same relapse-onset MS the only difference is that PPMSers have missed out on the relapsing-phase of the disease. 

Friday, December 13, 2013

Are you sure that you have MS?

A dirty fact: "Approximately 1 in 20 people diagnosed with MS don't have MS." 

There is no one test that can be done to diagnose multiple sclerosis (MS). MS is diagnosed by combing a set of clinical and MRI findings, electric or neurophysiological investigations and laboratory tests. If these tests fulfill a set of so called MS diagnostic criteria the neurologist makes a diagnosis of MS. 

The underlying principle of making a diagnosis of MS is showing dissemination of lesions in space and time and excluding other possible diagnoses that can mimic MS. The diagnostic criteria have evolved over time from being based purely on clinical attacks, to those including electrical and spinal fluid tests, to the modern era in which we use MRI to help confirm dissemination in time and space. 

Dissemination in time means to attacks or MS lesions occurring at least 30 days apart. Dissemination in space means lesions occurring in different locations, for example the optic nerve and spinal cord. 

The electrical or neurophysiological tests are called evoked potential (EPs) and test electrical conduction in a particular pathway. They can be useful to show lesions in pathways that are not evident on the neurological examination or seen on MRI. The EPs can also show slow electrical conduction which is one of the hallmarks of diseases that affect myelin, the insulation of nerves that are responsible for speeding up electrical conduction.


The laboratory tests are typically done to exclude other diseases that can mimic MS. One test that is useful in helping making the diagnosis of MS is examining the spinal fluid for the presence of oligoclonal bands (OCBs), which are the fingerprint of a specific type of immune activation within the central nervous system (CNS). The OCB fingerprint is relatively specific for the diagnosis of MS in the correct clinical context. 


I have spent some time explaining this all to you as we neurologists get the diagnosis wrong in approximately 5% of MSers. In other words 1 in 20 people who have a diagnosis of MS in life don't have MS when their brains are studied at postmortem when the die. This data is based on a large study that looked at the brains of all people who died with a diagnosis of MS in a region of Denmark. 

Why is the getting the correct diagnosis of MS so important? Firstly, some of the treatments we us in MS have life threatening complications; you don't want to expose people without MS to these complications. Some diseases that mimic MS can be made worse by MS DMTs. Finally, a diagnosis of MS has many psychological, social, financial and economic implications for people. Just having a diagnosis of MS, even if you turn out to have benign disease, has implications for the person concerned. For example, it may affect your life choices and may impact on your ability to get insurance cover to name to obvious examples. I would therefore advise you to make sure you have MS and not an MS mimic. 

Common MS mimics:
  1. Cerebrovascular disease 
  2. Acute disseminated encephalomyelitis or ADEM 
  3. Neuromyelitis optica or NMO
  4. Behcet’s syndrome 
  5. Migraine
  6. Sarcoidosis
  7. SLE or systemic lupus erythematosus
  8. Antiphospholipid antibody syndrome
  9. Leukodystrophies 

The evolving definition of MS based on diagnostic criteria:

Clinical criteria only

Clinical, EPs and CSF analysis