Diagnosing PPMS; not an easy task!

PubmedKelly et al. A proposed modification to the McDonald 2010 criteria for the diagnosis of primary progressive multiple sclerosis. Mult Scler. 2012 Nov.

BACKGROUND: The diagnostic criteria for primary-progressive multiple sclerosis (PPMS) have undergone revision over the last 20 years. Cerebrospinal fluid oligoclonal bands (CSFOBs) have received less emphasis in recent revisions of the McDonald criteria. The aim of this study was to examine the sensitivity of the diagnostic criteria for PPMS with particular reference to spinal cord criteria and examine the utility of CSFOBs in a cohort of PPMSers.

METHODS: All new PPMS diagnoses between 1990 and 2011 were identified. Baseline clinical details and paraclinical evaluations including MRI of the brain, spinal cord, CSF and visually evoked responses (VERs) were assessed. The proportion of MSers who met the requirements for diagnosis of PPMS on the basis of Thompson’s and the McDonald Criteria (2001, 2005, 2010) were determined.

RESULTS: There were 88/95 PPMSers who had at least two diagnostic investigations. The sensitivity of Thompson’s and the McDonald 2001 criteria was 64%; the McDonald 2010 revisions gave the highest sensitivity (77%); the McDonald 2005 criteria had intermediate sensitivity (74%). The combination of CSFOBs and MRI of the brain yielded the greatest number of MSers demonstrating dissemination in space (DIS) on only two investigations. VERs did not aid diagnosis. Reducing requirements for the number of spinal cord lesions (symptomatic or not) to one increased diagnostic sensitivity to 84%.

CONCLUSION: An alternative criterion requiring two of: i) MRI of the brain with one or more lesions in two of three regions typical for demyelination; ii) the presence of one T2-weighted spinal cord plaque (typical for demyelination); iii) CSFOBs; would increase the diagnostic sensitivity for PPMS

“The problem with this paper is that the author’s have not really considered what a diagnosis of MS means? The truth is that the “gold standard”, i.e. the 2001 criteria have never been validated. Therefore I prefer to use the the term accuracy. True validation requires a post-mortem follow-up to check that the ante-mortem diagnosis (in-life) is confirmed in death. Another issue is the positive and negative predictive value of the criteria, with PPMS this is critical; i.e. if you fulfil the contemporary criteria what is the likelihood that you have PPMS or more importantly the likelihood you do not have PPMS? The negative and positive predictive values vary depending on how common PPMS is in the part of the world the criteria are being tested or applied.” 

“This rant may be confusing; I promise to post a piece on it to simplify the message in the near future.”

“I never make a diagnosis of PPMS without spinal fluid analysis; it is vital to exclude MS mimics and to make sure that there is evidence of immune activation within the CNS or spinal cord. More recently it has been shown  that PPMSers with a negative spinal fluid analysis do better than PPMSers with a positive CSF analysis.Why? I think this suggests  that they may be two different diseases. As a result of this observation the two PPMS trials that are currently running (fingolimod and ocrelizumab) both require trial subjects to have abnormal CSF findings. So despite the current diagnostic criteria not requiring an abnormal CSF the steering committees who designed these trials have rejected the 2010 and 2005 criteria and have applied the 2001 criteria. Good on them!”

“I am sure a lot of you will have questions and comments on this post. For example, my neurologist has diagnosed me with PPMS without doing a lumbar puncture? Is that okay?”

7 thoughts on “Diagnosing PPMS; not an easy task!”

  1. What about RRMS with negative CSF analysis – could that be a different disease than RRMS with positive CSF analysis? (I had negative CSF analysis six years ago and have wondered what that means for the course of the disease or if a test done now would be likely to be positive.)There is a terrible lack of treatment options for people with PPMS. I am glad there are these trials being run on PPMS.

  2. Erm, so is the spinal fluid of a PPMSer different to that of a RRMSer. Never heard of it before, please explain Prof G.

    1. No difference between RRMS and PPMS; they both have OCBs! If you don't have OCBs your prognosis is better!

  3. I think the idea here is that by requiring spinal analysis for the PPMSers in the trial, they're requiring a higher bar for the diagnosis of PPMS thus keeping out patients who might be misdiagnosed or have a different form of PPMS. A PPMS trial is challenging enough without having misdiagnosed patients among the analysis, or patients without evidence of immune activation around the spinal cord/brain, because the likelihood that a drug would help them is less if they don't have that immune activation? And people with PPMS who have never had a spinal tap might consider asking for one, because if it shows no oligoclonal bands, then they are likely to have a better course, and it is helpful to have predictive information like that when dealing with a miserable disease like MS. If there's a possibility that PPMS is two different diseases, it would seem to be a good idea to try and separate them so that the trial only includes one of the two.

  4. I was diagnosed with ms type not specified at diagnosis. I presented with difficulty in walking,positive csf for oligoclonal bands, blood serum taken at same time showed no bands.Diseases that mimic ms were excluded. Two years later I was undiagnosed and told I had ME.This was due to the fact that my MRI was negative.My mobility was slowely getting worse but I decided to try and get on with my life. My kids were angry and we were all confused and didnt know whether to be happy or not even though things were getting no better.Two years later things got progressively worse continuous urinary tract infections,bowel problems and finally septacaemia whihc I was lucky to recover from.I was sent home mobility shot and told ppms. Another two years down the line spsticity in arms and legs has got worse,there are objective signs of ms,positive csf but because of an equivocal mri the diagnosis is in question again for the third time. Its enough to send a person round the bend. Its hard enough to come to terms with the diagnosis its like going through the grieving process but not once three times for the same person. Would you leave the diagnosis of ppms if all other conditions had been eliminated.Would they be eligable for a drug trial? Meanwhile Im left trying to cope with not being able to walk, poor sleep due to pain and spasticity. The effects on a family and the damage its done is beyond repair. Researchers may discuss and revise criteria but behind the criteria is a human being and a family.(This is a mild version of events!!)

  5. This is interesting. I never felt my diagnosis of RRMS was accurate. I had been having sypmtoms for over twenty five years by the time I was diagnosed. One 5mm C-spine lesion that was enhancing, optic neuritis, multiple (approximately 20) brain lesions, including Dawsons Fingers. Several T1 lesions. Positive for 3 O-bands. A T-spine MRI was not done at the time. Six years later a T-spine MRI showed a large non-enhancing lesion with multi-level atrophy of the T-spine and that lesion may well have been present at the time of my diagnosis.Seems to fit the criteria for PPMS, or am I mistaken?

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