Plug and play

My last post was about an on-line tool to assist in reading MRI scans to differentiate PSP from some other diagnostic possibilities.  But the formal diagnostic criteria for PSP are still based on traditional history and neurological exam, with MRI as a confirmatory adjunct. This post is about an on-line tool to assist physicians in using those formal criteria.

Starting in the 1980s, a number of researchers, including me, published diagnostic criteria for PSP.  Although these were later validated by autopsy results, they were not so at the time of publication.  Just as important, they tended to be either insufficiently sensitive or insufficiently specific (see my preceding post for definitions of those).  You want sensitivity if you’re trying to measure the prevalence of the disease and don’t want to miss any cases.  You want specificity if you’re trying to recruit a group of people with PSP for a study of causes or treatments and don’t want to risk including anyone without actual PSP.

So, in 1986, Dr. Irene Litvan, now at UCSD, then at the NIH, organized an international group of leading PSP experts to create new criteria.  They produced two sets for living patients: “possible PSP” was more sensitive and “probable PSP” was more specific.  “Definite PSP” was reserved for autopsy-confirmed cases, and the project also included a new set of criteria for that, which served as the “gold standard” by which to validate the first two. 

The new sets were called the NINDS-SPSP Criteria after the National Institute of Neurological Disorders and Stroke (the part of the NIH involved) and the Society for PSP (the former name of CurePSP), which provided a grant for the project. 

The NINDS-SPSP criteria were a hit and remained the world’s standard until researchers realized that those criteria took no heed of the clinical variants of PSP that were starting to be described in 2005.  The classic form of PSP now received the name “PSP-Richardson syndrome” after the leader of the group in Toronto who first described the disease in 1963.  It turns out that PSP-RS explains only about half of all PSP!  The most common of the newly-described variants is PSP-parkinsonism, accounting for about 25% to 40% of all PSP.  Six other much less common ones have been reported, each of which starts with and emphasizes one of the features that starts later in the course of PSP-RS.  Towards the later stages, all of the variants acquire most of the classic features of PSP-RS and all tend to look the same by that point. 

Sorry for that digression.

So in 2015, Dr. Guenter Höglinger, then in Munich, now in Hannover, convened a group to devise a new set of criteria to tease out the different types of PSP and to identify PSP in its earliest stages.  Of course, there aren’t yet enough autopsied cases to provide the stastistical power needed to validate their criteria for the less common PSP types, but that’s changing.  In any event, the new criteria were published in 2017 and dubbed the “MDS PSP Criteria” to recognize the support of the Movement Disorder Society.

Just one problem: they’re very complicated, occupying 7 pages of tables in the journal. To remedy that, Dr. Hoglinger and colleagues have created an on-line form that performs the same diagnostic algorithm as all those tables.  It’s free and it’s at  I’d suggest that you try it out, but many of the data fields require the results of a neurological exam performed by an experienced neurologist.  Furthermore, many of the questions ask things like whether the patient has any evidence of certain alternative diagnoses, and that’s not something that a layperson is likely to know.  But feel free to forward the link to your favorite neurologist for their use.  The different PSP subtypes have different rates of progression, so identifying one’s subtype could be useful.

A new definition of PSP

When you design a research project in PSP, it’s important to make sure that everyone in the subject group with PSP in fact has PSP. Otherwise, you degrade the statistical power of the trial to detect any benefit of the treatment. The standard diagnostic criteria for PSP (called the “NINDS-SPSP Criteria” and spearheaded by Irene Litvan, MD, now of UCSD) were published in 1996 and have worked well for that purpose; Their positive predictive value (the fraction of patients satisfying the criteria who actually have PSP) and specificity (the fraction of those without PSP who fail to satisfy the criteria) are close to 100%.
But as we now enter the new era of trials of experimental neuroprotective treatment for PSP, we would like to diagnose the disease at an earlier stage, when such interventions are most likely to be effective, and the NINDS-SPSP Criteria don’t do that so well, with a sensitivity of about 80% overall, certainly lower in early cases. Another shortcoming is that the various phenotypes of PSP that have been described since 2005 won’t in many cases satisfy the criteria, which were designed for the “original flavor,” now called PSP-Richardson’s syndrome.
So time has marched on and we need a new set of criteria. Günter Höglinger, MD, Professor at the German Center for Neurodegenerative Disorders in Munich and probably the world’s leading clinical researcher in PSP, organized an international effort to revise the criteria. I’m privileged to serve on the four-person Steering Committee. A year ago we started to hash things out by email and conference calls, using the published articles on clinical features of PSP that use either autopsy or the NINDS-SPSP Criteria as a gold standard. The group, comprising 33 people from 11 countries, met in Munich on March 9 and 10 to turn our rough draft into a final version suitable for submission to a journal for peer review.
The new criteria recognize the various phenotypes of PSP. They are PSP-Richardson syndrome (about 55% of all PSP), PSP-parkinsonism (30%), PSP-frontal dementia (5%), PSP-ocular motor (1%), PSP- pure akinesia with gait freezing (1%), PSP-corticobasal syndrome (1%), PSP-progressive non-fluent aphasia (1%), and PSP-cerebellar (<1%). The remaining few percent are combinations of these or still-unrecognized forms.
The new criteria also delineate various “oligosymptomatic” or “prodromal” (the wording remains unsettled) forms, which may or may not develop into one of the diagnosable phenotypes. For example, there is now evidence that someone in the PSP age group with gradually progressive gait freezing for several years and a normal MRI, even without other abnormalities, will almost always prove to have PSP. The same is true for someone with bilateral rigidity and bradykinesia who fails to respond to levodopa and has some sort of nonspecific, undiagnosable visual symptoms or dizziness. Neither of these patients would satisfy the proposed new criteria for any of the PSP phenotypes, but they may still be worth identifying for inclusion in a longitudinal cohort study of people who are at risk of developing PSP. Our new criteria do that.
I’ll keep you updated.