Riluzole Treatment, Survival and Diagnostic Criteria in Parkinson Plus Disorders: The NNIPPS Study

Gilbert Bensimon; Albert Ludolph; Yves Agid; Marie Vidailhet; Christine Payan; P. Nigel Leigh


Brain. 2009;132(1):156-171. 

In This Article

Summary and Introduction

Parkinson plus diseases, comprising mainly progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are rare neurodegenerative conditions. We designed a double-blind randomized placebo-controlled trial of riluzole as a potential disease-modifying agent in Parkinson plus disorders (NNIPPS: Neuroprotection and Natural History in Parkinson Plus Syndromes). We analysed the accuracy of our clinical diagnostic criteria, and studied prognostic factors for survival. Patients with an akinetic-rigid syndrome diagnosed as having PSP or MSA according to modified consensus diagnostic criteria were considered for inclusion. The psychometric validity (convergent and predictive) of the NNIPPS diagnostic criteria were tested prospectively by clinical and pathological assessments. The study was powered to detect a 40% decrease in relative risk of death within PSP or MSA strata. Patients were randomized to riluzole or matched placebo daily and followed up to 36 months. The primary endpoint was survival. Secondary efficacy outcomes were rates of disease progression assessed by functional measures. A total of 767 patients were randomized and 760 qualified for the Intent to Treat (ITT) analysis, stratified at entry as PSP (362 patients) or MSA (398 patients). Median follow-up was 1095 days (range 249-1095). During the study, 342 patients died and 112 brains were examined for pathology. NNIPPS diagnostic criteria showed for both PSP and MSA excellent convergent validity with the investigators' assessment of diagnostic probability (point-biserial correlation: MSA r pb = 0.93, P < 0.0001; PSP, r pb = 0.95, P < 0.0001), and excellent predictive validity against histopathology [sensitivity and specificity (95% CI) for PSP 0.95 (0.88-0.98) and 0.84 (0.77-0.87); and for MSA 0.96 (0.88-0.99) and 0.91 (0.86-0.93)]. There was no evidence of a drug effect on survival in the PSP or MSA strata (3 year Kaplan-Meier estimates PSP-riluzole: 0.51, PSP-placebo: 0.50; MSA-riluzole: 0.53, MSA-placebo: 0.58; P = 0.66 and P = 0.48 by the log-rank test, respectively), or in the population as a whole (P = 0.42, by the stratified-log-rank test). Likewise, rate of progression was similar in both treatment groups. There were no unexpected adverse effects of riluzole, and no significant safety concerns. Riluzole did not have a significant effect on survival or rate of functional deterioration in PSP or MSA, although the study reached over 80% power to detect the hypothesized drug effect within strata. The NNIPPS diagnostic criteria were consistent and valid. They can be used to distinguish between PSP and MSA with high accuracy, and should facilitate research into these conditions relatively early in their evolution.

Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are disabling and fatal neurodegenerative disorders for which no disease-modifying treatment is available. For the majority of patients with PSP and MSA, many of whom present with an atypical Parkinsonian or akinetic-rigid syndrome ('Parkinson plus disorder') the course is one of relentless progression, increasing disability and death with a median survival of 5-10 years from onset of symptoms (Litvan et al., 1996a; Testa et al., 1996, 2001; Ben-Shlomo et al., 1997; Schrag et al., 1999, 2008; Litvan, 2003; Golbe and Ohman-Strickland, 2007).

PSP and MSA have similar prevalence rates estimated at 2-7 per 100 000 person years (Golbe et al., 1988; Ben-Shlomo et al., 1997; Bower et al., 1997; Schrag et al., 1999; Nath and Burn, 2000; Nath et al., 2001; Vanacore et al., 2001a, b; Watanabe et al., 2002). These are probably underestimates, however, because current diagnostic criteria are based on retrospective clinicopathological studies (Litvan et al., 1996a, b, d, 2003; Litvan, 2003) and both delayed diagnosis and mis-diagnosis are common. Although published consensus diagnostic criteria are highly specific they are relatively insensitive and a definite diagnosis can only be made through histopathology (Litvan et al., 2003). Since it is likely that neuroprotective strategies are best tested at a relatively early stage of disease, more sensitive diagnostic criteria are required for trials of potential disease-modifying agents. Although PSP and MSA often present as akinetic-rigid syndromes, each has distinctive pathological features. In MSA, a key feature is glial cytoplasmic inclusions with accumulation of α-synuclein in oligodendrocytes and neurons (Papp et al., 1989; Lantos and Papp, 1994; Spillantini and Goedert, 2000) whilst in PSP the hallmark is accumulation of abnormally phosphorylated microtubule-associated tau protein (τ) in neurons and glia (Hauw et al., 1994; Dickson et al., 2007). Although the pathogenic mechanisms underlying MSA and PSP are unknown, there is evidence that glutamate toxicity may contribute to neuronal damage in these and other neurodegenerative diseases (Albin and Greenamyre, 1992; Albers and Augood, 2001; Mattson, 2003; Przedborski, 2005). The benzothiazole drug riluzole has a number of pharmacological effects that contribute to neuroprotection in experimental paradigms of neurodegenerative diseases including anti-excitotoxic activity, blocking of voltage dependent sodium-channels, free-radical scavenging, anti-apoptotic and neurotrophic effects and inhibition of protein aggregation (Doble, 1999; Heiser et al., 2002; Yoo et al., 2005; Caumont et al., 2006; Shortland et al., 2006). In a rodent model of MSA, riluzole improved some measures of neuronal damage (Diguet et al., 2005; Scherfler et al., 2005). Riluzole (up to 200 mg daily) is well tolerated and prolongs survival in amyotrophic lateral sclerosis (Bensimon et al., 1994; Lacomblez et al., 1996; Miller et al., 2007). Thus far, riluzole remains the only agent shown to modify disease progression in a human neurodegenerative disorder.

In order to test the hypothesis that riluzole may slow disease progression in PSP and MSA, we carried out a phase-III, randomized double-blind placebo controlled trial in 44 centres in France, Germany and the UK. The study design incorporated ancillary objectives including natural history, development and validation of more sensitive diagnostic criteria and functional measures of disease severity and progression, cognition, quality of life, health economics, MRI changes, pathology and the establishment of brain and DNA banks. We describe here the design and main outcomes of the NNIPPS trial in terms of the efficacy and safety of riluzole, the psychometric validity of the NNIPPS diagnostic criteria in relation to clinic and pathology and the major factors influencing prognosis for PSP and MSA.


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