Riluzole is a presynaptic glutamate release inhibitor, which protects motor neuron from toxic neural excitation. The most common adverse events due to riluzole is elevated liver enzyme levels, specifically ALT (6.9%), AST (6.6%), and γ-GTP (3.8%), as well as nausea (3.8%), according to a treatment outcome study in the pharmaceutical reference. In a previous study, ALT levels elevated 2–4 times the normal range in 7.8% of the cases and AST levels elevated 4 times the normal range in 14.2% of the cases were reported, with 6.5% of the cases showing elevation of both enzymes; 6.5% cases resulted in drug withdrawal in that study, and enzyme levels returned to normal within 2 months after riluzole discontinuation . Another study reported elevated ALT in 6.7% cases and elevated AST in 3.8% cases . In addition to liver enzyme levels, asthenia prevalence of 8.5% (versus 7.0% in placebo) and nausea prevalence of 4.9% (versus 3.5% in placebo) has been reported . All adverse events, except for urinary urgency, noted in this study have been reported in previous research studies or pharmaceutical references (Table 3). All five cases with elevated liver enzyme (5.4%) showed elevated ALT and AST levels, whereas only two cases showed elevated γ-GTP levels; this trend is consistent with previously reported trends [4, 15]. A study investigating dose-dependent effects of riluzole has suggested that hepatotoxicity reflects metabolic toxicity of riluzole [15, 17]. In this study, all cases with elevated liver enzymes that discontinued riluzole presented a history of medication for diabetes or hyperlipidemia (Tables 2 and 3); this may reflect increased metabolic ability. In addition, in some cases, biochemical analyses before riluzole administration revealed elevated γ-GTP; this also suggests that metabolic ability before medication is important. Since biochemical analysis does not always indicate asthenia and symptoms sometimes resemble disease progression, repeated interviews to assess general fatigue would be useful for making decision to discontinue riluzole considering patient’s quality of life (QOL).
Although the incidence of riluzole-induced IP is 0.1% in Japan according to a pharmaceutical reference, the incidence rate in our study was much higher at 4.3%. Because ALS patients complain of dyspnea with disease progression, IP might be overlooked sometimes. The proposed mechanism underlying IP in riluzole-administered patients includes dosage-dependent cell-mediated allergy along with increased CD8-positive lymphocytes in bronchoalveolar lavage and DLST . We speculate that IP in our cases was caused by riluzole-induced allergy. In case 2, prolonged history of smoking may have triggered IP. Therefore, conducting repeated interviews and chest X-rays, as required, are important to differentiate adverse events from disease progression.
A double-blind trial of riluzole has shown that AST levels increased after 42 to 267 days of treatment initiation . A dose-ranging study of riluzole has reported that the median duration of AST increase was 51 days in the 100 mg-dosing group . Some case reports have shown elevated liver enzymes after 3 weeks, 4 weeks, and 6 months of riluzole initiation [6, 17], while in some other case reports of IP, this duration was 3 weeks, 4 weeks, and 2 months [13, 20]. Based on a phase III clinical trial and drug-use survey performed for 18 months  and the abovementioned reports of adverse events occurring from 7 days to 9 months, we considered our follow-up period of a median of 15.5 months to be sufficiently long. Indeed, in our cases, all adverse events occurred within 6 months after riluzole initiation, suggesting that careful follow-up for the first 6 months after riluzole initiation is important. Despite a sufficiently long follow-up, this report was retrospective and duration of drug administration was variable. Further investigations including prospective data and cases with comparable starting points and follow-up periods are warranted. Moreover, a selection bias existed because of the single-center nature of this study, and studies including more patients from multiple centers are imperative.
All but three cases of IP, which required steroid treatment, showed improvement soon after drug discontinuation. Only one IP case not require steroid treatment was diagnosed as IP with ground glass opacity (GGO) on chest X-ray and represented a very early stage of the event. Although responses to steroids were good, the three IP cases could have been mild. Furthermore, the need for steroids could have been eliminated if patients had earlier detection, as in the GGO case.
Riluzole has been reported to be well tolerated for long periods of up to 7 years or more in the real-world setting [10, 14]. However, recurrent pancreatitis in two ALS patients associated with riluzole treatment has been reported recently ; both patients were diagnosed with pancreatitis within 3 months after riluzole initiation. Once again, these reports emphasize the importance of careful observation of adverse events in the first 6 months after riluzole administration.
Although survival benefits of riluzole are debatable, some reports have suggested early benefits such that riluzole induced partial normalization of cortical and peripheral axonal hyperexcitability in the early stage of ALS  or increased survival in the last clinical stage of ALS . In the light of these reports, it is advisable to continue riluzole as long as possible unless QOL is affected by the adverse events. When QOL is affected due to adverse events, riluzole should be discontinued rather than tapering administration, which is supported by the fact that all but three cases of IP in this study showed improvement simply with riluzole discontinuation [7, 9, 14, 16].
IP could be treated and lethal in most cases. Therefore, all ALS patients should be carefully followed up through interviews after riluzole initiation, especially for the first 6 months. When patients complain of respiratory problems, such as dyspnea or dry cough, chest X-ray should be recommended.
Riluzole was discontinued in 20 ALS patients (20/92) in this study. Moreover, incidence of IP was higher in this study than that reported in past studies, and strategies to differentiate IP from disease progression are warranted. Finally, careful follow-up for the first 6 months after the initiation of riluzole treatment is crucial, including thorough interviews, chemical analyses, and chest X-ray, as required.