Hypersensitivity pneumonitis possibly caused by riluzole therapy in ALS

Abstract

3. Cock H, Schapira AHV. Mitochondrial DNA mutations and mitochon-drial dysfunction in epilepsy. Epilepsia 1999;40(suppl 3):33-40. 4. Campistol J, Chavez B, Vilaseca MA, Artuch R. Antiepileptic drugs and carnitine. Rev Neurol 2000;suppl 1:105-109. 5. Krahenbuhl S, Brandner S, Kleinle S, Liechti S, Straumann D. Mito-chondrial diseases represent a risk factor for valproate-induced fulmi-nant liver failure. Liver 2000;20:346-348. 6. Budd SL, Nicholls DG. Mitochondria, calcium regulation, and acute glu-tamate excitotoxicity in cultured cerebellar granule cells. A 69-year-old man with sporadic amyotrophic lateral sclerosis (ALS) presented with complaints of increasing and disabling shortness of breath and dry cough for 3 months. A chest X-ray, taken for routine purposes 6 months before the start of symptoms, was normal. The patient was diagnosed with ALS 33 months before presentation. Riluzole 1,2 50 mg twice daily was started 1 year later. He was treated with omeprazole 20 mg per day for more than 10 years, for a grade IV esophagitis. Ten days before the respiratory complaints started, omeprazole was switched to lansoprazole 15 mg per day. After receiving antibiotics for a total of 20 days, without effect, the patient consulted a pulmonologist, who diagnosed him with pulmonary fibrosis. He was treated with methylprednisolone for 8 weeks (32 mg per day tapered every fortnight). This improved his general condition, but had only a minor effect on the coughing and dyspnea. After methylprednisolone was stopped, the complaints soon recurred and the patient presented himself to our clinic. Clinical examination revealed ALS with predominant lower limb involvement: the patient was capable of walking with a walker, but was restricted to a wheelchair due to his dyspnea. The patient manifested an increased respiratory rate and use of accessory respiratory muscles. Lung auscultation was normal. Arterial blood gas at room air showed hypoxia (pH 7.49, oxygen tension 57 mm Hg, carbon dioxide tension 37 mm Hg). Laboratory tests revealed normal blood counts, normal liver and renal function and electrolytes, and increased erythrocyte sedimentation rate (63 mm/hour [normal value, 1 to 10 mm/hour]) and lactate dehydroge-nase (701 U/L [normal value, 240 to 480 U/L]); antinuclear and antineutrophil cytoplasmic antibodies were negative. A chest X-ray was suggestive of interstitial lung disease (figure, A). Lung function measurements showed restrictive lung disease (forced vital capacity of 65% and total lung capacity of 57% of the predicted value) and a severe decrease of carbon monoxide diffusion (26% of the predicted value). Chest CT showed enlargement of the interlobular septa and bronchial structures (figure, C). Bronchos-copy results were normal. Broncho-alveolar lavage fluid stained negative for tuberculosis and contained no pathogenic bacteria or malignant cells. It contained 358 leukocytes per L (normal value, 50 to 250 per L), 51.5% of which were lymphocytes (normal value, 0.0 to 20.0%). Thoracoscopic lung biopsy was performed, because less inva-sive technical investigations yielded no definite diagnosis and the patient was deteriorating. Anatomopathology revealed a picture suggestive of hypersensitivity pneumonitis (HP) (figure, E and F). On the diagnosis of HP and exclusion of other potential causes, mainly by taking a detailed history of past and present exposures, riluzole and lansoprazole were discontinued and methylpred-nisolone 32 mg per day was restarted. Three weeks later, the patient showed recovery from dyspnea and was walking with his walker again; the cough had disappeared. Control arterial blood gas showed complete normalization, control chest X-ray and CT showed significant resolution (figure 1, B and D), lung function showed partial recuperation (forced vital capacity of 78%), and carbon monoxide diffusion showed a significant increase to 40%. Discussion. Neither the adverse events database of the distributor of riluzole (Aventis) nor the literature revealed reports of adverse events similar to the one reported here. 3,4 Omeprazole compromises the effect of riluzole by enhancing its metabolization, via induction of cytochrome p450 1A2, as can be read in the instruction leaflet of riluzole, supplied by Aventis. Lansoprazole does not have this effect. We hypothesize that the deleterious effect of riluzole in this patient only became apparent after switching omeprazole to lansoprazole, because this switch preceded the onset of symptoms in our patient by only 10 days. The prior 21 months of exposure to riluzole omeprazole may have allowed the patient to develop a subclinical reaction to ri-luzole. That lansoprazole would be the cause of the HP is highly unlikely, in view of the short exposure to lansoprazole at the time of first symptoms (10 days) and the long-term widespread use of the compound without reports of similar adverse reactions. The diagnosis of HP is supported by the biochemical, radio-Figure. (A) Chest X-ray at presentation showed a normal mediastinum, normal lung hili, and a normal heart, but diffuse interstitial enhancement suggestive of interstitial lung disease. (B) Control chest X-ray, taken 3 weeks after cessation of riluzole therapy, showed resolution of the in-terstitial enhancement seen at presentation (see A). (C) Chest CT scan at presentation, at the level of the truncus pulmonalis, showed enlargement of the interlobular septa and bronchial structures (traction bronchiectasies). The lymph nodes are of normal size; there are no confluent al-veolar infiltrates. (D) Control chest CT scan (level of the truncus pulmonalis), taken 3 months after cessation of ri-luzole, showed that the enlargement of interlobular septa and bronchial structures seen in C had diminished. (E) Pathologic examination of an open lung biopsy showed both the interstitial mononuclear infiltrate and loose epi-thelioid granulomas (a granuloma is delimited by the ar-rowheads), characteristic of hypersensitivity pneumonitis (hematoxylin-eosin [H-E], original magnification 100).