Janus Kinase Inhibitor: A Possible Cause of Hyperammonemic Encephalopathy?

Hyperammonemia is a toxic metabolic condition that can result from hepatic failure or a urea-cycle disorder, and it can cause irreparable damage to the brain as hyperammonemic encephalopathy (HE). 1 Tyrosine kinase inhibitors (TKIs) that disrupt the signal transduction pathways of protein kinases are another cause of HE. 2 We report a case of HE that developed following treatment with tofacitinib, which is a Janus kinase (JAK) inhibitor that is a subclass of TKIs. 3 A 48-year-old male with a history of hypertension and ankylosing spondylitis was brought to the emergency department due to vomiting and mental confusion followed by stuporous mental change, irritability, and one brief generalized tonic-clonic seizure episode.He had been taking medications at the following daily doses: methotrexate 2.5 mg, prednisolone 5 mg, pregabalin 150 mg, amlodipine/valsartan 5/80 mg, naproxen 500 mg, acetaminophen/tramadol 650/75 mg, and secukinumab 300 mg.The last drug was changed to tofacitinib 5 mg BID per day, which he had taken for 3 days before arrival.His initial serum ammonia level was 210 mol/L (normal range, 11-35 mol/L), but abdominal computed tomography (CT) showed no evidence of hepatic impairment (e.g., parenchymal lesion or bile-duct dilatation in liver) or obstructive lesions in the urinary tract.A cerebrospinal fluid study produced normal findings: opening pressure of 13 mm H2O, colorless fluid, 0/L white blood cells, 0/L red blood cells, 37.9 mg/dL protein, and 85 mg/dL glucose (serum glucose, 144 mg/dL).He developed status epilepticus (SE) including right-side-dominant eyelid and facial twitching with occasional concomitant myoclonic jerking in both arms and legs, the intensity and duration of which were correlated with the serum ammonia level (Fig. 1A).The seizure was refractory to medications administered in accordance with SE guidelines.Aggressive ammonia lowering treatment with L-arginine, lactulose, and rifaximin along with continuous renal replacement therapy resulted in the serum ammonia level temporarily dropping to 63 mol/L, but it subsequently increased to 883 mol/L (Fig. 1A).He progressed to brain death on the third day after admission when the refractory seizure disappeared, at which time his serum ammonia level had decreased to 149 mol/L (Fig. 1A).Brain diffusion-weighted imaging (DWI) on the fourth day after admission demonstrated diffuse hyperintensities over the bilateral frontal, parietal, temporal, occipital, cingulate, and insular cortices, thalami, and midbrain with cerebral edema (Fig. 1B).The serum levels of various amino acids were all within the normal limits (Supplementary Table 1 in the online-only Data Supplement).The urinary orotic acid level was 38.3 mmol/mol Cr (normal, not detected).Brain CT performed 8 days after admission revealed global swelling with sulcal effacement (Supplementary Fig. 1 in the online-only Data Supplement).The patient died 7.5 months after symptom onset.Ammonia is generated from the catabolism of amino acids present in dietary protein.Ureacycle disorders can be diagnosed from the levels of amino acids and urinary organic acids according to a diagnostic algorithm for late-onset hyperammonemia. 4The most common