Eye rolling as a manifestation of clobazam toxicity in a child with epilepsy

Abstract

A four-year-old male with symptomatic generalized epilepsy presented with ataxia, eye rolling, and episodes of back arching which were of non-epileptic origin following the introduction of clobazam at 0.75mg/kg/day. Concurrent antiepileptic medication was lamotrigine at 13mg/kg/day. Clobazam plasma levels were within the normal range, while N-desmethylclobazam (DCLB) concentrations were between five and seven times above the upper limit of the normal range. The plasma elimination half-life for DCLB was prolonged, suggesting a genetic variability in DCLB metabolism leading to toxicity. Reduction in the dose of clobazam to 0.3mg/kg/day was associated with resolution of the non-epileptic neurological symptoms, reduction in DCLB plasma levels, and maintenance of seizure control.

Clobazam Therapeutic Drug Monitoring

“…Four of these cases 41,42,84,85 had N-desmethylclobazam concentrations >3000 ng/mL; 3 cases 41,42,85 had concentrations > 4 times 3000 ng/mL, including 1 case 85 >10 times 3000 ng/mL. N-desmethylclobazam concentrations were not measured in 2 cases, 83,86 but their clobazam concentrations were >3000 ng/mL or 10 times higher than the upper recommended limit of 300 ng/mL.…”

“…One of them still had serum N-desmethylclobazam concentrations in the therapeutic range 20 days after clobazam discontinuation, 42 and the other required complete clobazam discontinuation for 10 days to reduce serum concentrations by one-third. 41 Both cases appear to have been treated with dosages in the usual recommended ranges, but they were too high for these specific patients, which may have led to saturation of N-desmethylclobazam metabolism.…”

“…10 Therefore, higher levels of N-desmethylclobazam in CYP2C19 PMs may be associated with a better chance of response but some risk of increased ADRs. On the other hand, there are two published cases 41,42 of severe signs of clobazam intoxication in CYP2C19 PMs (see Table 2). In these 2 patients, N-desmethylclobazam had extraordinarily long-half lives.…”

“…Table 2 describes 6 reports of clobazam intoxication, 41,42,83–86 including 2 deaths 85,86 that occurred at elevated serum concentrations. Four of these cases 41,42,84,85 had N-desmethylclobazam concentrations >3000 ng/mL; 3 cases 41,42,85 had concentrations > 4 times 3000 ng/mL, including 1 case 85 >10 times 3000 ng/mL.…”

“…Table 3 presents a comprehensive review of the few published studies reporting data on the N-desmethylclobazam/clobazam ratio. 21,22, 40,41, 48, 61,64, 69,87–91 The data suggest that: (1) very high ratios (>25) indicate that the patient is a CYP2C19 PM, or is taking a drug which is a CYP3A inducer and a CYP2C19 inhibitor, such as felbamate; (2) ratios of 10–25 are compatible with the patient taking a CYP3A inducer; and (3) ratios <10 are compatible with “normal” patients [who are: (a) not taking CYP3A inducers, (b) not taking CYP2C19 inhibitors, and (c) not CYP2C19 PMs]. These ratio ranges are rough approximations calculated by reviewing the limited available studies, which were not designed to study this ratio.…”