Five cases of West syndrome complicated by nephrocalcinosis during combination therapy with ACTH and zonisamide

  Adrenocorticotrophic hormone (ACTH) has been used as a first-line therapy to treat West syndrome. Among the potential side-effects of ACTH therapy, nephrocalcinosis (NC) or urolithiasis cannot be ignored. The etiologies of NC in ACTH-treated patients are multifactorial. Possible causes include increased urine calcium (Ca) and phosphorous (P) excretion, osteoporosis, and/or abnormal levels of parathyroid hormone.<br>  Zonisamide (ZNS) is an antiepileptic agent that is widely used in Japan, sometimes concomitant with ACTH therapy. ZNS is also known to be associated with urolithiasis. It is speculated that ZNS has weak carbonic anhydrase inhibitor effects resulting in alkalized urine and increased urine calcium excretion, which, in turn, cause urolithiasis.<br>  We report 5 children who developed NC or urolithiasis with West syndrome treated with ACTH (NC group).<br>  To examine the risk factors for NC, duration of ACTH therapy, total dose of ACTH, usage of ZNS, serum Ca level, serum P level, serum alkaline phosphatase (ALP) level, urine Ca/Cr ratio, %TRP and urine pH during ACTH therapy were examined retrospectively.<br>  For the purpose of comparison, we examined those parameters in 4 other patients who had developed neither NC nor urolithasis during treatment using ACTH (non-NC group).<br>  All patients with NC group had been treated with ZNS as opposed to only one in non-NC group. Total dose of ACTH was higher in the NC group than in the non-NC group. (NC 0.37±0.10 mg/kg, non-NC 0.26±0.01 mg/kg, p=0.07). Duration of ACTH therapy was significantly longer in the NC group. (NC 41.8±9.4 days, non-NC 27.5±2.6 days, p=0.02).<br>  No remarkable changes were seen in serum Ca levels during ACTH therapy. Urine Ca/Cr ratio increased, with a much higher mean peak level in the NC group (NC 2.0±0.7, non-NC 0.7±0.6, p=0.03). One patient who did not developed NC despite administration of ZNS expressed normal urine Ca/Cr ratio during ACTH therapy.<br>  Serum P levels and %TRP decreased, but no significant difference was seen between the NC and non-NC groups. Serum ALP level decreased in all except one patient with preexisting hyperalkaline phosphatemia. Urine pH did not show any particular tendency.<br>  In our study, patients with West syndrome on ACTH therapy were in the risky environment for urolithialis:urine Ca and P excretion increased, turnover of the bone lowered (decreased serum Alp). Risk factors for NC were 1) administration of ZNS, 2) high dose and long duration of treatment with ACTH, and 3) high urine Ca/Cr ratio. During ACTH therapy, particularly in combination with ZNS, renal echo-sonography and urine Ca/Cr ratio have to be monitored closely. Thiazide therapy or changing to antiepileptic agents other than ZNS can be alternative management if any abnormalities are detected.