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Treatment of newly diagnosed epilepsies: the shortcomings of SANAD

Standard and New Antiepileptic Drugs (SANAD), a randomized controlled trial (RCT) examining the longer-term outcomes of standard versus new antiepileptic drugs (AEDs),1–3 was promoted widely in the UK, even before its publication.4 It was advocated as a ‘robust method’ to inform treatment of newly diagnosed epilepsies where other RCTs ‘fail to inform clinical practice or policy’.1 It concluded that lamotrigine was superior to carbamazepine or other comparator AEDs for focal seizures, sodium valproate was superior for generalized seizures, and that these results were applicable across all age groups. Recommendations were based on retention rates, reflecting both efficacy and adverse events. The claims made, however, are unsound, particularly regarding children. For an RCT to give meaningful results, the condition treated should be defined to the same standards as current best practice. This was not so with SANAD (especially for children) – clinical suspicion of ‘epilepsy’ requiring treatment was a sufficient criterion to take part. Electroencephalography (EEG) and brain imaging were optional. In ‘newly diagnosed epilepsy’, current best practice starts with meticulous medical diagnosis, including exclusion of non-epileptic paroxysmal events, determination of the type(s) of epileptic seizure, and then, possibly, the epileptic syndrome. This is challenging and must draw on all available information, including detailed history and the results of investigations. At presentation, a syndrome diagnosis is reported as possible for 47% of patients on clinical grounds, increasing to 77% with the addition of EEG; neuroimaging shows epileptogenic lesions in 13%.4 Quoting a recent review of research methodology: ‘No amount of statistical significance or sophisticated analysis will compensate for a poor or absent research hypothesis, inadequate study design, or biased data’.5 Epilepsies are syndromes and diseases with disparate causes, manifestations, and management strategies. Epileptic seizures are similarly heterogeneous. AEDs, therapeutic in one patient, may be deleterious for another. In the SANAD trial, recruited patients were randomized according to physicians’ preference to treat either with carbamazepine (arm A) or valproate (arm B).3 They were not advised to equate arm A with focal and arm B with generalized epileptic seizures, as implied by the subsequent publications.1,2 Carbamazepine is efficacious for focal seizures but aggravates typical absences and myoclonic jerks in idiopathic generalized epilepsy. Valproate is effective for generalized seizures but with significant adverse effects, notably in women of childbearing age. In RCTs (including SANAD), no new AED has shown superior efficacy than carbamazepine for focal or valproate for generalized seizures. In SANAD, carbamazepine was at a disadvantage in comparison with lamotrigine in regard to efficacy and tolerability: (1) at least 10% of patients in arm A did not have focal epilepsies – carbamazepine is likely to be ineffective and may exacerbate generalized epilepsies; and (2) the higher drop-out due to rash was particularly common with carbamazepine – rates of rash with carbamazepine and lamotrigine depend on titration O pnion Treatment of newly diagnosed epilepsies: the shortcomings of SANAD