Another neurological effect of phenytoin is a transient focal lesion in the splenium of the corpus callosum. Splenial lesions are characteristically oval or round, measure less than 2 cm in size, and demonstrate hyperintense signal on T2-weighted sequences, hypointense signal on T1-weighted sequences, and restricted diffusion (Fig. 27.2).

Patients with chronic use of phenytoin may also present with acromegalic features with calvarial hyperostosis and coarsening of the face, hands, and feet. The incidence of calvarial thickening in epileptic patients treated with phenytoin is approximately 33 %. On imaging, progressive diffuse, smooth intramedullary expansion can be observed (Fig. 27.3).

Fetal hydantoin syndrome is a known disorder caused by the in utero exposure of phenytoin. Patients taking phenytoin during their pregnancy have two to three times the risk of birth defects compared to the general population. Although not all exposed fetuses develop the syndrome, the risk of expressing the full syndrome is 5–10 %, while the risk of expressing isolated features is 33 %. The differences in expression are determined by maternal genetic characteristics and ability to detoxify the intermediate metabolites of phenytoin. The effect of phenytoin in the metabolism of folic acid plays a crucial role in the increased risk of spina bifida. The classic features of fetal hydantoin syndrome include a dysmorphic appearance (with craniofacial anomalies, such as hypertelorism, deep nasal bridge, small nose, and cleft lip or palate), mental retardation, growth deficiencies, and limb defects. Other features include microcephaly, ocular defects, spina bifida, and cardiovascular anomalies.

Signs and symptoms related to acute cerebellar dose-related toxicity usually reverse following discontinuation of the medication. However, other effects such as cerebellar atrophy and calvarial thickening may be permanent despite a change in anticonvulsive therapy. Nevertheless, the clinical implications of calvarial thickening are mainly cosmetic.