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Pharmacokinetic interactions between antiepileptic drugs: clinical considerations. Rufinamide: clinical pharmacokinetics and concentration-response relationship in patients with epilepsy. Drug stimulated biotransformation of hormonal steroid contraceptives: clinical implications. Plasma levels of primidone and its metabolite phenobarbital: effect of age and associated therapy. Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonicclonic seizures. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Efficacy of phenobarbital monotherapy in treatment of neonatal seizures-relationship to blood vessels. A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures. Transplacental vitamin K prevents hemorrhagic disease of infants of epileptic mothers. Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case-control study. Teratogenic and pharmacokinetic studies of primidone during pregnancy and in the offspring of epileptic women. Individual and crossed tolerance to the anticonvulsant effect and neurotoxicity of phenobarbital and primidone in mice. Correlation between age and plasma level/dosage for phenobarbital in infants and children. Rapid introduction of primidone using phenobarbital loading: acute primidone toxicity avoided. The "forgotten" cross-tolerance between phenobarbital and primidone: it can prevent acute primidone-related toxicity. Comparison of the effectiveness of phenobarbital, mephobarbital, primidone, diphenylhydantoin, ethotoin, metharbital, and methylphenylethylhydantoin in motor seizures. A comparison of the effectiveness of primidone versus carbamazepine in epileptic outpatients. Phenobarbital treatment and major depressive disorder in children with epilepsy: a naturalistic follow-up. Depressive symptoms in epilepsy: prevalence, impact, aetiology, biological correlates and effect of treatment with antiepileptic drugs. Cognitive effects of long-term treatment with phenobarbital and valproic acid in school children. Phenobarbital-induced absence seizure in benign childhood epilepsy with centrotemporal spikes. Phenobarbital-associated bone marrow aplasia: a case report and review of the literature. Grand mal seizures and acute intermittent porphyria: the problem of differential diagnosis and treatment. Incidence of anticonvulsant osteomalacia and effect of vitamin D: controlled therapeutic trial. Its narrow therapeutic profile has limited its use to the treatment of childhood absence epilepsy. Some studies have also suggested a potential therapeutic effect in epileptic negative myoclonus (1). Antiepileptic Effects the presumed mechanism of action against absence seizures is reduction of low-threshold T-type calcium currents in thalamic neurons (11,12).

It likely reflects direct or indirect basal ganglia activation, in addition to widespread subcortical and cortical involvement of different neural networks, as Automatisms the broad term of "automatisms" refers to stereotyped complex behavior seen during seizures. Gastaut and Broughton (51) listed five subclasses of automatisms: alimentary, mimetic, gestural, ambulatory, and verbal. This list does not include stereotyped bicycling or pedaling movements or sexual automatisms. Oroalimentary automatisms such as lip smacking, chewing, swallowing, and other tongue movements tend to occur early in the seizure, often with hand automatisms, and may be elicited by electrical stimulation of the amygdala (20). They may occur without loss of consciousness in temporal lobe seizures when the ictal discharge is confined to the amygdala and anterior hippocampus (2). Hand automatisms, also referred to as simple discrete movements by Maldonado and colleagues (27) or bimanual automatisms, are rapid, repetitive, pill-rolling movements of the fingers or fumbling, grasping movements in which the patient may pull at sheets and manipulate any object within reach. In our experience, they did not, unless accompanied by tonic/dystonic posturing in the opposite limb. In these patients, the seizures may begin with bilateral hand automatisms that are interrupted by dystonic posturing on one side while the automatisms continue on the other side (ipsilateral to the ictal discharge) (45) (Table 12. Like oroalimentary automatisms, the hand automatisms suggest onset from the mesial temporal region. In extratemporal seizures with unilateral tonic posturing, thrashing to-andfro movements, which are more proximal and not discrete, are sometimes seen in the opposite limb. Although usually symmetric, unilateral blinking has been reported ipsilateral to the seizure focus (54). A mechanism similar to unilateral hand automatisms may be operative, but this has not been documented. Rapid, forced eye blinking when the seizure begins is thought to indicate occipital lobe onset (54). Seizures arising from the occipital region may produce version of the eyes to the opposite side (44). Truncal or body movements may be seen, usually in the middle or late third of the seizure, when the patient attempts to sit up, turn over, or get out of bed (28). Bicycling or pedaling movements of the legs are more commonly observed in complex partial seizures arising from the mesial frontal and orbitofrontal regions (24) than in temporal lobe seizures. They are sometimes seen in temporal lobe seizures but probably reflect spread of the ictal discharge to the mesial frontal cortex. Mimetic automatisms, with changes in facial expression, grimacing, smiling, or pouting, are common in complex partial seizures (44). Crying has been noted in complex partial seizures arising from the nondominant temporal lobe (44). Sexual or genital automatisms such as pelvic or truncal thrusting, masturbatory activity, or grabbing or fondling of the genitals are relatively uncommon during complex partial seizures. However, they have been reported in complex partial seizures of frontal lobe origin, as well as in those arising from the temporal lobes (44). Leutmezqwer and colleagues (56) postulate that discrete genital automatisms such as fondling or grabbing the genitals are seen in temporal lobe seizures, whereas hypermotoric sexual automatisms such as pelvic or truncal thrusting usually occur in frontal lobe seizures. So, in summary, although various types of automatisms may have a useful localizing value, it is mainly unilateral distal limb automatisms with contralateral dystonia that is useful as a lateralizing sign. It is performed with the hand ipsilateral to the epileptogenic focus in 75% to 90% of the cases when seen in the context of a temporal lobe automotor seizure, but has no lateralizing value when seen with an extratemporal seizure. Postulated mechanisms leading to its occurrence include ictal activation of the amygdala with subsequent olfactory hallucinations or increased nasal secretions, and postictal contralateral hand movement abnormalities or neglect (44,55). A and B: Distribution of the field of an interictal spike from a patient with temporal lobe epilepsy. A and B: Distribution of the field of interictal spikes occurring in runs from a patient with frontal lobe complex partial seizures. Bitemporal sharp-wave foci are noted in 25% to 33% of patients and may be independent or synchronous. Mesial temporal spikes may not be well seen at the surface, and intermittent rhythmic slowing may be the only clue to deep-seated spikes (57). Less frequently, sharp-wave foci are seen in the midtemporal or posterior temporal region. Interictal foci may be mapped according to amplitude, and the relative frequency of various sharp-wave foci may be taken into account during monitoring of epilepsy surgery candidates.

These studies have reported normal osteoid seam width and normal or increased mineralization rates. Other potential influencing factors including effects on bone quality may explain the increased fracture risk. Bone specimens in rats treated with levetiracetam, phenytoin, and valproate had evidence of changes in bone quality (34). Biochemical competence was affected in those rats treated with low-dose levetiracetam. Increased markers of bone turnover have been reported, however, in persons with epilepsy treated with carbamazepine (43,44). Polytherapy may independently result in increased abnormalities of bone metabolism (45,46). Therefore, seizure control is of clear importance in preventing fracture in persons with epilepsy. Interestingly, in one study traumatic fractures were more likely to occur in men (55%), whereas pathologic fractures were more common in women (57%) (38). Vestergaard and colleagues (6) reported that seizure-related fractures accounted for 33. Fractures of the spine, forearms, femurs, lower legs, and feet and toes were significantly increased after the diagnosis of epilepsy. This finding is in agreement with a recent Danish case-control study including 124,655 fracture cases, which concluded that liver-inducing potential per se was not responsible for the increased fracture risk (39). Reported alterations in bone and mineral metabolism although not seen consistently include reduced calcium, reduced phosphate, reduced 25-hydroxyvitamin D levels, and elevated markers of bone formation and resorption. In vitro studies support cytochrome P450 enzyme induction leading to increased catabolism of vitamin D. Decreased cortical bone mass as measured by quantitative ultrasound of the phalanges has been described in carbamazepine-treated subjects (50,51). Similarly, inconsistent reports of hypocalcemia, hypophosphatemia, decreased vitamin D metabolites, and elevated markers of bone turnover exist. For instance, a study of male subjects without epilepsy treated with carbamazepine for 10 weeks did not have significant elevations on markers of bone formation and resorption (52), while other studies report elevated markers of bone formation and resorption in carbamazepine-treated subjects (43,44). Interestingly, elevated risk of fracture was observed in persons treated with carbamazepine (39). A 2-year longitudinal study performed by Verrotti and colleagues in 60 adolescents taking carbamazepine compared serum markers of bone formation and resorption after starting carbamazepine in normal subjects with epilepsy (44). They were age and gender matched with controls and divided by developmental status into three groups: prepuberty, puberty, and postpuberty. Following 2 years of carbamazepine treatment, they found a significant increase in several serum markers of collagen and bone turnover. Urinary cross-linked N-telopeptides of type 1 collagen excretion, a marker of osteoclastic activity, was increased 10-fold. These findings suggest that increased bone turnover occurred despite normal vitamin D levels. Valproate has been associated with reversible Fanconi syndrome (57,58), suggesting that valproate may cause renal tubular dysfunction with increased urinary loss of calcium and phosphorus. This effect was present despite increased weight, which is typically associated with a protective effect on bone mineralization. Prescription indication may have influenced the findings as gabapentin is commonly used for indications other than epilepsy including pain. Lamotrigine monotherapy treatment in young women with epilepsy was not associated with bone loss (22) or significant findings in calcium or markers of bone resorption and bone formation (59). A limited preliminary clinical study found no effects (61), but a rat study suggests there may be changes in bone quality secondary to low-dose levetiracetam administration (34). As carbonic anhydrase inhibitors, they can promote a renal acidosis resulting in among other things secondary abnormalities in bone. Interestingly though, carbonic anhydrase also potentiates the action of osteoclasts and inhibitors may have a bone-sparing effect.