The classification of psychiatric clinical phenomena in patients with epilepsy is frequently based on their temporal relation with seizure occurrence. Hence, we refer to ictal psychiatric symptoms when symptoms are the clinical expression of the actual seizure; peri-ictal psychiatric symptoms refer to symptomatology preceding and/or following the ictus (i.e., postictal); and interictal symptoms are those that present independently of the seizure occurrence. A pathogenic role of the epileptic process on psychiatric phenomena is obvious in peri-ictal disorders, but to a significantly lesser degree in interictal disorders. Yet, at some point in their practice, all epileptologists have encountered cases of patients with florid “interictal” psychiatric and cognitive disturbances that become apparent around the beginning of a seizure disorder and remit and/or significantly improve upon its elimination. We use the term epileptic encephalopathies to refer to this type of psychiatric and cognitive disturbances. The purpose of this chapter is to review the available data on two epileptic encephalopathies: (i) the acquired epileptic aphasia of childhood (also known as Landau-Kleffner Syndrome [LKS]), in which the “nonepileptic” clinical disturbances are the major expression of the epileptic disorder, and cure of the seizure disorder is often followed by partial to full recovery of language function (1) and (ii) the epileptic encephalopathy associated with hypothalamic hamartomas with gelastic epilepsy (HHGE) presenting characteristically with severe psychiatric and cognitive disturbances associated with the onset of a variety of epileptic seizures, particularly gelastic seizures, and also including complex partial, secondary generalized tonic-clonic (GTC) seizures, and at times atonic or tonic seizures (2). These severe psychiatric and cognitive disturbances remit or improve significantly with the cessation of the seizures following a successful surgical treatment.

As shown subsequently, the severity of the actual clinical seizures may range from very rare or nonexistent such as in LKS but with electroencephalographic (EEG) recordings showing abundant epileptiform activity in the form of a continuous spike and wave during slow wave sleep (CSWS) pattern. Gelastic seizures associated with hypothalamic hamartomas are more likely to be refractory to antiepileptic drugs (AEDs) and often of several types.

The underlying pathogenic mechanisms of the psychiatric and cognitive disturbances of these two epileptic encephalopathies are suspected to be closely tied to the epileptic activity and its impact on brain structures that mediate specific cognitive, affective, and behavioral functions. To date, however, the mechanisms responsible have yet to be established. In the case of LKS, for example, some of the possible culprits include (i) a direct impact of interictal spikes on cognitive functions and (ii) neuronal (and specifically synaptic) changes triggered by continuous interictal bombardment, among others. In HHGE, thalamic and subthalamic electrographic involvement by frequent ictal and interictal activity is possible. Alternatively, hypothalamic endorphin dysfunction has been implicated but never proven.

The impact of interictal epileptiform activity on cognitive functions was studied extensively by Binnie et al. (3,4). Although it is still the source of much debate, there appears to be agreement that generalized and focal discharges can often be associated with disturbed cognition. Schwab (5) in 1939 was the first to demonstrate an absent or delayed response during a generalized epileptiform discharge using a simple reaction task test. Aarts et al. (6) coined the term transient cognitive impairment to reflect this phenomenon. Binnie et al. (4) described transient cognitive impairment in 50% of 91 patients during generalized or focal discharges. Right-sided discharges were associated with impairment in visual spatial tasks, whereas errors in verbal tasks were demonstrated during left-sided discharges. The authors observed that the error rates increased if the stimulus was presented in the midst of the discharge. If the epileptiform discharge occurred within 2 seconds before the stimulus, the degree of disruption was greater. Kasteleijn-Nolst Trenite et al. (7) reported similar findings with respect to the type of deficit in relation to the side of discharge in 36% of a group of 69 children. The relationship between the occurrence of epileptiform discharge and cognitive functions is complex, as increased concentration on a task can result in a decrease in the rate of epileptiform discharges (8).

With respect to the second potential mechanism, Grigonis and Murphy (9) demonstrated disruption in the formation of normal synaptic connections by focal epileptic discharges in the brain of young animals. Along the same lines, Morrell attributed the pathogenic mechanisms mediating language disturbances in LKS to the interference of the normal process of synaptic organization in language cortex by the constant “bombardment” of interictal epileptic activity (10,11): “It is well known that different neural systems have critical periods in development during which the adult patterns of synaptic engagement are gradually established. At such times, there is first a superabundant outgrowth of axon terminals resulting in a temporary hyper-innervation of the synaptic target; this extravagant outgrowth appears to be entirely under genetic control. Over the remainder of the critical period, the synaptic contacts are extensively pruned. The pruning is selective; it is dependent on and controlled by synaptic use, i.e., environmental input. Synaptic contacts activated by use become cemented, so to speak, while those not environmentally engaged wither away (12,13,14,15,16,17,18). Neural networks for linguistic function develop late and their circuitry remains malleable during the first 8 to 10 years of life (19,20,21,22). We hypothesize, then, that the impact of epileptic activity originating from this anlage of speech cortex may result in chaotic and behaviorally meaningless activation of synaptic contacts that would have been ‘pruned’ under normal circumstances. Such epileptic activity may set up permanent, inappropriate and nonfunctional linkages.”