Bypassing the Blood-Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Abstract

Epilepsies are common chronic neurological diseases characterized by recurrent unprovoked seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiseizure drugs (ASDs). Systemic pharmacotherapies for epilepsies are facing two main challenges. First, adverse effects from (often life-long) systemic drug treatment are common, and second, about one-third of patients with epilepsy have seizures refractory to systemic pharmacotherapy. Especially the drug resistance in epilepsies remains an unmet clinical need despite the recent introduction of new ASDs. Apart from other hypotheses, epilepsy-induced alterations of the blood-brain barrier (BBB) are thought to prevent ASDs from entering the brain parenchyma in necessary amounts, thereby being involved in causing drug-resistant epilepsy. Although an invasive procedure, bypassing the BBB by targeted intracranial drug delivery is an attractive approach to circumvent BBB-associated drug resistance mechanisms and to lower the risk of systemic and neurologic adverse effects. Additionally, it offers the possibility of reaching higher local drug concentrations in appropriate target regions while minimizing them in other brain or peripheral areas, as well as using otherwise toxic drugs not suitable for systemic administration. In our review, we give an overview of experimental and clinical studies conducted on direct intracranial drug delivery in epilepsies. We also discuss challenges associated with intracranial pharmacotherapy for epilepsies.

Keywords: basal ganglia; convection-enhanced delivery; drug-resistant epilepsy; focal epilepsy; intracerebral drug delivery; microinfusion; microinjection; seizures; targeted drug delivery; temporal lobe epilepsy.

Figure 1

Circuitries involved in generation, propagation, and modulation of focal or focal to bilateral tonic-clonic seizures emanating from limbic/cortical structures as in temporal lobe epilepsies. For a better overview, only one hemisphere is shown, although interhemispheric epileptic networks are crucial for secondary generalization of seizures [32]. Seizure activity emanating from limbic circuitry or neocortical regions does not spread randomly through the brain but rather involves specific anatomical routes [12,33,34,35,36,37]. Targeting the seizure focus in the neocortex (highlighted in blue) or the subcortical temporal lobe network comprising hippocampus, dentate gyrus, amygdala, entorhinal, perirhinal, and piriform cortices (highlighted in yellow) is an obvious approach for intracranial drug delivery. Brain areas remote to the seizure focus play an important role in the control and propagation of different types of epilepsies/seizures. The basal ganglia (highlighted in red), especially the substantia nigra pars reticulata (SNr) and the subthalamic nucleus (STN), have been profoundly investigated in preclinical studies as a common seizure gating and control mechanism, being relatively nonselective as to the type of seizure or seizure origin they can influence [36,38,39]. Therefore, these regions are highly attractive targets for the investigation of therapeutic intracranial drug delivery approaches. Further structures, including thalamic regions and brainstem regions (highlighted in green), are also investigated in this respect. Refer to the text for more details. a+p, anterior+posterior subregions of SNr; AN, anterior thalamic nucleus; CM, centromedian thalamic nucleus; DLPFC, dorsolateral prefrontal cortex; GABA, gamma-aminobutyric acid; GPe, external globus pallidus; GPi, internal globus pallidus; MD, mediodorsal thalamus; NAcc, nucleus accumbens; OFC, orbitofrontal cortex; PPN, pedunculopontine nucleus; SNc, substantia nigra pars compacta; VA, ventral anterior nucleus; VA, ventral anterior thalamic nucleus; VL, ventral lateral thalamic nucleus; VM, ventromedial thalamic nucleus.

Figure 2

Overview of application routes for intracranial drug delivery in epilepsies resistant to systemically administered antiseizure drugs. Drugs can be delivered to the brain, aiming to target the seizure focus directly (intraparenchymal route) or indirectly (intracerebroventricular, icv, and transmeningeal route). Furthermore, drugs can be targeted directly (intraparenchymal route) to epileptic network structures remote to the seizure focus, such as basal ganglia or thalamic regions.

Figure 3

Overview showing different intracranial drug delivery techniques used to modulate epileptic brain networks. Drugs can be delivered acutely for proof-of-principle or chronically into or close to the target region of the epileptic network by controlled-release polymers (e.g., wafers, microparticles) or by an implanted catheter/cannula combined with a drug reservoir or connected to a (subcutaneously) implanted or external microinfusion pump. Depending on the technique, the spread of the drug into the brain parenchyma occurs by passive diffusion or convection-enhanced distribution. In the case of programmable microinfusion pumps, discontinuous (intermittent) drug release is achievable, thereby reducing the risk of development of pharmacological tolerance. Adding a seizure prediction/detection unit offers the possibility of responsive (closed-loop) drug delivery. For details, refer to the text.

Figure 4

Schematic drawing of the experimental setup used by our group for chronic intracerebral delivery of vigabatrin [56] and muscimol [57] by convection-enhanced delivery in rats. A battery-powered programmable microinfusion pump was implanted subcutaneously and connected to a catheter/cannula system bilaterally targeting the subthalamic nucleus (STN).