CNS 31: Epilepsy Pathophysiology

In this discussion, we will go over the neurophysiology of seizure initiation and propagation, and the pathophysiology of epilepsy.

Introduction to Epilepsy

Quick definitions:

• Seizure – abnormal and excessive synchronization of cortical neurons
• Epilepsy – recurrent seizures that occur without any systemic or acute neurologic insults
• Epileptogenesis – Sequence of events that lead to epilepsy by converting a normal neuronal network to a hyperexcitable one.

Epilepsy is the 2nd most common neurologic disorder in the world. It’s estimated that 1 in 26 people will develop epilepsy. There is some evidence that age can affect the incidence of epilepsy, being presented most commonly in very young or very old population groups.

The International League Against Epilepsy stated that it is considered epilepsy if the patients present with one of the following:

• Having at least 2 unprovoked seizures occur more than 24 hours apart
• Having one unprovoked seizure and having at least 75% of having a recurrent seizure based on EEG
• Having at least 2 seizures occur in a set of reflex epilepsy

Reflex epilepsy is seizures provoked by external stimulant or internal mental processes

Types of Seizures

There are two types of seizures: partial and generalized

Partial seizures are seizures that focus on certain areas of the brain. Simple partial seizures are without loss of consciousness, and complex partial seizures are having a loss of consciousness.

• Simple partial seizures (20-120 seconds, 14%): no mental confusion, visual changes, sensory changes “aura”
• Complex partial seizures (30-120 seconds, 36%): Confusion diminishes over a few seconds to a few minutes, with no full body convulsions, lip smacking, or odd sensations “automatism.”
  • Tonic-clonic can last 1-2 minutes with unilateral tonic/clonic convulsion.

Generalized seizures are seizures that cover the entire brain. There are many types of generalized seizures: Absence, myoclonic, clonic, tonic, tonic-clonic, and atonic seizures.

• Primary Generalized Seizure (start from both hemispheres) – Fall may occur
  • Tonic-clonic (grand mal) – 25%
  • Absence (petit mal)
  • Myoclonic – sharp contraction of muscle usually in the extremities
  • Atonic (drop seizure) – partial or complete loss of muscle tone leading to that part becoming limb as seen in the droopy lip or dropping things.
• Secondarily Generalized Tonic-Clonic Seizure – begin as partial seizures then spread to the entire brain.

Types of Epilepsies

There are also two types of epilepsies: idiopathic (unknown cause – genetic link) and symptomatic (known causes – head injury, stroke.)

Basic Mechanisms of Focal Seizure Initiation and Propagation

1. Hypersynchronous or a single high-frequency burst of action potential discharges begin in a discrete region of the cortex
   • The burst of action potentials is caused by sustained neuronal depolarization, which plateaus out upon the completion of the action potential burst and rapid repolarization occurs normally. This is known as a paroxysmal depolarization shift.
   • The action potential burst is due to glutamate and an influx of extracellular calcium, leading to the opening of the sodium channel and an influx of sodium into neurons. This causes a repetitive action potential, and then the hyperpolarization occurs by the activation of GABA, Cl influx, or by K efflux.
   • Interictal spike is a marker on the EEG that precedes seizure.
   • Ictal State is an EEG marker during seizures. It is characterized by hyperexcitability.
   • T-type calcium channels only exist in the thalamus (TRN and TC nuclei.) They can oscillate and increase the thalamic output to the cortex. Some antiepileptic drugs target these channels.
2. The discharges spread to neighboring regions
3. Seizure Propagation
   • This stage is characterized by
     • A loss of surrounding neuron inhibition – usually prevents intact hyperpolarization, but the repetitive discharges increase extracellular potassium, which blunts the hyperpolarization and encourages depolarization of the neighboring neurons. These neighboring neurons’ depolarization induced the activation of the NMDA receptor, which causes more calcium influx. An accumulation of calcium in the presynaptic terminals leads to an enhanced neurotransmitter release.
     • A spread of seizure activity via local cortical connection
     • A spread of seizure activity to distant areas via long associate pathways (corpus callosum and white matter.)

There are several proposed mechanisms for how altering a neuron leads to bursting activity. These mechanisms can be separated into intrinsic mechanisms and extrinsic mechanisms.

Intrinsic mechanisms are changes that occur to the neurons and ion channels. Extrinsic mechanisms are changes caused by non-neural cells or extracellular ions.

Neuroanatomy of Seizures

Seizures arise primarily from the cerebral cortex. Partial seizures – temporal lobe. Generalized seizures – cortex and thalamus.

The aberrant interaction between the thalamus and cortex may be due to the weird oscillatory rhythms of the thalamus by the GABA-B receptors, calcium channels, and potassium channels in the thalamic neurons.

Epileptogenesis

This is a transformation of a normal neuronal network to a hyperexcitable one. This progress can take months to years between the initial CNS injury to the first seizure. During this process, the seizure threshold is gradually lower in the affected region until spontaneous seizure happens.

There are many genetic and idiopathic forms of epilepsy.

The study of the hippocampus in patients with MTLE has shown that some forms of epileptogenesis are related to structural changes in neuronal networks. For example, when there is a highly selective loss of neurons, it affects the excitability of the network and inhibition of the excitatory neurons in the dentate gyrus.

Temporal Lobe Epilepsy (TLE)

TLE is the most common form of epilepsy. It also has a high degree of hippocampus involvement. Because it is the most common, a lot of research focus has been on TLE.

It is believed that the focal point of the seizure occurs in the mesial temporal lobe in the cortical area. After the signal establishment, there is a vicious cycle, which includes seizures, neuronal injury, rewiring of neuronal networks, increased excitability, and enhanced further seizures, within the hippocampus that leads to sustained contractable seizures.

An animal study on temporal lobe epilepsy where the animals were given a drug to induce seizure showed that 1) the hippocampus is important in TLE, 2) new neurons are generated from seizure activity, and 3) axonal and neuronal reorganization occurs post-epilepsy.

Another animal study also demonstrated that new neurons are generated. These new neurons are integrated abnormally as well as branched abnormally.

A human pathological tissue section compared normal control dentate gyrus with TLE dentate gyrus. The TLE dentate gyri were widely dispersed, had no compact cell layer, or uneven border, and had a formation of the bilayer.

There are known expression patterns of ion channels that have an important role in the genetic risk associated with epilepsy. Some implicated in genetic epilepsy are K, Ca, and N channels.

GABA Hypothesis of Epilepsy

This hypothesis implies that a reduction in GABA inhibition results in epilepsy, which means that an enhancement of GABA inhibition results in anti-epileptic effects. The IPSPs gradually decrease in amplitude during the repetitive circuit, leading to a decrease in GABA release and desensitization of GABA-A / alternation in ion gradient due to Cl accumulation.

GABA and GAD have reduced production in the foci as well as in the CSF. A reduction in GABA binding in the brain region is backed by PET studies in vivo. This leads to a reduced BZD receptor binding in human epileptic foci.

Glutamate System in Epilepsy

Glutamate has been implicated as well. Patients with absence seizures have high levels of plasma glutamate.

In patients with TLE, there is either a normal or reduced EAAT1 and EAAT2 were reported.

In an animal study, NMDA activation results in a burst of firing, and NMDA antagonists enhance the frequency and reduce the duration of burst firing.

Role of Glial Cells in Epilepsy

Stimulation of astrocytes induces de-synchronization. Some glial proteins can modulate membrane channels. Gliosis is found in some epilepsies. Gliosis is an abnormal accumulation of glial cells and astrocytes reported in some epilepsy.

Astrocytes can become a reaction in epileptic foci. In MTS, the most common TLE pathology is characterized by astroglial and microglial proliferation, leading to increase complexity and arborization of glial processes. This leads to the glial scar-like formation in the late stage of MTS (morphological changes.)

In an epileptic brain, physiological and molecular changes cause a rectifying K current. This may underly epileptic hyperexcitability. Loss of glutamine synthetase has been observed as well, which decreases GABA production.

Febrile Seizures

This is when a seizure is accompanied by a high fever without CNS infection and usually occurs in infants and young children. The most common type is simple (15 seconds to a few minutes), and not specific to one part of the body. Complex seizures can be longer (15 minutes).

Lennox-Gastaut SYndrome (LGS)

LGS is a rare and severe child epilepsy, presented in roughly 5% of childhood epilepsy. The onset is usually between 3-5 years. It is more common in males than females. There can be multiple types of seizures with the most common being tonic seizures where muscles stiffen and contract uncontrollably.

LGS usually happens during sleep or wakefulness and can cause a brief loss of consciousness.

Most children with LGS have an intellectual disability prior to seizures. The etiology is unknown, but it is suspected that perinal or prenatal insult, a vascular insult to the brain, and gene mutation may play a role.

LGS does not respond well to anti-epileptic drugs.

Status Epilepticus

This is a medication emergency associated with significant morbidity and mortality. This is when seizures last longer than 5 minutes or have more than one seizure in 5 minutes period without a return to normal functioning between episodes.

It is important to target GABA markers to terminate seizures. Early treatment with fast benzodiazepines followed by fosphenytoin is the most wide use strategy.

There are multiple causes of status epilepticus, such as infection, trauma, genetics, and medication.