Epilepsy · Grey Matter

Epilepsy is a lasting tendency of the brain to produce epileptic seizures, which are brief episodes of abnormal, excessive or synchronous neuronal activity whose signs depend on where in the brain they start and how far they spread.

Epilepsy. Epilepsy is a lasting tendency of the brain to produce epileptic seizures, which are brief episodes of abnormal, excessive or synchronous neuronal activity whose signs depend on where in the brain they start and how far they spread.

A seizure happens when a population of neurons that normally fire in loose, varied patterns is recruited into firing together, in a fast rhythm that inhibition no longer contains. Where it begins sets what is felt or seen: in the visual cortex it can produce coloured lights or shapes, in motor cortex jerking of one limb, in the temporal lobe a strange familiarity or a fixed stare. A focal seizure stays within one network of one hemisphere; it can spread, through the cortex and through the loops between cortex and thalamus, until both hemispheres are involved (a focal to bilateral tonic-clonic seizure). A generalised seizure engages networks in both hemispheres from its onset.

One seizure is not epilepsy. A seizure can be provoked by fever, low blood sugar, alcohol withdrawal or drugs in any brain; epilepsy is diagnosed when seizures recur unprovoked, or when one seizure comes with a high risk of more.

Synchrony is the signature. On an EEG a seizure appears as rhythmic, high-amplitude discharges that evolve in frequency and spread, the opposite of the low, irregular trace of an awake cortex.

The causes range from genetic changes in ion channels and synaptic proteins to scars from injury, stroke, infection or malformations of cortical development; in many people no cause is found.

Most seizures end by themselves within a couple of minutes. How they stop (inhibition recovering, energy and ion changes, and in some models spreading depolarisation) is an active research question.

Treatment is mostly antiseizure medication that lowers excitability or raises inhibition, among them the drugs that bind SV2A; surgery or stimulation is considered when medicines fail.

A seizure is the excitation-inhibition balance lost in time as well as in size.

The defining change is many neurons firing together, which is also what makes it visible on the scalp.

Questions: What does a seizure look like on an EEG, and what can the EEG miss? During a seizure the trace changes from low, irregular activity to rhythmic discharges that grow in amplitude, change frequency over seconds and spread to neighbouring electrodes, followed after the seizure by slowing. Between seizures, brief sharp waves and spikes in one region can mark tissue prone to seizures. Because the scalp EEG needs several square centimetres of synchronous cortex, a small or deep seizure can be invisible on it, which is one reason electrodes are sometimes placed inside the skull to find where seizures start. What does the chloride inside neurons have to do with seizures? Inhibition through GABA-A receptors works only while chloride inside neurons is kept low by KCC2. In the newborn brain, where the switch from NKCC1 to KCC2 is still under way, GABA inhibits weakly, which is one explanation for why neonatal seizures often resist drugs that enhance GABA-A receptors. In adult epileptic tissue and after intense activity, KCC2 can fall or chloride can build up, so GABA loses part of its brake when it is needed most. Restoring the chloride gradient is therefore studied as a treatment strategy, though blocking NKCC1 with bumetanide has not shown clear benefit in newborns. Why is the hippocampus so often where focal seizures start? The hippocampus is built to change: densely recurrent excitatory circuits that strengthen quickly with use, which makes it good at storing associations and also prone to runaway synchronous firing. It is vulnerable to the injuries that start epilepsy (prolonged febrile seizures, hypoxia, encephalitis), and the most common lesion found in surgery for drug-resistant temporal lobe epilepsy is hippocampal sclerosis: loss of neurons, scarring and rewiring such as the sprouting of mossy fibres back onto their own cells. Seizures starting there often begin with a rising feeling in the stomach, déjà vu or fear, the signature of the medial temporal lobe. How can a diet reduce seizures, and how well does it work? A diet very high in fat and very low in carbohydrate makes the liver produce ketone bodies that partly replace glucose as the brain's fuel, and it changes how excitable neurons are by routes still being worked out (ketone bodies themselves, adenosine, ATP-sensitive potassium channels, and decanoic acid, which blocks AMPA receptors directly). In a randomised trial in children whose epilepsy resisted drugs, 38 % on the diet had their seizures more than halved after three months against 6 % of controls. It is a medical treatment with real side effects, started and followed by a specialist team. How can a seizure that starts in the visual cortex spread to both hemispheres? A focal seizure in the occipital lobe first produces what that cortex makes, typically coloured lights or shapes, and it can spread along the cortex to neighbouring areas. It becomes bilateral when the discharge recruits networks that reach both hemispheres, above all the loops between cortex and thalamus: imaging during focal to bilateral tonic-clonic seizures shows the thalamus becoming involved at the moment of spread, and the thalamus relays the rhythm to widespread cortex on both sides. How far a given seizure spreads depends on how well inhibition along the way holds. How do benzodiazepines stop a seizure? Benzodiazepines bind GABA-A receptors at a site between an alpha and a gamma subunit, apart from where GABA binds, and make GABA open the channel more often. They amplify the inhibition the interneurons are already delivering and need GABA present to act, which is why they are relatively safe on their own and why they act fast in an emergency. Stronger inhibition restores the brake on the synchronised firing of a seizure. Their limits follow from the same mechanism: receptors are internalised during prolonged seizures, so the drugs work best given early, and where chloride has built up inside neurons GABA itself inhibits less. How do levetiracetam and brivaracetam reduce seizures by binding SV2A? Both drugs bind the same pocket of SV2A, brivaracetam with about 15 to 30 times higher affinity, and across related compounds the strength of binding tracks antiseizure potency, which is the main evidence that SV2A is their target. The leading hypothesis is that binding reduces how many vesicles are ready for release, and that the effect shows mostly at synapses driven hard and repeatedly, as during the build-up of a seizure, while ordinary transmission changes little. The step from binding to fewer released vesicles is still being worked out, so the mechanism is best stated as a well-supported hypothesis. How can stimulating a nerve in the neck reduce seizures in the brain? Most fibres of the vagus nerve carry signals from the body to the brainstem, so pulses applied to the nerve in the neck reach the nucleus of the solitary tract and, through it, the locus coeruleus, the raphe nuclei and the thalamus. The leading explanations are that this raises noradrenaline and serotonin across the cortex and makes cortical activity less synchronous, though the exact mechanism is not settled. On average seizures fall by about half after a year of treatment, about half of people have at least a 50 % reduction, and few become seizure-free. Is an epileptic aura a warning before the seizure, or the seizure itself? It is the seizure itself, at its start: a focal seizure with awareness kept, small enough to be felt and remembered and not yet large enough to show to an observer. Its content reveals where it begins, such as coloured lights in the occipital lobe, a rising feeling from the stomach or déjà vu in the mesial temporal lobe, and a tingle in one hand in the sensory strip. Sometimes it stays that size and ends; sometimes it spreads, awareness is lost, and it may become a convulsive seizure, so the aura is both the first sign and a guide to where the seizures start. What decides whether a perturbation in the cortex fades, becomes spreading depression or becomes a seizure? Most perturbations fade, because inhibition and ion clearance absorb them. In a seizure, neurons keep their gradients and fire too much and too synchronously, since inhibition no longer contains the excitation; in spreading depression the gradients themselves collapse and the tissue goes silent. The two are often described as different distances from a resting state, a seizure closer to normal physiology and spreading depression closer to a full loss of the gradients, and which one occurs depends on local conditions such as extracellular potassium, energy supply and the state of inhibition. They can also follow each other: seizures can trigger spreading depression, which in some models ends the seizure and stops it from spreading. What happens in the tonic and in the clonic phase of a convulsive seizure? In the tonic phase, about 10 to 20 seconds long, the discharge drives the motor system continuously, so muscles contract together and stay contracted; the EEG shows fast activity building into high-amplitude polyspikes. In the clonic phase the discharge is broken by pauses, each a slow wave on the EEG during which inhibition gains ground, and every burst between pauses is a jerk. The pauses lengthen until the seizure ends, usually within a minute or two, and the exhausted brain enters the postictal state of sleep and confusion. If running near a critical point is useful, how does it relate to a seizure? Near the critical point a network has the widest dynamic range: in slice experiments by Shew and colleagues, cortical networks distinguished the widest span of input strengths when their avalanches followed the critical power law, and responded poorly when drugs pushed them to either side. Reducing inhibition made the networks supercritical, with large, synchronised events that dominate activity, a regime that resembles epileptic activity. The criticality hypothesis therefore links the brain's sensitivity and its vulnerability to the same position. It is a hypothesis: whether seizures are best described as a shift past a critical point is still debated, and other mechanisms (failure of specific interneurons, ion changes) can produce them. Why is synchrony, rather than just more firing, the signature of a seizure? A healthy cortex is busy but loosely coordinated: inhibition keeps each neuron's firing to brief, scattered windows, so neighbours rarely fire in lockstep. When inhibition falls behind excitation, a recruited group excites its neighbours faster than they can be held back, and the activity locks into a shared fast rhythm that pulls in more and more tissue. The international definition of a seizure names exactly this (abnormal excessive or synchronous neuronal activity), and synchrony is also what makes a seizure large on the EEG, because aligned currents add up while scattered ones cancel.