Pathological basis of the epilepsies

The pathophysiology of epilepsy is poorly understood and so far there is no clear association between the abnormal function of a specific group of neurons and the genesis of seizures. It is generally agreed that epileptogenesis involves the complex interaction of multiple factors. In some cases lesions such as those arising from traumatic haemorrhage can cause secondary seizures, whereas other forms of brain damage, for example that caused by ischaemic stroke, are less likely to cause seizures. Microscopic changes involving glial proliferation and loss of neurons have been identified in epileptic patients, and a loss of those neurons containing inhibitory neurotransmitters has been particularly implicated in the aetiology of the disease. Whether such changes are the cause or the consequence of the seizures is uncertain.

There is considerable controversy regarding the possible genetic basis of the epilepsies. It has been calculated that there are at least 100 different trait markers that may predispose some individuals to the disease, and it has been shown that identical seizure disorders may be present in patients who frontal site

Temporal site occipital site frontal site temporal site occipital site normal EEG

normal EEG

frontal site

Temporal site

1 sec gene rallied seizure EEC (tonlc-clonic type)

norma onset don c post- I_J

record 111 |t:ri" phaw convulsive |

phase OÖIKM

Figure 12.1. Changes in the cortical EEG of a patient showing tonic-clonic type generalized seizures.

either have, or do not have, a particular genetic marker. Clearly this is an important area of research for the future.

Animal models

Animal models have been developed not only in an attempt to screen potential antiepileptic drugs but also to define more precisely the possible aetiology of the condition. In mice, there are at least 12 single locus mutations that produce neurological syndromes with spontaneous seizures. One particular species, the ''tottering mouse'', shows spontaneous seizures which resemble absence attacks both in terms of the behavioural and the EEG changes. The only specific cellular pathology which has been found in this model is a selective outgrowth of axons from the locus coeruleus which results in an increase in the noradrenaline content of the neocortex, site temporal Site ocdpUal site l_l

1 sec generalised seizure EEG (ateence seizure type)

frontal temporal occipital site normal LEG

normal LEG


occipital site


Figure 12.2. Changes in the cortical EEG of a patient showing absence seizures.


Figure 12.2. Changes in the cortical EEG of a patient showing absence seizures.

hippocampus, cerebellum and thalamus. The seizures are attenuated in this species by the local injection of the neurotoxin 6-hydroxydopamine, which destroys the noradrenergic terminals. However, it should be noted that this neurotoxin usually results in the lowering of the seizure threshold in most species of animal, so the precise relevance of these findings in the ''tottering mouse'' to the human condition is unclear.

Strong sensory stimuli (e.g. 90 dB sound) can precipitate tonic-clonic seizures in some strains of mice, the DBA/2 strain being particularly susceptible, while posturally induced seizures in ''epileptic-like'' mice have been extensively studied and have been shown to be associated with abnormalities in both the adenosine triphosphatases (ATPases) and various biogenic amine neurotransmitters.

Beagle dogs show a high incidence of epileptic seizures, including those of the secondary type; complex partial and generalized tonic-clonic seizures frequently occur in this species. However, the nearest model to normal EEG

frontal site temporal site occipi Lai site normal EEG

frontal site temporal site occipi Lai site

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