CAT | Epilepsy
Until about 40 years ago most doctors believed that inheritance was a major factor in causing epilepsy. This belief is still strong amongst the population at large. Doctors are often told ‘It can’t be epilepsy because there is nothing like that in the family,. These views were held in the past with such force in some states of America and in some Scandinavian countries that it was illegal for people with epilepsy to marry. It is certainly true that genetic factors do play a part in epilepsy, but not an overwhelming part.
There are some genetic diseases in which inheritance is through a dominant gene. Genes come in pairs, one from each parent. One member of the pair may always be dominant in influencing the structure or biochemistry of the offspring. If a child or adult has the gene, then, in broad terms he or she has the disease, although there are variations in the severity of the disease. One of the parents; carrying the gene will therefore not only show the effects of the gene himself or herself, but will transmit the effective gene to, on average, half his or her children. Tuberous sclerosis and neurofibromatosis, both disorders affecting the structure of nerve cells and surrounding tissue, are transmitted in this way.
There are other genetic diseases in which the gene is recessive. In recessive inheritance, the effects of the gene are only expressed if a child has a double dose of the relevant gene—one abnormal gene from each parent. The parents, although themselves carriers, do not show the abnormality as the other member of their pair of genes is normal. There are certain rare disorders of metabolism of the brain, collectively known as the lipidoses, which are inherited by recessive genes. Fatty substances known as lipids are important constituents of the membranes surrounding the nerve cells. A disorder of the structure and function of the cell membrane may well lead to paroxysmal discharge of nerve cells—an epileptic seizure.
It must be stressed that these diseases are rare. They have been mentioned first only because the mechanism of their inheritance is most clearly understood.
There is, however, also good evidence that primary generalized idiopathic epilepsy is also inherited. In order to explain this, it is easier to trace back from a child with epilepsy to his parents, rather than first considering the chances of a prospective parent with epilepsy having an epileptic child. The characteristic EEG is seen in about 40 per cent of brothers and sisters of children with primary generalized epilepsy, even if these brothers and sisters have not had any apparent seizures. That is to say, the abnormality which causes the abnormal EEG record is inherited, but this abnormality is not necessarily expressed in clinically apparent seizures. A smaller proportion of the parents of children with primary generalized epilepsy will also show the characteristic EEG changes. We know from following the children with these EEG changes that the characteristic discharges become much less frequent with age, so the absence of discharge in adult life does not mean that the parent did not have unrecorded and unapparent discharges in childhood. From mathematical studies of the proportion of the abnormal EEG records of many families with primary generalized epilepsy, it is possible to calculate that the pattern of inheritance is probably that of a dominant gene.
Energetic research studies are ongoing in several centres to identify the gene. It will probably turn out that there is more than one gene, each giving a similar clinical picture. This has already been shown to be true for the much more clearly defined disorder of tuberouss sclerosis, a disorder in which there are nests of abnormally developed nerve cells and their supporting cells (known as glial cells), some of them calcified and some sufficiently large to be seen on a brain scan. It is now known that two dominant genes on separate chromosomes can result in what appears to be an identical picture. (A chromosome is the microscopically visible structure within the nucleus of a cell which contains the genetic material—the DNA.)
As we have already explained, for a child to show an abnormality in cases of dominant inheritance, only one member of the pair of relevant genes (one from the father and one from the mother) needs to be abnormal. However, the effects of other gene pairs may to some extent succeed in suppressing this gene from expressing itself in obvious seizures. This means that about only one third of the children to whom it is transmitted will have seizures. Furthermore, even if the gene is expressed in seizures, the result may only be a few absence seizures in childhood.
The variability in clinical expression of the genetic abnormality accounts for the occurrence of primary generalized epilepsy in a child of parents neither of whom has ever had a known seizure. In such an instance one assumes that one parent does indeed have the gene, and, had an EEG been recorded in his or her childhood, the typical EEG discharge would have been seen.
Another aspect is the inheritance of a convulsive threshold. Any one of us can be made to have a seizure ii the stimulus is strong enough, and some of us do at lower levels of stimulus—at lower thresholds—than others. The inheritance of this level of threshold is probably
polygenic—that is to say, several genes, some recessive and some dominant, interact to produce the final result. Another example of polygenic inheritance is height. Tall parents tend to have tall children, but height is not determined by a single gene.
This inherited convulsive threshold is a background, as it were, to the whole of the area. It influences even those cases in which epilepsy clearly seems to be secondary to some obvious cause, such as a severe head injury causing local cortical scarring. Head injuries obviously are not inherited as such. Nevertheless there is a slight tendency for those who develop epilepsy after head injury to have a family history of epilepsy more often than those who do not develop epilepsy after what may be regarded as a comparable injury. What is being inherited here, through a number of different genes, is a lower-than-average convulsive threshold. The children of such head-injured parents are not likely to have seizures unless some additional cerebral damage affects them. It would be an unlikely family in which two members suffered severe head injuries, so that the risk of ‘inheriting’ epilepsy from a parent with epilepsy secondary to some structural brain damage is small. It follows that one good reason for a paediatrician or neurologist to do his or her best to find a ’cause’ for epilepsy is so that they can best advise about the risk of brothers or sisters or daughters or sons being affected.
There is, however, one group of people in whom inherited and acquired characteristics interplay in a complex way. The tendency to febrile convulsions is inherited, through one or more genes.
A febrile convulsion, if very prolonged (lasting longer than 20-30 minutes), may rarely damage one or other temporal lobes of the brain through lack of oxygen occurring during the seizure. The scar in the temporal lobe may then act as a focus from which paroxysmal discharge—seizures—spread in later childhood and adult life.
The first duty of a doctor asked by a young couple, one of whom has epilepsy, about the chances of any child of theirs having epilepsy, is to characterize the seizure type as accurately as possible, using the description of the seizures and the EEC if it is clear that the prospective parent is having partial seizures, of generalized seizures which have a clear focal onset, either clinically or demonstrated on the EEG then, these seizures are almost certainly secondary to some area of cortical scarring or developmental abnormalities. The risk of any child of this marriage having epilepsy is only moderately higher than the risk of the population at large. It is, however, somewhat higher than the risk of the average child because of the inheritance of the convulsive threshold. If it is clear that the prospective parent has primary generalized epilepsy, then we have to say that about half his or her children will carry the gene, but only about one child in six will have definite seizures. The chances of epilepsy being a significant problem in the life of a child of a parent with primary generalized epilepsy is no more than of the order of five per cent, the others perhaps having only a minor EEG abnormality if that is specifically looked for.
A small fraction of the genetic material (DNA) is carried outside the nucleus in small particles in the cell known as mitochondria. These are only derived from the maternal ovum, not being present in sperm. There are therefore a few rare disorders in which inheritance is only through the maternal line. Some of these are associated with epilepsy.
*17/188/2*
One aspect of human nature is to search for causal links between events. The onset of epileptic seizures in a previously healthy child or adult results in great heart-searching in the family, and raking over past events in an attempt to find some reasons. Yet it has to be admitted that the most careful medical assessment of past events or current state allows a paediatrician or neurologist to assign a cause or causes of epilepsy in only a minority of subjects, and then often on the basis of circumstantial evidence.
Take head injury, for example. If a child is known to have cut her head falling in the playground, and then has her first seizure two weeks later, many parents will link the two events, and attribute the onset of epilepsy to this minor head injury on no basis other than coincidence in time. A minor head injury at work followed some weeks later by a first seizure unfortunately may lead to litigation between employer and employee, as the latter holds that he ‘was perfectly all right before the accident’. The association of events in time is, however, no evidence of cause. Severe head injuries may, however, result in the development of epilepsy, so-called
post-traumatic epilepsy. Somewhere in the continuum of mild to moderate to severe head injuries there must be a zone where there is reasonable doubt as to whether epilepsy was or was not caused by the injury.
The same arguments apply when assessing the effects of a difficult birth and the possible relationship of that to the subsequent development of epilepsy. There is no doubt that a very difficult labour, especially if the baby is small, may cause significant brain damage, severe learning difficulties, cerebral palsy, and epilepsy may result. However, after many difficult or prolonged labours the child develops perfectly normally and twins are no more likely to develop seizures than single births. It used to be thought that forceps or breech deliveries might be blamed for the subsequent development of epilepsy. However, a follow-up study of all children born in one week showed that epilepsy was no more likely to develop after such births than after normal unassisted deliveries. It is now known that in many children born with cerebral palsy or severe learning difficulties there are problems in cerebral development that precede birth. Although sometimes these may be visible on scanning, in other cases the abnormality is no more than a subtle disorder of organization of the developing nerve cells visible only microscopically in tissue obtained at surgical operation or after death. These may, however, be sufficient to cause seizures.
Having given these warnings against uncritically linking life events and the development of epilepsy, what are the factors which can be said, with a fair degree of confidence, to cause epilepsy? The causes are different at different ages. Some causes, such as a structural congenital brain abnormality may cause seizures in the neonatal period, and the abnormally organized brain may cause seizures throughout life, as is indicated by the long continuing arrow. Other causes occur only at one age, and their effect then ceases. Metabolic disturbances in the neonatal period, such as hypoglycaemia, are examples of this.
*16/188/2*
Bacterial meningitis can damage the brain at any age from the newborn period to old age. Vigorous and early treatment with antibiotics and corticosteroid drugs nearly always prevents damage to the cortex, which lies immediately under the meningeal covering of the brain. However, if the treatment is delayed, or the organism is resistant to the antibiotic chosen, the damaged cortical cells may act as seizure foci in subsequent years. Meningitis due to tuberculosis is particularly likely to result in later epilepsy.
A bacterial brain abscess usually now results from blood-borne bacteria which are deposited in the cerebral hemispheres in a patient who is acutely ill with septicaemia. However, most blood-borne bacteria from an infection are filtered out from venous blood as this passes through the capillaries of the lungs. An exception occurs if there is a hole between right and left sides of the heart. Some bacteria may then pass directly from the venous circulation into the left ventricle and into the cerebral circulation. This accounts for the high incidence of cerebral abscess in those with these types of congenital heart disease.
An abscess may also form by direct extension into the brain from a local infection—for example, severe middle ear suppuration or frontal sinusitis may cause abscesses respectively in the temporal or frontal lobes of the brain.
Acute abscesses can certainly cause epileptic seizures, but, even if successfully treated by drainage and by antibiotics, further seizures may arise from the scar. In an attempt to avoid this, many surgeons now excise totally the capsule of the abscess rather than simply aspirate the pus.
Viral meningitis is a self-limiting illness, and epilepsy does not occur after this. Sometimes, however, the viruses are present within the substance of the brain, rather than remaining confined to the surface. This is called encephalitis, and seizures may result. Two of the more common viruses causing seizures in this way are the herpes and cytomegaloviruses. Cytomegalovirus usually affects the fetal (unborn baby’s) brain, and the herpes virus usually affects infants, young children, and adults. The HIV virus can also cause seizures, either by itself or, through depressing the immune system, allowing invasion of the brain by other viruses, and often by a small organism known as Toxoplasma.
Some viruses behave in a very strange way in the brain. Measles, for example, is an illness which affects nearly all children without significant late effects. The illness is terminated by the production of antibodies. A tiny number of children, however, do not succeed in eradicating the virus from their brains, and, some years later a new measles-related illness begins—sub-acute sclerosing pan-encephalitis—in which seizures and mental deterioration are prominent. Fortunately this is now becoming very rare with the wider use of measles vaccine.
Parasites can also cause epilepsy. The pork tapeworm Taenia solium may cause epilepsy if the cystic stage of the tapeworm, usually found in pigs, occurs in the muscles and brain of man. In developing countries, calcified cysts are found in the brains of many of the rural population and this disorder, cysticercosis, and tuberculosis accounts for a lot of the greater incidence of epilepsy in such populations. The dog tapeworm Toxocara has also been incriminated in the development of epilepsy, though with less certain evidence. Toxoplasmosis, possibly acquired through infection in utero from domestic animals is certainly associated with seizures.
Creutzfeldt-Jakob disease is a rare disorder caused by an infectious agent which is not a bacteria or a virus. One route of transmission is through surgical instruments (ordinary sterilization does not kill it) or through tissue transplantation (for example, corneal transplantation). It is related to ‘mad-cow, disease (BSE, bovine spongiform encephalopathy). Affected adults may have seizures as part of the serious neurological illness.
*22/188/2*
Damage to cerebral nerve cells may occur through physical trauma. In war time, head injuries due to penetrating injuries from shrapnel are a potent source of epilepsy. About 45 per cent of survivors develop later seizures. In civilian life most head injuries are closed—that is to say there is no penetration of the skull. However, the impact of the head with the dashboard or road in road traffic injuries may cause the later development of post-traumatic epilepsy.
Professor Bryan Jennett of Glasgow has done a great deal to sort out the factors in a head injury that are most likely to cause later epilepsy. The first is the duration of the post-traumatic amnesia. This is the name given to the period after a head injury when patients, although conscious, are not recording in their memory on-going events, even though they may seem to be behaving rationally at the time. A typical story is for a man to have no recollection of relatives visiting him in hospital, even though he talked and joked with them. The duration of
post-traumatic amnesia may vary from a few minutes, when the term ‘concussion’ is often loosely applied, to many weeks or even months. The mechanism of the amnesia is not known, but a useful analogy is to consider a blancmange in a mould (the brain on the skull). A vigorous tap or shaking of the mould may cause oscillations so violent within the blancmange that cracks appear within its structure, even though the mould remains intact. Such shearing forces can be demonstrated within the brains of animals subject to experimental head injuries. The longer the duration of post-traumatic amnesia, the greater the chance of the development of later epilepsy.
The second factor which Professor Jennett found to be important was the presence of focal neurological signs, such as changes in the reflexes, after the injury. Presumably these just reflect a greater degree of disruption of the brain.
The third factor was the presence of local damage to the cortical surface of the brain, as judged by the presence of a tear in the dura—the membrane covering the brain. The impact of the head on a sharp corner may cause a depressed fracture, with fragments of bone tearing the dura and becoming embedded in the cortex.
Professor Jennett found that if all three factors were present in one case (a prolonged amnesia of more than 24 hours after the head injury, focal neurological signs, and a dural tear), then there was a 40 per cent chance of developing epileptic seizures later. If none of these factors was present the risk was about two per cent.
Professor Jennett also noted that some head-injured patients had a seizure in the first week after the injury. The occurrence of such an event perhaps the marker of an inherited low convulsive threshold or of extensive cortical damage—was a potent predictor of late
post-traumatic epilepsy. A seizure in the first week, accompanied by a long post-traumatic amnesia and focal neurological signs was followed by later seizures in 60 per cent of cases, even if the dura were not torn.
There are other types of brain injury apart from those caused by the ubiquitous road traffic and industrial accidents. Cerebral trauma also occurs, unavoidably, during cranial operations. For example, small balloon-like swellings called ‘aneurysms’ on arteries at the base of the brain are never, by themselves, responsible for epilepsy. In order to avoid the risk of haemorrhage, operation may be advised. The surgeon, in approaching the aneurysms in order to clip the neck of the ‘balloons’, has to handle and retract, albeit very gently, normal brain. Unfortunately seizures may follow such handling of cerebral tissues.
*20/188/2*