Brain, Vol. 122, No. 6, 1007-1008,
June 1999
© 1999 Oxford University Press
Editorial |
Hippocampal sclerosis and temporal lobe epilepsy: cause or consequence?
Dept of Neurophysiology,University of Birmingham, UK
Hippocampal sclerosis is a very common feature of temporal lobe epilepsy (complex partial seizures or limbic epilepsy). It is found in approximately 50–75% of temporal lobe resections made for medically intractable limbic epilepsy (Honavar and Meldrum, 1997
); indeed the presence of sclerosis is a good indicator for a positive outcome to surgery. A very long-standing question is whether hippocampal sclerosis is the consequence of repeated seizures, or whether it plays a role in the development of the epileptic focus. Longitudinal MRI studies will, no doubt, soon provide an answer to the question of whether sclerosis represents part of a pathological progression of the hippocampal epileptic focus in humans (Meierkord et al., 1997; Van Paesschen et al., 1998).
Several lines of work suggest that hippocampal sclerosis is not absolutely necessary for long-lasting epileptic foci. First, there are a significant number of cases of limbic seizures in humans who lack sclerosis. Secondly, several laboratory models exist where either chronic foci or persistent reductions in seizure threshold can occur in the absence of hippocampal sclerosis. Limbic kindling and intrahippocampal tetanus toxin are two good examples. The tetanus toxin model, in adult rats, results in spontaneous recurrent seizures over periods of several weeks, with a very low incidence of gross neuronal loss or hippocampal sclerosis (Mellanby et al., 1977; Jefferys et al., 1992). Interestingly, injecting the same toxin into neonatal rats, at 10 days after birth, results in an epileptic syndrome that persists to adulthood, with spontaneous epileptic seizures in vivo and epileptic discharges in brain slices in vitro (Lee et al., 1995). This occurs in the absence of hippocampal sclerosis but with a number of more subtle histological abnormalities (Jiang et al., 1998).
While hippocampal sclerosis may not be necessary for chronic epileptic foci it could still promote their development. In this issue of Brain, Milward and colleagues (Milward et al., 1999) report experiments to test this hypothesis. The idea for this study came from the minority of rats that develop fully chronic epilepsy after intrahippocampal injection of tetanus toxin made when they were adult; Mellanby hypothesized that hippocampal sclerosis, reported in a minority of rats injected with tetanus toxin (Mellanby et al., 1977; Jefferys et al., 1992), could predispose them to relapse into a very long-lasting epilepsy (Mellanby, 1993).
Milward and colleagues' experiment is deceptively simple, but technically very difficult (Milward et al., 1999). They produce hippocampal sclerosis by four vessel occlusion, which produces cerebral ischaemia and, if timed appropriately, neuronal loss which is most intense in the hippocampal CA1 region. They then challenged the rats with intrahippocampal tetanus toxin to determine whether the loss of CA1 increased the incidence of the very long-lasting epileptic foci. The result was a very clear `no'.
The loss of CA1 actually reduced the numbers of epileptic fits seen during the 4 weeks after injection, and delayed their onset. Milward and colleagues reasonably speculate that this is the result of interrupting pathways joining a `distributed focus' required for full-blown seizures in this model (G. T. Finnerty, M. A. Whittington and J. G. R. Jefferys, unpublished).
One possible objection is that the hippocampal sclerosis produced by cerebral ischaemia is the `wrong sort of sclerosis' for limbic epilepsy. The histopathology appears broadly similar between the experimental model and temporal lobe epilepsy in humans. It does differ in that the lesions in the ischaemia model are of the CA1 region of the hippocampus; in temporal lobe epilepsy in humans, CA1 is often damaged, but not as often as CA3/4. What is clear, from Milward and colleagues (Milward et al., 1999), is that histologically identified hippocampal sclerosis does not necessarily promote enduring epileptic foci, and that the most straightforward form of the hypothesis, that sclerosis is a factor in causing chronic epileptic foci in the hippocampal area, does not hold up to experimental scrutiny. With the increasing use of non-invasive imaging this conclusion may sound a warning against too ready an assumption that the presence of hippocampal sclerosis will inevitably result in limbic epilepsy. On the other hand, sclerosis resulting from chronic epilepsy remains a useful marker for neurosurgery, as one element of a full clinical investigation.
References
Honavar M, Meldrum BS. Epilepsy. In: Graham DI, Lantos PL, editors.Greenfield's Neuropathology. 6th ed. London: Arnold. 1997. p. 931–71.
Jefferys JGR, Evans BJ, Hughes SA, Williams SF. Neuropathology of the chronic epileptic syndrome induced by intrahippocampal tetanus toxin in rat: preservation of pyramidal cells and incidence of dark cells. Neuropathol Appl Neurobiol 1992; 18: 53–70.[Web of Science][Medline]
Jiang M, Lee CL, Smith KL, Swann JW. Spine loss and other persistent alterations of hippocampal pyramidal cell dendrites in a model of early-onset epilepsy. J Neurosci 1998; 18: 8356–68.
Lee CL, Hrachovy RA, Smith KL, Frost JD Jr, Swann JW. Tetanus toxin-induced seizures in infant rats and their effects on hippocampal excitability in adulthood. Brain Res 1995; 677: 97–109.[Web of Science][Medline]
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Mellanby J. Tetanus toxin as a tool for investigating the consequences of excessive neuronal excitation. In: DasGupta BR, editor. Botulinum and tetanus neurotoxins. New York: Plenum Press; 1993. p. 291–7.
Mellanby J, George G, Robinson A, Thompson P. Epileptiform syndrome in rats produced by injecting tetanus toxin into the hippocampus. J. Neurol Neurosurg Psychiatry 1977; 40: 404–14.
Milward AJ, Meldrum BS, Mellanby JH. Forebrain ischaemia with CA1 cell loss impairs epileptogenesis in the tetanus toxin limbic seizure model. Brain 1999; 122: 1009–16.
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