231

colposcopic and histological help and the colposcopy and secretarial staff for their support. Part of the study

was

funded by the

Department of Health.

REFERENCES Codling BW, Bigrigg A. Cervical screening and government policy. Br Med J 1989; 299: 855. 2. Campion MJ, Singer A, Mitchell MS. Complacency in diagnosis of cervical cancer. Br Med J 1987; 294: 1337-40. 3. Fox M. Cervical smears: new terminology and new demands. Br Med J 1987; 294: 1307-08. 4. Woodman LJ, Jordan JA. Colposcopic service in the West Midlands 1.

region. Br Med J 1989; 299: 899-901. WJ, Davies WAR, Davies JO, Shepherd AM. Medical dilatation of the non-pregnant cervix. The effect of ethinyl oestradiol on the visibility of the transformation zone. Br J Obstet Gynaecol 1986; 93: 508-11. 6. Carrier R. Practical colposcopy, 2nd ed. Paris: Laboratoire Cartier, 1984. 7. Prendiville W, Cullimore J, Norman S. Large loop excision of the transformation zone (LLETZ): a new method of management for women with cervical intra-epithelial neoplasia. Br J Obstet Gynaecol 1989; 96: 1054-60. 8. Codling BW, Bigrigg MA, Pearson P, Read MD, Swingler GR. The development of an effective and economical method of histological interpretation of tissue removed by diathermy loop excision. Poster presented at 7th World Congress of Cervical Pathology and 5. Prendiville

Colposcopy (Rome, May 13, 1990). J Exp Clin Cancer Res 1990; 9 (suppl): 1 (P) (abstr). 9. Bigrigg MA, Codling BW, Pearson P, Read MD, Swingler GR. Report on the specificity of cervical cytology in predicting the histological degree of cervical intraepithelial neoplasia. Presented at 7th World Congress of Cervical Pathology and Colposcopy (Rome, May 13, 1990). J Exp Clin Cancer Res 1990; 9 (suppl): 73 (FC) (abstr). 10. West JH, Marsh G, Hallam N, Harper C, Charnock M. Acceptability to patients of large loop excision of the transformation zone as an outpatient treatment under local anaesthesia. Presentation to annual meeting of British Society of Colposcopy and Cytology (Sheffield, March 29-31, 1990). 11. Phipps JH, Gunasekara PC, Lewis BV. Occult cervical carcinoma revealed by large loop diathermy. Lancet 1989; ii: 453. 12. Fenton D, Beck S, Slater D, Peel J. Occult cervical carcinoma revealed by large loop diathermy. Lancet 1989; ii: 807. 13. McIndoe GAJ, Smith JR, Tidy JA, Yahya A, Mason WP, Anderson MC. Occult cervical carcinoma revealed by large loop diathermy. Lancet 1989; ii: 807 Byrne PF, Sant Cassia LJ. Occult cervical carcinoma revealed by large loop diathermy. Lancet 1989; ii: 807. 15. Hallam N, West J, Charnock M, Gray W. Diathermy loop excision and the cervix. Lancet 1989; ii: 1160. 16. Bellina JM, Wright VC, Varos JI, Ripello MA, Hohenschutz U. Carbon monoxide laser management of cervical intraepithelial neoplasia. Am J Obstet Gynecol 1981; 141: 828-31. 17. Baggish MS, Dorsey JH, Adelson M. A ten year experience treating cervical intraepithelial neoplasia with the CO2 laser. Am J Obstet Gynecol 1989; 162: 60-68.

14.

EPILEPSY OCTET Anatomy, physiology, and pathology of epilepsy B. S. MELDRUM

Anatomy An

epileptic seizure is the result of a sudden excessive discharge of cells in part of the brain. Since the clinical components of the seizure are determined by the site of origin and the pattern of spread of the abnormal discharge, the task of defining the anatomical basis of epilepsy is closely related to that of differentiating the various clinical syndromes of epilepsy. The main clinical differentiation is into focal or partial epilepsies (called localisation-related by the Commission on Classification and Terminology of the International League Against Epilepsy) and generalised epilepsies (see S. Shorvon, this series). However, this differentiation is not absolute: in many patients seizures have a focal or regional origin (as judged from clinical signs and from electroencephalographic [EEG] records) but progress to generalised seizures (secondarily generalised seizures) associated with bilaterally synchronous EEG discharges.! It is therefore reasonable to ask whether all seizures might have a focal origin, with very rapid generalisation giving rise to so-called generalised seizures. Focal cortical seizures and simple partial seizures The character of these seizures is entirely determined by their site of origin, and patients may present with motor, somatosensory, special sensory, autonomic, or psychic symptoms. Focal motor seizures commonly originate in or near the primary motor cortex but may involve the secondary motor area on the medial aspect of the frontal

lobe. Intracortical spread is mainly via anatomical connections (horizontal fibres in layer VI are important2). In the hippocampus contiguous spread via extracellular ionic changes and local current flow may be substantial. The Jacksonian march is associated with a strictly localised seizure propagating at a speed of mm/s.2 An "inhibitory surround" due to activation of intrinsic GABAergic neurons may limit local cortical (and homotopic) spread of seizure

activity. Activation of basal ganglia, thalamic, and brainstem nuclei accompanies some clinical signs of focal seizure activity. The transition from clonic to tonic activity may reflect a change in the pattern of cortical discharge, but when seizure activity becomes more generalised it reflects a sequence of events in the brainstem.

Complex-partial (psychomotor, temporal lobe, limbic) seizures

Typical complex partial seizures usually originate in one mesial temporal lobe but may start in other limbic structures or in cortical areas that project to limbic areas (including frontal and occipital cortex). Depth electrode studies by Wieser3have contributed to the differentiation of several types of complex partial seizures in terms of the origin and spread of electrical discharges-eg, hippocampal or ADDRESS Department of Neurology, Institute of Psychiatry. London SE5 8AF, UK (Prof B. S Meldrum, MB)

232

secondary generalisation

(medio-basal) propagation from hippocampus and related regions. The lower part indicates hypothetical routes of transhemispheric spread through commissures and brainstem structures. SMA supplementary motor area, THAL thalamus, M B mammillary body, H I PP - hippocampus; NA=amygdala; ENTO=entorhinal cortex, PARAHIPP=parahippocampal gyrus, CC=corpus callosum, VHC=ventral hippocampal commissure; DHC=dorsal hippocampal commissure; AC=anterior commissure, rspl 23 = retrosplenial cmgulate gyrus, Brodmann’s area 23. (Reproduced from Wieser3with permission ) Fig 1-Pathways

of limbic seizure

structures to cortical

=

=

mesiobasal limbic, amygdalar, lateral posterior temporal, and opercular. These anatomically defined seizure types appear to be associated with different groups of

predominant symptoms.4,5 Nevertheless, spread usually such as the parahippocampal cortex, hippocampus, and amygdala (fig 1) and patients tend to show similar clinical signs. The circuit within which seizure activity becomes established can sometimes be broken by removal of the amygdala and

involves

certain

common

structures

hippocampus (amygdalo-hippocampectomy of Yasargil), or by resection of the anterior temporal lobe. This is not necessarily the case when the original focus is extratemporal.6 (3js spike and wave) associated with symmetrical

Generalised seizures : absence

Absence attacks are neocortical discharges with simultaneous thalamic involvement. Clinical and experimental data7 indicate that a rhythmic reverberation or oscillation within the thalamus and cortex is the basis of 3/s spike and wave discharges. Penfield and JasperS proposed a "centrencephalic hypothesis"-that a brainstem region responsible for the maintenance of consciousness was involved in the triggering and generalisation of such seizures. Experimental and clinical studies by Gloor9 have suggested that the trigger sites are more probably cortical, with retrograde or

=

anterograde spread of synchronous activity to the thalamus. However, a primary role for the thalamus remains a possibility. Bancaud and colleagueslO showed that electroclinical absences could be triggered by unilateral electrical stimulation of the mesial frontal cortex. Animal experiments suggest that synchronisation between the two hemispheres depends on transmission via the corpus callosum rather than on a common brainstem source.

Myoclonic syndromes One attempt" to differentiate the many forms of myoclonus anatomically recognises three forms: (a) primary cortical (focal, multifocal, or generalised), in which the myoclonic latencies indicate a rostro-caudal spread of activity; (b) primary brainstem (reticular), in which the sequential spread is both ascending and descending; and (c) segmental or spinal. Only the cortical form is generally believed to be a true form of epilepsy. Neonatal seizures Neonatal seizures may be manifest as various rhythmic patterned movements or as postural spasms. They are widely thought to originate in the brainstem or midbrain, without cortical involvement in the abnormal discharges. However, in some cases slow abnormal discharges may be recorded from the cortex. 12

233

Physiology Although much is known about the physiological basis of the abnormal discharges accompanying seizure phenomena, the cellular mechanisms responsible for epileptogenesis remain conjectural. There may be a primary defect in the neuronal membrane that results in an instability of the resting membrane potential; possible underlying mechanisms include an abnormality of potassium conductance, a defect in the voltage-sensitive calcium channels, or a deficiency in the membrane ATPases linked to ion transport. There may be primary defects in the GABAergic inhibitory system or in the sensitivity or arrangement of the receptors involved in excitatory neurotransmission. A description of the electrical and cellular basis of epilepsy should defme the circumstances that give rise to the initial epileptic discharge (ictal or interictal), specify what constitutes and what causes the interictal to ictal transition, and analyse the synaptic and non-synaptic mechanisms by which epileptic discharges spread and the mechanisms that lead to termination of epileptic activity. Despite considerable information about these processes none can be described with complete certainty.l3°a The different kinds of epilepsy probably arise from different physiological abnormalities.

Interictal and ictal discharges

Fig 2 illustrates widely accepted views about the relation between gross and cellular recordings of ictal and interictal events. Interictal spikes (recorded with a focal or more general distribution by EEG) correspond at the cellular level to the synchronous occurrence in principal neurons of a paroxysmal depolarising shift in the resting membrane potential, which is associated with a brief burst of action potentials and followed by a phase of hyperpolarisation. Such an event can be triggered by a synchronous volley in afferent fibres or by the spontaneous discharge of "pacemaker" epileptic neurons. In experimental models in which sustained discharges resembling in-vivo ictal discharges can be produced by convulsant drugs or ionic manipulations, interictal discharges become more frequent

phase of hyperpolarisation disappears so that paroxysmal depolarisations with burst firing are closely recurrent. Such a discharge is associated with an increase in extracellular potassium concentration and a decrease in and the

extracellular calcium. In partial seizures the localised burst firing is initially associated with enhanced inhibitory activity in projection areas. With repetition inhibitory activity fades and excitatory neurotransmission predominates, leading to synchronised burst firing in related cortical areas or deep brain nuclei. In this way seizure activity spreads within the limbic system (amygdala, entorhinal cortex, hippocampus, &c) or from cortex to basal ganglia and thalamus. Termination of seizure activity is associated with arrest of burst firing and replacement of the paroxysmal depolarising shifts by sustained hyperpolarisation, probably as a consequence of active inhibitory processes. Outputs of the basal ganglia system (substantia nigra and the pallidal system) appear to play a critical part in modulating the generalisation of seizure activity .14

Pathology Primary non-specific pathological changes with secondary epilepsy Epilepsy occurs in association with many underlying abnormalities, including developmental defects; vascular lesions; venous thromboses and subdural haematoma; primary or secondary neoplasia; traumatic lesions; microbial or viral infections; parasitic disorders such as toxoplasmosis, cerebral malaria, and cysticercosis;5 and degenerative disorders, ranging from lesions induced by perinatal asphyxia to Huntington’s chorea. These conditions do not necessarily cause epilepsy and may be only coincidentally present. However, they may show a temporal and spatial relation to the onset of seizures and surgical removal of the affected areas may be followed by the disappearance of seizures-features that are often taken to imply a causal role. Seizures with

secondary pathological changes Status epilepticus may be followed by acute degenerative changes affecting neurons in the hippocampus (especially the endfolium and the CAl zone) and the cortex. Hippocampal or temporal lobe sclerosis is a common necropsy finding in institutionalised patients with epilepsy and is the most frequent abnormality when the anterior temporal lobe is removed during the surgical treatment of intractable seizures. In patients with intractable seizures there is often a history of febrile convulsions in early childhood ;4 if such convulsions are prolonged (> 30 min) they are presumed to be the cause of the hippocampal lesion. The extent to which recurrent or prolonged limbic seizures in later life contribute to cell loss in the hippocampus is hard to evaluate. In one study16 seizures appeared to accelerate the loss that occurs with ageing. Cellular changes

I Ut:j.JUldll:>CltlUI1

:>IUII ru,::,

Fig 2-Schematic diagram of relations between cortical discharges (surface EEG) and extracellular and intracellular activity in an epileptic focus. An isolated intenctal discharge is shown on the left. Tonic-clonic ictal activity is shown on the right. (Reproduced by permission of the Amencan Physiological Society, taken from fig 1 in ref 30.)

contributing to epileptogenesis In the 19th century both gliosis and dendritic degeneration were described in association with epilepsy. Dendritic degeneration is a non-specific finding, but may be associated with membrane changes, including receptor hypersensitivity, that could contribute to epileptogenesis. Another common finding (also first described in the 19th century) associated with both generalised seizures and complex partial seizures is an abnormality of cortical maturation often called microdysgenesis. This may be

234

clusters of abnormally large neurons in the cortex, dystopic groups of neurons in the subcortical white matter. It has been proposed that such abnormalities manifest

as

or as

predispose to diverse types of epilepsy including primary generalised epilepsy, West’s syndrome, and temporal lobe epilepsy.17,18 However, their relevance remains uncertain; as largely some pathologists regard ectopic neurons artifactual whereas others believe them to be a marker for increased susceptibility to epilepsy. A selective loss of inhibitory terminals or cell bodies has been described by Ribak and colleagues in the epileptic focus created by alumina in monkey cortex. 19,20 Measurement of glutamic acid decarboxylase activity in focal epileptic tissue has suggested that GABA synthesis may be impaired in a minority of patients with focal seizures.21 However, an immunocytochemical study in temporal lobectomy specimens found no evidence of a selective reduction in neurons containing glutamate decarboxylase in the focus.22 A deficit in the GABA/ benzodiazepine receptor complex may be a predisposing or contributory cause of epilepsy. The number of benzodiazepine receptors in the midbrain appears to be reduced in two genetically determined epilepsy syndromes in rodents.23 A positron emission tomography study with the "C labelled benzodiazepine receptor ligand Ro 15-1788 in man has shown a decrease in benzodiazepine receptor number in the presumed epileptic focus in patients with

partial epilepsy. 24 Preliminary studies

with radioactive ligands to identify the sites of action of glutamate and related excitatory transmitters suggest that there may be increases in the density of such sites, both in children with various types of generalised seizures and in adults with temporal lobe seizures.25,26 Electrophysiological studies provide evidence for hypersensitivity of NMDA (N-methyl-D-aspartate) receptors in the hippocampus of rats in which an epileptic tendency was induced by repetitive electrical stimulation27 and in the cortex of patients with focal epilepsy.28

epilepsy.28 Another morphological change has been described relating to excitatory neurotransmission in the mossy fibre system in experimental epilepsy and in man. This fibre system originates in the dentate granule cells in the hippocampus and usually terminates within the dendritic fields of the CA3 and CA4 principal neurons (the terminations being associated with kainate receptors). In adults with temporal lobe epilepsy and apparently also in children with various types of generalised epilepsy these fibres terminate abnormally in the inner molecular layer of the dentate gyrus, as a result of sprouting induced either by loss of other inputs or by abnormal neuronal discharges.26,29 Thus there are many neuronal morphological changes associated with epilepsy, but their precise role in the initiation of seizures remains

to

be established.

I thank the following colleagues for their comments during the preparation of this paper: Dr C. D. Binnie, Dr C. J. Bruton, Dr J. Engel, and Dr H. G. Wieser.

REFERENCES H, Zifkin B, Maggauda A, Mariani E. Symptomatic partial epilepsies with secondary bilateral synchrony; differentiation from symptomatic generalized epilepsies of the Lennox Gastaut type. In: Wieser HG, Elger CE, eds. Presurgical evaluation of epilepsy. Berlin: Springer, 1987: 308-16. 2. Petsche H, Pockberger H, Rappelsberger P. Mechanisms leading to the propagation of self-sustained seizure activities. In: Wieser HG, Speckmann EJ, Engel J, eds. The epileptic focus. London: John Libbey, 1987: 59-81. 1. Gastaut

3. Wieser HG. Human limbic seizures: EEG studies, origin, and patterns of spread. In: Meldrum BS, Ferrendelli J, Wieser HG, eds. The anatomy of epileptogenesis. London: John Libbey, 1988: 127-38. 4. Duncan JS, Sagar HJ. Seizure characteristics, pathology, and outcome after temporal lobectomy. Neurology 1987; 37: 405-09. 5. Wieser HG. The phenomenology of limbic seizures. In: Wieser HG, Speckmann EJ, Engel J, eds. The epileptic focus. London: John Libbey, 1987: 113-36 6. Brey R, Laxer KD. Type I/II complex partial seizures: no correlation with surgical outcome. Epilepsia 1985; 26: 657-60. 7. Williams D. The thalamus and epilepsy. Brain 1965; 88: 539-56. 8. Penfield W, Jasper H. Epilepsy and the functional anatomy of the human brain. Boston: Little, Brown, 1954. 9. Gloor P. Generalised epilepsy with spike-and-wave discharge: a reinterpretation of its electrographic and clinical manifestations. Epilepsia 1979; 20: 571-88. 10. Bancaud J, Talairach J, Morel P, et al. "Generalized" epileptic seizures elicited by electrical stimulation of the frontal lobe in man. Electroenceph Clin Neurophysiol 1974; 37: 275-82. 11. Hallett M, Chadwick D, Adam J, Marsden CD. Reticular reflex myoclonus: a physiological type of human post-hypoxic myoclonus. J Neurol Neurosurg Psychiatry 1977; 40: 253-64. 12. Kellawy P, Mizrahi EM. Neonatal seizures. In: Luders H, Lesser RP, eds. Epilepsy: electroclinical syndromes. London: Springer, 1987: 13-47. 13. Dichter MA, Ayala GF. Cellular mechanisms of epilepsy: a status report. Science 1987; 237: 157-64. 14. Meldrum BS. Initiation and neuroanatomical spread of seizure activity. In: Pedley TA, Meldrum BS, eds. Recent advances in epilepsy 4. Edinburgh: Churchill Livingstone, 1988: 1-20. 15. Bittencourt PRM, Gracia CM, Lorenzana P. In: Pedley TA, Meldrum BS, eds. Epilepsy and parasitosis of the central nervous system. Recent advances in epilepsy 4. Edinburgh: Churchill Livingstone, 1988; 123-59. 16. Dam AM. Epilepsy and neuron loss in the hippocampus. Epilepsia 1980; 21: 617-29. 17. Hardiman O, Burke T, Phillips J, et al. Microdysgenesis in resected temporal neocortex: incidence and clinical significance in focal epilepsy. Neurology 1988; 38: 1041-17. 18. Meencke HJ, Janz D. The significance of microdysgenesia in primary generalized epilepsy: an answer to the considerations of Lyon and Gastaut. Epilepsia 1985; 26: 368-71. 19. Ribak CE, Harris AB, Vaughn JE, Roberts E. Inhibitory, GABAergic nerve terminals decrease at sites of focal epilepsy. Science 1979; 205: 211-14. 20. Ribak CE, Jourbran C, Kesslak JP, Bakay RAE. A selective decrease in the number of GABAergic somata occurs in pre-seizing monkeys with alumina gel granuloma. Epilepsy Res 1989; 4: 126-38. 21. Lloyd KG, Bossi L, Morselli PL, Rougier M, Loiseau P, Munari C. Biochemical evidence for dysfunction of GABA neurons in human epilepsy. In: Bartholini G, Friedman JC, Langer SZ, Morselli PL, Wick A, eds. Epilepsy and GABA receptor agonists. New York: Raven, 1985: 43-52. 22. Babb TL, Pretorius JK, Kupfer WR, Crandall PH. Glutamate decarboxylase-immunoreactive neurons are preserved in human epileptic hippocampus. J Neurosci 1989; 9: 2562-74. 24. Olsen RW, Wamsley JK, McCabe RT, Lee RJ, Lomax P, Seyfried TN. Midbrain GABA receptor deficit in genetic animal models of epilepsy. In: Nistico G, Morselli Pl, Lloyd KG, Fariello RG, Engel J, eds. Neurotransmitters, seizures and epilepsy III. New York: Raven, 1986: 279-91. 24. Savic I, Persson A, Roland P, Pauli S, Sedvall G, Widen L. In-vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci. Lancet 1988; ii: 863-66. 25. Geddes JW, Cahan LD, Cooper SM, Kim RC, Choi BH, Cotman CW. Altered density and distribution of excitatory amino acid receptors in temporal lobe epilepsy. Exp Neurol (in press). 26. Represa A, Robain O, Tremblay E, Ben-Ari Y. Hippocampal plasticity in childhood epilepsy. Neurosci Lett 1989; 99: 351-55. 27. Mody I, Stanton PK, Heinemann U. Activation of N-methyl-Daspartate receptors parallels changes in cellular and synaptic properties of dentate gyrus granule cells after kindling. J Neurophysiol 1988; 59: 1033-54. 28. Avoli M, Olivier A. Bursting in human epileptogenic neocortex is depressed by an N-methyl-D-aspartate antagonist. Neurosci Lett 1987; 76: 249-54. 29. Sutula T, Cascino G, Cavazos J, Parada I, Ramirez L. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol 1989; 26: 321-30. 30. Ayala GF, Matsumoto H, Gumnit RJ. Excitability changes and inhibitory mechanisms in neocortical neurons during seizures. J Neurophysiol 1970; 33: 73-85.