Penicillin, ceftazidime, and the epilepsies

400

groups since 1973.2 For England and Wales over this period, rises are largely restricted to older groups, with

increases for young adult women and decreases for middle-aged men.16-18 Scandinavian countries have generally shown increases in all age groups since 1960, although this finding has been less consistent in some 9 young adult groups.l9 Some of this recorded increase is undoubtedly due to the various types of bias. The difficulty is to determine how much. Indications of reliability of registry data include the proportion of cases diagnosed histologically (a high proportion indicates good quality data but conversely may suggest incomplete case-finding); the proportion of cases registered only from death certificate information (if high, incidence rate is likely to be too low); and the mortality/incidence ratio (should be less than 1 unless rates are falling very fast, should be close to 1 for cancers with poor survival, and changes over time should correlate with known changes in survival rates).20 Failure of the all-site incidence curve to continue to increase with age suggests under-reporting in older age groups. Wild fluctuations in rates are unlikely to represent true changes except for rare sites in small populations.2O Estimating the effect of biases on recorded rates and searching for causes of true trends identified is more easily and appropriately done by cancer site. Cancer rates are highly dependent on a few common cancers, and trends are likewise influenced by trends in these sites. Although it may be politically expedient to talk in terms of cancer as an entity, the public health implications of this approach are limited. Some environmental and behavioural risk factors are common to several cancers, but it is unlikely that any are common to all. Whatever the overall trends, there is little doubt that there have been some substantial changes: increases in lung cancer rates, with a more recent levelling off in some countries;2,13,15 decreases in stomach cancer rates world wide;13 and increases in melanoma, breast cancer in older women, and prostate cancer.2,13,14 We should now be looking for the causes of the site-specific trends that we cannot explain, and for ways of avoiding the risk factors that we have already identified. Epstein SS. Losing the war against cancer: who’s to blame and what to do about it. Int J Hlth Serv 1990; 20: 53-71. 2. Doll R. Progress against cancer: an epidemiological assessment. Am J Epidemiol 1991; 134: 675-88. 3. World Health Organisation. World health statistics annual 1988. Geneva: WHO, 1988. 4. Doll R, Payne P, Waterhouse J, eds. Cancer incidence in five continents. 1.

Berlin: Springer-Verlag, 1966. 5. Doll R, Muir C, Waterhouse J, eds. Cancer incidence in five continents, vol II. Berlin: Springer-Verlag, 1970. 6. Waterhouse J, Muir C, Correa P, Powell J, eds. Cancer incidence in five continents, vol III. IARC scientific publications no 15. Lyon: IARC, 1976. 7. Waterhouse J, Muir C, Shanmugaratnam K, Powell J, eds. Cancer incidence in five continents, vol IV. IARC scientific publications no 42. Lyon: IARC, 1982. 8. Muir C, Waterhouse J, Mack T, Powell J, Whelan S. eds. Cancer incidence in five continents, vol V. IARC scientific publications no 88. Lyon: IARC, 1987. 9. Doll R, Peto R. The causes of cancer. Oxford: Oxford University Press, 1981.

N, Chan CW, Dhom G, et al. Latent carcinoma of prostate at autopsy in seven areas. Int J Cancer 1977; 20: 680-88. 11. Swerdlow AJ. Cancer registration in England and Wales: some aspects relevant to interpretation of the data. J R Statist Soc A 1986; 149: 146-60. 12. Smith P. Comparison between registries: age-standardized rates. In. Muir C, Waterhouse J, Mack T, Powell J, Whelan S, eds. Cancer incidence in five continents, vol V. IARC scientific publications no 88. Lyon: IARC, 1987: 790-95. 13. Hoel DG, Davis DL, Miller AB, Sondik EJ, Swerdlow AJ. Trends in cancer mortality in 15 industrialized countries, 1969-86. J Natl Cancer Inst 1992; 84: 313-20. 14. Blyth F, Beral V. Monitoring cancer trends. Br J Cancer 1991; 63: 479-80. 15. Peto R, Lopez AD, Boreham J, Thun M, Heath C. Mortality from tobacco in developed countries: indirect estimation from national vital statistics. Lancet 1992; 339: 1268-78. 16. Office of Population Censuses and Surveys. Cancer Registration Surveillance 1968-1978, England and Wales. London: OPCS, 1983. 17. Office of Population Censuses and Surveys. Cancer Statistics Registration, England and Wales 1982. London: HM Stationery Office, 1985. 18. Office of Population Censuses and Surveys. Cancer Statistics Registration, England and Wales 1986. London: HM Stationery Office, 1991. 19. Hakulinen T, Andersen A, Malker B, Pukkala E, Schou G, Tulinius H. Trends in cancer incidence in the Nordic countries: a collaborative study of the five Nordic cancer registries. Acta Pathol Microbiol Immunol Scand 1986; 288 (suppl); 1-151. 20. Muir C, Waterhouse J. Comparability and quality of data: reliability of registration. In: Muir C, Waterhouse J, Mack T, Powell J, Whelan S, eds. Cancer incidence in five continents, vol V. IARC scientific publications no 88. Lyon: IARC, 1987: 45-59. 10. Breslow

Penicillin, ceftazidime, and the

epilepsies Johnson and Walker1 were the first to recognise that the intraventricular administration of penicillin could cause convulsions. In their patient, the convulsions were generalised clonic spasms of the arms and legs. They proceeded2 to do experiments on cats and monkeys, in which application of penicillin to the surface of the cortex was found to produce myoclonic jerks contralateral to the site of application. The cortical application of penicillin in anaesthetised animals subsequently became the standard in-vivo model of focal neocortical epilepsy. There is abundant evidence3that, at low concentrations, penicillin produces this epileptogenic effect by competitive antagonism of y-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in higher centres of the brain. The chemical configuration of penicillin matches that of GABA and this drug attaches to the GABA receptor. This chemical structure is unrelated to the p-lactam ring, which endows penicillin with its antibiotic activity. The thalamus plays an important part in focal cortical epilepsy. It is essential for generation of the oscillations that follow an interictal spike, since cooling of the thalamus blocks this after-discharged Sensitivity of different cortical laminae and cortical regions (somatosensory, visual, motor) to locally applied epileptogenic agents is closely related to the density of termination of thalamocortical afferents.6 Although penicillin does not readily cross the blood-brain barrier, parenteral administration of large doses (or of normal doses in patients with renal

401

neural

hyperexcitability, generalised non-convulsive epilepsy (absence seizures) with spike and wave discharges on the electroencephalogram (EEG).7 These discharges have a frequency of about 3 Hz. Spike and wave discharges depend on interactions insufficiency),

can

cause

which takes the form of

between the thalamus and the cortex; neither centre is able to sustain the discharges on its own. Gloor and Fariello8 believe that such discharges are caused by a primary diffuse hyperexcitability of cortical neurons, with secondary dysfunction in thalamocortical projecting systems as an essential ingredient. The thalamocortical circuits involved in spike and wave generation are those that normally sustain a physiological EEG wave activity at 10 Hz, the characteristic spindles of early phases of slow-wave

sleep. In cats, the earliest epileptiform effect of parenteral penicillin is gradual enhancement of the primary evoked potential in layer IV in the striate cortex;9 this is exactly where neocortex is most sensitive to penicillin injected into the visual cortex of catsl° and into the somatosensory cortex of rats." With topical or parenteral administration of penicillin, changes in cortical electrical activity show the same sequence of laminar distribution of discharging neurons and spread of hypersynchronous activity.9 This finding strongly suggests that the spike and wave discharge caused by parenteral penicillin is mainly due to

cortical hyperexcitability. What about primary abnormalities in the thalamus? A strain of rats that spontaneously exhibit absence seizures associated with spike and wave activity have such defects. The thalamus contains a large concentration of the receptor subtype GABA-B and there is evidence of excessive GABA-B receptor function as an underlying factor in the generation of and wave discharges. In general, excessive GABA receptor activity depresses neural activity because GABA is an inhibitory neurotransmitter. However, when excitatory and inhibitory synaptic activities are both exaggerated, intense feedback between pools of excitatory and inhibitory neurons causes tidal waves of excitation and inhibition reflected in the EEG as spike and wave activity. These observations indicate that, in various animal models, spike and wave discharges may result either from hyperexcitability of the cerebral cortex or from excessive excitatory and inhibitory function in the thalamus. Either factor leads to the oscillatory feedback underlying spike and wave discharges. Similarly, in patients, different primary lesions may give the same end result. Clinical interest in this subject has been revived by the observation that high concentrations of the

spike

third-generation cephalosporin, ceftazidime, may cause absence seizures with spike and wave discharges.13 The structure of cephalosporins relevant to mimicking GABA is close to that of penicillin, and it seems likely that ceftazidime produces the same

clinical effects in a pharmacologically similar manner. Neuroscientists use this side-effect of the (3-lactam antibiotics to study basic neural mechanisms with a view to investigating novel treatments for epilepsy. Johnson HC, Walker A. Convulsive factor in commercial penicillin. Arch Surg 1945; 50: 69-74. 2. Johnson HC, Walker A. Intraventricular penicillin. JAMA 1945; 127: 1.

217-19. 3. Olsen RW, Ticku

MK, van Ness PC, Greenlee D. Effects of drugs on &ggr;-aminobutyric acid receptors, uptake and synthesis in vitro. Brain Res

1978; 139: 277-94. DR, Game CJA, Johnston GAR, McCulloch RM, MacLachlan RM. Convulsive action of penicillin. Brain Res 1972; 43: 242-45. 5. Gasteiger EL, Albowitz B, Barken M. Interictal afterdischarge in focal penicillin epilepsy: block by thalamic cooling. Exp Neurol 1985; 88:

4. Curtis

349-59. 6. Holmes O, Wallace MN, Campbell A. Comparison of penicillin epileptogenesis in rat somatosensory and motor cortex. Q J Exp Physiol 1987; 72: 439-52. 7. Prince DA, Farrell D. ’Centrencephalic’ spike and wave discharge following parenteral penicillin injection in the cat. Neurology 1969; 19: 309-10. 8. Gloor P, Fariello RG. Generalised epilepsy: some of its cellular mechanisms differ from those of focal epilepsy. Trends Neurol Sci 1988; 11: 63-68. 9. Chatt AB, Ebersole JS. Convulsant-induced neocortical epilepsy: neuronal networks and anticonvulsant actions in vivo. In: Faigold CL, Fromm GH, ed. Drugs for control of epilepsy. Boca Raton: CRC Press, 1992: 143-74. 10. Chatt AB, Ebersole JS, The laminar sensitivity of cat striate cortex to pencillin induced epileptogenesis. Brain Res 1982; 241: 382-87. 11. Lockton JW, Holmes O. Site of initiation of penicillin induced epilepsy in the cortex cerebri of the rat. Brain Res 1980; 190: 301-04. 12. Vergnes M, Marescaux C, Micheletti G, Depaulis A, Rumbach L. Warter JM. The enhancement of spike and wave discharges by GABAmimetic drugs in rats with spontaneous petit-mal-like epilepsy. Neurosci Lett 1984; 44: 91-94. 13. Jackson GD, Berkovic SL. Ceftazidime encephalopathy: absence status and toxic hallucinations. J Neurol Neurosurg Psychiatry 1992; 55: 333-34.

Selection for audit The medical profession is afflicted with a need to conduct audit. Practitioners in some disciplines, especially those who do not carry out procedures on patients, are almost frantic in their search for topics, cases, or problems for medical audit. Others, because of their type of work, are able naturally to pursue objectives that are obvious. Nevertheless, the initial enthusiasm for counting operations, outpatient

re-referrals, inadequate discharge letters,

attendances,

or

notes, inadequate summaries may soon some other method be maintained and

Clinicians may want whereby their interest can regularly stimulated. A new, somewhat subjective wane.

approach published

for the attention of anaesthetists might be of use to other groups. How does one know which case or condition, out of the several hundred each week in an average operating schedule, might be interesting? Scott et al2 suggest that a linear analogue score of likely outcome determined before a procedure (in their case anaesthesia) should be compared with the perceived outcome similarly allocated after the procedure. Individuals who fall outside predetermined boundaries, good or bad, are for detailed study. The time scale is naturally brief for surgeons and