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. 1994 Jul;57(7):797–804. doi: 10.1136/jnnp.57.7.797

In vivo demonstration of altered benzodiazepine receptor density in patients with generalised epilepsy.

I Savic 1, S Pauli 1, J O Thorell 1, G Blomqvist 1
PMCID: PMC1073018  PMID: 8021664

Abstract

Electrophysiological data suggest that an abnormal oscillatory pattern of discharge in cortical and thalamic neurons may be the major mechanism underlying primary generalised epilepsy. No neurochemical or anatomical substrate for this theory has hitherto been demonstrated in humans and the pathophysiology of primary generalised epilepsy remains unknown. By means of PET and the benzodiazepine (BZ) ligand [11C]flumazenil it has been previously shown that the BZ receptor density is reduced in the epileptic foci of patients with partial epilepsy. In the present study the method was further developed and used in a comparative analysis of cortical, cerebellar, and subcortical BZ receptor binding in patients with primary generalised tonic and clonic seizures (n = 8), and healthy controls (n = 8). Patients with generalised seizures had an increased BZ receptor density in the cerebellar nuclei (p = 0.006) and decreased density in the thalamus (p = 0.003). No significant changes were seen in the cerebral and cerebellar cortex or in the basal ganglia. The observed alterations suggest that the gamma-amino-butyric acid (GABA)-BZ system may be affected in the cerebello-thalamocortical loop of patients with generalised epilepsy and indicate possible targets for selective pharmacological treatment.

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Selected References

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  1. Abadie P., Baron J. C., Bisserbe J. C., Boulenger J. P., Rioux P., Travère J. M., Barré L., Petit-Taboué M. C., Zarifian E. Central benzodiazepine receptors in human brain: estimation of regional Bmax and KD values with positron emission tomography. Eur J Pharmacol. 1992 Mar 17;213(1):107–115. doi: 10.1016/0014-2999(92)90239-z. [DOI] [PubMed] [Google Scholar]
  2. Avoli M., Gloor P. Interaction of cortex and thalamus in spike and wave discharges of feline generalized penicillin epilepsy. Exp Neurol. 1982 Apr;76(1):196–217. doi: 10.1016/0014-4886(82)90112-1. [DOI] [PubMed] [Google Scholar]
  3. Bergström M., Boëthius J., Eriksson L., Greitz T., Ribbe T., Widén L. Head fixation device for reproducible position alignment in transmission CT and positron emission tomography. J Comput Assist Tomogr. 1981 Feb;5(1):136–141. doi: 10.1097/00004728-198102000-00027. [DOI] [PubMed] [Google Scholar]
  4. Blomqvist G., Pauli S., Farde L., Eriksson L., Persson A., Halldin C. Maps of receptor binding parameters in the human brain--a kinetic analysis of PET measurements. Eur J Nucl Med. 1990;16(4-6):257–265. doi: 10.1007/BF00842777. [DOI] [PubMed] [Google Scholar]
  5. Dam M. Number of Purkinje cells in patients with grand mal epilepsy treated with diphenylhydantoin. Epilepsia. 1970 Sep;11(3):313–320. doi: 10.1111/j.1528-1157.1970.tb03895.x. [DOI] [PubMed] [Google Scholar]
  6. Greitz T., Bohm C., Holte S., Eriksson L. A computerized brain atlas: construction, anatomical content, and some applications. J Comput Assist Tomogr. 1991 Jan-Feb;15(1):26–38. [PubMed] [Google Scholar]
  7. Halldin C., Stone-Elander S., Thorell J. O., Persson A., Sedvall G. 11C-labelling of Ro 15-1788 in two different positions, and also 11C-labelling of its main metabolite Ro 15-3890, for PET studies of benzodiazepine receptors. Int J Rad Appl Instrum A. 1988;39(9):993–997. doi: 10.1016/0883-2889(88)90044-5. [DOI] [PubMed] [Google Scholar]
  8. Holthoff V. A., Koeppe R. A., Frey K. A., Paradise A. H., Kuhl D. E. Differentiation of radioligand delivery and binding in the brain: validation of a two-compartment model for [11C]flumazenil. J Cereb Blood Flow Metab. 1991 Sep;11(5):745–752. doi: 10.1038/jcbfm.1991.131. [DOI] [PubMed] [Google Scholar]
  9. Hunkeler W., Möhler H., Pieri L., Polc P., Bonetti E. P., Cumin R., Schaffner R., Haefely W. Selective antagonists of benzodiazepines. Nature. 1981 Apr 9;290(5806):514–516. doi: 10.1038/290514a0. [DOI] [PubMed] [Google Scholar]
  10. Julien R. M., Laxer K. D. Cerebellar responses to penicillin-induced cerebral cortical epileptiform discharge. Electroencephalogr Clin Neurophysiol. 1974 Aug;37(2):123–132. doi: 10.1016/0013-4694(74)90002-9. [DOI] [PubMed] [Google Scholar]
  11. Litton J., Bergström M., Eriksson L., Bohm C., Blomqvist G., Kesselberg M. Performance study of the PC-384 positron camera system for emission tomography of the brain. J Comput Assist Tomogr. 1984 Feb;8(1):74–87. doi: 10.1097/00004728-198402000-00016. [DOI] [PubMed] [Google Scholar]
  12. Lüddens H., Wisden W. Function and pharmacology of multiple GABAA receptor subunits. Trends Pharmacol Sci. 1991 Feb;12(2):49–51. doi: 10.1016/0165-6147(91)90495-e. [DOI] [PubMed] [Google Scholar]
  13. Meencke H. J., Janz D. Neuropathological findings in primary generalized epilepsy: a study of eight cases. Epilepsia. 1984 Feb;25(1):8–21. doi: 10.1111/j.1528-1157.1984.tb04149.x. [DOI] [PubMed] [Google Scholar]
  14. Mimaki T., Deshmukh P. P., Yamamura H. I. Decreased benzodiazepine receptor density in rat cerebellum following neurotoxic doses of phenytoin. J Neurochem. 1980 Dec;35(6):1473–1475. doi: 10.1111/j.1471-4159.1980.tb09029.x. [DOI] [PubMed] [Google Scholar]
  15. Nevander G., Ingvar M., Auer R., Siesjö B. K. Status epilepticus in well-oxygenated rats causes neuronal necrosis. Ann Neurol. 1985 Sep;18(3):281–290. doi: 10.1002/ana.410180303. [DOI] [PubMed] [Google Scholar]
  16. Olsen R. W., Wamsley J. K., McCabe R. T., Lee R. J., Lomax P. Benzodiazepine/gamma-aminobutyric acid receptor deficit in the midbrain of the seizure-susceptible gerbil. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6701–6705. doi: 10.1073/pnas.82.19.6701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pappata S., Samson Y., Chavoix C., Prenant C., Mazière M., Baron J. C. Regional specific binding of [11C]RO 15 1788 to central type benzodiazepine receptors in human brain: quantitative evaluation by PET. J Cereb Blood Flow Metab. 1988 Jun;8(3):304–313. doi: 10.1038/jcbfm.1988.65. [DOI] [PubMed] [Google Scholar]
  18. Savic I., Ingvar M., Stone-Elander S. Comparison of [11C]flumazenil and [18F]FDG as PET markers of epileptic foci. J Neurol Neurosurg Psychiatry. 1993 Jun;56(6):615–621. doi: 10.1136/jnnp.56.6.615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Savic I., Persson A., Roland P., Pauli S., Sedvall G., Widén L. In-vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci. Lancet. 1988 Oct 15;2(8616):863–866. doi: 10.1016/s0140-6736(88)92468-3. [DOI] [PubMed] [Google Scholar]
  20. Savic I., Widen L., Thorell J. O., Blomqvist G., Ericson K., Roland P. Cortical benzodiazepine receptor binding in patients with generalized and partial epilepsy. Epilepsia. 1990 Nov-Dec;31(6):724–730. doi: 10.1111/j.1528-1157.1990.tb05513.x. [DOI] [PubMed] [Google Scholar]
  21. Savic I., Widén L., Stone-Elander S. Feasibility of reversing benzodiazepine tolerance with flumazenil. Lancet. 1991 Jan 19;337(8734):133–137. doi: 10.1016/0140-6736(91)90799-u. [DOI] [PubMed] [Google Scholar]
  22. Seitz R. J., Bohm C., Greitz T., Roland P. E., Eriksson L., Blomqvist G., Rosenqvist G., Nordell B. Accuracy and precision of the computerized brain atlas programme for localization and quantification in positron emission tomography. J Cereb Blood Flow Metab. 1990 Jul;10(4):443–457. doi: 10.1038/jcbfm.1990.87. [DOI] [PubMed] [Google Scholar]

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