relative concentrations of the two phosphate species (H2PO4- and HPO42-) present. The MRS measurement of tissue pH is a composite value of pH, and pHe. In normal tissues it is believed that pH measured in this way is intracellular. This assumption might not hold for tumours, since their extracellular volume can be much larger than in normal tissues. The proportion of Pi signal coming from the intracellular volume can be calculated if total tissue water content and the fractional volume of extracellular water are known. In animal tumours, if the extracellular volume does not exceed 50%, pHMRS largely represents intracellular pH.8 Many human tumours, especially brain tumours and sarcomas (pH 7-01—7 35), have a similar or even slightly higher pH, than their respective normal tissues.3,9 Positron emission tomography studies support the findings of high brain tumour pH.lO These pHMRS values mean that human tumours are alkaline in comparison to their extracellular fluid-the exact opposite of normal tissues. Because it was widely assumed that microelectrode measurements of acidic pHe implied acidic pH,, there have been many proposalsll for the development of drugs that would localise in these supposedly acidic tumour cells. Since it is now clear that pH; is more alkaline than pHe, drugs intended to partition preferentially across the cell membrane will actually partition into the acidic extracellular fluid. For some purposes this may not matter. Conjugates that release free drug at acid pH12 would benefit from being localised in the extracellular fluid. Ionising radiation and hyperthermia are more effective in cultured cell lines at low pH, although treatment of human tumours in vivo by these methods suggests that the converse may occur.13 High lactate concentrations are observed concurrently with high pH, and this finding can be attributed to the fact that tumour cells readily extrude protons from the cell but retain the lactate ion. According to Spencer and Lehninger 14 and V eech, 15 this is to be expected, since lactate distributes across the cell membrane as a reciprocal of H distribution, which means that high pH, in comparison to pHe would be expected to be accompanied by high intracellular lactate. Thus, after 60 years of "acidic tumours", we have to be more precise and be aware that tumours have a neutral to alkaline pHi in comparison with their extracellular environment, which is often acidic. It may be possible to exploit this difference to develop new

approaches to cancer therapy.

1. Anon. The Nobel prizeman. Lancet 1931; ii: 1035. 2. Warburg O. The metabolism of tumours. English translation by F. Dickens. London: Constable, 1930. 3. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumours: a review. Cancer Res 1989; 49: 6449-65. 4. Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 1984; 2: 343-66. 5. Griffiths JR. Review: Are cancer cells acidic? Br J Cancer 1991; 64: 425-27.

6. Griffiths JR, Cady E, Edwards RHT, McCready VR, Wilkie DR, Wiltshaw E. 31P-NMR studies of a human tumour in situ. Lancet 1983; i: 1435-36. 7. Prichard JW, Alger JR, Behar KL, Petroff OAC, Shulman RG. Cerebral metabolic studies in vivo by 31P NMR. Proc Natl Acad Sci USA 1983; 80: 2748-51. 8. Stubbs M, Bhujwalla ZM, Tozer GM, et al. An assessment of31P MRS as a method of measuring pH in rat tumours. NMR Biomed (in press). 9. Oberhaensli RD, Hilton-Jones D, Bore PJ, Hands LJ, Rampling RP, Radda GK. Biochemical investigation of human tumours in vivo with

phosphorus-31 magnetic


spectroscopy. Lancet 1986; ii:

8-11. 10.

Ginos JZ, Kearfott KJ, Junck L, Bigner D. In vivo of regional brain tissue pH using positron emission tomography. Ann Neurol 1984; 15 (suppl): 98-102. Tannock IF, Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 1989; 49: 4373-84. Lavie E, Hirschberg DL, Schreiber G, et al. Monoclonal antibody L6-daunomycin conjugates constructed to release free drug at the lower pH of tumor tissue. Cancer Immunol Immunother 1991; 33: 223-30. Van Den Berg AP, Wike-Hooley JL, Broekmeyer-Reurink MA, Van der Zee J, Reinhold HS. The relationship between the unmodified initial tissue pH of human tumours and the response to combined radiotherapy and local hyperthermia treatment. Eur J Cancer Clin Oncol 1989; 25: 73-78. Spencer TL, Lehninger A. L-Lactate transport in Ehrlich ascites tumour cells. Biochem J 1976; 154: 405-14. Veech RL. The metabolism of lactate. NMR Biomed 1991; 4: 53-58.

Rottenberg DA, measurements




14. 15.





epilepsy Advances in magnetic resonance imaging (MRI) techniques have led to considerable improvements in the detection of lesions in patients with epilepsy; MRI also offers new insights into the aetiology of this condition. Scars, tumours, and vascular and atrophic lesions are the most common abnormalities detected on neuroimaging studies. Use of volumetric data acquisition, a technique that generates fine slices of high anatomical resolution, has revealed a high frequency of embryofetal lesions (eg, neuronal migration abnormalities1-5) in extratemporal epilepsies. These abnormalities are common in childhood but were thought to be uncommon in adult cases. Similar techniques have shown a high frequency of hippocampal lesions in temporal lobe epilepsy.‘ Surgical treatment for epilepsy is becoming increasingly popular; in some series researchers have found a relation between resection of lesions displayed by neuroimaging and postoperative seizure control.9,10 In many centres providing surgery for epilepsy, the emphasis of preoperative assessment has shifted from invasive electrophysiology to imaging

techniques. Temporal lobe epilepsy, the most common partial epilepsy in adult practice, is usually a consequence of hippocampal sclerosis; other causes are vascular, dysembryoplastic, and neoplastic lesions. MR abnormalities in hippocampal sclerosis are a high signal on T2 weighted studies," and hippocampal volume loss in volumetric studies. T2 weighted studies show high signal when tissue water content is increased whereas volumetric studies allow fine slices of high anatomical resolution that are suitable for accurate volume estimates. Both techniques have a


high sensitivity and specificity; volumetric studies can delineate the anatomical extent of the volume loss. Studies of T2 weighted images have shown a relation between increased signal and gliosis in the damaged hippocampus,11,12 although gliosis per se does not result in prolonged T2 relaxation.14 The resolution of the volumetric studies will lead to better definition of clinical subtypes, and possibly the identification of high-risk surgical candidates. The finding that hippocampal volume symmetry is not altered by seizures originating at extratemporal sites6 may assist in the characterisation of these groups. Other abnormalities underlying temporal lobe epilepsy are readily identified on MR images, especially when fine contiguous slices are used. Since volumetric techniques give information about both hippocampal and neocortical temporal disease, they are probably the best MR method in temporal lobe epilepsy. In extratemporal epilepsies the lesions are usually harder to detect than the shrunken, gliotic hippocampus of temporal lobe epilepsy. If one excludes tumours and trauma, pathological series have shown a high frequency of embryofetal lesions (including macrogyrias, polymicrogyrias, and cortical dysplasias), gliosis, and atrophy. 5,15 The macrogyrias, polymicrogyrias, and cortical dysplasias are often indistinguishable on MR studies, so the term focal cortical dysplasia is used to describe these patterns.16 Neuronal migration disorders have a characteristic distribution, which may be recognised on MRI2,3,17 Many originate before the fetal brain develops the response of gliosis,17 and the subtle anatomical features of these lesions may be easily overlooked. The advent of volumetric MR methods that permit rapid acquisition of fine, contiguous images with high spatial resolution, combined with reformatting techniques, has led to further insights. With this approach, abnormalities have been detected in 60 % of patients with computed-tomography-negative frontal lobe epilepsy, and the lesions in this study were predominantly developmental in type. Functional imaging, as provided by positron emission tomography (PET) and single photon emission tomography (SPET), gives additional information about neocortical metabolism. 18,19 Nevertheless, anatomical resolution is poor, and localised neocortical abnormalities are seldom seen when a structural lesion has not been identified on AI-RI .20 Functional MR imaging21 may supplant PET and SPET in the study of neocortical metabolism in epilepsy. Magnetic resonance spectroscopy with either P-31 or H-1 nuclei has been useful in lateralising seizures, although results have been

conflicting.2z 1. Shorvon SD, Cook MJ, Manford M, Fish DR, Straughan K, Stevens JM. Volumetric MRI in CT negative frontal lobe epilepsy. Neurology 1992; 42 (suppl 3): 206. 2. Palmini A, Andermann F, Olivier A, Tampieri D, Robitaille Y. Focal neuronal migration disorders and intractable partial epilepsy: results of surgical treatment. Ann Neurol 1991; 30: 750-57.

3. Palmini A, Andermann F, Olivier A, et al. Neuronal migration disorders a contribution of modern neuroimaging to the etiologic diagnosis of epilepsy. Can J Neurol Sci 1991; 18: 580-87. 4. Kuzniecky R, Berkovic S, Andermann F, Melanson D, Olivier A, Robitaille Y. Focal cortical myoclonus and rolandic cortical dysplasia. clarification by magnetic resonance imaging. Ann Neurol 1988; 23: 317-25. 5. Jellinger K. Neuropathological aspects of infantile spasms. Brain Dev 1987; 9: 349-57. 6. Cook MJ, Fish DR, Shorvon SD, Straughan K, Stevens JM. Hippocampal volumetrics in temporal and frontal lobe epilepsies. Brain (in press). 7. Jack CR Jr, Sharbrough FW, Twomey CK, et al. Temporal lobe seizures: lateralisation with MR volume measurements of the hippocampal formation. Radiology 1990; 175: 423-29. 8. Ashtari M, Barr WB, Schaul N, Bogerts B. Three dimensional fast low angle shot imaging and computerised volume measurements of the hippocampus in patients with chronic epilepsy of the temporal lobe. AJNR 1991; 12:941-47. 9. Awad IA, Katz A, Hahn JF, Kong AK, Ahl J, Luders H. Extent of resection in temporal lobectomy for epilepsy. I. Interobserver analysis and correlation with seizure outcome. Epilepsia 1989; 30: 756-62. 10. Nayel MH, Awad IA, Luders H. Extent of mesiobasal resection

determines outcome after temporal lobectomy for intractable complex partial seizures. Neurosurgery 1991; 29: 55-60. 11. Jackson GD, Berkovic SF, Tress BM, Kalnins RM, Fabinyi GC, Bladin PF. Hippocampal sclerosis can be reliably detected by magnetic resonance imaging. Neurology 1990; 40: 1869-75. 12. Bronen RA, Cheung G, Charles JT, et al. Imaging findings in hippocampal sclerosis: correlation with pathology. AJNR 1991; 12: 933-40. 13. Cascino

GD, Jack CR, Parisi JE, et al. Magnetic resonance imagingbased volume studies in temporal lobe epilepsy: pathological correlations. Ann Neurol 1991; 30: 31-36. 14. Barnes D, McDonald WI, Landon DN, Johnson G. The characterisation of experimental gliosis by quantitative nuclear magnetic resonance imaging. Brain 1988; 111: 83-94. 15. Rasmussen T, Characteristics of a pure culture of frontal lobe epilepsy. Epilepsia 1983; 24: 482—93. 16. Barkovich AJ, Kjos BO. Non-lissencephalic cortical dysplasias: correlation of imaging findings with clinical deficits. AJNR 1992; 13: 95-103. 17. Barkovich AJ, Gressens P, Everard P. Formation, maturation, and disorders of brain neocortex. AJNR 1992; 13: 423-46. 18. Editorial. SPECT and PET in epilepsy. Lancet 1989; i: 135-37. 19. Krausz Y, Cohen D, Konstantini S, Meiner Z, Yaffe S, Atlan H. Bram SPECT imaging in temporal lobe epilepsy. Neuroradiology 1991; 33: 274-76. 20. Henry TR, Sutherling WW, Engel J Jr, Risinger MW, Levesque MF. The role of positron emission tomography in presurgical assessment of partial epilepsies of neocortical origin. In: Luders H, ed. Surgery of epilepsy. New York: Raven, 1991: 243-50. 21. Belliveau JW, Kennedy DN, McKinstry RC, et al. Functional mapping of the human visual cortex by magnetic resonance imaging. Science 22.

1991; 254: 716-19. Hugg JW, Matson GB, Duyn JH, Maudsley AA, Laxer KD, Weiner MW. P-31 MR spectroscopic imaging of focal epilepsy. Radiology 1991, 181: 113.

On the falsification of ideas The philosopher Karl Popper is 90, an anniversary rightly noted in the press, scientific! and general.2 Like Marcel Proust, though with rather less justification, Popper is probably more mentioned than read. Logik der Forschung has been around for almost sixty years, and the English translation for over thirty, but few

research-workers will have looked at it. No blame attaches: they inhabit a world of vita brevis and that philosophical treatise is more ars longissima. There are, fortunately, more homely presentations, and

scientists, most notably Peter Medawar, have expressed their admiration in manageable prose. For some

research-workers to have a better grounding, any grounding, in the philosophy of science would not

Magnetic resonance imaging in epilepsy.

343 relative concentrations of the two phosphate species (H2PO4- and HPO42-) present. The MRS measurement of tissue pH is a composite value of pH, an...
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