Magnetic resonance imaging in epilepsy
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343 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 resonance spectroscopy. Lancet 1986; ii: 8-11. 10. Rottenberg DA, Ginos JZ, Kearfott KJ, Junck L, Bigner D. In vivo measurements of regional brain tissue pH using positron emission tomography. Ann Neurol 1984; 15 (suppl): 98-102. 11. Tannock IF, Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 1989; 49: 4373-84. 12. 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. 13. 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. 14. Spencer TL, Lehninger A. L-Lactate transport in Ehrlich ascites tumour cells. Biochem J 1976; 154: 405-14. 15. Veech RL. The metabolism of lactate. NMR Biomed 1991; 4: 53-58. Magnetic resonance imaging in 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
Transcript of Magnetic resonance imaging in epilepsy
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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 believedthat pH measured in this way is intracellular. Thisassumption might not hold for tumours, since theirextracellular volume can be much larger than innormal tissues. The proportion of Pi signal comingfrom the intracellular volume can be calculated if totaltissue water content and the fractional volume ofextracellular water are known. In animal tumours, ifthe extracellular volume does not exceed 50%, pHMRSlargely represents intracellular pH.8Many human tumours, especially brain tumours
and sarcomas (pH 7-01—7 35), have a similar or evenslightly higher pH, than their respective normaltissues.3,9 Positron emission tomography studies
support the findings of high brain tumour pH.lOThese pHMRS values mean that human tumours are
alkaline in comparison to their extracellular fluid-theexact opposite of normal tissues. Because it was widelyassumed that microelectrode measurements of acidic
pHe implied acidic pH,, there have been manyproposalsll for the development of drugs that wouldlocalise in these supposedly acidic tumour cells. Sinceit is now clear that pH; is more alkaline than pHe, drugsintended to partition preferentially across the cellmembrane will actually partition into the acidicextracellular fluid. For some purposes this may notmatter. Conjugates that release free drug at acid pH12would benefit from being localised in the extracellularfluid. Ionising radiation and hyperthermia are moreeffective in cultured cell lines at low pH, althoughtreatment of human tumours in vivo by these methodssuggests that the converse may occur.13
High lactate concentrations are observed
concurrently with high pH, and this finding can beattributed to the fact that tumour cells readily extrudeprotons from the cell but retain the lactate ion.
According to Spencer and Lehninger 14 and V eech, 15this is to be expected, since lactate distributes acrossthe cell membrane as a reciprocal of H distribution,which means that high pH, in comparison to pHewould be expected to be accompanied by highintracellular lactate.
Thus, after 60 years of "acidic tumours", we have tobe more precise and be aware that tumours have aneutral to alkaline pHi in comparison with theirextracellular environment, which is often acidic. It
may be possible to exploit this difference to developnew 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 tumourpH 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. Cerebralmetabolic 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 asa 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 withphosphorus-31 magnetic resonance spectroscopy. Lancet 1986; ii:8-11.
10. Rottenberg DA, Ginos JZ, Kearfott KJ, Junck L, Bigner D. In vivomeasurements of regional brain tissue pH using positron emissiontomography. Ann Neurol 1984; 15 (suppl): 98-102.
11. Tannock IF, Rotin D. Acid pH in tumors and its potential for therapeuticexploitation. Cancer Res 1989; 49: 4373-84.
12. Lavie E, Hirschberg DL, Schreiber G, et al. Monoclonal antibodyL6-daunomycin conjugates constructed to release free drug at thelower pH of tumor tissue. Cancer Immunol Immunother 1991; 33:223-30.
13. Van Den Berg AP, Wike-Hooley JL, Broekmeyer-Reurink MA, Van derZee J, Reinhold HS. The relationship between the unmodified initialtissue pH of human tumours and the response to combined
radiotherapy and local hyperthermia treatment. Eur J Cancer ClinOncol 1989; 25: 73-78.
14. Spencer TL, Lehninger A. L-Lactate transport in Ehrlich ascites tumourcells. Biochem J 1976; 154: 405-14.
15. Veech RL. The metabolism of lactate. NMR Biomed 1991; 4: 53-58.
Magnetic resonance imaging inepilepsy
Advances in magnetic resonance imaging (MRI)techniques have led to considerable improvements inthe detection of lesions in patients with epilepsy; MRIalso offers new insights into the aetiology of thiscondition. Scars, tumours, and vascular and atrophiclesions are the most common abnormalities detectedon neuroimaging studies. Use of volumetric dataacquisition, a technique that generates fine slices ofhigh anatomical resolution, has revealed a highfrequency of embryofetal lesions (eg, neuronal
migration abnormalities1-5) in extratemporalepilepsies. These abnormalities are common inchildhood but were thought to be uncommon in adultcases. Similar techniques have shown a highfrequency of hippocampal lesions in temporal lobeepilepsy.‘ Surgical treatment for epilepsy is
becoming increasingly popular; in some seriesresearchers have found a relation between resection oflesions displayed by neuroimaging and postoperativeseizure control.9,10 In many centres providing surgeryfor epilepsy, the emphasis of preoperative assessmenthas shifted from invasive electrophysiology to imagingtechniques.Temporal lobe epilepsy, the most common partial
epilepsy in adult practice, is usually a consequence ofhippocampal sclerosis; other causes are vascular,dysembryoplastic, and neoplastic lesions. MRabnormalities in hippocampal sclerosis are a highsignal on T2 weighted studies," and hippocampalvolume loss in volumetric studies. T2 weightedstudies show high signal when tissue water content isincreased whereas volumetric studies allow fine slicesof high anatomical resolution that are suitable foraccurate volume estimates. Both techniques have a
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high sensitivity and specificity; volumetric studies candelineate the anatomical extent of the volume loss.Studies of T2 weighted images have shown a relationbetween increased signal and gliosis in the damagedhippocampus,11,12 although gliosis per se does notresult in prolonged T2 relaxation.14 The resolution ofthe volumetric studies will lead to better definition ofclinical subtypes, and possibly the identification ofhigh-risk surgical candidates. The finding that
hippocampal volume symmetry is not altered byseizures originating at extratemporal sites6 may assistin the characterisation of these groups. Otherabnormalities underlying temporal lobe epilepsy arereadily identified on MR images, especially when finecontiguous slices are used. Since volumetric
techniques give information about both hippocampaland neocortical temporal disease, they are probablythe best MR method in temporal lobe epilepsy.
In extratemporal epilepsies the lesions are usuallyharder to detect than the shrunken, gliotichippocampus of temporal lobe epilepsy. If oneexcludes tumours and trauma, pathological serieshave shown a high frequency of embryofetal lesions(including macrogyrias, polymicrogyrias, and corticaldysplasias), gliosis, and atrophy. 5,15 The macrogyrias,polymicrogyrias, and cortical dysplasias are often
indistinguishable on MR studies, so the term focalcortical dysplasia is used to describe these patterns.16Neuronal migration disorders have a characteristicdistribution, which may be recognised on MRI2,3,17Many originate before the fetal brain develops theresponse of gliosis,17 and the subtle anatomicalfeatures of these lesions may be easily overlooked. Theadvent of volumetric MR methods that permit rapidacquisition of fine, contiguous images with highspatial resolution, combined with reformattingtechniques, has led to further insights. With thisapproach, abnormalities have been detected in 60 % ofpatients with computed-tomography-negative frontallobe epilepsy, and the lesions in this study werepredominantly developmental in type.
Functional imaging, as provided by positronemission tomography (PET) and single photonemission tomography (SPET), gives additionalinformation about neocortical metabolism. 18,19
Nevertheless, anatomical resolution is poor, andlocalised neocortical abnormalities are seldom seenwhen a structural lesion has not been identified onAI-RI .20 Functional MR imaging21 may supplant PETand SPET in the study of neocortical metabolism inepilepsy. Magnetic resonance spectroscopy witheither 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, StevensJM. Volumetric MRI in CT negative frontal lobe epilepsy. Neurology1992; 42 (suppl 3): 206.
2. Palmini A, Andermann F, Olivier A, Tampieri D, Robitaille Y. Focalneuronal migration disorders and intractable partial epilepsy: results ofsurgical treatment. Ann Neurol 1991; 30: 750-57.
3. Palmini A, Andermann F, Olivier A, et al. Neuronal migration disordersa contribution of modern neuroimaging to the etiologic diagnosis ofepilepsy. 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 Dev1987; 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 hippocampalformation. Radiology 1990; 175: 423-29.
8. Ashtari M, Barr WB, Schaul N, Bogerts B. Three dimensional fast lowangle shot imaging and computerised volume measurements of thehippocampus 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 ofresection in temporal lobectomy for epilepsy. I. Interobserver analysisand correlation with seizure outcome. Epilepsia 1989; 30: 756-62.
10. Nayel MH, Awad IA, Luders H. Extent of mesiobasal resectiondetermines outcome after temporal lobectomy for intractable complexpartial 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 magneticresonance imaging. Neurology 1990; 40: 1869-75.
12. Bronen RA, Cheung G, Charles JT, et al. Imaging findings inhippocampal sclerosis: correlation with pathology. AJNR 1991; 12:933-40.
13. Cascino GD, Jack CR, Parisi JE, et al. Magnetic resonance imaging-based volume studies in temporal lobe epilepsy: pathologicalcorrelations. Ann Neurol 1991; 30: 31-36.
14. Barnes D, McDonald WI, Landon DN, Johnson G. The characterisationof experimental gliosis by quantitative nuclear magnetic resonanceimaging. 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, anddisorders 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 ofpartial epilepsies of neocortical origin. In: Luders H, ed. Surgery ofepilepsy. New York: Raven, 1991: 243-50.
21. Belliveau JW, Kennedy DN, McKinstry RC, et al. Functional mappingof the human visual cortex by magnetic resonance imaging. Science1991; 254: 716-19.
22. Hugg JW, Matson GB, Duyn JH, Maudsley AA, Laxer KD, WeinerMW. P-31 MR spectroscopic imaging of focal epilepsy. Radiology1991, 181: 113.
On the falsification of ideas
The philosopher Karl Popper is 90, an anniversaryrightly noted in the press, scientific! and general.2 LikeMarcel Proust, though with rather less justification,Popper is probably more mentioned than read. Logikder Forschung has been around for almost sixty years,and the English translation for over thirty, but fewresearch-workers will have looked at it. No blameattaches: they inhabit a world of vita brevis and thatphilosophical treatise is more ars longissima. Thereare, fortunately, more homely presentations, andsome scientists, most notably Peter Medawar, haveexpressed their admiration in manageable prose. Forresearch-workers to have a better grounding, anygrounding, in the philosophy of science would not
