344
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
345
amiss, but how helpful is popperian thought to the research clinic and laboratory of the 1990s? No idea, Popper argues, cannot be improved upon. "Truth" is a mirage, and scientists have to settle for hypothesis, constantly challenging and refining and even discarding-but always choosing some medium less lasting than tablets of stone to set it out. As Alan Ryan notes,2 this process requires two virtues: "a readiness to make bold guesses and the honesty to recognise when they are wrong". Neither virtue is much in evidence these days. The Lancet has been receiving formal hypotheses for about thirty years, yet they are often nothing of the sort, being little more than miniature reviews or anodyne restatements of current thinking. Those who have genuine ideas will often wait nervously until their own experiments confirm that they are not way off beam, or they hold on to the notion for even less worthy reasons. Rare is that quantum leap of imagination bridging two come
of evidence that no-one before has connected-and when such papers arrive they may be greeted by unimaginative referees with those dread phrases "mere speculation" or "interesting idea, but where’s the hard evidence?". So, is the journal about to abandon the hypothesis section? No, but more boldness and conciseness would be welcome: "the more rigid and therefore more at-risk theory to be viewed as preferable to the more flexible (or more flabby)".1 Propagators of hypotheses are never wrong—or they do not admit it, preferring to wriggle on the end of the hook. If well and trully gaffed, they will claim that a wrong idea has nonetheless led to much useful work and discussion, which may even be true sometimes. Most papers do not carry at the end of the introduction a clear-cut hypothesis that is about to be tested, and when they do no-one can be sure that the words were not written when the data were already in-a reflection of the defects of the
pathways
I(ntroduction),M(ethods),R(esults),A(nd),D(iscussion) convention that Medawar was so scathing about. There is a strong case for public deposition of hypotheses, lodged in advance of execution of a study. At a statistical level, falsification is proving elusive. Clinically relevant results are, rightly, now accompanied by confidence intervals. The result of a drug trial-null hypotheses, by the way, do seem totally non-popperian in their functional lack of inspiration-may be conventionally significant in favour of A while not excluding a small benefit in favour of B. Apparently negative studies are far worse. X and her colleagues, using very similar methods, seem not to confirm the findings and/or hypothesis of Y and his group, yet lack of confidence leaves the loophole that Y could just be right after all. Narrowing this uncertainty via meta-analysis or overview takes, as we all now know, years of effort. Even though strict popperian thinking may be more for disciplines that lack the biological and ethical restraints of clinical medicine, room must somehow be left for it in the training of biomedical scientists.
1. Bondi H. The philosopher for science. Nature 1992; 358: 363. 2. Ryan A. Carrying the beacon of reason. Times July 28, 1992: 10. 3. Popper K. Unended quest. London: Fontana/Collins, 1976. 4. Magee B. Popper. London: Fontana/Collins, 1973.
5. Medawar P. Pluto’s republic. Oxford: Oxford University Press, 1982. 6. Medawar PB. Induction and intuition in scientific thought. London: Methuen, 1969.
When
a
patient
says
no
The patient who is adult and competent yet refuses that doctors think necessary, even lifesaving, poses difficulties enough for the health professions. The Jehovah’s Witness is the example that comes most immediately to mind. The dilemma often arises in a setting that is urgent. Much medical, legal, and ethical discussion has appeared in the journals over the past few years and looks likely to continue with the case known as T. We do not know what this 20-year-old woman has said or will have to say to her medical attendants upon recovery after treatment that she had declined before falling unconscious but which her father and her doctors had wanted and the courts have allowed. If her response is gratitude and a recognition that she had been under pressure when she refused, the reaffirmation by the Court of Appeal1 that doctors could go ahead with care deemed in her best interests will seem wise and an excellent precedent. The three judges in the case gave their reasons a few days later, a privilege of leisure not accorded clinicians. More important, they have provided guidelines.2How many doctors now, when a Jehovah’s Witness, for example, says no to a recommended blood transfusion make no effort at persuasion? In the end, however, they do respect such wishes-and have had the verdict against a wellintentioned Canadian doctor to remind them of what might happen if they were to over-rule such a request.3 T is not a Jehovah’s Witness but seems to have been influenced by her mother, who was. The Appeal Court judges were shocked at the disclaimer form T signed. The consequences of refusal should be treatment
expressed be
done
more
"forcibly", they insist;
more must
that refusals that seem to doctors are made in the face of incomprehensible the full facts; and hospital staff from now on will have to check that no undue influence has been brought to bear. If that influence comes from a parent at the bedside, as in T, the court’s directions will be easy to follow. But what of other pressures, less obvious but no less powerful? Young people can come under bizarre influences and take up weird beliefs without being so disturbed that mental health legislation could be brought into play. Although Lord Donaldson and his colleagues may have taken the right view in T, they may have compounded an already very difficult clinical problem. to
ensure
1. Brahams D. Right to refuse treatment. Lancet 1992; 340:297. 2. Tan YH. Decision on treatment did not cover emergency. Independent, July 31, 1992: 22. 3. Brahams D. Unwanted life-sustaining treatment. Lancet 1990; 335: 1210.
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
345
amiss, but how helpful is popperian thought to the research clinic and laboratory of the 1990s? No idea, Popper argues, cannot be improved upon. "Truth" is a mirage, and scientists have to settle for hypothesis, constantly challenging and refining and even discarding-but always choosing some medium less lasting than tablets of stone to set it out. As Alan Ryan notes,2 this process requires two virtues: "a readiness to make bold guesses and the honesty to recognise when they are wrong". Neither virtue is much in evidence these days. The Lancet has been receiving formal hypotheses for about thirty years, yet they are often nothing of the sort, being little more than miniature reviews or anodyne restatements of current thinking. Those who have genuine ideas will often wait nervously until their own experiments confirm that they are not way off beam, or they hold on to the notion for even less worthy reasons. Rare is that quantum leap of imagination bridging two come
of evidence that no-one before has connected-and when such papers arrive they may be greeted by unimaginative referees with those dread phrases "mere speculation" or "interesting idea, but where’s the hard evidence?". So, is the journal about to abandon the hypothesis section? No, but more boldness and conciseness would be welcome: "the more rigid and therefore more at-risk theory to be viewed as preferable to the more flexible (or more flabby)".1 Propagators of hypotheses are never wrong—or they do not admit it, preferring to wriggle on the end of the hook. If well and trully gaffed, they will claim that a wrong idea has nonetheless led to much useful work and discussion, which may even be true sometimes. Most papers do not carry at the end of the introduction a clear-cut hypothesis that is about to be tested, and when they do no-one can be sure that the words were not written when the data were already in-a reflection of the defects of the
pathways
I(ntroduction),M(ethods),R(esults),A(nd),D(iscussion) convention that Medawar was so scathing about. There is a strong case for public deposition of hypotheses, lodged in advance of execution of a study. At a statistical level, falsification is proving elusive. Clinically relevant results are, rightly, now accompanied by confidence intervals. The result of a drug trial-null hypotheses, by the way, do seem totally non-popperian in their functional lack of inspiration-may be conventionally significant in favour of A while not excluding a small benefit in favour of B. Apparently negative studies are far worse. X and her colleagues, using very similar methods, seem not to confirm the findings and/or hypothesis of Y and his group, yet lack of confidence leaves the loophole that Y could just be right after all. Narrowing this uncertainty via meta-analysis or overview takes, as we all now know, years of effort. Even though strict popperian thinking may be more for disciplines that lack the biological and ethical restraints of clinical medicine, room must somehow be left for it in the training of biomedical scientists.
1. Bondi H. The philosopher for science. Nature 1992; 358: 363. 2. Ryan A. Carrying the beacon of reason. Times July 28, 1992: 10. 3. Popper K. Unended quest. London: Fontana/Collins, 1976. 4. Magee B. Popper. London: Fontana/Collins, 1973.
5. Medawar P. Pluto’s republic. Oxford: Oxford University Press, 1982. 6. Medawar PB. Induction and intuition in scientific thought. London: Methuen, 1969.
When
a
patient
says
no
The patient who is adult and competent yet refuses that doctors think necessary, even lifesaving, poses difficulties enough for the health professions. The Jehovah’s Witness is the example that comes most immediately to mind. The dilemma often arises in a setting that is urgent. Much medical, legal, and ethical discussion has appeared in the journals over the past few years and looks likely to continue with the case known as T. We do not know what this 20-year-old woman has said or will have to say to her medical attendants upon recovery after treatment that she had declined before falling unconscious but which her father and her doctors had wanted and the courts have allowed. If her response is gratitude and a recognition that she had been under pressure when she refused, the reaffirmation by the Court of Appeal1 that doctors could go ahead with care deemed in her best interests will seem wise and an excellent precedent. The three judges in the case gave their reasons a few days later, a privilege of leisure not accorded clinicians. More important, they have provided guidelines.2How many doctors now, when a Jehovah’s Witness, for example, says no to a recommended blood transfusion make no effort at persuasion? In the end, however, they do respect such wishes-and have had the verdict against a wellintentioned Canadian doctor to remind them of what might happen if they were to over-rule such a request.3 T is not a Jehovah’s Witness but seems to have been influenced by her mother, who was. The Appeal Court judges were shocked at the disclaimer form T signed. The consequences of refusal should be treatment
expressed be
done
more
"forcibly", they insist;
more must
that refusals that seem to doctors are made in the face of incomprehensible the full facts; and hospital staff from now on will have to check that no undue influence has been brought to bear. If that influence comes from a parent at the bedside, as in T, the court’s directions will be easy to follow. But what of other pressures, less obvious but no less powerful? Young people can come under bizarre influences and take up weird beliefs without being so disturbed that mental health legislation could be brought into play. Although Lord Donaldson and his colleagues may have taken the right view in T, they may have compounded an already very difficult clinical problem. to
ensure
1. Brahams D. Right to refuse treatment. Lancet 1992; 340:297. 2. Tan YH. Decision on treatment did not cover emergency. Independent, July 31, 1992: 22. 3. Brahams D. Unwanted life-sustaining treatment. Lancet 1990; 335: 1210.
