759
subjects and proxy pairs, although there was good overall correlation between patients and proxies for overall health, functional status, and social activity, there were highly significant discrepancies for 60
emotional
state
and satisfaction. to
Quality-of-life scoring systems are limited by the fact that they describe the health of the individual at a single point in time. If a scoring system is reapplied to an individual after a short period, the reliability may be over-rated because of effects of memory. If longer intervals are allowed, the reliability may be underrated because of changes in actual health status.l1 A further limitation is failure adequately to address the effects of a specific disease or its treatment. For example, specific organ damage such as progressive renal impairment may not be identified by a broadbased questionnaire, although such sequelae may be highly relevant to the outcome for the individual. A broad core instrument as described, supplemented by a brief questionnaire focusing on the disease, the treatment, or an organ, may be better. A normal population is not without morbidity, and to assess the true impact of childhood malignancy and its treatment the perceptions of the normal population must be evaluated as a control. A global health assessment, scoring sensory, emotional, and cognitive deficits, does at least address the issue of quality of life and the outcome for the child as a whole. Such assessments would provide the best information if used prospectively, classifying health status before treatment, during treatment, and then serially at follow-up. One challenge will be to find time to apply these instruments in the "late effects" oncology clinics that are already busy and rapidly expanding. There is clearly a need to validate such assessments in large populations, and to determine how they can be used to identify specific problems. Whether recalling patients who are thought to be cured perpetuates illness behaviour, and therefore might be unhelpful to the patient, is another issue. By the year 2000, an estimated one in a thousand American adults aged between 20 and 29 years will have survived a childhood malignancy. 12 This improvement in survival is a result of the introduction of new kinds of combination chemotherapy and radiotherapy, to some extent bone marrow transplantation, and, perhaps most important of all, the expertise provided by centralised paediatric cancer services.13 In the future, treatment protocols will need to be designed not only to give the greatest possible chance of cure but also to do the smallest possible
long-term damage. 1. Vietta
TJ, Shuster JJ, Amylon M,
et al (Pediatric Oncology Group). childhood cancer: the Pediatric Oncology Group experience. Pediatrics 1992; 89: 597-600. 2.Robison LL, Nesbit ME, Sather HN, Meadows AT, Ortega JA, Hammond GD. Height of children successfully treated for acute lymphoblastic leukemia: a report from the Late Effects Study Committee of Children’s Cancer Study Group. Med Pediatr Oncol 1985; 13: 14-21. 3. Shalet SM. Endocrine consequences of treatment of malignant disease. Arch Dis Child 1989; 64: 1635-41.
Progress against
4. Steinherz
toxicity
LJ, Steinherz PG, 4
to
20 years after
Tan CTC, Heller G, Murphy L. Cardiac completing anthracycline therapy. JAMA
1991; 266: 1672-77. 5.
Makipernaa A, Heino M, Laitinen LA, Siimes MA. Lung function following treatment of malignant tumors with surgery, radiotherapy or cyclophosphamide: a follow up study after 11-27 years. Cancer 1989;
63: 625-30. 6. Moore IM, Kramer JH, Wara W, Halberg F, Ablin AR. Cognitive function in children with leukemia. Effect of radiation dose and time since irradiation. Cancer 1991; 68: 1913-17. 7. Feeny D, Furlong W, Barr RD, Torrance GW, Rosenbaum P, Weitzman S. A comprehensive multiattribute system for classifying the health status of survivors of childhood cancer. J Clin Oncol 1992; 10: 923-28. 8. Aaronson NK. Methodologic issues in assessing the quality of life of cancer patients. Cancer 1990; 67: 844-50. 9. Slevin ML, Plant H, Lynch D, Drinkwater J, Gregory WM. Who should measure quality of life, the doctor or the patient? Br J Cancer 1988; 57: 109-12. 10. Epstein AM, Hall JA, Tognetti J, Son LH, Conant L. Using proxies to evaluate quality of life. Med Care 1989; 27 (suppl): S91-98. 11. Nelson EC, Landgraf JM, Hays RD, Wasson JH, Kirk JW. The functional status of patients. How can it be measured in physicians’ offices? Med Care 1990; 28: 1111-26. 12. Meadows AT, Hobbie WL. The medical consequences of cure. Cancer 1986; 58: 524-28. 13. Stiller CA. Centralisation of cancer treatment and survival rates for cancer. Arch Dis Child 1988; 63: 23-30.
Diagnosing juvenile myoclonic epilepsy A
big advance in epileptology has been the recognition of syndromes with distinct aetiology, clinical features, treatment, and prognosis.1 There is no better example of the importance of syndrome classification than juvenile myoclonic epilepsy (JME). JME accounts for between 5-4 and 10-2% of cases of epilepsy, 2-7 but, despite clinical and electroencephalographic features that should enable its easy identification, the rate of misdiagnosis remains high.4-6 Accepted practice for management of "epilepsy" will often be inappropriate in this condition-eg, the withholding of treatment in patients who have had a single generalised tonic-clonic seizure, drug withdrawal after two or three years’ freedom from seizures, and stopping sodium valproate or substituting carbamazepine in women who plan to become pregnant. Accurate diagnosis does more than improve patient management and wellbeing; it also allows proper advice on prognosis, genetic risk, and employment. Failure to diagnose JME represents a serious medical error; how can diagnostic accuracy and management be improved? Patients with JME may experience generalised tonic-clonic seizures, myoclonic jerks, and typical absences. A characteristic case is of a teenager who has a generalised tonic-clonic seizure on rising early in the morning after a late-night party well supplied with alcohol. Neurological examination shows no abnormality but there is a family history of seizures. The patient is neither investigated further nor
treated. The myoclonic jerks of JME generally appear when the patient reaches the mid-teens, preceding generalised tonic-clonic seizures by a few months.2-7 The jerks occur mainly on awakening, are usually but not always bilateral, and are not associated with
760
impairment of consciousness. They may be so severe that the patient drops objects or falls, but often are mild and interpreted as clumsiness or tremor. A series of such jerks may herald a generalised tonic-clonic seizure. About one-third of patients experience typical absences, which may antedate myoclonic jerks by several years. Seizure-precipitating factors include sleep deprivation, alcohol, stress, menstruation, and flashing lights. Over 80% of patients are well controlled by treatment with sodium valproate alone with or in combination clonazepam or phenobarbitone, but relapse is the norm on discontinuation of antiepileptic medication even after many years seizure-free.2--7,9,10 Carbamazepine is not effective, even though recommended for generalised tonic-clonic seizures in the British National
Formulary. 11 Grunewald and co-workers,in London, have identified 22 patients with JME among 180 referrals to an epilepsy clinic. None of these had been
diagnosed previously, even by experienced neurologists. The most common misdiagnosis was "complex partial seizures with secondary generalisation" or the unacceptably vague term "epilepsy". Control of seizures was often poor since patients were treated mainly with carbamazepine; on substitution of appropriate medication they improved strikingly. Avoidable morbidity in this group, in addition to the psychological and social effects of poor seizure control, included the loss of driving licence or employment, injury to self or child, inappropriate withdrawal of medication either during pregnancy or when fits were well controlled, and status epilepticus. To elicit the characteristic history of myoclonic jerks is something of an art. It may be necessary physically to demonstrate mild myoclonic jerks confined to the hands, and to inquire about morning tremulousness or clumsiness ("do you spill your morning tea?"). If the patient reports normal hypnogogic jactitations, then the concept has been understood. Diagnostic yield may be improved by emphasising the close relation of jerks to fatigue and sleep deprivation. Unilaterally predominant jerks and those preceding generalised tonic-clonic seizures must not be interpreted as focal epilepsy. Diagnosis of typical absences and their differentiation from complex partial seizures can be equally difficult. The general conception of typical absences (petit mal) is of childhood phenomena associated with severe impairment of consciousness. In contrast, in patients with JME absences tend to be inconspicuous with little disturbance of consciousness.12 They may be described by patients merely as a momentary lapse in concentration and they are not associated with automatisms. Complex partial seizures tend to last longer and are more often associated with experiential phenomena and automatisms. Electroencephalography can help greatly since in most untreated patients it will show generalised discharges of spikes or multiple spikes and
slow waves enhanced by overbreathing.2,12 One-third of patients also show photosensitivity. These abnormalities are most pronounced with sleepdeprived electroencephalography. 30% of patients, however, show additional focal abnonnalities3,4 that may bolster an erroneous clinical diagnosis of complex partial seizures. Physicians should be ever alert to the
possibility of JME. 1. Gram L. Epileptic seizures and syndromes. Lancet 1990; 336: 7-9. 2. Tsuboi T, Christian W. Epilepsy. A clinical, electroencephalographic and statistical study of 466 patients, Berlin: Springer-Verlag, 1976. 3. Obeid T, Panayiotopoulos CP. Juvenile myoclonic epilepsy: a study in Saudi Arabia. Epilepsia 1989; 29: 280-82. 4. Grünewald RA, Chroni E, Panayiotopoulos CP. Delayed diagnosis of juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 1992; 55: 497-99. 5. Delgado-Escueta AV, Enrile-Bacsal FE. Juvenile myoclonic epilepsy of Janz. Neurology 1984; 34: 285-94. 6. Panayiotopoulos CP, Tahan R, Obeid T. Juvenile myoclonic epilepsy: factors of error involved in the diagnosis and treatment. Epilepsia 1991; 32: 672-76. 7. Janz D. Juvenile myoclonic epilepsy: epilepsy with impulsive petit mal. Cleveland Clin J Med 1989; 56: S23-S33. 8. Hopkins A, Garman A, Clarke C. The first seizure in adult life. Lancet 1988; i: 721-26. 9. Obeid T, Panayiotopoulos CP. Clonazepam in juvenile myoclonic epilepsy. Epilepsia 1987; 30: 603-06. 10. Jeavons PM, Clark JE, Maheshwari MC. The treatment of generalised epilepsies of childhood and adolescence with sodium valproate. Dev Med Child Neurol 1977; 19: 9-25. 11. BMA and Royal Pharmaceutical Society. British National Formulary, 23. London: BMA/RPS, 1992. 12. Panayiotopoulos CP, Obeid T, Waheed G. Absences in juvenile myoclonic epilepsy: a clinical and video-electroencephalographic study. Ann Neurol 1989; 25: 391-97.
Developmental biology: impact on medicine For most doctors, the first and last encounter with the science of developmental biology is when they study human embryology during their undergraduate years. After that, it is usually sufficient to know whether something is or is not an embryological defect and to act accordingly. However, in the past ten years there has been a revolution in our understanding of animal development that cannot fail ultimately to have a profound impact on human medicine. This breakthrough has arisen from a fusion of classic experimental embryology with modern molecular biology and developmental genetics.1 The first animal to have been "solved" is the humble fruit fly, Drosophila, success depending crucially on the relative ease of experimental genetics with this organism. Drosophila has a short life cycle, so it is possible to handle and examine huge numbers of flies and hence to detect rare mutational events. In the late 1970s researchers came to realise that mutations in the genes that controlled early development would probably be lethal, and therefore have been missed in previous genetic work in which only adult flies had been studied. Screens were carried out to identify all the genes that, when mutated, would give rise to dead larvae with some identifiable anatomical abnonnality-for example, missing segments or
subjects and proxy pairs, although there was good overall correlation between patients and proxies for overall health, functional status, and social activity, there were highly significant discrepancies for 60
emotional
state
and satisfaction. to
Quality-of-life scoring systems are limited by the fact that they describe the health of the individual at a single point in time. If a scoring system is reapplied to an individual after a short period, the reliability may be over-rated because of effects of memory. If longer intervals are allowed, the reliability may be underrated because of changes in actual health status.l1 A further limitation is failure adequately to address the effects of a specific disease or its treatment. For example, specific organ damage such as progressive renal impairment may not be identified by a broadbased questionnaire, although such sequelae may be highly relevant to the outcome for the individual. A broad core instrument as described, supplemented by a brief questionnaire focusing on the disease, the treatment, or an organ, may be better. A normal population is not without morbidity, and to assess the true impact of childhood malignancy and its treatment the perceptions of the normal population must be evaluated as a control. A global health assessment, scoring sensory, emotional, and cognitive deficits, does at least address the issue of quality of life and the outcome for the child as a whole. Such assessments would provide the best information if used prospectively, classifying health status before treatment, during treatment, and then serially at follow-up. One challenge will be to find time to apply these instruments in the "late effects" oncology clinics that are already busy and rapidly expanding. There is clearly a need to validate such assessments in large populations, and to determine how they can be used to identify specific problems. Whether recalling patients who are thought to be cured perpetuates illness behaviour, and therefore might be unhelpful to the patient, is another issue. By the year 2000, an estimated one in a thousand American adults aged between 20 and 29 years will have survived a childhood malignancy. 12 This improvement in survival is a result of the introduction of new kinds of combination chemotherapy and radiotherapy, to some extent bone marrow transplantation, and, perhaps most important of all, the expertise provided by centralised paediatric cancer services.13 In the future, treatment protocols will need to be designed not only to give the greatest possible chance of cure but also to do the smallest possible
long-term damage. 1. Vietta
TJ, Shuster JJ, Amylon M,
et al (Pediatric Oncology Group). childhood cancer: the Pediatric Oncology Group experience. Pediatrics 1992; 89: 597-600. 2.Robison LL, Nesbit ME, Sather HN, Meadows AT, Ortega JA, Hammond GD. Height of children successfully treated for acute lymphoblastic leukemia: a report from the Late Effects Study Committee of Children’s Cancer Study Group. Med Pediatr Oncol 1985; 13: 14-21. 3. Shalet SM. Endocrine consequences of treatment of malignant disease. Arch Dis Child 1989; 64: 1635-41.
Progress against
4. Steinherz
toxicity
LJ, Steinherz PG, 4
to
20 years after
Tan CTC, Heller G, Murphy L. Cardiac completing anthracycline therapy. JAMA
1991; 266: 1672-77. 5.
Makipernaa A, Heino M, Laitinen LA, Siimes MA. Lung function following treatment of malignant tumors with surgery, radiotherapy or cyclophosphamide: a follow up study after 11-27 years. Cancer 1989;
63: 625-30. 6. Moore IM, Kramer JH, Wara W, Halberg F, Ablin AR. Cognitive function in children with leukemia. Effect of radiation dose and time since irradiation. Cancer 1991; 68: 1913-17. 7. Feeny D, Furlong W, Barr RD, Torrance GW, Rosenbaum P, Weitzman S. A comprehensive multiattribute system for classifying the health status of survivors of childhood cancer. J Clin Oncol 1992; 10: 923-28. 8. Aaronson NK. Methodologic issues in assessing the quality of life of cancer patients. Cancer 1990; 67: 844-50. 9. Slevin ML, Plant H, Lynch D, Drinkwater J, Gregory WM. Who should measure quality of life, the doctor or the patient? Br J Cancer 1988; 57: 109-12. 10. Epstein AM, Hall JA, Tognetti J, Son LH, Conant L. Using proxies to evaluate quality of life. Med Care 1989; 27 (suppl): S91-98. 11. Nelson EC, Landgraf JM, Hays RD, Wasson JH, Kirk JW. The functional status of patients. How can it be measured in physicians’ offices? Med Care 1990; 28: 1111-26. 12. Meadows AT, Hobbie WL. The medical consequences of cure. Cancer 1986; 58: 524-28. 13. Stiller CA. Centralisation of cancer treatment and survival rates for cancer. Arch Dis Child 1988; 63: 23-30.
Diagnosing juvenile myoclonic epilepsy A
big advance in epileptology has been the recognition of syndromes with distinct aetiology, clinical features, treatment, and prognosis.1 There is no better example of the importance of syndrome classification than juvenile myoclonic epilepsy (JME). JME accounts for between 5-4 and 10-2% of cases of epilepsy, 2-7 but, despite clinical and electroencephalographic features that should enable its easy identification, the rate of misdiagnosis remains high.4-6 Accepted practice for management of "epilepsy" will often be inappropriate in this condition-eg, the withholding of treatment in patients who have had a single generalised tonic-clonic seizure, drug withdrawal after two or three years’ freedom from seizures, and stopping sodium valproate or substituting carbamazepine in women who plan to become pregnant. Accurate diagnosis does more than improve patient management and wellbeing; it also allows proper advice on prognosis, genetic risk, and employment. Failure to diagnose JME represents a serious medical error; how can diagnostic accuracy and management be improved? Patients with JME may experience generalised tonic-clonic seizures, myoclonic jerks, and typical absences. A characteristic case is of a teenager who has a generalised tonic-clonic seizure on rising early in the morning after a late-night party well supplied with alcohol. Neurological examination shows no abnormality but there is a family history of seizures. The patient is neither investigated further nor
treated. The myoclonic jerks of JME generally appear when the patient reaches the mid-teens, preceding generalised tonic-clonic seizures by a few months.2-7 The jerks occur mainly on awakening, are usually but not always bilateral, and are not associated with
760
impairment of consciousness. They may be so severe that the patient drops objects or falls, but often are mild and interpreted as clumsiness or tremor. A series of such jerks may herald a generalised tonic-clonic seizure. About one-third of patients experience typical absences, which may antedate myoclonic jerks by several years. Seizure-precipitating factors include sleep deprivation, alcohol, stress, menstruation, and flashing lights. Over 80% of patients are well controlled by treatment with sodium valproate alone with or in combination clonazepam or phenobarbitone, but relapse is the norm on discontinuation of antiepileptic medication even after many years seizure-free.2--7,9,10 Carbamazepine is not effective, even though recommended for generalised tonic-clonic seizures in the British National
Formulary. 11 Grunewald and co-workers,in London, have identified 22 patients with JME among 180 referrals to an epilepsy clinic. None of these had been
diagnosed previously, even by experienced neurologists. The most common misdiagnosis was "complex partial seizures with secondary generalisation" or the unacceptably vague term "epilepsy". Control of seizures was often poor since patients were treated mainly with carbamazepine; on substitution of appropriate medication they improved strikingly. Avoidable morbidity in this group, in addition to the psychological and social effects of poor seizure control, included the loss of driving licence or employment, injury to self or child, inappropriate withdrawal of medication either during pregnancy or when fits were well controlled, and status epilepticus. To elicit the characteristic history of myoclonic jerks is something of an art. It may be necessary physically to demonstrate mild myoclonic jerks confined to the hands, and to inquire about morning tremulousness or clumsiness ("do you spill your morning tea?"). If the patient reports normal hypnogogic jactitations, then the concept has been understood. Diagnostic yield may be improved by emphasising the close relation of jerks to fatigue and sleep deprivation. Unilaterally predominant jerks and those preceding generalised tonic-clonic seizures must not be interpreted as focal epilepsy. Diagnosis of typical absences and their differentiation from complex partial seizures can be equally difficult. The general conception of typical absences (petit mal) is of childhood phenomena associated with severe impairment of consciousness. In contrast, in patients with JME absences tend to be inconspicuous with little disturbance of consciousness.12 They may be described by patients merely as a momentary lapse in concentration and they are not associated with automatisms. Complex partial seizures tend to last longer and are more often associated with experiential phenomena and automatisms. Electroencephalography can help greatly since in most untreated patients it will show generalised discharges of spikes or multiple spikes and
slow waves enhanced by overbreathing.2,12 One-third of patients also show photosensitivity. These abnormalities are most pronounced with sleepdeprived electroencephalography. 30% of patients, however, show additional focal abnonnalities3,4 that may bolster an erroneous clinical diagnosis of complex partial seizures. Physicians should be ever alert to the
possibility of JME. 1. Gram L. Epileptic seizures and syndromes. Lancet 1990; 336: 7-9. 2. Tsuboi T, Christian W. Epilepsy. A clinical, electroencephalographic and statistical study of 466 patients, Berlin: Springer-Verlag, 1976. 3. Obeid T, Panayiotopoulos CP. Juvenile myoclonic epilepsy: a study in Saudi Arabia. Epilepsia 1989; 29: 280-82. 4. Grünewald RA, Chroni E, Panayiotopoulos CP. Delayed diagnosis of juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 1992; 55: 497-99. 5. Delgado-Escueta AV, Enrile-Bacsal FE. Juvenile myoclonic epilepsy of Janz. Neurology 1984; 34: 285-94. 6. Panayiotopoulos CP, Tahan R, Obeid T. Juvenile myoclonic epilepsy: factors of error involved in the diagnosis and treatment. Epilepsia 1991; 32: 672-76. 7. Janz D. Juvenile myoclonic epilepsy: epilepsy with impulsive petit mal. Cleveland Clin J Med 1989; 56: S23-S33. 8. Hopkins A, Garman A, Clarke C. The first seizure in adult life. Lancet 1988; i: 721-26. 9. Obeid T, Panayiotopoulos CP. Clonazepam in juvenile myoclonic epilepsy. Epilepsia 1987; 30: 603-06. 10. Jeavons PM, Clark JE, Maheshwari MC. The treatment of generalised epilepsies of childhood and adolescence with sodium valproate. Dev Med Child Neurol 1977; 19: 9-25. 11. BMA and Royal Pharmaceutical Society. British National Formulary, 23. London: BMA/RPS, 1992. 12. Panayiotopoulos CP, Obeid T, Waheed G. Absences in juvenile myoclonic epilepsy: a clinical and video-electroencephalographic study. Ann Neurol 1989; 25: 391-97.
Developmental biology: impact on medicine For most doctors, the first and last encounter with the science of developmental biology is when they study human embryology during their undergraduate years. After that, it is usually sufficient to know whether something is or is not an embryological defect and to act accordingly. However, in the past ten years there has been a revolution in our understanding of animal development that cannot fail ultimately to have a profound impact on human medicine. This breakthrough has arisen from a fusion of classic experimental embryology with modern molecular biology and developmental genetics.1 The first animal to have been "solved" is the humble fruit fly, Drosophila, success depending crucially on the relative ease of experimental genetics with this organism. Drosophila has a short life cycle, so it is possible to handle and examine huge numbers of flies and hence to detect rare mutational events. In the late 1970s researchers came to realise that mutations in the genes that controlled early development would probably be lethal, and therefore have been missed in previous genetic work in which only adult flies had been studied. Screens were carried out to identify all the genes that, when mutated, would give rise to dead larvae with some identifiable anatomical abnonnality-for example, missing segments or
