- Email: [email protected]
DIAZEPAM IN SPASTICITY
1161
found in 912 well women examined by mammography. This finding, howclinically not invalidate the other results, because, does ever, even in the successful series, the yield of cases is small-2-8 per 1000 per year. The wide use of these screening techniques would certainly reveal a number of unsuspected breast cancers. But they are expensive in time and equipment, and the need for repeated screening makes their extensive application economically unattractive. Moreover, the persistent question is whether or not early diagnosis by screening means better results of treatment. An answer is being sought in various ways.2 In a New York trial,8 a large population has been randomly divided into two groups: one attend screening clinics where they are regularly examined, both clinically and by mammography, and treated if necessary; the second group are not subjected to screening and come for treatment when an abnormality is found in the breast. This trial is still in its early stages, but it should eventually be possible to tell whether or not the patients who have breast cancer in the screened group have a better prognosis. Real progress may depend on the application of more sensitive methods of breast examination or on establishing some hormonal, immunological, or clinical basis for detecting high-risk patients. no tumours were
and
EFFECT OF FETAL NEUROBLASTOMAS ON THE MOTHER
NEUROBLASTOMAS, perhaps the most common of the solid childhood cancers, have long attracted attention because of their often bizarre signs. Metastatic deposits are often the first sign of these cancers. Beckwith and Perrin1 have shown that small deposits of neuroblastomatous tissue can often be found in children up to the age of three months, but not thereafter. It is well known that neuroblastomas undergo " spontaneous regression " more commonly than any other human cancereither by disappearance of the neoplastic cells or by maturation into benign ganglioneuromas. These changes are seemingly influenced by the age of the patient,2 the sex, and perhaps by the site of the primary tumour. There is a peak of mortality about the fourth year of life, but neuroblastomas can develop in intrauterine life; and there is no association with hemihypertrophy or any other congenital malformation or defect.4 The tumours are not apparently influenced by the nerve growth factors discovered by Levi-Montalcini.5,6s The recognition of the secretion of catecholamines by neuroblastomas, ganglioneuromas, and phxochromocytomas, and the estimation of these substances and their metabolites in the urine, has provided not only another diagnostic test but also a means of monitoring the progress of the disease in affected children. Some differences seem to exist between the three types of Beckwith, J. B., Perrin, E. V. Am. J. Path. 1963, 43, 1089. Bill, A. H. J. pediat. Surg. 1968, 3, 103. 3. Marsden, H. B., Steward, J. K. Tumors in Childhood; chap. 6. Berlin, 1968. 4. Miller, R. W., Fraumeni, J. F., Hill, J. A. Am. J. Dis. Child. 1968, 115, 253. 5. Levi-Montalcini, R. Harvey Lect. 1966, 60, 217. 6. Bill, A. H. J. pediat. Surg. 1968, 3, 727. 1. 2.
catecholamine-secreting tumours3 in that, while phaeochromocytomas have a storage mechanism and thus may or may not release these active compounds, neuroblastomas and ganglioneuromas have no storage capacity. As neuroblastomas can develop in utero, it might be supposed that, if much neuroblastomatous tissue was present in the fetus, catecholamines might be released which could pass into the maternal circulation and affect the mother. If they were identifiable, the possibility would exist of very early recognition of neuroblastoma in the newborn child. A recent report7 from Holland suggests that there are signs and symptoms in mothers in whose fetuses neuroblastomas are developing. In 6 such patients sweating, pallor, headaches, palpitations, and sometimes hypertension appeared in the last weeks of pregnancy, and all had tingling in the fingers and some in the toes. This information was volunteered by the mothers rather than extracted by questioning. How often this happens and the full extent of the syndrome in the mothers has yet to be established.
DIAZEPAM IN SPASTICITY
IN the past twenty years the search has ranged a drug which will reduce muscle tone in spastic limbs without producing unacceptable sideeffects. Such a drug would be useful in ambulant patients with multiple sclerosis and other spinal-cord disorders which result in a degree of spasticity sufficient to impair mobility, and more particularly in severely disabled or bedridden patients with similar disorders who are often disturbed by painful flexor spasms or who, if left untreated, often .have permanent flexion contractures which make nursing and management difficult. A great many drugs, including mephenesin and its derivatives, tigloidine, zoxazolamine, chlorpromazine, and chlordiazepoxide, have been recommended in the past and each has been widely used. In severe cases intrathecal injection of phenol has been valuable, but this technique carries some risk of impairing sphincter control. The effect of various neurectomies combined with tenotomy9 has sometimes proved only temporary. Randall et al.10 recommended chlordiazepoxide as a muscle relaxant, but they, in common with others, noted that in the ambulant patient this drug sometimes relieved extensor spasticity to such an extent that the patient had increased difficulty in walking because the knees gave way. More recently several workers 11,12 have found that diazepam seems to be the best remedy for the relief of spasticity in patients with various types of uppermotor-neurone lesion. Kendall,13 giving this drug in a double-blind trial, found some improvement in 10 cases of hemiplegia. Cook and Nathan14 concluded
widely for
7. Voute, P. A.,
Wadman, S. K.,
van
Putten,
W.
J. Clin. Pediat. 1970,
9, 206. 8. Nathan, P. Lancet, 1959, ii, 1099. 9. Platt, G., Russell, W. R., Willison, R. G. ibid. 1958, i, 757. 10. Randall, L. O., Heise, G. A., Schallek, W., Bagdon, R. E., Banziger, R., Boris, A., Moe, R. A., Abrams, W. B. Curr. ther. Res. 1961,
3, 405. Leavitt, L. A., Ocampo, R., Vallbona, C., Spencer, W. A., Iddings, D. West. Med. 1963, 4, 16. 12. Fowlks, E. W., Strickland, D. A., Peirson, G. A. Am. J. phys. Med. 1965, 44, 9. 13. Kendall, P. H. Ann. phys. Med. 1964, 7, 225. 14. Cook, J. B., Nathan, P.W. J. neurol. Sci. 1967, 5, 33. 11.
1162
that some of the effects of diazepam were due to an action of the drug on the spinal cord independent of its other actions at supraspinal levels of the neuraxis. Wilson and McKechnie 15 reported a double-blind crossover trial of oral diazepam in 21 cases of spastic paraplegia. Daily doses of between 8 mg. and 16 mg. were significantly superior to placebo tablets in lessening spasticity in the lower limbs, in relieving painful spasms, and in making the patients easier to nurse. Wilson 16 has now examined the effect of parenteral diazepam in 29 patients with spastic weakness of the limbs. An intramuscular dose of 15 mg. usually gave good relaxation with few side-effects, but larger doses were needed if the patient was already taking the drug by mouth. He recommends an intramuscular test dose of 5 mg. before going on to larger doses. Given intramuscularly, this drug usually gives prompt relief of painful flexor spasms in paraplegic patients, so it can be used to determine whether limb deformities are due to increased flexor tone or to fibrous contractures. It is also helpful in facilitating physiotherapy and as a preliminary to the application of callipers or splints. While some patients have difficulty in tolerating large doses because of drowsiness, it seems clear that diazepam is the most effective remedy at present available for spasticity; and it may be even more effective intramuscularly than by mouth.
ponsible. Several patients who have survived a hyperpyrexial reaction have later had no untoward effect from local or spinal anaesthesia. Hyperkalaemia and myoglobinuria have been observed in patients who have survived the hyperpyrexia for long enough. On p. 1137 this week Dr. Denborough and his colleagues describe a further fatal in which the serum-creatine-phosphokinase, case potassium, and phosphate all rose to very high levels in the twenty-four hours in which the patient survived in a moribund state. These suggestions of muscle damage, taken with the stiffness and muscle spasms, point to the skeletal muscle as the seat of this condition, though up to this point secondary skeletal muscle damage cannot be excluded. ’More direct evidence of an underlying abnormality of skeletal muscle has come from Johannesburg.1 In a very large family of mixed Caucasian and African extraction, 3 patients had died of malignant hyper" pyrexia during anaesthesia. " A surprising number of the relatives had a high level of serum-creatinephosphokinase. In more than 100 members extending over three generations the abnormality of serumcreatine-phosphokinase seemed to be inherited as a mendelian dominant trait with variable penetrance. Clinical and electromyographic investigation of the family was entirely normal. In a second family an asymptomatic sister had a high serum level of the enzyme.
MALIGNANT HYPERPYREXIA AND MYOPATHY HYPERPYREXIA is fortunately a rare complication of general anaesthesia. It may arise during, or up to twenty-four hours after, the anaesthetic, and it is
heralded by an increased tightening of the jaws. Abnormal stiffness follows in the respiratory muscles, felt as increasing difficulty during positive-pressure respiration; and spasms and occasionally spontaneous flexion of the limbs may develop. Increasing impairment of respiratory function leads to cyanosis, tachycardia, and a falling blood-pressure. At this time the central body temperature may be as high as 112°F (44-4°C), and convulsions are frequent. The early recognition of hyperpyrexia and its treatment with immediate cooling and correction of acidosis and hypovolaemia has saved some of these patients, but the very high mortality-rate has justified the title " malignant". A number of families have been reported in whom several members have had malignant hyperpyrexia; and the inheritance has been compatible with that of an autosomal dominant gene. Unexpected (nonanaesthetic) sudden deaths have been unusually common in these families. Originally the surgical drapes, the hot humid operating-theatre, and the inhibition of
sweating by atropine premedication were thought to have conspired to produce the hyperpyrexia. But the rarity of the condition and the later reports of familial cases made it clear that an idiosyncratic response was killing these patients. Malignant hyperpyrexia has followed all forms of general anaesthesia, ranging from open-drop " ether, through oxygen and nitrous oxide alone, to the more complex modern anxsthetic regimens. No one general anxsthetic agent is res"
15. 16.
Wilson, L. A., McKechnie, A. A. Scott. med. J. 1966, 11, 46. Wilson, L. A. Geront. clin. 1970, 12, 168.
Prompted by this report, Dr. Denborough and his colleagues now report (p. 1138) a similar inquiry in their previously investigated family.2 3 out of 15 relatives tested had high levels of serum-creatinephosphokinase. 2 of these 3 had a mild but definite myopathy affecting predominantly the muscles of the lower limb girdle. Our contributors suggest that all patients who are to undergo general anaesthesia should be asked about any family history of anaesthetic deaths, and that they should also have estimations of serumcreatine-phosphokinase (though that is probably a counsel of perfection). These findings strongly suggest a link between a myopathy and malignant hyperpyrexia, and the results of further investigation of the myopathy are awaited with interest. Further support for the link comes from Steers et al.,3 who describe a fatal case of pyrexia in which 2 of the patient’s relatives had a hypertrophic myopathy similar to that described by Bames4 in 1932. At least two explanations for the association may be suggested. The myopathy may be due to and underlying defect of the sarcolemmal membrane, predisposing to the production of repeated action potentials upon exposure to general anaesthetics and thereby to excessive muscle activity and heat production. Alternatively, the myopathy may be a secondary manifestation of a primary generalised metabolic disturbance, much as thyrotoxicosis and hypercorticism can produce a myopathy while causing many more generalised bodily disturbances. 1. Isaacs, H., Barlow, M. B. Br. med. J. 1970, i, 275. 2. Denborough, M. A., Forster, J. F. A., Lovell, R. R. H., Maplestone, P. A., Villiers, J. D. Br. J. Anœsth. 1962, 34, 395. 3. Steers, A. J. W., Tallack, J. A., Thompson, D. E. A. Br. med. J. 4.
May 9, 1970, p. 341. Barnes, S. Brain, 1932, 55,
1.
found in 912 well women examined by mammography. This finding, howclinically not invalidate the other results, because, does ever, even in the successful series, the yield of cases is small-2-8 per 1000 per year. The wide use of these screening techniques would certainly reveal a number of unsuspected breast cancers. But they are expensive in time and equipment, and the need for repeated screening makes their extensive application economically unattractive. Moreover, the persistent question is whether or not early diagnosis by screening means better results of treatment. An answer is being sought in various ways.2 In a New York trial,8 a large population has been randomly divided into two groups: one attend screening clinics where they are regularly examined, both clinically and by mammography, and treated if necessary; the second group are not subjected to screening and come for treatment when an abnormality is found in the breast. This trial is still in its early stages, but it should eventually be possible to tell whether or not the patients who have breast cancer in the screened group have a better prognosis. Real progress may depend on the application of more sensitive methods of breast examination or on establishing some hormonal, immunological, or clinical basis for detecting high-risk patients. no tumours were
and
EFFECT OF FETAL NEUROBLASTOMAS ON THE MOTHER
NEUROBLASTOMAS, perhaps the most common of the solid childhood cancers, have long attracted attention because of their often bizarre signs. Metastatic deposits are often the first sign of these cancers. Beckwith and Perrin1 have shown that small deposits of neuroblastomatous tissue can often be found in children up to the age of three months, but not thereafter. It is well known that neuroblastomas undergo " spontaneous regression " more commonly than any other human cancereither by disappearance of the neoplastic cells or by maturation into benign ganglioneuromas. These changes are seemingly influenced by the age of the patient,2 the sex, and perhaps by the site of the primary tumour. There is a peak of mortality about the fourth year of life, but neuroblastomas can develop in intrauterine life; and there is no association with hemihypertrophy or any other congenital malformation or defect.4 The tumours are not apparently influenced by the nerve growth factors discovered by Levi-Montalcini.5,6s The recognition of the secretion of catecholamines by neuroblastomas, ganglioneuromas, and phxochromocytomas, and the estimation of these substances and their metabolites in the urine, has provided not only another diagnostic test but also a means of monitoring the progress of the disease in affected children. Some differences seem to exist between the three types of Beckwith, J. B., Perrin, E. V. Am. J. Path. 1963, 43, 1089. Bill, A. H. J. pediat. Surg. 1968, 3, 103. 3. Marsden, H. B., Steward, J. K. Tumors in Childhood; chap. 6. Berlin, 1968. 4. Miller, R. W., Fraumeni, J. F., Hill, J. A. Am. J. Dis. Child. 1968, 115, 253. 5. Levi-Montalcini, R. Harvey Lect. 1966, 60, 217. 6. Bill, A. H. J. pediat. Surg. 1968, 3, 727. 1. 2.
catecholamine-secreting tumours3 in that, while phaeochromocytomas have a storage mechanism and thus may or may not release these active compounds, neuroblastomas and ganglioneuromas have no storage capacity. As neuroblastomas can develop in utero, it might be supposed that, if much neuroblastomatous tissue was present in the fetus, catecholamines might be released which could pass into the maternal circulation and affect the mother. If they were identifiable, the possibility would exist of very early recognition of neuroblastoma in the newborn child. A recent report7 from Holland suggests that there are signs and symptoms in mothers in whose fetuses neuroblastomas are developing. In 6 such patients sweating, pallor, headaches, palpitations, and sometimes hypertension appeared in the last weeks of pregnancy, and all had tingling in the fingers and some in the toes. This information was volunteered by the mothers rather than extracted by questioning. How often this happens and the full extent of the syndrome in the mothers has yet to be established.
DIAZEPAM IN SPASTICITY
IN the past twenty years the search has ranged a drug which will reduce muscle tone in spastic limbs without producing unacceptable sideeffects. Such a drug would be useful in ambulant patients with multiple sclerosis and other spinal-cord disorders which result in a degree of spasticity sufficient to impair mobility, and more particularly in severely disabled or bedridden patients with similar disorders who are often disturbed by painful flexor spasms or who, if left untreated, often .have permanent flexion contractures which make nursing and management difficult. A great many drugs, including mephenesin and its derivatives, tigloidine, zoxazolamine, chlorpromazine, and chlordiazepoxide, have been recommended in the past and each has been widely used. In severe cases intrathecal injection of phenol has been valuable, but this technique carries some risk of impairing sphincter control. The effect of various neurectomies combined with tenotomy9 has sometimes proved only temporary. Randall et al.10 recommended chlordiazepoxide as a muscle relaxant, but they, in common with others, noted that in the ambulant patient this drug sometimes relieved extensor spasticity to such an extent that the patient had increased difficulty in walking because the knees gave way. More recently several workers 11,12 have found that diazepam seems to be the best remedy for the relief of spasticity in patients with various types of uppermotor-neurone lesion. Kendall,13 giving this drug in a double-blind trial, found some improvement in 10 cases of hemiplegia. Cook and Nathan14 concluded
widely for
7. Voute, P. A.,
Wadman, S. K.,
van
Putten,
W.
J. Clin. Pediat. 1970,
9, 206. 8. Nathan, P. Lancet, 1959, ii, 1099. 9. Platt, G., Russell, W. R., Willison, R. G. ibid. 1958, i, 757. 10. Randall, L. O., Heise, G. A., Schallek, W., Bagdon, R. E., Banziger, R., Boris, A., Moe, R. A., Abrams, W. B. Curr. ther. Res. 1961,
3, 405. Leavitt, L. A., Ocampo, R., Vallbona, C., Spencer, W. A., Iddings, D. West. Med. 1963, 4, 16. 12. Fowlks, E. W., Strickland, D. A., Peirson, G. A. Am. J. phys. Med. 1965, 44, 9. 13. Kendall, P. H. Ann. phys. Med. 1964, 7, 225. 14. Cook, J. B., Nathan, P.W. J. neurol. Sci. 1967, 5, 33. 11.
1162
that some of the effects of diazepam were due to an action of the drug on the spinal cord independent of its other actions at supraspinal levels of the neuraxis. Wilson and McKechnie 15 reported a double-blind crossover trial of oral diazepam in 21 cases of spastic paraplegia. Daily doses of between 8 mg. and 16 mg. were significantly superior to placebo tablets in lessening spasticity in the lower limbs, in relieving painful spasms, and in making the patients easier to nurse. Wilson 16 has now examined the effect of parenteral diazepam in 29 patients with spastic weakness of the limbs. An intramuscular dose of 15 mg. usually gave good relaxation with few side-effects, but larger doses were needed if the patient was already taking the drug by mouth. He recommends an intramuscular test dose of 5 mg. before going on to larger doses. Given intramuscularly, this drug usually gives prompt relief of painful flexor spasms in paraplegic patients, so it can be used to determine whether limb deformities are due to increased flexor tone or to fibrous contractures. It is also helpful in facilitating physiotherapy and as a preliminary to the application of callipers or splints. While some patients have difficulty in tolerating large doses because of drowsiness, it seems clear that diazepam is the most effective remedy at present available for spasticity; and it may be even more effective intramuscularly than by mouth.
ponsible. Several patients who have survived a hyperpyrexial reaction have later had no untoward effect from local or spinal anaesthesia. Hyperkalaemia and myoglobinuria have been observed in patients who have survived the hyperpyrexia for long enough. On p. 1137 this week Dr. Denborough and his colleagues describe a further fatal in which the serum-creatine-phosphokinase, case potassium, and phosphate all rose to very high levels in the twenty-four hours in which the patient survived in a moribund state. These suggestions of muscle damage, taken with the stiffness and muscle spasms, point to the skeletal muscle as the seat of this condition, though up to this point secondary skeletal muscle damage cannot be excluded. ’More direct evidence of an underlying abnormality of skeletal muscle has come from Johannesburg.1 In a very large family of mixed Caucasian and African extraction, 3 patients had died of malignant hyper" pyrexia during anaesthesia. " A surprising number of the relatives had a high level of serum-creatinephosphokinase. In more than 100 members extending over three generations the abnormality of serumcreatine-phosphokinase seemed to be inherited as a mendelian dominant trait with variable penetrance. Clinical and electromyographic investigation of the family was entirely normal. In a second family an asymptomatic sister had a high serum level of the enzyme.
MALIGNANT HYPERPYREXIA AND MYOPATHY HYPERPYREXIA is fortunately a rare complication of general anaesthesia. It may arise during, or up to twenty-four hours after, the anaesthetic, and it is
heralded by an increased tightening of the jaws. Abnormal stiffness follows in the respiratory muscles, felt as increasing difficulty during positive-pressure respiration; and spasms and occasionally spontaneous flexion of the limbs may develop. Increasing impairment of respiratory function leads to cyanosis, tachycardia, and a falling blood-pressure. At this time the central body temperature may be as high as 112°F (44-4°C), and convulsions are frequent. The early recognition of hyperpyrexia and its treatment with immediate cooling and correction of acidosis and hypovolaemia has saved some of these patients, but the very high mortality-rate has justified the title " malignant". A number of families have been reported in whom several members have had malignant hyperpyrexia; and the inheritance has been compatible with that of an autosomal dominant gene. Unexpected (nonanaesthetic) sudden deaths have been unusually common in these families. Originally the surgical drapes, the hot humid operating-theatre, and the inhibition of
sweating by atropine premedication were thought to have conspired to produce the hyperpyrexia. But the rarity of the condition and the later reports of familial cases made it clear that an idiosyncratic response was killing these patients. Malignant hyperpyrexia has followed all forms of general anaesthesia, ranging from open-drop " ether, through oxygen and nitrous oxide alone, to the more complex modern anxsthetic regimens. No one general anxsthetic agent is res"
15. 16.
Wilson, L. A., McKechnie, A. A. Scott. med. J. 1966, 11, 46. Wilson, L. A. Geront. clin. 1970, 12, 168.
Prompted by this report, Dr. Denborough and his colleagues now report (p. 1138) a similar inquiry in their previously investigated family.2 3 out of 15 relatives tested had high levels of serum-creatinephosphokinase. 2 of these 3 had a mild but definite myopathy affecting predominantly the muscles of the lower limb girdle. Our contributors suggest that all patients who are to undergo general anaesthesia should be asked about any family history of anaesthetic deaths, and that they should also have estimations of serumcreatine-phosphokinase (though that is probably a counsel of perfection). These findings strongly suggest a link between a myopathy and malignant hyperpyrexia, and the results of further investigation of the myopathy are awaited with interest. Further support for the link comes from Steers et al.,3 who describe a fatal case of pyrexia in which 2 of the patient’s relatives had a hypertrophic myopathy similar to that described by Bames4 in 1932. At least two explanations for the association may be suggested. The myopathy may be due to and underlying defect of the sarcolemmal membrane, predisposing to the production of repeated action potentials upon exposure to general anaesthetics and thereby to excessive muscle activity and heat production. Alternatively, the myopathy may be a secondary manifestation of a primary generalised metabolic disturbance, much as thyrotoxicosis and hypercorticism can produce a myopathy while causing many more generalised bodily disturbances. 1. Isaacs, H., Barlow, M. B. Br. med. J. 1970, i, 275. 2. Denborough, M. A., Forster, J. F. A., Lovell, R. R. H., Maplestone, P. A., Villiers, J. D. Br. J. Anœsth. 1962, 34, 395. 3. Steers, A. J. W., Tallack, J. A., Thompson, D. E. A. Br. med. J. 4.
May 9, 1970, p. 341. Barnes, S. Brain, 1932, 55,
1.