- Email: [email protected]
Benzodiazepine sensitivity in Leber's hereditary optic neuroretinopathy
1223
1. Cornelis G, Laroche Y, Balligand G, Sory M-P, Wauters G Yersinia enterocolitica, a primary model for bacterial invasiveness. Rev Infect Dis 1987; 9: 64-87. 2. Jones BL, Saw MH, Hanson MF, Mackie MJ, Scott JG, Murphy WG. Yersinia enterocolitica septicaemia from blood transfusion. Transfusion Med 1992; 2 (suppl
1)· 86. I, Norlander L, Wolf-Watz H. Temperature-inducible outer-membrane protein of Yersinia pseudotuberculosis and Yersima enterocolitica is associated with the virulence plasmid. Infect Immun 1982; 37: 506-12. 4. CDC. Update: Yersinia enterocolitica bacteraemia and endotoxic shock associated with red blood cell transfusions: United States, 1991. MMWR 1991; 40: 176-78. 5. Scott J, Boulton FE, Govan JRW, Miles RS, McClelland DBL, Prowse CV. A fatal 3. Bolin
transfusion reaction associated with blood contaminated with Pseudomonas Vox Sang 1988; 54: 201-04.
fluorescens.
Lamotrigine for generalised epilepsies SIR,-4Controlled trials of new antiepileptic drugs are done initially in adults with chronic drug-resistant epilepsy. Such patients usually have partial seizures with or without secondary generalisation. Lamotrigine is now licensed in Ireland and the UK as add-on treatment in these seizure types. In reviewing their experience of 82 patients treated with lamotrigine on a namedpatient basis, Timmings and Richens1 excluded 22 patients with no response or unacceptable adverse events and found that, among the remaining 60, those with primary generalised epilepsy did at least as well as those with partial epilepsies. Our experience also suggests an important role for lamotrigine in primary generalised epilepsy. Since 1987 we have treated 72 chronic drug-resistant adult epileptic patients with lamotrigine, of whom 63 had partial seizures with or without secondary generalisation, 4 had primary generalised epilepsy, and 5 seizures of uncertain classification. Without excluding any, we found that of the patients with partial seizures with or without secondary generalisation, 30% had improved seizure control of 50% or greater. This finding is similar to that in controlled and uncontrolled studies.2 Only 1 of these patients (with frequent secondary generalised attacks) has become seizure-free. However, of the 4 with primary generalised epilepsy, 2 have been seizure-free for up to 3 years and 2 have improved by over 75%. Overall experience suggests that efficacy of lamotrigine in patients with chronic partial epilepsies is not quite as good as that with vigabatrin, although individual patients may do better on one drug than the other. The overall response rate (! 50% fall in seizure frequency) of around one-third with lamotrigine can be compared with a rate of approximately one-half with vigabatrin.3 However, lamotrigine may prove to be more effective than vigabatrin for primary generalised seizures. Furthermore, we have been impressed with 3 intractable patients who had failed to respond to temporal lobectomies and who subsequently considerably improved (> 80% reduction in seizure frequency) on lamotrigine plus vigabatrin, having shown modest or no response to either drug given individually.4 These patients had clinical and electroencephalographic evidence of frequent secondary generalisation (which may have accounted for their poor response to neurosurgery), which improved after the addition of lamotrigine to vigabatrin. The potential value of this combination of two new drugs has also been noted by Dr G. Schapel (Queen Elizabeth Hospital, Woodville, South Australia). Because vigabatrin, which increases inhibition by raising gamma-aminobutyric acid concentrations, seems more useful for partial seizures and lamotrigine, which reduces excitation (perhaps by inhibiting glutamate release), seems more useful for generalised seizures, studies of the combination in intractable patients with both seizure types are indicated. Department of Neurology, King’s College Hospital, London SE5 9RS, UK 1. Timmings PL, Richens A
J. STEWART E. HUGHES E. H. REYNOLDS
Lamotrigine in primary generalised epilepsy. Lancet 1992; 339: 1300-01. 2. Binnie C. An overview. efficacy of lamotrigine. In Richens A, ed. Clinical update on lamotrigine: a novel antiepileptic agent. Royal Tunbridge Wells: Wells Medical, International Clinical Practice Series, 1992: 31-41. 3. Ring HA, Reynolds EH. Vigabatrin. In: Pedley TA, Meldrum BS, eds. Recent advances in epilepsy, No 5. Edinburgh: Churchill Livingstone, 1992: 177-95. 4 Kirker A, Reynolds EH. Vigabatrin and lamotrigine in a patient with intractable epilepsy. Acta Neurol Scand 1990; 82 (suppl 133): S38-39. 5. Stewart J, Hughes E, Kirker S, Reynolds EH. Combined vigabatrin and lamotrigine for very intractable epilepsy. Seizure 1992; 1 (Suppl A): 13-39.
Ondansetron and
hyperemesis gravidarum
SiR,—In a case of life-threatening hyperemesis gravidarum in which the expected benefit to the patient was thought to outweigh any possible risk to the fetus, we decided to administer ondansetron as an anti-emetic. A 21-year-old pregnant primigravida in her 6th gestational week was admitted on Feb 2,1992, with 8-16 vomits daily. The patient was treated for 1 month with intravenous metoclopramide 10 mg three times daily and dimenhydrinate suppository 100 mg twice daily without success. During the month, the patient could not take anything by mouth and she received continuous intravenous infusion of fluids. The patient’s condition began to deteriorate (dehydration, loss of weight, electrolyte imbalance) to the point of needing urgent and intensive care. Her condition was considered so life-threatening for her as well as the fetus that we decided to administer ondansetron after informing the patient and her immediate family about possible risks. Ondansetron 8 mg was administered in the 11 th gestational week intravenously three times a day. The patient vomited only once during the first day of treatment and stopped vomiting from the second day. Ondansetron had to be continued for 14 days, because every time we decided to stop treatment the patient started to vomit. Because of her significant improvement, the patient began to eat and drink normally from the second day onwards. We followed up this pregnancy until the patient gave birth to a full-term healthy girl of 3-2kg. The second stage of labour lasted 2 h
only. 3rd Department of Obstetrics and
Gynaecology,
Obstetric and Gynaecological Centre of Athens, "Helena E Venizelou", Athens 115 21, Greece
EVAN GUIKONTES ANASTASIOS SPANTIDEAS
JOHN DIAKAKIS
Hiccough relief with cisapride SIR,-Persistent hiccough is distressing, and management can 84-year-old man, who had had a previous mild cerebrovascular accident, presented with renal failure as a result of
prove difficult. An
obstructive uropathy. The obstruction was cleared and renal function returned to normal. However, hiccoughs, which were originally attributed to the above diagnoses, persisted. Treatment with
chlorpromazine, baclofen,
naproxen, and
metoclopramide
unsuccessful. The patient was subsequently found to have gastrooesophageal reflux and he was started on cisapride. The hiccoughs resolved. Withdrawal of cisapride was associated with hiccough recurrence, and rechallenge relieved the hiccough. was
Medicine for the Elderly, Stracathro Hospital,
Brechin,
Angus DD9 7QA, UK
M. C. DUFFY H. EDMOND K. CAMPBELL J. D. FULTON
Benzodiazepine sensitivity in Leber’s hereditary optic neuroretinopathy SIR,-In Leber’s hereditary optic neuropathy (LHON), 50-62% of patients have a mutation in the ND4 and 14% in the NDof the mitochondrially encoded subunits of complex I (NADH-ubiquinone oxidoreductase) of the respiratory chain.l,22 Patients with LHON have reduced complex I activity, which demonstrates that these mtDNA mutations cause functional disturbances.3-5 Affected and non-affected LHON family members may develop cardiac arrhythmia with fatal outcome.6 LHON patients may be exceptionally sensitive to ordinary doses of drugs that normally have little respiratory depressant activity.7 We describe a patient with LHON who developed severe respiratory
insufficiency after oxazepam. Our patient is a 33-year-old
man from a large Finnish family with LHON. His visual symptoms manifested in 1978 and led to
1224
permanent blindness due to bilateral optic atrophy. Blood and muscle specimens showed a mitochondrial DNA mutation at nt 11778 of ND4. Electronmicroscopical analysis of muscle revealed clusters of abnormally numerous and somewhat enlarged mitochondria both between the myofibrils and below the sarcolemma.9 Later, he became alcoholic with epileptic seizures, alcohol gastritis, and pancreatitis. In 1981, he had primary syphilis, treated with antibiotics. In October, 1991, the patient was admitted with hallucinations and headache. He was conscious but disoriented. Temperature was 37-9°C. Apart from mild sinus tachycardia, physical examination was normal and laboratory tests were normal. There were no signs of infection in urine or on chest radiography. Cerebrospinal fluid (CSF) was normal. Semiquantitative serum analysis for benzodiazepines gave a weak positive reaction. Arterial blood gas analysis showed pH 7-35, PaC02 83 kPa, base excess + 65, and Pa02 60 kPa. After some hours he was alert and discharged himself. The next morning the patient returned and was increasingly restless. Incipient delirium tremens was suspected and a 50 mg tablet of oxazepam was given. After a couple of hours his respiratory rate slowed. He was cyanotic; blood gas analysis showed pH 7 31, PACO, 9 IkPa, and Pa02 60 kPa. In the intensive care unit, he was given intravenous flumazenil to antagonise the benzodiazepine. This treatment was initially beneficial, but eventually PACO, rose to 14 9 kPa. He was intubated and artificially ventilated. Repeated CSF tap was normal. Computed tomography of the brain showed only mild cortical atrophy. 24 hours later the patient recovered with no further need for artificial ventilation. When asked, he admitted having taken oxazepam at home before admission. The patient was transferred to a psychiatric ward because of delirium. Later he was instructed not to use benzodiazepines and was discharged. The acute episode of severe hypoventilation was associated with oxazepam administration. The biochemical nature of ND4 mutation is not clear, although decrease in the oxidation rate of NAD-linked substrates in patients with this mutation has been demonstrated.15,9 The defect is reflected also in structurally abnormal mitochondria in muscle biopsy specimens of patients with LHON,4,9 as seen in our case. The clinical symptoms of mitochondriopathies are ascribed to energy failure in selected tissues, especially in those with high oxidative energy production. LHON mainly affects optic nerves but the disease is not restricted to the visual pathways. Patients may develop severe cardiac and neurological symptoms. Apparently, in mitochondriopathies including LHON, various tissues function on the verge of failure. This is supported by sudden metabolic incompensations described in other n-jitochondriopathies.11 Departments of Ophthalmology and Internal Medicine; Department of Pathology, Division of Neuropathology; and Department of Clinical Genetics, University of Turku, Turku 20520,
Finland; and Department of Medical Chemistry, University of Helsinki, Helsinki
E. NIKOSKELAINEN M. ASOLA H. KALIMO M-L. SAVONTAUS A. MAJANDER
1. Nikoskelainen EK. Leber hereditary optic neuropathy. Curr Opin Ophthalmol 1991; 2: 531-37. 2. Brown MD, Voljavec AS, Lott MT, Torroni A, Yang CC, Wallace DC. Mitochondrial DNA complex I and III mutations associated with Leber’s hereditary optic neuropathy. Genetics 1992; 130: 163-73. 3. MajanderA, Huoponen K, Savontaus M-L, Nikoskelainen R, Wikstrom M. Electron transfer properties of NADH-ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON). FEBS Lett 1991; 292: 289-92. 4. Larsson N-G, Anderson O, Holme E, Oldfors A, Wahlström J. Leber’s hereditary optic neuropathy and complex I deficiency in muscle. Ann Neurol 1991; 30: 701-08. 5. Howell N, Bindoff LA, McCullough DA, et al. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet 1991; 49: 939-50 6. Bower SPC, Hawley I, Mackey DA. Cardiac arrhythmia and Leber’s hereditary optic neuropathy. Lancet 1992; 339: 1427-28. 7. Hunter AR. Idiopathic alveolar hypoventilation in Leber’s disease. Unusual sensitivity to mild analgesic and diazepam. Anaesthesia 1984; 39: 781-83.
8. Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber’s hereditary optic neuropathy II The fundus findings in the affected family members. Arch Ophthalmol 1983; 101: 1059-68. 9. Nikoskelainen E, Hassinen IE, Paljarvi L, Lang H, Kalimo H. Leber’s hereditary optic neuroretinopathy, a mitochondrial disease? Lancet 1984; ii: 1474. 10. Morgan-Hughes JA. Mitochondrial diseases. In: Mastaglia FL, Lord Walton of Detchant, eds. Skeletal muscle pathology. Edinburgh: Churchill Livingstone,
1992; 367-424.
Magnesium deficiency and cardiovascular disease SiR,—Iread with interest, and with some fulfillment, Dr Woods and colleagues’ article (the LIMIT-2 trial, June 27, p 1553) on the possible role of magnesium in the pathogenesis, prevention, and treatment of cardiovascular disease. Reviewing previous work, I was unable to find any studies predating our own that demonstrated rather convincingly the effect of magnesium deficiency not only in the pathogenesis of cardiovascular atherosclerosis in rats, dogs, and non-human primates but with the regressions of these lesions, on administration of high levels of dietary magnesium (4 to 6 x normal requirements) in animals with lesions induced by feeding and which were maintained on atherogenic diets.1-5 The basis of having undertaken these studies in the late 1950s and early 1960s was our previous observation that magnesium deficiency uncoupled oxidative phosphorylation in isolated mitochondria as did the administration of thyroxine which seemed to increase magnesium requirements Also, we noted defects in oxidative phosphorylation by heart mitochondria in young rats after only four days on a magnesium-deficient diet. At this time no change in the oxidative phosphorylation of liver or kidney mitochondria was shown.1 Thus, the metabolism of cardiac tissue seemed to be
peculiarly susceptible to magnesium deprivation. The mechanism by which magnesium deficiency exerts itself is not clear but there are several possibilities. One is, as we have shown, that magnesium deficiency enhances metastatic calcification, especially in the kidney, and could be expected to result in hypertension leading to cardiovascular atherosclerosis, which, indeed, occurred.2,7Another possibility is that the hypercholesterolaemia that arises with an atherogenic diet results in an increased magnesium requirement since the beneficial effects of high dietary magnesium occurred without affecting the serum cholesterol or lipid concentrations.1-5 Finally, magnesium deficiency may enhance the pathogenesis of coronary atherosclerosis not only by disrupting oxidative processes, potassium transport across cell membranes, and transmembrane potentials,5,8 but also by influencing the oxidation of low-densitylipoprotein cholesterol, which is receiving some attention as an enhancing mediator of coronary heart disease.9,10 I am not sure of its origin but the saying, "What goes around, comes around", remains appropriate. In 1976, the President’s Biological Research Panel (USA) addressed itself to the lags between initial discovery and clinical application in cardiovascular pulmonary medicine and surgery. In view of the lag times among the 132 discoveries listed and the first clinical application in just this one specialty, 43 were applied in less than 10 years; 27 in 10-24 years; 39 in 25-49 years; 18 in 50-90 years, and 5 in 100 years or more.lIs it not time to look beyond dietary cholesterol and eggs and fat, and so on, and perhaps look at micronutrients, anti-oxidants, and vitamins and their possible aetiological and therapeutic roles?
Department of Pathology, Nutrition Pathology Unit, Boston University School of Medicine, Boston, Massachusetts 02118, USA
JOSEPH J. VITALE
1. Vitale
JJ, White PL, Nakamura M, et al. Interrelationships between experimental hypercholesterolaemia, magnesium requirement and experimental atherosclerosis. J Exp Med 1957; 106: 757-66. 2. Hellerstein EE, Vitale JJ, White PL, et al. Influence ofdietary magnesium on cardiac and renal lesions in young rats fed an atherogenic diet.J Exp Med 1957; 106: 767-76.
3. Nakamura M, Vitale JJ, Hegsted DM, Hellerstein EE. The effect of dietary magnesium and thyroxine on progression and regression of cardiovascular lipid deposition in the rat, J Nutr 1960; 7: 347-55. 4. Vitale JJ, Hellerstein EE, Nakamura M, Lown B. Effects of magnesium-deficient diet upon puppies. Circ Res 1961; 9: 387-94.
1. Cornelis G, Laroche Y, Balligand G, Sory M-P, Wauters G Yersinia enterocolitica, a primary model for bacterial invasiveness. Rev Infect Dis 1987; 9: 64-87. 2. Jones BL, Saw MH, Hanson MF, Mackie MJ, Scott JG, Murphy WG. Yersinia enterocolitica septicaemia from blood transfusion. Transfusion Med 1992; 2 (suppl
1)· 86. I, Norlander L, Wolf-Watz H. Temperature-inducible outer-membrane protein of Yersinia pseudotuberculosis and Yersima enterocolitica is associated with the virulence plasmid. Infect Immun 1982; 37: 506-12. 4. CDC. Update: Yersinia enterocolitica bacteraemia and endotoxic shock associated with red blood cell transfusions: United States, 1991. MMWR 1991; 40: 176-78. 5. Scott J, Boulton FE, Govan JRW, Miles RS, McClelland DBL, Prowse CV. A fatal 3. Bolin
transfusion reaction associated with blood contaminated with Pseudomonas Vox Sang 1988; 54: 201-04.
fluorescens.
Lamotrigine for generalised epilepsies SIR,-4Controlled trials of new antiepileptic drugs are done initially in adults with chronic drug-resistant epilepsy. Such patients usually have partial seizures with or without secondary generalisation. Lamotrigine is now licensed in Ireland and the UK as add-on treatment in these seizure types. In reviewing their experience of 82 patients treated with lamotrigine on a namedpatient basis, Timmings and Richens1 excluded 22 patients with no response or unacceptable adverse events and found that, among the remaining 60, those with primary generalised epilepsy did at least as well as those with partial epilepsies. Our experience also suggests an important role for lamotrigine in primary generalised epilepsy. Since 1987 we have treated 72 chronic drug-resistant adult epileptic patients with lamotrigine, of whom 63 had partial seizures with or without secondary generalisation, 4 had primary generalised epilepsy, and 5 seizures of uncertain classification. Without excluding any, we found that of the patients with partial seizures with or without secondary generalisation, 30% had improved seizure control of 50% or greater. This finding is similar to that in controlled and uncontrolled studies.2 Only 1 of these patients (with frequent secondary generalised attacks) has become seizure-free. However, of the 4 with primary generalised epilepsy, 2 have been seizure-free for up to 3 years and 2 have improved by over 75%. Overall experience suggests that efficacy of lamotrigine in patients with chronic partial epilepsies is not quite as good as that with vigabatrin, although individual patients may do better on one drug than the other. The overall response rate (! 50% fall in seizure frequency) of around one-third with lamotrigine can be compared with a rate of approximately one-half with vigabatrin.3 However, lamotrigine may prove to be more effective than vigabatrin for primary generalised seizures. Furthermore, we have been impressed with 3 intractable patients who had failed to respond to temporal lobectomies and who subsequently considerably improved (> 80% reduction in seizure frequency) on lamotrigine plus vigabatrin, having shown modest or no response to either drug given individually.4 These patients had clinical and electroencephalographic evidence of frequent secondary generalisation (which may have accounted for their poor response to neurosurgery), which improved after the addition of lamotrigine to vigabatrin. The potential value of this combination of two new drugs has also been noted by Dr G. Schapel (Queen Elizabeth Hospital, Woodville, South Australia). Because vigabatrin, which increases inhibition by raising gamma-aminobutyric acid concentrations, seems more useful for partial seizures and lamotrigine, which reduces excitation (perhaps by inhibiting glutamate release), seems more useful for generalised seizures, studies of the combination in intractable patients with both seizure types are indicated. Department of Neurology, King’s College Hospital, London SE5 9RS, UK 1. Timmings PL, Richens A
J. STEWART E. HUGHES E. H. REYNOLDS
Lamotrigine in primary generalised epilepsy. Lancet 1992; 339: 1300-01. 2. Binnie C. An overview. efficacy of lamotrigine. In Richens A, ed. Clinical update on lamotrigine: a novel antiepileptic agent. Royal Tunbridge Wells: Wells Medical, International Clinical Practice Series, 1992: 31-41. 3. Ring HA, Reynolds EH. Vigabatrin. In: Pedley TA, Meldrum BS, eds. Recent advances in epilepsy, No 5. Edinburgh: Churchill Livingstone, 1992: 177-95. 4 Kirker A, Reynolds EH. Vigabatrin and lamotrigine in a patient with intractable epilepsy. Acta Neurol Scand 1990; 82 (suppl 133): S38-39. 5. Stewart J, Hughes E, Kirker S, Reynolds EH. Combined vigabatrin and lamotrigine for very intractable epilepsy. Seizure 1992; 1 (Suppl A): 13-39.
Ondansetron and
hyperemesis gravidarum
SiR,—In a case of life-threatening hyperemesis gravidarum in which the expected benefit to the patient was thought to outweigh any possible risk to the fetus, we decided to administer ondansetron as an anti-emetic. A 21-year-old pregnant primigravida in her 6th gestational week was admitted on Feb 2,1992, with 8-16 vomits daily. The patient was treated for 1 month with intravenous metoclopramide 10 mg three times daily and dimenhydrinate suppository 100 mg twice daily without success. During the month, the patient could not take anything by mouth and she received continuous intravenous infusion of fluids. The patient’s condition began to deteriorate (dehydration, loss of weight, electrolyte imbalance) to the point of needing urgent and intensive care. Her condition was considered so life-threatening for her as well as the fetus that we decided to administer ondansetron after informing the patient and her immediate family about possible risks. Ondansetron 8 mg was administered in the 11 th gestational week intravenously three times a day. The patient vomited only once during the first day of treatment and stopped vomiting from the second day. Ondansetron had to be continued for 14 days, because every time we decided to stop treatment the patient started to vomit. Because of her significant improvement, the patient began to eat and drink normally from the second day onwards. We followed up this pregnancy until the patient gave birth to a full-term healthy girl of 3-2kg. The second stage of labour lasted 2 h
only. 3rd Department of Obstetrics and
Gynaecology,
Obstetric and Gynaecological Centre of Athens, "Helena E Venizelou", Athens 115 21, Greece
EVAN GUIKONTES ANASTASIOS SPANTIDEAS
JOHN DIAKAKIS
Hiccough relief with cisapride SIR,-Persistent hiccough is distressing, and management can 84-year-old man, who had had a previous mild cerebrovascular accident, presented with renal failure as a result of
prove difficult. An
obstructive uropathy. The obstruction was cleared and renal function returned to normal. However, hiccoughs, which were originally attributed to the above diagnoses, persisted. Treatment with
chlorpromazine, baclofen,
naproxen, and
metoclopramide
unsuccessful. The patient was subsequently found to have gastrooesophageal reflux and he was started on cisapride. The hiccoughs resolved. Withdrawal of cisapride was associated with hiccough recurrence, and rechallenge relieved the hiccough. was
Medicine for the Elderly, Stracathro Hospital,
Brechin,
Angus DD9 7QA, UK
M. C. DUFFY H. EDMOND K. CAMPBELL J. D. FULTON
Benzodiazepine sensitivity in Leber’s hereditary optic neuroretinopathy SIR,-In Leber’s hereditary optic neuropathy (LHON), 50-62% of patients have a mutation in the ND4 and 14% in the NDof the mitochondrially encoded subunits of complex I (NADH-ubiquinone oxidoreductase) of the respiratory chain.l,22 Patients with LHON have reduced complex I activity, which demonstrates that these mtDNA mutations cause functional disturbances.3-5 Affected and non-affected LHON family members may develop cardiac arrhythmia with fatal outcome.6 LHON patients may be exceptionally sensitive to ordinary doses of drugs that normally have little respiratory depressant activity.7 We describe a patient with LHON who developed severe respiratory
insufficiency after oxazepam. Our patient is a 33-year-old
man from a large Finnish family with LHON. His visual symptoms manifested in 1978 and led to
1224
permanent blindness due to bilateral optic atrophy. Blood and muscle specimens showed a mitochondrial DNA mutation at nt 11778 of ND4. Electronmicroscopical analysis of muscle revealed clusters of abnormally numerous and somewhat enlarged mitochondria both between the myofibrils and below the sarcolemma.9 Later, he became alcoholic with epileptic seizures, alcohol gastritis, and pancreatitis. In 1981, he had primary syphilis, treated with antibiotics. In October, 1991, the patient was admitted with hallucinations and headache. He was conscious but disoriented. Temperature was 37-9°C. Apart from mild sinus tachycardia, physical examination was normal and laboratory tests were normal. There were no signs of infection in urine or on chest radiography. Cerebrospinal fluid (CSF) was normal. Semiquantitative serum analysis for benzodiazepines gave a weak positive reaction. Arterial blood gas analysis showed pH 7-35, PaC02 83 kPa, base excess + 65, and Pa02 60 kPa. After some hours he was alert and discharged himself. The next morning the patient returned and was increasingly restless. Incipient delirium tremens was suspected and a 50 mg tablet of oxazepam was given. After a couple of hours his respiratory rate slowed. He was cyanotic; blood gas analysis showed pH 7 31, PACO, 9 IkPa, and Pa02 60 kPa. In the intensive care unit, he was given intravenous flumazenil to antagonise the benzodiazepine. This treatment was initially beneficial, but eventually PACO, rose to 14 9 kPa. He was intubated and artificially ventilated. Repeated CSF tap was normal. Computed tomography of the brain showed only mild cortical atrophy. 24 hours later the patient recovered with no further need for artificial ventilation. When asked, he admitted having taken oxazepam at home before admission. The patient was transferred to a psychiatric ward because of delirium. Later he was instructed not to use benzodiazepines and was discharged. The acute episode of severe hypoventilation was associated with oxazepam administration. The biochemical nature of ND4 mutation is not clear, although decrease in the oxidation rate of NAD-linked substrates in patients with this mutation has been demonstrated.15,9 The defect is reflected also in structurally abnormal mitochondria in muscle biopsy specimens of patients with LHON,4,9 as seen in our case. The clinical symptoms of mitochondriopathies are ascribed to energy failure in selected tissues, especially in those with high oxidative energy production. LHON mainly affects optic nerves but the disease is not restricted to the visual pathways. Patients may develop severe cardiac and neurological symptoms. Apparently, in mitochondriopathies including LHON, various tissues function on the verge of failure. This is supported by sudden metabolic incompensations described in other n-jitochondriopathies.11 Departments of Ophthalmology and Internal Medicine; Department of Pathology, Division of Neuropathology; and Department of Clinical Genetics, University of Turku, Turku 20520,
Finland; and Department of Medical Chemistry, University of Helsinki, Helsinki
E. NIKOSKELAINEN M. ASOLA H. KALIMO M-L. SAVONTAUS A. MAJANDER
1. Nikoskelainen EK. Leber hereditary optic neuropathy. Curr Opin Ophthalmol 1991; 2: 531-37. 2. Brown MD, Voljavec AS, Lott MT, Torroni A, Yang CC, Wallace DC. Mitochondrial DNA complex I and III mutations associated with Leber’s hereditary optic neuropathy. Genetics 1992; 130: 163-73. 3. MajanderA, Huoponen K, Savontaus M-L, Nikoskelainen R, Wikstrom M. Electron transfer properties of NADH-ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON). FEBS Lett 1991; 292: 289-92. 4. Larsson N-G, Anderson O, Holme E, Oldfors A, Wahlström J. Leber’s hereditary optic neuropathy and complex I deficiency in muscle. Ann Neurol 1991; 30: 701-08. 5. Howell N, Bindoff LA, McCullough DA, et al. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet 1991; 49: 939-50 6. Bower SPC, Hawley I, Mackey DA. Cardiac arrhythmia and Leber’s hereditary optic neuropathy. Lancet 1992; 339: 1427-28. 7. Hunter AR. Idiopathic alveolar hypoventilation in Leber’s disease. Unusual sensitivity to mild analgesic and diazepam. Anaesthesia 1984; 39: 781-83.
8. Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber’s hereditary optic neuropathy II The fundus findings in the affected family members. Arch Ophthalmol 1983; 101: 1059-68. 9. Nikoskelainen E, Hassinen IE, Paljarvi L, Lang H, Kalimo H. Leber’s hereditary optic neuroretinopathy, a mitochondrial disease? Lancet 1984; ii: 1474. 10. Morgan-Hughes JA. Mitochondrial diseases. In: Mastaglia FL, Lord Walton of Detchant, eds. Skeletal muscle pathology. Edinburgh: Churchill Livingstone,
1992; 367-424.
Magnesium deficiency and cardiovascular disease SiR,—Iread with interest, and with some fulfillment, Dr Woods and colleagues’ article (the LIMIT-2 trial, June 27, p 1553) on the possible role of magnesium in the pathogenesis, prevention, and treatment of cardiovascular disease. Reviewing previous work, I was unable to find any studies predating our own that demonstrated rather convincingly the effect of magnesium deficiency not only in the pathogenesis of cardiovascular atherosclerosis in rats, dogs, and non-human primates but with the regressions of these lesions, on administration of high levels of dietary magnesium (4 to 6 x normal requirements) in animals with lesions induced by feeding and which were maintained on atherogenic diets.1-5 The basis of having undertaken these studies in the late 1950s and early 1960s was our previous observation that magnesium deficiency uncoupled oxidative phosphorylation in isolated mitochondria as did the administration of thyroxine which seemed to increase magnesium requirements Also, we noted defects in oxidative phosphorylation by heart mitochondria in young rats after only four days on a magnesium-deficient diet. At this time no change in the oxidative phosphorylation of liver or kidney mitochondria was shown.1 Thus, the metabolism of cardiac tissue seemed to be
peculiarly susceptible to magnesium deprivation. The mechanism by which magnesium deficiency exerts itself is not clear but there are several possibilities. One is, as we have shown, that magnesium deficiency enhances metastatic calcification, especially in the kidney, and could be expected to result in hypertension leading to cardiovascular atherosclerosis, which, indeed, occurred.2,7Another possibility is that the hypercholesterolaemia that arises with an atherogenic diet results in an increased magnesium requirement since the beneficial effects of high dietary magnesium occurred without affecting the serum cholesterol or lipid concentrations.1-5 Finally, magnesium deficiency may enhance the pathogenesis of coronary atherosclerosis not only by disrupting oxidative processes, potassium transport across cell membranes, and transmembrane potentials,5,8 but also by influencing the oxidation of low-densitylipoprotein cholesterol, which is receiving some attention as an enhancing mediator of coronary heart disease.9,10 I am not sure of its origin but the saying, "What goes around, comes around", remains appropriate. In 1976, the President’s Biological Research Panel (USA) addressed itself to the lags between initial discovery and clinical application in cardiovascular pulmonary medicine and surgery. In view of the lag times among the 132 discoveries listed and the first clinical application in just this one specialty, 43 were applied in less than 10 years; 27 in 10-24 years; 39 in 25-49 years; 18 in 50-90 years, and 5 in 100 years or more.lIs it not time to look beyond dietary cholesterol and eggs and fat, and so on, and perhaps look at micronutrients, anti-oxidants, and vitamins and their possible aetiological and therapeutic roles?
Department of Pathology, Nutrition Pathology Unit, Boston University School of Medicine, Boston, Massachusetts 02118, USA
JOSEPH J. VITALE
1. Vitale
JJ, White PL, Nakamura M, et al. Interrelationships between experimental hypercholesterolaemia, magnesium requirement and experimental atherosclerosis. J Exp Med 1957; 106: 757-66. 2. Hellerstein EE, Vitale JJ, White PL, et al. Influence ofdietary magnesium on cardiac and renal lesions in young rats fed an atherogenic diet.J Exp Med 1957; 106: 767-76.
3. Nakamura M, Vitale JJ, Hegsted DM, Hellerstein EE. The effect of dietary magnesium and thyroxine on progression and regression of cardiovascular lipid deposition in the rat, J Nutr 1960; 7: 347-55. 4. Vitale JJ, Hellerstein EE, Nakamura M, Lown B. Effects of magnesium-deficient diet upon puppies. Circ Res 1961; 9: 387-94.