1154 had been submitted for laboratory exwere swabs. We therefore feel justified in saying that none of the 138 represent genuine falsepositive results. We believe that this is due to a conscious recognition of the implications of error and hence the careful checks within the laboratory combined with an assessment of all .he other available information in every new case.
only
a
single specimen
amination, and 5 of these
That massive hypoxic cell damage does not occur in high-altitude brain oedema, nor in acute hypertensive encephalopathy is suggested by the complete reversibility of both conditions after treatment. Department of Clinical Physiology,
Bispebjerg Hospital, DK-2400 Copenhagen,
N. A. LASSEN
Denmark. Public Health Laboratory, General Hospital, Middlesbrough, Teesside.
D. P. CASEMORE P. R. MORTIMER
Wellcome Surgical Research Institute, Bearsden Road,
GEOGRAPHICAL DISTRIBUTION OF TIC DOULOUREUX IN ESSEX
REYE’S SYNDROME
SIR,—Lee et al. (Sept. 27, p. 606) suggest that the abnormal
SIR,-It may be of interest that there seems to be a geographical distribution of tic douloureux (trigeminal neuralgia) in Essex. On average I see about 6 cases each year and they almost all come from the Colne Valley area and north-east coastal strip, while there have been very few referrals from the area south of the Colne. This may be an artefact of referral pattern, but I do not think so, and I wonder whether similar local differences exist in other areas. Essex County Hospital, Lexden Road, Colchester, CO3 3NB.
M. FROST
HIGH-ALTITUDE CEREBRAL ŒDEMA
SIR,-Professor Houston and
Dr Dickinson (Oct. 18, p. that the cerebral form of evidence 758) present convincing illness is to cerebral due oedema. They suggest high-altitude that the oedema is caused by massive hypoxic cell damage resulting in oedema of the histiotoxic type, in Klatzo’s terminology.’ From the observations presented, we are led to the opposite view-namely, that the brain oedema is more likely to
be of the vasogenic type.1 In our view the oedema is caused by increased pressure in the cerebral microcirculation, as in acute arterial hypertension
causing hypertensive encephalopathy. In severe acute hypertension, the normal autoregulatory vasconstrictor response to increase in pressure breaks down, resulting in forced dilatation of the arterioles and a (multifocal) increase in cerebral blood-flow, with rupture of the blood/brain barrier and rapid oedema formation, probably due to transcapillary and transarteriolar filtration.2-4 Increased hypertension was first noted by Ekstrom-Jodal et al.,5 who also presented evidence that the upper threshold of cerebral autoregulation (the breakthrough point) was probably lower during hypercapnia, a strong cerebral vasodilator stimulus. Later Johansson et al.6 noted the effect when the cerebral vessels verine : induced hypertension then same
were
dilated with papa-
produced much
more
oedema.6 In
high-altitude illness arterial hypoxia (often accentuated by lung complications and by inadequate hyperventilation after acute exposure to hypoxia) constitutes a cerebral vasodilator stimulus. In this situation even moderate hypertension as provoked by exercise, in particular isometric exercise, would be expected to cause a breakthrough of cerebral autoregulation and vasogenic multifocal cerebral oedema. The retinal findings in high-altitude cerebral cedema seem to be similar to those in acute hypertensive encephalopathy and this may perhaps be taken to support our hypothesis.
properties of ornithine transcarbamylase found by us in a patient with Reye’s syndrome’ may be an artefact produced by the conditions under which we assayed the enzyme. This is clearly not the case, since the liver biopsy from the patient with Reye’s syndrome was assayed at the same time and under identical conditions as a control which showed no substrate inhibition and had Michaelis constants similar to published values. Admittedly, substrate inhibition by ornithine is a common feature of ornithine transcarbamylase, but non-linear double-reciprocal plots are not obtained at pH 7 until ornithine concentrations are raised above 5mM. This result is in agreement with that of Snodgrass,2 who also obtained linear doublereciprocal plots at pH 7.2with ornithine concentrations below 5 mM. It is true that the highest concentration of the variable substrate, ornithine, was below the Michaelis constant obtained for the patient with Reye’s syndrome. The range of concentrations was chosen on the basis of the known Michaelis constants for normal human ornithine transcarbamylase, and, once having found that the constant was markedly elevated in the patient, there was insufficient tissue left from the needle biopsy to repeat the kinetic analysis at a new range of concentrations. Nevertheless, the difference in Michaelis constants between the patient and control was so great (18 times higher) that we believe we were justified in claiming that the patient had an abnormal ornithine transcarbamylase. Finally, we do not wish to create the impression that all cases of Reye’s syndrome are due to enzymatic abnormalities of the type we described. In fact, we were careful to point out in our report’ that several varieties of Reye’s syndrome may exist, and that multiple factors may be responsible for the climcopathological changes associated with the syndrome. It would not be surprising, therefore, to find normal ornithine-transcarbamylase kinetics in a proportion of patients with Reye’s syndrome. However, this diagnosis was not established in the patient reported by Lee et al., since multiple episodes of acute encephalopathy associated with significant hyperbilirubinæmia and normal liver histology are features which do not correspond to the picture described by Reye et al. In addition, the old Brown and Cohen ass at for ornithine transcarbamylase employed by Lee et al. at pH 84 produces errors due to rapid formation of urea and CO2 from carbamyl phosphate at these elevated pHs; and neither Brown and Cohen nor Snodgrass now use this crude procedure in unmodified form. Thus, the pertinence of Lee et al.’s findings to Reye’s syndrome remains uncertain. Department of Pediatrics, University of California, San
Francisco, California 94143, U.S.A.
167.
N A. Circ. Res
1974, suppl.
i, p
M. MICHAEL THALER
Biochemistry Department, La Trobe University, Bundoora, Victoria,
1. Klatzo, I.J. Neuropath. exp. Neurol. 1967, 26, 1. 2. Lassen, N. A., Agnoli, A. Scand.J. clin. Lab. Invest 1972, 30, 113. 3. Skinhøj, E., Strandgaard, S. Lancet, 1973, i, 461. 4. Strandgaard, S., MacKenzie, E. T., Sengupta, D., Rowan, J. O, I assen, N A., Harper, A. M. Circ. Res. 1974, 34, 435. 5. Ekström-Jodal, B., Häggendal, E., Linder, L. -E., Nilsson, N J. Eur. Neurol.
1971-72, 6, 6. 6. Johansson, B., Strandgaard, S., Lassen,
A. M. HARPER
Glasgow G61 1QH.
Australia 3083
1. 2. 3 4.
NICHOLAS
J. HOOGENRAAD
Thaler, M. M., Hoogenraad, N. J., Boswell, O. Lancet, 1974, ii, 438. Snodgrass, P. J. Biochemistry, 1968, 7, 3047. Reye, R. D. K., Morgan, G., Baral, J. Lancet, 1963, ii, 740 Brown, G. W., Jr., Cohen, P. P.J. biol. Chem. 1959, 234, 1769
only
a
single specimen
amination, and 5 of these
That massive hypoxic cell damage does not occur in high-altitude brain oedema, nor in acute hypertensive encephalopathy is suggested by the complete reversibility of both conditions after treatment. Department of Clinical Physiology,
Bispebjerg Hospital, DK-2400 Copenhagen,
N. A. LASSEN
Denmark. Public Health Laboratory, General Hospital, Middlesbrough, Teesside.
D. P. CASEMORE P. R. MORTIMER
Wellcome Surgical Research Institute, Bearsden Road,
GEOGRAPHICAL DISTRIBUTION OF TIC DOULOUREUX IN ESSEX
REYE’S SYNDROME
SIR,—Lee et al. (Sept. 27, p. 606) suggest that the abnormal
SIR,-It may be of interest that there seems to be a geographical distribution of tic douloureux (trigeminal neuralgia) in Essex. On average I see about 6 cases each year and they almost all come from the Colne Valley area and north-east coastal strip, while there have been very few referrals from the area south of the Colne. This may be an artefact of referral pattern, but I do not think so, and I wonder whether similar local differences exist in other areas. Essex County Hospital, Lexden Road, Colchester, CO3 3NB.
M. FROST
HIGH-ALTITUDE CEREBRAL ŒDEMA
SIR,-Professor Houston and
Dr Dickinson (Oct. 18, p. that the cerebral form of evidence 758) present convincing illness is to cerebral due oedema. They suggest high-altitude that the oedema is caused by massive hypoxic cell damage resulting in oedema of the histiotoxic type, in Klatzo’s terminology.’ From the observations presented, we are led to the opposite view-namely, that the brain oedema is more likely to
be of the vasogenic type.1 In our view the oedema is caused by increased pressure in the cerebral microcirculation, as in acute arterial hypertension
causing hypertensive encephalopathy. In severe acute hypertension, the normal autoregulatory vasconstrictor response to increase in pressure breaks down, resulting in forced dilatation of the arterioles and a (multifocal) increase in cerebral blood-flow, with rupture of the blood/brain barrier and rapid oedema formation, probably due to transcapillary and transarteriolar filtration.2-4 Increased hypertension was first noted by Ekstrom-Jodal et al.,5 who also presented evidence that the upper threshold of cerebral autoregulation (the breakthrough point) was probably lower during hypercapnia, a strong cerebral vasodilator stimulus. Later Johansson et al.6 noted the effect when the cerebral vessels verine : induced hypertension then same
were
dilated with papa-
produced much
more
oedema.6 In
high-altitude illness arterial hypoxia (often accentuated by lung complications and by inadequate hyperventilation after acute exposure to hypoxia) constitutes a cerebral vasodilator stimulus. In this situation even moderate hypertension as provoked by exercise, in particular isometric exercise, would be expected to cause a breakthrough of cerebral autoregulation and vasogenic multifocal cerebral oedema. The retinal findings in high-altitude cerebral cedema seem to be similar to those in acute hypertensive encephalopathy and this may perhaps be taken to support our hypothesis.
properties of ornithine transcarbamylase found by us in a patient with Reye’s syndrome’ may be an artefact produced by the conditions under which we assayed the enzyme. This is clearly not the case, since the liver biopsy from the patient with Reye’s syndrome was assayed at the same time and under identical conditions as a control which showed no substrate inhibition and had Michaelis constants similar to published values. Admittedly, substrate inhibition by ornithine is a common feature of ornithine transcarbamylase, but non-linear double-reciprocal plots are not obtained at pH 7 until ornithine concentrations are raised above 5mM. This result is in agreement with that of Snodgrass,2 who also obtained linear doublereciprocal plots at pH 7.2with ornithine concentrations below 5 mM. It is true that the highest concentration of the variable substrate, ornithine, was below the Michaelis constant obtained for the patient with Reye’s syndrome. The range of concentrations was chosen on the basis of the known Michaelis constants for normal human ornithine transcarbamylase, and, once having found that the constant was markedly elevated in the patient, there was insufficient tissue left from the needle biopsy to repeat the kinetic analysis at a new range of concentrations. Nevertheless, the difference in Michaelis constants between the patient and control was so great (18 times higher) that we believe we were justified in claiming that the patient had an abnormal ornithine transcarbamylase. Finally, we do not wish to create the impression that all cases of Reye’s syndrome are due to enzymatic abnormalities of the type we described. In fact, we were careful to point out in our report’ that several varieties of Reye’s syndrome may exist, and that multiple factors may be responsible for the climcopathological changes associated with the syndrome. It would not be surprising, therefore, to find normal ornithine-transcarbamylase kinetics in a proportion of patients with Reye’s syndrome. However, this diagnosis was not established in the patient reported by Lee et al., since multiple episodes of acute encephalopathy associated with significant hyperbilirubinæmia and normal liver histology are features which do not correspond to the picture described by Reye et al. In addition, the old Brown and Cohen ass at for ornithine transcarbamylase employed by Lee et al. at pH 84 produces errors due to rapid formation of urea and CO2 from carbamyl phosphate at these elevated pHs; and neither Brown and Cohen nor Snodgrass now use this crude procedure in unmodified form. Thus, the pertinence of Lee et al.’s findings to Reye’s syndrome remains uncertain. Department of Pediatrics, University of California, San
Francisco, California 94143, U.S.A.
167.
N A. Circ. Res
1974, suppl.
i, p
M. MICHAEL THALER
Biochemistry Department, La Trobe University, Bundoora, Victoria,
1. Klatzo, I.J. Neuropath. exp. Neurol. 1967, 26, 1. 2. Lassen, N. A., Agnoli, A. Scand.J. clin. Lab. Invest 1972, 30, 113. 3. Skinhøj, E., Strandgaard, S. Lancet, 1973, i, 461. 4. Strandgaard, S., MacKenzie, E. T., Sengupta, D., Rowan, J. O, I assen, N A., Harper, A. M. Circ. Res. 1974, 34, 435. 5. Ekström-Jodal, B., Häggendal, E., Linder, L. -E., Nilsson, N J. Eur. Neurol.
1971-72, 6, 6. 6. Johansson, B., Strandgaard, S., Lassen,
A. M. HARPER
Glasgow G61 1QH.
Australia 3083
1. 2. 3 4.
NICHOLAS
J. HOOGENRAAD
Thaler, M. M., Hoogenraad, N. J., Boswell, O. Lancet, 1974, ii, 438. Snodgrass, P. J. Biochemistry, 1968, 7, 3047. Reye, R. D. K., Morgan, G., Baral, J. Lancet, 1963, ii, 740 Brown, G. W., Jr., Cohen, P. P.J. biol. Chem. 1959, 234, 1769
