130
The statement that only 3 patients had cognitive impairment is perplexing. It would be expected that all patients with HIV encephalitis have ADC.3 Possible explanations for this discrepancy are that there was a non-neurologist assessment of ADC or that patient evaluation was remote from the time of death. Discussion of possible mechanisms of neuronal loss should include quinolinic acid-a neurotoxin, acting via the N-methyl-Daspartate receptor, which is increased in HIV-infected patients, especially those with ADC.4 National Centre in HIV Epidemiology and Clinical Research, St Vincent’s Medical Centre, Sydney, NSW 2010, Australia
BRUCE JAMES BREW
1. Brew BJ, Sidtis J, Petito CK, Price RW. The neurological complications of AIDS and human immunodeficiency virus infection. In: Plum F, ed. Advances in contemporary neurology. Philadelphia: FA Davis, 1988: 1-49. 2. Tross S, Price RW, Navia B, et al. Neuropsychological characterization of the AIDS dementia complex: a preliminary report. AIDS 1988; 2: 81-88. 3. Price RW, Brew BJ, Sidtis J, Rosenblum M, Scheck AC, Cleary P. The brain in AIDS: central nervous system HIV-1 infection and the AIDS dementia complex. Science 1988; 239: 586-92. 4. Heyes MP, Brew BJ, Martin A, et al. Qumolinic acid in the cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status. Ann Neurol 1991; 29: 202-09.
it is still not clear whether areas of inflammatory change in the brain also those areas with striking neuronal loss. Dr Brew demonstrates the difficulty in correlating pathological and clinical features. Subcortical dementia is a confusing term. Clinically, the syndrome has characteristic features; nonetheless, several of the diseases, it transpires, have histopathological lesions in the cerebral cortex.B We concentrated on the neuropathological features of HIV-associated brain disease and not on clinical correlations. However, finding serious cortical neuronal loss does not per se support a subcortical dementia. Whilst Brew is correct to remark on the apparent correlation between HIV encephalitis and AIDS dementia complex the precise neuropathological substrate remains unclear.9 The demonstration of neuronal loss in cases with minimal pathological change suggests that neuronal loss and not the degree of HIV encephalitis may present a pathological counterpart of ADC. The correlation of neuropathological and clinical features is a pressing issue and we agree entirely with Brew’s suggestion for future study. are
1. 2.
*** These letters have been shown whose reply follows.-ED. L.
to
Dr Everall and
colleagues,
SIR,-Dr Reimund and Dr Martin mention the potential
complications of
zidovudine. Clinical neurotoxicity, in the form of
seizures, has been attributed to this drugl but the neuropathological effect of zidovudine is not known. Nor do we know the significance of zidovudine globules in the brain. Nutritional and metabolic disorders are important factors to be considered, but their significance has not been established in AIDS. We are well acquainted with the work referred to on pellagra2-it was done in this department-but none of the characteristic features of pellagra were found in our cases. While such confounding variables cannot be discounted, the HIV-infected individuals we studied were collected over a five-year period when treatment (including use ofzidovudine), physical state, and illness duration would have varied greatly since the management of AIDS improved over this time. Nevertheless the neuronal numerical density of the HIV group was consistently lower than that of the control group and the standard deviation was modest. This implies that the one consistent factor, HIV infection, was the principal reason for the neuronal loss. All the salient histological features of our cases are in our paper. Many studies, of a variety of neurodegenerative disorders, identify neuronal loss but not neurons "dropping-out". To support their statement that neuronal loss is often characterised by residual eosinophilic bodies Reimund and Martin cite a report of a patient with a 41-year history of an unusual twilight state.3 There is now a lot of published work on toxic interactions between the HIV envelope protein gp120 and neuronal receptors4 as a cause of neuronal loss that is ascribed to HIV. In response to your correspondents’ last question-yes, we are doing an extensive quantitative morphometric study of different areas of the brain, together with immunocytochemistry. Dr Emerich and Professor Sanberg raise issues about the mechanism of the neuronal loss. Our study was to clarify, by quantitative morphometry, the association of HIV with neuronal loss. We discussed the role of gp120 in mediating this damage. Quinolinic acid an excitotoxin, binds to the NMDA receptor (a subtype of glutamate receptor), and seems to be an important factor in mediating gp 120 neurotoxicity. This neurotoxicity only occurs in the presence of glutamate and the increased quinolinic acid is seen as an endogenous glutamate agonist that facilitates gp120 toxicity in vivo.4 This interaction between gp120 and glutamate may also explain the ability of NMDA antagonists to prevent mononuclear cells killing rat and chick neurons in vitros since analysis of the soluble factors secreted by HIV-infected macrophages did not implicate excitotoxins.6 Furthermore, HIV encephalitis is associated with higher levels of unintegrated HIV DNA. However,
IAN EVERALL PHILIP LUTHERT PETER LANTOS
Department of Neuropathology, Institute of Psychiatry, London SE5 8AF, UK
Hagler DN, Frame PT. Azidothymidine neurotoxicity. Lancet 1986; ii: 1392-93. Leigh D. Pellagra and the nutritional neuropathies: a neuropathological review, J Ment
Sci 1952; 98: 130-42. 3. Arai N, Honda Y, Amano N, Yagishita S, Misugi K. Foamy spheroid bodies in the substantia nigra. Report of an unusual case with recurrent attacks of peculiar twilight state. J Neurol 1988; 235: 330-34. 4. Lipton SA. HIV-related neurotoxicity. Brain Pathol 1991; 1: 193-99. 5. Giullian D, Vaca K, Noonan CC. Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science 1990; 250: 1593-96 6. Pulliam L, Herndier BG, Tang NM, McGrath MS. Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains. J Clin Invest 1991; 87: 503-12. 7. Pang S, Koyanagi Y, Miles S, Wiley C, Vinters HV, Chen ISY. High levels of unintegrated HIV-1 DNA in brain tissue of AIDS dementia patients. Nature 1990; 343: 85-89. 8. Cummings JL, Benson DF. Subcortical dementia: review of an emerging concept. Arch Neurol 1984; 41: 874-79. 9. Price RW, Brew B, Sidtis J, Rosenblum M, Scheck AC, Cleary P. The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science 1988; 239: 586-92.
Blood-pressure measurement
in pregnancy
ways forward for pregnancy; automated
SiR,—Your May 18 editorial outlines three blood
pressure
measurement
in
sphygmomanometers, self-monitoring, and use of systolic blood pressure to defme hypertension. Although not widely studied, there seems to be a substantial difference between the auscultated fourth and fifth sounds in patients with moderate or severe hypertension in pregnancy, and this difference increases with systolic blood pressure-eg, a systolic blood pressure value of 170 mm Hg is associated with an auscultated fourth sound recorded at 125 mm Hg and an auscultated fifth sound at 95 mm Hg. The widespread introduction of automated blood-pressure measurement devices in delivery units means this difference is of practical importance, and may not be widely appreciated. Most automated devices display a diastolic blood pressure that approximates to the auscultated fifth sound, yet the threshold for the treatment of severe hypertension in many units is an auscultated fourth sound at 110 mm Hg. With the use of automated devices the goalposts have been changed, and if midwives and clinicians accept uncritically the diastolic measurement from an automated device, the patient may be exposed to prolonged periods of sustained severe hypertension with its attendant morbidity and mortality. These unfortunate consequences have been noted in three major teaching units in the UK in the past twelve months. The simplest ways to prevent these difficulties are to avoid automated blood pressure measurement devices in patients with moderate or severe hypertension in pregnancy, or to adopt your suggestion of the use of systolic blood pressure to define hypertension in these circumstances.
6 Cavendish Gardens, Sneyd Park, Bristol BS9 1RQ, UK
M. J. QUINN
The statement that only 3 patients had cognitive impairment is perplexing. It would be expected that all patients with HIV encephalitis have ADC.3 Possible explanations for this discrepancy are that there was a non-neurologist assessment of ADC or that patient evaluation was remote from the time of death. Discussion of possible mechanisms of neuronal loss should include quinolinic acid-a neurotoxin, acting via the N-methyl-Daspartate receptor, which is increased in HIV-infected patients, especially those with ADC.4 National Centre in HIV Epidemiology and Clinical Research, St Vincent’s Medical Centre, Sydney, NSW 2010, Australia
BRUCE JAMES BREW
1. Brew BJ, Sidtis J, Petito CK, Price RW. The neurological complications of AIDS and human immunodeficiency virus infection. In: Plum F, ed. Advances in contemporary neurology. Philadelphia: FA Davis, 1988: 1-49. 2. Tross S, Price RW, Navia B, et al. Neuropsychological characterization of the AIDS dementia complex: a preliminary report. AIDS 1988; 2: 81-88. 3. Price RW, Brew BJ, Sidtis J, Rosenblum M, Scheck AC, Cleary P. The brain in AIDS: central nervous system HIV-1 infection and the AIDS dementia complex. Science 1988; 239: 586-92. 4. Heyes MP, Brew BJ, Martin A, et al. Qumolinic acid in the cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status. Ann Neurol 1991; 29: 202-09.
it is still not clear whether areas of inflammatory change in the brain also those areas with striking neuronal loss. Dr Brew demonstrates the difficulty in correlating pathological and clinical features. Subcortical dementia is a confusing term. Clinically, the syndrome has characteristic features; nonetheless, several of the diseases, it transpires, have histopathological lesions in the cerebral cortex.B We concentrated on the neuropathological features of HIV-associated brain disease and not on clinical correlations. However, finding serious cortical neuronal loss does not per se support a subcortical dementia. Whilst Brew is correct to remark on the apparent correlation between HIV encephalitis and AIDS dementia complex the precise neuropathological substrate remains unclear.9 The demonstration of neuronal loss in cases with minimal pathological change suggests that neuronal loss and not the degree of HIV encephalitis may present a pathological counterpart of ADC. The correlation of neuropathological and clinical features is a pressing issue and we agree entirely with Brew’s suggestion for future study. are
1. 2.
*** These letters have been shown whose reply follows.-ED. L.
to
Dr Everall and
colleagues,
SIR,-Dr Reimund and Dr Martin mention the potential
complications of
zidovudine. Clinical neurotoxicity, in the form of
seizures, has been attributed to this drugl but the neuropathological effect of zidovudine is not known. Nor do we know the significance of zidovudine globules in the brain. Nutritional and metabolic disorders are important factors to be considered, but their significance has not been established in AIDS. We are well acquainted with the work referred to on pellagra2-it was done in this department-but none of the characteristic features of pellagra were found in our cases. While such confounding variables cannot be discounted, the HIV-infected individuals we studied were collected over a five-year period when treatment (including use ofzidovudine), physical state, and illness duration would have varied greatly since the management of AIDS improved over this time. Nevertheless the neuronal numerical density of the HIV group was consistently lower than that of the control group and the standard deviation was modest. This implies that the one consistent factor, HIV infection, was the principal reason for the neuronal loss. All the salient histological features of our cases are in our paper. Many studies, of a variety of neurodegenerative disorders, identify neuronal loss but not neurons "dropping-out". To support their statement that neuronal loss is often characterised by residual eosinophilic bodies Reimund and Martin cite a report of a patient with a 41-year history of an unusual twilight state.3 There is now a lot of published work on toxic interactions between the HIV envelope protein gp120 and neuronal receptors4 as a cause of neuronal loss that is ascribed to HIV. In response to your correspondents’ last question-yes, we are doing an extensive quantitative morphometric study of different areas of the brain, together with immunocytochemistry. Dr Emerich and Professor Sanberg raise issues about the mechanism of the neuronal loss. Our study was to clarify, by quantitative morphometry, the association of HIV with neuronal loss. We discussed the role of gp120 in mediating this damage. Quinolinic acid an excitotoxin, binds to the NMDA receptor (a subtype of glutamate receptor), and seems to be an important factor in mediating gp 120 neurotoxicity. This neurotoxicity only occurs in the presence of glutamate and the increased quinolinic acid is seen as an endogenous glutamate agonist that facilitates gp120 toxicity in vivo.4 This interaction between gp120 and glutamate may also explain the ability of NMDA antagonists to prevent mononuclear cells killing rat and chick neurons in vitros since analysis of the soluble factors secreted by HIV-infected macrophages did not implicate excitotoxins.6 Furthermore, HIV encephalitis is associated with higher levels of unintegrated HIV DNA. However,
IAN EVERALL PHILIP LUTHERT PETER LANTOS
Department of Neuropathology, Institute of Psychiatry, London SE5 8AF, UK
Hagler DN, Frame PT. Azidothymidine neurotoxicity. Lancet 1986; ii: 1392-93. Leigh D. Pellagra and the nutritional neuropathies: a neuropathological review, J Ment
Sci 1952; 98: 130-42. 3. Arai N, Honda Y, Amano N, Yagishita S, Misugi K. Foamy spheroid bodies in the substantia nigra. Report of an unusual case with recurrent attacks of peculiar twilight state. J Neurol 1988; 235: 330-34. 4. Lipton SA. HIV-related neurotoxicity. Brain Pathol 1991; 1: 193-99. 5. Giullian D, Vaca K, Noonan CC. Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science 1990; 250: 1593-96 6. Pulliam L, Herndier BG, Tang NM, McGrath MS. Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains. J Clin Invest 1991; 87: 503-12. 7. Pang S, Koyanagi Y, Miles S, Wiley C, Vinters HV, Chen ISY. High levels of unintegrated HIV-1 DNA in brain tissue of AIDS dementia patients. Nature 1990; 343: 85-89. 8. Cummings JL, Benson DF. Subcortical dementia: review of an emerging concept. Arch Neurol 1984; 41: 874-79. 9. Price RW, Brew B, Sidtis J, Rosenblum M, Scheck AC, Cleary P. The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science 1988; 239: 586-92.
Blood-pressure measurement
in pregnancy
ways forward for pregnancy; automated
SiR,—Your May 18 editorial outlines three blood
pressure
measurement
in
sphygmomanometers, self-monitoring, and use of systolic blood pressure to defme hypertension. Although not widely studied, there seems to be a substantial difference between the auscultated fourth and fifth sounds in patients with moderate or severe hypertension in pregnancy, and this difference increases with systolic blood pressure-eg, a systolic blood pressure value of 170 mm Hg is associated with an auscultated fourth sound recorded at 125 mm Hg and an auscultated fifth sound at 95 mm Hg. The widespread introduction of automated blood-pressure measurement devices in delivery units means this difference is of practical importance, and may not be widely appreciated. Most automated devices display a diastolic blood pressure that approximates to the auscultated fifth sound, yet the threshold for the treatment of severe hypertension in many units is an auscultated fourth sound at 110 mm Hg. With the use of automated devices the goalposts have been changed, and if midwives and clinicians accept uncritically the diastolic measurement from an automated device, the patient may be exposed to prolonged periods of sustained severe hypertension with its attendant morbidity and mortality. These unfortunate consequences have been noted in three major teaching units in the UK in the past twelve months. The simplest ways to prevent these difficulties are to avoid automated blood pressure measurement devices in patients with moderate or severe hypertension in pregnancy, or to adopt your suggestion of the use of systolic blood pressure to define hypertension in these circumstances.
6 Cavendish Gardens, Sneyd Park, Bristol BS9 1RQ, UK
M. J. QUINN
