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PULMONARY FAT EMBOLISATION AFTER BONE MARROW TRANSPLANTATION
715 DO BENZODIAZEPINES CAUSE CEREBRAL ATROPHY?
StR,-Post-mortem examinations and pneumoencephalographic studies have shown that alcoholism is often associated with’cerebral atrophy (or shrinkage), and computed tomographic (CT) scans have confirmed this.1 among possible causes, pre-existing brain damage, malnutrition, repeated head injuries, alcoholic liver disease, vascular lesions, toxicity of acetaldehyde, and a direct toxic effect of alcohol have all been considered. However, the correlation between the amount and duration of alcohol intakeand the partial reversibility after long term abstinence3,4 points to a direct toxic effect of alcohol (or acetaldehyde) on the nervous structures. People with benzodiazepine dependence have a clinical picture of addiction similar to that in alcoholism, but without the
hyperosmolality, liver damage, high acetaldehyde levels, and coagulation abnormalities. Little is known about the brain size of5 benzodiazepine dependents. We could not confirm Lader’s finding of cerebral atrophy in our first patients so we analysed twenty-eight consecutive patients with benzodiazepine dependence who had no evidence of further heavy drug or alcohol intake or pre-existing brain damage. We compared their CTs with those of patients of the same age from our headache clinic with normal physical and EEG findings and no history of addiction and with those of alcoholics fulfilling the criteria of DSM IIL6 Alcoholics were matched for age and duration of abuse. We also compared CTs from patients with combined benzodiazepine-alcohol abuse with those from alcoholics and controls. Our definition of benzodiazepine dependence is given
elsewhere.7 We assessed, on a ’Siretom 2000’, ventricular size by measuring the intercaudate width8and the largest width of the third ventricle. Sulcal, sylvian, and interhemispheric fissure widening were graded.9 Atrophy was graded 0 or 1 (normal) and 2-7 (abnormal). All radiological indices of brain size were comparable for benzodiazepine dependents and controls, but significantly different for alcoholics and patients with combined benzodiazepine-alcohol abuse (table). Our findings suggest that isolated abuse of benzodiazepines is not associated with cerebral atrophy, though the number of patients was small and the longest duration of dependence was only 18 years. Lader5 did not consider past or present heavy drinking as a cause ’
1. Ron MA. Syndromes of alcohol-related brain damage. Br Med Bull 1982; 38: 91-94. 2 Cala LA, Jones B, Mastaglia FL, Wiley B. Brain atrophy and intellectual impairment in heavy drinkers: a clinical, psychometric and computerized tomography study. Aust NZ J Med 1978; 8: 147-53. 3 Carlen PL, Wortzman G, Holgate RC, Wilkinson DA, Rankin JG. Reversible cerebral atrophy in recently abstinent chronic alcoholics measured by computed tomography 4
scans. Science 1978; 200: 1076-78. Ron MA, Acker W, Shaw GK, Lishman WA. Computerized tomography of the brain in chronic alcoholism. Brain 1982; 105: 497-514.
Hirnatrophie bei chronischer Valium-Anwendung? Cited in: ArzneiTelegramm 1982, 5: 51. 6. Diagnostic and statistical manual of mental disorders, 3rd ed. American Psychiatric Association, 1980. 7 Kemper N, Poser W, Poser S. Benzodiazepin-Abhängigkeit. Deutsch M Wschr 1980; 5 Lader M
105: 1707-12. 8. Huckman MS, Fox
atrophy in his benzodiazepine dependents (personal communication). Most of our benzodiazepine dependents turned out to have a history of alcohol abuse and had to be eliminated from the isolated benzodiazepine abuse group. Patients with combined benzodiazepine-alcohol dependence show some degree of cerebral atrophy in their CTs (table). The clinical signs and symptoms of chronic benzodiazepine abuse are similar to the effects of heavy drinking. If it can be substantiated by necropsy that benzodiazepine dependence is not associated with
of cerebral
J, Topel J. The validity of criteria for the evaluation of cerebral atrophy by computed tomography. Neuroradiology 1975; 116: 85-92. 9. Lishman WA, Ron MA, Acker W. Computed tomography of the brain and psychometric assessment of alcoholic patients: a British study In: Richter D, ed. Addiction and brain damage. London: Croom Helm, 1980: 215-27.
visible brain damage, this abuse disorder could be studied as a model of "pure dependence" without the secondary brain changes involved in alcoholism.
PULMONARY FAT EMBOLISATION AFTER BONE MARROW TRANSPLANTATION
SIR,-Lung complications are common in patients with bone transplants (BMT). They usually take the form of interstitial pneumonitis, vascular abnormalities, and pneumonias due to a variety of organisms including bacteria, viruses, fungi, and Pneumocystis carinii.l Some patients have an acute haemorrhagic pulmonary oedema of unknown aetiology which is associated with fever, rash, fluid retention, uraemia, hypoalbuminaemia, andlow central venous pressure.2Other patients acquire lymphocytic bronchitis as an expression of graft-versus-host disease.3 We have recently found at necropsy widespread intravascular fat droplets (figure) in the lungs of eight out of nine patients who had received allogeneic bone marrow grafts for acute leukaemia, and in marrow
whom tissue was examined for fat in either frozen or resin embedded sections. This finding does not appear to have been previously reported as a complication of BMT. The absence of intravascular lipid in any other organ examined suggests that it is embolic. The emboli take the form of small homogeneous lipid droplets confined to the microvasculature and are also present in areas of haemorrhage. Fragments of bone marrow, commonly seen after fractures, were not observed. We do not know if acute haemorrhagic pulmonary oedema is related to the emboli. Of the eight patients with emboli, four had acute haemorrhagic pulmonary oedema, three had interstitial pneumonitis, and one had focal alveolar haemorrhages. Bacterial bronchopneumonia was also present in one patient with interstitial pneumonitis. The effect of fat embolism on the lung may depend upon the chemical composition of the intravascular lipid: free fatty acids are thought to be more damaging than neutral lipid.4 JP, Depledge MH, Powles RL, Morgenstern GR, Trickey BS, Dady PJ. The histopathology of the lung following bone marrow transplantation J Clin Pathol (in press). Powles RL, Morgenstern GR. Allogeneic bone marrow transplantation using mismatched family donors. In: White D, ed. Cyclosporin A. Amsterdam: Elsevier,
1. Sloane
2.
1982. 3. Berschorner
WE, Saral R, Hutchins GM, Tutschka PJ, Santos GW. Lymphocytic bronchitis associated with graft-versus-host disease in recipients of bone-marrow
transplants. N Engl J Med 1978; 299: 1030-36. 4. Peltier LF. Fat embolism III: The toxic properties of neutral fat and free Surgery 1956; 40: 665-70.
COMPARISON OF MEASURES OF BRAIN ATROPHY BETWEEN BENZODIAZEPINE DEPENDENTS, ALCOHOLICS DEPENDENCE), AND CONTROLS (MATCHED FOR AGE)
Values are meanstSD.
W. POSER S. POSER D. ROSCHER A. ARGYRAKIS
Departments of Psychiatry, Neurology, and Neuroradiology, University of Göttingen, 3400 Göttingen, West Germany
fatty acids.
(MATCHED FOR AGE AND DURATION OF
Dependents were compared with controls by Nemenyi’s test (intercaudate width and diameter of 3rd ventricle) or chi square test for multiple comparisons.
716
Lung function studies have shown that two types of abnormality consistently occur after BMT: a transient restrictive ventilatory defect which reaches a nadir at about 4-6 weeks, and an impairment of gas transfer which, although showing some improvement, does 5 not return to pre-transplant values, at least within the first year.5 The ventilatory defect may be due to transient interstitial oedema. The cause of the impaired gas transfer is not known but many patients show no thickening of the alveolar walls, suggesting that it is not due to an increase in alveolar-capillary diffusion distance. In the absence of other abnormalities, poor perfusion of alveoli due to multiple emboli with an associated increase in ventilation/perfusion mismatching is a possible explanation. The cause of the embdti is not yet understood but pulmonary oedema associated with fat embolisation has been described in immunocompromised patients receiving steroids6,7 and it has been suggested that the emboli could be derived from a steroid-induced fatty liver8 or from local action on low-density serum All our patients except the one without emboli had received prednisolone at high doses (200-1500 mg per day). However, none, of our cases had a significant degree of fatty change in the liver. The , emboli are not likely to be derived from the transplant itself because the interval between grafting and death was usually several weeks,
lipoproteins.9
5
6.
Depledge MH, Barrett A, Powles RL. Lung function after bone marrow grafting. Int J Rad Oncol Biol Phys (in press). Moran TJ. Cortisone induced alterations in lipid metabolism. Arch Pathol 1962; 73: 52-64.
7. Pastore
L, Kessler S Pulmonary fat embolization in the immuno-compromised
patient. Am J
Surg Pathol 1982; 6:
315-22.
8. Hill RB. Fatal fat embolism from steroid-induced
fatty liver. N Engl J Med 1961; 265:
318-20. 9.
Mahley RW, Gray ME, LeQuire VS. Role of plasma lipoproteins in cortisone-induced fat embolism. Am
J Pathol 1972, 66:
43-64.
Semi-thin resin embedded section stained with toluidine-blue. There are numerous dark globules of lipid within alveolar capillaries as well as within a larger vessel at the top of the picture. (x 250.)
possibility cannot be altogether excluded-indeed, the highest density of emboli was seen in a patient who received a fourth transfusion of marrow only 2 days before death. No correlation was found between the presence of fat emboli in the lung and any other factor, including the use of artificial ventilation, the dose or route of administration of cyclosporin, the presence of graft-versus-host disease, the dose or dose rate of total body irradiation, and the use of intravenous lipid feeding. but this
Department of Histopathology and Experimental Pathology, Charing Cross Hospital Medical School, London W6 8RF
F. J. PARADINAS
Department of Histopathology, Royal Marsden Hospital, Sutton
J. P. SLOANE
Lung Function Unit,
Royal Marsden Hospital, Sutton
M. H. DEPLEDGE
Leukaemia Unit, Royal Marsden Hospital, Sutton
G. R. MORGENSTERN
Ludwig Institute for Cancer Research (London Branch), Royal Marsden Hospital, Sutton
J.
Department of Pathology, Cardiothoracic Institute, Brompton Hospital, London SW3
B. CORRIN
P. MONAGHAN D. B. ROBERTS
PEPTIDASES IN AMNIOTIC FLUID: LOW VALUES IN CYSTIC FIBROSIS
SIR,-There have been several attempts at antenatal diagnosis for
cystic fibrosis, but of the methods that
have been studied in detail has proved reliable enough for routine use; the false negative rates have been too high. Mr Carbarns and colleagues (Feb 2, p 329) reported a preliminary study of the activity of peptidases in supernatant amniotic fluid. An assay of y-glutamyltranspeptidase (EC 2.3.2.2, GGTP) or microsomal aminopeptidase (EC 3.4.11.2, APM) distinguished cystic fibrosis from normal pregnancies, peptidase activity being significantly lower in the amniotic fluid from affected pregnancies, especially early in the second trimester. Dr David Brock kindly told us about this work last year and we have been doing a similar study, none
activity in supernatant amniotic fluid. pregnancies; 0 pregnancies at risk for cystic fibrosis, born unaffected; 0 at risk for cystic fibrosis born affected. GGTP
$== normal
=
=
StR,-Post-mortem examinations and pneumoencephalographic studies have shown that alcoholism is often associated with’cerebral atrophy (or shrinkage), and computed tomographic (CT) scans have confirmed this.1 among possible causes, pre-existing brain damage, malnutrition, repeated head injuries, alcoholic liver disease, vascular lesions, toxicity of acetaldehyde, and a direct toxic effect of alcohol have all been considered. However, the correlation between the amount and duration of alcohol intakeand the partial reversibility after long term abstinence3,4 points to a direct toxic effect of alcohol (or acetaldehyde) on the nervous structures. People with benzodiazepine dependence have a clinical picture of addiction similar to that in alcoholism, but without the
hyperosmolality, liver damage, high acetaldehyde levels, and coagulation abnormalities. Little is known about the brain size of5 benzodiazepine dependents. We could not confirm Lader’s finding of cerebral atrophy in our first patients so we analysed twenty-eight consecutive patients with benzodiazepine dependence who had no evidence of further heavy drug or alcohol intake or pre-existing brain damage. We compared their CTs with those of patients of the same age from our headache clinic with normal physical and EEG findings and no history of addiction and with those of alcoholics fulfilling the criteria of DSM IIL6 Alcoholics were matched for age and duration of abuse. We also compared CTs from patients with combined benzodiazepine-alcohol abuse with those from alcoholics and controls. Our definition of benzodiazepine dependence is given
elsewhere.7 We assessed, on a ’Siretom 2000’, ventricular size by measuring the intercaudate width8and the largest width of the third ventricle. Sulcal, sylvian, and interhemispheric fissure widening were graded.9 Atrophy was graded 0 or 1 (normal) and 2-7 (abnormal). All radiological indices of brain size were comparable for benzodiazepine dependents and controls, but significantly different for alcoholics and patients with combined benzodiazepine-alcohol abuse (table). Our findings suggest that isolated abuse of benzodiazepines is not associated with cerebral atrophy, though the number of patients was small and the longest duration of dependence was only 18 years. Lader5 did not consider past or present heavy drinking as a cause ’
1. Ron MA. Syndromes of alcohol-related brain damage. Br Med Bull 1982; 38: 91-94. 2 Cala LA, Jones B, Mastaglia FL, Wiley B. Brain atrophy and intellectual impairment in heavy drinkers: a clinical, psychometric and computerized tomography study. Aust NZ J Med 1978; 8: 147-53. 3 Carlen PL, Wortzman G, Holgate RC, Wilkinson DA, Rankin JG. Reversible cerebral atrophy in recently abstinent chronic alcoholics measured by computed tomography 4
scans. Science 1978; 200: 1076-78. Ron MA, Acker W, Shaw GK, Lishman WA. Computerized tomography of the brain in chronic alcoholism. Brain 1982; 105: 497-514.
Hirnatrophie bei chronischer Valium-Anwendung? Cited in: ArzneiTelegramm 1982, 5: 51. 6. Diagnostic and statistical manual of mental disorders, 3rd ed. American Psychiatric Association, 1980. 7 Kemper N, Poser W, Poser S. Benzodiazepin-Abhängigkeit. Deutsch M Wschr 1980; 5 Lader M
105: 1707-12. 8. Huckman MS, Fox
atrophy in his benzodiazepine dependents (personal communication). Most of our benzodiazepine dependents turned out to have a history of alcohol abuse and had to be eliminated from the isolated benzodiazepine abuse group. Patients with combined benzodiazepine-alcohol dependence show some degree of cerebral atrophy in their CTs (table). The clinical signs and symptoms of chronic benzodiazepine abuse are similar to the effects of heavy drinking. If it can be substantiated by necropsy that benzodiazepine dependence is not associated with
of cerebral
J, Topel J. The validity of criteria for the evaluation of cerebral atrophy by computed tomography. Neuroradiology 1975; 116: 85-92. 9. Lishman WA, Ron MA, Acker W. Computed tomography of the brain and psychometric assessment of alcoholic patients: a British study In: Richter D, ed. Addiction and brain damage. London: Croom Helm, 1980: 215-27.
visible brain damage, this abuse disorder could be studied as a model of "pure dependence" without the secondary brain changes involved in alcoholism.
PULMONARY FAT EMBOLISATION AFTER BONE MARROW TRANSPLANTATION
SIR,-Lung complications are common in patients with bone transplants (BMT). They usually take the form of interstitial pneumonitis, vascular abnormalities, and pneumonias due to a variety of organisms including bacteria, viruses, fungi, and Pneumocystis carinii.l Some patients have an acute haemorrhagic pulmonary oedema of unknown aetiology which is associated with fever, rash, fluid retention, uraemia, hypoalbuminaemia, andlow central venous pressure.2Other patients acquire lymphocytic bronchitis as an expression of graft-versus-host disease.3 We have recently found at necropsy widespread intravascular fat droplets (figure) in the lungs of eight out of nine patients who had received allogeneic bone marrow grafts for acute leukaemia, and in marrow
whom tissue was examined for fat in either frozen or resin embedded sections. This finding does not appear to have been previously reported as a complication of BMT. The absence of intravascular lipid in any other organ examined suggests that it is embolic. The emboli take the form of small homogeneous lipid droplets confined to the microvasculature and are also present in areas of haemorrhage. Fragments of bone marrow, commonly seen after fractures, were not observed. We do not know if acute haemorrhagic pulmonary oedema is related to the emboli. Of the eight patients with emboli, four had acute haemorrhagic pulmonary oedema, three had interstitial pneumonitis, and one had focal alveolar haemorrhages. Bacterial bronchopneumonia was also present in one patient with interstitial pneumonitis. The effect of fat embolism on the lung may depend upon the chemical composition of the intravascular lipid: free fatty acids are thought to be more damaging than neutral lipid.4 JP, Depledge MH, Powles RL, Morgenstern GR, Trickey BS, Dady PJ. The histopathology of the lung following bone marrow transplantation J Clin Pathol (in press). Powles RL, Morgenstern GR. Allogeneic bone marrow transplantation using mismatched family donors. In: White D, ed. Cyclosporin A. Amsterdam: Elsevier,
1. Sloane
2.
1982. 3. Berschorner
WE, Saral R, Hutchins GM, Tutschka PJ, Santos GW. Lymphocytic bronchitis associated with graft-versus-host disease in recipients of bone-marrow
transplants. N Engl J Med 1978; 299: 1030-36. 4. Peltier LF. Fat embolism III: The toxic properties of neutral fat and free Surgery 1956; 40: 665-70.
COMPARISON OF MEASURES OF BRAIN ATROPHY BETWEEN BENZODIAZEPINE DEPENDENTS, ALCOHOLICS DEPENDENCE), AND CONTROLS (MATCHED FOR AGE)
Values are meanstSD.
W. POSER S. POSER D. ROSCHER A. ARGYRAKIS
Departments of Psychiatry, Neurology, and Neuroradiology, University of Göttingen, 3400 Göttingen, West Germany
fatty acids.
(MATCHED FOR AGE AND DURATION OF
Dependents were compared with controls by Nemenyi’s test (intercaudate width and diameter of 3rd ventricle) or chi square test for multiple comparisons.
716
Lung function studies have shown that two types of abnormality consistently occur after BMT: a transient restrictive ventilatory defect which reaches a nadir at about 4-6 weeks, and an impairment of gas transfer which, although showing some improvement, does 5 not return to pre-transplant values, at least within the first year.5 The ventilatory defect may be due to transient interstitial oedema. The cause of the impaired gas transfer is not known but many patients show no thickening of the alveolar walls, suggesting that it is not due to an increase in alveolar-capillary diffusion distance. In the absence of other abnormalities, poor perfusion of alveoli due to multiple emboli with an associated increase in ventilation/perfusion mismatching is a possible explanation. The cause of the embdti is not yet understood but pulmonary oedema associated with fat embolisation has been described in immunocompromised patients receiving steroids6,7 and it has been suggested that the emboli could be derived from a steroid-induced fatty liver8 or from local action on low-density serum All our patients except the one without emboli had received prednisolone at high doses (200-1500 mg per day). However, none, of our cases had a significant degree of fatty change in the liver. The , emboli are not likely to be derived from the transplant itself because the interval between grafting and death was usually several weeks,
lipoproteins.9
5
6.
Depledge MH, Barrett A, Powles RL. Lung function after bone marrow grafting. Int J Rad Oncol Biol Phys (in press). Moran TJ. Cortisone induced alterations in lipid metabolism. Arch Pathol 1962; 73: 52-64.
7. Pastore
L, Kessler S Pulmonary fat embolization in the immuno-compromised
patient. Am J
Surg Pathol 1982; 6:
315-22.
8. Hill RB. Fatal fat embolism from steroid-induced
fatty liver. N Engl J Med 1961; 265:
318-20. 9.
Mahley RW, Gray ME, LeQuire VS. Role of plasma lipoproteins in cortisone-induced fat embolism. Am
J Pathol 1972, 66:
43-64.
Semi-thin resin embedded section stained with toluidine-blue. There are numerous dark globules of lipid within alveolar capillaries as well as within a larger vessel at the top of the picture. (x 250.)
possibility cannot be altogether excluded-indeed, the highest density of emboli was seen in a patient who received a fourth transfusion of marrow only 2 days before death. No correlation was found between the presence of fat emboli in the lung and any other factor, including the use of artificial ventilation, the dose or route of administration of cyclosporin, the presence of graft-versus-host disease, the dose or dose rate of total body irradiation, and the use of intravenous lipid feeding. but this
Department of Histopathology and Experimental Pathology, Charing Cross Hospital Medical School, London W6 8RF
F. J. PARADINAS
Department of Histopathology, Royal Marsden Hospital, Sutton
J. P. SLOANE
Lung Function Unit,
Royal Marsden Hospital, Sutton
M. H. DEPLEDGE
Leukaemia Unit, Royal Marsden Hospital, Sutton
G. R. MORGENSTERN
Ludwig Institute for Cancer Research (London Branch), Royal Marsden Hospital, Sutton
J.
Department of Pathology, Cardiothoracic Institute, Brompton Hospital, London SW3
B. CORRIN
P. MONAGHAN D. B. ROBERTS
PEPTIDASES IN AMNIOTIC FLUID: LOW VALUES IN CYSTIC FIBROSIS
SIR,-There have been several attempts at antenatal diagnosis for
cystic fibrosis, but of the methods that
have been studied in detail has proved reliable enough for routine use; the false negative rates have been too high. Mr Carbarns and colleagues (Feb 2, p 329) reported a preliminary study of the activity of peptidases in supernatant amniotic fluid. An assay of y-glutamyltranspeptidase (EC 2.3.2.2, GGTP) or microsomal aminopeptidase (EC 3.4.11.2, APM) distinguished cystic fibrosis from normal pregnancies, peptidase activity being significantly lower in the amniotic fluid from affected pregnancies, especially early in the second trimester. Dr David Brock kindly told us about this work last year and we have been doing a similar study, none
activity in supernatant amniotic fluid. pregnancies; 0 pregnancies at risk for cystic fibrosis, born unaffected; 0 at risk for cystic fibrosis born affected. GGTP
$== normal
=
=