FATAL ENCEPHALOPATHY IN ACUTE POISONING PHOSPHORUS INSECTICIDES A CLINICO-PATHOLOGIC STUDY OF TWO CASES J. de Reuck*, F. Colardyn**
WITH ORGANO-
and J. Willems***
SUMMARY The clinico-pathologic findings in two patients with an acute organophosphorus intoxication, who died from an atypical central neurologic disorder, are presented. The necropsy showed severe hemorrhagic necrosis of the walls of the third and of the fourth ventricles, resembling lesions observed in severe forms of Wernicke’s encephalopathy. The pathogenesis of this unusual complication is discussed.
INTRODUCTION
Nervous system function may be deranged as part of an acute and sometimes fatal poisoning with organophosphorus compounds. The brain findings are atypical and consist of hyperemia with capillary dilation and severe edema (ENGLUND, 197 1). A delayed neurotoxicity is produced by some of these compounds and consists mainly of a severe motor polyneuropathy, characterized by a long-lasting flaccid paralysis of the distal muscles of the upper and lower extremities, and sometimes accompanied by degeneration of the cortico-spinal tracts in the spinal cord (ADAMS and VICTOR, 1977). Degeneration of the myelin sheaths and of the axons are the main histologic lesions (NAMBA et al., 1971; JOHNSON, 1975). An unexpected type of fatal encephalopathy in two cases of acute organophosphorus intoxication is presented here.
CASE REPORTS
Case 1 An 2%year old man, with a previous history of chronic alcoholism, was admitted to the intensive care department, approximately 5 hours after ingestion of an unknown amount of alcohol, chlordiazepoxide and trichlornate, an organophosphorus cholinesterase inhibitor, used as an insecticide. On admission the patient was confused and desoriented. Bilateral miosis, fasciculations of several muscles, diffuse sweating, diarrhea and tachycardia were the main physical findings. Cholinesterase activity was absent in serum and inhibited for 30% in red blood cells. Gastric lavage * Neuropathology Unit, Departments of Neurology and Pathology. ** Intensive Care Department. *** J. F. & C. Heymans Institute of Pharmacology, University of Ghent, Belgium. Clin. Neurol. Neurosurg., 1979. Vol. 81-4
248 was performed, and atropine and the cholinesterase reactivator obidoxim were administered. Also ampicillin and a vitamine B complex were given intravenously. Serum cholinesterase activity was absent during the whole course of the disease whereas the activity in red bloodcells further decreased until the 4th day of hospitalisation and started to normalize from then on. Atropine was given until the 8th day of hospitalisation. After an initial improvement of the symptoms of cholinesterase poisoning, the neurologic state of the patient became suddenly worse on the 4th day after admission. He developed high fever, bronchopneumonia, gastric bleeding and acidosis. His consciousness decreased and the four extremities became hypertonic with excessively brisk and clonic tendon reflexes, but without Babinski signs. Optic disks and cranial nerves were normal. Repeated hemocultures remained sterile. The patient was treated with intravenous saline and blood infusions, gentamycin, cefazolin, clindamycin, cimetidine, corticosteroids and vitamine B. The next day he was more deeply comatose. He had hypotension and hypothermia for a period of 24 hours; however, there was no decrease in diuresis. The eyes were fixed in midline position on doll’s head manoeuvre, but occasionally short episodes of ocular bobbing were present. The pupils were still miotic and non-reactive to light. The cornea1 reflexes were absent. The muscle tonus and the tendon reflexes were now decreased and Babinski signs were present. The patient reacted weakly to pain stimuli. A lumbar puncture revealed a slightly cloudy fluid with a normal pressure, a protein content of 136 mg/lOO ml and a moderate leucocytosis; the glucorachia was normal and cultures remained sterile. EEG showed flattened curves with the sporadic appearance of a-waves in the frontal regions. Bilateral, carotid and vertebral angiograms performed the next day were normal. In spite of intensive treatment the patient went into respiratory arrest on the 6th day of hospitalisation and from then on required artificial ventilation. He became more and more deeply comatose and after an attack of gram-negative sepsis by Klebsiella Pneumoniae he died 20 days after admission. The necropsy revealed massive gastro-intestinal bleeding. due to three gastric ulcers, severe bronchopneumonia and pleuritis, acute tubular necrosis and a fatty liver. The fresh brain weighed 1420 g. External examination showed a fragile and hemorrhagic brainstem. The basilar and the vertebral arteries were patent. Coronal sections of the cerebral hemispheres and horizontal sections of brain-stem and cerebellum disclosed an extensive hemorrhagic necrosis of the medial part of both thalami and hypothalami, and of the mesencephalon and the pons, mainly near the aqueduct and the floor of the fourth ventricle. The cerebral cortex, the subcortical white matter, the striati, the cerebellum and the medulla appeared grossly normal. The microscopic examination revealed necrosis with massive infiltration by red blood cells and macrophages in the paraventricular regions df the diencephalon (Fig. 1) and in the major part of the brainstem. In the areas surrounding the hemorrhagic lesions of the thalamus and hypothalamus, chromatolytic and pyknotic neurons, proliferation of microglial cells and fibrillary astrocytes, and
249 Fig. 1. Coronal section of the right thalamus and hypothalamus in case 1. Note the hemorrhagic necrosis, restricted to the regions adjacent to the wail of the third ventricle (Luxol fast blue, 4 x ).
capillary hyperplasia with pericapillary hemorrhages were observed. There was also a severe neuronal loss in the mamillary bodies (Fig. 2) and diffuse demyelination of the mamillo-thalamic tracts. Also a rounded area of necrosis, involving partly claustrum, external capsule and putamen of the left hemisphere was observed. The cerebral cortex and the cerebellum appeared to be spared, except for some agonal changes. Microscopic examination of several muscle samples revealed, mainly in those of the quadriceps femoris muscle and to a lesser degree in the deltoid, diaphragm and intercostal muscles, waxy-degeneration and lysis of individual fibres (Fig. 3). The interstitial connective tissue, the nerve fibres and the blood vessels were normal. Case 2 An unconscious 50-year old man, with a previous history of recurrent depressions, was admitted to the intensive care department approximately 6 hours after ingestion of an unknown amount of dimethoate, an organophosphorus insecticide. The
Fig. 2. Severe neuronal loss and spongiosis case I (Luxol fast blue. 400 X).
of the neuropile.
with astroglial
proliferation
in a mamillary
body of
physical findings were: miosis, dyspnoe, tachycardia and diffuse sweating. The cholinesterase activity in serum and red bloodcells was absent. Gastric lavage was performed and atropine, vitamine B complex and the cholinesterase reactivator P,S were administered. Eight hours later the patient awoke. Sixteen hours after admission he developed respiratory difficulties, a short episode of hypotension, bradycardia and cardiac arrest, due to bronchial obstruction due to abundant secretions. Shortly after reanimation he was again conscious but artificial ventilation was continued, accompagnied by high doses of atropine. On the third day of hospitalisation dopamine had to be administered because of the occurrence of shock and after a second cardiac arrest the patient needed positive and expiratory pressure ventilation for bilateral lung infiltrations with low PO,. At that time the plasma cholinesterase activity had normalized, but the activity in the red bloodcells remained inhibited for almost 90%. The patient remained unconscious. There was a mild anisocoria, the left pupil being larger than the right, with absence of light and cornea1 reflexes. The eyes were fixed in a midline position. The tendon reflexes were positive and symmetrical, without Babinski signs. The patient reacted weakly to pain stimuli. During the next few days the patient became more and more deeply comatose and died on the 9th day of hospitalisation. The necropsy revealed only severe bronchopneumonia. The fresh brain weighed
Fig. 3. Waxy-degeneration
and lysis of some fibers in the quadriceps
femoris
muscle of case 1 (H.E., 400X).
1300 g. On external examination leptomeningeal hemorrhages were present on the convex surface of both occipital lobes and the brain-stem appeared to be softened. The arteries at the base of the brain showed severe atherosclerosis, but no occlusion could be found on careful dissection. Coronal sections of the cerebral hemispheres showed a large number of small bleedings and necrotic foci in the paraventricular regions of the thalami, hypothalami and mamillary bodies. The cerebral cortex, the white matter and the basal ganglia appeared to be spared. Also small and large hemorrhagic lesions were seen in the mesencephalon and in the pons, while the cerebellum and the medulla had a normal appearance. The microscopic examination showed severe neuronal loss and degeneration in the medial nucleus of the thalamus, the hypothalamus, the mamillary bodies and the pons. There was also proliferation of microglial cells and astrocytes with hyperplasia of capillaries. A large number of pericapillary hemorrhages were present (Fig. 4 and 5). In the right lenticular nucleus a sharply bounded necrotic and hemorrhagic lesion, invaded by macrophages, was observed. The cerebellar cortex showed a marked loss of Purkinje-cells, while the granular and molecular layers were spared. In the cerebral cortex only a mild and diffuse loss of neurons was seen.
DISCUSSION
Both cases presented,
showed clinical signs of a cholinesterase
poisoning due to
Fig. 4. Extensive necrosis with perivascular hemorrhages in the subependymal (Luxol fast blue, 64x f.
thalamic structures of case 2
ingestion of an unknown amount of an organophosphorus cholinesterase inhibitor. Both were treated in approximateiy the same way (WILLEMS, 1976) and high doses of vitamine B complex were given intravenously. Although the cholinesterase activity in serum and red bloodcells was severely inhibited, the clinical evolution at first seemed to be favorable. After an initial partial improvement the situation suddenly worsened, with the appearance of bulbar signs in the first patient and with severe neuro-vegetative dysregulation in the second patient. The brain findings consisted of severe hemorrhagic necrosis of the diencephalon and of the brainstem in the regions adjacent to the third and fourth ventricles and around the aqueduct. Besides their acute neurotoxicity, causing central and peripheral signs of cholinergic hyperactivity, some organophosphorus compounds can produce a delayed neurotoxicity, involving peripheral nerves and the posterior columns of the spinal cord (NAMBA et al., 197 1). However, trichlornate and dimethoate, which are the products ingested by the first and the second patient respectively, are known not to produce this delayed neurotoxicity (JOHNSON, 1975). The muscle fiber necrosis, observed in the first case, can be related to the known necrotizing effects of organophosphorus cholinesterase inhibitors on the motor end-plates (DE REUCK and WILLEMS, 1975). The neuropathologic findings in the cases presented were similar to those
253
Fig. 5. Hemorrhagic necrosis with perivascular infiltration by lymphocytes and plasmocytes in the basis pontis of case 2 (Luxol fast blue, 400 x).
observed in severe forms of Wernicke’s encephalopathy (VICTOR et al., 1971). Perhaps the only unusual finding was the marked extension of the hemorrhagic necrosis to the central pontine region. No clear evidence is available why these patients with an acute organophosphorus intoxication should develop a severe form of Wernicke’s encephalopathy. The first patient was an alcoholic, but from the first day of hospitalisation onwards he received thiamine intravenously and only developed symptoms of a central neurologic disorder on the 4th day of hospitalisation. No alcohol abuse was noted in the second patient. Also neither patient, prior to admission, suffered from malnutrion or chronic disease, which could be held responsible for the occurrence of Wernicke’s encephalopathy (LAPLANE and MOREL-MAROGER, 1973; EBELS, 1978). However, the similarity of the neuropathologic findings with Wernicke’s encephalopathy in the cases presented suggests that the ‘biochemical lesion’ is related to the thiamine metabolism. ITOKAWA and COOPER (1970) have shown that high doses of acetylcholine will release thiamine from perfused animal brain preparations. It can be postulated that the increased levels of acetylcholine in the brains of the cases presented had led to thiamine depletion in the regions of predilection of Wemicke’s encephalopathy.
254 REFERENCES ADAMS, R. D. and VICTOR, M. (1977) Principles
of neurology. New York, McGraw-Hill. 8 13. common is Wernicke-Korsakoff syndrome? Lancet ii, 781. ENGLUND, G. (1971) Pesticides. In: Pathology of the nervous system, II, 1691. Ed. by J. Minckler, New York, McGraw Hill. ITOKAWA, Y. and COOPER, 1.R. (1970) Ion movements and thiamine. II. The release of the vitamin from membrane fragments. Biochim. Biophys. Acta 196,274. JOHNSON, M. K. (1975) Organophosphorus esters causing delayed neurotoxic effects. Mechanism of action and structure/activity studies. Arch. Toxicol. 34,259. LAPLANE, D. and MOREL-MAROGER, A. (1973) Complications nerveuses de I’alcoolisme. In: Encyclopedic Medico-Chirurgicale - Systeme Nerveux. 17045 GlO, Paris. NAMBA, T.,NOLTE, c.,JACKREL, J.and GROB, D. (1971) Poisoning due to organophosphate insecticides. Amer. J. Med. 50,475. REUCK, J.DE and WILLEMS, J.(1975) Acute parathion poisoning. Myopathic changes in the diaphragm. J. Neurol. 208,309. VICTOR, M., ADAMS, R. D. and COLLINS, G. H. (1971) The Wernicke-Korsakoff syndrome. Philadelphia, Davis Co. WILLEMS, I.(1976) Therapy in organophosphate poisoning. Acta Clin. Belg. 31.21. EBELS,E.J.(1978) How
GOVERT
Samanmlling Het werkramebestanddeel van Ticlld
VAN
WIJNKADE
48 I3144
EG
MAASSLUIS
I TEL.
(018991
1 75 55
zame gevallen to, de noodzaak van stopzetten van de behandelmg allergle werd I,, u,,zonderl,,ke gevailen “ermeld. 811 tcepassing van hoge doswngen kunnen hemorragleen voorkomen
II tlclopldlnehydrochlorlde.
ECnFarmacoklinixhe studies hebben aangetoond. dat Ticlld een uitgesproken mhaberende aktiveeit uitoefent ten oprlchte van somm~ge plaatjerfunkter. deze Inhibiti.? w zich namehik door een verlenging van de bloedlngstijd, alsmede door en vermindering van de adhesweit en van de aggregatte va” de bloedDlaatjes. Dlt effekt treedt op b,, agqqarte door verschlilende ,nd”cere”de stoffen lander me% adenosinedifosfaat of ADP)
Hu,d-
Doswing en psbruiksanwijzing In funkte van de indwiduele biokqxhe gegevens vareert de doss tusen 2 B 4 dragees per dag. De gebrulkell,ke doserIng IS 2 dragees per dag. d.w L. Mn draw? ‘s motgens en B&n dragee ‘5 avonds Hoge doses worde” slechts kortdurend in het beg,” “8” de behandeltng voorgeschreven en daarna. I” funkt,e “a” de b,olog,sche en kl,n,scheevolutle “ermmderd. Aangeraden wordt Tlcltd ttjdens de maaltljden in te nemen VOO~Orpun~~bIl Bil assoctatie van Tlclid met antlcoagulantla, IE een bljzondere waakzaamheid geboden ondanks bet felt da gedurende bet vetloop van de kl,“lsche studies gee” enkel lncldent waaigenomen werd dat htermee I” betrekk,nq staat.
Contn indiknia Hemopathie& met verlengdeblwdmgstijd. Gabtuik tiidens de rrne
Wiizs van bowran Onder 25=‘C. Houdbaarhakl
Over gebrulk van deze siof in de zwangerschap blj de mew bestaan owoIdoende gegevens om de mogelljke schadelijkheld te beoordelen. Er zijn tot dusver geen aanwilzlngen voor schadelijkheid bii dierproeven.
AIs bovengenoemde rrchtlqn betreffende de bewarmg !n acht wordtgenomen, behoudt Ttcltd al z~ln therapeutlsche elgenschappen gedurende minnens 2 Par. Hwdahvorm Verpakking
5
30 draqees 6 250 mq.
WITH ORGANO-
and J. Willems***
SUMMARY The clinico-pathologic findings in two patients with an acute organophosphorus intoxication, who died from an atypical central neurologic disorder, are presented. The necropsy showed severe hemorrhagic necrosis of the walls of the third and of the fourth ventricles, resembling lesions observed in severe forms of Wernicke’s encephalopathy. The pathogenesis of this unusual complication is discussed.
INTRODUCTION
Nervous system function may be deranged as part of an acute and sometimes fatal poisoning with organophosphorus compounds. The brain findings are atypical and consist of hyperemia with capillary dilation and severe edema (ENGLUND, 197 1). A delayed neurotoxicity is produced by some of these compounds and consists mainly of a severe motor polyneuropathy, characterized by a long-lasting flaccid paralysis of the distal muscles of the upper and lower extremities, and sometimes accompanied by degeneration of the cortico-spinal tracts in the spinal cord (ADAMS and VICTOR, 1977). Degeneration of the myelin sheaths and of the axons are the main histologic lesions (NAMBA et al., 1971; JOHNSON, 1975). An unexpected type of fatal encephalopathy in two cases of acute organophosphorus intoxication is presented here.
CASE REPORTS
Case 1 An 2%year old man, with a previous history of chronic alcoholism, was admitted to the intensive care department, approximately 5 hours after ingestion of an unknown amount of alcohol, chlordiazepoxide and trichlornate, an organophosphorus cholinesterase inhibitor, used as an insecticide. On admission the patient was confused and desoriented. Bilateral miosis, fasciculations of several muscles, diffuse sweating, diarrhea and tachycardia were the main physical findings. Cholinesterase activity was absent in serum and inhibited for 30% in red blood cells. Gastric lavage * Neuropathology Unit, Departments of Neurology and Pathology. ** Intensive Care Department. *** J. F. & C. Heymans Institute of Pharmacology, University of Ghent, Belgium. Clin. Neurol. Neurosurg., 1979. Vol. 81-4
248 was performed, and atropine and the cholinesterase reactivator obidoxim were administered. Also ampicillin and a vitamine B complex were given intravenously. Serum cholinesterase activity was absent during the whole course of the disease whereas the activity in red bloodcells further decreased until the 4th day of hospitalisation and started to normalize from then on. Atropine was given until the 8th day of hospitalisation. After an initial improvement of the symptoms of cholinesterase poisoning, the neurologic state of the patient became suddenly worse on the 4th day after admission. He developed high fever, bronchopneumonia, gastric bleeding and acidosis. His consciousness decreased and the four extremities became hypertonic with excessively brisk and clonic tendon reflexes, but without Babinski signs. Optic disks and cranial nerves were normal. Repeated hemocultures remained sterile. The patient was treated with intravenous saline and blood infusions, gentamycin, cefazolin, clindamycin, cimetidine, corticosteroids and vitamine B. The next day he was more deeply comatose. He had hypotension and hypothermia for a period of 24 hours; however, there was no decrease in diuresis. The eyes were fixed in midline position on doll’s head manoeuvre, but occasionally short episodes of ocular bobbing were present. The pupils were still miotic and non-reactive to light. The cornea1 reflexes were absent. The muscle tonus and the tendon reflexes were now decreased and Babinski signs were present. The patient reacted weakly to pain stimuli. A lumbar puncture revealed a slightly cloudy fluid with a normal pressure, a protein content of 136 mg/lOO ml and a moderate leucocytosis; the glucorachia was normal and cultures remained sterile. EEG showed flattened curves with the sporadic appearance of a-waves in the frontal regions. Bilateral, carotid and vertebral angiograms performed the next day were normal. In spite of intensive treatment the patient went into respiratory arrest on the 6th day of hospitalisation and from then on required artificial ventilation. He became more and more deeply comatose and after an attack of gram-negative sepsis by Klebsiella Pneumoniae he died 20 days after admission. The necropsy revealed massive gastro-intestinal bleeding. due to three gastric ulcers, severe bronchopneumonia and pleuritis, acute tubular necrosis and a fatty liver. The fresh brain weighed 1420 g. External examination showed a fragile and hemorrhagic brainstem. The basilar and the vertebral arteries were patent. Coronal sections of the cerebral hemispheres and horizontal sections of brain-stem and cerebellum disclosed an extensive hemorrhagic necrosis of the medial part of both thalami and hypothalami, and of the mesencephalon and the pons, mainly near the aqueduct and the floor of the fourth ventricle. The cerebral cortex, the subcortical white matter, the striati, the cerebellum and the medulla appeared grossly normal. The microscopic examination revealed necrosis with massive infiltration by red blood cells and macrophages in the paraventricular regions df the diencephalon (Fig. 1) and in the major part of the brainstem. In the areas surrounding the hemorrhagic lesions of the thalamus and hypothalamus, chromatolytic and pyknotic neurons, proliferation of microglial cells and fibrillary astrocytes, and
249 Fig. 1. Coronal section of the right thalamus and hypothalamus in case 1. Note the hemorrhagic necrosis, restricted to the regions adjacent to the wail of the third ventricle (Luxol fast blue, 4 x ).
capillary hyperplasia with pericapillary hemorrhages were observed. There was also a severe neuronal loss in the mamillary bodies (Fig. 2) and diffuse demyelination of the mamillo-thalamic tracts. Also a rounded area of necrosis, involving partly claustrum, external capsule and putamen of the left hemisphere was observed. The cerebral cortex and the cerebellum appeared to be spared, except for some agonal changes. Microscopic examination of several muscle samples revealed, mainly in those of the quadriceps femoris muscle and to a lesser degree in the deltoid, diaphragm and intercostal muscles, waxy-degeneration and lysis of individual fibres (Fig. 3). The interstitial connective tissue, the nerve fibres and the blood vessels were normal. Case 2 An unconscious 50-year old man, with a previous history of recurrent depressions, was admitted to the intensive care department approximately 6 hours after ingestion of an unknown amount of dimethoate, an organophosphorus insecticide. The
Fig. 2. Severe neuronal loss and spongiosis case I (Luxol fast blue. 400 X).
of the neuropile.
with astroglial
proliferation
in a mamillary
body of
physical findings were: miosis, dyspnoe, tachycardia and diffuse sweating. The cholinesterase activity in serum and red bloodcells was absent. Gastric lavage was performed and atropine, vitamine B complex and the cholinesterase reactivator P,S were administered. Eight hours later the patient awoke. Sixteen hours after admission he developed respiratory difficulties, a short episode of hypotension, bradycardia and cardiac arrest, due to bronchial obstruction due to abundant secretions. Shortly after reanimation he was again conscious but artificial ventilation was continued, accompagnied by high doses of atropine. On the third day of hospitalisation dopamine had to be administered because of the occurrence of shock and after a second cardiac arrest the patient needed positive and expiratory pressure ventilation for bilateral lung infiltrations with low PO,. At that time the plasma cholinesterase activity had normalized, but the activity in the red bloodcells remained inhibited for almost 90%. The patient remained unconscious. There was a mild anisocoria, the left pupil being larger than the right, with absence of light and cornea1 reflexes. The eyes were fixed in a midline position. The tendon reflexes were positive and symmetrical, without Babinski signs. The patient reacted weakly to pain stimuli. During the next few days the patient became more and more deeply comatose and died on the 9th day of hospitalisation. The necropsy revealed only severe bronchopneumonia. The fresh brain weighed
Fig. 3. Waxy-degeneration
and lysis of some fibers in the quadriceps
femoris
muscle of case 1 (H.E., 400X).
1300 g. On external examination leptomeningeal hemorrhages were present on the convex surface of both occipital lobes and the brain-stem appeared to be softened. The arteries at the base of the brain showed severe atherosclerosis, but no occlusion could be found on careful dissection. Coronal sections of the cerebral hemispheres showed a large number of small bleedings and necrotic foci in the paraventricular regions of the thalami, hypothalami and mamillary bodies. The cerebral cortex, the white matter and the basal ganglia appeared to be spared. Also small and large hemorrhagic lesions were seen in the mesencephalon and in the pons, while the cerebellum and the medulla had a normal appearance. The microscopic examination showed severe neuronal loss and degeneration in the medial nucleus of the thalamus, the hypothalamus, the mamillary bodies and the pons. There was also proliferation of microglial cells and astrocytes with hyperplasia of capillaries. A large number of pericapillary hemorrhages were present (Fig. 4 and 5). In the right lenticular nucleus a sharply bounded necrotic and hemorrhagic lesion, invaded by macrophages, was observed. The cerebellar cortex showed a marked loss of Purkinje-cells, while the granular and molecular layers were spared. In the cerebral cortex only a mild and diffuse loss of neurons was seen.
DISCUSSION
Both cases presented,
showed clinical signs of a cholinesterase
poisoning due to
Fig. 4. Extensive necrosis with perivascular hemorrhages in the subependymal (Luxol fast blue, 64x f.
thalamic structures of case 2
ingestion of an unknown amount of an organophosphorus cholinesterase inhibitor. Both were treated in approximateiy the same way (WILLEMS, 1976) and high doses of vitamine B complex were given intravenously. Although the cholinesterase activity in serum and red bloodcells was severely inhibited, the clinical evolution at first seemed to be favorable. After an initial partial improvement the situation suddenly worsened, with the appearance of bulbar signs in the first patient and with severe neuro-vegetative dysregulation in the second patient. The brain findings consisted of severe hemorrhagic necrosis of the diencephalon and of the brainstem in the regions adjacent to the third and fourth ventricles and around the aqueduct. Besides their acute neurotoxicity, causing central and peripheral signs of cholinergic hyperactivity, some organophosphorus compounds can produce a delayed neurotoxicity, involving peripheral nerves and the posterior columns of the spinal cord (NAMBA et al., 197 1). However, trichlornate and dimethoate, which are the products ingested by the first and the second patient respectively, are known not to produce this delayed neurotoxicity (JOHNSON, 1975). The muscle fiber necrosis, observed in the first case, can be related to the known necrotizing effects of organophosphorus cholinesterase inhibitors on the motor end-plates (DE REUCK and WILLEMS, 1975). The neuropathologic findings in the cases presented were similar to those
253
Fig. 5. Hemorrhagic necrosis with perivascular infiltration by lymphocytes and plasmocytes in the basis pontis of case 2 (Luxol fast blue, 400 x).
observed in severe forms of Wernicke’s encephalopathy (VICTOR et al., 1971). Perhaps the only unusual finding was the marked extension of the hemorrhagic necrosis to the central pontine region. No clear evidence is available why these patients with an acute organophosphorus intoxication should develop a severe form of Wernicke’s encephalopathy. The first patient was an alcoholic, but from the first day of hospitalisation onwards he received thiamine intravenously and only developed symptoms of a central neurologic disorder on the 4th day of hospitalisation. No alcohol abuse was noted in the second patient. Also neither patient, prior to admission, suffered from malnutrion or chronic disease, which could be held responsible for the occurrence of Wernicke’s encephalopathy (LAPLANE and MOREL-MAROGER, 1973; EBELS, 1978). However, the similarity of the neuropathologic findings with Wernicke’s encephalopathy in the cases presented suggests that the ‘biochemical lesion’ is related to the thiamine metabolism. ITOKAWA and COOPER (1970) have shown that high doses of acetylcholine will release thiamine from perfused animal brain preparations. It can be postulated that the increased levels of acetylcholine in the brains of the cases presented had led to thiamine depletion in the regions of predilection of Wemicke’s encephalopathy.
254 REFERENCES ADAMS, R. D. and VICTOR, M. (1977) Principles
of neurology. New York, McGraw-Hill. 8 13. common is Wernicke-Korsakoff syndrome? Lancet ii, 781. ENGLUND, G. (1971) Pesticides. In: Pathology of the nervous system, II, 1691. Ed. by J. Minckler, New York, McGraw Hill. ITOKAWA, Y. and COOPER, 1.R. (1970) Ion movements and thiamine. II. The release of the vitamin from membrane fragments. Biochim. Biophys. Acta 196,274. JOHNSON, M. K. (1975) Organophosphorus esters causing delayed neurotoxic effects. Mechanism of action and structure/activity studies. Arch. Toxicol. 34,259. LAPLANE, D. and MOREL-MAROGER, A. (1973) Complications nerveuses de I’alcoolisme. In: Encyclopedic Medico-Chirurgicale - Systeme Nerveux. 17045 GlO, Paris. NAMBA, T.,NOLTE, c.,JACKREL, J.and GROB, D. (1971) Poisoning due to organophosphate insecticides. Amer. J. Med. 50,475. REUCK, J.DE and WILLEMS, J.(1975) Acute parathion poisoning. Myopathic changes in the diaphragm. J. Neurol. 208,309. VICTOR, M., ADAMS, R. D. and COLLINS, G. H. (1971) The Wernicke-Korsakoff syndrome. Philadelphia, Davis Co. WILLEMS, I.(1976) Therapy in organophosphate poisoning. Acta Clin. Belg. 31.21. EBELS,E.J.(1978) How
GOVERT
Samanmlling Het werkramebestanddeel van Ticlld
VAN
WIJNKADE
48 I3144
EG
MAASSLUIS
I TEL.
(018991
1 75 55
zame gevallen to, de noodzaak van stopzetten van de behandelmg allergle werd I,, u,,zonderl,,ke gevailen “ermeld. 811 tcepassing van hoge doswngen kunnen hemorragleen voorkomen
II tlclopldlnehydrochlorlde.
ECnFarmacoklinixhe studies hebben aangetoond. dat Ticlld een uitgesproken mhaberende aktiveeit uitoefent ten oprlchte van somm~ge plaatjerfunkter. deze Inhibiti.? w zich namehik door een verlenging van de bloedlngstijd, alsmede door en vermindering van de adhesweit en van de aggregatte va” de bloedDlaatjes. Dlt effekt treedt op b,, agqqarte door verschlilende ,nd”cere”de stoffen lander me% adenosinedifosfaat of ADP)
Hu,d-
Doswing en psbruiksanwijzing In funkte van de indwiduele biokqxhe gegevens vareert de doss tusen 2 B 4 dragees per dag. De gebrulkell,ke doserIng IS 2 dragees per dag. d.w L. Mn draw? ‘s motgens en B&n dragee ‘5 avonds Hoge doses worde” slechts kortdurend in het beg,” “8” de behandeltng voorgeschreven en daarna. I” funkt,e “a” de b,olog,sche en kl,n,scheevolutle “ermmderd. Aangeraden wordt Tlcltd ttjdens de maaltljden in te nemen VOO~Orpun~~bIl Bil assoctatie van Tlclid met antlcoagulantla, IE een bljzondere waakzaamheid geboden ondanks bet felt da gedurende bet vetloop van de kl,“lsche studies gee” enkel lncldent waaigenomen werd dat htermee I” betrekk,nq staat.
Contn indiknia Hemopathie& met verlengdeblwdmgstijd. Gabtuik tiidens de rrne
Wiizs van bowran Onder 25=‘C. Houdbaarhakl
Over gebrulk van deze siof in de zwangerschap blj de mew bestaan owoIdoende gegevens om de mogelljke schadelijkheld te beoordelen. Er zijn tot dusver geen aanwilzlngen voor schadelijkheid bii dierproeven.
AIs bovengenoemde rrchtlqn betreffende de bewarmg !n acht wordtgenomen, behoudt Ttcltd al z~ln therapeutlsche elgenschappen gedurende minnens 2 Par. Hwdahvorm Verpakking
5
30 draqees 6 250 mq.
