Brain Involvement in Organophosphate Poisoning

ENVIRONMENTAL RESEARCH ARTICLE NO.

74, 104–109 (1997)

ER973758

Brain Involvement in Organophosphate Poisoning1 Aysun Yılmazlar and Gu¨rayten Özyurt Department of Anesthesiology and Intensive Care, Uludag˘ University Medical Faculty, Bursa, Turkey Received July 16, 1996

toms and plasma cholinesterase activity, for monitoring the clinical prognosis of organophosphate poisonings. © 1997 Academic Press

Organophosphate poisonings cause substantial morbidity and mortality worldwide; however, the neurological effects have not been clearly established. We have studied cerebral perfusion to investigate neurotoxic effects. Clinical effects, plasma cholinesterase activity, and brain single photon emission computerization tomography (SPECT) data were investigated in 16 patients with organophosphate poisonings. The subjects were from an adult intensive care unit in a university hospital. Cholinesterase activity in plasma was determined upon admission and then every day in the morning. Brain SPECT studies were performed during the first week, at the end of therapy, and 3 months after discharge. Patients were classified into 3 groups using a modified Namba classification: latent poisoning (Group A); mild and moderate poisoning (Group B); or severe poisoning (Group C). None of the 6 patients in Group A showed any symptoms; 3 patients in Group B had muscarinic and nicotinic effects; 5 patients in Group C had muscarinic, nicotinic, and central nervous system symptoms. The average plasma cholinesterase for Groups A, B, and C were 54.16 ± 9.10, 42.2 ± 12.02, and 13 ± 4.84 U/ml, respectively (normal range of plasma cholinesterase is 40– 80 U/ml). Only 1 patient from Group A required treatment with oxime; 2 patients from Group B and all patients in Group C were given oxime, atropine sulfate, and mechanical ventilation. In the brain SPECT studies, the patients in Group A showed fewer perfusion defect areas than did Group B and C patients. All cases showed perfusion defects especially in the parietal lobe. In addition, perfusion improvement took more time for Group C than for the other groups. The intensive care unit stays of Group C were statistically longer than for Groups A and B. We concluded that brain SPECT is a highly sensitive diagnostic method, together with clinical symp-

INTRODUCTION

Acute organophosphate (OP) pesticide poisonings cause substantial morbidity and mortality worldwide, but, whether organophosphates cause chronic neurological sequelae has not been clearly established (1). The first account of the synthesis of OP was given by Clermont in 1854. During World War II, several highly toxic compounds were developed (2). Recent estimates suggest that each year worldwide there are 3 million acute severe pesticide poisonings with 220,000 deaths (1). In Turkey, more than 200 chemicals are registered as pesticides. Among these, insecticides constitute an important group and OP compounds are possibly most widely used in our country (2). The OP insecticides have become increasingly common and responsible for human toxicity. These compounds are anti-cholinesterase (anti-ChE) agents (2). They are of particular interest to anesthetists, as patients in the acute and intermediate phases of OP poisoning may show severe cardiorespiratory disturbances requiring critical or intensive care (2). The acute effects of OP have been well documented, and they are well known to be associated with neurological effects. Case reports and series suggest that acute OP intoxication can cause longterm neuropsychological sequelae (1,3,4). Therefore, cerebral perfusion should be evaluated to investigate the cerebral effects of OP in these poisonings (5–7). In this prospective study, the correlation between clinical symptoms, activity of plasma ChE, and data from brain single photon emission computerization tomography (SPECT) were investigated in 16 cases of organophosphate poisoning.

1 Presented at North American Congress of Clinical Toxicology, Rochester, NY, 1995.

104 0013-9351/97 $25.00 Copyright © 1997 by Academic Press All rights of reproduction in any form reserved.

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BRAIN INVOLVEMENT IN ORGANOPHOSPHATE POISONING

MATERIALS AND METHODS

TABLE 1 Characteristics of the OP-Poisoned Patients (n = 16)

Sixteen patients admitted to the intensive care unit with OP insecticide intoxication from July 1992 to August 1993 were studied. In addition to history and clinical examination, the following investigations were carried out on all patients: the name of the OP and route of intoxication, ECG, arterial pressure, hourly urine output, blood and urine analysis, ChE activity, and chest X-ray. Eight milligrams of atropine infusion was used over 24 hr and 2 × 250 mg oxime was administered iv over 20 min. In addition, antibiotics, fluids, vitamins, and H2-receptor blockers were used. Mechanical ventilation was applied whenever respiratory failure occurred. Plasma ChE activity analysis was performed the first day a patient was admitted and then every day in the morning during therapy in the Pharmacology Department by the spectrophotometric method (8). The normal ChE range using this method is 40–80 U/ml. Mann–Whitney U tests were as used for statistical evaluation (9). Brain SPECT studies to document cerebral perfusion were performed by the Nuclear Medicine Department 3 times on each patient: in the first week, at the end of therapy and 3 months after discharge. Tc-99-HMPAO (technetium-99-hexamethilen paraamino oxime) was injected iv and the study was performed up to 2 hr postinfusion. A General Electric 3200xRT gamma camera was used. Statistical evaluation of patient days in the intensive care unit was determined by the Mann– Whitney U test (9). The distribution and severity of clinical symptoms varied, according to the modified Namba classification (10): latent poisoning—no clinical manifestations, plasma ChE activity inhibited 10–50%, treatment unnecessary, prognosis good; mild poisoning— patient complains of fatigue, headache, dizziness, numbness of extremities, nausea and vomiting, excessive sweating and salivation, abdominal pain and diarrhea, plasma activity 20–50% of normal, treatment oxime and atropine, prognosis is good; moderate poisoning—generalized weakness, difficulty in speech, muscular fasciculations, miosis, plasma ChE activity 10–20% of normal, treatment oxime, atropine and mechanical ventilation, prognosis is good; severe poisoning—unconsciousness, marked miosis and loss of pupillary reflex to light, muscular fasciculations, flaccid paralysis, secretions from the mouth and nose, the rales in the lungs, respiratory difficulty and cyanosis, plasma ChE activity less than 10% of normal, treatment oxime and atropine, prognosis fatal if not treated.

Group A Group B Group C

n

%

Age (mean ± SD)

Female/male

6 5 5

37.5 31.2 31.2

19.8 ± 2.1 27.0 ± 14.6 36.0 ± 16.9

2/4 2/3 2/3

The patients in our study were classified into three groups according to the modified Namba classification, as follow: latent poisoning (Group A); mild and moderate poisoning (Group B); and severe poisoning (Group C). RESULTS

The three patient groups had similar demographic characteristics of age and gender, with six patients in Group A, five patients in Group B, and five patients in Group C (Table 1). The OP chemicals and routes of intoxication are given in Table 2. Clinical Symptoms None of the six patients in Group A showed any symptoms of muscarinic, nicotinic, or central nervous system toxicity. They were hospitalized because they had the history of exposure to OP compounds. Three patients of Group B had sweating, salivation, lacrimation, and bradycardia. All five patients in Group C had muscarinic effects (sweating, salivation and lacrimation, diarrhea, miosis, bradycardia), nicotinic effects (muscle fasciculations and weakness), and CNS symptoms (coma, confusion, Cheyne–Stokes respiration, dyspnea, tremors) (Table 3).

TABLE 2 Names of the OP Agents and Routes of Exposure Route

Group A Supracide (methidathion) Group B Tamaron (methamidophos) Ragor (demethoate) Group C Novacron (monocrotophos) Kortion (korthion-M) DDVP (dichlorvos)

Oral

Dermal

Inhalation

6

—

—

3

1

1

4

1

—

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YILMAZLAR AND ÖZYURT

TABLE 3 Clinical Symptoms, Activity of Plasma Cholinesterase (ChE) and Therapy

Muscarinic

Nicotinic

CNS

ChE (U/ml) at admission (Normal value, 40–80 U/ml)

—

—

—

54.2 ± 9.1

—

1

—

3

2

—

42.2 ± 12.0

2

2

2

5

5

5

13.0 ± 4.8

5

5

5

Symptoms

Group A n46 Group B n45 Group C n45

Therapy

Atropine

Oxime + bolus

Mechanical ventilation

Note. Muscarinic symptoms: increased sweating, salivation, and lacrimation; diarrhea, miosis, bradycardia. Nicotinic symptoms: muscle fasciculation and weakness. CNS symptoms: coma, confusion, Cheyne–Stokes respiration, dyspnea, tremors.

Cholinesterase Activities The average ChE activities for Groups A, B, and C were 54.2 ± 9.1, 42.2 ± 12.0, and 13.0 ± 4.8 U/ml, respectively (Table 3) (normal range of plasma cholinesterase is 40–80 U/ml). There was a statistically

significant (P < 0.05) inhibition of ChE activity in Group C in comparison with Groups A and B (Fig. 1). Therapy Only one patient from Group A was given oxime after the admission. Two patients from Group B and

FIG. 1. The differences in mean plasma cholinesterase activities in Group A, B, and C patients. Group A and B were only measured through Day 3.

BRAIN INVOLVEMENT IN ORGANOPHOSPHATE POISONING

107

all patients in Group C were given oxime, atropine sulphate and mechanical ventilatory support (Table 3). Brain SPECT Studies Group A. One patient had two cortical defects (left and right posterior parietal); three patients had one cortical defect each (left parieto-occipital, left posterior parietal focal defect, right parieto-occipital hypoperfusion); and two patients were evaluated as normal (Table 4) (Fig. 2). Group B. One patient had three cortical defects (left frontal, left parietal, and left basal ganglia); one patient had two cortical defects (left posteriorparietal and right parieto-temporal); and three patients had one cortical defect each (right frontal, left parieto-temporal, left parietal) (Table 4). Group C. Four patients had two cortical defects each (right posterior and left parieto-occipital; right and left posterior-parietal; right upper parietal and left fronto-parietal; left fronto-parietal and right frontal) and one patient had three defects (left parieto-occipital, left basal ganglia, and two-sided posterior parietal defects) (Table 4). The second and third SPECT studies showed improvements in brain perfusion as seen by the smaller size of the defects or reperfusion of the defective areas (Table 4) (Fig. 2). The perfusion improvement took longer in Group C patients than Group A and B patients. All cases showed same perfusion defects, especially in the parietal lobe and near the parietal lobe of the brain (Table 5). Intensive care unit stays of patients in Group C

FIG. 2. First, second, and third brain SPECT study of a Group C patient. (Arrows) Hypoperfusion areas. (A) The first Tc99-HMPAO SPECT scan displayed bilateral frontal and left parietal hypoperfusions (arrows). (B) The second SPECT realized 12 days after the first study showed only left frontal and parietal hypoperfusions (arrows). (C) The SPECT realized 3 months after the first study showed only left parietal hypoperfusion (arrow).

were longer than those of patients in Group A and B (Table 6.). DISCUSSION

TABLE 4 Number of Defects Detected in Brain SPECT Studies

First week Group A Group B Group C Attend of therapy Group A Group B Group C 3 months after discharge Group A Group B Group C a b

Normal

1 Defect

2 Defects

3 Defects

2 — —

3 3 —

1 1 4

— 1 1

5 3 —

1 1 —

— — 3a

— 1a 1a

6 3 —

— ? —

— — 3a

— 1a ?b

Hypoperfusion. The patients did not return for control check-ups.

There is growing concern regarding the effects of acute and chronic pesticide exposure. In 1974, the World Health Organization (WHO) used data from 19 countries to estimate that approximately 500,000 cases of acute pesticide poisonings occurred annually. Of the resulting 9000 or more deaths, 99% of the deaths occurred in developing countries (2). Many, but not all, of the reports of central nervous system symptoms associated with OP poisoning are based on studies in experimental animals (11–13). In a previous study, we showed that SPECT findings are useful in evaluating neurological and psychiatric changes in patients with OP poisoning (14). To our knowledge, this report was the first to show impaired brain function with SPECT after OP intoxication. In this study, we investigated the correlation be-

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TABLE 5 Localization of the Perfusion Defects Diagnosed with Brain SPECT Ganglia

Parietal

Parieto-occipital

Parieto-temporal

Frontal

Fronto-parietal

Basal ganglia

Group A Group B Group C

3 3 3

2 — 3

— 2 —

— 2 1

— — 2

— 1 —

tween clinical symptoms, ChE activity, therapy, and brain SPECT results in cases of OP poisoning. There are also some reports about the relationship between symptoms of OP poisoning and ChE activity (15,16). Nagymajtenyi et al., recommended that whenever ChE inhibition was detected in humans, central nervous system functions should be tested (15). In this study we also found out that very low level of cholinesterase activity correlated with CNS symptoms in severely poisoned patients. The inhibition of ChE activity persisted also until the 10th day of treatment. Although there are quite a few studies of neuropathy and neurotoxicity relating to OP poisoning (17– 21), we have not found any brain SPECT reports. Drewes and Singh suggested that the cerebral insults of hypoxia and ischemia arising from OP poisoning are due to respiratory and cardiac failure (23). For this reason we tried to prevent cerebral hypoxia and ischemia by monitoring and utilizing mechanical ventilation in our patients. Shimosegawa et al., studied brain SPECT after carbon monoxide intoxication (22). They measured cerebral perfusion and glucose metabolism 1 year after carbon monoxide intoxication. Although 1 year had passed they identified blood perfusion and glucose metabolism disorders in the basal ganglia (22). In follow-up, this pathology was reversed within 6 months to 1 year. We examined the changes in brain perfusion at three phases in this study. We found brain perfusion defects present in higher numbers and larger areas at the admission stage and the beginning of therapy. The number and sizes of defects decreased after the first SPECT. Many of the defects changed by the second and the third examination. Increases in the defect number and enlargement TABLE 6 Intensive Care Unit Stays and the Patients’ Outcome

Group A Group B Group C

Days (mean ± SD)

Recovery

Death

3.2 ± 2.1 5.0 ± 3.0 27.0 ± 6.7 (P < 0.05)

6 5 4

0 0 1

of areas affected was related to the severity of poisoning, which also was correlated with persistence through 3 months. Defects were most often seen in parietal and parietal-related areas and in proximity to the parietal lobes. The results of this study must be confirmed by further studies. ACKNOWLEDGMENT . We thank Dr. Ilknur Gu¨nes¸ for the brain SPECT studies in the Department of Nuclear Medicine, Uludag˘ University Medical Faculty.

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