Intoxication due to alkylmercury-treated seed - 1971-72 outbreak in Iraq: Clinical aspects

Intoxication due to alkylmercury-treated seed- 1971-72 outbreak in Iraq: clinical aspects S. F. AL-DAMLUJI a & THE CLINICAL COMMITTEE ON MERCURY POISONING b Sixty-six hospitalized patients suffering from chronic methylmercury poisoning were examined in Baghdad during 1972. The poisoning was attributed to consumption of home-made bread prepared from seed wheat treated with mercurial fungicide. The age incidence ranged between 4 and 70 years. Of the various clinical features encountered, neurological symptoms and signs were predominant and included muscular weakness, numbness, unsteady gait, paraesthesia, dysarthria, mental disturbances and, in severe cases, blindness, partial deafness, stupor, coma, and death. Involvement of the cardiovascular, urinary, gastrointestinal and haemopoietic systems, which was commonly encountered in ethylmercury poisoning in the 1960 outbreak in Iraq, was unusual. The severity of symptoms and signs was, broadly speaking, dose-dependent; high exposure led to severe clinical manifestations, but variations existed. Criteria, based on the clinical manifestations, were set for grading the severity of cases. The series included 2 asymptomatic cases, 20 mild, 20 moderate, 14 severe, and 10 very severe. In the latter group 5 patients died from failure of the central nervous system. The severely poisoned patients died irrespective of the medical treatment received. After 2 years of observation, most patients graded as mild or moderate cases lost their symptoms completely. Severe cases improved slowly, although ataxia, diminution of visual field and acuity and paraesthesia were still present. Thus, the previously accepted view that neurological signs were irreversible has been disproved. Following the 1960 outbreak of poisoning with organomercurial compounds due to the ingestion of treated seeds,1'2'3'4 no cases were observed anywhere in Iraq in spite of the use of the dressed seed in limited and carefully controlled quantities. This was not due to misdiagnosis, as most of the practising physicians are aware of the condition and its manifestations. On 27 December 1971, the Director-General of Preventive Medicine, Ministry of Health, Dr S. K. Al-Tikriti and one of us (S.F.D.) were urgently summoned to see 47 patients from Al-Hawija, a rural area near Kirkuk, with symptoms indicative of poisoning with organo- mercurial compounds. Within the next 4 months 6530 patients were admitted to hospitals in provinces throughout the country. There were 459 deaths attributed to methylmercury poisoning. - Professor and Head, Department of Medicine, College of Medicine, University of Baghdad, Baghdad, Iraq. b The members of the Clinical Committee are: Professor Salem F. Damluji (Chairman), Dr Mehdi Murtadha (Secretary), Dr Abdul-Hamid Al-Abbasi, Professor Laman Amin-Zaki, Professor Farhan Bakir, and Dr Sami El-Hassani of the Department of Medicine, College of Medicine, University of Baghdad; Dr Khaldoon Al-Janabi and Dr Khaldoon Al-Omar of the Karama Hospital; Dr Jafar Kuwaiti of the Al-Shaab Hospital; Dr FuadAudeau of theKadhimain Hospital; and Dr Muhammed Ali Majid of the Medical City, Baghdad. - 65 - 66 This paper presents an analysis of 66 cases (25 males and 41 females, aged 4-70 years) of poisoning with methylmercury as a result of eating bread made from seed wheat dusted with the mercury-containing fungicide. All were admitted to the Medical City Teaching Hospital, Karama, Al-Shaab, and Kadhimain Hospitals, Baghdad, during the first 4 months of 1972. The age and sex distribution is shown in Table 1. TABLE 1. AGE AND SEX INCIDENCE OF 66 CASES OF METHYLMERCURY POISONING Several members of the affected families came under observation. The clinical studies made on infants and young children of these families are reported elsewhere. 5,6 The patients were interrogated regarding the amount of bread consumed and period during which it was eaten, the mode of onset of symptoms and the progress of the illness. A prepared form, with detailed information, based on experience of mercury poisoning in the 1960 outbreak, was completed by the responsible clinicians. Clinical and laboratory examinations included: quantitative estimates of organic and total mercury in the blood, hair, and 24-h urine specimens; routine urine and blood analyses; bone marrow cytological studies; blood chemistry analysis and estimation of serum electrolytes; renal and liver function tests; serum protein electrophoresis; electrocardiography; electroencephalo- graphy; nerve conduction studies; examination of the cerebrospinal fluid; and visual perimetry. The patients were examined at regular intervals, and tests were repeated fre- quently. The average stay in hospital was 3 months. Some of the patients studied were re-admitted 6 months, 1 year, and 2 years later for clinical and laboratory follow-up. An average of 3 medium-sized loaves of bread was eaten daily by most of the patients for periods varying between 15 and 180 days. The average weight of the loaf was approxi- mately 200 g, of which 69% was solid material. The bread was made from whole wheat and the fungicide was eaten along with the seed coat of the grain. Some patients prepared the bread from mixed treated and untreated grain. On the basis of our experience with the 1960 outbreak of organomercury poisoning in Iraq, the clinical picture at the time of admission was classified as follows: (1) Asymptomatic form: No clinical symptoms or signs, but significant elevation of mercury levels in tissues (2 cases; both patients admitted to having eaten contaminated bread). Age (years) Male (No.) Female (No.) 5-9 4 3 10-19 12 7 20-29 2 12 30-39 2 10 40-49 1 5 50-59 2 3 60-69 1 1 70-74 1 - Total 25 41 67 (2) Mild form: The essential features were muscle weakness, paraesthesia, abdominal discomfort, and bowel irregularity (20 cases). (3) Moderate form: Ataxia, dysarthria, tremor, changed reflexes, and a positive Babinski response (20 cases). (4) Severe form: The above symptoms plus constriction of visual fields, hearing defect, ataxia, disturbance of sensation and mental symptoms (14 cases). (5) Very severe form: Bedridden patients, with blindness, deafness, dysphagia, and crying pains (5 cases). (6) Fatal cases: Severely affected patients who died in hospital (5 cases). CLINICAL OBSERVATIONS In all cases, the onset was gradual. The latent interval between eating contaminated bread and the appearance of symptoms ranged from 10 to 150 days (average 3 weeks). The severity of clinical manifestations and the amount of mercury found in tissues were broadly speaking proportional to the amount of fungicide eaten, although variations existed. No significant difference between the sexes was observed. The early symptoms, as shown in Table 2, were mainly motor weakness, slow cerebration, impaired hearing and epigastric discomfort. Thereafter, other symptoms and signs developed in 1-4 weeks. Some members of the same affected family deteriorated rapidly and died at home within a few weeks after eating contaminated bread, while in others the affection followed a slow course and they were admitted to hospital later. However, the clinical picture, except for the rapid course, remained essentially the same. General appearance On admission, patients with mild intoxication looked healthy. Patients with moderately severe intoxication complained of weakness in the limbs, disturbed coordination, slightly ataxic gait, dysarthric speech, and hearing defects, and a few had mental symptoms. They were able to feed themselves, though with clumsy hand movements. Patients with severe intoxication were bedridden, mentally disturbed, and suffered from severe dysarthria and deafness. Some of them had lost weight and were emaciated. Pallor was not a common feature of this group. In very severe intoxication patients were in a stuporous state, unable to speak, or murmuring unintelligibly and screaming at intervals, and had double incontinence and choreo-athetotic movements. Before death, fatal cases went into coma, with periods of 5-10 min of crying pains that subsided gradually, apathy, and incontinence. Swallowing was difficult and intravenous feeding had to be instituted. As coma deepened, generalized flaccidity preceded a peaceful death. Details are shown in Table 3. Psychic changes Patients with mild intoxication were alert and fully conscious. Anxiety was pre- dominant in this category. Almost half of the patients complained of headache, dizziness, insomnia, and irritability. In the severely affected groups, fatigue, forgetfulness, drowsiness, stupor, depression, alternating mania and depression, confusi(ll, an; crying pains were encountered. Deterioration of memory and judgement was uncommon. Table 4 summarizes these details. 68 TABLE 2. EARLY SUBJECTIVE SYMPTOMS IN METHYLMERCURY POISONING Clinical group.l (No. of patients) Symptom Asympto- Mild Moderate Severe Very Fatal Total (%) matic (20) (20) (14) severe (5)(2) (2) 2) 1) 5 Motor weakness - 8 29 14 5 5 61 (92.4) Slow cerebration - 1 7 12 4 4 28 (42.4) Impaired hearing - 3 7 9 4 5 28 (42.4) Epigastric discomfort - 9 11 5 2 1 28 (42.4) Lethargy - 3 6 9 5 4 27 (40.9) Constipation - 5 7 9 1 4 26 (39.4) Polydipsia - 8 5 7 3 2 25 (37.9) Irritability - 3 3 12 2 4 24 (36.4) Frequency of micturition - 6 7 6 3 2 24 (36.4) Nausea, vomiting - 5 7 5 1 4 22 (33.3) Metallic taste in mouth - 5 5 4 2 1 17 (25.8) Salivation - 1 2 9 1 2 15 (22.7) Anorexia - 1 3 5 3 2 14 (21.2) Paraesthesia - 5 4 3 1 - 13 (19.7) Burning sensation in - 2 2 7 1 1 13 (19.7) mouth Fever - 2 4 3 - - 9 (13.6) Urgency - - - 1 _ _ 1 ( 1.5) Impotence - 1 - 1 ( 1.5) - For definition, see text. 69 TABLE 3. GENERAL APPEARANCE IN PATIENTS WITH METHYLMERCURY POISONING Clinical groupa (No. of patients) Symptom Asymp to- Mild Moderate Severe Very Fatal Total (%) matic (20) (20) (14) severe (5)(2) (2) 2) 1) 5 Weight loss, emaciation - - 2 4 2 3 11 (16.7) Pallor and toxic 1 2 _ 2 5 ( 7.6) appearance Inability to sit or - 1 6 13 4 3 27 (40.9) stand Bedridden - - 2 10 5 5 22 (33.8) Apathy - - 6 10 4 4 24 (36.4) Lethargy - 1 7 9 4 4 25 (37.9) Drowsiness - - 3 5 1 - 9 (13.6) Confusion - - - 3 1 - 4 ( 6.1) Stupor - - _ 2 1 3 ( 4.5) Coma -_ - - 3 4 7 (10.6) - For definition, see text. TABLE 4. PSYCHOLOGICAL AND MENTAL SYMPTOMS IN PATIENTS WITH METHYLMERCURY POISONING Clinical groupa (No. of patients) Symptom Asympto- Mild Moderate Severe Very Fatal Total (%) mat ic (20) (20) (14) severe (5)(2) (2) 2) 1) 5 Headache - 12 9 9 4 1 35 (53.0) Sleep disturbances - 7 12 8 3 4 34 (51.5) Dizzinessb - 7 8 9 3 3 30 (45.5) Irritability - 3 5 12 4 4 28 (42.4) Slow cerebration - - 7 10 5 4 26 (39.4) Crying pains - - - 5 2 4 11 (16.7) Emotional instability - 2 4 2 - - 8 (12.1) Impaired memory - - 2 4 ? ? 6 ( 9.1) Euphoria - 1 4 1 ? ? 6( 9.1) Mania, depression - - - 4 ? ? 4 ( 6.1) - For definition, see text. - In some patients this symptom was difficult to inquire about. 70 Nervous system Tables 5 and 6 summarize the neurological symptoms and signs, respectively. Loss of motor power and coordination were frequent findings, affecting mainly the muscles of the extremities, and, to a lesser extent, the trunk. The tone was either spastic, rigid, or hypotonic in half of the cases. True paralysis was not present, but generalized paresis could be detected (32 cases). Muscular tenderness, especially affecting the thighs, calves, arms, and forearms, was found in less than half of the patients. In a limited number of the moribund cases, trophic changes, and fasciculation were present. TABLE 5. NEUROLOGICAL SYMPTOMS IN PATIENTS WITH METHYLMERCURY POISONING Clinical group- (No. of patients) Symptom Asympto- Mild Moderate Severe Very Fat Total (M) matic (20) (20) (14) severe (5)(2) (2) 20 (4 Muscle weakness - 10 16 13 5 4 48 (72.7) Numbness, paraesthesia - 10 14 13 5 4 46 (69.7) Unsteady gait (ataxia) - 2 17 14 5 5 43 (65.2) Slurred or scanning - 2 15 13 5 5 40 (60.6) speech Muscle pains - 3 12 5 2 3 25 (37.9) Dysphagia - - - 4 1 1 6 ( 9.1) a For definition, see text. 71 TABLE 6. NEUROLOGICAL SIGNS IN PATIENTS WITH METHYLMERCURY POISONING Clinical groups (No. of patients) a Sign Asympto- Mild Moderate Severe Very Fatal Total ( matic (20) (20) (20) severe (5l(2) (2) 2) 2) 5 Ataxia - 1 18 14 5 3 41 (62.1) Impairment of speech and - 2 15 13 5 5 40 (60.6) writing Hyperref lexia - 5 15 10 5 2 37 (56.1) Paresis - 2 11 11 5 3 32 (48.5) Incoordination (Romberg - - 7 14 4 4 29 (43.9) test) Intention tremor and - 1 9 7 5 3 25 (37.9) myoclonic twitch Muscle tenderness - 3 12 5 2 3 25 (37.9) Spastic tone 1 1 8 5 2 1 18 (27.3) Sensory disturbances - - 7 5 3 ? 15 (22.7) Flaccid tone 1 1 4 5 1 2 14 (21.2) Muscle wasting - - 1 4 2 5 12 (18.2) Sphincteric loss - - 1 5 3 2 11 (16.7) Babinski sign positive - 1 2 3 2 3 11 (16.7) Hypersalivation - - 2 3 1 - 6 ( 9.1) Hyporeflexia - - 2 1 - 2 5 ( 7.6) Hyperlacrimation - - - 1 2 1 4 ( 6.1) Chewing, grasping - - - 1 2 3 ( 4.5) Trophic changes - - - - 1 1 ( 1.5) - Some of the physical signs could not be tested in all patients. Tendon reflexes were either brisk, diminished, or absent, particularly the ankle and knee jerks. Some patients had general hyperreflexia, in others it was limited to the lower extremities. Moribund patients had areflexia before death. Superficial reflexes remained intact in the majority of patients. However, a bilateral or unilateral dorsiflexor plantar (Babinski) response was seen in 11 patients. Sensory disturbances were observed in all groups and consisted mainly of numbness of the hands, forearms, and lower legs and of a tingling sensation. Less comnmon types of distribution of numbness were those affecting one side of the body, the lower limbs, or one arm and the reciprocal leg. Such symptoms were present initially in one-fifth of the cases only. Circumoral paraesthesia and a burning sensation in the mouth, gums, and tongue were also noted. Mild blunting of superficial sensation (pain and touch), mainly in the hands and feet, was encountered in one-third of the moderately and severely affected patients. Position sense and two-point discrimination was defective in the fingers and 72 toes in a few patients. Astereognosis was seen in 6 patients. Temperature, light touch, deep sensibility and vibration senses were unaffected. One patient had muscular cramps in his calf muscles. Electrophysiological studies made on peripheral nerves did not reveal any abnormality.7 Ataxia and dysarthria were comon features in all severe cases. Patients with moderately severe intoxication had to be assisted in walking, while those with severe intoxication had difficulty in sitting up in bed. The lower limbs were more severely affected than the upper limbs. Disturbance of speech (scanning and slurred speech) was present in those with ataxia. In some moribund patients, swallowing was impossible and the attempt caused agonizing pain and nasal regurgitation of fluids. Nystagmus was present in 5 patients. Jerky and uncoordinated movements were seen in the severe cases. The majority had a fine intention tremor. It was bilateral and involved mainly the upper limbs, hands, and fingers, and in 2 patients the lips, eyelids, and lower limbs. Two patients had a jerky movement of the hand and trunk. Choreo-athetosis was also seen in 2 patients. Coarse tremor was unconmmon. Special senses and other systems More than half of the patients studied had visual disturbances, as shown in Table 7. The mild cases were affected to a less extent. Severely affected patients had diminution of visual acuity, difficulty with near vision, and constriction of the visual field. Bilateral partial or total blindness was encountered in 13 patients. The optic discs showed papillitis in 13 patients and optic atrophy in 1 patient only. Three patients had black spots before their eyes and 2 had alternate black and red spots, which were temporary. The majority of patients could recognize colour, but 8 patients had yellow vision. TABLE 7. OPHTHALMOLOGICAL ABNORMALITIES IN METHYLMERCURY POISONING Clinical groupa (No. of patients) Symptom Asympto- MildModerateic;eModVeryra Total (7 matic (20) (20) (14) severe 5(2) ~~~~~~~~(5) Constriction of visual - 5 10 10 4 ? 29 (43.9) field Diminished visual acuity - 4 12 7 1 ? 24 (36.4) Optic neuritis (papil- - 1 3 6 1 2 13 (19.7) litis) Blindness - - 4 2 4 3 13 (19.7) Yellow vision - 2 - 5 1 ? 8 (12.1) Nystagmus - - 2 1 2 ? 5 ( 7.6) Diplopia - _ 2 ? ? ? 2 ( 3.0) Weakness of external eye _ - - _ 1 1 2 ( 3.0) movement a - For definition, see text. 73 Table 8 summarizes the other symptoms and signs observed in these patients. Less than half of the patients in this series complained of hearing disturbance at the onset of symptoms, and total deafness was rare. Partial hearing loss, as detected by audiometry, a tuning fork, or response to spoken words in very severe cases, was present in one-third of the patients. The degree of hearing loss was proportional to the clinical severity of the case. Tinnitus and vertigo were frequent complaints. As noted above, 5 patients had nystagmus. Olfactory disturbances were present in 5 patients, and an equal number of patients complained of abnormalities of taste. TA,BLE 8. OTHER SYMPTOMS AND SIGNS OBSERVED IN PATIENTS WITH METHYLMERCURY POISONING Clinical group-a (No. of patients) Symptoms and Asympto- Mild Moderate Severe Very Fatal Total l signs t matic (20) (20) (14) severe (5)signs ~~(2) (2) 2) 1) 5 1. Special senses Hearing defect - 3 5 7 4 5 24 (36.4) Smell - - - 3 2 ? 5 (7.6) Taste - - 1 2 2 ? 5 (7.6) 2. Mouth and gastro- intestinal system Abdominal pains - 8 15 6 3 2 34 (51.5) Nausea, vomiting - 3 7 9 1 2 22 (33.3) Thirst - 5 10 4 2 ? 21 (31.8) Hypertrophied gums - 5 7 4 1 1 18 (27.3) Diarrhoea, consti- - 4 3 4 1 2 14 (21.2) pation Anorexia - 3 3 5 1 2 14 (21.2) Sore gums - 4 4 2 2 ? 12 (18.2) Stomatitis - 2 2 1 2 3 10 (15.2) Dysphagia - - - 4 1 1 6 ( 9.1) Coloured stools - - - - - 1 1 ( 1.5) Palpable liver - - - _ _ 1 1 ( 1.5) Palpable spleen - - - - 1 - 1 ( 1.5) 3. Miscellaneous Joint pains - 7 11 7 3 ? 28 (42.4) Palpitation - 1 5 4 1 ? 11 (16.7) Sacroiliac pain - 2 6 2 - ? 10 (15.2) Fever - 1 3 4 - - 8 (12.1) Chest pain - 3 1 2 - 1 7 (10.6) Skin lesion - 1 2 - - 1 4 (6.1) Heart murmur - 1 1 _ - - 2 (3.0) - For definition, see text. 74 Two patients had bilateral external rectus muscle weakness and another a slight upper motor neurone facial weakness. Ptosis was not seen. Manifest squint was present in one severely affected patient when examined 2 years after the initial examination. Sphincteric disturbances were present in 11 patients. Involuntary urination, defaecationorboth were noted in the severely affected groups. Excessive salivation was present in 6 patients and lacrimation in 4 patients. Hyper- hidrosis was not seen. In the moribund cases, the clinical picture resembled encephalitis. Some patients had stretching movements indicative of decerebrate rigidity. Primitive reflexes, spontaneous chewing, and sucking were present in these patients. Less than half of the patients complained of epigastric discomfort at the onset of symptoms. Upon admission, 14 patients had a change of bowel habit, 21 had polydipsia, 22 nausea and vomiting, 14 anorexia, and 6 dysphagia. Most of these symptoms disappeared a few weeks later. A burning sensation of the mouth, tongue, and gums was not uncommon. Seventeen patients had a metallic taste in the mouth and 12 had sore gums. A blue line at the gum margin was not seen. Urinary disturbances were rare in clinically established cases. However, 24 patients reported polyuria at the onset of symptoms; this disappeared later. One patient was impotent. Three women had oligomenorrhea. Two patients were 6 months pregnant at the time of admission to hospital; one of them aborted and the other delivered at full term, but the child died 24 hours later. Six women were lactating. On the skin a brownish-red pigmentation involving the trunk, particularly the chest, back and axillae, which were covered with bran-like scales, was observed in 2 patients. Exfoliation of the skin in the region of the chest, abdomen, and limbs was present in a third case. An erythematous rash, about 2-4 mm in diameter, with itching all over the body, was seen in 1 patient. No vasomotor perspiration or alopecia was seen. No abnormalities were detected on examination of the chest. A faint apical systolic murmur was heard in 2 patients. The blood pressure was within normal range in all cases. Eleven patients complained of palpitation. Electrocardiography was reported abnormal in less than one-third of the cases, the abnormality being mainly S-T changes. Eight patients had fever, 10 had sacroiliac pain and 7 chest pain. LABORATORY RESULTS In most cases, no abnormality could be detected on urine examination. Microscopical haematuria, pyuria, or cylindruriawere absent in all cases, including the very severe and moribund categories. Haemoglobin level, packed cell volume, and reticulocyte count were normal in all patients except in 2 women who had microcytic hypochromic anaemia. The white cell counts were within normal range, but eosinophilia in the peripheral blood (ranging from 5% to 35%) was present in two-thirds of the cases. Those patients had no helminthic infestation. Bone marrow revealed normal cellularity in all cases, and an increase in the eosinophil series in 1 patient only. 75 The following tests, performed on all patients, were reported normal: platelet count, fragility test, bleeding time, clotting time, prothrombin time, serum alkaline phosphatase, SGPT, serum cholesterol, serum electrolytes, and bromsulfalein retention. No abnormal finding could be detected on examination of the cerebrospinal fluid. Cytogenital studies of patients with increased levels of mercury in their red blood cells revealed a higher but not statistically significant proportion of chromosomal aber- rations in the form of breaks in their lymphocytes than that in the non-exposed individuals. Numerical chromosomal aberrations were not observed. COURSE IN HOSPITAL AND FOLLOW-UP Fatal cases in this series were among the severely poisoned groups only, and the patients died irrespective of the medical treatment they received. All patients who presented at the time of admission with mild or moderately severe symptoms improved gradually, and no patient in these groups deteriorated later or died. Improvement took place 2-3 months after patients stopped eating the contaminated bread and, in a few cases, even before their admission to hospital. However, a comparison made between the treated and untreated patients (mild5and moderate cases) revealed that the chelating agents used definitely speeded recovery. Gastrointestinal symptoms were the first to disappear. Patients with mild and moderately severe symptoms recovered their neurological functions slowly. Most of these symptoms had disappeared when patients were examined 1-1/2 years later. Numbness and paraesthaesia were the last symptoms to disappear. Some findings in individual cases are shown in Table 9. The surviving severe bedridden patients had recovered their ability to sit up in bed, to feed themselves and even to walk when examined a year later. Their mental symptoms improved dramatically. Visual loss improved to a moderate degree. Ataxia, dysarthria, and paraesthesia improved to a lesser extent. Children made a more speedy recovery than adults. Patients with moderately severe and severe symptoms were able to walk unaided, attend school, and pass examinations success- fully. Blind children recovered some degree of vision and were able to see distant objects with a constricted visual field. Rehabilitation, physiotherapy, and encouragement had a dramatic effect on the outcome of the illness. DISCUSSION A detailed clinical and laboratory study of 21 inpatients (16 adult females and 5 children aged 4-8 years) poisoned with ethylmercury (Granosan M) in Iraq was made by Damluji.3 These patients are comparable with those described above as regards social and economic background and age, and as regards the mode of handling the fungicide, the amount of contaminated bread consumed and the period during which it was eaten. At the outset of the present outbreak it was claimed that the responsible mercurial was an ethyl compound. However, differences in the clinical manifestations, and in progress and outcome, directed our attention to the possibility that a different compound of mercury might be responsible. That the agent in this outbreak was methylmercury was confirmed later by analytical studies of the treated seed, and of blood and hair samples collected from the patients. The outstanding differences in the clinical manifestations were: (1) Nervous system lesions: In poisoning by both mercurial compounds, disorders of the nervous system dominated the clinical picture. Neurological manifestations were more severe and recovery from them less rapid in cases of methylmercury poisoning. In these Nt 10 rI. 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(2) Involvement of the kidneys: In ethylmercury poisoning renal disorders were common. The majority of patients had polyuria and weight loss at the onset of symptoms, with elevated blood urea, oliguria and urinary changes (albuminuria, microscopical haema- turia, pyuria, and cylindruria) in established cases. In methylmercury poisoning, urinary changes were rare. (3) Gastrointestinal symptoms: Nausea, vomiting, dehydration, anorexia, constipation and severe abdominal cramps were constant features of the ethylmercury poisoning. These symptoms were less frequently encountered in methylmercury poisoning, and disappearedwithin a short time after patients were admitted to hospital. (4) Cardiac involvement: Alteration of cardiac rate (tachycardia or bradycardia) and rhythm, a moderate rise of blood pressure and pericardial effusion were frequently observed in patients severely affected by ethylmercury. These findings were rare in the present series. Electrocardiography was reported as abnormal in the vast majority of patients with ethylmercury poisoning and consisted of frequent ectopic beats, increased irritability of the heart, a prolonged P-R interval indicating impaired conduction, a prolonged Q-T segment4 and S-T deviation with inversion of the T wave, indicating severe myocardialdamage.48 In methylmercury poisoning, the electrocardiograms were reported abnormal in only one-third of the cases, the main abnormality being changes in the S-T segment. (5) Skin lesions: Cutaneous lesions were more widely seen in ethylmercury poisoning, and consisted of pigmentation, rash, itching, exfoliation of skin, and falling of hair. (6) Cause of death: Patients with severe ethylmercury poisoning died mainly from renal failure. Respiratory tract infection (caused by resistant organisms) was a contri- butory factor and pulmonary consolidation was a common finding on postmortem examination. In methylmercury poisoning, patients died quietly as a result of failure of vital functions of the brain. A comparison can be made between these clinical findings and those described in Minamata and Niigata disease, which followed the eating of seafood contaminated withmethyl- mercury. Although the route of administration of the mercurial compound in Minamata9 and Niigata disease was different from that in the cases in Iraq, the clinicopathological features corresponded well to our cases, with some differences. A comparison of the per- centage of various signs and symptoms is shown in Table 10. The main differences were: (1) Visual changes: Concentric constriction of bilateral visual fields was observed in all Minamata cases, in 74% of the Niigata cases and in 44% of the Iraqi patients. Visual acuity, optic fundi, ocular movements and pupillary reflexes were normal, without nystagmus, in Minamata cases, while in the Iraqi series, diminution of visual acuity and inability to see near objects was present in 36% of cases, optic neuritis in 20%, eye muscle paresis in 3%, and nystagmus in 8% of cases. (2) Sensory disturbances: Hyperesthesia and thermohyperesthesia were seen in all the Japanese cases. These were absent in the Iraqi patients. Blunting of pain sensation was present in 100% of the Minamata cases, 95% of the Niigata cases and in 23% of the Iraqi cases. Electromyography of 5 patients from the Minamata series revealed irregular fluctuation of discharge of neuromuscular units during voluntary contraction of muscles, probably related to ataxic disturbances. In the Iraqi patients the results of these studies were reported to be normal and did not reveal any sensation abnormality. There was no change in the conduction velocity. 78 TABLE 10. PERCENTAGE RATE OF VARIOUS CLINICAL MANIFESTATIONS OF METHYLMERCURY POISONING IN THE MINAMATA, NIIGATA, AND IRAQ EPIDEMICS Constriction of visual field 100 74 44 Disturbance of sensation 100 95 70 Ataxia 80-90- 72 62 Disturbance in speech 88 ? 61 Impairment of hearing 85 68 36 Impairment of gait 82 ? 65 Tremor 76 ? 38 Disturbance in chewing and 94 ? 5-9 swallowing Brisk and increased tendon 38 8 56 reflexes Impairment of superficial 100 23 sensation Salivation 24 ? 9 Mental disturbance 71 43 8-9 Hyperhidrosis 24 ? 0 Contracture 9 common 0 Joint pain ? common 42 Weakness of external eye movement 0 0 3 Yellow vision 0 0 12 Abdominal pains 0 0 52 Nausea/vomiting 0 0 33 Skin lesions 0 0 6 - Varies for different symptoms. (3) Gastrointestinal symptoms were present in less than half of the cases in Iraq, predominantly during the early weeks of illness. They were not described in either Japanese series. (4) Cutaneous manifestations were absent in the Japanese cases. (5) Clinical forms: The Japanese authors divided their patients into 4 main groups - those with a common form, those with an acute fulminant form, those with a chronic form with irritative phenomenon, and those with a chronic form with contractures. The majority of our cases fit into the common form. The moribund cases in the Iraqi series could well fit into the acute fulminant form, patients with very severe symptoms in the Iraqi series who did not succumb made a gradual recovery. The description "chronic form with irri- tative phenomenon" was applied to those cases that started with the common form but later Minamata Niigata Symptom or sign cases2l cases22 Iraq cases (total 34) (total 40) (total 66) 79 developed psychic excitement and motor irritability. No case of this description or of the chronic form with muscular contracture has been seen in Iraq. (6) Course of illness and prognosis: In the Iraqi series, there was an extensive improvement in sensory, motor, and visual functions in the mild and moderate cases. Patients with severe symptoms made a slow but definite recovery. In the Japanese series, the course of the illness was more chronic, symptoms appeared several months or years after fish containing mercury had been consumed, and the majority of patients deteriorated slowly and eventually died. The cause of the difference in clinical findings between the Japanese and Iraqi cases is not clear. It is possible that the presence of ethylmercury contained in the methyl- mercury in quantities varying from 0.88% to 7.88%10 is responsible for the appearance of gastrointestinal and cutaneous symptoms, and of optic papillitis. Up to the present, damage from mercury poisoning was believed to be irreversible. Hunter et al.11 reported on 4 cases of mercurialism among workers engaged in the manufacture of seed fungicide (methylmercury compound), one of whom died later from severe disable- ment.12 A grim outlook was Sredicted for all patients with mercury poisoning. This was supported by Hill,13 Ahlmark, 4 Brown,15 Hay,,l6 the Japanese authors on methylmercury poisoning (Minamata and Niigata disease),9 by the report of an expert committee on methyl- mercury in fish,17 and a leading article in the British Medical Journal.18 In this study, it was evident from the start that the very severely affected patients would die irrespective of the treatment they received. Necropsy studies made on infants and adults alike revealed extensive cellular necrosis in the brain (T. Al-Saleem, personal communication). Similar findings were observed by Shiraki & Takeuchi. 19 In spite of that, in both treated and untreated groups a remarkable improvement of function was found in some of the patients with very severe and in all those with moderately severe and mild symptoms when they were examined 1 and 2 years after exposure. Some of the patients with moderately severe and mild intoxication lost their symptoms completely. Physical therapy speeded the recovery of motor functions.20 Similar observations have been made on the patients who were poisoned with ethylmercury in 1960 when they were examined 13 years later (see page 12 ). Although the anatomical damage produced by organomercurial compounds in the cerebral and cerebellar cortex and in the putamen is irreversible, the reversibility of such symptoms as motor weakness, ataxia, blindness, deafness, and mental symptoms may indicate either that new neurological pathways have come into play or that a functional improvement can occur in spite of the central cellular necrosis of the brain. RESUME INTOXICATIONS DUES AU TRAITEMENT DES SEMENCES PAR DES COMPOSES METHYLMERCURIELS - ASPECTS CLINIQUES DE L'EPIDEMIE SURVENUE EN IRAK EN 1971-72 Soixante-six malades hospitalis6s souffrant d'intoxication chronique par des composes m6thylmercuriels ont Wt4 examin6s a Bagdad en 1972. L'intoxication a ete attribuee a la consommation de pain de menage fait avec des semences de bl trait6es par un fongicide mercuriel. Les ages des sujets s'echelonnaient de 4 a 70 ans. Sur le plan clinique on a observe surtout des sympt8mes et signes neurologiques tels que' asthenie musculaire, paresth4sie, demarche chancelante, dysarthrie, troubles mentaux; dans les cas graves il y a eu c6cit6, surdit4 partielle, stupeur, coma et mort. Les 80 atteintes des systemes cardio-vasculaire, urinaire, gastro-intestinal et h6matopol6tique, couramment observees lors de 1'episode d'intoxication par 4thylmercuriels qui s'6tait produit en Irak en 1960 ont 6td rares. La gravit6 des sympt^mes et des signes d6pendait, en gros, de l'importance de la dose absorb6e; a une forte exposition correspondaient des manifestations cliniques aigu-es, avec pourtant 2es variations. Sur la base des manifestations cliniques, on a 6tabli des crit&res pour I'appr6ciation de la gravit4 des cas. La s4rie observ4e comprenait 2 cas asymptomatiques, 20 b4nins, 20 moderes, 14 graves et 10 tres graves. Cinq malades du dernier groupe sont morts d'une d6faillance du systeme nerveux central. Les victimes d'intoxications graves ont toutes succombe, quel que fOt le traitement administr6. Apr&s deux ans d'observation, la plupart des sujets class6s parmi les cas benins ou mod6r6s n'ont plus pr4sent4 aucun symptOme. Certains cas graves ont accuse une lente am4lioration mais l'ataxie, la diminution de l'acuite et du champ visuels et la paresth6sie ont persist6. L'hypothese pr6c6demment admise concernant l'irr4versibilit6 des signes neurologiques a donc 6t6 d6mentie. REFERENCES 1. JALALI, M. A. & ABBASI, A. H. Poisoning by ethylmercury toluene sulphonanilide. Br. J. ind. Med., 18: 303-308 (1961) 2. KANTARJIAN, A. D. Neurology, 7: 639 (1961) 3. DAMLUJI, S. Mercurial poisoning with the fungicide Granosan M. J. Fac. Med. Baghdad, 4: 83-103 (1962) 4. DAHHAN, S. & ORFALI, H. Electrocardiographic changes in mercury poisoning. Am. J. Cardiol., 14: 178-183 (1964) 5. AMIN-ZAKI, L. ET AL. Intra-uterine methylmercury poisoning in Iraq. Pediatrics, 54: 587-595 (1974) 6. AMIN-ZAKI, L. ET AL. Studies of infants postnatally exposed to methylmercury. J. Pediatr., 85: 81-84 (1974) 7. LEQUESNE, P. ET AL. Electrophysiological studies of peripheral nerves in patients with organic mercury poisoning. J. Neurol. Neurosurg. Psychiatr., 37: 333-339 (1974) 8. DAHHAN, S. & ORFALI, H. Mercury poisoning and electrocardiographic changes. J. Fac. Med. Baghdad, 4: 104 (1962) 9. KUTSUNA, M. ed. Minamata disease. Kumamoto University, Japan, 1968 10. BAKIR, F. ET AL. Methylmercury poisoning in Iraq. Science, 181: 230-241 (1973) 11. HUNTER, D. ET AL. Poisoning by methylmercury compounds. Quar. J. Med., 9: 193-219 (1940) 12. HUNTER, D. & RUSSELL, D. S. Focal cerebral and cerebellar atrophy in a human subject due to organic mercury compounds. J. Neurol. Neurosurg. Psychiatr., 17: 235-241 (1954) 81 13. HILL, W. H. A report on two deaths from exposure to the fumes of di-ethyl mercury. Can. J. Public Health, 34: 158-160 (1943) 14. AHLMARK, A. Poisoning by methylmercuric compounds. Br. J. ind. Med., 5: 117-119 (1948) 15. BROWN, I. Chronic mercurialism: cause of clinical syndrome of amyotrophic lateral sclerosis. Am. Med. Assoc. Arch. Neurol. Psychiatr., 72: 674-681 (1954) 16. HAY, W. J. ET AL. Organic mercurial encephalopathy. J. Neurol. Neurosurg. Psychiatr., 26: 199-202 (1963) 17. SWEDEN, NATIONAL INSTITUTE OF PUBLIC HEALTH. Methyl mercury in fish; a toxicolo- gical epidemiologic evaluation of risks. Nord. hyg. Tidskr., Suppl. 4 (1971) 18. Br. med. J., 1: 126 (1971) 19. SHIRAKI, H. & TAKEUCHI, T. Minamata disease. In: Pathology of the central nervous system, Vol. II. New York, McGraw-Hill, 1971 20. DAMLUJI, S. F. ET AL. Mercury in the environment. Br. med. J., 4: 489 (1972) 21. TOKUOMI, Y. Minamata disease in human adults. In: Kutsuna, M. ed. Minamata disease. Kumamoto University, Japan, 1968, pp. 37-72 22. TSUBAKI, T. Clinical and epidemiological aspects of organic mercury intoxication. In: Proceedings of Symposium on Mercury in Man's Environment, Ottawa, February 1971. 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