Chapter 33: Toxic Conditions

CHAPTER 33 Toxic Conditions CONTENTS A. Summary ......................... B. Toxic Effects of Various Drugs .......... 1. Autonomic Drugs ................. 1312 1312 1312 2. Other Drugs . .................... C. Endogenous Toxic States .............. 1317 1317 A. Summary Some of the pupillary effects of intoxication are encountered in other chapters of this book. Thus, toxins produced by bacteria are included among infectious di ea es (Chapter 32). Untoward effects of spinal or of general anesthesia during surgical procedures, those of ocular iron splinters, leading to siderosis, and those due to carbon monoxide poisoning-together with the sequelae of other forms of hypoxia or anoxia-are discu ed under the headings "Trauma" and "Afferent Lesion " (Chapters 43 and 17, respectively). Alcohol intoxication was mentioned in connection with the Argyll Robertson syndrome (Chapter 19); and the effects of toxic doses of a number of drugs-such as the opiates, sedatives, and other psychoactive drugs-in the chapter on pharmacology (Chapter 14). Pupillary size and reactions understandably were not of great interest in many of the life-threatening conditions brought about by severe intoxications; but sometimes they furnished diagnostic hints: occasionally, internal ophthalrnoplegia was a sign of botulism poisoning. In other patients the pupils would fail to react to light due to retinal or optic nerve damage; or brisk light reflexes in blind patients indicated that the loss of vision was cerebral rather than due to impairment of the retina or the primary optic pathways. And large, fixed pupils with accommodative loss pointed to atropinic poisoning in children who had eaten some unknown kind of berries. I have not searched for literature on these subjects, and have tabulated only the few publications that happened to cross my desk. The lists could be extended indefinitely, since overdoses of practically any drug can affect the pupils in one way or another. But this is the proper subject of texts on toxicology, and only a brief outline is given here. Exogenous poisons gain access to the body by being eaten, by being inhaled in the form of dust or vapors, by absorption through the skin by cuts, animal bites, and so forth. Drugs instilled into the eye can cause (usually less severe) toxic side effects by entering the general circulation, especially when they are allowed to drain through the tear ducts to the large absorption area of the nasal mucous membranes. In other cases the instilled drugs' direct effects upon the iris and ciliary muscle produce local damage to the effectors. Exogenous poisons affect the pupils directly by their pharmacologic mechanism, or indirectly by systemic or neurologic damage they cause by forming toxic metabolites within the body, and by the general toxic state of the victim, especially the level of consciousness. For example, in coma, miosis is the rule, no matter what the cause, unless prevented by anti-cholinergic properties of the drug, or overcome by massive outpouring of adrenergic substances under the influence of extreme stress. Conversely, during convulsions the pupils are dilated and fixed to light, regardless of the pharmacologic nature of the poison. Endogenous intoxications result from many kinds of metabolic dysfunction-for instance, those due to diseases of the liver or kidney-which bring about increased release into the blood (or reduced elimination) of water, chlorides, phosphates, urea and other nitrogen compounds, and so forth, and consequent shifts in electrolyte and acid-base balance. These changes affect the nervous system in various ways, and the pupils are contracted or enlarged, and their reflexes reduced accordingly. B. Toxic Effects of Various Drugs 1. Autonomic Drugs The history and mechanism of these drugs are described in Chapter 14. In toxic doses their effects are dominated by their pharmacologic mode of action. Thus, atropine and similarly acting drugs such as gelsenium (from the wild woodbine Gelsenium sempervirens), scopolamine (hyoscine), stramonium (several plants), or duboisine ( daturine) block parasympathetic functions. Depending upon the dose taken in, and on wide interper1312 sonal variations in drug sensitivity, the physical signs of poisoning with these drugs include dilated pupils that are fixed to light and to near vision but can be enlarged further upon sympathetic stimulation; loss of accommodation of the lens to a near point; dry mucous membranes, a rapid pulse and rising blood pressure; a flushed face and warm, dry skin; and constipation. With higher doses there may be ptosis, diplopia, malfunction of the vesicular sphincter, pharyngeal spasms, vertigo, and a ~ ~ ("l ss ::, ::, CD -· 0 V, ::, ~ O' ~ ~ e 8. ~ o ~ ::, r-' 0.. -· 0.. '< ... (JQ ::,;-- (1) ~ 8. ... ~ ~ o,...,vin~~(l)-,::t ~ 0 0 .., CJQ (1) a o ~o·..,n--"' g:g-e:c ~ t s-~ ~ ~'< ~::!. -· (1) (/l .., g_ o g (1) - g_~ (1) (1) ::, ::;· (;I ('t) 0.. v, ~;:l~~(l);:l" ~ •J ::,;-('t) '< ::, ~ 0. 0 8 0 ~ (JQ ... .., n. "' ::; ..,. ::i ~ Clo.. ... (1) 0 ~ 2'"' ~gg~'O::,"'-~' --• .,..,0..(l)Ot: ("l S - ~ . 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C. ~ ::, 0 c' ~ : 8 "'1 ),-,,(=~ C. ::, 0 ~- p;· "' (IQ ::, 0 g = '< $.: (1)-P, ::, ::r "' (1) -· ~-~-~a, C - "' (') '-' 7· ~ a ~ "°'O ~~ '< Co) (1) 3 "'ocq;a,_§. 0 $.: ~-cS'Q-;. ~-a~"' . ('b ::, ::, V, (1) (1) ::r n. ~ ::, 0.. :::-: 0..::, 0 (JQ O' .., 0 ~ O' ~- 0 c'b"(/l (/l ("l fij" s ~ '< .., t: 0 s - a- 0 ::, ~ ~ (/l ;:::: O' ..... c'b" o.. (1) ~ §: ::i~. (JQ ::, 8, 3 ri' - '< 0.. 0...., ::!. t: ::r ('t) ~ ~ (JQ V, ,..., 0 ~ - ::, s g- ~ ~ ::;· ~ (/l s 0.. :_ ~ ~ ~ (JQ ::+' -- -0 ;::, (1) YEAR 1705 1757 1757 1852 1853 1857 1863 1875 1876 1877 1878 1878 1878 1878 1879 1881 1886 1887 1891 1892 1892 1892 1893 1899 1901 1901 1901 1905 1911 1921 1921 1926 1928 1929 1935 1935 1936 1953 1953 SGBSTA~CE AND ROUTE stramonium (Jimsonweed): leaves eaten as salad cnglish nightshade (atropine): systemic use nightshade (solanum): s:z::stemicuse lauc!anumas antidote for belladonna 22 isoning: systemic belladonna (atropine) as antidote for morphine poisoning systemic poisoning by use ol atropine eye arops Jones atropine: useo as ointment on tFic sltin Plass gelsenium sempervirens: fatal poisoning by its Ringer & Murell s:z::stemicuse hyosc:z::amine:larg:e closes 2ut into e:z::e were toxic Pearse belladonna (atropine) placed into the ear Tansle:z:: Fronmliller g:elsenium: s:z::stemic use side effects of ocular applications of atropine and Galezowski of duboisine duboisia m:z::ro22roides: not sure to be 22isonous Gerrard toxic effects of duboisa myroporoides, given as ~arme e:z::edrops Kowalewskv atro2ine ps:z::chosisu2on 02fithalmic use Deutschmann atro2ine J22isoning:( nr) h:z::oscineused as "cerebral sedative" Bruce Buchner forensic as12ects of atro2ine 22isoning Adler h_yoscine J22isoning:b:z::e:z::edro2s Richet monke:z::swere sub-sensitive to atro12ine henbane (containing: scoeolamine): 4 cases J22isoning: RudolJ2h Schafer case of h:z::oscineintoxication: s:z::stemic, 5 grams Binz 2 cases of atro2ine 20 isoning: Tonc!eur 2 chilaren ate fruit of datura stramonium ingestion of seeds of datura stramonium Benesch Friedlaender sistemic poisoning: b:z::stramonium a boy clranK 50x adult dose of atropine solution Selo almost fatal atro2ine I!QiBoningby eye clro2s Holtz a man ate 3 rioe berries of belladonna Kanngiesser atropine poisonong in 6-year-old by systemic use; Gassul 12-:z::ear-old22isoned b:z::atro2ine e:z::edro2s atro2ine ointment rubbed into the e:z::eaccidentall:z:: Macdonald Barre &Rei.linger systemic belladonna 22isoning: Barnard stro12hantin-m:z::driasis (nr) mydriatic use of stramonium (Jimson weea) Patton repeated use!, rabbits' sensitivity to atropine Araki stramomum poisonmg (nr) Jennings Juice of datura stramonium into eye Genet & Delord use care not to cause toxic effects by atropine eye Nordheim drops atropine poisoning in children by use as eye drops af Ursi n AUTHOR Beverly Bromfield GataKer Lussana Lindsay a =-- -· 0 -· 3 •.fh Table 33-1. Toxic reactions to anti-cholinergic drugs (1) .., YEAR AUTHOR 1954 1956 1956 Lendle Allies Longo 1957 Simmons 1959 1960 Morone Mitchell & Mitchell Weintraub Beswick Simcoe Binkhorst & al. Urretes-Zaval(a Werner Antweiler & al. Golda:z::& al Carpenter 1960 1962 1962 1963 1963 1965 1966 1966 1967 1967 1967 1968 1968 1969 1969 1970 1971 1974 1974 1974 1974 1976 1977 1977 1978 1978 Cromwell,& Ketchum Simmons Di Giacomo Madill SUBSTANCE AND ROUTE toxic effects of homatropine eye drops children 2oisoned b:z::s:z::stemicatro2ine effects of atropine and scopolamine on behavioral and EEG slee2 accidental Jimsonweed (stramonium) m:z::driasis effects of manv ophthalmic drugs incl. toxic Jimsonweed: J22isoning of children stramonium QOisoning cyclo2entolate 2s:z::chosis ( as e:z::edro2s) toxici!Y of cycloQentolate 2sychotic reactions from cyclo2entolate dro2s bad ocular effects of atrooine treatment enz:z::mesversus atro2ine sensitivit:z:: toxicolog::z:: of various troeines Jimsonweed mydriasis (stramonium) ~ 87 came down with precipitous mental deterioration after cyclopentolate-mydrias is delirium due to scopolamine Jimson weed 2oisoning LSD-like signs of stramonium-bellaaonna atropine-scopolamine as antioote for anticholiesterase intoxication fatal "lomotil" poisoning (dephenoxylate HCl Harvies & Rossiter 2lus atro2ine) "lomotil"- poisoning: fever, slow, shallow Riley breathing I J2in-2oint 2u2ils ( child survived l Bierstecker &al. mydriasis epidemic by airborne particles of duboisa myo2oroides s2illed from sacks mydriasis from accidental Jimsonweed Thompson 2articles into the eye (farmers, etc . ) Letter, JAMA atro2ine QUQils mydriasis by accidental contamination with Moore&Nold atro2ine into the eye poisoning with seeds of kechubong in Singapore Quek &Cheah ( datura fastiosa ? ) accidental atroeine-administration into the eye Weinstock toxicity of cyclo2entolate eye dro12s Awan mydriasis to propantheline bromide as antiNissen & 2ers12irant (unilateral, rubbed into e:z::e) Nielsen 4-year-old picked flowers (datura Wrightii), Re.a.der containing belladonna alkaloids Ca2uto & Schnitzer systemic effects of mydriatics in neonates effects of intravenous atropine (nr) Lifshiz & Lazar ADDITIONAL CASES: 1979 1980 1984 Schwartz &Apt mydriasis from large doses of i. v. atropine or glycopyrrolate during anesthesia, Balamoutsos &al mydriasis from anticholinergic effect of drugs used for muscle relaxation Frucht & al. mydriasis and cycloplegia from large doses of dysopyramide to prevent side-effects of neostigmine TOXIC SIGNS OF ATROPINIC DRUGS: 1. Mild J2h_ysicalsigns: mydriasis, cycloplegia, loss of light reflex, dry mucous membranes, constipation 2. Severe Ehysical signs: rapid pulse, rising blood pressure, flushed face; skin warm and dry, ptosis, diplopia; malfunction of bladder 3, Mental signs: writing with large, scrambled letters; dullness, confusion, excitement, fear, paranoia, disorientation, motor unrest, auditory and visual hallucinations 4. Fatal si~ Cheyne-Stokes respiration, coma, cardiac and respiratory arrest ➔ death ..... ~ ..... ~ 1314 / V. Pupillary Pathology: Pupillary Signs in Various Diseases (stramonium) in their eyes while working in the field (Patton, 1929; Genet and Delord, 1936; Simmons, 1957; Thompson, 1971 and literature cited there; Savitt, 19 6). Bierstecker and colleagues described the occurrence of a puzzling epidemic of unilateral mydriasis that wa explained when it was found that small particles of Duboi ia myoporoides had escaped from a broken bag at the docks and had been picked up by the wind and blown into the eyes of passers-by. Some anti-perspirants and co metics contain atropinic substances that can be rubbed into the eye by mistake; and anti-congestants frequently contain atropine that may lead to mydriasis in per on who practice enthusia tic self-medication with the e drug , or who u e them in the form of aeroso,ls (Helprin and Clarke, 1986; Jannum and Mickel, 1986). Recently a ra h of reports was elicited by the introduction of scopolamine-containing skin patches for transdermal absorption to prevent motion sickness (Carlston, 19 2; Chiaramonte, 1982; Flora, 1982· Hodgson, 1982; Lepore, 1982; McCrary and Webb, 1982; Roper and Hale, 1982; Verdier and Kennerdell, 1982; Biena et al., 19 3; Koehler et al., 1983; Hirsch, 1984; Price, 1985; Vincent and Vincent, 1985; Patterson et al., 1986; Ro en, 1986; Rosenberg, 1987). The effects of toxic doses of cholinergic drugs also are stamped by their pharmacologic mode of action, that is, they are ign of parasympathetic excitation. The first of these drugs that came to the attention of Western cientists, physostigmine ( eserine) was indeed used as a poi on in its native land in the belief that it could separate the innocent from the guilty (see this history in Chapter 14). While it could not accomplish this, it was noted that eserine as well as pilocarpine-introduced to Europe from South America during the 1870s-could antagonize atropine in persons poisoned by that drug. Eserine and pilocarpine further were able to induce sweating and other secretions; and they were, for a time, used systemically to combat fever, until their toxic side effects proved too disturbing. But their miotic action in the form of eyedrops has remained useful to the present. Toxic doses of eserine, pilocarpine, muscarine, and organophosphorous anti-cholinesterase compounds developed later for use as insecticides (and as military gases) bring about profuse sweating and salivation, bronchial secretion and bronchial spasms, bradycardia ( occasionally tachycardia and heart pain, by way of indirect mechanisms), vascular hypotension (or hypertension), abdominal cramps, nausea, vomiting, and diarrhea. Sensations of giddiness and general weakness develop; with higher doses there is vascular collapse, coma, and death. The pupils are constricted by the powerful cholinergic action of these drugs, but during convulsive seizures they dilate to some extent and refuse to react to light. Widespread use of cholinesterase-blocking insecticides (parathion, TEPP, and others) brought on toxic reactions in workers who dusted or sprayed these substances in the fields and occasionally in consumers of fruit or of other food grown in these fields. There was, for instance, an outbreak of parathion poisoning in Greece in 1971, with 246 persons known to have been affected, and probably many more unreported cases. Chronic use of cholinesterase-inhibiting agents as eyedrops in patients with glaucoma can-in sensitive subjects-cause some of the signs of cholinergic poisoning in attenuated form. Further, the tight miosis and accommodative spasm may cause headache, pain in and around the eye, myopia with blurred far vision, and limitation of the visual field. Finally, prolonged use of strong miotics was found to damage the iris: iris cysts developed, and there were pigmentary anomalies at the pupil border, as well as stromal atrophy and (rarely) retinal detachment or lens changes (Table 33-2). Mioticinduccd iris cysts were first described by Vogt (1920); and they became important in the 1950s when new, potent anti-cholinesterase drugs such as DFP and echothiophate began to be used for the treatment of children with squint. Adrenergic drugs used for diagnostic mydriasis also may bring about deleterious systemic side effects. Phenylephrine, in the commonly used concentration of 10%, is the chief culprit in this regard. In premature and newborn babies and in some elderly patients with a vulnerable cardiovascular system, dangerous rises of blood pressure and of pulse frequency have been encountered (for some recent publications, see Holtmann and Meyer, 1972; Matthews et al., 1977; Caputo and Schnitzer, 1978; File and Patton, 1980; Rosales et al., 1981; Levine, 1982; LaRoche, 1987). In my opinion 10% phenylephrine should be banned as a poison. Besides, a drop or two of a mixture of low-concentration anticholinergic drug-such as 0.5% or less tropicamide and no more than 1% phenylephrine-will dilate the pupils just as quickly and as extensively and will be more than ample if preceded by a drop of corneal anesthetic. 2 Effects of systemic treatment with sympatholytic drugs such as reserpine or alpha-methyl-dopa for vascular hypertension may surprise the ophthalmologist by making it appear as if the patient had bilaterally equal Homer's syndrome, which is practically unheard-of otherwise (see Oona, 1974; Oono and Uga, 1979; and Chapter 25). Mallampalli and co-workers (1987) described a patient with large, fixed pupils due to monoamine oxidase overdose; and Freysz and co-workers (1986) an incident of cardiac arrest after poisoning with a beta-adrenergic blocker. 2. Ophthalmologists also should be reminded that careful placing of one small drop into the patient's conjunctiva! sac (perhaps repeated, after gentle blotting, a minute later) will result in as much ocular penetration as liberally squirting the solutions so that they run down the patient's face, with excess snuffed through the tear duct to the large absorption area of the nasal mucous membranes, and from there occasionally even swallowed (see Chapter 14). Table 33-2. Poisoning by cholinergic drugs YEAR AUTHOR 1848 Daniell 1855 Christison 1863 Mitchell 1863 Robertson 1863 Fraser 1863 Zehender 1864 Kleinw!ichter 1869 Schmiedeberg & KOJ2]2e 1875 Crequy 1875 Ringer & Gould 1877 Curshmann 1878 Demme 1878 Marme 1882 Vulpian 1892 1909 Leibholz Eppinger & Hess Shark Vog! Dragstedt Haggn &Woodart Du Bois &al. Dunphy 1916 1920 1945 1947 1949 1949 1949 1950 1950 1952 1954 Feldman Bielstru:e Johnson Sedan Gerewitz Hallermann 1955 1955 1955 1956 1956 Funder Straub &Conrads Weekers & Laver~e Christensen &al. Gerewitz 1957 Dixon 1957 1958 Gougnard Weekers &Gastin 1954 DESCRIPTIONS the ordeal bean of calabar (eserine-~isoning:) ordeal bean of Calabar (eserine; see Chapter 14) toxic side effects of eserine, relieved by atropine local and svstemic effects of ordeal bean of calabar local and svstemic effects of ordeal bean of Calabar local and svstemic effects of ordeal bean of Calabar used calabar extract to treat atroeine eoisoning muscarine, the alkaloid of the mushroom amanita muscaria a man was frightened by poor vision after systemic use of jaborandi (pilocarpine) jaborandi (pilocarpine) used to treat atropine ~isoning toxic side effects of pilocarpinum: vomiting, weakness, colla2se ( given to induce sweating) systemic use of pilocarpine to induce sweating & salivation pilocarpum muriaticum ( Merck) given systemically for sweating I salivation I bronchial secretion jaborandi caused mydriasis by stimulating the abdominal symEathetic (text of toxicology) poisoning by physostigmine (nr) systemic pilocarpine:tried to counteract atropine QQisoningin a child ( did not work) histor:t: of Eh:t:sostigmineI including toxici!.}'. iris cysts UEQntreatment with 2ilocar2ine or eserine trial by ordeal of Calabar {nr) hexaeth_yltetra12hos2hate (IIETP, insecticide) toxici!.}'.of 2arathion (anti-cholinesterase comEQund) systemic mecholyl can cause toxic effects; carbamino:t:lchloride is ver:t: toxic Eilocar:eine works 122orl_y as antidote for atro:eine miosis in TEPP ooisoning resists atropine EQisoning of cro2-duster with TEPP DFP: descri:etion of toxic effects miotic cysts in 12 of 349 12atients treated with miotics excreecences of pigmentary iris layer after 21 days of treatment with mintacol miotic iris cysts due to mintacol and DFP miotic iris cysts reinal detachment after treatment with DFP hy:eer:elastic :eigment nodules in the iris after miotics tight miosis in Argyll Robertson's syndrome does not cause iris C,YstsI but treatment with miotics does parathion: in 2 poisoned children onset of miosis was relativel:t: late I while other toxic s i~s were present toxici!_yof BC 48 (cholinesterase inhibitor) miotic cysts in glaucoma patients - YEAR AUTHOR 1959 1959 Abraham Drance & Carr 1959 Leopold &al. 1959 Pillat &Gittler 1960 1963 1966 Drance Katlin de Roetth &al. DESCRIPTIONS miotics mav cause irido-cvclitis toxicity of BC 48 (tosmilen, decamecarium bromide): headache vomiting nausea abdominal nain • 1 iritis blood cholinesterase levels in normal subjects &in patients treated with anticholinesterase agents toxic reactions to tosmilen eye drops, treated with atroeine iris damage and svstemic effects of nhosoholine iodide toxicity of anticholinesterase agents in rabbits systemic effects &+blood cholinesterase in patients treated with phospholine iodide Axelsson side effects of treatment with long-acting Axelsson &Nyman cholinesterase inhibitors ( eye drops) Nyman &Biers teker Ishikawa &al ey_edisease due to organic 2hos2horous insecticides Tsachalinas parathion: 246 cases from spraying of olive trees in Greece: 192 miosis, 42 normal, 6 mydriasis; all had other si~s (15 coma 1 1 death) 1972 O~ta chronic toxicity_with organoEhosEhate ~sticides (dog) 1974 Hopmann & Wanke severe organophosphate poisoning treated with large doses of atropine 1974 Ltideritz &al, parathion poisoning (with criminal intent) 1976 Klose & O"26, attempted suicide by injection of 3, 75 gr. Gutesohn demeton methyl: unconscious with respiratory arrest, treated successfully with purified serum cholinesterase and atro2ine 1977 Fisch &al, potential hazards of pesticides (experiments on dogs): miosis and reduced blood cholinesterase upon wearing insecticide-treated collars 1970} 1970 1970 1971 1971 SIGNSOF CHOLINERGICPOISONING: 1. ACUTE SIGNS: profuse sweating, salivation, bronchial secretion and bronchial spasms, pulmonary edema; increased respiratory rate (respiratory insufficiency or arrest); diuresis, bradycardia (occasional tachycardia with heart pain); vascular hypertension (less often hypotension); abdominal cramps, nausea, vomiting, diarrhea; sensations of giddiness &general weakness, vascular collapse, coma, and death; The pupils were constricted by the strong cholinergic action of these drugs, but during convulsive seizures they dilated. CHRONICUSE of cholinesterase-inhibiting agents as eye drops in patients with glaucoma or in miotic treatment for squint could bring on some of these signs in attenuated form. In addition, the tight miosis and accommodative spasm caused headache, pain in &around the eye, myopia with blurred far vision, & limitation of the visual field; muscle cramps, sometimes involving the EOM, Finally, prolonged use of miotics could bring on also could be precipitated. ocular damage: pigmentary anomalies, iris cysts, stromal atrophy, & (rarely) retinal detachment. Such changes were first described by Vogt (1920) and became important in the 1950's when new, potent drugs were used to treat squint. Table33-3. Pupillarydeficitdueto acuteor chronicalcoholintoxication - YEAR AUTHOR 1873 Magnan & Joylet 1879 Sancter 1881 Rominee 1886 Bernhardt 1886 OEEenheim 1886 Uhthoff 1887 1888 Moeli Thomsen 1890 Eperon 1890 Thomsen 1891 Siemer ling 1892 Eiseniolir 1894 Jacob!Ius 1895 Boedecker 1896 Hoclie 1896 Klewe 1899 Guillery 1899 Marimo 1900 Lauder 1900 von Gudden 1900 Raimann 1902 1903 1903 Gamble Cramer Meyer & Raecke 1904} Vogt 1905 1905 Hilbner 1906 Bertozzi 1906 Rodiet & Cans 1907 Ploeger IAR TYPE OF DAMAGE intravenous alcohol in dogs caused convulsions with large, fixed pupils acute aicolioI ooisonin2' resembled coma: ouoils were small alcoholic amblyoeia 8 cases with alcoholic neuritis: none with Arg,yll Robertson alcoholic polyneuritis and paralysis 30,000 admissions, 1000 alcoholic: 6% had abnormal pupils: 25 unequal 1 25 imEaired light reflexes 1 10 Argyll Robertson sometimes light reflexes of alcoholics were (reversibly) lost Wernicke's acute hemorrhagic encephalitis with multiple small hemorrhages in the central grey around the agueduct 7500 patients poisoned by alcohol, nicotine, or both: 65 had toxic amblyopia 3 cases with alcoholic oolvneuritis and normal pupils alcoholism ( statistics) Wernicke's acute hemorrhag!c ence2halitis & midbrain defects Wernicke's encephalitis with small, sluggish pupils & EOM pathology acute hemorrhagic encephalitis with midbrain lesions: 3rd & 6th nerve paresis & Argyll Robertson pupils reduced, sluggish pupil reactions improved during prolonged abstinence alcoholic pseudo-tabes: pupils were small or large, and very slugi2:sh reduced or absent pupil reflexes in severe intoxication: pupils were not affected b_yalcohol doses that slowed the EOM the eueils were very sensitive to alcoholic 22isoning alcohol neuritis: good light reflexes 2 EOOrreactions to near several hundred acutely intoxicated patients: excited, in deep sleep, or obtunded; light reflexes were inhibited in excitement; pupils mydriatic in seizures, returned to normal when patients sobered ue alcoholic neuritis or neurologic foci: pupils varied, with miosis, AR1 mydriasis ➔imEroved ueon treatment toxic amblyoeia: euEils fixed to light I reactive to near in normal people the pupils remained normal during intoxication Korsakoff's syndrome with anisocoria and sluggish pupils no effect of alcohol ingestion in normals, but 1/3 of idiots had small, slow, unequal Puoils and reduced consciousness 12 normal students after 1/2 bottle of wine had normal pupils; various eueil siggs in chronic alcoholism 29 mentally impaired alcoholics had miosis, anisocoria, and reduced light reflexes alcohol intoxication: pupils were (non-progressively) small and sluggish alcoholism ( among other subjects) - YEAR AUTHOR 1908} Neussel 1910 1910 Margulies 1910 1910 Stapel Weiler 1911 Barnes 1911 Benoit TYPE OF DAMAGE according to Weiler, 1910, chronic alcoholics had increased light reflexes, only 3% had them reduced 500 chronic alcoliolics: 28 had slow, distorted, fixed, unequal, or Ar~ll Robertson pupils; improved on treatment dissertation on acute alcohol intoxication moderate, acute doses in normals liad no pup1l1ary effects; saw some slow 2u2ils in alcoholic neuritis saw Argyll Robertson pupils in alcoholics ➔ reversed when the 2atient sobered up methyl alcohol ➔comatose with widely dilated pupils ➔ oetic atro2hy with poor light reflexes alcoholic pupil defects regressed when natients remained abstinent alcohol-nicotine intoxication with amblyoQia men who had died from alcoholism had slight mydriasis methyl alcohol 2QiSoning Dissertation on alcohol QOisoning (methyl alcohol) Behr Moretti Nonne Hirschberg Le~ Stadelmann & methyl alcohol poisoning in Berlin Mairnus Lev, Korsakoff's syndrome: (reversible) Argyll Robertson syndrQm~ 1913 Bonhoeffer alcoholic 2seudo-tabes with Argyll Robertson 2u2ils 1913 Mees slugg!sh 1 unegual, variable QU!lilSin alcohol 2sychQi:iis 1914 Firth methvl alcohol poisoning --+dissociated pupils (tabiform \ 1919 Fuchs transient or ~rmanent Arg,yll Robertson in severe alcoholism 1921 Dreyfus 1922 Mosso alcohol amblyoeia with sector iris atro2hy dissertation on eueil siggs in chronic alcoholism 1923 Hesse 30 2atients with alcohol-tobacco amblyoQia & fairly good QUQilS 1923 Sattler 1926 Barre &Lieou alcohol oolvneuritis with small, unequal, ooorlv reacting nunils 1927 Menninger 58 alcoholics: 43% had small EUEils1 36% fixed to light alcoholic with fixed EUEils2 died 2 weeks after admission 1927 Peter Ad, -mvdriasis said to be orolon1<edin chronic alcoholism 1934 Balodis 1941 Constantinescu poor or absent light reflex without miosis, mydriasis, or & Constantin anisocoria said to be tyeical for alcoholism 1943 Skoglund normal men had large euEils after acute alcohol ingestion 1953 Bennett & al. 323 cases of acute methyl alcohol eoisoning 1953 Guisoni chronic alcoholic eatient with Arlie's S,Y!!drome the higher the blood alcohol level, the more often pupil pathology: 1961 Schleyer & Wichmann small 2 large, slugg!sh (experiments) 1965 de Molfetta alcohol-tobacco amblyoeia: miosis with eoor EUEilcontractions 1975 MUller neurologic findings in chronic alcoholism 1977 Hayreh & al, ocular toxicity of methol alcohol in 6 monkeys alcoholism (see Chapter 13) 1977-} Rubin 1980 1979 Myers & al. alcoholic patients with neuropathy failed to show cholinergic supersensitivity of their iris sphincter 1911 1911 1911 1912 1912 1912 Morone ( 1959) discussed pupillary reactions in alcoholic patients with neuropathy; with alcoholic optic nerve disease or small midbrain lesions which are commonlv seen there are nunillary deficits /literature\ rgyll Robertson syndrome; EOM - extraocularmuscles. Ad. - supersensitivity = adrenaline-supersensitivity. 33. Toxic Conditions 2. Other Drugs While the pupillary changes in atropinic and in cholinergic poisoning result directly from the pharmacologic mechanism of these drugs, the effects of many other poisons are not specific but are secondary to impairment of the retina, the afferent pathways or the midbrain, or to alterations in the patients' general condition. Thus, in acute alcohol intoxication the pupils usually were medium-sized or larger, and the light reflexes were inhibited in varying degrees; and when the patients awoke sober the next day, their pupils were normal. In delirium tremens they were dilated and fixed, and in alcoholic coma they were small and poorly reactive. Chronic alcoholism can cause toxic amblyopia, especially when alcohol is adulterated with methyl alcohol. The retinal and optic nerve damage interferes with afferent conduction, and light reflexes are diminished accordingly. Some chronic alcoholic patients developed Wernicke's disease (polioencephalitis hemorrhagica superioris) because their poor nutrition led to thiamine deficiency. This disease, characterized by horizontal and vertical nystagmus, abducens and lateral gaze palsies, ataxic gait, and mental confusion, causes multiple small hemorrhages and glial and vascular proliferations, especially around the third and fourth ventricles and t~e Sylvian aqueduct. In such cases the pupils are often mvolved: they are enlarged or miotic, sluggish, or fixed to light or to light and near vision. The "inverse Argyll Robertson syndrome" with active light reflexes and poor or no pupillary contractions to near vision is also sometimes seen (Table 33-3). These defects are not surprising in view of the location of the lesions. / 1317 Many other drugs have different effects, depending on dose and on sensitivity of the patient. Thus, acute administration of relatively small doses of nicotine contracted the pupils, probably due to stimulation of the pupilloconstrictor neurons in the ciliary ganglion; but larger doses of nicotine led to mydriasis, due to the ganglion-blocking action of this drug. This also happened after poisoning with the ganglion-blocking agents HETP (hexaethyl tetraphosphate) and tetraethyl ammoniumbromide. Chronic nicotine poisoning with mall doses, such as in workers in tobacco factories, led to amblyopia with associated lo s of pupillary light reflexes, especially when nicotine toxicity was combined with alcohol abuse. And the same developed in patients with other kinds of toxic amblyopia, as after exposure to lead, quinine, or other poisons ( ee Table 33-4). This Table also shows that many substances to which patients are exposed in their professions (heavy metals, solvents, fumes), to which they are exposed accidentally (snake or scorpion bites, bee stings, mu hroom and other plant poisons), or which were used in attempted murder or suicide (strychnine, cyanides, etc.), acted upon the pupils in the ways just described: by way of injury to the eye, the visual pathways, or the nervous system; or by way of the pathologic state of the affected individual (coma, convulsion , etc.). The latter mechanisms could override the drugs' pharmacologic effect , as happens during terminal convulsions of patients poisoned by cholinergic drugs. Undoubtedly this variability of consequences is responsible for the many conflicting findings about pupillary behavior due to poi on . C. Endogenous Toxic States Endogeno_us intoxications affect the pupils indirectly and nonspec1fically. Malfunction or failure of vital organs such as the lungs, liver, pancreas, or kidneys or damage to endocrine glands, cause deficiencies of metabolic funct!01~s a~d abnormal release into the blood (or redu_c~d ehmmation) of breakdown products. Defective nutntton and neurotoxic substances in the tissue fluids !nj~re the brain and peripheral nerves directly, and mdtrectly by way of vascular occlusions and hemorr~ages. The toxic general, neurologic, and psychiatric signs ~es~mble those brought on by exogenous poisons. And similarly, the pupillary signs merely accompany the ge~eral state of the patient, or are related to focal lesions such as optic atrophy, midbrain hemorrhages peri~heral neuropathy, and so forth. Accordingly, th~ pupil~ may be ei~her large or small, briskly reactive, sluggis~, or fixed m the same disease, depending upon the patient's condition at the moment. __F<;>rexample, ~rb (1880) described pupillary ng1d1ty to hght m advanced uremia. Fiirstner (18~8), w~o saw epileptoid convulsions, aphasia, co_rttcal blm~ness, and hemiplegia due to uremia, said the pupils were small before convulsive epi- sodes, together with increased tendon reflexes and reduced skin reflexes; but during attacks they were large _an? ~ed. Schmidt-Rimpler (1898) described mydnas1s m uremia and eclampsia, and Marburg (1903) agreed that the pupils were large and fixed. Scherr and co-workers (1962) noticed that the m_ydriasis and loss of light reflexes were associated with severe hypocalcemia and acidosis, and returned promptly to normal after treatment corrected these metabolic defects. Rock':l and co-workers (1975, 1976) claimed that pup1llary signs in patients with renal failure !reated_ by kidney dialysis indicated sympathetic msuffictency. They based this opinion on finding reduced pupillary dilations to the noradrenalinerelea~ing drug tyramine, instilled into the eye. But t~e differences between the normal and the pat1e~t groups were not impressive; and further, the patients had been treated with reserpine and with alpha-methyl-dopa (for hypertension) until 4 days b~fore examination. It is well known that adrenerg1c depletion after chronic treatment with these drugs usually persists longer than 4 days after the end of treatment. 1318 / V. Pupillary Pathology: Pupillary Signs in Various Diseases Table 33-4. YEAR Pupillary changes due to intoxication with various substances AUTHOR SUBSTANCES AND EFFECTS 1841 Houghton Poisoned by "butter of antimony" /nr) 1842 Bernard toxicologic work on effects of nicotine in cats and dogs 1843 Orfila general toxicologic text; among other effects, pupil dilation in dog due to nicotine 1852 Lussana strvchnine caused mydriasis: said to be due to contraction of radial iris fibers -:;-1~8~5-;;6_ ___ 1_.::.in:..:to:..::..:;xi.::.·;.:c:..:a:.;.t:::i.::.o:.:n=.s in rubber workers due to inhalation of carbon sulphide (nr} 1-:;:D-'e_;:l"'p_e.,..c_h--,,--=1856 Lawrie & Cowan strychnine: er 22, while drunk, took strychnine in alcohol & sulphuric acid ~ convulsions with large, fixed pupils ~recovered 1863 Demme used curare as antidote for tetanus ( pupil described} 1871 Nagel used strycnine to treat severe amblyopia in a child: said the child was cured 1871 Schiff effect of strychnine on the pupil ; dilation with very large doses 1872 Aldridrrn ate laburnum seeds ~pupils widelv dilated 1873 Beenen dissertation on the effects of strychnine, including the pupil 1875 Taylor forensic aspects of poisoning (nr) 1876 Bordier narcotic effects of "protoxyde d'azote" - favorably inlluenced by quinine sulfate 1878 Duigenam case of poisoning by aconite --.recovered ( pupils discussed; nr) 1878 Hill overdose of sweet spirits of nitre: child age 2 drank 3-4 oz: unconscious, almost pulseless I pupils widely dilated and fixed (died) 1878 Kennler self-experiments on acute poisoning with saponin (used as local anesthetic; nr) 1878 Martin nicotine amblyopia (dissertation; pupils discussed; nr) 1878 Mueller - Warnek potassium cvanide . su blethal poisoning ➔(-'lip..c:uc,..;;pi;c.l..:d...,ic;;:s...;:c.c.uc.:s.ccs..:e..:d-'-';'-s'n-'-'r=-· )'----a--:,----.-,------1 1978 Richards snake poisoning (probably cobra) of Cl"40: pupils seemed normal & reactive 1 78 Souwers potassium cyanide (photographer handling the drug) pupils tixect--+treated with chloral & potassium bromide and morphine ~pupils reactive ---.recovered 1881 Plugge aconite poisoning /pupil discussed; nr) 1882 Anders iodoform ooisoning: pupils dilated ( used as antiseptic ror cniwren) 1882 Czerni iodoform poisoning (pupils contracted, according to Hadlich, 188<::) 1882 Hadlich cited others that iodoform poisoning went with miotic or mydriatic pupils 1882 Hoeftmann iodoform intoxication ( nr) 1882 Kocher iodoform noisoning (used as antiseptic); according toTiadlich, pupils dilated 1882 Kcinig iodoform ( antiseptic in wounds) in 48 cases: pupils miotic in some, large in others 1882 KUster and 17 iodoform (discussion, but pupils not mentioned.) other authors ~ Mikulicz iodoform in surgery (intoxication): pupils dilated, according to Hadlich 18 6 Handford fatal case of mushroom poisoning (nr) 1887 Church corrosive sublimate: child very ill, with pupils widely dilated &fixed (died) 1888 Bornemann sulfonal intoxication (pupil mentioned; nr) 1887 Ulrich quinine and chloral poisoning: variable miosis, sometimes preceded or followed bv mvdriasis 1889 Gibson & Felkin woman treated for rheumatism with salicylic acid got pin-point, fixed pupils for 30 hours; recovered 1889 Hogarth sulphonal poisoning ( given as hypnotic) : 3 cases with dilated verv slu 0 ·<rish nuPils 1889 Rehm untoward side e!lects oI sulphonal (nr) 1889 van Rey santonine-poisoning ( nr) 1889 Ullmann sulfonal as hypnotic caused intoxication (nr) 1889 Wilkinson case of tobacco poisoning (pupil mentioned; nr) 1890 Dillingham poisoning by sulphonal (used as hypnotic; nr) 1890 Hauber digitalis poisoning: bilateral optic atrophy; pupils small ..:1:..:8:..:9:..0:.....i..:l:.:(n=a..,g"'g'-=s _____ fatal case of sulphonal poisoning (nr) 1 1891 Bresslauer toxic effects of sulphonal (pupils mentioned; nr) 1891 Mackenzie paraldehyde poisoning: miotic, fixed pupils 1892 Dowling nicotine toxicity: effect on vision and pupils in tobacco workers 1892 Platt case of bromoform poisoning (pupil mentioned; nr) 18 93 Bach exophthalmos, abnormal pupil reactions & EOM defects due to lead poisoning (nr) 1893 Jnoko mushroom poisoning: mydriasis visual hallucinations violet vision 1896 van Bohm bromoform poisoning: child drank left-over bottle -.cyanotic with minimal pupils -.recovered ( drug had been used for whooping cough) case of bromotorm noisoning (nr) 1896 Czygan ocular effects of various poisons ( including nicotine; nr) Marimo 1899 case of bromoform poisoning (nr) 1900 Engster pupillary effects of bromide in treatment of epilepsy (nr) de la Tourette 1900 3-year-old child swallowed 2-3 teaspoons of oil of eucalyptus _. stupor with pin1900 Wood Point PUPils (fixed) -.recovered ....:l:..:9::..:0=-•l:::.......i-.:H=-=in=m=a=n.:_ ____ _Q 36 ate 4 or 5 whole nutmegs: pupils 3/4 dilated & fixed (recovered) 1 1902 Brieger instilled dart-poison from East Africa ( accocanthera abessynica) into rabbits' eyes _.prolonged, tight miosis but no loss of corneal sensitivity mydriasis due to chlorodyne poisoning (nr) 1902 Powell bromoform noisonine: <nr) 1903 Dillard nutmeg poisoning: pupils normal in shock-like condition without loss of conscious1906 Hamond ness arsenicals caused mydriasis due to sphincter palsy , & degeneratve ON char..ges 1908 Bach 180 pages in Graefe-Saemisch handbook on ocular changes due to poison 1911 Uhthoff 1912 EOM Bumke = extraocular 166 pages muscles; CNS in Lewandowsky's = central nervous handbook system; on exogenous _., = followed poisons by. vs. CNS 33. Toxic Conditions Table 33-4 (continued) YEAR AUTHOR 1913 1913 Dorrell Magitot 1915 1919 1922 Brose Smith Burk 1923 Blatt 1923 Jesus 1923 1924 1927 1928 1929 1929 Meyer Frigerio & Vissich Schaltenbrand Seto Neiding & Feldmann Mitomo Barnard Rameev Alvis 1930 Neporent 1930 Tournade & Malmejac 1931 1931 Baisi Blatt 1931 Gurvi~ 1931 1932 1932 1933 1933 1933 1934 1934 1935 Notkin &al. Adinolfi Schwarz Cazeneuve & al. Roth Tietze Balcet Bruwers Kunz & Isenschwind Marcovitz & Al2ers Poppi 1924 1924 1925 1935 1935 1936 1937 1940 1945 1949 1949 1951 1952 1954 1955 1955 1955 1955 1957 1957 1958 1959 1959 1960 CNS= (W!!} -Gonzales Lodato Mikuni Jess Gerstle Heymans & Hoorens Luco & Marconi Wien& Mason Weinstein Turtz Drance Druault-Toufes SUBSTANCES AND EFFECTS reflex dilation to sensory stimuli was reduced in patients with tobacco amblyopia alcoholic man took quinine for 2. 5 months; lost consciousness and awoke next day hearine: was restored but vision remained noor; ouoils reacted deaf & blind; ophthalmoplegia interna due to lead poisoning (nr) blindness with widely dliated, fixed pupils due fo qumine pcnsomng child ate potassium hydrogen oxalate; collapsed witli pupils maximal and fixed after injection of scopolamine convulsions ; recovered ~ 40, very ill after snake bite (vipera berus) with 8mm, fixed pupils & cycloplegia & ptosis OU; 3 days later pupils became smaller, and she recovered scorpion bite __,. muscle spasms, miotic, fixed pupils; a second patient had mvdriasis __yohimbine poisoning ( alpha -adrenergic blocker; nr) (ruooer tactory): pseudo~ 34, poisoned by industrial vapors of carbonic suuate tabes with optic atrophy motor disturbances in acute oulooca2nine poisoning: (nr) ocular effects of eel serum deficits) effects of lead poisoning on typographic workers (central nervous ---+ effects of eel serum on the CNS, circulation, respiration, salivation & pupils mydriasis in rats clue to strophantine, d1g1tahs, and 4 other crrugs intoxication by quinine ancl blindness witli unreactive pupils ethyl hydrocuprein, used for pneumonia, caused blinclness & large, fixed pupils 2atient recovered but vision remained e2or and EUEils sluggish 88 workers poisoned with industrial lead; 9 had eye changes: narrowing of field, 2 had anisocoria & 4 OQtic atroehy es2ecially for color, reduced light reflexes; dogs given cigarette smoke via tracheotomy tube: enlarged pupils, increased blood pressure; most signs looked like acute release of adrenaline; injected nicotine had similar results ocular signs of slow ooisoning by vaoors of tetraethvl lead ( nr) 21 had pupil detects, summary on 320 case reports & 1 own case of lead poisoning: own case had fundus vasoconstriction, optic atrophy with 2 accommodative palsy; large, very sluggish 2u2ils and accomodative deficit & defective 20 workers in lead factory: 9 field loss, reduced acuity, fundus changes pupils cam:ehor 2roduced convulsions with large, fixed QUQilS -.small afterward bilateral blindness and 2aEillary edema due to guinine intoxication benzene fumes or ingested benzene caused EQl~euritis, with pu2ils affected in some gasoline and lubricant gases may cause anisocoria (nr} intoxication by "heavy benzene" (nr} methyl bromide and tetrachloride QOisoning (nr} methvl octenvl amine hydrochloride (nr) said lead 22isoning caused mydriasis, erolonged by adrenaline ( nr} to alcohol amblyopia but toxic effects of trichloroethylene upon the eye: similar not as severe: QOlY9:euritis I retrobulbar neuritis I absence of light reflex 2 patients with mushroom poisoning: cerebral & general signs and miotic, sluggish QUQilS ( no consistent relation to general signs} bulbocapnine in cats: at peak action pupils were fixed to light and to catalepsy; senSOEJ:'.: stimuli frogs with systemic nicotine ooisoning got mvdriasis miosis. or both ( 1 in each eve) e~eriments on effects of bee QOison u2on the eye ocular effects of poisoning oy industrial solvents anisocoria said to be caused by excessive doses of vitanine A for 40 days mydriasis in intoxication by hexamethonium (ganglion blocker) experiments on cats with tetraethvl ammonium bromide (ganglion blocker) strong mydriasis in e~eriments on tetraethyl ammonium bromide tetraethyl ammonium bromide decreased intraocular pressure xanto:esia I mydriasis fields, retrobulbar neuritis due to digitalis QOisoning I flimmer quinine amaurosis in Q 20 1 g!ven to induce abortion: QUQils large & fixed to light c ostalinon (tin alkyl compound) as treatment for boils: 2 patients had mydriasis with sluggish reflexes Garcia-Miranda intoxication with saturnine (nr} Lincoff ~48, supersensitive to quinine sulfate treatment for vascular disorder: blind, partly deaf, pupils large & fixed -.vision returned to 20/20 with field defect Kahnemann sprayed plants with lead-arsenic comeound --.1eft-sided miosis & poor reactions Romanogli attem2ted suicicle with quinine ____.EUQilS mydriatic Drischel & Zett digitalis said to affect motility of normal human 12upil ( used as eye drops} Green 9 28, nutmeg poisoning: semi-stupor, low BP &pulse rate, small, fixed pupils --+ recovered Morone mydriatic. areflexic pupils after ingestion of methyl alcohol ( also other clrugs) Levin bromine intoxication with delirium, hallucinations, visual problems; pupils had disturbed reactions to light & near, and accommodation was impaired central / nervous system; BP= blood pressure; (nr) = not read, and not obvious from title. 1319 1320 / V. Pupillary Pathology: Pupillary Signs in Various Diseases Table 33-4 - YEAR 1961 (continued) AUTHOR Truitt SUBSTANCES A D EFFECTS & al 8 hours after ingestion of toxic dose of nutmeg, pupils were constricted; the patient fluctuated between euphoria and anxiety, with dry mouth & tachycardia 1961 ZeE~ 9 34, bitten in foot by viper, had maximal mydriasis & bilateral ptosis tor 48 h. 1962 Grant (WH) transient blindness with wide mydriasis after subletlial closes o! cyanides 1963 Payne nutmeg poisoning: #1 was agitated, apprehensive, with flushed face and fast pulse, #2 had the same general increased BP, dry mouth & normal pupils ---.recovered; si~ but dilated (reactive) EUEils; this one also recovered 1965 Miglior & al. tobacco-alcohol ambllopia 1965 Atkinson & al. intra-carotid injections of nicotine in cats caused transient mydriasis, inhibited by sympatholytic drugs but not by removal of the superior cervical ganglion (thus due mostly to release of noradrenaline from the adrenal glands and sympathetic ~glia, and reaching the eye with the blood) 1966 Knox &al. ischemic stromal iris atrophy with loss of pigment at the pupil edge after quinine poisoning with amblyopia 1967 Harenko neurologic and other defects in chronic bromisovalum poisoning: pupils were 5% fixed 1 36% sluggish, 59% normal in 44 cases 1968 Nilsson & al. quinuclidine (synthetic, intended for antimalarial treatment) : tests on rats showecl mydriasis at 1.6 - 0.6 mg/kg (atropine= 0.15/kg) 1969 Golubev changes in pupil diameter ot rats after administration ot industrial poisons (etny1 alcohol, aldehydes, glycols heterocyclic compounds , ketones , xvlene) 1969 Roberts &Adams 12 subjects inhaled cigarette smoke --.pupils dilated O. 75mm or more, with return to baseline in about 3 minutes; accommodation decreased 1.25D for< 5 min. 1969 Walsh & Hoyt case of amblyopia with dilated, fixed pupils, due to quinine poisoning; have large cha2ter on ocular effects of many 22isonous substances I incl. nutmeg mldriasis histamine, anti1972 Hermans harmful effects on visual apparatus of many drugs : analgesics, compounds (nr) histaminics anorexigenic ~ Bedford toad venom toxici!J'. in small animals in the UK (nr) 1974 Hirayama & al. ganglion blocking action of IS-toxin and surugatoxin from the japanese ivory shell Babylonia ja2onica ( ganglion blocking agents, effects on various mammalian tissues) influence of chloroquine (intravenous injections) on visual fields and on the 1974} Tokuda 1977 threshold of Eu;eillarl light reflexes 1975 nutmeg poisoning: oil of nutmeg instilled into the cat's eye had no effect; injected Ahmad & into the vitreous it caused miosis, with Eersistent light reflexes &uveitis next day Thom2son 1975 geese and ducks were sensitized to light by ingestion of ammimajus seeds. When Barishak & al. exposed to sunlight the pupils became large & the animals were found to have iris atrophy ( vacuolization and atrophy of muscles) m72%of ___ m1osis m 88% of those Wltb narcotics; 1976 Mitchell & al. ingestion of drugs by children: those with Ehenothiazines; in 35% of those with ethanol, 31% with barbiturates, etc. neurotoxic solvents MBK (2-hexanone) and MBK metabolites were fed to guinea 1978 Abdel-Rahman body weight increased, and locomotor & al. pigs: pupillary responses were decreased, say that some drugs may work via their metabolites activity decreased; general effects and mydriasis 1978 v • Miihlendahl & toxicity of cyproheptadiul: Krienke ADDITIONAL 1939 1944 1978 1980 1981 --1986 1987 CASES: Alvaro Ridley Abdel-Rahman & al. Gangitano& Keltner Rosales & al. Freysz &al. Mallampalli &al snake venom in 02hthalmology (n.r.) snake venom in ophthalmology (n.r.) fed 2-hexanone and its metabolites (neurotoxi.c solvents) to guinea pigs increased body weight & decreased locomotion; 2u2il reactions were badly deteriorated defects of pupil reactions and of visually evoked potentials by quinine amblyopia 2.5% phenylephrine eye drops caused marked rises in blood pressure infants cardiac arrest after beta-adrenergic blocker overdose fixed pupils after overdose of monoamine oxidase inhibitor in premature NOTE: This list is a haphazard accumulation of data spread over the decades in the pupillary literature. It is given here merely because it reflects preoccupations at different times, and to serve as a starting point to find citations for those wishing to study the pupillary effects of toxic doses of various substances.