Indian j?. Ptdiatr. 46 : 58, ]979
EXTRAPYRBMIDAL SYNDROME FOLLOWING CHLOROQUINE THERAPY* SUNIT SINOHI, PRATIBHA SINOHf, MEFIARBAN SINOH New Delhi
Malaria has agai, assumed epidemic proportions in India. Physicians working in tropical countries are often faced with varioug side effects and toxic manifestations following administration of antimalarial drugs. Chloroquine is considered essentially nontoxic when used for chemosuppression of malaria (C~tchpool, 1974). However, gastrointestinal upsets, headaches blurring of vision, pruritis and urticaria may occur during chloroquine therapy. Lupus erythematosus, lichenoid skin lesions, toxic psychosis with hallucinations and agitations and peripheral neuropathies with loss of reflexes are reported with high doses (Ro]lo 1975, Catchpool 1974). Prolonged use has been implicated in the causation of pigmentary degeneration of the retina. Recently, Bhargava a a/ (1973) and Eroniniand Eronini (1977) have reported the extrapyramidal syndrome (EPS) loltowing chloroquine therapy in adults. The clinical manifestations included upward rolling of the eyeballs, retraction of nect~ and back, trismus with marked difficulty in speech and coarse tremors. We record' our observations on four instances of EPS in children following chloroquine therapy for malaria.
Report of Cases Case 1. S, a 289 to the All-India
girl, was admitted Institute of Medical
*From the Department of Paediatrics, AU-India Institute of Medical Sciences, New Delhi.ll0016. Received on J u n e 20,197s.
Sciences Ho.-pital with a 4-day history of intermittent high grade pyrexia with chills and rigors. Following treatment with oral chloroquine in the recommended thera. peutic dosage, the fever responded, but she become drowsy and developed paroxysms of involuntary movements oft he tongue, torticollis, torsion dystonia of the limbs and paroxysms of tonic muscular spasms. The spasms occurred after every half an hour and lasted each time for about 2-3 minutes On admission, the child was drowsy and had slight neck stiffness. The rest of the systemic examination was essentially normal. The cellular components of peripheral blood and cerebrospinal fluid were entirely within normal limits. She como pletely recovered spontaneously within 48 hours. Case 2. V . L . , a 12-year-old female, was brought to the hospital for 15 days history of intermittent high grade fever with chilis and rigors. On examination, the oral temperature was 40~ tile liver was enlarged by 3 cm. and spleen 9 cm. b'elow thecostal margin. Laboratory data showed haemoglobin 7.1 g per 100ml, total leucocyte count 6,800 per mm3 with polymorphs 7 I, lymhocytes 28, eosinophils 1. Schizonts of P. vivax were seen in the peripheral blood. She was started on chloroquine sulfate in the recommended therapeutic dose. After an interval of 4 days she developed coarse tremors of the hands, upwards rolling of the eyeballs, episodic deviation of the angle of the mouth towards
f~NOHI RT AL.--EXTRAPYRAMIDAL SYNDROME POLLOWINO CHLOROQUINE THERAPY
the left and trlsmus. These symptoms disappeared spontaneously within 8 hours. S., a 6-year-old girl, developed episodes of opisthotonous, upward rolling of the eyeballs, protrusion of the tongue, intermittent writhing movement o f the upper limbs and drowsiness, following ingestion of 6 tablets of chloroquine sulfate (chloroquine base 900 rag) for suspected diagnosis of malaria. She spontaneously recovered from EPS over a period of about 48 hours. Cas#.~.
Case 4. M.R.S., a 7-year-old boy gave a his-
tary of high grade fever with chills and rigors of one day duration. He developed r tonic spasms of the neck, uprolling of the eyeballs and writhing contortions of all limbs, about 2 hours following intravenous administration of 100 mg of chloruquine (as phosphate). Eight hours later, an additional 100 mg chloroquine (as phosphate) was given intravenously for the mistaken diagnosis of cerebr~:l malaria. On examination, the child was drowsy, had generalized stiffness, torticollis and trismus. Systemic examination was non-contributory. Laboratory investigations showed a total leucocyte count of 12,500 per mm a with po]ymorphs 62, lymphocytes 38 and absence of malarial parasites in the peripheral blood. Cerebrospinal fluid was normal. The child recovered gradually over a period of 48 hours without any specific therapy. Discussion All patients had fever with chills "and rigors and typical features of EPS ensued following chloroquine therapy. Upward rolling of the eyeballs, trismus, torticollis and torsion dystonia of the limbs were main
59
clinlea] manifestations. Drowsiness was a prominent feature in 2 patients. None of the patients received any phenothiazines nor was there any evidence of cerebral malaria. Spgneaneous recovery occurred in all patients within 48 hours. Eronini and Eronini (!977) used bc~=:r.~plne for the treatment of chloroquine induced EPS which appears to be unnecessary in the light of our observations. EPS has been documented following administration of. various drugs, such as, phenothiazines (Lader 1970, De Silva et al 1973, Swett 1974), Colemah and Hayes 1975, Sharma And Lahori 1975, Ladhani 1974), reserpine, diphenyihydantoin (Peters et al 1966, Price and Frank i950,'Patel and Crichton 1968 Jan and Kilman 1974), diphetihydramine {Lavenstein and Cantor 1976), diazoxide (Pohl 1975)and lithium (Shopsin'anb Gershon 1975, Branchey et al. 1976). Amodiaquine, another antimalarial, has also been recently reported to cause involuntary movements (Aklndele and Odejide 1976). The exact mechanism of production of EPS remains uncertain. Neurochemical control of the extrapyramidal system, especially the substantia nigra, neostriatum and pallidum play an important role in the control of motor and psychomotor activity (Poirier 1974). The presence of relatively large amounts of dopamine, acetylcholine and gamma amino butyric acid (GABA within these structures suggest that these substances may exert an important putative influence in the control of motor activity. An imbarance between levels of these neurochemical mediators as a consequence of histopathological alterations or pharmacological treatment leads to
~0
I/qDIANJOURNAL Of PEDIATRIC!
different modalities of e x t r a p y r a m l d a l disorders. Most investigators agree that phenothiazine induced EPS involves blockado of d o p a m i n e receptors. Alternatively, e.holinecgic overactivity due to phenothiazincs m a y also induce extrapyramidal dysfunction (Synder et al, 1974). However, chloroqulne has no structural similarity to phenothiazines and is not known to have any cholinergic activity. I n view of other dose-related central nervous system toxic manifestations and rather excessive amounts ofchloroquine t a k e n by case 3 and 4, EPS following chloroquine appears to be doserelated rather than idiosyncratic.
VOL. 46, No. 373 DeSilva, K.L., Muller, p,J.,Pearce, J.(1973) Acute drug induced ext61 ""r syndrome. PrartitiotTer, 211. 318. Eronini, E.M.U., Eeonlni, I~.A. (1977). Chloro. quine iuduced involuntary movements. Brit. Med. J. 1, 945. Jon,J.'E., Kilman, M.R., (1976). Extrapyramidal disturbances and vascular changes during diphenyl hydantoin intoxication. Canad Mec. dssoc. 7. 111,636. Lader, M.H. (1970L Drug induced ex~rapyramidal syndromes. 37.R. Coil Phys. Lond. 5, 87. Ladhani, F.M. (1974).Severe extrapyramidal manifestations following fluphenazine overdose. MLd..7. Australia, 2 26. Lavenstin, B,L., Cantor, F.K. (1976). Acute dystonia--Unusual reaction to diphenhydramine.
.~AMA, 236, 291. Patelg H., Crichton, J.U. (1968L Neurological hazards of diphenylhydantion in childhood, .,7. Pediatr, 73. 676. Peters, H.A, Eichmun P L., Price ].M., Kozelika F.L, Reese, H.H. (196~) Abnormal copper and tryptophan metabolism and chelation therapy in anticonvulsant dru~ intolerance. Dis..Very. S~s. 57, 07. Pohl,J.E. (1975). Development and management ofextrapyramidal symptoms in hypertensive patients treated with diazoxide..Amer, tteart~. 89, 401. Poirier, L.J. (1974). Naurological mechanisms involved in experimentally induced extrapyramidal disturbances, Co,fi,a Neurol. 36, 223. Price. W.C. and Frank, M.E. (i950). Accidental References acute dilantin po,soning, J. Pedialr. 36, 6,52. Akir,delde, 1~.O., J Od'enie, A.O. (~976). AmodiaRollo, J.M. (1975). In the Pharmacological Basis quine induced involuntary movemer,ts. Brit. Med.). of Therapeutics, Editors, Goodman, L.S., and Gilman, 2,214. A , McMillan Publishing Co. Inc, VI Ed, p. 104~. 9 Bhargava, R.K., Parekh, K.I.., l-lakim, A., Gori, Sharma, D.B., Lahori, U.C. (1975). Acute M.N., Bhandari, N.C. (1975). Extrapyramidal s5ndrome phenothiazi~e intoxication in children. Indian Pediatr,, following administration of antimalarials. ,4ss~. Phys. 12, 725. India, 21, 969. Shopsir,, B. Gershon, S. (t97-~). Cogwheci rigidity Branchey, M.H.,Charles,J., Simpson, G M (1976). related to lilhium maintenance. Aratr.37. Ps)chiat. 132, Extrapyramidal side effects in )ithium maintenance 5?6. therapy. Amer..7. Psychiatry. 133, 444-. Swett, C. Ir. (1974). Drug induced dystonia, dratr Catchpoo|. J.F. 0074). In Review 9f Medical .7. Psychiat. 152, 532:. Pharmacology. Editors~Meyer, F.H, Jawetg, s Synder, S.H, Greenberg, D., Yamamumuru, H.I. Gbldfien, A. IV Ed. Lange Medical Publication~, P. 600. (1974}. Antischizophrenic drugs; affinity for muscuramic Coleman, H..J., Hayes, P.E. (197.5). Drug induced cholinergicreceptor sites in brain predicts extrapyraextrapyramidal effects--A review. D/s. At,'rv.Sys. $6, midal effects,J. Psrchiatr. Res !1 91. 561. Summary T h e clinical profile of e x t r a p y r a m i d a l manifestations following chloroqulne ther, a p y f o r the t r e a t m e n t o f . malaria in 4 childten is "described. T h e characteristic features included u p w a r d rolling of the eyeballs, trismus torticollis ar, d bizar~'e writhing torsion dy~tonia of the limbs. T h e effect appears to be dose-related rather than idiosyncratic and is self limited because spontane6us recovery occurred in all patients within 48 hours.
EXTRAPYRBMIDAL SYNDROME FOLLOWING CHLOROQUINE THERAPY* SUNIT SINOHI, PRATIBHA SINOHf, MEFIARBAN SINOH New Delhi
Malaria has agai, assumed epidemic proportions in India. Physicians working in tropical countries are often faced with varioug side effects and toxic manifestations following administration of antimalarial drugs. Chloroquine is considered essentially nontoxic when used for chemosuppression of malaria (C~tchpool, 1974). However, gastrointestinal upsets, headaches blurring of vision, pruritis and urticaria may occur during chloroquine therapy. Lupus erythematosus, lichenoid skin lesions, toxic psychosis with hallucinations and agitations and peripheral neuropathies with loss of reflexes are reported with high doses (Ro]lo 1975, Catchpool 1974). Prolonged use has been implicated in the causation of pigmentary degeneration of the retina. Recently, Bhargava a a/ (1973) and Eroniniand Eronini (1977) have reported the extrapyramidal syndrome (EPS) loltowing chloroquine therapy in adults. The clinical manifestations included upward rolling of the eyeballs, retraction of nect~ and back, trismus with marked difficulty in speech and coarse tremors. We record' our observations on four instances of EPS in children following chloroquine therapy for malaria.
Report of Cases Case 1. S, a 289 to the All-India
girl, was admitted Institute of Medical
*From the Department of Paediatrics, AU-India Institute of Medical Sciences, New Delhi.ll0016. Received on J u n e 20,197s.
Sciences Ho.-pital with a 4-day history of intermittent high grade pyrexia with chills and rigors. Following treatment with oral chloroquine in the recommended thera. peutic dosage, the fever responded, but she become drowsy and developed paroxysms of involuntary movements oft he tongue, torticollis, torsion dystonia of the limbs and paroxysms of tonic muscular spasms. The spasms occurred after every half an hour and lasted each time for about 2-3 minutes On admission, the child was drowsy and had slight neck stiffness. The rest of the systemic examination was essentially normal. The cellular components of peripheral blood and cerebrospinal fluid were entirely within normal limits. She como pletely recovered spontaneously within 48 hours. Case 2. V . L . , a 12-year-old female, was brought to the hospital for 15 days history of intermittent high grade fever with chilis and rigors. On examination, the oral temperature was 40~ tile liver was enlarged by 3 cm. and spleen 9 cm. b'elow thecostal margin. Laboratory data showed haemoglobin 7.1 g per 100ml, total leucocyte count 6,800 per mm3 with polymorphs 7 I, lymhocytes 28, eosinophils 1. Schizonts of P. vivax were seen in the peripheral blood. She was started on chloroquine sulfate in the recommended therapeutic dose. After an interval of 4 days she developed coarse tremors of the hands, upwards rolling of the eyeballs, episodic deviation of the angle of the mouth towards
f~NOHI RT AL.--EXTRAPYRAMIDAL SYNDROME POLLOWINO CHLOROQUINE THERAPY
the left and trlsmus. These symptoms disappeared spontaneously within 8 hours. S., a 6-year-old girl, developed episodes of opisthotonous, upward rolling of the eyeballs, protrusion of the tongue, intermittent writhing movement o f the upper limbs and drowsiness, following ingestion of 6 tablets of chloroquine sulfate (chloroquine base 900 rag) for suspected diagnosis of malaria. She spontaneously recovered from EPS over a period of about 48 hours. Cas#.~.
Case 4. M.R.S., a 7-year-old boy gave a his-
tary of high grade fever with chills and rigors of one day duration. He developed r tonic spasms of the neck, uprolling of the eyeballs and writhing contortions of all limbs, about 2 hours following intravenous administration of 100 mg of chloruquine (as phosphate). Eight hours later, an additional 100 mg chloroquine (as phosphate) was given intravenously for the mistaken diagnosis of cerebr~:l malaria. On examination, the child was drowsy, had generalized stiffness, torticollis and trismus. Systemic examination was non-contributory. Laboratory investigations showed a total leucocyte count of 12,500 per mm a with po]ymorphs 62, lymphocytes 38 and absence of malarial parasites in the peripheral blood. Cerebrospinal fluid was normal. The child recovered gradually over a period of 48 hours without any specific therapy. Discussion All patients had fever with chills "and rigors and typical features of EPS ensued following chloroquine therapy. Upward rolling of the eyeballs, trismus, torticollis and torsion dystonia of the limbs were main
59
clinlea] manifestations. Drowsiness was a prominent feature in 2 patients. None of the patients received any phenothiazines nor was there any evidence of cerebral malaria. Spgneaneous recovery occurred in all patients within 48 hours. Eronini and Eronini (!977) used bc~=:r.~plne for the treatment of chloroquine induced EPS which appears to be unnecessary in the light of our observations. EPS has been documented following administration of. various drugs, such as, phenothiazines (Lader 1970, De Silva et al 1973, Swett 1974), Colemah and Hayes 1975, Sharma And Lahori 1975, Ladhani 1974), reserpine, diphenyihydantoin (Peters et al 1966, Price and Frank i950,'Patel and Crichton 1968 Jan and Kilman 1974), diphetihydramine {Lavenstein and Cantor 1976), diazoxide (Pohl 1975)and lithium (Shopsin'anb Gershon 1975, Branchey et al. 1976). Amodiaquine, another antimalarial, has also been recently reported to cause involuntary movements (Aklndele and Odejide 1976). The exact mechanism of production of EPS remains uncertain. Neurochemical control of the extrapyramidal system, especially the substantia nigra, neostriatum and pallidum play an important role in the control of motor and psychomotor activity (Poirier 1974). The presence of relatively large amounts of dopamine, acetylcholine and gamma amino butyric acid (GABA within these structures suggest that these substances may exert an important putative influence in the control of motor activity. An imbarance between levels of these neurochemical mediators as a consequence of histopathological alterations or pharmacological treatment leads to
~0
I/qDIANJOURNAL Of PEDIATRIC!
different modalities of e x t r a p y r a m l d a l disorders. Most investigators agree that phenothiazine induced EPS involves blockado of d o p a m i n e receptors. Alternatively, e.holinecgic overactivity due to phenothiazincs m a y also induce extrapyramidal dysfunction (Synder et al, 1974). However, chloroqulne has no structural similarity to phenothiazines and is not known to have any cholinergic activity. I n view of other dose-related central nervous system toxic manifestations and rather excessive amounts ofchloroquine t a k e n by case 3 and 4, EPS following chloroquine appears to be doserelated rather than idiosyncratic.
VOL. 46, No. 373 DeSilva, K.L., Muller, p,J.,Pearce, J.(1973) Acute drug induced ext61 ""r syndrome. PrartitiotTer, 211. 318. Eronini, E.M.U., Eeonlni, I~.A. (1977). Chloro. quine iuduced involuntary movements. Brit. Med. J. 1, 945. Jon,J.'E., Kilman, M.R., (1976). Extrapyramidal disturbances and vascular changes during diphenyl hydantoin intoxication. Canad Mec. dssoc. 7. 111,636. Lader, M.H. (1970L Drug induced ex~rapyramidal syndromes. 37.R. Coil Phys. Lond. 5, 87. Ladhani, F.M. (1974).Severe extrapyramidal manifestations following fluphenazine overdose. MLd..7. Australia, 2 26. Lavenstin, B,L., Cantor, F.K. (1976). Acute dystonia--Unusual reaction to diphenhydramine.
.~AMA, 236, 291. Patelg H., Crichton, J.U. (1968L Neurological hazards of diphenylhydantion in childhood, .,7. Pediatr, 73. 676. Peters, H.A, Eichmun P L., Price ].M., Kozelika F.L, Reese, H.H. (196~) Abnormal copper and tryptophan metabolism and chelation therapy in anticonvulsant dru~ intolerance. Dis..Very. S~s. 57, 07. Pohl,J.E. (1975). Development and management ofextrapyramidal symptoms in hypertensive patients treated with diazoxide..Amer, tteart~. 89, 401. Poirier, L.J. (1974). Naurological mechanisms involved in experimentally induced extrapyramidal disturbances, Co,fi,a Neurol. 36, 223. Price. W.C. and Frank, M.E. (i950). Accidental References acute dilantin po,soning, J. Pedialr. 36, 6,52. Akir,delde, 1~.O., J Od'enie, A.O. (~976). AmodiaRollo, J.M. (1975). In the Pharmacological Basis quine induced involuntary movemer,ts. Brit. Med.). of Therapeutics, Editors, Goodman, L.S., and Gilman, 2,214. A , McMillan Publishing Co. Inc, VI Ed, p. 104~. 9 Bhargava, R.K., Parekh, K.I.., l-lakim, A., Gori, Sharma, D.B., Lahori, U.C. (1975). Acute M.N., Bhandari, N.C. (1975). Extrapyramidal s5ndrome phenothiazi~e intoxication in children. Indian Pediatr,, following administration of antimalarials. ,4ss~. Phys. 12, 725. India, 21, 969. Shopsir,, B. Gershon, S. (t97-~). Cogwheci rigidity Branchey, M.H.,Charles,J., Simpson, G M (1976). related to lilhium maintenance. Aratr.37. Ps)chiat. 132, Extrapyramidal side effects in )ithium maintenance 5?6. therapy. Amer..7. Psychiatry. 133, 444-. Swett, C. Ir. (1974). Drug induced dystonia, dratr Catchpoo|. J.F. 0074). In Review 9f Medical .7. Psychiat. 152, 532:. Pharmacology. Editors~Meyer, F.H, Jawetg, s Synder, S.H, Greenberg, D., Yamamumuru, H.I. Gbldfien, A. IV Ed. Lange Medical Publication~, P. 600. (1974}. Antischizophrenic drugs; affinity for muscuramic Coleman, H..J., Hayes, P.E. (197.5). Drug induced cholinergicreceptor sites in brain predicts extrapyraextrapyramidal effects--A review. D/s. At,'rv.Sys. $6, midal effects,J. Psrchiatr. Res !1 91. 561. Summary T h e clinical profile of e x t r a p y r a m i d a l manifestations following chloroqulne ther, a p y f o r the t r e a t m e n t o f . malaria in 4 childten is "described. T h e characteristic features included u p w a r d rolling of the eyeballs, trismus torticollis ar, d bizar~'e writhing torsion dy~tonia of the limbs. T h e effect appears to be dose-related rather than idiosyncratic and is self limited because spontane6us recovery occurred in all patients within 48 hours.
