Abstract
Quinolines are neurotoxic drugs that have been widely used in malaria treatment and prevention, particularly in military settings. Poisoning by quinoline drugs, including by the previously commonly used drugs quinacrine, chloroquine, and mefloquine, can cause a lasting disorder named neuropsychiatric quinism, resulting from chronic encephalopathy and associated brain and brainstem dysfunction. Neuropsychiatric quinism is characterized by chronic symptoms that may mimic several psychiatric and neurologic disorders, including posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI). Neuropsychiatric quinism may have been widely unrecognized in veteran populations, and its symptoms misattributed to other causes, including cerebral malaria. Diagnosis of neuropsychiatric quinism is primarily clinical, and management of the disorder is primarily conservative. The unrecognized effects of neuropsychiatric quinism in veteran populations are likely to have confounded a significant body of military research and clinical diagnosis. These effects suggest the need to screen veterans for a past history of symptomatic exposure to quinolines, and to approach the development of new quinoline drugs for military use with caution.
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References
Greenwood D. The quinine connection. J Antimicrob Chemother. 1992;30(4):417–27.
Sullivan DJ. Cinchona alkaloids: quinine and quinidine. In: Staines HM, Krishna S, editors. Treatment and prevention of malaria. Basel: Springer Basel; 2012. p. 45–68.
Hofheinz W, Merkli B. Quinine and quinine analogues. In: Peters W, Richards W, editors. Antimalarial drugs II: current antimalarials and new drug developments. Berlin: Springer; 1984. p. 61–81.
Bateman DN, Dyson EH. Quinine toxicity. Adverse Drug React Acute Poisoning Rev. 1986;5(4):215–33.
Balfour AJ. The bite of Jesuits’ bark. Aviation, space, and environmental medicine. Aviat Space Environ Med. 1989;60(7 Pt 2):A4–5.
Summers WK, Allen RE, Pitts FN. Does physostigmine reverse quinidine delirium? West J Med. 1981;135(5):411–4.
Nevin RL, Croft AM. Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives. Malar J. 2016;15:332.
Russell PF. Plasmochin, plasmochin with quinine salts and atabrine in malaria therapy. Arch Intern Med. 1934;53(2):309–20.
Nevin RL. Idiosyncratic quinoline central nervous system toxicity: historical insights into the chronic neurological sequelae of mefloquine. Int J Parasitol Drugs Drug Resist. 2014;4(2):118–25.
Loken AC, Haymaker W. Pamaquine poisoning in man, with a clinicopathologic study of one case. Am J Trop Med Hyg. 1949;29(3):341–52.
Kono R. Introductory review of subacute myeolo-optico-neuropathy (SMON) and its studies done by the SMON Research Commission. Jpn J Med Sci Biol. 1975;28 Suppl(4):1–21.
Shiraki H. Neuropathology of subacute myelo-optico-neuropathy, “SMON”. Jpn J Med Sci Biol. 1971;24(4):217–43.
Ricoy JR, Ortega A, Cabello A. Subacute myelo-optic neuropathy (SMON). First neuro-pathological report outside Japan. J Neurol Sci. 1982;53(2):241–51.
Schmidt IG, Schmidt LH. Neurotoxicity of the 8-aminoquinolines. I. Lesions in the Central Nervous System of the Rhesus Monkey Induced by Administration of Plasmocid. J Neuropathol Exp Neurol. 1948;7(4):368–98.
Schmidt IG, Schmidt LH. Neurotoxicity of the 8-aminoquinolines. II. Reactions of various experimental animals to plasmocid. J Comp Neurol. 1949;91(3):337–67.
Schmidt IG, Schmidt LH. Neurotoxicity of the 8-aminoquinolines. III. The effects of pentaquine, isopentaquine, primaquine, and pamaquine on the central nervous system of the rhesus monkey. J Neuropathol Exp Neurol. 1951;10(3):231–56.
Dow G, Bauman R, Caridha D, Cabezas M, Du F, Gomez-Lobo R, et al. Mefloquine induces dose-related neurological effects in a rat model. Antimicrob Agents Chemother. 2006;50(3):1045–53.
Ismail T, Mauerhofer E, Slomianka L. The hippocampal region of rats and mice after a single i.p. dose of clioquinol: loss of synaptic zinc, cell death and c-Fos induction. Neuroscience. 2008;157(3):697–707.
Fusetti M, Eibenstein A, Corridore V, Hueck S, Chiti-Batelli S. Mefloquine and ototoxicity: a report of 3 cases. Clin Ter. 1999;150(5):379–82.
Bernard P. Alterations of auditory evoked potentials during the course of chloroquine treatment. Acta Otolaryngol. 1985;99(3–4):387–92.
Telgt DS, van der Ven AJ, Schimmer B, Droogleever-Fortuyn H. a, Sauerwein RW. Serious psychiatric symptoms after chloroquine treatment following experimental malaria infection. Ann Pharmacother. 2005;39(3):551–4.
Wittes R. Adverse reactions to chloroquine and amodiaquine as used for malaria prophylaxis: a review of the literature. Can Fam Physician. 1987;33(November):2644–9.
West JB, Henderson AB. Plasmochin intoxication. Bull US Army Med Dep. 1944;82(November):87–99.
Hardgrove M, Applebaum IL. Plasmochin toxicity; analysis of 258 cases. Ann Intern Med. 1946;25:103–12.
Nevin RL. Limbic encephalopathy and central vestibulopathy caused by mefloquine: a case report. Travel Med Infect Dis. 2012;10(3):144–51.
Hart CW, Naunton RF. The ototoxicity of chloroquine phosphate. Arch Otolaryngol. 1964;80:407–12.
De Oliveira JAA. Antimalarial drug - quinine. In: Audiovestibular toxicity of drugs. Boca Raton: CRC Press; 1989. p. 147–63.
Livezey J, Oliver T, Cantilena L. Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine. Drug Saf Case Rep. 2016;3(1):7.
Lysack JT, Lysack CL, Kvern BL. A severe adverse reaction to mefloquine and chloroquine prophylaxis. Aust Fam Physician. 1998;27(12):1119–20.
Chansky PB, Werth VP. Accidental hydroxychloroquine overdose resulting in neurotoxic vestibulopathy. BMJ Case Rep. 2017;2017 https://doi.org/10.1136/bcr-2016-218786.
Singhi S, Singhi P, Singh M. Extrapyramidal syndrome following chloroquine therapy. Indian J Pediatr. 1979;46(373):58–60.
Newell HW, Lidz T. The toxicity of atabrine to the central nervous system. Am J Psychiatry. 1946;102:805–18.
Patchen LC, Campbell CC, Williams SB. Neurologic reactions after a therapeutic dose of mefloquine. N Engl J Med. 1989;321(20):1415–6.
Martin AN, Tsekes D, White WJ, Rossouw D. Chloroquine-induced bilateral anterior shoulder dislocation: a unique aetiology for a rare clinical problem. BMJ Case Reports. 2016;2016 https://doi.org/10.1136/bcr-2015-214292.
Ferrier TM, Schwieger AC, Eadie MJ. Delayed onset of partial epilepsy of temporal lobe origin following acute clioquinol encephalopathy. J Neurol Neurosurg Psychiatry. 1987;50(1):93–5.
Craige B, Eichelberger L, Jones R, Alving A, Pullman TN, Whorton CM. The toxicity of large doses of pentaquine (SN-13,276), a new antimalarial drug. J Clin Invest. 1948;27(3 Pt 2):17–24.
Clayman CB, Arnold J, Hockwalk RS, Yount EH, Edgcomb JH, Alving AS. Toxicity of primaquine in Caucasians. J Am Med Assoc. 1952;149(17):1563–8.
Saboisky JP, Butler JE, McKenzie DK, Gorman RB, Trinder JA, White DP, et al. Neural drive to human genioglossus in obstructive sleep apnoea. J Physiol. 2007;585(Pt 1):135–46.
Fleury Curado T, Fishbein K, Pho H, Brennick M, Dergacheva O, Sennes LU, et al. Chemogenetic stimulation of the hypoglossal neurons improves upper airway patency. Sci Rep. 2017;7:44392.
Ramchandren S, Gruis KL, Chervin RD, Lisabeth LD, Concannon M, Wolfe J, et al. Hypoglossal nerve conduction findings in obstructive sleep apnea. Muscle Nerve. 2010;42(2):257–61.
Gebhart F. Some psychoactive prescription drugs associated with violence. Drug Topics. 2011;March:37.
Moore TJ, Glenmullen J, Furberg CD. Prescription drugs associated with reports of violence towards others. PLoS One. 2010;5(12):e15337.
Mohan D, Mohandas E, Rajat R. Chloroquine psychosis: a chemical psychosis. J Natl Med Assoc. 1981;73(11):1073–6.
Good MI, Shader RI. Lethality and behavioral side effects of chloroquine. J Clin Psychopharmacol. 1982;2(1):40–7.
Jousset N, Rougé-Maillart C, Turcant A, Guilleux M, Le Bouil A, Tracqui A. Suicide by skull stab wounds: a case of drug-induced psychosis. Am J Forensic Med Pathol. 2010;31(4):378–81.
Nevin RL, Ritchie EC. The mefloquine intoxication syndrome: a significant potential confounder in the diagnosis and management of PTSD and other chronic deployment-related neuropsychiatric disorders. In: Posttraumatic stress disorder and related diseases in Combat Veterans. Cham: Springer International Publishing; 2015. p. 257–78.
Ritchie EC, Block J, Nevin RL. psychiatric side effects of mefloquine: applications to forensic psychiatry. J Am Acad Psychiatry Law. 2013;41(June):224–35.
Ringqvist Å, Bech P, Glenthøj B, Petersen E. Acute and long-term psychiatric side effects of mefloquine: a follow-up on Danish adverse event reports. Travel Med Infect Dis. 2015;13(1):80–8.
Engel GL, Romeno J, Ferris EB, Schmidt LH. Malaria Report #212: the effect of atabrine on the central nervous system. In: Malaria Rreports Volume 2. Washington, DC: Board for the Coordination of Malarial Studies; 1944.
Boudreau E, Schuster B, Sanchez J, Novakowski W, Johnson R, Redmond D, et al. Tolerability of prophylactic Lariam regimens. Trop Med Parasitol. 1993;44(3):257–65.
Nevin RL. A serious nightmare: psychiatric and neurologic adverse reactions to mefloquine are serious adverse reactions. Pharmacol Res Perspect. 2017;5(4):e00328.
Nevin RL, Byrd AM. Neuropsychiatric adverse reactions to mefloquine: a systematic comparison of prescribing and patient safety guidance in the US, UK, Ireland, Australia, New Zealand, and Canada. Neurology Ther. 2016;5(1):69–83.
European Medicines Agency. Pharmacovigilance Risk Assessment Committee (PRAC). Minutes of the meeting on 23–26 October 27. EMA/PRAC/782491/2017. 2017.
Eick-Cost AA, Hu Z, Rohrbeck P, Clark LL. Neuropsychiatric outcomes after mefloquine exposure among U.S. Military Service Members. Am J Trop Med hyg. 2017;96(1):159–66.
Wells TS, Smith TC, Smith B, Wang LZ, Hansen CJ, Reed RJ, et al. Mefloquine use and hospitalizations among US service members, 2002-2004. Am J Trop Med Hyg. 2006;74(5):744–9.
Nevin RL. Misclassification and bias in military studies of Mefloquine. Am J Trop Med Hyg. 2017;97(1):305.
Tickell-Painter M, Maayan N, Saunders R, Pace C, Sinclair D. Mefloquine for preventing malaria during travel to endemic areas. Cochrane Database Syst Rev 2017;10(10):CD006491.
Forrester A. Malaria and insanity. Lancet. 1920;195(5027):16–7.
Masters J. The Road Past Mandalay. New York: Bantam; 1979. p. 160–7.
Rooney D. Military Mavericks: extraordinary men of battle. London: Cassell Military Paperbacks; 1999. p. 190–1.
Stafford J. Unique in medical history – “Guadalcanal Neurosis” plagues invalids returning from fighting in South Pacific. Pittsburgh: The Pittsburgh Press; 1943. p. 1.
Greiber MF. Psychoses associated with the administration of atabrine. Am J Psychiatry. 1947;104(5):306–14.
Towne AN. Sicily. In: Doctor danger forward: a World War II Memoir of a Combat Medical Aidman, First Infantry Division. Jefferson: McFarland & Company, Inc; 2000. p. 61–78.
Couch J. The Day Gen. Patton Slapped a Soldier. The Washington Post. 1979; p. D5.
Dekever P. Patton’s costly slap; Mishawaka soldier’s claim to fame result of battle fatigue — and a general’s temper. Sound Bend (Indiana) Tribune. 2002; p. F8.
The Science News-Letter. Better antimalarial drug. Sci News Lett. 1946;49(2):30–1.
Garrison PL, Hankey DD, Coker WG, Donovan WN, Jastremski B, Coatney GR, et al. Cure of Korean vivax malaria with pamaquine and primaquine. J Am Med Assoc. 1952;149(17):1562–3.
Archibald HC, Tuddenham RD. Persistent stress reaction after combat: a 20-year follow-up. Arch Gen Psychiatry. 1965;12:475–81.
Hall W, MacPhee D. Do Vietnam veterans suffer from toxic neurasthenia? Aust N Z J Psychiatry. 1985;19(1):19–29.
Baskett SJ, Henager J. Differentiating between post-Vietnam syndrome and preexisting psychiatric disorders. South Med J. 1983;76(8):988–90.
Van Putten T, Emory WH. Traumatic neuroses in Vietnam returnees. A forgotten diagnosis? Arch Gen Psychiatry. 1973;29(5):695–8.
Pettera RL, Johnson BM, Zimmer R. Psychiatric management of combat reactions with emphasis on a reaction unique to Vietnam. Mil Med. 1969;134(9):673–8.
Silver SM, Iacono CU. Factor-analytic support for DSM-III’s post-traumatic stress disorder for Vietnam veterans. J Clin Psychol. 1984;40(1):5–14.
Varney NR, Roberts RJ, Springer JA, Connell SK, Wood PS. Neuropsychiatric sequelae of cerebral malaria in Vietnam veterans. J Nerv Ment Dis. 1997;185(11):695–703.
Gunderson CH, Daroff RB. Neurology in the Vietnam War. In: Tatu L, Bogousslavsky J, editors. Frontiers in neurology and neuroscience. Basel, Switzerland: Karger; 2016. p. 201–13. https://doi.org/10.1159/000442657.
UNDP-World Bank-WHO. Development of mefloquine as an antimalarial drug UNDP-World Bank-WHO update. Bull World Health Org. 1983;61(2):169–78.
Nevin RL. Rational risk-benefit decision-making in the setting of military mefloquine policy. J Parasitol Res. 2015;2015:260106.
McCarthy S. Malaria prevention, mefloquine neurotoxicity, neuropsychiatric illness, and risk-benefit analysis in the Australian Defence Force. J Parasitol Res. 2015;2015:287651.
Nevin RL. Mefloquine and posttraumatic stress disorder. In: Ritchie EC, editor. Textbook of military medicine forensic and ethical issues in military behavioral health. Washington, DC: Borden Institute; 2015. p. 277–96.
Magill A, Cersovsky S, DeFraites R. Special considerations for US Military Deployments. In: Brunette GW, editor. CDC health information for international travel: the Yellow Book 2012. New York: Oxford University Press; 2012. p. 561–5.
Nevin RL. Screening for symptomatic mefloquine exposure among veterans with chronic psychiatric symptoms. Fed Pract. 2017;34(3):12–4.
Grupp D, Rauber A, Fröscher W. Neuropsychiatric disturbances after malaria prophylaxis with mefloquine. Aktuelle Neurologie. 1994;21:134–6.
Stürchler D, Handschin J, Kaiser D, Kerr L, Mittelholzer ML, Reber R, et al. Neuropsychiatric side effects of mefloquine. New Engl J Med. 1990;322(24):1752–3.
Jacob RG, Furman JM, Durrant JD, Turner SM. Panic, agoraphobia, and vestibular dysfunction. Am J Psychiatry. 1996;153(4):503–12.
Yardley L, Britton J, Lear S, Bird J, Luxon LM. Relationship between balance system function and agoraphobic avoidance. Behav Res Ther. 1995;33(4):435–9.
Maxwell NM, Nevin RL, Stahl S, Block J, Shugarts S, Wu AHB, et al. Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy. Clin Case Rep. 2015;3(6):379–87.
Summers MR, Nevin RL. Stellate Ganglion Block in the treatment of post-traumatic stress disorder: a review of historical and recent literature. Pain Pract. 2017;17(4):546–53.
Gray SN. An overview of the use of neurofeedback biofeedback for the treatment of symptoms of traumatic brain injury in military and civilian populations. Med Acupunct. 2017;29(4):215–9.
Nevin RL, Ritchie EC. FDA Black Box, VA Red Ink? A successful service-connected disability claim for chronic neuropsychiatric adverse effects from mefloquine. Fed Pract. 2016;33(10):20–4.
Australian Department of Veterans’ Affairs. Mefloquine Information. 2016. Available from: http://www.dva.gov.au/health-and-wellbeing/medical-conditions/mefloquine-information
Hookham M. MoD cash for soldier hit by malaria drug seizures MoD cash for soldier hit by Lariam drug seizures. The Sunday Times 2018 Jan 14; p. 8.
Tigue M. Settlement in malaria drug case. The Irish Times 2017. Available from: https://www.thetimes.co.uk/article/settlement-in-malaria-drug-case-hpknzwf0p
Nevin RL. Mefloquine exposure may confound associations and limit inference in military studies of posttraumatic stress disorder. Mil Med. 2017;182(11/12):1757.
Nevin RL. Confounding by symptomatic mefloquine exposure in military studies of post-traumatic stress disorder. Behav Med. 2018;44(2):171–2. https://doi.org/10.1080/08964289.2017.1330248.
Nevin RL. Re: McGuire JM. The incidence of and risk factors for emergence delirium in U.S. military combat veterans. J Perianesthesia Nurs. American Society of PeriAnesthesia Nurses. 2013;28(6):334–5.
Conflict of Interest Statement
Dr. Nevin serves as consultant and expert witness in legal cases involving claims of adverse effects from antimalarial drugs.
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Nevin, R.L. (2019). Neuropsychiatric Quinism: Chronic Encephalopathy Caused by Poisoning by Mefloquine and Related Quinoline Drugs. In: Ritchie, E., Llorente, M. (eds) Veteran Psychiatry in the US. Springer, Cham. https://doi.org/10.1007/978-3-030-05384-0_20
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