Multiple System Atrophy the Putative Causative Role of Environmental Toxins

ORIGINAL CONTRIBUTION Multiple System Atrophy The Putative Causative Role of Environmental Toxins

Philip A. Hanna, MD; Joseph Jankovic, MD; Joel B. Kirkpatrick, MD

Background: Whereas a number of studies have inves- system atrophy after environmental toxin exposure. tigated the putative role of environmental toxins in the pathogenesis of idiopathic Parkinson disease, the possi- Results: Eleven patients had a notable history of heavy bility of such a role in multiple system atrophy has re- exposure to environmental toxins. One patient with ceived little attention. multiple system atrophy confirmed by postmortem evaluation was exposed to high concentrations of mala- Design and Setting: Review of records of patients ex- thion, diazinon, and formaldehyde, while the other amined in the Parkinson’s Disease Center and Move- patients with multiple system atrophy had well- ment Disorder Clinic, Baylor College of Medicine, Hous- documented high exposures to agents including ton, Tex, from July 1, 1977, to February 4, 1998. n-hexane, benzene, methyl isobutyl ketone, and pesti- cides. The case studied pathologically demonstrated Patients: We reviewed 100 consecutive medical rec- extensive advanced glial changes, including glial cyto- ords of patients who satisfied the diagnostic criteria for plasmic inclusions in deep cerebellar white matter, multiple system atrophy formulated by the Consensus brainstem, cortex (superior frontal, insula) and puta- Committee of the American Autonomic Society and the men, with notable cell loss and depigmentation of the American Academy of Neurology. substantia nigra and locus ceruleus.

Intervention: The type and amount of toxin exposure Conclusion: While many studies report a possible role were verified by history and examination of records when- of environmental toxins in Parkinson disease, such a role ever possible. Severity of parkinsonism was assessed by is even more likely in multiple system atrophy, as this is clinical rating scales. a sporadic disease.

Main Outcome Measure: Development of multiple Arch Neurol. 1999;56:90-94

NUMBER of studies have RESULTS evaluated the possibility of a causative role of environ- Of the 100 patients with MSA, there were mental toxins in Parkinson 11 cases with a notable history of heavy disease (PD), but the pos- exposure to environmental toxins (Table). Asibleroleofthesetoxinsintheetiologyofmul- Three illustrative cases are presented be- tiple system atrophy (MSA) has not been in- low in more detail. vestigated. Multiple system atrophy is a spo- Althoughweroutinelyqueryallpatients radic, progressive, adult-onset disorder with about possible toxic exposure, we found that overlappingfeaturesofShy-Dragersyndrome, only 1 of the 100 patients with PD had po- striatonigral degeneration, and olivoponto- tential exposure. He had lived on a farm all cerebellar atrophy, and may be designated his life with reported exposure to herbicides MSA-A(Shy-Dragersyndrome–predominant and pesticides, but the degree and type of ex- autonomic dysfunction), MSA-P (striatoni- posure were unknown to the patient. gral degeneration–predominant parkinson- ism), and MSA-C (olivopontocerebellar CASE 1 atrophy–predominantcerebellarataxia).1 The 3 disorders are linked by the presence of a Amushroomfarmerwasreferredtoourclinic recently discovered histological marker, the in January 1991, at age 46 years, with a 31⁄2- From the Department of glial cytoplasmic inclusion.2 This report de- year history of decreased dexterity and rest Neurology, Parkinson’s Disease scribes11patientsdiagnosedclinicallyashav- tremoroftherightupperextremityalongwith Center and Movement Disorders Clinic (Drs Hanna ing MSA who had a history of notable toxin progressive freezing of gait and falling. Fur- and Jankovic), and Department exposure antecedent to the development of ther symptoms included moderate depres- of Pathology (Dr Kirkpatrick), symptoms of MSA. A postmortem examina- sion, severe snoring, prominent dysarthria, Baylor College of Medicine, tion of the brain in 1 patient confirmed the and frequent episodes of postural lighthead- Houston, Tex. diagnosis of MSA. edness with occasional syncopal episodes.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 showed a 5- to 7-Hz tremor with random brief electromyo- graphic bursts consistent with myoclonus. Magnetic reso- SUBJECTS AND METHODS nance imaging of the brain demonstrated diffuse cortical atrophy. The results of cerebrospinal fluid examination were We reviewed 100 consecutive medical records of pa- normal. These studies were obtained during a hospital ad- tients examined in the Parkinson’s Disease Center and mission, shortly after the clinic visit, that was remarkable Movement Disorder Clinic, Baylor College of Medi- for aspiration pneumonia with near–respiratory arrest that cine, Houston, Tex, from July 1, 1977, to February required temporary ventilator support. A tracheotomy was 4, 1998, who satisfied the diagnostic criteria for MSA later performed secondary to severe obstruction and cen- formulated by the Consensus Committee of the tral sleep apnea. In addition, the patient demonstrated American Autonomic Society and the American Acad- marked orthostatic hypotension with decreases in blood 1 emy of Neurology. In addition, consecutive medi- pressure of more than 30 mm Hg from supine to standing. cal records of 100 patients with PD were reviewed. The patient’s condition declined steadily, and he died of respiratory complications. The autopsy, performed on November 3, 1992, showed findings consistent with MSA. Extensive advanced glial changes including glial cyto- The patient reported having worked for 2 years (ap- plasmic inclusions were seen particularly in the deep cer- proximately 4 years before the examination) in a mush- ebellar white matter (Figure 1), brainstem, cortex (su- room farm, where he was exposed to high concentra- perior frontal, insula, and hippocampus), and putamen tions of the organophosphorous pesticides malathion and by Bielschowsky and ubiquitin stains (Figure 2). There diazinon, and to formaldehyde. His task was to sterilize was prominent involvement (cell loss with depigmenta- a7.5ϫ7.5-m room (which had only 1 ventilator) by tion) of the substantia nigra and locus ceruleus. In ad- spraying these chemicals within the room (including on dition, there was widespread cortical neuronal loss, par- the ceiling). This exposure was for at least 2 hours every ticularly in the frontal and temporal regions (with relative night, during which the patient was drenched with these sparing of the hippocampus) with neurofibrillary tangles chemicals, as he did not wear any protective clothing or and neuropil threads, without senile plaques. Sections mask. One other worker in the same plant allegedly de- of the midbrain show a moderate loss of substantia ni- veloped PD. The onset of the foregoing symptoms oc- gra neurons, pigment extravasation into the surround- curred nearly 6 months after the patient stopped work- ing neuropil, neuronophagia, and occasional Lewy bod- ing in the mushroom factory. ies. Occasional Lewy body inclusions were also seen in The patient had been taking carbidopa-levodopa for the cortical areas (superior frontal in particular) and rarely 2 years before the clinic visit, with only mild improve- in the thalamus, putamen, and globus pallidus. In addi- ment in his symptoms for nearly 11⁄2 years. The le- tion, neuronal cytoplasmic inclusion bodies were pres- vodopa therapy was, however, complicated by severe dys- ent in the tegmentum of the pons. An incidental vascu- kinesias manifested by choreiform movements of the head lar malformation was seen in the midbrain tectum near and extremities. Medications included clonazepam, 0.5 the inferior colliculus. mg orally every night, and carbidopa-levodopa 25/100, 2 tablets 3 times a day. Family history was noncontribu- CASE 7 tory except for a lifelong history of tremor of the right arm in the patient’s father. There was no reported intra- A 50-year-old fireman was examined in December 1997 venous illicit drug use or neuroleptic exposure. with a 2-year history of dysarthria and stuttering, de- Initial examination disclosed intact speech, lan- creased upper-limb dexterity most prominent on the left, guage, and cognitive functioning. There was mild limi- anterocollis, a shuffling gait, and a 3-month history of tation of upgaze, but the extraocular movements were dysphagia, urinary incontinence, postural lightheaded- otherwise normal. The patient had action-induced my- ness, heavy snoring, and decreased sexual function. He oclonus involving the pectoral muscles as well as the 4 had previously worked in pest control for 10 years, with extremities. A 6- to 7-Hz flexion-extension tremor at rest extensive exposure to various pesticides including dia- and during posture holding was seen in the right arm and zinon and chlordane. He primarily sprayed against roaches both legs. There was also dystonic posturing of the right and termites for 8 to 9 hours a day, most commonly while arm. Rigidity was 3+ (0-4 scale) in the neck and right arm, crawling under homes or working in attics with poor ven- 2+ in the left arm, and 4+ bilaterally in the lower ex- tilation, and typically without wearing a protective mask tremities, and body bradykinesia was rated 4+. He was or clothing. He had no response to carbidopa-levodopa unable to rise from a chair without assistance and had while taking a maximum of1goflevodopa per day. His markedly stooped posture with prominent freezing and father reportedly was alcoholic with upper-extremity severe difficulty with gait initiation. Deep-tendon re- tremor. flexes were symmetrical, with flexor plantar responses. The patient complained of postural lightheadedness, Results of a sensory examination were unremarkable. but orthostatic blood pressure changes could not be docu- An electroencephalogram was normal, and there was mented on examination. He had severe stuttering, lateral no electroencephalographic correlate associated with the oscillating head tremor, and facial tremor, with anterocol- myoclonus. Electromyography and nerve conduction stud- lis and hypomimia. There was mild 4-extremity tremor at ies showed normal motor and sensory conduction studies rest. Rigidity and bradykinesia were of moderate degree and in the right arm and leg. A polyelectromyographic study worse on the left side. Gait testing showed decreased left-

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Coworkers With Patient No./Sex/Age, y Clinical Features Occupation Toxic Exposure History Parkinsonism 1/M/46 Parkinsonism, dysautonomia, Mushroom farm 2-y history of spraying malathion, diazinon, 1 poor levodopa response worker and formaldehyde in poorly ventilated room 2/M/56 Parkinsonism, anarthria, Communication 15-y history of installing communications 0 blepharospasm, anterocollis, engineer systems with exposure to pesticides, dysautonomia, levodopa cyanide gas, wood-cleaning solution nonresponsive containing hydrocarbons 3/M/59 Parkinsonism, spastic gait with Chemical plant 20-y history of direct daily exposure to 1 extensor plantar responses, supervisor benzene, n-hexane, methyl isobutyl ketone, anterocollis with no tremor, naphtha, phosgene, epichlorohydrin, dysautonomia, nonsustained sulfuric acid, formaldehyde, and carbon response to levodopa disulfide 4/M/72 Parkinsonism with predominant Entomologist 30-y history of examining cotton plants in the 2 gait and postural impairment, fields for 8-9 h/d shortly after they were anterocollis, dysautonomia, sprayed with pesticides (primarily levodopa nonresponsive malathion and diazinon) 5/M/74 Parkinsonism, dysautonomia, Chemical engineer Worked in same oil refinery for 30 y, exposed Ն3 levodopa nonresponsive to fumes (particularly benzene) 6/M/60 Parkinsonism, dysautonomia, Laboratory 15-y exposure to bismuth, cobalt, iron, nickel, 2 (Shy-Drager, levodopa nonresponsive technician at chromium, silica, and acrylonitrile; urine “Parkinson chemical plant examination showed elevated nickel and disease”) zinc levels 7/M/50 Parkinsonism, severe dysarthria Fireman, pest From 1975 to 1984, worked in pest control, 0 and dysphagia, control spraying insecticides (primarily diazinon dysautonomia, anterocollis, and chlordane) for 8-9 h/d levodopa nonresponsive 8/M/47 Parkinsonism, dysautonomia, Industrial plant Approximately 5-y history of exposure to 2 sleep apnea, nonsustained worker benzene and other hydrocarbons mild response to levodopa 9/F/60 Parkinsonism; anterocollis; Homemaker Lived immediately adjacent to melon fields for Aware of 8 people dysautonomia; mild, nearly 30 y, sprayed weekly by plane with in her nonsustained response to pesticides; her car was covered by thick immediate levodopa film after each session vicinity with “Parkinson disease” 10/M/70 Parkinsonism, severe Aeronautical worker 26-y history of inspecting airplane engines 0 dysarthria, dysphagia, typically in enclosed environment with anterocollis, dysautonomia, constant exposure to large amounts of levodopa unresponsive kerosene fumes 11/M/65 Parkinsonism, urine Horticulturist 25-y history of spraying pesticides including 0 incontinence, orthostasis, malathion, diazinon, and sexual dysfunction trichlorophenoxyacetic acid

Figure 1. Numerous glial cytoplasmic inclusions (arrows) within glial cells Figure 2. A glial cytoplasmic inclusion (arrow) taken from a section of the located in the deep cerebellar white matter adjacent to the fourth ventricle putamen (ubiquitin, original magnification ϫ400). (Bielschowsky stain, original magnification ϫ400).

arm swing but was otherwise unremarkable. A T2- extending into the putamen, with hyperintensity in a lin- weighted magnetic resonance image of the brain dis- ear fashion along the lateral border of the putamen, con- played hypointensity of the globus pallidus bilaterally, sistent with findings seen in patients with MSA.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 CASE 11 tal toxins and PD. Since MSA is a sporadic disorder, without strong evidence of genetic cause, the hypothesis of toxin- A 65-year-old horticulturist was examined in our clinic induced MSA may be more plausible than that of toxin- in February 1998 with a 11⁄2-year history of a slowly pro- induced PD. Furthermore, in addition to our cases, MSA- gressive akinetic-rigid syndrome with a slow, shuffling like disorders have been reported as a result of exposure to gait and decreased dexterity of his upper limbs; sexual certain toxins. For example, manganese intoxication, re- dysfunction; orthostatic hypotension with supine blood ported in manganese miners, in those manufacturing dry pressure of 108/50 mm Hg dropping to 70/50 mm Hg batteries, and in those with long-term ingestion of potas- when he was upright; and snoring with reported apnea sium permanganate, can produce clinical, neuroimaging, and daytime sighing. He had recently begun taking car- and pathological findings that may overlap with those of bidopa-levodopa, with mild benefit. He had worked for MSA.20,21 Pezzoli et al4 described a woman who developed 25 years as a horticulturist, having retired 1 year before parkinsonian symptoms at age 45 years after a 20-year ex- the onset of symptoms. This work included the near- posure to glues that containedn-hexane. Although her con- daily spraying of pesticides, most commonly malathion, dition initially responded to levodopa, it later deteriorated diazinon, and trichlorophenoxyacetic acid, for at least 1 and she developed autonomic dysfunction, axonal neuropa- to 2 hours per day. He “almost never” wore a mask, gloves, thy, and anemia caused by bone marrow suppression. Patho- or other protective gear while spraying these agents. logical examination of the brain showed severe dopamin- Examination disclosed moderate hypomimia, mild ergic neuronal loss with marked gliosis in the substantia bilateral upper-extremity kinetic tremor, moderate 4- nigra, with nearly complete loss of tyrosine hydroxylase im- extremity rigidity, and bradykinesia, worse in the legs. munostaining in the striatum. Neuronal loss was also pres- Gait testing displayed decreased arm swing with marked ent in the locus ceruleus, pedunculopontine nucleus, and postural instability. Magnetic resonance imaging of the periaqueductalgraymatter.Othertoxinsthathavebeendocu- brain demonstrated marked signal hypointensity on T2- mented to cause MSA-like parkinsonian disorders include weighted images in the globus pallidus bilaterally, ex- inorganic mercury,3 methanol,22 carbon tetrachloride,23 car- tending into the putamen, with hyperintensity in a lin- bon disulfide,24 and cyanide.25 ear fashion along the lateral border of the putamen. The role of environmental toxins in the pathogenesis of PD has been emphasized in the past, but the recent dis- COMMENT covery of a mutation in the gene on chromosome 4 that codes for ␣-synuclein suggests that perhaps genetic factors alone The common link among the patients described herein, all are sufficient to cause the disease.26 In contrast, there is no of whom had the clinical features of MSA, was an unusu- evidence of genetic predisposition in MSA, and, therefore, ally heavy exposure to occupational toxins. As this is not the possibility of environmental causes seems more likely. an epidemiological study, we cannot prove that the toxic While a toxin-induced model of MSA, similar to the MPTP exposures caused the development of MSA in these pa- model of PD, is still lacking, there are toxins that can cause tients. Certain of the toxins, however, such as n-hexane, an MSA-like disorder in experimental animals. For example, pesticides, cyanide, and formaldehyde, have been linked intrastriatal injection of 3-nitropropionic acid (a mitochon- to the development of parkinsonism.3,4 Further support of drial toxin) into experimental rats produces degeneration the causative role of these toxins in these cases is that the of intrinsic striatal neurons, the transverse fiber bundles of majority of our patients had colleagues with a parkinso- the internal capsule in the striatum as well as the nigrostria- nian disorder, who had a history of exposure similar to that tal dopamine system.27 The behavioral and pathological fea- of the patients, suggesting the possibility of a “cluster.” turesledtheauthorstoconcludethatthismayserveasamodel Theories of environmental toxin exposure having of MSA. Deutch et al28 reported that intraperitoneal injec- a role in parkinsonian disorders have drawn more atten- tion of 3-acetylpyridine in rats produces neurochemical and tion from the scientific community since the discovery histological changes consistent with olivopontocerebellar of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6- atrophy. In addition to causing degeneration of the nigro- tetrahydropyridine (MPTP) and the evidence of a pos- striatal dopaminergic pathway, this neurotoxin also causes sible environmental cause of the amyotrophic lateral scle- degeneration of the climbing fibers that normally originate rosis–parkinsonism–dementia complex of Guam.5 MPTP in the inferior olive and terminate in the cerebellum. produces selective degeneration of the substantia ni- Although a variety of toxins have been implicated in gra6,7 and locus ceruleus,8,9 and eosinophilic intraneuro- the pathogenesis of MSA in our cases, organic solvents ap- nal inclusions similar to Lewy bodies.9,10 MPTP is a li- pear to be particularly common. Organic solvents also have pophilic protoxin, requiring conversion into 1-methyl- been reported to contribute to the development of another 4-phenylpyridinium ion by monoamine oxidase B in glia.11 parkinson-plus disorder, progressive supranuclear palsy.29 1-Methyl-4-phenylpyridinium ion is then taken up into That report described 4 such cases: a housewife with exten- dopaminergic neurons and blocks complex I of the elec- siveexposuretoliquidinsecticides,2lithographerswithdaily tron transport chain, which ultimately leads to free radi- exposure to “solvents,” and a banker who was an avid hor- cal formation and subsequent cell death. ticulturist and was exposed to “insecticides with organic sol- A number of epidemiological studies have suggested ventbases.”Exposuretoorganicsolvents(benzene, n-hexane, the possible role of environmental toxins in the develop- methyl isobutyl ketone, and epichlorohydrin) and pesticides ment of PD,12-19 but similar data are lacking in parkinson- (malathion,diazinon,andchlordane)wasprominentlynoted plusdisorders,suchasMSA.Althoughintriguing,thesestud- in our patients. Toxic exposure to organic solvents may re- ies have failed to establish a clear link between environmen- sult in a variety of behavioral, sensory, and motor deficits,

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 although MSA has not been previously attributed to this class 9. Forno LS, Langston JW, Delanney LE, et al. Locus ceruleus lesions and eosino- of toxins.30 Methyl isobutyl ketone is an industrial and phar- philic inclusions in MPTP-treated monkeys. Ann Neurol. 1986;20:449-455. 10. Forno LS, Langston JW, Delanney LE, Irwin I. An electron microscopic study of MPTP- maceutical solvent. Peripheral neuropathy has been reported induced inclusion bodies in an old monkey. Brain Res. 1988;488:150-157. 31 after occupational exposure to methyl butyl ketone. Pes- 11. Ransom BR, Kunis DM, Irwin I, Langston JW. Astrocytes convert the parkinsonism- ticides include the organochlorines, organophosphates (dia- inducing neurotoxin, MPTP, to its active metabolite, MPP+. Neurosci Lett. 1987; zinon, malathion), carbamates, pyrethrins, and rotenone. 75:323-328. Long-term exposure to these agents may cause peripheral 12. Rajput AH, Uitti RJ, Stern W, et al. Geography, drinking water chemistry, pesti- 32 cides and herbicides and the etiology of Parkinson’s disease. Can J Neurol Sci. as well as central nervous system abnormalities, but de- 1987;14:414-418. spite the implication of pesticides in the development of par- 13. Tanner CM, Chen B, Wang WZ, et al. Environmental factors in the etiology of kinsonism in various epidemiological studies,15,17 pesticide- Parkinson’s disease. Can J Neurol Sci. 1987;14:419-423. induced MSA has not been documented. 14. Tanner CM, Chen B, Wang W, et al. Environmental factors and Parkinson’s dis- Our case 1 demonstrates the typical histological fea- ease: a case-control study in China. Neurology. 1989;39:660-664. 15. Ho SC, Woo H, Lee CM. Epidemiologic study of Parkinson’s disease in Hong Kong. tures of MSA: a wide distribution of glial cytoplasmic in- Neurology. 1989;39:1314-1318. clusions, as well as neuronal cytoplasmic inclusions, and 16. Koller W, Vetere-Overfield B, Gray C, et al. Environmental risk factors in Parkin- neuropil threads.33-41 In addition, similar to other re- son’s disease. Neurology. 1990;40:1218-1221. ported cases of MSA,34 this patient had marked degenera- 17. Golbe LI, Farrell TM, Davis PH. Follow-up study of early life protective and risk tion in the substantia nigra and locus ceruleus. The rela- factors in PD. Mov Disord. 1990;5:66-70. 18. Tanner CM, Grabler P, Goetz CG. Occupation and the risk of Parkinson’s dis- tive sparing of the striatum, in contrast to the typical, ease: a case-control study of young-onset versus old-onset patients [abstract]. pathologically proved, sporadic cases of MSA, suggests that Neurology. 1990;40(suppl 1):422. Abstract 1112S. the toxin(s) preferentially damaged the most vulnerable ar- 19. Semchuk KM, Love EJ, Lee RG. Parkinson’s disease: a test of the multifactorial eas, namely the substantia nigra and locus ceruleus. etiologic hypothesis. Neurology. 1993;43:1173-1180. We recognize that objective evidence proving a caus- 20. Calne DB, Chu NS, Huan CC, et al. Manganism and idiopathic parkinsonism: simi- larities and differences. Neurology. 1994;44:1583-1586. ative relationship between the toxin exposure and the de- 21. Olanow CW, Good PF, Shinotoh H, et al. Manganese intoxications in the rhesus velopment of MSA in our patients is lacking. Neverthe- monkey: a clinical, imaging, pathologic, and biochemical study. Neurology. 1996; less, the striking and prolonged exposure of the toxins, 46:492-498. the suggestion of clusters in some cases, and the ab- 22. McLean DR, Jacobs H, Mielke BW. Methanol poisoning. Ann Neurol. 1980;8: 161-167. sence of alternative explanations for the occurrence of 23. 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Effects of ␣-phenyl-tert-butyl nitrone on neuronal survival and motor function following intrastriatal injections of quinolinate or 3- This study was supported in part by the National Par- nitropropionic acid. Neuroscience. 1997;76:749-761. kinson Foundation, Miami, Fla. 28. Deutch AY, Rosin DL, Goldstein M, Roth RH. 3-Acetylpyridine-induced degen- Reprints: Joseph Jankovic, MD, Department of Neu- eration of the nigrostriatal dopamine system: an animal model of olivopontocer- rology, Parkinson’s Disease Center and Movement Disor- ebellar atrophy-associated parkinsonism. Exp Neurol. 1989;105:1-9. ders Clinic, Baylor College of Medicine, 6550 Fannin St 29. McCrank E, Rabheru K. Four cases of progressive supranuclear palsy in pa- tients exposed to organic solvents. Can J Psychiatry. 1989;34:934-935. #1801, Houston, TX 77030. 30. White RF, Proctor SP. Solvents and neurotoxicity. Lancet. 1997;349:1239-1242. 31. Lolin Y. 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