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. ARCH NEUROL / VOL 56, JAN 1999 90 ©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- a7.537.5-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