Neuroleptic‐induced Parkinsonism: Clinicopathological study

Case 1

A 65‐year‐old man with a long history of bipolar disorder (BPD) was treated with chlorpromazine 75 mg three times daily (TID) since age 41 and lithium 300 mg TID since around age 50. At age 60, he noticed resting tremor in the left upper limb (UL), which worsened over the next 5 years and involved the right side. A trial on benztropine by the family physician produced confusion and hallucinations. Examination at the MDCS at age 65 revealed bilateral UL action tremor, more pronounced on the left, bilateral UL rigidity and bradykinesia. Diagnosis of parkinsonism, stage 2,16, 17 secondary to neuroleptic use was made. Because of asymmetrical parkinsonism findings, it was considered that he may have underlying PD pathology unmasked by neuroleptics, he was started on selegiline 5 mg once‐daily. It made his “stomach sour” and was therefore discontinued. He was switched to trihexyphenidyl 2 mg TID 2 weeks before his next visit 6 months later when his parkinsonism was essentially unchanged at stage 2 disability.17 He continued with chlorpromazine (though at a reduced dose of 50 mg TID), lithium, and trihexyphenidyl and was followed at the MDCS for 5 years. At age 69, orofacial tardive dyskinesias were noted and his wife noted that his memory was not good—he was on trihexyphenidyl 2 mg four times daily (QID), and it was recommended that the dose be reduced. At his last visit to the MDCS at age 70, his parkinsonism was at H & Y stage 2.16, 17 Toward the end, he was in a nursing home and his medications included quetiapine and lithium; he was no longer on trihexyphenidyl or chlorpromazine. He died at age 85.

On autopsy, the brain weighed 1,410 g and was grossly normal. There were neurofibrillary tangles throughout the brain and amyloid deposits in the hippocampus. There was no loss of pigmented neurons in the SN or in the locus ceruleus (LC). α‐Syn staining was negative. The final pathological diagnosis was mild Alzheimer's disease and mild cortical amyloid angiopathy.

Case 2

He had been on long‐term treatment with metoclopramide 10 mg twice‐daily (BID) for reflux owing to a large hiatus hernia. He had onset of gait difficulty at age 78 followed by gait initiation failure, gait freezing, and bilateral UL resting tremor. The metoclopramide dose was reduced to once‐daily. He was started on levodopa/carbidopa 100/25 mg 1 tablet BID 6 weeks before first evaluation at the MDCS, with reported improvement in tremor. On examination at age 83, he had bilateral UL rigidity, right side worse, definite bradykinesia in all four limbs, and UL postural and kinetic tremors. He had mild orofacial chewing movements intermittently. He had a flexed posture and was unable to stand from sitting position without assistance; gait was wide based and shuffling with minimal arm swing. He was diagnosed with PD, H & Y stage 4,16, 17 and the l‐dopa/carbidopa 100/25 mg was increased to 1 tablet QID, with a final maintenance dose of 2 tablets five times daily. There was some improvement of symptoms, though he remained at H & Y stage 4. Metoclopramide was continued by the family physician and the dose increased to 10 mg TID before his death at age 85.

At autopsy, the brain weighed 1,680 g and was grossly normal except for a hemorrhagic infarct in the right posterior angular gyrus. There were rare cerebral neurofibrillary tangles, but no loss of pigmented neurons in the SN or LC. There were no pathological findings consistent with clinical features of parkinsonism. α‐Syn staining was negative.

Case 3

At age 69, he was admitted to local hospital for confusion and treated with lorazepam 0.5 to 1.0 mg up to six times daily as needed (PRN) and risperidone 0.5 mg TID. He was discharged to a nursing home on those drugs. One month later, he was admitted to the Royal University Hospital Saskatoon for confusion and personality change. Clinical diagnosis was encephalopathy. He was investigated extensively. The peripheral blood counts and electrolytes were normal. Multiple electroencephalograms were normal and nerve conduction study was normal. Cerebral angiograms were normal; notably, there was no evidence of vessel occlusion, aneurysm, malformation, or other evidence of vasculitis. Carotid doppler was normal. CT of the brain revealed mild cerebral atrophy and an ill‐defined hypodensity in the left corona radiata. MRI of the brain, MR diffusion study, and MRA of the head revealed diffuse cerebral and cerebellar atrophy and periventricular and subcortical foci of T2 hyperintensity and patchy T2 signal in the left pons. Regional cerebral blood perfusion SPECT study revealed no abnormality.

Cerebrospinal fluid (CSF) was normal for proteins, glucose, and white cell count. Polymerase chain reaction for herpes simplex was negative. CSF culture revealed no organisms. CSF was faintly positive for 14‐3‐3 proteins by immunoblotting. Definite diagnosis for the cause of encephalopathy was not made. He was discharged to the nursing home and was continued on risperidone 0.5 mg TID. Four months later, his wife noted that he was tremulous, had shuffling gait, and visual hallucinations. He could walk less than half a block alone, provided somebody was with him, but after that he needed active support. Examination at that time revealed, mild but definite bradykinesia in all four limbs, bilateral UL mild resting tremor, bilateral kinetic and postural tremor, bilateral mild rigidity, and flexed posture with slow shuffling gait. His Mini–Mental Status Examination (MMSE) score was 21/30. He was diagnosed as having parkinsonism and dementia, likely Lewy body dementia given his visual hallucinations and variable cognition and behavior. His disability was rated at stage 4.0 H & Y.17 He was treated with rivastigmine 1.5 mg once‐daily (OD) for 1 week and then increased to BID. It was recommended that the risperidone be changed to quetiapine; however, that was not pursued by the family physician and he was continued on risperidone. There was no symptomatic improvement on rivastigmine. He was reevaluated at the MDCS 6 months later. His MMSE was 18/30 and H & Y stage was 5. He was incontinent of urine and sometimes stool. His tremor had become worse and hallucinations were “too bad” to describe. l‐dopa/carbidopa 100/25 mg OD was initiated. It was increased over 1 week to 1 tablet TID and rivastigmine dose was recommended to increase to 3 mg TID. At his final visit to the MDCS nearly 8 months later on his 71st birthday, his condition had declined further. By then, rivastigmine had been stopped. At that time, he was recommended to increase the l‐dopa/carbidopa 100/25 mg to 1.5 tablets TID. There was no symptomatic benefit. He continued to decline over the next 5 years while in a nursing home. The risperidone was continued until his death at age 75.

At autopsy, the brain weighed 1,380 g. Microscopically there was a moderate loss of pigmented neurons in the LC and a mild loss in the SN. α‐Syn immunostaining was negative, as was that for ubiquitin, TDP‐43, and FUS, thus ruling out common forms of tau‐negative degenerations. Tau immunostaining revealed changes consistent with an Alzheimer's disease neuropathological score of “low” according to 2012 National Institute on Aging‐Alzheimer's Association guidelines.18 Thus, although not ruled out, a definite diagnosis of Alzheimer's disease could not be made, and the cause for his dementia could not be established.

Case 4

He was seen at age 55 years in our clinic in May 1974. He had a long history of depression, anxiety, and insomnia. He was hospitalized under psychiatry at age 42 and was noted to have obvious tremor. He received electroconvulsive treatment and was started on chlorpromazine and benztropine. Chlorpromazine was continued until his death. He had onset of UL tremor at age 23, and at age 50, was diagnosed as PD by the family physician and treated with l‐dopa. That was discontinued because of severe nausea, but had no symptomatic benefit. Examination at the MDCS at age 55 revealed a slow head tremor with both vertical and horizontal components, moderate bilateral UL resting tremor and more pronounced action tremor, and mild bradykinesia and rigidity in both ULs and unstable posture—stage 3 H & Y.17 He was diagnosed as having essential tremor and parkinsonism, secondary to antipsychotics. He was not willing to try antiparkinson drugs. He died of myocardial infarction at age 58.

On autopsy, the brain weighed 1,400 g and was grossly normal. There was no loss of pigmentation of SN or other pathology consistent with parkinsonism noted grossly or microscopically. Brain histology otherwise was normal.

Case 5

At age 61, he had noticed bilateral UL tremor during writing, which became worse at age 65 subsequent to the death of his wife. He was hospitalized for depression and was treated with electroconvulsive therapy and started on phenothiazine at age 66. Examination at the MDCS 2 months later revealed moderate bilateral UL postural and action tremor; the right side was worse. In addition, there was right UL resting tremor mostly at the thumb, and mild bradykinesia and rigidity in the left UL. Because his primary problem was tremor, he was started on propranolol. Three months later, propranolol was discontinued because he did not think it was effective (though objectively the tremor appeared improved). At that visit, he had UL postural, action, and resting tremor and questionable rigidity, but no definite bradykinesia. Diagnosis of PD was made. He died at age 67 of myocardial infarction.

On autopsy, the brain weighed 1,350 g. There was marked cerebral arteriosclerosis and enlarged perivascular spaces, in the basal ganglia. The brain was otherwise grossly and microscopically normal. There was no loss of SN or LC neurons.

Case 6

He was hospitalized at age 69 with a 2‐week history of confusion, agitation, and combative tendencies after he had hit his head against the stairs. He was treated with intramuscular chlorpromazine 50 mg TID, with additional doses given as necessary. Six days later, he was noted to have bilateral, small‐amplitude resting tremor in the upper limbs and moderate generalized rigidity and bradykinesia. A diagnosis of NIP was made. The following day, he received chlorpromazine 75 mg intramuscular and 2 mg of benztropine orally. Both drugs were discontinued the next day. The parkinsonian manifestations subsided completely during the next 7 days. He developed respiratory symptoms and he died 1 month later.

At autopsy, pulmonary embolism and bronchopneumonia were confirmed as the cause of death. The brain weighed 1,500 g and was grossly normal. Moderate loss of SN pigmented nerve cells, gliosis, and frequent intracytoplasmic Lewy bodies were found. Lewy bodies were also observed in the LC. DA and homovanillic acid levels were moderately reduced in the caudate and the putamen. The final diagnosis was preclinical PD unmasked by neuroleptics.10

Case 7

He was known to have bipolar disorder and was treated with haloperidol 2 mg TID and benztropine for 3 months, before his hospitalization in May 1977 at age 59. On examination, he had moderate generalized rigidity, bradykinesia, and resting tremor in both ULs. The neuroleptics and benztropine were discontinued. The parkinsonian features resolved over the next 2 weeks. He died suddenly 2 months later at age 59.

At autopsy, acute pulmonary edema was detected. Histological examination of the brain revealed slight loss of SN pigmented cells and numerous intracytoplasmic Lewy bodies (LB). Biochemical assay of the striatum showed no measurable reduction of DA levels.10