A 71‐YEAR‐OLD WOMAN WITH PSP‐LIKE SYMPTOMS

Clinical History

A 71‐year‐old female had been well until approximately 2 years before admission, when a neurologist noted muscle rigidity, decreased arm swing while walking, mask‐like face, pill rolling tremor and some difficulty in writing. Levodopa/carbidopa (up to 200mg/day) was not effective and was withheld because of exacerbation of tingling sensation of lower extremities. Four months before admission, she complained of visual hallucinations of children or objects. Endoscopic examination identified gastric ulcer as a cause of melena and anemia, which lead her to this admission.

General physical examination showed anemia and inspiratory stridor. Neurological findings suggestive of progressive supranuclear palsy (PSP) were as follows: 1) (subcortical) dementia (she showed forgetfulness, slow thinking, apathy, and depression, on the other hand, apparent aphasia, apraxia, or agnosia were absent), 2) supranuclear gaze palsy, 3) pseudobulbar palsy, 4) dorsiflexion of neck, rigidity of neck, absence of tremor and no cog‐wheel rigidity of extremities, and 5) postural reflex disturbance.

Laboratory examination showed BUN 32.9 mg/dl and Hb 10.7 mg/dl, but was otherwise unremarkable. During this admission levodopa/carbidopa up to 400mg/day was tried without clinical improvement. Sudden cardiopulmonary arrest on the 24th hospital day was followed by repeated respiratory tract infections until she died on the 58th hospital day.

Clinical diagnosis was 1) dopa‐unresponsive parkinsonism compatible with PSP, 2) hypoxic‐ischemic encephalopathy, 3) pneumonia, and 4) gastric ulcer.

Neuro‐radiology

An MRI showed no apparent atrophy of the midbrain tegmentum but small T2 and FLAIR high intensities were present (Figure 1a).

Figure 1.

 

Gross and Microscopic Pathology

The autopsy showed aspiration pneumonia with organization, gastric ulcer (scar), gastrointestinal tract hemorrhage, atrophy of organs, and malnutrition.

Brain weight was 985g. Cortical atrophy was mild in frontal and parietal lobes and moderate in temporal tips. Cerebral cortices became thin and brown especially from the central region to occipital lobes. Cerebral white matter showed swelling and discoloration. Dentate nucleus showed mild discoloration. The substantiae nigrae were thin and pale (Fig 1b). The loci cerulei were pale.

Ischemic changes, such as loss of neurons, sponginess, marked gemistocytic astrocytosis with some ischemic neurons, were scattered in the entire cerebral cortices, putamen, globus pallidus externa, substantia nigra, pontine nuclei, and cerebellum. The dentate nucleus showed spongy changes and neuronal loss. Loss of pigmented neurons of the substantia nigra was accentuated in the ventrolateral tier. Lewy bodies were detected in the substantia nigra (Fig 2), the oculomotor nucleus, the loci cerulei, and the dorsal motor nucleus of the Vagus (Fig 3 alpha‐synuclein) but were not apparent in cerebral cortices or in the amygdala. Plaque pathology was Braak A and tangle pathology was Braak III. In the heart, there was also axonal depletion in epicardial nerve fascicles of the left ventricle as shown by SMI‐31 immunostains (Fig 4a) and this was more easily appreciated with immunostains for tyrosine hydroxylase (TH)‐positive axons (Fig 4b). These sometimes contained alpha‐synuclein deposits.

Figure 2.

 

Figure 3.

 

Figure 4.

 

The putamen shows the neuronal loss, sponginess, and gemistocytic astrocytosis (Fig 5a). Gallyas‐silver impregnation demonstrated argyrophilic structures around hypoxic ischemic foci. Gallyas positive structures were abundant in the putamen (Fig 5b), the dentate gyrus of hippocampus, and frequent in cerebral cortices and Purkinje cells, but infrequent in substantia nigra and subthalamic nucleus. The Gallyas‐positive structures were granular in appearance and never exhibited fibrillary structures like NFTs (Fig 6). They were not stained with AT8 isoform‐specific antibodies (RD3, RD4), Bodian or Campbell‐Switzer staining. Tuft shaped astrocytes were not seen.

Figure 5.

 

Figure 6.

 

What is the diagnosis?

Diagnosis

Parkinson disease and hypoxic‐ischemic encephalopathy.

Discussion

PSP‐like clinical manifestations of this patient: supranuclear gaze palsy, rigidity and dorsiflexion of the neck, dopa‐unresponsive parkinsonism, and subcortical dementia are compatible with its clinical diagnostic criteria 8. Neuropathological examination showed predominantly Lewy body pathology and scattered hypoxic ischemic foci.

Because the clinical picture of this patient was compatible with PSP, we screened the entire brain with Gallyas‐silver impregnation method 11. Gallyas‐positive structures were found in the substanita nigra, subthalamic nucleus, putamen, dentate gyrus and CA4 of hippocampus, cerebral cortex, and Purkinje cells. Because these findings are partly overlapping with those observed with neurofibrillary tangles in PSP 4, our initial histological diagnosis included PSP, in addition to Lewy body disease and hypoxic‐ischemic encephalopathy, which shared among several leading neuropathologist in this area. Because this diagnosis of PSP was based on the assumption that these Gallyas‐positive structures are NFTs of PSP (Figure 6), one may ask whether these Gallyas‐positive structures are NFTs of PSP? On further examination, however, these Gallyas‐positive structures were found to be 1) negative for AT8, 2) granular in cytoplasm without fibrillary structure, 3) abundant around ischemic foci. These features are different from NFTs but rather compatible with those recently reported in ischemic lesions 5, 7. Moreover, typical tuft‐shaped astrocytes were absent. We, therefore, declined our initial histological diagnosis of PSP. Because trivial ischemic lesions are one of the most frequent findings in human autopsy brains, it is worth paying attention to possible induction of Gallyas‐postive structures around ischemic foci for correct interpretation. Cytopathological differentiation from NFTs is possible based on the absence of AT8 immunoreactivity and fibrillary structures.

One may wonder how PSP‐like features were dominant in this patient with Lewy pathology even without authentic PSP lesions. It has been reported that Lewy body pathology is possibly related to clinical features mimicking PSP 1, 2, 3, 9 even without concomitant lesions characteristic of PSP. Copresence of PSP lesions 6 or argyrophilic grains 10 may feature clinical manifestations. Anyway, it remains still unanswered how Lewy pathology leads to PSP‐like manifestations.

Abstract

A 71‐year‐old female developed dementia, supranuclear gaze palsy, pseudobulbar palsy, dorsiflexion of neck, rigidity of neck, absence of tremor or cog‐wheel rigidity of extremities, and postural reflex disturbance. Levodopa/carbidopa prescribed without clinical improvement. Sudden cardiopulmonary arrest on the 24th hospital day was followed by repeated respiratory infection until she died on the 58th hospital day. Ischemic changes were scattered in entire cerebral cortices, putamen, external part of globus pallidus, substantia nigra, pontine nuclei, and cerebellum. Furthermore, Lewy bodies were detected in the substantia nigra, oculomotor nucleus, loci cerulei, and dorsal motor nucleus of vagus. Gallyas‐silver impregnation demonstrated argyrophilic structures around hypoxic ischemic foci: the putamen, dentate gyrus and CA4 of hippocampus, cerebral cortices, Purkinje cells, substantia nigra and subthalamic nucleus. These Gallyas‐positive structures were 1) negative for AT8, 2) granular in cytoplasm without fibrillary structure, 3) abundant around ischemic foci. Typical tuft‐shaped astrocytes were absent. Because trivial ischemic lesions are one of the most frequent findings in human autopsy brains, it is worth paying attention to possible induction of Gallyas‐positive structures around ischemic foci for correct interpretation.