Progressive supranuclear palsy

A 66-year-old man had suffered from a slow and steady decline in both physical and cognitive function for four years. he showed bradyk'mesia and small step gait with supranuclear vertical gaze palsy, especially upward gaze palsy. He was started on levodopa therapy but without response. A diagnosis of progressive supranuclear palsy was clinically suspected. He died at age 69. Pathologically, many [alpha]-synuclein positive inclusions were detected both in the brain stem and cerebral cortices, and the diagnosis of dementia with Lewy bodies was made. Scattered [alpha]-synuclein-positive inclusions and threads, which may be a pathological substrate for supranuclear gaze palsy, were identified in the rostal midbrain. From a review of five cases of dementia with Lewy bodies with supranuclear gaze palsy including this case, the absence of falls in the early stage of the disease, fluctuation of cognition, hallucination and vertical gaze palsy with a more severe defect in the upward direction distinguished dementia with Lewy bodies with vertical gaze palsy from progressive supranuclear palsy. In the differential diagnosis of parkinsonism with gaze palsy, clinicians should consider dementia with Lewy bodies with gaze palsy as well as progressive supranuclear palsy. [Neurol Res 2003; 25: 533-537]

Keywords: Dementia with Lewy bodies; diffuse Lewy body disease; supranuclear gaze palsy; progressive supranuclear palsy

INTRODUCTION

Dementia with Lewy bodies (DLB) is a clinicopathological entity characterized by progressive cognitive decline, often accompanied with recurrent visual hallucinations, fluctuating cognition and spontaneous motor features of parkinsonism1. Recently, it was reported that depression and REM sleep behavior disorder may be additional features supportive of a diagnosis of DLB2. Pathologically, diffuse appearance of Lewy bodies (LB) in the cerebral cortices is the hallmark of DLB1, and [alpha]-synuclein (aS) was found to be a central constituent of LB3. DLB is now recognized to be the second most common cause of degenerative dementia after Alzheimer's disease (AD)4. However, clinical underdiagnosis of DLB remains an important problem, and AD is the most frequent misdiagnosis of autopsyconfirmed DLB cases2,5.

In most cases, it is not difficult to distinguish DLB from progressive supranuclear palsy (PSP), and it is reported that supranuclear gaze palsy, gait instability and the absence of delusions distinguish PSP from DLB6. Therefore, in differential diagnosis of parkinsonian syndromes, defects in vertical gaze tend to be identified with PSP7. However, several cases of DLB with supranuclear gaze palsy have been described7 10. We here describe another case of DLB with supranuclear gaze palsy and review the cases reported previously.

Case REPORT

A previously healthy 62-year-old man began to experience a slow and steady decline in physical function, largely due to bradykinesia and small steppage gait. His memory had also become mildly impaired, as reported by his family. At the age of 66, he was admitted to the hospital for assessment and therapeutic studies.

On admission, he showed supranuclear vertical gaze palsy, especially upward gaze palsy with minimal limitation of lateral gaze. The oculocephalic reflex was preserved. he was bradykinetic and rigid bilaterally without tremor. His gait was unsteady, and he walked with a broad base. Deep tendon reflexes were slightly decreased with no pathological reflex. There was no postural hypotension. Coordination and sensation were normal. There was also mental impairment with episodic confusion. His IQ (WAIS-R) was 62 (verbal IQ 73, practical IQ 54) and Hasegawa Dementia Scale revised (HDS-R) score was 9 (out of a possible 30). Head MRI showed minimal atrophy of the tegmentum of the midbrain. he was started on levodopa therapy with no response. A diagnosis of progressive supranuclear palsy (PSP) was clinically suspected.

After discharge, his movement gradually grew worse, and he became bedridden at age 67. His speech became progressively slurred, and he began to experience difficulty in swallowing. he died of aspiration pneumonia at age 69.

Neuropathological examination

At necropsy, he was found to have bilateral lower lobe bronchopneumonia. The fixed brain weighed 1,380 g. Macroscopic examination revealed no significant cerebral atrophy. Meninges and vessels were normal. The tegmentum of the midbrain was slightly atrophie. Pallor was noted in the substantia nigra, and the locus ceruleus was unidentifiable macroscopically. The cerebellum was normal.

Tissue blocks were taken from the mid-frontal and orbito-frontal areas; superior and middle temporal, inferior parietal, and occipital cortices; anterior cingulate; amygdala; hippocampus; striatum; thalamus; midbrain; pons; medulla; and cerebellum. Midbrain regions related to vertical eye movement, including the rostal interstitial nucleus of the medial longitudinal fasciculus (riMLF) and the nuclei of Cajal and Darkschewitsch were also examined.

Formalin-fixed, paraffin-embedded 6 [mu]m sections were stained with hematoxylin-eosin (HE), KluverBarrera (KB), and Gallyas-Braak (GB) silver impregnation. The following immunocytochemical markers were used: anti-[alpha]-synuclein ([alpha]S) (MDV2: an antibody against residues 1-15 of the N terminus of human [alpha]S, rabbit polyclonal, 1 :4,000) (courtesy of Dr Kenyi Veda, Tokyo lnst. Psychiatry), anti-[alpha]S (EQV1 : an antibody against residues 1-15 of the N terminus of the NAC portion of human [alpha]aS, rabbit polyclonal, 1 :4,000, K. Ueda), anti-[alpha]S (PQE3: an antibody against residues 108-122 of the C terminus of human [alpha]S, rabbit polyclonal, 1 :4,000, K. Ueda), anti-[beta]-synuclein ([beta]S) (REE1: an antibody against residues 86-100 of human ssS, rabbit polyclonal, 1:4,000, K. Ueda), anti-synphilin 1 (rabbit polyclonal, 1:1,000) (courtesy of Drs Simone Engelender, Yuji Tanaka, and Christopher A. Ross, The Johns Hopkins University School of Medicine, Baltimore, MD, USA)11.

The characterization and specificity of antibodies against [alpha]S and [beta]S have been reported previously as follows: EQV1 and PQE3 recognize only "S, MDV2 reacts with both [alpha]S and [beta]S, and REE1 detects only [beta]S12-14. Taking these characteristics into consideration, we regarded the MDV2-positive, EQV1-positive, PQE3-positive, REE1-negative pattern as "S immunoreactivity. The characterization and specificity of the antibody against synphilin 1 has also been reported11.

Deparaffinized sections were incubated with 1% H^sub 2^O^sub 2^ in methanol for 30 min to eliminate endogenous peroxidase activity in the tissue and then pre-treated with formic acid (FA) (99%, 5 min; Sigma Chemicals, St. Louis, MO, USA) in 50 mM TRIS-HCI buffer, pH 7.4, containing SmM EDTA. After blocking with 10% normal serum, sections were incubated overnight at 4[degrees]C with one of the primary antibodies. The sections were washed in PBS and incubated with biotinylated anti-rabbit secondary antibody, followed by avidin-biotinylated horseradish peroxidase complex (ABC Elite kit, Vector, Burlingame, CA, USA). The reaction was visualized with 0.2% 3,3'-diaminobenzidine in 50 mM TRIS-HCI buffer, pH 7.4, containing 0.003% H^sub 2^O^sub 2^. Counterstaining was carried out with hematoxylin.

Microscopic findings

Concentric hyaline intracytoplasmic eosinophilic inclusions (Lewy bodies; LBs), accompanied by cell loss, gliosis and free pigment, were found in the substantia nigra and locus ceruleus (Figure la,b). LBs were easily identified on he sections, but appeared more plentiful with a-synuclein immunostaining. Scattered ?-synuclein-positive inclusions and threads were identified in the periaqueductal gray matter, riMLF, and nuclei of Cajal and Darkschewitsch (Figure Ie) as well as in the nucleus basalis of Meynert, Edinger-Westphal nuclei, pontine raphe nucleus, pontine reticular formation, and dorsal vagal nucleus. No abnormalities were seen in the oculomotor, trochlear, or abducent nuclei. The brainstem contained no neurofibrillary tangles (NFT). In the dentate nucleus of the cerebellum, glumose degeneration in small amounts was detected without obvious neuronal loss. No abnormality was seen in the cerebellar cortex or cerebellar white matter.

Microscopic examination revealed many cortical Lewy bodies in the neocortex, entorhinal region, insula, cingulate, and amygdala (Figure 1c). LBs were easily identified on he sections, but appeared more plentiful with [alpha]-synuclein immunostaining (Figure 1d). They were most abundant in the amygdala followed by the parahippocampus. They occurred predominantly in pyramidal neurons of laminae 3, 5, and 6 in the neocortex and were often arranged in small groups. The diagnosis of DLB was made on the basis of widespread LB: more than 6 LB per area in the cingulate and transentorhinal region, and 3-5 LB per area in the middle frontal, middle temporal, and inferior parietal lobule: Lewy body score 71. [alpha]-synuclein immunoreactive neurites were present in the hippocampal CA2-3 region, and NAC-positive star-like astrocytes, recently reported in DLB15,16, were also found in the neocortex, entorhinal region, insula, cingulate, amygdale, and basal ganglia (Figure 1f).

Throughout the neocortex, there were numbers of senile plaques, most of which were of the diffuse nonneuritic type, whereas quite a few NFT were detected only in the parahippocampus.

DISCUSSION

Clinical features (Table 1)

As far as we know, four cases of DLB with supranuclear gaze palsy have been described in detail (four reports). These four cases were originally reported as 'diffuse Lewy body disease'. However, all four cases showed memory problems and dementia in their clinical course, and pathologically had many cortical LBs in the cortices. Therefore, these four cases can be recognized as DLB.

The clinical features of the autopsied DLB patients with supranuclear gaze palsy, including our case, are summarized in Table 1. All five cases were male, and two had a family history of parkinsonism. Their ages at onset were 62-71 years old and the durations of their diseases were 3-14 years.

Rigidity and akinesia were present in all cases, and in four cases, the laterally of parkinsonism was not clear. Resting tremor was described in only two cases, and all cases showed no responsiveness to I-dopa therapy. Vertical gaze palsy, bilateral parkinsonism and unresponsiveness to l-dopa therapy tend to be identified with PSP.

All cases showed gait disturbance, but frequent falls were recognized only in the advanced stage of two cases. Memory disturbance was present in all cases, but fluctuation of cognition in three and hallucination in two. From the above, the absence of falls in the early stage of the disease, fluctuation of cognition, and hallucination distinguished DLB with vertical gaze palsy from PSP.

Gaze palsy in DLB

All five cases showed vertical gaze palsy (Table 1). Three cases showed more severe upward gaze palsy, one showed more severe downward, and in one case it is not mentioned which, upward or downward gaze palsy, was more severe. One case with more severe downward gaze palsy initially showed upward gaze palsy only, which later was accompanied by a defect in downward gaze of greater degree. Therefore, all four cases mentioned initially showed more severe upward gaze palsy. Four cases also had an associated defect in horizontal gaze. From the above, vertical gaze palsy with a more severe defect in upward gaze may be important to differentiate DLB with gaze palsy from PSP.

Louis et al17 reported that only one of 28 cases with pathologically confirmed DLBD showed gaze palsy, and Litvan et al.6 found supranuclear vertical gaze palsy in only one of 14 cases with pathologically confirmed DLBD. Therefore, gaze palsy in DLB is not common, but it is important that vertical gaze palsy was detected in a small number of cases with DLB. In the differential diagnosis of parkinsonism with gaze palsy, clinicians should consider DLB with gaze palsy as well as PSP.

Neuropathological findings (Table 2)

Neuropathological findings are summarized in Table 2. Brain weights were 1,192-1,380g, and severe cerebral atrophy was not recognized. Atrophy of the brain stem was present in two cases.

Microscopic examination revealed many cortical LBs in all five cases. Senile plaques throughout the neocortex were present in four cases, and NFTs in the parahippocampus and/or hippocampus were described in three, but NFTs in the neocortices were not detected in any case. Therefore, four of five cases were classified as common form DLBD18. In all cases, LBs were found in the substantia nigra (SN), locus ceruleus (LC), and nucleus nervi vagi, and quite a few NFTs in the brain stem were detected in two.

Vertical gaze centers have been described in the rostal midbrain, riMLF, nuclei of Cajal and Darkschewitsch and periaqueductal gray matter19. In three of four cases examined, LBs were found in the riMLF and nuclei of Cajal and Darkschewitsch. In one case with supra-nuclear gaze palsy, examination of those nuclei revealed no LBs , but examination with anti-[alpha]-synuclein antibodies was not performed in that case. Therefore, it can not be concluded that there was no pathological accumulation of [alpha]-synuclein in the nuclei of that case. In this limited study, we could not come to a conclusion as to the pathological basis of the ophthalmoplegia. However, the presence of a-synuclein positive structures in the riMLF, nucleus of Darkschewitsch and interstitial nucleus of Cajal indicates some degree of clinicopathologic correlation.

CONCLUSION

Gaze palsy is not common in patients with DLB, but it is significant that vertical gaze palsy has been detected in a small number of DLB cases. Vertical gaze palsy, bilateral parkinsonism and unresponsiveness to I-dopa therapy in DLB with gaze palsy tend to be identified as PSP, but the absence of falls in the early stage of the disease, fluctuation of cognition, hallucination, and vertical gaze palsy with a more severe defect in upward gaze distinguish DLB with vertical gaze palsy from PSP. Vertical gaze centers have been described in the rostal midbrain, and the presence of [alpha]-synuclein-positive structures in the rostal midbrain may indicate some degree of clinicopathologic correlation. In the differential diagnosis of parkinsonism with gaze palsy, clinicians should consider DLB with gaze palsy as well as PSP.

ACKNOWLEDGEMENTS

The authors thank Ms M. Onbe for her skillful technical assistance. This work was partly supported by a Research Grant from Zikei Institute of Psychiatry, Japan. The authors thank Dr K. Ueda (Tokyo Inst. Psychiatry), Dr S. Engelender, Dr Y. Tanaka and Dr C.A. Ross (Johns Hopkins University School of Medicine) for supplying antibodies

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Hanae Nakashima*, Seishi Terada*, Hideki Ishizu[dagger], Yasuyuki Tanabe[double dagger], Osamu Yokota*, Takeshi Ishihara*, Hiroshi Takata[double dagger], Yuetsu Ihara[double dagger], Toshiyuki Hayabara[double dagger] and Shigetoshi Kuroda*

*Department of Neumpsychiatry, Okayama University Graduate School of Medicine and Dentistry, Okayama 1 Department of Laboratory Medicine, Zikei Institute of Psychiatry, Okayama

[double dagger]Clinical Research Institute and Department of Neurology, National Minami-Okayama Hospital, Okayama, Japan

Correspondence and reprint requests to: Dr Seishi Terada, Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. [terada_1@cc.okayama-u.ac.jp] Accepted for publication March 2003.

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