Profound midbrain atrophy in patients with Wilson’s disease and neurological symptoms?

Wilson’s disease (WD) is characterized by impaired hepatic copper secretion and subsequent copper accumulation in many organs predominantly liver and brain, secondary to loss of function mutations in the copper transport protein ATP7B. If the disease is recognized too late or treatment is not adequate, brain copper accumulation leads to progressive neurodegeneration with a variety of clinical symptoms. The nigrostriatal dopaminergic system seems rather vulnerable. Midbrain atrophy, however, has not been recognized as one of the prime features of patients with WD. Here we report quantification of midbrain diameter in 41 patients with WD. Data were correlated to the severity of neurological symptoms and the integrity of dopaminergic neurons measured via dopamine transporter binding. For control, we measured midbrain diameter in 18 patients with no evidence for brainstem dysfunction and 5 patients with progressive supranuclear palsy (PSP). Patients with WD had a reduced midbrain diameter (15.5 ± 0.4 mm) compared to controls (18.5 ± 0.2 mm). WD patients without neurological symptoms had midbrain diameter that were not different from controls (18.0 ± 0.3 mm), while patients with neurological symptoms showed midbrain atrophy similar to patients with PSP (14.4 ± 0.3 mm versus 14.1 ± 0.3). There was a strong and significant correlation between midbrain atrophy and the severity of neurological symptoms (r= −0.68, p < 0.001) while midbrain atrophy and dopamine transporter binding correlated significantly but was less pronounced (r=0.46, p < 0.001). In summary, we were able to show, that midbrain diameter is an easy to perform quantification of neurodegeneration induced by brain copper accumulation and that other structures than substantia nigra dopaminergic neurons seem to contribute to midbrain atrophy in WD.     

具有帕金森样症状患者相关疾病探讨

目的探讨具有帕金森样症状(PLS)患者的相关疾病。方法收集我院近3年来因PLS而住院的78例患者的临床资料(病史、临床表现和辅助检查结果),按中华医学会神经病学分会运动障碍及帕金森病学组制定的诊断标准确定诊断。结果本组78例患者,出院诊断分别为:帕金森病(PD)36例,继发性帕金森综合征(PS)26例(血管性16例、脑外伤后3例、CO中毒后3例、脑炎后2例,杀虫剂中毒后2例),多系统萎缩(MSA)4例,进行性核上性麻痹(PSP)4例,路易体痴呆(DLB)2例,肝豆状核变性(WD)2例,特发性震颤(ET)2例,基底节钙化症(BGC)1例,皮质基底节变性(CBD)1例。结论具备PLS的疾病谱很广,其中PD大约占60%,另有30～40%的非PD患者具有类似表现,称为非典型帕金森综合征(AP),如多系统萎缩(MSA)、进行性核上性麻痹(PSP)、Wilson病(WD)、路易体痴呆(DLB),基底节钙化症(BGC)、皮质基底节变性(CBD)等,容易误诊,应注意鉴别。     

Clinical heterogeneity in progressive supranuclear palsy: Problems of clinical diagnostic criteria of NINDS‐SPSP in a retrospective study of seven Japanese autopsy cases

Progressive supranuclear palsy (PSP) is known to display variable atypical clinical features. In the absence of clinical markers to diagnose PSP, neuropathological examination is the “gold standard” for diagnosis. We retrospectively investigated clinical features in seven autopsy‐confirmed cases of PSP. Only three patients (42.9%) matched the clinical diagnostic criteria of PSP proposed by the National Institute of Neurological Disorders and Stroke and the Society for PSP (NINDS‐SPSP) at the time of death. In addition, only one patient (14.3%) matched these criteria at the time of the initial symptoms. Such underdiagnosis of PSP was mainly caused by heterogeneity, variety of the timing, and presence of symptoms in exclusion criteria. The present study also demonstrated that the clinical features of PSP may change dramatically according to the disease stage. Target symptoms should be selected based on time and stage to optimize patient quality of life.     

Photophobia, visual hallucinations, and REM sleep behavior disorder in progressive supranuclear palsy and corticobasal degeneration: a prospective study

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) have overlapping clinical features that can make clinical distinction between these two entities difficult. The present study compared the frequency of photophobia, visual hallucinations, and REM sleep behavior disorder (RBD) in patients clinically diagnosed with PSP to those clinically suspected to have CBD. Photophobia occurred in all 10 (100%) PSP patients vs 2 (18%) patients with clinically suspected CBD (p=0.0002). Visual hallucinations and RBD occurred in patients with PSP and CBD but were rare occurrences (5% for each symptom). The presence of photophobia is significantly more frequent in clinically diagnosed PSP than CBD and can be used as a feature in differentiating between the two diseases in clinical practice. Visual hallucinations and RBD occur infrequently in PSP and CBD and are not useful symptoms in clinical differentiation.     

Cognitive deficits in progressive supranuclear palsy on the Repeatable Battery for the Assessment of Neuropsychological Status

Progressive supranuclear palsy (PSP) is associated with a variety of cognitive deficits, as well as motor and psychiatric disturbances. As clinical trials for PSP evolve, briefer screening instruments will be needed to determine cognitive effects of interventions. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) may fill this gap. Three hundred four participants diagnosed with Richardson’s syndrome of PSP were evaluated with the RBANS, as well as other scales typically used in PSP. RBANS performances for these participants fell significantly below expectations for the Total Scale score and all five Indexes. Cognitive scores on the RBANS were also significantly related to other markers of PSP (e.g., motor and functional abilities, depression, global cognition). Compared to other clinical conditions from the literature, patients with PSP show impairment on tests of visuospatial perception and construction and attention. Although additional research is needed, the current study supports the clinical applicability of the RBANS in patients with PSP, as well as its potential for future clinical trials.     

Genetic variation at the tau locus and clinical syndromes associated with progressive supranuclear palsy.

A number of different clinical syndromes have been associated with progressive supranuclear (PSP) tau pathology. Previous reports have suggested that atypical clinical phenotypes of PSP occur in familial disease, and might be associated with mutations of MAPT. We examined the association of PSP-susceptibility tau haplotypes in pathologically diagnosed PSP, separated according to initial clinical features into classic PSP and atypical PSP groups (PSP-Parkinsonism, PSP-P). These patients were screened for mutations in exons 1 and 10 of MAPT. No mutations were found in 75 patients (21 PSP-P), and H1c was associated with both Richardson's syndrome and PSP-P compared with controls. Routine screening for MAPT mutations in atypical PSP is not recommended.     

Diagnosis and management of progressive supranuclear palsy

Because of the relevance of an early and accurate diagnosis for prognosis, management, and participation of patients in research, the classical clinical features--features that should raise suspicion of progressive supranuclear palsy (PSP) and those that should make the diagnosis of PSP unlikely--are discussed in this article. The accuracy of currently used clinical diagnostic criteria and the role of laboratory investigations in the diagnosis of PSP are reviewed. New terminology for the clinical diagnostic criteria for PSP is proposed. The main neuropathologic and neurochemical features supporting current main symptomatic and hypothesized experimental biologic therapies are suggested.     

Midbrain hypometabolism as early diagnostic sign for progressive supranuclear palsy

OBJECTIVE: Progressive supranuclear palsy (PSP) is often misdiagnosed in early phase. The purpose of this study is to investigate the feature of [(18)F]fluoro-2-deoxy-d-glucose (FDG) positron emission tomography images for the early diagnosis of PSP. METHODS: We studied 15 patients with PSP and 16 normal subjects. Using SPM99 and analysis of covariance to eliminate the effect of aging, the differences between PSP and normals were displayed as a statistical map. In the PSP, we also investigated the correlation with duration and with the subscores of Unified Parkinson's Disease Rating Scale. RESULTS: The glucose metabolism of midbrain was significantly lower in PSP than in normals. However, correlation was not found between the metabolism of midbrain and clinical deterioration. CONCLUSIONS: The statistical map clearly demonstrated the hypometabolism of midbrain in PSP, which is independent of the clinical deterioration. The hypometabolism of midbrain is one of the most promising sign for early diagnosis of PSP.     

Accuracy of clinical diagnosis of progressive supranuclear palsy.

We assessed the accuracy of clinical diagnosis of progressive supranuclear palsy (PSP, Steele-Richardson-Olszewski disease) and the validity of existing sets of clinical diagnostic criteria for PSP (see Appendix) using neuropathologically examined cases from the Queen Square Brain Bank for Neurological Disorders. Diagnosis of PSP was made by 40 different physicians, and 60 cases clinically diagnosed as PSP when last assessed in life were studied. In 47 cases (78%), the diagnosis of PSP was confirmed pathologically. False-positive diagnoses included Parkinson's disease with significant additional cortical Lewy body (n = 3) or Alzheimer (n = 1) pathology, multiple system atrophy (n = 4), and corticobasal degeneration, Pick's disease, motor neurone disease, cerebrovascular disease, and a sporadic case of frontotemporal dementia and parkinsonism linked to chromosome 17 (1 case each). Most cases of PSP were diagnosed accurately by neurologists at the final assessment. Although application of National Institute of Neurological Disorders and the Society for PSP possible category marginally improved the accuracy of initial clinical diagnosis, none of the existing operational criteria could significantly improve accuracy of the final clinical diagnosis.     

Cognitive and magnetic resonance imaging aspects of corticobasal degeneration and progressive supranuclear palsy.

OBJECTIVE: To identify cognitive and MRI features important for the clinical diagnosis of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP); these diseases share several clinical features and are often difficult to distinguish on clinical grounds. METHODS: Cognitive functions and MRI characteristics were examined in 16 patients with CBD and 28 patients with PSP, all diagnosed according to current clinical criteria (none was examined by autopsy). RESULTS: MRI findings differed significantly between the two groups: 87.5% of patients with CBD but none with PSP had asymmetric frontoparietal atrophy, whereas 89.3% of patients with PSP but only 6.3% of those with CBD had midbrain atrophy. Cognitive examination showed that ideomotor apraxia (De Renzi's test) was significantly more frequent in CBD, and executive functions (Nelson's test) were significantly more impaired in patients with PSP. CONCLUSIONS: MRI findings of asymmetric frontoparietal atrophy in CBD and midbrain atrophy in PSP are the most consistent and useful aids to careful clinical evaluation for differentiating between the two diseases.     

Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias.

OBJECTIVE: To evaluate the inter-rater reliability and validity of clinical diagnostic criteria for neurodegenerative dementias. BACKGROUND: Inter-rater accuracy of the diagnosis of AD has been explored, but there are few accuracy studies for progressive supranuclear palsy (PSP) and frontotemporal lobe dementia (FTD). Furthermore, there have been no simultaneous accuracy studies in a mixed sample of patients with cortical and subcortical neurodegenerative processes. METHODS: Four experienced clinicians reviewed first-visit clinical data abstracted from the records of 40 pathologically diagnosed demented subjects. They were asked to apply the NINCDS-ADRDA criteria for AD, the NINDS-SPSP clinical criteria for PSP, the Lund and Manchester criteria for FTD, and the Consensus Guidelines for the Clinical Diagnosis of Dementia with Lewy Bodies (DLB). Results: The generalized K for AD was 0.73, for PSP 0.82, for FTD 0.75, and for DLB 0.37. The K pool test showed a statistically significant difference between DLB and the other disease processes, and no differences were observed among AD, FTD, and PSP. The mean sensitivity for AD was 95%, for PSP 75%, for FTD 97%, and for DLB 34%. The mean specificity for AD was 79%, for PSP 98.5%, for FTD 97%, and for DLB 94%. CONCLUSIONS: We found improved inter-rater reliability for the diagnosis of AD among clinicians compared with earlier studies. Similarly, there was a near-perfect and substantial inter-rater agreement for the diagnosis of PSP and FTD. The sensitivity for the diagnosis of AD was high, although clinicians overdiagnosed this condition. However, there was a reasonable accuracy for the diagnosis of PSP and FTD. Heterogeneity of the clinical presentation of DLB significantly affected inter-rater agreement and accuracy. The use of multiple diagnostic criteria for cortical and subcortical dementia increases the level of clinical diagnostic accuracy.     

Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria

Background : PSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome. Objective : We aimed to provide an evidence‐ and consensus‐based revision of the clinical diagnostic criteria for PSP. Methods : We searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy‐confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in two modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2‐day meeting, and refined in three further Delphi rounds. Results : Defined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context‐dependent exclusion criteria. We identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features. Conclusions : Here, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence. © 2017 International Parkinson and Movement Disorder Society     

Progressive supranuclear palsy: what's new?

Progressive supranuclear palsy (PSP) has been described as a clinical syndrome characterized by an impairment of voluntary control of gaze (supranuclear palsy), postural and gait instability, and behavioral and cognitive deficits including a frontal syndrome and psychic retardation. However, in the recent years, at least four other clinical forms of PSP have been recognized: PSP-Parkinsonism, "pure akinesia with gait freezing", PSP with cortico-basal syndrome, and PSP with speech apraxia. PSP-Parkinsonism mimics the signs and symptoms of idiopathic Parkinson's disease, including a significant reactivity to levodopa. "Pure akinesia with gait freezing" is characterized by a difficulty of self-initiation of motor programs, usually walking program. PSP with cortico-basal syndrome mimics cortico-basal degeneration (CBD) in that unilateral or asymmetric limb dystonia and apraxia are prominent signs. PSP with speech apraxia is an isolated syndrome of progressive anarthria. All these clinical syndromes are due to brain accumulation of phosphorylated tau protein. The differences in clinical expression within the framework of PSP can be explained by the differences in the topographical distribution of the lesions. PSP is considered as a primary tau disease ("tauopathy") such as CBD and some forms of fronto-temporal lobar degeneration. At the level of neuropathology, the pattern of tau abnormal inclusions differentiates PSP from other tau diseases, but some overlaps are reported. Moreover, several of the clinical forms of PSP partially or fully overlap with the other tauopathies. As a whole, the emergence of new clinical forms of PSP challenges the nosology of tauopathies and our understanding of these diseases.     

Coexistence of PSP and MSA: a case report and review of the literature

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy characterized by Parkinsonism, vertical gaze palsy, and early falls. The neuropathology is characterized by neurofibrillary tangles, tufted astrocytes, and coiled bodies, but some brains show other pathologic processes. To investigate the frequency of α-synuclein pathology in PSP with immunohistochemistry and to report the clinical and pathological features of a case of PSP with concomitant Multiple system atrophy (MSA) (PSP/MSA), 290 cases of PSP were screened for α-synuclein pathology with immunohistochemistry. Double-labeling immunohistochemistry was performed on a case of PSP/MSA. Among the PSP cases screened for α-synuclein pathology, a single case of PSP/MSA was detected. The patient was an 86-year-old woman with clinical features consistent with PSP. She had no documented dysautonomia or cerebellar signs, and imaging studies were not diagnostic of MSA. Pathological examination showed τ-immunoreactive neuronal and glial lesions consistent with PSP as well as α-synuclein immunoreactive glial cytoplasmic inclusions diagnostic of MSA. Double-immunolabeling studies showed no co-localization of α-synuclein and τ in most neuronal and glial lesions. Based upon the findings in this case, the neuropathologic changes of PSP and MSA are distinct and independent processes, but they can occasionally coexist.     

Corticobasal degeneration and atypical progressive supranuclear palsy: their symptomatology, laboratory examination and differential diagnosis]

Corticobasal degeneration (CBD) and atypical progressive supranuclear palsy (PSP) were reviewed with special reference to their symptomatology, laboratory examination and differential diagnosis. In our survey of the autopsy cases of CBD in Japan, only about 60% of the pathologically confirmed CBD cases were correctly diagnosed clinically, meaning that atypical (non-classical) clinical forms are common in CBD. Concerning the autopsy cases of PSP in Japan, 75% of the PSP cases had correct clinical diagnosis. In literatures, the clinically atypical CBD includes (1) frontotemporal dementia, also with primary progressive aphasia and frontal lobe dementia as subforms, (2) PSP-like form, and (3) others. The clinically atypical PSP comprises (1) pure akinesia, (2) pure easy falling syndrome (Yuasa), (3) no postural instability, (4) no gaze palsy, (5) asymmetric parkinsonism, (6) no or severe dementia, etc.. PSP with cortical manifestations such as primary progressive aphasia and CBD-like features were also reported. The atypical CBD and PSP probably reflect the distribution of tau pathology different from that in typical forms. Except for the report that phosphorylated tau is increased in CSF in CBD, but not in PSP (Urakami et al), no reliable laboratory data have been available on clinical differentiation between atypical CBD and PSP.     

进行性核上性麻痹的临床特点以及MRI和PET-CT分析

目的总结临床诊断为进行性核上性麻痹(PSP)病例,分析PSP的临床特点以及MRI和PET-CT表现,以探索PSP的诊断及治疗方法。方法回顾性分析5例PSP患者的临床资料,总结该病的MRI和PET-CT表现及临床特点。结果 5例患者均呈慢性隐匿性起病,进行性加重,中晚期出现核上性凝视麻痹、头后仰、轴性肌张力增高、动作迟缓和反复跌倒。头颅MRI可见中脑萎缩明显,脚间池扩大,中脑和脑桥长轴的垂直线比值在0.35~0.43区间,脑桥与中脑的面积比值在0.10~0.15区间,5例患者磁共振帕金森综合征指数(MRPI)均13.55。PET-CT示双侧额叶、中脑、丘脑、纹状体等部位可有不同程度的葡萄糖代谢减低,5例患者均有双侧纹状体多巴胺代谢减低。唑吡坦对患者运动障碍改善似有帮助。结论 PSP的诊断仍以临床表现为主,影像学特异性改变有助诊断。目前尚无确切有效的治疗。     

What features improve the accuracy of the clinical diagnosis of progressive supranuclear palsy‐parkinsonism (PSP‐P)?

Progressive supranuclear palsy‐parkinsonism (PSP‐P) is a primary tauopathy characterised by neurofibrillary degeneration, which is frequently mistaken for Parkinson's disease (PD), multiple system atrophy (MSA), and vascular parkinsonism (VP) at presentation. The aim of this study was to identify particular clinical features (green flags) that may be helpful in differentiating PSP‐P from these other disorders. We identified 37 patients with PSP‐P from 726 patients archived at the Queen Square Brain Bank. Using a retrospective case notes review the clinical features were compared between the PSP‐P group and Lewy body associated parkinsonism (PD, n = 444 and dementia with Lewy bodies (DLB), n = 46), MSA (n = 90), and VP (n = 19), using the χ²‐test for proportions for a two‐by‐two contingency table. The sensitivity, specificity, and positive predictive values (PPV) and negative predictive values (NPV) were calculated for individual clinical features. A specificity of >0.85 or a PPV of >0.85 were considered reliable discriminators. No clinical features were predictive of PSP‐P, but late drug induced dyskinesias (specificity 0.92, PPV 0.99), late autonomic dysfunction (specificity 0.94, PPV 0.99) and any visual hallucinations (specificity 0.94, PPV 0.99) were better in distinguishing PD and PSP‐P than predicted using operational diagnostic criteria for PD. PSP‐P shares many clinical features with PD and DLB, MSA and VP, but visual hallucinations, drug induced dyskinesias and autonomic dysfunction are very uncommon and may be helpful exclusion criteria. © 2010 Movement Disorder Society     

Progressive supranuclear palsy (PSP): Richardson syndrome and other PSP variants

Phenotypic heterogeneity of progressive supranuclear palsy (PSP) has been increasingly reported in the literature and can be the source of incorrect clinical diagnosis particularly in the early stages of the disease when the classically associated symptoms of early falls and supranuclear gaze palsy may not be apparent. In addition to Richardson syndrome (RS), several atypical clinical phenotypes have been described. Advances in genetic, neuroimaging, and biochemical/molecular technologies contribute to the identification of these clinical subtypes in the context of typical PSP pathological findings. Our goal is to review the phenomenology reported in the literature that is associated with confirmed histopathological changes consistent with a PSP diagnosis and to highlight the clinical spectrum of PSP. A systematic review of the literature in PubMed through July 2015 using MeSH terms and key words related to PSP was conducted. Articles describing PSP classifications, diagnostic criteria, and case reports were reviewed and summarized. Additional PSP phenotypes not seen in recent clinicopathological studies are included. These include primary lateral sclerosis, pallido‐nigro‐luysian degeneration, axonal dystrophy, and multiple system atrophy in the spectrum of atypical PSP variants beyond the traditionally classified PSP subtypes. This review is intended to help with the diagnostic challenges of atypical PSP variants. We believe that large multicenter clinicopathological studies will help expand our understanding of etiology and specific mechanisms of neurodegeneration and will aid in the appropriate interpretation of outcomes when conducting clinical and basic science research.