Pure akinesia as initial presentation of PSP: A clinicopathological study

doi:10.1016/j.parkreldis.2007.11.004

Parkinsonism & Related Disorders

Volume 14, Issue 6, August 2008, Pages 517-519

https://doi.org/10.1016/j.parkreldis.2007.11.004 Get rights and content

Abstract

Pure akinesia (PA) is a rare neurodegenerative condition that may represent a limited expression of progressive supranuclear palsy (PSP). Only a few pathological studies have been reported and its classification remains unclear. We report the case of a 57-year-old Caucasian man who was initially clinically diagnosed with classical PA. After four years the patient developed additional symptoms and signs compatible with the diagnosis of clinically probable PSP. The diagnosis of PSP was confirmed by post-mortem examination. Genetic analysis of the MAPT gene revealed an A0/A0 genotype, which has been repeatedly associated with the PSP phenotype, and might discriminate between PA and other gait disorders. Our case strengthens the hypothesis that PA should be considered as initial manifestation of PSP.

Introduction

Pure akinesia (PA) is a rare disorder characterized by akinesia of gait, handwriting, and speech, with no rigidity, tremor, or dementia, and accompanied by a lack of response to levodopa [1], [2]. First described by Imai and Narabayashi in 1974 [1], only 11 autopsy cases of PA have been reported to date ([3], references therein). Some of these patients developed clinical evidence of progressive supranuclear palsy (PSP) while in some others the only signs were those of isolated PA. However, post-mortem studies almost invariably showed abnormalities consistent with PSP. PSP is an atypical parkinsonian syndrome characterized by supranuclear gaze palsy, axial dystonia, bradykinesia, dysarthria, pseudobulbar palsy, postural instability, and cognitive disturbances [4]. Pathologically, PSP is characterized by globose, tau-containing neurofibrillary tangles (NFT_s), neurophil threads (NTs), and marked cell loss in the basal ganglia and several brainstem nuclei [5]. In addition, evidence for genetic predisposition to PSP, consisting of over-representation of homozygosity for the MAPT “A0 allele” has been reported [6]. Here we describe an autopsy-proven case presenting initially with a typical PA syndrome which subsequently evolved into a full-blown PSP syndrome.

Section snippets

Case report

A 57-year-old man enjoyed excellent health until he developed progressive gait and balance disturbances. A neurological examination performed by one of the authors (PPP) showed a slow shuffling broad-based gait with no rigidity, tremor, disturbance in eye movements, speech or cognitive impairment. Two years later, he developed gait ignition failure, freezing episodes with festination, festinating speech and micrographia. There was no response to levodopa. At age 61, the patient showed marked

Discussion

Clinical studies have indicated that PA may represent a pre-ocular motor form of PSP [7]. Most of the pathological studies of PA have been seen in Japanese patients ([1], [2], [3], references therein) although a European study has reported neuropathological evidence of primary progressive freezing gait (PPFG) [8]. Here, we report a patient who showed classical features of PA which evolved into full-blown autopsy-proven PSP syndrome four years following disease onset. To the best of our

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Citation Excerpt :
Aside from pathology within the brainstem saccade generator, PSP has come to be regarded as a heterogenous multisystem disorder involving the basal ganglia and the cerebellum, with different clinical manifestations and nomenclatures (Birdi et al., 2002). The subtypes of PSP include Richardson syndrome (RS), presenting with the full-blown constellation of symptoms; PSP-parkinsonism (PSPp), characterized by parkinsonism and a moderate initial therapeutic response to levodopa (Williams et al., 2005, 2007); and pure akinesia and gait freezing (PAGF) without rigidity, tremor, or ophthalmoplegia and with poor response to levodopa (Imai et al., 1993; Homma et al., 1987; Matsuo et al., 1991; Facheris et al., 2008). Additionally, cerebellar types of PSP (PSPc) exhibiting overt cerebellar symptoms and mimicking spinocerebellar ataxia (SCA) have recently come to be recognized as a subtype, more common in east Asian populations, with pathological confirmation (Kanazawa et al., 2009, 2013; Jellinger, 2010).
To study whether the velocity profile of horizontal saccades could be used as an indicator of brainstem and cerebellar output dysfunction, depending on progressive supranuclear palsy (PSP) subtype.
We compared the velocity profiles in 32 PSP patients of various subtypes with 38 age-matched normal subjects, including Richardson syndrome (RS), PSP-parkinsonism (PSPp), and pure akinesia (PAGF), and cerebellar subtypes of PSP (PSPc).
PSP patients showed reduced peak velocity along with increased duration, especially in the deceleration phase. This alteration was more prominent for larger target eccentricities (20–30 degrees), and correlated with disease severity. The changes were most pronounced in PSPc patients, with irregular increases and decreases in velocity profile, followed by RS patients, whereas the change was smaller in PSPp and normal in PAGF patients.
Saccade velocity profile can be an indicator of brainstem and/or cerebellar output. Altered velocity profile of PSP patients may reflect the pathology in the brainstem, but may also reflect cerebellar dysfunction, most prominently in PSPc.
Saccade velocity profile may be used as an indicator of latent cerebellar/brainstem dysfunction.
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However, several studies report PSP to be the most frequent underlying pathology (PSP-PAGF) [14,15]. A syndrome with similar nomenclature, namely pure akinesia (PA), also has been linked to PSP-pathology and likely constitutes the same syndrome [16]. Consistently, oculomotor changes and/or postural instability have been observed approximately 9 years after onset, but cases with autopsy-confirmed PSP exist in whom these key symptoms never developed [15].
Traditionally, the clinical picture of progressive supranuclear palsy (PSP) was defined by early postural instability with falls, supranuclear vertical gaze palsy, symmetric akinesia and rigidity, frontal and subcortical dementia, and pseudobulbar palsy, leading to death after a mean disease duration of approximately six years. A definite diagnosis of PSP depends on neuropathological confirmation. In recent years, clinico-pathological studies have drawn attention to various “atypical” clinical manifestations of PSP. In these, a clinical diagnosis of PSP is delayed or never accomplished. Comprehensive understanding of the natural history of PSP is required to permit an early and accurate diagnosis. Based on current evidence, this review provides an update on the clinical spectrum of PSP.
Deterioration of horizontal saccades in progressive supranuclear palsy
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Citation Excerpt :
Saccade recordings were conducted as part of their clinical assessment, after obtaining informed consent, following the protocols approved by the Ethics Committee of The University of Tokyo, and in accordance with the ethical standards of the Declaration of Helsinki. PSP subtypes were classified based on previous reports (Imai and Narabayashi, 1974; Imai et al., 1993; Homma et al., 1987; Matsuo et al., 1991; Mochizuki et al., 2003; Williams et al., 2005, 2007, 2009; Fachiers et al., 2008; Kanazawa et al., 2009; Shirota et al., 2010; Jellinger, 2010). Among our 36 PSP patients, 22 were diagnosed with RS, 2 with PAGF, 6 with PSPc, and 6 with PSPp.
To investigate horizontal saccade changes according to disease stage in patients with progressive supranuclear palsy (PSP).
We studied visually and memory guided saccades (VGS and MGS) in 36 PSP patients at various disease stages, and compared results with those in 66 Parkinson’s disease (PD) patients and 58 age-matched normal controls.
Both vertical and horizontal saccades were affected in PSP patients, usually manifesting as “slow saccades” but sometimes as a sequence of small amplitude saccades with relatively well preserved velocities. Disease progression caused saccade amplitude reduction in PSP but not PD patients. In contrast, VGS and MGS latencies were comparable between PSP and PD patients, as were the frequencies of saccades to cue, suggesting that voluntary initiation and inhibitory control of saccades are similar in both disorders. Hypermetria was rarely observed in PSP patients with cerebellar ataxia (PSPc patients).
The progressively reduced accuracy of horizontal saccades in PSP suggests a brainstem oculomotor pathology that includes the superior colliculus and/or paramedian pontine reticular formation. In contrast, the functioning of the oculomotor system above the brainstem was similar between PSP and PD patients.
These findings may reflect a brainstem oculomotor pathology.
Gait and balance disorders in patients with atypical parkinsonian syndromes
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Les syndromes parkinsoniens « plus » d’origine dégénérative constituent un ensemble hétérogène de pathologies avec l’atrophie multisystématisée, la paralysie supranucléaire progressive, la démence à corps de Lewy et la dégénérescence cortico-basale. Leur profil évolutif se distingue de la maladie de Parkinson par l’apparition précoce de troubles de la marche et de l’équilibre, d’un freezing de la marche isolé ou primary progressive freezing of gait ou d’une akinésie pure ou isolée. L’origine de ces symptômes reste mal connue. L’association de la perte neuronale du circuit dopaminergique nigrostriatal et de lésions corticales, en particulier dans la dégénérescence cortico-basale et la démence à corps de Lewy, et/ou du tronc cérébral, en particulier dans la paralysie supranucléaire progressive, pourrait rendre compte de la sévérité des signes moteurs et de l’absence ou la faible amélioration par le traitement par lévodopa. D’autres thérapeutiques symptomatiques ont été proposées, médicamenteuses ou chirurgicales, avec des résultats le plus souvent décevants. Les méthodes de rééducation centrées sur le contrôle de l’équilibre peuvent apporter une amélioration transitoire.
The degenerative Parkinsonian “Plus” syndromes form a heterogeneous spectrum of pathologies comprising multiple system atrophy, progressive supranuclear palsy, Lewy body disease and cortico-basal degeneration. Their developmental profile is distinguished from that of Parkinson's disease by the early appearance of gait and balance disorders, isolated freezing of gait, primary progressive freezing of gait or an isolated or “pure” akinesia. The origin of these symptoms however remains poorly understood. The association of nigrostriatal dopamine neuron loss with either cortical lesions, in the case of cortico-basal degeneration and Lewy body disease, and/or of the brainstem, in the case of progressive supranuclear palsy, explains both the severity of the motor symptoms and the lack of, or minimal, improvement following levodopa therapy. Other symptomatic drug and surgical treatments have been proposed, but with generally disappointing results. Physiotherapeutic techniques targeting balance control can bring some temporary improvements.
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Case reportPure akinesia as initial presentation of PSP: A clinicopathological study

Abstract

Introduction

Section snippets

Case report

Discussion

Akinesia-concerning 2 cases of pure akinesia

Skinkej Xenkyu Shimpo

Dopa-unresponsive pure akinesia or freezing – a condition within a wide spectrum of PSP?

Adv Neurol

Autopsy case of pure akinesia showing pallidonigro-luysian atrophy

Neuropathology

Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele–Richardson–Olszewski syndrome): report of the NINDS–SPSP international workshop

Neurology

Preliminary NINDS neuropathologic criteria for Steele–Richardson–Olszewski syndrome (progressive supranuclear palsy)

Neurology

Case report
Pure akinesia as initial presentation of PSP: A clinicopathological study