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The phenotypic spectrum of progressive supranuclear palsy
Parkinsonism and Related Disorders xxx (2015) 1e3
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
The phenotypic spectrum of progressive supranuclear palsy € glinger a, b, * G. Respondek a, b, G.U. Ho a b
Department of Neurology, Klinikum Rechts der Isar, Technical University, Ismaninger Strasse 22, D-81675, Munich, Germany Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE], Site Munich, Feodor-Lynen Str. 17, D-81677, Munich, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 September 2015 Accepted 19 September 2015
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. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Phenotypes Progressive supranuclear palsy PSP Tauopathy
1. Introduction Progressive supranuclear palsy [PSP] is a sporadic, adult-onset tauopathy with an estimated prevalence of approximately 6.5 per 100.000 [1]. A seminal description of eight cases with PSP by J.C. Richardson, J.C. Steele, and J. Olszewski in 1963 has delineated a clinical syndrome comprising a combination of early postural instability, vertical supranuclear gaze palsy, slow and hypometric saccades, frontotemporal dysfunction, levodopa-resistant bradykinesia and axial rigidity [2], which is now termed PSP-Richardson's syndrome (PSP-RS) [3]. PSP is a neuropathologically defined disease entity. While characteristic pathological features, such as cerebral filamentous tau inclusions in neurons and glia, define the disease entity called “definite PSP” [4], early postural instability with falls in combination with supranuclear vertical gaze palsy are mandatory for a clinical diagnosis of “probable PSP”, and early postural instability with falls with saccadic abnormalities or supranuclear gaze palsy alone qualify for a diagnosis of “possible PSP” (NINDS-SPSP criteria) [4]. Steele and colleagues postulated that the clinical spectrum of PSP would grow over time [5]. This prediction has proven correct, as reports on atypical clinical presentations of PSP are constantly increasing. Symptoms considered atypical for PSP were described as early as the 1980's [6,7]. More recently, definitions of PSP subgroups, termed PSP-phenotypes, have been * Corresponding author. Dept. of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen Str. 17, D81677, Munich, Germany. €glinger). E-mail address: [email protected] (G.U. Ho
proposed [3]. There is ongoing debate whether these phenotypes represent separate entities, since clinical syndromes may overlap and may progress into PSP-RS at later disease stages [8,9]. However, different modes of initial presentation seem to predict different patterns of disease progression and survival time [3,8,9]. Current operational criteria for the clinical diagnosis of PSP do not capture these atypical presentations [9]. The need for a sensitive diagnosis will become even more vital with the emergence of diseasemodifying therapies. Hence, it is important to highlight consistent clinical syndromes that correlate with PSP-pathology. Here, we will review the different modes of (initial) clinical presentation of PSP that have been described in the literature. 2. PSP with Richardson's syndrome (PSP-RS) The clinical picture of PSP with Richardson's syndrome (PSP-RS) was initially described in 1963 by Richardson, Steele, and Olszewski [2]. PSP-RS is the most thoroughly studied phenotype of PSP and is highly predictive for an underlying PSP pathology [4,9]. It is characterized by vertical supranuclear gaze palsy, severe postural instability with early falls, pseudobulbar palsy, axial rigidity, symmetric and levodopa-resistant akinesia and cognitive dysfunction [2,10]. Vertical supranuclear gaze palsy is defined as a limitation of gaze in the vertical plane, which can be overcome by the vestibuloocular reflex. It is preceded by slowing of vertical saccades [4]. Other non-specific ocular signs, such as diplopia, photophobia, and eyelid apraxia, may appear early in the course of PSP-RS [3]. Postural instability with falls is the most frequent initial symptom of PSP-RS; it occurs in the majority of patients during the first year
http://dx.doi.org/10.1016/j.parkreldis.2015.09.041 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
€glinger, The phenotypic spectrum of progressive supranuclear palsy, Parkinsonism and Please cite this article in press as: G. Respondek, G.U. Ho Related Disorders (2015), http://dx.doi.org/10.1016/j.parkreldis.2015.09.041
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€glinger / Parkinsonism and Related Disorders xxx (2015) 1e3 G. Respondek, G.U. Ho
of the disease [10]. Pseudobulbar features of PSP-RS include dysphagia and dysarthria, which are supportive features in the diagnosis of PSP [2,4,5]. Progressive dysphagia may cause aspiration pneumonia, which is the most common cause of death in PSPRS [10]. Akinesia and rigidity typically are symmetric, with axial predominance, and respond poorly to levodopa therapy [10]. Tremor is rarely evident [10]. There is a typical array of cognitive impairments in PSP-RS. Frontal dysfunction, particularly in the form of behavioral and personality changes, is consistently seen in PSP-RS and may appear early in the clinical course [9e12]. Apathy seems to be more frequent than disinhibition [11]. Executive deficits, reduced verbal fluency and a positive applause sign also are common frontal features of PSP-RS [11,12]. The disease course in patients with PSP-RS is rapidly progressive, with death occurring after a median duration of 6e8 years [9,10]. Cases with early postural instability and falls, but without oculomotor deficits e at least during the first years of disease e have been described [6,9]. In contrast, some patients develop supranuclear gaze palsy very early, while postural instability and falls occur late or remain absent [9]. Whether these variants represent separate entities in terms of etiopathology remains to be studied. With regard to disease duration, these two variants do not substantially differ from PSP-RS [9]. 3. PSP with predominant parkinsonism (PSP-P) In 2005, an analysis of 103 definite PSP cases identified a PSP phenotype distinct from PSP-RS, namely PSP with parkinsonism (PSP-P) [3]. Bradykinesia and extrapyramidal rigidity with asymmetric distribution and response to levodopa dominate the early clinical course. Tremor is frequently reported, while falls and eye movement abnormalities develop later or never occur [3,9,13]. Cognitive dysfunction rarely is present at the beginning [3,9,13]. These features constitute a syndrome that may be indistinguishable from Parkinson's disease (PD) during the first years of illness. However, in some patients with PSP-P, the early occurrence of dysphagia and dysarthria, as well as subtle eye symptoms (e.g., blurred vision, diplopia, eyelid apraxia) may hint toward a diagnosis of PSP rather than PD [13]. PSP-P has a more benign disease course and longer survival compared with PSP-RS. A median disease duration of approximately 9e12 years is reported [3,9]. 4. PSP with pure akinesia with gait freezing (PSP-PAGF) Pure akinesia with gait freezing (PAGF), also known as primary progressive freezing of gait (PPFG), is a syndrome with prominent, levodopa-resistant gait freezing, occasionally accompanied by akinesia, and the rapid development of both hypophonia and micrographia [14,15]. PAGF may be a manifestation of various neurodegenerative diseases. 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]. Disease duration of more than 13 years seems to be common in patients with PSP-PAGF [14,15]. 5. PSP with corticobasal syndrome (PSP-CBS) Corticobasal syndrome (CBS) is characterized by a combination of cortical and basal ganglia dysfunction, which usually is asymmetric and includes: levodopa-resistant rigidity and akinesia, ideomotor apraxia, limb dystonia, reflex myoclonus, alien limb phenomena, cortical sensory loss, postural instability, and frontal
lobe dysfunction [17]. The term CBS initially was used interchangeably with corticobasal degeneration (CBD), a tauopathy with neuropathological features distinct from PSP [17]. Subsequently, CBS has been associated with a variety of other pathologies, including PSP, Alzheimer's disease (AD), Pick's disease (PiD), and Creutzfeldt-Jakob Disease (CJD) [18]. According to published clinico-pathological studies, the lack of clinical and imaging findings specific for one or the other pathology makes an accurate in vivo diagnosis impossible [19]. “Key features” of PSP, such as postural instability and vertical gaze palsy, also may develop later in the clinical course of CBD-CBS [19]. The median disease duration of PSP-CBS is similar to that of PSP-RS [9]. 6. PSP with predominant speech and/or language dysfunction (PSP-AOS and PSP-PNFA) Autopsy-proven PSP has been associated with syndromes characterized by language or speech dysfunction, namely progressive non-fluent aphasia (PNFA) and apraxia of speech (AOS). AOS is a motor speech disorder with slow and effortful speech, dysprosody, and buccofacial apraxia [20,21]. PNFA is characterized by non-fluent spontaneous speech with hesitancy, agrammatism and phonemic errors with preserved understanding of word meaning [20,21]. AOS may present simultaneously with PNFA [20,21]. PNFA is not closely associated with any single pathological diagnosis; it has been linked to frontotemporal lobar degeneration (FTLD) with TDP pathology, PSP, CBD, and PiD [20]. Likewise, AOS has been associated with various neurodegenerative diseases [20]. Still, AOS seems to be more predictive for PSP pathology than pure PNFA, and autopsy-confirmed PSP cases presenting with PNFA without AOS are rarely reported [21]. In the majority of cases, typical features of PSP, such as postural instability, falls, supranuclear vertical gaze palsy, behavioral changes, and akinetic, develop later [20,21]. 7. PSP with predominant frontotemporal dysfunction (PSPFTD) Frontotemporal dementia is a common feature of PSP-RS [9e11]. However, PSP also has been associated with a predominant frontotemporal dysfunction (PSP-FTD) [9,12,22]. The relative prevalence of PSP-FTD among autopsy-confirmed PSP patients has been reported as 5e20% [9,12,22]. A clinical picture of behavioral changes and cognitive dysfunction dominates and resembles that of the behavioral variant of frontotemporal dementia (bvFTD) [23]. The most frequent coexisting symptoms at initial presentation are falls, bradykinesia, and tremor [12]. Classical symptoms of PSP appear as the disease progresses [9,12,22]. The median survival time of patients with PSP-FTD is approximately 8 years [11,12,22], similar to that of PSP-RS. 8. PSP with cerebellar ataxia (PSP-C) Rare cases with autopsy-confirmed PSP and a predominantly cerebellar presentation (PSP-C) have been described [24,25]. Cerebellar features in PSP may be more common in Japan than in other populations [24] and include limb and gait ataxia [24,25]. All reported cases developed parkinsonism, supranuclear gaze palsy and postural instability later in the course of the disease. A comparative study of pathologically confirmed cases of PSP-C and the cerebellar variant of multiple system atrophy (MSA-C) found an older age at onset and a higher frequency of falls and gaze palsy in PSP-C [24]. Dysautonomia was absent in all cases with PSP-C [24]. The median disease duration in PSP-C is 7 years [24].
€glinger, The phenotypic spectrum of progressive supranuclear palsy, Parkinsonism and Please cite this article in press as: G. Respondek, G.U. Ho Related Disorders (2015), http://dx.doi.org/10.1016/j.parkreldis.2015.09.041
€glinger / Parkinsonism and Related Disorders xxx (2015) 1e3 G. Respondek, G.U. Ho
9. PSP with primary lateral sclerosis (PSP-PLS) Primary lateral sclerosis (PLS) is characterized by features of upper motor neuron dysfunction, including bulbar symptoms of dysarthria and dysphagia, weakness, spasticity, hyperactive reflexes, and Babinski signs [26]. In tau-negative FTD, a syndrome comprising motor neuron dysfunction combined with behavioral and cognitive changes, sometimes accompanied by supranuclear gaze palsy, is well-established [27]. Motor neuron disease, parkinsonism and dementia are hallmark features of a rare tauopathy called amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) [28]. However, in autopsy-confirmed PSP, PLS is rarely reported (PSP-PLS) [26,29]. In some cases of PSP-PLS, parkinsonism, postural instability and falls, supranuclear gaze palsy and cognitive deficits coexisted [26]. In others, the key features of PSP were absent throughout the course [29]. Limb apraxia also has been noted in several cases [26]. Disease duration is variable and ranged between 3 and 12 years in the reported patients [26,29]. 10. Conclusion Based on nosological descriptions of autopsy-confirmed cases, a variety of clinical phenotypes of PSP have been identified. They differ not only in their initial clinical presentation, but also in their subsequent clinical course and disease duration. Classification into phenotypes may raise awareness of the diversity of potential clinical presentations of PSP and thereby increase the sensitivity of the clinical diagnosis. However, the co-existence of two or more phenotypes in one patient [9], and the non-specificity of clinical syndromes with respect to the underlying pathology still pose a diagnostic dilemma. To increase diagnostic accuracy in the atypical variants of PSP, it will be important to delineate predominant clinical signs and symptoms sensitive and specific for an underlying PSP pathology. Tau-PET imaging very likely will become a useful tool to predict post-mortem diagnosis in the near future [30]. A neuropathologically validated prospective cohort study in patients with very early disease stages will help to determine early clinical markers predictive for a definite diagnosis of PSP. Conflict of interest None. References [1] U. Nath, Y. Ben-Shlomo, R. Thomson, H.R. Morris, N.W. Wood, A.J. Lees, D.J. Burn, The prevalence of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) in the UK, Brain 124 (2001) 1438e1449. [2] J.C. Richardson, J.C. Steele, J. Olszewski, Supranuclear ophthalmoplegia, pseudobulbar palsy, nuchal dystonia and dementia, Trans. Am. Neurol. Assoc. 8 (1963) 25e29. [3] D.R. Williams, R. de Silva, D.C. Paviour, A. Pittman, H.C. Watt, L. Kilford, J.L. Holton, T. Revesz, A.J. Lees, Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism, Brain 128 (2005) 1247e1258. [4] I. Litvan, Y. Agid, D. Calne, G. Campbell, B. Dubois, R.C. Duvoisinet, C.G. Goetz, L.I. Golbe, J. Grafman, J.H. Growdon, M. Hallet, J. Jankovic, N.P. Quinn, E. Tolosa, D.S. Zee, Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop, Neurology 47 (1996) 1e9. [5] J.C. Steele, J.C. Richardson, J. Olszewski, Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia, Arch. Neurol. 10 (1964) 333e359. [6] F. Dubas, F. Gray, R. Escourolle, Steele-Richardson-Olszewski disease without ophthalmoplegia. 6 clinico-anatomic cases, Rev. Neurol. Paris 139 (1983) 407e416.
3
[7] P.J. Davis, C. Bergeron, D.R. McLachlan, Atypical presentation of progressive supranuclear palsy, Ann. Neurol. 17 (1985) 337e343. [8] D.R. Williams, A.J. Lees, Progressive supranuclear palsy: clinico-pathological concepts and diagnostic challenges, Lancet Neurol. 8 (2009) 270e279. [9] G. Respondek, M. Stamelou, C. Kurz, L.W. Ferguson, A. Rajput, W.Z. Chiu, J.C. van Swieten, C. Troakes, S. Al Sarraj, E. Gelpi, C. Gaig, E. Tolosa, W.H. Oertel, €glinger, Movement A. Giese, S. Roeber, T. Arzberger, S. Wagenpfeil, G.U. Ho Disorder Society-endorsed PSP Study Group, the phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases, Mov. Disord. 29 (2014) 1758e1766. [10] I. Litvan, C.A. Mangone, A. McKee, M. Verny, A. Parsa, K. Jellinger, L. D'Olhaberriague, K. Ray Chaudhuri, R.K.B. Pearce, Natural history of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) and clinical predictors of survival: a study, J. Neurol. Neurosurg. Psychiatry 60 (1996) 615e620. [11] Y. Yatabe, M. Hashimoto, K. Kaneda, K. Honda, Y. Ogawa, S. Yuuki, S. Matsuzaki, A. Tuyuguchi, H. Kashiwagi, M. Ikeda, Neuropsychiatric symptoms of progressive supranuclear palsy in a dementia clinic, Psychogeriatrics 11 (2011) 54e59. [12] L. Donker Kaat, A.J. Boon, W. Kamphorst, R. Ravid, H.J. Duivenvoorden, J.C. van Swieten, Frontal presentation in progressive supranuclear palsy, Neurology 69 (2007) 723e729. [13] D.R. Williams, A.J. Lees, What features improve the accuracy of the clinical diagnosis of progressive supranuclear palsydparkinsonism (PSP e P)? Mov. Disord. 25 (2010) 357e362. [14] S.A. Factor, D.S. Higgins, J. Qian, Primary progressive freezing gait: a syndrome with many causes, Neurology 66 (2006) 411e414. [15] D.R. Williams, J.L. Holton, K. Strand, T. Revesz, A.J. Lees, Pure akinesia with gait freezing: a third clinical phenotype of progressive supranuclear palsy, Mov. Disord. 22 (2007) 2235e2241. [16] M.F. Facheris, S. Maniak, F. Scaravilli, B. Schüle, C. Klein, P.P. Pramstaller, Pure akinesia as initial presentation of PSP: a clinico-pathological study, Park. Relat. Disord. 14 (2008) 517e519. [17] M.J. Armstrong, I. Litvan, A.E. Lang, T.H. Bak, K.P. Bhatia, B. Borroni, A.L. Boxer, D.W. Dickson, M. Grossman, M. Hallett, K.A. Josephs, A. Kertesz, S.E. Lee, €ster, M. Vidailhet, B.L. Miller, S.G. Reich, D.E. Riley, E. Tolosa, A.I. Tro W.J. Weiner, Criteria for the diagnosis of corticobasal degeneration, Neurology 29 (2013) 496e503. [18] Y. Tsuboi, K.A. Josephs, B.F. Boeve, I. Litvan, R.J. Caselli, J.N. Caviness, R.J. Uitti, A.D. Bott, D.W. Dickson, Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome, Mov. Disord. 20 (2005) 982e988. [19] T. Scaravilli, E. Tolosa, I. Ferrer, Progressive supranuclear palsy and corticobasal degeneration: lumping versus splitting, Mov. Disord. 20 (2005) 21e28. [20] K.A. Josephs, B.F. Boeve, J.R. Duffy, G.E. Smith, D.S. Knopman, J.E. Parisi, R.C. Petersen, D.W. Dickson, Atypical progressive supranuclear palsy underlying progressive apraxia of speech and nonfluent aphasia, Neurocase Neural Basis Cogn. 11 (2005) (2005) 283e296. [21] K.A. Josephs, J.R. Duffy, Apraxia of speech and nonfluent aphasia: a new clinical marker for corticobasal degeneration and progressive supranuclear palsy, Curr. Opin. Neurol. 21 (2008) 688e692. [22] A. Hassan, J.E. Parisi, K.A. Josephs, Autopsy-proven progressive supranuclear palsy presenting as behavioral variant frontotemporal dementia, Neurocase Neural Basis Cogn. 18 (2013) 478e488. [23] K.A. Josephs, R.C. Petersen, D.S. Knopman, B.F. Boeve, J.L. Whitwell, J.R. Duffy, J.E. Parisi, D.W. Dickson, Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP, Neurology 66 (2006) 41e48. [24] M. Kanazawa, M. Tada, O. Onodera, H. Takahashi, M. Nishizawa, T. Shimohata, Early clinical features of patients with progressive supranuclear palsy with predominant cerebellar ataxia, Park. Relat. Disord. 19 (2013) 1149e1151. [25] Y. Iwasaki, K. Mori, M. Ito, S. Tatsumi, M. Mimuro, M. Yoshida, An autopsied case of progressive supranuclear palsy presenting with cerebellar ataxia and severe cerebellar involvement, Neuropathology 33 (2013) 561e567. [26] K.A. Josephs, O. Katsuse, D.A. Beccano-Kelly, W.L. Lin, R.J. Uitti, Y. Fujino, B.F. Boeve, M.L. Hutton, M.C. Baker, D.W. Dickson, Atypical progressive supranuclear palsy with palsy with corticospinal tract degeneration, J. Neuropathol. Exp. Neurol. 65 (2006) 396e405. , I. Holmerov € bel, [27] R. Rusina, G.G. Kovacs, J. Fiala, J. Hort, P. Ridzon a, T. Stro j, FTLD-TDP with motor neuron disease, visuospatial impairment and a R. Mate progressive supranuclear palsy-like syndrome: broadening the clinical phenotype of TDP-43 proteinopathies. A report of three cases, BMC Neurol. 11 (2011) 50. [28] J.C. Steele, Parkinsonismedementia complex of Guam, Mov. Disord. 20 (2005) 99e107. [29] S. Nagao, O. Yokota, R. Nanba, H. Takata, T. Haraguchi, H. Ishizu, C. Ikeda, N. Takeda, E. Oshima, K. Sakane, S. Terada, Y. Ihara, Y. Uchitomi, Progressive supranuclear palsy presenting as primary lateral sclerosis but lacking, gaze palsy, aphasia, or dementia, J. Neurol. Sci. 323 (2012) 1e2. [30] V. Kepe, Y. Bordelon, A. Boxer, S.C. Huang, J. Liu, F.C. Thiede, J.C. Mazziotta, M.F. Mendez, N. Donoghue, G.W. Small, J.R. Barrio, PET imaging of neuropathology in tauopathies: progressive supranuclear palsy, J. Alzheimers Dis. 36 (2013) 145e153.
€glinger, The phenotypic spectrum of progressive supranuclear palsy, Parkinsonism and Please cite this article in press as: G. Respondek, G.U. Ho Related Disorders (2015), http://dx.doi.org/10.1016/j.parkreldis.2015.09.041
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
The phenotypic spectrum of progressive supranuclear palsy € glinger a, b, * G. Respondek a, b, G.U. Ho a b
Department of Neurology, Klinikum Rechts der Isar, Technical University, Ismaninger Strasse 22, D-81675, Munich, Germany Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE], Site Munich, Feodor-Lynen Str. 17, D-81677, Munich, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 September 2015 Accepted 19 September 2015
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. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Phenotypes Progressive supranuclear palsy PSP Tauopathy
1. Introduction Progressive supranuclear palsy [PSP] is a sporadic, adult-onset tauopathy with an estimated prevalence of approximately 6.5 per 100.000 [1]. A seminal description of eight cases with PSP by J.C. Richardson, J.C. Steele, and J. Olszewski in 1963 has delineated a clinical syndrome comprising a combination of early postural instability, vertical supranuclear gaze palsy, slow and hypometric saccades, frontotemporal dysfunction, levodopa-resistant bradykinesia and axial rigidity [2], which is now termed PSP-Richardson's syndrome (PSP-RS) [3]. PSP is a neuropathologically defined disease entity. While characteristic pathological features, such as cerebral filamentous tau inclusions in neurons and glia, define the disease entity called “definite PSP” [4], early postural instability with falls in combination with supranuclear vertical gaze palsy are mandatory for a clinical diagnosis of “probable PSP”, and early postural instability with falls with saccadic abnormalities or supranuclear gaze palsy alone qualify for a diagnosis of “possible PSP” (NINDS-SPSP criteria) [4]. Steele and colleagues postulated that the clinical spectrum of PSP would grow over time [5]. This prediction has proven correct, as reports on atypical clinical presentations of PSP are constantly increasing. Symptoms considered atypical for PSP were described as early as the 1980's [6,7]. More recently, definitions of PSP subgroups, termed PSP-phenotypes, have been * Corresponding author. Dept. of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen Str. 17, D81677, Munich, Germany. €glinger). E-mail address: [email protected] (G.U. Ho
proposed [3]. There is ongoing debate whether these phenotypes represent separate entities, since clinical syndromes may overlap and may progress into PSP-RS at later disease stages [8,9]. However, different modes of initial presentation seem to predict different patterns of disease progression and survival time [3,8,9]. Current operational criteria for the clinical diagnosis of PSP do not capture these atypical presentations [9]. The need for a sensitive diagnosis will become even more vital with the emergence of diseasemodifying therapies. Hence, it is important to highlight consistent clinical syndromes that correlate with PSP-pathology. Here, we will review the different modes of (initial) clinical presentation of PSP that have been described in the literature. 2. PSP with Richardson's syndrome (PSP-RS) The clinical picture of PSP with Richardson's syndrome (PSP-RS) was initially described in 1963 by Richardson, Steele, and Olszewski [2]. PSP-RS is the most thoroughly studied phenotype of PSP and is highly predictive for an underlying PSP pathology [4,9]. It is characterized by vertical supranuclear gaze palsy, severe postural instability with early falls, pseudobulbar palsy, axial rigidity, symmetric and levodopa-resistant akinesia and cognitive dysfunction [2,10]. Vertical supranuclear gaze palsy is defined as a limitation of gaze in the vertical plane, which can be overcome by the vestibuloocular reflex. It is preceded by slowing of vertical saccades [4]. Other non-specific ocular signs, such as diplopia, photophobia, and eyelid apraxia, may appear early in the course of PSP-RS [3]. Postural instability with falls is the most frequent initial symptom of PSP-RS; it occurs in the majority of patients during the first year
http://dx.doi.org/10.1016/j.parkreldis.2015.09.041 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
€glinger, The phenotypic spectrum of progressive supranuclear palsy, Parkinsonism and Please cite this article in press as: G. Respondek, G.U. Ho Related Disorders (2015), http://dx.doi.org/10.1016/j.parkreldis.2015.09.041
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€glinger / Parkinsonism and Related Disorders xxx (2015) 1e3 G. Respondek, G.U. Ho
of the disease [10]. Pseudobulbar features of PSP-RS include dysphagia and dysarthria, which are supportive features in the diagnosis of PSP [2,4,5]. Progressive dysphagia may cause aspiration pneumonia, which is the most common cause of death in PSPRS [10]. Akinesia and rigidity typically are symmetric, with axial predominance, and respond poorly to levodopa therapy [10]. Tremor is rarely evident [10]. There is a typical array of cognitive impairments in PSP-RS. Frontal dysfunction, particularly in the form of behavioral and personality changes, is consistently seen in PSP-RS and may appear early in the clinical course [9e12]. Apathy seems to be more frequent than disinhibition [11]. Executive deficits, reduced verbal fluency and a positive applause sign also are common frontal features of PSP-RS [11,12]. The disease course in patients with PSP-RS is rapidly progressive, with death occurring after a median duration of 6e8 years [9,10]. Cases with early postural instability and falls, but without oculomotor deficits e at least during the first years of disease e have been described [6,9]. In contrast, some patients develop supranuclear gaze palsy very early, while postural instability and falls occur late or remain absent [9]. Whether these variants represent separate entities in terms of etiopathology remains to be studied. With regard to disease duration, these two variants do not substantially differ from PSP-RS [9]. 3. PSP with predominant parkinsonism (PSP-P) In 2005, an analysis of 103 definite PSP cases identified a PSP phenotype distinct from PSP-RS, namely PSP with parkinsonism (PSP-P) [3]. Bradykinesia and extrapyramidal rigidity with asymmetric distribution and response to levodopa dominate the early clinical course. Tremor is frequently reported, while falls and eye movement abnormalities develop later or never occur [3,9,13]. Cognitive dysfunction rarely is present at the beginning [3,9,13]. These features constitute a syndrome that may be indistinguishable from Parkinson's disease (PD) during the first years of illness. However, in some patients with PSP-P, the early occurrence of dysphagia and dysarthria, as well as subtle eye symptoms (e.g., blurred vision, diplopia, eyelid apraxia) may hint toward a diagnosis of PSP rather than PD [13]. PSP-P has a more benign disease course and longer survival compared with PSP-RS. A median disease duration of approximately 9e12 years is reported [3,9]. 4. PSP with pure akinesia with gait freezing (PSP-PAGF) Pure akinesia with gait freezing (PAGF), also known as primary progressive freezing of gait (PPFG), is a syndrome with prominent, levodopa-resistant gait freezing, occasionally accompanied by akinesia, and the rapid development of both hypophonia and micrographia [14,15]. PAGF may be a manifestation of various neurodegenerative diseases. 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]. Disease duration of more than 13 years seems to be common in patients with PSP-PAGF [14,15]. 5. PSP with corticobasal syndrome (PSP-CBS) Corticobasal syndrome (CBS) is characterized by a combination of cortical and basal ganglia dysfunction, which usually is asymmetric and includes: levodopa-resistant rigidity and akinesia, ideomotor apraxia, limb dystonia, reflex myoclonus, alien limb phenomena, cortical sensory loss, postural instability, and frontal
lobe dysfunction [17]. The term CBS initially was used interchangeably with corticobasal degeneration (CBD), a tauopathy with neuropathological features distinct from PSP [17]. Subsequently, CBS has been associated with a variety of other pathologies, including PSP, Alzheimer's disease (AD), Pick's disease (PiD), and Creutzfeldt-Jakob Disease (CJD) [18]. According to published clinico-pathological studies, the lack of clinical and imaging findings specific for one or the other pathology makes an accurate in vivo diagnosis impossible [19]. “Key features” of PSP, such as postural instability and vertical gaze palsy, also may develop later in the clinical course of CBD-CBS [19]. The median disease duration of PSP-CBS is similar to that of PSP-RS [9]. 6. PSP with predominant speech and/or language dysfunction (PSP-AOS and PSP-PNFA) Autopsy-proven PSP has been associated with syndromes characterized by language or speech dysfunction, namely progressive non-fluent aphasia (PNFA) and apraxia of speech (AOS). AOS is a motor speech disorder with slow and effortful speech, dysprosody, and buccofacial apraxia [20,21]. PNFA is characterized by non-fluent spontaneous speech with hesitancy, agrammatism and phonemic errors with preserved understanding of word meaning [20,21]. AOS may present simultaneously with PNFA [20,21]. PNFA is not closely associated with any single pathological diagnosis; it has been linked to frontotemporal lobar degeneration (FTLD) with TDP pathology, PSP, CBD, and PiD [20]. Likewise, AOS has been associated with various neurodegenerative diseases [20]. Still, AOS seems to be more predictive for PSP pathology than pure PNFA, and autopsy-confirmed PSP cases presenting with PNFA without AOS are rarely reported [21]. In the majority of cases, typical features of PSP, such as postural instability, falls, supranuclear vertical gaze palsy, behavioral changes, and akinetic, develop later [20,21]. 7. PSP with predominant frontotemporal dysfunction (PSPFTD) Frontotemporal dementia is a common feature of PSP-RS [9e11]. However, PSP also has been associated with a predominant frontotemporal dysfunction (PSP-FTD) [9,12,22]. The relative prevalence of PSP-FTD among autopsy-confirmed PSP patients has been reported as 5e20% [9,12,22]. A clinical picture of behavioral changes and cognitive dysfunction dominates and resembles that of the behavioral variant of frontotemporal dementia (bvFTD) [23]. The most frequent coexisting symptoms at initial presentation are falls, bradykinesia, and tremor [12]. Classical symptoms of PSP appear as the disease progresses [9,12,22]. The median survival time of patients with PSP-FTD is approximately 8 years [11,12,22], similar to that of PSP-RS. 8. PSP with cerebellar ataxia (PSP-C) Rare cases with autopsy-confirmed PSP and a predominantly cerebellar presentation (PSP-C) have been described [24,25]. Cerebellar features in PSP may be more common in Japan than in other populations [24] and include limb and gait ataxia [24,25]. All reported cases developed parkinsonism, supranuclear gaze palsy and postural instability later in the course of the disease. A comparative study of pathologically confirmed cases of PSP-C and the cerebellar variant of multiple system atrophy (MSA-C) found an older age at onset and a higher frequency of falls and gaze palsy in PSP-C [24]. Dysautonomia was absent in all cases with PSP-C [24]. The median disease duration in PSP-C is 7 years [24].
€glinger, The phenotypic spectrum of progressive supranuclear palsy, Parkinsonism and Please cite this article in press as: G. Respondek, G.U. Ho Related Disorders (2015), http://dx.doi.org/10.1016/j.parkreldis.2015.09.041
€glinger / Parkinsonism and Related Disorders xxx (2015) 1e3 G. Respondek, G.U. Ho
9. PSP with primary lateral sclerosis (PSP-PLS) Primary lateral sclerosis (PLS) is characterized by features of upper motor neuron dysfunction, including bulbar symptoms of dysarthria and dysphagia, weakness, spasticity, hyperactive reflexes, and Babinski signs [26]. In tau-negative FTD, a syndrome comprising motor neuron dysfunction combined with behavioral and cognitive changes, sometimes accompanied by supranuclear gaze palsy, is well-established [27]. Motor neuron disease, parkinsonism and dementia are hallmark features of a rare tauopathy called amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) [28]. However, in autopsy-confirmed PSP, PLS is rarely reported (PSP-PLS) [26,29]. In some cases of PSP-PLS, parkinsonism, postural instability and falls, supranuclear gaze palsy and cognitive deficits coexisted [26]. In others, the key features of PSP were absent throughout the course [29]. Limb apraxia also has been noted in several cases [26]. Disease duration is variable and ranged between 3 and 12 years in the reported patients [26,29]. 10. Conclusion Based on nosological descriptions of autopsy-confirmed cases, a variety of clinical phenotypes of PSP have been identified. They differ not only in their initial clinical presentation, but also in their subsequent clinical course and disease duration. Classification into phenotypes may raise awareness of the diversity of potential clinical presentations of PSP and thereby increase the sensitivity of the clinical diagnosis. However, the co-existence of two or more phenotypes in one patient [9], and the non-specificity of clinical syndromes with respect to the underlying pathology still pose a diagnostic dilemma. To increase diagnostic accuracy in the atypical variants of PSP, it will be important to delineate predominant clinical signs and symptoms sensitive and specific for an underlying PSP pathology. Tau-PET imaging very likely will become a useful tool to predict post-mortem diagnosis in the near future [30]. A neuropathologically validated prospective cohort study in patients with very early disease stages will help to determine early clinical markers predictive for a definite diagnosis of PSP. Conflict of interest None. References [1] U. Nath, Y. Ben-Shlomo, R. Thomson, H.R. Morris, N.W. Wood, A.J. Lees, D.J. Burn, The prevalence of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) in the UK, Brain 124 (2001) 1438e1449. [2] J.C. Richardson, J.C. Steele, J. Olszewski, Supranuclear ophthalmoplegia, pseudobulbar palsy, nuchal dystonia and dementia, Trans. Am. Neurol. Assoc. 8 (1963) 25e29. [3] D.R. Williams, R. de Silva, D.C. Paviour, A. Pittman, H.C. Watt, L. Kilford, J.L. Holton, T. Revesz, A.J. Lees, Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism, Brain 128 (2005) 1247e1258. [4] I. Litvan, Y. Agid, D. Calne, G. Campbell, B. Dubois, R.C. Duvoisinet, C.G. Goetz, L.I. Golbe, J. Grafman, J.H. Growdon, M. Hallet, J. Jankovic, N.P. Quinn, E. Tolosa, D.S. Zee, Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop, Neurology 47 (1996) 1e9. [5] J.C. Steele, J.C. Richardson, J. Olszewski, Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia, Arch. Neurol. 10 (1964) 333e359. [6] F. Dubas, F. Gray, R. Escourolle, Steele-Richardson-Olszewski disease without ophthalmoplegia. 6 clinico-anatomic cases, Rev. Neurol. Paris 139 (1983) 407e416.
3
[7] P.J. Davis, C. Bergeron, D.R. McLachlan, Atypical presentation of progressive supranuclear palsy, Ann. Neurol. 17 (1985) 337e343. [8] D.R. Williams, A.J. Lees, Progressive supranuclear palsy: clinico-pathological concepts and diagnostic challenges, Lancet Neurol. 8 (2009) 270e279. [9] G. Respondek, M. Stamelou, C. Kurz, L.W. Ferguson, A. Rajput, W.Z. Chiu, J.C. van Swieten, C. Troakes, S. Al Sarraj, E. Gelpi, C. Gaig, E. Tolosa, W.H. Oertel, €glinger, Movement A. Giese, S. Roeber, T. Arzberger, S. Wagenpfeil, G.U. Ho Disorder Society-endorsed PSP Study Group, the phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases, Mov. Disord. 29 (2014) 1758e1766. [10] I. Litvan, C.A. Mangone, A. McKee, M. Verny, A. Parsa, K. Jellinger, L. D'Olhaberriague, K. Ray Chaudhuri, R.K.B. Pearce, Natural history of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) and clinical predictors of survival: a study, J. Neurol. Neurosurg. Psychiatry 60 (1996) 615e620. [11] Y. Yatabe, M. Hashimoto, K. Kaneda, K. Honda, Y. Ogawa, S. Yuuki, S. Matsuzaki, A. Tuyuguchi, H. Kashiwagi, M. Ikeda, Neuropsychiatric symptoms of progressive supranuclear palsy in a dementia clinic, Psychogeriatrics 11 (2011) 54e59. [12] L. Donker Kaat, A.J. Boon, W. Kamphorst, R. Ravid, H.J. Duivenvoorden, J.C. van Swieten, Frontal presentation in progressive supranuclear palsy, Neurology 69 (2007) 723e729. [13] D.R. Williams, A.J. Lees, What features improve the accuracy of the clinical diagnosis of progressive supranuclear palsydparkinsonism (PSP e P)? Mov. Disord. 25 (2010) 357e362. [14] S.A. Factor, D.S. Higgins, J. Qian, Primary progressive freezing gait: a syndrome with many causes, Neurology 66 (2006) 411e414. [15] D.R. Williams, J.L. Holton, K. Strand, T. Revesz, A.J. Lees, Pure akinesia with gait freezing: a third clinical phenotype of progressive supranuclear palsy, Mov. Disord. 22 (2007) 2235e2241. [16] M.F. Facheris, S. Maniak, F. Scaravilli, B. Schüle, C. Klein, P.P. Pramstaller, Pure akinesia as initial presentation of PSP: a clinico-pathological study, Park. Relat. Disord. 14 (2008) 517e519. [17] M.J. Armstrong, I. Litvan, A.E. Lang, T.H. Bak, K.P. Bhatia, B. Borroni, A.L. Boxer, D.W. Dickson, M. Grossman, M. Hallett, K.A. Josephs, A. Kertesz, S.E. Lee, €ster, M. Vidailhet, B.L. Miller, S.G. Reich, D.E. Riley, E. Tolosa, A.I. Tro W.J. Weiner, Criteria for the diagnosis of corticobasal degeneration, Neurology 29 (2013) 496e503. [18] Y. Tsuboi, K.A. Josephs, B.F. Boeve, I. Litvan, R.J. Caselli, J.N. Caviness, R.J. Uitti, A.D. Bott, D.W. Dickson, Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome, Mov. Disord. 20 (2005) 982e988. [19] T. Scaravilli, E. Tolosa, I. Ferrer, Progressive supranuclear palsy and corticobasal degeneration: lumping versus splitting, Mov. Disord. 20 (2005) 21e28. [20] K.A. Josephs, B.F. Boeve, J.R. Duffy, G.E. Smith, D.S. Knopman, J.E. Parisi, R.C. Petersen, D.W. Dickson, Atypical progressive supranuclear palsy underlying progressive apraxia of speech and nonfluent aphasia, Neurocase Neural Basis Cogn. 11 (2005) (2005) 283e296. [21] K.A. Josephs, J.R. Duffy, Apraxia of speech and nonfluent aphasia: a new clinical marker for corticobasal degeneration and progressive supranuclear palsy, Curr. Opin. Neurol. 21 (2008) 688e692. [22] A. Hassan, J.E. Parisi, K.A. Josephs, Autopsy-proven progressive supranuclear palsy presenting as behavioral variant frontotemporal dementia, Neurocase Neural Basis Cogn. 18 (2013) 478e488. [23] K.A. Josephs, R.C. Petersen, D.S. Knopman, B.F. Boeve, J.L. Whitwell, J.R. Duffy, J.E. Parisi, D.W. Dickson, Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP, Neurology 66 (2006) 41e48. [24] M. Kanazawa, M. Tada, O. Onodera, H. Takahashi, M. Nishizawa, T. Shimohata, Early clinical features of patients with progressive supranuclear palsy with predominant cerebellar ataxia, Park. Relat. Disord. 19 (2013) 1149e1151. [25] Y. Iwasaki, K. Mori, M. Ito, S. Tatsumi, M. Mimuro, M. Yoshida, An autopsied case of progressive supranuclear palsy presenting with cerebellar ataxia and severe cerebellar involvement, Neuropathology 33 (2013) 561e567. [26] K.A. Josephs, O. Katsuse, D.A. Beccano-Kelly, W.L. Lin, R.J. Uitti, Y. Fujino, B.F. Boeve, M.L. Hutton, M.C. Baker, D.W. Dickson, Atypical progressive supranuclear palsy with palsy with corticospinal tract degeneration, J. Neuropathol. Exp. Neurol. 65 (2006) 396e405. , I. Holmerov € bel, [27] R. Rusina, G.G. Kovacs, J. Fiala, J. Hort, P. Ridzon a, T. Stro j, FTLD-TDP with motor neuron disease, visuospatial impairment and a R. Mate progressive supranuclear palsy-like syndrome: broadening the clinical phenotype of TDP-43 proteinopathies. A report of three cases, BMC Neurol. 11 (2011) 50. [28] J.C. Steele, Parkinsonismedementia complex of Guam, Mov. Disord. 20 (2005) 99e107. [29] S. Nagao, O. Yokota, R. Nanba, H. Takata, T. Haraguchi, H. Ishizu, C. Ikeda, N. Takeda, E. Oshima, K. Sakane, S. Terada, Y. Ihara, Y. Uchitomi, Progressive supranuclear palsy presenting as primary lateral sclerosis but lacking, gaze palsy, aphasia, or dementia, J. Neurol. Sci. 323 (2012) 1e2. [30] V. Kepe, Y. Bordelon, A. Boxer, S.C. Huang, J. Liu, F.C. Thiede, J.C. Mazziotta, M.F. Mendez, N. Donoghue, G.W. Small, J.R. Barrio, PET imaging of neuropathology in tauopathies: progressive supranuclear palsy, J. Alzheimers Dis. 36 (2013) 145e153.
€glinger, The phenotypic spectrum of progressive supranuclear palsy, Parkinsonism and Please cite this article in press as: G. Respondek, G.U. Ho Related Disorders (2015), http://dx.doi.org/10.1016/j.parkreldis.2015.09.041