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Mini Review Corresponding author Harini Sarva, Department of Neurology, Maimonides Medical Center, 883 65th Street, Brooklyn, NY Progressive Supranuclear Palsy 11220, USA, Tel: 7182837470; Fax: 7186356082; Email: Cerebellar Variant Submitted: 26 May 2016 Accepted: 07 June 2016 Harini Sarva* Published: 10 June 2016 Department of Neurology, Maimonides Medical Center, USA ISSN: 2333-7087 Copyright Abstract © 2016 Sarva Progressive Supranuclear Palsy (PSP) is an atypical Parkinsonism noted for OPEN ACCESS postural instability, early falls, and a supranuclear vertical gaze palsy. However, since its original description, several variants were described. One of the rarer variants is Keywords PSP-C, further adding to the diverse clinical. As a result, misdiagnosis of PSP-C as • Progressive supranuclear palsy multiple system atrophy, or a spinocerebellar degeneration is not uncommon. Accurate • Cerebellar variant antemortem diagnosis would prove invaluable not only for prognostic implications but • Dentate nucleus also for development of potential treatments. • Superior cerebellar peduncle

ABBREVIATIONS early dysphagia and dysarthria, and early onset of cognitive impairment [4]. Since these criteria were developed, several PSP: Progressive Supranuclear Palsy; PSP-C: Progressive different variants were described: Richardson’s Syndrome Supranuclear Palsy-Cerebellar Variant; MSA: Multiple System Atrophy; RS: Richardson’s Syndrome; PSP-P: Progressive apathy, intellectual slowing); PSP-parkinsonism (asymmetric, Supranuclear Palsy-Parkinsonism indolent(symmetric Parkinson’s axial rigidity, disease supranuclear features with gaze a transient palsy, response retrocollis, to INTRODUCTION levodopa); PSP-pure akinesia with gait freezing (pronounced gait freezing but without , rigidity, dementia, or eye movement al., [1] is an atypical parkinsonism characterized by supranuclear Progressive supranuclear palsy, first described by Steele et vertical gaze palsy, dysphagia, dysarthria, balance problems, andabnormalities agrammatism); within PSP-Cthe first (prominent, five years); early PSP-progressive cerebellar signs); non- falls, and cognitive impairment [1,2]. Prevalence is estimated andfluent PSP-corticobasal aphasia (non-fluent syndrome speech, phonemic (progressive, errors, asymmetric hesitancy, by accumulation of tau protein and neuropil threads in the sensory loss, or severe bradykinesia unresponsive to levodopa) at 6-7 cases per 100000 [3]. Pathologically, PSP is defined subthalamic nucleus, red nucleus, pallidum, striatum, substantia [3].dyspraxia, However, alien these limb distinctions phenomena, are jerky not dystonia, well established; cortical nigra, pontine tegmentum, medulla, oculomotor nucleus, and thus, prevalence of these subtypes may vary considerably. A dentate nucleus [3]. The National Institute of Neurological Disorders and Stroke and the Society for Progressive cases demonstrated that 24% were classic RS and 76% were Supranuclear Palsy (NINDS-SPSP) [4] workshop proposed the atypicalmulticenter cases, autopsy suggesting study that of 100 the pathologicallyNINDS-SPSP criteria confirmed has PSPlow

PSP. Age of onset over the age of 40, gradual progression, and lack is quite rare and its frequency among several studies varies following diagnostic categories: possible, probable, and definite of other neurological disorders are required for all categories. considerablysensitivity but [2]. high In specificity this mini forreview, diagnosis the epidemiology, [5]. PSP-C specifically clinical Possible PSP requires downward or upward vertical gaze palsy features, and pathology of PSP-C are discussed. or both slow vertical saccades and prominent postural instability Clinical variability of PSP with falls in the first year of onset. Probable PSP requires vertical cerebellar features [1], several pathologically proven studies of gaze palsy and postural instability with falls within the first year. criteria included recent encephalitis, cortical phenomena (alien PSPSince assessed its first its clinical description, variability in which [6-10]. four A of study nine of cases 12 cases had Definite PSP requires histopathological confirmation. Exclusion hand syndrome), hallucinations or delusions unrelated to [6] demonstrated that postural instability and falls were present dopaminergic therapy, Alzheimer’s dementia, prominent and in all patients and were an early feature. Downgaze was early cerebellar features, severe asymmetric parkinsonism, not present in half during the early phase and at last neuro- prominent autonomic dysfunction, neuroradiologic evidence of basal ganglia or brainstem infarctions, and evidence of one.ophthalmological Symmetric features examination, of RS were two not patients found in never all and developed half had Supportive criteria included symmetric akinesia and rigidity asymmetricvertical gaze signs. palsy. Of Cerebellar note 8/12 type were limb correctly wasdiagnosed found inas onlyPSP Whipple’s disease confirmed by polymerase chain reaction. antemortem [6]. In another series of 16 cases, balance or gait affecting proximal more than distal musculature, retrocollis, Cite this article: Sarva H (2016) Progressive Supranuclear Palsy Cerebellar Variant. J Neurol Transl Neurosci 4(1): 1062. Sarva (2016) Email:

Central Bringing Excellence in Open Access less frequent in PSP-C. Three had mild autonomic symptoms, two with urinary incontinence and another with intermittent difficulty was the initial presentation in nine [7]. Only four were deathcorrectly [7]. identifiedOther eye asmovements PSP within apart three from years supranuclear of onset. One vertical case having frank supranuclear vertical gaze palsy and two with slow gazewas initially palsy should diagnosed alert with physicians a spinocerebellar to PSP: slowed ataxia downward prior to syncope. Eye movement abnormalities were also varied, with one had probable and three had possible PSP-C [2]. These inconsistent saccades. Two had normal eye movements of the five cases, one command saccades, failure to suppress the vestibular reflex, their validation as it is possible these patients did not have PSP-C. absent Bell’s phenomena, apraxia of eyelid opening, and square- results further support the need for consensus definitions and percentwave jerks had [7]. cerebellar In a study features of 103 [8]. cases, two major phenotypes of cerebellar features noted at other stages of disease. This is were demonstrated: 54% with RS and 32% with PSP-P [8], one They may have been misclassified as PSP-C due to the presence in 39% of PSP patients in one study [2]. In another study of 134 cerebellar variant after their study of 22 cases demonstrated suggested by the development of some degree of Kanazawa et al., [9] proposed the classification of a PSP cerebellar degeneration [10]. A subsequent Austrian study of three with cerebellar ataxia and pathologically pronounced speechpatients later [9], in three the ofdisease 15 PSP course cases of developed disease [9]. cerebellar Another ataxiastudy 30 cases (18 with RS and 12 with PSP-P) did not reveal early at the onset while four others developed ataxia of gait, limbs, or predominant cerebellar signs [11]. Two in the RS group (6.7%) also had cases with early development of cerebellar features developed cerebellar signs late in their course, however [10]. characteristic of PSP-C with others developing ataxia later in the having PSP-C. Thus, PSP-C is a rare clinical variant in the United In an effort to better classify PSP, The Natural History An American study [2] of 1085 cases identified five patients as course (inconsistent with PSP-C criteria) [15]. States with a frequency of about 1%, similar to other Western and Neuro protection in Parkinson Plus Syndromes (NNIPPS) countries and less compared with Japan [2,12]. It is possible study developed antemortem diagnostic criteria, which had a that the underreporting of PSP-C may be due to the masking of cerebellar features by the severe akinesia and rigidity that eventually develop [13]. It is also possible that other features may havingvery high supranuclear sensitivity ophthalmoplegiaand specificity when and posturalcompared instability with their or pathological diagnoses [16,17]. These criteria define PSP as due to a sensory neuropathy. It is not uncommon in patients they improved antemortem diagnosis in their study of over be mistaken for ataxia such as apraxia, dystonia, or instability with neurodegenerative disease to have other comorbidities 600falls patients,developing cerebellar within the features first three could years not beof disease.reliably assessed.Although such as cerebrovascular disease or peripheral neuropathy which These criteria are however still not commonly used in clinical or research practice but are under further review [16,17]. may lead to ataxic symptoms and possible over-reporting of Pathological and imaging evidence of cerebellar pathology ataxia [2].Although these pathological studies provide us with Kanazawa et al., noted a high number of tau-positive an opportunity to study confirmed cases of PSP, they are quite limited. They rely on retrospective descriptions of clinical findings and many did not have video confirmation of the examinations, [11].inclusion A subsequent bodies inpathological Purkinje report cells in of a those 69 year-old with cerebellarman with themselvesrelying heavily to selection on the examiner’s bias, as the written most atypicaldescriptions. cases Also, are often they involvement compared with those without cerebellar ataxia, rely on brain banks from major academic centers which lend brainstem, and cerebellum [18]. Cerebellar atrophy was most notedataxic in gait the demonstrated white matter and atrophy dentate of thenucleus. frontotemporal Microscopically, lobe, included [2,5]. Though adding to our understanding of PSP, they describeDiagnosis various of PSP-C subtypes without consensus definitions. basal ganglia, brainstem, and inferior olivary nucleus, and PSP-C commonly occurs in older men with an average cerebellarneurofibrillary dentate tangles nucleus. were prominent The dentate in the nucleus cerebral also cortex, had severe gliosis. Superior cerebellar peduncles were atrophic, occur. Falls and supranuclear gaze palsy appear within two years duration of six years. Initially gait impairment and truncal ataxia positive inclusions. Olivopontocerebellar degeneration (OPCA) particularly on the right side. Purkinjee cells contained tau- of onsetFormal and diagnostic there is no criteria significant of PSP-C dysautonomia based on clinical [12]. features was greater than other known, typical PSP cases but less than in other causes of OPCA [18]. Diffuse cytoplasmic, phospho-tau in four pathologically proven cases [14] include the following: immunoreactivity, tau-positive thread-like processes, and coiled A)which slowly developed progressive in the course;first two B) years age of greater disease than and MRI40 years; findings C) bodies or oligodendroglial tau-positive inclusions were present in the cerebellar dentate nucleus or cerebellar white matter in the PSP-C cases from the Mayo Clinic patient series [2]. Despite supranuclear gaze palsy; D) truncal and limb ataxia developing the presence of cerebellar pathology in these cases, a direct includewithin two profound years ofdysautonomia symptom onset; and hotand cross E) postural bun sign instability on MRI. relationship between cerebellar degeneration and clinical signs Probablewith falls within PSP-C two requires years allof symptom of the above onset. inclusionExclusion criteria.criteria could not be established [2,11]. In one series, 99 cases of PSP had similar tau-positive inclusions in the dentate nucleus as those diagnosing antemortem PSP-C requires cerebellar features to be Possible PSP-C requires A+B+D+E [14]. Thus, adequately PSP patients had cytoplasmic phosphor-tau immunoreactivity all of the PSP-C cases in the American series met all the required found in the PSP-C cases. Three of five with PSP-C and 61 of 97 predominant within the first two years of onset. However, not cells was not different between the two groups. There were but without obvious NFT formation. Linear density of Purkinje diagnostic criteria [2]. Early falls and vertical gaze palsy were J Neurol Transl Neurosci 4(1): 1062 (2016) 2/4 Sarva (2016) Email:

Central Bringing Excellence in Open Access cerebellar afferent system, cerebellum, and basal ganglia. Thus, cortical predominance) had shorter disease duration than RS and no significant differences in the burden of tau pathology in the et al., noted that those with the unclassified PSP (cerebellar and severity of cerebellar pathology was found [2], particularly when no correlation between the frequency of cerebellar ataxia and the 13-24PSP-P [11].months, Interestingly, after which cerebellar typical PSP ataxia features may developedbe self-limited [13]. as four of 28 probable PSP patients had ataxia which lasted from developmentthe definition of PSP-C PSP-C is as so opposed variable. to Thus, the further pathological study changesinto the DISCUSSION & CONCLUSION seenexact in pathological PSP in general changes such as which involvement specifically of cerebellar contribute dentate to the PSP-C is a rare variant of PSP, which may be more prominent nucleus, is required. Its involvement across all subtypes suggests in Japan. It further adds to the phenotypic variability of PSP that it is not a reliable causative marker for PSP-C and is likely a and misdiagnosis can occur. Older age of onset, shorter disease result of PSP being a multi-network disease.

Radiologic characteristics were studied in a single case of a duration and prominent early cerebellar findings within the first 72 year-old Japanese man with PSP-C who had serial MRI’s [19]. thetwo developmentyears are hallmarks. of the disease.Pathological Treatment and radiographic remains similar findings, to Initial MRI was unremarkable but a MRI performed two years though demonstrating cerebellar pathology, do not fully explain later showed dilatation of the pontocerebellar cistern and atrophy other forms and is limited. Larger studies are required to assess of the superior cerebellar peduncles. A third MRI performed the true prevalence of this condition as well as appropriate four years after symptom onset showed increased dilatation treatment options. of the pontocerebellar cistern, proportional but smallpons REFERENCES and cerebellum with fourth ventricular dilatation, and rostral midbrain atrophy. Quantitative analysis demonstrated that the 1. Steele JC, Richardson JC, Olszewski J. Progressive Supranuclear Palsy. A Heterogeneous Degeneration Involving the Brain Stem, Basal dilated pontocerebellar cistern occupied more of the posterior Ganglia and Cerebellum with Vertical Gaze and Pseudobulbar Palsy,

(20% of posterior fossa); and third (29.9% of posterior fossa). Althoughfossa space the with cistern each MRI: was first enlarged (12.6% the of posterior cerebellar fossa); hemispheric second 2. NuchalKoga S, DystoniaJosephs KA,and Ogaki Dementia. K, Labb Arché C, Neurol. Uitti RJ, 1964; Graff-Radford 10: 333-359. N, et al. the enlarged pontocerebellar cistern along with the relatively Cerebellar ataxia in progressive supranuclear palsy: An autopsy study smallfissures pons were and not cerebellum progressively to be enlarged. a characteristic The authors MRI feature postulated [19]. 3. ofBarsottini PSP-C. Mov OG, Disord. Felício 2016; AC, 31: Aquino 653-662. CC, Pedroso JL. Progressive supranuclear palsy: new concepts. Arq Neuropsiquiatr. 2010; 68: 938-946. years of disease, when the proposed diagnostic criteria require cerebellarThus, this may features be helpful to be as present. changes However, were noted this in radiographicthe first two 4. Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of progressive supranuclear with minimal or no cerebellar features also have alterations palsy (Steel-Richardson-Olszewski syndrome): Report of the NINDS- SPSP International Workshop. Neurology. 1996; 47: 1-9. offinding the does superior not directly cerebellar explain peduncle, the cerebellar the primary signs as cerebellar patients radiological studies using standard FLAIR MRI sequences [20], et al. The phenotypic spectrum of progressive supranuclear palsy: a outflow tracts, and the cerebellar dentate nucleus as shown in 5. Respondek G, Stamelou M, Kurz C, Ferguson LW, Rajput A, Chiu WZ,

retrospective multicenter study of 100 definite cases. Mov Disord. higherdiffusion spatial tensor resolution) imaging studies[22] as [21],well as and transcranial RESOLVE (Readoutmagnetic 6. 2014; 29: 1758-1766. stimulationSegmentation [23] of suggesting Long Variable impaired Echo-Trains cerebellar inhibition which provides in PSP. Supranuclear Palsy: neuropathologically based diagnostic clinical Collins SJ, Ahlskog JE, Parisi JE, Maraganore DM. Progressive

7. criteria. J Neurol Neurosurg Psychiatry. 1995; 58: 167-173. isThus, needed while to radiographicallyaccurately diagnose cerebellar it antemortem. nuclei and outflow tracts al. Progressive supranuclear palsy diagnosis and confouding features: may be involved, they are not specific for PSP-C and further study Birdi S, Rajput AH, Fenton M, Donat JR, Rozdilsky B, Robinson C, et Treatment and prognosis 8. ReportWilliams on DR, 16 deautopsied Silva R, cases.Paviour Mov DC, Disord. Pittman 2002; A, Watt 17: 1255-1264.HC, Kilford L, et There is no neurorestorative therapy for any form of PSP al. Characteristics of two distinct clinical phenotypes in pathologically and treatment is symptomatic. Levodopa, cholinesterase proven progressive supranuclear palsy: Richardson’s syndrome and inhibitors, and serotonin reuptake inhibitors provide modest yet 9. PSP-parkinsonism.Koga S, Aoki N, Uitti Brain; RJ, van 2005. Gerpen 128: JA, 1247-1258. Cheshire WP, Josephs KA, et al. large series noted a greater than 30% improvement in symptoms When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 frominconsistent dopaminergic benefit treatment [3]. Interestingly, (levodopa 32% or dopamine of 97 cases agonists). from a However, the duration of therapy was not recorded [8]. Botulinun 10. patients.Jellinger K.Neurology. Cerebellar 2015; involvement 85: 404-412. in progressive supranuclear palsy. toxinPSP may in begeneral used forhas focal a graver dystonias prognosis [3]. when compared with 11. MovKanazawa Disord. M, 2010; Shimohata 25: 1104-1105. T, Toyoshima Y, Tada M, Kakita A, Morita Parkinson’s disease [3] but even among the variants there may T, et al. Cerebellar involvement in progressive supranuclear palsy: A be differences. Studies suggest that those with an asymmetric clinicopathological study. Mov Disord. 2009; 24: 1312-1318. PD-like presentation respond more to levodopa and may 12. Shimohata T, Kanazawa M, Yoshida M, Saito Y, Iwai K, Yasuda T. considerations in PSP-C are more limited. However, Kanazawa actually live longer than those with classic RS [5,7,8]. Prognostic Clinical and imaging findings of progressive supranuclear palsy with predominant cerebellar ataxia. Mov Disord. 2016; 31: 760-762. J Neurol Transl Neurosci 4(1): 1062 (2016) 3/4 Sarva (2016) Email:

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13. Sawa N, Kataoka H, Kiriyama T, Izumi T, Taoka T, Kichikawa K, et al. Cerebellar dentate nucleus in progressive supranuclear palsy. Clin 19. Neurol Neurosurg. 2014; 118: 32-36. 2013; 33: 561-567. M. A serial MRI study in a patient with progressive supranuclear palsy 14. Shimohata T, Kanazawa M, Takahashi H, Nishizawa M. Kanazawa M, Shimohata T, Endo K, Koike R, Takahashi H, Nishizawa Clinicopathological features and diagnostic criteria for progressive 20. withKataoka cerebellar H, Tonomura ataxia. ParkinsonismY, Taoka T, Ueno Relat S. Disord.Signal changes 2012; 18: of 677-679.superior

supranuclear palsy with predominant cerebellar ataxia. Mov Disord. progressive supranuclear palsy. Parkinsonism Relat Disord. 2008; 14: cerebellar peduncle on fluid-attenuated inversion recovery in 2015;Kanazawa 30: 329. M, Tada M, Onodera O, Takahashi H, Nishizawa M, 15. 21. 63-65.Blain CR, Barker GJ, Jarosz JM, Coyle NA, Landau S, Brown RG, et Shimohata T. Early clinical features of patients with progressive al. Measuring brain stem and cerebellar damage in parkinsonian supranuclear palsy with predominant cerebellar ataxia. Parkinsonism syndromes using diffusion tensor MRI. Neurology. 2006; 67: 2199- 16. RelatBensimon Disord. G, Ludolph2013; 19: A, 1149-1151. Agid Y, Vidailhet M, Payan C, Leigh PN, et al. Riluzole treatment, survival and diagnostic criteria in Parkinson plus 22. 2205.Hara K, Watanabe H, Ito M, Tsuboi T, Watanabe H, Nakamura R, et al. Potential of a new MRI for visualizing cerebellar involvement in 17. disorders:Payan CA, Viallet the NNIPPS F, Landwehrmeyer study. Brain. 2009;BG, Bonnet 132: 156-171.AM, Borg M, Durif F, et progressive supranuclear palsy. Parkinsonism Relat Disord. 2014; 20: al. Disease severity and progression in progressive supranuclear palsy and multiple system atrophy: Validatation of the NNIPPS--Parkinson 23. plus scale. PLoS One. 2011; 6: 22293. 157-161. S, et al. Cerebellar dysfunction in progressive supranuclear palsy: A 18. Iwasaki Y, Mori K, Ito M, Tatsumi S, Mimuro M, Yoshida M. An Shirota Y, Hamada M, Hanajima R, Terao Y, Matsumoto H, Ohminami autopsied case of progressive supranuclear palsy presenting with 2419. transcranial magnetic stimulation study. Mov Disord. 2010; 25: 2413-

cerebellar ataxia and severe cerebellar involvement. Neuropathology.

Cite this article Sarva H (2016) Progressive Supranuclear Palsy Cerebellar Variant. J Neurol Transl Neurosci 4(1): 1062.

J Neurol Transl Neurosci 4(1): 1062 (2016) 4/4