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Progressive spasticity, supranuclear gaze palsy and postural instability, without parkinsonism: what’s in a phenotype?
Accepted Manuscript Progressive spasticity, supranuclear gaze palsy and postural instability, without parkinsonism: what’s in a phenotype?
L. Ricciardi, M.J. Edwards, A. Fasano, K.P. Bhatia, M. Stamelou PII: DOI: Reference:
S0022-510X(18)30185-0 doi:10.1016/j.jns.2018.04.016 JNS 15865
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
13 October 2017 19 March 2018 10 April 2018
Please cite this article as: L. Ricciardi, M.J. Edwards, A. Fasano, K.P. Bhatia, M. Stamelou , Progressive spasticity, supranuclear gaze palsy and postural instability, without parkinsonism: what’s in a phenotype?. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2018), doi:10.1016/ j.jns.2018.04.016
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Progressive spasticity, supranuclear gaze palsy and postural instability, without parkinsonism: what’s in a phenotype? Ricciardi L,1 Edwards MJ, 1,2 Fasano A,3,4 Bhatia KP, 2 Stamelou M 2,5,6 ¹ Neurosciences Research Centre, Institute of Molecular and Clinical Sciences, St George's University of London, United Kingdom 2
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Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, WC1N 3BG, United
Kingdom 3
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Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease, Toronto
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Western Hospital, UHN, Division of Neurology, University of Toronto, Toronto, Ontario, Canada, 4
Krembil Research Institute, Toronto, Ontario, Canada
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Movement Disorders Department, HYGEIA Hospital, Athens, Greece
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Neurology Clinic, Philipps-University, Marburg, Germany
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Address correspondence to: Prof. Maria Stamelou, Parkinson’s disease and Movement Disorders Department, HYGEIA
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Hospital, Erythrou Stavrou 9, 15123, Athens, Greece, Tel. 0030 210 6867330, email: [email protected]
ACCEPTED MANUSCRIPT Abstract We present a series of patients with vertical supranuclear gaze palsy, postural instability with falls, and progressive spasticity, who mimic Progressive Supranuclear Palsy - Richardson’s syndrome (PSP-R) but have no parkinsonism, and in whom dopamine
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transporter imaging is normal. We suggest possible aetiologies for this constellation of symptoms, discuss the possible origin of
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these signs and highlight this phenotype as it may mimic atypical parkinsonism and in particular PSP.
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Keywords: progressive supranuclear palsy, primary lateral sclerosis, postural instability, falls, DAT imaging
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No conflicts of interest.
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ACCEPTED MANUSCRIPT Introduction Progressive supranuclear palsy (PSP) is an atypical parkinsonian condition, presenting classically with axial-predominant parkinsonism, postural instability with early falls and supranuclear gaze palsy (SGP), while dopamine transporter imaging (DAT
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imaging) is typically abnormal [1]. Here, we present 3 patients who manifest vertical SGP, postural instability with falls and
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progressive spasticity, but have normal DAT imaging. We wish to highlight this phenotype as it may mimic progressive
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supranuclear palsy (PSP) in particular Richardson’s syndrome (PSP-R) [2, 3] and we discuss the possible underlying diseases.
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Case descriptions
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Table 1 shows clinical details of our 3 patients, similarities and differences among them are underlined. Patients have given written
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informed consent to be videotaped.
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Our patients’ mean age at symptom onset was 66.310.5. All of them had approximately 3 years of disease duration at first
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consultation. The initial symptom had been slurred speech in two and reduced dexterity of the left arm in one. All patients had emotional lability, vertical SGP, oculomotor apraxia, moderate to severe dysarthria, dysphagia, gait abnormalities, freezing of gait
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and postural instability. Pyramidal signs such as spastic increase in tone, brisk reflexes, Hoffman’s sign and extensor plantar responses were observed in all. There was no evidence of cognitive dysfunction from history or clinical examination (Table 1).
ACCEPTED MANUSCRIPT All patients had a normal MRI brain and spine (apart from minor white matter ischemic lesions in case 3) (Table) and normal DAT imaging (Supplementary Figure 1). All had Flurodeoxyglucose Positron Emission Tomography (FDG-PET) showing hypometabolism in precentral regions with normal basal ganglia metabolism (Figure 1). Genetic tests for C9ORF72, PGRN, FUS,
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and POLG were performed in two cases with negative results. Patient 3 was followed up for one year and she progressively
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deteriorated: her gait, posture, balance and speech worsened. She completely lost power in her left upper limb with sparing of the
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right hemibody. She had lost voluntary control over eyelid movements, which kept closing during automatic blinking – either spontaneous or reflex – and during conjugate movements of extra-ocular muscles. She was injected few times with botulinum toxin
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to treat this with minimal response.
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Discussion
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Here we describe 3 patients with vertical SGP and postural instability with falls, progressive spasticity and without evidence of dopaminergic deficit in the basal ganglia (normal DAT imaging and basal ganglia uptake in FDG-PET). These patients would fulfil
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newly proposed clinical criteria for probable PSP [4] Several additional features of these patients such as the eyelid apraxia,
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reduced blinking and the surprised look would point to this disorder. However, upper motor neuron signs are rare in PSP and when present, they do not prevail the clinical picture [3]. In a large neuropathologically confirmed series of 100 PSP brains, none of the patients presented with predominant upper motor neuron signs [3]. Adult-onset progressive and prominent upper motor neuron signs in the absence of parkinsonism, would rather suggest a motor neuron disease and, here specifically, due to the absence of
ACCEPTED MANUSCRIPT lower motor neuron signs, primary lateral sclerosis (PLS) or upper motor neuron (UMN)-dominant/bulbar onset amyotrophic lateral sclerosis (ALS). Several clinical features of our patients, but also the FDG-PET findings point to this direction. Eye movement abnormalities are well described in motor neuron disease and include vertical SGP, broken smooth pursuit, and
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gaze impersistence [5-8]. Usually, in ALS these signs present later in the disease course, in contrast to the patients presented here, who developed SGP in the first 2 years of their disease [8]. In UMN-dominant or bulbar onset ALS slow vertical saccades have
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been reported to be much more common [7]. In patients with ALS and vertical SGP it is suggested that this probably reflects
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involvement of the brainstem and in particular the riMLF (the rostral interstitial nucleus of the medial longitudinal fasciculus) in the midbrain, similarly to PSP, which houses the burst neurons for conjugate vertical saccades [8].
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Postural instability with early falls are reported in ALS, and in some early cases of PLS, in some of them even early in the disease
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course, while DAT imaging, F-DOPA or basal ganglia FDG-PET, are usually normal, arguing that the origin of postural instability in these patients is not in the basal ganglia [9, 10]. Thus, in our view, the term “parkinsonian” or “extrapyramidal” for these patients is
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not justified [9, 10]. Similarly, other motor signs such as hypomimia and freezing that have been termed as “parkinsonian” in PLS
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patients with normal DAT imaging, may have different origin: PLS patients have supranuclear facial diplegia, with automaticvoluntary dissociation, which may give rise to an expressionless face;[5, 6] freezing, start hesitation, difficulty initiating gait as well as postural instability, might be attributable to damage of non-dopaminergic structures outside the basal ganglia, probably within the frontal cortex or the brainstem as highlighted by cases of primary progressive freezing of gait with normal DAT imaging and no
ACCEPTED MANUSCRIPT parkinsonism [11]. Of note, precentral (mostly medial) regions of the frontal lobes with or without involvement of the corpus callosum, is actually the main localization of pathology in PLS, reflected in the FDG-PET findings. Further clinical clues may be helpful to differentiate PLS from PSP: the mean age of onset in PLS varies from 45.4-53.7, [5] thus
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around a decade earlier than PSP (mean 63 years) [2] although our patients presented their symptoms in their late 60s. Whilst
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dysarthria may be the initial symptom both in bulbar onset PLS and PSP, the development of complete anarthria is described in
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PLS, as in our patients here but to our knowledge, has never been reported early in the disease course in PSP [3]. Similarly, profound spasticity, head retraction reflex and brisk jaw reflex with jaw clonus are quite rare in PSP[2, 3]. Another interesting
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feature is the eyelid apraxia. Lid-closing apraxia is thought to represent a supranuclear palsy of eyelid closure, a facial “apraxia”
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due to precentral degeneration and degeneration of the cortico-geniculate tracts, which fits well with the pathology distribution in
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PLS, demonstrated in our patients (in the video, the examiner attempts to close the patients eyelids, and the patient does so even
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before the examiner touches him); whereas eye-opening apraxia (or lid-inhibition) often accompanied by blepharospasm has been reported in PSP. [12, 13] As with most clinical signs, these features should be regarded as diagnostic pointers rather than
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pathognomonic signs. Cognition was not impaired in our patients, which would also be unusual for PSP, but longer follow-up will be
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needed to conclude on this feature in these patients. Thus, our patients presented here have clinically PLS or UMN-ALS, however, it is impossible to conclude on their final diagnosis without pathology, which is the main limitation of our report. Indeed, PSP pathology has been described to underlie a phenotype
ACCEPTED MANUSCRIPT with predominant spasticity, lacking further characteristic features of PSP, albeit rarely, but patients reported did not have vertical SGP or also had lower motor neuron signs.[10] A PLS phenotype has been described in some patients that had a tauopathy that resembled PSP pathology (4R tauopathy with tufted astrocytes), albeit with some differences (Gallyas-negative), that led the
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authors to describe them as “atypical PSP” and the syndrome PLS-PSP. [14]However, there are some clinical differences that may
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point away from this possibility: clinically these patients had true parkinsonism, with rigidity and bradykinesia, marked asymmetry,
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and a minority had SGP, in some of them PET showed hypometabolism in the basal ganglia and pathology involvement of putamen and substantia nigra. Also a patient with a PLS phenotype that had corticobasal degeneration pathology has been reported. [15]
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This is particularly relevant for our patient 3, as she displayed a great degree of asymmetry as seen in cortico-basal syndrome but also in rare variants of PLS.
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Of course, there are other conditions that could present with supranuclear gaze palsy such as Whipple’s or IGLON5 antibodies, or
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profound spasticity, such as hereditary spastic paraplegias, but these are unlikely here. Our case series underlines the importance
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of recognising these distinct clinical phenotypes, for diagnostic and prognostic reasons but also for identifying phenotypically
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homogenous populations to study prospectively. Legends
ACCEPTED MANUSCRIPT Figure 1 legend: FDG-PET scans of patient 1 (panel A) and patient 3 (panel B) show hypometabolism in precentral regions with normal basal ganglia metabolism (red arrows). Video legend: Progressive spasticity, supranuclear gaze palsy and postural instability in three patients.
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Patient 1 and 2 have a vertical supranuclear gaze palsy, they both are unable to voluntary close their eyes and they use their hand
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to do so. When the examiner attempts to close patient 1’s eyelids, the eyes close before the examiner touches him. They both have a brisk jaw jerk; brisk reflexes with spread; Hoffman’s sign; clonus (on the left in patient 1 and bilaterally in patient 2). Patient 3:
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repeated finger tapping is slow on the left side, she has no power in left upper limb. Foot tapping is slow bilaterally. Brisk reflexes,
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especially on the left upper limb. Hoffman’s sign on the left. Babinski’s sign on the left. Gait is slow, broad based with reduced arm
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swing on the left. Patients provided consent to be filmed for publication on line.
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ACCEPTED MANUSCRIPT References: [1] K. Seppi, C. Scherfler, E. Donnemiller, I. Virgolini, M.F. Schocke, G. Goebel, K.J. Mair, S. Boesch, C. Brenneis, G.K. Wenning, W. Poewe, Topography of dopamine transporter availability in progressive supranuclear palsy: a voxelwise [123I]beta-CIT SPECT analysis, Archives of neurology 63(8) (2006) 1154-60. [2] I. Litvan, Y. Agid, D. Calne, G. Campbell, B. Dubois, R.C. Duvoisin, C.G. Goetz, L.I. Golbe, J. Grafman, J.H. Growdon, M. Hallett, 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 NINDSSPSP international workshop, Neurology 47(1) (1996) 1-9. [3] 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, A. Giese, S. Roeber, T. Arzberger, S. Wagenpfeil, G.U. Hoglinger, The phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases, Movement disorders : official journal of the Movement Disorder Society 29(14) (2014) 1758-66. [4] G.U. Hoglinger, G. Respondek, M. Stamelou, C. Kurz, K.A. Josephs, A.E. Lang, B. Mollenhauer, U. Muller, C. Nilsson, J.L. Whitwell, T. Arzberger, E. Englund, E. Gelpi, A. Giese, D.J. Irwin, W.G. Meissner, A. Pantelyat, A. Rajput, J.C. van Swieten, C. Troakes, A. Antonini, K.P. Bhatia, Y. Bordelon, Y. Compta, J.C. Corvol, C. Colosimo, D.W. Dickson, R. Dodel, L. Ferguson, M. Grossman, J. Kassubek, F. Krismer, J. Levin, S. Lorenzl, H.R. Morris, P. Nestor, W.H. Oertel, W. Poewe, G. Rabinovici, J.B. Rowe, G.D. Schellenberg, K. Seppi, T. van Eimeren, G.K. Wenning, A.L. Boxer, L.I. Golbe, I. Litvan, P.S.P.S.G. Movement Disorder Societyendorsed, Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria, Mov Disord 32(6) (2017) 853-864. [5] P.H. Gordon, B. Cheng, I.B. Katz, M. Pinto, A.P. Hays, H. Mitsumoto, L.P. Rowland, The natural history of primary lateral sclerosis, Neurology 66(5) (2006) 647-53. [6] M.A. Singer, S. Kojan, R.J. Barohn, L. Herbelin, S.P. Nations, J.R. Trivedi, C.E. Jackson, D.K. Burns, P.J. Boyer, G.I. Wolfe, Primary lateral sclerosis: clinical and laboratory features in 25 patients, J Clin Neuromuscul Dis 7(1) (2005) 1-9. [7] C. Donaghy, R. Pinnock, S. Abrahams, C. Cardwell, O. Hardiman, V. Patterson, R.C. McGivern, J.M. Gibson, Slow saccades in bulbar-onset motor neurone disease, J Neurol 257(7) (2010) 1134-40. [8] C. Donaghy, M.J. Thurtell, E.P. Pioro, J.M. Gibson, R.J. Leigh, Eye movements in amyotrophic lateral sclerosis and its mimics: a review with illustrative cases, J Neurol Neurosurg Psychiatry 82(1) (2011) 110-6. [9] I.M. Norlinah, K.P. Bhatia, K. Ostergaard, R. Howard, G. Arabia, N.P. Quinn, Primary lateral sclerosis mimicking atypical parkinsonism, Mov Disord 22(14) (2007) 2057-62. [10] N. Mabuchi, H. Watanabe, N. Atsuta, M. Hirayama, H. Ito, H. Fukatsu, T. Kato, K. Ito, G. Sobue, Primary lateral sclerosis presenting parkinsonian symptoms without nigrostriatal involvement, J Neurol Neurosurg Psychiatry 75(12) (2004) 1768-71. [11] A. Fasano, S. Baldari, D. Di Giuda, R. Paratore, C. Piano, A.R. Bentivoglio, P. Girlanda, F. Morgante, Nigro-striatal involvement in primary progressive freezing gait: insights into a heterogeneous pathogenesis, Parkinsonism & related disorders 18(5) (2012) 578-84. [12] R.W. Russell, Supranuclear palsy of eyelid closure, Brain : a journal of neurology 103(1) (1980) 71-82. [13] L.I. Golbe, P.H. Davis, F.E. Lepore, Eyelid movement abnormalities in progressive supranuclear palsy, Movement disorders : official journal of the Movement Disorder Society 4(4) (1989) 297-302.
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ACCEPTED MANUSCRIPT [14] Y.J. Fu, Y. Nishihira, S. Kuroda, Y. Toyoshima, T. Ishihara, M. Shinozaki, A. Miyashita, Y.S. Piao, C.F. Tan, T. Tani, R. Koike, K. Iwanaga, M. Tsujihata, O. Onodera, R. Kuwano, M. Nishizawa, A. Kakita, T. Ikeuchi, H. Takahashi, Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity, Acta neuropathologica 120(1) (2010) 21-32. [15] M. Hasselblatt, S. Follinger, P. Steinbach, A. Schwan, W. Paulus, Corticobasal degeneration presenting with progressive spasticity, Neurology 68(10) (2007) 791-2.
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ACCEPTED MANUSCRIPT
Table 1: Detailed clinical, laboratory and instrumental data of our patients. Case 1
Case 2
Gender
Male
Female
Age at onset
56
66
Disease duration at first consultation
3 years
3 years
Main symptoms at onset
Slurred speech
Slurred speech
Additional symptoms during the course of disease
Progressive speech disorder, jaw spasms, gait difficulty and falls, emotional lability
Progressive speech disorder, dysphagia, postural instability, difficulty walking and turning over in bed, emotional lability
Left upper limb, rigidity, clumsiness and uselessness. Dysphagia, dysarthria and eyelid opening apraxia. Gait difficulties, slowness. Constipation. Depression
Neurological examination
Vertical SGP, ocular apraxia, bilateral supranuclear facial weakness, anarthria. Brisk jaw jerk. Brisk reflexes UL and LL. Bilateral spastic catch UL; increased tone in LL. Babinski’s sign on the left. FOG and postural instability.
Vertical SGP, spastic dysarthria. Brisk jaw jerk. Asymmetrical spastic tetraparesis. Brisk reflexes. Bilateral spastic catch UL. Bilateral Babinski's sign.
Hypomimia, dysarthria. Oculomotor apraxia. Brisk reflexes more on the left UL. Increased tone on the left UL. Slow, broad based gait, reduced arm swing on the left. Slow repeated finger tapping bilaterally more on the left. Bilateral palmo-mental reflex and brisk jaw jerk. Babinski’s sign on the left
Ocular apraxia
Yes
Yes
Yes
Cognitive examination
MMSE 29/30; mild impairment in executive functions, speed/attention,
Not performed
Normal
(at first consultation)
Case 3
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SC
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PT
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AC
Female 77
3 years
Reduced dexterity in left hand
ACCEPTED MANUSCRIPT calculation Family history
Negative
Negative
Negative
Levodopa response
Not evaluated
No response
No response
MRI brain and whole spine
Normal
Normal
DAT scan
Normal
Normal
FDG-PET
Hypometabolism in left precentral region, normal basal ganglia metabolism
Hypometabolism in the left precentral region, normal basal ganglia metabolism
Hypoperfusion in the right inferior frontal gyrus, normal basal ganglia metabolism
Other investigations
CSF, EMG/NCS, MEP: normal
CSF, EMG/NCS, MEP: normal
EMG/NCS: normal.
Genetic
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SC
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C9ORF72, PGRN, FUS genes: no pathogenic mutations detected
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C9ORF72, PGRN, FUS, POLG: no pathogenic mutations detected
Minor bilateral deep white matter ischemic changes. Normal
MEP: absent in left UL and LL. Not performed
Abbreviations: SGP: supranuclear gaze palsy; UL: upper limbs, LL: lower limbs; FOG: freezing of gait; MMSE: mini mental state examination; MRI: magnetic resonance imaging; DAT scan: dopamine transporters imaging, FDG-PET: fluorodeoxyglucose-positron emission tomography; CSF: Cerebrospinal fluid; EMG: electromyography; NCS: nerve conduction study; MEP: motor evoked potentials; C9ORF72: chromosome 9 open reading frame 72 gene; PGRN: Progranulin gene; FUS: fused-in-sarcoma gene; POLG: polymerase-gamma gene
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ACCEPTED MANUSCRIPT Highlights
We describe three patients with vertical supranuclear gaze palsy, postural instability with falls and profound progressive spasticity The patients fulfilled criteria for probable progressive supranuclear palsy (PSP) but without parkinsonism Indeed, in all patients there was no evidence of dopaminergic deficit in the basal ganglia (normal DAT imaging and basal ganglia uptake in FDG-PET) In contrast, all patients had FDG-PET showing hypometabolism in precentral regions, as seen in primary lateral sclerosis A distinct phenotype of supranuclear gaze palsy, falls and spasticity without parkinsonism and without evidence of dopaminergic deficit in imaging is described. The underlying pathology of this phenotype is probably heterogenous.
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L. Ricciardi, M.J. Edwards, A. Fasano, K.P. Bhatia, M. Stamelou PII: DOI: Reference:
S0022-510X(18)30185-0 doi:10.1016/j.jns.2018.04.016 JNS 15865
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
13 October 2017 19 March 2018 10 April 2018
Please cite this article as: L. Ricciardi, M.J. Edwards, A. Fasano, K.P. Bhatia, M. Stamelou , Progressive spasticity, supranuclear gaze palsy and postural instability, without parkinsonism: what’s in a phenotype?. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2018), doi:10.1016/ j.jns.2018.04.016
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Progressive spasticity, supranuclear gaze palsy and postural instability, without parkinsonism: what’s in a phenotype? Ricciardi L,1 Edwards MJ, 1,2 Fasano A,3,4 Bhatia KP, 2 Stamelou M 2,5,6 ¹ Neurosciences Research Centre, Institute of Molecular and Clinical Sciences, St George's University of London, United Kingdom 2
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Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, WC1N 3BG, United
Kingdom 3
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Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease, Toronto
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Western Hospital, UHN, Division of Neurology, University of Toronto, Toronto, Ontario, Canada, 4
Krembil Research Institute, Toronto, Ontario, Canada
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Movement Disorders Department, HYGEIA Hospital, Athens, Greece
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Neurology Clinic, Philipps-University, Marburg, Germany
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Address correspondence to: Prof. Maria Stamelou, Parkinson’s disease and Movement Disorders Department, HYGEIA
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Hospital, Erythrou Stavrou 9, 15123, Athens, Greece, Tel. 0030 210 6867330, email: [email protected]
ACCEPTED MANUSCRIPT Abstract We present a series of patients with vertical supranuclear gaze palsy, postural instability with falls, and progressive spasticity, who mimic Progressive Supranuclear Palsy - Richardson’s syndrome (PSP-R) but have no parkinsonism, and in whom dopamine
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transporter imaging is normal. We suggest possible aetiologies for this constellation of symptoms, discuss the possible origin of
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these signs and highlight this phenotype as it may mimic atypical parkinsonism and in particular PSP.
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Keywords: progressive supranuclear palsy, primary lateral sclerosis, postural instability, falls, DAT imaging
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No conflicts of interest.
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ACCEPTED MANUSCRIPT Introduction Progressive supranuclear palsy (PSP) is an atypical parkinsonian condition, presenting classically with axial-predominant parkinsonism, postural instability with early falls and supranuclear gaze palsy (SGP), while dopamine transporter imaging (DAT
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imaging) is typically abnormal [1]. Here, we present 3 patients who manifest vertical SGP, postural instability with falls and
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progressive spasticity, but have normal DAT imaging. We wish to highlight this phenotype as it may mimic progressive
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supranuclear palsy (PSP) in particular Richardson’s syndrome (PSP-R) [2, 3] and we discuss the possible underlying diseases.
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Case descriptions
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Table 1 shows clinical details of our 3 patients, similarities and differences among them are underlined. Patients have given written
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informed consent to be videotaped.
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Our patients’ mean age at symptom onset was 66.310.5. All of them had approximately 3 years of disease duration at first
C C
consultation. The initial symptom had been slurred speech in two and reduced dexterity of the left arm in one. All patients had emotional lability, vertical SGP, oculomotor apraxia, moderate to severe dysarthria, dysphagia, gait abnormalities, freezing of gait
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and postural instability. Pyramidal signs such as spastic increase in tone, brisk reflexes, Hoffman’s sign and extensor plantar responses were observed in all. There was no evidence of cognitive dysfunction from history or clinical examination (Table 1).
ACCEPTED MANUSCRIPT All patients had a normal MRI brain and spine (apart from minor white matter ischemic lesions in case 3) (Table) and normal DAT imaging (Supplementary Figure 1). All had Flurodeoxyglucose Positron Emission Tomography (FDG-PET) showing hypometabolism in precentral regions with normal basal ganglia metabolism (Figure 1). Genetic tests for C9ORF72, PGRN, FUS,
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and POLG were performed in two cases with negative results. Patient 3 was followed up for one year and she progressively
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deteriorated: her gait, posture, balance and speech worsened. She completely lost power in her left upper limb with sparing of the
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right hemibody. She had lost voluntary control over eyelid movements, which kept closing during automatic blinking – either spontaneous or reflex – and during conjugate movements of extra-ocular muscles. She was injected few times with botulinum toxin
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to treat this with minimal response.
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Discussion
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Here we describe 3 patients with vertical SGP and postural instability with falls, progressive spasticity and without evidence of dopaminergic deficit in the basal ganglia (normal DAT imaging and basal ganglia uptake in FDG-PET). These patients would fulfil
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newly proposed clinical criteria for probable PSP [4] Several additional features of these patients such as the eyelid apraxia,
A
reduced blinking and the surprised look would point to this disorder. However, upper motor neuron signs are rare in PSP and when present, they do not prevail the clinical picture [3]. In a large neuropathologically confirmed series of 100 PSP brains, none of the patients presented with predominant upper motor neuron signs [3]. Adult-onset progressive and prominent upper motor neuron signs in the absence of parkinsonism, would rather suggest a motor neuron disease and, here specifically, due to the absence of
ACCEPTED MANUSCRIPT lower motor neuron signs, primary lateral sclerosis (PLS) or upper motor neuron (UMN)-dominant/bulbar onset amyotrophic lateral sclerosis (ALS). Several clinical features of our patients, but also the FDG-PET findings point to this direction. Eye movement abnormalities are well described in motor neuron disease and include vertical SGP, broken smooth pursuit, and
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gaze impersistence [5-8]. Usually, in ALS these signs present later in the disease course, in contrast to the patients presented here, who developed SGP in the first 2 years of their disease [8]. In UMN-dominant or bulbar onset ALS slow vertical saccades have
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been reported to be much more common [7]. In patients with ALS and vertical SGP it is suggested that this probably reflects
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involvement of the brainstem and in particular the riMLF (the rostral interstitial nucleus of the medial longitudinal fasciculus) in the midbrain, similarly to PSP, which houses the burst neurons for conjugate vertical saccades [8].
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Postural instability with early falls are reported in ALS, and in some early cases of PLS, in some of them even early in the disease
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course, while DAT imaging, F-DOPA or basal ganglia FDG-PET, are usually normal, arguing that the origin of postural instability in these patients is not in the basal ganglia [9, 10]. Thus, in our view, the term “parkinsonian” or “extrapyramidal” for these patients is
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not justified [9, 10]. Similarly, other motor signs such as hypomimia and freezing that have been termed as “parkinsonian” in PLS
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patients with normal DAT imaging, may have different origin: PLS patients have supranuclear facial diplegia, with automaticvoluntary dissociation, which may give rise to an expressionless face;[5, 6] freezing, start hesitation, difficulty initiating gait as well as postural instability, might be attributable to damage of non-dopaminergic structures outside the basal ganglia, probably within the frontal cortex or the brainstem as highlighted by cases of primary progressive freezing of gait with normal DAT imaging and no
ACCEPTED MANUSCRIPT parkinsonism [11]. Of note, precentral (mostly medial) regions of the frontal lobes with or without involvement of the corpus callosum, is actually the main localization of pathology in PLS, reflected in the FDG-PET findings. Further clinical clues may be helpful to differentiate PLS from PSP: the mean age of onset in PLS varies from 45.4-53.7, [5] thus
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around a decade earlier than PSP (mean 63 years) [2] although our patients presented their symptoms in their late 60s. Whilst
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dysarthria may be the initial symptom both in bulbar onset PLS and PSP, the development of complete anarthria is described in
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PLS, as in our patients here but to our knowledge, has never been reported early in the disease course in PSP [3]. Similarly, profound spasticity, head retraction reflex and brisk jaw reflex with jaw clonus are quite rare in PSP[2, 3]. Another interesting
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feature is the eyelid apraxia. Lid-closing apraxia is thought to represent a supranuclear palsy of eyelid closure, a facial “apraxia”
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due to precentral degeneration and degeneration of the cortico-geniculate tracts, which fits well with the pathology distribution in
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PLS, demonstrated in our patients (in the video, the examiner attempts to close the patients eyelids, and the patient does so even
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before the examiner touches him); whereas eye-opening apraxia (or lid-inhibition) often accompanied by blepharospasm has been reported in PSP. [12, 13] As with most clinical signs, these features should be regarded as diagnostic pointers rather than
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pathognomonic signs. Cognition was not impaired in our patients, which would also be unusual for PSP, but longer follow-up will be
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needed to conclude on this feature in these patients. Thus, our patients presented here have clinically PLS or UMN-ALS, however, it is impossible to conclude on their final diagnosis without pathology, which is the main limitation of our report. Indeed, PSP pathology has been described to underlie a phenotype
ACCEPTED MANUSCRIPT with predominant spasticity, lacking further characteristic features of PSP, albeit rarely, but patients reported did not have vertical SGP or also had lower motor neuron signs.[10] A PLS phenotype has been described in some patients that had a tauopathy that resembled PSP pathology (4R tauopathy with tufted astrocytes), albeit with some differences (Gallyas-negative), that led the
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authors to describe them as “atypical PSP” and the syndrome PLS-PSP. [14]However, there are some clinical differences that may
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point away from this possibility: clinically these patients had true parkinsonism, with rigidity and bradykinesia, marked asymmetry,
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and a minority had SGP, in some of them PET showed hypometabolism in the basal ganglia and pathology involvement of putamen and substantia nigra. Also a patient with a PLS phenotype that had corticobasal degeneration pathology has been reported. [15]
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This is particularly relevant for our patient 3, as she displayed a great degree of asymmetry as seen in cortico-basal syndrome but also in rare variants of PLS.
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Of course, there are other conditions that could present with supranuclear gaze palsy such as Whipple’s or IGLON5 antibodies, or
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profound spasticity, such as hereditary spastic paraplegias, but these are unlikely here. Our case series underlines the importance
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of recognising these distinct clinical phenotypes, for diagnostic and prognostic reasons but also for identifying phenotypically
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homogenous populations to study prospectively. Legends
ACCEPTED MANUSCRIPT Figure 1 legend: FDG-PET scans of patient 1 (panel A) and patient 3 (panel B) show hypometabolism in precentral regions with normal basal ganglia metabolism (red arrows). Video legend: Progressive spasticity, supranuclear gaze palsy and postural instability in three patients.
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Patient 1 and 2 have a vertical supranuclear gaze palsy, they both are unable to voluntary close their eyes and they use their hand
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to do so. When the examiner attempts to close patient 1’s eyelids, the eyes close before the examiner touches him. They both have a brisk jaw jerk; brisk reflexes with spread; Hoffman’s sign; clonus (on the left in patient 1 and bilaterally in patient 2). Patient 3:
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repeated finger tapping is slow on the left side, she has no power in left upper limb. Foot tapping is slow bilaterally. Brisk reflexes,
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especially on the left upper limb. Hoffman’s sign on the left. Babinski’s sign on the left. Gait is slow, broad based with reduced arm
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swing on the left. Patients provided consent to be filmed for publication on line.
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ACCEPTED MANUSCRIPT References: [1] K. Seppi, C. Scherfler, E. Donnemiller, I. Virgolini, M.F. Schocke, G. Goebel, K.J. Mair, S. Boesch, C. Brenneis, G.K. Wenning, W. Poewe, Topography of dopamine transporter availability in progressive supranuclear palsy: a voxelwise [123I]beta-CIT SPECT analysis, Archives of neurology 63(8) (2006) 1154-60. [2] I. Litvan, Y. Agid, D. Calne, G. Campbell, B. Dubois, R.C. Duvoisin, C.G. Goetz, L.I. Golbe, J. Grafman, J.H. Growdon, M. Hallett, 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 NINDSSPSP international workshop, Neurology 47(1) (1996) 1-9. [3] 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, A. Giese, S. Roeber, T. Arzberger, S. Wagenpfeil, G.U. Hoglinger, The phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases, Movement disorders : official journal of the Movement Disorder Society 29(14) (2014) 1758-66. [4] G.U. Hoglinger, G. Respondek, M. Stamelou, C. Kurz, K.A. Josephs, A.E. Lang, B. Mollenhauer, U. Muller, C. Nilsson, J.L. Whitwell, T. Arzberger, E. Englund, E. Gelpi, A. Giese, D.J. Irwin, W.G. Meissner, A. Pantelyat, A. Rajput, J.C. van Swieten, C. Troakes, A. Antonini, K.P. Bhatia, Y. Bordelon, Y. Compta, J.C. Corvol, C. Colosimo, D.W. Dickson, R. Dodel, L. Ferguson, M. Grossman, J. Kassubek, F. Krismer, J. Levin, S. Lorenzl, H.R. Morris, P. Nestor, W.H. Oertel, W. Poewe, G. Rabinovici, J.B. Rowe, G.D. Schellenberg, K. Seppi, T. van Eimeren, G.K. Wenning, A.L. Boxer, L.I. Golbe, I. Litvan, P.S.P.S.G. Movement Disorder Societyendorsed, Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria, Mov Disord 32(6) (2017) 853-864. [5] P.H. Gordon, B. Cheng, I.B. Katz, M. Pinto, A.P. Hays, H. Mitsumoto, L.P. Rowland, The natural history of primary lateral sclerosis, Neurology 66(5) (2006) 647-53. [6] M.A. Singer, S. Kojan, R.J. Barohn, L. Herbelin, S.P. Nations, J.R. Trivedi, C.E. Jackson, D.K. Burns, P.J. Boyer, G.I. Wolfe, Primary lateral sclerosis: clinical and laboratory features in 25 patients, J Clin Neuromuscul Dis 7(1) (2005) 1-9. [7] C. Donaghy, R. Pinnock, S. Abrahams, C. Cardwell, O. Hardiman, V. Patterson, R.C. McGivern, J.M. Gibson, Slow saccades in bulbar-onset motor neurone disease, J Neurol 257(7) (2010) 1134-40. [8] C. Donaghy, M.J. Thurtell, E.P. Pioro, J.M. Gibson, R.J. Leigh, Eye movements in amyotrophic lateral sclerosis and its mimics: a review with illustrative cases, J Neurol Neurosurg Psychiatry 82(1) (2011) 110-6. [9] I.M. Norlinah, K.P. Bhatia, K. Ostergaard, R. Howard, G. Arabia, N.P. Quinn, Primary lateral sclerosis mimicking atypical parkinsonism, Mov Disord 22(14) (2007) 2057-62. [10] N. Mabuchi, H. Watanabe, N. Atsuta, M. Hirayama, H. Ito, H. Fukatsu, T. Kato, K. Ito, G. Sobue, Primary lateral sclerosis presenting parkinsonian symptoms without nigrostriatal involvement, J Neurol Neurosurg Psychiatry 75(12) (2004) 1768-71. [11] A. Fasano, S. Baldari, D. Di Giuda, R. Paratore, C. Piano, A.R. Bentivoglio, P. Girlanda, F. Morgante, Nigro-striatal involvement in primary progressive freezing gait: insights into a heterogeneous pathogenesis, Parkinsonism & related disorders 18(5) (2012) 578-84. [12] R.W. Russell, Supranuclear palsy of eyelid closure, Brain : a journal of neurology 103(1) (1980) 71-82. [13] L.I. Golbe, P.H. Davis, F.E. Lepore, Eyelid movement abnormalities in progressive supranuclear palsy, Movement disorders : official journal of the Movement Disorder Society 4(4) (1989) 297-302.
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ACCEPTED MANUSCRIPT [14] Y.J. Fu, Y. Nishihira, S. Kuroda, Y. Toyoshima, T. Ishihara, M. Shinozaki, A. Miyashita, Y.S. Piao, C.F. Tan, T. Tani, R. Koike, K. Iwanaga, M. Tsujihata, O. Onodera, R. Kuwano, M. Nishizawa, A. Kakita, T. Ikeuchi, H. Takahashi, Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity, Acta neuropathologica 120(1) (2010) 21-32. [15] M. Hasselblatt, S. Follinger, P. Steinbach, A. Schwan, W. Paulus, Corticobasal degeneration presenting with progressive spasticity, Neurology 68(10) (2007) 791-2.
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Table 1: Detailed clinical, laboratory and instrumental data of our patients. Case 1
Case 2
Gender
Male
Female
Age at onset
56
66
Disease duration at first consultation
3 years
3 years
Main symptoms at onset
Slurred speech
Slurred speech
Additional symptoms during the course of disease
Progressive speech disorder, jaw spasms, gait difficulty and falls, emotional lability
Progressive speech disorder, dysphagia, postural instability, difficulty walking and turning over in bed, emotional lability
Left upper limb, rigidity, clumsiness and uselessness. Dysphagia, dysarthria and eyelid opening apraxia. Gait difficulties, slowness. Constipation. Depression
Neurological examination
Vertical SGP, ocular apraxia, bilateral supranuclear facial weakness, anarthria. Brisk jaw jerk. Brisk reflexes UL and LL. Bilateral spastic catch UL; increased tone in LL. Babinski’s sign on the left. FOG and postural instability.
Vertical SGP, spastic dysarthria. Brisk jaw jerk. Asymmetrical spastic tetraparesis. Brisk reflexes. Bilateral spastic catch UL. Bilateral Babinski's sign.
Hypomimia, dysarthria. Oculomotor apraxia. Brisk reflexes more on the left UL. Increased tone on the left UL. Slow, broad based gait, reduced arm swing on the left. Slow repeated finger tapping bilaterally more on the left. Bilateral palmo-mental reflex and brisk jaw jerk. Babinski’s sign on the left
Ocular apraxia
Yes
Yes
Yes
Cognitive examination
MMSE 29/30; mild impairment in executive functions, speed/attention,
Not performed
Normal
(at first consultation)
Case 3
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AC
Female 77
3 years
Reduced dexterity in left hand
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Negative
Negative
Negative
Levodopa response
Not evaluated
No response
No response
MRI brain and whole spine
Normal
Normal
DAT scan
Normal
Normal
FDG-PET
Hypometabolism in left precentral region, normal basal ganglia metabolism
Hypometabolism in the left precentral region, normal basal ganglia metabolism
Hypoperfusion in the right inferior frontal gyrus, normal basal ganglia metabolism
Other investigations
CSF, EMG/NCS, MEP: normal
CSF, EMG/NCS, MEP: normal
EMG/NCS: normal.
Genetic
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SC
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C9ORF72, PGRN, FUS genes: no pathogenic mutations detected
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C9ORF72, PGRN, FUS, POLG: no pathogenic mutations detected
Minor bilateral deep white matter ischemic changes. Normal
MEP: absent in left UL and LL. Not performed
Abbreviations: SGP: supranuclear gaze palsy; UL: upper limbs, LL: lower limbs; FOG: freezing of gait; MMSE: mini mental state examination; MRI: magnetic resonance imaging; DAT scan: dopamine transporters imaging, FDG-PET: fluorodeoxyglucose-positron emission tomography; CSF: Cerebrospinal fluid; EMG: electromyography; NCS: nerve conduction study; MEP: motor evoked potentials; C9ORF72: chromosome 9 open reading frame 72 gene; PGRN: Progranulin gene; FUS: fused-in-sarcoma gene; POLG: polymerase-gamma gene
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ACCEPTED MANUSCRIPT Highlights
We describe three patients with vertical supranuclear gaze palsy, postural instability with falls and profound progressive spasticity The patients fulfilled criteria for probable progressive supranuclear palsy (PSP) but without parkinsonism Indeed, in all patients there was no evidence of dopaminergic deficit in the basal ganglia (normal DAT imaging and basal ganglia uptake in FDG-PET) In contrast, all patients had FDG-PET showing hypometabolism in precentral regions, as seen in primary lateral sclerosis A distinct phenotype of supranuclear gaze palsy, falls and spasticity without parkinsonism and without evidence of dopaminergic deficit in imaging is described. The underlying pathology of this phenotype is probably heterogenous.
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