Accepted Manuscript Normal dopamine transporter imaging does not exclude Multiple System Atrophy John McKinley, MB(Hons), MMedSc, MRCP(UK) Martin O’Connell, FRCPI Michael Farrell, FRCPI, FRCPC, FRCPath Timothy Lynch, BSc, MB, FRCPI, FRCP(Lond) PII:
S1353-8020(14)00175-8
DOI:
10.1016/j.parkreldis.2014.04.022
Reference:
PRD 2331
To appear in:
Parkinsonism and Related Disorders
Received Date: 13 December 2013 Revised Date:
14 April 2014
Accepted Date: 15 April 2014
Please cite this article as: McKinley J, O’Connell M, Farrell M, Lynch T, Normal dopamine transporter imaging does not exclude Multiple System Atrophy, Parkinsonism and Related Disorders (2014), doi: 10.1016/j.parkreldis.2014.04.022. 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 Parkinsonism and Related Disorders Letter Submission
John McKinley MB(Hons), MMedSc, MRCP(UK)1 Martin O’Connell FRCPI2 Michael Farrell FRCPI, FRCPC, FRCPath3 Timothy Lynch BSc, MB, FRCPI, FRCP(Lond)1
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Title: Normal dopamine transporter imaging does not exclude Multiple System Atrophy.
Corresponding author:
M AN U
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1. Department of Neurology, Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles St Dublin 7. 2. Department of Radiology, Mater Misericordiae University Hospital, 57 Eccles St Dublin 7. 3. Department of Neuropathology and Dublin Brain Bank, Beaumont Hospital, Dublin 9.
Word count: 657 References: 8
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Dr John McKinley, Dublin Academic Medical Centre Fellow in Movement Disorders, Dublin Neurological Institute, 57 Eccles St, Dublin 7. Email: [email protected], telephone: 00447834228893.
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Key words: MSA, Dopamine transporter imaging, SPECT. Running title: MSA normal DaTSCAN Financial Disclosures:
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Drs McKinley, O’Connell and Professor Farrell report no disclosures. Professor Lynch receives honoraria from Abbot, Boehringer Ingelheim, Lundbeck and Orion. He has received educational grants from Bayler Schering, Biogen Idec, Lundbeck and Medtronic. He has received grants from the Irish Institute of Clinical Neuroscience, the Mater College and PRTL1 funding. Professor Lynch sits on the advisory boards of Abbot, Novartis, UCB Pharma, Teva, Merck Serono and Biogen Idec. Research Funding: N/A
1
ACCEPTED MANUSCRIPT To the editors:
A 56-year-old man had a 10-year history of erectile dysfunction and incomplete bladder emptying resulting in mild renal dysfunction. Ultrasonography identified moderate bilateral hydronephrosis and bladder
RI PT
trabeculation. Recurrent syncope from postural hypotension (149/97 mmHg supine, 97/62mmHg standing), post-prandial presyncope and aching leg
muscles were present for 7 years. A 5-year history of slowness walking, slurred speech and progressive unsteadiness was also present. On
SC
examination, posture was stooped with instability, gait was broad-based and reflexes were exaggerated with bilateral extensor plantar responses. Polyminimyoclonus of the outstretched hands was accompanied by
M AN U
bradykinesia, ptosis and miosis of the left pupil with hip flexion weakness. The initial working diagnosis was of predominantly cerebellar type MSA (MSA-C).
However, a 123I-FP-CIT single photon emission computed tomography
TE D
(SPECT) scan was normal, throwing doubt upon the diagnosis of MSA-C (see figure 1a). Multiple additional investigations were performed including genetic analysis for polymerase gamma (POLG) mutations, mitochondrial genomic mutations and autosomal dominant spinocerebellar ataxias. A muscle biopsy
EP
(thigh) demonstrated marked type 2 fibre atrophy and myofibrillary degeneration of type 1 fibres, appearances of early denervation. Anal
AC C
sphincter EMG was abnormal. Oral levodopa therapy provided a modest improvement in gait. Over a 12-month period he developed further symmetrical akinesia and rigidity before dying of a pulmonary embolus within a year of normal dopamine transporter imaging.
Post-mortem brain examination did not demonstrate any cerebellar atrophy. Microscopically there was chronic Purkinje cell loss with neuronal loss and some pigmentary incontinence of the substantia nigra, but with preservation of a majority of nigral neurons. There was generalized alpha synuclein-positive glial cytoplasmic inclusions but with major involvement of the striatum, cerebellar white matter and the substantia nigra (figure 1b demonstrates 2
ACCEPTED MANUSCRIPT nigral pathology and figure 1c cerebellar pathology). Lewy bodies and neurofibrillary tangles were not identified. These clinical and pathological findings were compatible with a diagnosis of definite MSA with a pathological grading of OPCA I-II with SND I as per the proposed grading system of
RI PT
Jellinger and colleagues [1].
Normal dopamine transporter (DAT) imaging after 10 years of MSA with clear Parkinsonism is noteworthy as DAT SPECT evidence of subclinical
nigrostriatal dysfunction is present in the majority of patients with possible/
SC
probable MSA-C [2]. In patients with a clinical diagnosis of Parkinsonism, 123IIoflupane SPECT has a sensitivity of 97% in identifying nigrostriatal degeneration [3], aiding diagnosis and impacting on management of patients
M AN U
with clinically uncertain Parkinsonian syndromes [4]. In distinguishing presynaptic Parkinsonism from other etiologies, DAT SPECT has been shown to have a positive predictive value of 100% [5]. Relative preservation of nigral neurons may explain the normal DAT scan in our patient. We postulate that Parkinsonism resulted from post-synaptic degeneration of nigrostriatal
TE D
dopaminergic transmission although striatal cell loss was not documented on pathological examination [6]. This possibility is supported by a modest initial and subsequently waning response to levodopa in life. In clinicopathological series, MSA-P cases demonstrate a correlation between the severity grade of
EP
nigral pathology and Parkinsonism [1]. This correlation is not seen in MSA-C, in which a variety of OPCA severity grades are associated with varying
AC C
degrees of nigral degeneration “ with or without correlating clinical parkinsonian signs” [1]. Ozawa et al, in a clinicopathological series of 100 cases of MSA identified Parkinsonism in 87.5% of ‘OPCA’-type MSA cases with grade 1 nigral pathology and notably given that concomitant putaminal involvement was seen in all cases, they speculate that the combination of pathology in these two structures results in clinical Parkinsonism [7].
Our patient had several rare clinical features (ptosis, miosis, weakness and muscular atrophy) reminiscent of those seen in the historical “full syndrome” described by Shy and Drager in 1960 [8]. We believe that it is important that
3
ACCEPTED MANUSCRIPT the clinician is not deterred from a clinical diagnosis of MSA by normal DAT
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EP
TE D
M AN U
SC
RI PT
imaging.
4
ACCEPTED MANUSCRIPT References:
1. Jellinger KA, Seppi K and Wenning GK. Grading of neuropathology in Multiple System Atrophy: proposal of a novel scale. Movement Disorders 2005. 20(supp12): S29-S36.
RI PT
2. Munoz E, Iranzo A, Rauek S, Lomena F, Gallego J, Ros D et al. Subclinical nigrostriatal dopaminergic denervation in the cerebellar
subtype of multiple system atrophy (MSA-C). Journal of Neurology 2011; 258(12):2248-2253.
SC
3. Benamer HT, Patterson J, Grosset DG, Booij J, de Bruin K, van Royen E et al. Accurate differentiation of Parkinsonism and Essential Tremor using visual assessment of [123I]-FP-CIT SPECT imaging: The [123I]-FP-
M AN U
CIT study group. Movement Disorders 2000; 15(3): 503-510. 4. Catafau AM and Tolosa E. Impact of Dopamine Transporter SPECT using 123I-Ioflupane on diagnosis and managements of patients with clinically uncertain Parkinsonian syndromes. Movement Disorders 2004; 19(10): 1175-1182.
5. Booij J, Speelman JD, Horstink MWIM, Wolters EC. The clinical
TE D
benefit of imaging with [123I]-FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism. European Journal of Nuclear Medicine 2001; 28(3):
EP
266-272.
6. Wenning GK, Tison F, Shlomo B, Daniel SE and Quinn NP. Multiple
AC C
System Atrophy: a review of 203 pathologically proven cases. Movement Disorders 1997. 12(2):133-147.
7. Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, Kilford L, Healy DG, Wood NW, Lees AJ, Holton JL and Revesz T. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 2004. 127: 2657-2671 8. Shy GM and Drager GA. A neurological syndrome associated with orthostatic hypotension. A clinic-pathologic study. Archives of Neurology 1960; 2: 511-527.
5
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ACCEPTED MANUSCRIPT
Figure 1:
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(a) 123I-FP-CIT SPECT scan demonstrating normal radioligand uptake. (b) Immunostaining of substantia nigra showing α-synuclein positive glial inclusions (arrows) and background pigmentary incontinence.
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glial inclusions.
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(c) Cerebellar white matter showing numerous α-synuclein immunopositive
6
ACCEPTED MANUSCRIPT Author contributions:
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EP
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M AN U
SC
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Dr McKinley wrote the manuscript and it was reviewed and/or revised by Dr O’Connell and Professors Farrell and Lynch.
7
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EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1353-8020(14)00175-8
DOI:
10.1016/j.parkreldis.2014.04.022
Reference:
PRD 2331
To appear in:
Parkinsonism and Related Disorders
Received Date: 13 December 2013 Revised Date:
14 April 2014
Accepted Date: 15 April 2014
Please cite this article as: McKinley J, O’Connell M, Farrell M, Lynch T, Normal dopamine transporter imaging does not exclude Multiple System Atrophy, Parkinsonism and Related Disorders (2014), doi: 10.1016/j.parkreldis.2014.04.022. 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 Parkinsonism and Related Disorders Letter Submission
John McKinley MB(Hons), MMedSc, MRCP(UK)1 Martin O’Connell FRCPI2 Michael Farrell FRCPI, FRCPC, FRCPath3 Timothy Lynch BSc, MB, FRCPI, FRCP(Lond)1
RI PT
Title: Normal dopamine transporter imaging does not exclude Multiple System Atrophy.
Corresponding author:
M AN U
SC
1. Department of Neurology, Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles St Dublin 7. 2. Department of Radiology, Mater Misericordiae University Hospital, 57 Eccles St Dublin 7. 3. Department of Neuropathology and Dublin Brain Bank, Beaumont Hospital, Dublin 9.
Word count: 657 References: 8
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Dr John McKinley, Dublin Academic Medical Centre Fellow in Movement Disorders, Dublin Neurological Institute, 57 Eccles St, Dublin 7. Email: [email protected], telephone: 00447834228893.
EP
Key words: MSA, Dopamine transporter imaging, SPECT. Running title: MSA normal DaTSCAN Financial Disclosures:
AC C
Drs McKinley, O’Connell and Professor Farrell report no disclosures. Professor Lynch receives honoraria from Abbot, Boehringer Ingelheim, Lundbeck and Orion. He has received educational grants from Bayler Schering, Biogen Idec, Lundbeck and Medtronic. He has received grants from the Irish Institute of Clinical Neuroscience, the Mater College and PRTL1 funding. Professor Lynch sits on the advisory boards of Abbot, Novartis, UCB Pharma, Teva, Merck Serono and Biogen Idec. Research Funding: N/A
1
ACCEPTED MANUSCRIPT To the editors:
A 56-year-old man had a 10-year history of erectile dysfunction and incomplete bladder emptying resulting in mild renal dysfunction. Ultrasonography identified moderate bilateral hydronephrosis and bladder
RI PT
trabeculation. Recurrent syncope from postural hypotension (149/97 mmHg supine, 97/62mmHg standing), post-prandial presyncope and aching leg
muscles were present for 7 years. A 5-year history of slowness walking, slurred speech and progressive unsteadiness was also present. On
SC
examination, posture was stooped with instability, gait was broad-based and reflexes were exaggerated with bilateral extensor plantar responses. Polyminimyoclonus of the outstretched hands was accompanied by
M AN U
bradykinesia, ptosis and miosis of the left pupil with hip flexion weakness. The initial working diagnosis was of predominantly cerebellar type MSA (MSA-C).
However, a 123I-FP-CIT single photon emission computed tomography
TE D
(SPECT) scan was normal, throwing doubt upon the diagnosis of MSA-C (see figure 1a). Multiple additional investigations were performed including genetic analysis for polymerase gamma (POLG) mutations, mitochondrial genomic mutations and autosomal dominant spinocerebellar ataxias. A muscle biopsy
EP
(thigh) demonstrated marked type 2 fibre atrophy and myofibrillary degeneration of type 1 fibres, appearances of early denervation. Anal
AC C
sphincter EMG was abnormal. Oral levodopa therapy provided a modest improvement in gait. Over a 12-month period he developed further symmetrical akinesia and rigidity before dying of a pulmonary embolus within a year of normal dopamine transporter imaging.
Post-mortem brain examination did not demonstrate any cerebellar atrophy. Microscopically there was chronic Purkinje cell loss with neuronal loss and some pigmentary incontinence of the substantia nigra, but with preservation of a majority of nigral neurons. There was generalized alpha synuclein-positive glial cytoplasmic inclusions but with major involvement of the striatum, cerebellar white matter and the substantia nigra (figure 1b demonstrates 2
ACCEPTED MANUSCRIPT nigral pathology and figure 1c cerebellar pathology). Lewy bodies and neurofibrillary tangles were not identified. These clinical and pathological findings were compatible with a diagnosis of definite MSA with a pathological grading of OPCA I-II with SND I as per the proposed grading system of
RI PT
Jellinger and colleagues [1].
Normal dopamine transporter (DAT) imaging after 10 years of MSA with clear Parkinsonism is noteworthy as DAT SPECT evidence of subclinical
nigrostriatal dysfunction is present in the majority of patients with possible/
SC
probable MSA-C [2]. In patients with a clinical diagnosis of Parkinsonism, 123IIoflupane SPECT has a sensitivity of 97% in identifying nigrostriatal degeneration [3], aiding diagnosis and impacting on management of patients
M AN U
with clinically uncertain Parkinsonian syndromes [4]. In distinguishing presynaptic Parkinsonism from other etiologies, DAT SPECT has been shown to have a positive predictive value of 100% [5]. Relative preservation of nigral neurons may explain the normal DAT scan in our patient. We postulate that Parkinsonism resulted from post-synaptic degeneration of nigrostriatal
TE D
dopaminergic transmission although striatal cell loss was not documented on pathological examination [6]. This possibility is supported by a modest initial and subsequently waning response to levodopa in life. In clinicopathological series, MSA-P cases demonstrate a correlation between the severity grade of
EP
nigral pathology and Parkinsonism [1]. This correlation is not seen in MSA-C, in which a variety of OPCA severity grades are associated with varying
AC C
degrees of nigral degeneration “ with or without correlating clinical parkinsonian signs” [1]. Ozawa et al, in a clinicopathological series of 100 cases of MSA identified Parkinsonism in 87.5% of ‘OPCA’-type MSA cases with grade 1 nigral pathology and notably given that concomitant putaminal involvement was seen in all cases, they speculate that the combination of pathology in these two structures results in clinical Parkinsonism [7].
Our patient had several rare clinical features (ptosis, miosis, weakness and muscular atrophy) reminiscent of those seen in the historical “full syndrome” described by Shy and Drager in 1960 [8]. We believe that it is important that
3
ACCEPTED MANUSCRIPT the clinician is not deterred from a clinical diagnosis of MSA by normal DAT
AC C
EP
TE D
M AN U
SC
RI PT
imaging.
4
ACCEPTED MANUSCRIPT References:
1. Jellinger KA, Seppi K and Wenning GK. Grading of neuropathology in Multiple System Atrophy: proposal of a novel scale. Movement Disorders 2005. 20(supp12): S29-S36.
RI PT
2. Munoz E, Iranzo A, Rauek S, Lomena F, Gallego J, Ros D et al. Subclinical nigrostriatal dopaminergic denervation in the cerebellar
subtype of multiple system atrophy (MSA-C). Journal of Neurology 2011; 258(12):2248-2253.
SC
3. Benamer HT, Patterson J, Grosset DG, Booij J, de Bruin K, van Royen E et al. Accurate differentiation of Parkinsonism and Essential Tremor using visual assessment of [123I]-FP-CIT SPECT imaging: The [123I]-FP-
M AN U
CIT study group. Movement Disorders 2000; 15(3): 503-510. 4. Catafau AM and Tolosa E. Impact of Dopamine Transporter SPECT using 123I-Ioflupane on diagnosis and managements of patients with clinically uncertain Parkinsonian syndromes. Movement Disorders 2004; 19(10): 1175-1182.
5. Booij J, Speelman JD, Horstink MWIM, Wolters EC. The clinical
TE D
benefit of imaging with [123I]-FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism. European Journal of Nuclear Medicine 2001; 28(3):
EP
266-272.
6. Wenning GK, Tison F, Shlomo B, Daniel SE and Quinn NP. Multiple
AC C
System Atrophy: a review of 203 pathologically proven cases. Movement Disorders 1997. 12(2):133-147.
7. Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, Kilford L, Healy DG, Wood NW, Lees AJ, Holton JL and Revesz T. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 2004. 127: 2657-2671 8. Shy GM and Drager GA. A neurological syndrome associated with orthostatic hypotension. A clinic-pathologic study. Archives of Neurology 1960; 2: 511-527.
5
SC
RI PT
ACCEPTED MANUSCRIPT
Figure 1:
M AN U
(a) 123I-FP-CIT SPECT scan demonstrating normal radioligand uptake. (b) Immunostaining of substantia nigra showing α-synuclein positive glial inclusions (arrows) and background pigmentary incontinence.
AC C
EP
glial inclusions.
TE D
(c) Cerebellar white matter showing numerous α-synuclein immunopositive
6
ACCEPTED MANUSCRIPT Author contributions:
AC C
EP
TE D
M AN U
SC
RI PT
Dr McKinley wrote the manuscript and it was reviewed and/or revised by Dr O’Connell and Professors Farrell and Lynch.
7
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EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
