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Markedly asymmetric presentation in multiple system atrophy
Parkinsonism and Related Disorders 19 (2013) 901e905
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Markedly asymmetric presentation in multiple system atrophy Amit Batla a, Maria Stamelou a, Katerina Mensikova b, Michaela Kaiserova b, Lucie Tuckova c, Petr Kanovsky d, Niall Quinn e, Kailash P. Bhatia a, * a
Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom Movement Disorders Center, Department of Neurology, Palacky University Medical School, Olomouc, Czech Republic c Department of Pathology, Palacky University Medical School, Olomouc, Czech Republic d Department of Neurology, Palacky University Medical School, University Hospital, Olomouc, Czech Republic e National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 March 2013 Received in revised form 26 April 2013 Accepted 5 May 2013
Background: Multiple system atrophy (MSA) presents with fairly symmetrical, levodopa unresponsive parkinsonism and additional features like autonomic dysfunction, cerebellar and corticospinal tract involvement. Marked asymmetry in atypical parkinsonism suggests alternative diagnosis like Corticobasal syndrome (CBS). Methods: We describe five unusual cases, who presented initially with markedly asymmetric parkinsonism, rigid dystonic abnormal limb posturing and subsequently developed clinical and/or radiological features consistent with probable MSA-P. Results: Using the internationally accepted diagnostic criteria, the patients fulfilled the diagnostic criteria for probable MSA-P after 5 years from disease onset. Case 4 and 5 had characteristic MRI features and Case 2 was pathologically confirmed. Conclusions: We use these cases to highlight that MSA-P MSA-P can present rarely with very marked asymmetry, dystonic limb and myoclonic jerks leading to a diagnosis of CBS at onset. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Corticobasal syndrome Corticobasal degeneration Multiple system atrophy Parkinsonism Atypical parkinsonism Asymmetry
1. Introduction Multiple system atrophy (MSA) is an atypical parkinsonian syndrome typically presenting with fairly symmetrical, levodopa unresponsive parkinsonism and additional features like autonomic dysfunction, cerebellar and corticospinal tract involvement [1]. Other characteristic features include a jerky tremor, dysarthria, dysphonia, dysphagia, stridor, inspiratory sighs, orofacial dystonia, anterocollis, camptocormia or Pisa syndrome, and cold extremities [1,2]. Cognition is typically not affected [2]. Corticobasal syndrome (CBS) is characterized by progressive levodopa unresponsive, asymmetric parkinsonism, dystonia and focal cortical signs (e.g. cortical myoclonus, apraxia, cortical sensory loss, alien limb phenomena) [3]. CBS is the typical phenotype in corticobasal degeneration (CBD), but can be also due to other disorders like progressive supranuclear palsy, frontotemporal
* Corresponding author. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology Queen Square, London WC1N 3BG, United Kingdom. Tel.: þ44 203 108 0023. E-mail address: [email protected] (K.P. Bhatia). 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.05.004
dementia and others [3]. However, CBS has not been described as a phenotype for MSA. Here we describe five patients who initially presented with markedly asymmetric atypical parkinsonism and were initially diagnosed as CBS. They were subsequently diagnosed as MSA based on pathology in one and Probable MSA based on clinical and radiologic features (in 2 cases) that developed later in disease course. We wish to highlight that amongst atypical parkinsonism, MSA may rarely present as with marked asymmetry and some other features like myoclonus suggesting CBS at onset. Written consent for videos and participation in research was taken from the patients included. Supplementary video related to this article can be found online at 10.1016/j.parkreldis.2013.05.004. 2. Case 1 This 70-year-old lady first noticed difficulty using her right hand at the age of 64 years, which progressed and the hand became clumsy, useless and slow in performing tasks. Over the next two years, she additionally developed gait difficulty with festination. Levodopa did not improve her symptoms. On examination at that time she had broken smooth pursuit but normal saccades. There
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A. Batla et al. / Parkinsonism and Related Disorders 19 (2013) 901e905
was a jerky postural tremor of the right arm, which was held rigid and dystonic. There were stimulus sensitive myoclonic jerks of both upper limbs right more than left. She had ideomotor apraxia on right side. There was no cortical sensory loss, and no cognitive dysfunction. There were no cerebellar or pyramidal signs. A diagnosis of CBS was made [4]. Four years after onset she developed marked autonomic dysfunction with postural hypotension and urinary incontinence. She became wheelchair bound within few months, and developed a marked anterocollis. She developed swallowing problems and respiratory difficulties with stridor and inspiratory sighs, later necessitating tracheostomy (Video case 1) (Table 1). Her cognition remained intact despite this progression (verbal IQ 96 and performance IQ was 104). The diagnosis was revised and she was diagnosed as probable MSA-Parkinsonism (MSA-P) [1]. Autonomic tests done at 5 years suggested marked autonomic dysfunction. The MRI suggested nonspecific small vessel disease. Dopamine transporters imaging (DaTSCAN) showed bilaterally, asymmetric reduced dopaminergic uptake left > right. Electrophysiology suggested positive and negative myoclonus of cortical origin. 3. Case 2 This 64 years old lady was first noticed to have difficulty with writing (agramatism and agraphia) the right hand. Over the next two years dystonia and rigidity of right upper and lower limbs developed. On examination at two years she had an asymmetric parkinsonian that did not respond to levodopa. MRI brain was normal. The clinical diagnosis of CBS was made at that visit. Subsequently over 5 years postural instability, orthostatic hypotension, pyramidal signs and the bladder dysfunction appeared. She developed severe dysphonia, inspiratory stridor and camptocormia. Autonomic testing supported orthostatic hypotension, and the urodynamic study suggested detrusor hyperreflexia. She required tracheostomy and gradually became immobile and bedridden; but her cognition was still fairly good (MMSE score 26). The diagnosis was revised and she was diagnosed as probable MSAP [1]. Finally, the patient died due to bronchopneumonia after (approximately) 5 years of the disease course. The neuropathological examination of the brain was done; on macroscopic examination the cerebellar atrophy (Fig. 1a), atrophy of the pons base (Fig. 1b) and atrophy with grayish discoloration of putamen (Fig. 1c) were present which is contrasted with normal coronal section for comparison. On microscopic and immunohistochemical examination, there was a typical alpha-synucleinopathy with argyrophilic oligodendroglial cytoplasmic inclusions in the striatum, cerebellum and oblongata present (Fig. 1d and e), confirming the definite diagnosis of multiple system atrophy Fig. 2. 4. Case 3 This 76-year-old gentleman presented with a postural tremor in the right hand which began at the age of 72 years. This was associated with abnormal posturing of the hand and decline in dexterity for routine activities. On examination two years after onset he had slowing of saccades but normal range of eye movements. He had dystonic posturing of the right hand with postural tremor and some myoclonic jerks in the outstretched arms. At 2 years due to the atypical asymmetric parkinsonism which did not respond to Levodopa he was diagnosed as CBS. Three years subsequently he developed autonomic disturbance with erectile dysfunction, and a tendency to fall on standing from chair. REM sleep behavior disorder and swallowing difficulty with frequent choking were added on in the fourth
year. When seen five years after onset he had urinary problems needing an indwelling catheter. On examination at 5 years his saccades were mildly slow as before (Table 1). There was asymmetric rigidity with bilateral jerky tremor more on right side (video case 3). His cognition was intact. His diagnosis was revised to MSA-P. In terms of investigations there was evidence of orthostatic hypotension on autonomic tests. His brain MRI had been done twice and was normal. On electrophysiology the jerks were cortical in origin with positive and negative myoclonus. 5. Case 4 A 67-year-old female presented with a 4 year history starting as difficulty with her left leg and could not put her shoe on. She also noticed some dragging of her left foot. On examination one year after onset the left hand was held rigid, mildly flexed and she had a few jerks of her left hand fingers. There was no clear apraxia. At one years due to the atypical asymmetric parkinsonism which did not respond to Levodopa she was diagnosed as CBS. Two years subsequently, she developed urinary urgency and frequency with orthostatic hypotension suggesting autonomic disturbance. On examination at 5 years there was asymmetric rigidity with jerky tremor on left side (video case 4). Cognition was intact. Clinical diagnosis was revised to MSA-P and MRI brain showed hemosiderin deposition in the lateral aspect of the right putamen, and loss of volume in middle cerebral peduncle. 6. Case 5 This 51 year-old lady first noticed difficulty using the left hand at the age of 45 yrs. This was associated with slowness, rigidity and a postural tremor of the left forearm. She developed dystonic posturing of her arm and difficulty in using it purposefully. 2 years after the onset she had asymmetric parkinsonism and right-sided myoclonus. On examination she had slow saccades and dystonic left limb with multifocal stimulus sensitive myoclonus. She had some difficulty with copying gestures but no clear apraxia. She was diagnosed as CBS at this visit. Subsequently her gait became slower and she started to fall. She developed bladder dysfunction and other autonomic features. On examination at 5 years she had anterocollis and severe quivery dysarthria. She was still asymmetric at 5 years from onset. Her cognition had still been good though she had been completely bedridden since one year. The diagnosis was revised and she was diagnosed as probable MSA-P [1]. The investigations supported orthostatic hypotension on autonomic tests. MRI brain 5 years into the illness showed mineralization of globi pallidi and dorsal putamina with iron, greater in amount on the left, suggestive of MSA (previous scan at 2 years being normal). DaT scan suggested asymmetric loss of dopaminergic uptake. Myoclonus was electrophysiologically cortical in origin. 7. Discussion We described here five patients presenting with markedly asymmetric parkinsonism with dystonia initially diagnosed as CBS [4] that later in the disease course (5 years after onset) became less asymmetric and developed autonomic features and respiratory problems that led to a final diagnosis of probable MSA-P [1]. Case 4 and 5 had characteristic MRI features and Case 2 was pathologically confirmed. The main signs that led to CBS diagnosis initially (asymmetric akineticerigid syndrome, limb dystonia, myoclonus and ideomotor
A. Batla et al. / Parkinsonism and Related Disorders 19 (2013) 901e905
903
Fig. 1. a Prominent cerebellar atrophy (when compared with normal cerebellum on the right). b Atrophy of the pons. c Atrophy and greyish dyscoloration of the putamen on both sides, matched with a section from a normal brain. d Typical alpha-synucleinopathy with olidendroglial argyrophylic cytoplasmic inclusions (striatum). e Typical alphasynucleinopathy with oligodendroglial argyrophylic cytoplasmic inclusions (cerebellum).
apraxia (in case 1)), are considered typical for CBD [5], and are rare in MSA [2]. Marked persistent asymmetry is seen in only 8.6%e33% [6] of the MSA cases, whereas is reported in up to 60% in pathological [5] and up to 95% in clinical series of CBS [7]. Limb dystonia occurs less frequently in MSA than CBS (15e30% [8] vs. 70%, respectively) [9] and anterocollis which is the most common form of dystonia in MSA [8] is uncommon in CBS [5,9]. Focal reflex myoclonus in CBS [4] is usually focal, stimulus sensitive, asymmetric limb myoclonus and commonly associated with limb dystonia [9]. In contrast, the myoclonus in MSA usually presents as a symmetric, fine distal jerky tremor or polyminimyoclonus [2,10,11] The myoclonus seen in two of our patients initially was documented as typical focal reflex myoclonus consistent with CBS, but was later superimposed by the typical jerky tremor seen in MSA. Ideomotor apraxia is a characteristic feature of CBS and has been reported in 75e92% of the cases, while is rare and mild in pathologically proven MSA patients [2]. Only two of our patients had documented ideomotor apraxia (case 1 and 5). However, apraxia is not necessary to diagnose CBS if any other features of focal cortical involvement are present [4].
In hind sight, there were some clues which were against a diagnosis of CBS in our patients. There was normal cognition, and lack of apraxia in three of the patients. Cognitive impairment is well recognized in CBS with language, frontal and visuospatial impairment (13), while is largely preserved in MSA even in advanced stages of the disease [2] and in fact dementia is an exclusion criterion for the diagnosis of MSA [1]. Early impairment of eye movements with slow saccades is well described in CBS [3,4] while it is generally accepted that early presence of gaze palsy is against the diagnosis of MSA [1,2]. Interestingly, the autonomic features that are mandatory for diagnosis in MSA [1] and can be the presenting feature at onset in up to 41% of the MSA patients, were absent in the first two years and appeared later in the disease course in our patients, hence MSA was thought to be initially unlikely. Autonomic features are present in up to 97% in pathological series at final visit in MSA [10]. In contrast, severe autonomic features in CBS are uncommon (0e 28.5%) [4]. In summary, these cases highlight the fact that MSA-P can present rarely with very marked asymmetry, dystonic limb and
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A. Batla et al. / Parkinsonism and Related Disorders 19 (2013) 901e905
Fig. 2. a MRI case 4 SWI sequence showing iron deposition in lateral aspect of the right putamen. b MRI Case 5 GRE sequence showing Iron deposition in globi pallidi and dorsal putamina.
myoclonic jerks leading to CBS diagnosed at onset. In addition to autonomic features, preserved cognition and respiratory difficulties may be helpful in the clinical diagnosis of MSA.
Disclosures Amit Batla has no financial disclosures pertaining to this work. Katerina Mensikova was supported by the grant IGA UP LF2012-013. Kailash P Bhatia received funding for travel from GlaxoSmithKline, Orion Corporation, Ipsen, and Merz Pharmaceuticals, LLC; serves on the editorial boards of Movement Disorders and Therapeutic Advances in Neurological Disorders; receives royalties from the publication of Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders (Oxford University Press, 2008) and Marsden’s book of movement disorders (Oxford University Press, 2012); received speaker honoraria from GlaxoSmithKline, Ipsen, Merz Pharmaceuticals, LLC, and Sun Pharmaceutical Industries Ltd.; personal compensation for scientific advisory board for GSK and Boehringer Ingelheim; received research support from Ipsen and from the Halley Stewart Trust through Dystonia Society UK, and the Wellcome Trust MRC strategic neurodegenerative disease initiative award (Ref. number WT089698), a grant from the Dystonia Coalition and a grant from Parkinson’s UK (Ref. number G-1009). Maria Stamelou has no financial disclosures pertaining to this work.
Michaela Kaiserova was supported by the grant from IGA UP LF-2012-013. Lucie Tuckova was supported by the grant IGA UP LF-2012-013. Petr Kanovsky received speaker honoraria from Merz, Allergan, Ipsen, Medtronic, UCB and Abbott, personal compensation for scientific advisory board for Merz, GSK and Novartis, and was supported by the grant IGA MZ CR e NT12221-5/2011. Appendix A. Supplementary data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.parkreldis.2013.05.004. References [1] Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71:670e6. [2] Quinn NP. How to diagnose multiple system atrophy. Mov Disord 2005;20(Suppl. 12):S5e10. [3] Boeve BF. The multiple phenotypes of corticobasal syndrome and corticobasal degeneration: implications for further study. J Mol Neurosci 2011;45:350e3. [4] Lang AE, Riley DE, Bergeron C. Cortico-basal ganglionic degeneration. In: Calne DB, editor. Neurodegenerative diseases. Philadelphia: WB Saunders; 1994. p. 877e94. [5] Litvan I, Grimes DA, Lang AE, Jankovic J, McKee A, Verny M, et al. Clinical features differentiating patients with postmortem confirmed progressive supranuclear palsy and corticobasal degeneration. J Neurol 1999;246(Suppl. 2). II1-5.
A. Batla et al. / Parkinsonism and Related Disorders 19 (2013) 901e905 [6] Iodice V, Lipp A, Ahlskog JE, Sandroni P, Fealey RD, Parisi JE, et al. Autopsy confirmed multiple system atrophy cases: mayo experience and role of autonomic function tests. J Neurol Neurosurg Psychiatry 2012. [7] Kollensperger M, Geser F, Ndayisaba JP, Boesch S, Seppi K, Ostergaard K, et al. Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry. Move Disord Off J Move Disord Soc 2010;25:2604e12. [8] Boesch SM, Wenning GK, Ransmayr G, Poewe W. Dystonia in multiple system atrophy. J Neurol Neurosurg Psychiatry 2002;72:300e3.
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[9] Stamelou M, Alonso-Canovas A, Bhatia KP. Dystonia in corticobasal degeneration: a review of the literature on 404 pathologically proven cases. Mov Disord 2012;27:696e702. [10] Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, Quinn NP. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain 1994;117(Pt 4):835e45. [11] Wenning GK, Litvan I, Jankovic J, Granata R, Mangone CA, McKee A, et al. Natural history and survival of 14 patients with corticobasal degeneration confirmed at postmortem examination. J Neurol Neurosurg Psychiatry 1998;64:184e9.
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Markedly asymmetric presentation in multiple system atrophy Amit Batla a, Maria Stamelou a, Katerina Mensikova b, Michaela Kaiserova b, Lucie Tuckova c, Petr Kanovsky d, Niall Quinn e, Kailash P. Bhatia a, * a
Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom Movement Disorders Center, Department of Neurology, Palacky University Medical School, Olomouc, Czech Republic c Department of Pathology, Palacky University Medical School, Olomouc, Czech Republic d Department of Neurology, Palacky University Medical School, University Hospital, Olomouc, Czech Republic e National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 March 2013 Received in revised form 26 April 2013 Accepted 5 May 2013
Background: Multiple system atrophy (MSA) presents with fairly symmetrical, levodopa unresponsive parkinsonism and additional features like autonomic dysfunction, cerebellar and corticospinal tract involvement. Marked asymmetry in atypical parkinsonism suggests alternative diagnosis like Corticobasal syndrome (CBS). Methods: We describe five unusual cases, who presented initially with markedly asymmetric parkinsonism, rigid dystonic abnormal limb posturing and subsequently developed clinical and/or radiological features consistent with probable MSA-P. Results: Using the internationally accepted diagnostic criteria, the patients fulfilled the diagnostic criteria for probable MSA-P after 5 years from disease onset. Case 4 and 5 had characteristic MRI features and Case 2 was pathologically confirmed. Conclusions: We use these cases to highlight that MSA-P MSA-P can present rarely with very marked asymmetry, dystonic limb and myoclonic jerks leading to a diagnosis of CBS at onset. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Corticobasal syndrome Corticobasal degeneration Multiple system atrophy Parkinsonism Atypical parkinsonism Asymmetry
1. Introduction Multiple system atrophy (MSA) is an atypical parkinsonian syndrome typically presenting with fairly symmetrical, levodopa unresponsive parkinsonism and additional features like autonomic dysfunction, cerebellar and corticospinal tract involvement [1]. Other characteristic features include a jerky tremor, dysarthria, dysphonia, dysphagia, stridor, inspiratory sighs, orofacial dystonia, anterocollis, camptocormia or Pisa syndrome, and cold extremities [1,2]. Cognition is typically not affected [2]. Corticobasal syndrome (CBS) is characterized by progressive levodopa unresponsive, asymmetric parkinsonism, dystonia and focal cortical signs (e.g. cortical myoclonus, apraxia, cortical sensory loss, alien limb phenomena) [3]. CBS is the typical phenotype in corticobasal degeneration (CBD), but can be also due to other disorders like progressive supranuclear palsy, frontotemporal
* Corresponding author. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology Queen Square, London WC1N 3BG, United Kingdom. Tel.: þ44 203 108 0023. E-mail address: [email protected] (K.P. Bhatia). 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.05.004
dementia and others [3]. However, CBS has not been described as a phenotype for MSA. Here we describe five patients who initially presented with markedly asymmetric atypical parkinsonism and were initially diagnosed as CBS. They were subsequently diagnosed as MSA based on pathology in one and Probable MSA based on clinical and radiologic features (in 2 cases) that developed later in disease course. We wish to highlight that amongst atypical parkinsonism, MSA may rarely present as with marked asymmetry and some other features like myoclonus suggesting CBS at onset. Written consent for videos and participation in research was taken from the patients included. Supplementary video related to this article can be found online at 10.1016/j.parkreldis.2013.05.004. 2. Case 1 This 70-year-old lady first noticed difficulty using her right hand at the age of 64 years, which progressed and the hand became clumsy, useless and slow in performing tasks. Over the next two years, she additionally developed gait difficulty with festination. Levodopa did not improve her symptoms. On examination at that time she had broken smooth pursuit but normal saccades. There
902
A. Batla et al. / Parkinsonism and Related Disorders 19 (2013) 901e905
was a jerky postural tremor of the right arm, which was held rigid and dystonic. There were stimulus sensitive myoclonic jerks of both upper limbs right more than left. She had ideomotor apraxia on right side. There was no cortical sensory loss, and no cognitive dysfunction. There were no cerebellar or pyramidal signs. A diagnosis of CBS was made [4]. Four years after onset she developed marked autonomic dysfunction with postural hypotension and urinary incontinence. She became wheelchair bound within few months, and developed a marked anterocollis. She developed swallowing problems and respiratory difficulties with stridor and inspiratory sighs, later necessitating tracheostomy (Video case 1) (Table 1). Her cognition remained intact despite this progression (verbal IQ 96 and performance IQ was 104). The diagnosis was revised and she was diagnosed as probable MSA-Parkinsonism (MSA-P) [1]. Autonomic tests done at 5 years suggested marked autonomic dysfunction. The MRI suggested nonspecific small vessel disease. Dopamine transporters imaging (DaTSCAN) showed bilaterally, asymmetric reduced dopaminergic uptake left > right. Electrophysiology suggested positive and negative myoclonus of cortical origin. 3. Case 2 This 64 years old lady was first noticed to have difficulty with writing (agramatism and agraphia) the right hand. Over the next two years dystonia and rigidity of right upper and lower limbs developed. On examination at two years she had an asymmetric parkinsonian that did not respond to levodopa. MRI brain was normal. The clinical diagnosis of CBS was made at that visit. Subsequently over 5 years postural instability, orthostatic hypotension, pyramidal signs and the bladder dysfunction appeared. She developed severe dysphonia, inspiratory stridor and camptocormia. Autonomic testing supported orthostatic hypotension, and the urodynamic study suggested detrusor hyperreflexia. She required tracheostomy and gradually became immobile and bedridden; but her cognition was still fairly good (MMSE score 26). The diagnosis was revised and she was diagnosed as probable MSAP [1]. Finally, the patient died due to bronchopneumonia after (approximately) 5 years of the disease course. The neuropathological examination of the brain was done; on macroscopic examination the cerebellar atrophy (Fig. 1a), atrophy of the pons base (Fig. 1b) and atrophy with grayish discoloration of putamen (Fig. 1c) were present which is contrasted with normal coronal section for comparison. On microscopic and immunohistochemical examination, there was a typical alpha-synucleinopathy with argyrophilic oligodendroglial cytoplasmic inclusions in the striatum, cerebellum and oblongata present (Fig. 1d and e), confirming the definite diagnosis of multiple system atrophy Fig. 2. 4. Case 3 This 76-year-old gentleman presented with a postural tremor in the right hand which began at the age of 72 years. This was associated with abnormal posturing of the hand and decline in dexterity for routine activities. On examination two years after onset he had slowing of saccades but normal range of eye movements. He had dystonic posturing of the right hand with postural tremor and some myoclonic jerks in the outstretched arms. At 2 years due to the atypical asymmetric parkinsonism which did not respond to Levodopa he was diagnosed as CBS. Three years subsequently he developed autonomic disturbance with erectile dysfunction, and a tendency to fall on standing from chair. REM sleep behavior disorder and swallowing difficulty with frequent choking were added on in the fourth
year. When seen five years after onset he had urinary problems needing an indwelling catheter. On examination at 5 years his saccades were mildly slow as before (Table 1). There was asymmetric rigidity with bilateral jerky tremor more on right side (video case 3). His cognition was intact. His diagnosis was revised to MSA-P. In terms of investigations there was evidence of orthostatic hypotension on autonomic tests. His brain MRI had been done twice and was normal. On electrophysiology the jerks were cortical in origin with positive and negative myoclonus. 5. Case 4 A 67-year-old female presented with a 4 year history starting as difficulty with her left leg and could not put her shoe on. She also noticed some dragging of her left foot. On examination one year after onset the left hand was held rigid, mildly flexed and she had a few jerks of her left hand fingers. There was no clear apraxia. At one years due to the atypical asymmetric parkinsonism which did not respond to Levodopa she was diagnosed as CBS. Two years subsequently, she developed urinary urgency and frequency with orthostatic hypotension suggesting autonomic disturbance. On examination at 5 years there was asymmetric rigidity with jerky tremor on left side (video case 4). Cognition was intact. Clinical diagnosis was revised to MSA-P and MRI brain showed hemosiderin deposition in the lateral aspect of the right putamen, and loss of volume in middle cerebral peduncle. 6. Case 5 This 51 year-old lady first noticed difficulty using the left hand at the age of 45 yrs. This was associated with slowness, rigidity and a postural tremor of the left forearm. She developed dystonic posturing of her arm and difficulty in using it purposefully. 2 years after the onset she had asymmetric parkinsonism and right-sided myoclonus. On examination she had slow saccades and dystonic left limb with multifocal stimulus sensitive myoclonus. She had some difficulty with copying gestures but no clear apraxia. She was diagnosed as CBS at this visit. Subsequently her gait became slower and she started to fall. She developed bladder dysfunction and other autonomic features. On examination at 5 years she had anterocollis and severe quivery dysarthria. She was still asymmetric at 5 years from onset. Her cognition had still been good though she had been completely bedridden since one year. The diagnosis was revised and she was diagnosed as probable MSA-P [1]. The investigations supported orthostatic hypotension on autonomic tests. MRI brain 5 years into the illness showed mineralization of globi pallidi and dorsal putamina with iron, greater in amount on the left, suggestive of MSA (previous scan at 2 years being normal). DaT scan suggested asymmetric loss of dopaminergic uptake. Myoclonus was electrophysiologically cortical in origin. 7. Discussion We described here five patients presenting with markedly asymmetric parkinsonism with dystonia initially diagnosed as CBS [4] that later in the disease course (5 years after onset) became less asymmetric and developed autonomic features and respiratory problems that led to a final diagnosis of probable MSA-P [1]. Case 4 and 5 had characteristic MRI features and Case 2 was pathologically confirmed. The main signs that led to CBS diagnosis initially (asymmetric akineticerigid syndrome, limb dystonia, myoclonus and ideomotor
A. Batla et al. / Parkinsonism and Related Disorders 19 (2013) 901e905
903
Fig. 1. a Prominent cerebellar atrophy (when compared with normal cerebellum on the right). b Atrophy of the pons. c Atrophy and greyish dyscoloration of the putamen on both sides, matched with a section from a normal brain. d Typical alpha-synucleinopathy with olidendroglial argyrophylic cytoplasmic inclusions (striatum). e Typical alphasynucleinopathy with oligodendroglial argyrophylic cytoplasmic inclusions (cerebellum).
apraxia (in case 1)), are considered typical for CBD [5], and are rare in MSA [2]. Marked persistent asymmetry is seen in only 8.6%e33% [6] of the MSA cases, whereas is reported in up to 60% in pathological [5] and up to 95% in clinical series of CBS [7]. Limb dystonia occurs less frequently in MSA than CBS (15e30% [8] vs. 70%, respectively) [9] and anterocollis which is the most common form of dystonia in MSA [8] is uncommon in CBS [5,9]. Focal reflex myoclonus in CBS [4] is usually focal, stimulus sensitive, asymmetric limb myoclonus and commonly associated with limb dystonia [9]. In contrast, the myoclonus in MSA usually presents as a symmetric, fine distal jerky tremor or polyminimyoclonus [2,10,11] The myoclonus seen in two of our patients initially was documented as typical focal reflex myoclonus consistent with CBS, but was later superimposed by the typical jerky tremor seen in MSA. Ideomotor apraxia is a characteristic feature of CBS and has been reported in 75e92% of the cases, while is rare and mild in pathologically proven MSA patients [2]. Only two of our patients had documented ideomotor apraxia (case 1 and 5). However, apraxia is not necessary to diagnose CBS if any other features of focal cortical involvement are present [4].
In hind sight, there were some clues which were against a diagnosis of CBS in our patients. There was normal cognition, and lack of apraxia in three of the patients. Cognitive impairment is well recognized in CBS with language, frontal and visuospatial impairment (13), while is largely preserved in MSA even in advanced stages of the disease [2] and in fact dementia is an exclusion criterion for the diagnosis of MSA [1]. Early impairment of eye movements with slow saccades is well described in CBS [3,4] while it is generally accepted that early presence of gaze palsy is against the diagnosis of MSA [1,2]. Interestingly, the autonomic features that are mandatory for diagnosis in MSA [1] and can be the presenting feature at onset in up to 41% of the MSA patients, were absent in the first two years and appeared later in the disease course in our patients, hence MSA was thought to be initially unlikely. Autonomic features are present in up to 97% in pathological series at final visit in MSA [10]. In contrast, severe autonomic features in CBS are uncommon (0e 28.5%) [4]. In summary, these cases highlight the fact that MSA-P can present rarely with very marked asymmetry, dystonic limb and
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A. Batla et al. / Parkinsonism and Related Disorders 19 (2013) 901e905
Fig. 2. a MRI case 4 SWI sequence showing iron deposition in lateral aspect of the right putamen. b MRI Case 5 GRE sequence showing Iron deposition in globi pallidi and dorsal putamina.
myoclonic jerks leading to CBS diagnosed at onset. In addition to autonomic features, preserved cognition and respiratory difficulties may be helpful in the clinical diagnosis of MSA.
Disclosures Amit Batla has no financial disclosures pertaining to this work. Katerina Mensikova was supported by the grant IGA UP LF2012-013. Kailash P Bhatia received funding for travel from GlaxoSmithKline, Orion Corporation, Ipsen, and Merz Pharmaceuticals, LLC; serves on the editorial boards of Movement Disorders and Therapeutic Advances in Neurological Disorders; receives royalties from the publication of Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders (Oxford University Press, 2008) and Marsden’s book of movement disorders (Oxford University Press, 2012); received speaker honoraria from GlaxoSmithKline, Ipsen, Merz Pharmaceuticals, LLC, and Sun Pharmaceutical Industries Ltd.; personal compensation for scientific advisory board for GSK and Boehringer Ingelheim; received research support from Ipsen and from the Halley Stewart Trust through Dystonia Society UK, and the Wellcome Trust MRC strategic neurodegenerative disease initiative award (Ref. number WT089698), a grant from the Dystonia Coalition and a grant from Parkinson’s UK (Ref. number G-1009). Maria Stamelou has no financial disclosures pertaining to this work.
Michaela Kaiserova was supported by the grant from IGA UP LF-2012-013. Lucie Tuckova was supported by the grant IGA UP LF-2012-013. Petr Kanovsky received speaker honoraria from Merz, Allergan, Ipsen, Medtronic, UCB and Abbott, personal compensation for scientific advisory board for Merz, GSK and Novartis, and was supported by the grant IGA MZ CR e NT12221-5/2011. Appendix A. Supplementary data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.parkreldis.2013.05.004. References [1] Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71:670e6. [2] Quinn NP. How to diagnose multiple system atrophy. Mov Disord 2005;20(Suppl. 12):S5e10. [3] Boeve BF. The multiple phenotypes of corticobasal syndrome and corticobasal degeneration: implications for further study. J Mol Neurosci 2011;45:350e3. [4] Lang AE, Riley DE, Bergeron C. Cortico-basal ganglionic degeneration. In: Calne DB, editor. Neurodegenerative diseases. Philadelphia: WB Saunders; 1994. p. 877e94. [5] Litvan I, Grimes DA, Lang AE, Jankovic J, McKee A, Verny M, et al. Clinical features differentiating patients with postmortem confirmed progressive supranuclear palsy and corticobasal degeneration. J Neurol 1999;246(Suppl. 2). II1-5.
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