Letters
Figure 2. Histopathological Slide With Castleman Follicle
However, the rarity of both Castleman disease and immunemediated cerebellitis strongly suggest a new association not previously described. Sarah Lee, MD Scheherazade Le, MD Author Affiliations: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California. Corresponding Author: Sarah Lee, MD, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Dr, A343, Stanford, CA 94305 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Hadjivassiliou M. Immune-mediated acquired ataxias. Handb Clin Neurol. 2012;103:189-199. 2. Rosenfeld MR, Dalmau J. Central nervous system paraneoplastic disease. Handb Clin Neurol. 2012;105:853-864.
Atretic germinal center surrounded by concentric rings of lymphocytes with “onion-skinning” appearance (hematoxylin-eosin; original magnification ×100).
3. Vernino S. Paraneoplastic cerebellar degeneration. Handb Clin Neurol. 2012; 103:215-223. 4. Bonekamp D, Horton KM, Hruban RH, Fishman EK. Castleman disease: the great mimic. Radiographics 2011;31(6):1793-1807. 5. Iorio R, Damato V, Mirabella M, et al. Cerebellar degeneration associated with mGluR1 autoantibodies as a paraneoplastic manifestation of prostate adenocarcinoma. J Neuroimmunol. 2013;263(1-2):155-158.
Discussion | The cerebellum is a frequent immunologic target, perhaps because its Purkinje cells possess multiple optimal antigens. The most commonly described cerebellar syndromes are paraneoplastic, but many others have been described in the setting of non-neoplastic disease such as gluten ataxia, anti-GAD antibodies, or postinfectious cerebellitis.1 Immune-mediated ataxias tend to affect the cerebellar vermis first: imbalance, speech, and vision changes are common initial presentations. An early magnetic resonance image may show meningeal enhancement; atrophy is seen on later scans.2,3 Paraneoplastic cerebellar degeneration generally c arries a poor prognosis but immune-mediated cerebellar syndromes can have variable outcomes.1,3 Our patient was lost to follow-up before maintenance immunotherapy could be instituted or more aggressive immunomodulatory therapies could be trialed, which may have improved his long-term outcome. Castleman disease is a lymphoproliferative disorder subcategorized by morphology (unicentric vs multicentric) and histopathology (hyaline vascular, plasma cell, or human herpesvirus 8–associated variants). Although Castleman disease is by definition non-neoplastic, its more aggressive plasma cell and human herpesvirus 8–associated forms have been described with other paraneoplastic disorders such as POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome and Kaposi sarcoma, as well as with hematologic malignancies such as Hodgkin and non-Hodgkin lymphoma, which in turn have been associated with cerebellar syndromes.3,4 Our patient had the more common hyaline vascular form (representing approximately 90% of Castleman disease cases); this subtype has rare autoimmune or paraneoplastic associations. A specific autoantibody in this case was not identified. Neither anti-mGluR1 nor CASPR2 antibodies were tested; both have been found in cases of unexplained cerebellar ataxia.5,6 jamaneurology.com
6. Becker EB, Zuliani L, Pettingill R, et al. Contactin-associated protein-2 antibodies in non-paraneoplastic cerebellar ataxia. J Neurol Neurosurg Psychiatry. 2012;83(4):437-440.
COMMENT & RESPONSE
Glucocerebrosidase Gene Mutation and Preclinical Markers of Parkinson Disease To the Editor In a study published in JAMA Neurology, Beavan et al1 reported a 2-year follow-up study of 30 patients with a diagnosis of type 1 Gaucher disease, 28 heterozygous glucocerebrosidase gene (GBA) mutation carriers, and 26 control individuals.1 It is well known that GBA mutations are a confirmed genetic risk for developing Parkinson disease (PD).2 Previously, Winder-Rhodes et al2 found that GBA mutations were present at a frequency of 3.5% in a UK PD population, confirming the important contribution of this gene in the clinical progression of PD. Indeed, the authors found that the hazard ratio for progression both to dementia and Hoehn and Yahr Scale stage 3 were significantly greater in GBA mutation carriers.2 In addition to confirming the well-established role of the GBA gene in PD, the study by Beavan et al1 emphasized the significant value of GBA mutations also in the prodromal motor and nonmotor features of PD. The authors went further by showing that those with Gaucher disease and heterozygous carriers exhibited worse scores of depression, rapid eye movement sleep behavior disorder, olfactory and cognitive assessment scores, and Unified Parkinson’s Disease Rating Scale part III scores. Notably, this study confirmed the results previously collected by the authors in the same cohort.3 In line with the current literature, the clinical markers investigated by Beavan et al1 are coherent with the prodrome of PD.4 Previous studies that investigated the risk factors and early features of PD highlighted the importance of detecting the neurodegenerations in as early a stage as possible for the efficacy of any neuroprotective or disease-modifying therapy.5 Addition(Reprinted) JAMA Neurology June 2015 Volume 72, Number 6
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Manitoba User on 06/12/2015
723
Letters
ally, the GBA gene seems involved not only in the onset of preclinical disease features, but also in a higher rate of clinical progression as shown by the significantly different deterioration from baseline over 2 years in those with Gaucher disease and heterozygous carriers compared with the control participants.1 Collectively, these studies show that alterations in the GBA gene are a potential causative factor in basal ganglia dysfunction in some patients. However, a remaining question is which are the specific alterations that lead to developing PD in a group of mutation-positive individuals. Furthermore, the reported alterations in nonmotor preclinical markers of PD in this genetic group could also reflect a role of GBA in dysfunctional pathways not only related to basal ganglia network, but also involving global brain neurodegeneration. Detailed assessments of the different components of the neuronal networks governed by the GBA gene product are needed to resolve the remaining conundrums. Antonella Macerollo, MD Author Affiliation: Department of Basic Medical Sciences, Neuroscience and Sense Organs, Aldo Moro University of Bari, Bari, Italy. Corresponding Author: Antonella Macerollo, MD, Department of Basic Medical Sciences, Neuroscience and Sense Organs, Aldo Moro University of Bari, Piazza Giulio Cesare 11, 70125 Bari, Italy ([email protected]). Conflict of Interest Disclosures: None reported. 1. Beavan M, McNeill A, Proukakis C, Hughes DA, Mehta A, Schapira AH. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol. 2014;72(2):201-208. 2. Winder-Rhodes SE, Evans JR, Ban M, et al. Glucocerebrosidase mutations influence the natural history of Parkinson’s disease in a community-based incident cohort. Brain. 2013;136(Pt 2):392-399. 3. Schrag A, Horsfall L, Walters K, Noyce A, Petersen I. Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study. Lancet Neurol. 2015;14(1):57-64. 4. McNeill A, Duran R, Proukakis C, et al. Hyposmia and cognitive impairment in Gaucher disease patients and carriers. Mov Disord. 2012;27(4):526-532. 5. Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al. PREDICT-PD: identifying risk of Parkinson’s disease in the community: methods and baseline results. J Neurol Neurosurg Psychiatry. 2014;85(1):31-37.
In Reply We thank Dr Macerollo for the interesting commentary on our article.1 Mutations in the glucocerebrosidase (GBA) gene are widely recognized to be an important and common genetic risk factor for Parkinson disease (PD),2 and they are found in British patients with PD at a higher frequency than any other known PD-associated gene.3 In 2012, we continued the clinical evaluation of a unique cohort of GBA mutation–positive individuals for the early prodromal features of PD.1 What was perhaps surprising about this nonparkinsonian GBA–positive cohort at the initial assessment in 2010 was a significant difference from control individuals even at the baseline evaluation.4 At baseline, GBA mutation–positive individuals demonstrated hyposmia and cognitive impairment.4 Importantly, we found that olfaction and cognition remained significantly lower in GBA mutation– positive individuals compared with control individuals at 2 years’ follow-up.1 We further identified a significant deterioration across clinical markers in GBA mutation–positive individuals, consistent with the prodrome of PD. Within this 724
group, 10% appeared to be progressing at a more rapid rate. It is interesting to compare our results, which identified 10% of GBA mutation–positive individuals developing parkinsonian motor features, with the reported estimate that 10% of patients with PD carry a mutation in GBA.2 Improved insight into possible disease mechanisms lays the basis for the development of new therapies to slow the rate of progression or stop the disease process.5 Thus, it is imperative to develop an early biomarker set to identify individuals at greatest risk for the development of PD. In this study, we attempted to identify patients likely to develop PD through the use of early clinical markers.1 This study cohort would be an ideal population to study a neuroprotective strategy or diseasemodifying therapy. As observed by Dr Macerollo, our data favor a link between the GBA mutation and a higher frequency of nonmotor symptoms and rate of clinical progression. Our work1 and those of others6,7 may suggest that the GBA mutation represents a poor prognostic marker for an individual who develops PD. The evidence from longitudinal studies demonstrates that patients with GBA-associated PD show a more rapid disease progression dominated by accelerated motor impairment with greater risk for progression to Hoehn and Yahr Scale stage 37 and a greater preponderance to dementia or cognitive decline.6 Dr Macerollo asks about the specific alterations that lead to developing PD in a group of GBA mutation–positive individuals. We can only hypothesize that other genetic or possibly environmental factors may be of relevance here. Study of GBA mutation–positive individuals who do not go on to develop PD could provide insight into factors that may afford protection from PD. Michelle Beavan, MRCP(UK) Anthony H. V. Schapira, DSc, MD, FRCP, FMedSci Author Affiliations: Department of Clinical Neurosciences, UCL Institute of Neurology, University College London, London, England. Corresponding Author: Anthony H. V. Schapira, DSc, MD, FRCP, FMedSci, Department of Clinical Neurosciences, UCL Institute of Neurology, University College London, Rowland Hill Street, London NW3 2PF, England (a.schapira @ucl.ac.uk). Conflict of Interest Disclosures: None reported. 1. Beavan M, McNeill A, Proukakis C, Hughes DA, Mehta A, Schapira AHV. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol. 2015;72(2):201-208. 2. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361 (17):1651-1661. 3. Neumann J, Bras J, Deas E, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain. 2009;132(pt 7):1783-1794. 4. McNeill A, Duran R, Proukakis C, et al. Hyposmia and cognitive impairment in Gaucher disease patients and carriers. Mov Disord. 2012;27(4):526-532. 5. Schapira AHV, Olanow CW, Greenamyre JT, Bezard E. Slowing of neurodegeneration in Parkinson’s disease and Huntington’s disease: future therapeutic perspectives. Lancet. 2014;384(9942):545-555. 6. Brockmann K, Srulijes K, Pflederer S, et al. GBA-associated Parkinson’s disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord. 2014;30(3):407-411. 7. Winder-Rhodes SE, Evans JR, Ban M, et al. Glucocerebrosidase mutations influence the natural history of Parkinson’s disease in a community-based incident cohort. Brain. 2013;136(pt 2):392-399.
JAMA Neurology June 2015 Volume 72, Number 6 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Manitoba User on 06/12/2015
jamaneurology.com
Figure 2. Histopathological Slide With Castleman Follicle
However, the rarity of both Castleman disease and immunemediated cerebellitis strongly suggest a new association not previously described. Sarah Lee, MD Scheherazade Le, MD Author Affiliations: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California. Corresponding Author: Sarah Lee, MD, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Dr, A343, Stanford, CA 94305 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Hadjivassiliou M. Immune-mediated acquired ataxias. Handb Clin Neurol. 2012;103:189-199. 2. Rosenfeld MR, Dalmau J. Central nervous system paraneoplastic disease. Handb Clin Neurol. 2012;105:853-864.
Atretic germinal center surrounded by concentric rings of lymphocytes with “onion-skinning” appearance (hematoxylin-eosin; original magnification ×100).
3. Vernino S. Paraneoplastic cerebellar degeneration. Handb Clin Neurol. 2012; 103:215-223. 4. Bonekamp D, Horton KM, Hruban RH, Fishman EK. Castleman disease: the great mimic. Radiographics 2011;31(6):1793-1807. 5. Iorio R, Damato V, Mirabella M, et al. Cerebellar degeneration associated with mGluR1 autoantibodies as a paraneoplastic manifestation of prostate adenocarcinoma. J Neuroimmunol. 2013;263(1-2):155-158.
Discussion | The cerebellum is a frequent immunologic target, perhaps because its Purkinje cells possess multiple optimal antigens. The most commonly described cerebellar syndromes are paraneoplastic, but many others have been described in the setting of non-neoplastic disease such as gluten ataxia, anti-GAD antibodies, or postinfectious cerebellitis.1 Immune-mediated ataxias tend to affect the cerebellar vermis first: imbalance, speech, and vision changes are common initial presentations. An early magnetic resonance image may show meningeal enhancement; atrophy is seen on later scans.2,3 Paraneoplastic cerebellar degeneration generally c arries a poor prognosis but immune-mediated cerebellar syndromes can have variable outcomes.1,3 Our patient was lost to follow-up before maintenance immunotherapy could be instituted or more aggressive immunomodulatory therapies could be trialed, which may have improved his long-term outcome. Castleman disease is a lymphoproliferative disorder subcategorized by morphology (unicentric vs multicentric) and histopathology (hyaline vascular, plasma cell, or human herpesvirus 8–associated variants). Although Castleman disease is by definition non-neoplastic, its more aggressive plasma cell and human herpesvirus 8–associated forms have been described with other paraneoplastic disorders such as POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome and Kaposi sarcoma, as well as with hematologic malignancies such as Hodgkin and non-Hodgkin lymphoma, which in turn have been associated with cerebellar syndromes.3,4 Our patient had the more common hyaline vascular form (representing approximately 90% of Castleman disease cases); this subtype has rare autoimmune or paraneoplastic associations. A specific autoantibody in this case was not identified. Neither anti-mGluR1 nor CASPR2 antibodies were tested; both have been found in cases of unexplained cerebellar ataxia.5,6 jamaneurology.com
6. Becker EB, Zuliani L, Pettingill R, et al. Contactin-associated protein-2 antibodies in non-paraneoplastic cerebellar ataxia. J Neurol Neurosurg Psychiatry. 2012;83(4):437-440.
COMMENT & RESPONSE
Glucocerebrosidase Gene Mutation and Preclinical Markers of Parkinson Disease To the Editor In a study published in JAMA Neurology, Beavan et al1 reported a 2-year follow-up study of 30 patients with a diagnosis of type 1 Gaucher disease, 28 heterozygous glucocerebrosidase gene (GBA) mutation carriers, and 26 control individuals.1 It is well known that GBA mutations are a confirmed genetic risk for developing Parkinson disease (PD).2 Previously, Winder-Rhodes et al2 found that GBA mutations were present at a frequency of 3.5% in a UK PD population, confirming the important contribution of this gene in the clinical progression of PD. Indeed, the authors found that the hazard ratio for progression both to dementia and Hoehn and Yahr Scale stage 3 were significantly greater in GBA mutation carriers.2 In addition to confirming the well-established role of the GBA gene in PD, the study by Beavan et al1 emphasized the significant value of GBA mutations also in the prodromal motor and nonmotor features of PD. The authors went further by showing that those with Gaucher disease and heterozygous carriers exhibited worse scores of depression, rapid eye movement sleep behavior disorder, olfactory and cognitive assessment scores, and Unified Parkinson’s Disease Rating Scale part III scores. Notably, this study confirmed the results previously collected by the authors in the same cohort.3 In line with the current literature, the clinical markers investigated by Beavan et al1 are coherent with the prodrome of PD.4 Previous studies that investigated the risk factors and early features of PD highlighted the importance of detecting the neurodegenerations in as early a stage as possible for the efficacy of any neuroprotective or disease-modifying therapy.5 Addition(Reprinted) JAMA Neurology June 2015 Volume 72, Number 6
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Manitoba User on 06/12/2015
723
Letters
ally, the GBA gene seems involved not only in the onset of preclinical disease features, but also in a higher rate of clinical progression as shown by the significantly different deterioration from baseline over 2 years in those with Gaucher disease and heterozygous carriers compared with the control participants.1 Collectively, these studies show that alterations in the GBA gene are a potential causative factor in basal ganglia dysfunction in some patients. However, a remaining question is which are the specific alterations that lead to developing PD in a group of mutation-positive individuals. Furthermore, the reported alterations in nonmotor preclinical markers of PD in this genetic group could also reflect a role of GBA in dysfunctional pathways not only related to basal ganglia network, but also involving global brain neurodegeneration. Detailed assessments of the different components of the neuronal networks governed by the GBA gene product are needed to resolve the remaining conundrums. Antonella Macerollo, MD Author Affiliation: Department of Basic Medical Sciences, Neuroscience and Sense Organs, Aldo Moro University of Bari, Bari, Italy. Corresponding Author: Antonella Macerollo, MD, Department of Basic Medical Sciences, Neuroscience and Sense Organs, Aldo Moro University of Bari, Piazza Giulio Cesare 11, 70125 Bari, Italy ([email protected]). Conflict of Interest Disclosures: None reported. 1. Beavan M, McNeill A, Proukakis C, Hughes DA, Mehta A, Schapira AH. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol. 2014;72(2):201-208. 2. Winder-Rhodes SE, Evans JR, Ban M, et al. Glucocerebrosidase mutations influence the natural history of Parkinson’s disease in a community-based incident cohort. Brain. 2013;136(Pt 2):392-399. 3. Schrag A, Horsfall L, Walters K, Noyce A, Petersen I. Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study. Lancet Neurol. 2015;14(1):57-64. 4. McNeill A, Duran R, Proukakis C, et al. Hyposmia and cognitive impairment in Gaucher disease patients and carriers. Mov Disord. 2012;27(4):526-532. 5. Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al. PREDICT-PD: identifying risk of Parkinson’s disease in the community: methods and baseline results. J Neurol Neurosurg Psychiatry. 2014;85(1):31-37.
In Reply We thank Dr Macerollo for the interesting commentary on our article.1 Mutations in the glucocerebrosidase (GBA) gene are widely recognized to be an important and common genetic risk factor for Parkinson disease (PD),2 and they are found in British patients with PD at a higher frequency than any other known PD-associated gene.3 In 2012, we continued the clinical evaluation of a unique cohort of GBA mutation–positive individuals for the early prodromal features of PD.1 What was perhaps surprising about this nonparkinsonian GBA–positive cohort at the initial assessment in 2010 was a significant difference from control individuals even at the baseline evaluation.4 At baseline, GBA mutation–positive individuals demonstrated hyposmia and cognitive impairment.4 Importantly, we found that olfaction and cognition remained significantly lower in GBA mutation– positive individuals compared with control individuals at 2 years’ follow-up.1 We further identified a significant deterioration across clinical markers in GBA mutation–positive individuals, consistent with the prodrome of PD. Within this 724
group, 10% appeared to be progressing at a more rapid rate. It is interesting to compare our results, which identified 10% of GBA mutation–positive individuals developing parkinsonian motor features, with the reported estimate that 10% of patients with PD carry a mutation in GBA.2 Improved insight into possible disease mechanisms lays the basis for the development of new therapies to slow the rate of progression or stop the disease process.5 Thus, it is imperative to develop an early biomarker set to identify individuals at greatest risk for the development of PD. In this study, we attempted to identify patients likely to develop PD through the use of early clinical markers.1 This study cohort would be an ideal population to study a neuroprotective strategy or diseasemodifying therapy. As observed by Dr Macerollo, our data favor a link between the GBA mutation and a higher frequency of nonmotor symptoms and rate of clinical progression. Our work1 and those of others6,7 may suggest that the GBA mutation represents a poor prognostic marker for an individual who develops PD. The evidence from longitudinal studies demonstrates that patients with GBA-associated PD show a more rapid disease progression dominated by accelerated motor impairment with greater risk for progression to Hoehn and Yahr Scale stage 37 and a greater preponderance to dementia or cognitive decline.6 Dr Macerollo asks about the specific alterations that lead to developing PD in a group of GBA mutation–positive individuals. We can only hypothesize that other genetic or possibly environmental factors may be of relevance here. Study of GBA mutation–positive individuals who do not go on to develop PD could provide insight into factors that may afford protection from PD. Michelle Beavan, MRCP(UK) Anthony H. V. Schapira, DSc, MD, FRCP, FMedSci Author Affiliations: Department of Clinical Neurosciences, UCL Institute of Neurology, University College London, London, England. Corresponding Author: Anthony H. V. Schapira, DSc, MD, FRCP, FMedSci, Department of Clinical Neurosciences, UCL Institute of Neurology, University College London, Rowland Hill Street, London NW3 2PF, England (a.schapira @ucl.ac.uk). Conflict of Interest Disclosures: None reported. 1. Beavan M, McNeill A, Proukakis C, Hughes DA, Mehta A, Schapira AHV. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol. 2015;72(2):201-208. 2. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361 (17):1651-1661. 3. Neumann J, Bras J, Deas E, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain. 2009;132(pt 7):1783-1794. 4. McNeill A, Duran R, Proukakis C, et al. Hyposmia and cognitive impairment in Gaucher disease patients and carriers. Mov Disord. 2012;27(4):526-532. 5. Schapira AHV, Olanow CW, Greenamyre JT, Bezard E. Slowing of neurodegeneration in Parkinson’s disease and Huntington’s disease: future therapeutic perspectives. Lancet. 2014;384(9942):545-555. 6. Brockmann K, Srulijes K, Pflederer S, et al. GBA-associated Parkinson’s disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord. 2014;30(3):407-411. 7. Winder-Rhodes SE, Evans JR, Ban M, et al. Glucocerebrosidase mutations influence the natural history of Parkinson’s disease in a community-based incident cohort. Brain. 2013;136(pt 2):392-399.
JAMA Neurology June 2015 Volume 72, Number 6 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Manitoba User on 06/12/2015
jamaneurology.com
