Movement Disorders Vol. 24, No. 10, 2009, pp. 1519–1545 Ó 2009 Movement Disorder Society
Brief Reports
No Lewy Pathology in Monkeys with Over 10 Years of Severe MPTP Parkinsonism
In both Parkinson’s disease (PD) and the 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model, nigrostriatal dopaminergic neurons are more selectively targeted than other brain regions, and dopaminergic replacement therapies give symptomatic relief.1 However, a major difference between idiopathic PD and MPTP-primate models is the extensive abnormal deposition of a-synuclein in the form of insoluble neuronal Lewy bodies and neurites in PD but not in this animal model.2 The recent identification of Lewy bodies in human fetal transplants surviving 11–16 years suggests that such lesions accumulate over a decade,3 consistent with longitudinal postmortem studies.4 To determine whether this time frame is sufficient for abnormal a-synuclein accumulation in the MPTP-primate model, two cynomolgus monkeys (Macaca fascicularis) were treated with MPTP and their brains examined after 10 years of Parkinsonism.
Glenda Halliday, PhD,1* Maria Trinidad Herrero, MD,2 Karen Murphy, BSc (Hons),1 Heather McCann, BMedSci (Path),1 Francisco Ros-Bernal, BSc,2 Carlos Barcia, PhD,2 Hideo Mori, MD,3 Francisco J. Blesa, BSci,4 and Jose´ A. Obeso, MD4 1
Prince of Wales Medical Research Institute and School of Medical Sciences, Faculty of Medicine University of New South Wales, Sydney, Australia; 2 Experimental Neuroscience, Department of Anatomy, Medical School, University of Murcia and CIBERNED, Murcia, Spain; 3Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; 4Department of Neurology and Neuroscience Division, Clinica Universitaria and Medical School, Neuroscience Center, CIMA and CIFA, University of Navarra and CIBERNED, Pamplona, Spain
METHODS Animals Two 8-year-old control (Monkey 1 and 2) and two 14-year-old cynomolgus (Macaca fascicularis) monkeys, previously made parkinsonian at 2 years of age with intermittent intravenous injections of 0.3 mg/kg MPTP for 2 years (Monkey 3 and 4, see Table 1 and5,6), were sacrificed with a lethal pentobarbital injection after ketamine anesthesia, their brains removed and hemisected with one half (three right and one left) fixed for 3 days in 4% paraformaldehyde dissolved in 0.1 M phosphate buffer and the other half dissected, frozen in dry ice, and stored at 2808C. All monkeys were from the same provider and were kept under similar living conditions with all studies carried out in accordance with the Declaration of Helsinki and with the Guide for the Care and Use of Laboratory Animals adopted and promulgated by the United States National Institutes of Health and the European Union.
Abstract: The recent knowledge that 10 years after transplantation surviving human fetal neurons adopt the histopathology of Parkinson’s disease suggests that Lewy body formation takes a decade to achieve. To determine whether similar histopathology occurs in 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-primate models over a similar timeframe, the brains of two adult monkeys made parkinsonian in their youth with intermittent injections of MPTP were studied. Despite substantial nigral degeneration and increased a-synuclein immunoreactivity within surviving neurons, there was no evidence of Lewy body formation. This suggests that MPTP-induced oxidative stress and inflammation per se are not sufficient for Lewy body formation, or Lewy bodies are human specific. Ó 2009 Movement Disorder Society Key words: a-synuclein; monkeys; MPTP; parkinsonism; substantia nigra
*Correspondence to: Prof. Glenda Halliday, Prince of Wales Medical Research Institute, Barker Street, Randwick, NSW 2031, Australia. E-mail:
[email protected] Potential conflict of interest: The authors have nothing to disclose. Received 3 December 2008; Revised 6 January 2009; Accepted 14 January 2009 Published online 15 June 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22481
Histopathology The fixed hemibrain was cut coronally, and the brainstem and cerebellum were cut transversely at 2.5 mm. Samples were taken from superior frontal
1519
1520
G. HALLIDAY ET AL. TABLE 1. Details of experimental age, symptoms, age at death, and neuropathological parameters
Macaque
M1
M2
M3
M4
Experimental age
Not applicable
Not applicable
Symptoms (severity)
None
None
2–3 yr old, 12 MPTP injections over 2 yr Severe (motor score of 17/25),5 stable akinesia and rigidity with limited mobility, a flexed posture of the trunk, facial hypomimia, instability, freezing and action tremor in the upper limbs. 14 35.4 Yes Yes
2–3 yr old, 14 MPTP injections over 2 yr Moderate (motor scale of 14/25),5 stable akinesia and rigidity with a flexed posture of the trunk and a postural action tremor of the upper limbs and occasionally of the head. 14 31.2 Yes Yes
Age at autopsy (yr) Hemisphere volume (ml) Severe SN cell loss Cortical Ab deposition
8 34.6 No No
8 32.7 No No
SN, substantia nigra.
(Brodmann area 6) and anterior cingulate (area 24) cortices at the anterior caudate level, precentral cortex (area 4) dyed red before sectioning, primary visual cortex (area V1) around the calcarine sulcus, hippocampus at the level of the lateral geniculate nucleus, amygdala, midbrain, midpons and cerebellum, and medulla oblongata through the dorsal motor nucleus of the vagus nerve. Tissue samples were paraffin-embedded, sectioned at 10 lm and stained with haematoxylin and eosin, modified Bielschowsky and Gallyas silver stains, and peroxidase immunohistochemistry for tyrosine hydroxylase (TH, sc-7847, Santa Cruz Biotechnology, USA, diluted 1:300 following 0.2 M citrate buffer microwave antigen retrieval), a-synuclein (sheep polyclonal raised against amino acids 116–131, a gift from W.P. Gai, Flinders University, Australia, diluted 1:500 following 1 mM EDTA pH 8.0 microwave antigen retrieval), phosphorylated a-synuclein (mouse monoclonal P-S129, a gift from W.P. Gai, Flinders University, Australia, diluted 1:10,000 following formic acid and 0.2 M citrate buffer microwave antigen retrieval), ubiquitin (Z0458 Dako, Denmark, diluted 1:200), phosphotau (AT8, MN1020 Pierce Endogen, Rockford, USA, diluted 1:10,000), Ab (mouse monoclonal clone IE8, a gift from C. Masters, University of Melbourne, Australia, diluted 1:100 following formic acid antigen retrieval), and Tar DNA binding protein 43 (TDP43, 10782-2-AP ProteinTech Group, Chicago, USA, diluted 1:500 following 0.2 M citrate buffer microwave antigen retrieval). Tissue samples from the hippocampus and temporal cortices and brainstem of a case with dementia with Lewy bodies (aged 78 at death, 6 years disease duration) and the midbrain of a human control case (aged 85, no significant pathological abnormalities) were included as positive controls, and the specificity of the reaction tested by removal of primary antibodies resulting in no reaction product.
Movement Disorders, Vol. 24, No. 10, 2009
RESULTS The fixed hemispheres were of similar size (Table 1) with no external abnormalities. Examination of the cut slices revealed discoloration of the substantia nigra and globus pallidus in control M2 and MPTP-primates M3 and M4 (Fig. 1E) compared with control M1 (Fig. 1A), consistent with increasing age. Histological examination revealed punctate ubiquitin-immunoreactive structures in the upper layers of the cortex and in the hippocampus and amygdala in control M2 and MPTP-primates M3 and M4 (data not shown), consistent with previously described age-related changes observed in humans and other species.7–9 Other pathological abnormalities were only seen in the MPTP-primates. In these primates, there was severe loss of neurons and gliosis in the substantia nigra pars compacta (SNc, Fig. 1C versus 1G). The loss of the A9 dopaminergic SNc neurons was selective, as nearby and remote TH-immunoreactive neurons remained intact, including the A8 and A10 midbrain dopaminergic neurons (Fig. 1B versus 1F), pontine noradrenergic neurons (Fig. 1J versus 1K), and the catecholaminergic neurons in the medulla oblongata (data not shown). In the MPTP-primates, TH-immunoreactive fibers and terminals were absent from the basal ganglia but were present in the cortex and amygdala (data not shown). Selective regions contained abnormal protein accumulation only in the MPTP-primates. Increased a-synuclein and phosphorylated a-synuclein immunoreactivity was observed in the few remaining SNc neurons with an increase in punctate structures in the neuropil (Fig. 1D versus 1H). Similar punctate but not intraneuronal staining was observed in the SNc with ubiquitin immunohistochemistry (data not shown). The increased intraneuronal a-synuclein immunoreactivity was not in the structural form of Lewy bodies but appeared as a substantial mass of particles within the
FIG. 1. Histopathological comparison of control and MPTP-treated primates. A, E: Transverse brainstem slices through the midbrain reveal discoloration of the substantia nigra in control M2 and MPTP-primates M3 and M4 (E) compared with control M1 (A). B, F: Tyrosine hydroxylase (TH) immunoreactivity is abundant in both the substantia nigra pars compacta (arrows) and A8 dopaminergic cell group (open arrowhead) of the controls (M1 shown in B), but there is selective loss of the A9 TH-positive neurons in the pars compacta (arrows) of the MPTP-primates, while the A8 group is unaffected (open arrowhead, M4 shown in F). C, G: Haematoxylin and eosin staining shows severe neuronal loss and gliosis in the substantia nigra pars compacta of the MPTP-primates (M4 shown in G) compared with the controls (M1 shown in C). D, H, I: a-Synuclein immunoreactivity appears as diffuse and punctate in the neuropil and as granules within the cytoplasm of substantia nigra neurons in controls (M1 shown in D). In MPTP-primates (M4 shown in H) small dense aggregates of a-synuclein immunoreactivity are observed in surviving neurons and in the neuropil. a-Synuclein-immunoreactive Lewy bodies are present in pigmented and nonpigmented locus coeruleus neurons in Parkinson’s disease (I). Lewy bodies are not observed in the MPTP-primates (H) or controls. J, K: Tyrosine hydroxylase (TH) immunoreactivity is not reduced in the locus coeruleus of MPTP-primates (M3 shown in K) compared with controls (M1 shown in J).
1522
G. HALLIDAY ET AL.
neuronal cytoplasm (Fig. 1H versus 1I). No other abnormal intraneuronal protein immunoreactivity was observed in the brainstem using the protocols outlined. Within the amygdala and temporal cortices, extracellular Ab aggregations were observed only in the MPTPprimates (data not shown). Phosphorylated tau immunoreactivity was not associated with these Ab plaques (data not shown). DISCUSSION This study confirms that intravenous intoxication with MPTP in primates results in Parkinsonism with selective dopaminergic loss and a-synuclein aggregation in the SNpc.10,11 From recent studies,12 it would appear that this aggregation is related to the death of these neurons. We directly addressed the hypothesis that substantial time is required post nigral insult for the classic cellular aggregation of a-synuclein into Lewy bodies. Despite the MPTP-primates studied having Parkinsonism for over a decade, no classic a-synuclein-immunopositive Lewy body inclusions were observed in any of the brain regions sampled. This is consistent with similar studies in MPTP-primates with shorter parkinsonian durations,10–12 as well as with primate models of Parkinsonism using viral vector-mediated overexpression of a-synuclein in the ventral midbrain.13 Our conclusions need to be tempered by two confounding factors. First, the limited number of animals studied. Second, the age reached by these monkeys, despite being much higher than usual for MPTP experiments, may not be sufficient to facilitate Lewy body formation. Nevertheless, Lewy bodies have not been encountered even in older animals treated with MPTP (J. Kordower, personal communication). Indeed, in all of these primate models, the severity of a-synuclein-immunostained pathology is significantly less than that found in cases with idiopathic PD, and similar to pathology observed in patients with parkin gene deletions (neuronal loss largely restricted to the substantia nigra).14–17 In contrast, transplanted fetal midbrain dopaminergic neurons surviving for similar timeframes in the brains of patients with PD contain classic neuronal Lewy body inclusions, with the number of neurons affected relating to transplant survival time.3 This suggests that the possible underlying mechanisms for Lewy body formation are not likely to be exclusively related to increased oxidative stress, excitotoxicity, or inflammation (all occur in the MPTP-primate model), leaving the concept of permissive templating, as recently canvassed.3,18,19 It also suggests that two
Movement Disorders, Vol. 24, No. 10, 2009
mechanisms occur, one that initially targets nigral neuronal loss (oxidative stress, excitotoxicity, and/or inflammation) and the other responsible for Lewy body formation (permissive templating). It remains unclear what then underlies the initial protein aggregation that is templated in PD. In most parkin deletion cases and MPTP-primate models, the selective nigral loss underlying their Parkinsonism occurs in teenage or early adulthood, rather than in advanced age as observed in sporadic PD. In fact, it is age rather than disease duration that influences the severity of Lewy body pathology in PD,4,20 and age is considered the most important determinant of clinical progression in PD.21 Age is a factor known to increase a-synuclein protein in nigral neurons22 by increasing its posttranslational stabilization rather than mRNA expression,23 whereas MPTP increases both the posttranslational stabilization and mRNA expression of asynuclein.11,24 The greater lifespan of humans may in fact make Lewy bodies unique to humans compared with other primates through an aging neural environment that allows permissive templating. Further modeling of these long-term effects is necessary.
Acknowledgments: For the primate work, MT Herrero received support from the Spanish Ministry of Science (SAF2004/07656/C02-02), Fundacio´n Se´neca (FS/05662/PI/07), and CIBERNED (Area 5). The histology was funded by the Prince of Wales Medical Research Institute. Glenda Halliday is a Principal Research Fellow of the National Health and Medical Research Council of Australia. Other grants held over the last year by GM Halliday are from the National Health and Medical Research Council of Australia (projects #400909, #401537, #510148, #510186; equipment #520950), Australian Research Council (SPIRIT #LP0776735) and GlaxoSmithKline Australia (Postgraduate Support Grant), by MT Herrero are from Spanish Ministry of Science (SAF 2007-62262) and Consejerı´a de Industria CARM (BIO-MED 0701-0006), by H Mori are from the Japanese Ministry of Health, Labor and Welfare (Intractable Diseases, Health and Labor Sciences Research Grants), and by JA Obeso are from the Spanish Government-Science And Education Department (*SAF2005-08416-C02-01*) and Novartis Pharmaceutica (Role of Homocysteine in cognitive impairment in Parkinson’s disease). K Murphy, H McCann, F Ros-Bernal, C Barcia, and FJ Blesa have no financial disclosures. We thank Heidi Cartwright for the preparation of the figure.
Author Roles: GM Halliday: Conception and organization of the histopathology, and writing of the first draft of the manuscript. Statistical design not applicable. MT Herrero: Conception, organization, and execution of the monkey experiments and long term care, and manuscript review and critique. Statistical design not applicable.
NO -SYNUCLEIN DEPOSITION IN MPTP MONKEYS K Murphy: Execution of the histopathology, and manuscript review and critique. Statistical design not applicable. H McCann: Execution of the histopathology, and manuscript review and critique. Statistical design not applicable. F Ros-Bernal: Execution of the monkey experiments and long term care, and manuscript review and critique. Statistical design not applicable. C Barcia: Execution of the monkey experiments and long term care, and manuscript review and critique. Statistical design not applicable. H Mori: Conception of parkin comparison, and manuscript review and critique. Statistical design not applicable. FJ Blesa: Execution of the monkey experiments, and manuscript review and critique. Statistical design not applicable. JA Obeso: Conception and organization of the entire project, and manuscript review and critique. Statistical design not applicable.
REFERENCES 1. Capitanio JP, Emborg ME. Contributions of non-human primates to neuroscience research. Lancet 2008;371:1126– 1135. 2. Maries E, Dass B, Collier TJ, Kordower JH, Steece-Collier K. The role of a-synuclein in Parkinson’s disease: insights from animal models. Nature Rev Neurosci 2003;4:727–738. 3. Brundin P, Li JY, Holton JL, Lindvall O, Revesz T. Research in motion: the enigma of Parkinson’s disease pathology spread. Nature Rev Neurosci 2008;9:741–745. 4. Halliday G, Hely M, Reid W, Morris J. The progression of pathology in longitudinally followed patients with Parkinson’s disease. Acta Neuropathol 2008;115:409–415. 5. Herrero MT, Hirsch EC, Kastner A, et al. Does neuromelanin contribute to the vulnerability of catecholaminergic neurons in monkeys intoxicated with MPTP? Neuroscience 1993;56:499– 511. 6. Barcia C, Sanchez Bahillo A, Fernandez-Villalba E, et al. Evidence of active microglia in substantia nigra pars compacta of parkinsonian monkeys 1 year after MPTP exposure. Glia 2004; 46:402–409. 7. Borras D, Ferrer I, Pumarola M. Age-related changes in the brain of the dog. Vet Pathol 1999;36:202–211. 8. Dickson DW, Wertkin A, Kress Y, Ksiezak-Reding H, Yen SH. Ubiquitin immunoreactive structures in normal human brains. Distribution and developmental aspects. Lab Invest 1990;63:87– 99. 9. Iseki E, Odawara T, Li F, et al. Age-related ubiquitin-positive granular structures in non-demented subjects and neurodegenerative disorders. J Neurol Sci 1996;142:25–29. 10. Kowall NW, Hantraye P, Brouillet E, Beal MF, McKee AC, Ferrante RJ. MPTP induces a-synuclein aggregation in the substantia nigra of baboons. Neuroreport 2000;11:211–213. 11. Purisai MG, McCormack AL, Langston WJ, Johnston LC, Di Monte DA. a-Synuclein expression in the substantia nigra of MPTP-lesioned non-human primates. Neurobiol Dis 2005;20: 898–906. 12. McCormack AL, Mak SK, Shenasa M, Langston WJ, Forno LS, Di Monte DA. Pathologic modifications of a-synuclein in 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated squirrel monkeys. J Neuropathol Exp Neurol 2008;67:793–802. 13. Eslamboli A, Romero-Ramos M, Burger C, et al. Long-term consequences of human a-synuclein overexpression in the primate ventral midbrain. Brain 2007;130:799–815.
1523
14. Hayashi S, Wakabayashi K, Ishikawa A, et al. An autopsy case of autosomal-recessive juvenile Parkinsonism with a homozygous exon 4 deletion in the parkin gene. Mov Disord 2000;15:884– 888. 15. Sasaki S, Shirata A, Yamane K, Iwata M. Parkin-positive autosomal recessive juvenile Parkinsonism with a-synuclein-positive inclusions. Neurology 2004;63:678–682. 16. Gouider-Khouja N, Larnaout A, Amouri R, et al. Autosomal recessive Parkinsonism linked to parkin gene in a Tunisian family. Clinical, genetic and pathological study. Parkinsonism Relat Disord 2003;9:247–251. 17. Mori H, Kondo T, Yokochi M, et al. Pathologic and biochemical studies of juvenile Parkinsonism linked to chromosome 6q. Neurology 1998;51:890–892. 18. Braak H, Del Tredici K. Invited Article: nervous system pathology in sporadic Parkinson disease. Neurology 2008;70:1916– 1925. 19. Hardy J. Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘permissive templating’ as a general mechanism underlying neurodegeneration. Biochem Soc Trans 2005;33:578–581. 20. Kempster PA, Williams DR, Selikhova M, Holton J, Revesz T, Lees AJ. Patterns of levodopa response in Parkinson’s disease: a clinico-pathological study. Brain 2007;130:2123–2128. 21. Levy G. The relationship of Parkinson disease with aging. Arch Neurol 2007;64:1242–1246. 22. Chu Y, Kordower JH. Age-associated increases of a-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: is this the target for Parkinson’s disease? Neurobiol Dis 2007;25:134–149. 23. Li W, Lesuisse C, Xu Y, Troncoso JC, Price DL, Lee MK. Stabilization of a-synuclein protein with aging and familial Parkinson’s disease-linked A53T mutation. J Neurosci 2004;24:7400– 7409. 24. Klivenyi P, Siwek D, Gardian G, et al. Mice lacking a-synuclein are resistant to mitochondrial toxins. Neurobiol Dis 2006;21: 541–548.
Movement Disorders, Vol. 24, No. 10, 2009
1524
I. KRAOUA ET AL.
Parkinsonism in Gaucher’s Disease Type 1: Ten New Cases and a Review of the Literature Ichraf Kraoua, MD,1 Je´roˆme Stirnemann, MD,2 Maria Joa˜o Ribeiro, MD, PhD,3 Tiphaine Rouaud, MD,4 Marc Verin, MD, PhD,4 Agne`s Annic, MD,5 Christian Rose, MD, PhD,6 Luc Defebvre, MD, PhD,5 Liliane Re´me´nieras, MD,7 Michae¨l Schu¨pbach, MD,1 Nadia Belmatoug, MD,8 Marie Vidailhet, MD,1,9 and Fre´de´ric Sedel, MD, PhD1* 1 Federation of Nervous System Diseases, Reference Center for Lysosomal Diseases, Salpeˆtrie`re Hospital, Assistance Publique-Hoˆpitaux de Paris, France; 2 Department of Internal Medicine, Jean Verdier Hospital, Assistance Publique-Hoˆpitaux de Paris, Paris X111 University, France; 3Service Hospitalier Fre´de´ric Joliot, I2BM, DSV, CEA, Orsay, France; 4Department of Neurology, University Hospital of Rennes, Rennes, France; 5 Department of Neurology, University Hospital of Lille, Lille, France; 6Department of Onco-Haematology, Saint Vincent de Paul Hospital, Lille, France; 7 Department of Haematology, University Hospitals of Limoges, Limoges, France; 8Department of Internal Medicine, Reference Center for Lysosomal Diseases, Beaujon Hospital, Assistance Publique-Hoˆpitaux de Paris, France; 9INSERM U679, Pierre et Marie Curie (Paris 6) University, France
Abstract: Parkinsonism has been described in patients with Gaucher’s disease (GD). We reviewed the 10 cases of patients with both parkinsonism and GD recorded in the French national GD registry, as well as 49 previously published cases. Relative to the general population, parkinsonism in GD patients (1) was more frequent, (2) occurred at an earlier age, (3) responded less well to levodopa, and (4) was more frequently associated with signs of cortical dysfunction. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) were ineffective on GD-associated parkinsonism, suggesting that parkinsonism itself is not an indication for ERT or SRT in this setting. Ó 2009 Movement Disorder Society Key words: Gaucher; glucocerebrosidase; parkinsonism; Parkinson’s disease; Lewy body dementia
*Correspondence to: Dr. Fre´de´ric Sedel, Federation of Nervous System Diseases and Reference Centre for Lysosomal Diseases, Salpeˆtrie`re Hospital, 47 Boulevard de l’Hoˆpital, 75651 Paris cedex 13, France. E-mail:
[email protected] Potential conflict of interest: None reported. Received 9 February 2009; Accepted 17 March 2009 Published online 9 June 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22593
Movement Disorders, Vol. 24, No. 10, 2009
Gaucher’s disease (GD) is the most frequent inherited lysosomal storage disorder.1 It is due to autosomal recessive inherited glucocerebrosidase (GBA) deficiency resulting in glucocerebroside accumulation, mainly in macrophage lysosomes. Enzyme replacement therapy (ERT) is the treatment of choice, whereas miglustat, a small sugar molecule, can be used to inhibit glucocerebroside synthesis and accumulation.1 GD is classified into three variants, based on age at onset, the disease course, and the presence or absence of neurological signs.1,2 Type 1 (non-neuronopathic) GD accounts for around 95% of cases. Clinical manifestations can appear at any age and usually include hepatosplenomegaly, thrombocytopenia, and bone involvement. The course is chronic and the nervous system is, by definition, respected. This classification of GD into neuronopathic forms (types 2 and 3) and a non-neuronopathic form (type 1) has been challenged by recent studies showing heterogeneous neurological disorders in patients with GD type 1.3–5 An association between GD and parkinsonism was initially described in case reports6–11 and then in a series of six patients described by Neudorfer et al.12 Thirty-seven well-characterized cases has since been published.13–25 It is difficult, however, to obtain an accurate clinical picture from these reports. In addition, recent studies have demonstrated that heterozygous mutations in the GBA gene contribute to vulnerability to parkinsonism.26–28 The aim of this study was to obtain a more precise picture of GD-associated parkinsonism (PD/GD), based on a retrospective analysis of 10 cases contained in the French national GD registry and on a review of the 49 previously published cases. PATIENTS AND METHODS From January 2002 to September 2008, 485 patients with GD were enrolled in the French national GD registry. In France, the diagnosis of GD is based on measurement of enzyme activity, and only a subset of patients are genotyped. Although neurological data are not systematically collected in the French GD registry, parkinsonism was mentioned in 11 patients and was confirmed by neurologists in every case (Table 1). The clinical data were sufficiently informative in 10 cases, which are analyzed here. Genotyping was available for 4 of these 10 patients. Six patients were managed at Salpeˆtrie`re Hospital in Paris, and their neurological examinations and chart review were performed by one of us (F.S.). Data on the remaining four patients were obtained from the referring clinicians.
PARKINSONISM IN GAUCHER’S DISEASE TYPE 1 Positron emission tomography (PET) was performed in two cases (#1 and #2), twice on the same day, using two different radiotracers: 18F-fluoro-levodopa to evaluate presynaptic dopa decarboxylase activity, and 11Craclopride to estimate postsynaptic D2 dopamine receptor density. The 18F-fluoro-L-dopa uptake constant and 11 C-raclopride binding potential were compared with mean normal control values (Table 3). The literature was scanned via the NIH Pubmed database with the key words ‘‘parkinsonism,’’ ‘‘Parkinson,’’ ‘‘Gaucher,’’ and ‘‘glucocerebrosidase,’’ and using the authors’ own bibliography. Cases published more than once were excluded by careful perusal of publications and personal communications. Seven cases were excluded because of insufficient data. Finally, 49 cases of GD/PD were selected from 22 articles.
RESULTS AND DISCUSSION The characteristics of the 10 French patients are summarized in Table 1, and those of the 49 published cases in Table 2. Parkinsonism was recorded in 11 (2%) of the 485 patients in the French GD registry. As neurological disorders are not systematically recorded in this registry, the real frequency of parkinsonism in GD patients is probably higher. In two published cohorts of patients with GD type 1, PD was noted in 6.9%19 and 1.33% of cases.4 Overall, although comparisons should be corrected for age in larger cross-sectional studies, the prevalence of PD in GD patients seems to be higher than the prevalence of IPD, which is generally estimated at 0.3% in the entire population and 1% over 60 years of age.29 The N370S mutation, which is usually considered to be ‘‘neuroprotective,’’ was the most common mutation both in the literature (27/35) and in our series (4/4), followed by the L444P mutation (8/25 and 2/4 patients, respectively). By pooling our data with those taken from the literature, median age at onset of PD in patients with GD was 49 years, compared with 60 to 71 years for IPD, depending on the study.30 This comparison must be interpreted with care, however, given the relatively small numbers of cases and the different populations. PD/GD patients share certain features with IPD patients, such as asymmetric onset, akinesia, and rigidity. Resting tremor was noted in 69% of cases in the literature and 60% of our patients (6/10), and a similar prevalence is found in IPD. Dementia was observed in 6 of our 10 patients and in 38.7% of published cases. Too little information
1525
was available in most cases to characterize the precise cognitive deficit. All our six patients had signs of executive dysfunction. In addition, we noted motor and visuoconstructive apraxia reminiscent of cortical dysfunction in patient #2, #3, and #4. All these three patients had visual hallucinations, leading to diagnosis of Lewy body dementia (LBD). Interestingly, heterozygotes for GBA mutations also have a higher risk of developing LBD.31 Here again, these apparent differences between PD/GD and IPD should not be overstated, given the small number of GD patients with detailed neuropsychological studies. Furthermore, the prevalence of dementia in IPD is about 30% at diagnosis and 60% after 12 years.32 Other neurological disorders occasionally reported in PD/GD include supranuclear gaze palsy, myoclonus, deafness, seizures, ataxia, pyramidal signs, polyneuropathy, and dysautonomia (Table 2). None of these were observed in our patients. Brain MRI, when performed, was reported to be normal. In our patient #1 and #2, 18F-fluoro-L-dopa uptake was decreased bilaterally and asymmetrically in the caudate and putamen (see Table 3 and Fig. 1). In contrast, 11C-raclopride binding in the caudate and putamen nuclei was normal in both patients (Table 3 and Fig. 1). These findings, together with those in another published case,24 are highly reminiscent of IPD, which features decreased uptake of 18F-fluoro-L-dopa consistent with asymmetric dopaminergic denervation, together with near-normal 11C-raclopride binding indicative of postsynaptic interneuron integrity. Sustained responses to L-dopa, defined as a subjective improvement of >50% lasting >5 years, occurred in five of eight of our patients but in only 22% of cases reported in the literature. This suggests that L-dopa responsiveness is much lower than in IPD. However, many published reports did not mention the response to L-dopa, and the term ‘‘sustained response’’ was not always clearly defined. Dyskinesias were noted in 5 of our 10 patients and in eight published cases, but the relevant data were unavailable for the other patients. Parkinsonism progressed in all GD patients who received ERT. This is not surprising, as exogenous enzymes are readily excluded from the CNS by the blood-brain barrier. Miglustat, which crosses the blood-brain barrier, has been reported to halt the progression of parkinsonism in a patient with GD.22 However, two of our patients were treated with miglustat 300 mg/day, and both stopped receiving this treatment after 1 year because of progression of parkinsonism (patient #1) or dementia (patient #2).
Movement Disorders, Vol. 24, No. 10, 2009
Movement Disorders, Vol. 24, No. 10, 2009
M
M
M
M
M
F
F
F
F
2
3
4
5
6
7
8
9
10
NA
NA
N370/RecNciI
N370S/L444P
NA
NA
NA
N370S/L444P
N370S/N370S
NA
Genotype
67b
64
74
79
72
60
69
72
65
61
41
47.5b
55
63
4
NA
30
48
47
NA
60
15
58.5b
61
72
60
51
45
52
63
62
57
38
1
ST
Manifestations of Parkinsonism
Asymmetric onset, rigidity, akinesia, discrete tremor HSMG, T 2 Asymmetric onset, rigidity, akinesia T, HSMG,O 2 Asymetric onset, rigidity, akinesia HSMG, T 2 Asymmetric onset, rigidity, akinesia, resting tremor, postural instability, falls T 1 Asymmetric onset, rigidity, akinesia, resting tremor, postural instability HSMG, O 2 Asymmetric onset, rigidity, akinesia, axial signs 1 Asymmetric onset, Nonea rigidity, akinesia, resting tremor HSMG, T, O 1 Asymmetric onset, rigidity, akinesia resting tremor, postural instability, falls SMG, T, O 2 Asymmetric onset, rigidity, akinesia HSMG, T, O 2 Asymmetric onset, rigidity, akinesia, resting tremor T: 8/10, HSMG: 4/10 Asymmetric onset 7/10, O: 6/10 10/10, rigidity, akinesia 10/10, tremor 6/10
HSMG, T, O, Pm
Manifestations of GD
2
1
1 1 NA
1 2
1 (63)
2
1 1 (66) 1 (71)
2
6/9
5/8
NA
NA
1 (64)
NA
NA
2
1 (60)
5/8
2
1 (60)
1 (51)
1 (58)
2
2
1 (60)
1
2
1 (40)
4/6
NA
NA
NA
1
1
1
NT
2
1
2
Dementia Dopa Dyskinesia Fluctuations (age at efficacy (age at (age at onset) >5 yr onset) onset) TT
E
E
E
DBS
E
DBS
E
E
M
E/M/DBS
–
–
NA
NT
NA
NT
–
–
NT
–
Effect of ERT on parkinsonism
b
Diagnosis was made after GD was diagnosed in his sister. Median values. ERT, enzyme replacement therapy; E, enzyme replacement therapy, F, female; GD, Gaucher’s disease; HSMG, hepatosplenomegaly; M, male; NA, not available; NT, not treated; O, osseous involvement; SMG, splenomegaly; DBS, deep brain stimulation; ST, splenectomy; T, thrombopenia; TT, treatment; M, miglustat.
a
Total M:F 5 1.5
M
Gender
1
Case
Age at last Age at Age at follow onset onset of up of GD Parkinsonism
TABLE 1. Summary of clinical, enzymatic, and genetic data in 10 French patients with GD and parkinsonism
1526 I. KRAOUA ET AL.
M/F 5 1.6
M M F M F
M M F
F
M M M
M M M M F F F M M M F
M
F
Mean values
1 2 3 4 5
6 7 8
9
10 11 12
13 14 15 16 17 18 19 20 21 22 23
24
25
Sex
23
46
6 67 22 22 23 53 64 30 62 30 9
10 41 49
60
47 26 49
12 61 24 38 17
35
43
49
33 74 43 44 43 59 55 40 63 45 47
NA 49 NA
NA
50 39 NA
44 65 51 50 56
48
Age at Median age diagnosis at onset of of GD Parkinsonism (yr) (yr)
H, S, Hem
H, S, Hem, O
H, S, O H, S, Hem H, S, Hem, O H, S, Hem H, S, Hem H, S, Hem S, Hem S, O, Hem H, S, Hem S, Hem H
S, O H, S, Hem H, S, Hem
O
H, S, O H, O S,O
S 5 70.8, Hem 5 69, H 5 64.5, O 5 37.5 H, O Hem H, Hem, O Hem H, Hem, O
GD signs (%) 80.9
1 1 2 2 1 2 1 NA NA NA NA NA 1 NA 1 1 1 1 1 NA 2 NA NA NA 1
56.5
1 2 1 2 1 2 1 1 2 1 1 1 1 2 1 2 1 1 2 2 1 1 1 2 1
1
1
2 1 1 1 1 1 1 1 1 1 2
NA 1 NA
NA
2 1 NA
1 1 2 1 1
69.2
NA
1
1 NA 1 1 1 1 1 1 1 1 1
NA 1 1
NA
1 1 NA
2 2 1 2 2
86.8
1
1
1 1 1 1 1 1 1 1 1 1 1
NA 1 1
NA
NA NA NA
NA NA NA NA NA
100
NA
1
2 2 2 NA NA NA NA 2 2 2 2
NA 1 1
NA
2 2 1
1 2 2 1 2
38.7
Cognitive Splenectomy Asymetric Tremor Akinesia Rigidity decline (%) PD (%) (%) (%) (%) (%)
Deafness Deafness 2 2 Bulbar signs Ataxia 2 Psy, saccades abnormalities Myoclonus, SGP 2
SGP SGP deafness Neck dystonia, chorea, SGP, pyramidal sd SGP
2
Myoclonus NA NA NA Complex seizures NA NA 2
28.5
Additional neurological syndromes* (%)
Transient
None
Good None Poor Transient Transient Good Good None None Poor Poor
NA Good NA
NA
NA NA NA
Good 5 22.6, poor 5 25.8, transient 5 16, none 5 35.5 NA NA NA NA NA
Response to levodopa (%)
TABLE 2. Parkinsonism and Gaucher’s disease type 1: previously published cases
1
1
1 1 1 1 1 1 2 1 1 1 NA
1 2 2
2
2 1 1
1 2 1 2 1
68
2
2
2 2 2 2 2 2 2 2 2 2 2
2 2
2
NA 2 2
2 NA 2 NA 2
0
1
2
2 2 2 1 1 2 2 2 2 2 2
2 2 2
2
2 2 2
2 2 2 2 2
16.7
Positive effect of ERT on ERT parkinsonism Surgery (%) (%) (%)
G377S/G377S
G377S/G377S
L444P/F213I N370S/N370S N370S/L444P N370S/L444P G377S/G377S N370S/? N370S/? R463C/R120W N370S/V394L N370S/c.1263–1317 N370S/N370S
N370S/N370S N370S/N370S N370S 1 IVS4-2A > G; (2203) A > G N370S 1 IVS4-2A > G; (2203) A > G L444P/D409H L444P/L444P L444P/L444P
N370S/c.84dupG N370S/N370S N370S/Rec N370S/N370S N370S/L444P
Genotype
17
20
24 22 21 19 19 19 19 18 18 18 18
5 23 23
5
25 25 5
25 25 25 25 25
Reference
M M F M M M F F F F M M F F M
35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
40 27 NA 5 32 32 32 32 32 17 25 56 NA 29 40
28 60 NA 53 40 44 48 NA 19
50 39 NA 33 48.8 48.8 48.8 48.8 48.8 48 38 46 55 43 39
48 62 47 59 50 60 45 40 42
NA S, Hem S,O H, S, Hem H, S, Hem H, S, Hem H, S, Hem H, S, Hem H, S, Hem H, S, Hem, O S, Hem O, Hem O, Hem H, S, Hem S, Hem
H, S, O H, S, Hem 2 H, Hem H H, S, O 2 S H, S, Hem
GD signs (%)
NA 2 1 1 1 1 2 2 2 1 1 2 2 1 2
NA NA 2 1 1 2 2 2 1 NA NA NA NA NA NA NA NA NA 1 NA 1 NA 1 NA
NA NA NA NA 1 1 NA NA 1 NA 2 NA 1 1 1 2 2 2 2 1 2 NA 1 2
1 1 NA 1 1 NA NA 2 1 NA 1 NA 1 1 1 1 1 1 1 1 1 1 1 2
NA 1 NA NA NA 1 1 1 1 NA 1 NA 1 1 1 1 1 1 1 1 1 1 1 1
1 NA NA 1 1 1 1 1 1
Splenectomy Asymetric Tremor Akinesia Rigidity (%) PD (%) (%) (%) (%)
1 2 NA NA NA NA NA NA NA 2 2 2 1 2 2
1 NA NA NA 1 1 NA 1 2
Cognitive decline (%) 2 2 2 2 2 2 2 2 SGP, myoclonus 2 2 NA 2 2 2 2 2 Myoclonus 2 2 2 SGP 2 2
Additional neurological syndromes* (%)
NA None NA None None None None Good Good Transient None Good NA NA NA
NA Poor NA Poor Poor Poor Transient Poor None NA NA NA NA NA NA NA NA NA 1 2 NA NA 2 2
NA 1 NA 1 NA 1 2 1 1 NA NA NA NA NA NA NA NA NA 2 NA NA NA NA NA
NA 2 NA NA NA NA NA NA 2
2 2 2 1 1 2 2 2 2 2 1 2 2 2 2
2 2 NA 2 2 2 2 1 1
Positive effect of ERT on Response to ERT parkinsonism Surgery levodopa (%) (%) (%) (%)
NA N370S/IVS2 1 1 NA NA NA NA NA NA NA NA NA NA NA NA NA
N370S/c.84–85 insG N370S/N370S N370S/c.500 ins T N370S/? N370S/? N370S/N370S N370S/N370S N370S/N370S L444P/D409H
Genotype
15 14 13 12 12 12 12 12 12 10 11 9 8 7 6
17 17 17 17 17 17 17 17 16
Reference
Nonavailable data (NA) were excluded from mean calculations. *Includes SGP, 16.3% myoclonus, 9.3% deafness, 6.9% epilepsy (1 case), ataxia (1 case), bulbar signs (1 case). A, anemia; F, female; H, hepatomegaly; Hem, hematologic signs (include anemia, thrombopenia, or leucopenia); M, male; O, osseous involvement; Psy, psychiatric disorders; S, splenomegaly; SGP, supranuclear gaze palsy;, 2, no; 1, yes.
M M M M F M F M F
26 27 28 29 30 31 32 33 34
Age at Median age diagnosis at onset of of GD Parkinsonism Sex (yr) (yr)
TABLE 2. (Continued)
PARKINSONISM IN GAUCHER’S DISEASE TYPE 1
1529
TABLE 3. Uptake values in controls and patients 1 and 2 obtained for each radiotracer Right caudate
Left caudate
Right putamen
Left putamen
0.0123 6 0.0014 0.0055 0.0088
0.0123 6 0.0013 0.0035 0.0077
0.0118 6 0.0009 0.0033 0.0056
0.0116 6 0.0014 0.0030 0.0049
2.75 6 0.24 3.02 2.13
2.75 6 026 3.08 2.05
2.98 6 0.16 3.70 2.87
3.03 6 0.25 4.20 2.73
18
Uptake constant, F-fluoro-L-dopa Controls (mean 6 SD) Patient 1 Patient 2 Binding potential, 11C-raclopride Controls (mean 6 SD) Patient 1 Patient 2
Author Roles: Research project: Conception: Fre´de´ric Sedel, Jerome Stirnemann, Nadia Belmatoug, Marie Vidailhet; Organization: Fre´de´ric Sedel, Ichraf Kraoua, Nadia Belmatoug, Jerome Stirnemann; Execution: Ichraf Kraoua, Tiphaine Rouaud, Marc Verin, Agne`s Annic, Christian Rose, Luc Defebvre, Liliane Re´me´nieras, Michae¨l Schu¨pbach; PET studies: Maria-Joao Ribeiro. Statistical analysis: Design and execution: Frederic Sedel, Ichraf Kraoua, Marie Vidailhet; Manuscript: Writing of the first draft: Ichraf Kraoua; Review and critique: Fre´de´ric Sedel, Jerome Stirnemann, Nadia Belmatoug, Marie Vidailhet, Tiphaine Rouaud, Marc Verin, Agne`s Annic, Christian Rose, Luc Defebvre, Liliane Re´me´nieras, Michae¨l Schu¨pbach, Maria-Joao Ribeiro.
REFERENCES
FIG. 1. Fusion of MRI and 18F-fluoro-L-dopa images (A), and 11Craclopride (B) in a control (1) and in patient #1 (2). [Color figure can be viewed in the online issue, which is available at www. interscience.wiley.com.]
In conclusion, although this study is limited by its retrospective nature, PD/GD seems to differ from IPD in the following respects: (1) younger age at onset, (2) a poorer or transient response to L-dopa, (3) and a higher incidence of cognitive dysfunction reminiscent of LBD. In contrast, PD/GD shares with IPD its asymmetric onset, akinesia, rigidity, resting tremor and, in some cases, dopa-induced dyskinesias. Although GD may be a risk factor for PD, the vast majority of patients with GD type 1 will never develop neurological problems. Although further prospective studies are needed, parkinsonism should not itself be considered an indication for ERT or SRT. Acknowledgment: Dr. Kraoua has received funding from Genzyme.
1. Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet 2008;372:1263–1271. 2. Erikson A, Bembi B, Schiffmann R. Neuronopathic forms of Gaucher’s disease. Bailliere Clin Haematol 1997;10:711–723. 3. Pastores GM, Barnett NL, Bathan P, Kolodny EH. A neurological symptom survey of patients with type I Gaucher disease. J Inherit Metab Dis 2003;26:641–645. 4. Biegstraaten M, van Schaik IN, Aerts JMFG, Hollak CEM. ‘‘Non-neuronopathic’’ Gaucher disease reconsidered. Prevalence of neurological manifestations in a Dutch cohort of type I Gaucher disease patients and a systematic review of the literature. J Inherit Metab Dis 2008;31:337–349. 5. Capablo JL, Saenz de Cabezon A, Fraile J, Alfonso P, Pocovi M, Giraldo P. Neurological evaluation of patients with Gaucher disease diagnosed as type 1. J Neurol Neurosurg Psychiatry 2008; 79:219–222. 6. van Bogaert L, Froehlich A. Un cas de maladie de Gaucher de l’adulte avec syndrome de Raynaud, pigmentation, et rigidite´ du type extra-pyramidal aux members inferieurs. Ann Med 1939; 45:57–70. 7. Philippart M, Menkes JH. Isolation and characterization of the principal cerebral glycolipids in the infantile and adult forms of Gaucher’s disease. In: Aronson SM, Volk BW, editors. Inborn Disorders of Sphingolipid Metabolism. New York: Pergamon Press; 1967. pp. 389–400. 8. Neil JF, Glew RH, Peters SP. Familial psychosis and diverse neurologic abnormalities in adult-onset Gaucher’s disease. Arch Neurol 1979;36:95–99. 9. Sack GH. Clinical diversity in Gaucher’s disease. Johns Hopkins Med J 1980;146:166–170. 10. McKeran RO, Bradbury P, Taylor D, Stern G. Neurological involvement in type 1 (adult) Gaucher’s disease. J Neurol Neurosurg Psychiatry 1985;48:172–175.
Movement Disorders, Vol. 24, No. 10, 2009
1530
R. SAVICA ET AL.
11. Turpin JC, Dubois G, Brice A, et al. Parkinsonian symptomatology in a patient with type I (adult) Gaucher’s disease. In: Salvayre L, editor. Lipid Storage Disorders. New York: Plenum Press; 1987. 103–109. 12. Neudorfer O, Giladi N, Elstein D, et al. Occurrence of Parkinson’s syndrome in type I Gaucher disease. QJM 1996;89:691–694. 13. Tylki-Szymanska A, Millat G, Maire I, Czartoryska B. Type I and III Gaucher disease in Poland: incidence of the most common mutations and phenotypic manifestations. Eur J Hum Genet 1996;4:334–337. 14. Machaczka M, Rucinska M, Skotnicki AB, Jurczak W. Parkinson’s syndrome preceding clinical manifestation of Gaucher disease. Am J Hematol 1999;6:216–219. 15. Wong H, Topaloglu N, Treser R, Schiffmann R. Dementia with Lewy bodies and Parkinson’s disease in a type I Gaucher disease patient. J Neuropathol Exp Neurol 2000;59:141. 16. Tayebi N, Callahan M, Madike V, et al. Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol Genet Metab 2001;73:313–321. 17. Tayebi N, Walker J, Stubblefield B, et al. Gaucher disease with parkinsonism manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab 2003;79:104–109. 18. Varkonyi J, Rosenbaum H, Baumann N, et al. Gaucher disease associated with parkinsonism: four further case reports. Am J Med Genet 2003;116A:348–351. 19. Bembi B, Zambito Marsala S, Sidransky E, et al. Gaucher’s disease with Parkinson’s disease. Clinical and pathological aspects. Neurology 2003;61:99–101. 20. Guimaraes J, Amaral O, Sa Miranda MC. Adult-onset neuronopathic form of Gaucher’s disease: a case report. Park Relat Disord 2003;9:261–264. 21. Spitz M, Rosenerg R, Sileira PAA, Barbosa ER. Parkinsonism in type 1 Gaucher’s disease. J Neurol Neurosurg Psychiatry 2006;77:709–710. 22. Hughes DA, Ginsberg L, Baker R, et al. Effective treatment of an elderly patient with Gaucher’s disease and parkinsonism: a case report of 24 months oral substrate reduction therapy with miglustat. Park Relat Disord 2007;13:365–368. 23. Raja M, Azzoni A, Giona F, et al. Movement and mood disorder in two brothers with Gaucher disease. Clin Genet 2007;72:357– 361. 24. Kono S, Shirakawa K, Ouchi Y, et al. Dopaminergic neuronal dysfunction associated with parkinsonism in both a Gaucher disease patient and a carrier. J Neurol Sci 2007;252: 181–184. 25. Goker-Alpan O, Lopez G, Vithayathil J, Davis J, Hallett M, Sidransky E. The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch Neurol 2008;65:1353– 1357. 26. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Engl J Med 2004;351:1972–1977. 27. Lwin A, Orvisky E, Groker-Alpan O, LaMarca ME, Sidransky E. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 2004;81:70–73. 28. Sidransky E. Gaucher disease and parkinsonism. Mol Genet Metab 2005;84:302–304. 29. De Lau L, Breteler M. Epidemiology of Parkinson’s disease. Lancet Neurol 2006;5:525–535. 30. Elbaz A, Bower JH, Peterson BJ, et al. Survival study of Parkinson disease in Olmsted County, Minnesota. Arch Neurol 2003; 60:91–96. 31. Goker-Alpan O, Giasson BI, Eblan MJ, et al. Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology 2006;67:908–910. 32. Buter TC, van den Hout A, Matthews FE, Larsen JP, Brayne C, Aarsland D. Dementia and survival in Parkinson disease: a 12year population study. Neurology 2008;70:1017–1022.
Movement Disorders, Vol. 24, No. 10, 2009
Bell’s Palsy Preceding Parkinson’s Disease: A Case-Control Study Rodolfo Savica, MD,1,2 James H. Bower, MD, MSc,2 Demetrius M. Maraganore, MD,2 Brandon R. Grossardt, MS,3 and Walter A. Rocca, MD, MPH1,2* 1
Division of Epidemiology, Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA; 2Department of Neurology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA; 3 Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
Abstract: We investigated the association of Bell’s palsy (BP) with the subsequent risk of Parkinson’s disease (PD) using a case-control study design. We matched 196 incident cases of PD in Olmsted County, MN, to 196 general population controls with same age (61 year) and sex, and we reviewed the complete medical records of cases and controls in a medical records-linkage system to detect BP. Six of the 196 patients with PD and none of the 196 controls were diagnosed with BP before PD (exact binomial probability, P 5 0.02). The median age at occurrence of BP was 49.5 years (range, 15–84 years) and the median time between BP and the onset of PD was 27.5 years (range, 2–54 years). The findings were similar using a standardized incidence ratio (SIR) approach, but were not statistically significant. This initial association between BP and PD awaits replication. Ó 2009 Movement Disorder Society Key words: Bell’s palsy; Parkinson’s disease; case-control study; risk factors
A recent study of a three-generation Mexican family showed the occurrence of both Parkinson’s disease (PD) and Bell’s palsy (BP) in 2 of 21 members. In addition, 1 family member had both BP and essential tremor (ET), and 5 additional members had isolated BP.1 Prompted by this report, and by the observation
Dr. Savica conducted the study while on leave from the Department of Neurosciences, Psychiatry, and Anesthesiology, University of Messina, Italy. *Correspondence to: Dr. Walter A. Rocca, Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail:
[email protected] Potential conflict of interest: None reported. Received 17 November 2008; Revised 25 February 2009; Accepted 24 March 2009 Published online 15 June 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22616
BELL’S PALSY AND PARKINSON’S DISEASE of some PD patients with preceding BP in our clinical series, we formally tested the association between BP and PD in a case-control study conducted in Olmsted County, MN.2-4 METHODS Cases and Controls We used the medical records-linkage system of the Rochester Epidemiology Project to identify all subjects residing in Olmsted County who developed PD from 1976 through 1995. Details about the study population and the identification of incident cases were reported elsewhere.5 Our diagnostic criteria included two steps: the definition of parkinsonism as a syndrome and the definition of PD within the syndrome. Parkinsonism was defined as the presence of at least two of four cardinal signs: rest tremor, bradykinesia, rigidity, and impaired postural reflexes. PD was defined as the presence of parkinsonism with all three of the following criteria: (1) No other cause (e.g., repeated stroke with step-wise progression; repeated head injury; history of encephalitis; neuroleptic treatment within 6 months before onset; hydrocephalus; brain tumor). (2) No documentation of unresponsiveness to levodopa at doses of at least 1 g/day in combination with carbidopa (applicable only to patients who were treated). (3) No prominent or early (within 1 year of onset) signs of more extensive nervous system involvement (e.g., dementia or dysautonomia) not explained otherwise.5 Our clinical classification of patients with PD through medical record review was found to be valid compared with a direct examination by a movement disorders specialist, as reported elsewhere.6 Onset of PD was defined as the year in which a cardinal sign of PD was first noted by the patient, by family members, or by a care provider (as recorded in the medical record). Each case was individually matched by age (61 year) and sex to a general population control residing in Olmsted County and free of PD, other parkinsonism, or tremor of any type in the index year (year of onset of PD in the matched case). The list of all county residents from which potential controls were randomly drawn was provided by the medical records-linkage system.7 Records of potential controls were reviewed by a neurologist (D.M.M.) to exclude the presence of PD, other types of parkinsonism, or tremor of any type before or during the index year. The presence of dementia or other neurologic diseases was not an exclusion criterion. Our exclusion of parkinsonism in controls through medical record review was found to be valid compared with a direct examination by a move-
1531
ment disorders specialist, as reported elsewhere.6 Further details about the identification of controls were reported elsewhere.6 Ascertainment of Bell’s Palsy The complete medical records of cases and controls archived by the medical records-linkage system were reviewed by a neurologist (R.S.) who abstracted all information related to possible BP (e.g., age at onset, duration of symptoms, and side of the palsy). The neurologist abstracted only symptoms or diagnoses that occurred before the onset of PD or the index date. To avoid a possible bias in the abstraction of data,8 we only included subjects who were given a diagnosis of BP by their caregiving physicians (historically, at the time of medical evaluation). In addition, we conducted an independent search for all the International Classification of Diseases codes related to facial palsies using the electronic diagnostic index of the Rochester Epidemiology Project (International Classification of Diseases, Adapted Code for Hospitals—H-ICDA).9 We searched for 34 codes in the 03500 block plus the code 05312. Of the 392 cases or controls, 11 subjects were found to have at least one code of interest. However, one case had a facial palsy following a surgery, one case had a congenital facial palsy, and one case had no details about the palsy within the medical record. Similarly, two controls had facial palsy following surgery. These 3 cases and 2 controls were considered free of BP. The remaining 6 patients with BP preceding PD were the same as those identified via active records review by the neurologist (R.S.). Data Analysis We used the exact binomial probability to estimate a P value for the difference in frequency of BP between cases and controls. The odds ratio was not estimable because none of the controls were exposed. To confirm our findings, we also compared the number of BP events observed among cases with the number of BP events expected using the age- and sex-specific incidence rates from the overall Olmsted County population.10 This method also allowed us to explore the association in men and women separately. RESULTS We identified 202 incident patients with PD from 1976 through 1995, and these patients were matched by age and sex with 202 controls. However, 6 individuals (5 cases and 1 control) did not authorize the use of their medical records for research and the corresponding pairs
Movement Disorders, Vol. 24, No. 10, 2009
1532
R. SAVICA ET AL. TABLE 1. Clinical characteristics of the six patients with Bell’s palsy preceding Parkinson’s disease
Patient number 1 2 3 4 5 6
Sex*
Age at onset of BP
Side affected by BP
Duration of BP
Age at onset of PD
Years from BP to PD
Laterality of PD
Initial symptom of PD
Type of PD
L-dopa response
W W M W M W
84 15 61 58 41 34
L R L L L R
1 month 2 months 1 month 1 month 20 days unknown
86 69 91 73 72 59
2 54 30 15 30 25
L R L L R R
IG IG Rigidity Tremor Tremor Tremor
AR AR Tremora Tremora Tremora Tremora
Yes Yes Not takenb Yes Yes Yes
*The overall sample of patients with PD (cases) included 121 (61.7%) men and 75 (38.3%) women. a Tremor-predominant form of PD. b Patient number 3 did not receive L-dopa because the symptoms of PD were mild and progressed slowly. BP, Bell’s palsy; PD, Parkinson’s disease; W, woman; M, man; R, right; L, left; IG, impaired gait; AR, akinetic-rigid.
could not be studied. Therefore, we included 196 casecontrol pairs for a total of 392 individuals. Among the cases, 121 (61.7%) were men and 75 (38.3%) were women; the median age at onset of PD was 71 years (range, 41–97 years). The distribution by age and sex was similar in controls because of the matched design. Six of the 196 patients with PD and none of the 196 controls had BP before the index-year. The difference in frequency was statistically significant (P 5 0.02). Table 1 summarizes the clinical features of the 6 subjects with BP. The median age at onset of BP was 49.5 years (range, 15–84 years) and the median age at onset of PD was 72.5 years (range, 59–91 years). The median time between the occurrence of BP and PD was 27.5 years (range, 2–54 years). All subjects were L-dopa responsive, except one who did not receive Ldopa because the symptoms were mild and progressed slowly. None of the 6 patients was affected by diabetes mellitus. Using incidence rates of BP from Olmsted County, we expected 2.72 BP events among the 196 cases, yielding an overall standardized incidence ratio (SIR) of 2.21 (95% CI 5 0.81 to 4.80; P 5 0.12). The SIR was 1.29 in men (95% CI 5 0.16 to 4.65; P 5 0.92) and 3.41 in women (95% CI 5 0.93 to 8.74; P 5 0.06). DISCUSSION In this population-based case-control study, we found a previously unrecognized association between BP and PD. There is a previous description of the concurrent presence of BP, ET, and PD in a Mexican family. In particular, both BP and PD were present in the same individual in 2 of the 21 family members (over three generations).1 However, we are not aware of any additional studies that reported this association. The association observed in our study may be due to chance (Type 1 error) and needs to be replicated. If the finding is replicated, it may have three possible explana-
Movement Disorders, Vol. 24, No. 10, 2009
tions. First, some unknown genetic factors may be associated with both BP and PD. This hypothesis is consistent with the aggregation of BP and PD in one family.1 However, there is no other supporting evidence. Second, the development of BP prior to PD could be a manifestation of the early degeneration of the peripheral nervous system that precedes the motor onset of PD.11 The fairly long median time between BP and the diagnosis of PD (27.5 years) may support this hypothesis. However, there are no previous descriptions of facial nerve involvement in the parkinsonian degenerative process, and BP does not correlate with any specific neuropathological findings. Third, BP could represent an early inflammatory reaction against antigens in the nervous system that later leads to PD. In support of this hypothesis, both BP and PD have been associated with inflammatory mechanisms.4,12–14 Our case-control study has several strengths. First, it was based on a series of incident PD cases and on well-defined general population controls, thus avoiding referral bias and prevalence-incidence bias.8 Second, we were able to detect BP before the occurrence of PD using medical records information, thus avoiding recall bias.8 Third, the ascertainment of BP was confirmed by using electronic diagnostic codes, thus excluding a possible bias in data abstraction.8 Our study also has a number of limitations. First, there is limited prior evidence in support of this association; thus, the finding could be due to chance. Second, the small number of subjects with BP in our study limited the statistical power. Third, some subjects who suffered from mild BP may have remained unrecognized and undiagnosed; thus, they were not documented in the medical records-linkage system. This underascertainment should be uncommon and similar for cases and controls. In summary, we report an association between BP and PD, and we expect that this initial finding will prompt further epidemiologic or laboratory studies.
VERTICAL OKN IN PARKINSON’S DISEASE Acknowledgments: This work was supported by the NIH grants R01 NS033978 and R01 AR030582. The authors have no substantial direct or indirect commercial financial incentive associated with publishing the article. Author roles: (1) Research project: A. Conception (Savica, Rocca), B. Organization (Savica, Rocca), C. Execution (Savica, Rocca); (2) Statistical Analysis: A. Design (Savica, Grossardt, Rocca), B. Execution (Grossardt, Savica), C. Review and Critique (Grossardt, Savica, Rocca); (3) Manuscript: A. Writing of the first draft (Savica), B. Review and Critique (Bower, Maraganore, Grossardt, Rocca).
REFERENCES 1. Deng H, Le WD, Hunter CB, Mejia N, Xie WJ, Jankovic J. A family with Parkinson disease, essential tremor, bell palsy, and parkin mutations. Arch Neurol 2007;64:421–424. 2. Frigerio R, Elbaz A, Sanft KR, et al. Education and occupations preceding Parkinson disease: a population-based case-control study. Neurology 2005;65:1575–1583. 3. Bower JH, Maraganore DM, Peterson BJ, McDonnell SK, Ahlskog JE, Rocca WA. Head trauma preceding PD: a case-control study. Neurology 2003;60:1610–1615. 4. Bower JH, Maraganore DM, Peterson BJ, Ahlskog JE, Rocca WA. Immunologic diseases, anti-inflammatory drugs, and Parkinson disease: a case-control study. Neurology 2006;67:494–496. 5. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976-1990. Neurology 1999;52:1214–1220. 6. Elbaz A, Peterson BJ, Yang P, et al. Nonfatal cancer preceding Parkinson’s disease: a case-control study. Epidemiology 2002;13: 157–164. 7. Melton LJ, III. History of the Rochester Epidemiology Project. Mayo Clin Proc 1996;71:266–274. 8. Sackett DL. Bias in analytic research. J Chronic Dis 1979;32:51–63. 9. Commission on Professional and Hospital Activities, National Center for Health Statistics. H-ICDA, hospital adaptation of ICDA, 2d ed. Ann Arbor, MI, 1973. 10. Katusic SK, Beard CM, Wiederholt WC, Bergstralh EJ, Kurland LT. Incidence, clinical features, and prognosis in Bell’s palsy, Rochester, Minnesota, 1968-1982. Ann Neurol 1986;20:622–627. 11. Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K. Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 2007;113:421–429. 12. Paolino E, Granieri E, Tola MR, Panarelli MA, Carreras M. Predisposing factors in Bell’s palsy: a case-control study. J Neurol 1985;232:363–365. 13. Chen H, Jacobs E, Schwarzschild MA, et al. Nonsteroidal antiinflammatory drug use and the risk for Parkinson’s disease. Ann Neurol 2005;58:963–967. 14. McGeer PL, McGeer EG. Inflammation and neurodegeneration in Parkinson’s disease. Parkinsonism Relat Disord 2004;10 (Suppl 1):S3–S7.
1533
Vertical Optokinetic Nystagmus in Parkinson’s Disease Christopher M. Knapp, MD,1 Irene Gottlob, MD,1 Rebecca J. McLean, MD,1 Yusuf A. Rajabally, MD,2 Richard J. Abbott, MD,2 Suzanne Rafelt, BSc,3 and Frank A. Proudlock, PhD1* 1
Ophthalmology Group, Faculty of Medicine and Biological Sciences, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom; 2Department of Neurology, University Hospitals of Leicester, Leicester General Hospital, Leicester, United Kingdom; 3Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, United Kingdom Abstract: Parkinson’s disease (PD) is associated with a number of oculomotor deficits; however, little is known about changes in vertical optokinetic nystagmus (OKN) associated with PD. We recorded eye movements in 14 PD patients and 14 age-matched controls in response to large field OKN stimulation using stimulus velocities of 208/second and 408/second. We compared asymmetry of horizontal and vertical responses in the two groups. We found vertical OKN to be strongly asymmetric in PD with reduced gains for downward-moving stimuli. This asymmetry was significantly greater than that recorded in control volunteers. We postulate that this could result from an abnormal pursuit/early OKN system in PD leading to greater influence of the delayed OKN system. Ó 2009 Movement Disorder Society Key words: optokinetic nystagmus; Parkinson’s disease; asymmetry; eye movements; dopamine
Parkinson’s disease (PD), a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta, is associated with several oculomotor deficits. These include diminished ability in generating volitional saccades and in suppressing visually guided saccades with generation of visually guided saccades less affected.1,2 Early studies also suggest reduced responses in optokinetic nystagmus (OKN) and smooth pursuit gains,3–7 whereas
*Correspondence to: Dr. Frank Proudlock, Ophthalmology Group, Faculty of Medicine and Biological Sciences, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, United Kingdom. E-mail:
[email protected] Potential conflict of interest: Nothing to report. Received 15 April 2008; Revised 26 March 2009; Accepted 27 March 2009 Published online 9 June 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22634
Movement Disorders, Vol. 24, No. 10, 2009
1534
C.M. KNAPP ET AL.
more recent studies suggest no differences to control volunteers.8 The majority of studies into oculomotor deficits associated with PD have investigated horizontal ocular movements. A small number of studies have investigated vertical saccades and smooth pursuit9–11; however, little is known about the effect of PD on vertical OKN (vOKN). In the clinic, OKN is usually tested with the Barany drum, which stimulates a small area of the visual field. Full-field stimulation biases responses toward the subcortical component of OKN because of greater stimulation of peripheral retina.12 In normals, most studies describe asymmetric vOKN gain with preference for upward-moving stimuli13,14 although the literature is equivocal.15,16 The reasons behind this are unclear although the asymmetric inputs from upper and lower visual fields as we navigate through space17 and/or from the otoliths resulting from gravity13 have both been implicated. In addition, we have recently shown that vOKN asymmetry is idiosyncratic with the degree and direction of asymmetry remaining relatively consistent for a normal individual.18 In one previous study in 5 patients with PD, no vOKN bias was observed.8 We have recorded horizontal (hOKN) and vOKN in a larger group of PD patients comparing asymmetry of vOKN gains to age-matched controls. METHODS Fourteen PD patients (11 men, 3 women, age range 35–85 years, mean 67.8 years) with a Hoehn & Yahr19 severity scale of 1–3 were recruited for the study along with 14 age-matched healthy controls (6 men, 8 women, age range 43–83, mean 64.9 years). Patients were recruited from neurology clinics in Leicester General Hospital, UK. Diagnosis was made by a neurologist on the basis of at least two of three hemiparkinsonian syndromes of bradykinesia, rigidity, and/or tremor. Thirteen of the 14 PD patients were on medication at time of testing (see Table 1 for medications). There was no history of any known ophthalmological or otological disorder in either group of subjects and no known neurological abnormalities in the control group. All subjects had normal eye movements (saccades and pursuit) when tested clinically. OKN was not tested clinically. The study received local ethical approval and was performed in accordance with tenets of the declaration of Helsinki. The OKN stimuli were projected onto a rear projection screen of 1.75 m width and 1.17 m height using a VisLab projection system (SensoMotoric Instruments
Movement Disorders, Vol. 24, No. 10, 2009
TABLE 1. Clinical details of Parkinson’s patients including Hoehn & Yahr grade (H & Y), duration of the disease, and medications with levodopa equivalent dosage
Patients
Age
Sex
H&Y
Disease duration (yr)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
72 63 71 75 73 68 75 85 65 75 46 69 35 78
M M F M M M M F M M F M M M
1.5 1 2 2 1.5 2.5 2 2 2 3 2 2 1 3
6 5 7 11 7 7 408/second) were also significant factors but group was not (F 5 0.69, P 5 0.41). For horizontal
1535
OKN gains, speed was the only significant factor (F 5 71.2, P 5 1.0 3 10212, 208/second > 408/second; F 5 0.16, P 5 0.69 for group; F 5 0.38, P 5 0.54 for direction; and F 5 1.71, P 5 0.19 for group 3 direction). There were no significant effects of group or direction on beat frequency in horizontal or vertical directions (P > 0.1). However, lower speeds were significantly associated with higher vertical beat frequencies (F 5 12.1, P 5 0.0008). Vertical and horizontal asymmetries were also compared for OKN gain (Fig. 1D) and beat frequency (Fig. 1E). For gains, group was a significant effect on vertical asymmetry (F 5 7.13, P 5 0.013, PD > controls) but not on horizontal asymmetry (F 5 1.17, P 5 0.29). Speed did not influence vertical (F 5 0.03, P 5 0.86) or horizontal (F 5 1.57, P 5 0.22) asymmetry of gain. Neither group nor speed significantly influenced horizontal and vertical asymmetry of beat frequency (P > 0.05 for all factors). The association between the severity of the disease (Hoehn & Yahr scale) and mean vertical asymmetry of gain was not significant (r 5 0.33, P 5 0.25) although impairment of mean downward OKN gain at 408/seconds was near to significance (r 5 20.49, P 5 0.07). There was also a near-significant negative trend between the L-dopa equivalent of prescribed medication and mean vertical asymmetry of OKN gain (r 5 20.53, P 5 0.07), indicating that, if anything, increasing dosage removes the pattern of vertical asymmetry associated with PD patients.
DISCUSSION The main finding of this study is that PD results in a consistent vOKN asymmetry with reduced responses to downward-moving stimuli. This vOKN asymmetry is stronger than that seen in age-matched controls. The majority of literature in young healthy adults also describes a vOKN preference for upward-moving stimuli13,14 although there is some disagreement with certain groups reporting either a downward preference16 or symmetrical OKN.8,15 Use of a full-field stimuli and faster stimulus velocities tends to accentuate the upward preference. We have recently shown that vOKN asymmetry is idiosyncratic, that is, although between-subject variability is high, a certain individual will tend to show a certain direction and degree of vertical asymmetry.18 The reasons behind this are unclear. vOKN asymmetry was not observed in the control group in this study (although P 5 0.15 for 408/seconds). This could be due to using a nonfull-
Movement Disorders, Vol. 24, No. 10, 2009
FIG. 1. (A) Original eye movement recordings for a 65-year-old PD patient (Hoehn & Yahr 5 2) and a control volunteer of 68 years. Movements upward on the trace indicate either rightward or upward eye movements. Brisk OKN responses consisting of fast and slow phases can be observed in all stimulus directions for the control volunteer and in rightward, leftward, and upward directions for the PD patient. A weak OKN response to downward-moving stimuli was observed in the PD patient with less consistent fast and slow phases. Mean OKN gains are shown for individual PD patients and controls in response to stimuli moving in (B) vertical and (C) horizontal directions. Connecting lines indicate the degree of vertical and horizontal for each individual. PD patients showed strong vOKN asymmetry especially at 408/second. Means of all subjects (with standard deviations in brackets) are shown in italics. Mean vertical and horizontal asymmetry indices for PD patients and controls are shown for (D) OKN gain and (E) OKN beat frequency of the fast phases. Error bars 5 SEM, HAI 5 horizontal asymmetry indices, and VAI 5 vertical asymmetry indices.
VERTICAL OKN IN PARKINSON’S DISEASE field stimulus, slower stimulus velocities or possible the use of an older age group. The change in vOKN asymmetry with age has not been previously described. The most interesting finding in this study is that PD exaggerates vertical OKN asymmetry beyond that observed in a normal control group. The cause of vOKN asymmetry in either healthy individuals or patients with PD is unclear. Asymmetric sensory inputs from the visual field and otoliths have both been implicated as the cause of physiological vOKN asymmetry. The greater motion in the lower visual field induced by forward motion such as walking has been suggested may lead to reduced downward OKN because of suppression of stimuli.17 Alternatively, evidence has accumulated that input from the otoliths is important in generating vOKN asymmetry.13 OKN contains two components: an early component (OKNe), which builds up and decays quickly and usually dominates the OKN response in humans; and a delayed component (OKNd), which builds up and decays much slower. The delayed component and in particular its decay, called optokinetic afternystagmus (OKAN), is highly asymmetric with a small response following downward stimuli with the head in an upright position.13,20 When otolith input is altered, e.g., in space, and when the head is either tilted or upside down, OKAN and also of vOKN overall can become symmetrical or reverse its asymmetry.13,20 One possibility is that the early OKN component in PD is weaker compared with controls leading to greater influence of the delayed OKN component resulting in greater vOKN asymmetry. In support of this, a number of studies suggest that the smooth pursuit system is deficient in PD.4–7 Because the pursuit system shares similar neural circuitry to the early OKN system, both may be affected by PD. In addition to the basal ganglia, PD leads to changes in several structures in the CNS, such as the cerebellum and occipital cortex, which could lead to vOKN asymmetry.21 Another alternative is that the deficit may related to the generation of OKN quick phases. Quick phases are produced by the premotor burst neurons in the rostral interstitial nucleus of medial longitudinal fasciculus,22 which are under the control of the superior colliculus and central mesencephalic reticular formation. These all lie in close proximity to the substantia nigra in the mesencephalon. The possible confounding effects of medication are unclear. L-dopa, for example, increases reflexive saccades latencies and reduces antisaccades errors.23 These are associated with higher cortical processing, which are however not directly related to OKN. Here, we
1537
show that increasing L-dopa equivalent dosage does not lead to greater vertical asymmetry in OKN gain. Acknowledgments: We thank the Ulverscroft Foundation for their financial support. Author Roles: Christopher M. Knapp: (1) Research project: A. Execution; (2) Statistical Analysis: A. Execution, B. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. Irene Gottlob: (1) Research project: A. Conception, B. Organization; (2) Statistical Analysis: A. Review and Critique; (3) Manuscript: A. Review and Critique. Rebecca J. McLean: (1) Research project: A. Organization, B. Execution. Yusuf A. Rajabally: (1) Research project: A. Conception, B. Execution; (3) Manuscript: A. Review and Critique. Richard J. Abbott: (1) Research project: A. Execution. Suzanne Rafelt: (2) Statistical Analysis: A. Execution, B. Review and Critique. Frank A. Proudlock: (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique.
REFERENCES 1. Chan F, Armstrong IT, Pari G, Riopelle RJ, Munoz DP. Deficits in saccadic eye-movement control in Parkinson’s disease. Neuropsychologia 2005;43:784–796. 2. Vidailhet M, Rivaud S, Gouider-Khouja N, et al. Saccades and antisaccades in parkinsonian syndromes. Adv Neurol 1999;80: 377–382. 3. Nakamura T, Kanayama R, Sano R, et al. Quantitative analysis of ocular movements in Parkinson’s disease. Acta Otolaryngol Suppl 1991;481:559–562 4. White OB, Saint-Cyr JA, Tomlinson RD, Sharpe JA. Ocular motor deficits in Parkinson’s disease. III. Coordination of eye and head movements. Brain 1988;111 (Part 1):115–129. 5. Rascol O, Clanet M, Montastruc JL, et al. Abnormal ocular movements in Parkinson’s disease. Evidence for involvement of dopaminergic systems. Brain 1989;112 (Part 5):1193–1214. 6. Waterston JA, Barnes GR, Grealy MA, Collins S. Abnormalities of smooth eye and head movement control in Parkinson’s disease. Ann Neurol 1996;39:749–760. 7. Lekwuwa GU, Barnes GR, Collins CJ, Limousin P. Progressive bradykinesia and hypokinesia of ocular pursuit in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999;66:746–753. 8. Garbutt S, Riley DE, Kumar AN, Han Y, Harwood MR, Leigh RJ. Abnormalities of optokinetic nystagmus in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 2004;75:1386–1394. 9. Grant MP, Leigh RJ, Seidman SH, Riley DE, Hanna JP. Comparison of predictable smooth ocular and combined eye-head tracking behaviour in patients with lesions affecting the brainstem and cerebellum. Brain 1992;115 (Part 5):1323–1342. 10. Rottach KG, Riley DE, DiScenna AO, Zivotofsky AZ, Leigh RJ. Dynamic properties of horizontal and vertical eye movements in parkinsonian syndromes. Ann Neurol 1996;39:368–377. 11. Vidailhet M, Rivaud S, Gouider-Khouja N, et al. Eye movements in parkinsonian syndromes. Ann Neurol 1994;35:420–426. 12. Murasugi CM, Howard IP. Up-down asymmetry in human vertical optokinetic nystagmus and afternystagmus: contributions of the central and peripheral retinae. Exp Brain Res 1989;77:183– 192.
Movement Disorders, Vol. 24, No. 10, 2009
1538
U. WALTER ET AL.
13. Clement G. A review of the effects of space flight on the asymmetry of vertical optokinetic and vestibulo-ocular reflexes. J Vestib Res 2003;13:255–263. 14. Ogino S, Kato I, Sakuma A, Takahashi K, Takeyama I. Vertical optokinetic nystagmus in normal individuals. Acta Otolaryngol Suppl 1996;522:38–42. 15. Baloh RW, Richman L, Yee RD, Honrubia V. The dynamics of vertical eye movements in normal human subjects. Aviat Space Environ Med 1983;54:32–38. 16. Schor C, Narayan V. The influence of field size upon the spatial frequency response of optokinetic nystagmus. Vis Res 1981;21: 985–994. 17. Guedry FE, Benson A. Tracking performance during sinusoidal stimulation of the vertical and horizontal semicircular canals. In: Busdy DE, editor. Recent advances in aerospace medicine. Dordecht: Reidel Publishing Co; 1970. p 276–288. 18. Knapp CM, Gottlob I, McLean RJ, Proudlock FA. Horizontal and vertical look and stare optokinetic nystagmus symmetry in healthy adult volunteers. Invest Ophthalmol Vis Sci 2008;49: 581–588. 19. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17:427–442. 20. Wei G, Lafortune SH, Ireland DJ, Jell RM. Human vertical optokinetic nystagmus and after-response, and their dependence upon head orientation with respect to gravity. J Vestib Res 1994;4:37–47. 21. Hurley MJ, Jenner P. What has been learnt from study of dopamine receptors in Parkinson’s disease? Pharmacol Ther 2006; 111:715–728. 22. Horn AK, Buttner-Ennever JA. Premotor neurons for vertical eye movements in the rostral mesencephalon of monkey and human: histologic identification by parvalbumin immunostaining. J Comp Neurol 1998;392:413–427. 23. Hood AJ, Amador SC, Cain AE, et al. Levodopa slows prosaccades and improves antisaccades: an eye movement study in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2007;78:565– 570.
Deep Brain Stimulation in Dystonia: Sonographic Monitoring of Electrode Placement into the Globus Pallidus Internus Uwe Walter, MD,1*,Alexander Wolters, MD,1 Matthias Wittstock, MD,1 Reiner Benecke, MD,1 Henry W. Schroeder, MD,2 and Jan-Uwe Mu¨ller, MD2 1
Department of Neurology, University of Rostock, Rostock, Germany; 2Department of Neurosurgery, Ernst-Moritz-Arndt University, Greifswald, Germany Video
Abstract: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective treatment in primary dystonia. Its success depends on the implantation accuracy of the DBS electrode into the targeted GPi. Discrepancies of up to 4 mm between the initial target, selected on preoperative MRI, and the final DBS lead location are caused mainly by caudal brain shift that occurs once the cranium is open. Nowadays, transcranial sonography (TCS) can display echogenic deep brain structures with higher image resolution compared to MRI under clinical conditions. Here, we demonstrate for the first time the use of a contemporary clinical high-end TCS system for intraoperative monitoring of DBS electrode position. Herewith, a high-resolution real-time imaging of closely located microelectrodes and of the DBS lead through the intact skull is feasible. Simultaneous color-coded sonographic imaging of arteries near the anatomical target allows further intraoperative refinement of DBS lead positioning, simultaneously preventing hemorrhages. Ó 2009 Movement Disorder Society Key words: dystonia; deep brain stimulation; transcranial sonography; globus pallidus internus
Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective treatment in primary dystonia.1–3 Its success depends on the implantation accu-
Additional Supporting Information may be found in the online version of this article. *Correspondence to: Dr. Uwe Walter, Department of Neurology, University of Rostock, Gehlsheimer Str, 20 D-18147, Rostock, Germany. E-mail:
[email protected] Potential conflict of interest: The authors report no conflicts of interest. Received 30 January 2009; Revised 22 April 2009; Accepted 26 April 2009 Published online 1 June 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22663
Movement Disorders, Vol. 24, No. 10, 2009
SONOGRAPHY FOR DEEP BRAIN ELECTRODE PLACEMENT
1539
FIG. 1. Setting and typical images of intraoperative transcranial sonography (TCS) in a patient in whom deep brain stimulation (DBS) electrodes were implanted bilaterally into the GPi. (A) Aspect of the patient with the head fixed in the stereotactic frame. The arrow denotes the access for the ultrasound transducer. (B) Aspect of the patients head with inserted microelectrodes through the bore hole. The arrow denotes the position of the ultrasound transducer. (C) Fusion image of preoperative MRI and corresponding intraoperative TCS scan parallel to the stereotactic trajectories (red and green lines). (D) Intraoperative TCS image corresponding to the fusion image in (C). The weakly echogenic thalami (T) and midbrain (M) are encircled for better recognition. (E) Intraoperative TCS image corresponding to the TCS image in (D). Two closely located microelectrodes are clearly visualized (arrows). Inserted panel in the left lower corner: photograph of the microelectrode. (F) Intraoperative TCS image showing the tip of the final DBS lead (white arrow) and its distance to the posterior communicating artery (black arrow) and the perforating branch to the GPi (blue arrow). Considering the previously determined imaging artefact of the DBS lead tip, monitoring of its distance to the perforating artery near the anatomical target allowed the intraoperative decision to slightly further insert the DBS lead for improvement of targeting accuracy. Inserted panel in the left lower corner: photograph of the DBS lead.
racy of the DBS electrode array (‘‘lead’’) into the targeted GPi. Discrepancies of up to 4 mm (average 2 mm) between the initial target, selected on preoperative MRI, and the final DBS lead location are caused mainly by caudal brain shift that occurs once the cranium is open.4 Intraoperative MRI may overcome targeting inaccuracy but is expensive and not widely available.5 Transcranial sonography (TCS) allows real-time gray-scale imaging of the brain through the intact skull and, simultaneously, color-coded sonography (TCCS) of basal cerebral arteries.6 Nowadays, TCS can display echogenic deep brain structures with higher image resolution compared with MRI under clinical conditions.7 In patients with idiopathic generalized and segmental dystonia, TCS depicts the GPi with abnormal increased echogenicity,8,9 a finding caused by increased amounts of copper and manganese.10–13 Here, we present first results on the use of intraoperative TCS for electrode placement into the GPi.
PATIENTS AND METHODS Human Skull Phantom For measuring the size of TCS imaging artefacts of intracranial DBS lead, a human skull phantom with a filling mimicking physical properties of brain tissue was used as described earlier in detail.7 To detect possible heating during insonation, a thermo couple was fixed to the DBS lead tip and connected to a digital thermometer (metering precision, 0.1 centigrade).
Patients After approval by the local ethics committee, intraoperative TCS was applied in two patients with primary segmental dystonia refractory to conservative treatment in whom DBS electrodes were implanted bilaterally into the GPi. The first patient was a 38-year-old man who suffered from segmental brachiofacial dystonia with a severity of 15 points on the Tsui Rating Scale14
Movement Disorders, Vol. 24, No. 10, 2009
1540
U. WALTER ET AL.
and 27 points on the severity subscale of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS).15 The second patient was a 62-year-old woman who had combined cervical dystonia, blepharospasm, and spasmodic dysphonia (Tsui Rating Scale, 6 points; TWSTRS, 15 points). Both patients were preoperatively assessed for sufficient transcranial bone windows to allow adequate TCS of deep brain structures. Surgical Procedures Surgical procedures were performed as described previously,2 using a Leksell stereotactic head frame (Fig. 1A). Using preoperative MRI, trajectories were planned on an iPlan stereotactic planning station (BrainLAB; Feldkirchen, Germany). In the operating room, under monitored anaesthesia care, a 10-mm burr hole was drilled and the dura opened (Fig. 1B). Using guide tubes that terminated 35 to 40 mm superior to the stereotactic target, five microelectrodes with a diameter each of 0.5 mm (Fig. 1E) were inserted serially. After completion of the recordings and removal of the microelectrodes, a Medtronic type 3,387 quadripolar DBS lead (Medtronic, Inc., Minneapolis, MN) with a diameter of 1.27 mm (Fig. 1F) was inserted down the appropriate guide tube. Intraoperative TCS TCS was conducted under aseptic conditions through the intact temporal (preauricular) skull employing the clinical ultrasound system Acuson Antares (Siemens; Erlangen, Germany) equipped with a 1.8–4.2 MHz transducer (type PX4-1) (Fig. 1B). Parameter settings were dynamic range 50 dB, postprocessing preset G. Using the guide tubes at the stereotactic frame for orientation, the transducer was twisted so that a coronary brain section parallel to the trajectory was displayed (Fig. 1C–E). Arteries near the GPi were visualized on TCCS (Fig. 1F).
RESULTS Phantom TCS Studies Using the skull phantom, we found constant temperature (22.38C) of the intracranial DBS lead when exposed to TCS or TCCS for 30 minutes each with ultrasound frequencies of 2.0, 2.5, or 3.1 MHz (ultrasound intensity: mechanical index 1.4). In lateral direction of insonation, applied to monitor electrode depth, the highly echogenic imaging artefact of the metal part of the DBS lead was found to exceed the 1-mm rubber
Movement Disorders, Vol. 24, No. 10, 2009
tip by minimum 0.1 mm (range, 0.1–1.5 mm, depending on image brightness). In axial direction of insonation, the imaging artefact exceeding the real boundary of the DBS lead was smaller (range, 0.3–0.6 mm; resulting seeming DBS lead diameter, 1.9–2.5 mm, depending on image brightness). Intraoperative TCS Studies In the intraoperative setting, the microelectrodes and the final DBS lead were clearly visualized on TCS in both patients (Fig. 1E, F; Video). The sizes of imaging artefacts were equal to the sizes determined in the phantom studies. Bearing in mind that the imaging artefact of the metal parts of the DBS lead exceeded the real size of the 1-mm rubber tip by at least 0.1 mm, monitoring of its distance to the neighboring arteries allowed the intraoperative decision to further insert the DBS lead for improvement of targeting accuracy in our patients (Fig. 1F; Video). In both patients, the bilateral DBS lead tips were found on TCS to be located correctly in the GPi at nearly symmetric depth (right–left difference, each,
