Longitudinal assessment of reflexive and volitional saccades in Niemann-Pick Type C disease during treatment with miglustat

Orphanet Journal of Rare Diseases

Dennis Velakoulis⁴  Elizabeth A. Bowman¹  Matthew J. Stainer²  Mark Walterfang⁴  Larry A. Abel³ 

[1]Melbourne Neuropsychiatry Centre, University of Melbourne, Melbourne, Australia

[2]Active Vision Lab, School of Psychology, The University of Aberdeen, Aberdeen, Scotland

[3]Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Australia

[4]Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, Australia

关键词: Antisaccade;    Velocity;    Gain;    Saccades;    Miglustat;    Niemann-Pick type C;   

Others  :  1235014
DOI  :  10.1186/s13023-015-0377-8

 received in 2015-08-04, accepted in 2015-12-10,  发布年份 2015

【 摘 要 】

Background

Niemann-Pick Type C disease (NPC), is an autosomal recessive neurovisceral disorder of lipid metabolism. One characteristic feature of NPC is a vertical supranuclear gaze palsy particularly affecting saccades. However, horizontal saccades are also impaired and as a consequence a parameter related to horizontal peak saccadic velocity was used as an outcome measure in the clinical trial of miglustat, the first drug approved in several jurisdictions for the treatment of NPC. As NPC-related neuropathology is widespread in the brain we examined a wider range of horizontal saccade parameters and to determine whether these showed treatment-related improvement and, if so, if this was maintained over time.

Methods

Nine adult NPC patients participated in the study; 8 were treated with miglustat for periods between 33 and 61 months. Data were available for 2 patients before their treatment commenced and 1 patient was untreated. Tasks included reflexive saccades, antisaccades and self-paced saccades, with eye movements recorded by an infrared reflectance eye tracker. Parameters analysed were reflexive saccade gain and latency, asymptotic peak saccadic velocity, HSEM-α (the slope of the peak duration-amplitude regression line), antisaccade error percentage, self-paced saccade count and time between refixations on the self-paced task. Data were analysed by plotting the change from baseline as a proportion of the baseline value at each test time and, where multiple data values were available at each session, by linear mixed effects (LME) analysis.

Results

Examination of change plots suggested some modest sustained improvement in gain, no consistent changes in asymptotic peak velocity or HSEM-α, deterioration in the already poor antisaccade error rate and sustained improvement in self-paced saccade rate. LME analysis showed statistically significant improvement in gain and the interval between self-paced saccades, with differences over time between treated and untreated patients.

Conclusions

Both qualitative examination of change scores and statistical evaluation with LME analysis support the idea that some saccadic parameters are robust indicators of efficacy, and that the variability observed across measures may indicate locally different effects of neurodegeneration and of drug actions.

【 授权许可】

   
2015 Abel et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

【 参考文献 】

• [1]Sevin M, Lesca G, Baumann N, Millat G, Lyon-Caen O, Vanier MT et al.. The adult form of Niemann–Pick disease type C. Brain. 2007; 130:120-33.
• [2]Vanier MT. Niemann-Pick disease type C. Orphanet J. Rare Dis. 2010; 5:1-18. BioMed Central Full Text
• [3]Mengel E, Klünemann H-H, Lourenço CM, Hendriksz CJ, Sedel F, Walterfang M et al.. Niemann-Pick disease type C symptomatology: an expert-based clinical description. Orphanet J. Rare Dis. 2013; 8:166. BioMed Central Full Text
• [4]Rottach KG, von Maydell RD, Das VE, Zivotofsky AZ, Discenna AO, Gordon JL et al.. Evidence for independent feedback control of horizontal and vertical saccades from Niemann-Pick type C disease. Vis Res. 1997; 37(24):3627-38.
• [5]Solomon D, Winkelman C, Zee DS, Gray L, Buettner-Ennever JA. Niemann-Pick Type C disease in two affected sisters: Ocular motor recordings and brain-stem neuropathology. Ann N Y Acad Sci. 2005; 1039:436-45.
• [6]Inchingolo P, Spanio M. On the identification and analysis of saccadic eye movements--A quantitative study of the processing procedures. IEEE Trans Biomed Eng. 1985; BME-32:683-95.
• [7]Patterson MC, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C et al.. Long-term miglustat therapy in children with Niemann-Pick Disease Type C. J Child Neurol. 2010; 25:300-5.
• [8]Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 2007; 6(9):765-72.
• [9]Wraith JE, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luz C et al.. Miglustat in adult and juvenile patients with Niemann–Pick disease type C: Long-term data from a clinical trial. Molec Genet Metab. 2010; 99:351-7.
• [10]Gaymard B, Ploner CJ, Rivaud S, Vermersch AI, Pierrot-Deseilligny C. Cortical control of saccades. Exp Brain Res. 1998; 123:159-63.
• [11]Ettinger U, Kumari V, Chitnis XA, Corr PJ, Sumich AL, Rabe-Hesketh S et al.. Relationship between brain structure and saccadic eye movements in healthy humans. Neurosci Lett. 2002; 328:225-8.
• [12]Fletcher WA, Sharpe JA. Saccadic eye movement dysfunction in Alzheimer’s disease. Ann Neurol. 1986; 20:464-71.
• [13]Hershey LA, Whicker L, Abel LA, Dell’Osso LF, Traccis S, Grossniklaus D. Saccadic latency measurements in dementia. Arch Neurol. 1983; 40:592-3.
• [14]Pierrot-Deseilligny C, Rivaud S, Pillon B, Fournier E, Agid Y. Lateral visually-guided saccades in progressive supranuclear palsy. Brain. 1989; 112:471-87.
• [15]Garbutt S, Matlin A, Hellmuth J, Schenk AK, Johnson JK, Rosen H et al.. Oculomotor function in frontotemporal lobar degeneration, related disorders and Alzheimer’s disease. Brain. 2008; 131:1268-81.
• [16]Abel LA, Bowman EA, Velakoulis D, Fahey MC, Desmond P, Macfarlane MD et al. Saccadic Eye Movement Characteristics in Adult Niemann-Pick Type C Disease: Relationships with Disease Severity and Brain Structural Measures. Plos One. 2012;7(11). doi:10.1371/journal.pone.0050947.
• [17]Klunemann HH, Elleder M, Kaminski WE, Snow K, Peyser JM, O’Brien JF et al.. Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. Ann Neurol. 2002; 52(6):743-9.
• [18]Abel LA, Walterfang M, Fietz M, Bowman EA, Velakoulis D. Saccades in adult Niemann-Pick disease type C reflect frontal, brainstem, and biochemical deficits. Neurol. 2009; 72:1083-6.
• [19]Walterfang M, Macfarlane MD, Looi JCL, Abel LA, Bowman EA, Fahey MC et al.. Pontine-to-midbrain ratio indexes ocular-motor function and illness stage in adult Niemann–Pick disease type C. Eur J Neurol. 2012; 19:462-7.
• [20]Baayen RH. Analyzing Linguistic Data: A practical introduction to statistics using R. Cambridge University Press, Cambridge; 2008.
• [21]Kliegl R, Wei P, Dambacher M, Yan M, Zhou X. Experimental effects and individual differences in linear mixed models: estimating the relationship between spatial, object, and attraction effects in visual attention. Front. Psychol. Quantitative Psychol. Meas. 2011;1. doi:10.3389/fpsyg.2010.00238.
• [22]Baayen RH, Davidson DJ, Bates DM. Mixed-effects modeling with crossed random effects for subjects and items. J Mem Lang. 2008; 59:390-412.
• [23]Kliegl R, Masson MEJ, Richter EM. A linear mixed model analysis of masked repetition priming. Vis Cogn. 2010; 18:655-81.
• [24]Bates D, Maechler M, Bolker B. Linear mixed-effect models using S4 classes. R package version 0.999999-0. 2012. http://CRAN. R-project.org/package=lme4. Accessed 29 June 2015 webcite
• [25]Wickham H. ggplot2: elegant graphics for data analysis. Springer, New York; 2009.
• [26]Walterfang M, Fietz M, Fahey M, Sullivan D, Leane P, Lubman DI et al.. The neuropsychiatry of Niemann-Pick Type C disease in adulthood. J. Neuropsychiatry Clin. Neurosci. 2006; 18:158-70.
• [27]Lobel E, Kahane P, Leonards U, Grosbras M-H, Lehericy S, Le Bihan D et al.. Localization of human frontal eye fields: anatomical and functional findings of functional magnetic resonance imaging and intracerebral electrical stimulation. J Neurosurg. 2001; 95:804-15.