INCREASING CAMP LEVELS BY INHIBITING PHOSPHODIESTERASE 4D IMPROVES NERVE CONDUCTION AND FUNCTIONAL RECOVERY IN A MOUSE MODEL FOR CHARCOT MARIE TOOT 1A

Abstract

Methods: Non-linear mixed effects modeling software (NONMEM) was used to describe the PK of IVIg. Total IgG levels were measured in a model-building cohort consisting of 177 GBS patients with 589 sequential serum samples, and an independent validation cohort consisting of 177 GBS patients with 689 sequential serum samples. Model robustness was evaluated using goodness-of-fit plots, visual predictive checks, realistic parameter estimates, and shrinkage. Cov-ariates were analyzed in a stepwise manner; forward inclusion followed by stricter backward elimination. Results: The PK of IVIg treatment in GBS was best described using a two-compartment model. Allometric scaling was used to correct for bodyweight. The PK model accurately described the daily increment in serum IgG levels during a standard IVIg course, followed by the initial rapid fall and gradual decline to steady-state levels. Apparent clearance of IgG increased with 31% in patients receiving concomitant methylprednisolone treatment, with 22% in patients with a GBS disability score of 3 or 4, and with 83% in patients with a disability score of 5. The model was successfully validated in the second cohort. Conclusions: This is the first model describing the PK of high dose IVIg in patients with GBS. Disease severity and concomitant methyl-prednisolone treatment were identified as important covariates to explain variability in IgG levels. The validated model provides a tool to predict the PK of alternative regimens of IVIg in GBS to design future trials and personalize treatment. Introduction: Tremor often occurs in chronic inflammatory demyelin-ating polyneuropathy (CIDP) and may, in addition to weakness and sensory impairment, lead to disability. We aimed to assess the influence of tremor in CIDP on disability assessment. Methods: In this cross-sectional study, we compared CIDP patients with and without a relevant tremor using the INCAT disability scale (INCAT-DS, arm and leg score separately) and the following impairment scales: the MRC sum score (MRC-SS), INCAT sensory score (INCAT-SS) and grip strength, using the Mann-Whitney U test. We defined a relevant tremor as an intention or postural tremor of >1 cm or at a least a moderate tremor during specific arm motor tasks measured using the Fahn-Tolosa-Marín subscale B (FTM-B) of at least one hand. Using multivariate linear regression models, we investigated the association between the INCAT-DS arm disability score as dependent variable and the presence of a relevant tremor (yes or no) or tremor severity, using the FTM-B sum score, as independent variables, when corrected for other impairment scales. Results: 19 % (14/72) of patients had a relevant tremor. The INCAT arm disability score was significantly higher in patients with a relevant tremor compared to patients without (2.0 vs 1.0 points, p = 0.019), while there were no significant differences in grip strength, the MRC-SS and INCAT-SS of the arms. Presence of relevant tremor and tremor severity were independent predictors of INCAT arm disability score, when corrected for grip strength, the MRC-SS and INCAT-SS of the arms. Conclusions: In patients with CIDP, presence of tremor and tremor severity predict arm disability, independent of muscle strength and sensory deficits. This may be relevant for clinical practice and research, as tremor is thought to be less responsive to treatment than other causes of disability in CIDP.