Autoimmune encephalitis : The clinical value of antibodies directed to extracellular antigens

Het doel van dit proefschrift is om meer inzicht te geven in de meest voorkomende ziekten die geassocieerd zijn met antistoffen tegen extracellulaire antigenen. Vroege herkenning van subtiele epileptische aanvallen is essentieel voor de vlotte herkenning en behandeling van een anti-LGI1 encefalitis. Anti-LGI1 encefalitis is sterk geassocieerd met HLA-DR7 en HLA-DRB4. De syndromen geassocieerd met Caspr2-antistoffen zijn gevarieerd, waaronder encefalitis, het syndroom van Morvan, en neuromyotonie, maar er zijn opvallend sterke overeenkomsten tussen patiënten wat betreft epidemiologische kenmerken en kernsymptomen. VGKC-positiviteit in afwezigheid van antistoffen tegen LGI1 en Caspr2 is geen marker voor een auto-immuun ontsteking en is in de klinische praktijk niet bijdragend. Het eerste EEG bij patienten met een anti-NMDAR encefalitis heeft een voorspellende waarde voor de uiteindelijke klinische uitkomst

From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time

AbstractA wide variety of clinical syndromes has been associated with antibodies to voltage-gated potassium channels (VGKCs). Six years ago, it was discovered that patients do not truly have antibodies to potassium channels, but to associated proteins. This enabled the distinction of three VGKC-positive subgroups: anti-LGI1 patients, anti-Caspr2 patients and VGKC-positive patients lacking both antibodies. Patients with LGI1-antibodies have a limbic encephalitis, often with hyponatremia, and about half of the patients have typical faciobrachial dystonic seizures. Caspr2-antibodies cause a more variable syndrome of peripheral or central nervous system symptoms, almost exclusively affecting older males. Immunotherapy seems to be beneficial in patients with antibodies to LGI1 or Caspr2, stressing the need for early diagnosis. Half of the VGKC-positive patients lack antibodies to both LGI1 and Caspr2. This is a heterogeneous group of patients with a wide variety of clinical syndromes, raising the question whether VGKC-positivity is truly a marker of disease in these patients. Data regarding this issue are limited, but a recent study did not show any clinical relevance of VGKC-positivity in the absence of antibodies to LGI1 and Caspr2. The three VGKC-positive subgroups are essentially different, therefore, the lumping term ‘VGKC-complex antibodies’ should be abolished

From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time

A wide variety of clinical syndromes has been associated with antibodies to voltage-gated potassium channels (VGKCs). Six years ago, it was discovered that patients do not truly have antibodies to potassium channels, but to associated proteins. This enabled the distinction of three VGKC-positive subgroups: anti-LGI1 patients, anti-Caspr2 patients and VGKC-positive patients lacking both antibodies. Patients with LGI1-antibodies have a limbic encephalitis, often with hyponatremia, and about half of the patients have typical faciobrachial dystonic seizures. Caspr2-antibodies cause a more variable syndrome of peripheral or central nervous system symptoms, almost exclusively affecting older males. Immunotherapy seems to be beneficial in patients with antibodies to LGI1 or Caspr2, stressing the need for early diagnosis. Half of the VGKC-positive patients lack antibodies to both LGI1 and Caspr2. This is a heterogeneous group of patients with a wide variety of clinical syndromes, raising the question whether VGKC-positivity is truly a marker of disease in these patients. Data regarding this issue are limited, but a recent study did not show any clinical relevance of VGKC-positivity in the absence of antibodies to LGI1 and Caspr2. The three VGKC-positive subgroups are essentially different, therefore, the lumping term ‘VGKC-complex antibodies’ should be abolished

Factors determining social participation in the first year after kidney transplantation: a prospective study

BACKGROUND: This study describes changes in social participation in the first year after kidney transplantation and examines the influence of clinical factors, health status, transplantation-related symptoms, and psychological characteristics on change in social participation. METHODS: A prospective study was performed on a cohort of primary kidney transplant recipients, transplanted between March 2002 and March 2003. Data on participation in obligatory activities (i.e., employment, education, household tasks) and leisure activities (i.e., volunteer work, assisting others, sports, clubs/associations, recreation, socializing, going out) were collected by in-home interviews (n=61) at 3 months (T1) and 1 year posttransplantation (T2). Analysis of covariance was performed. RESULTS: Data showed an increase in participation in obligatory activities and diversity of leisure participation between T1 and T2, although pre-end-stage renal disease level was not regained and differed from the general population. On T1, the majority of employed recipients were on sick leave, but returned to work on T2. Employment rate remained stable. An increase in obligatory participation was predicted by clinical factors (i.e., peritoneal dialysis, initial hospitalization), whereas change in leisure participation was related to serum albumin and cognitive capacity. No effects were found for type of donation, comorbidity, and renal function. CONCLUSIONS: We found that mainly clinical factors were associated with an increase in participation in society. Although health-status related factors and the psychological attribute self-efficacy may be related to recovery of social participation, their effect was outweighed by the strength of clinical predictors in multivariate analysis

Pediatric autoimmune encephalitis: Recognition and diagnosis

OBJECTIVE: The aims of this study were (1) to describe the incidence of autoimmune encephalitis (AIE) and acute dissemi

Seasonal variation of anti-PD-1 outcome in melanoma—Results from a Dutch patient cohort

Despite the improved survival rates of patients with advanced stage melanoma since the introduction of ICIs, many patients do not have (long-term) benefit from these treatments. There is evidence that the exposome, an accumulation of host-extrinsic factors including environmental influences, could impact ICI response. Recently, a survival benefit was observed in patients with BRAF wild-type melanoma living in Denmark who initiated immunotherapy in summer as compared to winter. As the Netherlands lies in close geographical proximity to Denmark and has comparable seasonal differences, a Dutch validation cohort was established using data from our nationwide melanoma registry. In this study, we did not observe a similar seasonal difference in overall survival and are therefore unable to confirm the Danish findings. Validation of either the Dutch or Danish findings in (combined) patient cohorts from other countries would be necessary to determine whether this host-extrinsic factor influences the response to ICI-treatment. Analysis and support of clinical decision makin

Trends in survival and costs in metastatic melanoma in the era of novel targeted and immunotherapeutic drugs

BACKGROUND: The objective of this study was to evaluate trends in survival and health care costs in metastatic melanoma in the era of targeted and immunotherapeutic drugs. MATERIALS AND METHODS: Data on survival and health care resource use were retrieved from the Dutch Melanoma Treatment Registry. The Kaplan–Meier method was used to estimate overall survival. Health care costs and budget impact were computed by applying unit costs to individual patient resource use. All outcomes were stratified by year of diagnosis. RESULTS: Baseline characteristics were balanced across cohort years. The percentage of patients receiving systemic treatment increased from 73% in 2013 to 90% in 2018. Patients received on average 1.85 [standard deviation (SD): 1.14] lines of treatment and 41% of patients received at least two lines of treatment. Median survival increased from 11.8 months in 2013 [95% confidence interval (CI): 10.7-13.7 months] to 21.1 months in 2018 (95% CI: 18.2 months-not reached). Total mean costs were €100 330 (SD: €103 699); systemic treatments accounted for 84% of the total costs. Costs for patients who received systemic treatment [€118 905 (SD: €104 166)] remained reasonably stable over the years even after the introduction of additional (combination of) novel drugs. From mid-2013 to 2018, the total budget impact for all patients was €452.79 million. CONCLUSION: Our study shows a gain in survival in the era of novel targeted and immunotherapeutic drugs. These novel drugs came, however, along with substantial health care costs. Further insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in the treatment of patients with metastatic melanoma

Clinical outcome of patients with metastatic melanoma of unknown primary in the era of novel therapy

Melanoma of unknown primary (MUP) is considered different from melanoma of known primary (MKP), and it is unclear whether these patients benefit equally from novel therapies. In the current study, characteristics and overall survival (OS) of patients with advanced and metastatic MUP and MKP were compared in the era of novel therapy. Patients were selected from the prospective nation-wide Dutch Melanoma Treatment Registry (DMTR). The following criteria were applied: diagnosis of stage IIIc unresectable or IV cutaneous MKP (cMKP) or MUP between July 2012 and July 2017 and treatment with immune checkpoint inhibition and/or targeted therapy. OS was estimated using the Kaplan-Meier method. The stratified multivariable Cox regression model was used for adjusted analysis. A total of 2706 patients were eligible including 2321 (85.8%) patients with cMKP and 385 (14.2%) with MUP. In comparative analysis, MUP patients more often presented with advanced and metastatic disease at primary diagnosis with poorer performance status, higher LDH, and central nervous system metastases. In crude analysis, median OS of cMKP or MUP patients was 12 months (interquartile range [IQR] 5 - 44) and 14 months (IQR 5 - not reached), respectively (P = 0.278). In adjusted analysis, OS in MUP patients was superior (hazard rate 0.70, 95% confidence interval 0.58-0.85; P < 0.001). As compared to patients with advanced and metastatic cMKP, MUP patients have superior survival in adjusted analysis, but usually present with poorer prognostic characteristics. In crude analysis, OS was comparable indicating that patients with MUP benefit at least equally from treatment with novel therapies