Previous studies have explored the effect of granulocyte colony stimulating factor (G-CSF) administration on the outcome of assisted reproductive technology (ART), and came into controversial conclusions. The present meta-analysis aims to assess whether G-CSF administration has beneficial effect on the outcome after ART.The electronic databases Pubmed, Embase and Google Scholar were searched up to May 2016. Articles that studied the effect of G-CSF administration on the outcome after ART were included in the present meta-analysis. Odds ratio (OR) with 95 % confidence interval (95 % CI) were calculated to assess the effect of G-CSF administration on the outcome after ART. The outcomes of interest were implantation rate (IR) and pregnancy rate (PR).Four cohort studies with 1101 embryos transplantation assessed the effect of G-CSF administration on IR and 6 studies with 621 cycles assessed the role of G-CSF administration in PR. Meta-analysis did not found an increased embryo IR in G-CSF administration cycles [OR 1.59 (95 % CI 0.74–3.41). whereas the PR with G-CSF administration was significantly higher compared with cases without G-CSF administration [OR 2.03 (95 % CI 1.19–3.46)]. Additionally, we found that G-CSF administrated subcutaneously resulted in significantly higher PR [OR 3.12 (95 % CI 1.67–5.81)] and IR [OR 2.82 (95 % CI 1.29–6.15)] compared with control group, whereas G-CSF administrated via local uterine infusion had no beneficial effect on the PR [OR 1.42 (95 % CI 0.91–2.24)] and IR [OR 1.10 (95 % CI 0.76–1.60)] after ART.G-CSF administration may have beneficial effect on clinical pregnancy outcome after ART. Subcutaneous injection may be an optimal route of G-CSF administration. Further cohort studies are required to explore the mechanisms undergone the effect and investigate the best route and dose of G-CSF administration.The online version of this article (doi:10.1186/s12958-016-0197-2) contains supplementary material, which is available to authorized users. Successful embryo implantation required good-quality embryos and receptive endometrium. Studies indicated that endometrial receptivity should responsible for 2/3 embryo implantation failure. As shown in our previous papers, endometrial thickness is an important index evaluating endometrial receptivity , 2. And So far, many therapies have been attempt to enhance the endometrial thickness and improve the endometrial receptivity, such as extending estrogen administration , low-dosLately, granulocyte colony-stimulating factor (G-CSF) has been used in the treatment of thin endometrium. Five years ago, Gleicher et al applied G-CSF in 4 infertile women with unresponsive thin endometrium for the first time, and resulted in successful pregnancy . SubsequIn the present review, we aim to further evaluate whether G-CSF administration has beneficial effect on the outcome of ART with thin endometrium or with RIF and perform a systematic review and meta-analysis of the available literatures.The electronic databases Pubmed, Embase and Google Scholar were searched up to May 2016. We included papers which explore the effect of G-CSF administration on thin endometrium and/or clinical outcome after ART treatment. The keywords were as follows: [(“G-CSF” or “CSF” or “granulocyte-stimulating factor”) and  and (“in vitro fertilization” or “IVF” or “intracytoplasmic sperm injection” or “ICSI” or “frozen embryo transfer” or “FET” or “infertility treatment” or “assisted reproductive technology”)]. There were no limitations on the time and the type of the publications.Titles and abstracts of all identified studies were screened and the full paper of the preselected articles was reviewed by two researchers. A 2 × 2 table was extracted from the articles. Any discrepancies between the two reviewers were resolved by group discussion.Cohort studies with control group and RCTs investigating the effect of G-CSF administration on the endometrium and/or ART outcomes were considered to be eligible for inclusion. Studies without control group were excluded even if the content was related. Papers written in non-English were excluded.The patient population comprised infertile women with all ages, receiving the IVF or intracytoplasmic sperm injection (ICSI) or frozen embryo transfer (FET) treatment. Cycles with donor oocyte/sperm and intrauterine abnormalities were excluded from analysis.The main study outcomes were embryo implantation rate , clinical pregnancy rate . All clinical outcomes were calculated per cycle.Each selected study was scored for their relevance and methodological quality by using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklists for Observational Studies. In addition, some information, such as sample size, study design, blinding, selection bias, information bias, attrition bias, and the stimulation protocol used were taken into consideration. Two reviewers completed the quality assessment, and any disagreements about inclusion were resolved by group discussion.2 statistic quantified the heterogeneity between studies statistically. The heterogeneity was considered as low when the value was less than 50 %  and IR [OR 2.82 (95 % CI 1.29–6.15)], whereas G-CSF administrated via uterine infusion had no beneficial effect on the PR [OR 1.42 (95 % CI 0.91–2.24)] and IR [OR 1.10 (95 % CI 0.76–1.60)] after ART. But the exact reason for this phenomenon is not clear.As far as the strength, the meta-analysis resulted in a more accurate estimation with the pooled ORs value than single study. The pooled results of included studies indicated that G-CSF administration has a beneficial effect on pregnancy and implantation after IVF/ICSI/FET cycles with thin endometrium or RIF. When evaluating the effect of G-CSF administration on pregnancy, six studies were included, and the combined OR was above one with 95 % CI 1.19–3.46. While evaluating the effect of G-CSF administration on implantation, the combined OR showed an increased trend in IR but the difference had no significances (95 % CI 0.74–3.41).Besides, there were also some limitations. A major limitation of the present study was the high level of heterogeneity among these included studies’ characteristics: different study object (cycle with thin endometrium / RIF), different treatment types (IVF / ICSI / FET) and different routes (subcutaneous injection / intrauterine infusion) and dose of G-CSF administration. Besides, small number of study subjects in the literature and lack of adjustment for meaningful confounders were all the flaws of the present study. Notwithstanding these drawbacks, the present systematic review and meta-analysis provides a valuable summary of the results of scientific publications so far.The present meta-analysis and systematic review suggested that G-CSF administration has beneficial effect on the clinical pregnancy outcome after IVF/ICSI/FET cycles. In spite of the small number of studies included and the variable characteristics of these studies, we suggest that administration of G-CSF subcutaneously would be an optimal treatment for those suffering thin endometrium or RIF. Further cohort studies are required to explore the mechanisms undergone the effect and investigate the best route and dose of G-CSF administration.


On behalf of my coauthors, I thank Dr. Drayman for his interest in our recent paper in which we examined whether plaques can contain more than one parental virus . We founDr. Drayman presents two explanations for the high frequency of observed chimeric plaque formation: (i) plaques are not products of coinfection, but instead overlapping plaques were picked and thus appear to be chimeric, and (ii) chimeric plaques are the products of coinfection, which provides a fitness advantage that increases the probability of successful plaque formation. Based on his simulations, Dr. Drayman proposes that plaques contain multiple parental viruses not because of coinfection but because of overlapping plaques.Indeed, during our study we were aware of and concerned about the possibility that chimeric plaques were from overlapping plaques rather than bona fide coinfection. However, two results presented in the paper and a third result from our more recent study suggest that chimeric plaques are the products of bona fide coinfection and that coinfection provides a fitness advantage that aids infection.First, we reasoned that if overlapping plaques were responsible for “chimeric” plaques, then plates with more plaques present should have more overlapping plaques and therefore have more “chimeric” plaques. In Fig. 1D, we showed that this is not the case: chimeric plaques were not overrepresented on plates with higher plaque numbers, indicating that cross-contamination or overlapping plaques were unlikely , we demoOverall, we think it likely that the majority of chimeric plaques are products of coinfection and that coinfection provides a fitness advantage that aids plaque formation. However, it is certainly possible that a subset of chimeric plaques may be due to overlapping plaques rather than coinfection, as Dr. Drayman suggests. But getting back to Dr. Drayman’s initial question—why is the apparent coinfection frequency much higher in the plaque-based assay than in the flow cytometry-based assay? We do not know the answer, but we hypothesize that plaque formation is much more difficult than expression of a reporter protein during a single cycle of infection in the flow cytometry assay and therefore that coinfection promotes productive plaque formation.


ABO incompatible kidney transplantation (ABOi-KT) is an important approach for overcoming donor shortages. We evaluated the effect of ABOi-KT on living donor KT.Two nationwide transplantation databases were used. We evaluated the impact of ABOi-KT on overall living donor transplant activity and spousal donation as subgroup analysis. In addition, we compared the clinical outcome between ABOi-KT and ABO compatible KT (ABOc-KT) from spousal donor, and performed a Cox proportional hazards regression analysis to define the risk factors affecting the allograft outcomes.The introduction of ABOi-KT increased overall living donor KT by 12.2% and its portion was increased from 0.3% to 21.7% during study period. The ABOi-KT in living unrelated KT was two times higher than that of living related donor KT (17.8 vs.9.8%). Spousal donor was a major portion of living unrelated KT (77.6%) and ABOi-KT increased spousal donation from 10% to 31.5% in living donor KT. In addition, increasing rate ABOi-KT from spousal donor was 10 times higher than that of living related donor. The clinical outcome  of ABOi-KT from spousal donor was comparable to that of ABOc-KT. Neither ABO incompatibility nor spousal donor was associated with acute rejection or allograft failure on multivariate analysis.ABOi-KT increased overall living donor KT, and ABOi-KT from spousal donor is rapidly increasing with favorable clinical outcomes. During the past three decades, the structure of the Korean family has changed from large families to nuclear families. Additionally, the birth rate per one reproducible woman has decreased significantly from 2.82 in 1980 to 1.2 in 2014.ABO blood type incompatibility was an important barrier of kidney transplantation (KT). We previously reported that the most common reason for the enrollment of donor kidney exchange program was ABO blood type incompatibility and the most common intended donor-recipient relationship was spousal. ThereforIn Korea, the ABOi-KT started in 2007 and has rapidly increased since then. Thus, th5 Among these cases, we used data from 2003 to 2014 (the period for which donor information was fully satisfied). The second database was the Korean Organ Transplantation Registry established by the Korean Society for Transplantation [http://www.konos.go.kr/konosis/common/bizlogic.jsp (accessed 10th), and Korean Organ Transplantation Registry of the Korean Society for Transplantation is available at http://www.kotry.org.We used two databases in this study. The first database from Korean Network for Organ Sharing was used to evaluate the effect of ABOi-KT on number of KT. It contains all the KT cases in Korea since 2000 .5 Among antation , 7, to eDeclaration of Helsinki.We divided the patients into ABOi-KT from spousal donors, ABOc-KT from spousal donors and living related donor KT. The baseline characteristics of each group are presented in 2 or 500 mg/body at the initiation of their program, but the dose tended to be reduced later to 200 mg/body or 100 mg/m2. Pre-transplant plasmapheresis was routinely performed in all patients. One plasma volume was exchanged with either albumin solution or fresh frozen plasma by the conventional method in most patients, but in a minority of patients, double filtration plasmapheresis was also used. Intravenous immunoglobulin (100 or 200 mg/kg) was administered after plasmapheresis in all but one center.The preconditioning protocols were highly uniform across the centers. They conPneumocystis jirovecii and cytomegalovirus infection. The anti-A or anti-B titer was measured using the saline method for IgM and indirect Coombs’ test for IgG.The target anti-A/B antibody titer on the transplant day was 1:8 or 1:16. Post-transplant preemptive plasmapheresis during the first two weeks was not performed routinely, but as needed, in patients with high anti-A/B titer or rising creatinine while awaiting the biopsy result. Tacrolimus-based triple immunosuppressants were the most popular regimen and started with the initiation of pre-transplant plasmapheresis. The target trough level of tacrolimus during the first post-transplant month was 8–12 ng/mL, and the dose of mycophenolate mofetil during the first month was 1.5 g/day in most patients. Interleukin-2 receptor blockade (97%) was used as an induction. Most of the centers adopted infection prophylaxis for The clinical outcome of ABOi-KT from spousal donors was evaluated in terms of the biopsy-proven acute rejection (BPAR)-free survival rate, the allograft and patient survival rates and renal allograft function assessed by the estimated glomerular filtration rate (eGFR), compared to those of the ABOc-KT and living related donor KT. BPAR was diagnosed according to Banff 2007 classification. Serum crAdditionally, we compared the clinical outcomes of ABOi-KT (128 of 150) and ABOc- KT (256 of 566) after propensity score matching. It was performed using donor age, donor gender, recipient age, causes of ESRD, re-transplantation and sensitization .Trends in the number of ABOi donor and spousal donor in temporal relation were analyzed using the Cochrane-Armitage trend test. Associations of year with the percent increase of spousal donor KT and living related donor KT were compared by multiple linear regression analysis. Continuous data were presented as the mean ± standard deviation (or standard error) or the median with the interquartile range according to their distribution. The data were compared using an ANOVA with post hoc analysis, Student’s t-test or the Mann-Whitney test, depending on the data type. Categorical data were compared using χ2 0.952, P < 0.001 for the increased rate of spousal donor KT, P < 0.05 for each year, P = 0.081, P = 0.033, P = 0.177, P = 0.275 and P = 0.05 respectively, The incidence of BPAR in the ABOi-KT and ABOc-KT from spousal donors was not significantly different , but spousal donor KT (P = 0.196) and ABOi-KT (P = 0.336) were not risk factors for graft failure (P = 0.485).Fifty five patients failed graft function during the study period. Three patients (2.0%) were the ABOi-KT from spousal donors, and 15 patients (2.7%) were the ABOc-KT from spousal donors. The overall graft survival for ABOi-KT from spousal donors at 3-year post-transplantation (96.3%) was not significantly different from the ABOc-KT .The patient survival rate until 3 years post-transplantation showed no difference between spousal donor KT and living related donor KT, overall The causes of death are shown in P = 0.007). Other risk factors for patient death were older recipient age and no usage of calcineurin inhibitors or steroids  per year, but the number of ABOi-KT rapidly increased to 217 cases per year during 8 years, which accounted for 21.7% of the total living donor KT. Between living related and unrelated donor KT, The absolute number of ABOi-KT in living unrelated donor KT was less than living related donor KT (164 vs. 207) but its portion was two times higher than living related donor KT (17.8 vs. 9.8%). Our experience suggests that ABOi-KT is an important approach to overcome donor shortage by increasing both living related and unrelated donors KT, and its effect is more definite in living unrelated donors.Our study focused on spousal donation after introduction of ABOi-KT because spouses have become important alternatives to living related donors in Korea. In our study, we confirmed that spouses were major portion of living unrelated donors (77.6%) and ABOi-KT increased its portion from 10% to 31.5% in living donor KT. Furthermore, the rate of increase of ABOi-KT was almost 10 times higher than that of living related donor KT (312 vs. 35%). This finding suggests that spousal donors are important source of living donor KT, and spousal donation will be more increased with introduction of ABOi-KT.Most of previous reports about clinical outcomes of ABOi-KT or spousal donor KT were single center reports , 11–14, Interestingly, most cases of mortality in ABOi-KT developed within 6 months post-transplantation, and the most common cause of death was infection. This finding was consistent with previous reports that strong pre-transplant desensitization increases infection-related mortality during the early post-transplantation period in ABOi-KT.–19 RecenThis study has some limitations. First, the baseline or posttransplant anti-A/B antibody titers were not included. Second, we did not consider center effect. But, basic protocol including rituximab and plasmapheresis was similar. Third, recipients of our study group were too young (42.8 ± 12.6 years old) to represent general KT candidate. Forth, our data did not include information whether BPAR is due to antibody or T-cell mediated rejection. The last, we could not observe long-term clinical outcome due to short term follow-up (26 ± 10 months) in this cohort.In conclusion, our study shows that the ABOi-KT contributed to the significant increase of living donor KT, and ABOi-KT from spousal donor is rapidly increasing with favorable clinical outcomes. These results suggest that ABOi-KT from spousal donors is a useful and acceptable alternative to overcome organ shortages.S1 File(XLSX)Click here for additional data file.


To investigate the diagnostic and prognostic values of cerebrospinal fluid (CSF) CYFRA 21-1 in patients with leptomeningeal carcinomatosis (LMC).Concentration of CSF CYFRA 21-1 was detected using electro-chemiluminescent immunoassay. The difference in level of CYFRA 21-1 between 61 patients with LMC and 200 patients with other neurological disease was evaluated, and diagnostic performance of CSF CYFRA 21-1 was investigated. In LMC patients treated with ventriculo-lumbar perfusion (VLP) chemotherapy, prognostic performance of CSF CYFRA 21-1 was evaluated.The CSF CYFRA 21-1 was significantly higher in LMC patients than that in patients with other neurological diseases (p<0.001). The sensitivity, specificity, accuracy, and positive and negative predictive values were 80.3%, 95.0%, 91.6%, 83.1%, and 94.1% for CSF CYFRA 21-1, and 65.6%, 100%, 92.0%, 100%, and 90.5% for CSF cytology, respectively. The use of high CSF CYFRA 21-1 and/or positive CSF cytology findings resulted in an increased sensitivity of 85.3%, without compromising specificity. LMC patients with high CSF CYFRA 21-1 were more frequently accompanied by positive CSF cytology results than those with low CSF CYFRA 21-1. The median overall survival was longer in LMC patients with low CSF CYFRA 21-1 than in those with high CSF CYFRA 21-1 (p=0.031). During VLP chemotherapy, the clinical responses were found to be correlated with the biological responses, including the level of CSF CYFRA 21-1 and intracranial pressure.CSF CYFRA 21-1 might be regarded as an additional diagnostic tool for LMC and a potential significant prognostic biomarker in LMC patients treated with VLP chemotherapy. Leptomeningeal carcinomatosis (LMC) is defined as multifocal seeding of metastatic carcinogenic cells in the leptomeninges and cerebrospinal fluid (CSF) in patients with solid tumors , 2. ReceCYFRA 21-1 is a soluble epithelial cytokeratin 19 fragment belonging to the intermediate filament protein family, which is responsible for the mechanical integrity of the cell and cellular processes , 13. CYFFor these reasons, in the present study, we first aimed to investigate the diagnostic performance of CSF CYFRA 21-1 for LMC in cancer patients and in a large control group comprising patients with other neurological diseases (ONDs). Second, we aimed to evaluate the prognostic value of CSF CYFRA 21-1 for predicting OS and treatment response in patients with LMC treated with VLP chemotherapy.In the patients with LMC and OND, the male-to-female ratios were 23:38 and 72:128, and the median ages at sampling were 54 and 40 years, respectively (Table The CSF CYFRA 21-1 level was significantly higher in LMC patients than in patients with OND (2.94 (1.20-500.00) vs. 1.39 (0.82-1.73) ng/ml, median (range), p<0.001; Figure The diagnostic cut-off value of CSF CYFRA 21-1 was determined as 1.61 ng/ml by ROC curve analysis, with CSF CYFRA 21-1 over the upper normal limit observed in 49/61 (80.3%) patients. Consequently, a level of ≥1.61 ng/ml was defined as high CSF CYFRA 21-1. The demographics and laboratory characteristics were similar between LMC patients with high and low CSF CYFRA 21-1, whereas CSF cytology-positive findings were more prevalent in LMC patients with high CSF CYFRA 21-1 compared to those with low CSF CYFRA 21-1  vs. 2.3 (1.3-101.8) ng/ml, p = 0.402). The proportion of patients with high CSF CYFRA 21-1 did not significantly differ between the two groups (26/32 [81%] vs. 23/29 [79%]).Of the 37 LMC patients treated with VLP chemotherapy with a 15 ml/h perfusion rate, 31 84%) patients died at the end of the study. The median overall survival for the entire LMC cohort was 5 months . The prognostic cut-off value was determined as 2.94 ng/ml. The median OS was longer in LMC patients with low CSF CYFRA 21-1 than in those with high CSF CYFRA 21-1.  and a negative correlation with the KPS scores (sr = −0.404). The negative correlation between the individual level of CSF CYFRA 21-1 and KPS score at each assessed time point was maintained when analyzed with ICP as a covariate (pr = −0.496).The longitudinal treatment responses during VLP chemotherapy in 6 patients are demonstrated in Figure In the present study, the level of CSF CYFRA 21-1 was significantly higher in the LMC than OND group, and the combination of high CSF CYFRA 21-1 and/or positive CSF cytology results reduced the number of undiagnosed cases. The median level of CSF CYFRA 21-1 and proportion of high CSF CYFRA 21-1 cases were higher in samples obtained from lumbar subarachnoid space than those in intra-ventricular space, although there was no statistical significance. The LMC patients with high CSF CYFRA 21-1 were more frequently accompanied by abnormal CSF cytology findings than those with low CSF CYFRA 21-1. Furthermore, the median OS in patients with low CSF CYFRA 21-1 was longer than that in patients with high CSF CYFRA 21-1. Clinical responses during VLP chemotherapy showed correlations with the biological responses, including CSF CYFRA 21-1 and ICP.The diagnosis of LMC has been traditionally made either by the detection of malignant cells in the CSF or contrast enhancement in the subarachnoid space on MRI , 2, 4. HA previous study showed both high sensitivity (82.9%) and specificity (97.1%) of CSF CYFRA 21-1, with a high cut-off value (5.5 ng/ml) in LMC patients with lung cancer, as compared to the current study . In the Not only a diverse spectrum of diseases in the control group, but also various primary tumors in the LMC group were included in the current study. The primary tumor origin included various organs such as lung, breast, ovary, stomach, and colon. Histologically, adenocarcinoma, large cell endocrine, small cell, signet ring cell, and epithelial cell origin cancers were observed as the primary tumor in LMC patients. As CYFRA 21-1, an epithelial cytokeratin fragment, is known to be useful for the diagnosis of LMC in patients with epithelial cell-originated primary tumors , we coulThe detection rate of malignant cells in CSF has been reported to be influenced by the applicable sampling site , hence wThe median OS was longer in patients with low CSF CYFRA 21-1 than in those with high CSF CYFRA 21-1; however, in the multivariable analysis, CSF CYFRA 21-1 level did not show the statistical significance in predicting OS. Only high CSF protein level, which was identified as a significant prognostic factor in our previous study , remaineIn a previous study of our institution, the response rate of ICP was the main modality of treatment response assessment in LMC patients treated with VLP chemotherapy . In currThe retrospective nature and recruitment of LMC patients from a single referral center were methodological limitations of current study that may have resulted in an unintentional selection bias. Additionally, as CSF samples were not obtained at the time of LMC diagnosis but rather collected at Ommaya insertion; the samples might not exactly reflect the LMC status at the time of diagnosis. These altogether warrant further prospective studies with larger sample size and also validation in specific type of primary tumor.In conclusion, based on the large, as well as diverse, spectrum of control and LMC patients with various types of primary tumors, we suggest CSF CYFRA 21-1 as an additional potential diagnostic indicator for LMC and a prognostic biomarker for patients with LMC treated with VLP chemotherapy. With CSF CYFRA 21-1, we might better detect and predict clinical outcomes of LMC, which would be vital to select the candidates who might most benefit from VLP chemotherapy.Between 2013 and 2016, 61 CSF samples from LMC patients with diverse primary solid tumors, treated at the National Cancer Center in Korea, and reserved available 200 CSF samples from patients with OND (n=200) as the control group, obtained from 3 referral centers, were evaluated for the CYFRA 21-1 level. The diagnosis of LMC was made by positive CSF cytology and/or magnetic resonance imaging (MRI) scans showing LMC. The CSF CYFRA 21-1 levels were measured retrospectively from the reserved CSF samples stored at −80°C. CSF from the intra-ventricular or lumbar subarachnoid space was obtained as part of the preoperative evaluation prior to Ommaya reservoir insertion for VLP chemotherapy or intra-ventricular chemotherapy. VLP chemotherapy was performed with a perfusion rate of 15 ml/h and a daily methotrexate dose of 24 mg in 37 of the 61 LMC patients, who enrolled into an ongoing clinical trial for evaluation of the optimal perfusion rate for VLP chemotherapy. Two patients, who participated in a previous clinical trial [3]2+ in the presence of tripropylamine results in chemiluminescent emission, which was detected by a photomultiplier. Finally, the CYFRA 21-1 concentration was determined using a calibration curve.CSF CYFRA 21-1 concentrations were detected by the Cobas e170 analyzer with Elecsys CYFRA 21-1, which uses an electro-chemiluminescent immunoassay  . All tesThe primary outcome for prognosis was OS, defined as the time elapsed from the start of VLP chemotherapy to death. The Karnofsky performance status (KPS) and prior/concurrent radiotherapy and systemic chemotherapy regimens, which could affect the prognosis of patients with LMC, were estimated at the start of VLP chemotherapy. The treatment response was evaluated by the clinical, cytological, and biological responses, defined as improvement of the KPS, disappearing malignant cells in the CSF, and decreasing CSF CYFRA 21-1 levels and intracranial pressure (ICP), respectively. To avoid the immediate effect of VLP drainage on the CSF flow in the measurement of ICP and the dilution effect of VLP drainage in the estimation of the level of CSF CYFRA 21-1, the treatment responses were measured immediately before the next VLP chemotherapy cycle.This study was approved by the institutional review board committee at the National Cancer Center. A written informed consent was obtained from all patients.The characteristics of 61 LMC patients and 200 controls were summarized in Table A Cox proportional hazard model was used to investigate the prognostic value of various factors associated with OS, including CSF CYFRA 21-1, protein levels, KPS, ICP, presence of prior/concurrent radiotherapy, and prior systemic chemotherapy over 3 different regimens, which were previously described prognostic factors for LMC , 23, 24.


While infrequent, cerebrospinal fluid (CSF) leaks are known to occur after surgical resection of vestibular schwannomas. Early signs of CSF leak often include headache and altered mental status. If untreated, life-threatening complications can occur, including brainstem herniation and meningitis. The appropriate surgical treatment for a CSF leak requires accurate localization of the source. While the most likely location of a CSF leak after lateral skull base surgery is through the aerated portions of the temporal bone, we present a unique case of a man with a prolonged CSF leak after an acoustic tumor removal who was ultimately found to have an occult spinal perineural (Tarlov) cyst as the source. Accurate localization was ultimately achieved with CT myelogram after empirically obliterating his mastoid failed to restore intracranial CSF volume. Tarlov cysts are the most common cause of idiopathic intracranial hypotension, and this case highlights the importance of considering this entity in the differential diagnosis of postoperative CSF leaks. Cerebrospinal fluid (CSF) leaks after resection of vestibular schwannomas occur in approximately 10% of cases [While the most likely source of CSF leak after skull base surgery is in the operated area, this is not always the case. We present a unique report of a man with prolonged CSF leak after skull base surgery from an occult spinal perineural cyst to highlight this rare but important exception to the rule.   A 56-year-old man underwent suboccipital surgical resection of a 2.7 cm vestibular schwannoma without a lumbar drain Figure . In the Brain magnetic resonance imaging (MRI) with contrast showed signs of significant intracranial hypotension, including brain stem sagging, flattening of the pons, diffuse dural thickening, enhancement and partial effacement of the basal cisterns, and mild uncal herniation Figure . A tempoA presumed diagnosis of iatrogenic CSF otorhinorrhea was treated with Eustachian tube plugging and mastoid obliteration with abdominal fat graft. However, no definitive source of CSF was identified intraoperatively. Symptoms initially improved; however, one month later his headaches returned, and a repeat MRI was unchanged.Given the concern for an occult extracranial CSF leak, imaging of the spine was performed. While the MRI did not show evidence of spinal CSF extravasation, a CT myelogram revealed multiple small perineural cysts of the thoracic spine Figure . These wInitially described by Tarlov in 1935, perineural (Tarlov) cysts are CSF-filled cysts that arise at the junction of the dorsal ganglion and nerve root . Most coIn our patient, several factors led us to erroneously conclude that the CSF leak was at the surgical site. These factors included the timing of the leak after surgery, the self-reported rhinorrhea, and ambiguous temporal bone CT findings. Furthermore, the patient did not endorse several characteristic symptoms of Tarlov cysts, including radicular pain and bowel or bladder dysfunction. However, his symptoms of a positional headache, fatigue, and decreased mental clarity recurred after standard surgical obliteration of the mastoid and plugging of the Eustachian tube, which led us to suspect an extracranial site of CSF loss. Ultimately, the CT myelogram was diagnostic.Tarlov cysts are the main cause of spontaneous intracranial hypotension. Given the onset of symptoms several months after surgery, we hypothesize that this case was caused by a spontaneous cyst rupture, unrelated to our operation. However, it is possible that the cyst ruptured perioperatively due to changes in CSF pressure from CSF loss, positioning, and intracranial irrigation, as has been reported for subarachnoid hemorrhage surgery . AdditioWhen CSF leaks occur after skull base surgery, they are typically treated with either conservative measures, surgical repair of the operated site, or obliteration of downstream CSF pathways. However, CSF leaks can occur at distant sites, including anywhere along the spinal column. We present a rare case of an occult CSF leak from perineural cysts which occurred after surgical resection of a vestibular schwannoma. The source of the leak was identified only after failure of mastoid obliteration with Eustachian tube plugging led to consideration of a remote source of the leak. While rare, perineural (Tarlov) cysts are the most common cause of spontaneous intracranial hypotension, and they should be considered in the differential diagnosis of postoperative CSF leaks.


To follow the temporal changes of cerebrospinal fluid (CSF) biomarker levels innarcoleptic patients with unexpected hypocretin level at referral.n = 155, 95 males, 60 females, 36children) or atypical cataplexy  werereferred to our center. Cerebrospinal hypocretin deficiency was found in 95.5% and 20%of patients with definitive and atypical cataplexy, respectively. CSF hypocretin-1(n = 6) and histamine/tele-methylhistamine (n = 5)levels were assessed twice  in four patients with definiteand in two with atypical cataplexy and hypocretin level greater than 100 pg/mL atbaseline.From 2007 to 2015, 170 human leukocyte antigen (HLA) DQB1*06:02-positive patients withprimary narcolepsy and definite . Hypocretin level decreased from 106 to 27 pg/mL in one patient withatypical cataplexy, and remained stable in the other (101 and 106 pg/mL). CSF histamineand tele-methylhistamine levels remained stable, but for one patient showing increasedfrequency of cataplexy and a strong decrease (−72.5%) of tele-methylhistamine levelsseveral years after disease onset. No significant association was found between relativeor absolute change in hypocretin level and demographic/clinical features.These findings show that in few patients with narcolepsy with cataplexy, symptoms andCSF marker levels can change over time. In these rare patients with cataplexy withoutbaseline hypocretin deficiency, CSF markers should be monitored over time with potentialfor immune therapies in early stages to try limiting hypocretin neuron loss. Definite cataplexy may occur in the absence of hypocretin deficiency in rare cases,especially when close to disease onset. Symptoms and cerebrospinal fluid marker levels canchange over time in few patients with narcolepsy with cataplexy that may favor diseaseheterogeneity. In patients with cataplexy without baseline hypocretin deficiency,cerebrospinal fluid markers should be monitored over time with potential for immunetherapies in early stages when the “autoimmune” destructive process is not too advanced totry limiting hypocretin neuron loss.2 Hypocretin-1(HCRT-1) level in the cerebrospinal fluid (CSF) of patients with NT1 is typically reduced tolow or undetectable levels already at diagnosis. Conversely, only 10–20% of patients withnarcolepsy without cataplexy have low CSF HCRT-1 levels at diagnosis.3 A brain study of two patients with narcolepsy without cataplexy showedpartial loss of hypocretin neurons, suggesting that the presence of cataplexy in narcolepsycould be linked to the severity of hypocretin neuron loss.4 In children with NT1, disease onset is often rapid anddramatic, with the full clinical picture of excessive daytime sleepiness (EDS) and cataplexyoccurring within several days.5Conversely, a progressive appearance of NT1 symptoms is frequent in adults. Moreover,clinical follow-up of adult patients with narcolepsy without cataplexy showed that 10%developed cataplexy many years after EDS onset.6 A slow appearance of NT1 symptoms together with a progressive decline ofCSF HCRT-1 from intermediate to low levels has been recently described in an adultpatient.7 However, the naturalhistory of hypocretin neuron loss and CSF HCRT-1 level reduction remains unclear.Narcolepsy type 1 (NT1), also known as narcolepsy with cataplexy or hypocretin-deficiencysyndrome, is a rare chronic sleep disorder characterized by the specific and subtotal lossof hypocretin neurons, which could be immune mediated.9 without changes in CSF HAor tele-methylHA (t-MHA) levels.10 Toour best knowledge, no study has described the temporal changes of CSF HA and t-MHA levelsin narcolepsy. Therefore, CSF HA/t-MHA levels were also monitored in five of thesepatients.Here, we report the results of the repeated assessment of CSF HCRT-1 levels in six patientswith narcolepsy symptoms and unexpected CSF HCRT-1 level (>100 pg/mL) at baseline.Moreover, it has been reported that the number of histamine (HA) neurons is increased in thetuberomammillary nucleus in patients with NT1,11–13 Possible or atypical cataplexy was determined based on the medicalhistory and the presence of at least one of the following signs: infrequent episodes (< 1episode per year), absence of typical triggering factors (for adults only), long duration(>2 min), altered consciousness, unilateral localization, or spontaneous resolution. Allpatients were HLA DQB1*06:02 positive and narcolepsy was not secondary to another medicalcondition. Polysomnography (PSG) and multiple sleep latency test (MSLT) recordings performedaccording to AASM guidelines and CSF HCRT-1 levels were available for all patients.Between 2007 and 2015, 155 patients  with definitecataplexy and 15 patients  with possible/atypicalcataplexy were referred to the Reference National Center for Narcolepsy of Montpellier,France. Definite or possible/atypical cataplexy was defined by the presence of episodes ofmuscle weakness triggered by strong emotions.All patients with definite cataplexy had low CSF HCRT-1 levels , with the exception of four subjects (2.6%) with normal(>200 pg/mL) and three (1.9%) with intermediate HCRT-1 levels (between 110 and 200pg/mL). All patients with narcolepsy with possible/atypical cataplexy  had normal CSF HCRT-1 levels, but three patients had low HCRT-1 level (includingone patient with undetectable level and two with levels between 100 and 110 pg/mL). Due theunexpected results at referral (baseline measurement), CSF HCRT-1 level was measured twicein four of the seven patients with definite cataplexy and normal/intermediate CSF HCRT-1level, and in two patients with possible/atypical cataplexy and CSF HCRT-1 level between 100and 110 pg/mL. All patients gave their informed consent to take part in the study, which wasapproved by the local ethics committee (Montpellier-France).125 radioimmunoassay (RIA)  with anintra-assay variability less than 10% and an inter-assay variability between 20% and30%.14 CSF HCRT-1 levels lowerthan 110 pg/mL were considered as low, between 110 and 200 pg/mL as intermediate, and above200 pg/mL as normal. All values were back-referenced to the Stanford reference samples .14 CSF HA and t-MHA levels were determined in duplicateusing a previously described method through derivatization of primary amines using 4-bromobenzenesulfonyl chloride and subsequent analysis by reversed-phase liquidchromatography with mass spectrometry detection.15 Intra-assay coefficientvariations were 10.6% for HA and 8.1% for t-MHA, and inter-assay coefficient variations were10.9% for HA and 11.0% for t-MHA.15All patients had a lumbar puncture between 05:00 and 07:00 pm, and CSF samples were storedimmediately at −80°C until the measurement of HCRT-1, HA, and t-MHA levels. HCRT-1 levelswere determined in duplicate for each CSF sample by the standard validated directIp <.05. Statistical analyses were performed using SAS, version 9.4 .Spearman’s rank order correlations were used to determine associations between continuousvariables. The Kruskall–Wallis test was used to compare continuous and categorical variableswith more than two categories. The significance level was set at The clinical, neurophysiological, and biological data of the six patients with lumbarpuncture performed twice  are described inA 10-year-old girl from Martinique (one of the French West Indies islands) presented withthe typical clinical phenotype of NT1. EDS started at the age of 10 without any triggeringfactor and with the appearance of definite cataplexy 1 month later. She also reportedvivid nightmares, hypnagogic hallucinations, and sleep paralysis. PSG-MSLT, performed 1month later, revealed one nocturnal sleep onset rapid eye movement period (SOREMP) and amean sleep latency of 3.6 min with three SOREMPs. She was homozygous for HLA DQB1*06:02.CSF HCRT-1 level, which was normal (282 pg/mL) at referral (1 month after cataplexyonset), became undetectable (<10 pg/mL) at the second evaluation carried out 18 monthslater. Baseline CSF HA and t-MHA levels were 412 and 971 pM, respectively, and remainedstable (317 and 1109 pM) at the second measurement .A 40-year-old Caucasian woman developed daily and definite cataplexy at the age of 39,few months after vaccination with the Pandemrix® vaccine. Three months after cataplexyonset, she described the occurrence of severe EDS, hypnagogic hallucinations, and sleepparalysis. Baseline PSG-MSLT and CSF HCRT-1 measurements were performed at referral (20months after cataplexy onset) and showed normal mean sleep latency (12 min) without anySOREMP and intermediate CSF HCRT-1 level (163 pg/mL). Due to symptom persistence, PSG-MSLTand CSF sampling were repeated 10 months later in drug-free conditions. PSG-MSLT showed amean sleep latency of 8 min, five SOREMPs, including one at nighttime. CSF HCRT-1 levelwas undetectable (<10 pg/mL). CSF HA and t-MHA levels remained stable .A 17-year-old girl from Martinique presented with EDS that had started at the age of 16.Two months later she developed atypical partial cataplexy that became rapidly infrequent(<1/year) and was never triggered by emotional factors, such as laugh or surprise.PSG-MSLT performed 21 months after EDS onset showed a mean sleep latency of 4.4 min withfour SOREMPs. CSF HCRT-1 level was 106 pg/mL. At the age of 19, treatment withmethylphenidate alone was introduced to control EDS. A second CSF sampling carried out atthis time showed that HCRT-1 level was decreased to 27 pg/mL while she had no morecataplexy episodes. CSF HA level was also slightly reduced compared with baseline (from279 to 177 pM), while t-MHA level increased from 349 to 651 pM.A 45-year-old Caucasian woman was addressed to our unit at the age of 45 after a caraccident caused by EDS. She reported EDS onset at the age of 25 and the appearance ofinfrequent (<1/month) but definite partial cataplexy 7 years later. At referral,PSG-MSLT recording showed nocturnal SOREMP with a mean sleep latency of 3.8 min and fiveSOREMPs. CSF HCRT-1 level was intermediate (182 pg/mL) with high HA (918 pM) and t-MHA(1438 pM) levels. Few months after the baseline assessment, cataplexy frequency increasedin the absence of any particular event. Treatment with sodium oxybate led to incompleteresolution of cataplexy. A second lumbar puncture performed 8 months after the baselinemeasurement showed undetectable CSF HCRT-1 level (<10 pg/mL) with almost stable CSF HA(1088 pM) and t-MHA (1163 pM) levels.A 27-year-old Caucasian woman presented with EDS, frequent hypnagogic hallucinations, andsleep paralysis since the age of 17, with only three episodes of neck muscle weaknesstriggered by laugh at the age of 26. PSG-MSLT recording revealed nocturnal SOREMP, meansleep latency of 10 min, and five SOREMPs. CSF HCRT-1 level was 101 pg/mL. Despitetreatment with modafinil and methylphenidate, cataplexy severity and frequencyprogressively increased to more than one episode per week. A second CSF sampling performed24 months later showed stable HCRT-1 levels (106 pg/mL). Conversely, CSF t-MHA level wasstrongly decreased (from 3139 pM at the first sampling to 865 pM), while HA level remainedstable (220 and 193 pM).A 54-year-old Caucasian woman presented with severe EDS since the age of 30. She reportedthe occurrence of monthly episodes of partial, definite cataplexy, without hypnagogichallucinations or sleep paralysis, since the age of 40. PSG-MSLT performed twice indrug-free conditions with an interval of 8 months showed a mean sleep latency of 2.8 minwithout any SOREMP, and then of 3.4 min with one SOREMP. Baseline (at the age of 54) CSFHCRT-1 level was normal (250 pg/mL). Treatment with modafinil reduced EDS. Cataplexyfrequency also decreased to one episode per year. One year later, a third PSG-MSLTrecording carried out 2 weeks after modafinil withdrawal showed a mean latency of 5.6 minwith one SOREMP. CSF sampling on the same occasion indicated that HCRT-1 level was stable(289 pg/mL). CSF HA or t-MHA levels were not measured.r = −0.90; p = .04).A strong CSF HCRT-1 reduction was observed in four of the six patients, including threein whom the first CSF sampling was carried out within 2 years after disease onset . No signn = 170) with EDS and definite or possible/atypical cataplexy at ournarcolepsy reference center. At the second evaluation, CSF HCRT-1 concentration was reducedto undetectable levels (<10 pg/mL) in three patients, to 27 pg/mL in one patient, andremained stable in the two others. In contrast, CSF HA levels remained stable, whereas CSFt-MHA level strongly decreased only in one patient.We report the results of the repeated CSF HCRT-1 measurement in six of the ten patientswith unexpected baseline HCRT-1 results (>100 pg/mL) among all patients of the labeled I125-hypocretin ligand. HA and t-MHA were alsoquantified in duplicate using a previously specific, sensitive, robust, and validatedmethod.15 Altogether, ourmeasurements confirmed that quantifications of HCRT-1, HA, and t-MHA are reproducibleincluding intra- and inter-assay variability in agreement with the criteria outlined in theregulatory bioanalysis guidances (US and European).Here, we found that definite cataplexy, the pathognomonic symptom of narcolepsy, may occurin the absence of CSF HCRT-1 deficiency , even in the context ofthe HLA DQB1*06:02 genotype and when narcolepsy is not secondary to another medicalcondition. Moreover, the second CSF HCRT-1 measurement indicates that levels may decreaseover time. On the other hand, in patients 5 and 6, CSF HCRT-1 levels remained stable withlevels at 101–106 pg/mL for patient 5 with atypical rare cataplexy, and greater than 200pg/mL at both assessments for patient 6 with baseline definitive cataplexy. To confirm thesefindings, we re-measured the CSF HCRT-1 levels in the last four available samples induplicate in a single RIA assay using a similar pooled sample as an internal standardsolution. We found mean intra- and inter-assay coefficient variations of 7% and 28%,respectively. These results confirmed the low intra-assay and intermediate inter-assayvariabilities as already reported for RIA hypocretin quantification,19 In contrast, a more progressive development is usuallydescribed in adults, with often several months or years between EDS and cataplexyonset.20 Indeed, follow-upassessment of narcoleptic patients without cataplexy showed that 10% developed cataplexymany years after EDS onset.6 Themechanism underlying the slow occurrence of narcoleptic symptoms remains unknown. Wehypothesize that a progressive or multiple-hit process targets HCRT neurons, depending onthe different immune response to the underlying triggers  in patients with highly predisposing genetic background .21 This leads first to partial neuron loss, as described inNT2 ,4 and thento almost 90% of cell loss, as often described in NT1 .23 However, we cannot exclude that other neurotransmitters might be involvedin aggravating or compensating HCRT neuron loss and disease symptoms. For instance, patient5 displayed increased frequency of cataplexy together with a strong decrease (−72.5%) oft-MHA levels several years after disease onset. A relationship between cataplexy and HAactivity has been already described in animal models of narcolepsy24 and inhumans, where significant cataplexy improvement is observed upon treatment with an inverseagonist of the HA receptor H3.25HCRT neuron loss progression may vary among patients with narcolepsy, in agreement with thedisease heterogeneity. The occurrence of EDS and cataplexy symptoms and disease progressionare often different in drug-free patients with narcolepsy with abrupt or progressive onset.Among the population of 155 patients with definite cataplexy, cataplexy occurred beforesleepiness in 3.5% of them (mean delay between 1 and 5 years), within the same year in67.5%, and cataplexy started after sleepiness onset in 29% (mean delay >3 years).Moreover, EDS and cataplexy symptoms may show some fluctuations during the follow-up. Thiscould be linked to different pathogenic mechanisms based on the patient response toenvironmental stimuli . A severe and abrupt NT1 onset hasoften been reported in children, whether triggered by Pandemrix® vaccination ornot.26 This kind ofclinical improvement is often reported in the course of autoimmune disorders, showingpartial remission after an abrupt acute onset phase.27 Moreover, some patients with narcolepsy may cope with, or even avoidtriggering factors to prevent cataplexy recurrence; however, this cannot entirely explaincataplexy fluctuations over time.1Several neurotransmitters are certainly involved in compensatory mechanisms to regulatecataplexy severity.13Moreover, in two patients with cataplexy at baseline (3 and 6), cataplexy episodes becamerare or absent in drug-free conditions, while HCRT decreased to very low levels only inpatient 3. Such spontaneous improvement in cataplexy frequency and intensity over time hasbeen previously described in drug-free adults and children with HCRT deficiency, suggestingthat besides HCRT, additional players are also involved.11–13 Therefore, weadvocate precise guidelines for cataplexy assessment based on home or in-laboratory videorecording to be further validated by narcolepsy experts.This study has some limitations. First, we cannot exclude some potential inter-assayvariability in CSF biomarker measurements, with values obtained between 10% and 28%. Despitethe use of standard validated techniques of measurements of HCRT-1, HA, and t-MHA followingthe guidelines, the variabilities found may lower the clinical significance of our results.Second, we may acknowledge the differences in disease duration at baseline evaluation and inthe interval between the two CSF measurements. Third, although cataplexy was assessed byphysicians with a strong expertise in narcolepsy, its diagnosis was based on the patient’smedical history and recall bias cannot be excluded. Moreover, the definition of cataplexy isnot very precise and the distinction between definite and possible/atypical cataplexy ispoorly codified.29 Finally, we suggest that CSF biomarkers should be repeatedly evaluated inthe case of cataplexy in the absence of CSF HCRT-1 deficiency at baseline.To conclude, we report that definite cataplexy may occur in the absence of CSF HCRT-1deficiency especially when close to disease onset, even in the context of the HLA DQB1*06:02genotype and when not secondary to another medical condition. HCRT neuron loss progressionmay vary among patients with narcolepsy, in agreement with the disease heterogeneity. Ourfindings may highlight the potential for immune-based therapies in early stages to save HCRTneurons, especially when the “autoimmune” destructive process is not too advanced .This was not an industry-supported study. Support for this research was provided by theFrench Ministry of Research and Higher Education, Project Agence Nationale de laRecherche-2014-ImmunitySleep, and Aviesan-ITMO 2014—BioNarcoImmunity.YD has been an invited speaker and consultant for UCB Pharma, JAZZ, and BIOPROJET. PR is anemployee of Bioprojet-Biotech. Other coauthors had no conflict of interest.


The aim of this study was to report the basic cerebrospinal fluid (CSF) profile in patients with primary progressive multiple sclerosis (PPMS).The results of CSF analysis from 254 patients with PPMS were collected at four university hospitals in Germany. Routine CSF parameters and different indices of intrathecal immunoglobulin synthesis were evaluated. We assessed possible correlations between the various CSF parameters and the expanded disability status scale (EDSS) both at the time of lumbar puncture and during the course of the disease.ALB) was elevated in 29.6% of the patients, while intrathecal immunoglobulin G (IgG) oligoclonal bands (OCBs) were detected in 91.1% of the patients. CSF-lactate levels as well as local IgM- and IgA-synthesis were correlated with the yearly disease progression rate, as assessed by EDSS.The median cell count and albumin concentration in the CSF did not deviate from normal values. The CSF-serum albumin-quotient (QWe present the results of the hitherto largest and most detailed CSF biomarker profile in a cohort of 254 patients with PPMS. As reported previously, OCBs are the most sensitive marker for intrathecal IgG synthesis. CSF-lactate concentrations are positively correlated with the progression rate, which might suggest that mitochondrial dysfunction plays a relevant role in PPMS. The negative correlation between intrathecally produced IgM and IgA and disease progression may indicate their hitherto unexplored protective role. Primary progressive multiple sclerosis (PPMS) is currently considered an entity in multiple sclerosis (MS) disease spectrum, representing about 15% of MS patients. Indeed,LP), EDSS at the last documented follow-up (EDSSFU), and treatments. Age at clinical onset and initial complaints were obtained from the available medical records and assessed according to the first documented neurological symptoms attributable to the disease. We divided the initial complaints into four main categories: motor, sensory, cerebellar, and other. The “other” category comprised brain stem syndromes, visual disturbances, cognitive symptoms, complex partial seizures, and bladder dysfunction. The clinical severity of MS was assessed using the EDSS score. I. Iloc coLP or disease progression rates and intrathecal IgG synthesis, except in the PPMSTN group. However, because of the small number of patients in this group, these results should be evaluated with caution.In our study, the frequency of elevated IgG-index values was lower than in the cohort described by Izquierdo et al.. HoweverThe MRZ reaction has been proposed as a highly specific (rule-in rather than rule-out) marker of MS, 41, whiData reports on the prevalence of intrathecal IgM synthesis in PPMS are scarce. We only found one such study, which reported elevated IgM index in 32.3% of its 29 patients with chronic progressive MS. Increasin-vitro results, may be explained by the stimulatory effects of IgM on the oligodendrocytes as well as axonal protection[For the first time, a negative correlation between absolute levels of intrathecally produced IgM and IgA in CSF and disease progression has been reported in a large PPMS cohort. The correlation we found might indicate a possible protective role  for IgM and IgA in PPMS. This role, postulated from rotection, 49.loc) relationships between the QALB and QIgX[By using the IgX index and the Reiber formula to calculate the absolute amounts of intrathecal synthesis of immunoglobulins in mg/l, it becomes clear that the discrepancies among the prevalence of intrathecal IgG, IgM, and IgA synthesis are caused by the linear (IgX index) versus non-linear  the high diagnostic sensitivity of intrathecally produced OCBs, which mainly consisted of pattern 2; b) the positive correlation of CSF-lactate levels with clinical severity and yearly progression rates; and c) the possible protective role of intrathecally synthesized IgM and IgA, which may be of therapeutic relevance.


Serum and CSF were collected on admission. Patients with other specific diagnoses were controls (n = 15). The recomBead Borrelia AI assay and the recomBead CXCL13 assay (Mikrogen) were applied together with total IgM index. The overall sensitivity for recomBead Borrelia AI (IgM and IgG together) was 74% and the specificity was 97%. However, the highest sensitivity (91%) at an acceptable level of specificity (90%) was obtained by recomBead Borrelia AI together with CXCL13 and total IgM index, showing a positive predictive value of 84% and a negative predictive value of 95%. Thus, the recomBead Borrelia AI assay performs with moderate sensitivity and high specificity in paediatric LNB patients. The major advantage seems to be increased sensitivity in the possible LNB group compared to the IDEIA assay. The diagnostic sensitivity may be further increased by using a combination of early markers, such as CXCL13 in CSF and total IgM index.For laboratory diagnostics of Lyme neuroborreliosis (LNB), the recomBead Borrelia antibody index (AI) assay has shown promising results in a mixed age population, but has not previously been evaluated with specific focus on paediatric patients. The aim of the study was to evaluate the recomBead Borrelia AI assay in cerebrospinal fluid (CSF) for the laboratory diagnosis of LNB in children. We also wanted to explore whether early markers, such as CXCL13 in CSF and/or total IgM index could be useful as complementary diagnostic tools. Children being evaluated for LNB in a Swedish Lyme endemic area were included in the study ( Borrelia antibody tests, based on whole-cell sonicates, showed low specificity . Al. Al20]. ire, UK) . PleocytL in CSF . Serum aBorrelia antibodies in CSF  and were considered as controls.Patients who did not meet the criteria for either definite LNB or possible LNB were classified as non-LNB and patients with other specific diagnoses were classified as other diagnosis Table . The nonall patients (n = 146) being evaluated for LNB  are shown in Table https://lakemedelsverket.se/upload/halso-och-sjukvard/behandlingsrekommendationer/Borrelia-rek_webb_bokm%c3%a4rken.pdf); i.e. ceftriaxone i.v. 50–100 mg/kg/dos once daily in 10–14 days for children <8 years of age and doxycycline p.o. 4 mg/kg once daily in 10–14 days for children 8 years of age or older. Some of the patients also presented with a cutaneous manifestation, such as erythema migrans (EM) or lymphocytoma (n = 23)  were patients presenting with acute facial nerve palsy (n = 30) or headache and unspecific symptoms (such as fatigue or problems with food intake or sleep) (n = 58). Non-LNB patients had no pleocytosis in CSF and no intrathecal anti-Borrelia antibodies, i.e. did not meet the criteria for definite LNB or possible LNB (Table Borrelia antibodies in serum (n = 14) or on vague/incorrect indication (n = 4).Children in the non-LNB group (NB Table  and are n = 15) (Table n = 5) with high fever, meningeal signs and pleocytosis (two of them had enterovirus verified by PCR in CSF), post-infectious encephalitis (n = 1), idiopathic intracranial hypertension with headache (n = 4), stroke with hemiplegia (n = 1) and recurrent one-sided migraine headache (n = 4).Another control group was included in the study. Those were patients who received other specific diagnoses after lumbar puncture and further investigation was performed n = 5 , a multiplex bead array using Luminex xMAP technology and, in this study, a BioPlex 200 system  was used together with the software Xponent, version 33.1.871.0 . The test includes 13 recombinant ne beads . Albuminne beads . The recne beads  by the En = 37) and non-LNB (n = 88) from this present material (data not shown).The same Luminex-based platform as described above was used for the recomBead CXCL13 assay (Mikrogen Diagnostik) and applied according to the manufacturer’s instructions for evaluation of CXCL13 in CSF. The measuring range for CXCL13 was 9–1000 pg/mL, and sample results above 1000 pg/mL were not diluted and reanalysed, and were thus regarded as >1000 pg/mL. Equivocal test results, as defined by the manufacturer (190–300 pg/mL) were considered as positive. The cut-off was modified to 160 pg/mL based on a separate receiver operating characteristic (ROC) curve calculation on patients with definite LNB  and non-LNB (n = 88) from this present material (data not shown).The total IgM index was used as part of the recomBead Borrelia AI assay but also as a single IgM index calculation (as described above). The cut-off for the single IgM index was set at 0.148 mg/L, based on a separate ROC curve calculation on patients with definite LNB . ROC curve analyses were made using MedCalc version 16.1  and the area under the curve (AUC) was used for the calculation of diagnostic performance.SPSS software, version 21  was used for statistical calculations. A Among children with definite LNB, 33 out of 37 patients (89%) were positive with the recomBead Borrelia AI assay, whereas in the possible LNB group, 10 out of 21 patients (48%) were AI-positive (Table n = 58) was 74% for the recomBead Borrelia AI assay and the specificity for controls (n = 103) was 97%  LNB patients were positive in serum (IgG and/or IgM), which gives the recomBead Borrelia antibody assay in serum an overall sensitivity of 66% (data not shown). Ninety-two out of 103 (89%) controls were negative in serum (IgG and/or IgM), which gives a specificity of 89% (data not shown).n = 58) was 88% for the recomBead CXCL13 assay in CSF and the specificity for controls (n = 103) was 93%  were positive for CXCL13 in CSF (median 923 pg/mL) and in the possible LNB group, 15 out of 21 children (71%) were positive for CXCL13 median 489 pg/mL) (Table 89 pg/mL n = 58) was 84% and the specificity for controls (n = 103) was 98%.The results for the total IgM index alone among different patient groups are shown in Table As both recomBead CXCL13 in CSF and total IgM index are apparently sensitive markers for LNB Table , they wen = 58) of 91% and an overall specificity for controls (n = 103) of 90%  were positive with the combination of tests and in the possible LNB group, 16 out of 21 children (76%) were positive Table . In non-n = 3) or total IgM index (n = 1) alone  with elevated recomBead Borrelia AI and/or CXCL13 and/or total IgM index (Table n = 3) were recomBead Borrelia AI-positive but none had elevated IgM index or pleocytosis in CSF. Furthermore, five patients (n = 5) had elevated CXCL13 in CSF, with a median value of 330 pg/mL (range 161–424).When analysing the test results in relation to clinical information more in detail, there were a few patients in the non-LNB group (ex Table . Three on = 1) presented with acute idiopathic facial nerve palsy with short duration of symptoms (1–2 days), no pleocytosis but slightly elevated CXCL13 in CSF (161 pg/mL), positive recomBead AI and elevated anti-Borrelia antibodies in serum . Two more patients (n = 2) presented with acute idiopathic facial nerve palsy with short duration of symptoms (1–2 days), no pleocytosis but elevated CXCL13 in CSF (422 and 330 pg/mL respectively), no anti-Borrelia antibodies in CSF or serum and no other probable diagnosis. One girl (n = 1) had been afflicted with an acute sensorineural hearing loss, had no pleocytosis in CSF, no anti-Borrelia antibodies in CSF or serum but had elevated CXCL13 in CSF (424 pg/mL). This patient also remembered a red skin lesion on the neck (possibly undiagnosed EM).One child (n = 3) presented with headache (duration 1–2 weeks), no pleocytosis and no anti-Borrelia antibodies in CSF. One of these patients had elevated CXCL13 in CSF (237 pg/mL) and two were positive for recomBead Borrelia AI.In addition, three patients (n = 3) had elevated CXCL13 and/or total IgM index . Both patients had elevated total IgM index  and one had elevated CXCL13 in CSF (310 pg/mL). One patient had intracranial hypertension, no pleocytosis in CSF, no anti-Borrelia antibodies in CSF or serum, no other obvious diagnosis but elevated CXCL13 (204 pg/mL) in CSF.Among patients with other diagnosis, a few children  also had elevated CXCL13 in CSF and/or total IgM index, further supporting the early LNB diagnosis.The results from the present study of well-characterised paediatric LNB patients from a representative clinical setting show that the recomBead Borrelia AI assay has a high specificity of 97% but a lower sensitivity of 74%. However, children with LNB often present with short duration of symptoms (early LNB) and intrathecal anti- started , 7. ThesBorrelia spirochete from patient specimens [When analysing diagnostic performances of different tests, it is desirable to have a gold standard to confirm the diagnosis and classify patients correctly. However, in laboratory diagnostics of LNB, there is no gold standard due to difficulties in culturing the pecimens . Consequpecimens  and theyIn order to further strengthen the sensitivity in early LNB, we wanted to explore both CXCL13 in CSF and total IgM index as early LNB markers and to evaluate whether they could be useful as complementary tools in laboratory diagnostics of LNB in children. Since the chemokine CXCL13 in CSF has proven to be a valid early marker for LNB in previous studies , 13, it Borrelia antigens (recomBead Borrelia AI) in combination with early markers such as CXCL13 and total IgM index seems to be a promising way to go in laboratory diagnostics of LNB in paediatric patients. Furthermore, since both albumin and IgM in serum and CSF are already included as part of the recomBead Borrelia AI assay, it seems easy and efficacious to use data for the total IgM index as a complementary early marker for LNB in order to further improve sensitivity in LNB diagnostics. Although the results for total IgM index are, to an extent, already included in the recomBead Borrelia AI calculation, it is evident from our results that including total IgM index to the recomBead Borrelia AI results adds diagnostic value.Our results show that both CXCL13 and total IgM index add useful information in combination with the recomBead Borrelia AI assay Tables  and 6. TThe serum/CSF samples had been stored in −70 °C from admission (2010–2013) until time for analysis 2015) without being thawed, rendering uncompromised sample quality. Furthermore, samples from all patient groups were handled in the same way and previous studies indicate that serum proteins such as albumin and immunoglobulins, as well as CXCL13, are stable during prolonged storage  without .Concerning the recomBead Borrelia serum assay, both the sensitivity and specificity were lower than in the recomBead Borrelia AI assay. Among LNB patients with positive recomBead Borrelia AI, only 30 out of 43 (69%) were also positive in serum (IgG and/or IgM), confirming that CSF is required for LNB diagnostics, which is in congruence with previous studies . An invaAmong LNB patients with pleocytosis in CSF but negative recomBead Borrelia AI, 12 out of 21 were positive in both serum (IgG and/or IgM) and CXCL13. Thus, in some cases, serum antibodies may support the LNB diagnosis. However, one needs to keep in mind that serum antibody results are always ambiguous in interpretation due to uncertainties of cross-reactivity to other infections (elevated IgM), as well as previous LB infections (elevated IgG) .Borrelia antibodies in CSF, but elevated CXCL13 in CSF, were reported in detail since they are interesting and may represent patients with very early LNB being misdiagnosed as non-LNB. Since the role of CXCL13 is to recruit inflammatory cells into the central nervous system [A few non-LNB patients with short duration of symptoms, no pleocytosis and no anti-s system , it woulThe recomBead Borrelia antibody index (AI) assay performs with moderate sensitivity in paediatric Lyme neuroborreliosis (LNB) patients and the major advantage seems to be increased sensitivity in the possible LNB group compared to the IDEIA assay. Thus, the two assays complement each other in sensitivity but have comparable high specificity. The recomBead Borrelia AI assay is more expensive and requires measurements of albumin and total immunoglobulin levels in serum and cerebrospinal fluid (CSF). Therefore, it may be used in IDEIA-negative paediatric patients with CSF pleocytosis . The diagnostic sensitivity may be further increased by using a combination of early markers, such as CXCL13 in CSF and total IgM index.


The World Health Organization recommends TT surveys to be conducted in adults aged 15+ years (TT 15 survey) and certifies elimination of TT as a public health problem when there is less than 1 unknown case per 1,000 people of all ages. There is no standard survey method to accurately confirm this elimination prevalence threshold of 0.1% because rare conditions require large and expensive prevalence survey samples. The aim of this study was to develop an accurate operational research method to measure the total backlog of TT in people of all ages and detect when the elimination threshold is achieved.Between July to October 2016, an innovative Community-based, Mapping, Mop-up and Follow-up (CMMF) approach to elimination of TT as a public health problem was developed and tested in Esoit, Siana, Megwara and Naikara sub-locations in Narok County in Kenya. The County had ongoing community-based TT surgical camps and case finders. TT case finders were recruited from existing pool of Community health volunteers (CHV) in the Community Health Strategy Initiative Programme of the Ministry of Health. They were trained, validated and supervised by experienced TT surgeons. A case finder was allocated a population unit with 2 to 3 villages to conduct a de jure pre-survey census, examine all people in the unit and register those with TT . Identified cases were confirmed by TT surgeons prior to surgery. Operated patients were reviewed at 1 day, 2 weeks and 3-6 months. The case finders will also be used to identify and refer new and recurrent cases. People with other eye and medical conditions were treated and referred accordingly. Standardised data collection and computer based data capture tools were used. Case finders kept registers with details of all persons with TT, those operated and those who refused to be operated . These details informed decision and actions on follow-up and counselling. Progress towards achievement of elimination threshold was assessed by dividing the number of TT cases diagnosed by total population in the population unit multiplied by 1,000.Narok County Government adopted both the CMMF approach and TT all survey method. All persons in 4,784 households in the four sub-locations were enumerated and examined. The total population projection was 29,548 and pre-survey census 22,912 people. Fifty-three cases of TT were diagnosed. The prevalence was 0.23% and this is equivalent to 2.3 cases per thousand population of all ages. Prior to this study, the project required to operate on at least 30 cases (excess cases) to achieve the elimination threshold of 1 case per 1000 population.The total backlog of TT was confirmed and the project is now justified to lay claim of having eliminated TT as a public health problem in the study area. TT all method may not be appropriate in settings with high burden of TT. Nomadic migrations affect estimation of population size. Non-trachomatous TT could not be ruled-out. Trachoma is the leading infectious cause of blindness in the world and TT the monitoring indicator for the potentially blinding stage . TT is aThe 2010 and 2014 impact surveys indicated that only 2 southern segments  had remaThis operational research was initiated in 2016 as part of a trachoma elimination project in Narok County in Kenya . The metA community-based, mapping, mop-up and follow-up (CMMF) approach for elimination of TT was designed and validated where case finders were deployed to enumerate, examine all household members for TT and register all TT cases  in their population units. Narok trachoma project offered free community-based surgical services to all persons with TT. The operated patients were reviewed at 1 day, 2 weeks and 3-6 months. Surveillance system was put in place where the case finders diagnosed and referred recurrent and new (incident) cases. The difference between the previous and new approaches are shown in The Kenya National Bureau of Statistics (NBS) provided population projections derived from the national 2009 census report . BesidesTT was diagnosed if there were one or more eye lashes touching the eye-ball.People of all ages  living in the Narok trachoma elimination project area were eligible to participate in this operational research.Non-residents such as traders and tourists were excluded. Local people living in shops in trading centres were also excluded on assumption they would be enumerated in their rural households.Case finders were recruited from an existing pool of CHV in the MOH Community Health Strategy Initiative (CHS) where Counties are divided into geo-medical units referred to as Community Health Units (CHUs). A CHU comprised of approximately 5,000 people served by 2 Community Health Extension Workers (CHEWs) and 50 Community Health Volunteers (CHVs). A CHV serves 20 households with approximately 100 people . CHVs arAll households were visited  and all Clinical examination was done at the household using x 2.5 dioptres binocular loupes and torches. The following details were recorded in the study data collection form: date of visit/examination, administrative unit, village, telephone contact, age, sex, diagnosis and eye with TT. Certified TT surgeon confirmed all cases identified by case finders. Case finders kept registers with details of all patients with TT, those operated and refusals in their population unit. These details were used to inform decision and actions to be taken during follow-up and counselling. Health facility staff recorded patient's details, surgical procedures and follow-up plan. Post-operative follow-up was routinely done at 1 day, 2 weeks and 3-6 months.Standardised data collection tool was used. The information was sent to the office of trachoma focal person and entered in excel spreadsheet by health records information officers. The analysis was simple hence it was possible to do it using a spreadsheet. The percentage population coverage was calculated by dividing the number of people enumerated during the pre-survey census by the population projection estimate by the NBS times one hundred. The authors considered the total number of TT cases confirmed in a population or administrative unit to be the total backlog in the unit. The prevalence was computed by dividing the number of cases by the population from which the cases were diagnosed multiplied by 100. The level of achievement of TT elimination threshold was assessed by dividing the number of TT cases diagnosed by total population multiplied by 1,000. The term ''threshold cases'' was used to refer to the number of cases which if operated would reduce the backlog to less than 1 case per 1,000 people while the term ''excess cases''was used to refer to the backlog minus ''threshold cases''. Inter-observer agreement was expressed as a percentage of the observations where a case finder and a TT surgeon (reference examiner) recorded the same diagnosis. An agreement of 80% or higher was set as the minimum requirement for recruitment of case finders in this survey. Where indicated Kappa values were computed using a statistical software and interpreted in line with the Landis and Koch classification  as folloThis operational research utilised Health Management Information System data provided by Narok County Government and Division of Ophthalmic Services of the Ministry of Health. Details for individual persons are not included. Trachoma project team conducted community mobilisation and took informed verbal consent from community leaders, heads of households and examined individuals. Persons and households which were not willing to be examined/visited during the routine TT screening activities were not forced to do so. The County Government and partners offered free community based surgery for TT and cataract plus treatment for other eye conditions through an existing Primary Eye Care Project. People with complicated eye and medical conditions were treated and/or referred accordingly.This operational research resulted in development of the CMMF approach which includes of an innovative TTall survey method anchored on existing community-based surgical services.All cases identified by TT case finders were confirmed to have TT. Therefore, there was 100% agreement on the diagnosis of TT between the case finders and the surgeons. This was attributed to the strict two-stage recruitment criteria for case finders and prolonged training period. The was no indication to calculate Kappa values in this study because all the persons identified to have TT by the case finders were confirmed to be having TT.Surveys were conducted in 4,784 households in 4 sub-location namely: Esoit, Siana, Megwara and Naikara . Siana aA total of 53 cases of TT were diagnosed in a population of 22,912 people in the studied population units. The mean prevalence of TT was 53/22,912 x 100 = 0.23%. This was equivalent to 2.3 cases per thousand population. The project required to operate on at least 30 cases (excess cases) to achieve the elimination threshold of 1 case per 1000 population. The backlog and excess cases for the 4 sub-locations are in The CMMF approach will enable Narok to lay claim of having eliminated TT as a public health because the approach reveals all TT cases in the studied areas and the project has capacity to tackle the backlog. The elimination threshold is a dynamic process which requires effective health care systems to identify and treatment new cases to sustain it . This neThe CMMF approach introduced a paradigm shift from the traditional low productivity “supply driven” TT surgical service delivery model to a more effective “demand driven” model. The total backlog and prevalence of TT in the study area were confirmed using validated community-based case finders. TT elimination threshold had not been achieved.There is no standard trachoma prevalence survey method to accurately confirm attainment of the very low elimination of TT threshold of 1 case per thousand population;TT is relatively easy to diagnose and even lay people living in the endemic areas in Narok County have local names for it.Utilises non-technical community-based case finders to measure the actual backlog of TT and monitor achievement of elimination threshold as part of ongoing project activities;Reduces project cost by eliminating the need for periodic TT impact surveys.The authors declare no competing interests.


Introduction: Suboccipital craniotomy is a workhorse neurosurgical operation for approaching the posterior fossa but carries a high risk of pseudomeningocele and cerebrospinal fluid (CSF) leak. We describe our experience with a simple T-shaped fascial opening that preserves the occipital myofascial cuff as compared to traditional methods to reduce this risk.Methods: A single institution, retrospective review of prospectively collected database was performed of patients that underwent a suboccipital craniectomy or craniotomy. Patient data was reviewed for craniotomy or craniectomy, dural graft, and/or sealant use as well as CSF complications. A pseudomeningocele was defined as a subcutaneous collection of cerebrospinal fluid palpable clinically and confirmed on imaging. A CSF leak was defined as a CSF-cutaneous fistula manifested by CSF leaking through the wound. All patients underwent regular postoperative visits of two weeks, one month, and three months.Results: Our retrospective review identified 33 patients matching the inclusion criteria. Overall, our cohort had a 21% (7/33) rate of clinical and radiographic pseudomeningocele formation with 9% (3/33) requiring surgical revision or a separate procedure. The rate of clinical and radiographic pseudomeningocele formation in the myofascial cuff preservation technique was less than standard techniques . Revision or further surgical procedures were also reduced in the myofascial cuff preservation technique vs. the standard technique (6% vs 13%).Conclusions: Preservation of the myofascial cuff during posterior fossa surgery is a simple and adoptable technique that reduces the rate of pseudomeningocele formation and CSF leak as compared with standard techniques.   Suboccipital craniotomy is a workhorse neurosurgical operation for approaching the posterior fossa -2. BecauThe technique of suboccipital craniotomy typically involves a midline or hockey stick incision, a wide subperiosteal detachment of the posterior musculature from the occipital bone, and dorsal spinal elements. The potential for dead space, combined with the difficulty in reattachment of the musculoligamentous tissues to the occipital bone, creates a direct conduit for cerebrospinal fluid to reach the skin. This is compounded by the thin and typically friable dura of the posterior fossa -7.We describe our experience during posterior fossa surgery with a simple technique that preserves the occipital myofascial cuff formed from the insertion of the paraspinous musculature of the occipital bone. A T-shaped fascial opening is performed during the initial dissection that allows for watertight reattachment of the paraspinal musculature to the spinal elements and occipital bone, reducing dead space and eliminating a CSF conduit to the skin. Our hypothesis is that this simple technical nuance should reduce the rate of pseudomeningocele formation or cerebrospinal fistula. To the authors’ knowledge, there has been no previous study investigating the efficacy of this technique.We performed a retrospective review of a prospectively collected database of patients that underwent a suboccipital craniotomy or craniectomy preserving the myofascial cuff compared to the traditional method. Each procedure had a midline incision, suboccipital craniotomy or craniectomy, dural graft, and sealant. This limited the major technical difference between techniques to the preservation of the myofascial cuff. We analyzed each patient’s postoperative course for any surgical complications, with particular attention paid to pseudomeningocele formation, CSF leak, and wound dehiscence, or meningitis. A pseudomeningocele was defined as a subcutaneous collection of cerebrospinal fluid palpable clinically and confirmed on imaging. A CSF leak was defined as a CSF-cutaneous fistula manifested by CSF leaking through the wound. All patients underwent postoperative imaging in the form of computed tomography (CT) or magnetic resonance imaging (MRI) immediately after surgery and at three to six months follow-up. All patients underwent regular postoperative visits at 14 days, six weeks, and three months. Patients with preoperative hydrocephalus, cerebellar hematoma or infarction requiring emergent surgery, or didn’t have all technical components performed were excluded.The technique of suboccipital craniotomy or craniectomy has been previously described. A brief summary follows. Informed consent was obtained prior to all operations. After the induction of general anesthesia and appropriate intravenous access and neuromonitoring is obtained, the patient is then positioned prone in the Mayfield head holder in a flexed position to enhance exposure to the posterior fossa. A midline incision is planned from the inion or above to the level of the spinous process of C2. The incision is then carried deeper with Bovie® electrocautery  in the midline to the level of the fascia and suboccipital muscles. The occipital bone at the superior nuchal line is invested with a tough fibrous band consisting of the attachments of the trapezius muscles bilaterally and deeper, the semispinalis capitis muscles. In the standard approach, all muscles are detached in the midline in a subperiosteal fashion from the inion down for deeper exposure of the bony elements. At this stage, rather than a wide detachment of the musculature, a “T” shaped incision is made of the fascia to leave a transverse fascial cuff at the superior nuchal line as is illustrated in Figure The fascia on each side of the midline is then reflected laterally with the underlying musculature. After completion of the intended intradural portion of the operation, the dura is closed in a watertight fashion, when possible. A dural sealant is applied to the suture line. The muscles are reapproximated to reduce dead space with O Vicryl® sutures . The fascia on each of the midline is then closed medially and superiorly along the transverse fascial cuff in watertight fashion with interrupted O Vicryl sutures as shown in Figure The rest of the wound is then closed in layers in the usual manner followed by a non-absorbable suture used to close the cutaneous layer in a running fashion. A drain is not placed.A 34-year-old non-obese female with occipital headaches diagnosed with a Chiari malformation underwent an uneventful suboccipital craniectomy with duraplasty. Due to worsening headaches, a postoperative MRI shown in Figure The opening pressure was noted to be above 50 cm H20 with remarkable relief of symptoms after the procedure. An ophthalmological evaluation confirmed papilledema. The patient was diagnosed with idiopathic intracranial hypertension (IIH) and was treated with a lumboperitoneal shunt. Her symptoms immediately improved and her pseudomeningocele resolved at six months. This case highlights the reliability of the “T”-fascial closure, which the authors believe helped prevent a CSF fistula despite intracranial hypertension.Our retrospective review identified 33 patients matching the inclusion criteria. The mean age was 43 years old (range: 21-78). Twenty-one patients underwent surgery for a Chiari 1 malformation and 12 for primary or metastatic tumor. An autologous pericranium graft (n = 5) or bovine pericardial graft (n = 28) was performed in cases to achieve a watertight closure. In patients without a watertight closure, an onlay collagen-based graft was placed on top of the remaining dura. A dural sealant was used in all cases. The bone flap was repositioned anatomically in eight cases. All patients had a minimum of at least six months follow-up.Overall, our cohort had a 21% (7/33) rate of clinical and radiographic pseudomeningocele formation with 9% (3/33) requiring surgical revision or a separate procedure. Of those utilizing the myofascial cuff preservation technique, there was a 12% (2/17) rate of a clinical and radiographic pseudomeningocele formation compared to 31% (5/16) in the standard cohort. The rate of permanent CSF diversion or revision was also less in the myofascial cuff preservation group at 6% (1/17) compared to 13% (2/16) in the standard. In all patients with persistent pseudomeningocele formation, there was no wound compromise nor evidence of CSF drainage.Pseudomeningocele formation and CSF leak represent a significant complication after posterior fossa surgery. Cerebrospinal fluid leak rates in the published literature range between 1.5% - 23% -9. A stuA variety of technical modifications has been proposed to reduce the rate of pseudomeningocele formation and CSF leak after posterior fossa surgery. Performing a craniotomy versus craniectomy reduces pseudomeningocele formation -12. The The technique described herein focuses on eliminating potential dead space and adding another water-tight layer to posterior fossa wound closures -18. To oThe surgical technique is simple, fast, and only requires one additional step during exposure. Adding a second water-tight layer of closure is particularly helpful in patients with prior surgery or radiation where dural closure is not possible. In particular, the most superior aspect tends to be the most difficult position to close, due to the lack of attachment along the superior nuchal line. This is easily remedied by performing a T-shaped cuff at the initial dissection and allows for a firm attachment upon closure. The increased strength of this technique was demonstrated in the patient wherein a clinically relevant pseudomeningocele had formed but there was no drainage despite increased opening CSF pressures from the patient's idiopathic intracranial hypertension. This may be due to the fascial closure’s ability to allow for the more superficial layers to heal due to the impeded flow of CSF.There are several inherent weaknesses of this analysis. First, because of the non-blinded retrospective nature of the study, there may be bias in reviewing the clinical and radiographic evidence of pseudomeningocele formation. Second, there is a multitude of factors that contribute to CSF-related complications after posterior fossa surgery. Our limited series cannot control for all these factors. The type of dural graft or dural sealant used was not standardized in all cases. A prospective randomized controlled study is needed to clearly demonstrate a reduced rate of CSF-related complications.Preservation of the myofascial cuff for watertight fascial closure during posterior fossa surgery reduces the rate of pseudomeningocele formation and cerebrospinal fluid leak as compared with standard techniques. This restorative anatomical technique is simple, easily adoptable without added morbidity, and worth incorporating. A larger prospective multi-institutional study is necessary to corroborate these findings.