The diagnostic value of the central vein sign in radiologically isolated syndrome.

OBJECTIVE: The radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS). Increasing evidence suggests that the central vein sign (CVS) enhances lesion specificity, allowing for greater MS diagnostic accuracy. This study evaluated the diagnostic performance of the CVS in RIS. METHODS: Patients were prospectively recruited in a single tertiary center for MS care. Participants with RIS were included and compared to a control group of sex and age-matched subjects. All participants underwent 3 Tesla magnetic resonance imaging, including postcontrast susceptibility-based sequences, and the presence of CVS was analyzed. Sensitivity and specificity were assessed for different CVS lesion criteria, defined by proportions of lesions positive for CVS (CVS+) or by the absolute number of CVS+ lesions. RESULTS: 180 participants (45 RIS, 45 MS, 90 non-MS) were included, representing 5285 white matter lesions. Among them, 4608 were eligible for the CVS assessment (970 in RIS, 1378 in MS, and 2260 in non-MS). According to independent ROC comparisons, the proportion of CVS+ lesions performed similarly in diagnosing RIS from non-MS than MS from non-MS (p = 0.837). When a 6-lesion CVS+ threshold was applied, RIS lesions could be diagnosed with an accuracy of 87%. MS could be diagnosed with a sensitivity of 98% and a specificity of 83%. Adding OCBs or Kappa index to CVS biomarker increased the specificity to 100% for RIS diagnosis. INTERPRETATION: This study shows evidence that CVS is an effective imaging biomarker in differentiating RIS from non-MS, with similar performances to those in MS.

Kappa Free Light Chain Index Predicts Disease Course in Clinically and Radiologically Isolated Syndromes.

BACKGROUND AND OBJECTIVES: To evaluate whether the kappa free light chain index (K-index) can predict the occurrence of new T2-weighted MRI lesions (T2L) and clinical events in clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS). METHODS: All consecutive patients presenting for the diagnostic workup, including CSF analysis, of clinical and/or MRI suspicion of multiple sclerosis (MS) since May 1, 2018, were evaluated. All patients diagnosed with CIS and RIS with at least 1-year follow-up were included. Clinical events and new T2L were collected during follow-up. The K-index performances in predicting new T2L and a clinical event were evaluated using time-dependent ROC analyses. The time to clinical event or new T2L was estimated using survival analysis according to the binarized K-index using an independent cutoff of 8.9, and the ability of each variable to predict outcomes was compared using the Harrell c-index. RESULTS: One hundred and eighty two patients (146 CIS and 36 RIS, median age 39 [30; 48] y-o, 70% females) were included with a median follow-up of 21 [13, 33] months. One hundred five (58%) patients (85 CIS and 20 RIS) experienced new T2L, and 28 (15%; 21 CIS and 7 RIS) experienced a clinical event. The K-index could predict new T2L over time in CIS (area under the curve [AUC] ranging from 0.86 to 0.96) and in RIS (AUC ranging from 0.84 to 0.54) but also a clinical event in CIS (AUC ranging from 0.75 to 0.87). Compared with oligoclonal bands (OCBs), the K-index had a better sensitivity and a slight lower specificity in predicting new T2L and clinical events in both populations. In the predictive model, the K-index was the variable that best predict new T2L in both CIS and RIS but also clinical events in CIS (c-index ranging from 0.70 to 0.77), better than the other variables, including OCB. DISCUSSION: This study provides evidence that the K-index predicts new T2L in CIS and RIS but also clinical attack in patients with CIS. We suggest adding the K-index in the further MS diagnosis criteria revisions as a dissemination-in-time biomarker.

Diagnostic significance of antineutrophil cytoplasmic antibody (ANCA) titres: a retrospective case-control study.

OBJECTIVES: To investigate the reliability of elevated titres of antineutrophil cytoplasmic antibody (ANCA) and to identify a cut-off titre in discriminating between ANCA-associated vasculitides (AAV) and its mimickers. METHODS: This retrospective observational single-centre study included patients over 18 years with positive myeloperoxidase (MPO)-ANCA and/or proteinase 3 (PR3)-ANCA immunoassays over an 8-year period (January 2010 to December 2018), via their electronic medical files. Patients were classified according to the 2022 ACR/EULAR criteria and alternative diagnoses categorised either as non-AAV autoimmune disorders (ANCA-AI) or disorders without autoimmune features (ANCA-O). Findings from the AAV group were compared with those of ANCA-AI and ANCA-O groups and followed by a multivariate logistic stepwise regression analysis of features associated with AAV. RESULTS: 288 ANCA-positive patients of which 49 had AAV were altogether included. There was no difference between patients between the ANCA-AI (n=99) and the ANCA-O (n=140) groups. The AUC for titres discriminating AAV from mimickers was 0.83 (95% CI, 0.79 to 0.87). The best threshold titre, irrespective of PR3-ANCA or MPO-ANCA, was 65 U/mL with a negative predictive value of 0.98 (95% CI, 0.95 to 1.00). On multivariate analysis, an ANCA titre ≥65 U/mL was independently associated with AAV with an OR of 34.21 (95% CI 9.08 to 129.81; p<0.001). Other risk factors were: pulmonary fibrosis (OR, 11.55 (95% CI, 3.87 to 34.47, p<0.001)), typical ear nose and throat involvement (OR, 5.67 (95% CI, 1.64 to 19.67); p=0.006) and proteinuria (OR, 6.56 (95% CI, 2.56 to 16.81; p<0.001)). CONCLUSION: High PR3/MPO-ANCA titres can help to discriminate between AAV and their mimickers in patients presenting with small-calibre vasculitides, with a threshold titre of 65 U/mL and above.

The radiologically isolated syndrome: revised diagnostic criteria.

The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1-2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.

Kappa Free Light Chain Biomarkers Are Efficient for the Diagnosis of Multiple Sclerosis: A Large Multicenter Cohort Study.

BACKGROUND AND OBJECTIVES: Kappa free light chains (KFLC) seem to efficiently diagnose MS. However, extensive cohort studies are lacking to establish consensus cut-offs, notably to rule out non-MS autoimmune CNS disorders. Our objectives were to (1) determine diagnostic performances of CSF KFLC, KFLC index, and KFLC intrathecal fraction (IF) threshold values that allow us to separate MS from different CNS disorder control populations and compare them with oligoclonal bands' (OCB) performances and (2) to identify independent factors associated with KFLC quantification in MS. METHODS: We conducted a retrospective multicenter study involving 13 French MS centers. Patients were included if they had a noninfectious and nontumoral CNS disorder, eligible data concerning CSF and serum KFLC, albumin, and OCB. Patients were classified into 4 groups according to their diagnosis: MS, clinically isolated syndrome (CIS), other inflammatory CNS disorders (OIND), and noninflammatory CNS disorder controls (NINDC). RESULTS: One thousand six hundred twenty-one patients were analyzed (675 MS, 90 CIS, 297 OIND, and 559 NINDC). KFLC index and KFLC IF had similar performances in diagnosing MS from nonselected controls and OIND (p = 0.123 and p = 0.991 for area under the curve [AUC] comparisons) and performed better than CSF KFLC (p < 0.001 for all AUC comparisons). A KFLC index of 8.92 best separated MS/CIS from the entire nonselected control population, with better performances than OCB (p < 0.001 for AUC comparison). A KFLC index of 11.56 best separated MS from OIND, with similar performances than OCB (p = 0.065). In the multivariate analysis model, female gender (p = 0.003), young age (p = 0.013), and evidence of disease activity (p < 0.001) were independent factors associated with high KFLC index values in patients with MS, whereas MS phenotype, immune-modifying treatment use at sampling, and the FLC analyzer type did not influence KFLC index. DISCUSSION: KFLC biomarkers are efficient tools to separate patients with MS from controls, even when compared with other patients with CNS autoimmune disorder. Given these results, we suggest using KFLC index or KFLC IF as a criterion to diagnose MS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that KFLC index or IF can be used to differentiate patients with MS from nonselected controls and from patients with other autoimmune CNS disorders.

Air pollution exposure induces a decrease in type II interferon response: A paired cohort study.

BACKGROUND: While air pollution is a major issue due to its harmful effects on human health, few studies focus on its impact on the immune system and vulnerability to viral infections. The lockdown declared following the COVID-19 pandemic represents a unique opportunity to study the large-scale impact of variations in air pollutants in real life. We hypothesized that variations in air pollutants modify Th1 response represented by interferon (IFN) γ production. METHODS: We conducted a single center paired pilot cohort study of 58 participants, and a confirmation cohort of 320 participants in Nice (France), with for each cohort two samplings at six months intervals. We correlated the variations in the production of IFNγ after non-specific stimulation of participants' immune cells with variations in key regulated pollutants: NO2, O3, PM2.5, and PM10 and climate variables. Using linear regression, we studied the effects of variations of each pollutant on the immune response. FINDINGS: In the pilot cohort, IFNγ production significantly decreased by 25.7% post-lockdown compared to during lockdown, while NO2 increased significantly by 46.0%. After the adjustment for climate variations during the study period (sunshine and temperature), we observed a significant effect of NO2 variation on IFNγ production (P=0.03). In the confirmation cohort IFNγ decreased significantly by 47.8% and after adjustment for environmental factors and intrinsic characteristics we observed a significant effect of environmental factors: NO2, PM10, O3, climatic conditions (sunshine exposure, relative humidity) on variation in IFNγ production (P=0.005, P<0.001, P=0.001, P=0.002 and P<0.001 respectively) but not independently from the BMI at inclusion and the workplace P=0.007 and P<0.001 respectively). INTERPRETATION: We show a weakening of the antiviral cellular response in correlation with an increase of pollutants exposition. FUNDING: Agence Nationale de la Recherche, Conseil Départemental des Alpes-Maritimes and Region Sud.

A role for metformin in the treatment of Dupuytren disease?

Dupuytren disease (DD) is a hand-localized fibrotic disorder characterized by a scar-like, collagen-rich cord. Treatment usually comprises surgical removal of the cord, but is associated with a high relapse rate, in some cases requiring finger amputation. There is currently no consensual medical approach for treating DD. Numerous preclinical studies have highlighted antifibrotic properties of metformin, and the aim of this study was to assess a potential antifibrotic role of metformin in DD. Fibroblasts from DD cords (DF) and phenotypically normal palmar fascia (PF) were extracted from surgical specimens and cultured. The fibrotic status of DF and PF was compared at baseline, and under profibrotic (TGF-ß stimulation) and antifibrotic (metformin stimulation) conditions, using quantitative RT-PCR, western blot, immunocytochemistry, and a functional fibroblast contraction assay. At baseline, DF showed higher levels of fibrotic markers and contraction capacity compared with PF. Both types of fibroblasts responded to TGF-ß stimulation. Treatment of DF and PF with metformin did not affect basal levels of fibrotic markers and contraction but largely prevented their induction by TGF-ß. In conclusion, our data show that metformin inhibits TGF-ß-induced expression of fibrotic markers and contraction in hand-derived fibroblasts. This supports the case for a clinical trial to assess the repurposing of metformin as an adjuvant to surgery, to prevent, reduce, or delay recurrence in at-risk DD patients.

Kappa Free Light Chains, Soluble Interleukin-2 Receptor, and Interleukin-6 Help Explore Patients Presenting With Brain White Matter Hyperintensities.

Introduction: Many patients are referred to multiple sclerosis (MS) tertiary centers to manage brain white matter hyperintensities (WMH). Multiple diagnoses can match in such situations, and we lack proper tools to diagnose complex cases. Objective: This study aimed to prospectively analyze and correlate with the final diagnosis, cerebrospinal fluid (CSF) interleukin (IL)-1ß, soluble IL-2 receptor (CD25), IL-6, IL-10, and kappa free light chains (KFLC) concentrations in patients presenting with brain WMH. Methods: All patients over 18 years addressed to our MS tertiary center for the diagnostic workup of brain WMH were included from June 1, 2020, to June 1, 2021. Patients were separated into three groups-MS and related disorder (MSARD), other inflammatory neurological disorder (OIND), and non-inflammatory neurological disorder (NIND) groups-according to clinical presentation, MRI characteristics, and biological workup. Results: A total of 176 patients (129 women, mean age 45.8 ± 14.7 years) were included. The diagnosis was MSARD (n = 88), OIND (n = 35), and NIND (n = 53). Median CSF KFLC index and KFLC intrathecal fraction (IF) were higher in MSARD than in the OIND and NIND groups; p < 0.001 for all comparisons. CSF CD25 and IL-6 concentrations were higher in the OIND group than in both the MSARD and NIND groups; p < 0.001 for all comparisons. KFLC index could rule in MSARD when compared to NIND (sensitivity, 0.76; specificity, 0.91) or OIND (sensitivity, 0.73; specificity, 0.76). These results were similar to those with oligoclonal bands (sensitivity, 0.59; specificity, 0.98 compared to NIND; sensitivity, 0.59; specificity, 0.88 compared to OIND). In contrast, elevated CSF CD25 and IL-6 could rule out MSARD when compared to OIND (sensitivity, 0.58 and 0.88; specificity, 0.95 and 0.74, respectively). Discussion: Our results show that, as OCBs, KFLC biomarkers are helpful tools to rule in MSARD, whereas elevated CSF CD25 and IL-6 rule out MSARD. Interestingly, CSF IL-6 concentration could help identify neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, and central nervous system (CNS) vasculitis. These results need to be confirmed within more extensive and multicentric studies. Still, they sustain that KFLC, CSF CD25, and CSF IL-6 could be reliable biomarkers in brain WMH diagnostic workup for differentiating MSARD from other brain inflammatory MS mimickers.

Glial Fibrillary Acidic Protein (GFAP) Astrocytopathy Presenting as Mild Encephalopathy with Reversible Splenium Lesion.

INTRODUCTION: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is scarce and usually presents as meningoencephalomyelitis. Here, we offer the case of an atypical presentation of GFAP-astrocytopathy. CASE PRESENTATION: We report the case of a 26-year-old woman admitted to our neurology department for a 3-week progressive and worsening neurologic picture, with secondary worsening. Initial imaging showed a Mild Encephalitis with Reversible Splenium of corpus callosum lesion (MERS). Full infectious and autoimmune workup then revealed positivity of GFAP antibodies, leading us to diagnose GFAP astrocytopathy. DISCUSSION: Our case is the first reported association between MERS and GFAP astrocytopathy in an adult patient. Clinical presentation of GFAP astrocytopathy usually includes various neurologic symptoms and can lead to misdiagnosis.

Marburg Multiple Sclerosis Variant: Complete Remission with Very Early Administration of Mitoxantrone-A Case Report.

Marburg variant is a severe and fulminant pseudotumor form of multiple sclerosis (MS) with high morbidity and mortality rates. Because of its scarcity, it remains incompletely characterized and physicians' experiences will influence the treatment. We report the inflammatory explosive case of a 31-year-old woman presenting with rapid neurological degradation of histology proven Marburg's disease, successfully treated with early administration of Mitoxantrone (MITX). To our knowledge, it is the first case describing complete remission after MITX in a biopsy-proven condition.

Should we still only rely on EDSS to evaluate disability in multiple sclerosis patients? A study of inter and intra rater reliability.

BACKGROUND: Few studies assessed reliability and inter-rater variability of EDSS and functional parameters (FP) rating. OBJECTIVE: To evaluate inter-rater variability and errors in EDSS and FP rating in junior (JN) and MS Neurologists (MSN). METHOD: Patients with MS were examined by a JN and a MSN on the same day. Each assessor rated FP and EDSS, then used a smartphone app to get an automated calculation for each FP ("smartphone" FP, sFP) and for EDSS ("smartphone" EDSS, sEDSS) from the description of the neurological exam. Inter-rater variability was assessed comparing JN and MSN ratings for each method. Intra-rater variability was assessed comparing traditional and digital rating for a given assessor. RESULT: 103 patients were included. Perfect agreement between JN and MSN was met for 67% and 70% of patients regarding EDSS and sEDSS. Disagreement that could lead to a significant difference in terms of level of disability occurred in 17% for EDSS and 12% for sEDSS (p=0.07). Regarding intra-rater reliability, we found 38 rating discrepancies for JN and 14 for MSN (p=0.04). CONCLUSION: We found a significant inter-rater variability as well as a substantial frequency of rating errors in JN. The use of less subjective, easier-to-rate scales should be encouraged.

Cerebrospinal Fluid IL-17A Could Predict Acute Disease Severity in Non-NMDA-Receptor Autoimmune Encephalitis.

Introduction: Most of our knowledge into autoimmune encephalitis (AE) comes from N-Methyl-D-Aspartate Receptor (NMDAR) encephalitis. The concentrations of cytokines in cerebrospinal fluid (CSF) including IL-17A have been found to be increased and associated with poor outcome. However, data on the cytokine concentration in CSF and its correlation with outcome is lacking for other types of AE. Objective: To report the concentrations of CSF sIL-2R, IL-6, IL-8, IL-10 and IL-17A and to correlate it with acute disease severity and the 1-year outcome in non-NMDAR AE. Methods: We measured the CSF concentration of each cytokine in 20 AE patients, and compared IL-6 and IL-17A concentrations with 13 patients with CNS demyelinating diseases and 20 non-inflammatory controls. Patients were > 18yr and had at least 1-year clinical follow-up. Intracellular and NMDAR antibody (Ab) -mediated encephalitis were excluded. A mRS ≤ 2 was retained as a 1-year good outcome. Results: The IL-17A concentration in CSF was higher in AE patients than in both control groups (p<0.01). No difference was observed in CSF concentration of IL-6 between groups. At disease onset, a high CSF IL-17A concentration correlated with a high modified Rankin Scale (p<0.05), a high Clinical Assessment Scale for Autoimmune Encephalitis score (p<0.001) and ICU admission (p<0.01). There was no correlation between the concentration of all CSF cytokines and the 1-year clinical outcome. Conclusion: Our results show that CSF IL-17A could be interesting to assess initial severity in non-NMDAR AE. Thus, CSF IL-17A could be an interesting therapeutic target and be useful to assess early selective immunosuppressive therapy.

Low prevalence of JAK2 V617F mutation in patients with thrombosis and normal blood counts: a retrospective impact study.

To determine the prevalence of the V617F Janus Kinase 2 (JAK2) mutation in patients with thrombosis without other biological signs of underlying myeloproliferative neoplasm (MPN) and identify associated risk factors for thrombosis. Over a 10-year period, data were collected from patients with thrombotic events and who had also been screened for the V617F JAK2 mutation. Patients with signs of underlying MPN, such as haematocrit levels ≥ 50% and/or platelet counts ≥ 450 × 109/L and/or splanchnic thrombosis were excluded from the study. Of 340 patients fulfilling inclusion criteria, JAK2 mutation was found in 9 (2.65%), the allele burden being at least 2% in 4 (1.1%). Upon follow-up, MPN was diagnosed in the latter 4. Univariate analysis of the whole cohort showed that age (54 ± 15 vs. 64 ± 13, p = 0.027), platelet count (317 ± 111 vs. 255 ± 75, p = 0.017), C-reactive protein level > 5 mg/L (OR 7.29, p = 0.014), and splenomegaly (OR 54.5, p = 0.0002) were significantly associated with JAK2 mutation. There was also a trend for an increased risk of cerebral venous thrombosis (OR 6.54, p = 0.064). Logistic regression confirmed a significant association between splenomegaly and JAK2 mutation (OR 43.15 [95%CI, 3.05-610.95], p = 0.0054). The V617F JAK2 mutation is rarely found in patients with thrombotic events without overt MPN. Splenomegaly, however, is a statistically and clinically relevant indicator of a potential JAK2 mutation in patients with non-splanchnic thrombotic events. Such patients should require further assessment and a close follow-up.

Impact of Simulation-Based Learning on National Ranking Medical Examination Results in France: A Randomized Trial (SimECNi Study).

INTRODUCTION: In France, the National Ranking Examination (ECNi) evaluates medical students based on their clinical reasoning. Simulation-based education on ECNi preparation has not been assessed. Our objective is to establish the added value of high-fidelity (HF) simulation-based learning in ECNi preparation compared with the current standard. METHODS: We performed a controlled, prospective study. Fifth-year medical students from Nancy and Nice participated in a 3-phase process. In phase 1, students were tested on 6 themes (A-F) that were each presented as an ECNi clinical case and were randomized into 2 groups (#1 and #2). A 20-point grading scale was used. In phase 2, group #1 carried out HF simulation on themes A, B, and C, whereas group #2 did so on themes D, E, and F. Students were tested, in phase 3, with a new set of clinical cases on the same 6 themes. Progression in scores between phases 1 and 3 was analyzed. RESULTS: One hundred sixty-six medical students randomized into 2 groups partook in the study. In phase 1, there was no significant difference in scores between groups. In phase 3, group #1 had significantly higher scores than group #2 for cases A, B, and C. Scores were significantly higher in group #2 for cases D, E, and F. Average scoring significantly improved between phases 1 and 3 with a 1.4-point gain for cases A, B, and C in group #1 and a 2.10-point gain for cases D, E, and F in group #2. CONCLUSIONS: Our study shows that HF simulation learning significantly increases ECNi-like test results when compared with traditional forms.

A case report of exogenous lipoid pneumonia associated with avocado/soybean unsaponifiables.

BACKGROUND: Exogenous lipoid pneumonia is a rare disease resulting from intra-alveolar accumulation of lipids of mineral, vegetal, or animal origin, that induce a foreign body type of inflammatory reaction in the lungs. Gastroesophageal reflux disease and other esophageal abnormalities have often been associated with this disease. CASE PRESENTATION: We herein report the case of an 83-year-old patient in whom a follow-up chest computed tomography scan, for a lingular consolidation, showed multifocal ground glass and consolidative opacities with areas of low attenuation, suggestive of exogenous lipid pneumonia. The patient had been on piascledine capsules (avocado/soybean unsaponifiables) for 20 years and had a hiatal hernia with documented gastroesophageal reflux disease. After thorough history taking, no other predisposing factors were found. The diagnosis was confirmed using oil red staining of bronchoalveolar lavage showing lipid-laden macrophages and extracellular lipid droplets. CONCLUSIONS: To our knowledge, this is the first case of ELP secondary to avocado/soybean unsaponifiables in the literature.

Immunoglobulin G4-related hypertrophic pachymeningitis: A case-oriented review.

Objective: Meningeal involvement in Immunoglobulin G (IgG)-4-related disease is rare and only described in case reports and series. Because a review into the disease is lacking, we present 2 cases followed by a literature review of IgG4-related hypertrophic pachymeningitis (IgG4-HP). Methods: Two IgG4-HP cases were reported, one involving the spinal cord and responding to surgical management and a second involving the brain and responding to Rituximab therapy. We then review clinical cases and case-series of histologically proven IgG4-HP that were published in the PubMed-NCBI database. Results: Forty-two case reports and 5 case-series were studied (60 patients, 20 women). The median age was 53. Eighteen patients had systemic involvement and 24 had single-organ IgG4-HP. Fifty-five percent of patients had an elevated serum IgG4. Treatment was surgical in 20/53 cases. Steroid therapy and immunosuppressors were effective in 85% and more than 90% of the cases, respectively. The rate of disease relapse was 42.1% after steroid therapy was discontinued. Discussion/conclusion: IgG4-HP is characterized by the lack of extra-neurologic organ-involvement and systemic signs. Histopathologic studies should be performed as it is crucial for diagnosis because serum markers are rarely informative. 18F-FDG positon tomography can be useful to characterize systemic forms. There is no specific CSF marker for IgG4-HP and the diagnostic value of CSF IgG4 levels needs to be studied with larger samples. We provide a treatment algorithm for IgG4-HP. Such treatment strategies rely on early surgery, steroids, and early immunosuppressive therapy to prevent neurologic complications.