Anti-PD-1 cancer immunotherapy induces central nervous system immune-related adverse events by microglia activation.

Cancer treatment with anti-PD-1 immunotherapy can cause central nervous system immune-related adverse events (CNS-irAEs). The role of microglia in anti-PD-1 immunotherapy-induced CNS-irAEs is unclear. We found that anti-PD-1 treatment of mice caused morphological signs of activation and major histocompatibility complex (MHC) class II up-regulation on microglia. Functionally, anti-PD-1 treatment induced neurocognitive deficits in mice, independent of T cells, B cells, and natural killer cells. Instead, we found that microglia mediated these CNS-irAEs. Single-cell RNA sequencing revealed major transcriptional changes in microglia upon anti-PD-1 treatment. The anti-PD-1 effects were mediated by anti-PD-1 antibodies interacting directly with microglia and were not secondary to peripheral T cell activation. Using a proteomics approach, we identified spleen tyrosine kinase (Syk) as a potential target in activated microglia upon anti-PD-1 treatment. Syk inhibition reduced microglia activation and improved neurocognitive function without impairing anti-melanoma effects. Moreover, we analyzed CNS tissue from a patient cohort that had received anti-PD-1 treatment. Imaging mass cytometry revealed that anti-PD-1 treatment of patients was associated with increased surface marker expression indicative of microglia activation. In summary, we identified a disease-promoting role for microglia in CNS-irAEs driven by Syk and provide an inhibitor-based approach to interfere with this complication after anti-PD-1 immunotherapy.

Spectrum of MRI findings in central nervous system affection in Lyme neuroborreliosis.

Affections of the central nervous system (CNS) rarely occur in Lyme neuroborreliosis (LNB). CNS manifestations can have residual neurological symptoms despite antibiotic treatment. We explored the spectrum of CNS affections in patients with LNB in a tertiary care center in a region endemic for Lyme borreliosis. We retrospectively included patients treated at a tertiary care center from January 2020-December 2021 fulfilling the case criteria for LNB as stated in the current German guideline on LNB. Clinical data, cerebrospinal fluid (CSF) findings and MRI imaging were collected. We included 35 patients with LNB, 24 with early manifestations and 11 with CNS-LNB. CNS-LNB patients had encephalomyelitis (n = 6) or cerebral vasculitis (n = 5). Patients with early LNB and CNS-LNB differed regarding albumin CSF/serum quotient and total protein in CSF. Duration from onset of symptoms until diagnosis was statistically significantly longer in patients with encephalomyelitis. MRI findings were heterogeneous and showed longitudinal extensive myelitis, perimedullar leptomeningeal enhancement, pontomesencephalic lesions or cerebral vasculitis. CNS-LNB can present with a variety of clinical syndromes and MRI changes. No clear pattern of MRI findings in CNS-LNB could be identified. The role of MRI consists in ruling out other causes of neurological symptoms.

Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.

BACKGROUND: Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far. OBJECTIVE: To analyze systematically the CSF profile in COVID-19. METHODS: Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease. CONCLUSIONS: The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

Autoantibody-associated psychiatric syndromes: a systematic literature review resulting in 145 cases.

BACKGROUND: Autoimmune encephalitis (AE) is an important consideration during the diagnostic work-up of secondary mental disorders. Indeed, isolated psychiatric syndromes have been described in case reports of patients with underlying AE. Therefore, the authors performed a systematic literature review of published cases with AE that have predominant psychiatric/neurocognitive manifestations. The aim of this paper is to present the clinical characteristics of these patients. METHODS: The authors conducted a systematic Medline search via Ovid, looking for case reports/series of AEs with antineuronal autoantibodies (Abs) against cell surface/intracellular antigens combined with predominant psychiatric/neurocognitive syndromes. The same was done for patients with Hashimoto encephalopathy/SREAT. Only patients with signs of immunological brain involvement or tumors in their diagnostic investigations or improvement under immunomodulatory drugs were included. RESULTS: We identified 145 patients with AE mimicking predominant psychiatric/neurocognitive syndromes. Of these cases, 64% were female, and the mean age among all patients was 43.9 (±22.1) years. Most of the patients had Abs against neuronal cell surface antigens (55%), most frequently against the NMDA-receptor (N = 46). Amnestic/dementia-like (39%) and schizophreniform (34%) syndromes were the most frequently reported. Cerebrospinal fluid changes were found in 78%, electroencephalography abnormalities in 61%, and magnetic resonance imaging pathologies in 51% of the patients. Immunomodulatory treatment was performed in 87% of the cases, and 94% of the patients responded to treatment. CONCLUSIONS: Our findings indicate that AEs can mimic predominant psychiatric and neurocognitive disorders, such as schizophreniform psychoses or neurodegenerative dementia, and that affected patients can be treated successfully with immunomodulatory drugs.

Cerebrospinal Fluid Biomarkers in Relation to MRZ Reaction Status in Primary Progressive Multiple Sclerosis.

The MRZ reaction (MRZR) comprises the three antibody indices (AIs) against measles, rubella, and varicella zoster virus, reflecting an intrathecal polyspecific B cell response highly specific for multiple sclerosis (MS). Thus, MRZR can be used to confirm a diagnosis of primary progressive MS (PPMS) but its pathophysiological and wider clinical relevance is unclear. This study aimed to investigate whether PPMS patients with a positive MRZR (MRZR+) differ from those with a negative MRZR (MRZR-) according to cerebrospinal fluid (CSF) biomarkers of B cell activity, neuroaxonal damage or glial activity, and clinical features. (1) Methods: In a multicenter PPMS cohort (n = 81) with known MRZR status, we measured B cell-activating factor (BAFF), chemokine CXC ligand 13 (CXCL-13), soluble B cell maturation antigen (sBCMA), soluble transmembrane activator and CAML interactor (sTACI), and chitinase-3-like protein 1 (CHI3L1) in the CSF with enzyme-linked immunosorbent assays (ELISAs). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were detected in serum and CSF using single molecule array (SIMOA) technology. (2) Results: MRZR+ patients (45.7% of all PPMS patients) revealed higher levels of NfL in CSF compared to MRZR- patients (54.3%). There were positive correlations between each of sBCMA, sTACI, and intrathecal immunoglobin G (IgG) synthesis. Additionally, NfL concentrations in serum positively correlated with those in CSF and those of GFAP in serum. However, MRZR+ and MRZR- patients did not differ concerning clinical features (e.g., age, disease duration, Expanded Disability Status Scale (EDSS) at diagnosis and follow-up); CSF routine parameters; CSF concentrations of BAFF, CXCL-13, sBCMA, sTACI, CHI3L1, and GFAP; or serum concentrations of GFAP and NfL. (3) Conclusions: In PPMS patients, MRZR positivity might indicate a more pronounced axonal damage. Higher levels of the soluble B cell receptors BCMA and transmembrane activator and CAML interactor (TACI) in CSF are associated with a stronger intrathecal IgG synthesis in PPMS.

Probable Autoimmune Depression in a Patient With Multiple Sclerosis and Antineuronal Antibodies.

BACKGROUND: In a subgroup of patients with mood disorders, clear-cut organic disorders are responsible for depressive symptoms (e.g., autoimmune diseases such as multiple sclerosis or systemic lupus erythematosus). In these cases, an organic affective disorder can be diagnosed. CASE PRESENTATION: The authors present the case of a 59-year-old male patient who developed a severe depressive episode over approximately 6 months and was, therefore, admitted to the hospital. In retrospect, he reported that, at age 39, he suffered from self-limiting sensory disturbances and muscle weakness in both legs. The current magnetic resonance imaging of his brain showed several conspicuous FLAIR-hyperintense supratentorial white matter lesions compatible with chronic inflammatory brain disease. Imaging of the spinal axis revealed no clear spinal lesions. Cerebrospinal fluid (CSF) analyses showed CSF-specific oligoclonal bands. Therefore, multiple sclerosis was diagnosed. Further CSF analyses, using tissue-based assays with indirect immunofluorescence on unfixed murine brain tissue, revealed a (peri-)nuclear signal and a strong neuritic signal of many neurons, especially on granule cells in the cerebellum, hippocampus, and olfactory bulb, as well as in the corpus callosum. Additionally, antinuclear antibody (ANA) titers of 1:12,800 and a lymphopenia were detected in blood tests. Further system clarification showed no suspicion of rheumatic or oncological disease. Anti-inflammatory treatment led to rapid and sustained improvement. CONCLUSION: The present patient suffered from a probable "autoimmune depression" in the context of newly diagnosed multiple sclerosis with typical MRI and CSF pathologies, alongside mild concomitant latent systemic autoimmune process (with high-titer ANAs and lymphopenia) and unknown antineuronal antibodies. The case report illustrates that a depressive syndrome suggestive of primary idiopathic depressive disorder may be associated with an autoimmune brain involvement. The detection of such organic affective disorders is of high clinical relevance for affected patients, as it enables alternative and more causal treatment approaches.

Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer.

BACKGROUND: People with urothelial carcinoma of the bladder are at risk for recurrence and progression following transurethral resection of a bladder tumour (TURBT). Mitomycin C (MMC) and Bacillus Calmette-Guérin (BCG) are commonly used, competing forms of intravesical therapy for intermediate- or high-risk non-muscle invasive (Ta and T1) urothelial bladder cancer but their relative merits are somewhat uncertain. OBJECTIVES: To assess the effects of BCG intravesical therapy compared to MMC intravesical therapy for treating intermediate- and high-risk Ta and T1 bladder cancer in adults. SEARCH METHODS: We performed a systematic literature search in multiple databases (CENTRAL, MEDLINE, Embase, Web of Science, Scopus, LILACS), as well as in two clinical trial registries. We searched reference lists of relevant publications and abstract proceedings. We applied no language restrictions. The latest search was conducted in September 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared intravesical BCG with intravesical MMC therapy for non-muscle invasive urothelial bladder cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the literature, extracted data, assessed risk of bias and rated the quality of evidence according to GRADE per outcome. In the meta-analyses, we used the random-effects model. MAIN RESULTS: We identified 12 RCTs comparing BCG versus MMC in participants with intermediate- and high-risk non-muscle invasive bladder tumours (published from 1995 to 2013). In total, 2932 participants were randomised. Time to death from any cause: BCG may make little or no difference on time to death from any cause compared to MMC (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.79 to 1.20; participants = 1132, studies = 5; 567 participants in the BCG arm and 565 in the MMC arm; low-certainty evidence). This corresponds to 6 fewer deaths (40 fewer to 36 more) per 1000 participants treated with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Serious adverse effects: 12/577 participants treated with BCG experienced serious non-fatal adverse effects compared to 4/447 participants in the MMC group. The pooled risk ratio (RR) is 2.31 (95% CI 0.82 to 6.52; participants = 1024, studies = 5; low-certainty evidence). Therefore, BCG may increase the risk for serious adverse effects compared to MMC. This corresponds to nine more serious adverse effects (one fewer to 37 more) with BCG. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Time to recurrence: BCG may reduce the time to recurrence compared to MMC (HR 0.88, 95% CI 0.71 to 1.09; participants = 2616, studies = 11, 1273 participants in the BCG arm and 1343 in the MMC arm; low-certainty evidence). This corresponds to 41 fewer recurrences (104 fewer to 29 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations, imprecision and inconsistency. Time to progression: BCG may make little or no difference on time to progression compared to MMC (HR 0.96, 95% CI 0.73 to 1.26; participants = 1622, studies = 6; 804 participants in the BCG arm and 818 in the MMC arm; low-certainty evidence). This corresponds to four fewer progressions (29 fewer to 27 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Quality of life: we found very limited data for this outcomes and were unable to estimate an effect size. AUTHORS' CONCLUSIONS: Based on our findings, BCG may reduce the risk of recurrence over time although the Confidence Intervals include the possibility of no difference. It may have no effect on either the risk of progression or risk of death from any cause over time. BCG may cause more serious adverse events although the Confidence Intervals once again include the possibility of no difference. We were unable to determine the impact on quality of life. The certainty of the evidence was consistently low, due to concerns that include possible selection bias, performance bias, given the lack of blinding in these studies, and imprecision.

The MRZ reaction and a quantitative intrathecal IgG synthesis may be helpful to differentiate between primary central nervous system lymphoma and multiple sclerosis.

Some patients with primary central nervous system lymphoma (PCNSL) may initially present with similar clinical, magnetic resonance imaging, and routine cerebrospinal fluid (CSF) findings as those observed in multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, appears to be the most specific CSF marker for MS. This study aimed to determine whether a positive MRZR and other routine CSF markers help differentiate between MS and PCNSL. Data regarding brain biopsy, CSF routine tests, cytopathological examination and immunophenotyping of CSF cells were assessed in 68 PCNSL patients. MRZR was determined, as possible, in PCNSL patients (n = 37) and in those with MS (n = 74; age and sex matched to PSCNL patients) and psychiatric disorders (PD; n = 78). Two stringency levels for a positive antibody index (AI) evaluation (AI ≥ 1.5 and 2.0) were applied, and MRZR was considered positive in cases with ≥ 2 positive AIs (MRZR-2). Using the common AI threshold of ≥ 1.5, MS patients exhibited positive MRZR-2 (58.1%) more frequently than PCNSL (8.1%) and PD patients (2.6%; p < 0.0001 for each comparison with the MS group) corresponding to a positive predictive value (PPV) of 89.6% and a negative predictive value (NPV) of 78.0%. On applying the stricter AI threshold of ≥ 2.0, 37.8% of MS patients were MRZR-2 positive; however, all patients with PCNSL and PD were MRZR-2 negative (p < 0.0001 for each comparison with the MS cohort) resulting in a PPV of 100% and an NPV of 71.4%. Consequently, a positive MRZR-2 result may contribute toward the distinction between MS and PCNSL owing to its high specificity and PPV for MS in the context of the present study. Among the other CSF parameters only a quantitative intrathecal IgG synthesis (present in 49.3% of MS patients but in none of the PCNSL or PD patients; p < 0.0001 for each comparison with the MS group) reliably indicated MS rather than PCNSL.

Prevalence of anti-SOX1 reactivity in various neurological disorders.

OBJECTIVES: Anti-SOX1 antibodies are associated with small cell lung cancer (SCLC) and predict a paraneoplastic etiology in Lambert-Eaton myasthenic syndrome (LEMS). In 2010, a study described these antibodies in a small cohort of putative non-paraneoplastic, immune-mediated neuropathies. In this respect, we investigated the seroprevalence and specificity of anti-SOX1 antibodies in a large cohort of neurological disorders. METHODS: Overall, serum samples of 1493 consecutive patients were screened for anti-SOX1 reactivity by an ELISA: 471 with well-defined neurological disorders (multiple sclerosis, motor neuron disease, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy), 185 with polyneuropathy (PNP) of unknown origin, and 837 with neurological syndromes of suspicious paraneoplastic etiology. These were compared to eight positive controls with definite paraneoplastic neurological syndromes (PNS) and 92 healthy individuals. We also collected demographic and clinical data, including well-characterized onconeural antibodies in anti-SOX1-positive patients. RESULTS: Fifteen patients (1.0%) showed anti-SOX1 reactivity: two with multiple sclerosis, two with PNP of unknown origin, and 11 suspicious PNS cases. Remarkably, 9/15 anti-SOX1-positive patients had a PNP. However, antibody concentrations were significantly lower compared to positive controls, and none additionally harbored well-characterized onconeural antibodies. During a follow-up of at least four years, only five patients had cancer: one thyroid, one Hodgkin lymphoma, two breast, and one patient had multiple malignancies - prostate, penis, cecum, liver, and non-small cell lung cancer. However, none had SCLC, typically associated with SOX1 antibodies. CONCLUSIONS: The seroprevalence of anti-SOX1 antibodies in patients with various neurological disorders is low. These patients predominantly have PNPs, which might represent a group of immune-mediated diseases.

"Non-classical" paraneoplastic neurological syndromes associated with well-characterized antineuronal antibodies as compared to "classical" syndromes - More frequent than expected.

OBJECTIVES: Paraneoplastic neurological syndromes (PNSs) are rare disorders in association with cancer and sub-divided into "classical" and "non-classical" syndromes according to a 2004 consensus paper proposed by a panel of PNS experts. "Classical" PNSs are regarded to account for the vast majority of cases. However, systematic reports on clinical PNS manifestations are rare. Therefore, we analyzed the spectrum of PNS in our clinic. METHODS: We retrospectively investigated medical records from consecutive patients diagnosed with definite PNS and serological evidence of well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2, and amphiphysin) analyzed between 1991 and 2014 in our clinic. RESULTS: Of the 50 patients identified with onconeural antibody-positive PNS, 28 patients (56.0%) had "classical" PNS, and 22 (44.0%) "non-classical" PNS. Subacute cerebellar degeneration was the most frequent "classical" syndrome, brainstem encephalitis and subacute sensorimotor neuronopathy the most frequent "non-classical" syndromes. Anti-Hu antibodies were most frequent in both groups. 86.1% of patients developed neurological symptoms before the cancer was known. No differences between "classical" and "non-classical" syndromes were detected with respect to age, tumor entities and median time to diagnosis. However, whereas most patients with "classical" syndromes were females, there was no gender predominance in patients with "non-classical" PNS and the latter had significantly more frequent peripheral neurological syndromes. CONCLUSIONS: The so-called "non-classical" PNSs in association with well-characterized onconeural antibodies were more common in our patient population than expected. Therefore, in neurological disorders of unclear etiology with a subacute onset and atypical presentation further diagnostic work-up including investigation of onconeural antibodies is necessary.

Massive exacerbation of multiple sclerosis after withdrawal and early restart of treatment with natalizumab.

We present a 46-year-old woman with a relapse of multiple sclerosis (MS) that began 3 months after withdrawal from long-term treatment with natalizumab. Shortly after restart of a single dose of natalizumab she developed a fulminant MS rebound with stupor and tetraparesis. Cerebral MRI showed massive progression in the number of lesions and tumefactive lesions with ring gadolinium-enhancement. Stereotactic brain biopsy revealed acute demyelination and B-cell dominated inflammation. The patient improved during therapeutic plasma exchange. We speculate that early restart of natalizumab in the case of a relapse may worsen disease evolution possibly by modifying regulatory immune effector processes during an inflammatory rebound phase. A restart of natalizumab in MS patients suffering from a recent relapse or with signs of active inflammation should be considered with caution.

VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro.

Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A165a and VEGF-A165b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A165a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeability, vasodilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A165b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A165b was detected in hippocampal and cortical neurons. VEGF-A165b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A165b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3-kinase activation. Recombinant human VEGF-A165b is a neuroprotective agent that effectively protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A165b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A165b expression suggests that non-isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons.