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Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral disease of the brain—caused by human polyomavirus 2. It affects patients whose immune system is compromised by a corresponding underlying disease or by drugs. Patients with an underlying lymphoproliferative disease have the worst prognosis with a mortality rate of up to 90%. Several therapeutic strategies have been proposed but failed to show any benefit so far. Therefore, the primary therapeutic strategy aims to reconstitute the impaired immune system to generate an effective endogenous antiviral response. Recently, anti-PD-1 antibodies and application of allogeneic virus-specific T cells demonstrated promising effects on the outcome in individual PML patients. This article aims to provide a detailed overview of the literature with a focus on these two treatment approaches. Supplementary Information The online version contains supplementary material available at 10.1007/s00415-021-10952-5.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a curative treatment for hematologic malignancies. Acute and chronic graft-versus-host disease (GvHD) are the major immune-mediated complications after alloHSCT. However, there is controversy whether neurologic complications after alloHSCT might represent manifestations of GvHD. We report three patients who acquired distinct, severe immune-mediated peripheral or central nervous system diseases after alloHSCT without other, concomitant GvHD manifestations. One patient had been diagnosed with B-cell chronic lymphocytic leukemia and two patients with high risk myelodysplastic syndrome. Patient #1 presented as LGI1- and GAD-IgG positive immune-mediated encephalitis, patient #2 was diagnosed with MOG-IgG positive encephalomyelitis, and patient #3 had chronic inflammatory polyneuropathy associated with SSA(Ro)-IgG positive Sjögren’s syndrome. 100% donor chimerism was detectable in the peripheral blood in all three. The specific antibodies were undetectable in donors’ and patients’ blood before alloHSCT suggesting that the antibodies had arisen from the transplanted donor immune system. Early intensive immunotherapy led to improvement of clinical symptoms and stability of the neurological disease, however, at the cost of losing the graft-versus-malignancy effect in one patient. In conclusion, we provide evidence of isolated, severe allo-immune diseases of the peripheral and central nervous system as complications of alloHSCT (“neuro-GvHD”). Interdisciplinary surveillance and thorough diagnostic work-up are needed for early diagnosis and treatment of neuro-immunologic complications after alloHSCT to improve the otherwise poor outcome.

Objective The interplay between systemic inflammation, activity of lymphoid organs and lymphoma activity in CD19-targeting chimeric antigen receptor (CAR)-T-cell immunotherapy, and its significance for response and toxicity, is not well defined. Methods Using serial 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), metabolic parameters of lymphoma and lymphoid organs were analyzed in ten patients receiving Tisagenlecleucel (an autologous CD19 CAR-T cell product) for relapsed or refractory diffuse large B-cell lymphoma. The prevalence and severity of toxicity (e.g., neurotoxicity) were noted. Results Achieving remission required early metabolic response (P = 0.0476). Early suppression of metabolic activity of lymphoid organs (spleen, P = 0.0368; lymph nodes, P = 0.0470) was associated with poor outcome. Lymphoma metabolic activity was significantly higher in patients with neurotoxicity (P = 0.0489). Conclusions Early metabolic changes in lymphoma lesions and off-target lymphoid organs parallel medium-term response to CAR-T-cell therapy. PET can identify patients at risk for severe toxicity.

Background Progressive multifocal leukoencephalopathy (PML) is caused by an opportunistic infection with JC polyoma virus (JCPyV) and mainly affects immunocompromised patients. It leads to pronounced demyelination of the central nervous system (CNS) resulting in severe disability or even death. Detection of JCPyV DNA in the cerebrospinal fluid (CSF) is usually accepted as proof for the diagnosis of PML. Routine CSF parameters, like CSF cell count, protein concentration, Qalbumin, or intrathecal immunoglobulin synthesis are mostly considered normal. However, this has not been investigated systematically. Methods We analyzed routine CSF parameters in a cohort of 108 PML patients that were treated at four different neurological centers in Germany. The patients exhibited different underlying conditions with natalizumab-treated multiple sclerosis (n = 54) and human immunodeficiency virus (HIV)-infection (n = 25) being the most frequent. The data were collected at the respective centers in accordance with local requirements and then jointly analyzed. The total PML cohort was compared with a control group of patients with normal pressure hydrocephalus (NPH) and idiopathic intracranial hypertension (IIH). Multiple sclerosis and HIV patients were additionally compared with their own non-PML control groups. Results The PML group showed an elevated cell count (p Conclusions This comprehensive, retrospective study on CSF diagnostic analysis in PML patients provides insight into the CSF of those patients. It demonstrates that CSF composition in PML patients may be specific for the underlying condition that predisposes for the development of PML and thus data have to be interpreted in this context.

Background The determination of kappa free light chains (KFLC) in cerebrospinal fluid (CSF) is an upcoming biomarker for the detection of an intrathecal immunoglobulin synthesis. Since renal function impairment leads to altered serum KFLC and albumin concentrations, interpretation of KFLC in CSF may be influenced by these parameters. Methods In this two-center study, the influence of renal function (according to the CKD-EPI creatinine equation) on KFLC and albumin concentrations was investigated in patients with “physiological” (n = 139), “non-inflammatory” (n = 146), and “inflammatory” (n = 172) CSF profiles in respect to the KFLC index and the evaluation in quotient diagrams in reference to the hyperbolic reference range (KFLC IF). Results All sample groups displayed declining KFLC indices and KFLC IF values with decreasing renal function ( P-values between Kappa(lim), suggesting possible false negative KFLC results. Conclusions The influence of renal function should be considered while interpreting KFLC results in patients with neuroinflammatory diseases. The interpretation of KFLC in quotient diagrams is less susceptible to renal function impairment than the KFLC index and should be preferentially used.

Background and ObjectivesAnti-IgLON5 disease is a recently described neurologic disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are underreported. We describe the frequency and types of movement disorders in a series of consecutive patients with this disease.MethodsIn this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by 3 experts in movement disorders.ResultsSeventy-two patients were included. In 41 (57%), the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least 1 movement disorder with a median of 3 per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients [72%]), chorea (24 [33%]), bradykinesia (20 [28%]), dystonia (19 [26%]), abnormal body postures or rigidity (18 [25%]), and tremor (15 [21%]). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients [32%]) including dystonia (13), myorhythmia (6), chorea (4), or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31 (43%) patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only 7 (13%) cases.DiscussionMovement disorders are a frequent and leading cause of initial neurologic consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

A growing body of evidence initially suggested that patients with multiple sclerosis (MS) might be more susceptible to coronavirus disease 2019 (COVID-19). Moreover, it was speculated that patients with MS treated with immunosuppressive drugs might be at risk to develop a severe diseases course after infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2). However, the recently published data have shown that MS patients do not have a higher risk for severe COVID-19. Although there is no indication that patients with MS and immunomodulatory/immunosuppressive therapy are generally at a higher risk of severe COVID-19, it is currently being emphasized that the hazards of poorly treated MS may outweigh the putative COVID-19 dangers. In this review, we discuss the challenges and considerations for MS patients in the COVID-19 pandemic.

The reactivation of human JC polyoma virus (JCPyV) results in lytic infection of oligodendrocytes and neuronal cells. The corresponding clinical picture is called progressive multifocal leukoencephalopathy (PML) and results mostly from a disease-related or drug-induced immunosuppression. The opportunistic brain infection leads to a progressive demyelination of multiple areas of the central nervous system. Patients can present with various neurological deficits ranging from slight motoric symptoms to marked aphasia or reduced vigilance. Currently, there is no effective causal therapy for PML. Survival depends on the ability to achieve timely immune reconstitution. If the immune system cannot be restored, PML progresses rapidly and often ends fatally within months. Recently, some evidence for positive response has been reported in patients treated with immune checkpoint inhibitor therapy. Here, we provide a case series of three PML patients with underlying hematological malignancies who were treated with anti-PD-1-antibody pembrolizumab at Hannover Medical School. All patients received an extensive diagnostic follow-up including cerebrospinal fluid analysis, brain imaging, and lymphocyte-phenotyping via flow cytometry. Our patients had very different outcomes, with the only patient showing a specific anti-JCPyV immune response in the sense of an increased JCPyV antibody index clearly benefiting most from the treatment. Our results partly support the hypothesis that anti-PD-1 therapy may represent a promising treatment option for patients with PML. However, there is a current lack of pre-therapeutic stratification regarding the therapeutic response rates. Before larger studies can be initiated to further evaluate the efficacy of anti-PD-1 antibodies in PML, it is imperative to develop a reliable strategy for selecting suitable patients.

Many neuroimmunological diseases, such as encephalopathy, encephalitis, myelitis and acute disseminated encephalomyelitis (ADEM) have occurred more frequently after infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which indicates a parainfectious or postinfectious association. The most likely underlying mechanisms include virus-triggered overactivation of the immune system with hyperinflammation and cytokine storm but potentially also the development of specific autoantibodies against central nervous system (CNS) tissue. These were predominantly detected in the cerebrospinal fluid of severely ill coronavirus disease 2019 (COVID-19) patients. In contrast, direct damage after invasion of SARS-CoV‑2 into the brain and spinal cord does not seem to play a relevant role. Susceptibility to infection with SARS-CoV‑2 in patients with multiple sclerosis, myasthenia or other neuroimmunological diseases including the risk for severe disease courses, is not determined by the administered immunotherapy but by known risk factors, such as age, comorbidities and the disease-related degree of disability. Therefore, immunotherapy in these patients should not be delayed or discontinued. The contribution of neuroimmunological mechanisms to long-term sequelae after survival of a COVID-19 illness, such as fatigue, impairment of memory, sleep dysfunction or anxiety, will require long-term clinical follow-up, preferentially in COVID-19 register studies.Zahlreiche neuroimmunologische Krankheitsbilder wie Enzephalopathien, Enzephalitiden, Myelitiden oder ADEM (akute disseminierte Enzephalomyelitis) sind nach einer Infektion mit SARS-CoV‑2 („severe acute respiratory syndrome coronavirus 2“) gehäuft aufgetreten, was für einen para- oder postinfektiösen Zusammenhang spricht. Ursächlich ist wahrscheinlich eine virusgetriggerte Überaktivierung des Immunsystems mit Hyperinflammation und Zytokin-Sturm, aber möglicherweise auch die Bildung spezifischer Autoantikörper gegen Gewebe des Zentralnervensystems, die sich vor allem im Liquor schwerkranker COVID-19(„coronavirus disease 2019“)-Patienten finden lassen. Eine direkte Schädigung durch die Invasion von SARS-CoV‑2 ins Gehirn oder Rückenmark scheint keine relevante Rolle zu spielen. Bei Patienten mit Multipler Sklerose, Myasthenie oder anderen neuroimmunologischen Krankheitsbildern wird die Anfälligkeit für eine SARS-CoV-2-Infektion sowie das Risiko eines schweren Verlaufs nicht durch die immunmodulierende Therapie bestimmt, sondern durch bekannte Risikofaktoren wie Alter, Komorbiditäten und den krankheitsbedingten Grad der Behinderung. Immuntherapien sollten bei diesen Patienten daher nicht verschoben oder pausiert werden. Inwieweit neuroimmunologische Mechanismen auch für Langzeitfolgen nach überstandener COVID-19-Erkrankung – wie Fatigue, Gedächtnis‑, Schlaf- oder Angststörungen – verantwortlich sind, werden klinische Verlaufsuntersuchungen u. a. in COVID-19-Registerstudien zeigen.

ZusammenfassungZahlreiche neuroimmunologische Krankheitsbilder wie Enzephalopathien, Enzephalitiden, Myelitiden oder ADEM (akute disseminierte Enzephalomyelitis) sind nach einer Infektion mit SARS-CoV‑2 („severe acute respiratory syndrome coronavirus 2“) gehäuft aufgetreten, was für einen para- oder postinfektiösen Zusammenhang spricht. Ursächlich ist wahrscheinlich eine virusgetriggerte Überaktivierung des Immunsystems mit Hyperinflammation und Zytokin-Sturm, aber möglicherweise auch die Bildung spezifischer Autoantikörper gegen Gewebe des Zentralnervensystems, die sich vor allem im Liquor schwerkranker COVID-19(„coronavirus disease 2019“)-Patienten finden lassen. Eine direkte Schädigung durch die Invasion von SARS-CoV‑2 ins Gehirn oder Rückenmark scheint keine relevante Rolle zu spielen. Bei Patienten mit Multipler Sklerose, Myasthenie oder anderen neuroimmunologischen Krankheitsbildern wird die Anfälligkeit für eine SARS-CoV-2-Infektion sowie das Risiko eines schweren Verlaufs nicht durch die immunmodulierende Therapie bestimmt, sondern durch bekannte Risikofaktoren wie Alter, Komorbiditäten und den krankheitsbedingten Grad der Behinderung. Immuntherapien sollten bei diesen Patienten daher nicht verschoben oder pausiert werden. Inwieweit neuroimmunologische Mechanismen auch für Langzeitfolgen nach überstandener COVID-19-Erkrankung – wie Fatigue, Gedächtnis‑, Schlaf- oder Angststörungen – verantwortlich sind, werden klinische Verlaufsuntersuchungen u. a. in COVID-19-Registerstudien zeigen.

Neurology: Neuroimmunology & Neuroinflammation ; official journal of the American Academy of Neurology 8(6), e1062 (2021). doi:10.1212/NXI.0000000000001062, Published by Lippincott Williams & Wilkins, Philadelphia, Pa.

Therapy with immune checkpoint inhibitors (ICIs) has improved overall survival and cancer-related morbidity of cancer treatment even in cancer entities with poor prognosis. Since the approval of the first ICI, ipilimumab, for treatment of advanced melanoma by the Food and Drug Administration (FDA) in 2011, the spectrum of indications and approved ICIs has grown, rapidly. Up to now, seven different ICIs for more than 20 indications are available. However, their mechanisms of action can lead to immune-related adverse events (irAEs). In particular, neurological irAEs are clinically relevant. Although they are rare, an early and accurate diagnosis is challenging and neurological disease course and sequelae are potentially fatal. Between 08/2017 and 03/2020, 31 patients received ICI treatment at Hannover Medical School and presented with neurological adverse events (N-irAEs). Treated malignancies were metastatic melanoma, bronchial carcinoma, and urothelial cell carcinoma. All patients received comprehensive neurological diagnostics including clinical examination and magnetic resonance imaging (MRI). Cerebrospinal fluid (CSF) analysis was obtained in 21 patients and electroneurography was performed in 22 patients. Although N-irAEs were suspected in all 31 patients, 11 patients had other conditions leading to neurological symptoms including tumor metastases in seven patients and hemorrhagic or ischemic stroke in four patients. In the following, these patients are referred to as the differential diagnosis (DD) group. Patients with N-irAEs suffered from immune mediated neuropathy (9/20), myositis and/or myasthenic syndrome (6/20), or encephalitis/cerebellitis (5/20). Except for cell count, CSF results did not differ between the N-irAEs and the DD group. Symptoms related to N-irAEs are rather unspecific potentially mimicking other tumor-related symptoms such as metastases. Patients with malignancy are predominantly not treated by neurologists. Because of the complexity of neurological symptoms, detailed neurological investigations in specialized institutions are necessary in patients with new neurological symptoms and need to be critically discussed with treating oncologists.

Background: Progressive multifocal leukoencephalopathy (PML) is caused by an opportunistic infection with JC polyoma virus (JCPyV) and mainly affects immunocompromised patients. It leads to pronounced demyelination of the central nervous system (CNS) resulting in severe disability or even death. Detection of JCPyV DNA in the cerebrospinal fluid (CSF) is usually accepted as proof for the diagnosis of PML. Values from routine CSF parameters, like CSF cell count, protein concentration, Qalbumin levels, or intrathecal immunoglobulin synthesis are mostly considered as normal; however, this has not been investigated systematically. Methods: We therefore analyzed those standard CSF parameters in a cohort of 108 PML patients that were treated at four different neurological centers in Germany. The patients exhibited different underlying conditions with natalizumab treatment in multiple sclerosis (n=54) and human immunodeficiency virus (HIV)-infection (n=25) being the most frequent. The data were collected at the respective centers in accordance with local requirements and then jointly analyzed. The results of the total PML cohort were compared with a control group of patients with normal pressure hydrocephalus (NPH) and idiopathic intracranial hypertension (IIH) or an HIV group without PML, respectively. Results: The PML group showed an elevated cell count (pConclusions: This comprehensive, retrospective study on diagnostic results in PML patients provides insight into the CSF findings in patients with PML. It demonstrates that CSF changes in PML patients may be specific for the underlying condition that predisposes for the development of PML and thus data have to be interpreted in this context.

ObjectiveThe use of alemtuzumab, a humanized monoclonal anti-CD52 antibody has changed the therapy of highly active relapsing-remitting MS (RRMS). Alemtuzumab infusion depletes most lymphocytes in peripheral blood, whereas differential recovery of immune cells, probably those with a less CNS-autoreactive phenotype, is supposed to underlie its long-lasting effects. To determine whether alemtuzumab significantly reduces immunoglobulin levels in blood and CSF of treated patients, we analyzed blood and CSF samples of 38 patients with MS treated with alemtuzumab regarding changes in immunoglobulin levels.MethodsBlood and CSF samples of patients were collected at the beginning of alemtuzumab treatment and at 12, 24, and 36 months after the first administration of the drug. Specimens were analyzed regarding immunoglobulin concentrations in blood and CSF.ResultsWe observed significant and dose-dependent reductions of immunoglobulin levels (IgG, IgM, and IgA) in serum and CSF 12 and 24 months following 2 courses of alemtuzumab. Patients with persistent or returning disease activity who were treated with a third course of alemtuzumab exhibited even further decrease in IgG levels compared with matched controls treated twice. Here, alemtuzumab-treated patients with IgG levels below the lower limits of normal were more susceptible to pneumonia, sinusitis, and otitis, whereas upper respiratory tract and urinary tract infections were not associated therewith.ConclusionsOur results suggest to monitor IgG levels for safety reasons in patients treated with alemtuzumab—in particular when additional treatment courses are required—and to consider preventive action in critical cases.Classification of evidenceThis study provides Class IV evidence that for patients with RRMS alemtuzumab reduces immunoglobulin levels.

Background: Metastatic spread into the cerebrospinal fluid (CSF) represents a severe complication of malignant disease with poor prognosis. Although early diagnosis is crucial, broad spectrums of clinical manifestations, and pitfalls of magnetic resonance imaging (MRI) and CSF diagnostics can be challenging. Data are limited how CSF parameters and MRI findings relate to each other in patients with leptomeningeal metastasis. Methods: Patients with malignant cells in CSF cytology examination diagnosed between 1998 and 2016 at the Department of Neurology in the Hannover Medical School were included in this study. Clinical records, MRI findings and CSF parameters were retrospectively analyzed. Results: One hundred thirteen patients with leptomeningeal metastasis were identified. Seventy-six patients (67%) suffered from a solid malignancy while a hematological malignancy was found in 37 patients (33%). Cerebral signs and symptoms were most frequently found (78% in solid vs. 49% in hematological malignancies) followed by cranial nerve impairment (26% in solid vs. 46% in hematological malignancies) and spinal symptoms (26% in solid vs. 27% in hematological malignancies). In patients with malignant cells in CSF MRI detected signs of leptomeningeal metastasis in 62% of patients with solid and in only 33% of patients with hematological malignancies. Investigations of standard CSF parameters revealed a normal CSF cell count in 21% of patients with solid malignancies and in 8% of patients with hematological malignancies. Blood-CSF-barrier dysfunction was found in most patients (80% in solid vs. 92% in hematological malignancies). Elevated CSF lactate levels occurred in 68% of patients in solid and in 48% of patients with hematological malignancies. A high number of patients (30% in solid vs. 26% in hematological malignancies) exhibited oligoclonal bands in CSF. Significant correlations between the presence of leptomeningeal enhancement demonstrated by MRI and CSF parameters (cell count, lactate levels, and CSF/Serum albumin quotient) were not found in both malignancy groups. Conclusion: CSF examination is helpful to detect leptomeningeal metastasis since the diagnosis can be challenging especially when MRI is negative. CSF cytological investigation is mandatory whenever leptomeningeal metastasis is suspected, even when CSF cell count is normal.

Background: The humanized anti-α4 integrin monoclonal antibody natalizumab has proven to be very effective in patients with highly active relapsing-remitting multiple sclerosis (MS), but harbors the risk of progressive multifocal leukoencephalopathy (PML). Recently, new therapeutic options have become available for patients with high risk of developing PML while on natalizumab treatment. One of these new therapeutics is the oral synthetic purine analogue cladribine. In order to determine whether therapy with cladribine is effective and safe in patients with MS who previously had been treated with natalizumab, we analyzed clinical, radiological, and laboratory data of 17 patients whose disease modifying treatment (DMT) was switched from natalizumab to cladribine. Methods: A total of 17 patients with prior natalizumab treatment were switched to a DMT with cladribine because of a John Cunningham virus (JCV) antibody index above 1.5 ( N = 13), ongoing disease activity ( N = 6), magnetic resonance imaging (MRI) disease activity ( N = 4), or patients preference ( N = 2). A chart review and follow up of those patients was performed. In addition to MRI and laboratory data, clinical data regarding MS relapses and disease progression or possible adverse events were analyzed. Results: The median duration of cladribine treatment between February 2018 and April 2019 amounted to 9.7 months (range: 1.5–15 months). None of our 17 patients presented with a clinical relapse. Only two patients showed a new T2 lesion on brain MRI, but without any signs of PML. As expected, reduction of lymphocyte count was frequent in cladribine-treated patients, but only four patients exhibited lymphopenia grade 2 (500–800/µl). Conclusions: In our cohort the switch from natalizumab to cladribine treatment was effective and safe. So far, no serious adverse events other than lymphopenia have been observed, especially no cases of PML.

Progressive multifocal leukoencephalopathy (PML), caused by infection with John Cunningham polyoma virus (JCPyV) in immune-compromised patients, is a serious demyelinating disease of the central nervous system. This disease often leads to major neurological impairments and consecutive disability. No effective treatment for PML has been found as yet. As JCPyV-PCR of the cerebrospinal fluid (CSF) may be negative in some cases, a reliable diagnosis might prove to be difficult as well. So far, two case reports suggested CSF-tau to be a promising biomarker for PML. Our study included 10 patients with assured diagnosis of PML and varying underlying diseases. In all but one the CSF-tau concentration was normal. Our results indicate that CSF-tau is not an appropriate biomarker for PML. peerReviewed

ObjectiveProgressive multifocal leukoencephalopathy (PML) is a devastating demyelinating opportunistic infection of the brain caused by the ubiquitously distributed JC polyomavirus. There are no established treatment options to stop or slow down disease progression. In 2018, a case series of 3 patients suggested the efficacy of allogeneic BK virus-specific T-cell (BKV-CTL) transplantation.MethodsTwo patients, a bilaterally lung transplanted patient on continuous immunosuppressive medication since 17 years and a patient with dermatomyositis treated with glucocorticosteroids, developed definite PML according to AAN diagnostic criteria. We transplanted both patients with allogeneic BKV-CTL from partially human leukocyte antigen (HLA) compatible donors. Donor T cells had directly been produced from leukapheresis by the CliniMACS IFN-γ cytokine capture system. In contrast to the previous series, we identified suitable donors by HLA typing in a preexamined registry and administered 1 log level less cells.ResultsBoth patients' symptoms improved significantly within weeks. During the follow-up, a decrease in viral load in the CSF and a regression of the brain MRI changes occurred. The transfer seemed to induce endogenous BK and JC virus-specific T cells in the host.ConclusionsWe demonstrate that this optimized allogeneic BKV-CTL treatment paradigm represents a promising, innovative therapeutic option for PML and should be investigated in larger, controlled clinical trials.Classification of EvidenceThis study provides Class IV evidence that for patients with PML, allogeneic transplant of BKV-CTL improved symptoms, reduced MRI changes, and decreased viral load.

Approval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic is a challenge for all participants in the healthcare system. At the beginning of the pandemic, many physicians asked themselves what risk their patients, especially those with chronic diseases, were exposed to. We present an overview of all patients with multiple sclerosis (MS) and SARS-CoV-2 infection published in the literature so far. In total, there are publications on 873 SARS-CoV-2 positive MS patients and information on the outcome can be given for 700 patients. With regard to the different disease modifying therapies (DMTs), by far the most cases were described under anti-CD20 treatment (n = 317). The mortality rate of all MS patients was 4% and a further 3% required invasive or non-invasive ventilation. When looking at the severe and fatal cases, it is particularly noticeable that patients without DMTs, with previous cardiovascular diseases, or with a severe degree of disability are at risk. Immunosuppressive therapy itself does not appear to be a substantial risk factor. Rather, it is reasonable to assume that the therapies could be protective, either directly, by mitigating the cytokine storm, or indirectly, by reducing the disease activity of MS.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the management of various cancers with previously poor prognosis. Despite its great efficacy, the therapy is associated with a wide spectrum of immune-related adverse events (irAE) including neurological symptoms which can affect all parts of the central and peripheral nervous system. Even though these events are rare, they are of high relevance as the rate of residual symptoms or even fatal outcomes is remarkable. To provide a detailed overview of neurological adverse events associated with immune checkpoint-inhibitor therapy we conducted a literature search. While focusing on ipilimumab, nivolumab, and pembrolizumab therapy, all available case reports as well as larger case series and clinical trials have been considered. Eighty-two case reports about checkpoint-inhibitor therapy induced symptoms of the peripheral nervous system have been published, while only 43 case reports addressed central nervous system abnormalities. The frequency of immune checkpoint-inhibitor therapy inducing neurological adverse events is about 1% in larger studies. Especially neuromuscular adverse events exhibit distinct clinical and diagnostic characteristics. Additionally, several affected patients presented with overlap-syndromes, which means that symptoms and diagnostic findings indicating myositis, myasthenia gravis, and neuropathy were present in one individual patient at the same time. Thus, neurological and particularly neuromuscular adverse events of immune checkpoint-inhibitor therapy may constitute a new disease entity.

Ocrelizumab, a humanized monoclonal anti-CD20 antibody, has shown pronounced effects in reduction of disease activity in multiple sclerosis (MS) patients and has recently been approved for the treatment of patients with relapsing MS (RMS) and primary progressive MS (PPMS). CD20 is mainly expressed by B cells, but a subset of T cells (CD3+CD20+ T cells) also expresses CD20, and these CD20+ T cells are known to be a highly activated cell population. The blood of MS patients was analyzed with multicolor flow cytometry before and two weeks after treatment with ocrelizumab regarding the phenotype of peripheral blood mononuclear cells. CD20-expressing CD3+ T cells were found in blood samples of all MS patients, accounted for 2.4% of CD45+ lymphocytes, and constituted a significant proportion (18.4%) of all CD20+ cells. CD3+CD20+ T cells and CD19+CD20+ B cells were effectively depleted two weeks after a single administration of 300 mg ocrelizumab. Our results demonstrate that treatment with ocrelizumab does not exclusively target B cells, but also CD20+ T cells, which account for a substantial amount of CD20-expressing cells. Thus, we speculate that the efficacy of ocrelizumab might also be mediated by the depletion of CD20-expressing T cells.

Background & Aims Biliary atresia (BA) is a rare disease in infants, with unknown mechanisms of pathogenesis. It is characterized by hepatobiliary inflammatory, progressive destruction of the biliary system leading to liver fibrosis, and deterioration of liver function. Interleukin (IL) 17A promotes inflammatory and autoimmune processes. We studied the role of IL17A and cells that produce this cytokine in a mouse model of BA and in hepatic biopsy samples from infants with BA. Methods We obtained peripheral blood and liver tissue specimens from 20 patients with BA, collected at the time of Kasai portoenterostomy, along with liver biopsies from infants without BA (controls). The tissue samples were analyzed by reverse transcription quantitative polymerase chain reaction (PCR), in situ PCR, and flow cytometry analyses. BA was induced in balb/cAnNCrl mice by rhesus rotavirus infection; uninfected mice were used as controls. Liver tissues were collected from mice and analyzed histologically and by reverse transcriptase PCR; leukocytes were isolated, stimulated, and analyzed by flow cytometry and PCR analyses. Some mice were given 3 intraperitoneal injections of a monoclonal antibody against IL17 or an isotype antibody (control). Results Livers from rhesus rota virus−infected mice with BA had 7-fold more Il17a messenger RNA than control mice ( P = .02). γδ T cells were the exclusive source of IL17; no T-helper 17 cells were detected in livers of mice with BA. The increased number of IL17a-positive γδ T cells liver tissues of mice with BA was associated with increased levels of IL17A, IL17F, retinoid-orphan-receptor C, C-C chemokine receptor 6, and the IL23 receptor. Mice that were developing BA and given antibodies against IL17 had lower levels of liver inflammation and mean serum levels of bilirubin than mice receiving control antibodies (191 μmol/L vs 78 μmol/L, P = .002). Liver tissues from patients with BA had 4.6-fold higher levels of IL17 messenger RNA than control liver tissues ( P = .02). Conclusions In livers of mice with BA, γδ T cells produce IL17, which is required for inflammation and destruction of the biliary system. IL17 is up-regulated in liver tissues from patients with BA, compared with controls, and might serve as a therapeutic target.