[A man in his fifties with near-syncope episodes and persistent dizziness]. / En mann i 50-årene med nærbesvimelser og vedvarende svimmelhet.

BACKGROUND: A previously healthy male patient in his fifties presented with subacute onset of severe, diffuse dysautonomia with orthostatic hypotension as the main symptom. A lengthy interdisciplinary workup revealed a rare condition. CASE PRESENTATION: Over the course of a year, the patient was twice admitted to the local department of internal medicine because of severe hypotension. Testing showed severe orthostatic hypotension with normal cardiac function tests and no apparent underlying cause. On referral to neurological examination, symptoms of a broader autonomic dysfunction were discovered, with symptoms of xerostomia, irregular bowel habits, anhidrosis and erectile dysfunction. The neurological examination was normal, except for bilateral mydriatic pupils. The patient was tested for ganglionic acetylcholine receptor (gAChR) antibodies. A strong positive result confirmed the diagnosis of autoimmune autonomic ganglionopathy. There were no signs of underlying malignancy. The patient received induction treatment with intravenous immunoglobulin and later maintenance treatment with rituximab, resulting in significant clinical improvement. INTERPRETATION: Autoimmune autonomic ganglionopathy is a rare but likely underdiagnosed condition, which may cause limited or widespread autonomic failure. Approximately half of the patients have ganglionic acetylcholine receptor antibodies in serum. It is important to diagnose the condition as it can cause high morbidity and mortality, but responds to immunotherapy.

Serum neurofilament as a predictor of 10-year grey matter atrophy and clinical disability in multiple sclerosis: a longitudinal study.

BACKGROUND: The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in multiple sclerosis (MS) is still unclear. OBJECTIVE: Investigate the relation between sNfL levels over a 2-year period in patients with relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years. METHODS: 85 patients, originally enrolled in a multicentre, randomised trial of ω-3 fatty acids, participated in a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24. The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained using FreeSurfer. RESULTS: Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or recently present) predicted lower total (ß=-0.399, p=0.040) and deep (ß=-0.556, p=0.010) GM volume, lower mean cortical thickness (ß=-0.581, p=0.010) and higher T2 lesion count (ß=0.498, p=0.018). Of the clinical outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant hand Nine-Hole Peg Test (ß=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions present or recently present) did not predict GM atrophy or disability progression. CONCLUSION: Higher sNfL levels during periods of active inflammation predicted more GM atrophy and specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM atrophy is mainly due to neuroaxonal degradation within new lesions.

CDR2L Is the Major Yo Antibody Target in Paraneoplastic Cerebellar Degeneration.

The pathogenesis of Yo-mediated paraneoplastic cerebellar degeneration (PCD) is unclear. We applied cerebrospinal fluid and serum from PCD patients as well as CDR2 and CDR2L antibodies to neuronal tissue, cancer cell lines, and cells transfected with recombinant CDR2 and CDR2L to elucidate which is the major antigen of Yo antibodies. We found that Yo antibodies bound endogenous CDR2L, but not endogenous CDR2. However, Yo antibodies can bind the recombinant CDR2 protein used in routine clinical testing for these antibodies. Because Yo antibodies only bind endogenous CDR2L, we conclude that CDR2L is the major antigen of Yo antibodies in PCD. ANN NEUROL 2019;86:316-321.

Optimization of Receptor Occupancy Assays in Mass Cytometry: Standardization Across Channels with QSC Beads.

Receptor occupancy, the ratio between amount of drug bound and amount of total receptor on single cells, is a biomarker for treatment response to therapeutic monoclonal antibodies. Receptor occupancy is traditionally measured by flow cytometry. However, spectral overlap in flow cytometry limits the number of markers that can be measured simultaneously. This restricts receptor occupancy assays to the analysis of major cell types, although rare cell populations are of potential therapeutic relevance. We therefore developed a receptor occupancy assay suitable for mass cytometry. Measuring more markers than currently available in flow cytometry allows simultaneous receptor occupancy assessment and high-parameter immune phenotyping in whole blood, which should yield new insights into disease activity and therapeutic effects. However, varying sensitivity across the mass cytometer detection range may lead to misinterpretation of the receptor occupancy when drug and receptor are detected in different channels. In this report, we describe a method for optimization of mass cytometry receptor occupancy measurements by using antibody-binding quantum simply cellular (QSC) beads for standardization across channels with different sensitivities. We evaluated the method in a mass cytometry-based receptor occupancy assay for natalizumab, a therapeutic antibody used in multiple sclerosis treatment that binds to α4-integrin, which is expressed on leukocyte cell surfaces. Peripheral blood leukocytes from a treated patient were stained with a panel containing metal-conjugated antibodies for detection of natalizumab and α4-integrin. QSC beads with known antibody binding capacity were stained with the same metal-conjugated antibodies and were used to standardize the signal intensity in the leukocyte sample before calculating receptor occupancy. We found that QSC bead standardization across channels corrected for sensitivity differences for detection of drug and receptor and generated more accurate results than observed without standardization. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

The kynurenine pathway and cognitive performance in community-dwelling older adults. The Hordaland Health Study.

INTRODUCTION: Tryptophan, its downstream metabolites in the kynurenine pathway and neopterin have been associated with inflammation and dementia. We aimed to study the associations between plasma levels of these metabolites and cognitive function in community-dwelling, older adults. METHODS: This cross-sectional study included 2174 participants aged 70-72 years of the community-based Hordaland Health Study. Tryptophan, kynurenine, neopterin and eight downstream kynurenines were measured in plasma. Kendrick Object Learning Test (KOLT), Digit Symbol Test (DST) and the Controlled Oral Word Association Test (COWAT) were all outcomes in standardized Zellner's regression. The Wald test of a composite linear hypothesis of an association with each metabolite was adjusted by the Bonferroni method. Age, body mass index, C-reactive protein, depressive symptoms, diabetes, education, glomerular filtration rate, hypertension, previous myocardial infarction, prior stroke, pyridoxal 5'phosphate, sex and smoking were considered as potential confounders. RESULTS: Higher levels of the kynurenine-to-tryptophan ratio (KTR) and neopterin were significantly associated with poorer, overall cognitive performance (p < 0.002). Specifically, KTR was negatively associated with KOLT (ß -0.08, p = 0.001) and COWAT (ß -0.08, p = 0.001), but not with DST (ß -0.03, p = 0.160). This pattern was also seen for neopterin (KOLT: ß -0.07; p = 0.001; COWAT: ß -0.06, p = 0.010; DST: ß -0.01, p = 0.800). The associations were not confounded by the examined variables. No significant associations were found between the eight downstream kynurenines and cognition. CONCLUSION: Higher KTR and neopterin levels, biomarkers of cellular immune activation, were associated with reduced cognitive performance, implying an association between the innate immune system, memory, and language.

Cerebellar degeneration-related proteins 2 and 2-like are present in ovarian cancer in patients with and without Yo antibodies.

BACKGROUND: Cerebellar degeneration-related protein 2 (CDR2) has been presumed to be the main antigen for the onconeural antibody Yo, which is strongly associated with ovarian cancer and paraneoplastic cerebellar degeneration (PCD). Recent data show that Yo antibodies also target the CDR2-like protein (CDR2L). We, therefore, examined the expression of CDR2 and CDR2L in ovarian cancer tissue from patients with and without Yo antibodies and from various other cancerous and normal human tissues. METHODS: Ovarian cancer tissue and serum samples from 16 patients were included in the study (four with anti-Yo and PCD, two with anti-Yo without PCD, five with only CDR2L antibodies, and five without onconeural antibodies). Clinical data were available for all patients. The human tissues were examined by western blot and immunohistochemistry using rabbit CDR2 and CDR2L antibodies. RESULTS: Ovarian cancers from all 16 patients expressed CDR2 and CDR2L proteins. Both proteins were also present in normal and cancer tissue from mammary tissue, kidney, ovary, prostate, and testis. CONCLUSION: CDR2L is present in ovarian cancers from patients with and without Yo antibodies as was shown previously for CDR2. In addition, both CDR2 and CDR2L proteins are more widely expressed than previously thought, both in normal and cancerous tissues.

[Multiple sclerosis - a mitochondria-mediated disease?] / Multippel sklerose ­ en mitokondriemediert sykdom?

BACKGROUND Mitochondria play an important role in the pathogenesis of various neurodegenerative disorders, including Parkinson's disease. Neurodegenerative changes occur early in the course of multiple sclerosis (MS). This article aims to present information on a possible association between mitochondrial dysfunction and multiple sclerosis.MATERIAL AND METHOD The article is based on original and review articles selected following a literature search in PubMed, restricted to articles written in English, and concluded in May 2016. The literature search resulted in a total of 2276 articles. After a discretionary evaluation by the authors, 71 articles were read in full. Of these, 19 were used as references. In addition, we included 15 articles from reference lists and seven from the authors' own literature archive.RESULTS Mitochondrial changes have been demonstrated in affected areas of the brains of patients with MS. Although some of the changes may be attributed to mitochondrial damage that is secondary to inflammation, others may be compensatory due to the increased energy demands of demyelinated axons. The type of mitochondrial damage varies and is dependent on the pathology that triggers it.INTERPRETATION Mitochondrial damage secondary to inflammation, combined with increased energy demands secondary to demyelination, may result in a chronic energy deficiency in the central nervous system. This in turn may lead to neurodegeneration. Improved knowledge of the role of mitochondria in MS, both secondary to inflammation and possibly as a direct contributor to neurodegeneration, may provide a better understanding of the pathogenesis of the disease and perhaps contribute to new treatment options.

Paraneoplastic CDR2 and CDR2L antibodies affect Purkinje cell calcium homeostasis.

Paraneoplastic cerebellar degeneration (PCD) is characterized by loss of Purkinje cells (PCs) associated with progressive pancerebellar dysfunction in the presence of onconeural Yo antibodies. These antibodies recognize the cerebellar degeneration-related antigens CDR2 and CDR2L. Response to PCD therapy is disappointing due to limited understanding of the neuropathological mechanisms. Here, we report the pathological role of CDR antibodies on the calcium homeostasis in PCs. We developed an antibody-mediated PCD model based on co-incubation of cerebellar organotypic slice culture with human patient serum or rabbit CDR2 and CDR2L antibodies. The CDR antibody-induced pathology was investigated by high-resolution multiphoton imaging and biochemical analysis. Both human and rabbit CDR antibodies were rapidly internalized by PCs and led to reduced immunoreactivity of calbindin D28K (CB) and L7/Pcp-2 as well as reduced dendritic arborizations in the remaining PCs. Washout of the CDR antibodies partially recovered CB immunoreactivity, suggesting a transient structural change in CB calcium-binding site. We discovered that CDR2 and CB co-immunoprecipitate. Furthermore, the expression levels of voltage-gated calcium channel Cav2.1, protein kinase C gamma and calcium-dependent protease, calpain-2, were increased after CDR antibody internalization. Inhibition of these signaling pathways prevented or attenuated CDR antibody-induced CB and L7/Pcp-2 immunoreactivity loss, morphological changes and increased protein expression. These results signify that CDR antibody internalization causes dysregulation of cell calcium homeostasis. Hence, drugs that modulate these events may represent novel neuroprotective therapies that limit the damaging effects of CDR antibodies and prevent PC neurodegeneration.

Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study.

BACKGROUND: The immunogenicity of influenza vaccines in MS patients undergoing immunomodulatory treatment is not well studied. OBJECTIVES: This explorative study investigated the influence of immunomodulatory treatment on MS patients receiving pandemic H1N1 (swine flu) vaccination in 2009 and seasonal influenza vaccination in 2010. METHODS: We investigated the immune response to pandemic H1N1 vaccination among 113 MS patients and 216 controls during the pandemic of 2009. We also investigated the serological response to seasonal influenza vaccination (2010 - 2011 season) among 49 vaccinated and 62 non-vaccinated MS patients, versus 73 controls. We evaluated these vaccine responses by haemagglutination inhibition assay. RESULTS: MS patients receiving immunomodulatory treatment had reduced protection (27.4%), compared to controls (43.5%) (p = 0.006), after pandemic H1N1 vaccination (2009). The rates of protection were not influenced by interferon beta treatment (44.4% protected), but were reduced among patients receiving glatiramer acetate (21.6%), natalizumab (23.5%), and mitoxantrone (0.0%). A similar pattern emerged after MS patients received a seasonal influenza vaccination in 2010. CONCLUSIONS: These findings suggest that MS patients receiving immunomodulatory therapies other than interferon beta should be considered for a vaccine response analysis and perhaps be offered a second dose of the vaccine, in cases of insufficient protection.

Paraneoplastic Hu and CRMP5 antibodies are present in smokers without cancer or neurological disease.

BACKGROUND AND OBJECTIVE: We investigated if the paraneoplastic Hu and collapsin response mediator protein 5 (CRMP5) antibodies could be used as early markers for lung cancer in smokers with or without chronic obstructive pulmonary disease (COPD). METHODS: Hu and CRMP5 antibodies were measured by radioimmunoprecipitation assay (RIPA) in sera from 552 smokers; 379 with and 173 without COPD. Three hundred blood donors served as controls. The positive sera were also tested by indirect immunofluorescence and line blot with recombinant proteins. The 552 smokers were matched with data from the Cancer Registry of Norway, and the hospital medical records from the subjects positive for Hu and CRMP5 antibodies were reviewed. The mean follow-up time was 4.4 years (range 2.5-5.7 years). RESULTS: The RIPA showed that 5/379 (1.3%) smokers with COPD had Hu antibodies and 1/379 (0.3%) smokers with COPD had CRMP5 antibodies. Only the smoker with the highest RIPA index had Hu antibodies also detected by immunofluorescence and line blot. One of 173 (0.6%) smokers without COPD had Hu antibodies, but none had CRMP5 antibodies. None of the 300 controls had Hu antibodies, but 2/300 (0.7%) had CRMP5 antibodies. Hu antibodies remained positive for more than 5 years. No cancer or neurological disease was recorded in the Hu or CRMP5 positive patients. The total cancer frequency in the smokers with and without COPD was 70/552 (13%). CONCLUSIONS: Hu and CRMP5 antibodies were not associated with cancer or neurological disease in a large cohort of smokers and are therefore not always paraneoplastic.

Paraneoplastic cerebellar and brainstem disorders.

Paraneoplastic cerebellar and brainstem disorders are a heterogeneous group that requires prompt recognition and treatment to help prevent irreversible neurologic injury. Paraneoplastic cerebellar degeneration is best characterized by Yo antibodies in patients with breast or ovarian cancer. Tr (DNER) antibodies in patients with Hodgkin lymphoma can also present with a pure cerebellar syndrome and is one of the few paraneoplastic syndromes found with hematological malignancy. Opsoclonus-myoclonus-ataxia syndrome presents in both pediatric and adult patients with characteristic clinical findings. Other paraneoplastic brainstem syndromes are associated with Ma2 and Hu antibodies, which can cause widespread neurologic dysfunction. The differential for these disorders is broad and also includes pharmacological side effects, infection or postinfectious processes, and neurodegenerative diseases. Although these immune-mediated disorders have been known for many years, mechanisms of pathogenesis are still unclear, and optimal treatment has not been established.

Altered exosomal miRNA profiles in patients with paraneoplastic cerebellar degeneration.

OBJECTIVE: Patients with ovarian cancer (OC) may develop anti-Yo-associated paraneoplastic cerebellar degeneration (PCD)-a cerebellar ataxia associated with tumor-induced autoimmunity against CDR2 and CDR2L proteins. Dysregulation of circulating exosomal microRNAs (miRNAs) occur in OC. Here, we investigated whether PCD is associated with changes in the exosomal miRNA profiles of OC patients. METHODS: Serum exosomes were isolated from patients with OC (n = 15), patients with OC and anti-Yo-associated PCD (n = 14) and healthy controls (HC, n = 15). Small RNA sequencing was used to identify differentially expressed miRNAs. Receiver operating characteristic curves were used to evaluate biomarker sensitivity and specificity, and miRNA target prediction analysis was employed to elucidate gene targets. RESULTS: OC patients with PCD exhibited a distinct exosomal miRNA expression profile. We detected 103 differentially expressed exosomal miRNAs in PCD patients compared to OC patients without PCD and 139 differentially expressed exosomal miRNAs compared to controls. Particularly miR-486-5p, miR-4732-5p, miR-98-5p and miR-21-5p exhibited notable sensitivity and specificity for discriminating PCD patients from both OC patients without PCD and healthy controls. miRNA target prediction showed that several of the differentially expressed miRNAs in PCD patients targeted the CDR2 and CDR2L genes. INTERPRETATION: Our results demonstrate that OC patients with anti-Yo-associated PCD exhibit a distinct exosomal miRNA profile compared to OC patients without PCD. Several of the differentially expressed exosomal miRNAs in PCD patients showed diagnostic potential and may hold relevance for understanding the pathogenesis of PCD.

The Norwegian Stroke in the Young Study (NOR-SYS): rationale and design.

BACKGROUND: Ischemic stroke in young adults is a major health problem being associated with a higher vascular morbidity and mortality compared to controls, and a stroke recurrence rate of 25% during the first decade. The assumed cause of infarction and the detected risk factors determine the early- and long-term treatment. However, for many patients the cause of stroke remains unknown. Risk factor profile and etiology differ in young and elderly ischemic stroke patients, and atherosclerosis is the determined underlying condition in 10 to 15%. However, subclinical atherosclerosis is probably more prevalent and may go unrecognized. METHODS/DESIGN: NOR-SYS is a prospective long-term research program. Standardized methods are used for anamnestic, clinical, laboratory, imaging, and ultrasound data collection in ischemic stroke patients aged ≤60 years, their partners and joint adult offspring. The ultrasound protocol includes the assessment of intracranial, carotid and femoral arteries, abdominal aorta, and the estimation of VAT. To date, the study is a single centre study with approximately 400 patients, 250 partners and 350 adult offspring expected to be recruited at our site. DISCUSSION: NOR-SYS aims to increase our knowledge about heredity and the development of arterial vascular disease in young patients with ischemic stroke and their families. Moreover, optimization of diagnostics, prophylaxis and early intervention are major targets with the intention to reduce stroke recurrence and other clinical arterial events, physical disability, cognitive impairment and death.

[Neuromyelitis optica]. / Neuromyelitis optica.

BACKGROUND: Neuromyelitis optica (NMO) is a rare autoimmune inflammatory disease of the central nervous system that is characterized mainly by recurrent optic neuritis and longitudinally extensive transverse myelitis. The aim of this article is to present current knowledge on the clinical features, diagnosis, pathogenesis and treatment of the condition. METHOD: The article is based on a discretionary selection of English-language original articles, meta-analyses and review articles found in PubMed, and on the authors' own experience with the patient group. RESULTS: Neuromyelitis optica was previously assumed to be a variant of multiple sclerosis (MS), but the discovery of aquaporin-4 antibodies in patients with neuromyelitis optica has led to this view being revised. The cause of the condition is still unknown, but it has been shown that the antibodies bind selectively to a water channel expressed mainly on astrocytes at the blood-brain-barrier, which has an important role in the regulation of brain volume and ion homeostasis. Clinically, the condition presents as optic neuritis and/or transverse myelitis. A diagnosis is made on the basis of case history, clinical examination, MRI of the brain and spinal cord, analysis of cerebrospinal fluid, visual evoked potentials and a blood test with analysis of aquaporin-4 antibodies. Once a diagnosis has been made, rapid treatment is important. In the acute phase, intravenous methylprednisolone is recommended. There are several options for preventative treatment, but the primary recommendations are oral prednisolone and azathioprine or intravenous infusion of rituximab. Treatment is distinct from the treatment of MS and some of the immunomodulatory drugs commonly used in MS can lead to worsening of neuromyelitis optica. INTERPRETATION: The condition is an important differential diagnosis of MS, but differs from MS in terms of clinical features, prognosis and treatment. Patients have a high risk of sequelae following relapses, and therefore early diagnosis and treatment is important.

Case Report: Limbic encephalitis following treatment with durvalumab for small-cell lung cancer.

Background: Durvalumab is an immune checkpoint Inhibitor (ICIs) that is used in the treatment of malignant tumors, such as lung cancer and melanoma. ICIs are associated with immune-related adverse events including autoimmune encephalitis, although both paraneoplastic phenomena and ICI treatment may lead to autoimmunity. Case presentation: We describe a 72-year old male patient with small-cell lung cancer, who during adjuvant treatment with Durvalumab developed GABABR1 and GAD65 antibodies and both diabetes and autoimmune limbic encephalitis. Because he was followed prospectively as part of a treatment study, we had access to repeated serum samples and cognitive assessments over time prior to developing encephalitis and diabetes, in addition to later assessments. A high titer of GABABR1 antibodies appeared early, while GAD65 antibodies appeared later with a lower titer in parallel with the development of diabetes. As he subsequently developed clinical signs of encephalitis, verified by EEG and brain MRI, he also had CSF GABABR1 antibodies. Durvalumab was discontinued and steroid treatment with subsequent plasmapheresis were started, resulting in reduction of both CSF and serum antibody levels. Clinical signs of encephalitis gradually improved. Conclusion: This case illustrates the importance of being aware of possible serious autoimmune adverse reactions, including neurological syndromes such as encephalitis, when treating patients with high risk of para-neoplasia with ICIs. In addition, the case shows the development of autoantibodies over time.

[Baby with respiratory problems and cardiac arrest]. / Et spedbarn med pustevansker og hjertestans.

A ten-month-old girl was admitted to hospital with respiratory and gastrointestinal symptoms. Her condition deteriorated the following day, and she presented with symptoms of inspiratory stridor, facial palsy and ventricular fibrillation. She was resuscitated and intubated, and a normal spinal puncture was performed. Further investigation revealed areflexia, general hypotonia and reduced ejection fraction. Neurophysiological investigation showed long F-response, and renewed cerebrospinal fluid testing showed albuminocytologic dissociation, both typical signs of acute inflammatory demyelinating polyneuropathy (AIDP). Antitoxin was administered to the baby on suspicion of botulism, but immunological and microbiological testing ruled out infectious aetiology. She showed rapid improvement after i.v. immunoglobulin therapy, and was completely restituted/recovered 6 months after the incident.

CDR2 antigen and Yo antibodies.

Paraneoplastic cerebellar degeneration (PCD) is often associated with Yo antibodies that are directed against human cerebellar degeneration-related protein 2 (CDR2). Such antibodies may also be found in ovarian cancer patients without PCD. We studied if there was an association between Yo antibody production and differences in CDR2 cDNA sequence, mRNA or CDR2 expression in ovarian cancers. We found similar CDR2 cDNA sequence, mRNA and protein levels in primary ovarian cancers, with or without associated Yo antibodies. CDR2 was also present in other cancers, as well as in normal ovary tissue. The results suggest that Yo antibodies are not only related to the expression of CDR2 alone, but also to immune dysregulation.

Serum biomarkers in primary mitochondrial disorders.

The aim of this study was to explore the utility of the serum biomarkers neurofilament light chain, fibroblast growth factor 21 and growth and differentiation factor 15 in diagnosing primary mitochondrial disorders. We measured serum neurofilament light chain, fibroblast growth factor 21 and growth and differentiation factor 15 in 26 patients with a genetically proven mitochondrial disease. Fibroblast growth factor 21 and growth and differentiation factor 15 were measured by enzyme-linked immunosorbent assay and neurofilament light chain with the Simoa assay. Neurofilament light chain was highest in patients with multi-systemic involvement that included the central nervous system such as those with the m.3242A>G mutation. Mean neurofilament light chain was also highest in patients with epilepsy versus those without [49.74 pg/ml versus 19.7 pg/ml (P = 0.015)], whereas fibroblast growth factor 21 and growth and differentiation factor 15 levels were highest in patients with prominent myopathy, such as those with single-mitochondrial DNA deletion. Our results suggest that the combination of neurofilament light chain, fibroblast growth factor 21 and growth and differentiation factor 15 is useful in the diagnostic evaluation of mitochondrial disease. Growth and differentiation factor 15 and fibroblast growth factor 21 identify those with muscle involvement, whereas neurofilament light chain is a clear marker for central nervous system involvement independent of underlying mitochondrial pathology. Levels of neurofilament light chain appear to correlate with the degree of ongoing damage suggesting, therefore, that monitoring neurofilament light chain levels may provide prognostic information and a way of monitoring disease activity.

Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis.

Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, react with intracellular neuronal antigens. These antibodies are characteristically found in patients with underlying malignancy, and neurological impairment is the result of neuronal death. Within the last few years, major advances have been made in understanding the pathogenesis of neurological disorders associated with antibodies against neuronal cell surface antigens. In contrast, the events that lead to neuronal death in conditions associated with antibodies directed against intracellular antigens, such as anti-Yo and anti-Hu, remain poorly understood, and the respective roles of antibodies and T lymphocytes in causing neuronal injury have not been defined in an animal model. In this review, we discuss current knowledge of these two groups of antibodies in terms of their discovery, how they arise, the interaction of both types of antibodies with their molecular targets, and the attempts that have been made to reproduce human neuronal injury in tissue culture models and experimental animals. We then discuss the emerging area of autoimmune neuronal injury associated with immune checkpoint inhibitors and the implications of current research for the treatment of affected patients.