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.

Serum neurofilament light chain associates with symptom burden in Lyme neuroborreliosis patients: a longitudinal cohort study from Norway.

OBJECTIVES: Serum neurofilament light chain (sNfL), an indicator of neuronal damage, is increasingly recognized as a potential biomarker for disease activity in neurodegenerative disorders. In this study, we wanted to investigate sNfL as a prognostic marker in a large, well-defined population of 90 patients with Lyme neuroborreliosis (LNB). In addition, we sought to explore associations between symptoms and sNfL levels during the acute phase of LNB. MATERIALS AND METHODS: Patients diagnosed with definite or possible LNB were recruited from a double-blinded, placebo-controlled, multi-center trial, in which the participants were randomly assigned to 2 or 6 weeks of oral doxycycline treatment. The sNfL levels were measured using a single molecule array assay at both diagnosis and 6-month follow-up, and analysed against clinical parameters, variations in symptom burden and long-term complaints as assessed by a composite clinical score. RESULTS: At the time of diagnosis, approximately 60% of the patients had elevated sNfL levels adjusted for age. Notably, mean sNfL levels were significantly higher at diagnosis (52 pg/ml) compared to 6 months after treatment (12 pg/ml, p < 0.001), when sNfL levels had normalized in the majority of patients. Patients with objective signs of spinal radiculitis had significantly higher baseline sNfL levels compared to patients without spinal radiculitis (p = 0.033). CONCLUSION: Our findings suggest that sNfL can serve as a biomarker for peripheral nerve tissue involvement in the acute phase of LNB. As found in an earlier study, we confirm normalization of sNfL levels in blood after treatment. We found no prognostic value of acute-phase sNfL levels on patient outcome.

Development and Optimization of a Multilayer Rat Purkinje Neuron Culture.

Elucidation of the mechanisms involved in neurodegenerative diseases of the cerebellum has been hampered by the lack of robust single cell models to study Purkinje neurons and replicate at the same time in vivo features. Cerebellar Purkinje neurons are difficult to grow in dispersed cell culture, and only limited work has been done using rat cells. We developed a refined protocol for growing rat Purkinje neurons from embryonic and postnatal tissue ex vivo that results in well-developed, mature, functional, and synaptically active neurons. The rat Purkinje neurons generated are responsive to paracrine factors and genetic manipulation, allowing great experimental flexibility at the single-cell level. This ex vivo model can be used to investigate disease mechanisms that disturb Purkinje neuron morphology, function, and communication in high- and low-throughput screening formats.

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.

Case report: Seropositive myasthenia gravis complicated by limbic encephalitis positive for antibodies to AMPAR and Lgi1.

Objectives: Autoantibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and leucine-rich glioma-inactivated 1 (Lgi1) are associated with autoimmune encephalitis. We described an acetylcholine receptor (AChR)-positive patient with myasthenia gravis who developed limbic encephalitis with antibodies to AMPAR and Lgi1. Methods: A single-case report with detailed, prospective clinical and biomarker data including serial laboratory testing and histopathology. Results: A 49-year-old woman was diagnosed with anti-AChR antibody-positive generalized myasthenia gravis in 1983. After 9 months of the removal of thymoma in 1984, she developed influenza-like symptoms and then symptoms of limbic encephalitis. Retrospective analysis of serum showed high concentrations of anti-AMPAR and lower concentrations of anti-Lgi1 antibodies. Cerebral CT was normal, EEG showed bifrontal dysrhythmia, and CSF showed mild pleocytosis. Immuno-histochemical examination of the thymoma confirmed staining for Glur2, a subunit of AMPAR. The patient recovered with mild sequelae, but low levels of anti-AMPAR and anti-Lgi1 antibodies were detectable for over 25 years subsequently. Discussion: This case confirms earlier reports of AMPAR-associated autoimmune encephalitis co-occurring with thymoma and myasthenia gravis and is unique in its observational length. It shows, moreover, that antibodies to AMPAR and Lgi1 can persist despite clinical recovery.

A cerebellar degeneration-related protein 2-like cell-based assay for anti-Yo detection in patients with paraneoplastic cerebellar degeneration.

BACKGROUND AND PURPOSE: Commercially available tests for Yo antibody detection have low specificity for paraneoplastic cerebellar degeneration (PCD) because these assays use cerebellar degeneration-related protein 2 (CDR2) as the antigen, not CDR2-like (CDR2L). We aimed to test the hypothesis that use of a CDR2L cell-based assay (CBA), as an additional screening technique, would increase the accuracy of Yo-PCD diagnosis. METHODS: An in-house CBA to test for anti-CDR2L antibodies was developed and used to screen sera from 48 patients with confirmed anti-Yo-associated PCD. Fifteen non-Yo PCD patients, 22 patients with ovarian cancer without neurological syndromes, 50 healthy blood donors, 10 multiple sclerosis, 15 Parkinson's disease, and five non-paraneoplastic ataxic patients were included as controls. Sera were also tested by western blot analysis using recombinant CDR2 and CDR2L proteins developed in house, by the commercially available line immunoassays from Ravo Diagnostika and Euroimmun, and by the CDR2 CBA from Euroimmun. RESULTS: The CDR2L CBA identified all 48 patients with Yo-PCD. No CDR2L CBA reaction was observed in any of the control sera. The western blot technique had lower sensitivity and specificity as sera from eight and six of the 48 Yo-PCD patients did not react with recombinant CDR2 or CDR2L, respectively. CONCLUSIONS: The CDR2L CBA is highly reliable for identification of Yo-PCD. Although our findings indicate that, currently, the combination of CDR2 and CDR2L yields the most reliable test results, it remains to be evaluated if a test for single anti-CDR2L positivity will serve as a sufficient biomarker for Yo-PCD diagnosis.

[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.

Case report: Pain in anti-DPPX encephalitis.

Encephalitis due to antibodies targeting dipeptidyl-peptidase-like protein 6 (DPPX), a potassium channel subunit, is rare. The illness is typically characterized by a triad of weight loss, CNS hyperexcitability and cognitive symptoms, but recent reports suggest that the clinical picture may be more heterogeneous. Here, we describe the case of a 63-year-old female who was admitted to the hospital with severe extremity pain, which had been preceded by diarrhea and weight loss. She later developed cognitive changes, and her general condition rapidly deteriorated. Extensive workup did not reveal gastrointestinal illness or underlying malignancies. MRI of the brain was normal. Analyses of blood and cerebrospinal fluid showed normal cell counts but high titres of DPPX antibodies in blood and cerebrospinal fluid. The patient was treated with intravenous methylprednisolone followed by rituximab. At 1-year follow-up, she was without pain and had completely recovered. In this case, DPPX-associated autoimmune encephalitis was dominated by severe extremity pain, illustrating that sensory symptoms may be one of the main complaints in these patients. It is important for clinicians to be aware of the heterogeneous clinical picture in this serious condition, since correct diagnosis and treatment with immunosuppressants are associated with favorable prognosis.

Expression of cerebellar degeneration-related proteins CDR2 and CDR2L in human and rat brain tissue.

Patients with ovarian cancer and paraneoplastic cerebellar degeneration, a cancer-related immune disorder, often have anti-Yo antibody. Here we studied the distributions of anti-Yo antigens CDR2L and CDR2 in rat and human brain using immunohistochemistry and western blot. CDR2L localized mainly to the Purkinje cells and large neurons scattered in the brain stem. CDR2 was detected in vascular smooth muscle cells of rat and human and in cells lining the ventricle system in rats. The observed distribution of CDR2L is compatible with the hypothesis that this antigen is the major target of anti-Yo. CDR2 and CDR2L are expressed by different cell subtypes.

CRMP5 Antibodies-Diagnostic Challenges.

CRMP5-associated paraneoplastic neurological syndromes (PNS) are rare, and only few studies describe larger cohorts of patients with CRMP5 antibodies. We have included 24 patients with CRMP5 antibodies and compared clinical findings with diagnostic findings from two different line assays (Ravo and Euroimmun), staining of cerebellar sections and results of a newly developed cell-based assay for detection of CRMP5 antibodies, CRMP5-CBA. We found that peripheral neuropathy and cerebellar ataxia together with lung cancer were the most common diagnoses associated with CRMP5 antibodies. CRMP5-CBA was easy to perform, identified all relevant cases for CRMP5-associated PNS and is therefore a valuable add-on for verification of CRMP5 positivity in diagnosis of PNS.

Wearing-off symptoms during standard and extended natalizumab dosing intervals: Experiences from the COVID-19 pandemic.

Natalizumab effectively prevents disease activity in relapsing-remitting multiple sclerosis, but many treated patients report subjective wearing-off symptoms at the end of the 4-week interval between infusions. Extended interval dosing (EID) is a promising strategy to mitigate the risk of natalizumab-associated progressive multifocal leukoencephalopathy, but it is unknown whether EID affects wearing-off symptoms. In this observational study, we evaluated if prevalence or intensity of wearing-off symptoms changed when natalizumab dosing intervals were extended from 4 to 6 weeks in 30 treated patients during the outbreak of COVID-19 in Norway. New or increased wearing-off symptoms during EID were reported by 50%. Symptom increase was more frequent among patients with pre-existing wearing-off symptoms during standard dosing compared to patients without such pre-existing symptoms [p = 0.0005]. Our observations support the need to study the effect of EID on wearing-off symptoms in randomized controlled trials.

Clinical management of chronic inflammatory demyelinating polyneuropathy (CIDP) in Europe and India: An exploratory study.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disorder causing inflammatory demyelination of peripheral nerves and consecutive disability. Diagnostic criteria and treatments are well established, but it is unknown how clinical practice may differ in different geographical regions. In this multicentre study, clinical management of CIDP was compared in 44 patients from Germany, India and Norway regarding diagnostic and therapeutic procedures. All centres used EFNS/PNS diagnostic criteria for CIDP but diagnostic workup varied regarding screening for infectious diseases, genetic testing and nerve biopsy. Intravenous immunoglobulin and prednisolone were the most common therapies in all centres with differences in indication and dosage. Patients from the Indian cohort were the most severely affected with less diverse therapeutic approaches, whereas psychological strain did not differ significantly from the two other cohorts. Our exploratory study discloses an unaddressed issue in management of CIDP that should be further investigated to optimise standard of care for CIDP worldwide.

Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes.

OBJECTIVE: The contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS. METHODS: A panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project. RESULTS: The panel proposed to substitute "classical syndromes" with the term "high-risk phenotypes" for cancer and introduce the concept of "intermediate-risk phenotypes." The term "onconeural antibody" was replaced by "high risk" (>70% associated with cancer) and "intermediate risk" (30%-70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided. CONCLUSIONS: The proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.

Facial Onset Sensory and Motor Neuronopathy: New Cases, Cognitive Changes, and Pathophysiology.

PURPOSE OF REVIEW: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). RECENT FINDINGS: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. SUMMARY: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.

Neurosarcoidosis - a patient series. / Nevrosarkoidose ­ en pasientserie.

BACKGROUND: Neurosarcoidosis is a rare form of sarcoidosis that affects the nervous system. The aim of the study was to survey clinical manifestations, findings from assessments and treatment strategies for patients with neurosarcoidosis. MATERIAL AND METHOD: The study performed a retrospective assessment of 17 patients with definitive, probable and possible neurosarcoidosis diagnosed in the period 2008-2019 at the Department of Neurology, Haukeland University Hospital. RESULTS: The average prevalence of definitive, probable or possible neurosarcoidosis in Norway's Vestland county was 2.7 per 100 000 inhabitants in the period in question. Onset took the form of central nervous affection (8 of 17), hydrocephalus (5 of 17) and cranial neuropathy (5 of 17). Sarcoidosis-like findings were made in 14 of 17 patients by means of contrast-enhanced magnetic resonance tomography (MRT) of the central nervous system, in 7 of 8 patients by positron emission tomography (PET), and in 12 of 16 patients by computed tomography (CT) of the thorax. There were cerebrospinal fluid abnormalities in 15 of 15 patients, with biopsy verification for 13 of 15. The symptoms of 16 of 17 patients improved or stabilised with prednisolone and/or other immunotherapy. INTERPRETATION: Neurosarcoidosis affects both the central and the peripheral nervous system. Cerebrospinal fluid analysis and contrast-enhanced MRT are important means of detecting inflammation. A biopsy is necessary for making a definitive diagnosis, but is not always feasible. PET can be used as a supplement to other examinations to assess various organ manifestations and to pinpoint biopsy sites. Corticosteroid therapy, and in some cases other immunotherapy, elicits a good response.

Paraneoplastic Cerebellar Degeneration: The Importance of Including CDR2L as a Diagnostic Marker.

OBJECTIVE: Investigate the value of including cerebellar degeneration-related protein 2-like (CDR2L) as a marker in commercial diagnostic tests for anti-Yo-associated paraneoplastic cerebellar degeneration (PCD). METHODS: We included sera and CSF samples from 24 patients with suspected PCD (6 of whom had PCD with underlying gynecologic or breast cancer), who were positive for Yo antibodies using the commercially available, paraneoplastic neurologic syndromes (PNS) 14 Line Assay from Ravo Diagnostika. The samples were further evaluated using the EUROLINE PNS 12 Ag Line Assay and a cell-based assay (CBA) from Euroimmun. For confirmation of positive lineblot results, we used indirect immunofluorescence of rat cerebellar sections. We also tested all samples in 2 assays developed in-house: a CBA for CDR2L and a Western blot analysis using recombinant cerebellar degeneration-related protein 2 (CDR2) and CDR2L proteins. RESULTS: In PNS 14 and PNS 12 Ag Line Assays, anti-CDR2 reactivity was observed for 24 (100%) and 20 (83%) of the 24 samples, respectively. Thirteen of 24 subjects (54%) were also positive using the Euroimmun CBA. Rat cerebellar immunofluorescence was the best confirmatory test. In our in-house CBA for CDR2L and Western blot for CDR2 and CDR2L, only the 6 patients with confirmed PCD reacted with CDR2L. CONCLUSIONS: Commercially available tests for Yo antibody detection have low specificity for PCD because these assays use CDR2 as antigen. By adding a test for CDR2L, which is the major Yo antigen, the accuracy of PCD diagnosis greatly improved. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a CBA for CDR2L accurately identifies patients with PCD.

Cerebrospinal fluid proteome shows disrupted neuronal development in multiple sclerosis.

Despite intensive research, the aetiology of multiple sclerosis (MS) remains unknown. Cerebrospinal fluid proteomics has the potential to reveal mechanisms of MS pathogenesis, but analyses must account for disease heterogeneity. We previously reported explorative multivariate analysis by hierarchical clustering of proteomics data of MS patients and controls, which resulted in two groups of individuals. Grouping reflected increased levels of intrathecal inflammatory response proteins and decreased levels of proteins involved in neural development in one group relative to the other group. MS patients and controls were present in both groups. Here we reanalysed these data and we also reanalysed data from an independent cohort of patients diagnosed with clinically isolated syndrome (CIS), who have symptoms of MS without evidence of dissemination in space and/or time. Some, but not all, CIS patients had intrathecal inflammation. The analyses reported here identified a common protein signature of MS/CIS that was not linked to elevated intrathecal inflammation. The signature included low levels of complement proteins, semaphorin-7A, reelin, neural cell adhesion molecules, inter-alpha-trypsin inhibitor heavy chain H2, transforming growth factor beta 1, follistatin-related protein 1, malate dehydrogenase 1 cytoplasmic, plasma retinol-binding protein, biotinidase, and transferrin, all known to play roles in neural development. Low levels of these proteins suggest that MS/CIS patients suffer from abnormally low oxidative capacity that results in disrupted neural development from an early stage of the disease.