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Background: The complement system has been suggested to be involved in the pathophysiology of amyotrophic lateral sclerosis (ALS), a progressive motor neuron disease. In the present study, we compared levels of selected complement markers to clinical outcome in ALS patients., Methods: This observational, explorative cohort study included 92 ALS patients, 61 neurological controls (NCs) admitted for suspected aneurysmal subarachnoid haemorrhage, and 96 neurologically healthy controls (NHCs). Peripheral blood and cerebrospinal fluid (CSF) were obtained for the measurement of ficolin-1, -2, and -3; collectin-11, MBL, MASP-3, MAP-1, C4, C3, PTX-3, and complement activation products C4c, C3bc, and sC5b-9. We recorded clinical outcomes of ALS patients for 24 to 48 months after inclusion in order to analyse the effects of the complement markers on survival time., Results: Compared with both control groups, ALS patients exhibited increased collectin-11, C4 and sC5b-9 in plasma, as well as increased ficolin-3 in CSF. Ficolin-2 was significantly decreased in plasma of the ALS patients compared with NHCs, but not with NCs. The concentration of collectin-11, C3 and C3bc correlated negatively with the revised ALS functional rating scale (ALSFRS-R). No association was found between levels of complement markers and survival as estimated by hazard ratios., Conclusion: ALS patients exhibit aberrant expression of selected mediators of the lectin complement pathway as well as increased activation of the terminal complement pathway, corroborating the notion that the complement system might be involved in the pathophysiology of ALS., Competing Interests: The authors report no conflicts of interest for this work., (© 2021 Kjældgaard et al.)

Essential tremor can be a debilitating disease. In many cases, medical treatment is ineffective and/or holds significant side effects. Surgical treatment using deep brain stimulation is only possible in few and selected cases. The introduction of MR-guided focused ultrasound enables surgeons to make small and specific lesions in the thalamus with few side effects and limited risk for the patient. The effectiveness has been documented in several international studies and is summarised in this review.

We present a case of stiff person syndrome (SPS) with a description of the diagnostic challenges and a discussion of the implication of novel antibodies. SPS is a rare neurological disorder presenting with severe rigidity, muscle spasms and impaired gait function, and diagnosis is often delayed due to low awareness. SPS is classically associated with antibodies directed against glutamic acid decarboxylase or amphiphysin. However, recent advances have contributed to our understanding because of detection of several new antibodies, which cause SPS, mostly with additional neurological/systemic manifestations.

Objective: To verify the previously reported association between long-term use of β2-adrenoreceptor (β2AR) agonist and antagonist with reduced and increased risk of Parkinson disease (PD), respectively., Methods: We obtained odds ratios (ORs) associating time of β2AR agonist and antagonist use with PD risk in nationwide Danish health registries., Results: We included 2,790 patients with PD and 11,160 controls. Long-term β2AR agonist use was associated with reduced PD risk (OR 0.57, 95% confidence interval [CI] 0.40-0.82) in this cohort. Unexpectedly, short-term β2AR agonist use was equally associated (OR 0.64, 95% CI 0.42-0.98). Because β2AR agonists are prescribed mostly for chronic obstructive pulmonary disease (COPD), often caused by long-term nicotine abuse, we analyzed other markers of smoking. Diagnosis of COPD (OR 0.51, 95% CI 0.37-0.69) and use of inhaled corticosteroids (OR 0.78, 95% CI 0.59-1.02) or inhaled anticholinergics (OR 0.41, 95% CI 0.25-0.67) were also inversely associated with PD. Increased PD risk was not found for all β2AR antagonists but only for propranolol and metoprolol. Associations were markedly stronger for short-term than long-term use., Conclusion: We confirmed β2AR agonist use to be associated with reduced PD risk and β2AR antagonist use with increased PD risk. However, our data indicate the association of β2AR agonists to be indirectly mediated by smoking, which is repeatedly associated with reduced risk of PD. The association of β2AR antagonists indicates reverse causation, with PD symptoms triggering their prescription rather than β2AR antagonists causing PD. Thus, current epidemiologic data do not support a causal link between β2AR agonists and antagonists and PD risk., (© 2019 American Academy of Neurology.)

Background: The incidence of pediatric autoimmune encephalitis (AIE) is unknown. Our aim was to assess the incidence of pediatric AIE in Denmark 2011-17., Methods: In a nationwide population-based setting, we retrieved data on all children tested for AIE before age 18 years. We reviewed medical records in a) children with AIE antibodies (n = 18) to assess whether children fulfilled the AIE consensus criteria, b) children tested negative for AIE antibodies who were registered with an AIE diagnostic code to estimate the incidence of "antibody negative but probable AIE", and c) a reference cohort (n = 596) to determine the positive predictive value of International Classification of Diseases (ICD) codes used for anti-NMDAR encephalitis., Results: 375 children were tested for AIE 2011-17 (median age 11.1 years; 54% girls); 18 children (5%) had AIE antibodies (percentage tested positive): CSF GAD 65 -IgG (3.1%), plasma NMDAR-IgG (2.8%), CSF NMDAR-IgG (1.8%), plasma GAD 65 -IgG (1.0%), and plasma CASPR2-IgG (0.4%). Five children fulfilled the criteria for probably/definite anti-NMDAR encephalitis (incidence: 0.07/100,000 person-years; 95% CI = 0.03-0.17), and 4 children with anti-GAD 65 associated AIE (incidence = 0.055/100,000 person-years, 95% CI = 0.021-0.15). The incidence of "antibody negative but probable AIE" was 0.055/100,000 person-years (95% CI = 0.021-0.15). The positive predictive value of ICD diagnostic codes used for anti-NMDAR encephalitis was 8%., Conclusions: We diagnosed only children with anti-NMDAR, anti-GAD 65 , and "antibody negative but probable AIE". Before examining AIE antibodies, clinical presentation, paraclinical studies (CSF, EEG, and MRI), and incidence of pediatric AIEs should be considered. Updating the ICD to include AIE codes is warranted., (Copyright © 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Recent studies have identified specific immunoglobulin (Ig) G4 antibodies against the paranodal proteins neurofascin 155 and contactin 1 in subgroups of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These patients present with distinct clinical phenotypes and poor response to first-line therapy with intravenous Ig. Detection of these antibodies in patients with CIDP has diagnostic, prognostic, and therapeutic implications. This review summarises the current knowledge on clinical characteristics, pathogenesis and treatment of these patients.

The classic immunologic alteration of the cerebrospinal fluid (CSF) in Guillain-Barré syndrome (GBS), albuminocytologic dissociation, has been known since the original paper by Guillain, Barré, and Strohl. Albuminocytologic dissociation has been also described in other forms of the GBS spectrum, such as axonal motor or motor-sensory forms (AMAN, AMSAN), the anti-GQ1b spectrum of Miller Fisher syndrome, and Bickerstaff brainstem encephalitis. Cytokines, chemokines, antibodies, complement components, and molecules with a putative neuroprotective role or indicating axonal damage have also been examined using different methods. Besides these candidate approaches, proteomics has been recently applied to discover potential biomarkers. The overall results support the immunopathogenesis of GBS, but albuminocytologic dissociation remained the only consistent CSF biomarker supporting the diagnosis of GBS. Chronic inflammatory neuropathies also comprise a heterogeneous group of diseases. Increased protein in the CSF is a supportive factor of chronic inflammatory demyelinating polyneuropathy, especially in the absence of definite electrophysiologic criteria. A number of other markers have also been investigated in the CSF of patients with chronic inflammatory neuropathies, similar to GBS. However, none has been used in supporting diagnosis, differentiating among syndromes, or predicting the clinical course and treatment responses., (Copyright © 2017 Elsevier B.V. All rights reserved.)

GABAB receptor (gamma-aminobutyric acid type B receptors - GABABR) encephalitis is a rare manifestation of autoimmune encephalitides. We report four cases - including the first two Hungarian patients - with some peculiar features. One patient developed subacute disorientation and almost complete loss of short-term memory, but no epilepsy. Without immunotherapy, his memory spontaneously improved up to mild cognitive impairment in six weeks. GABABR antibodies persisted in his serum, and 18 months later, FDG-PET detected abnormal mediastinal lymph nodes and small cell lung cancer (SCLC). Another patient had persistently decreased sodium content in the peripheral blood. In those three patients who died, CSF was abnormal, but CSF was not pathological in the patient, who spontaneously improved. Brain MRI indicated signal intensity changes in the medial temporal areas in three cases. SCLC was found in three patients. Only the patient, who spontaneously improved, survived for more than 24 months. In summary, our cases show that (i) GABABR encephalitis may develop without epilepsy; (ii) the severe short-term memory loss can spontaneously improve; (iii) persistent hyponatremia can be present in the blood; (iv) the patient with benign course without epilepsy and CSF abnormality survived; (v) spontaneously remitting encephalitis can precede SCLC by 1.5 year, which emphasizes that repeated search for cancer is of paramount importance even in cases with spontaneous improvement.

Objective: To examine if there is widespread inflammation in the brain of patients with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) syndrome by using histology and ultra-high-field MRI at 7.0T., Methods: We performed a detailed neuropathologic examination in 4 cases, including 1 autopsy case, and studied 2 additional patients by MRI at 7.0T to examine (1) extension of inflammation to areas appearing normal on 3.0T MRI, (2) potential advantages of 7.0T MRI compared to 3.0T MRI in reflecting widespread inflammation, perivascular pathology, and axonal damage, and (3) the possibility of lymphoma., Results: In the autopsy case, perivascular inflammation dominated by CD4+ T cells was not only detected in the brainstem and cerebellum but also in brain areas with normal appearance on 3.0T MRI, including supratentorial regions and cranial nerve roots. There was no evidence of lymphoma in any of the 4 patients. The 7.0T MRI in clinical remission also revealed supratentorial lesions and perivascular pathology in vivo with contrast-enhancing lesions centered around a small venous vessel. Ultra-high-field MRI at 7.0T disclosed prominent T1 hypointensities in the brainstem, which were not seen on 3.0T MRI. This corresponded to neuropathologic detection of axonal injury in the autopsy case., Conclusion: Our findings suggest more widespread perivascular inflammation and postinflammatory axonal injury in patients with CLIPPERS.

Autoimmune encephalitis with antibodies against neuronal surface antigens is diagnosed with increasing frequency in recent years. If treated early and aggressively, these conditions often respond favourably to immunotherapy. We describe the clinical features, diagnosis and treatment of the two most common types of autoimmune encephalitis with antibodies against the N-methyl-D-aspartate receptor or the leucine-rich glioma-inactivated 1 protein. Together, these two conditions comprise 80% of the autoimmune encephalitis cases diagnosed in Denmark. Autoimmune encephalitides with rare antibodies are also summarized.

Human neural stem cells (NSCs) from the developing embryo or the subventricular zone of the adult brain can potentially elicit brain repair after injury or disease, either via endogenous cell proliferation or by cell transplantation. Profound knowledge of the diverse signals affecting these cells is, however, needed to realize their therapeutic potential. Glutamate and group I metabotropic glutamate receptors (mGluRs) affect proliferation and survival of rodent NSCs both during embryonic and post-natal development. To investigate the role of group I mGluRs (mGluR1 and mGluR5) on human NSCs, we differentiated an immortalized, forebrain-derived stem cell line in the presence or absence of glutamate and with addition of either the group I mGluR agonist DHPG or the selective antagonists, MPEP (mGluR5) and LY367385 (mGluR1). Characterization of differentiated cells revealed that both mGluR1 and mGluR5 were present on the cells. Addition of glutamate to the growth medium significantly increased cell proliferation and reduced cell death, resulting in increased cell numbers. In the presence of glutamate, selective activation of group I mGluRs reduced gliogenesis, whereas selective inhibition of group I mGluRs reduced neurogenesis. Our results substantiate the importance of glutamate signalling in the regulation of human NSCs and may as such be applied to promote proliferation and neuronal differentiation., (© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Cerebrotendinous xanthomatosis (CTX) is a rare, but treatable lipid storage disorder caused by mutation in the CYP27A1 gene. The disorder results in deposition of cholestanol in various tissues. The classical CTX phenotype includes diarrhoea, juvenile cataract, xanthoma and progressive neurological symptoms. Studies have shown that progression of symptoms can be halted or even reversed, if treatment with chenodeoxycholic acid is initiated early. The diagnosis of CTX is often delayed due to lack of awareness of the disease. We describe the history, clinical features, biochemical, genetic and magnetic resonance imaging findings of the first reported case of CTX in Denmark.

Slices of developing brain tissue can be grown for several weeks as so-called organotypic slice cultures. Here we summarize and review studies using hippocampal slice cultures to investigate mechanisms and treatment strategies for the neurodegenerative disorders like stroke (cerebral ischemia), Alzheimer's disease (AD) and epilepsia. Studies of non-excitotoxic neurotoxic compounds and the experimental use of slice cultures in studies of HIV neurotoxicity, traumatic brain injury (TBI) and neurogenesis are included. For cerebral ischemia, experimental models with oxygen-glucose deprivation (OGD) and exposure to glutamate receptor agonists (excitotoxins) are reviewed. For epilepsia, focus is on induction of seizures with effects on neuronal loss, axonal sprouting and neurogenesis. For Alzheimer's disease, the review centers on the use of beta-amyloid (Abeta) in different models, while the section on repair is focused on neurogenesis and cell migration. The culturing techniques, set-up of models, and analytical tools, including markers for neurodegeneration, like the fluorescent dye propidium iodide (PI), are reviewed and discussed. Comparisons are made between hippocampal slice cultures and other in vitro models using dispersed cell cultures, experimental in vivo models, and in some instances, clinical trials. New techniques including slice culturing of hippocampal tissue from transgenic mice as well as more mature brain tissue, and slice cultures coupled to microelectrode arrays (MEAs), on-line biosensor monitoring, and time-lapse fluorescence microscopy are also presented.

Generation of dentate granule cells and its modulation by glutamate receptor antagonists, growth factors and pilocarpine-induced seizure-like activity was investigated in rat hippocampal slice cultures derived from 1-week-old rats and grown for 2 weeks. Focussing on the dentate granule cell layer facing CA1 and the immediate subgranular zone, exposure for 3 days to the NMDA receptor blocking agents MK-801 (10 microM) or APV (25 microM) in the culture medium, increased the number of TOAD-64/Ulip/CRMP-4 (TUC-4)-positive cells as counted in the slice cultures at the end of the 3-day treatment period. Exposure to IGF-I (200 ng/ml) and EGF (20 ng/ml) also increased the number of TUC-4-positive cells. Combining APV with IGF-I/EGF had an additive effect. Similar results were obtained by 3 days treatment with the AMPA receptor antagonist CNQX (25 microM). Surprisingly, addition of 5 mM pilocarpine reduced the number of TUC-4-positive cells, just as combining pilocarpine with the neurogenesis-stimulating compounds, prevented or reduced the increase of TUC-4-positive cells. None of the treatments were found to induce dentate granule cell death within the observed period. Labeling of dividing cells by adding 5-bromo-2-deoxyuridine (BrdU) to the culture medium did not result in cells double-labeled with BrdU and TUC-4. The induced increase in TUC-4-positive cells therefore represent neuronal differentiation of existing neural precursor cells when investigated at the 3-day time point. We conclude that 3 days treatment of 2-week-old hippocampal slice cultures with IGF-I and EGF and NMDA and AMPA glutamate receptor antagonists increase granule cell neurogenesis from preexisting neural precursors.

Stimulation of group I metabotropic glutamate receptors (mGluRs) has been shown to protect against N-methyl-D-aspartate receptor-mediated cell death, but the underlying cellular mechanism is unknown. Using cDNA microarrays we have now compared gene expressions in organotypic hippocampal slice cultures after neuroprotective activation of group I mGluRs with (S)-3,5-dihydroxyphenylglycine (DHPG; 10 microM, 2 h) with untreated control cultures. Total RNA was extracted from the cultures immediately after the neuroprotective treatment, reverse transcribed to cDNA with incorporation of [32]P-dCTP, and then hybridized to the arrays. Of a total of 1128 genes on the Neuroarray, 33 genes displayed significant changes in expression after DHPG-treatment (six up- and 27 downregulated). These genes have been associated with regulation of synaptic excitation, inflammation, cell adhesion, cell death, and transcription. The small GTPase RAB5B associated with endocytosis emerged as a primary candidate gene for neuroprotection, and its expression was confirmed by Western blot analysis and real time polymerase chain reaction. By providing insight into genes involved in neuroprotection these data may help to identify novel therapeutic targets.