Explore the vast range of titles available.

Background Autoantibodies against the paranodal protein contactin-1 have recently been described in patients with severe acute-onset autoimmune neuropathies and mainly belong to the IgG4 subclass that does not activate complement. IgG3 anti-contactin-1 autoantibodies are rare, but have been detected during the acute onset of disease in some cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown. Methods In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison. Results Conduction blocks were measured in rats injected with the “acute” IgG more often than after injection of “chronic” IgG (83.3% versus 35%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the “acute” IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the “acute IgG”. We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1. Conclusions Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis.

Objectively assessing horse movement symmetry as an adjunctive to the routine lameness evaluation is on the rise with several commercially available systems on the market. Prerequisites for quantifying such symmetries include knowledge of the gait and gait events, such as hoof to ground contact patterns over consecutive strides. Extracting this information in a robust and reliable way is essential to accurately calculate many kinematic variables commonly used in the field. In this study, optical motion capture was used to measure 222 horses of various breeds, performing a total of 82 664 steps in walk and trot under different conditions, including soft, hard and treadmill surfaces as well as moving on a straight line and in circles. Features were extracted from the pelvis and withers vertical movement and from pelvic rotations. The features were then used in a quadratic discriminant analysis to classify gait and to detect if the left/right hind limb was in contact with the ground on a step by step basis. The predictive model achieved 99.98% accuracy on the test data of 120 horses and 21 845 steps, all measured under clinical conditions. One of the benefits of the proposed method is that it does not require the use of limb kinematics making it especially suited for clinical applications where ease of use and minimal error intervention are a priority. Future research could investigate the extension of this functionality to classify other gaits and validating the use of the algorithm for inertial measurement units.

Differences in peak vertical ground reaction forces (dFzpeak) between contralateral forelimbs and hindlimbs are considered the gold standard for quantifying weight-bearing lameness. However, measuring kinematics for the same purpose is more common and practical. Vertical movement asymmetries (VMA) of the horse’s upper body have previously been correlated to fore- and hindlimb lameness. But the combined response of head, withers and pelvis VMA to fore- and hindlimb dFzpeak has not yet been thoroughly investigated. Deriving the kinetic responses from kinematics would help the interpretation and understanding of quantified weight-bearing lameness. In this retrospective study, 103 horses with a wide range of fore- and hindlimb dFzpeak had been trotted on a force-measuring treadmill synchronized with an optical motion capture system. VMA of the head, withers and pelvis as well as dFzpeak were extracted. Multiple linear mixed models and linear regressions of kinematic variables were used to model the dFzpeak. It was hypothesised that all included VMA would have a significant influence on the dFzpeak outcome variables. The results showed a complex relationship between VMA and dFzpeak where both amplitude and timing of the VMA were of importance. On average, the contribution percentage of VMA to fore/hind dFzpeak were 66/34% for head, 76/24% for withers and 33/67% for pelvis. The linear regressions for the fore/hindlimb models achieved mean measurement root mean squared errors of 0.83%/0.82% dFzpeak. These results might help determine the clinical relevance of upper body VMA and distinguish between primary fore, hind, ipsilateral and diagonal weight-bearing lameness.

Oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) in more than 95% of patients with multiple sclerosis (MS) in the Western hemisphere. Here we evaluated the intrathecal, polyspecific antiviral immune response as a potential diagnostic CSF marker for OCB-negative MS patients. We tested 46 OCB-negative German patients with paraclinically well defined, definite MS. Sixteen OCB-negative patients with a clear diagnosis of other autoimmune CNS disorders and 37 neurological patients without evidence for autoimmune CNS inflammation served as control groups. Antibodies against measles, rubella, varicella zoster and herpes simplex virus in paired serum and CSF samples were determined by ELISA, and virus-specific immunoglobulin G antibody indices were calculated. An intrathecal antibody synthesis against at least one neurotropic virus was detected in 8 of 26 (31%) patients with relapsing-remitting MS, 8 of 12 (67%) with secondary progressive MS and 5 of 8 (63%) with primary progressive MS, in 3 of 16 (19%) CNS autoimmune and 3 of 37 (8%) non-autoimmune control patients. Antibody synthesis against two or more viruses was found in 11 of 46 (24%) MS patients but in neither of the two control groups. On average, MS patients with a positive antiviral immune response were older and had a longer disease duration than those without. Determination of the intrathecal, polyspecific antiviral immune response may allow to establish a CSF-supported diagnosis of MS in OCB-negative patients when two or more of the four virus antibody indices are elevated.

Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3Δex1-6) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.

Stiff-person syndrome (SPS) with antibodies to amphiphysin is a paraneoplastic disorder of the central nervous system with a putative autoimmune pathogenesis. Proof of a causal role of the antibodies is still lacking for this and all other antibody-associated paraneoplastic syndromes of the central nervous system. We obtained the plasma filtrate of a patient with breast cancer and SPS that responded to therapeutic plasmapheresis. The purified IgG fraction included high-titre antibodies to the synaptic protein amphiphysin. In a cotransfer design, this IgG fraction was injected intraperitoneally into female Lewis rats that had received encephalitogenic T-helper (Th) lymphocytes specific for myelin basic protein, to induce an immune-mediated leaky blood–brain barrier. The rats were followed up with behavioural tests, video photography, and electromyography. The injection of the IgG fraction including antibodies to amphiphysin resulted in a dose-dependent stiffness with spasms resembling human SPS. Control IgG injected into rats that had received the same encephalitogenic Th cells had no effect. IgG binding was demonstrated in the central nervous system of rats that showed signs of the disorder. These experiments support the hypothesis of a pathogenetic role of antibodies to amphiphysin, thus adding paraneoplastic SPS to the group of antibody-mediated autoimmune disorders. These findings provide a strong argument for a direct pathogenetic role of anti-amphiphysin in this type of SPS and support therapeutic attempts to eliminate these autoantibodies by plasmapheresis. The experimental approach used could help to elucidate the role of autoantibodies in other paraneoplastic syndromes, such as SPS with antibodies to glutamic acid decarboxylase, and others including anti-Hu-associated subacute cerebellar degeneration and limbic encephalitis.

Multifocal motor neuropathy is an immune mediated disease presenting with multifocal muscle weakness and conduction block. IgM auto-antibodies against the ganglioside GM1 are detectable in about 50% of the patients. Auto-antibodies against the paranodal proteins contactin-1 and neurofascin-155 and the nodal protein neurofascin-186 have been detected in subgroups of patients with chronic inflammatory demyelinating polyneuropathy. Recently, auto-antibodies against neurofascin-186 and gliomedin were described in more than 60% of patients with multifocal motor neuropathy. In the current study, we aimed to validate this finding, using a combination of different assays for auto-antibody detection. In addition we intended to detect further auto-antibodies against paranodal proteins, specifically contactin-1 and neurofascin-155 in multifocal motor neuropathy patients' sera. We analyzed sera of 33 patients with well-characterized multifocal motor neuropathy for IgM or IgG anti-contactin-1, anti-neurofascin-155 or -186 antibodies using enzyme-linked immunosorbent assay, binding assays with transfected human embryonic kidney 293 cells and murine teased fibers. We did not detect any IgM or IgG auto-antibodies against contactin-1, neurofascin-155 or -186 in any of our multifocal motor neuropathy patients. We conclude that auto-antibodies against contactin-1, neurofascin-155 and -186 do not play a relevant role in the pathogenesis in this cohort with multifocal motor neuropathy.

Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear. We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11)C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient's amygdala/hippocampus complex. No motor abnormalities were found in recipient rats. The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region.

ObjectiveAutoantibodies against paranodal proteins have been described in patients with inflammatory neuropathies, but their association with pathology of nodes of Ranvier is unclear. We describe the clinical phenotype and histopathological changes of paranodal architecture of patients with autoantibodies against contactin-1, identified from a cohort with chronic inflammatory demyelinating polyradiculoneuropathy (n=53) and Guillain-Barré syndrome (n=21).MethodsWe used ELISA to detect autoantibodies against contactin-1. Specificity of the autoantibodies was confirmed by immunoblot assay, binding to contactin-1-transfected human embryonic kidney cells, binding to paranodes of murine teased fibres and preabsorption experiments. Paranodal pathology was investigated by immunofluorescence labelling of dermal myelinated fibres.ResultsHigh reactivity to contactin-1 by ELISA was found in four patients with chronic inflammatory demyelinating polyradiculoneuropathy and in none of the patients with Guillain-Barré syndrome, which was confirmed by cell binding assays in all four patients. The four patients presented with a typical clinical picture, namely acute onset of disease and severe motor symptoms, with three patients manifesting action tremor. Immunofluorescence-labelling of paranodal proteins of dermal myelinated fibres revealed disruption of paranodal architecture. Semithin sections showed axonal damage but no classical signs of demyelination.InterpretationWe conclude that anti-contactin-1-related neuropathy constitutes a presumably autoantibody-mediated form of inflammatory neuropathy with distinct clinical symptoms and disruption of paranodal architecture as a pathological correlate. Anti-contactin-1-associated neuropathy does not meet morphological criteria of demyelinating neuropathy and therefore, might rather be termed a ‘paranodopathy’ rather than a subtype of demyelinating inflammatory neuropathy.