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Purpose of Review: The human central nervous system (CNS) can mistakenly be the target of adaptive cellular and humoral immune responses causing both functional and structural impairment. We here provide an overview of neuron-directed autoimmunity as a novel class of inflammatory CNS disorders, their differential diagnoses, clinical hallmarks, imaging features, characteristic laboratory, electrophysiological, cerebrospinal fluid and neuropathological findings, cellular and molecular disease mechanisms, as well as therapeutic options., Recent Findings: A growing number of immune-mediated CNS disorders of both autoimmune and paraneoplastic origin have emerged, in which neurons seem to be the target of the immune response. Antibodies binding to a variety of synaptic and extrasynaptic antigens located on the neuronal surface membrane can define distinct entities. Clinically, these disorders are characterized by subacute CNS-related [and sometimes peripheral nervous system (PNS)-related] symptoms involving a variety of cortical and subcortical gray matter areas, which often reflect the expression pattern and function of the respective target antigen. Antibodies seem to be pathogenic and cause (reversible) disturbance of synaptic transmission and neuronal excitability by selective functional inhibition or crosslinking and internalization of their antigen in the absence of overt cytotoxicity, at least at early disease stages. Whether at later disease stages antibody-mediated cytotoxicity, cytotoxic CD8+ T cells, or other detrimental immune mechanisms contribute to neuronal impairment is unclear at present., Summary: Adaptive humoral autoimmunity directed to neuronal cell-surface antigens offers first and unique insights and provokes further investigation into the systemic, cellular, and molecular consequences of immune-mediated disruption of distinct neuronal signaling pathways within the living human CNS.

Purpose of Review: This review highlights recent advances in our understanding of autoimmune autonomic ganglionopathy (AAG) including serological diagnosis, clinical observations, pathophysiology, and treatment., Recent Findings: Classical AAG is a subacute disorder associated with antibodies against ganglionic acetylcholine receptors. Recent observations demonstrate that these antibodies cause a specific inhibition of synaptic transmission in autonomic ganglia and antibody levels correlate in a predictable way with severity of autonomic failure. Ganglionic acetylcholine receptor antibodies can be associated with other neurological disorders including chronic or restricted forms of autonomic dysfunction and with neurological or paraneoplastic disorders unrelated to the autonomic nervous system. Treatment of AAG is based on case reports. It is clear that AAG patients respond to immunomodulatory treatments but combination immunotherapy may be required to achieve a clinical response. Recently, additional clinical observations indicate that AAG patients may also show signs of treatment-responsive cognitive impairment., Summary: The pathophysiology and varied clinical presentation of AAG are becoming more clear. AAG is a treatable antibody-mediated disorder of autonomic ganglionic synaptic transmission. Future studies will continue to define the optimal diagnostic and therapeutic approach to autoimmune autonomic disorders.

Purpose of Review: The aim of this article is to review opsoclonus, with particular emphasis on its immunopathogenesis and pathophysiology., Recent Findings: Infections (West Nile virus, Lyme disease), neoplasms (non-Hodgkin's lymphoma, renal adenocarcinoma), celiac disease, and allogeneic hematopoietic stem cell transplantation can cause opsoclonus. Newly identified autoantibodies include antineuroleukin, antigliadin, antiendomysial, and anti-CV2. Evidence suggests that the autoantigens of opsoclonus reside in postsynaptic density, or on the cell surface of neurons or neuroblastoma cells (where they exert antiproliferative and proapoptotic effects). Most patients, however, are seronegative for autoantibodies. Cell-mediated immunity may also play a role, with B and T-cell recruitment in the cerebrospinal fluid linked to neurological signs. Rituximab, an anti-CD20 monoclonal antibody, seems efficacious as an adjunctive therapy. Although changes in synaptic weighting of saccadic burst neuron circuits in the brainstem have been implicated, disinhibition of the fastigial nucleus in the cerebellum, or damage to afferent projections to the fastigial nucleus, is a more plausible pathophysiologic mechanism which is supported by functional magnetic resonance imaging findings in patients., Summary: There is increasing recognition that both humoral and cell mediated immune mechanisms are involved in the pathogenesis of opsoclonus. Further studies are needed to further elucidate its immunopathogenesis and pathophysiology in order to develop novel and efficacious therapy.

Purpose of Review: Immune-mediated inner-ear disorders may present to different medical disciplines and new research findings emerge rapidly. The purpose of this review is to draw the different strands together to produce an overview describing the clinical presentation of immune-mediated inner-ear disorders and to discuss useful diagnostic criteria with a focus on tissue-specific and tissue-non-specific antibodies., Recent Findings: The importance of diagnosing an immune-mediated inner-ear disorder is highlighted in the context of it being one of few forms of treatable inner-ear disorder with a good response to immunosuppressive therapy. Due to a lack of reliable tests, the criteria upon which the diagnosis of immune-mediated inner-ear disease is based are often arbitrary. Previous and current research focuses mainly on the investigation of the aetiology of immune-mediated disorders, studying the presence of autoantibodies and the antigens responsible for their production. The prognostic and therapeutic values of inner-ear-specific antibodies are still unclear. Various antigens have been suggested. However, most antigens identified have been ubiquitous proteins not specific to the inner ear and therefore lack logical association with localized inner-ear pathology., Summary: Early diagnosis of immune-mediated inner-ear disorders with prompt treatment may prevent irreversible damage to inner-ear structures. Accordingly, it is important to include immune-mediated inner-ear disorders in the differential diagnosis of patients presenting with 'idiopathic' audiovestibular dysfunction. To enable early diagnosis, we recommend that the current available routine immunological laboratory tests (antinuclear, antineutrophil cytoplasmic, antiendothelial cell, antiphospholipid/anticardiolipin and antithyroid antibodies) are used when assessing a patient with suspected immune-mediated inner-ear disorder.

Purpose of Review: Recently, autoaggressive immunological responses were included among the causative agents of basal ganglia dysfunction. Autoaggressive immune-mediated illnesses secondary to group A beta-haemolytic streptococcal infections present with motor and psychiatric symptoms, due to basal ganglia involvement. These disorders have been associated with serum antineuronal antibodies, relatively specific to human basal ganglia tissue. This review summarizes the most recent studies concerning antibasal ganglia antibodies, focusing on the associated phenotypes and the hypotheses concerning their pathogenicity., Recent Findings: The spectrum of post-streptococcal neuropsychiatric disorders associated with antibasal ganglia antibodies seems broader than previously recognized. Other than chorea, tics and obsessive-compulsive disorder, which constituted the bulk of previously described disorders associated with antibasal ganglia antibodies, post-streptococcal neuropsychiatric disturbances include a wider range of motor and behavioural abnormalities, in keeping with the multifunctional role of the basal ganglia. An encephalitis lethargica-like illness following streptococcal infection was reported, and unusual adult-onset movement disorders associated with antibasal ganglia antibodies were documented. Moreover, investigators provided preliminary evidence for a pathogenic role of autoantibodies in Sydenham's chorea, the prototypic post-streptococcal neuropsychiatric disorder., Summary: Antibasal ganglia antibodies are relatively specific in identifying post-streptococcal neuropsychiatric disorders, which constitute a wider spectrum of movement disorders than previously recognized. Although their sensitivity in diagnosing Sydenham's chorea seems excellent, it is not yet possible to extrapolate this sensitivity to all the recently identified post-streptococcal neuropsychiatric disorders. The antigens targeted by these autoantibodies and their pathogenic importance are currently under investigation. Preliminary evidence suggests that antibasal ganglia antibodies may be pathogenic.

Purpose of Review: The physiological properties of nerve and muscle are influenced by pathological changes and the aim of this review is to discuss recent contributions of electrophysiological studies to the understanding and diagnosis of selected peripheral nerve disorders. The relationships between pathology and physiology emphasize the close interdependence between electrophysiological studies, clinical deficits and other laboratory information. Attention should be paid to the strengths and limitations of electrophysiological methods, considering their impact on diagnosis and treatment of patients., Recent Findings: Several studies have shown particular pathophysiological profiles associated with different antibody subtypes in autoimmune peripheral neuropathies and this association further supports the suggestion of pathological specificity in both acute and chronic neuropathy. The sensitivity and specificity of physiological profiles therefore become increasingly important since some of these neuropathies are accessible to treatment. On the other hand, the pathophysiological and clinical profiles may be heterogeneous in patients with some disorders. This could be related to a more indistinct division between different types of pathology with increased understanding of pathogenetic mechanisms. Moreover, new insights into disturbed axonal function have stimulated attempts to develop methods to explore normal and diseased human nerve function., Summary: The exploration of axonal membrane and ion-channel function has become accessible using studies of excitability and are of potential value where conventional studies only provide nonspecific evidence of the number of fibers and the integrity of myelin. These studies will presumably become increasingly important in the years ahead considering the lack of understanding of the functional disturbances in axonal neuropathies.

Purpose of Review: To update recent advances in the pathogenesis, pathophysiology and treatment of some autonomic neuropathies., Recent Findings: When evaluating a patient with subacute autonomic neuropathy, certain autoantibodies are important in diagnosis and may influence management. Ganglionic antibody may be pathogenetically important while the paraneoplastic antibodies alert the clinician to the presence of an occult neoplasm. Autonomic failure is an integral component of diabetic neuropathy. Sildenafil is safe and efficacious in treating erectile dysfunction in diabetic patients. Sympathetic cardiac hyperinnervation can occur concurrently with denervation in diabetic neuropathy The gene mutations for hereditary sensory and autonomic neuropathies I, III, and IV are now known and there is clear unmyelinated fiber loss. Additional options for treatment of orthostatic hypotension include erythropoietin and, surprisingly, water. Botulinum toxin is efficacious, at least for a time, for the treatment of palmar and axillary hyperhidrosis., Summary: Ganglionic antibody likely mediates autoimmune autonomic neuropathy. Sympathetic cardiac hyperinnervation can occur and could potentially cause arrhythmia and sudden death. Knowledge of gene mutations of hereditary sensory and autonomic neuropathies I, III and IV could lead to more secure diagnosis of the disorders. Effective treatment of essential hyperhidrosis with botulinum toxin injection has been demonstrated. It might be possible to improve treatment of orthostatic hypotension acutely with water imbibation and chronically with erythropoieting.