LGI1 antibody encephalitis: acute treatment comparisons and outcome.

OBJECTIVE: To compare acute treatment responses and long-term outcome in leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis. METHODS: Retrospective case series of 118 patients with LGI1 antibody encephalitis evaluated at Mayo Clinic across all US sites from 1 May 2008 to 31 March 2019. Patient clinical data were identified and analysed through the neuroimmunology laboratory and electronic medical record. LGI1 antibody detection was by cell-based indirect immunofluorescence assay of serum, cerebrospinal fluid or both. Clinical outcomes were faciobrachial dystonic seizure (FBDS) resolution, modified Rankin Scale (mRS) score, Kokmen Short Test of Mental Status (STMS) score (0-38 point scale) and neuropsychometric testing results. RESULTS: Compared with intravenous immunoglobulin (IVIg) (n=21), patients treated with single-agent acute corticosteroids (intravenous, oral or both) (n=49) were more likely to experience resolution of FBDS (61% vs 7%, p=0.002) and improvements in mRS score (ΔmRS score 2 vs 0, p=0.008) and median Kokmen STMS scores (ΔKokmen STMS score 5 points vs 0 points, p=0.01). In 54 patients with long-term follow-up (≥2 years), the median mRS score was 1 (range 0-6) and the median Kokmen STMS score was 36 (range 24-38) after all combinations of immunotherapy. Neuropsychometric testing in 32 patients with long-term follow-up (≥2 years) demonstrated short-term memory impairments in 37%. CONCLUSIONS: Corticosteroids appeared more effective acutely than IVIg in improving LGI1 antibody encephalitis in this retrospective comparison of immunotherapies. While improvement with immunotherapy is typical and long-term outcome is favourable, short-term memory deficits are noted in approximately a third of the patients.

The effectiveness of marine reserve systems constructed using different surrogates of biodiversity.

Biological sampling in marine systems is often limited, and the cost of acquiring new data is high. We sought to assess whether systematic reserves designed using abiotic domains adequately conserve a comprehensive range of species in a tropical marine inter-reef system. We based our assessment on data from the Great Barrier Reef, Australia. We designed reserve systems aiming to conserve 30% of each species based on 4 abiotic surrogate types (abiotic domains; weighted abiotic domains; pre-defined bioregions; and random selection of areas). We evaluated each surrogate in scenarios with and without cost (cost to fishery) and clumping (size of conservation area) constraints. To measure the efficacy of each reserve system for conservation purposes, we evaluated how well 842 species collected at 1155 sites across the Great Barrier Reef seabed were represented in each reserve system. When reserve design included both cost and clumping constraints, the mean proportion of species reaching the conservation target was 20-27% higher for reserve systems that were biologically informed than reserves designed using unweighted environmental data. All domains performed substantially better than random, except when there were no spatial or economic constraints placed on the system design. Under the scenario with no constraints, the mean proportion of species reaching the conservation target ranged from 98.5% to 99.99% across all surrogate domains, whereas the range was 90-96% across all domains when both cost and clumping were considered. This proportion did not change considerably between scenarios where one constraint was imposed and scenarios where both cost and clumping constraints were considered. We conclude that representative reserve systems can be designed using abiotic domains; however, there are substantial benefits if some biological information is incorporated.

Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials.

Protein stabilization and oligonucleotide therapies are being tested in transthyretin amyloid polyneuropathy (TTR FAP) trials. From retrospective analysis of 97 untreated TTR FAP patients, we test the adequacy of Neuropathy Impairment Score+7 tests (NIS+7) and modifications to comprehensively score impairments for use in such therapeutic trials. Our data confirms that TTR FAP usually is a sensorimotor polyneuropathy with autonomic features which usually is symmetric, length dependent, lower limb predominant and progressive. NIS+7 adequately assesses weakness and muscle stretch reflexes without ceiling effects but not sensation loss, autonomic dysfunction or nerve conduction abnormalities. Three modifications of NIS+7 are suggested: 1) use of Smart Somatotopic Quantitative Sensation Testing (S ST QSTing); 2) choice of new autonomic assessments, e.g., sudomotor testing of distributed anatomical sites; and 3) use of only compound muscle action potential amplitudes (of ulnar, peroneal and tibial nerves) and sensory nerve action potentials of ulnar and sural nerve - than the previously recommended attributes suggested for the sensitive detection of diabetic sensorimotor polyneuropathy. These modifications of NIS+7 if used in therapeutic trials should improve characterization and quantification of sensation and autonomic impairment in TTR FAP and provide better nerve conduction tests.

Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.

OBJECTIVE: To evaluate a trial of immunotherapy as an aid to diagnosis in suspected autoimmune epilepsy. METHOD: We reviewed the charts of 110 patients seen at our autoimmune neurology clinic with seizures as a chief complaint. Twenty-nine patients met the following inclusion criteria: (1) autoimmune epilepsy suspected based on the presence of ≥ 1 neural autoantibody (n = 23), personal or family history or physical stigmata of autoimmunity, and frequent or medically intractable seizures; and (2) initiated a 6- to 12-week trial of IV methylprednisolone (IVMP), IV immune globulin (IVIg), or both. Patients were defined as responders if there was a 50% or greater reduction in seizure frequency. RESULTS: Eighteen patients (62%) responded, of whom 10 (34%) became seizure-free; 52% improved with the first agent. Of those receiving a second agent after not responding to the first, 43% improved. A favorable response correlated with shorter interval between symptom onset and treatment initiation (median 9.5 vs 22 months; p = 0.048). Responders included 14/16 (87.5%) patients with antibodies to plasma membrane antigens, 2/6 (33%) patients seropositive for glutamic acid decarboxylase 65 antibodies, and 2/6 (33%) patients without detectable antibodies. Of 13 responders followed for more than 6 months after initiating long-term oral immunosuppression, response was sustained in 11 (85%). CONCLUSIONS: These retrospective findings justify consideration of a trial of immunotherapy in patients with suspected autoimmune epilepsy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with suspected autoimmune epilepsy, IVMP, IVIg, or both improve seizure control.

MRI findings in autoimmune voltage-gated potassium channel complex encephalitis with seizures: one potential etiology for mesial temporal sclerosis.

BACKGROUND AND PURPOSE: Autoimmune voltage-gated potassium channel complex encephalitis is a common form of autoimmune encephalitis. Patients with seizures due to this form of encephalitis commonly have medically intractable epilepsy and may require immunotherapy to control seizures. It is important that radiologists recognize imaging characteristics of this type of autoimmune encephalitis and suggest it in the differential diagnosis because this seizure etiology is likely under-recognized. Our purpose was to characterize MR imaging findings in this patient population. MATERIALS AND METHODS: MR imaging in 42 retrospectively identified patients (22 males; median age, 56 years; age range, 8-79 years) with seizures and voltage-gated potassium channel complex autoantibody seropositivity was evaluated for mesial and extratemporal swelling and/or atrophy, T2 hyperintensity, restricted diffusion, and enhancement. Statistical analysis was performed. RESULTS: Thirty-three of 42 patients (78.6%) demonstrated enlargement and T2 hyperintensity of mesial temporal lobe structures at some time point. Mesial temporal sclerosis was commonly identified (16/33, 48.5%) at follow-up imaging. Six of 9 patients (66.7%, P = .11) initially demonstrating hippocampal enhancement and 8/13 (61.5%, P = .013) showing hippocampal restricted diffusion progressed to mesial temporal sclerosis. Conversely, in 6 of 33 patients, abnormal imaging findings resolved. CONCLUSIONS: Autoimmune voltage-gated potassium channel complex encephalitis is frequently manifested as enlargement, T2 hyperintensity, enhancement, and restricted diffusion of the mesial temporal lobe structures in the acute phase. Recognition of these typical imaging findings may help prompt serologic diagnosis, preventing unnecessary invasive procedures and facilitating early institution of immunotherapy. Serial MR imaging may demonstrate resolution or progression of radiologic changes, including development of changes involving the contralateral side and frequent development of mesial temporal sclerosis.

Critical research needs for managing coral reef marine protected areas: perspectives of academics and managers.

Marine protected areas (MPAs) are a primary policy instrument for managing and protecting coral reefs. Successful MPAs ultimately depend on knowledge-based decision making, where scientific research is integrated into management actions. Fourteen coral reef MPA managers and sixteen academics from eleven research, state and federal government institutions each outlined at least five pertinent research needs for improving the management of MPAs situated in Australian coral reefs. From this list of 173 key questions, we asked members of each group to rank questions in order of urgency, redundancy and importance, which allowed us to explore the extent of perceptional mismatch and overlap among the two groups. Our results suggest the mismatch among MPA managers and academics is small, with no significant difference among the groups in terms of their respective research interests, or the type of questions they pose. However, managers prioritised spatial management and monitoring as research themes, whilst academics identified climate change, resilience, spatial management, fishing and connectivity as the most important topics. Ranking of the posed questions by the two groups was also similar, although managers were less confident about the achievability of the posed research questions and whether questions represented a knowledge gap. We conclude that improved collaboration and knowledge transfer among management and academic groups can be used to achieve similar objectives and enhance the knowledge-based management of MPAs.

TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.

OBJECTIVE: To improve understanding of TRPV4-associated axonal Charcot-Marie-Tooth (CMT) neuropathy phenotypes and their debated pathologic mechanism. METHODS: A total of 17 CMT2C phenotypic families with vocal cord and diaphragmatic involvement and 36 clinically undifferentiated CMT2 subjects underwent sequencing analysis of the coding region of TRPV4. Functional studies of mutant proteins were performed using transiently transfected cells for TRPV4 subcellular localization, basal and stimulated Ca(2+) channel analysis, and cell viability assay with or without channel blockade. RESULTS: Two TRPV4 mutations R232C and R316H from 17 CMT2C families were identified in the ankyrin repeat domains. The R316H is a novel de novo mutation found in a patient with CMT2C phenotype. The family with R232C mutation had individuals with and without vocal cord and diaphragm involvement. Both mutant TRPV4 proteins had normal subcellular localization in HEK293 and HeLa cells. Cells transfected with R232C and R316H displayed increased intracellular Ca(2+) levels and reversible cell death by the TRPV channel antagonist, ruthenium red. CONCLUSION: TRPV4 ankyrin domain alterations including a novel de novo mutation cause axonal CMT2. Individuals with the same mutation may have nondistinct CMT2 or have phenotypic CMT2C with vocal cord paresis. Reversible hypercalcemic gain-of-function of mutant TRPV4 instead of loss-of-function appears to be pathologically important. The reversibility of cell death by channel blockade provides an attractive area of investigation in consideration of treatable axonal degeneration.

Clinical spectrum of voltage-gated potassium channel autoimmunity.

OBJECTIVE: To document neurologic, oncologic, and serologic associations of patients in whom voltage-gated potassium channel (VGKC) autoantibodies were detected in the course of serologic evaluation for neuronal, glial, and muscle autoantibodies. METHODS: Indirect immunofluorescence screening of sera from 130,000 patients performed on a service basis for markers of paraneoplastic neurologic autoimmunity identified 80 patients whose IgG bound to the synapse-rich molecular layer of mouse cerebellar cortex in a pattern consistent with VGKC immunoreactivity. Antibody specificity was confirmed in all cases by immunoprecipitation of detergent-solubilized brain synaptic proteins complexed with (125)I-alpha-dendrotoxin. RESULTS: Clinical information was available for 72 patients: 51% women, median age at symptom onset 65 years, and median follow-up period 14 months. Neurologic manifestations were acute to subacute in onset in 71% and multifocal in 46%; 71% had cognitive impairment, 58% seizures, 33% dysautonomia, 29% myoclonus, 26% dyssomnia, 25% peripheral nerve dysfunction, 21% extrapyramidal dysfunction, and 19% brainstem/cranial nerve dysfunction. Creutzfeldt-Jakob disease was a common misdiagnosis (14%). Neoplasms encountered (confirmed histologically in 33%) included 18 carcinomas, 5 adenomas, 1 thymoma, and 3 hematologic malignancies. Hyponatremia was documented in 36%, other organ-specific autoantibodies in 49%, and a co-existing autoimmune disorder in 33% (including thyroiditis 21%, type 1 diabetes mellitus 11%). Benefit was reported for 34 of 38 patients (89%) receiving immunotherapy and was marked in 50%. CONCLUSIONS: The spectrum of neurologic manifestations and neoplasms associated with voltage-gated potassium channel (VGKC) autoimmunity is broader than previously recognized. Evaluation for VGKC antibodies is recommended in the comprehensive autoimmune serologic testing of subacute idiopathic neurologic disorders.

Striking a balance between biodiversity conservation and socioeconomic viability in the design of marine protected areas.

The establishment of marine protected areas is often viewed as a conflict between conservation and fishing. We considered consumptive and nonconsumptive interests of multiple stakeholders (i.e., fishers, scuba divers, conservationists, managers, scientists) in the systematic design of a network of marine protected areas along California's central coast in the context of the Marine Life Protection Act Initiative. With advice from managers, administrators, and scientists, a representative group of stakeholders defined biodiversity conservation and socioeconomic goals that accommodated social needs and conserved marine ecosystems, consistent with legal requirements. To satisfy biodiversity goals, we targeted 11 marine habitats across 5 depth zones, areas of high species diversity, and areas containing species of special status. We minimized adverse socioeconomic impacts by minimizing negative effects on fishers. We included fine-scale fishing data from the recreational and commercial fishing sectors across 24 fisheries. Protected areas designed with consideration of commercial and recreational fisheries reduced potential impact to the fisheries approximately 21% more than protected areas designed without consideration of fishing effort and resulted in a small increase in the total area protected (approximately 3.4%). We incorporated confidential fishing data without revealing the identity of specific fisheries or individual fishing grounds. We sited a portion of the protected areas near land parks, marine laboratories, and scientific monitoring sites to address nonconsumptive socioeconomic goals. Our results show that a stakeholder-driven design process can use systematic conservation-planning methods to successfully produce options for network design that satisfy multiple conservation and socioeconomic objectives. Marine protected areas that incorporate multiple stakeholder interests without compromising biodiversity conservation goals are more likely to protect marine ecosystems.

Myelin protein zero mutation His39Pro: hereditary motor and sensory neuropathy with variable onset, hearing loss, restless legs and multiple sclerosis.

BACKGROUND: Mutations of myelin protein zero (MPZ) may cause inherited neuropathy with variable expression. OBJECTIVE: To report phenotypic variability in a large American kindred with MPZ mutation His39Pro. PATIENTS: Genetic testing was performed on 77 family members and 200 controls. Clinical and electrophysiological field study assessments were available for review in 47 family members. RESULTS: His39Pro was found in all 10 individuals prospectively identified with neuropathy. 200 normal controls were without mutation. Symptoms of neuropathy began in adulthood and were slowly progressive except for one acute-onset painful sensory neuropathy. Associated features included premature hearing loss (n = 7), nocturnal restless leg symptoms (n = 8) and multiple sclerosis in one. CONCLUSIONS: MPZ mutation His39Pro may be associated with acute-onset neuropathy, early-onset hearing loss and restless legs. The relationship with multiple sclerosis in the proband remains uncertain.

SPTLC1 and RAB7 mutation analysis in dominantly inherited and idiopathic sensory neuropathies.

BACKGROUND: The variable clinical features of hereditary sensory and autonomic neuropathy (HSAN I) suggest heterogeneity. Some cases of idiopathic sensory neuropathy could be caused by missense mutations of SPTLC1 and RAB7 and not be recognised as familial. OBJECTIVE: To screen persons with dominantly inherited HSAN I and others with idiopathic sensory neuropathies for known mutations of SPTLC1 and RAB7. PATIENTS: DNA was examined from well characterised individuals of 25 kindreds with adult onset HSAN I for mutations of SPTLC1 and RAB7; 92 patients with idiopathic sensory neuropathy were also screened for known mutations of these genes. RESULTS: Of the 25 kindreds, only one had a mutation (SPTLC1 399T-->G). This kindred, and 10 without identified mutations, had prominent mutilating foot injuries with peroneal weakness. Of the remainder, 12 had foot insensitivity with injuries but no weakness, one had restless legs and burning feet, and one had dementia with hearing loss. No mutation of RAB7 was found in any of these. No known mutations of SPTLC1 or RAB7 were found in cases of idiopathic sensory neuropathy. CONCLUSIONS: Adult onset HSAN I is clinically and genetically heterogeneous and further work is required to identify additional genetic causes. Known SPTLC1or RAB7 mutations were not found in idiopathic sensory neuropathy.

Chronic immune sensory polyradiculopathy: a possibly treatable sensory ataxia.

BACKGROUND: Chronic inflammatory neuropathies can present with a sensory ataxia due to involvement of dorsal root ganglia (DRG) or sensory nerves. Selective inflammatory involvement of sensory nerve roots proximal to the DRG has been postulated. METHODS: The authors identified 15 patients with a sensory syndrome and normal nerve conduction studies. Sensory nerve root involvement was suggested by either somatosensory evoked potential (SSEP) or imaging abnormalities. CNS disease was excluded. RESULTS: All patients had gait ataxia, large fiber sensory loss, and paresthesias, and nine had frequent falls. The disease course was chronic and progressive (median duration 5 years, range 3 months to 18 years). Sural sensory nerve action potential amplitudes were preserved and SSEP abnormalities were consistent with sensory nerve root involvement. Five patients had enlargement of lumbar nerve roots on MRI with enhancement in three. The CSF protein was elevated in 13 of 14 patients tested. Three patients had lumbar sensory rootlet biopsies that showed thickened rootlets, decreased density of large myelinated fibers, segmental demyelination, onion-bulb formation, and endoneurial inflammation. Six patients who required aids to walk were treated with immune modulating therapy and all had marked improvement with four returning to normal ambulation. CONCLUSION: Based on the described clinical features, normal nerve conduction studies, characteristic somatosensory evoked potential (SSEP) abnormality, enlarged nerve roots, elevated CSF protein, and inflammatory hypertrophic changes of sensory nerve rootlet tissue, we suggest the term chronic immune sensory polyradiculopathy (CISP) for this syndrome. This condition preferentially affects large myelinated fibers of the posterior roots, may respond favorably to treatment, and may be a restricted form of chronic inflammatory demyelinating polyradiculoneuropathy.