Long-term outcomes in a 25-year-old female affected with lipin-1 deficiency.

Lipin-1 is a phosphatidic acid phosphohydrolase (EC 3.1.3.4) that catalyzes the dephosphorylation of phosphatidic acid to diacylglycerol and inorganic phosphate. Deficiency of this enzyme causes potentially fatal severe, recurrent episodes of rhabdomyolysis triggered by infection. The defect has only recently been recognized so little is known about the long-term outcome in adult patients with this disorder. We report the course and outcome of a 25-year-old female patient with lipin-1 deficiency after a recent episode of rhabdomyolysis requiring intensive care admission with a peak creatine kinase of 500 000 IU/L. One-year post discharge from intensive care, the patient has residual drop foot bilaterally consistent with bilateral common peroneal neuropathies in addition to a background residual distal myopathy.

Cycle ergometer training enhances plasma interleukin-10 in multiple sclerosis.

The objective was to determine plasma levels of pro- (IL-12p70/IL-6) and anti-inflammatory (IL-10) cytokines before and after cycle ergometer training in healthy control (HC) and people with multiple sclerosis (pwMS), and to correlate plasma cytokines with physical/mental health. Study participants cycled for 30 min at 65-75% age-predicted maximal heart rate, twice a week for 8 weeks during supervised sessions. We determined that plasma IL-10 expression was lower in pwMS, compared to HCs, and that exercise augmented IL-10 in pwMS to baseline levels in HCs. Furthermore, plasma isolated from pwMS displayed enhanced expression of the pro-inflammatory cytokines IL-12p70/IL-6. Plasma cytokine signatures correlated with physical/mental health. Overall, this study highlights the potential of a short-term exercise programme to regulate circulating cytokine profiles with relevance to pwMS.

Correction to: Cycle ergometer training enhances plasma interleukin-10 in multiple sclerosis.

Following publication the authors informed the Journal that the published version of this article contained a mistake. All occurrences of pg/µl found in the original article should be changed to pg/L. The original article has been corrected. The correction has no impact on the conclusions drawn in the manuscript.

Autoimmune Epilepsy: The Evolving Science of Neural Autoimmunity and Its Impact on Epilepsy Management.

Autoimmune epilepsy is increasingly recognized as a distinct clinical entity, driven in large part by the recent discovery of neural autoantibodies in patients with isolated or predominant epilepsy presentations. Detection of neural autoantibodies in high-risk epilepsy patients supports an immune-mediated cause of seizures and, if applicable, directs the search for an underlying cancer when the paraneoplastic association of the associated antibody is compelling. Early diagnosis of autoimmune epilepsy is crucial, as prompt initiation of immunosuppressive treatment increases the likelihood of achieving either seizure freedom or a substantial reduction in seizure frequency. A practical clinical approach that incorporates risk scores to guide patient selection on the basis of clinical features, neural autoantibodies, and a treatment trial of immunotherapy is suggested. Elucidating an immunological basis of epilepsy provides neurologists with wider treatment options (incorporating immune-suppressive treatment), in addition to standard antiepileptic drugs, which often improves patient outcomes.

Autoimmune Movement Disorders.

Autoimmune movement disorders are rare but potentially treatable entities. They can present with an excess or paucity of movement and may have other associated neurological symptoms. These disorders were originally recognized by their classic clinical presentations and the cancers associated with them. Recent emphasis has been targeted on associated, and sometimes causative, antibodies. Although some disorders have stereotypical presentations, the spectrum of abnormalities reported in association with antibodies is widening. Determining whether antibodies are incidental or pathogenic and, hence, foregoing or commencing immunotherapy treatment can be challenging for practicing neurologists. Physicians often have to make the decision to empirically treat patients while awaiting test results. Due to the lack of randomized controlled trials, the ideal immunotherapy treatments and regimens are unknown. Patients with intracellularly targeted antibodies tend to fare less well, while those with extracellularly targeted antibody disorders often respond to treatments reducing antibody production. This review aims to summarize reported adult-onset autoimmune movement disorders to date, and to provide a template for the workup and treatment of suspected disorders. Rarer antibodies that are not yet fully characterized, or reported in a few cases only, will not be covered in detail as these are not likely to be readily commercially available. Childhood disorders will be only be mentioned briefly in the discussion, as there is a separate article in this issue on autoimmune neurologic diseases in children.

'If there were water we should stop and drink': neurofibromatosis presenting with diabetes insipidus.

A 58-year-old right-handed woman presented to our institution with a 1-month history of polydipsia and polyuria. She had a remote history of neurofibroma excision by dermatology and, on examination, was noted to meet the clinical diagnostic criteria for neurofibromatosis type 1. Laboratory investigations revealed hypernatraemia and elevated serum osmolality, accompanied by reduced urinary osmolality. A subsequent water deprivation test confirmed central diabetes insipidus, which responded to treatment with desmopressin. MRI of the brain showed pituitary enlargement, which raised the possibility of an underlying pituitary adenoma or, alternatively, lymphocytic hypophysitis. Both conditions have rarely been described in neurofibromatosis.

Impact of short-term cycle ergometer training on quality of life, cognition and depressive symptomatology in multiple sclerosis patients: a pilot study.

In this pilot study, we investigate whether a routine cycle ergometry training programme has therapeutic potential in individuals with multiple sclerosis (MS) by improving quality of life (QOL) and depressive symptomatology, while ameliorating cognitive disturbances. Healthy volunteers and MS patients cycled for 30 min at 65-75% age-predicted maximal heart rate on a recumbent ergometer, with this session repeated twice a week for 8 weeks. QOL, depressive symptomatology and cognitive function were assessed pre- and post-exercise using the MS Quality of Life-54 (MSQOL-54) questionnaire, 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16) questionnaire and the Cambridge Neuropsychological Test Automated Battery (CANTAB), respectively. We determined that QOL was lower in MS patients, compared to healthy subjects, with a reduction in physical and mental health summary scores observed. Exercise improved both physical and mental health scores in MS patients. In support of this, exercise was shown to reduce depressive symptomatology in MS patients. Exercise was also associated with an improvement in visual sustained attention, executive function/cognitive flexibility and hippocampal-dependent visuospatial memory in patients. Overall, this study identifies a short-term exercise programme that improves physical and mental health, while reducing depressive symptomatology and cognitive dysfunction in MS.

Impact of Exercise on Innate Immunity in Multiple Sclerosis Progression and Symptomatology.

Multiple Sclerosis (MS), an idiopathic progressive immune-mediated neurological disorder of the central nervous system (CNS), is characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. It accounts for functional deterioration and lasting disability among young adults. A body of literature demonstrates that physical activity counteracts fatigue and depression and may improve overall quality of life in MS patients. Furthermore, much data indicates that exercise ameliorates chronic neuroinflammation and its related pathologies by tipping cytokine profiles toward an anti-inflammatory signature. Recent data has focused on the direct impact of exercise training on the innate immune system by targeting toll-like receptors (TLRs), signaling pattern recognition receptors that govern the innate immune response, shedding light on the physiological role of TLRs in health and disease. Indeed, TLRs continue to emerge as players in the neuroinflammatory processes underpinning MS. This review will highlight evidence that physical activity and exercise are potential immunomodulatory therapies, targeting innate signaling mechanism(s) to modulate MS symptom development and progression.

Alternating hemiparesis and orolingual apraxia as manifestations of methotrexate neurotoxicity in a paediatric case of acute lymphoblastic leukaemia.

A 15-year-old girl with a recent diagnosis of acute lymphoblastic leukaemia was admitted to hospital with pancytopaenia after having received high-dose intrathecal methotrexate 1 day prior. During the next week she had intermittent episodes of alternating hemiparesis associated with speech arrest lasting minutes to hours at a time. The episodes were not associated with altered level of consciousness or headache. MRI of the brain showed features consistent with methotrexate encephalopathy. This report discusses the typical clinical and radiological features of methotrexate neurotoxicity in addition to differential diagnoses and the proposed pathophysiological mechanisms.

Signal recognition particle immunoglobulin g detected incidentally associates with autoimmune myopathy.

INTRODUCTION: Paraneoplastic autoantibody screening of 150,000 patient sera by tissue-based immunofluorescence incidentally revealed 170 with unsuspected signal recognition particle (SRP) immunoglobulin G (IgG), which is a recognized biomarker of autoimmune myopathy. Of the 77 patients with available information, 54 had myopathy. We describe the clinical/laboratory associations. METHODS: Distinctive cytoplasm-binding IgG (mouse tissue substrate) prompted western blot, enzyme-linked immunoassay, and immunoprecipitation analyses. Available histories were reviewed. RESULTS: The immunostaining pattern resembled rough endoplasmic reticulum, and mimicked Purkinje-cell cytoplasmic antibody type 1 IgG/anti-Yo. Immunoblotting revealed ribonucleoprotein reactivity. Recombinant antigens confirmed the following: SRP54 IgG specificity alone (17); SRP72 IgG specificity alone (3); both (32); or neither (2). Coexisting neural autoantibodies were identified in 28% (low titer). Electromyography revealed myopathy with fibrillation potentials; 78% of biopsies had active necrotizing myopathy with minimal inflammation, and 17% had inflammatory myopathy. Immunotherapy responsiveness was typically slow and incomplete, and relapses were frequent on withdrawal. Histologically confirmed cancers (17%) were primarily breast and hematologic, with some others. CONCLUSIONS: Autoimmune necrotizing SRP myopathy, both idiopathic and paraneoplastic, is underdiagnosed in neurological practice. Serological screening aids early diagnosis. Cancer surveillance and appropriate immunosuppressant therapy may improve outcome. Muscle Nerve 53: 925-932, 2016.

Modulation of TLR3/TLR4 inflammatory signaling by the GABAB receptor agonist baclofen in glia and immune cells: relevance to therapeutic effects in multiple sclerosis.

The GABAB receptor agonist, baclofen, is used to treat muscle tightness and cramping caused by spasticity in a number of disorders including multiple sclerosis (MS), but its precise mechanism of action is unknown. Neuroinflammation drives the central pathology in MS and is mediated by both immunoreactive glial cells and invading lymphocytes. Furthermore, a body of data indicates that the Toll-like receptor (TLR) family of innate immune receptors is implicated in MS progression. In the present study we investigated whether modulation of GABAB receptors using baclofen can exert anti-inflammatory effects by targeting TLR3 and(or) TLR4-induced inflammatory signaling in murine glial cells and human peripheral blood mononuclear cells (PBMCs) isolated from healthy control individuals and patients with the relapse-remitting (RR) form of MS. TLR3 and TLR4 stimulation promoted the nuclear sequestration of NF-κB and pro-inflammatory cytokine expression in murine glia, while TLR4, but not TLR3, promoted pro-inflammatory cytokine expression in PBMCs isolated from both healthy donors and RR-MS patients. Importantly, this effect was exacerbated in RR-MS patient immune cells. We present further evidence that baclofen dose-dependently attenuated TLR3- and TLR4-induced inflammatory signaling in primary glial cells. Pre-exposure of PBMCs isolated from healthy donors to baclofen attenuated TLR4-induced TNF-α expression, but did not affect TLR4-induced TNF-α expression in RR-MS patient PBMCs. Interestingly, mRNA expression of the GABAB receptor was reduced in PBMCs from RR-MS donors when compared to healthy controls, an effect that might contribute to the differential sensitivity to baclofen seen in healthy and RR-MS patient cells. Overall these findings indicate that baclofen differentially regulates TLR3 and TLR4 signaling in glia and immune cells, and offers insight on the role of baclofen in the treatment of neuroinflammatory disease states including MS.

Paraneoplastic dentate ganglionopathy: clinical and neuroimmunologic studies.

We describe the clinical and neuropathological features of two cases of cerebellar degeneration with selective involvement of the dentate nucleus. Both cases were associated with malignancy, however known paraneoplastic antibodies were absent. Pathological studies at autopsy confirmed T-cell-mediated neuronal destruction in the cerebellum which was strikingly limited to the dentate nucleus in both patients. The occurrence of these pathological features has not been previously described in antibodynegative paraneoplastic disease, but bears similarities to Rasmussen’s encephalitis.

Paraneoplastic and autoimmune encephalopathies.

Immune-mediated encephalitis is an increasingly recognized cause of neurologic dysfunction including behavioral change, psychosis, movement disorders, seizures, autonomic instability, and coma. Associated antineuronal antibodies are of two main subtypes, those targeting neuronal cell surface antigens, which are pathogenic, and nonpathogenic antibodies targeting intracellular antigens. Antibody identification aids in screening for underlying cancers and prediction of outcome. Cancer is found most commonly with antibodies targeting intracellular neural components. Certain cancers, such as small-cell lung carcinoma, and breast and ovarian cancer are particularly immunogenic. When cancer is detected, oncologic treatment should be followed with immunotherapy. Nonpathogenic antibody disorders respond poorly to treatment, whereas pathogenic antibodies predict a favorable response to immune treatment. If no cancer is identified, then ongoing surveillance is recommended for 5 years after detection of most antineuronal antibodies.

Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study.

BACKGROUND: Complement activation after binding of an IgG autoantibody to aquaporin 4 (AQP4) is thought to be a major determinant of CNS inflammation and astrocytic injury in neuromyelitis optica. The aim of this study was to investigate the use of eculizumab--a therapeutic monoclonal IgG that neutralises the complement protein C5--in neuromyelitis optica spectrum disorders. METHODS: Between Oct 20, 2009, and Nov 3, 2010, we recruited patients from two US centres into an open-label trial. Patients were AQP4-IgG-seropositive, aged at least 18 years, had a neuromyelitis optica spectrum disorder, and had at least two attacks in the preceding 6 months or three in the previous 12 months. Patients received meningococcal vaccine at a screening visit and 2 weeks later began eculizumab treatment. They received 600 mg intravenous eculizumab weekly for 4 weeks, 900 mg in the fifth week, and then 900 mg every 2 weeks for 48 weeks. The coprimary endpoints were efficacy (measured by number of attacks [new worsening of neurological function lasting for more than 24 h and not attributable to an identifiable cause]) and safety. Secondary endpoints were disability (measured by expanded disability status scale), ambulation (Hauser score), and visual acuity. At follow-up visits (after 6 weeks and 3, 6, 9, and 12 months of treatment; and 3 and 12 months after discontinuation), complete neurological examination was undertaken and an adverse event questionnaire completed. This trial is registered with ClinicalTrials.gov, number NCT00904826. FINDINGS: We enrolled 14 patients, all of whom were women. After 12 months of eculizumab treatment, 12 patients were relapse free; two had had possible attacks. The median number of attacks per year fell from three before treatment (range two to four) to zero (zero to one) during treatment (p<0·0001). No patient had worsened disability by any outcome measure. Median score on the expanded disability status scale improved from 4·3 (range 1·0-8·0) before treatment to 3·5 (0-8·0) during treatment (p=0·0078). Two patients improved by two points and three improved by one point on the Hauser score; no change was recorded for the other patients. Visual acuity had improved in at least one eye by one point in four patients, and by two points in one patient; no change was recorded for other patients. One patient had meningococcal sepsis and sterile meningitis about 2 months after the first eculizumab infusion, but resumed treatment after full recovery. No other drug-related serious adverse events occurred. Eight attacks in five patients were reported within 12 months of eculizumab withdrawal. INTERPRETATION: Eculizumab seems to be well tolerated, significantly reduce attack frequency, and stabilise or improve neurological disability measures in patients with aggressive neuromyelitis optica spectrum disorders. The apparent effects of eculizumab deserve further investigation in larger, randomised controlled studies. FUNDING: Alexion Pharmaceuticals.

Autoimmune chorea in adults.

OBJECTIVES: To determine the characteristics of adult-onset autoimmune chorea, and compare paraneoplastic and idiopathic subgroups. METHODS: Thirty-six adults with autoimmune chorea were identified at Mayo Clinic (Rochester, MN) from 1997 to 2012. Medical record and laboratory data were recorded. Nonparaneoplastic (n = 22) and paraneoplastic cases (n = 14) were compared. RESULTS: Women accounted for 21 patients (58%). Median age at symptom onset was 67 years (range 18-87 years). We estimated the incidence for Olmsted County was 1.5 per million person-years. Symptom onset was subacute in all. Chorea was focal (20 patients) or generalized (16 patients). Although chorea predominated, other neurologic disorders frequently coexisted (29 patients); abnormal eye movements were uncommon (4 patients). No patient had NMDA receptor antibody or any immunoglobulin (Ig)G yielding a detectable immunofluorescence binding pattern restricted to basal ganglia. Two had synaptic IgG antibodies novel to the context of chorea (GAD65, 1; CASPR2, 1). In the paraneoplastic group, 14 patients had evidence of cancer. Of 13 with a histopathologically confirmed neoplasm, small-cell carcinoma and adenocarcinoma were most common; 6 patients had a cancer-predictive paraneoplastic autoantibody, with CRMP-5-IgG and ANNA-1 being most common. In the idiopathic group, 19 of the 22 patients had a coexisting autoimmune disorder (most frequently systemic lupus erythematosus and antiphospholipid syndrome); autoantibodies were detected in 21 patients, most frequently lupus and phospholipid specificities (19 patients). The paraneoplastic group was older (p = 0.001), more frequently male (p = 0.006), had more frequent weight loss (p = 0.02), and frequently had peripheral neuropathy (p = 0.008). CONCLUSIONS: Autoimmune chorea is a rare disorder with rapid onset. Male sex, older age, severe chorea, coexisting peripheral neuropathy, and weight loss increase the likelihood of cancer.

Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping.

OBJECTIVE: To determine, in patients identified as seropositive for neuronal voltage-gated potassium channel (VGKC) complex autoantibodies, the spectrum of clinical presentations and frequency of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) as defined antigenic neuronal targets in the VGKC macromolecular complex. DESIGN: Retrospective cohort study. SETTING: Clinical practice, Mayo Clinic Neuroimmunology Laboratory and Department of Neurology. PATIENTS: A total of 54 853 patients were evaluated, of whom 1992 were found to be VGKC complex IgG positive. RESULTS: From June 1, 2008, to June 30, 2010, comprehensive service serologic evaluation performed on 54853 patients with unexplained neurologic symptoms identified 1992 patients (4%) who were positive for VGKC complex IgG (values ≥ 0.03 nmol/L). Among 316 seropositive patients evaluated clinically at our institution, 82 (26%) were seropositive for LGI1 IgG and/or CASPR2 IgG. Of these 82 patients, 27% had low (0.03-0.09 nmol/L), 51% had medium (0.10-0.99 nmol/L), and 22% had high (≥ 1.00 nmol/L) VGKC complex IgG values. Leucine-rich glioma-inactivated protein 1 IgG positivity was associated with higher VGKC complex IgG values (P< .001) and cortical presentations (P< .001); CASPR2 IgG was associated with peripheral motor excitability (P= .009). However, neither autoantibody was pathognomonic for a specific neurologic presentation or correlated significantly with cancer. Neurologic phenotypes were diverse. Cerebrocortical manifestations (including cognitive impairment and seizures) were recorded in 76% of patients with LGI1 IgG alone (n=46) and 29% with CASPR2 IgG alone (n=28). Peripheral motor hyperexcitability was found in 21% of patients with CASPR2 IgG alone and 6.5% of patients with LGI1 IgG alone. CONCLUSIONS: The study emphasizes diverse and overlapping neurologic phenotypes across a range of VGKC complex IgG values and varying LGI1 IgG and CASPR2 IgG specificities. The frequent occurrence of LGI1 IgG and CASPR2 IgG in serum samples with low and medium VGKC complex IgG values supports the clinical significance of low values in clinical evaluation. Additional antigenic components of VGKC macromolecular complexes remain to be defined.