A feline model of spontaneously occurring autoimmune limbic encephalitis.

Autoimmune encephalitis (AE) is an important cause of encephalitis in humans and occurs at a similar rate to infectious encephalitis. It is frequently associated with antibodies against the extracellular domain of neuronal proteins. Among human AE, that with antibodies against leucine-rich glioma-inactivated 1 (LGI1) is one of the most prevalent forms, and was recently described in cats with limbic encephalitis (LE). In this study, we describe a large cohort (n = 32) of cats with AE, tested positive for voltage gated potassium channel (VGKC)-antibodies, of which 26 (81%) harboured LGI1-antibodies. We delineate their clinical and paraclinical features as well as long-term outcomes up to 5 years. Similar to human cases, most cats with LGI1-antibodies had a history of focal seizures (83%), clustering in the majority (88%), with interictal behavioural changes (73%). Among feline AE patients, there was no seizure type or other clinical characteristic that could distinguish LGI1-antibody positive from negative cats, unlike the pathognomic faciobrachial dystonic seizures seen in humans. Although six cats were euthanased in the first year for epilepsy-associated reasons, those attaining at least 1-year survival had good seizure control and quality of life with appropriate veterinary care and medication. Acute-phase immunotherapy (prednisolone) was given to the most severely unwell cases and its effect is retrospectively evaluated in 10 cats. Our data show LGI1-antibodies are an important cause of feline encephalitis, sharing many features with human AE. Further research should examine optimal therapeutic management strategies and the cause of LE in seronegative cats, building on paradigms established in the counterpart human disease.

LGI1-antibody associated epilepsy successfully treated in the outpatient setting.

We report six patients with anti-LGI1 associated epilepsy. Two patients presented with new-onset generalized tonic-clonic seizures, four developed faciobrachial dystonic seizures and two piloerection. All patients had significant cognitive complaints at the time of diagnosis. All patients described seizure reduction during the first week of carbamazepine, and seizure freedom was obtained at a median of 13 days (range 7-22), sustained after the initiation of immunosuppression. Median time from symptom onset to carbamazepine initiation was 164 days (range 38-206 days). We discuss the particular seizure response to sodium channel blocking antiepileptic drugs, alone or associated with immunosuppression in this antibody mediated seizures.

Acquired neuromyotonia in thymoma-associated myasthenia gravis: a clinical and serological study.

BACKGROUND AND PURPOSE: Acquired neuromyotonia can occur in patients with thymoma, alone or in association with myasthenia gravis (MG), but the clinical prognostic significance of such comorbidity is largely unknown. The clinico-pathological features were investigated along with the occurrence of neuromyotonia as predictors of tumour recurrence in patients with thymoma-associated myasthenia. METHODS: A total number of 268 patients with thymomatous MG were studied retrospectively. Patients with symptoms of spontaneous muscle overactivity were selected for autoantibody testing using immunohistology for neuronal cell-surface proteins and cell-based assays for contactin-associated protein 2 (CASPR2), leucine-rich glioma inactivated 1 (LGI1), glycine receptor and Netrin-1 receptor antibodies. Neuromyotonia was diagnosed according to the presence of typical electromyography abnormalities and/or autoantibodies against LGI1/CASPR2. RESULTS: Overall, 33/268 (12%) MG patients had a thymoma recurrence. Five/268 (2%) had neuromyotonia, four with typical autoantibodies, including LGI1 (n = 1), CASPR2 (n = 1) or both (n = 2). Three patients had Netrin-1 receptor antibodies, two with neuromyotonia and concomitant CASPR2+LGI1 antibodies and one with spontaneous muscle overactivity without electromyography evidence of neuromyotonia. Thymoma recurrence was more frequent in those with (4/5, 80%) than in those without (28/263, 10%, P < 0.001) neuromyotonia. Neuromyotonia preceded the recurrence in 4/5 patients. In univariate analysis, predictors of thymoma recurrence were age at thymectomy [odds ratio (OR) 0.95, 95% confidence interval (CI) 0.93-0.97], Masaoka stage ≥IIb (OR 10.73, 95% CI 2.38-48.36) and neuromyotonia (OR 41.78, 95% CI 4.71-370.58). CONCLUSIONS: De novo occurrence of neuromyotonia in MG patients with previous thymomas is a rare event and may herald tumour recurrence. Neuronal autoantibodies can be helpful to assess the diagnosis. These observations provide pragmatic risk stratification for tumour vigilance in patients with thymomatous MG.

Use of intravenous immunoglobulin for the treatment of autoimmune encephalitis: audit of the NHS experience.

OBJECTIVES: The treatments of limbic and other autoimmune encephalitis include immunosuppression, symptomatic treatment, and in the case of paraneoplastic syndromes, appropriate therapy for underlying neoplasms. When immunotherapy is considered, intravenous immunoglobulin is one option for treatment, either alone or in combination with corticosteroids. To date, however, evidence for the use of intravenous immunoglobulin in this context comes from case series/expert reviews as no controlled trials have been performed. We aimed to analyse the NHS England Database of intravenous immunoglobulin usage, which was designed to log use and guide procurement, to explore usage and therapeutic effect of intravenous immunoglobulin in autoimmune encephalitis in England. DESIGN: We conducted a retrospective audit and review of the NHS England Database on intravenous immunoglobulin use. SETTING: NHS England Database of intravenous immunoglobulin use which covers secondary and tertiary care prescribing and use of intravenous immunoglobulin for all patients in hospitals in England. PARTICIPANTS: Hospital in-patients with confirmed or suspected autoimmune/limbic encephalitis between September 2010 and January 2017. RESULTS: A total of 625 patients who were 18 years of age or older were treated with intravenous immunoglobulin for autoimmune encephalitis, of whom 398 were determined as having 'highly likely' or 'definite' autoimmune/limbic encephalitis. Ninety-six percent were treated with a single course of intravenous immunoglobulin. The availability and accuracy of reporting of outcomes was very poor, with complete data only available in 27% of all cases. CONCLUSIONS: This is the first review of data from this unique national database. Whilst there was evidence for clinical improvement in many cases of patients treated with intravenous immunoglobulin, the quality of outcome data was generally inadequate. Methods to improve quality, accuracy and completeness of reporting are crucial to maximise the potential value of this resource as an auditing tool.

Antiglycine receptor antibody related disease: a case series and literature review.

BACKGROUND AND PURPOSE: Antibodies to glycine receptors (GlyR-Abs) were first defined in progressive encephalopathy with rigidity and myoclonus (PERM) but were subsequently identified in other clinical presentations. Our aim was to assess the clinical associations of all patients identified with GlyR-Abs in Queensland, Australia, between April 2014 and May 2017 and to compare these to cases reported in the literature. METHODS: A literature review identified the clinical features of all published GlyR-Ab-positive cases through online databases. A case series was undertaken via collection of clinical information from all patients diagnosed or known to immunology, pathology or neurological services in Queensland during the study period of 3 years. RESULTS: In all, 187 GlyR-Ab-positive cases were identified in the literature. The majority (47.6%) had PERM, 22.4% had epilepsy, but the remaining 30% included mixed phenotypes consisting of cerebellar ataxia, movement disorders, demyelination and encephalitis/cognitive dysfunction. By contrast, in our series of 14 cases, eight had clinical presentations consistent with seizures and epilepsy and only three cases had classical features of PERM. There was one case each of global fatiguable weakness with sustained clonus, laryngeal dystonia and movement disorder with hemiballismus and tics. The rate of response to immune therapy was similar in all groups. CONCLUSION: Antibodies to glycine receptors are linked to a spectrum of neurological disease. The results of the literature review and our case series suggest a greater relationship between GlyR-Abs and epilepsy than previously reported.

Autoantibodies to central nervous system neuronal surface antigens: psychiatric symptoms and psychopharmacological implications.

RATIONALE: Autoantibodies to central nervous system (CNS) neuronal surface antigens have been described in association with autoimmune encephalopathies which prominently feature psychiatric symptoms in addition to neurological symptoms. The potential role of these autoantibodies in primary psychiatric diseases such as schizophrenia or bipolar affective disorder is of increasing interest. OBJECTIVES: We aimed to review the nature of psychiatric symptoms associated with neuronal surface autoantibodies, in the context of autoimmune encephalopathies as well as primary psychiatric disorders, and to review the mechanisms of action of these autoantibodies from a psychopharmacological perspective. RESULTS: The functional effects of the autoantibodies on their target antigens are described; their clinical expression is at least in part mediated by their effects on neuronal receptor function, primarily at the synapse, usually resulting in receptor hypofunction. The psychiatric effects of the antibodies are related to known functions of the receptor target or its complexed proteins, with reference to supportive genetic and pharmacological evidence where relevant. Evidence for a causal role of these autoantibodies in primary psychiatric disease is increasing but remains controversial; relevant methodological controversies are outlined. Non-receptor-based mechanisms of autoantibody action, including neuroinflammatory mechanisms, and therapeutic implications are discussed. CONCLUSIONS: An analysis of the autoantibodies from a psychopharmacological perspective, as endogenous, bioactive, highly specific, receptor-targeting molecules, provides a valuable opportunity to understand the neurobiological basis of associated psychiatric symptoms. Potentially, new treatment strategies will emerge from the improving understanding of antibody-antigen interaction within the CNS.

More than memory impairment in voltage-gated potassium channel complex encephalopathy.

BACKGROUND AND PURPOSE: Autoimmune encephalopathies (AEs) are a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly endorsed, few reports of AEs inclusively assess all cognitive domains in detail. Our aim was to perform an unbiased cognitive evaluation of AE patients with voltage-gated potassium channel complex antibodies (VGKCC -Abs) in order to delineate cognitive strengths and weaknesses. METHODS: Serial VGKCC -Ab AE subjects (n = 12) were assessed with a comprehensive evaluation of memory, executive functions, visuospatial skills and language. Clinical magnetic resonance imaging (MRI) (n = 10/12) was evaluated. Five subjects had serial cognitive testing available, permitting descriptive analysis of change. RESULTS: Subjects demonstrated mild to moderate impairment in memory (mean Z = -1.9) and executive functions (mean Z = -1.5), with variable impairments in language and sparing of visuospatial skills. MRI findings showed T2 hyperintensities in medial temporal lobe (10/10) and basal ganglia (2/10). Serial cognitive examination revealed heterogeneity in cognitive function; whereas most patients improved in one or more domains, residual impairments were observed in some patients. CONCLUSIONS: This study augments previous neuropsychological analyses in VGKCC -Ab AE by identifying not only memory and executive function deficits but also language impairments, with preservation of visuospatial functioning. The study further highlights the importance of domain-specific testing to parse out the complex cognitive phenotypes of VGKCC -Ab AE.

Progressive encephalomyelitis with rigidity and myoclonus: glycine and NMDA receptor antibodies.

BACKGROUND: The syndrome of progressive encephalopathy with limb rigidity has been historically termed progressive encephalomyelitis with rigidity and myoclonus (PERM) or stiff-person syndrome plus. METHODS: The case is presented of a previously healthy 28-year-old man with a rapidly fatal form of PERM developing over 2 months. RESULTS: Serum antibodies to both NMDA receptors (NMDAR) and glycine receptors (GlyR) were detected postmortem, and examination of the brain confirmed an autoimmune encephalomyelitis, with particular involvement of hippocampal pyramidal and cerebellar Purkinje cells and relative sparing of the neocortex. No evidence for an underlying systemic neoplasm was found. CONCLUSION: This case displayed not only the clinical features of PERM, previously associated with GlyR antibodies, but also some of the features associated with NMDAR antibodies. This unusual combination of antibodies may be responsible for the particularly progressive course and sudden death.

Hypothermia in VGKC antibody-associated limbic encephalitis.

Voltage-gated potassium channel antibody (VGKC-Ab)-associated limbic encephalitis (LE) is a recently described syndrome that broadens the spectrum of immunotherapy-responsive central nervous system disorders. Limbic encephalitis is typically characterised by a sub-acute onset of disorientation, amnesia and seizures, but the clinical spectrum is not yet fully defined and the syndrome could be under-diagnosed. We here describe the clinical profile of four patients with VGKC-Ab-associated LE who had intermittent, episodic hypothermia. One of the patients also described a prodrome of severe neuropathic pain preceding the development of limbic symptoms. Both of these novel symptoms responded well to immunosuppressive therapy, with concurrent amelioration of amnesia/seizures.

The validity and reliability of 6 sets of clinical criteria to classify Alzheimer's disease and vascular dementia in cases confirmed post-mortem: added value of a decision tree approach.

Data from 204 participants from the Oxford Project to Investigate Memory and Ageing, who were diagnosed post-mortem using the histopathological criteria of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), were used to assess the validity of the clinical criteria for Alzheimer's disease (AD) of the 'National Institute of Neurological and Communicative Disorders and Stroke/the Alzheimer's Disease and Related Disorders Association' (NINCDS/ADRDA). Cases who had been diagnosed as NINCDS/ADRDA 'probable AD' in life were usually confirmed at autopsy, but half of the NINCDS/ADRDA 'negative' cases were not (low specificity). It was hypothesized that the overall clinical impression may have taken precedence over the use of the actual criteria. We therefore investigated the validity and reliability of the clinical criteria using a computerized 'dementia diagnosis system' for each of 6 sets of criteria [Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), NINCDS/ADRDA and three sets of criteria specifically for vascular dementia (VaD): NINCDS-AIREN, State of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC), and Vascular Cognitive Impairment (VCI)] to classify a subset (n = 96) of the cases confirmed post-mortem. The use of the computerized system significantly (p = 0.01) increased the specificity (81%, similar to sensitivity) of the NINCDS/ADRDA diagnoses, which were shown to have 'moderate' inter-rater reliability. The DSM-IV criteria had good validity for AD when compared with post-mortem confirmation and showed 'substantial' inter-rater reliability. The ADDTC and VCI criteria for VaD had good specificity (88%) and sensitivity (75%), but only for one rater. The DSM-IV and NINCDS-AIREN criteria for VaD showed poor validity and inter-rater reliability. We conclude that the forced use of decision trees through a computerized system enhances the accuracy of the clinical diagnoses of dementia.