Summary Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.

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A clinical approach to diagnosis of autoimmune encephalitis

Since its discovery in 2007, the encephalitis associated with antibodies against the N-methyl-D-aspartate receptor (NMDAR) has entered the mainstream of neurology and other disciplines. Most patients with anti-NMDAR encephalitis develop a multistage illness that progresses from psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and breathing instability. The disorder predominantly affects children and young adults, occurs with or without tumour association, and responds to treatment but can relapse. The presence of a tumour (usually an ovarian teratoma) is dependent on age, sex, and ethnicity, being more frequent in women older than 18 years, and slightly more predominant in black women than it is in white women. Patients treated with tumour resection and immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) respond faster to treatment and less frequently need second-line immunotherapy (cyclophosphamide or rituximab, or both) than do patients without a tumour who receive similar initial immunotherapy. More than 75% of all patients have substantial recovery that occurs in inverse order of symptom development and is associated with a decline of antibody titres. Patients' antibodies cause a titre-dependent, reversible decrease of synaptic NMDAR by a mechanism of crosslinking and internalisation. On the basis of models of pharmacological or genetic disruption of NMDAR, these antibody effects reveal a probable pathogenic relation between the depletion of receptors and the clinical features of anti-NMDAR encephalitis.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(10)70253-2.pdf

Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis

Inflammatory reactions occur in the brain in various CNS diseases, including autoimmune, neurodegenerative, and epileptic disorders. Proinflammatory and antiinflammatory cytokines and related molecules have been described in CNS and plasma, in experimental models of seizures and in clinical cases of epilepsy. Inflammation involves both the innate and the adaptive immune systems and shares molecules and pathways also activated by systemic infection. Experimental studies in rodents show that inflammatory reactions in the brain can enhance neuronal excitability, impair cell survival, and increase the permeability of the blood-brain barrier to blood-borne molecules and cells. Moreover, some antiinflammatory treatments reduce seizures in experimental models and, in some instances, in clinical cases of epilepsy. However, inflammatory reactions in brain also can be beneficial, depending on the tissue microenvironment, the inflammatory mediators produced in injured tissue, the functional status of the target cells, and the length of time the tissue is exposed to inflammation. We provide an overview of the current knowledge in this field and attempt to bridge experimental and clinical evidence to discuss critically the possibility that inflammation may be a common factor contributing, or predisposing, to the occurrence of seizures and cell death, in various forms of epilepsy of different etiologies. The elucidation of this aspect may open new perspectives for the pharmacologic treatment of seizures.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1167.2005.00298.x

Brain inflammation in epilepsy: experimental and clinical evidence.

Objective: To describe a distinctive seizure semiology that closely associates with voltage-gated potassium channel (VGKC)-complex/Lgi1 antibodies and commonly precedes the onset of limbic encephalitis (LE). Methods: Twenty-nine patients were identified by the authors (n ¼ 15) or referring clinicians (n ¼ 14). The temporal progression of clinical features and serum sodium, brain magnetic resonance imaging (MRI), positron emission tomography/single photon emission computed tomography, and VGKC-complex antibodies was studied. Results: Videos and still images showed a distinctive adult-onset, frequent, brief dystonic seizure semiology that predominantly affected the arm and ipsilateral face. We have termed these faciobrachial dystonic seizures (FBDS). All patients tested during their illness had antibodies to VGKC complexes; the specific antigenic target was Lgi1 in 89%. Whereas 3 patients never developed LE, 20 of the remaining 26 (77%) experienced FBDS prior to the development of the amnesia and confusion that characterize LE. During the prodrome of FBDS alone, patients had normal sodium and brain MRIs, but electroencephalography demonstrated ictal epileptiform activity in 7 patients (24%). Following development of LE, the patients often developed other seizure semiologies, including typical mesial temporal lobe seizures. At this stage, investigations commonly showed hyponatremia and MRI hippocampal high T2 signal; functional brain imaging showed evidence of basal ganglia involvement in 5/8. Antiepileptic drugs (AEDs) were generally ineffective and in 41% were associated with cutaneous reactions that were often severe. By contrast, immunotherapies produced a clear, and often dramatic, reduction in FBDS frequency. Interpretation: Recognition of FBDS should prompt testing for VGKC-complex/Lgi1 antibodies. AEDs often produce adverse effects; treatment with immunotherapies may prevent the development of LE with its potential for cerebral atrophy and cognitive impairment. ANN NEUROL 2010;000:000–000

Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)60456-6.pdf

Epilepsy: new advances

Antibodies that immunoprecipitate (125)I-alpha-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan's syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with (125)I-alpha-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan's syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.

Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.

Antibodies to glutamic acid decarboxylase (GAD), the major pathway for the synthesis of c-aminobutyric acid(GABA) in humans, are found at elevated levels in a subgroup of patients with chronic epilepsy. To test whether the antibodies were associated with changes in cortical GABA levels we used magnetic resonance spectroscopy. Four patients with epilepsy and high serum GAD antibody levels (107-6,200 units/ml) and 10 healthy controls were recruited. A 3T GABA-optimized spectrum was obtained from a reproducible voxel in the cortex. Compared to the control group, the patient group had significantly lower GABA concentrations within the cortex. Demonstration of an association between high serum GAD antibodies and low cortical GABA levels in patients with epilepsy suggests that GAD antibodies are, at least, a marker of a specific disease process and support a role for immune-mediated GABAergic dysfunction.

Autoantibodies to glutamic acid decarboxylase in patients with epilepsy are associated with low cortical GABA levels

Antibodies to neuronal alpha7 acetylcholine receptor in patients with Rasmussen's encephalitis

Viral vectors for immunisation against potassium channel Kv1.2

Opsoclonus–myoclonus syndrome (OMS) in children is a rare disorder including a severe eye movement disturbance, myoclonia, ataxia and often developmental retardation. Both OMS forms, idiopathic or neuroblastoma-associated (paraneoplastic), have been suspected to be autoimmune. Recently,autoantibodieshavebeenfoundinOMSsera.WehereshowthatautoantibodiesinOMS,bothintracellularandsurfacebinding,belongmainly tothe IgG3subclass, although the total serum IgG3 levelis normal.These results supportthe autoimmunehypothesis andpoint toa protein autoantigen as antigenic target. © 2007 Elsevier B.V. All rights reserved.

B Lang

Papers

Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.

Autoantibodies to glutamic acid decarboxylase in patients with epilepsy are associated with low cortical GABA levels

Antibodies to neuronal alpha7 acetylcholine receptor in patients with Rasmussen's encephalitis

Viral vectors for immunisation against potassium channel Kv1.2

Short communication IgG subclass distribution of autoantibodies in pediatric opsoclonus-myoclonus syndrome