AUTOIMMUNE ENCEPHALITIS Learning Objectives Introduction Subsets of encephalitis

AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Autoimmune Encephalitis Saiju Jacob and Sarosh R Irani Saiju Jacob is a Consultant Neurologist at the Queen Elizabeth Neurosciences Centre in Birmingham. He has completed a Dphil fellowship in Oxford under the guidance of Prof Angela Vincent. He is interested in neuroimmunological diseases of the peripheral and central nervous systems. Sarosh R Irani is a Neurology Registrar in Oxford. He recently completed a Dphil with Professor Vincent, studying NMDAR-antibodies and helped discover Lgi 1, Caspr 2 and Contactin-2 as the true targets of VGKC-complex antibodies. Both authors would like to acknowledge the helpful comments of Professor Angela Vincent while writing this module. This session provides a review of the expanding spectrum of autoantibody-mediated central nervous system conditions. Edited by Tom Solomon and Agam Jung

Learning Objectives AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions By the end of this session you will be able to • Outline the different subsets of autoimmune encephalitis with particular reference to autoantibody-mediated encephalitis • Illustrate the pathogenesis of paraneoplastic and nonparaneoplastic autoimmune encephalitis • Define key clinical features in the different antibodymediated encephalitis • List the key investigation results in the different antibodymediated encephalitis • Summarise an approach to the management of antibodymediated encephalitis

Introduction AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Traditionally, the vast majority of encephalitides have been ascribed a microbiological aetiology. However, often this has been unproven and recently it has been recognised that many are due to immunological, often autoimmune, mechanisms. These autoimmune encephalitides have some characteristic clinical and paraclinical features which should allow the clinician to suspect the illness early on. This is important as many of these diseases respond well to prompt administration of available immunotherapies. In many of the more common forms of antibody-associated encephalitis, an autoantibody is likely to be directly pathogenic. In the minority of cases, the autoantibody is associated with the presence of a remote tumour (paraneoplastic) but more often these diseases are non-paraneoplastic and the trigger is unclear. Image: MRI showing Rt medial temporal lobe high signal changes (arrow) in limbic encephalitis

Subsets of Encephalitis AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Inflammation of the brain (encephalitis) commonly presents with amnesia, seizures and confusion. It has usually been thought to be due to infectious organisms. HSV-1 and enteroviruses are amongst the most common viruses implicated. A list of causes in descending frequency, from a recent study, is shown in the table below. An autoimmune aetiology should be considered early in the diagnosis, especially when the presentation is subacute or if specific clinical features and investigation results are present (described later). Occasionally, the presentation could be associated with an underlying remote neoplasia, as a 'paraneoplastic' syndrome. Adapted from Granerod J et al. Lancet Infect Dis. 2010; 10: 835 -44. HSV, hepes simplex virus; ADEM, acute disseminated encephalomyelitis; VGKC, voltage gated potassium channels; NMDAR, “NMDA” receptor; MTB, mycobacteria tuberculosis; VZV, varicella zoster virus.

AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Different Subsets of Autoimmune Encephalitis II Limbic encephalitis (LE) typically produces subacute memory impairment, confusion and seizures. Many patients have mesial temporal lobe inflammation radiologically and pathologically. Other clinical and paraclinical findings vary depending on the underlying cause. Based on the target of the antibodies, LE can be broadly classified into two types: • Antibodies against intracellular targets, which are almost always associated with a paraneoplastic LE. Prognosis is poor and treatment options limited. • Antibodies against neuronal cell surface antigens, which are more common and most often nonparaneoplastic. These patients tend to have a better prognosis. IMAGE: Picture of the limbic system

Paraneoplastic Encephalitis AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions These antibodies are usually against intracellular targets and are often referred to as 'onconeural antibodies'. Common examples include those directed against Hu, Ma 2, CV 2/CRMP 5 and amphiphysin. Clinical syndromes are diverse and although some improvement may occur after identification and removal of the primary tumour, the prognosis in general is poor. GAD antibodies also have been recently associated with LE, although this is not usually paraneoplastic. On the other hand, autoantibody-mediated limbic encephalitis has a good prognosis when identified early and treated with appropriate immunomodulatory therapies. Only the minority of cases are associated with an underlying tumour.

Paraneoplastic Encephalitis II AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions

AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Non-Paraneoplastic Encephalitis Over the last decade, several antibodies have been described, which are most often associated with non-paraneoplastic limbic encephalitis. These antibodies are directed against targets on neuronal cell surface membranes (unlike the paraneoplastic antibodies described earlier). Several antibodies directed at functionally important antigens have been described including: • Lgi 1, Caspr 2 and Contactin-2 (voltage gated potassium channel complex antibodies). • NMDA receptor antibodies • AMPA receptor antibodies • GABAB receptor antibodies • Glycine receptor antibodies We will review the important clinical and paraclinical features of some of these conditions.

AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions VGKC-complex Antibody Associated Limbic Encephalitis (LE) Antibodies against 'voltage gated potassium channels' ('VGKC') have been identified frequently in patients who usually present with a non-paraneoplastic LE. Patients usually present with subacute memory loss, confusion and seizures. Hyponatremia is found in a significant number of patients and can often be a clue to the diagnosis. These 'VGKC' antibodies were previously found in patients with peripheral nerve symptoms like neuromyotonia (characterised by cramps and fasciculations) or Morvan's syndrome (neurpmyotonia with autonomic, cognitive and sleep disturbances). In all these conditions, the VGKC-complex antibody levels fall in response to immunotherapy, which commonly involves intravenous immunoglobulins or plasma exchange. This is usually accompanied by a clinical improvement.

AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions VGKC-complex Antibody Associated Limbic Encephalitis II T 2 -weighted/FLAIR MRI shows medial temporal lobe high signal in 60% of patients. CSF changes are usually non-specific with mild lymphocytosis and marginally raised protein seen in around 25% of the patients. 'VGKC' antibodies are detected by immunoprecipitation of 125 I-α-dendrotoxin (DTX) labelled rabbit brain membranes which have been solubilised in a mild detergent. Dendrotoxin labels some Kv 1 channels. Recent studies have shown that the target for these antibodies may be the proteins complexed with VGKC, rather than the VGKCs themselves. These 'VGKC-complex' antigenic targets (see image) include: • Leucine-rich glioma inactivated 1 protein, Lgi 1 • Contactin-associated protein 2, Caspr 2 • Contactin-2/TAG-1 (rarely). These four proteins are coassociated in brain tissue.

AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions VGKC-complex Antibody Associated Limbic Encephalitis III Neuropsychiatric features, amnesia, confusion, serum hyponatraemia and MRI medial temporal lobe changes, all consistent with LE, are most commonly seen in patients with Lgi 1 antibodies. In contrast, Morvan's syndrome and neuromyotonia are more commonly associated with in Caspr 2 antibodies. Although the proportion of patients with underlying tumours is low, when present, they are almost always associated with Caspr 2 antibodies and are most frequently thymomas and less often small cell lung carcinoma. Until further refinement of these assays are available, radioimmunoassay for VGKC-complex antibodies should remain the gold standard for diagnosis in this group of patients, as a minority of VGKC-complex antibodies still do not have a defined antigen. Hippocampal cultures showing surface binding Caspr 2 (left) and Lgi 1 ig. G. From Irani et al. Brain 2010; 133: 2734

AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Faciobrachial Dystonic Seizures as a Prodrome to Lgi 1 antibody Encephalitis Recently, a novel adult-onset seizure semiology has been recognised with dystonic face and ipsilateral arm involvement. Seizures occur very frequently and are very brief. Almost all patients have Lgi 1 antibodies. Interestingly, many patients with these 'faciobrachial dystonic' seizures (FBDS) progress to develop a typical LE with amnesia and confusion. As the FBDS are often very sensitive to immunotherapies, and not so responsive to antiepileptic drugs, their recognition and early treatment may prevent the onset of a fullblown LE. Immunotherapies (IT), antiepileptic drugs (AEDs). From Irani et al. Ann Neurol. 2011; 69: 892.

NMDAR Encephalitis AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions The clinical syndrome of women with ovarian teratoma presenting with psychosis, memory loss, seizures, autonomic fluctuations, respiratory depression and coma has been recognised for at least 5 years. In 2007, antibodies known to be directed against neuronal surface antigens were shown to target N-methyl D-aspartate receptors (NMDAR). Initially, this was thought to be a rare paraneoplastic condition affecting young women with ovarian teratoma, the removal of which often combined with immunotherapy, improves the clinical outcome. This condition is now getting increasingly recognised in both sexes and in children and is more often non-paraneoplastic condition. Ovarian teratoma: gross and microscopic appearance

NMDAR Encephalitis AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Stages Recent evidence suggests that the disease may occur in a two stage process. An early stage in the illness is associated with psychosis, seizures, confusion and amnesia. 10 to 20 days later, patients develop a second phase of illness with basal ganglia and brainstem features such as involuntary movements, reduced consciousness and autonomic disturbances. Headache and fever precede the symptoms in some patients, suggesting an infectious trigger. However, changes in thermoregulation, also previously noted in patients with VGKC-complex antibodies, can be seen even later in the disease course without an apparent infection, possibly suggesting a hypothalamic dysregulation. MRI and CSF MRI is most often normal but the scans can show non-specific T 2 -weighted and fluid attenuated inversion recovery (FLAIR) high signal. The cortical structures, often the medial temporal lobes, are often involved before changes in the deep white matter. EEG shows spikes consistent with cortical involvement, during the first stage, and diffuse slowing (of subcortical origin), during the second stage. CSF predominantly shows lymphocytic pleocytosis, early in the disease course. Up to 30% patients may have raised CSF protein or oligoclonal bands, the latter more common in the late stages of the disease.

NMDAR Encephalitis AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Illustration of the occurrence of clinical features according to the stage of illness. From Irani et al. Brain 2010; 133: 1655.

NMDAR Encephalitis AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Diagnosis can be established using a cell-based immunofluorescent assay. Antibodies specifically target the NR 1 subunit of the NMDAR and this is considered the most sensitive assay. Serum shows higher NMDAR-antibody concentrations than CSF in the great majority of cases. Technical details determine whether CSF or serum is the preferred specimen and it is worth checking with the local laboratory before samples are taken. A thorough search for an underlying neoplasm should be undertaken in all patients, but as the phenotype is expanding a smaller proportion of patients appear to be paraneoplastic. Nevertheless, tumour recognition is crucial because of the relatively better prognosis after removal of teratomata. In the majority of patients, who do not have a tumour, early (<40 days), and probably aggressive, immunotherapy (IT) is recommended. Image: Patients improve with early immunotherapy. From Irani et al. Brain 2010; 133: 1655

AMPAR Encephalitis AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Alpha amino 3 -hydroxy 5 -methyl 4 -isoxazolepropionic acid receptor (AMPAR) are glutamate receptors. The Glu. R 1/2 subunits are present in the hippocampus and these subunits are the antigenic targets in a minority of patients with a typical LE. These patients do not commonly show hyponatraemia, in contrast to the Lgi 1 -antibody cases. The other differences, from the few reports currently available, is that many AMPAR-antibody patients have an underlying tumour (two thirds had a neoplasm of the breast, lung or thymus) and relapses are frequent. Replication from other laboratories is awaited.

GABAB antibody Encephalitis AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Unlike the excitotoxic glutamate receptors, GABAB receptors are inhibitory in function and antibodies against these produce symptoms similar to other patients with limbic encephalitis, often with prominent seizures. This appears less likely to be a paraneoplastic condition, with only about one-third of the patients having an underlying tumour, mostly small cell lung cancers. CSF and MRI features are similar to other types of limbic encephalitis, with more common temporal lobe epileptiform discharges in the EEG. A few patients may also have concomitant GAD antibodies. In addition to treating any underlying tumour, immunosuppressive therapy is beneficial in achieving symptom improvement.

Rasmussen’s Encephalitis AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Rasmussen's encephalitis is a rare but severe form of, probably autoimmune, encephalitis causing intractable seizures, progressive unihemispheric neurological dysfunction and unilateral cortical atrophy. Most patients present in childhood and early diagnosis with subsequent immunosuppressive therapy may be most effective in the initial stages of the disease. Focal seizures (epilepsia patialis continua) and progressive hemiparesis are the initial presenting features. EEG shows ipsilateral epileptogenic changes with MRI showing ipsilateral focal cortical atrophy with high signal changes in the grey/white matter. Antibodies against Glu. R 3 subunit of the ionotropic glutamate receptors have been proposed, although the evidence is controversial. Treatments include seizure control (including surgical techniques like hemispherectomy) and immunotherapy with a combination of corticosteroids, IVIG or plasma exchange.

Rasmussen’s Encephalitis II AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions From: Mikhail Kalinn, Wikipedia- Rasmussen’s encephalitis, MRI.

AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Glycine-receptor Mediated Encephalitis Unlike the 'classical' limbic encephalitis, patients with antibodies against the inhibitory glycine receptors present with a subacute onset of: • Muscle stiffness • Stimulus-sensitive muscle spasms • Myoclonus • Cerebellar ataxia • Autonomic changes Image: Cell-based assay for Glycine receptor antibodies, showing colocalisation of antibodies (red) with Glycine receptors (green)- Courtesy Dr MI Leite, University of Oxford

AUTOIMMUNE • • • • Glycine-receptor Mediated Encephalitis ENCEPHALITIS Stiff-person syndrome or PERM Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions This phenotype forms a subgroup of patients who have stiff-person syndrome or progressive encephalomyelitis with rigidity and myoclonus (PERM), with or without GAD antibodies. GAD and glycine antibodies may coexist in an individual patient. As GAD is an intracellular protein, it is highly likely that the glycine antibody is the pathogenic entity. Treatment Ideal treatment regimens are unknown, although a combination of plasma exchange, intravenous immunoglobulins and corticosteroids have been used with variable efficacy in most patients. Symptomatic therapy with Clonazepam may be used for myoclonus, Baclofen and benzodiazepines may be needed to treat the stiffness.

AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Pathogenisis of paraneoplastic and non-paraneoplastic encephalitis In paraneoplastic limbic encephalitis where antibodies are identified against intracellular antigens, it is thought that immune responses against neuronal antigens expressed in the tumour cells react with common epitopes seen in the neurons, causing the clinical features. Cytotoxic T cells are more likely responsible for the pathogenic mechanisms, rather than the onconeural antibodies themselves. On the other hand, antibodies against neuronal cell surface antigens have been shown to be pathogenic, by decreasing the number of specific receptor clusters in synapses in hippocampal neuronal cultures. This effect can be reversed by removal of the patient antibodies. Also, direct antibody-mediated complement deposition has been shown in vitro. From: Irani et al, Brain 2010, 133 1655.

AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Management of Antibody. Mediated Encephalitis In patients with paraneoplastic LE, with 'onconeural' antibodies (e. g. Hu, CV 2, Ma etc), management mainly involves the identification of the underlying tumour and its treatment. Immunotherapy is of limited benefit but may help to stabilise the condition. However, in patients with antibodies against the VGKC complex, NMDAR, AMPAR or GABAB, early immunomodulatory therapy in the form of plasma exchange, intravenous immunoglobulins and/or corticosteroids are useful in reducing the antibody levels and subsequent clinical improvement. All patients also need to have a work-up for identifying an underlying tumour, which can be seen a proportion of these patients. Patients with Rasmussen's encephalitis need aggressive antiepileptic therapy (including epilepsy surgery in pharmaco-resistant patients) and early immunosuppression. Glycine receptor antibody patients respond variably to immunomodulatory therapy, but should always be considered as a management option.

AUTOIMMUNE Management of Antibody. Mediated Encephalitis ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions From: Irani et al. Ann Neurol 2011; 69: 892

Key Points AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions • Limbic encephalitis (LE) is a type of inflammatory CNS disease producing encephalopathic symptoms (confusion, disorientation, memory loss) and seizures • Original descriptions attributed this to be a paraneoplastic condition associated with onconeural antibodies against intracellular targets, with relatively poor prognosis • Recent evidence suggest that this is mainly an autoimmune disease caused by antibodies directed against neuronal cell surface antigens • The first cell surface antigen described was the voltage gated potassium channel. However, we now know that the radioimmunoassay used in this test measures antibodies against proteins which are complexed with VGKCs – namely Lgi 1, Caspr 2 or Contactin 2 • Other antibodies identified in autoimmune LE include AMPAR and GABAB • Lgi 1 -antibody LE has some characteristic features including hyponatraemia and dystonic seizures • NMDAR-antibody encephalitis produces a characteristic progression of neuropsychiatric features and seizures to a movement disorder, dysautonomia and reduction in consciousness • Immunomodulation with plasma exchange, intravenous immunoglobulins or corticosteroids are the mainstay of therapy in these conditions, and generally have a good prognosis when they are non-paraneoplastic

Summary AUTOIMMUNE ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Having completed this module you should now be able to: • Outline the different subsets of autoimmune encephalitis with particular reference to autoantibody-mediated encephalitis • Illustrate the pathogenesis of paraneoplastic and non-paraneoplastic autoimmune encephalitis myelopathy/tropical spastic paraparesis • Define key clinical features in the different antibody-mediated encephalitis • List the key investigation results in the different antibody-mediated encephalitis • Summarise an approach to the management of antibody-mediated encephalitis Further reading: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Vincent A et al, Brain 2004; 127: 701 -12 Dalmau J et al. , Lancet Neurol 2008; 7: 1091 -1098. Granerod J et al, Lancet Infect Dis. 2010; 10: 835 -44 Irani SR et al. , Brain 2010; 133: 2734 -2748. Irani SR et al. , Brain 2010; 133: 1655 -1667. Lai M et al. , Ann Neurol 2009; 65: 424 -43. Lancaster E et al. , Lancet Neurol 2010; 9: 67 -76. Bien CG et al. , Brain 2005; 128: 454 -471. Irani SR et al, Ann Neurol 2011, 69: 892 Mas N et al, J Neurol Neurosurg Psychiatry 2011; 82: 1399 -401

Question 1 a AUTOIMMUNE Please answer true or false to the following question: ENCEPHALITIS • • • • Learning Objectives Introduction Subsets of encephalitis Paraneoplastic Non-paraneoplastic VGKC-complex limbic encephalitis NMDAR encephalitis AMPAR encephalitis GABAB encephalitis Rasmussen’s encephalitis Glycine-receptor encephalitis Pathogenesis Management Key Points Summary Questions Encephalitis is due to a virus in >80% of cases. TRUE FALSE

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