autoimmune encephalitis

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 Lgi1, Caspr2 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. Edited by Tom Solomon and Agam Jung 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 This session provides a review of the expanding spectrum of autoantibody-mediated central nervous system conditions.

Learning Objectives 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 non-paraneoplastic autoimmune encephalitis 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 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

Introduction 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. 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 Image: MRI showing Rt medial temporal lobe high signal changes (arrow) in limbic encephalitis

Subsets of Encephalitis 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. 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 Adapted from Granerod J et al. Lancet Infect Dis. 2010;10: HSV, hepes simplex virus; ADEM, acute disseminated encephalomyelitis; VGKC, voltage gated potassium channels; NMDAR, “NMDA” receptor; MTB, mycobacteria tuberculosis; VZV, varicella zoster virus.

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 non- paraneoplastic. These patients tend to have a better prognosis. 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 IMAGE: Picture of the limbic system

Paraneoplastic Encephalitis These antibodies are usually against intracellular targets and are often referred to as 'onconeural antibodies'. Common examples include those directed against Hu, Ma2, CV2/CRMP5 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. 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

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

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: Lgi1, Caspr2 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 T2-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 125I-α-dendrotoxin (DTX) labelled rabbit brain membranes which have been solubilised in a mild detergent. Dendrotoxin labels some Kv1 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, Lgi1 Contactin-associated protein 2, Caspr2 Contactin-2/TAG-1 (rarely). These four proteins are co- associated 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 Lgi1 antibodies. In contrast, Morvan's syndrome and neuromyotonia are more commonly associated with in Caspr2 antibodies. Although the proportion of patients with underlying tumours is low, when present, they are almost always associated with Caspr2 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. 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 Hippocampal cultures showing surface binding Caspr2 (left) and Lgi1 igG. From Irani et al. Brain 2010;133:2734

Faciobrachial Dystonic Seizures as a Prodrome to Lgi1-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 Lgi1 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 full- blown LE. 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 Immunotherapies (IT), antiepileptic drugs (AEDs). From Irani et al. Ann Neurol. 2011;69:892.

NMDAR Encephalitis 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. 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 Ovarian teratoma: gross and microscopic appearance

NMDAR Encephalitis 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 T2-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. 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

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 Diagnosis can be established using a cell-based immunofluorescent assay. Antibodies specifically target the NR1 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. 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 Image: Patients improve with early immuno-therapy. From Irani et al. Brain 2010;133:1655

AMPAR Encephalitis Alpha amino 3-hydroxy 5-methyl 4-isoxazolepropionic acid receptor (AMPAR) are glutamate receptors. The GluR1/2 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 Lgi1-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. 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

GABAB antibody Encephalitis 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. 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 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 GluR3 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. 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 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.

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 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 Image: Cell-based assay for Glycine receptor antibodies, showing co-localisation of antibodies (red) with Glycine receptors (green)- Courtesy Dr MI Leite, University of Oxford

Glycine-receptor Mediated Encephalitis Stiff-person syndrome or PERM 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. 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: Irani et al, Brain 2010,

Management of Antibody- Mediated Encephalitis In patients with paraneoplastic LE, with 'onconeural' antibodies (e.g. Hu, CV2, 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 anti-epileptic 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 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 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: Irani et al. Ann Neurol 2011;69:892

Key Points 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 Lgi1, Caspr2 or Contactin2 Other antibodies identified in autoimmune LE include AMPAR and GABAB Lgi1-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 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

Summary 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: Vincent A et al, Brain 2004; 127:701-12 Dalmau J et al., Lancet Neurol 2008;7: Granerod J et al, Lancet Infect Dis. 2010;10:835-44 Irani SR et al., Brain 2010; 133: Irani SR et al., Brain 2010; 133: Lai M et al., Ann Neurol 2009; 65: Lancaster E et al., Lancet Neurol 2010; 9:67-76. Bien CG et al., Brain 2005; 128: Irani SR et al, Ann Neurol 2011, 69:892 Mas N et al, J Neurol Neurosurg Psychiatry 2011;82: 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

Question 1a Please answer true or false to the following question: 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 Encephalitis is due to a virus in >80% of cases. TRUE FALSE

Question 1a Please answer true or false to the following question: 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 Encephalitis is due to a virus in >80% of cases. TRUE FALSE INCORRECT FALSE is the correct answer. Non-microbiological causes of encephalitis are becoming increasingly common. Click here to move on to the next question.

Question 1a Please answer true or false to the following question: 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 Encephalitis is due to a virus in >80% of cases. TRUE FALSE CORRECT FALSE is the correct answer. Non-microbiological causes of encephalitis are becoming increasingly common. Click here to move on to the next question.

Question 1b Please answer true or false to the following question: 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 Lg91/VGKC-complex mediated encephalitis produces hypokalaemia. TRUE FALSE

Question 1b Please answer true or false to the following question: 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 Lg91/VGKC-complex mediated encephalitis produces hypokalaemia. TRUE FALSE INCORRECT False is the correct answer. Many patients may have a hyponatremia. Click here to move on to the next question.

Question 1b Please answer true or false to the following question: 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 Lg91/VGKC-complex mediated encephalitis produces hypokalaemia. TRUE FALSE CORRECT FALSE is the correct answer. Many patients may have a hyponatremia. Click here to move on to the next question.

Question 1c Please answer true or false to the following question: 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 Hu and CV2 antibodies are seen in association with paraneoplastic neurological syndromes. TRUE FALSE

Question 1c Please answer true or false to the following question: 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 Hu and CV2 antibodies are seen in association with paraneoplastic neurological syndromes. TRUE FALSE CORRECT TRUE is the correct answer. Although these antibodies are not thought to be directly pathogenic. Click here to move on to the next question.

Question 1c Please answer true or false to the following question: 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 Hu and CV2 antibodies are seen in association with paraneoplastic neurological syndromes. TRUE FALSE INCORRECT TRUE is the correct answer. Although these antibodies are not thought to be directly pathogenic. Click here to move on to the next question.

Question 1d Please answer true or false to the following question: 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 Anti-Hu antibodies are typically seen in patients with testicular tumours. TRUE FALSE

Question 1d Please answer true or false to the following question: 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 Anti-Hu antibodies are typically seen in patients with testicular tumours. TRUE FALSE INCORRECT FALSE is the correct answer. Anti-Hu antibodies are mainly associated with SCLC. Anti-Ma2 antibodies are seen with testicular tumours. Click here to move on to the next question.

Question 1d Please answer true or false to the following question: 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 Anti-Hu antibodies are typically seen in patients with testicular tumours. TRUE FALSE CORRECT FALSE is the correct answer. Anti-Hu antibodies are mainly associated with SCLC. Anti-Ma2 antibodies are seen with testicular tumours. Click here to move on to the next question.

Question 1e Please answer true or false to the following question: 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 Epilepsia partialis continua is not a characteristic feature of Rasmussen encephalitis. TRUE FALSE

Question 1e Please answer true or false to the following question: 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 Epilepsia partialis continua is not a characteristic feature of Rasmussen encephalitis. TRUE FALSE INCORRECT FALSE is the correct answer. This is probably one of the most common clinical features. Click here to move on to the next question.

Question 1e Please answer true or false to the following question: 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 Epilepsia partialis continua is not a characteristic feature of Rasmussen encephalitis. TRUE FALSE CORRECT FALSE is the correct answer. This is probably one of the most common clinical features. Click here to move on to the next question.

Question 2 Please select the best single answer to the following question: 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 Which of the following clinical features is not well recognised in autoimmune : Memory impairment Seizures Psychosis Diploplia

Question 2 Please select the best single answer to the following question: 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 Which of the following clinical features is not well recognised in autoimmune : Memory impairment Seizures Psychosis Diploplia INCORRECT Try one of the alternative answers in order to progress or read more by using the links on the left hand side

Question 2 Please select the best single answer to the following question: 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 Which of the following clinical features is not well recognised in autoimmune encephalitis: Memory impairment Seizures Psychosis Diploplia CORRECT d) Is the correct answer. Double vision is not seen in limbic encephalitis and is usually due to extra-ocular muscle autoimmune diseases like myasthenia. Click here to move on to the next question.

Question 3 Match the statements to the most appropriate items below. To see if you are correct click on the item you believe to match with the statement in bold on each page: 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 One of the proteins complexed with voltage gated potassium channels which is the target in most cases with LE. An intracellular antigenic target Psychosis seen as early manifestation with this type of encephalitis Some cases of stimulus-sensitive muscle spasms have been attributed an antibody against this receptor Antibodies against AMPAR are targeted against these subunits Antibodies against this protein are often associated with Morvan’s syndrome and thymomas NMDAR Hu Caspr2 Lgi1 GluR1/2 Glycine receptor

Question 3 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 INCORRECT Try one of the alternative answers in order to progress or read more by using the links on the left hand side One of the proteins complexed with voltage gated potassium channels which is the target in most cases with LE. An intracellular antigenic target Psychosis seen as early manifestation with this type of encephalitis Some cases of stimulus-sensitive muscle spasms have been attributed an antibody against this receptor Antibodies against AMPAR are targeted against these subunits Antibodies against this protein are often associated with Morvan’s syndrome and thymomas NMDAR Hu Caspr2 Lgi1 GluR1/2 Glycine receptor

Question 3 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 CORRECT Move on to the next statement: One of the proteins complexed with voltage gated potassium channels which is the target in most cases with LE. An intracellular antigenic target Psychosis seen as early manifestation with this type of encephalitis Some cases of stimulus-sensitive muscle spasms have been attributed an antibody against this receptor Antibodies against AMPAR are targeted against these subunits Antibodies against this protein are often associated with Morvan’s syndrome and thymomas NMDAR Hu Caspr2 Lgi1 GluR1/2 Glycine receptor

Question 3 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 CORRECT Click here to move on to the next question One of the proteins complexed with voltage gated potassium channels which is the target in most cases with LE. An intracellular antigenic target Psychosis seen as early manifestation with this type of encephalitis Some cases of stimulus-sensitive muscle spasms have been attributed an antibody against this receptor Antibodies against AMPAR are targeted against these subunits Antibodies against this protein are often associated with Morvan’s syndrome and thymomas NMDAR Hu Caspr2 Lgi1 GluR1/2 Glycine receptor

Question 4a Please answer true or false to the following question: 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 Paraneoplastic limbic encephalitis is almost always secondary to lung cancer. TRUE FALSE

Question 4a Please answer true or false to the following question: 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 Paraneoplastic limbic encephalitis is almost always secondary to lung cancer. TRUE FALSE INCORRECT FALSE is the correct answer. Different types of tumours have been shown to associate with paraneoplastic encephalitis Click here to move on to the next question.

Question 4a Please answer true or false to the following question: 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 Paraneoplastic limbic encephalitis is almost always secondary to lung cancer. TRUE FALSE CORRECT FALSE is the correct answer. Different types of tumours have been shown to associate with paraneoplastic encephalitis. Click here to move on to the next question.

Question 4b Please answer true or false to the following question: 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 antibodies are most commonly directed against Kv1.2. TRUE FALSE

Question 4b Please answer true or false to the following question: 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 antibodies are most commonly directed against Kv1.2. TRUE FALSE INCORRECT FALSE is the correct answer. They are directed against the proteins associated with VGKCs, namely Lgi1, Caspr2 or Contactin-2. Click here to move on to the next question.

Question 4b Please answer true or false to the following question: 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 antibodies are most commonly directed against Kv1.2. TRUE FALSE CORRECT FALSE is the correct answer. They are directed against the proteins associated with VGKCs, namely Lgi1, Caspr2 or Contactin-2. Click here to move on to the next question.

Question 4c Please answer true or false to the following question: 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 Ovarian teratoma are typically described with AMPAR encephalitis. TRUE FALSE

Question 4c Please answer true or false to the following question: 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 Ovarian teratoma are typically described with AMPAR encephalitis. TRUE FALSE INCORRECT FALSE is the correct answer. NMDAR limbic encephalitis is associated with ovarian teratomas. Click here to move on to the next question.

Question 4c Please answer true or false to the following question: 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 Ovarian teratoma are typically described with AMPAR encephalitis. TRUE FALSE CORRECT FALSE is the correct answer. NMDAR limbic encephalitis is associated with ovarian teratomas. Click here to move on to the next question.

Question 4d Please answer true or false to the following question: 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 NMDAR encephalitis is highly contagious. TRUE FALSE

Question 4d Please answer true or false to the following question: 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 NMDAR encephalitis is highly contagious. TRUE FALSE INCORRECT FALSE is the correct answer. This is an antibody mediated disease and is not infectious. Click here to move on to the next question.

Question 4d Please answer true or false to the following question: 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 NMDAR encephalitis is highly contagious. TRUE FALSE CORRECT FALSE is the correct answer. This is an antibody mediated disease and is not infectious. Click here to move on to the next question.

Question 4e Please answer true or false to the following question: 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 GABAB receptors are excitotoxic. TRUE FALSE

Question 4e Please answer true or false to the following question: 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 GABAB receptors are excitotoxic. TRUE FALSE INCORRECT FALSE is the correct answer. GABAB receptors are inhibitory. Click here to finish the session

Question 4e Please answer true or false to the following question: 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 GABAB receptors are excitotoxic. TRUE FALSE CORRECT FALSE is the correct answer. GABAB receptors are inhibitory. Click here to finish the session

Congratulations on completing this module and thank you for using NeuroID: elearning.
We hope to see you at a NeuroID: Liverpool Neurological Infectious Diseases Course soon. Download a certificate and then to finish the session CLICK HERE.

NeuroID 2013: Liverpool Neurological Infectious Diseases Course
To learn more about neurological infectious diseases… NeuroID 2013: Liverpool Neurological Infectious Diseases Course Liverpool Medical Institution, UK Provisional date: May 2013 Ever struggled with a patient with meningitis or encephalitis, and not known quite what to do? Then the Liverpool Neurological infectious Diseases Course is for you! For Trainees and Consultants in Adult and Paediatric Neurology, Infectious Diseases, Acute Medicine, Emergency Medicine and Medical Microbiology who want to update their knowledge, and improve their skills. Presented by Leaders in the Field Commonly Encountered Clinical Problems Practical Management Approaches Rarities for Reference Interactive Case Presentations State of the Art Updates Pitfalls to Avoid Controversies in Neurological Infections Feedback from previous course: “Would unreservedly recommend to others” “An excellent 2 days!! The best course for a long time” Convenors: Prof Tom Solomon, Dr Enitan Carrol, Dr Rachel Kneen, Dr Nick Beeching, Dr Benedict Michael For more information and to REGISTER NOW VISIT:

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