Chapter 6 - Limbic Encephalitis PDF

Chapter 6 - Limbic Encephalitis from Section 3 - Specific Syndromes and Diseases Published online by Cambridge University Press: 27 January 2022 Josep Dalmau and Francesc Graus 1. 6.1 Introduction 167 2. 6.2 Historical Overview 167 3. 6.3 Diagnostic Criteria 169 4. 6.4 Neuronal Antibodies and...

Chapter 6 - Limbic Encephalitis from Section 3 - Specific Syndromes and Diseases Published online by Cambridge University Press: 27 January 2022 Josep Dalmau and Francesc Graus 1. 6.1 Introduction 167 2. 6.2 Historical Overview 167 3. 6.3 Diagnostic Criteria 169 4. 6.4 Neuronal Antibodies and Immunological Subtypes 176 5. 6.5 Neuropathology and Immunopathogenesis 183 6. 6.6 Treatment and Prognosis 183 6.1 Introduction Limbic encephalitis is a clinical-pathological entity characterized by subacute onset, usually in less than three months, of cognitive decline, behavioural changes, and seizures. The most typical deficit is impairment of short-term memory. Patients cannot form new memories and are unable to remember recent events, but they can retrieve old memories. Brain MRI shows fluid-attenuated inversion recovery (FLAIR) and T2 signal abnormalities bilaterally – less frequently unilaterally – involving the hippocampus and 1 amygdala. Symptoms are mainly caused by neuronal dysfunction of these two brain regions that form part of the limbic system, which also includes the septal nuclei, cingulate cortex, orbitofrontal cortex, anterior pole of the temporal lobe, and 2 hypothalamus. The leading cause of limbic encephalitis is autoimmune, either mediated by T cells or directly caused by antibodies that interact with synaptic receptors and other 3 proteins located in the neuronal membrane. In cases mediated by cytotoxic T cells, neuropathological studies demonstrate extensive inflammatory infiltrates in the perivascular space of small vessels and in the brain parenchyma. In addition, there are frequent cytotoxic CD8+ T cells in close apposition to neurons and likely causing the 4 neuronal loss. In contrast, inflammatory infiltrates are less extensive in limbic encephalitis mediated by antibodies against neuronal surface proteins or receptors; in addition, the presence of neuronophagic infiltrates is rare compared with disorders 5 mediated by T cells (see Chapter 7, Table 7.2). The estimated incidence of limbic encephalitis is 0.3 cases per 100,000 persons/year, representing the third most common type of autoimmune encephalitis after acute disseminated encephalomyelitis (ADEM) and anti-N-methyl-D-aspartate (NMDA) receptor 6 encephalitis. Although the initial descriptions of limbic encephalitis were always linked to the presence of an underlying cancer as the potential trigger of the inflammatory neurodegeneration, recent studies indicate that in the majority of cases the trigger of the 3, 7 inflammatory response or immune attack is unknown. In a series of 163 patients with limbic encephalitis, ~60% were non-paraneoplastic and >70% were associated with LGI1 8 (leucine-rich, glioma inactivated 1) antibodies (described in Chapter 7) (Figure 6.1). Figure 6.1 Frequency of antibodies in a series of 163 patients with limbic encephalitis. Association with cancer depends on the antibody: >70% (red), 40–70% (pink), 50% (see Chapter 7). 6.2 Historical Overview The initial clinical and pathological characterization of limbic encephalitis is in great part thanks to the work of J.A.N. Corsellis. He coined the term, linked the clinical symptoms with the neuropathology in the limbic areas, and suggested that the association with the underlying cancer in all patients with limbic encephalitis that he studied was more than coincidental. Corsellis initially trained in psychiatry and his superintendent at Runwell hospital in England asked him to move into neuropathology. He became a consultant neuropathologist in Runwell, where he started an impressive brain bank and transformed the Department of Neuropathology into a Research Center of Excellence. At the same time, he had access to the Maudsley laboratories at the Institute of Psychiatry in London, where he was appointed Chairman of Neuropathology in 1976. With his strong clinical background he made seminal contributions to the understanding of 9 neuropsychiatric diseases, including limbic encephalitis. In 1960, in collaboration with Brierley (as first author), Hierons and Nevin published three male patients with subacute downhill clinical course that started with depression followed by change of personality, memory loss, and confusion. One patient also developed dysarthria and gait unsteadiness. The neuropathological findings characterized by neuronal loss, gliosis, and inflammatory infiltrates were prominent in what the authors termed ‘the limbic lobe,’ which included the amygdala, the hippocampus, and cingulate gyri. Although tumour cells comparable to those of small-cell lung cancer (SCLC) were found in the mediastinal lymph nodes in one patient (case 2), the finding was considered not related to the 10 encephalitis that was not defined as limbic despite the neuropathological findings. In 1965, Henson and colleagues noticed that patients with paraneoplastic encephalomyelitis and SCLC had inflammatory infiltrates preferentially in four distinct areas of the nervous system: dorsal root ganglia, spinal cord, brainstem, and the temporal lobe areas. The inflammation in the temporal lobe was described as limbic encephalitis. Although their patients had not presented clinical symptoms attributable to the later localization, Henson and colleagues emphasized the close neuropathological resemblance between what they named ‘limbic encephalitis’ and the findings of the patients described years 11 earlier by Brierley et al. In 1968, Corsellis, probably influenced by the growing number of newly described paraneoplastic neurological syndromes (PNS) (defined at that time as 12 ‘remote effects of cancer on the nervous system’) reported the clinical and pathological findings of three new patients and suggested that the encephalitis was related to the underlying lung cancer. He emphasized the severe recent memory loss of the patients and linked the clinical features to the severe damage of the hippocampi. Therefore, after describing the clinico-pathological entity in 1960, Corsellis was also the first to use the term limbic encephalitis to define this distinct entity as a remote effect of cancer on the 13 nervous system, which subsequently became one of the most classical PNS. For more than a decade the aetiology of paraneoplastic limbic encephalitis remained 14 controversial until the description of Hu (ANNA1) antibodies in some patients with limbic encephalitis (and other PNS) associated with SCLC suggested an immune 15 pathogenesis. The fact that Hu (ANNA1) antibodies were directed against an antigen expressed by neurons and tumour cells was a critical observation that served to definitively establish a pathogenic link between limbic encephalitis and an autoimmune 16 response triggered by the tumour. The subsequent description of more cases of limbic encephalitis indicated that the clinical course was heterogeneous. For example, among patients with limbic encephalitis and SCLC, the subset of cases with Hu (ANNA1) antibodies frequently had clinical involvement of other areas of the nervous system (encephalomyelitis) and a poor outcome, whereas those that did not have Hu antibodies 17 responded better to therapy. Limbic encephalitis was considered a syndrome that almost always associated with cancer. However, in 2001 Vincent and colleagues characterized a new type of limbic encephalitis with antibodies against voltage-gated potassium channels (VGKCs). The syndrome did not associate with cancer and showed a good response to immunotherapy, suggesting that the disorder was mediated by antibodies against a membrane antigen 18 and caused functional rather than structural neuronal damage. A decade later several studies were seminal in the development of the concept of antibody-mediated 3 encephalitis. In the field of limbic encephalitis in particular one of these studies demonstrated that the antigen recognized by VGKC antibodies was not the VGKC itself 19 but an associated protein called LGI1 (leucine-rich, glioma inactivated 1), a finding that  20 was subsequently confirmed by other investigators. It was also found that subsets of patients with limbic encephalitis previously considered antibody-negative had in fact antibodies against synaptic antigens, mainly AMPA (α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and GABA (gamma-aminobutyric acid) b receptors and that these disorders could be either idiopathic or paraneoplastic 21–23 (Figure 6.2). Figure 6.2 Landmarks in our understanding of limbic encephalitis. AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CNS: central nervous system; GABAb: gamma-aminobutyric acid b; LGI1: leucine-rich, glioma inactivated 1; PNS: paraneoplastic neurological syndrome; VGKC: voltage-gated potassium channel (picture of the Kazbegi peak in the Caucasus mountains taken by one of the authors, FG). 6.3 Diagnostic Criteria The term limbic encephalitis has been misused over the years, frequently implying that any paraneoplastic disorder affecting the cerebral hemispheres is limbic encephalitis, despite the clinical and imaging features being different from those associated with this 24, 25 disorder. Another source of confusion originated in the epilepsy literature when patients with long-lasting epilepsy without other clinical features of limbic encephalitis (subacute onset of recent memory loss or behavioural changes) were diagnosed with 26 limbic encephalitis on the basis only of MRI findings. In order to improve the diagnosis and treatment of limbic encephalitis (and the proper use of the term that describes it), a 27 set of criteria were initially proposed by Gultekin et al. in 2000 and further refined in 28 1 2004 and 2016 (Box 6.1). According to these criteria, a definite diagnosis of limbic encephalitis can be made without neuronal antibodies in serum and cerebrospinal fluid 8 (CSF) because up to 12% of patients are antibody-negative. Box 6.1 Diagnostic Criteria of Definite Autoimmune Limbic Encephalitis * All four of the following requirements: 1. 1. Subacute onset (rapid progression 5/mm ) 2. b. EEG with epileptic or slow activity involving the temporal lobes 4. 4. Reasonable exclusion of alternative causes. * If one of the first three requirements is missing the level of ‘definite’ can only be reached by the demonstration of antibodies against cell surface, synaptic, or onconeural proteins. 18 * [ F]fluorodeoxyglucose positron emission tomography (FDG-PET) can be used to fulfil this requirement. 1 Slightly modified from. Clinical Vignette 6.1 A 54-year-old man developed low-grade fever, confusion, and disorientation when he was on a leisure cruise. Neurological examination was only relevant for severe short-term memory deficit (unable to form new memories) and frequent confabulations. The patient was unaware of his memory deficit; the language function was normal and there were no 3 motor, cerebellar, or sensory alterations. CSF examination showed 20 lymphocytes/mm and the protein concentration was 65 mg/dL. Brain MRI showed FLAIR hyperintense lesions in the mesial aspect of temporal lobes and frontal gyri (Figure 6.3). Immunological studies did not identify serum or CSF onconeural antibodies (Hu, Yo, Ri, CV2, amphiphysin, Ma2, Tr (DNER), Zic4, and SOX1), GAD, AK5, or cell surface antibodies (NMDAR, AMPAR, GABAAR, GABAbR, IgLON5, CASPR2, LGI1, DPPX, neurexin 3α, mGluR1, and mGluR5). Treatment with intravenous methylprednisolone and immunoglobulins did not change the memory deficits. Further work-up identified an adenocarcinoma of the lung restricted to the thorax. Despite chemotherapy and oral steroids the patient did not improve, and eventually died of an ischaemic stroke 18 months after symptom onset. At autopsy, the hippocampus of the cerebral hemisphere not affected by the stroke showed neuronal loss, gliosis, and inflammatory infiltrates. Immunohistochemical analysis showed extensive infiltrates of CD8+ T lymphocytes in the parenchyma and in close apposition to neurons (Figure 6.3). Comment The case of this patient shows that despite extraordinary advances in the characterization of new antibodies, there are still cases of limbic encephalitis that are antibody-negative. The neuropathological findings in this patient suggest that the neuronal damage is T cell mediated. The main aim of the proposed criteria of limbic encephalitis is to allow a prompt diagnosis without waiting for the results of antibody studies. The four diagnostic criteria are discussed in the text. Figure 6.3 Brain MRI and neuropathological findings in a patient with seronegative limbic encephalitis. (A) Axial FLAIR image showing high signal intensity in both hippocampi and gyrus recti. (B) Haematoxylin–eosin staining of hippocampus demonstrating perivascular and parenchymatous inflammatory infiltrates. Immunohistochemical analysis shows many CD8+ T cells (stained brown) in the parenchyma (C) and in close contact with neurons (D). (reprinted from reference 8 with permission) 6.3.1 Subacute Onset of Recent Memory Loss, Seizures, or Psychiatric Symptoms Suggesting Involvement of the Limbic System In patients with limbic encephalitis this combination of symptoms almost always develops in a few weeks, usually 100 times). The seizures can alternatively involve both sides, and associate with impaired 31, 43 awareness and speech arrest at the end of the seizure. 6.3.2 Bilateral MRI FLAIR/T2 Abnormalities Highly Restricted to Medial Temporal Lobes 46, 47 Since the initial MRI descriptions in patients with limbic encephalitis, this test has shown to be highly sensitive in demonstrating the characteristic location of the main inflammatory abnormalities that account for this distinct syndrome. The MRI findings typically reveal diffuse bilateral increased signal in T2 and FLAIR sequences involving the 48 hippocampus and amygdala of both temporal lobes. These lesions rarely enhance with gadolinium except in about 30% of patients with anti-Ma2 limbic encephalitis, where the 49 enhancement may suggest a glial tumour or metastasis. Although unilateral temporal 27 lesions are frequent in antibody-positive limbic encephalitis (~40%), a bilateral involvement is required as a criterion of limbic encephalitis when the antibody status is unknown. This is important because the list of alternative diagnoses is considerable in patients with unilateral lesions, including among other herpes simplex encephalitis and glioma (see exclusion of alternative causes below) (Figure 6.4). The hyperintense lesions in the temporal lobes may persist for many months or years, but in most cases they 48, 50 evolve to show progressive atrophy. Hippocampal volumetry to quantify the atrophy has been reported in anti-LGI1 limbic encephalitis. These studies show preferential atrophy of the CA3 hippocampal subfield that correlates with the deficit in episodic 38, 51 memory. Figure 6.4 Brain MRI features in limbic encephalitis. (A) Axial FLAIR MRI image showing increased signal abnormalities in the medial aspect of temporal lobes. (B) In patients with encephalitis associated with Ma2 antibodies (but very rarely with other antibodies) the areas with FLAIR changes may enhance after administration of gadolinium. Asymmetric and unilateral lesions may also occur in limbic encephalitis (C) and require the careful exclusion of gliomas or herpes simplex encephalitis. Brain MRI is normal in ~15% of patients with limbic encephalitis and LGI1 antibodies, but 7, 52 the frequency is much lower in those associated with onconeural antibodies. An unsettled issue is the role of fluorodeoxyglucose positron emission tomography (FDG- PET) to uncover temporal lobe lesions that might not be visible in the MRI or to identify brain metabolic abnormalities that can help to understand better the pathophysiology of 53 limbic encephalitis. In patients with paraneoplastic limbic encephalitis or associated with neuronal antibodies different from LGI1 (Table 6.1), FDG-PET characteristically demonstrates hypermetabolic changes in medial temporal lobes that in some cases 54–56 associate with normal MRI findings (Figure 6.5). The cause of the hypermetabolic abnormalities is controversial. They may represent persistent epileptic activity despite the 57, 58 absence of overt clinical seizures, or manifest the underlying inflammatory process. The latter possibility is supported by the fact that in cases of temporal lobe epilepsy from different aetiologies, interictal FDG-PET studies are (with a few exceptions) 59 hypometabolic. Although more experience is needed, serially obtained FDG-PET studies may be helpful in making clinical decisions. For example, if persistent clinical symptoms are the consequence of ongoing active disease or inflammation rather than a sequela, the FDG-PET may show persistent hypermetabolic changes (even with improvement of 60 the brain MRI), indicating the need for further immunotherapy.  a Table 6.1 FDG-PET findings in limbic encephalitis First author Case(s) description FDG-PET findings 1 patient with paraneoplastic limbic 61 Hypermetabolic changes in Provenzale encephalitis and bilateral both temporal lobes temporal lesions on brain MRI 2 patients with 56 paraneoplastic limbic Hypermetabolic changes in Fakhoury encephalitis and normal one temporal lobe MRI 62 2 patients (one Focal hypermetabolism in Kassubek paraneoplastic) with bilateral hippocampal areas First author Case(s) description FDG-PET findings bilateral temporal lesions on brain MRI 1 patient with paraneoplastic limbic 63 Focal hypermetabolism in Na encephalitis and bilateral bilateral hippocampal areas temporal lesions on brain MRI 1 patient with Ma2 58 Focal hypermetabolism in Scheid antibodies and abnormal left temporal lobe brain MRI 3 patients (2 Hypermetabolism in 54 paraneoplastic) with limbic temporal lobes in 2 patients Ances encephalitis. Normal MRI in (1 with normal MRI). Diffuse 1 hypometabolism in 1 1 patient with 64 paraneoplastic limbic Hypermetabolic changes in Troester encephalitis. Brain MRI not both temporal lobes described 1 patient with AMPAR 60 antibodies. At time of FDG- Hypermetabolic changes in Spatola PET MRI showed left temporal lobe hippocampal atrophy 1 patient with 65 paraneoplastic limbic Hypermetabolic changes in Maffione encephalitis and left left temporal lobe temporal lesion in the MRI 1 patient with Hu 44 Hypermetabolic changes in Rocamora antibodies and left left temporal lobe temporal lesion in the MRI 4 patients with Hu, Ri, or 55 Hypermetabolic changes in Baumgartner GAD antibodies. MRI temporal lobes normal in 1 1 patient with 66 Hypermetabolic changes in Su paraneoplastic, anti- right temporal lobe GABAbR-positive, limbic First author Case(s) description FDG-PET findings encephalitis and normal MRI 2 patients with paraneoplastic, anti- Hypermetabolic changes in 67 GABAbR-positive limbic Kim right (1 patient) and in both encephalitis and unilateral temporal lobes temporal lesion on brain MRI 1 patient with limbic 68 encephalitis, normal MRI, Hypermetabolic changes in Cózar Santiago neuronal antibodies were both temporal lobes not determined 1 patient with paraneoplastic limbic 69 Asymmetric hypermetabolic Castagnoli encephalitis, Hu antibodies. changes in temporal lobes Bilateral temporal lesions on brain MRI 1 patient with non- paraneoplastic limbic encephalitis, without Hypermetabolic changes in 70 b Taneja antibodies. MRI: T2 temporal lobes and basal hyperintense lesions in ganglia temporal lobes and basal ganglia 1 patient with Ma2, 2 with 71 CV2 antibodies,7 Normal in 4, Deuschl c seronegative. MRI normal hypometabolism in 6 in 2 patients. 1 patient with Hypermetabolism in right paraneoplastic LE, Hu hippocampus. 72 Longo antibodies. Bilateral Hypometabolic areas in temporal lesions on brain cortex of right cerebral MRI hemisphere a Cases associated with LGI1 antibodies not included (see Chapter 7). b LGI1 antibodies were not specifically determined. c Eight additional patients with GAD antibodies were not considered because the differentiation between epilepsy and limbic encephalitis was unclear. Figure 6.5 FDG-PET in limbic encephalitis. (A) Axial FLAIR image demonstrating hyperintense lesions in the medial aspect of temporal lobes (right > left) in a patient with anti-Ma2 limbic encephalitis. (B). FDG-PET showing medial temporal lobe hypermetabolism (more marked on the right side); the patient did not have seizures at the time of the test, suggesting that the hypermetabolism was due to the underlying inflammation. FDG-PET studies have been more frequently described in patients with limbic encephalitis associated with LGI1 antibodies; in these cases the results are not so uniform as those of patients with paraneoplastic limbic encephalitis (see Table 7.3). Some patients may show hypo- rather that hypermetabolic changes in the temporal lobes. In addition to hypermetabolic changes in the temporal lobes or diffusely involving cerebral cortex, 73 about 60% of patients show increased FDG activity in the basal ganglia. Semi- quantitative analysis of cerebral FDG uptake indicates that the cortical metabolism is normal and that the hypometabolism reported in some studies may represent the 74 relative change in cortical metabolism compared with striatal hypermetabolism. Basal ganglia hypermetabolism is not specific for anti-LGI1 encephalitis, given that it can also occur in patients with anti-NMDAR encephalitis, Sydenham chorea, or systemic lupus  73, 75–77 erythematosus. 6.3.3 CSF Pleocytosis or EEG with Epileptic or Slow Activity Involving the Temporal Lobes These two criteria indicate the presence of CNS inflammation (CSF pleocytosis, defined as 3 >5 WBC/mm ) and the anatomical location involved by the inflammation (temporal 1 dysfunction demonstrated by EEG). The reason that in the 2016 criteria of limbic encephalitis the EEG was offered as an alternative to CSF pleocytosis is that in approximately 50% of patients with limbic encephalitis there is no pleocytosis; the lack of pleocytosis is even higher (~77%) in patients with anti-LGI1 encephalitis, which is the 27, 52 most common subtype of limbic encephalitis. In addition, the frequency of pleocytosis depends on the time the CSF is examined, being more detectable at early 78 stages of the disease. 6.3.4 Reasonable Exclusion of Alternative Causes This criterion is crucial to avoid missing potentially treatable conditions that may mimic autoimmune limbic encephalitis. The most important differential diagnosis is with 79, 80 infectious encephalitis, particularly herpes simplex encephalitis (HSE). HSE is the most common cause of non-autoimmune limbic encephalitis, and almost always involves the temporal lobes. Clinical aspects that differentiate both entities include: acute onset (in hours of days), fever (>38 °C), and the presence of aphasia that is more frequent in 81 HSE. Typical brain MRI abnormalities in HSE include unilateral temporal lobe involvement usually accompanied by abnormalities in the insula or cingulate gyrus and extensive oedema and necrotic-haemorrhagic areas, which do not occur in autoimmune 82 limbic encephalitis. CSF analysis in HSE almost always shows pleocytosis, whereas in 27 autoimmune limbic encephalitis the CSF cell count is normal in at least 50% of patients. Viral reactivation of human herpesvirus 6 (HHV-6), causing diverse clinical manifestations including encephalitis, occurs in severely immunocompromised patients with 83, 84 haematopoietic stem cell or solid organ transplantation. HHV-6 encephalitis is very unusual in immunocompetent patients; it only affected 0.4% of 1,000 patients with 85 encephalitis enrolled in the California Encephalitis Project. Immunocompromised patients with HHV-6 encephalitis present with a predominant amnestic syndrome, seizures, and bilateral mesial temporal lobe T2/FLAIR MRI abnormalities 86, 87 indistinguishable from autoimmune limbic encephalitis (see Clinical Vignette 6.2). These symptoms may precede in several days the development of typical MRI changes, 88 which initially can be normal. Immunocompetent patients with HHV-6 encephalitis 85, 89 rarely have the typical MRI findings of limbic encephalitis. Clinical Vignette 6.2 A 57-year-old woman with metastatic melanoma diagnosed eight years earlier was admitted for new-onset seizures and confusion. She had been treated with multiple lines of oncological therapy, including the immune checkpoint inhibitors nivolumab and pembrolizumab, three years earlier. Due to progression of the disease she was enrolled in a protocol that included high-dose chemotherapy (cyclophosphamide and fludarabine) to induce aplasia followed by infusion of tumour-infiltrating T lymphocytes obtained from a metastatic lesion and interleukin 2. Two days after the infusion, she developed fever and a generalized maculopapular exanthema. The rash began to disappear within 24 hours after treatment with prednisone, but the fever persisted and on day 15 post- infusion she became confused, with severe agitation and delirium followed by generalized seizures that required admission to the ICU. After the seizures were controlled, she remained confused and disoriented. The neurological examination one day later showed that she was alert and disoriented, with severe short-term memory deficit. No focal deficits were identified. A brain MRI demonstrated increased FLAIR signal bilaterally involving the amygdala and hippocampus (Figure 6.6A). CSF examination 3 showed 28 lymphocytes/mm , and PCR for multiple infectious agents was negative except for HHV-6, with a viral load of 83,000 copies/mL. Serum and CSF studies for neural antibodies were negative. The patient was treated with ganciclovir and foscarnet with resolution of the infection, but she remained with severe memory deficits. Comment HHV-6 infection can cause limbic encephalitis in cancer patients who are severely immunosuppressed. In this patient, the severe chemotherapy-induced aplasia was probably an important risk factor for HHV-6 infection. In addition, the occurrence of the maculopapular skin rash shortly after the infusion of tumour-infiltrating T lymphocytes suggests that the HHV-6 replicated in vitro during the process of tumour-infiltrating T 90 lymphocyte expansion and infected the patient. Figure 6.6 Brain MRI features in human herpesvirus 6 encephalitis. (A) Axial FLAIR MRI image showing bilateral medial temporal abnormalities in a patient with HHV-6 encephalitis. (B) Similar changes are seen in a patient with paraneoplastic limbic encephalitis and Hu (ANNA1) antibodies (see Case Vignette 6.3). Gliomas are, after HSE, the most common mimic of limbic encephalitis (see Clinical Vignette 7.1). Patients with temporal lobe gliomas usually develop seizures, but the cognitive and behavioural functions are normal or substantially less affected than in patients with limbic encephalitis. The brain MRI almost always shows a unilateral temporal lobe FLAIR change that initially may not show contrast enhancement (or this is demonstrated in follow-up studies), and the biopsy or tumour resection eventually 91 demonstrates a malignant glioma. In a study including 306 patients with suspected diagnosis of autoimmune encephalitis, 6 (2%) were finally diagnosed with glioblastoma multiforme. The clinical features of these patients and 7 previously reported cases indicated that glioma patients may present with bilateral temporal lobe involvement and  92 CSF pleocytosis. In retrospect, 5 (38%) of these 13 patients fulfilled the criteria of definite limbic encephalitis, emphasizing the need to be very cautious in the diagnostic 8 assessment of patients with suspected limbic encephalitis without neuronal antibodies. Isolated new-onset status epilepticus or persistent seizures are a rare presentation of 93 limbic encephalitis. In this clinical setting, the MRI changes can be a consequence 94 rather than the cause of the seizures. After several days of uncontrolled seizures, the brain MRI may show increased FLAIR signal intensity in the hippocampus and 95 amygdala. Unlike the MRI lesions of limbic encephalitis, those caused by persistent epileptic activity are usually accompanied by involvement of other cortical regions and 96, 97 resolve after the seizures are controlled. One study suggested that changes in diffusion-weighted images help to differentiate between hippocampal oedema secondary to prolonged seizure activity and hippocampal inflammation caused by limbic encephalitis. The study found that 9/10 (90%) patients with unilateral medial temporal lobe T2 hyperintensity due to ipsilateral focal seizures had gyriform hippocampal and/or diffuse hippocampal diffusion restriction, whereas only 5 (9%) of 57 patients with medial temporal lobe T2 hyperintensity due to limbic encephalitis had diffusion restriction 98 (Figure 6.7). Figure 6.7 Medial temporal lobe MRI changes caused by prolonged seizures. (A) Axial FLAIR image demonstrating a hyperintense lesion (arrow) in the medial aspect of the left temporal lobe in a patient with bladder carcinoma and status epilepticus caused by a right parietal metastasis (not shown). (B) Diffusion-weighted image showing gyriform left hippocampal diffusion hyperintensity (arrow). (C) Apparent diffusion coefficient map showing diffusion restriction in the indicated region. (black area indicated with an arrow) Other disorders to be considered in the differential diagnosis of limbic encephalitis are 99 shown in Table 6.2. Besides infection by herpesvirus, HIV seroconversion, Whipple 100 101 disease, and neurosyphilis are other infectious disorders that can mimic limbic 102 encephalitis. Patients with neurosyphilis commonly present with seizures. There are a few reports of limbic encephalitis in the setting of systemic autoimmune diseases, such 103–105 as lupus, Sjögren, or Behçet. In these cases the occurrence of limbic encephalitis cannot be attributed to the underlying systemic disease until studies for neuronal antibodies have ruled out a concurrent autoimmune encephalitis. The same applies to patients with limbic encephalitis as a manifestation of Hashimoto encephalopathy (see Chapter 17). Although antibodies against the amino terminal domain of α-enolase have been proposed as biomarkers of this type of limbic encephalitis, these antibodies have 106, 107 only been described in a few reports and need validation. Moreover, the same α- enolase antibodies were identified in a patient with Creutzfeldt–Jakob disease and in patients with limbic encephalitis and LGI1 antibodies, emphasizing the need for comprehensive analysis of neuronal antibodies before considering that limbic 108, 109 encephalitis is a manifestation of Hashimoto encephalopathy. Table 6.2 Differential diagnosis of autoimmune limbic encephalitis Bilateral involvement of medial temporal CSF Distinctive Diagnostic Disorder lobes pleocytosis features tests Fever (>38 °C). MRI Herpes simplex haemorrhagic Herpes virus lesions beyond Yes Yes simplex virus 81 medial temporal encephalitis DNA in CSF lobes. Bilateral lesions uncommon. HHV-6 Predominantly HHV-6 DNA in 88 Yes Occasional occurs in encephalitis CSF immunosuppressed  Bilateral involvement of medial temporal CSF Distinctive Diagnostic Disorder lobes pleocytosis features tests patients. Initial MRI may be normal. Memory loss or behavioural changes usually 92, 110 Almost always less severe than in Glioma Rare Biopsy unilateral limbic encephalitis. MRI lesions may show contrast enhancement. None. MRI More common in lesions show children and young Status diffusion adults. MRI 96 Bilateral Unknown restriction epilepticus abnormalities and are beyond temporal usually lobes reversible Symptoms and MRI CSF 101 findings beyond Neurosyphilis Variable Yes treponemal medial temporal antibody tests lobe involvement Systemic symptoms (polyarthralgia, diarrhoea), oculomasticatory 100 T. whipplei Whipple Yes Yes myorhythmia. DNA in CSF Symptoms and MRI findings beyond medial temporal lobe involvement Systemic lupus Systemic and 103 Yes Yes serological Lupus criteria erythematosus abnormalities  Bilateral involvement of medial temporal CSF Distinctive Diagnostic Disorder lobes pleocytosis features tests SS-A, SS-B Sjögren Systemic symptoms antibodies; 104 Unilateral Unknown syndrome (sicca syndrome) salivary gland biopsy Systemic symptoms (recurrent oral, 105 Behçet Behçet disease Yes Yes genital ulcers, criteria uveitis, polychondritis) Neurogenetic Chronic evolution Genetic 111, 112 Yes No diseases of symptoms confirmation Lymph node Cervical biopsy Kikuchi–Fujimoto lymphadenopathy; showing 113 Yes Yes MRI abnormalities disease histiocytic beyond the necrotizing temporal lobes lymphadenitis 99 Positive HIV HIV Yes Yes Low CD4+ cell count serology 6.4 Neuronal Antibodies and Immunological Subtypes Determination of neuronal antibodies plays a very important role in the diagnosis of limbic encephalitis. Although their presence is not needed when all the criteria are met 8 (in fact 12% of cases are seronegative ) the detection of antibodies substantially decreases the risk of false diagnosis. Moreover, when the three aforementioned 1 diagnostic criteria are not fulfilled (Box 6.1), detection of neuronal antibodies serves to definitively establish the diagnosis of limbic encephalitis. In addition, the antibody type guides the search of the underlying tumour or indicates that this search is not necessary, 43 as occurs with LGI1 antibodies. Table 6.3 shows the most common tumour types associated with limbic encephalitis and the most prevalent antibodies. In general, the association between each antibody and the corresponding tumour type is not very high. However, when the tumour identified is different from that expected (e.g., breast cancer instead of SCLC in a patient with Hu (ANNA1) antibodies), analysis of expression of the neuronal antigen by the tumour helps to decide if a search for a second (occult) tumour 114 should continue. Although many tumour types have been described in association with limbic encephalitis, cancer of the lung, particularly SCLC, testicular tumours, breast cancer, thymoma, and Hodgkin lymphoma account for ~90% of the cases (Table 6.3). Table 6.3 Tumours associated with limbic encephalitis and neuronal antibodies a Most common Tumour Frequency antibodies Other antibodies 22 AMPAR ; b 17 42 115 SCLC 55% Hu and GABAbR amphiphysin ; 116 117 CV2 ; SOX1 118 119 Testicular tumours 15% Ma2/Ma CV2 120 AMPAR and 121 122 Thymoma 10% 116 GAD ; CASPR2 CV2 114 Lung Hu and Ma2/ 123 8% 49 Ri adenocarcinoma Ma 124 120 Ma2/Ma ; Breast 5% AMPAR 125 amphiphysin c126 Hodgkin 2% mGluR5 114 127 Other 5% Non-prevalent Hu ; Ma/Ma2 a Data obtained from reference 27 and personal files; b including neuroendocrine tumours; c most cases associate with an encephalitis without criteria of limbic encephalitis. An important utility of neuronal antibodies is that they help to estimate the likelihood of a patient’s response to treatment and clinical recovery. Whereas antibodies against intracellular antigens indicate probable T cell mediated irreversible neuronal damage and associate with a poor response to treatment, those against neuronal cell membrane antigens usually indicate a reversible neuronal dysfunction and associate with a more 3 favourable response to treatment. Lastly, although the core syndrome of limbic encephalitis is similar among different antibodies, several additional clinical or laboratory features are different according to the type of antibody. These antibody–clinical associations and the likelihood of a paraneoplastic aetiology are described below. 6.4.1 Neuronal Antibodies Associated with High Risk (>80%) of Paraneoplastic Limbic Encephalitis Hu (ANNA1) and Ma2 are the most common onconeural antibodies associated with 28 paraneoplastic limbic encephalitis. Hu (ANNA1) antibodies usually occur in 15 paraneoplastic encephalomyelitis and SCLC (see Clinical Vignette 6.3). This entity is characterized by inflammatory involvement of multiple areas of the nervous system, particularly the hippocampus and amygdala, brainstem and cerebellum, spinal cord, dorsal root ganglia, and myenteric plexus (Box 6.2). In some patients the limbic system is 11 the area predominantly or exclusively affected. About 10% of patients with paraneoplastic encephalomyelitis and Hu (ANNA1) antibodies initially present with limbic encephalitis that over time is accompanied by additional symptoms, suggesting a more 114 widespread involvement of the CNS. Box 6.2 Paraneoplastic Encephalomyelitis This term defines an inflammatory disorder that involves multiple areas of the nervous system and associates with extensive neuronal loss. Clinical symptoms depend on the 11 area of the CNS more severely affected. Paraneoplastic encephalomyelitis was initially described in patients with SCLC and later found associated with Hu (ANNA1), and less frequently with CV2 (CRMP5) or 15 amphiphysin, antibodies. Area affected by the immune disorder Clinical syndrome Predominant antibody Hippocampus/amygdala Limbic encephalitis Hu (ANNA1), GABAbR Brainstem/cerebellum Brainstem encephalitis Ma2 > Ri (ANNA2) > Hu Myelitis/motor CV2 (CRMP5) > Spinal cord neuronopathy amphiphysin > Hu Dorsal root ganglia Sensory neuronopathy Hu ≫ CV2 > amphiphysin Myenteric plexus Gastrointestinal dysmotility Hu Peripheral nerves Sensorimotor neuropathy CV2, amphiphysin The paraneoplastic encephalitides associated with Ma2 or Ri (ANNA2) antibodies share with paraneoplastic encephalomyelitis the same neuropathological findings, and in all of them T cell mediated mechanisms play a dominant pathogenic role. A panel of experts on PNS has recommended using the term ‘paraneoplastic encephalomyelitis’ only in cases with clinical involvement of multiple levels of the 128 nervous system without a clear predominant neurological syndrome. Clinical Vignette 6.3 A 52-year-old man with SCLC diagnosed 12 months earlier, and in remission, developed subacute onset of gait unsteadiness and dysphagia. At neurological examination he was alert, oriented, and cognitively intact. Cranial nerve examination showed a left facial palsy and the movements with the tongue were slow. There was no dysarthria, but the speech was dysphonic. Strength and motor coordination in arms and legs were normal, although he had a broad-based gait and was unable to walk in tandem, suggesting an ataxic gait of cerebellar origin. A brain CT scan was normal, and high titre Hu (ANNA1) antibodies were identified in serum. Treatment with oral prednisone, 1 mg/kg/day, did not improve the neurological symptoms. Two weeks later the patient developed in 24 h severe confusion and agitation and was readmitted. On admission, he was disoriented and had severe short-term memory deficits. CSF examination was normal except for the presence of Hu (ANNA1) antibodies. Brain MRI showed typical features of limbic encephalitis (Figure 6.6B). Oncological work-up demonstrated a relapse of the SCLC with multiple systemic metastases. Further therapy was not considered and the patient died two months later. Comment Patients with limbic encephalitis and Hu (ANNA1) antibodies frequently develop 17 symptoms beyond the limbic system (paraneoplastic encephalomyelitis). Although low serum titres of Hu (ANNA1) antibodies occur in up to 16% of patients with SCLC without neurological symptoms, in this patient the detection of high serum and CSF antibody 129 titres established that the neurological syndrome was paraneoplastic. Patients with SCLC and limbic encephalitis can have other onconeural antibodies (Table 6.3). Besides limbic encephalitis, patients with CV2 (CRMP5) antibodies develop 130 sensorimotor polyradiculoneuropathies, optic neuropathy, and chorea. Unlike Hu 116 (ANNA1) antibodies, CV2 (CRMP5) antibodies also associate with thymoma. Antibodies against the Ma2 protein (called anti-Ma2) or against Ma1 and Ma2 (called anti- Ma) are biomarkers of limbic encephalitis associated with testicular germ-cell tumours 131 (Clinical Vignette 6.4). Ma2 and Ma antibodies associate with the same neurological syndromes (limbic, diencephalic, upper brainstem), but Ma2 antibodies are more frequent in young male patients with testicular germ-cell tumours (mainly seminomas), whereas Ma antibodies predominate in older patients with no sex preference and lung or 127 gastrointestinal adenocarcinomas. A substantial increase in the frequency of anti-Ma2 encephalitis has been detected as a consequence of the increasing treatment of lung adenocarcinomas with immune checkpoint inhibitors that enhance anti-tumour, but also 132 autoimmune, responses (see Chapter 16). As occurs with Hu (ANNA1) antibodies, the limbic encephalitis associated with Ma/Ma2 antibodies can present as an isolated syndrome or part of a widespread encephalitis that also involves the hypothalamus and mesencephalon. In a series of 27 patients with limbic encephalitis and Ma/Ma2 antibodies, 7 (26%) had an isolated limbic syndrome, whereas the rest showed symptoms of hypothalamic (narcolepsia, hypersomnia, weight gain) or upper brainstem involvement (diplopia, eyelid apraxia, supranuclear gaze palsies). Brain MRI lesions show gadolinium enhancement in about 30–40% of patients with Ma/Ma2 antibodies, which is 49 very unusual in limbic encephalitis associated with other antibodies. Clinical Vignette 6.4 A 34-year-old man developed seizures and confusion 18 months after treatment of a non- seminomatous testicular tumour (T2N0M0). He suffered multiple daily temporal lobe seizures with epigastric aura, piloerection, and loss of awareness. He also complained of short-term memory loss and change of personality, which became child-like. Neurological examination did not show focal motor, cerebellar, or sensory deficits. Oncological evaluation confirmed that the tumour was in remission. Brain MRI (Figure 6.8A,B) showed increased FLAIR signal and volume of the right amygdala and hippocampus, suggestive of limbic encephalitis. CSF examination demonstrated 15 3 lymphocytes/mm and CSF-specific oligoclonal bands. Ma2 antibodies were identified in serum and CSF. Figure 6.8 Anti-Ma2 limbic encephalitis. (A, B) Coronal FLAIR MRI images showing increased signal in the right amygdala and hippocampus at diagnosis of anti-Ma2 limbic encephalitis. (C,D) Coronal FLAIR images one year later, showing atrophy of the right mesial temporal structures with persistence of the increased signal. (E) Subtraction ictal SPECT coregistered with MRI (SISCOM) showing increased ictal perfusion over the right hippocampus and parahippocampal gyrus during a right temporal lobe seizure. (F) Coronal FLAIR image showing resection of the temporal pole and the right mesial temporal structures. (G) Inflammatory infiltrate in the surgical specimen. The tissue section was immunostained with TIA-1 antibody, a marker of cytotoxic T cells. There are TIA-positive T cells in close apposition to neurons (H). Scale bars: G, 20 μm; H, 10 μm. (reprinted from reference 133 with permission) The patient was treated with intravenous methylprednisolone and immunoglobulins for several months, resulting in improvement of the memory deficit and personality change but persistence of temporal lobe seizures. A repeat MRI one year after symptom onset demonstrated atrophy of the right mesial temporal lobe (Figure 6.8C,D). Presurgical evaluation of the seizures showed increased ictal perfusion over the right hippocampus and parahippocampal gyrus during a seizure, and he underwent anteromedial temporal lobectomy (Figure 6.8E,F). Pathological studies demonstrated neuronal loss, gliosis, and inflammatory infiltrates mainly composed of T cells. Some T cells were found in close apposition to neurons and expressed markers of cytotoxicity (Figure 6.8G,H). A follow-up one year after surgery showed a partial reduction of the number of seizures (class III in 134 Engel classification ). At the last follow-up 10 years later, he still had seizures (partially controlled) and there was no evidence of tumour relapse. Comment This clinical case demonstrates that paraneoplastic limbic encephalitis may occur after tumour treatment and it does not necessarily associate with tumour relapse. Chronic 135 epilepsy after limbic or other types of autoimmune encephalitis is uncommon. However, if seizures persist the prognosis is not good and in many instances the epilepsy becomes drug-resistant, particularly when the associated antibodies are directed against intracellular antigens, such as Ma2. 6.4.2 Neuronal Antibodies Associated with Intermediate Risk (~50%) of Paraneoplastic Limbic Encephalitis GABAb and AMPA receptor antibodies were initially characterized by direct immunoprecipitation using live rat hippocampal neurons incubated with sera from 22, 23 patients with limbic encephalitis. Subsequent series of patients with these antibodies have shown that the associated encephalitis fulfil criteria of limbic encephalitis in ~60% of patients, whereas in the rest of cases the clinical and brain MRI features are different. Around 50% of patients with GABAbR antibodies have an underlying SCLC, and 120, 136 those with AMPAR antibodies have thymoma or breast cancer. The encephalitis associated with GABAbR antibodies is characterized by a high frequency of seizures (see also Chapter 9). Up to 75% of patients present with seizures that precede by a median of 10 days the development of memory loss, behavioural change, and 32 confusion. Moreover, in 10% of patients the first symptom is new-onset status 93, 137 epilepticus. Brain MRI shows changes compatible with limbic encephalitis in 61% of patients, whereas in the other cases the MRI is normal or demonstrates lesions outside 32, 42 the limbic system (Clinical Vignette 6.5). Clinical Vignette 6.5 A 47-year-old man was brought to the emergency room for a generalized tonic-clonic seizure when he was in the street. A brain CT scan was normal. He recovered from the seizures and was discharged home on anti-seizure medication and an appointment to the neurology clinic. Over the next two weeks he developed several episodes that started with abdominal discomfort followed by masticatory movements and loss of awareness that lasted several minutes. He also became forgetful and aggressive. The neurological examination disclosed a patient who was alert but confused and disoriented, with a substantial decrease of verbal output and short-term memory deficits. The rest of the neurological examination was normal. Brain MRI showed increased T2/FLAIR signal in 3 both hippocampi (Figure 6.9A), and CSF examination demonstrated 20 lymphocytes/mm and a protein concentration of 61 mg/dL. GABAbR antibodies were identified in serum and CSF. Body FDG-PET/CT demonstrated an enlarged mediastinal adenopathy with increased FDG uptake, which biopsy confirmed as SCLC (Figure 6.9B). The patient was treated with chemotherapy, intravenous methylprednisolone, and immunoglobulins with full recovery from the seizures and personality change but persistence of mild memory deficit. Six months later he had a tumour relapse that was accompanied by neurological deterioration with relapsing seizures, worsening memory deficits, and right hemiparesis and expressive aphasia. Repeat MRI studies showed progression of the left hyperintense lesion, which now involved an extensive region of the temporal lobe without contrast enhancement (Figure 6.9C). Despite further therapy, the patient died from systemic tumour progression three months later. Figure 6.9 Anti-GABAbR limbic encephalitis and lung cancer. (A) Coronal FLAIR image showing bilateral increased signal in the amygdala and hippocampus (right > left) at diagnosis (arrows). (B) Fusion of FDG-PET and CT scan showing a hypermetabolic mediastinal lymph node (arrow). (C) Axial FLAIR MRI image obtained at neurological relapse showing extensive progression of the inflammatory changes in the left temporal lobe. Comment Anti-GABAbR limbic encephalitis associated with SCLC has worse prognosis compared with other autoimmune encephalitis associated with antibodies against surface antigens and, therefore, aggressive immunotherapy in addition to treatment of the tumour should be considered. One study showed that 18 (95%) of 19 patients with limbic encephalitis, SCLC, and GABAbR antibodies had concurrent antibodies against the potassium channel tetramerization domain-containing (KCTD) 16 protein. In contrast, KCTD16 antibodies were identified in only 3 (33%) of 9 patients with anti-GABAbR encephalitis without 138 tumour, and 1 (4%) of 26 patients with SCLC and Hu antibodies. Our patient was not tested for KCTD16 antibodies, but these antibodies may be helpful to decide whether a patient with anti-GABAbR encephalitis without a detectable tumour should be closely followed for an occult SCLC. AMPAR antibodies associate with a form of autoimmune encephalitis that shows brain 120, 139 MRI features of limbic involvement in ~60% of the patients. Some patients present with severe psychotic features similar to those of patients with anti-NMDAR encephalitis 140, 141 (see Clinical Vignette 20.3). Unlike limbic encephalitis associated with GABAbR antibodies, seizures are an unusual presentation of limbic encephalitis with AMPAR antibodies. Most patients present with confusion, cognitive deficits including memory 139 loss, and behavioural changes. The presence of psychiatric manifestations or concurrent onconeural antibodies, mainly anti-CV2 (CRMP5), associate with a poor 120, 142, 143 response to therapy. There are no data to determine whether this risk factor for poor outcome also occurs in patients with anti-GABAbR encephalitis. The autoimmune encephalitis associated with Hodgkin lymphoma, also known as 144 Ophelia syndrome, may have two clinical presentations, one of typical limbic encephalitis and the other characterized by more extensive or diffuse clinical-radiological manifestations. The presentation with limbic dysfunction is characterized by insomnia, 145 short-term memory loss, depression, confusion, and less frequently seizures. The presentation with a more extensive involvement is characterized by fever, headache, nausea, and vomiting, followed in a few days by progressive confusion, agitation, hallucinations, and seizures. In the latter group of patients, the brain MRI is normal or 146 shows lesions outside the limbic system (Clinical Vignette 6.6). When metabotropic glutamate receptor (mGluR) 5 antibodies were initially identified in two patients, one of them had a classical limbic encephalitis, but the other had a more diffuse encephalitis 147 with MRI abnormalities involving parieto-occipital cortical regions. In a series of 11 patients with mGluR5 antibodies, a clinical profile of limbic encephalitis was identified in only 1 case. The other patients had behavioural changes, sometimes preceded by fever or headache, followed by cognitive impairment, seizures, or decreased level of consciousness (which occurred in 55% of patients). The brain MRI was normal in 50% of patients, and in the others it showed increased hyperintense lesions in multiple areas of 126 the cerebral hemispheres, basal ganglia or brainstem. Clinical Vignette 6.6 A 49-year-old man without history of medical or psychiatric disorders was admitted to the psychiatry ward with a presumptive diagnosis of acute psychosis. Two weeks before admission he started developing severe insomnia, agitation, paranoia, delusions, and manic behaviour with racing thoughts, difficulty maintaining attention, and euphoria. At admission the neurological examination was normal, without decreased level of consciousness or focal deficits. He was started on olanzapine, and on the fifth day he had a generalized tonic-clonic seizure. After recovering from the seizures, the neurological examination was unchanged. A brain MRI was normal and CSF examination disclosed 75 3 lymphocytes/mm and normal protein and glucose concentrations. Initial assessment for onconeural (Hu, Yo, Ri, CV2, Ma2, Tr, amphiphysin, SOX1) and cell surface neuronal antibodies (NMDAR, GABAbR, AMPAR, DPPX, LGI1, CASPR2) included in a commercial diagnostic test was negative. Because the possibility of autoimmune encephalitis was strongly suspected by his neurologist, samples of serum and CSF were sent to our lab, where additional studies showed the presence of mGluR5 antibodies. The patient was treated with intravenous and oral corticosteroids that led to full clinical recovery. A search for lymphoma, including a PET/CT scan, was negative, but two years later he was diagnosed with stage III Hodgkin lymphoma without recurrence of neurological or psychiatric symptoms. Comment The clinical picture of this patient emphasizes three important points: (1) mGluR5 antibodies can associate with a clinical profile different from that of limbic encephalitis; (2) assessment of serum and CSF samples in research laboratories should be considered in patients with high probability of autoimmune encephalitis despite the clinical or commercial antibody tests being negative; and (3) an initial negative PET/CT scan does not rule out the possibility of an underlying tumour. In patients with high risk of cancer (as suggested by some neuronal antibodies) we recommend tumour rescreening every 4–6 months for at least 2–3 years. 6.4.3 Neuronal Antibodies Not Associated with Cancer The most common subtype of autoimmune limbic encephalitis is not paraneoplastic and associates with LGI1 antibodies. Anti-LGI1 encephalitis represents ~60% of all cases of 8 148 limbic encephalitis and has characteristic clinical features that are described in detail in Chapter 7. The other two antibodies that associate with non-paraneoplastic limbic encephalitis are directed against adenylate kinase 5 (AK5) and glutamic acid decarboxylase (GAD). The syndrome of limbic encephalitis with AK5 antibodies develops as an almost pure subacute loss of working and episodic memory without seizures or 149 severe behavioural changes. The MRI shows bilateral medial temporal lobe involvement and CSF studies show mild pleocytosis and high levels of tau protein,  150, 151 suggesting severe neuronal damage (see Clinical Vignette 2.3). The term GAD antibody-associated limbic encephalitis is in our view controversial due to the fact that GAD antibodies can occur in patients with isolated, usually drug-resistant 152, 153 temporal lobe epilepsy, and this clinical profile is different from limbic 154 encephalitis. In the study that introduced the concept of GAD antibody-associated limbic encephalitis, all nine patients had a long clinical course of isolated epilepsy (median ~1 year) and only one had cognitive or psychiatric symptoms. The brain MRI was normal in five patients and during follow-up they developed hyperintense lesions in one 155 or both medial temporal lobes, which biopsy demonstrated inflammatory infiltrates. A careful review of cases published as GAD antibody-associated limbic encephalitis demonstrates that some patients, instead of limbic encephalitis, develop a clinical 154, 156–158 syndrome of autoimmune epilepsy, whereas others develop a subacute syndrome compatible with the diagnostic criteria of limbic encephalitis, sometimes 159–161 leading to chronic temporal lobe epilepsy. This sequence of events is unusual in other immunological types of limbic encephalitis, where the development of epilepsy (as 135 defined by the international league against epilepsy) is very rare. Lastly, patients older than 50 years who develop limbic encephalitis and harbour GAD antibodies should be 121, 162 examined for the presence of an underlying tumour such as SCLC or other. Limbic encephalitis with GAD antibodies has been also described in patients treated with 163 immune checkpoint inhibitors (see Chapter 16). 6.5 Neuropathology and Immunopathogenesis Neuropathological studies of paraneoplastic limbic encephalitis associated with SCLC and onconeural antibodies, mainly Hu (ANNA1) antibodies, usually show hippocampal neuronal loss, perivascular and parenchymatous inflammatory infiltrates, microglial 13, 15 nodules, and astrogliosis. Immunohistochemical studies show that perivascular infiltrates are mainly composed of B cells, whereas CD8+ cytotoxic T cells predominate in parenchymal infiltrates and often form neuronophagic nodules (T cells in close 5, 164, 165 apposition to neurons indicating T cell mediated neuronal damage; Figure 6.10). The exact mechanism of CD8+ T cell mediated neuronal degeneration is unknown, as is how different subtypes of neurons or brain regions are more affected than others. It has been postulated that neuronal populations at risk are more prone to express major histocompatibility class I (MHC I) molecules, which are involved in presenting processed antigens to the CD8+ T cells. It is unclear whether the Hu (ANNA1) peptides presented to the T cells are the same as those recognized by the antibodies or even if the antigen is 4 the same. Figure 6.10 Neuropathology of limbic encephalitis associated with Hu antibodies. (A) Haematoxylin and eosin staining of hippocampus demonstrating inflammatory infiltrates (arrows) and severe neuronal loss in the pyramidal cell layer (star). (B) Immunohistochemical analysis showing that many T cells (CD3+) are located in the brain parenchyma, (C) whereas B cells (CD20+) are mostly confined to perivascular regions. (D) In the parenchyma, CD8 + T cells expressing markers of cytotoxicity are found in close apposition to neurons. Scale bars: A–C, 50 μm; D, 10 μm. For limbic encephalitis associated with antibodies against neuronal surface antigens (LGI1, GABAbR, or AMPAR) the experience with neuropathological studies is rather limited (see Table 7.2). The main reason is that these patients often have reversible symptoms and the mortality rate is lower than that in patients with limbic encephalitis and onconeural antibodies. Nevertheless, the few autopsy or biopsy studies available 166 showed hippocampal infiltrates by plasma cells, or complement deposition on 5, 167 neurons along with T cell infiltrates and CD8+ T cells in close contact with neurons. This finding is less frequent than in limbic encephalitis associated with antibodies against intracellular antigens, but suggests that T cell mediated mechanisms are also somewhat 32, 166, 168 involved in the advanced stages of the cell surface immune responses. The antibody-mediated mechanisms in limbic encephalitis associated with antibodies against neuronal surface antigens are reviewed in Chapter 3. 6.6 Treatment and Prognosis The response to immunotherapy and outcome vary according to the type of antibody and presence or absence of an underlying tumour. In patients with antibodies against intracellular antigens (onconeural, GAD, and AK5 antibodies) first-line immunotherapies such as steroids, IVIg, and plasma exchange are usually ineffective. The addition of rituximab to these treatments may improve outcomes. In a small trial of nine patients with different PNS and Hu or Yo antibodies, rituximab resulted in substantial 169 improvement in one patient with limbic encephalitis and Hu antibodies. In a series of 15 patients with limbic encephalitis and onconeural antibodies, those treated with rituximab were more likely to have a better outcome than patients treated with first-line immunotherapies. However, the outcome of the group of patients treated with rituximab was less favourable (~50% of patients remained needing assistance for activities of daily living) than that observed in patients with limbic encephalitis and antibodies against 170 neuronal surface antigens. Most patients with LGI1 antibodies show substantial improvement (recovered or functionally independent) after treatment with steroids and immunotherapy, but overall only 35% return to their baseline cognitive function without  52 residual deficits (see Chapter 7). The responses to treatment of patients with cancer and GABAbR or AMPAR antibodies are better than those of patients with limbic encephalitis and onconeural antibodies, although less good than those of patients with LGI antibodies, and based on the experience with anti-NMDA receptor encephalitis the 32, 120 addition of rituximab to up-front treatment is probably indicated. New therapies are badly needed in limbic encephalitis, particularly those associated with antibodies against intracellular antigens. New treatment approaches have been suggested in some studies. In one of them a patient with SCLC treated with nivolumab and ipilimumab developed limbic encephalitis associated with Hu autoantibodies that responded to natalizumab, an anti-integrin α4 monoclonal antibody that prevents 171 migration of lymphocytes across the blood–brain barrier. Another study showed a clinical benefit of tocilizumab (a monoclonal antibody against interleukin 6 receptor) in the treatment of autoimmune encephalitis refractory to first-line immunotherapies and rituximab. The main limitation of this study is that only 34% of the patients had encephalitis associated with neuronal antibodies (thus, the exact aetiology of the others 172 was unclear) and the frequency of patients with limbic encephalitis was not provided. Further studies are needed to determine whether tocilizumab can be potentially useful in the treatment of antibody-positive limbic encephalitis. Acknowledgements Dr Ellen Gelpi, Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria and Neurological Tissue Bank, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain, for providing the histological pictures in Figure 6.3. Dr Rik Vandenberghe, Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium, for providing the images in Figure 6.5. Footnotes * If one of the first three requirements is missing the level of ‘definite’ can only be reached by the demonstration of antibodies against cell surface, synaptic, or onconeural proteins. 18 * [ F]fluorodeoxyglucose positron emission tomography (FDG-PET) can be used to fulfil this requirement. References 1 Graus, F, Titulaer, MJ, Balu, R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.CrossRefGoogle ScholarPubMed 2 Rolls, ET. Limbic systems for emotion and for memory, but no single limbic system. Cortex 2015;62:119–157.CrossRefGoogle ScholarPubMed 3 Dalmau, J, Graus, F. Antibody-mediated encephalitis. N Engl J Med 2018;378:840–851.CrossRefGoogle ScholarPubMed 4 Ehling, P, Melzer, N, Budde, T, Meuth, SG. CD8(+) T cell-mediated neuronal dysfunction and degeneration in limbic encephalitis. Front Neurol 2015;6:163.CrossRefGoogle Scholar 5 Bien, CG, Vincent, A, Barnett, MH, et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 2012;135:1622–1638.CrossRefGoogle ScholarPubMed 6 Dubey, D, Pittock, SJ, Kelly, CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018;83:166–177.CrossRefGoogle Scholar 7 Gultekin, SH, Rosenfeld, MR, Voltz, R, et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000;123(Pt 7):1481–1494.CrossRefGoogle ScholarPubMed 8 Graus, F, Escudero, D, Oleaga, L, et al. Syndrome and outcome of antibody-negative limbic encephalitis. Eur J Neurol 2018;25:1011–1016.CrossRefGoogle ScholarPubMed 9 Kasper, BS, Taylor, DC, Janz, D, et al. Neuropathology of epilepsy and psychosis: the contributions of J.A.N. Corsellis. Brain 2010;133:3795–3805.CrossRefGoogle ScholarPubMed 10 Brierley, JB, Corsellis, JAN, Hierons, R, et al. Subacute encephalitis of later adult life: mainly affecting the limbic areas. Brain 1960;83:357–368.CrossRefGoogle Scholar 11 Henson, RA, Hoffman, HL, Urich, H. Encephalomyelitis with carcinoma. Brain 1965;88:449–464.CrossRefGoogle ScholarPubMed 12 Brain, WR, Norris, FH. The Remote Effects of Cancer on the Nervous System. New York: Grune and Stratton, 1965.Google Scholar 13 Corsellis, JA, Goldberg, GJ, Norton, AR. ‘Limbic encephalitis’ and its association with carcinoma. Brain 1968;91:481–496.CrossRefGoogle Scholar 14 Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 39–1988: a 76-year-old man with confusion, agitation, and a gait disorder. N Engl J Med 1988;319:849–860.CrossRefGoogle Scholar 15 Dalmau, J, Graus, F, Rosenblum, MK, Posner, JB. Anti-Hu–associated paraneoplastic encephalomyelitis/sensory neuronopathy: a clinical study of 71 patients. Medicine (Baltimore) 1992;71:59–72.CrossRefGoogle ScholarPubMed 16 Graus, F, Elkon, KB, Cordon-Cardo, C, Posner, JB. Sensory neuronopathy and small cell lung cancer. Antineuronal antibody that also reacts with the tumor. Am J Med 1986;80:45–52.CrossRefGoogle ScholarPubMed 17 Alamowitch, S, Graus, F, Uchuya, M, et al. Limbic encephalitis and small cell lung cancer: clinical and immunological features. Brain 1997;120:923–928.CrossRefGoogle ScholarPubMed 18 Buckley, C, Oger, J, Clover, L, et al. Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol 2001;50:73–78.CrossRefGoogle ScholarPubMed 19 Lai, M, Huijbers, MG, Lancaster, E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010;9:776–785.CrossRefGoogle ScholarPubMed 20 Irani, SR, Alexander, S, Waters, P, et al. 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. Brain 2010;133:2734–2748.CrossRefGoogle ScholarPubMed 21 Dalmau, J, Geis, C, Graus, F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 2017;97:839–887.CrossRefGoogle ScholarPubMed 22 Lai, M, Hughes, EG, Peng, X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009;65:424–434.CrossRefGoogle ScholarPubMed 23 Lancaster, E, Lai, M, Peng, X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010;9:67–76.CrossRefGoogle Scholar 24 Nokura, K, Yamamoto, H, Okawara, Y, et al. Reversible limbic encephalitis caused by ovarian teratoma. Acta Neurol Scand 1997;95:367–373.CrossRefGoogle ScholarPubMed 25 Rajappa, S, Digumarti, R, Immaneni, SR, Parage, M. Primary renal lymphoma presenting with paraneoplastic limbic encephalitis. J Clin Oncol 2007;25:3783–3785.CrossRefGoogle ScholarPubMed 26 Bien, CG, Urbach, H, Schramm, J, et al. Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy. Neurology 2007;69:1236–1244.CrossRefGoogle ScholarPubMed 27 Gultekin, HS, Rosenfeld, MR, Voltz, RD, et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumor association in 50 patients. Brain 2000;123:1481–1494.CrossRefGoogle ScholarPubMed 28 Graus, F, Delattre, JY, Antoine, JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004;75:1135–1140.CrossRefGoogle ScholarPubMed 29 Newman, NJ, Bell, IR, McKee, AC. Paraneoplastic limbic encephalitis: neuropsychiatric presentation. Biol Psychiatry 1990;27:529–542.CrossRefGoogle ScholarPubMed 30 Iranzo, A, Graus, F, Clover, L, et al. Rapid eye movement sleep behavior disorder and potassium channel antibody-associated limbic encephalitis. Ann Neurol 2006;59:178–181.CrossRefGoogle ScholarPubMed 31 Irani, SR, Michell, AW, Lang, B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69:892–900.CrossRefGoogle ScholarPubMed 32 Maureille, A, Fenouil, T, Joubert, B, et al. Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis. J Neurol 2019;266:195–206.CrossRefGoogle ScholarPubMed 33 Harrison, NA, Johnston, K, Corno, F, et al. Psychogenic amnesia: syndromes, outcome, and patterns of retrograde amnesia. Brain 2017;140:2498–2510.CrossRefGoogle ScholarPubMed 34 Pertzov, Y, Miller, TD, Gorgoraptis, N, et al. Binding deficits in memory following medial temporal lobe damage in patients with voltage-gated potassium channel complex antibody-associated limbic encephalitis. Brain 2013;136:2474–2485.CrossRefGoogle ScholarPubMed 35 Butler, CR, Miller, TD, Kaur, MS, et al. Persistent anterograde amnesia following limbic encephalitis associated with antibodies to the voltage-gated potassium channel complex. J Neurol Neurosurg Psychiatry 2014;85:387–391.CrossRefGoogle Scholar 36 Baddeley, A. Working memory. Science 1992;255:556–559.CrossRefGoogle ScholarPubMed 37 Baddeley, A. The concept of episodic memory. Philos Trans Roy Soc Lond B Biol Sci 2001;356:1345–1350.CrossRefGoogle ScholarPubMed 38 Finke, C, Pruss, H, Heine, J, et al. Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol 2017;74:50–59.CrossRefGoogle ScholarPubMed 39 Kayser, MS, Kohler, CG, Dalmau, J. Psychiatric manifestations of paraneoplastic disorders. Am J Psychiatry 2010;167:1039–1050.CrossRefGoogle ScholarPubMed 40 Jang, Y, Lee, ST, Lim, JA, et al. Psychiatric symptoms delay the diagnosis of anti-LGI1 encephalitis. J Neuroimmunol 2018;317:8–14.CrossRefGoogle Scholar 41 Kayser, MS, Titulaer, MJ, Gresa-Arribas, N, Dalmau, J. Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-d-aspartate receptor encephalitis. JAMA Neurol 2013;70:1133–1139.CrossRefGoogle ScholarPubMed 42 Hoftberger, R, Titulaer, MJ, Sabater, L, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 2013;81:1500–1506.CrossRefGoogle Scholar 43 Gadoth, A, Pittock, SJ, Dubey, D, et al. Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients. Ann Neurol 2017;82:79–92.CrossRefGoogle ScholarPubMed 44 Rocamora, R, Becerra, JL, Fossas, P, et al. Pilomotor seizures: an autonomic semiology of limbic encephalitis? Seizure 2014;23:670–673.CrossRefGoogle ScholarPubMed 45 Tenyi, D, Bone, B, Horvath, R, et al. Ictal piloerection is associated with high-grade glioma and autoimmune encephalitis: results from a systematic review. Seizure 2019;64:1–5.CrossRefGoogle ScholarPubMed 46 Kohler, J, Hufschmidt, A, Hermle, L, Volk, B, Lucking, CH. Limbic encephalitis: two cases. J Neuroimmunol 1988;20:177–178.CrossRefGoogle ScholarPubMed 47 Lacomis, D, Khoshbin, S, Schick, RM. MR imaging of paraneoplastic limbic encephalitis. J Comput Assist Tomogr 1990;14:115–117.CrossRefGoogle ScholarPubMed 48 Urbach, H, Soeder, BM, Jeub, M, et al. Serial MRI of limbic encephalitis. Neuroradiology 2006;48:380–386.CrossRefGoogle ScholarPubMed 49 Dalmau, J, Graus, F, Villarejo, A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004;127:1831–1844.CrossRefGoogle ScholarPubMed 50 Dirr, LY, Elster, AD, Donofrio, PD, Smith, M. Evolution of brain MRI abnormalities in limbic encephalitis. Neurology 1990;40:1304–1306.CrossRefGoogle ScholarPubMed 51 Miller, TD, Chong, TT, Aimola Davies, AM, et al. Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis. Brain 2017;140:1212–1219.CrossRefGoogle ScholarPubMed 52 Arino, H, Armangue, T, Petit-Pedrol, M, et al. Anti-LGI1-associated cognitive impairment: presentation and long-term outcome. Neurology 2016;87:759–765.CrossRefGoogle ScholarPubMed 53 Morbelli, S, Arbizu, J, Booij, J, et al. The need of standardization and of large clinical studies in an emerging indication of [(18)F]FDG PET: the autoimmune encephalitis. Eur J Nucl Med Molec Imag 2017;44:353–357.CrossRefGoogle Scholar 54 Ances, BM, Vitaliani, R, Taylor, RA, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 2005;128:1764–1777.CrossRefGoogle ScholarPubMed 55 Baumgartner, A, Rauer, S, Mader, I, Meyer, PT. Cerebral FDG-PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody types. J Neurol 2013;260:2744–2753.CrossRefGoogle ScholarPubMed 56 Fakhoury, T, Abou-Khalil, B, Kessler, RM. Limbic encephalitis and hyperactive foci on PET scan. Seizure 1999;8:427–431.CrossRefGoogle ScholarPubMed 57 Salmon, E, Sadzot, B, Maquet, P, Franck, G. Results on coregistration of mediotemporal 18F-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) hyperactivity and 3D magnetic resonance imaging hyperintense lesions in limbic encephalitis. J Neuroimag 2002;12:282.CrossRefGoogle ScholarPubMed 58 Scheid, R, Lincke, T, Voltz, R, von Cramon, DY, Sabri, O. Serial 18F-fluoro-2-deoxy-D- glucose positron emission tomography and magnetic resonance imaging of paraneoplastic limbic encephalitis. Arch Neurol 2004;61:1785–1789.CrossRefGoogle ScholarPubMed 59 Henry, TR, Babb, TL, Engel, J Jr., et al. Hippocampal neuronal loss and regional hypometabolism in temporal lobe epilepsy. Ann Neurol 1994;36:925–927.CrossRefGoogle ScholarPubMed 60 Spatola, M, Stojanova, V, Prior, JO, Dalmau, J, Rossetti, AO. Serial brain (1)(8)FDG-PET in anti-AMPA receptor limbic encephalitis. J Neuroimmunol 2014;271:53–55.CrossRefGoogle Scholar 61 Provenzale, JM, Barboriak, DP, Coleman, RE. Limbic encephalitis: comparison of FDG PET and MR imaging findings. AJR Am J Roentgenol 1998;170:1659–1660.CrossRefGoogle ScholarPubMed 62 Kassubek, J, Juengling, FD, Nitzsche, EU, Lucking, CH. Limbic encephalitis investigated by 18FDG-PET and 3D MRI. J Neuroimaging 2001;11:55–59.CrossRefGoogle ScholarPubMed 63 Na, DL, Hahm, DS, Park, JM, Kim, SE. Hypermetabolism of the medial temporal lobe in limbic encephalitis on (18)FDG-PET scan: a case report. Eur Neurol 2001;45:187–189.CrossRefGoogle ScholarPubMed 64 Troester, F, Weske, G, Schlaudraff, E, Passlick, B, Kraemer, K. Image of the month. FDG- PET in paraneoplastic limbic encephalitis. Eur J Nucl Med Molec Imag 2009;36:539.CrossRefGoogle ScholarPubMed 65 Maffione, AM, Chondrogiannis, S, Ferretti, A, Al-Nahhas, A, Rubello, D. Correlative imaging with (18)F-FDG PET/CT and MRI in paraneoplastic limbic encephalitis. Clin Nucl Med 2013;38:463–464.CrossRefGoogle ScholarPubMed 66 Su, M, Xu, D, Tian, R. (18)F-FDG PET/CT and MRI findings in a patient with anti-GABA(B) receptor encephalitis. Clin Nucl Med 2015;40:515–517.CrossRefGoogle Scholar 67 Kim, TJ, Lee, ST, Shin, JW, et al. Clinical manifestations and outcomes of the treatment of patients with GABAB encephalitis. J Neuroimmunol 2014;270:45–50.CrossRefGoogle ScholarPubMed 68 Cozar Santiago Mdel, P, Sanchez Jurado, R, Sanz Llorens, R, Aguilar Barrios, JE, Ferrer Rebolleda, J. Limbic encephalitis diagnosed with 18F-FDG PET/CT. Clin Nucl Med 2016;41:e101–103.CrossRefGoogle ScholarPubMed 69 Castagnoli, H, Manni, C, Marchesani, F, et al. The role of 18F-FDG PET/CT in management of paraneoplastic limbic encephalitis combined with small cell lung cancer: a case report. Medicine (Baltimore) 2019;98:e16593.CrossRefGoogle ScholarPubMed 70 Taneja, S, Suri, V, Ahuja, A, Jena, A. Simultaneous 18F-FDG PET/MRI in autoimmune limbic encephalitis. Ind J Nucl Med 2018;33:174–176.Google ScholarPubMed 71 Deuschl, C, Ruber, T, Ernst, L, et al. 18F-FDG-PET/MRI in the diagnostic work-up of limbic encephalitis. PLoS One 2020;15:e0227906.CrossRefGoogle ScholarPubMed 72 Longo, R, Wagner, M, Savenkoff, B, et al. A paraneoplastic limbic encephalitis from an anorectal small cell neuroendocrine carcinoma: a case report. BMC Neurol 2019;19:304.CrossRefGoogle ScholarPubMed 73 Rey, C, Koric, L, Guedj, E, et al. Striatal hypermetabolism in limbic encephalitis. J Neurol 2012;259:1106–1110.CrossRefGoogle ScholarPubMed 74 Moloney, P, Boylan, R, Elamin, M, et al. Semi-quantitative analysis of cerebral FDG-PET reveals striatal hypermetabolism and normal cortical metabolism in a case of VGKCC limbic encephalitis. Neuroradiol J 2017;30:160–163.CrossRefGoogle Scholar 75 Maeder-Ingvar, M, Prior, JO, Irani, SR, et al. FDG-PET hyperactivity in basal ganglia correlating with clinical course in anti-NDMA-R antibodies encephalitis. J Neurol Neurosurg Psychiatry 2011;82:235–236.CrossRefGoogle ScholarPubMed 76 Krakauer, M, Law, I FDG PET brain imaging in neuropsychiatric systemic lupus erythematosis with choreic symptoms. Clin Nucl Med 2009;34:122–123.CrossRefGoogle ScholarPubMed 77 Goldman, S, Amrom, D, Szliwowski, HB Reversible striatalhypermetabolismin a case of Sydenham’s chorea. Mov Disord 1993;8:355–358.CrossRefGoogle ScholarPubMed 78 Psimaras, D, Carpentier, AF, Rossi, C. Cerebrospinal fluid study in paraneoplastic syndromes. J Neurol Neurosurg Psychiatry 2010;81:42–45.CrossRefGoogle ScholarPubMed 79 Venkatesan, A, Michael, BD, Probasco, JC, Geocadin, RG, Solomon, T. Acute encephalitis in immunocompetent adults. Lancet 2019;393:702–716.CrossRefGoogle ScholarPubMed 80 Tyler, KL. Acute viral encephalitis. N Engl J Med 2018;379:557–566.CrossRefGoogle ScholarPubMed 81 Oyanguren, B, Sanchez, V, Gonzalez, FJ, et al. Limbic encephalitis: a clinical-radiological comparison between herpetic and autoimmune etiologies. Eur J Neurol 2013;20:1566–1570.CrossRefGoogle ScholarPubMed 82 Chow, FC, Glaser, CA, Sheriff, H, et al. Use of clinical and neuroimaging characteristics to distinguish temporal lobe herpes simplex encephalitis from its mimics. Clin Infect Dis 2015;60:1377–1383.Google ScholarPubMed 83 Ward, KN. Child and adult forms of human herpesvirus 6 encephalitis: looking back, looking forward. Curr Opin Neurol 2014;27:349–355.CrossRefGoogle ScholarPubMed 84 Ongradi, J, Ablashi, DV, Yoshikawa, T, Stercz, B, Ogata, M. Roseolovirus-associated encephalitis in immunocompetent and immunocompromised individuals. J Neurovirol 2017;23:1–19.CrossRefGoogle ScholarPubMed 85 Isaacson, E, Glaser, CA, Forghani, B, et al. Evidence of human herpesvirus 6 infection in 4 immunocompetent patients with encephalitis. Clin Infect Dis 2005;40:890–893.CrossRefGoogle ScholarPubMed 86 Seeley, WW, Marty, FM, Holmes, TM, et al. Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology 2007;69:156–165.CrossRefGoogle ScholarPubMed 87 Vinnard, C, Barton, T, Jerud, E, Blumberg, E. A report of human herpesvirus 6-associated encephalitis in a solid organ transplant recipient and a review of previously published cases. Liver Transpl 2009;15:1242–1246.CrossRefGoogle Scholar 88 Bhanushali, MJ, Kranick, SM, Freeman, AF, et al. Human herpes 6 virus encephalitis complicating allogeneic hematopoietic stem cell transplantation. Neurology 2013;80:1494–1500.CrossRefGoogle ScholarPubMed 89 Yilmaz, M, Yasar, C, Aydin, S, et al. Human herpesvirus 6 encephalitis in an immunocompetent pregnant patient and review of the literature. Clin Neurol Neurosurg 2018;171:106–108.CrossRefGoogle Scholar 90 Filippova, A, Charles, J, Epaulard, O, et al. Exogenous human herpesvirus 6 reinfection after tumor-infiltrating T-lymphocyte therapy. Cytotherapy 2018;20:521–523.CrossRefGoogle ScholarPubMed 91 Athauda, D, Delamont, RS, Pablo-Fernandez, ED. High grade glioma mimicking voltage gated potassium channel complex associated antibody limbic encephalitis. Case Rep Neurologic Med 2014;2014:458790.Google ScholarPubMed 92 Vogrig, A, Joubert, B, Ducray, F, et al. Glioblastoma as differential diagnosis of autoimmune encephalitis. J Neurol 2018;265:669–677.CrossRefGoogle ScholarPubMed 93 Hainsworth, JB, Shishido, A, Theeler, BJ, Carroll, CG, Fasano, RE. Treatment responsive GABA(B)-receptor limbic encephalitis presenting as new-onset super-refractory status epilepticus (NORSE) in a deployed U.S. soldier. Epileptic Disord 2014;16:486–493.Google Scholar 94 Chevret, L, Husson, B, Nguefack, S, Nehlig, A, Bouilleret, V. Prolonged refractory status epilepticus with early and persistent restricted hippocampal signal MRI abnormality. J Neurol 2008;255:112–116.CrossRefGoogle ScholarPubMed 95 Tien, RD, Felsbe