limbic encephalitis-clinical guidance

Schott www.practical-neurology.com 143 Limbic encephalitis: a clinician’s guide L imbic encephalitis typically presents with subacute development of memory impairment, confusion, and alteration of consciousness, often accompanied by seizures and temporal lobe signal change on MRI. There is however no clear consensus as to the definition; even traditional distinctions between “encephalitis” and “encephalopathy”, and between “delirium” and “dementia” may be blurred in such patients. The term limbic encephalitis was initially coined to describe patients presenting with amnesia, psychiatric disturbances, and often seizures, and who had postmortem evidence both of occult neoplasia and fairly selective inflammation within the temporal lobes.1 More recently, however, it has also been used to describe patients with a similar phenotype but in whom an infectious or non-paraneoplastic autoimmune cause has been proven or suspected. Even in “typical” paraneoplastic limbic encephalitis, selective involvement of the limbic structures (hippocampus, amygdala, hypothalamus, insular and cingulate cortex) is often not proven histologically, but has been inferred from the clinical presentation and investigations including MRI and EEG. Jonathan M Schott Honorary Research Fellow, Dementia Research Centre, Institute of Neurology University College London, UK and Specialist Registrar, Department of Neurology, Royal Free Hospital, London UK Correspondence to: Dr JM Schott Institute of Neurology University College London, Queen Square, London WC1N 3BG, UK; jschott@dementia.ion.ucl.ac.uk Conversely, although medial temporal lobe MRI and EEG abnormalities are commonly seen, these may not always be present in patients with typical paraneoplastic limbic encephalitis.2 From a practical perspective, limbic encephalitis can be viewed as a syndrome of subacute onset—usually over days or weeks, at most a few months—with a range of underlying causes, the clinical features including: • cognitive, and particularly memory, impairment predominantly due to involvement of the limbic system • frequent but not invariable seizure activity arising from one or both temporal lobes • frequent but not invariable MRI signal change within limbic structures, particularly the hippocampus. This review aims to provide an overview of the important underlying causes that should be considered in patients presenting in this fashion, with particular reference to some of the recently described autoimmune findings. Although in many cases there is limited evidence to guide management, some suggestions for investigation and treatment are provided. Review by Jonathan M Schott Practical Neurology 2006; 6: 143-153 Practical Neurology144 10.1136/jnnp.2006.091827 Figure 1 Axial FLAIR MRI in herpes simplex encephalitis shows extensive signal change in the right temporal lobe (arrow). Herpes simplex is not only the commonest identified cause of viral encephalitis in general, but by far the commonest cause of viral limbic encephalitis in particular DiFFeReNTiAL DiAGNOSiS There are many causes of (sub)acute encephalopathy3 including: • metabolic disorders such as uraemia and hepatic failure • drugs including chemotherapeutic agents • toxins including alcohol • deficiency states including the Wernicke- Korsakoff syndrome • inflammatory disorders including acute disseminated encephalomyelitis • primary or secondary central nervous system (CNS) malignancy including lymphoma • neurodegenerative disorders including Creutzfeldt-Jacob disease. However, in patients with symptoms mainly referable to limbic lobe dysfunction, infective and immune mediated causes are the main diagnostic considerations. Of the infections, herpes viruses, and particularly herpes simplex, are the most important. In addition, an expanding range of immune mediated causes, including some connective tissue diseases, paraneoplastic limbic encephalitis, and voltage gated potassium channel associated encephalopathy appear to be particularly associated with this clinical phenotype. iNFeCTiOUS CAUSeS Infections must always be considered first and empirical treatment should not be delayed if there is any doubt about the diagnosis. Although a wide range of viral, bacterial, and tropical infections, and even neurosyphilis,4 have been reported in the context of a limbic encephalitis phenotype, herpes simplex is not only the commonest identified cause of viral encephalitis in general, but by far the commonest cause of viral limbic encephalitis in particular. In the immunocompetent host with viral encephalitis, 70% of cases are caused by herpes simplex type 1, but in immunocompromised patients with limbic encephalitis, herpes simplex type 2, and human herpes viruses (HHV) 6 and 7 are important possibilities. Patients with herpes simplex encephalitis typically present with a fairly abrupt onset of confusion, memory impairment, and often seizures.5 Fever is common but not invariable. Neuroimaging usually reveals signal change and swelling within the temporal lobes; this is often visible on CT, but is more easily seen using MRI (fig 1). Significant brain swelling may lead to raised intracranial pressure, sometimes requiring medical or even surgical treatment.5 Cerebrospinal fluid (CSF) examination commonly reveals a lymphocytosis and raised protein, but the gold standard for in vivo diagnosis is CSF polymerase chain reaction (PCR) for herpes viruses, which has a sensitivity and specificity of ~95%.6 Untreated, there is a case fatality of ~70%,7 and so treatment with intravenous aciclovir, which reduces case fatality to 20– 30% and has relatively few adverse effects (renal impairment and confusion), should not be delayed.5 Treatment in proven cases should continue for at least 14 days, longer in immunocompromised patients. Some authors recommend a repeat CSF PCR examination at the end of treatment to ensure viral clearance, and further treatment with aciclovir if continued infection is suspected, although there is limited evidence to support this approach.8 An often more difficult decision is when to stop treatment if the initial CSF PCR is negative. In this instance, in acutely ill patients, it may be Schott www.practical-neurology.com 145 Figure 2 Coronal (A) and axial (B) FLAIR MRI in an immunocompromised patient with HHV6 limbic encephalitis showing bilateral hippocampal signal change. (arrows). appropriate to send a second CSF sample for PCR, while continuing treatment for at least 14 days. Clearly in such instances, investigation for alternative causes becomes more pressing. In immunocompromised patients, and particularly those with HIV infection or who have undergone stem cell transplant,9 HHV6 infection or reactivation is an important consideration. Such patients present with fairly abrupt onset of memory impairment, sleep disturbance, and intermittent confusion, have MRI signal change that may be indistinguishable from other causes of limbic encephalitis, often with striking selective hippocampal involvement (fig 2), temporal lobe seizures, and sometimes an acellular CSF. Although the exact role of HHV6 in central nervous system diseases remains controversial, in this clinical scenario detection of HHV6 in the CSF by PCR should prompt treatment with ganciclovir and/or foscarnet,10 as there is some evidence to suggest that this may prevent hippocampal damage. Cases of HHV7 related limbic encephalitis appear to be much rarer, and are treated with foscarnet.10 CONNeCTive TiSSUe DiSORDeRS AND vASCULiTiS A number of connective tissue disorders, including systemic lupus erythematosus, Behçet’s disease, Sjögren’s syndrome, and relapsing polychondritis may present with subacute memory impairment, a range of psychiatric manifestations, and seizures. A similar syndrome may also be seen in primary central nervous system (CNS) vasculitis and other granulomatous disorders including sarcoidosis. Although in most cases there are additional CNS and systemic manifestations, there are rare reports of patients presenting with a fairly pure limbic encephalitis phenotype and even with selective MRI temporal lobe signal change..11–14 Diagnosing these conditionsDiagnosing these conditions is often then very challenging: • A careful history and examination may reveal clues such as a rash, arthralgia, sicca symptoms, pathergy, or oro-genital ulceration. • Investigations should include inflammatory markers, testing for the relevant autoantibodies in peripheral blood, imaging and CSF examination. • Brain biopsy may ultimately be required for definitive diagnosis, and may be the only means of diagnosing isolated CNS vasculitis.15 In a series of non-targeted right frontal lobe brain biopsies to investigate patients with atypical dementia in whom other investigations had failed to provide a diagnosis, an inflammatory cause was uncovered in 9% of patients.16 If confirmed, the mainstay of treatment for these inflammatory conditions is immunosuppression.15 PARANeOPLASTiC LiMBiC eNCePHALiTiS The association between a subacute encephalopathy and a distant tumour was first described by Brierley et al.17 Corsellis et al reported more cases in 1968, and coined the term paraneoplastic limbic encephalitis (PLE).1 A number of different tumours and associated antibodies are now recognised to be associated with this syndrome (table 1). The pathological A B Practical Neurology146 10.1136/jnnp.2006.091827 TABLe 1 Major paraneoplastic antibodies and commonly associated tumours associated with limbic encephalitis (adapted from voltz26) Antibody Associated tumour Anti-Hu Bronchial small cell carcinoma Anti-Ma2 (Anti-Ta) Testicular tumour CRMP5/CV2 Lymphoma, small cell lung ANNA-3 Bronchial small cell carcinoma TABLe 2 Percentage of patients with various clinical features and investigation results in paraneoplastic limbic encephalitis Clinical/investigation feature (Gultekin et al, 2000)2 (Lawn et al, 2003)20 Cognitive impairment 84 92 Psychiatric features 42 50 EEG abnormalities 82 100 CSF abnormalities 80 78 Serum antineuronal antibodies 60 64 MRI temporal lobe signal change 57 83 Epileptic seizures 50 58 Primary tumour Lung 50 54 Testis 20 8 Breast 8 13 changes within limbic structures include perivascular lymphocytic infiltration, neuronal cell loss, and reactive microglial proliferation.18 A variety of different criteria have been used for the diagnosis of PLE. The most recent consensus for a definite diagnosis of “classical” PLE requires: • an appropriate clinical phenotype developing over a maximum of 12 weeks (although proven cases with longer courses have been described); • neuropathological or neuroradiological (MRI/PET/SPECT) evidence of involvement of the limbic system; • and either a cancer discovered within five years following onset of PLE, or the presence of a well characterised onconeural antibody (table 1).19 The characteristics of patients presenting with PLE reported in two retrospective series 2, 20 are summarised in table 2. Although there is no consistent relation between phenotype and underlying malignancy,21 patients with anti-Hu antibodies commonly appear to have symptoms attributable to dysfunction outside the limbic system2; and patients with anti-Ma2 antibodies appear to have more frequent hypothalamic and brainstem involvement and abnormal MRI findings compared with other patients with PLE.2, 21 Importantly, serum antineuronal antibodies are not detected in ~40% of cases of proven PLE, and thus their absence does not exclude the diagnosis. Not all patients have temporal lobe MRI signal change; there is some evidence to suggest that PET imaging may be useful in demonstrating temporal lobe abnormalities in MRI negative cases.22 In the largest published series to date, PLE preceded the diagnosis of cancer in 60% of cases by an average of 3½ months, and when a tumour was identified, there was evidence neither of distant nor local spread in 75% of cases.2 This has implications for Schott www.practical-neurology.com 147 Figure 3 The green mamba snake (Dendroaspis angusticeps), source of dendrotoxin, used for the assay of certain VGKC antibodies. treatment, because not only is there a better prospect for curative therapy of the underlying tumour if it is detected early and has not metastasied, but there is also evidence that, as with other paraneoplastic syndromes,23 treatment of the underlying tumour rather than immunosuppression may lead to a better neurological outcome.2 Traditionally, searching for an underlying tumour has been by detailed imaging of chest, abdomen, and pelvis using high resolution CT, supplemented with mammography, testicular ultrasound, and tumour markers where appropriate. An alternative strategy is to use whole body fluoro-deoxyglucose positron emission tomography (FDG-PET) imaging, which is used routinely in several UK centres to stage established malignancy. Although few prospective data are available, in a large retrospective study specifically addressing this issue, FDG-PET detected a tumour in 37% of patients with suspected PLE in whom routine imaging was normal; the false positive rate was 10%.24 These and other results have led some authors to advocate FDG-PET as the primary investigative tool in suspected cases of PLE, and that this may be a cost effective strategy. There is also evidence to suggest that the combination of CT and PET may improve sensitivity and specificity.25 In practice, local policies, expertise, availability of imaging, and cost considerations will determine which techniques are preferred in an individual hospital. The mechanism by which distant malignancies cause limbic encephalitis is not clear. Although is seems likely that PLE is immune mediated, antineuronal antibodies may only be markers of cell mediated immunopathology, rather Ph ot o: G re go ry D im iji an /S PL Practical Neurology148 10.1136/jnnp.2006.091827 Figure 4 Coronal FLAIR MRI in a patient with VGKC antibody related limbic encephalitis before (A) and after (B) treatment. Medial temporal signal change (arrows) reduced after treatment with the development of medial temporal lobe atrophy (arrows). than pathogenic per se.26–28 There is some evidence to suggest that patients with certain paraneoplastic syndromes have a better prognosis from their underlying tumour than those without. This is presumed to occur as a result of an immune response directed against the primary neoplasm, the paraneoplastic syndrome resulting from cross reaction with common epitopes expressed within the nervous system.27 vOLTAGe GATeD POTASSiUM CHANNeL ASSOCiATeD LiMBiC eNCePHALOPATHY Voltage gated potassium channels (VGKC) are a diverse group of membrane bound proteins responsible for repolarising the nerve terminal after the passage of each action potential. One family of such channels, Shaker VGKC (Kv1), can assemble in a variety of combinations to form a wide diversity of different channels which are expressed in different parts of the nervous system, with Kv1.1 and Kv1.2 being strongly expressed in the molecular layer of the hippocampus. Antibodies to VGKC have been implicated in a number of different neurological conditions (see below), and they may be detected and quantified in serum or CSF by radioimmunoprecipitation using 125I-labelled α-dendrotoxin extracted from the green mamba snake (Dendroaspis angusticeps) (fig 3) which preferentially blocks Kv1.1, Kv1.2 and to a lesser extent Kv1.6 channels.29 Using this technique, the reference range in controls has been quoted as <100 picomolar (pM).29 Raised levels of VGKC antibodies are associated with a variety of acquired peripheral nerve hyperexcitability syndromes including cramp fasciculation syndrome, Isaac’s syndrome (acquired neuromyotonia), and Morvan’s syndrome, which comprises acquired neuromyotonia together with various CNS abnormalities including sleep disorders, autonomic dysfunction, and cognitive impairment.30 The similarity of the cognitive features associated with Morvan’s syndrome with those seen with apparently non-infective limbic encephalitis prompted investigators from Oxford to measure VGKC antibodies. Their first report described two patients with limbic encephalitis in whom an infective cause had been excluded, both of whom had raised VGKC antibodies and one of whom had temporal lobe signal change on MRI.31 One patient had a thymoma, the other had no detectable malignancy. The latter patient improved spontaneously with a parallel fall in VGKC level, and the first patient improved markedly, following plasma exchange, again with a decline in antibody level. Following further reports of treatment responsive, apparently non- paraneoplastic limbic encephalitis associated with raised levels of VGKC antibodies,32, 33 a series of 10 patients was published by Vincent et al,29 shortly followed by a series of seven patients from the Mayo clinic 34; all of these 17 patients had VGKC titres >400 pM. Although the spectrum of clinical features of VGKC associated limbic encephalitis continues to be defined, a number of core features have emerged. Patients usually present in middle Schott www.practical-neurology.com 149 Raised levels of VGKC antibodies are associated with a variety of acquired peripheral nerve hyperexcitability syndromes including cramp fasciculation syndrome, Isaac’s syndrome (acquired neuromyotonia), and Morvan’s syndrome age with subacute memory impairment, and a range of psychiatric features including confusion, disorientation, and behavioural change attributable to limbic dysfunction. Seizures occur in the majority, and may be very difficult to control. Neuropsychological testing, where possible, reveals fronto-temporal dysfunction with prominent episodic memory impairment and relative sparing of parietal lobe function. Hyponatraemia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) appears to be common, precedes treatment with anti-epileptic drugs, and may itself be resistant to treatment. Most patients have EEG abnormalities including diffuse slowing or focal, usually temporal lobe sharp waves, and MRI signal change in the temporal lobes (fig 4A). Most cases are not associated with occult neoplasia, and CSF examination findings are non-specific, showing at most a mild lymphocytosis and raised protein. Rare demonstration of matched oligoclonal bands, and VGKC antibodies in CSF and serum, both disappearing in convalescence, is suggestive of inflammation arising outside the central nervous system. Following treatment with varying combinations of plasma exchange, intravenous immunoglobulin (IVIg), and high dose oral steroids, most patients show a decline in VGKC antibody levels with parallel improvement in neuropsychology and seizure control. The steroids can be slowly tailed off over months, titrating against clinical state and VGKC antibody titre. Close attention to seizure control and careful monitoring of electrolytes including sodium should be continued. Seizures and hyponatraemia, which may initially be intractable, appear to remit following immunosuppression. MR signal change generally resolves, but medial temporal atrophy often remains (fig 4B), presumably explaining any persisting and at times profound cognitive deficits. Patients appear to do best if promptly treated, and there is evidence to suggest that maximum improvement