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Table of Contents
Year : 2019  |  Volume : 16  |  Issue : 4  |  Page : 240-243

Paraneoplastic limbic encephalitis mimicking acute herpetic encephalitis

1 Department of Neurology, Institute of Neurosciences, Indraprastha Apollo Hospitals, New Delhi, India
2 Department of Critical Care, Max Super Speciality Hospital, New Delhi, India

Date of Submission11-Oct-2019
Date of Acceptance19-Oct-2019
Date of Web Publication12-Dec-2019

Correspondence Address:
Pushpendra Nath Renjen
C-85, Anand Niketan, New Delhi - 110 021
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_61_19

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Paraneoplastic limbic encephalitis (PLE) is a rare disorder that typically follows a chronic or subacute course of personality changes, memory loss, seizures, and hallucinations. Early diagnosis is difficult, and characteristic symptoms can be mimicked by a variety of conditions. We present a case of PLE, initially presenting as acute herpetic encephalitis.

Keywords: Encephalitis, hallucinations, herpetic, limbic, paraneoplastic, seizures

How to cite this article:
Gupta C, Chaudhari D, Renjen PN, Mishra A, Garg S, Pradhan R. Paraneoplastic limbic encephalitis mimicking acute herpetic encephalitis. Apollo Med 2019;16:240-3

How to cite this URL:
Gupta C, Chaudhari D, Renjen PN, Mishra A, Garg S, Pradhan R. Paraneoplastic limbic encephalitis mimicking acute herpetic encephalitis. Apollo Med [serial online] 2019 [cited 2022 Dec 7];16:240-3. Available from: https://apollomedicine.org/text.asp?2019/16/4/240/272827

  Introduction Top

Limbic encephalitis (LE) is a rather rare disorder that mainly affects limbic structures and is characterized by mood-personality changes, sleep disturbances, seizures, hallucinations, and short-term memory loss that can progress to dementia. In most patients with typical LE, the diagnosis is suggested by the clinical presentation, combined with electroencephalography findings (epileptic activity in one or both temporal lobes and focal or generalized slow activity), magnetic resonance imaging (MRI) (hyperintense signals in the medial portion of one or both temporal lobes), and the indicated cerebrospinal fluid (CSF) inflammatory changes. Although nonparaneoplastic and paraneoplastic LE (PLE) have similar clinical features, the identification of the paraneoplastic cause commonly depends on finding the tumor, the paraneoplastic antibodies, or both.[1]

PLE results from the production of a neuronal protein by a tumor, which precipitates an immune-mediated reaction (humoral and T-cell mediated) against both the tumor and the central nervous system (CNS) itself. There are two types of PLE: one with antibodies to intracellular antigens such as Hu, Ma2, CRMP5, and amphiphysin, that is, considered to be T-cell mediated and LE with antibodies to cell-membrane antigens such as LGI1, CASPR2, N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and Gamma-aminobutyric acid. These antibodies are more likely directly involved in pathogenesis; thus, these forms of LE are more responsive to immune-based treatment. Although they are usually nonparaneoplastic, there is a variable percentage of an associating tumor.[1] PLE complicates several types of cancer, mainly small-cell lung carcinoma, testicular germ-cell neoplasms, breast cancer, thymoma, Hodgkin's lymphoma, or teratoma. PLE typically follows a subacute or chronic clinical course, with the progression of symptoms within weeks to months.[1],[2],[3]

  Case Report Top

A 38-year-old male known case of metastatic adenocarcinoma of the left lung for the last 2 years on regular radiotherapy and chemotherapy sessions presented to the emergency department with complaints of headache, nausea, multiple episodes of vomiting, and dysosmia for the last 1-day post 13th cycle of radiotherapy 2 days back. A day later, he became febrile followed by abnormal behavior, irrelevant talks, and was not recognizing his relatives. His serum sodium levels came out to be low – 129 meq/dl and were managed with high salt diet and antipyretics. A day later in the morning, he suffered from an episode of generalized tonic-clonic seizure lasted for 1–2 min associated with urinary incontinence. The patient was managed with antiepileptics. Postictal phase patient remained confused and disoriented. He continued to suffer high-grade fever spikes on and off and had respiratory distress. He was intubated a day later and put on mechanical ventilator support. MRI of the brain with contrast revealed bilaterally T2 symmetrical ring-enhancing lesions in the medial temporal lobes [Figure 1]. Possibility of herpes simplex virus encephalitis or paraneoplastic syndrome was considered. The patient continued to be febrile and remained in semi-conscious state. On examination, pupils were bilaterally normal in size and reacting to light, neck stiffness was present, and he was localizing to painful stimuli. CSF examination revealed lymphocytic pleocytosis. The patient was managed with intravenous (IV) acyclovir, IV steroids, and antiepileptics. The patient's neurological status continued to deteriorate despite treatment. CSF herpes simplex reverse-transcription polymerase chain reaction (PCR) assay was negative. The patient was worked up for paraneoplastic encephalitis. Onconeural antibodies – anti-Hu antibody serum titer – came to be positive. Rituximab was added. There was some initial improvement, but later, the patient developed multiorgan-resistant urine infection and septicemia and further cognitive decline and later death.
Figure 1: Magnetic resonance imaging of the brain with contrast showing bilateral T2 symmetrical ring-enhancing lesions in the medial temporal lobes

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  Discussion and Review of Literature Top

Herein, we report a patient who developed fever, headache, vomiting, altered sensorium, and seizures within a few days. MRI revealed bilateral enhancing lesions in the medial temporal lobes, compatible with LE. LE encompasses a group of clinic pathological entities that affect the medial temporal lobes and other limbic structures (cingulate gyrus, orbital cortex, and hypothalamus), leading to personality changes, seizures, alterations of consciousness, and anterograde amnesia. MRI is crucial in the diagnosis of these disorders, revealing characteristic medial temporal lesions which may or may not enhance after contrast administration. The differential diagnosis varies widely and includes infectious causes, paraneoplastic disorders, Hashimoto's encephalopathy, systemic lupus erythematosus, Sjogren's syndrome, toxic-metabolic encephalopathy (including Korsakoff's syndrome), primary angiitis of the CNS, syphilis, brain metastasis, low-grade glioma, and gliomatosis cerebri.[1]

Based on the acute clinical presentation and CSF results, herpetic encephalitis was initially suspected. However, the symmetric limbic pathology that was shown on MRI questioned the diagnosis since herpetic lesions mainly progress unilaterally across the whole temporal lobe. Moreover, serologic and PCR studies failed to detect any evidence of HSV or other herpes virus infection, and despite treatment with IV acyclovir, the patient had a rapidly progressive cognitive decline. Bilateral lesions in the medial temporal lobes could be also attributed to HHV-6 infection that has rarely been reported after allogeneic hematopoietic stem cell transplantation.[4] However, PCR was negative in our patient and excluded this diagnosis. Antibodies against Hu were detected. The association of LE with latent neuroendocrine cancer and antibodies to Hu set the diagnosis of anti-Hu PLE.[5]

Paraneoplastic disorders are, in general, autoimmune disorders that are triggered by tumors. In many cases, the target antigen is expressed by tumor tissue, such as HuD proteins in small-cell lung cancer (SCLC) and NMDA receptors (NMDARs) in ovarian teratoma.[6] In these patients, it is likely that presentation of the antigen in the context of the tumor triggers the autoimmune response. However, other patients without tumors may have identical clinical syndrome and immunological response (antibody specificity, neuropathology, etc.). It is important to detect tumors promptly for several reasons.

  1. Treating the relevant tumor is thought to be helpful for treating the autoimmune disorder
  2. Tumor therapy and immune therapy may need to be given simultaneously and in a coordinated fashion
  3. Treatment with steroids, rituximab, or cyclophosphamide could complicate tumor diagnosis in the case of tumors such as lymphoma.

In the case of “onconeuronal” antibodies to intracellular antigens such as Hu, the antibodies may occur more commonly in cancer patients than in patients with the autoimmune disease. For instance, low-titer serum Hu responses are common in SCLC patients without the anti-Hu neurological syndromes. For this reason, finding such an antibody should prompt a careful evaluation for tumors even if there is not a corresponding autoimmune disease.

PLE was established as a distinct clinical and pathological entity by the British neuropathologist Corsellis et al. in 1968. They described three patients with bronchial carcinoma who had developed a subacute onset of memory loss and had displayed inflammatory and degenerative changes in the limbic region on postmortem examination.[7] The current hypothesis for the pathogenesis of PLE implicates an autoimmune process involving antigens shared by tumor cells and neuronal cells in the mesial temporal and limbic structures, including cingulated gyrus, orbitofrontal cortex, and mammillary bodies.[1] The most frequently associated neoplasm is SCLC, followed by germ-cell tumor of the testis, breast cancer, Hodgkin's lymphoma, thymoma, and immature teratoma of the ovaries.[8]

PLE is an immune-mediated disorder, the best evidence for which comes from the demonstration of antineuronal antibodies in the patient's CSF and serum. These antibodies react with neuronal proteins that are usually expressed by the patient's tumor, and their detection is the basis of useful diagnostic tests. PLE usually follows a more protracted clinical course characterized by a gradual evolution of symptoms within weeks or months; thus, the acute onset of encephalopathy with fever and confusion in our patient, mimicking acute viral encephalitis, constitutes an uncommon presentation.

Patients with anti-Hu antibodies develop LE that may progress to widespread encephalomyelitis. Most patients are smokers, and the associated tumor is a lung tumor in 85% of patients (typically a small-cell lung carcinoma), while in 15% of patients, there is an extrathoracic neoplasm including the prostate, gastrointestinal, breast, bladder, pancreas, and ovary. However, approximately 50% of patients with these tumors and LE have no antibodies to Hu and better prognosis than patients with anti-Hu antibodies.[1],[2],[3] According to the previous published series of anti-Hu PLE, there has not been reported acute onset of symptoms mimicking viral encephalitis.[2],[3] The evolution of symptoms was subacute reaching a plateau within 6 months in 95% of patients, while it was chronic and mild, resulting in slow progression over years in 5%.[3]

Various cases of acute LE that are not associated with a herpetic infection have been recently reported in the literature. In Japan, cases of acute encephalitis with a clinical presentation similar with HSV encephalitis have been reported. These cases did not demonstrate evidence of HSV infection and have been named “nonherpetic acute limbic encephalitis” as a possible new subgroup of LE of unknown etiology.[9] However, among these cases described in Japan, there is a subgroup of severe but often reversible encephalitis that predominantly affects young women, called “juvenile acute nonherpetic encephalitis”. In many of these patients, an antibody against NR1/NR2 heteromers of the NMDAR was detected; thus, an NMDAR encephalitis was diagnosed.[10] NMDAR encephalitis usually affects young women and may initially present as a viral-like illness. About 50% of these patients have an underlying tumor, usually a cystic ovarian teratoma.[1] In addition, voltage-gated potassium channel complex antibodies LE (mainly LGI1) may present with acute to subacute onset memory loss, confusion, mediotemporal lobe seizures, agitation, and other psychiatric features, evolving over several days or weeks.[11]

Up to date, there is only a single case report in the literature of PLE with SCLC (both diagnosed at necropsy) that presented as acute viral encephalitis with headache, myalgia, and fever.[12] Two cases of PLE coexisting with HSE have also been reported: the first one with lung adenocarcinoma and antibodies to Ma2 that developed HSV encephalitis confirmed by CSF PCR after 6 weeks [13] and the second with antibodies to Hu (no identifiable neoplasm) that a HSV encephalitis was confirmed by postmortem immunocytochemistry and positive PCR performed on temporal tissue extracts.[14] In another case report, an elderly male with a history of smoking presented with symptoms mimicking viral encephalitis was evaluated for paraneoplastic syndrome and found to have large neuroendocrine cell tumor with positive anti-Hu antibodies.[15]

The median survival time after the diagnosis of PLE ranges between 22 and 43 months.[1] The overall poor outcome of PLE likely stems from both the delay in recognition and treatment and the resulting immune-mediated neuronal injury. Thus, we advocate the initiation of immune therapy as soon as a clinical suspicion of PLE is raised. Even with prompt treatment, irreversible neuronal damage and neuropsychiatric complications in our patient might have been unavoidable due to the delayed therapeutic effect of immune therapy in disorders of the CNS.[16] Long-term complications include recurrent seizures, anterograde amnesia, cognitive impairments, and chronic progressive encephalopathy with associated cerebral atrophy, particularly involving the mesial temporal and limbic structures.[17]

Early immune treatment is particularly important with the emergence of rituximab, an anti-CD20 antibody that depletes B-cells and potentially the source of paraneoplastic antibody production.[18] B-cells cross the blood–brain barrier, and intrathecal production of antibodies correlates with clinical severity in paraneoplastic disease.[19] There is early evidence that rituximab is safe and may improve neurological outcomes, as seen in adjunct therapy in children with paraneoplastic opsoclonus-myoclonus syndrome,[19] as well as in paraneoplastic syndromes related to intracellular autoantigens.[20] Since these studies are small and nonrandomized, we cannot make conclusive statements about the role of rituximab in the management of paraneoplastic diseases.

  Conclusion Top

In the setting of known cancer, the decision to treat patients for paraneoplastic neurological syndrome should be empirically considered. Early intervention with immune therapies in patients at the onset of presentation will probably translate into more favorable neurological outcomes, but definitive practice parameters will have to be developed judiciously, especially with the development of potentially more effective targeted therapies such as rituximab. Anti-Hu PLE must be encompassed in the differential diagnosis of acute encephalitis and is of great clinical significance, given that this rare disorder may respond well to immunosuppressive and antineoplastic treatment.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008;7:327-40.  Back to cited text no. 1
Graus F, Keime-Guibert F, Reñe R, Benyahia B, Ribalta T, Ascaso C, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: Analysis of 200 patients. Brain 2001;124:1138-48.  Back to cited text no. 2
Sillevis Smitt P, Grefkens J, de Leeuw B, van den Bent M, van Putten W, Hooijkaas H, et al. Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol 2002;249:745-53.  Back to cited text no. 3
Seeley WW, Marty FM, Holmes TM, Upchurch K, Soiffer RJ, Antin JH, et al. Post-transplant acute limbic encephalitis: Clinical features and relationship to HHV6. Neurology 2007;69:156-65.  Back to cited text no. 4
Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: Neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000;123 (Pt 7):1481-94.  Back to cited text no. 5
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Corsellis JA, Goldberg GJ, Norton AR. “Limbic encephalitis” and its association with carcinoma. Brain 1968;91:481-96.  Back to cited text no. 7
Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: Neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000;123 (Pt 7):1481-94.  Back to cited text no. 8
Mochizuki Y, Mizutani T, Isozaki E, Ohtake T, Takahashi Y. Acute limbic encephalitis: A new entity? Neurosci Lett 2006;394:5-8.  Back to cited text no. 9
Iizuka T, Sakai F, Ide T, Monzen T, Yoshii S, Iigaya M, et al. Anti-NMDA receptor encephalitis in Japan: Long-term outcome without tumor removal. Neurology 2008;70:504-11.  Back to cited text no. 10
Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: New developments and future challenges. Lancet Neurol 2011;10:759-72.  Back to cited text no. 11
Baldwin L, Henderson A. Paraneoplastic limbic encephalitis presenting as acute viral encephalitis. Lancet 1992;340:373.  Back to cited text no. 12
Rosenfeld MR, Eichen JG, Wade DF, Posner JB, Dalmau J. Molecular and clinical diversity in paraneoplastic immunity to ma proteins. Ann Neurol 2001;50:339-48.  Back to cited text no. 13
Sharshar T, Auriant I, Dorandeu A, Saghatchian M, Bélec L, Benyahia B, et al. Association of herpes simplex virus encephalitis and paraneoplastic encephalitis – A clinico-pathological study. Ann Pathol 2000;20:249-52.  Back to cited text no. 14
Markakis I, Papathanasiou A, Papageorgiou E, Siarkos K, Gkekas G. Paraneoplastic limbic encephalitis resembling acute herpetic encephalitis. Case Rep Neurol Med 2013;2013:608643.  Back to cited text no. 15
Irani S, Lang B. Autoantibody-mediated disorders of the central nervous system. Autoimmunity 2008;41:55-65.  Back to cited text no. 16
Benke T, Wagner M, Pallua AK, Muigg A, Stockhammer G. Long-term cognitive and MRI findings in a patient with paraneoplastic limbic encephalitis. J Neurooncol 2004;66:217-24.  Back to cited text no. 17
Dalakas MC. B cells as therapeutic targets in autoimmune neurological disorders. Nat Clin Pract Neurol 2008;4:557-67.  Back to cited text no. 18
Pranzatelli MR, Tate ED, Travelstead AL, Barbosa J, Bergamini RA, Civitello L, et al. Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol 2006;28:585-93.  Back to cited text no. 19
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