Paraneoplastic limbic encephalitis …

Francesc Graus MD PhD

Neuro-Oncology

Updated 05.14.2024
Released 05.17.1994
Expires For CME 05.14.2027

Paraneoplastic limbic encephalitis

Author: Francesc Graus MD PhD

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Editor: Rimas V Lukas MD

Paraneoplastic limbic encephalitis

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Introduction

Overview

Paraneoplastic limbic encephalitis is a subset of a larger group of autoimmune encephalitides characterized by the predominant involvement of the limbic system. Patients present with subacute onset of confusion, behavior changes, short-term memory loss, and seizures. Brain MRI shows hyperintense lesions in T2-weighted and FLAIR images involving the medial aspects of temporal lobes. Small cell lung carcinoma is the most common associated neoplasm followed by testicular germ cell tumors, thymomas, and Hodgkin lymphoma. The presence of neuronal antibodies in patients with limbic encephalitis supports an autoimmune pathogenesis and can guide the search for an underlying tumor. Since the initial description of antibodies that recognized intracellular antigens present in tumor cells and neurons (onconeural antibodies), there has been an ever-growing number of circulating neuronal antibodies associated with paraneoplastic and nonparaneoplastic limbic encephalitis, and other autoimmune encephalitis that target neuronal surface antigens. Unlike onconeural antibodies, antibodies against surface antigens do not always indicate that the limbic encephalitis is paraneoplastic, but patients harboring these antibodies usually improve with immunotherapy and they have a more favorable outcome.

Key points

	• Patients with limbic encephalitis present with varied combinations of short-term memory loss, seizures, and psychiatric disturbance.
	• The definite diagnosis of paraneoplastic limbic encephalitis requires: (1) the presence of a clinical syndrome that fulfills established criteria of limbic encephalitis, (2) a positive neuronal antibody associated with paraneoplastic neurologic syndromes, and (3) the diagnosis of a tumor within 5 years of limbic encephalitis diagnosis.
	• Small cell lung carcinoma, thymoma, testicular germ cell tumors, and Hodgkin disease are the tumors most often associated with paraneoplastic limbic encephalitis.
	• The presence of onconeural antibodies or particular antibodies against neuronal surface antigens in a patient with limbic encephalitis raises suspicion for an underlying tumor and can guide the search for the tumor.
	• Early diagnosis, the association with antibodies against surface antigens, and prompt treatment increase the likelihood of response to tumor treatment and immunotherapy.

Historical note and terminology

Paraneoplastic limbic encephalitis as a clinicopathologic entity was first described in 1968 (07). Although previous reports had identified the syndrome, the paper by Corsellis was the first to indicate a potential association of the neurologic syndrome with the underlying cancer. Starting in the mid-1980s, the discovery of anti-Hu (ANNA1) antibodies in some patients lent support to an autoimmune pathogenesis of paraneoplastic limbic encephalitis. Until year 2000, limbic encephalitis was believed to occur nearly always in association with a neoplasm, usually small cell lung carcinoma or, rarely, other tumors (22). However, studies over the past 10 to 15 years have yielded much new information (09), including: (1) identification of an ever-increasing number of antineuronal antibodies associated with limbic encephalitis; (2) expansion of the list of neoplasms most often associated with limbic encephalitis, particularly thymoma, testicular germ cell tumors, and Hodgkin disease; (3) recognition that paraneoplastic limbic encephalitis can largely be divided into subtypes based on linkages among particular tumors, neuronal antibodies, clinical features, and response to treatment; and (4) realization that paraneoplastic limbic encephalitis should probably be viewed as a subset of autoimmune limbic encephalitis, whose incidence is greater than previously believed. Analogous to Lambert-Eaton myasthenic syndrome, limbic encephalitis may be idiopathic or have a paraneoplastic etiology. Presently, the nonparaneoplastic form of limbic encephalitis associated with LGI1 antibodies is much more frequent than the paraneoplastic limbic encephalitis (36).

It must be emphasized that not all paraneoplastic encephalitis can be defined as limbic encephalitis. For example, the most common autoimmune encephalitis is that associated with NMDAR antibodies and up to 58% of women between 18 and 35 years with this encephalitis harbor an underlying ovarian teratoma. These women have a paraneoplastic encephalitis but the clinical and radiological profile is very different from that of limbic encephalitis (45). A panel of neurologists proposed the following clinical criteria to make the diagnosis of limbic encephalitis before the results of the determination of antineuronal antibodies or finding a tumor: (1) subacute onset (rapid progression < 3 months) of working memory deficit (“short-term memory loss”), seizures, or psychiatric symptoms suggesting involvement of the limbic system; (2) bilateral MRI FLAIR/ T2 abnormalities highly restricted to medial temporal lobes; (3) CSF pleocytosis (WBC > 5/mm3) or EEG with epileptic or slow activity involving the temporal lobes; and (4) reasonable exclusion of alternative causes (19). These criteria should raise the diagnostic confidence and support the onset of immunotherapy as soon as possible.

Abnormalities in temporal lobes indicative of limbic encephalitis

Axial FLAIR MRI showing increased signal abnormalities in the medial aspect of temporal lobes (arrows). (Contributed by Dr. Francesc Graus.)

Table 1. Diagnostic Criteria of Limbic Encephalitis

	All four of the following requirements:*
	(1) Subacute onset (rapid progression < 3 months) of working (“short-term memory loss”) and episodic memory deficit, seizures, or psychiatric symptoms suggesting involvement of the limbic system.
	(2) Bilateral MRI FLAIR/T2 abnormalities highly restricted to amygdala and medial temporal lobes.**
	(3) At least one of the following:
		(a) CSF pleocytosis (WBC > 5/mm3)
		(b) EEG with epileptic or slow activity involving the temporal lobes
	(4) Reasonable exclusion of alternative causes.
	* If one of the first three requirements is missing the level of “definite” and can only be reached by the detection of antibodies against cell surface, synaptic, or onconeural proteins. ** [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) can be used to fulfil this requirement.
(19)

The definite diagnosis of paraneoplastic limbic encephalitis requires, in addition to the criteria summarized in Table 1, the presence of a neuronal antibody that usually associates with cancer, and the histological confirmation of a tumor concordant with the antibody detected (for example, anti-Hu and small cell lung cancer). If the tumor found is not expected, the expression by the tumor cells of the antigen recognized by the associated neuronal antibody is required for a definite diagnosis of paraneoplastic limbic encephalitis (20). Although the presence of a neuronal antibody is required for a definite diagnosis, it is important to remember that approximately 10% of patients with paraneoplastic limbic encephalitis do not have demonstrable neuronal antibodies (16).

Expression of Hu antigen in a patient with sensory neuronopathy, Hu antibodies, and breast cancer

Photomicrograph of tumor immunostained with biotinylated anti-Hu IgG showing staining of some nuclei of tumor cells (dark blue color). Counterstaining with hematoxylin produces the light blue color of the negative cell nuclei. ...

Clinical manifestations

Presentation and course

	• Limbic encephalitis usually antedates the diagnosis of the underlying cancer.
	• Immune checkpoint inhibitor therapies have been associated with an increased frequency of limbic encephalitis.

In the majority of published cases of paraneoplastic limbic encephalitis, the neurologic syndrome was the presenting feature of the associated neoplasm, sometimes preceding discovery of the tumor by several months or longer.

There are reports of limbic encephalitis that develop in a patient with cancer after onset of treatment with immune check-point inhibitors (15), suggesting that the drugs enhance an immune response in a patient that was probably predisposed (52). It is important to emphasize that not all the encephalitis that occurs in the setting of immune checkpoint inhibitor therapy is limbic encephalitis (50). The diagnosis of limbic encephalitis induced by immune checkpoint inhibitors requires fulfillment of the criteria described in Table 1 (14). A summary of reported cases is presented in Table 2.

Table 2. Immune Checkpoint Inhibitors and Limbic Encephalitis

Drug (target)	Reported cases	Tumors	Antibodies	Good outcome
Ipilimumab (CTLA-4)	None with ipilimumab alone
Nivolumab (PD-1)	12 (three combined with ipilimumab)	Lung: 4 Kidney: 2 Melanoma: 2 Hodgkin; 2 Thymus: 1 Mesothelioma: 1	None: 4 Ma2: 3 Hu: 2 GAD: 2 SOX1: 1	6 (50%)
Pembrolizumab (PD-1)	5	Melanoma: 3 Lung: 2	None: 4 Caspr2: 1	3 (60%)
Cemiplimab (PD-1)	1	Sarcoma	Hu	No
Atezolizumab (PD-L1)	3	Lung: 3	Hu: 3	No
Avelumab (PD-L1)	None
Durvalumab (PD-L1)	2	Lung: 2	GABAbR: 1 Amphiphysin: 1	None

* With clinical information

Limbic encephalitis generally has a subacute onset evolving over days to weeks. Patients typically present either with an amnestic syndrome or affective disorder; most patients eventually develop features of both (22). The memory loss includes short-term anterograde amnesia and a variable period of retrograde amnesia. Denial of the deficit and confabulation are common. The psychiatric disorder usually includes some combination of depression, anxiety, emotional lability, and personality change. Hallucinations and paranoid delusions may occur. The memory deficit may be overlooked or overshadowed by predominant behavior and psychiatric problems. Other features include obsessive-compulsive behavior, disinhibited behavior, hyperphagia, and hypersexuality. Generalized or partial complex seizures occur in most patients, may be the initial neurologic feature, and can be medically intractable (19). Many, if not most, patients with the syndrome of paraneoplastic limbic encephalitis as described above also have clinical features indicating involvement of one or more "extra-limbic" areas of the nervous system. These clinical presentations roughly segregate according to the associated tumors and neuronal antibodies.

Prognosis and complications

Prognosis depends on the associated antibody. Patients with antibodies against surface receptors that are pathogenic usually recover from limbic encephalitis whereas those with onconeural antibodies, which predict a T cell mediated pathogenesis, do worse.

Clinical vignette

A 56-year-old man with a long smoking history developed left focal motor seizures with secondary generalization. EEG showed mild left frontotemporal slowing. Brain MR scan was normal, except for a small nonenhancing lesion in the left parietal lobe, consistent with an infarction. He began treatment with carbamazepine but later that month developed apathy, confusion, and short-term memory difficulty. Cerebral angiography was unremarkable, with no evidence for vasculitis. CSF contained four white blood cells/mm3, protein 37 mg/dl, and glucose 70 mg/dl. CSF cytology, cryptococcal antigen, and cultures were negative.

Over the next several weeks, the patient's mental status progressively deteriorated, with profound short-term memory loss, disorientation, shortened attention span, emotional lability, episodic agitation, and sexual disinhibition. Seizures became more frequent despite increase in the dose and number of antiepileptic drugs. Study of antineuronal antibodies confirmed positivity for GABAbR antibodies in serum and CSF. PET-CT scan of the whole body done 2 months after onset of symptoms showed a small, hyperintense mediastinal adenopathy; biopsy revealed small cell lung carcinoma. He received three boluses of 1 gram of methylprednisolone/day followed by oral prednisone 60 mg per day, with tapering doses over 2 months. Concurrently with beginning prednisone, he was started on monthly chemotherapy with carboplatin and etoposide, for a total of four courses. After the third cycle of chemotherapy, he attained a complete tumor remission. His confusion and memory loss significantly improved so that he was able to carry out activities of daily living but could not return to work. One year later his neurologic deficits were stable, and there was no evidence for tumor recurrence.

Biological basis

Etiology and pathogenesis

• Paraneoplastic limbic encephalitis is caused by a misdirected immune response against the nervous system, which is initially driven against tumor antigens that are also expressed in the brain.

The central theory of an autoimmune pathogenesis of neurologic paraneoplastic disorders is that the tumor cells express antigens identical or antigenically related to molecules normally expressed by neurons. In rare instances, an autoimmune response initially arising against "onconeural" antigens expressed by tumor cells subsequently attacks neurons expressing the same or related antigens (11). Many but not all patients with paraneoplastic (and nonparaneoplastic) limbic encephalitis have circulating neuronal antibodies. Some of these antibodies that react against neuronal surface antigens are believed to directly mediate neuronal dysfunction. For other subtypes of limbic encephalitis associated with onconeural antibodies that usually target intracellular antigens it is likely that cellular immune effectors rather than antibodies cause neuronal dysfunction and death. However, the actual mechanisms of neuronal injury remain poorly understood, and even in limbic encephalitis associated with potential pathogenic antibodies the additional effect of T cell mediated immune responses cannot be ruled out.

The most consistent and severe neuropathologic abnormalities in limbic encephalitis associated with onconeural antibodies and isolated seronegative cases (16) are present in the hippocampus and amygdala, with extensive neuronal loss, gliosis, and microglial nodules (03). Similar but less severe changes are often present in the parahippocampal gyrus, cingulate gyrus, insular cortex, orbital frontal cortex, basal ganglia, and diencephalon. Perivascular lymphocytic cuffing and leptomeningeal mononuclear cell infiltrates are patchy and variable. The intensity of inflammatory changes does not correlate well with the clinical severity or the degree of neuronal loss and gliosis.

In some patients with clinically "pure" paraneoplastic limbic encephalitis, the pathologic changes at autopsy are entirely confined to the limbic system. Most patients with limbic encephalitis and small cell lung cancer, and many patients with other associated tumors, have a multifocal encephalomyeloneuritis, with patchy neuronal loss or inflammatory infiltrates in any or all areas of the nervous system, including the cerebral hemispheres, basal ganglia, diencephalon, brain stem, cerebellum, gray matter of the spinal cord, dorsal root ganglia, and autonomic ganglia. The pathologic changes may be more widespread than would have been predicted based on patients' clinical manifestations.

There are very limited neuropathologic descriptions of patients with paraneoplastic limbic encephalitis and antibodies against neuronal surface antigens (AMPAR, GABAbR, or mGluR5). The good response to immunotherapy and the neuropathological findings in anti-NMDAR encephalitis and nonparaneoplastic limbic encephalitis with LGI1 antibodies (31; 03) would indicate that the typical findings of classical limbic encephalitis (T cell infiltrates and neuronal loss) should not be present in these patients. However, we have studied a patient with paraneoplastic limbic encephalitis, GABAbR antibodies, and small cell lung cancer that in the neuropathological study showed a prominent infiltrate of CD8+ T cells and neuronal loss (Graus unpublished).

Table 3. Neuronal Antibodies in Paraneoplastic Limbic Encephalitis

Antibody	Associated tumor(s)	Antigen
Hu (ANNA-1)	Small cell lung carcinoma	RNA-binding protein HuD
CRMP5 (CV2)	Small cell lung carcinoma, thymoma	Cytoplasmic protein collapsin response-mediator protein-5
SOX1	Small cell lung carcinoma	Nuclear protein SOX1
Amphiphysin	Breast, small cell lung carcinoma	Amphiphysin, synaptic vesicle-associated protein
Ma2	Testicular tumors, lung and gastrointestinal adenocarcinomas	Ma1 and Ma2 cytoplasmic/nucleolar proteins
GAD1	Small cell lung carcinoma	glutamic acid decarboxylase 65, synaptic protein
mGluR5	Hodgkin lymphoma	mGluR5 in hippocampal neuropil
AMPA receptor	Thymoma, lung cancer, breast carcinoma	hippocampal neuropil; Glu R1 and R2 glutamate receptor subunits
GABA(B) receptor	Small cell lung carcinoma	neuropil of hippocampus; B1 receptor subunit

(1) In young patients, anti-GAD antibodies are associated with pharmacoresistant epilepsy and enlarged amygdala but no cancer (30).

The neuronal antibodies more frequently associated with paraneoplastic limbic encephalitis are summarized in Table 3. Hu antibodies are found in patients with various clinical manifestations of multifocal encephalomyelitis (22; 17), and more than 80% have small cell lung carcinoma, with reports of other tumors including non-small cell lung cancer, neuroblastoma, and carcinoma of the breast or prostate (17). Among patients with limbic encephalitis and small cell lung carcinoma, approximately one half have Hu antibodies, a few patients have other antibodies (CRMP5, SOX1, amphiphysin), and the remainder who had no identifiable onconeural antibodies were later found to harbor antibodies against AMPAR and, particularly, GABAbR (24; 25). Probably GABAbR antibodies are as common as Hu antibodies in patients with paraneoplastic limbic encephalitis.

Limbic encephalitis is an early and prominent feature in 10% to 20% of patients with paraneoplastic encephalomyelitis and Hu antibodies. Most of these patients develop other multifocal signs and symptoms during the course of their illness (17). These include varied combinations of signs and symptoms referable to the extralimbic cerebral cortex, basal ganglia, brainstem, cerebellum, dorsal root ganglia, spinal cord, and autonomic system (22; 51).

Hu antibodies are a valuable clinical marker for paraneoplastic limbic encephalitis or encephalomyelitis, but it is currently thought that cellular immune effectors, and not Hu antibodies, are the mediators of neuronal injury. Evidence to support cell-mediated autoimmune neuronal injury includes the presence of CD8+ T lymphocytes clustered around neurons in the brain and dorsal root ganglia and the presence of oligoclonal T lymphocytes in the blood and dorsal root ganglia (41). T lymphocytes from patients' peripheral blood recognize and respond to peptides derived from the HuD onconeural antigen (42).

Patients with CRMP5 (CV2) antibodies and limbic encephalitis may show additional involvement of the extralimbic cerebral cortex or basal ganglia. Any of these antibodies can be present in patients with paraneoplastic limbic encephalitis, but none of them has a particular association with limbic encephalitis versus other neurologic syndromes. Small cell lung cancer is by far the tumor most commonly associated with these antibodies. It is not unusual for patients with small cell lung carcinoma and limbic encephalitis (or another CNS syndrome) to have more than one type of onconeuronal antibody.

Ma2 antibodies mainly occur in young men with testicular germ cell tumors (10) or non-small cell lung cancer treated with immune checkpoint inhibitors (52). There are a few reported patients with breast carcinoma or dysgerminoma in women. Some patients with Ma2 antibodies have a clinically "pure" limbic encephalitis, whereas the majority present with a combined syndrome reflecting involvement of the limbic system, diencephalon, and brainstem (10). Sleep dysfunction is common and includes excessive daytime drowsiness, narcolepsy, and REM sleep behavior disorder. Ocular motor disturbance usually includes supranuclear gaze palsy, especially affecting vertical gaze. Movement disorders include facial dystonia, rigidity, and bradykinesia, which may be severe. Autonomic dysfunction includes disturbed temperature regulation, labile blood pressure, and inappropriate secretion of antidiuretic hormone. Patients whose antibodies react with the Ma1 protein as well as the Ma2 protein tend to have more severe cerebellar and brainstem dysfunction than those whose antibodies react solely with Ma2 protein (10). Anti-Ma2 syndromes, including limbic encephalitis, are frequently reported after treatment with immune checkpoint inhibitors (52). Antibodies against Kelch-like protein 11 (KLHL11) have been also described in patients with testicular tumors and paraneoplastic neurologic syndromes, mainly brainstem encephalitis (13). However, KLHL11 antibodies are very unusual in patients with predominant or isolated paraneoplastic limbic encephalitis (23). Leucine zipper 4 (LUZP4) antibodies have been characterized in patients with testicular seminomas and different clinical syndromes including limbic encephalitis. However, LUZP4 antibodies are frequently associated (75% of patients) with Ma2, and particularly kelch-like protein 11 (KLHL11) antibodies indicating that in most cases, LUZP4 antibodies do not add diagnostic value to the detection of Ma2 or KLHL11 antibodies (12). Future studies are needed to clarify the real value of LUZP4 antibodies in the diagnosis of paraneoplastic neurologic syndromes.

The mechanisms of autoimmune neuronal injury in anti-Ma2-associated paraneoplastic limbic encephalitis are not known. Interstitial and perivascular infiltration of T lymphocytes in affected brain areas suggests cellular immune effectors (10). In one attempted animal model, adoptive transfer of rat T lymphocytes specific for the Ma1 onconeural protein caused meningeal and perivascular inflammatory infiltrates in recipient rats, but the recipient animals did not develop neuronal loss or clinical disease (38).

Several autoantibodies associated with paraneoplastic and nonparaneoplastic limbic encephalitis react with synaptic or neuronal cell surface proteins (08; 09). Anti-glutamic acid decarboxylase (GAD) and anti-amphiphysin are antibodies against intracellular synaptic proteins. Patients with anti-GAD usually present with nonparaneoplastic syndromes, ie, stiff-person syndrome or cerebellar ataxia (18), whereas anti-amphiphysin was initially recognized in patients with paraneoplastic stiff-person syndrome and breast cancer. These antibodies may rarely occur in patients with paraneoplastic limbic encephalitis and lung cancer (26). GAD antibodies also associate with a clinical syndrome of pharmaco-resistant epilepsy and MRI features suggestive of limbic encephalitis. The clinical syndrome, however, does not associate with cancer and lack the additional clinical features of limbic encephalitis (30).

Autoantibodies against N-methyl-D-aspartate receptors (NMDAR) have been identified in association with encephalitis and ovarian teratoma (mostly young women) (45) and in a few persons with other tumors, including testicular germ cell tumor, mediastinal teratoma, small cell lung carcinoma, or Hodgkin lymphoma. Tumors other than ovarian teratoma almost always occur in patients, male and female, older than 40 years (04). NMDAR antibodies are unusual among onconeural antibodies in that they may be more readily detected in CSF than in serum (45). NMDAR antibodies are mainly directed against the extracellular domain of the NR1 receptor subunit and stain the dendritic network and synaptic-enriched regions in the neuropil of the hippocampus. Teratomas from affected patients contain neural tissue elements that express NMDAR. IgG from patients with NMDAR antibodies cause cross-linking and internalization of NMDARs on cultured hippocampal neurons (35). Intracerebral infusion of anti-NMDAR patient CSF into rats caused reduction of hippocampal NMDAR immunostaining without affecting synaptic components or causing neuronal death (40). These findings support a direct effect of NMDAR antibodies in causing neuronal dysfunction in affected patients and are also consistent with the high percentage of patients who eventually make a good neurologic recovery.

As stated above, it is important to emphasize that very few patients with NMDAR antibodies present with a "typical" limbic encephalitis, whereas most patients have a more severe and complex, but fairly stereotyped clinical course. In adults and adolescents, this usually begins with subacute memory loss and severe behavior changes or psychiatric disorder; many patients are initially admitted to an acute psychiatric hospital. Children may present with seizures or a movement disorder without severe behavioral changes. Regardless of the initial symptoms, most patients go on to develop seizures and rapid deterioration in mental status to the point of unresponsiveness within 4 weeks of onset. Some patients become increasingly agitated, whereas others develop a catatonic-like state with eyes open, but they are mute, akinetic, and unresponsive. Most patients have additional features including: severe central hypoventilation, often requiring mechanical ventilation for an extended period; autonomic dysfunction including bradycardia/tachycardia, labile blood pressure, hyperthermia, or hyperhidrosis; and a movement disorder including orofacial dyskinesias, dystonic posturing, choreoathetoid movements, or general rigidity. In nearly all reported patients, the ovarian teratoma was previously unrecognized, and even when found was sometimes dismissed as "benign" and unrelated to the neurologic disorder. Patients generally recover after several months of aggressive supportive care. Resection of the ovarian teratoma or immunosuppressive therapy generally hastens the neurologic recovery and probably improves the ultimate neurologic outcome (45).

Although more than 10 antibodies against surface antigens have been described in patients with autoimmune encephalitis only three associated with paraneoplastic limbic encephalitis (09). Antibodies against the GABAb receptor have been identified in several patients with non-paraneoplastic limbic encephalitis, or limbic encephalitis associated with small cell lung carcinoma (27). Patients presented with subacute onset of seizures, antedating in days or weeks to the "full-blown" limbic encephalitis symptoms. In a series of 22 patients with paraneoplastic limbic encephalitis (four female) with GABAbR antibodies with a median age of 64 years (range 55 to 85), 20 had small cell lung carcinoma, one malignant thymoma, and one uncharacterized lung mass (33). The most frequent first symptom was isolated recurrent seizures in 17 patients (77%), and two presented de novo status epilepticus. After a median delay of 10 days (range 1-30), the recurrent seizures' phase was followed by an encephalitic phase. One studied identified that 18 of 19 (95%) patients with limbic encephalitis, GABAbR antibodies, and small cell lung carcinoma also had concomitant antibodies against the potassium channel tetramerization domain-containing 16 protein whereas these antibodies were found in only three of nine (33%) patients with anti-GABAbR limbic encephalitis without tumor, suggesting they could be useful to identify patients with a paraneoplastic origin of their limbic encephalitis (48).

Some patients with limbic encephalitis associated with thymoma, lung carcinoma, or breast carcinoma have antibodies against GluR1 and R2 glutamate receptor subunits of the AMPA receptor. Patients present with a subacute "classic" limbic encephalitis, with mesial temporal lobe lesions on MRI. The neurologic symptoms generally improve after tumor treatment and/or immunosuppression, though some patients suffer a relapsing neurologic course.

Limbic encephalitis was described in a young girl with Hodgkin lymphoma under the term of Ophelia syndrome (05). In 2011, antibodies against the mGluR5 metabotropic glutamate receptor were described in two patients with paraneoplastic encephalitis, one with criteria of limbic encephalitis and Hodgkin lymphoma. In a study Spatola and colleagues collected 10 patients with encephalitis and anti-mGluR5. Six of them presented an associated Hodgkin lymphoma but only one developed the typical clinical profile of limbic encephalitis (44).

Epidemiology

• The tumors more frequently associated with limbic encephalitis include: small cell lung cancer, testicular seminoma, thymoma, and Hodgkin disease.

The frequency of paraneoplastic limbic encephalitis is low, but the true incidence and prevalence is unknown due to the lack of robust epidemiological studies. Two population-based epidemiological studies of paraneoplastic neurologic syndromes have been conducted in recent years. One study, done in three regions of Italy, found an incidence of 0.89 per 100,000 persons-years and a prevalence of 4.37 per 100,000 persons, and limbic encephalitis represented 30% of all paraneoplastic neurologic syndromes (53). In a second study conducted in Olmsted County, Minnesota, the incidence of limbic encephalitis was 0.1 per 100,000 persons-years and a prevalence of 1.4 per 100,000 persons (43).

Approximately 50% to 60% of reported patients with paraneoplastic limbic encephalitis have small cell lung carcinoma (22). Other associated neoplasms include testicular germ cell tumors (10); thymoma (21); Hodgkin lymphoma (44; 37); non-Hodgkin lymphom; non-small cell lung cancer, particularly in the setting of Ma2 antibodies and treatment with immune checkpoint inhibitors (52); and breast carcinoma.

Because of the tumor associations, paraneoplastic limbic encephalitis occurs most commonly in middle-aged or older adults, although it may occur in adolescents or young adults when associated with Hodgkin lymphoma, ovarian teratoma, thymoma, testicular tumors, or neuroblastoma. Concerning the frequency of particular antibodies in paraneoplastic limbic encephalitis, anti-HU and anti-GABAbR are probably the most commonly described followed by anti-Ma2 and anti-AMPAR (16).

Differential diagnosis

Confusing conditions

For patients without a previous cancer diagnosis who present with limbic encephalitis, the most important differential diagnosis is with infectious encephalitis, particularly herpes simplex encephalitis, which almost always involves the temporal lobes (47). Acute onset in hours of days, high fever greater than 38ºC, and the presence of aphasia are more frequent in herpes simplex encephalitis. Brain MRI usually shows unilateral temporal lobe involvement and frequent extension to insula or cingulate gyrus. In addition, CSF analysis in herpes simplex encephalitis almost always shows pleocytosis whereas in paraneoplastic limbic encephalitis CSF cell herpes simplex encephalitis count is normal in at least 50% of patients (22). Limbic encephalitis caused by human herpesvirus 6 occurs in severely immune-compromised patients with hematopoietic stem cell and solid organ transplantation. Patients presents with clinical and MRI features indistinguishable from paraneoplastic limbic encephalitis (02).

Gliomas are after herpetic encephalitis the most common mimic of limbic encephalitis. Patients with temporal lobe gliomas usually present with seizures but the cognitive or behavior symptoms are much less severe that those observed in limbic encephalitis. In a study including 306 patients with suspected diagnosis of limbic encephalitis, six (2%) were finally diagnosed with glioblastoma. Lower grade infiltrating gliomas lacking robust enhancement and having a higher likelihood of presenting with seizures may be even more challenging to differentiate from an immune-mediated encephalitis. The analysis of these patients and seven previously reported indicated that glioma patients may present with bilateral temporal lobe involvement or show CSF pleocytosis (30%). Retrospectively, five (38%) of the 13 patients fulfilled the diagnostic criteria of definite limbic encephalitis, emphasizing the need to be very cautious in the diagnosis of limbic encephalitis that does not present with neuronal antibodies (54). Less common mimics include Kikuchi-Fujimoto disease that exceptionally present symptoms of limbic encephalitis (06), neurosyphilis (28), and limbic encephalitis related to COVID-19 infection (39) or vaccination to prevent COVID-19 (01). More information can be found in Table 4.

Table 4. Differential Diagnosis of Paraneoplastic Limbic Encephalitis

Disorder	Distinctive feature	CSF pleocytosis	Diagnostic tests
Herpes simplex virus encephalitis	Fever (> 38ºC). MRI hemorrhagic lesions, beyond medial temporal lobes	Yes	HSV DNA in CSF
HHV-6 encephalitis	Almost restricted to immunosuppressed patients	Occasional	HHV-6 DNA in CSF
Glioma	Contrast enhancement common, Almost always unilateral temporal lobe involvement	No	Biopsy
Status epilepticus	More common in children and young adults. MRI abnormalities beyond temporal lobes	Unknown	None. Reversible evolution of MRI findings sometimes leading to atrophy
Neurosyphilis	Symptoms and MRI findings beyond medial temporal lobe involvement	Yes	CSF treponemal antibody tests
Kikuchi-Fujimoto disease	Systemic symptoms, Symptoms and MRI findings beyond medial temporal lobe involvement	No	Pathological analysis of lymph node
COVID-19	Symptoms appear 1 to 2 weeks after systemic infection by SARS-CoV-2	Occasional	Fulfill criteria of limbic encephalitis in the setting of COVID-19

There is increasing recognition of patients whose clinical presentations are indistinguishable from those of paraneoplastic limbic encephalitis but in whom no tumor is ever discovered. Most cases of nonparaneoplastic, limbic encephalitis are believed to have an autoimmune pathogenesis. Some patients have neuronal antibodies but without a tumor; the most common such group is patients with nonparaneoplastic limbic encephalitis and LGI1 antibodies (see above discussion). Patients with LGI1 antibodies frequently present with multiple faciobrachial dystonic seizures before developing the amnestic and behavioral manifestations of limbic encephalitis (49).

Diagnostic workup

The first step is to confirm that the patient under evaluation fulfills the criteria of limbic encephalitis (19). MR imaging in about two thirds of patients with paraneoplastic limbic encephalitis shows areas of abnormal T2-weighted or FLAIR signal in the mesial temporal lobe and amygdala bilaterally and less commonly in the hypothalamus and basal frontal cortex (22). The lesions enhance with gadolinium in a minority of cases. Some patients additionally have extratemporal cortical or subcortical lesions. Patients with Ma2 antibodies may have MR lesions in the thalamus, hypothalamus, brainstem, and cervical spinal cord with or without lesion(s) in the mesial temporal lobes (10).

In many patients with limbic encephalitis, the MR lesions subsequently resolve with or without concomitant clinical improvement, sometimes evolving to temporal lobe atrophy.

At some time during the course of limbic encephalitis, the CSF in about two thirds of patients shows a mild lymphocytic pleocytosis or slight elevation of protein, or both (22; 10). Some patients additionally have oligoclonal bands or an elevated CSF IgG index. Normal CSF does not rule out paraneoplastic limbic encephalitis, and abnormal CSF does not distinguish paraneoplastic limbic encephalitis from nonparaneoplastic cases (19).

Approximately 75% of patients with limbic encephalitis have an abnormal EEG during the course of their illness (22). The findings are nonspecific. The most common EEG abnormality is slowing, either diffuse or localized to the frontal or temporal regions. There may be superimposed paroxysmal sharp waves and spikes with or without clinical seizures.

Fluorodeoxyglucose positron emission tomography may demonstrate unilateral or bilateral areas of hippocampal hypermetabolism in the acute phase of illness (29). The hypermetabolic areas do not necessarily correspond to lesions seen on MRI scans. The findings on PET scanning do not distinguish paraneoplastic limbic encephalitis from other causes of limbic encephalitis.

Patients with subacute neurologic symptoms referable to the temporal lobes or limbic system may come to a brain biopsy to rule out herpes encephalitis or other infectious processes, only to be subsequently diagnosed with paraneoplastic limbic encephalitis. Biopsy specimens in these patients show a variable degree of nonspecific changes, including neuronal loss, astrogliosis, or perivascular and leptomeningeal mononuclear cell infiltrates (22; 10).

Any middle-aged patient with a history of smoking cigarettes who develops limbic encephalitis should be suspected of harboring a small cell lung carcinoma. Chest CT or MR scanning is clearly more sensitive than a "plain" chest x-ray in detecting a small neoplasm (46). If present, anti-Hu, anti-GABAbR, anti-CRMP5 (CV2), or other serum neuronal antibodies are a highly specific marker for small cell lung carcinoma (rarely another tumor). Total body PET scanning may detect a lung neoplasm or other neoplasm in patients with suspected paraneoplastic syndromes and unrevealing or equivocal chest CT or MR scans (34). If a patient's initial evaluation for an occult tumor is unrevealing, which is not at all uncommon, the workup should be repeated at regular intervals for at least 3 years.

In young adults or nonsmokers presenting with limbic encephalitis, the most common neoplasms to consider are thymoma, Hodgkin lymphoma, and testicular germ cell tumor. These patients should have a thorough physical examination and CT or MR scanning of the chest and abdomen. Young men should also have testicular ultrasound, which can show a small tumor even after negative clinical examinations. Elevated serum alpha-fetoprotein or human chorionic gonadotropin in young men may indicate a nonseminomatous germ cell tumor. Serum anti-Ma2 antibodies are a marker for testicular germ cell tumors, although a negative assay does not rule out a tumor (10). There are reports of young men with anti-Ma2 antibodies, severe or progressive neurologic deficits, and normal testicular ultrasound except for testicular microcalcifications in whom orchiectomy revealed a microscopic intratubular germ cell tumor (32).

Management

• Treatment of paraneoplastic limbic encephalitis includes first-line immunotherapy with corticosteroids and treatment of the tumor.

The management steps for patients with limbic encephalitis include: (1) drug treatment of seizures and psychiatric symptoms; (2) exclusion of other diagnostic possibilities; (3) testing serum for neuronal antibodies; (4) workup for an underlying tumor; (5) treatment of the associated tumor; and (6) immunosuppressive therapy. If paraneoplastic limbic encephalitis is suspected and the underlying tumor is identified, prompt and aggressive antitumor treatment should be undertaken with the realization that neurologic improvement will occur in some, but not all, patients.

Discovery of serum neuronal antibodies in patients presenting with limbic encephalitis should raise high suspicion for a paraneoplastic etiology. There are good but not perfect associations between particular antibodies and associated tumors (Table 2). Empirical antitumor treatment without a histologic cancer diagnosis is not recommended. If the initial tumor workup for patients with limbic encephalitis and neuronal antibodies is unrevealing, the search needs to be repeated at regular intervals for at least 3 years (46). It is important to keep in mind that for each of the antibodies listed in Table 2, a percentage of patients with limbic encephalitis have the antibody but not an associated tumor.

If the tumor found is different from those commonly seen in paraneoplastic limbic encephalitis and positive neuronal antibodies, the expression by the tumor cells of the antigen recognized by the associated neuronal antibody is required for a definite diagnosis of paraneoplastic limbic encephalitis.

Expression of Hu antigen in a patient with sensory neuronopathy, Hu antibodies, and breast cancer

It is difficult to be dogmatic in recommending immunosuppressive therapy for patients with paraneoplastic limbic encephalitis. The decision needs to be made on an individual basis depending on the clinical circumstances:

(1) Patients in whom limbic encephalitis is the presenting feature of a neoplasm should have prompt tumor treatment. For these patients, the options are either to defer immunosuppressive treatment depending on the neurologic response to tumor treatment or to begin immunosuppressive treatment before or during tumor therapy. Although there are no studies, we favor the starting of the immunotherapy at the same time of the oncological treatment. There are no prospective randomized studies comparing the efficacy of various immunotherapies for limbic encephalitis. The most common approach, based on a retrospective series of anti-NMDAR encephalitis, is to start with corticosteroids (oral or intravenous) plus intravenous immunoglobulin, and then to consider "second-line" options, including intravenous pulse cyclophosphamide or rituximab, if necessary. It is not clear where plasma exchange should fit into this scheme (45).

(2) Patients with limbic encephalitis, antineuronal antibodies, and an unrevealing tumor workup should generally be given immunotherapy as commented above.

(3) Patients with limbic encephalitis that occurs in the setting of immune checkpoint inhibitors. The treatment of the drug must be stopped.

Outcomes

The course of paraneoplastic limbic encephalitis is variable and rather unpredictable but does roughly correlate with the associated tumor and antineuronal antibody type. Exceptionally, patients with clinically "pure" limbic encephalitis show spontaneous remission of the neurologic condition prior to any treatment. The efficacy of immunosuppressive therapy for paraneoplastic limbic encephalitis is often difficult to judge from the literature because many patients received tumor treatment concurrently with immunosuppressive therapy (22).

As a rule, patients with antibodies against intracellular antigens (Hu, CRMP5, CV2), Ma2 rarely improve after immunotherapy and tumor treatment. However, successful tumor treatment is correlated with a higher probability of achieving a stabilization or a partial improvement of the syndrome (22; 10). Rarely, patients do have neurologic improvement with immunosuppressive therapy independent of tumor therapy (10).

Patients with limbic encephalitis and antibodies against AMPA receptors or GABA(B) receptors frequently respond to tumor treatment or immunosuppressive treatment, but there is a tendency for neurologic relapse (25).

There are also reports of partial or complete reversal of paraneoplastic limbic encephalitis solely after successful treatment of the underlying thymoma, Hodgkin lymphoma, or ovarian carcinoma.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Francesc Graus MD PhD

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
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Editor

Rimas V Lukas MD

Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novartis and Novocure for speaking engagements, honorariums from Cardinal Health, Novocure, and Merck for advisory board membership, and research support from BMS as principal investigator.
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Former Authors

Edward J Dropcho MD

Patient Profile

Age range of presentation: 15 to 45 years: Paraneoplastic limbic encephalitis and Ma2 or mGluR5 antibodies

45+ years: Paraneoplastic limbic encephalitis and Hu, CRMP5, GABAbR, AMPAR antibodies, and Ma2 antibodies in the setting of immune checkpoint inhibitors
Sex preponderance: male=female except in anti-Ma2-associated limbic encephalitis, which is almost restricted to males with testicular cancer
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Encephalitis, myelitis, and encephalomyelitis, unspecified: G04.9

Encephalitis, myelitis, and encephalomyelitis in other diseases: G05.8
ICD-11: Paraneoplastic or autoimmune disorders of the central nervous system, brain or spinal cord: 8E4A.0

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Paraneoplastic limbic encephalitis

Associated Disorders

Germ cell tumors
Hodgkin lymphoma
Small-cell lung carcinoma
Thymoma

Differential Diagnosis

temporal lobe gliomas
toxic or metabolic encephalopathies
opportunistic CNS infections
drug-induced diffuse encephalopathy
Herpes simplex encephalitis
- Korsakoff psychosis
- non-paraneoplastic limbic encephalitis

Also Relevant

Antibody-mediated epilepsies
Lambert-Eaton myasthenic syndrome
Movement disorders associated with autoimmune encephalitis
Paraneoplastic cerebellar degeneration
Paraneoplastic sensory neuronopathy
- Paraneoplastic syndromes

Paraneoplastic limbic encephalitis

Introduction

Overview

Key points

Historical note and terminology

Table 1. Diagnostic Criteria of Limbic Encephalitis

Clinical manifestations

Presentation and course

Table 2. Immune Checkpoint Inhibitors and Limbic Encephalitis

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 3. Neuronal Antibodies in Paraneoplastic Limbic Encephalitis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Table 4. Differential Diagnosis of Paraneoplastic Limbic Encephalitis

Diagnostic workup

Management

Outcomes

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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