Gamma-aminobutiric acid-B receptor antibody-related limbic encephalitis due to small cell lung carcinoma: Two case reports

Abstract

BACKGROUND

Paraneoplastic limbic encephalitis (LE) is an inflammatory condition that affects the limbic system, cerebellum, and peripheral nervous system. It causes a range of symptoms including short-term memory loss, impaired cognitive function, behavioral and psychological disorders, and seizures. Paraneoplastic LE can occur when an immune response is activated due to antibodies targeting gamma-aminobutyric acid (GABA) B receptor (GABABR) interacting with antigens on tumor cells and the nervous system, resulting in tumors primarily as small cell lung carcinoma (SCLC).

CASE SUMMARY

We discuss two cases of GABABR antibody-related LE resulting from SCLC. The patients’ symptoms were managed with immunotherapy but ended in premature death due to chemotherapy-related complications.

CONCLUSION

Paraneoplastic syndrome is a notable cause of LE. Early intravenous immunoglobulin therapy may lead to temporary remission.

Key Words: Gamma aminobutyric acid-B receptor antibody; Paraneoplastic encephalitis; Small cell lung carcinoma; Epileptic seizures; Limbic encephalitis; Case report

Core Tip: Limbic encephalitis (LE) can occur as a paraneoplastic symptom or in the absence of a malignancy. Paraneoplastic encephalopathies are rare neurological disorders associated with antineuronal antibodies. Symptoms include memory loss, impaired mental function, behavioral disorders, and epileptic seizures. Antibodies against extracellular antigens, such as gamma-aminobutyric acid (GABA) B receptor (GABABR), are associated with a higher risk of tumor development. Glutamic acid decarboxylase antibodies have been linked to several neurological syndromes, which are hypothesized to result from decreased GABA ergic transmission. This article presents two cases of GABABR antibody-related LE resulting from small cell lung carcinoma with neurological symptoms that were managed with intravenous immunoglobulin therapy.

INTRODUCTION

Limbic encephalitis (LE) can arise as a paraneoplastic symptom, meaning it can occur prior to the diagnosis of neoplasia. However, LE can occur in the absence of malignancy. LE is caused by various anti-neuronal antibodies, including those that target intracellular structures, such as anti-Hu, anti-Ri, and anti-Ma2 antibodies to glutamic acid decarboxylase (GAD), anti-CV2, and anti-amphiphysin, and those that target extracellular structures, such as anti-gamma-aminobutyric acid (GABA) A receptor or B receptor (GABABR), N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, leucine-rich glioma inactivated 1 (LGI1), and contactin-associated protein 2. Antibodies against intracellular antigens are often associated with cancer, but this is not the case for antibodies against extracellular antigens. Nonetheless, extracellular antibodies can be detected by screening for potential malignancies[1,2].

Paraneoplastic encephalopathies are associated with anti-neuronal antibodies, including GABABR antibodies, which are most linked to small cell lung carcinoma (SCLC) but have also been found in other types of cancers, including breast, ovarian, testicular, and thymoma. Anti-NMDAR antibodies are associated with ovarian teratomas[2,3].

Paraneoplastic LE is a rare condition first described in 1968. Paraneoplastic neurological syndrome is a group of disorders that include Lambert-Eaton myalgia syndrome, paraneoplastic cerebellar degeneration, paraneoplastic LE, encephalomyelitis, and sensory neuronopathy[4,5]. Clinically, these disorders involve the limbic system, cerebellum, peripheral nervous symptoms, and neuromuscular junction[6]. Symptoms include loss of short-term memory, impairment of mental function, development of behavioral and psychological disorders, and epileptic seizures[6,7], which are caused by the interaction of antibodies with ectopic antigens on tumor cells and antigens of the nervous system triggering an immune response that specifically targets the limbic system. Notably, the target antigens of these antibodies are intracellular, suggesting their involvement in T-mediated cytotoxicity[8].

Patients diagnosed with this condition may exhibit a variety of antibodies in their blood serum or cerebrospinal fluid (CSF) that target basement membrane components and bind to various neurotransmitter receptors, including AMPA and GABABR as well as proteins associated with ion channels, such as LGI1, contactin-associated protein 2, or intracellular components[9]. Half of the patients with anti-GABABR antibodies are at risk of developing tumors, usually in the form of SCLC. Patients with this condition may experience symptoms of LE and frequent seizures[9,10].

GAD is an intracellular enzyme that plays a crucial role in the central nervous system by converting glutamate to GABA (the primary inhibitory neurotransmitter). GAD antibodies have been linked to several neurological syndromes such as stiff person syndrome, cerebellar ataxia, and LE, which are hypothesized to result from decreased GABA ergic transmission. The pathogenic role of GAD antibodies is currently being investigated. Some evidence suggests that GAD autoimmunity is primarily cell mediated. Detection of GAD antibodies in the serum or CSF are needed to diagnose these conditions[9,11,12].

This article presents two cases of GABABR antibody-related LE resulting from SCLC. The neurological symptoms were effectively managed with intravenous immunotherapy. These cases highlight the importance of early recognition and prompt treatment of paraneoplastic LE associated with SCLC. The successful use of intravenous immunotherapy underscores its potential as a valuable therapeutic option for managing neurological manifestations. Further research is warranted to elucidate the optimal treatment strategies and long-term outcomes in patients with GABABR antibody-related LE. Unfortunately, chemotherapy-related complications were the cause of death in both cases.

CASE PRESENTATION

Chief complaints

Case 1: A 62-year-old Greek female residing in a rural area of northern Greece was admitted to our hospital with convulsive seizures.

Case 2: A 54-year-old male was admitted to the emergency room of the AHEPA University Hospital due to agitation and disorientation following a grand mal seizure while sleeping the night before.

History of present illness

Case 1: Approximately 10 days before the hospital admission, the patient had developed febrile diarrhea syndrome.

Case 2: According to the patient’s relatives, he had suffered an unspecified loss of consciousness while working in the fields (his occupation was farming) 1 week prior to admission. He had then shown symptoms of mild disorientation during that week prior to admission.

History of past illness

Case 1 and case 2: There were no relevant past illnesses for either patient.

Personal and family history

Case 1: The patient had no significant personal or family medical history and was not taking any daily medication. She was a heavy smoker, consuming approximately one pack of cigarettes per day for the past 30 years (i.e. 30 pack-years).

Case 2: The patient’s medical history included hypertension that was treated with amlodipine, valsartan, and bisoprolol. He had also been a heavy smoker (40 cigarettes per day since teenage years).

Physical examination

Case 1: At admission, the patient’s vital signs were normal. After 1 day of hospitalization, she began to exhibit signs of declining consciousness and drowsiness along with agitation. Clinical neurological examination revealed no signs of neurological residue, aside from an altered mental status.

Case 2: Physical examination of the patient revealed agitation and disorientation.

Laboratory examinations

Case 1: At admission, laboratory testing revealed that the patient had a urinary tract infection. After 1 day of hospitalization, lumbar puncture revealed lymphocytic pleocytosis (approximately 110 cells/mm³). Serological tests conducted on the CSF and serum revealed a negative result for the most common infectious pathogens. Cytological testing of the CSF revealed lymphocytic pleocytosis. At this point, malignancy was suspected. To rule out central nervous system lymphoma as a potential diagnosis, bone marrow biopsy and CSF immunophenotype examination were performed, and the results were normal. To arrive at a diagnosis, we conducted western blotting of serum samples for specific autoimmune and onconeural antibodies. The results revealed the presence of antibodies against GABABR, Tr, recoverin, and Zic4 (Table 1).

Table 1 Αnti-neuronal antibodies (immunoglobulin G) in both cases.

Laboratory test	Case 1	Case 2
Amphiphysin	Negative	Negative
CV2/collapsin response mediator protein 5	Negative	Negative
Presurgical nasoalveolar molding 2 (Ma2/Ta)	Negative	Negative
Ri/ANNA-2	Negative	Negative
Yo/prostate cancer antigen-1	Negative	Negative
Hu/ANNA-1	Negative	Negative
Recoverin	Positive	Negative
SOX1	Negative	Negative
Zic4	Positive	Negative
Tr (delta/notch-like epidermal growth factor-related receptor)	Positive	Negative

ANNA: Antinuclear neuronal antibody type.

Case 2: Laboratory tests revealed a high D-dimer level. Because the patient was agitated, he was sedated while a lumbar puncture was performed. The CSF had 22-26 cells (monocytes) and a protein level of 65 mg/dL. The CSF PCR test was negative for bacteria and viruses, including the West Nile virus. Further serological tests were conducted to investigate autoimmune and paraneoplastic encephalitis. A highly positive immunoglobulin G (IgG) antibody titer for GABABR (320 immunofluorescence cell-based assay) was revealed (Table 1). Tumor testing showed negative results. The patient underwent bronchoscopy, bronchoalveolar lavage cytology, thoracoscopy, and biopsy of the tumor and mediastinal lymph nodes. Immunohistochemistry revealed cytokeratin (CK) 8⁺, CK 18⁺, synaptophysin⁺, CD56⁺, thyroid transcription factor-1⁺, chromogranin^-, and CD45^- cells, with an index of Ki67/MIB1 positive nuclei of 95%-98%.

Imaging examinations

Case 1: At admission, non-contrast brain computed tomography (CT) revealed no acute pathology, and the chest x-ray was normal. After 1 day of hospitalization, brain imaging with CT arteriography venography revealed no pathological findings, and normal fundoscopic findings were obtained. Additional brain imaging using new CT and magnetic resonance imaging (MRI) also yielded no results. After malignancy was suspected, a chest and upper-lower abdominal CT scan revealed lobed neoplastic proliferation in the right middle lobe as well as in the subcarinal, paraoesophageal, and perihilar lymph nodes. Whole-body positron emission tomography (PET)-CT revealed pathologically increased absorption of the mass. A fine-needle biopsy of the pulmonary mass was performed through video-assisted thoracoscopic surgery.

Case 2: Non-contrast brain CT revealed no acute pathology. CT pulmonary angiography was also performed and revealed an incidental finding of a lung tumor at the top of the right lung. The patient was confined to the intensive care unit for 1 month, and brain MRI showed no signs of pathology or enhancement.

MULTIDISCIPLINARY EXPERT CONSULTATION

Case 1 and case 2

Genetic testing was not performed in either case.

FINAL DIAGNOSIS

Case 1

She was diagnosed with primary pulmonary neoplasia, SCLC, and autoimmune paraneoplastic LE.

Case 2

He was diagnosed with SCLC and paraneoplastic LE.

TREATMENT

Case 1

After 1 day of hospitalization, the patient received empirical intravenous antibacterial and antiviral medications (ceftriaxone and acyclovir) to treat a suspected infection, along with antiepileptic medication (levetiracetam). This empirical treatment approach highlights the importance of early intervention in cases of suspected infections with neurological involvement. The combination of broad-spectrum antibiotics and antivirals addresses potential bacterial and viral etiologies, whereas antiepileptic medication helps manage and prevent seizures. Close monitoring of the patient's response to this initial treatment regimen is crucial to guide further diagnostic and therapeutic decisions. Levetiracetam was administered at a dose of 500 mg twice a day and gradually at a dose of 1500 mg three times a day. The gradual increase in levetiracetam dosage from 500 mg twice daily to 1500 mg three times daily suggests a careful titration process to achieve optimal seizure control, while minimizing potential side effects. This approach allows clinicians to assess a patient's response to medication and make necessary adjustments based on seizure frequency and severity. Additionally, the use of intravenous administration of the initial antibacterial and antiviral treatments ensures rapid delivery of these medications to promptly address the suspected infection. During hospitalization, the patient developed drug-resistant seizures and status epilepticus, which were eventually controlled with triple intravenous antiepileptic medications (levetiracetam 1500 mg three times a day, lacosamide 100 mg twice a day, and valproate sodium 1000 mg as one dose per day). The combination of three intravenous antiepileptic medications (levetiracetam, lacosamide, and valproate sodium) demonstrated the complexity of managing drug-resistant seizures and status epilepticus in this patient. This multi-drug approach likely aims to target different mechanisms of seizure activity, potentially providing a synergistic effect in controlling refractory seizures. After diagnosis, intravenous immunoglobulin G (IVIG) 20 g/24 hours 5-day was administered, which resulted in significant clinical improvement. The subsequent administration of IVIG suggests a potential autoimmune component in the patient's condition, highlighting the complex interplay between neurological and immunological factors in certain seizure disorders.

In addition to antiepileptic medications, the medical team closely monitored the patient's response to IVIG treatment and made dosage adjustments, as needed.

Case 2

The patient received empirical therapy for meningoencephalitis (dexamethasone, ceftriaxone, vancomycin, and acyclovir) until CSF PCR results were obtained, as well as antiepileptic treatment (lacosamide 100 mg twice a day and brivaracetam 100 mg twice a day). Empirical therapy covers a broad spectrum of potential pathogens, while awaiting definitive diagnostic results. Antiepileptic medications were administered concurrently to manage and prevent seizures, which are common meningoencephalitis complications. This comprehensive treatment approach demonstrates the importance of rapid intervention in suspected cases of central nervous system infections. After obtaining a highly positive IgG antibody titer for GABABR (320 immunofluorescence cell-based assays), the patient was treated with IVIG at 40 g/24 hours for 5 days. The patient required IVIG 40 g/24 hours IVIG booster due to the recurrence of agitation and disorientation, which did not respond to antiepileptic (brivaracetam-lacosamide) treatments during his hospitalization. Targeted immunomodulatory therapy aims to suppress the autoimmune response and reduce inflammation in the central nervous system. Treatment duration and dosage were carefully selected to maximize the therapeutic effect while minimizing potential side effects.

OUTCOME AND FOLLOW-UP

Case 1

After 50 days of hospitalization, the patient was discharged. She was able to walk with assistance and received instructions regarding her new medication regimen. After the initial admission, the patient was placed under oncologic supervision with regular chemotherapy sessions and imaging of the brain, chest, and abdomen. Unfortunately, after 5 months, the patient experienced new episodes of tonic-clonic seizures and altered mental status. Chest CT revealed relapse of the primary neoplastic lesion. Seven months after discharge, the patient began receiving a 5-day course of IVIG injections. The treatment was effective, and the patient continued to receive chemotherapy. Unfortunately, 1 year after the initial admission, the patient died due to adverse effects of the chemotherapy.

Case 2

Although the patient regained consciousness and orientation, he remained on mechanical ventilation because of respiratory insufficiency caused by a concurrent respiratory infection and critical myopathy symptoms. Electroencephalogram was performed after the patient stabilized (1 month after admission), and it showed no abnormalities. The patient required IVIG (40 g/24 hours) due to recurrence of agitation and disorientation, which did not respond to antiepileptic (brivaracetam and lacosamide) and antipsychotic treatments during his hospitalization. The patient was discharged in good condition and referred to the Pulmonary Oncology Clinical for further treatment. Unfortunately, the second chemotherapy session resulted in adverse effects that ultimately led to death.

DISCUSSION

GABABR antibodies are common in idiopathic and paraneoplastic LE. Common manifestations of LE due to anti-GABABR include seizures, status epilepticus, behavioral changes, confusion, memory impairment, subacute cerebellar ataxia, and opsoclonus-myoclonus syndrome. The high frequency of seizures observed in previous studies can be explained by the role of GABABR in seizure development. Anti-GABABR can be positive in paraneoplastic LE without onconeural antibodies (previously considered “seronegative”)[13,14]. Both presented clinical cases had seizures as the primary symptom, which is similar to most cases. Moreover, both patients required a combination of two or more antiepileptic drugs to control their epileptic activity, indicating a refractory pathophysiology of these seizures.

MRI findings can show increased fluid-attenuated inversion recovery signals in one or both temporal lobes, hippocampus, and amygdala. However, MRI findings can also appear normal, as in the present case. Therefore, clinicians should suspect LE in cases of sudden onset seizures, refractory status epilepticus, or disorientation in asymptomatic individuals. Negative MRI results do not exclude the possibility of this disease[15].

CSF analysis revealed mild lymphocytic pleocytosis and/or mild protein elevation. Almost half of the reported cases show elevated CSF leukocyte levels. CSF protein levels can be normal or slightly elevated, whereas glucose and chloride levels are typically normal[16]. CSF findings can be of great significance because they can lead to the earlier commencement of immunotherapy before positive antibody results are obtained.

Approximately 50% of the patients with anti-GABABR encephalitis are diagnosed with SCLC. However, it can also be diagnosed as thymoma, malignant melanoma, breast carcinoma, rectal carcinoma, multiple myeloma, esophageal carcinoma, sarcomatous carcinoma, and gastric adenocarcinoma in rare cases. Previous studies have reported that some patients have additional autoantibodies, such as antibodies targeting the voltage-gated calcium channel, GAD65, sex-determining region Y-box 1, and anti-GAD[10,16]. Rarely, anti-GABABR encephalitis can occur secondary to viral infection and should be classified as non-paraneoplastic-related anti-GABABR encephalitis. However, because of its close relationship with lung cancer, long-term follow-up is obligatory[16].

A diagnostic algorithm for highly suspected cases should include both serum and CSF tests for anti-GABABR antibodies. Once positivity has been detected, a chest CT should be performed. If the result is negative but anti-GABABR antibodies are positive, a whole-body PET-CT scan is indicated. Immediate treatment with immunosuppression, corticosteroids, IVIG, and plasma exchange (PLEX), either separately or in combination. Despite a poor overall prognosis, outcomes are disastrous when patients are not treated[17].

GABABR encephalitis has a poor prognosis compared with other types of autoimmune encephalitis. In our cases, we observed that the neurological symptoms demonstrated a favorable response to immunotherapy. However, it is necessary to administer an additional dose of immunotherapy that is also effective. The 2-year mortality rate of anti-GABABR encephalitis is significantly higher than that of other autoimmune encephalopathies, such as anti-NMDAR encephalitis (6%) and anti-LGI1 encephalitis (19%). This may be due to the higher risk of tumor development in patients with anti-GABABR encephalitis. The main cause of death in anti-GABABR encephalitis is tumor progression. Older age and systematic complications from the disease itself or its treatment are also major contributing factors[15,18].

In our study, the patients were older than 45 years and were smokers, indicating the importance of lung cancer investigations. Their neurological symptoms were effectively controlled by immunotherapy but required additional doses. Unfortunately, both patients died due to chemotherapy-related complications shortly after initial diagnosis.

Anti-GABABR encephalitis similarly affects men and women, and more than half have an associated tumor, almost always SCLC. The presenting symptoms are usually the typical symptoms of LE and can be caused by memory loss, confusion, agitation, depression, anxiety, and seizures, sometimes presenting as status epilepticus[19].

When the disorder is cancer related, the onset of encephalitis usually precedes cancer diagnosis. In fact, it must be emphasized that LE occurs at an early stage of disease development; therefore, the detection of paraneoplastic LE can lead to a quicker identification of the underlying malignancy and a better outcome. However, it is unfortunately common for the diagnosis of this syndrome to be still delayed[20].

Given the dearth of randomized control trials, treatment recommendations for paraneoplastic LE are based on principles derived from case series and expert opinion. The results of advanced antibody testing can be delayed; therefore, treatment of paraneoplastic LE is usually initiated prior to serologic confirmation of the diagnosis. A dual-armed treatment approach targeting both the underlying malignancy (if identified), and autoimmune encephalitis is generally recommended. Treatment of associated cancer is a priority to reduce the antigenic stimulus driving paraneoplastic LE[21]. If an associated tumor is not detected, cancer screening at regular intervals is recommended.

Patients who receive immunotherapy together with tumor control often show full or substantial recovery. Intravenous steroids, IVIG, and plasma are the first-line therapies. There is no solid evidence supporting the superiority of one agent over another, and current strategies are supported mostly by the findings of previous observational retrospective studies[22]. High-dose methylprednisolone and IVIG are the most chosen first-line agents owing to their availability, cost-effectiveness, and relatively good safety profiles. Conversely, PLEX is frequently postponed because of its low availability and tolerability. For patients who do not respond to these measures, second-line treatments with immunosuppressants such as cyclophosphamide, cyclosporine, and rituximab are indicated. Nevertheless, the wide range of immune cells that these treatments deplete could result in unfavorable side effects such as recurrent infections, an increased chance of tumorigenesis, or even a possible decline in antitumor immunity.

Chronic maintenance therapy can include IVIG and steroid tapering over 6–8 months and an additional immunosuppressant, such as azathioprine or mycophenolate mofetil.

The development of innovative therapeutic models that target immunological pathways involved in the etiology of paraneoplastic neurologic syndrome (PNS) is crucial given the potentially substantial adverse effects of conventional immunotherapies. Accordingly, natalizumab and tacrolimus have been investigated in patients with PNS, mostly involving Yo-Abs and Hu-Abs, whereas bortezomib, tocilizumab, and intrathecal methotrexate have been investigated in refractory cases involving Abs against cell-surface antigens. Unfortunately, the data were limited to small case series; hence, further investigation is needed to validate their applicability in PNS management.

Considering that paraneoplastic LE is uncommon, there is a dearth of published data, and the intrinsically varied outcomes of correlated malignancies make defining its prognosis challenging. Nonetheless, experts generally agree that the capacity to adequately treat the underlying tumor and identify it early is critical for neurological recovery. Improved clinical results have also been linked to prompt therapy initiation and subsequent escalation.

CONCLUSION

GABABR antibodies are common in LE and cause seizures, confusion, memory impairment, and other neurological symptoms. MRI findings can be normal or show increased signals in the temporal lobes, hippocampus, or amygdala. CSF analysis may reveal mild lymphocytic pleocytosis and/or elevated protein levels. Around 50% of anti-GABABR encephalitis cases are associated with SCLC, and long-term follow-up is necessary. The diagnostic algorithms included testing for anti-GABABR antibodies in the serum and CSF, followed by chest CT and whole-body PET-CT scans. Treatment involves intravenous steroids, IVIG, and tumor control. The prognosis is poor compared to that of other autoimmune encephalitis types, with a higher 2-year mortality rate, mainly due to tumor progression. Older age and systemic complications also contribute to the mortality. Prompt diagnosis and treatment of the underlying malignancy are crucial to achieve better outcomes.