Continuing Education Activity

Paraneoplastic limbic encephalitis is thought to be caused by an onconeural antibody to cancer that cross-reacts with self-antigen in the neurons and muscles. It is a rare paraneoplastic syndrome that affects the limbic structures of the brain, especially the medial temporal lobes. It may present with cognitive dysfunction, change in personality, seizure, irritability, hallucinations, disorientation, limbic paresis, disruption of consciousness, and short-term memory loss. This activity reviews the evaluation and treatment of paraneoplastic limbic encephalitis and highlights the role of the interprofessional team in diagnosing and managing patients with this condition.

Objectives:

• Differentiate between paraneoplastic LE and other neurological or psychiatric disorders through a comprehensive evaluation and exclusion process.

• Implement a standardized diagnostic approach, including thorough neurological examinations and appropriate laboratory and imaging tests, to confirm or rule out paraneoplastic LE.

• Apply evidence-based treatments for paraneoplastic LE, including tumor management and immunosuppressive therapies, considering individual patient characteristics and preferences.

• Collaborate with a multidisciplinary healthcare team, including oncologists, neurologists, and mental health professionals, to ensure comprehensive care.

Introduction

Paraneoplastic syndrome is a rare immune-mediated complication that arises as a remote effect of cancer, often occurring covertly.[1] This syndrome can manifest in various clinical presentations, including encephalitis, Lambert-Eaton myasthenic syndrome,[2] typical abdominal symptoms associated with neuroblastoma such as severe constipation and chronic flatulence,[3] myelopathies,[4] movement disorders,[5] new-onset hyperglycemia,[6] intrahepatic cholestasis,[7] and various endocrine symptoms involving corticotropin-releasing hormone, adrenocorticotropic hormone, antidiuretic hormone, among others.[8][9]

Paraneoplastic limbic encephalitis (LE) is a specific paraneoplastic syndrome characterized by inflammation and injury to the limbic structures, resulting in specific neuropsychiatric syndromes. Common clinical presentations include memory impairment, psychosis, mood and behavioral disturbances, cognitive decline, abnormal movements, altered levels of consciousness, dysautonomia, and seizures. Amygdala involvement may cause emotional disturbances and aggressive behavior, while hypothalamic involvement can disrupt appetite and libido.

Concerning the pathogenesis of paraneoplastic LE, autoantibodies fall into 2 primary categories. The first group targets cell-surface or synaptic antigens, provoking pathogenic responses that trigger antibody and complement-mediated immune damage. The second group targets intracellular antigens, specifically the classical onconeural antigens; these antibodies do not directly induce pathogenesis. Instead, the immunological injury is predominantly cell-mediated cytotoxicity. This second group is also more frequently associated with paraneoplastic syndromes, whereas antibodies directed against cell surface and synaptic antigens are often not paraneoplastic.[10]

The best approach for treating paraneoplastic LE involves addressing the underlying cancer if present. Repeated surveillance to detect any potential underlying cancer is indicated when no underlying cancer is identified, and immunotherapy can be a beneficial strategy for managing the syndrome.

Etiology

The etiology of paraneoplastic LE is usually an underlying cancer. Antibodies targeting intracellular antigens are more frequently linked to an underlying malignancy than antibodies directed against cell surface and synaptic antigens. Certain types of cancer are more prone to be associated with paraneoplastic LE, with small cell lung cancer (SCLC) being a notable example.

The more common antigens associated with paraneoplastic LE and underlying malignancies are listed as follows (see Table. Common Antigens Involved in Paraneoplastic LE):[10]

Table. Common Antigens Involved in Paraneoplastic LE

Antibodies to specific antigens, as detailed in the table above (see Table. Common Antigens Involved in Paraneoplastic LE), have been detected in many patients with paraneoplastic LE. However, these markers may be absent in some individuals.[14]. Additionally, paraneoplastic LE can be associated with solid tumors, whether they are primary or metastatic, and can occur in both occult and gross cancers[1]. In males, particularly around 40, testicular tumors represent the most commonly identified causes. However, overall, underlying lung cancer is the most prevalent cause of paraneoplastic LE. 

Not all cases of LE are necessarily paraneoplastic. This condition can also manifest in individuals with other autoimmune diseases such as Type 1 diabetes, systemic sclerosis, or infections.[15]

Epidemiology

Autoimmune encephalitis is increasingly prevalent.[15][16] Among its subtypes, paraneoplastic LE, though rare, should be considered a potential cause of altered mental status in young individuals, including children. This neurological paraneoplastic syndrome occurs in less than 1 per 10,000 patients. Notably, 50% of affected patients may have underlying lung cancer, 20% may have underlying testicular tumors, and 8% may have breast cancer diagnosis.[14][17] 

The onset of paraneoplastic LE may occur at any age, depending on the specific underlying cancer. SCLC tends to be more common in older individuals, while testicular cancer is more prevalent in younger men. 

Pathophysiology

Paraneoplastic LE is believed to be triggered by onconeural antibodies produced in response to cancer, which can cross-react with self-antigens in neurons and muscles.[1] While these antibodies contribute to this paraneoplastic syndrome, their absence does not exclude the syndrome. Therefore, additional research is required to elucidate the precise underlying mechanism of this condition.[1][17]

Classical paraneoplastic LE is more commonly associated with antibodies targeting intracellular antigens such as anti-Hu, Yo, Ri, Ma2, CRMP5, and amphiphysin. This group of LE is most widely associated with underlying cancer or real paraneoplastic.[18]

In this form of LE, the pathological process is primarily mediated by a predominant T-cell mechanism, as evidenced by cytotoxic T cells in pathological specimens. The antibodies are not directly pathogenic but are markers for concurrent cytotoxic T-cell-mediated autoimmunity. Neuronal tissues share similar antigenicity with intracellular tumor antigens, contributing to neurological manifestations.[19]

The second category of paraneoplastic LE is characterized by antibodies targeting cell-surface or synaptic antigens. This group includes antibodies against NMDAR, LGI1, CASPR2, and other receptors. The pathogenic mechanism involves an antibody or B-cell-mediated autoimmune encephalitis.[19]

This category of LE is less commonly associated with a paraneoplastic origin, and many patients with this autoimmune encephalitis do not have any underlying cancer. Typically, individuals affected by these types of LE tend to be younger. In anti-LGI1 and CASPR2 LE cases, an underlying cancer is associated with less than 20% of cases.[18]

Histopathology

An autopsy of a patient with paraneoplastic LE revealed multiple areas of micro-softening within the cerebral cortex. These areas were distributed in the limbic and nonlimbic regions and were accompanied by lymphocytic infiltration in the intraparenchymal vessels.[20] Additionally, the autopsy findings included evidence of T-cell—dominated inflammation, neural loss, and microglial activation.[21]

History and Physical

The clinical features of LE, including the paraneoplastic subtype, exhibit significant variability, primarily dependent upon the specific antibodies involved and the affected brain regions in the autoimmune process. The onset of LE is typically acute or subacute, marked by the rapid development of diverse neuropsychiatric and neurological symptoms. 

Notable clinical features that warrant particular attention in the patient's medical history encompass the following:

• Emerging psychiatric symptoms, such as new-onset psychosis, should be carefully assessed for associated features such as personality changes, depressive or manic episodes, delusions, hallucinations, or catatonia. Patients presenting with these symptoms are frequently misdiagnosed as having primary psychiatric conditions, underscoring the importance of accurately distinguishing their underlying medical condition. This differentiation is particularly vital for patients with anti-NMDA LE.[22]

• New onset seizures, especially medically refractory seizures, should be noted, as they often reflect the involvement of the medial temporal lobe, which is recognized as the most epileptogenic region of the brain. Specific types of LE may exhibit distinct epileptic semiology and EEG patterns. For instance, faciobrachial dystonic seizures highly indicate anti-LGI1 encephalitis, while the extreme delta brush EEG pattern is often observed in cases of anti-NMDAR LE.[23]

• Movement disorders, mainly when they manifest young, should be carefully evaluated. Orofacial dyskinesia is a prevalent feature among patients with anti-NMDAR LE. Additionally, Morvan syndrome is characteristic of individuals with anti-CASPR2 LE.

• Cognitive impairment stands out as the most consistently observed characteristic in cases of paraneoplastic LE.[24]

• Sleep disturbances are a frequently encountered but often underestimated aspect of this condition. Common sleep disorders associated with LE include REM sleep behavioral disorders, insomnia, periodic movements during sleep, hypersomnia, and fragmented sleep.[25]

LE is often diagnosed before the discovery of the underlying cancer.[11]. Occasionally, it may be mistaken for complications of chemotherapy. Therefore, when suspected of this syndrome, it is essential to conduct a comprehensive medical history and physical examination to identify the underlying cancer. Assessing cognitive function can be achieved through tools such as the Mini-Mental State Examination, clock test, or evaluation of instrumental activities of daily living.[26] Furthermore, this syndrome may be a part of a broader condition in which the inflammatory process involves the limbic system, brain stem, and spinal cord.[27]

Evaluation

Patients suspected of having paraneoplastic LE should undergo the following comprehensive diagnostic tests:

• Blood test: Check for monoclonal antibodies, including anti-Hu, anti-Ta, anti-Ma, anti-GABA B receptor, and anti-NMDA receptor antibodies. However, note that the absence of these antibodies does not definitively exclude the disease.

• MRI: T2-weighted images and fluid-attenuated inversion recovery sequences can provide supportive evidence for the diagnosis.[12] Hyperintense signals may be revealed in various brain regions, including the temporal lobe, hippocampal areas, insula, amygdala, or cingulate gyrus. It is important to note that MRI findings may sometimes appear later than the initial neurological symptoms of the syndrome.[28]

• Lumbar puncture: Ideally, lumbar puncture results should be negative for malignant cells or infection. However, they may indicate pleocytosis, elevated protein levels, increased immunoglobulin synthesis, and oligoclonal bands.[27]

• Electroencephalography (EEG): EEG will frequently show sharp and slow waves.[27]

Additional tests, such as PET-CT scans, can also be conducted. These scans help detect abnormal metabolic activities within the limbic system.

Diagnosing paraneoplastic LE can be challenging and is typically based on exclusion because clinical markers are often absent. In a study involving 1047 patients, the following 4 criteria were utilized to establish a diagnosis:

1. The clinical presentation must align with the syndrome, encompassing its characteristic symptoms and signs.

2. An interval of less than 4 years should exist between the onset of neurological symptoms or signs and the diagnosis of the associated tumor.

3. Other neuro-oncological complications must be excluded as potential causes.

4. Additionally, at least 1 of the following criteria should be met:
   1. CSF analysis reveals inflammatory changes but negative cytology.
   2. MRI imaging demonstrates abnormalities in the temporal lobe.
   3. EEG findings indicate epileptic activities localized in the temporal lobe.

Not all patients will meet these specific criteria. In some cases, the diagnosis of paraneoplastic LE can also be confirmed through neuropathological examination.[14]

Additional diagnostic criteria, such as the Graus and Saiz criteria, can also be employed to aid in diagnosing paraneoplastic LE. These criteria encompass:

• Subacute onset of seizure or confusion (occurring in <12 weeks).
• Evidence of neuropathological or radiological involvement of the limbic system. 
• Exclusion of other potential causes.
• Diagnosis of the associated tumor within 5 years of diagnosing the syndrome.[17]

Treatment / Management

Managing the underlying tumor is considered the primary approach to address paraneoplastic LE, leading to gradual improvements in the syndrome's signs and symptoms, even if radiological signs persist. This management can be achieved through chemotherapy or surgical tumor removal, and it is generally regarded as the first-line treatment option.[12][14][29] 

Along with supportive care, other available therapeutic options include high doses of corticosteroids, plasma exchange, high-dose immunoglobulin, and immunosuppressive drugs like azithromycin and rituximab.[11] Bortezomib may be considered in cases associated with anti-NMDA receptors, particularly when dealing with refractory cases.[1][17][24][30][30][31]

A combination of these drugs may be applied in certain cases.[17][31][32] However, research indicates that addressing the underlying tumor tends to be more effective than other therapeutic options, as steroids may occasionally be ineffective.[14]

The replacement fluid in plasma exchange may consist of human albumin or fresh frozen plasma. However, it is important to be aware of potential complications, including hypotension, allergic reactions, mild anemia, hypocalcemia, and catheter placement complications.[31][33][34]

Differential Diagnosis

Before establishing a diagnosis of paraneoplastic limbic encephalitis, it is essential to rule out several significant differential diagnoses, including:[35]

• Infectious encephalitis encompasses viral infections (specifically herpes simplex), fungal infections, and tuberculous infections.[36]

• Systemic autoimmune diseases such as systemic lupus and Behcet disease.

• Toxic-metabolic causes include substance abuse and Wernicke encephalopathy.

• Rapidly progressive neurodegenerative disorders such as Creutzfeld-Jakob disease.

• Neoplastic diseases with particular consideration given to lymphoma.

• Neurological complications stemming from chemotherapy or other relevant medical diseases.[37][38]

Prognosis

Timely diagnosis and treatment of malignant tumors are pivotal in enhancing the prognosis and expediting clinical recovery.[39] However, different autoantibodies are associated with varying prognostic outcomes as follows:

• Patients with anti-Hu antibodies, especially those with multifocal neurological symptoms, tend to have a poorer prognosis.

• Patients with anti-Ta antibodies are also often associated with a poor prognosis.

• Individuals without detectable autoantibodies in their blood generally exhibit a more favorable prognosis.[14]

• Patients with anti-GABA B receptor antibodies may respond better to immunosuppressant drugs than patients with anti-Hu antibodies.[39]

Complications

Achieving a full recovery of higher cerebral function in autoimmune encephalitis can sometimes be challenging. However, symptoms are often improved in the paraneoplastic subtype of autoimmune encephalitis after effectively managing the associated tumor through medical or surgical interventions.[40][41]

Postoperative and Rehabilitation Care

Following discharge from the hospital, rehabilitation may be necessary for an extended period, with certain patients requiring several months of ongoing rehabilitation.[15][42]

Consultations

Upon establishing the diagnosis of paraneoplastic LE, consultations with medical specialists should be arranged based on the patient's medical history and physical examination findings. These consultations may involve gynecologic oncologists, urological oncologists, pulmonologists, or other relevant physicians from various specialties.[43]

Deterrence and Patient Education

Patient education for paraneoplastic limbic encephalitis should focus on several key aspects to help individuals understand the condition and its management. LE often presents with frequent behavioral and neuropsychiatric symptoms, which can be misleading and lead to its misdiagnosis as a psychiatric issue. This misdiagnosis can result in delayed treatment and a worsened prognosis. Consequently, patients and clinicians must maintain a high index of suspicion for this significant diagnosis if there is any change in neurological or psychiatric health.

Furthermore, patient education plays a pivotal role in raising awareness about activities that could potentially increase the risk of malignancy, emphasizing avoiding risk factors like smoking. This proactive approach can contribute to early detection and improved outcomes.

Enhancing Healthcare Team Outcomes

Enhancing healthcare team outcomes for paraneoplastic LE involves the collaborative efforts of an interprofessional healthcare team comprising various specialists, healthcare providers, and support staff. This approach is essential for accurate diagnosis, effective treatment, and improved patient outcomes. Each member of the healthcare team contributes to achieving better outcomes as outlined below:

• Primary Care Physician: The patient's primary care physician often plays a crucial role in recognizing early symptoms and referring the patient to specialists for further evaluation and diagnosis.

• Neurologist: Neurologists are central to the diagnosis and management of LE. They conduct neurological assessments, order relevant tests, and guide treatment options.

• Oncologist: Oncologists are responsible for diagnosing and treating the underlying malignancy. They collaborate with the neurologist to determine the best approach, which may include surgery, chemotherapy, or radiation therapy.

• Radiologist: Radiologists interpret imaging studies, such as MRI scans, to identify abnormalities in the brain or surrounding structures, aiding in diagnosis and treatment planning.

• Pathologist: Pathologists analyze tissue samples to confirm the presence of malignancy and assess its characteristics, which informs treatment decisions.

• Neuropsychiatrist: As LE often presents with psychiatric symptoms, neuropsychiatrists are essential in evaluating and managing the behavioral and psychological aspects of the condition.

• Clinical Nurse Specialist/Nurse Practitioner: These healthcare professionals provide ongoing patient care, administer treatments, monitor for side effects, and educate patients and their families about the condition and treatment.

• Physical and Occupational Therapists: Rehabilitation specialists work to improve the patient's physical and cognitive function through tailored exercise and therapy programs.

• Psychologists and Counselors: Mental health professionals offer psychological support and counseling to help patients cope with the emotional and psychological challenges associated with the diagnosis and treatment.

• Pharmacists: Pharmacists ensure the safe and appropriate use of medications, including immunosuppressive drugs and symptom management medications.

• Caregivers and Family Members: The patient's caregivers and family members are integral to the healthcare team, offering support, assisting with daily care, and participating in decision-making.

Effective communication and collaboration among team members are essential. Regular case conferences, multidisciplinary meetings, and shared electronic medical records help ensure that all aspects of patient care are coordinated. By fostering collaboration among these healthcare professionals, patients with paraneoplastic limbic encephalitis can receive comprehensive and coordinated care, leading to earlier diagnosis, effective treatment, improved symptom management, and better overall outcomes.