It is is a rare paraneoplastic syndrome that affects the medial temporal lobe and may be presented with cognitive dysfunction with a subacute beginning, change in the personality, seizure in partial and generalized type, irritability, hallucinations, disorientation, limbic paresis, and disruption of consciousness and short-term memory loss[10],[19],[20]. A study of patients with this syndrome showed that most of the patients presented with an altered level of consciousness. Usually, early manifestations are psychiatric symptoms, so many patients may be treated in the psychiatric ward before making the diagnosis of paraneoplastic limbic encephalitis.[21]

Symptoms of this syndrome usually precede the diagnosis of the tumor[10]. It may appear to be complications of chemotherapy, so when this syndrome is suspected, a complete history and physical examination should be done to determine which cancer is the cause. Cognitive function may be accessed through a mini mental-state examination, clock test, or instrumental activity of daily living.[22] Also, this syndrome may be a part of the larger syndrome in which the brain stem and spinal cord are also involved in the inflammatory process.[23]

Any patient who is suspected to have paraneoplastic limbic encephalitis should undergo the following tests:

1. Blood test for monoclonal antibodies (anti-Hu, anti-Ta, anti-Ma, anti-GABA B receptor, and anti NMDA receptor) but the absence of this antibodies does not exclude the disease.
2. MRI may show hyperintense signals in the temporal lobe, hippocampal areas, insula, amygdala, or cingulate gyrus. T2-weighted images and fluid-attenuated inversion recovery will support the diagnosis[11], but signs may appear later than the initial neurological symptom of the syndrome.[24]
3. Lumber puncture should be negative for malignant cells or infection and may show pleocytosis, elevation of protein levels, and intensification of immunoglobulin synthesis and oligoclonal bands.[23]
4. EEG frequently shows sharp and slow waves in electroencephalography.[23]

Other tests may be done such as PET-CT which will show abnormal metabolic activities in the limbic system.

Diagnosis is difficult and should be by exclusion because clinical markers are often absent. A study on 1047 patients used the following criteria to diagnose paraneoplastic limbic encephalitis. The patient should achieve all of the following 4 points to make the diagnosis in this study:

1. The clinical picture of the syndrome; symptoms and signs
2. An interval of less than 4 years between the onset of the neurological symptoms or signs and the diagnosis of the tumor
3. Exclusion of other neuro-oncological complications
4. At least one of the following:

• CSF with inflammatory changes but negative cytology
• MRI showing abnormalities in the temporal lobe
• EEG showing epileptic activities in the temporal lobe

Not all of the patients will fulfill these criteria, but the diagnosis of paraneoplastic limbic encephalitis also may be done in the presence of neuropathological examination.[13]

Other diagnostic criteria which may be used include Graus and Saiz criteria. These include the following:

• Subacute onset of seizure or confusion (less than 12 weeks)
• Neuropathological or radiological involvement of limbic system 
• Exclusion of other causes
• Diagnosing the tumor within 5 years of diagnosing the syndrome [16]

Managing the tumor causes a gradual improvement of the syndrome's signs and symptoms despite the persistence of the radiological signs, either by chemotherapy or by removing the tumor surgically[11],[20], and it’s considered as the first line of treatment[13]. Supportive care is required in the patients, and other options include high doses of corticosteroid[10], plasma exchange, high dose immunoglobulin, immunosuppressive drugs such as azithromycin, and rituximab. In anti-NMDA associated disease, bortezomib may be used, especially in refractory cases.[1],[16],[19],[24],[25],[26]

A combination of these drugs may be applied in some patients.[16],[26],[27] But studies show that treating the tumor appeared to be more effective than any other options, and steroids may be sometimes ineffective.[13]

The replacement fluid in plasma exchange may be human albumin or fresh frozen plasma; some complications may be seen such as hypotension, allergic reactions, mild anemia, hypocalcemia and catheter placement complications.[26],[28],[29],

The diagnosis of paraneoplastic limbic encephalitis must be done mainly by exclusion. Other diseases which may present with similar signs and symptoms must be excluded before making the diagnosis, such as tumors like glioblastoma[30] and hypothalamic tumors, epilepsy, dementia, tuberculosis, viral encephalitis-like herpes, and bornavirus,[31] psychiatric disorders like dissociative disorder, neurological complications from the chemotherapy, and other relevant diseases.[32][33]

Early diagnosis and treatment of malignant tumors improve the diagnosis and facilitate the clinical recovery.[34]

Patients with anti-hu antibodies were found to have a poor prognosis and multifocal neurological symptoms, and patients with anti-Ta antibodies were found to have a poor prognosis, but patients who do not have autoantibodies in their blood appear to have a better prognosis.[13]

Patients with anti-GABA B receptor may respond to immunosuppressant drugs better than patients with anti-hu patients.[34]

Sometimes complete recovery of the higher cerebral function in autoimmune encephalitis may be difficult, but an improvement of the symptoms in the paraneoplastic subtype of the autoimmune encephalitis has been noticed after managing the tumor medically or surgically. [35][36]

After discharging the patients from the hospital, rehabilitation may last for a long time, with some patients needing several months of rehabilitation.[14][21]

After making the diagnosis of paraneoplastic limbic encephalitis, consultations may be made according to the presented history and physical examination. These may include consulting a gynecologic oncologist, urological oncologist, pulmonologist, or physicians from other specialties. [37]

Paraneoplastic limbic encephalitis is best managed by an interprofessional team that also includes oncology nurses. Because there are no specific markers, it is a diagnosis of exclsion. In most cases, if the primary malignancy is managed, the paraneoplastic syndrome will resolve. Several biological drugs can be used to control symptoms but cure is not possible until the primary malignancy has been treated.