Encephalitis, Paraneoplastic Limbic

Article Author:
Ibrahim Altabakhi
Article Editor:
Hani Babiker
Updated:
10/27/2018 12:31:46 PM
PubMed Link:
Encephalitis, Paraneoplastic Limbic

Introduction

Paraneoplastic syndrome is a rare immune-mediated complication which is caused by a remote effect of cancer that may be occult.[1] 

Paraneoplastic syndromes present in a different clinical manifestations, as an encephalitis, Lambert-Eaton syndrome[2], common abdominal symptoms which occurs commonly with neuroblastoma such as diarrhea, severe constipation and chronic flatulence[3], myelopathies[4], movement disorders[5], new-onset hyperglycemia[6], intrahepatic cholestasis[7], endocrine symptoms which produce corticotropin releasing hormone, adrenocorticotropic hormone, and antidiuretic hormone, and other various symptoms.[8][9]

Etiology

Antibodies to Ma2 (also known as anti-TA)[10], NMDA-receptor[11], anti-Hu[2], anti-metabotropic glutamate receptor 5 (mGluR5) antibodies[12], anti-GABA B[2] and anti-glutamate receptor[10] were found in many patients with paraneoplastic limbic encephalitis, although this marker may be absent in some patients[13]. It may be observed with solid tumors, in primary or metastatic occult and gross cancers[1]. In men around the age of 40, it has been found to be caused most commonly by testicular tumors, but overall underlying lung cancer is the most common cause; usually, paraneoplastic limbic encephalitis with anti Ta antibodies is associated with small cell lung carcinoma and anti Ta  antibodies is associated with testicular tumor in young men, but if the antibodies were negative, diverse tumors, such as lymphoma and leukemia, could be the cause.[12]

 It may not be paraneoplastic and presents with other autoimmune diseases (DM1), systemic sclerosis, or infections.[14]

Epidemiology

Autoimmune encephalitis showed an increase in the prevalence[15],[14]. One of the subtypes of it is paraneoplastic limbic encephalitis, which is a rare cause of altered mental status in young, but physicians should think of it as a cause of encephalopathy in children. It is one of the neurological paraneoplastic syndromes which occur in less than 1 per 10,000 patients; 50% of patients will have lung cancer, 20% will have testicular tumors, and 8% will have breast cancer.[13],[16]

Pathophysiology

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[1]. Although they are considered a cause of this paraneoplastic syndrome, the absence of them does not exclude the syndrome, so further studies are needed to know the exact mechanism of this syndrome.[16],[1]

Histopathology

An autopsy on a patient with paraneoplastic limbic encephalitis syndrome showed multiple areas of micro-softening in the cerebral cortex which are distributed in the limbic and non-limbic areas with lymphocytic infiltration in the intraparenchymal vessels.[17] Other findings were T-cell dominated inflammation, neural loss, and microglial activation.[18]

History and Physical

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]

Evaluation

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]

Treatment / Management

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],[26]

Differential Diagnosis

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]

Prognosis

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]

Complications

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]

Postoperative and Rehabilitation Care

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

Consultations

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]