Limbic Encephalitis – Causes, Symptoms, Treatment

Limbic Encephalitis (LE) is characterized by a rapidly progressive, non-infective inflammation with short-term memory loss, psychiatric symptoms, and seizures.[rx] Limbic encephalitis is a rare, subacute process involving the limbic system and hypothalamus. The term LE described memory loss and dementia in association with bronchial carcinoma.[rx] Initially LE was considered a rare disorder in association with cancer; most commonly associated with small cell lung cancer (SCLC), breast cancer, testicular tumors, teratomas, Hodgkin’s lymphoma, and thymomas but can occur in the absence of malignancy also.[rx,rx,rx]

Limbic encephalitis represents a group of autoimmune conditions characterized by inflammation of the limbic system and other parts of the brain. The cardinal sign of limbic encephalitis is a severe impairment of short-term memory; however, symptoms may also include confusion, psychiatric symptoms, and seizures. The symptoms typically develop over a few weeks or months, but they may evolve over a few days. Limbic encephalitis is often associated with an underlying neoplasm (paraneoplastic limbic encephalitis); however, some cases never have a neoplasm identified (non-paraneoplastic limbic encephalitis). Delayed diagnosis is common, but improvements are being made to assist in early detection. Various tests including imaging studies (MRI, PET) laboratory tests (CSF analysis), and tests that measure the electrical activity of the brain (EEG) may be utilized to confirm a diagnosis. Treatment includes removal of the neoplasm (if identified) and immunotherapy.^[rx][rx][rx]

Causes of Limbic Encephalitis

1. Infectious causes – Many infections of the brain can potentially cause inflammation of the limbic areas. A number of viruses, such as the herpes simplex virus (HSV) seem to preferentially target this area. Some people may therefore be given the diagnosis of LE whilst others are given the diagnosis herpes simplex encephalitis for the same condition. A clearer way for people would be to say that the person has ‘herpes simplex virus encephalitis affecting mainly the limbic areas of the brain’, but this is rather long-winded.

2. Autoimmune causes – A major role of our immune system is to recognize and eliminate an infection. But sometimes parts of the immune system called ‘antibodies’ may instead react with proteins of our own body to cause autoimmune diseases. When this reaction is against proteins of the limbic areas of the brain, this is called ‘autoimmune limbic encephalitis.

There are broadly two forms of autoimmune limbic encephalitis: paraneoplastic limbic encephalitis (PLE) and non-paraneoplastic limbic encephalitis (NPLE).

a) Paraneoplastic limbic encephalitis (PLE)

Sometimes when the immune system starts to react with the limbic areas, this happens because the person has a tumor in their body that activates the immune system. This activated immune system can, in turn, attack the brain. Doctors call this paraneoplastic limbic encephalitis the tumor (neoplasm) that affects the brain from a distance, via the immune system.

In many cases, PLE can be diagnosed by testing for one of the paraneoplastic autoantibodies in the patient’s blood and spinal fluid. Most individuals with PLE have cancer of the lung, thymus gland, ovary, breast, or testes. More rarely, other cancers can initiate the condition. The outcome is very dependent on the underlying tumor and the precise condition, often classified by the antibody. In some cases, the condition may improve or at least stabilize if the cancer is detected and treated effectively. However, unfortunately, in many cases treatment does not improve the patient’s neurological symptoms, probably because the immune system has irreversibly damaged the brain cells and the tumor cannot be controlled successfully.

b) Non-paraneoplastic limbic encephalitis (NPLE)

NPLE has only been clearly recognized in the last few years when doctors began to identify patients with symptoms similar to those with PLE but who did not have any of the marker paraneoplastic antibodies in their blood and never developed a tumor. NPLE is far more common than PLE.

It is becoming increasingly clear that NPLE is caused, at least in part, by specific antibodies in the patient’s blood that targets the patient’s brain, particularly the hippocampus and other limbic areas. Many of these patients improve if they are treated with drugs that suppress the immune system and reduce the levels of the antibodies. These drugs include steroids, intravenous immunoglobulins, and plasma exchange.

Limbic encephalitis is associated with an autoimmune reaction.^[rx] In non-paraneoplastic limbic encephalitis, this is typically due to infection (commonly herpes simplex virus) or as a systemic autoimmune disorder.^[rx] Limbic encephalitis associated with cancer or tumors is called paraneoplastic limbic encephalitis.

• Exposure to certain bacteria and viruses, including streptococcus and herpes simplex virus.
• A type of tumor called a teratoma, generally in the ovaries, causes the immune system to produce specific antibodies.
• Rarely, some cancers that can trigger an autoimmune response (when the immune system attacks the body’s own tissues).
• Aseptic Meningitis
• Bell palsy
• Brain metastasis
• Brucellosis
• Cardioembolic stroke
• Cauda Equina and Conus Medullaris syndrome
• Cavernous sinus syndromes
• Central nervous system complications in HIV
• Cerebral venous thrombosis
• Churg-Strauss disease
• Another autoimmune encephalitis
• Primary psychiatric disorder
• Viral encephalitis
• Neuroleptic malignant syndrome
• Catatonia
• Acute disseminated encephalomyelitis
• Mitochondrial encephalitis
• Cerebral space-occupying lesions
• Exposure to drugs, toxins, or withdrawal symptoms
• Intracranial hemorrhage
• Subdural hemorrhage
• Subarachnoid hemorrhage
• Cerebral sinus venous thrombosis
• Posterior circulation ischemic or hemorrhagic stroke
• Thrombosis of the basilar artery
• Vasculitis of the central nervous system
• Herpes simplex encephalitis
• Autoimmune encephalitis
• Uremic encephalopathy
• Hypoglycemia

• A dark area in one part of your visual field
• Visual disturbances such as loss of side vision or a dark shade drawn over part of your vision

Inner-ear symptoms include

• Hearing loss
• Dizziness
• Ringing in your ears

Diagnosis of Limbic Encephalitis

Another way of dividing autoimmune encephalitis is on the grounds of whether the antibodies are against intracellular antigens or cell surface antigens. The antibodies, in turn, correlate both to an underlying cause and pattern of involvement. As a general rule, antibodies targeted to intracellular antigens are more frequently associated with an underlying tumor.

• group I – antibodies to intracellular antigens
  • anti-Hu antibodies
    • most common
    • small cell carcinoma of the lung in 75% of cases
    • anti-Hu syndrome consists of paraneoplastic encephalomyelitis, paraneoplastic sub-acute sensory neuropathy, and paraneoplastic cerebellar degeneration
  • anti-Ma/Ta antibodies
    • better prognosis than anti-Hu
    • testicular tumors
    • diencephalic and brainstem involvement more common
    • ophthalmoplegia is common
  • anti-CV2 antibodies
    • small cell carcinoma of the lung and malignant thymoma
    • involvement of the striatum prominent
    • choreiform movement disorders common
  • anti-GAD (glutamic acid decarboxylase) antibodies
    • usually not associated with tumors
    • usually classical limbic involvement with prominent seizures and stiff person syndrome
  • anti-amphiphysin antibodies
    • small cell carcinoma of the lung and breast cancer
    • myelopathy, myoclonus and stiff person syndrome
  • anti-Ri antibodies
    • small cell carcinoma of the lung and breast cancer
    • brain stem involvement
    • opsoclonus-myoclonus syndrome
  • anti-Yo antibodies
    • ovarian cancer and breast cancer
    • typically presents with paraneoplastic cerebellar degeneration
• group II – antibodies to surface antigens
  • anti-NMDA antibodies
    • common
    • usually in children and young women with no underlying tumor
    • older patients may have underlying tumors (e.g. ovarian teratoma)
    • typically present with psychiatric symptoms
    • mild or often absent imaging changes
  • anti-VGKC (voltage-gated potassium channel) antibodies
    • common
    • classic features of “limbic encephalitis” with prominent seizures
    • extra-limbic involvement very uncommon
  • anti-GABA (gamma-aminobutyric acid) antibodies
    • similar to VGKC but less common
    • two subtypes:
      • GABA-A
        • frequent extralimbic involvement
      • GABA-B
        • not infrequent underlying cancer (pulmonary neuroendocrine tumors)
  • anti-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) antibodies
    • predominantly psychiatric symptoms
    • imaging changes limited to the hippocampi
  • anti-D2 dopamine antibodies
    • basal ganglia encephalitis
  • anti-GlyR1 (glyoxylate reductase) antibodies
    • stiff leg syndrome or stiff person syndrome, or progressive encephalomyelitis with rigidity and myoclonus
  • anti-mGluR1(metabotropic glutamate receptor) antibodies
    • lymphoma with cerebellar ataxia
  • anti-mGluR5 antibodies
    • associated with Ophelia syndrome
  • anti-GluR3 (glutamate receptor) antibodies
    • associated with Rasmussen encephalitis

Lab Test

A brain scan, can determine inflammation and differentiate it from other possible causes.

• Blood test  – for monoclonal antibodies (anti-Hu, anti-Ta, anti-Ma, anti-GABA B receptor, and anti NMDA receptor) but the absence of these antibodies does not exclude the disease. A complete blood count with differential is a general index of health. It checks the number of red and white blood cells in your blood. White blood cells fight infection. The count is usually elevated in meningitis.
• 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[rx], but signs may appear later than the initial neurological symptom of the syndrome.[rx]
• Lumbar puncture – should be negative for malignant cells or infection and may show pleocytosis, the elevation of protein levels, and intensification of immunoglobulin synthesis and oligoclonal bands.[rx] Lumbar puncture (spinal tap) helps determine via a test using the cerebral-spinal fluid, obtained from the lumbar region.
• 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.
• An electroencephalogram (EEG) – small electrodes are placed on your scalp, which picks up the electrical signals from your brain and shows abnormal brain activity
• Spinal fluid analysis – By doing a lumbar puncture (also called a spinal tap), your doctor can check the spinal fluid for an increase in white blood cells and protein. The bacteria, virus, parasite, or fungus causing the encephalitis also may be found in the spinal fluid. Examination of cerebrospinal fluid (CSF) shows elevated numbers of lymphocytes (but usually < 100 cells/μl); elevated CSF protein (but usually <1.5 g/l), normal glucose, elevated IgG index, and oligoclonal bands. Patients with antibodies to voltage-gated potassium channels may have a completely normal CSF examination.^[rx][rx][rx]
• Urine analysis –  A urinalysis is a simple test that looks at a small sample of your urine. It can help find problems that need treatment, including infections or kidney problems. It can also help find serious diseases in the early stages, like kidney disease, diabetes, or liver disease. A urinalysis is also called a “urine test.
• Polymerase chain reaction (PCR) testing – of the cerebrospinal fluid, to detect the presence of viral DNA which is a sign of viral encephalitis.
• Blood cultures identify bacteria in the blood – Bacteria can travel from the blood to the brain. N. meningitides and S. pneumonia can cause both sepsis and meningitis.
• Cerebrospinal fluid (CSF) – CSF is the fluid that surrounds your brain and spinal cord. It helps to support and protect the brain and spinal cord from trauma.
• Chest X-rays –  can reveal the presence of pneumonia, tuberculosis, or fungal infections. Meningitis can occur after pneumonia. A chest radiograph called a chest X-ray, or chest film is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures. Chest radiographs are the most common film taken in medicine
• Thyroid antibodies – both antithyroid peroxidase antibodies (anti-TPO, antithyroid microsomal antibodies, anti-M) and antithyroglobulin antibodies (anti-Tg) – in the disease are elevated, but their levels do not correlate with the severity.
• Electroencephalogram studies – while almost always abnormal (98% of cases), are usually not diagnostic. The most common findings are diffuse or generalized slowing or frontal intermittent rhythmic delta activity. Prominent triphasic waves, focal slowing, epileptiform abnormalities, and photo paroxysmal and photogenic responses may be seen.^[rx]
• A CT scan  – of the head may show problems like a brain abscess or sinusitis. Bacteria can spread from the sinuses to the meninges. A computerized tomography (CT) scan combines a series of X-ray images taken from different angles around your body and uses computer processing to create cross-sectional images (slices) of the bones, blood vessels, and soft tissues inside your body. CT scan images provide more detailed information than plain X-rays do.
• MRI – to be oversure about meningitis. Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves to generate images of the organs in the body.
• Anti NMDAR IgG antibodies – detected by indirect immunofluorescence assay in the serum and the CSF, are diagnostic for the disease. Antibody titers are higher in the CSF, and in some cases, diagnosis is possible after CSF testing with concurrent negative serum reports. CSF also can have low-grade hypercellularity and oligoclonal bands.[rx] Brain MRI can be normal, but nonspecific white and gray matter T2/FLAIR  signal hyperintensity can be present, most commonly in the hippocampus. Diffusion restriction positivity has been reported, as well as cerebellar atrophy, as the only irreversible radiologic finding with this encephalitis.[rx]
• Transvaginal ultrasonography – is the most crucial test for young women presenting with the illness due to the high incidence of underlying ovarian teratoma. If these tests are unrevealing, PET scans and exploratory laparotomy are options.[rx] In cases of negative initial screening, follow-up MRI of abdomen and pelvis should be repeated every six months for at least four years.[rx]
• Electroencephalography – Patients with ALE may occasionally have a normal EEG, which does not rule out the diagnosis.[rx] Usually, however, EEG shows slow-wave activity or epileptiform discharges from the temporal lobes of patients with ALE — a clue to brain inflammation. In a retrospective analysis of 19 patients with autoimmune encephalitis and seizures, 10 of 16 patients with ictal EEGs (63%) had seizure onset over the temporal lobe region, which closely mirrored the medial temporal lobe abnormalities seen on MRI in three-quarters of those studied.[rx] Importantly, EEG abnormalities of the temporal lobes without any observed changes on imaging are not sufficient to make a diagnosis of ALE in the absence of a positive antibody. In clinical practice, an EEG that shows slow-wave activity or epileptiform discharges from the temporal lobes in a patient with possible ALE should raise suspicion of the condition even if the initial MRI is normal; in such cases, repeat MRI may be considered, to look for the interval development of medial temporal lobe abnormalities.[rx]

Treatment Of Limbic Encephalitis 

Treatment (which is based on supportive care) is as follows

References

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