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Limbic Encephalitis

Enceph Limbic

Limbic encephalitis refers to an inflammation of the limbic system that is associated with functional and imaging changes. Limbic encephalitis may result from infection, autoimmune response or cancer.


Presentation

LE is generally characterized by subacute onset of symptoms, mainly cognitive impairment, disorientation, confusion and disturbances of memory [1]. Seizures are often observed and are not or only partially treatable with anti-epileptic drugs. Some patients will present with psychiatric symptoms and may show disturbances in behavior and suffer from hallucinations [8].

Because LE are often part of more generalized encephalitides, additional symptoms may be present. Paraneoplastic LE mediated by Ma2-antibodies, for instance, are accompanied by inflammations of hypothalamus and brain stem. Thus, sleep disorders, severe hypokinesis and gaze palsy may also be observed.

If blood samples are analyzed, the most common finding is hyponatremia. Almost 60% of LE patients display decreased serum sodium levels and this parameter may serve as a diagnostic marker. The precise relation between LE and sodium imbalances are not yet completely understood, but functional impairment of the hypothalamus due to inflammation may possibly be involved.

Of note, antibodies against voltage-gated potassium channel-associated proteins have been detected in patients suffering from faciobrachial dystonic seizures without any additional signs of LE being present. Therefore, such seizures should prompt serum sample analysis for these antibodies and eventually initiation of LE treatment. This could significantly improve these patients' prognosis.

Constitutional Symptom
  • We report the case of a 47-year old Caucasian man who presented with subacute onset of constitutional symptoms, diffuse lymphadenopathy, and stereotyped spells involving olfactory aura, nausea, disorientation, and unresponsiveness.[ncbi.nlm.nih.gov]
Piloerection
  • Ictal piloerection is an infrequent seizure semiology that is commonly overlooked as an ictal epileptic manifestation.[ncbi.nlm.nih.gov]
Memory Impairment
  • Subclinical seizure patterns and memory impairment persisted over one to two years after clinical seizure remission.[ncbi.nlm.nih.gov]
  • We are emphasising the importance of considering a rare diagnosis, voltage-gated Potassium channel antibody-associated limbic encephalitis, in an 80-year-old gentleman who presented with memory impairment, seizure and hyponatraemia.[ncbi.nlm.nih.gov]
  • Limbic encephalitis is a subacute onset syndrome characterized by short-term memory impairment, confusion, temporal lobe epilepsy, hypothalamic dysfunction, and psychiatric symptoms.[ncbi.nlm.nih.gov]
  • Clinical features include memory impairment, temporal lobe seizures and affective disturbance. We report the case of a 10-year-old girl with type 1 diabetes mellitus that presented with seizures, depressed mood and memory changes.[ncbi.nlm.nih.gov]
  • Paraneoplastic limbic encephalitis is a rare neurological syndrome and clinically characterized by cognitive dysfunction, memory impairment, seizures and psychiatric symptoms.[ncbi.nlm.nih.gov]
Personality Change
  • A 61-year-old Japanese man with a history of smoking cigarettes presented with seizure, confusion and personality change in acute onset.[ncbi.nlm.nih.gov]
  • In this case, the patient presented with personality change, cognitive impairment, complex partial seizures, ataxia, dyspraxia, and dysphasia.[ncbi.nlm.nih.gov]
  • Twelve (12/18) patients had memory deficits, 11 (11/18) patients had personality change, 7 (7/18) patients had disturbance of consciousness, and 3 (3/18) patients showed cerebellar dysfunction.[ncbi.nlm.nih.gov]
  • Abstract Paraneoplastic limbic encephalitis (PLE) is a rare disorder characterized by personality changes, irritability, depression, seizures, memory loss and sometimes dementia.[ncbi.nlm.nih.gov]
Quadriplegia
  • Follow-up NCS of the patient with anti-AMPA receptor encephalitis found reverse of the acute neuropathy, which was compatible with clinical recovery of quadriplegia.[ncbi.nlm.nih.gov]
Rotary Nystagmus
  • Examination revealed rotary nystagmus, ocular skew deviation, limb dysmetria, and gait ataxia. After two courses of intravenous immunoglobulin, there was minimal improvement. Anti-Ri antibodies were positive in serum only.[ncbi.nlm.nih.gov]

Workup

Important differential diagnoses include distinct types of infectious encephalitis, considering bacteria, virus, fungi and prions as possible causative agents, acute or chronic intoxication, Wernicke-Korsakoff syndrome, stroke, psychiatric disorders and cerebral neoplasms. In fact, there are case reports about LE being potentially misdiagnosed as Creutzfeldt Jakob disease [11]. Even though dementia usually develop over prolonged periods of time, certain types of dementia may progress rapidly and could then be confused with LE.

After obtaining the patients medical history, a thorough clinical examination, laboratory tests of blood samples and brain imaging should be carried out. Alterations characteristic for LE are best visualized by magnetic resonance imaging. Here, T2-weighted images may reveal hyper-intense areas in the temporomesial region. In more advanced cases, temporal lobe atrophy might be diagnosed [12]. Of note, such images do not allow for distinction of infectious, autoimmune and paraneoplastic LE. Computed tomography images might not show any pathological changes.

If the aforementioned diagnostic measures support a tentative diagnosis of LE, antibody titers for sporadic autoimmune or paraneoplastic LE should be determined. Increased antibody titers alone may indicate LE but may also result from other pathological conditions such as Morvan's syndrome or neuromyotonia.

Up to date, there are no clearly defined criteria that justify diagnosis of LE. However, efforts have been undertaken to establish such criteria [13]. It remains to be seen if they will eventually be included in any diagnostic guideline.

Generalized Slowing
  • Ten (10/18) patients had temporal lobe epileptic activity with or without general slowing on EEG. Seventeen patients received immunotherapy and 15 of them showed neurological improvement.[ncbi.nlm.nih.gov]

Treatment

Immunosuppression and immunoglobulin therapy are recommended to treat LE. In this context, methylprednisolone (i.v., 1000 mg per day, during 3 days) and immunoglobulin (i.v., 400 mg per kg body weight per day, during 5 days) should be administered [14] [15]. If the patient responds well to initial treatment, they should subsequently receive supportive care until complete recovery. Else, more aggressive immunosuppression is required. Therefor, rituximab or cyclophosphamide may be applied. In some cases, both compounds are combined. Further alternatives are mycophenolate mofetil and azathioprine.

Relapses require repeated immunosuppression. Here, long-term pulse therapies or continuous low dose immunosuppression may be helpful.

Patients suffering from paraneoplastic LE may require plasma exchanges. The underlying cancerous disease should be treated accordingly. Regular follow-ups should be conducted in the following years.

Prognosis

Prognosis depends on the form of LE and, in case of paraneoplastic LE, on staging and grading results of the underlying cancer. In any case, early diagnosis, initiation of therapy and possibly immunotherapy and tumor resection significantly improve the outcome [8]. In this line, paraneoplastic LE may serve as an early sign for cancer. The results of one study involving 50 patients revealed that paraneoplastic LE frequently precedes cancer and may be diagnosed more than three months before the latter [9].

Non-paraneoplastic autoimmune LE generally have a better prognosis than paraneoplastic LE [10]. If the autoimmune response is directed against cell surface antigens, e.g., voltage-gated potassium channels, cell surface receptors, prognosis is more favorable than in those cases were molecular targets are located intracellularly. Of note, the Ma2 antigen, frequently targeted by antibodies produced against breast and testicular cancers, is selectively expressed intracellularly but patients often do respond to therapy.

Etiology

Infectious LE may develop if pathogens invade the limbic area of the brain. While virus strains such as the herpes simplex virus preferentially target the limbic system, other infectious agents may cause a more general infectious encephalitis that also affects the limbic system. In this line, the term herpes simplex encephalitis refers to the same disease as viral LE. Other viruses that may provoke encephalitis but not necessarily cause LE are, for instance, viruses associated with tick-borne encephalitides, rubeola, rubella and rabies. Bacteria pertaining to the genus Treponema, Listeria or Borrelia may trigger encephalitis as well as Cryptococcus.

Non-infectious LE are mainly provoked by an autoimmune response. Here, the immune system produces antibodies that bind to molecular targets expressed in the limbic system, usually neuronal proteins [3]. For a long time, autoimmune-mediated LE has exclusively been ascribed to cancer. A primary tumor located outside of the central nervous system triggers an immune response and initiates the production of the above mentioned antibodies as well as cytotoxic T cell activity. Therefore, this form of LE is also called paraneoplastic LE.

In recent years and presumably due to diagnostic advances, non-infectious, non-paraneoplastic LE have been increasingly diagnosed. Patients do not show elevated serum concentrations of antibodies characteristic for paraneoplastic LE. This disease, however, seems to be caused by an autoimmune response, too. Auto-antibodies may target structures that are expressed in different parts of the brain, but there is an apparent preference for those proteins expressed in hippocampal neurons and those of other limbic areas.

Epidemiology

No reliable data regarding overall incidence and prevalence of LE can be presented. The majority of patients that present with LE is aged 40 years and older. It has been speculated that twice as many men as women are affected [4]. Otherwise, one would have to suppose that age, gender and racial preferences to mimic those of the underlying diseases. This applies particularly for paraneoplastic LE, small cell lung cancer, breast cancer and testicular cancer [5].

Sex distribution
Age distribution

Pathophysiology

Neurotrophic herpes simplex virus may persist for years in neuronal ganglia and may be re-activated in any given moment. Usually, herpes simplex virus utilizes the olfactory nerve to reach the brain, then spreads from its point of entry and infects the limbic system as well as other areas of the brain. The virus replicates inside infected cells, which are subsequently destroyed by virus-mediated lysis. Other infectious agents may use alternative routes to enter the central nervous system, they may affect distinct cell types and thus provoke different symptoms, but they are mainly causing direct damage to the brain.

Herein, they differ greatly from autoimmune LE pathogenesis. The precise trigger for sporadic autoimmune LE is not yet known, but potential auto-antibodies have recently been identified. Surface proteins associated with voltage-gated potassium channels have been proposed as possible target structures for auto-antibodies. It has also been speculated that autoimmune LE mediated by LGI1 and CASPR2 antibodies has a higher incidence than currently is assumed [6]. Indeed, this form may be underdiagnosed because routine screens do not test for the aforementioned antibodies. It is therefore necessary to raise the awareness. Less commonly, auto-antibodies may be directed against AMPA, NMDA and GABA receptors [7]. Of note, these antibodies may also be associated with paraneoplastic LE although those antibodies described in the following paragraph are more frequently related with the latter.

Cancer-related, additional antibodies account for paraneoplastic LE. It is often associated with small cell lung cancer, breast cancer, testicular cancer, thymoma, teratoma and Hodgkin's lymphoma. Frequent molecular targets are Hu and Ma2, and less commonly CRMP5 and amphiphysin. In healthy individuals, Hu-antigen expression is restricted to the central nervous system, but small cell lung cancer does express this same antigen. A positive correlation between smoking, small cell lung cancer, Hu-antibody production and paraneoplastic encephalomyelitis has been proven. As already indicated, Hu-antibodies mediate an autoimmune response against a wide variety of central nervous system cell types. In these patients, paraneoplastic LE is part of a broader paraneoplastic encephalomyelitis. In contrast, Ma2-antibodies evoke a more restricted autoimmune response against limbic system, hypothalamus and brain stem. If Ma2-antibodies are detected in women or men aged 50 years and older, these patients should be thoroughly examined for breast cancer. In men aged 50 years and younger, elevated serum levels of Ma2-antibodies strongly point at testicular cancer, although the tumor may not be easily detected [5].

Prevention

No preventive measures can be recommended except general hygiene measures to avoid infection with virus strains that possibly cause LE.

Summary

The limbic system is a functional unit composed of telencephalic, diencephalic and mesencephalic structures, the hippocampus, for instance, that is located in close proximity to the thalamus. An inflammation of the limbic system may be diagnosed as limbic encephalitis (LE) and may be provoked by infectious agents or an autoimmune response [1] [2]. With regards to infectious LE, the most common causative agent is herpes simplex virus. Autoimmune LE may develop sporadically or as part of a paraneoplastic syndrome. Small cell lung cancer, breast and testicular cancer are most frequently related with paraneoplastic LE.

Symptoms most frequently observed include seizures, cognitive impairment and memory disorders. A wide variety of symptoms may be present if the patient suffers from more generalized forms of encephalitis or meningoencephalitis. Treatment consists in immunosuppression and immunoglobulin therapy. Because paraneoplastic LE are a mere symptom of the underlying cancerous disease, the latter needs to be treated accordingly.

Patient Information

The limbic system is part of the brain. It is generally associated with emotions, memory and behavior, but is indeed connected with a wide variety of other brain sections. An inflammation of the limbic system is called limbic encephalitis (LE).

Causes

Some infectious agents, particularly herpes virus, may trigger LE. Other infectious diseases that may be accompanied by encephalitis are rubeola, rubella and certain diseases transmitted by ticks. These pathogens use nerves as guide structures to reach the brain.

LE may be caused by an autoimmune response, i.e., in these cases, the body of the patient uses its immune system against its own cells. It is not completely clear how such an autoimmune disease is set off, but it may happen if the patient is suffering from cancer.

Symptoms

The most common symptoms are seizures, cognitive impairment, disorientation, confusion and memory disturbances. In some cases, behavioral changes have been observed.

If other brain sections are also affected, additional symptoms may be experienced. This also applies for potentially present tumors.

Diagnosis

The above described symptoms are rather unspecific and the physician will have to rule out differential diagnoses, identify the causative pathogen in case of infectious LE and check the patient for any signs that they are suffering from cancer. In order to do so, brain scans will be carried out and blood samples as well as cerebrospinal fluid will be analyzed in a laboratory. Magnetic resonance imaging is usually most helpful to detect pathological alterations characteristic for LE.

Treatment

Unless the patient suffers from sporadic autoimmune LE, the underlying disease has to be treated. In case of infectious LE, such treatment may consist in antibiotics, while surgery, chemotherapy and irradiation might be indicated in patients suffering from cancer.

Direct treatment of LE consists in immunosuppressive and immunoglobulin therapy. Patients usually receive oral medication for some days. If the patient does not respond to treatment, stronger immunosuppressive drugs may be administered. This also applies in case of relapses.

Early diagnosis and initiation of treatment significantly improves the prognosis.

References

Article

  1. Tüzün E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist. 2007; 13(5):261-271.
  2. Anderson NE, Barber PA. Limbic encephalitis - a review. J Clin Neurosci. 2008; 15(9):961-971.
  3. Thieben MJ, Lennon VA, Boeve BF, Aksamit AJ, Keegan M, Vernino S. Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology. 2004; 62(7):1177-1182.
  4. Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol. 2011; 10(8):759-772.
  5. Manley GT, Smitt PS, Dalmau J, Posner JB. Hu antigens: reactivity with Hu antibodies, tumor expression, and major immunogenic sites. Ann Neurol. 1995; 38(1):102-110.
  6. Klein CJ, Lennon VA, Aston PA, et al. Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol. 2013; 70(2):229-234.
  7. Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol. 2009; 65(4):424-434.
  8. Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain. 2004; 127(Pt 3):701-712.
  9. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain. 2000; 123 ( Pt 7):1481-1494.
  10. Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011; 77(2):179-189.
  11. Geschwind MD, Tan KM, Lennon VA, et al. Voltage-gated potassium channel autoimmunity mimicking creutzfeldt-jakob disease. Arch Neurol. 2008; 65(10):1341-1346.
  12. Urbach H, Soeder BM, Jeub M, Klockgether T, Meyer B, Bien CG. Serial MRI of limbic encephalitis. Neuroradiology. 2006; 48(6):380-386.
  13. Bien CG, Elger CE. Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav. 2007; 10(4):529-538.
  14. Dalmau J, Tuzun E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007; 61(1):25-36.
  15. Alamowitch S, Graus F, Uchuya M, Rene R, Bescansa E, Delattre JY. Limbic encephalitis and small cell lung cancer. Clinical and immunological features. Brain. 1997; 120 ( Pt 6):923-928.

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Last updated: 2018-06-22 03:54