Limbic encephalitis

Limbic encephalitis is broadly grouped into two types: paraneoplastic limbic encephalitis and non-paraneoplastic limbic encephalitis.{{cn|date=July 2021}}

• Paraneoplastic limbic encephalitis (PNLE) is caused by cancer or tumor, and may be treated by removal of the tumor.
• Non-paraneoplastic limbic encephalitis (NPLE) is not associated with cancer. More common than PNLE, it is caused by an infection, auto-immune disorder, or other condition that may never be identified.{{Cite news|url=https://www.encephalitis.info/limbic-encephalitis|title=Limbic encephalitis|work=The Encephalitis Society|access-date=2017-12-23|language=en}}

Symptoms develop over days or weeks. The subacute development of short-term memory deficits is considered the hallmark of this disease, but this symptom is often overlooked, because it is overshadowed by other more obvious symptoms such as headache, irritability, sleep disturbance, delusions, hallucinations, agitation, seizures and psychosis, or because the other symptoms mean the patient has to be sedated, and it is not possible to test memory in a sedated patient.{{cn|date=July 2021}}

Limbic encephalitis is associated with an autoimmune reaction. In non-paraneoplastic limbic encephalitis, this is typically due to infection (commonly herpes simplex virus) or as a systemic autoimmune disorder.{{Cite journal|last1=Anderson|first1=N. E.|last2=Barber|first2=P. A.|date=September 2008|title=Limbic encephalitis - a review|journal=Journal of Clinical Neuroscience|volume=15|issue=9|pages=961–971|doi=10.1016/j.jocn.2007.12.003|issn=0967-5868|pmid=18411052|s2cid=6545575 |hdl=2292/13889|hdl-access=free}} Limbic encephalitis associated with cancer or tumors is called paraneoplastic limbic encephalitis.{{cn|date=July 2021}}

The diagnosis of limbic encephalitis is extremely difficult and it is usual for the diagnosis to be delayed for weeks. The key diagnostic test (detection of specific auto-antibodies in cerebrospinal fluid) is not routinely offered by most immunology laboratories. Some of the rarer auto-antibodies (e.g., NMDAR) have no commercially available assay and can only be measured by a very small number of research laboratories worldwide, further delaying diagnosis by weeks or months. Most patients with limbic encephalitis are initially diagnosed with herpes simplex encephalitis, because the two syndromes cannot be distinguished clinically. HHV-6 (human herpes virus 6) encephalitis is also clinically indistinguishable from limbic encephalitis.

There are two sets of diagnostic criteria used. The oldest are those proposed by Gultekin et al. in 2000.{{cite journal |vauthors=Gultekin SH, Rosenfeld MR, Voltz R, etal | title = Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients| journal = Brain| year = 2000| volume = 123| pages = 1481–1494| doi = 10.1093/brain/123.7.1481| issue = 7 | pmid=10869059| doi-access= }}

A revised set of criteria were proposed by Graus and Saiz in 2005.{{cite journal|vauthors=Graus F, Saiz A | title = Limbic encephalitis: a probably under-recognized syndrome| journal = Neurologia| year = 2005| volume = 20| issue = 1| pages = 24–30| pmid = 15704018}}

The main distinction between the two sets of criteria is whether or not the detection of a paraneoplastic antibody is needed for diagnosis.

The main antibodies within this group are those against Hu, Ma2, CV2, amphiphysin and Ri. The syndrome of anti-Ma2 encephalitis may be clinically mistaken for Whipple's disease.{{cite journal |vauthors=Castle J, Sakonju A, Dalmau J, etal | title = Anti-Ma2-associated encephalitis with normal FDG-PET: a case of pseudo-Whipple's disease| journal = Nat Clin Pract Neurol| year = 2006| volume = 2| pages = 566–572| doi = 10.1038/ncpneuro0287| pmid = 16990830| issue = 10| s2cid = 10797381}}

The main antibodies within this group are those against N-methyl-D-aspartate receptors (NMDAR) and the voltage-gated potassium channel-complex (VGKC-complex). Anti-NMDAR encephalitis is strongly associated with benign tumours of the ovary (usually teratomata or dermoid cysts). Anti-VGKC-complex encephalitis is most often not associated with tumours.{{cn|date=July 2021}}

Patients with NMDAR encephalitis are frequently young women who present with fever, headache and fatigue. This is often misdiagnosed as influenza, but progresses to severe behavioural and personality disturbance, delusions, paranoia and hallucinations.{{cite journal |vauthors=Koide R, Shimizu T, Koike K, etal | title = EFA6A-like antibodies in paraneoplastic encephalitis associated with immature ovarian teratoma: a case report| journal = J Neurooncol| year = 2007| volume = 81| issue = 1| pages = 71–74| doi = 10.1007/s11060-006-9200-7 | pmid = 16807779| s2cid = 6010024}} Patients may therefore initially be admitted to a psychiatric ward for acute psychosis or schizophrenia. The disease then progresses to catatonia, seizures and loss of consciousness. The next stage is hypoventilation (inadequate breathing) requiring intubation, orofacial dyskinesia and autonomic instability (dramatic fluctuations in blood pressure, temperature and heart rate).{{cite journal |vauthors=Dalmau J, Tuzun E, Wu HY, etal | title = Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma| journal = Ann Neurol| year = 2007| volume = 61| issue = 1| pages = 25–36| doi = 10.1002/ana.21050| pmid=17262855| pmc=2430743}}

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.{{cite journal |vauthors=Buckley C, Oger J, Clover L, etal | title = Potassium channel antibodies in two patients with reversible limbic encephalitis| journal = Ann Neurol| year = 2001| volume = 50| issue = 1| pages = 73–78| doi = 10.1002/ana.1097 | pmid=11456313| s2cid = 38993448}}{{cite journal |vauthors=Vincent A, Buckley C, Schott JM, etal | title = Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis| journal = Brain| year = 2004| volume = 127| pages = 701–712| doi = 10.1093/brain/awh077| issue = 3 | pmid=14960497| doi-access= free}}{{cite journal |vauthors=Thieben MJ, Lennon VA, Boeve BF, etal | title = Potentially reversible auto-immune limbic encephalitis with neuronal potassium channel antibody| journal = Neurology| year = 2004| volume = 62| pages = 1177–1182| doi = 10.1212/01.WNL.0000122648.19196.02| issue = 7| pmid = 15079019| s2cid = 30883641}}

Brain MRI is the mainstay of initial investigation pointing to limbic lobe pathology revealing increased T2 signal involving one or both temporal lobes in most cases.{{Cite journal|title = Clinical, Magnetic Resonance Imaging, and 7Electroencephalographic Findings in Paraneoplastic Limbic Encephalitis|last = Nicholas|first = D|date = 2003|journal = Mayo Clinic Proceedings|volume=78 |issue=11|pages=1363–1368|doi = 10.4065/78.11.1363|pmid = 14601695}}

Serial MRI in LE starts as an acute disease with uni- or bilateral swollen temporomesial structures that are hyperintense on fluid attenuation inversion recovery and T2-weighted sequences. Swelling and hyperintensity may persist over months to years, but in most cases progressive temporomesial atrophy develops.{{Cite journal|title = Serial MRI of limbic encephalitis|last = Horst|first = Urbach|date = 2006|journal = Neuroradiology |volume=48 |issue=6 |pages=380–386|doi = 10.1007/s00234-006-0069-0|pmid = 16586118| s2cid=7993234 }}

PET-CT is not an essential investigation but can help in suspected cases with MRI negative for early diagnosis.{{Cite journal|title = Limbic Encephalitis Diagnosed With 18F-FDG PET/CT|journal = Clinical Nuclear Medicine|date = 2016-02-01|issn = 1536-0229|pmid = 26571448|pages = e101–103|volume = 41|issue = 2|doi = 10.1097/RLU.0000000000001076|first1 = Maria Del Puig|last1 = Cózar Santiago|first2 = Raul|last2 = Sanchez Jurado|first3 = Rut|last3 = Sanz Llorens|first4 = Jose Enrique|last4 = Aguilar Barrios|first5 = Jose|last5 = Ferrer Rebolleda}}

EEG is mostly nonspecific slowing and epileptiform activity arising from temporal lobes.

Limbic encephalitis is a rare condition with no randomised-controlled trials to guide treatment. Treatments that have been tried include intravenous immunoglobulin, plasmapheresis, corticosteroids, cyclophosphamide and rituximab.

If an associated tumour is found, then recovery is not possible until the tumour is removed. Unfortunately, this is not always possible, especially if the tumour is malignant and advanced.

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{{Medical resources

| DiseasesDB = 30707

| ICD10 = {{ICD10|G|04|81|g|10}}

| ICD9 = 323.81

| ICDO =

| OMIM =

| MedlinePlus =

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| eMedicineTopic =

| MeshID = D020363

| SNOMED CT = 230192003

| Orphanet = 163892

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{{Paraneoplastic syndromes}}

{{CNS diseases of the nervous system}}

Category:Encephalitis

Category:Steroid-responsive inflammatory conditions