Limbic encephalitis

The limbic system within the brain.
Specialty| Neurology

Limbic encephalitis is a form of encephalitis, a disease characterized by inflammation of the brain.[1] Limbic encephalitis is caused by autoimmunity: an abnormal state where the body produces antibodies against itself. Some cases are associated with cancer and some are not.[1] Although the disease is known as "limbic" encephalitis, it is seldom limited to the limbic system and post-mortem studies usually show involvement of other parts of the brain.[2][3][4] The disease was first described by Brierley and others in 1960 as a series of three cases. The link to cancer was first noted in 1968[3] and confirmed by later investigators.[5]

The majority of cases of limbic encephalitis are associated with a tumor (diagnosed or undiagnosed). In cases caused by tumor, recovery can only occur following complete removal of the tumor, which is not always possible. Limbic encephalitis is classified according to the auto-antibody that causes the disease. The most common types are:

* Anti-Hu, which is associated with small-cell carcinoma of the lungs.
* Anti-Ma2, associated with germ-cell tumours of the testis.
* Anti-NMDAR, associated with tumors of the ovaries, commonly teratomata.

Since 1999, following the publication of a case report of a 15-year-old teenager of Indian descent from South Africa who developed subacute memory loss subsequent to herpes simplex type 1 encephalitis,[6] similar cases of non-paraneoplastic LE have been described, as has its association with auto-antibodies and response to steroid.[7][8] Limbic encephalitis associated with voltage-gated potassium channel antibodies (VGKC-Abs)[9] may frequently be non-paraneoplastic.[10] A recent study of 15 cases of limbic encephalitis found raised VGKC-Abs associated with non-paraneoplastic disorders and remission following immunosuppressive treatment.[11]

## Contents

* 1 Classification
* 2 Symptoms and signs
* 3 Cause
* 4 Diagnosis
* 4.1 Antibodies against intracellular neuronal antigens
* 4.2 Antibodies against cell membrane antigens
* 4.3 Investigation
* 4.3.1 Cerebrospinal fluid (CSF)
* 4.3.2 Neuroimaging
* 4.3.3 Neuro-electrophysiology
* 5 Treatment
* 6 History
* 7 References
* 8 External links

## Classification[edit | edit source]

Limbic encephalitis is broadly grouped into two types: paraneoplastic limbic encephalitis and non-paraneoplastic limbic encephalitis.[citation needed]

* 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.[12]

## Symptoms and signs[edit | edit source]

Symptoms develop over days or weeks. The subacute development of short-term memory deficits is considered the hallmark of this disease,[1] 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.[citation needed]

## Cause[edit | edit source]

Limbic encephalitis is associated with an autoimmune reaction.[1] In non-paraneoplastic limbic encephalitis, this is typically due to infection (commonly herpes simplex virus) or as a systemic autoimmune disorder.[13] Limbic encephalitis associated with cancer or tumors is called paraneoplastic limbic encephalitis.[citation needed]

## Diagnosis[edit | edit source]

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.[1] HHV-6 (human herpes virus 6) encephalitis is also clinically indistinguishable from limbic encephalitis.[1]

There are two sets of diagnostic criteria used. The oldest are those proposed by Gultekin et al. in 2000.[14]

Gultekin criteria

EITHER, Pathological demonstration of limbic encephalitis
OR, All four of:

* Short-term memory loss, seizures, or psychiatric symptoms suggestive of limbic system involvement
* <4 years between onset of neurological symptoms and cancer diagnosis
* Exclusion of metastases, infection, metabolic and nutritional deficits, stroke and side-effects of therapy that may cause limbic encephalopathy
* At least one of
* CSF with inflammatory findings
* Hyperintensity of the temporal lobes bilaterally on MRI FLAIR or T2
* EEG with epilepsy or slow activity involving the temporal lobes focally

A revised set of criteria were proposed by Graus and Saiz in 2005.[15]

Graus and Saiz criteria

All four of

* Subacute onset (<12 weeks) of seizures, short-term memory loss, confusion, and psychiatric symptoms
* Neuropathologic or radiologic evidence (MRI, SPECT, PET) of involvement of the limbic system
* Exclusion of other possible aetiologies of limbic dysfunction
* Demonstration of a cancer within 5 years of the diagnosis of neurologic symptoms, or the development of classic symptoms of limbic dysfunction in association with a well-characterized paraneoplastic antibody (Hu, Ma2, CV2, amphiphysin, Ri)

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

### Antibodies against intracellular neuronal antigens[edit | edit source]

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.[16]

### Antibodies against cell membrane antigens[edit | edit source]

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.[citation needed]

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.[17] 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).[18]

### Investigation[edit | edit source]

* Image of limbic encephalitis (and positive NMDAR antibodies in the CSF)- increased signal intensity is seen in the bilateral medial temporal lobes and hippocampi.

* FLAIR MRI-Indicates bright signal from medial temporal lobe consistent with limbic encephalitis arrow

#### Cerebrospinal fluid (CSF)[edit | edit source]

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.[19][20][21]

#### Neuroimaging[edit | edit source]

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.[22][14]

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.[23]

PET-CT is not an essential investigation but can help in suspected cases with MRI negative for early diagnosis.[24]

#### Neuro-electrophysiology[edit | edit source]

EEG is mostly nonspecific slowing and epileptiform activity arising from temporal lobes.[14]

## Treatment[edit | edit source]

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.[1]

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.

## History[edit | edit source]

Clinical Features  | Pathology  | Year  | Syndromes

|
|
|

Subacute onset of episodic memory impairment, disorientation and agitation, commonly associated with seizures, hallucinations, sleep disturbance  | Medial temporal lobe inflammation  | 1960  | Subacute encephalitis of later adult life mainly affecting the limbic areas[2]
1968  | Limbic Encephalitis association with Carcinoma[25][2]
2008  | Paraneoplastic LE with Lung Carcinoma, thymoma,[26]
2002  | Non Paraneoplastic LE[6]

## References[edit | edit source]

1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Tüzün E, Dalmau J (2007). "Limbic encephalitis and variants: classification, diagnosis and treatment". The Neurologist. 13 (5).
2. ↑ 2.0 2.1 2.2 Brierley JB, Corsellis JA, Hierons R, et al. (1960). "Subacute encephalitis of later adult life. Mainly affecting the limbic areas". Brain. 83 (3): 357–368. doi:10.1093/brain/83.3.357.
3. ↑ 3.0 3.1 Corsellis JA, Goldberg GJ, Norton AR (1968). ""Limbic encephalitis" and its association with carcinoma". Brain. 91 (3): 481–496. doi:10.1093/brain/91.3.481. PMID 5723018.
4. ↑ Bakheit AM, Kennedy PG, Behan PO (1990). "Paraneoplastic limbic encephalitis: clinico-pathological correlations". J Neurol Neurosurg Psychiatry. 53 (12): 1084–1088. doi:10.1136/jnnp.53.12.1084. PMC 488321. PMID 1963440.
5. ↑ Henson RA, Hoffman HL, Urich H (1965). "Encephalomyelitis with carcinoma". Brain. 88 (3): 449–464. doi:10.1093/brain/88.3.449.
6. ↑ 6.0 6.1 Mori, Masahiro; Kuwabara, Satoshi; Yoshiyama, Mitsuharu; Kanesaka, Toshihide; Ogata, Tsuyoshi; Hattori, Takamichi (2002-09-15). "Successful immune treatment for non-paraneoplastic limbic encephalitis". Journal of the Neurological Sciences. 201 (1–2): 85–88. doi:10.1016/s0022-510x(02)00188-0. ISSN 0022-510X. PMID 12163199.
7. ↑ Watanabe, Yasuhiro; Shimizu, Yasutaka; Ooi, Shinji; Tanaka, Keiko; Inuzuka, Takashi; Nakashima, Kenji (2003-05-01). "Steroid-responsive limbic encephalitis". Internal Medicine. 42 (5): 428–432. doi:10.2169/internalmedicine.42.428. ISSN 0918-2918. PMID 12793715.
8. ↑ Lang, Pierre Olivier; Sellal, François (2008-05-01). "[Non-paraneoplastic limbic encephalitis revealed by anterograde amnesia]". Presse Médicale. 37 (5 Pt 1): 775–782. doi:10.1016/j.lpm.2007.11.013. ISSN 0755-4982. PMID 18261871.
9. ↑ Buckley, C.; Oger, J.; Clover, L.; Tüzün, E.; Carpenter, K.; Jackson, M.; Vincent, A. (2001-07-01). "Potassium channel antibodies in two patients with reversible limbic encephalitis". Annals of Neurology. 50 (1): 73–78. doi:10.1002/ana.1097. ISSN 0364-5134. PMID 11456313.
10. ↑ Schott, J. M.; Harkness, K.; Barnes, J.; della Rocchetta, A. Incisa; Vincent, A.; Rossor, M. N. (2003-04-12). "Amnesia, cerebral atrophy, and autoimmunity". Lancet. 361 (9365): 1266. doi:10.1016/s0140-6736(03)12983-2. ISSN 0140-6736. PMID 12699955.
11. ↑ Pozo-Rosich, Patricia; Clover, Linda; Saiz, Albert; Vincent, Angela; Graus, Francesc (2003-10-01). "Voltage-gated potassium channel antibodies in limbic encephalitis". Annals of Neurology. 54 (4): 530–533. doi:10.1002/ana.10713. ISSN 0364-5134. PMID 14520669.
12. ↑ "Limbic encephalitis". The Encephalitis Society. Archived from the original on 2020-05-06. Retrieved 2017-12-23.
13. ↑ Anderson, N. E.; Barber, P. A. (September 2008). "Limbic encephalitis - a review". Journal of Clinical Neuroscience. 15 (9): 961–971. doi:10.1016/j.jocn.2007.12.003. ISSN 0967-5868. PMID 18411052.
14. ↑ 14.0 14.1 14.2 Gultekin SH, Rosenfeld MR, Voltz R, et al. (2000). "Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients". Brain. 123 (7): 1481–1494. doi:10.1093/brain/123.7.1481. PMID 10869059.
15. ↑ Graus F, Saiz A (2005). "Limbic encephalitis: a probably under-recognized syndrome". Neurologia. 20: 24–30.
16. ↑ Castle J, Sakonju A, Dalmau J, et al. (2006). "Anti-Ma2-associated encephalitis with normal FDG-PET: a case of pseudo-Whipple's disease". Nat Clin Pract Neurol. 2 (10): 566–572. doi:10.1038/ncpneuro0287. PMID 16990830.
17. ↑ Koide R, Shimizu T, Koike K, et al. (2007). "EFA6A-like antibodies in paraneoplastic encephalitis associated with immature ovarian teratoma: a case report". J Neurooncol. 81 (1): 71–74. doi:10.1007/s11060-006-9200-7. PMID 16807779.
18. ↑ Dalmau J, Tuzun E, Wu HY, et al. (2007). "Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma". Ann Neurol. 61 (1): 25–36. doi:10.1002/ana.21050. PMC 2430743. PMID 17262855.
19. ↑ Buckley C, Oger J, Clover L, et al. (2001). "Potassium channel antibodies in two patients with reversible limbic encephalitis". Ann Neurol. 50: 73–78. doi:10.1002/ana.1097. PMID 11456313.
20. ↑ Vincent A, Buckley C, Schott JM, et al. (2004). "Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis". Brain. 127 (3): 701–712. doi:10.1093/brain/awh077. PMID 14960497.
21. ↑ Thieben MJ, Lennon VA, Boeve BF, et al. (2004). "Potentially reversible auto-immune limbic encephalitis with neuronal potassium channel antibody". Neurology. 62 (7): 1177–1182. doi:10.1212/01.WNL.0000122648.19196.02.
22. ↑ Nicholas, D (2003). "Clinical, Magnetic Resonance Imaging, and 7Electroencephalographic Findings in Paraneoplastic Limbic Encephalitis". Mayo Clinic Proceedings. 78 (11): 1363–1368. doi:10.4065/78.11.1363. PMID 14601695.
23. ↑ Horst, Urbach (2006). "Serial MRI of limbic encephalitis". Neuroradiology. 48 (6): 380–386. doi:10.1007/s00234-006-0069-0. PMID 16586118.
24. ↑ Cózar Santiago, Maria Del Puig; Sanchez Jurado, Raul; Sanz Llorens, Rut; Aguilar Barrios, Jose Enrique; Ferrer Rebolleda, Jose (2016-02-01). "Limbic Encephalitis Diagnosed With 18F-FDG PET/CT". Clinical Nuclear Medicine. 41 (2): e101–103. doi:10.1097/RLU.0000000000001076. ISSN 1536-0229. PMID 26571448.
25. ↑ Corsellis, JA (1968). "Limbic encephalitis" and its association with carcinoma". Brain. 91 (3): 481–96. doi:10.1093/brain/91.3.481. PMID 5723018.
26. ↑ Dalmau, Josep; Gleichman, Amy J.; Hughes, Ethan G.; Rossi, Jeffrey E.; Peng, Xiaoyu; Lai, Meizan; Dessain, Scott K.; Rosenfeld, Myrna R.; Balice-Gordon, Rita (2008-12-01). "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies". The Lancet. Neurology. 7 (12): 1091–1098. doi:10.1016/S1474-4422(08)70224-2. ISSN 1474-4422. PMC 2607118. PMID 18851928.

## External links[edit | edit source]

Classification|

* ICD-10: G04.81
* ICD-9-CM: 323.81
* MeSH: D020363
* DiseasesDB: 30707
* SNOMED CT: 230192003

|

External resources|

* Orphanet: 163892

* v
* t
* e

Paraneoplastic syndromes

Endocrine|

* Hypercalcaemia
* SIADH
* Zollinger–Ellison syndrome
* Cushing's syndrome

Hematological|

* Multicentric reticulohistiocytosis
* Nonbacterial thrombotic endocarditis

Neurological|

* Paraneoplastic cerebellar degeneration
* Encephalomyelitis
* Limbic encephalitis
* Opsoclonus
* Polymyositis
* Transverse myelitis
* Lambert–Eaton myasthenic syndrome
* Anti-NMDA receptor encephalitis

Musculoskeletal|

* Dermatomyositis
* Hypertrophic osteopathy

Mucocutaneous|

| reactive erythema|

* Erythema gyratum repens
* Necrolytic migratory erythema

|

papulosquamous|

* Acanthosis nigricans
* Ichthyosis acquisita
* Acrokeratosis paraneoplastica of Bazex
* Extramammary Paget's disease
* Florid cutaneous papillomatosis
* Leser-Trélat sign
* Pityriasis rotunda
* Tripe palms

Other|

* Febrile neutrophilic dermatosis
* Pyoderma gangrenosum
* Paraneoplastic pemphigus

* v
* t
* e

Diseases of the nervous system, primarily CNS

Inflammation|

| Brain|

* Encephalitis
* Viral encephalitis
* Herpesviral encephalitis
* Limbic encephalitis
* Encephalitis lethargica
* Cavernous sinus thrombosis
* Brain abscess
* Amoebic

|

Brain and spinal cord|

* Encephalomyelitis
* Acute disseminated
* Meningitis
* Meningoencephalitis

Brain/
encephalopathy|

| Degenerative|

| Extrapyramidal and
movement disorders|

* Basal ganglia disease
* Parkinsonism
* PD
* Postencephalitic
* NMS
* PKAN
* Tauopathy
* PSP
* Striatonigral degeneration
* Hemiballismus
* HD
* OA

* Dyskinesia
* Dystonia
* Status dystonicus
* Spasmodic torticollis
* Meige's
* Blepharospasm
* Athetosis
* Chorea
* Choreoathetosis
* Myoclonus
* Myoclonic epilepsy
* Akathisia

* Tremor
* Essential tremor
* Intention tremor
* Restless legs
* Stiff-person

|

Dementia|

* Tauopathy
* Alzheimer's
* Early-onset
* Primary progressive aphasia
* Frontotemporal dementia/Frontotemporal lobar degeneration
* Pick's
* Dementia with Lewy bodies
* Posterior cortical atrophy

* Vascular dementia

Mitochondrial disease|

* Leigh syndrome

Demyelinating|

* Autoimmune
* Inflammatory
* Multiple sclerosis
* For more detailed coverage, see Template:Demyelinating diseases of CNS

Episodic/
paroxysmal|

| Seizures and epilepsy|

* Focal
* Generalised
* Status epilepticus
* For more detailed coverage, see Template:Epilepsy

|

Headache|

* Migraine
* Cluster
* Tension
* For more detailed coverage, see Template:Headache

Cerebrovascular|

* TIA
* Stroke
* For more detailed coverage, see Template:Cerebrovascular diseases

Other|

* Sleep disorders
* For more detailed coverage, see Template:Sleep

CSF|

* Intracranial hypertension
* Hydrocephalus
* Normal pressure hydrocephalus
* Choroid plexus papilloma
* Idiopathic intracranial hypertension
* Cerebral edema
* Intracranial hypotension

Other|

* Brain herniation
* Reye syndrome
* Hepatic encephalopathy
* Toxic encephalopathy
* Hashimoto's encephalopathy

Both/either|

| Degenerative|

| SA|

* Friedreich's ataxia
* Ataxia–telangiectasia

|

MND|

* UMN only:
* Primary lateral sclerosis
* Pseudobulbar palsy
* Hereditary spastic paraplegia

* LMN only:
* Distal hereditary motor neuronopathies
* Spinal muscular atrophies
* SMA
* SMAX1
* SMAX2
* DSMA1
* Congenital DSMA
* Spinal muscular atrophy with lower extremity predominance (SMALED)
* SMALED1
* SMALED2A
* SMALED2B
* SMA-PCH
* SMA-PME
* Progressive muscular atrophy
* Progressive bulbar palsy
* Fazio–Londe
* Infantile progressive bulbar palsy

* both:
* Amyotrophic lateral sclerosis

*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template