Limbic encephalitis
Last edited on : 26/09/2024
The limbic encephalitides (LE) are defined as a group of autoimmune inflammatory pathologies of the central nervous system characterized by an initially predominant temporal-mesial involvement. They are considered rare (epidemiology indeterminable) and are difficult to diagnose.
The majority of cases fall within the framework of a paraneoplastic neurological syndrome (related to the presence of an underlying cancer).
Their spontaneous prognosis is considered dreadful, and their response to treatments varies depending on the underlying neoplasia and the autoantibody involved.
Clinic
The clinical onset is generally acute to subacute (over a few days to a few weeks). However, severe hyper-acute forms mimicking herpes encephalitis or chronic forms mimicking a degenerative dementia are possible. Nevertheless, the description of the clinical characteristics of this pathology, which is quite stereotyped in the literature, should be relativized due to its rarity. Consequently, and due to the difficulty of diagnostic evocation, it is possible that mild cases manifesting as isolated memory, cognitive, or psychiatric disorders go unrecognized...
Common syndromic triad (limbic involvement, constant to varying degrees of expression, variable chronology of onset):
- Epilepsy: temporal epileptic seizures (often characterized by a sensation of ascending chest tightness followed by loss of contact and gestural and oral automatisms +- dystonic posture of the upper limb contralateral to the focus +- aphasia or dysphasia → postictal phase with confusion, aphasia and/or agitation, generalized tonic-clonic seizures (often brief with prolonged postictal state)], convulsive or non-convulsive status epilepticus.
- Memory disturbances predominantly affecting anterograde memory, constituting a true Korsakoff in the most severe cases.
- Psychiatric disorders (+- cognitive): mainly mood disorders, disinhibition, and hallucinations.
Variable symptomatology (extra-limbic involvement), often stereotyped according to the associated autoantibody:
Extra-limbic semiology |
Autoantibodies to suspect |
|---|---|
Sensory-predominant neuropathy |
Anti-Hu |
Myelopathy | |
Multi-focal involvement | |
Brainstem involvement |
Anti-Hu, anti-Ma2 |
Cerebellar syndrome |
Anti-Hu, anti-CV2, anti-GAD |
Pseudo-obstructive digestive syndrome | |
Stiff-person syndrome |
Anti-GAD, anti-amphiphysin |
Sensory-motor neuropathy |
Anti-CV2 |
Chorea | |
Sleep disturbances |
Anti-Ma2, anti-VGKC |
Hypothalamic-pituitary disorders |
Anti-Ma2 |
Neuromyotonia |
Anti-VGKC |
Facial dyskinesias |
Anti-NMDA |
Dystonic movements |
In the case of paraneoplastic limbic encephalitides, the presence of symptoms directly related to the neoplasia is rare, with the discovery of limbic encephalitis preceding the diagnosis of cancer in 70 to 90% of cases.
Immunological classification and associated cancers
As a principle, any limbic encephalitis justifies the performance of a thoraco-abdominopelvic CT scan and a PET-FDG-CT scan in search of an underlying neoplasia. Depending on the clinical picture and the type of antibodies highlighted, their repetition or other examinations may be justified.
Seropositive limbic encephalitides (≈ 80% of cases)
Type |
Main antibodies |
Frequency of associated neoplasms |
Associated neoplasms |
|---|---|---|---|
Intracellular target |
Anti-Hu |
> 95 % |
Small cell lung carcinoma |
|
Anti-Ma2 |
> 90 % |
Testicular > Small cell lung carcinoma | |
|
Anti-CV2 |
> 95% |
Small cell lung carcinoma > thymoma | |
|
Anti-amphiphysin |
> 80% |
Small cell lung carcinoma, breast | |
|
Anti-GAD |
Rare |
| |
|
Membrane target |
Anti-NMDA |
> 60% |
Ovarian teratoma |
|
Anti-AMPA |
> 70% |
Thymoma > breast > Small cell lung carcinoma | |
|
Anti-neurofilament |
> 50% |
Small cell lung carcinoma > thymoma | |
|
Anti-VGKC |
< 40% |
Small cell lung carcinoma > thymoma |
Today, we distinguish the following:
- Limbic encephalitis with intracellular-targeting antibodies (++ anti-Hu):
- suspected pathophysiological mechanism related to cellular immunity
- antibody levels not related to clinical severity, the antibody being merely a marker of the disease
- the vast majority of cases are paraneoplastic
- response to treatments is generally absent or poor.
- Limbic encephalitis with membrane-targeting antibodies:
- antibodies are thought to be directly pathogenic
- antibody levels directly related to clinical severity and therapeutic response
- paraneoplastic in ≈ 50% of cases
- treatment response is often good.
Some particular considerations:
- Limbic encephalitis with anti-Hu should generally be considered paraneoplastic, justifying the performance of iterative oncological assessments over an extended period. It typically progresses rapidly to a picture of multifocal encephalomyelitis with peripheral sensory involvement.
- Limbic encephalitis with anti-Ma2 is also generally to be regarded as paraneoplastic and is usually associated with diencephalic or brainstem involvement.
- Limbic encephalitis with anti-CV2 is also generally considered paraneoplastic. It is usually isolated or associated with sensory neuropathy.
- Limbic encephalitis with anti-NMDA is quite typical: female (90%) young (++ 30-40 years), prodromal flu-like syndrome (80%) followed within 2 weeks by psychiatric disorders (80%) of variable evolution (++ initial mood disorders → frequent hallucinations and delusions → possible evolution to catatonia) followed by abnormal movements (++ facial-buccal dyskinesias which are not evocative in the psychiatric context) and epileptic manifestations (75%). Specificities of complementary examinations: frequent hyponatremia, normal MRI in 50%, non-specific inflammatory CSF in 90%. Paraneoplastic in 60% of cases (ovarian or testicular teratoma in 90% of paraneoplastic cases → oncological assessment + pelvic MRI and/or endovaginal ultrasound + gynecological/urological advice).
- Limbic encephalitis with anti-VGKC is quite typical: massive memory disturbances and confusion/delirium (psychiatric disorders or non-convulsive status) dominating the clinical picture (great variety of associated signs). MRI is usually evocative with bilateral symmetric temporal-mesial hyperintensities in FLAIR. Treatment response is generally very favorable.
- “Anti-neuropile” antibodies are actually non-characterized antibodies, currently defined by an autoimmune reaction in the neuropile (grey matter between the cell bodies). Treatment response is variable.
- Limbic encephalitis with anti-amphiphysin, anti-GAD, and anti-AMPA are currently exceptionally described (case reports).
Seronegative limbic encephalitides (≈ 20% of cases)
A neoplasm is found in 15 to 20% of cases of limbic encephalitis where no autoantibody is identified, including Hodgkin's lymphomas. The evolution under treatment is variable.
Differential Diagnosis
The main confounding differential diagnoses of autoimmune limbic encephalitis are infectious encephalitides (++ herpes). More rarely, certain tumor lesions can also pose diagnostic problems.
In principle, any limbic encephalitis should be treated as an infectious encephalitis until microbiological examinations, including PCR, return negative.
Complementary Examinations
Objectives: positive diagnosis (MRI and blood biology being the most useful for this purpose), immunological typing (prognostic aim and guidance of oncological assessment), exclusion of differential diagnoses, search for cancers, symptomatic evaluation (electroencephalogram)
- Brain MRI (T1, FLAIR, spin echo, diffusion, gadolinium):
- It is abnormal in 80% of cases at the time of diagnosis
- T2 hyperintensities / FLAIR hippocampal ++ bilateral and symmetric, frequent involvement of nearby structures (amygdala, temporal poles, insulae). Frequent but slight contrast enhancement. Initial hippocampal edema giving way to atrophy. Rarely, involvement of various cortical areas. Never hemorrhage (if present → systematically suggest herpes encephalitis!).
- Main and sometimes indistinguishable radiological differential diagnosis: herpes encephalitis. Other differential diagnoses: tumors, Wernicke syndrome, toxic and metabolic encephalopathies,...
- Lumbar Puncture
- Formulation, cultures, PCR HSV and HHV6, immunoelectrophoresis, IgG/albumin index, pathological anatomy with immunophenotyping)
- Cerebrospinal fluid abnormal in 90% of cases
- Non-specific abnormalities: lymphocytic pleocytosis, hyperproteinorachia, oligoclonal bands, intrathecal synthesis of immunoglobulins
- Allows to argue various differential diagnoses: herpes encephalitis, carcinomatous meningitis, brain lymphoma, Wernicke-Korsakoff syndrome, metabolic encephalopathies, stroke
- Electroencephalogram:
- Abnormal in 90%. However, the abnormalities are generally non-specific
- Possible evocative abnormalities: bi-temporal independent pseudo-periodic spikes or slow waves, recruiting temporal discharges, electrical seizures
- Should be systematically performed in cases of proven limbic encephalitis with confusional syndrome to exclude a non-convulsive status
- Biology:
- Positive diagnosis: onconeural antibodies, lymphocyte typing
- For differential diagnosis: anti-TPO / Tg antibodies (SREAT?), ANA and ANCA (Sjögren's syndrome, systemic lupus erythematosus), serologies Lyme / HIV / syphilis, TSH / T3 / T4, blood glucose, electrolyte levels, renal and liver functions, hematology-CRP-ESR
- FDG-PET scan:
- Brain: rarely performed, often normal → to be reserved for cases of high suspicion with normal MRI to search for temporal hypermetabolism
- Whole body: systematic in search of neoplasia
- Thoraco-abdomino-pelvic CT scan: systematic in search of neoplasia
- Divers: variable examinations in search of specific neoplasias according to any identified onconeural antibody and/or differential diagnoses according to the clinical picture
Therapeutic Management - Treatments
There is no EBM but a relative consensus regarding the following management:
- Rapid and systematic oncological treatment in case of discovery of a neoplasm
- Immunological treatment
- Corticotherapy (e.g.: methylprednisolone 1 g/day IV for 3 to 5 days followed by oral corticosteroid therapy according to a tapering schedule)
- Immunosuppressants or monoclonal antibodies (cyclophosphamide, rituximab,…)
- Best theoretical indication for immunoglobulins and plasmapheresis: presence of membrane-targeting antibodies (NMDA, VGKC, AMPA)
- IV Immunoglobulins: 0.4 g/kg/day for 5 days – monthly treatments for six months (not reimbursed in Belgium for this indication)
- Plasmapheresis - number and frequency to be discussed with dialyzers
- Symptomatic management (antiepileptics, psychiatric treatment,...) and para-medical (social worker, physiotherapist,...)
It should be noted that as long as the infectious differential diagnoses have not been formally ruled out (cultures and PCR), it is reasonable to start and maintain empirical antiviral and antibiotic treatment regardless of the degree of clinical suspicion.
Prognosis
Given the rarity of this condition, we can only limit ourselves to general considerations:
- The prognosis related to the nature and stage of any underlying cancer is obviously decisive
- Regarding the prognosis specific to limbic encephalitis:
- the therapeutic response is all the more favorable the earlier the treatment is initiated
- the prognosis of limbic encephalitis associated with membrane-targeting antibodies seems better (frequently described reversibility under immunoglobulins or plasmapheresis +- oncological treatment) than those associated with antibodies directed against intracellular targets (very inconsistent and generally poor improvement). The prognosis of seronegative limbic encephalitides is intermediate.
Bibliography
Abboud H et al., Autoimmune (including paraneoplastic) encephalitis: Management, UpToDate, 2024
Bradley WG et al., Neurology in clinical practice, 5th ed., Butterworth-Heinemann, e-dition, 2007
Dalmau J et al., Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis, UpToDate, 2024
EMC, Traité de neurologie, Elsevier, 2018
Osborn AG, Diagnostic imaging : brain, Amirsys, USA, 2d ed., 2009