Limbic Encephalitis and Related Cortical Syndromes

Abstract

Patients with limbic encephalitis and related cortical syndromes develop neurologic and psychiatric symptoms due to autoimmune damage of limbic and extralimbic brain areas. Some patients develop limbic encephalitis as a paraneoplastic manifestation of systemic cancer, where immune tolerance is thought to be lost. Serum and cerebrospinal antibodies against neuronal antigens can be detected in most patients. According to the type of antibodies found, patients may be classified into two broad groups, with implications for neurological and cancer diagnosis, treatment and prognosis. Patients with antibodies to intracellular neuronal antigens (onconeuronal antibodies: Hu, Ma2, amphiphysin, CV2/CRMP5) almost invariably have an underlying neoplasm (lung, testis, breast, etc.), often require aggressive combined antineoplastic and immunomodulatory treatment and their prognosis is usually poor. Patients with antibodies to cell-membrane antigens may present with classical limbic encephalitis (anti-LGI1 antibodies, other) or with a more diffuse stereotyped encephalitis, combining psychiatric symptoms, seizures, dyskinesias, catatonia and central hypoventilation (NMDAR-encephalitis). These patients may or may not have an associated tumor (thymoma, ovarian teratoma, etc.), are likely to improve with immunomodulatory treatment (and tumor removal for paraneoplastic cases) and have, overall, a better prognosis. Immunotherapy in patients with limbic encephalitis may be escalated according to the severity of neurological symptoms, the associated antibodies and the predicted success of antineoplastic treatment. First-line immunotherapies include high dose steroids, intravenous immunoglobulins and plasma exchange. Second-line drugs include Rituximab and Cyclophosphamide. For some patients, maintenance treatment with immunosuppressants might be required to prevent deterioration or relapses. Supportive treatment includes antiepileptic drugs, psychopharmacologic agents and scrutiny and prophylaxis of opportunistic infections.

Autoimmune limbic encephalitis presenting as relapsing psychosis

“…Nonetheless, the successful reversal of symptoms in those individuals with a primarily psychiatric presentation7 9 26 has highlighted the importance of maintaining vigilance for this disorder as an organic cause of psychosis. Similarly, the initial co-occurrence of acute psychosis accompanied by episodic memory impairment, seizures or a movement disorder is suggestive of antibody-mediated encephalitis particularly if initial infective and neoplasm screens are negative 5 14 27. While the application of NMDAR antibody testing to chronic schizophrenia has been less rewarding,28 our case further highlights the need to consider this condition not only in those with initial psychosis4 10 26 but also in the setting of relapsing positive psychotic symptoms allied to progressive cognitive decline 25…”

“…Current guidance suggests the application of first-line immunotherapy in instances where initial clinical, MRI or CSF evaluation supports the diagnosis of autoimmune encephalitis 27 42. This initially involves a combination of high-dose intravenous methylprednisolone (1 mg/day for 5 days) and intravenous immunoglobulin (2 g/kg over 3 days).…”

“…seropositive, brain biopsy), more aggressive second-line therapies are considered, which may include rituximab and cyclophosphamide. Given the known higher relapse rate and likelihood of poor outcomes in patients with autoimmune anti-NMDAR encephalitis, some authorities advocate early and aggressive immunotherapy with a low threshold for switching to second-line agents if there is no clinical response 4 27. However, currently there is no evidence to suggest that any particular first-line agent is of benefit over another and importantly no clear guidance on when to initiate long-term immunosuppression although mycophenylate mofetil, azathioprine4 27 and methotrexate 7 have been cited as reasonable choices in patients requiring a prolonged course of steroids or maintenance immunosuppression.…”

“…Given the known higher relapse rate and likelihood of poor outcomes in patients with autoimmune anti-NMDAR encephalitis, some authorities advocate early and aggressive immunotherapy with a low threshold for switching to second-line agents if there is no clinical response 4 27. However, currently there is no evidence to suggest that any particular first-line agent is of benefit over another and importantly no clear guidance on when to initiate long-term immunosuppression although mycophenylate mofetil, azathioprine4 27 and methotrexate 7 have been cited as reasonable choices in patients requiring a prolonged course of steroids or maintenance immunosuppression. Importantly, while both CSF and serum antibody titres are known to fall with effective immunotherapy, the present literature does not suggest this to be of particular relevance in patients with improving clinical parameters 4 7…”

Isolated Chorea Associated with LGI1 Antibody

“…Antibodies to LGI1 produce a syndrome of LE (e.g., amnesia, confusion, hallucinations, and sleep disturbances), hyponatremia, and facio-brachial dystonic seizures 2. This autoimmune condition is non-paraneoplastic3 and highly responsive to corticosteroids 1,2,4,5. Movement disorders related to LGI1 are rare but include parkinsonism,6 tremor,6 and generalized chorea7 but they uniformly accompany other signs of LE.…”