Revisão crítica e atualizações em encefalites autoimunes: entendendo a sopa de letrinhas

Simabukuro, Mateus Mistieri; Silva, Guilherme Diogo da; Castro, Luiz Henrique Martins; Lucato, Leandro Tavares

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Sumário

INFLAMMATORY AND DEMYELINATING DISEASE • Arq. Neuro-Psiquiatr. 80 (5 Suppl 1) • Maio 2022 • https://doi.org/10.1590/0004-282X-ANP-2022-S122 copiar

Revisão crítica e atualizações em encefalites autoimunes: entendendo a sopa de letrinhas

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

As encefalites autoimunes compreendem um grupo de doenças mediadas por anticorpos contra antígenos de superfície neuronal ou sinapse, como canais iônicos ou receptores de neurotransmissores. Novas síndromes clínicas e os anticorpos a elas associados foram e ainda estão sendo caracterizados ao longo das últimas duas décadas. Dado que suas principais características clínicas são interdisciplinares, isto é, incluem -se sintomas neuropisquiátricos, disfunção cognitiva, crises epilépticas, distúrbio do movimento e do sono, há uma grande onda de interesse sobre esse campo de conhecimento. Algumas dessas doenças apresentam-se com uma síndrome bem definida, sendo possível reconhecê-las clinicamente. Diagnosticá-las corretamente é importante uma vez que se trata de doenças potencialmente tratáveis apesar da gravidade que lhes é característica. Por outro lado, o número crescente de anticorpos sendo descritos causam dúvida frequente sobre qual o melhor teste a solicitar e como interpretá-los. Nós aqui apresentamos uma revisão atualização resumida do conhecimento atual sobre as encefalites mediadas por anticorpos.

Palavras-chave:
Encefalite; Encefalite Anti Receptor de N-Metil-D-Aspartato; Encefalite Límbica; Síndromes Paraneoplásicas do Sistema Nervoso.

High-risk phenotype (formerly classical paraneoplastic neurological syndromes)	Clinical features	Antibody associations	Tumor associations	Differential Diagnosis
Encephalomyelitis (EM)	Clinical dysfunction of multiple levels of nervous system, including peripheral involvement, for example EM with peripheral neuropathy, EM with sensory neuronopathy (SNN)	Hu (also called antineuronal nuclear antibody 1, ANNA-1) or CV2/collapsin response-mediator protein 5 (CRMP5) antibodies	SCLC >> NSCLC, other neuroendocrine tumors, and neuroblastoma	Meningeal carcinomatosis (meningeal enhancement, low glucose or presence of tumoral cells in CSF), Neurosarcoidosis (systemic involvement may be shown by FDG-PET, biopsy showing non-caseating granulomas)
Limbic encephalitis	Diagnostic Criteria (Graus 201626. Graus F, Dalmau J. Role of 18F-FDG-PET imaging in the diagnosis of autoimmune encephalitis - Authors’ reply. Lancet Neurol . 2016 Sep 1;15(10):1010. https://doi.org/10.1016/S1474-4422(16)30130-2 https://doi.org/10.1016/S1474-4422(16)30... ) Diagnosis can be made when all four* of the following criteria have been met: 1 Subacute onset (rapid progression of less than 3 months) of working memory deficits, seizures, or psychiatric symptoms suggesting involvement of the limbic system 2 Bilateral brain abnormalities on T2-weighted fluid-attenuated inversion recovery MRI highly restricted to the medial temporal lobes† 3 At least one of the following: • CSF pleocytosis (white blood cell count of more than five cells per mm3) • EEG with epileptic or slow-wave activity involving the temporal lobes 4 Reasonable exclusion of alternative causes *If one of the first three criteria is not met, a diagnosis of definite limbic encephalitis can be made only with the detection of antibodies against cell-surface, synaptic, or onconeural proteins.	High risk antibodies (frequency of cancer>70%)		Infections (Herpes simplex, Human herpesvirus-6, Neurossyphilis, Whipple) Autoimmune systemic diseases (System Lupus Erythematosus, Sj:ogren, Behçet, Relapsing Polychondritis) Gliomas Lymphoma Status epilepticus Chronic temporal lobe epilepsy
		Hu	SCLC >> NSCLC, other neuroendocrine tumors, and neuroblastoma
		Ma2	Testicular cancer (young men) and NSCLC in older patient (with both Ma1 and Ma2 positivity)
		High-Risk Antibodies (30-70% of association with cancer)
		AMPAR	SCLC and malignant thymoma
		GABABR	SCLC (Paraneoplastic cases are more commonly observed in elderly men and smokers with associated anti-KCTD16 antibodies. Most young patients are not paraneoplastic)

		Lower-Risk antibodies (<30%)
		Caspr2	When phenotype os CASOR2 in LE, almost always non paraneoplastic, but if phenotype is Morvan Syndrome, half is associated with tumor
		LGI1	Thymoma and neuroendocrine
		GLYR	Malignant thymoma and Hodgkin lymphoma
		GAD	SCLC, other neuroendocrine tumors, and malignant thymoma
		AK5
Rapidly progressive cerebellar syndrome	Previously known as subacute cerebellar degeneration Rapidly progressive, severe, bilateral, cerebellar symptoms. Sometimes extra cerebellar dysfunction maybe present, including brainstem	Anti-Yo (also known as Purkinje cell antibody -1, PCA-1)		Autoimmune cerebellar ataxia antibodies against GAD (glutamic acid decarboxylase), mGLUR1, GLUK2, antibodies gluten ataxia Cerebellar multiple system atrophy Creutzfeldt-Jakob Disease
		Anti-Ri (ANNA-2, ANNA = antineuronal nuclear antibody)	Breast > lung (SCLC and NSCLC) Breast Cancer in Women and lung cancer in men
		Tr (DNER - elta/notch-like epidermal growth factor related receptor)	Hodgkin lymphoma
		Ma2 and/or Ma	Testicular cancer (young men) and NSCLC in older patient (with both Ma1 and Ma2 positivity)
		KLHL11 (Kelch-like protein 11)	Testicular cancer in young men
Opsoclonus-myoclonus	Involuntary high frequence chaotic multidirectional saccadic movements + nonrhythmic action myoclonus on trunk, limbs and head. Additional features eg. Cerebellar signs and or encephalopathy may be present	-	50% of OMS in children are paraneoplastic and closely associated with neuroblastoma in adults paraneoplastic etiology accounts for 40% of cases. In adults Patients with breast cancer and OMS usually have Ri (ANNA-2 antibodies)	Idiopathic OMS (younger, prodromal symptoms of viral infection/vaccination, less frequently encephalopathy), drugs (lithium, amiytityline, cocaine, phenytoin with diazepam, phenelzine with imipramine, cyclosporin) Neonatal - transient Celiac disease Stem cell transplant HIV Multiple sclerosis Thalamic hemorrhage
Sensory neuropathy	the diagnosis of classical sensory neuronopathy should be considered if all the following criteria are present: - subacute onset with a Rankin score of at least 3 before 12 weeks of evolution, - onset of numbness, and often pain, - marked asymmetry of symptoms at onset, - involvement of the arms, proprioceptive loss in the areas affected, - and electrophysiological studies that show marked, but not restricted, involvement of the sensory fibers with absent sensory nerve action potentials in at least one of the nerves studied.	Hu	SCLC >> NSCLC, other neuroendocrine tumors, and neuroblastoma	Idiopathic (most frequent etiology, painless, onset on lower limbs) Sjögren ́s syndrome Cisplatin/oxaliplatin treatment (usually 1 month after therapy, “coasting phenomenon - progression of sensory loss even after cessation of chemotherapy
		CV2/CRMP5	SCLC and thymoma
		amphiphysin antibodies	SCLC and breast cancer
Gastrointestinal pseudo-obstruction	Recurrent episodes of abdominal pain, distension, constipation without evidence of mechanical obstruction Due to myenteric plexus dysfunction and may be accompanied by other signs of autonomic dysfunction, Sensory neuropathy or encephalomyelitis	Hu	SCLC >> NSCLC, other neuroendocrine tumors, and neuroblastoma	Chagas, Diabetes, Parkinson’s Disease, Scleroderma Mechanical obstruction
Lambert-Eaton Myasthenic Syndrome	Progressive proximal lower limb weakness, progressing to upper limbs, distal muscles and finally ocular and bulbar muscles, majority of patients develop autonomic dysfunction (dry mouth, erectile dysfunction, constipation). Absent muscles reflex, which improve after repeat exercise or maximal voluntary contraction (facilitation). EMG shows incremental response after high-frequency nerve stimulation.	antibodies against P/Q type voltage-gated calcium channels (VGCCs) are present in nearly 90% - not necessary for diagnosis.	Present in paraneoplastic and non paraneoplastic LEMS. DELTA-P score for predicting tumor association 1 point for the presence of each of the following items at or within 3 months from onset: age at onset ≥ 50 years, smoking at diagnosis, weight loss ≥ 5%, bulbar involvement, erectile dysfunction, and Karnofsky performance status lower than 70 (Delta P of 4 or more points correspond to >90% of presence of SCLC.	Idiopathic LEMS Myasthenia gravis
		SOX-1	Strongly associates with SCLC or paraneoplastic syndromes associated with SCLC

Antibody	Median Age/Sex ratio (Male to Female)	Main clinical features	Tumor association
NMDAR	21 (2 months- 85 year)/1:4	Clinical features on children’s presentation are usually with neurological symptoms: seizures and dyskinesias; in adults: behavioral changes.	Varies with age and sex Teratoma in almost 50% of young women (aged between 12-45 year) Rare in children and males (6%) titulaer 2013, Graus 202129. Graus F, Dalmau J. Autoimmune encephalitis or autoimmune psychosis? Eur Neuropsychopharmacol. 2021 Sep 1;50:112-4. https://doi.org/10.1016/j.euroneuro.2021.05.004 https://doi.org/10.1016/j.euroneuro.2021... Elderly patients (23%), but usually tumors are carcinomas (titulaer late onset)
LGI1	64 years (31-84 years)/2:1	Limbic encephalitis. subtle focal seizures (66%, autonomic or dyscognitive) and faciobrachial dystonic seizures (FBDS, 47%) mostly occurred before onset of cognitive deficits, hyponatremia (60%). MRI normal in 26% od patients, unilateral hippocampal T2/FLAIR hypersignal in 60%, bilateral in 14% CSF cell count and protein unremarkable in 75%	Malignant thymoma and neuroendocrine (<10% of cases)
CASPR2	66 years(25-77)/9:1	Morvan Syndrome and Limbic Encephalitis Seventy-seven percent of the patients had 3 or more of the following symptoms: encephalopathy (cognitive deficits/seizures), cerebellar dysfunction, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, or weight loss. May have a more protracted clinical course. Median time to nadir of disease was 4 months, and in 30% of patients in 1 year. Increased T2/FLAIR signal in medial temporal lobes in 45% of patients	Tumor association varies with the syndrome. When clinical is Morvan Syndrome, tumor (usually thymoma) if found in 50% of patients When associated with other syndromes, association is low
AMPAR	56 years (23-81)/1:2.3	Limbic encephalitis, Limbic encephalitis with multifocal or diffuse encephalopathy, in rare cases with prominent psychiatric features Increased T2/FLAIR signal in medial temporal loes in 67% of patients	SCLC and malignant thymoma Presence of tumor is higher when other onconeural antibodies occur simultaneously
GABAbR	61 year (16-77)/ 1.5:1	Limbic encephalitis, prominent seizures Increased T2/FLAIR signal in medial temporal lobes in 45% of patients	SCLC Tumor association is higher in elderly men, smokers and co-occurrence of anti-KCTD16 antibodies
GABAaR	40 years (2 mo-88 years); 1:1	Seizures, confusion, behavioral changes. Encephalitis with frequent status epilepticus Cortical and subcortical multifocal abnormalities	Thymoma, paraneoplastic origin is more frequent in adults (60%) than in children (10%)
mGLUR1	55 year (43-64)/1.3	Subacute cerebellar syndrome	30% most hematologic
mGLUR5	29 year (6-75)/ 1.5:1	Encephalitis, main clinical features are psychiatric (Ophelia Syndrome), cognitive , movement disorders, sleep dysfunction, and seizures MRI abnormalities usually involving extra limbic regions	Hodgkin lymphoma in approximately 50% of patients
DPPX	52 year (13-76)/ 2.3:1	Prodrome with diarrhea and weight loss. Encephalitis with hyperekplexia, myoclonus and tremors	B cell neoplasms(<10%)
Neurexin 3-alfa	44 year (23-57)/2:4	Encephalitis, patients may have history or laboratory findings suggestive of systemic autoimmunity, such as increased antinuclear antibodies (ANA), Raynaud < arthralgias	No associated cancer
GluK2	28 years (14-75 )/1.6:1	Encephalitis with prominent clinicoradiological cerebellar involvement, cases of patients with obstructive hydrocephalus)	Few published cases, 2 patients with tumor (Hodgkin’s lymphoma, ovarian teratoma) In this paper there 5 additional patients that had other antibodies concurrent with Gluk2 antibodies, in those 4 had tumors (3 thymoma, 1 small cell lung cancer)
GlyR	50 year(1-75) /1:1	PERM (progressive encephalopathy with rigidity and myoclonus), Limbic encephalitis	(<10%) Malignant thymoma and Hodgkin lymphoma
MOG	37 year (1-74) 1:1	Msost important biomarker of autoimmune encephalitis in children, other than ADEM spectrum, Imaging may resemble that of GABAaR e anti-dopamine 2 receptor ). Phenotype associated with bilateral cortical involvement and leukodystrophy-like has a poor prognosis In adults, beyond the well known presentation (ADEM, optic neuritis, transverse myelitis, demyelinating brain or brainstem syndromes) patients may have overlap with anti-NMDAR encephalitis or present with a benign, unilateral, cerebral cortical encephalitis with epilepsy	Low risk, only 5 cases reported, mostly teratomas
IgLON5	62 year (42-91) 1,25:1	distinctive sleep disorder in association with one or more of the following symptoms: bulbar dysfunction, gait difficulties, oculomotor abnormalities, chorea, or cognitive deterioration.

Probable
Rapid onset (<3 months) of at least four of the six major groups of symptoms: Group 1: Psychiatric symptoms: abnormal(psychiatric) behavior or cognitive dysfunction Group 2: Language: Speech dysfunction ( pressured speech, verbal reduction, or mutism) Group 3: Seizures Group 4: Movement disorders: dyskinesias, rigidity, or abnormal postures Group 5: Decreased level of consciousness Group 6: Autonomic dysfunction or central hypoventilation
And at least one of the laboratory studies: Abnormal EEG (focal or diffuse slow or disorganized activity, epileptic activity, or extreme delta brush) CSF with pleocytosis or oligoclonal bands
Or 3 of the above groups of symptoms and identification of a systemic teratoma
Exclusion of recent history of herpes simplex virus encephalitis or Japanese B encephalitis, which might result in relpasong immune-mediated neurological symptoms
Definite
One or more of the six major groups of symptoms and IgG GluN1 antibodies (antibody testing should include CSF); if only serum is available, confirmatory tests should be included (eg, live neurons or tissue immunohistochemistry, in addition to a cell-based assay)
Exclusion of recent history of herpes simplex virus encephalitis or Japanese B encephalitis, which might result in relapsing immune-mediated neurological symptoms

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[1] Correspondence:
Mateus Mistieri Simabukuro; Email: mateus.simabukuro@hc.fm.usp.br.