Autoimmune Encephalitis

Transcription

1 Evaluation Approach for Suspected Autoimmune Encephalitis M.R ASHRAFI PROFESSOR OF PEDIATRIC NEUROLOGY CHILDREN S MEDICAL CENTER PEDIATRIC CENTER OF EXCELLENCE TEHRAN UNIVERSITY OF MEDICAL SCIENCES TEHRAN / APR-2017

2 Introduction Encephalitis is a broad term encompassing any inflammatory disease process of the brain that manifests clinically with alterations of consciousness and/or behavioral changes. Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis.

3 Introduction The estimated incidence of encephalitis in high-income countries is about 5 10 per inhabitants per year. Encephalitis affects patients of all ages and represents a significant burden to patients, families, and society.

4 Introduction The most frequently recognized causes of encephalitis are infectious, however, in the past 10 years an increasing number of non-infectious, mostly autoimmune, encephalitis cases have been identified.

5 Introduction Acute encephalitis is a debilitating neurological disorder that develops as a rapidly progressive encephalopathy (usually in less than 6 weeks) caused by brain inflammation.

6 Autoimmune Encephalitis Autoimmune encephalitis comprises an expanding group of clinical syndromes that can occur at all ages (<1 y to adult) but preferentially affects younger adults and children. Autoimmune conditions are not a common cause of encephalitis and despite a growing knowledge of AE, diagnosis is often considered late or not at all, resulting in poor outcomes.

7 Autoimmune Encephalitis Diagnosis Autoimmune encephalitis causes subacute deficits of memory and cognition, often followed by suppressed level of consciousness or coma. A careful history and examination may show early clues to particular autoimmune causes.

8 Autoimmune Encephalitis Diagnosis Ancillary testing with CSF analysis, brain MRI and EEG may be helpful for excluding other causes, managing seizures, and, rarely, for identifying characteristic findings. Appropriate autoantibody testing can confirm specific diagnoses, although this is often done in parallel with exclusion of infectious and other causes.

9 Evaluation approach for suspected AE

10 Evaluation approach for suspected AE Presentation with an autoimmune encephalitis in childhood is often subacute, with a varied constellation of symptoms, such as loss of consciousness, cognitive disorder, movement disorders, memory loss and seizure disorders.

11 ANTI-N-METHYL-D-ASPARTATE RECEPTOR ENCEPHALITIS The exact frequency of this syndrome is unknown but anti-nmdar encephalitis is by far the most common type of antibody-mediated encephalitis in children. In this disorder, the antibodies target the NR1 subunit of the NMDA receptor. Eric Lancaster, J Clin Neurol 2016;12(1) : 1-13

12 Evaluation approach for suspected AE Glutamate is a powerful excitatory neurotransmitter that is released by nerve cells in the brain. The NMDAR is a specific type of ionotropic glutamate receptor. It is responsible for sending signals between nerve cells, and under normal conditions it plays an important role in learning and memory.

13 ANTI-N-METHYL-D-ASPARTATE RECEPTOR ENCEPHALITIS In teenagers and young adults, the disorder usually presents with prominent psychiatric manifestations that may include rapidly progressive anxiety, agitation, delusional thoughts, bizarre behavior, labile affect, mood disturbances (mania), catatonic features, memory deficit, language disintegration, aggression, and insomnia or other sleep disturbances. In many cases, these symptoms had been preceded by a few days of prodromal headache, fever or viral-like symptoms.

14 ANTI-N-METHYL-D-ASPARTATE RECEPTOR ENCEPHALITIS The disorder also occurs in toddlers and infants (the youngest patient identified to date was 6 mo). This age group more frequently present with decreased level of consciousness, seizures (including SE), limb or oral dyskinesias, choreoathetoid movements, and autonomic instability which usually includes tachycardia, bradycardia, fluctuations of blood pressure, hypoventilation, hyperthermia and sialorrhea. Behavior changes include irritability, new-onset temper tantrums, agitation, aggression, reduced speech, mutism, and autistic-like regression.

15 Clinical Scenario

16 Constellation of symptoms in Childhood AE ANTI-N-METHYL-D-ASPARTATE RECEPTOR ENCEPHALITIS LIMBIC ENCEPHALITIS HASHIMOTO ENCEPHALOPATHY BICKERSTAFF ENCEPHALITIS OPSOCLONUS MYOCLONUS AND OTHER BRAINSTEM CEREBELLAR ENCEPHALITIDES CLIPPERS (Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement responsive to steroids ) AUTOIMMUNE ENCEPHALOPATHIES ASSOCIATED WITH EPILEPSY AND STATUS EPILEPTICUS (Rasmussen encephalitis, FIRES) ROHHAD (Rapid onset obesity with hypothalamic dysfunction, hypoventilaion, and autonomic dysregulation) BASAL GANGLIA ENCEPHALITIS PMP (Pseudomigraine syndrome with CSF pleocytosis ) HaNDL ( Headache with neurologic deficits and CSF lymphocytosis)

17 Evaluation approach for suspected AE

18 Evaluation approach for suspected AE Several features that may support suspicion of an autoimmune etiology include : CNS inflammation MRI findings Clinical response to immunotherapy

19 Evaluation approach for suspected AE CNS Inflammation Concurrent inflammatory findings in the CSF, including the presence of oligoclonal bands, lymphocytic pleocytosis, and elevated protein, may be present but are relatively nonspecific.

20 Evaluation approach for suspected AE CNS inflammation / Anti NMDAR-AE The cerebrospinal fluid (CSF) is initially abnormal in 80% of patients and becomes abnormal later in the disease in most other patients. Findings include moderate lymphocytic pleocytosis, normal or mildly increased protein concentration, and, in 60% of patients, CSF-specific oligoclonal bands. Clinical experience and laboratory investigations in patients with anti-nmdar encephalitis, Josep Dalmau, et al, Lancet Neurol 2011; 10: 63 74

21 Evaluation approach for suspected AE In addition, the presence of elevated CSF neopterin may serve as a useful marker of inflammation and may be a more sensitive marker of inflammation than CSF pleocytosis.

22 Evaluation approach for suspected AE MRI findings Magnetic resonance imaging (MRI) of the CNS may also demonstrate abnormalities that provide clues for diagnosis, particularly on fluidattenuated inversion recovery (FLAIR) or T2-weighted images.

23 Evaluation approach for suspected AE MRI findings / AntiNMDAR - AE Brain MRI is abnormal in approximately 35 % of anti NMDA cases, usually showing nonspecific cortical and subcortical T2 and FLAIR signal abnormalities, sometimes with transient cortical or meningeal enhancement; and often nonspecific white matter abnormalities.

24 Evaluation approach for suspected AE MRI FLAIR sequence coronal view showing bilateral high-signal changes in mesial temporal lobes and insular cortices.

25 Evaluation approach for suspected AE

26 Evaluation approach for suspected AE EEG findings Ancillary testing with EEG may prove useful in patients with autoimmune or infectious encephalitis for excluding subclinical seizures, for prognosis, and sometimes for suggesting particular diagnoses.

27 Evaluation approach for suspected AE EEG often showing diffuse slowing and sometimes more focal or epileptiform changes. An EEG pattern of extreme delta brush has been described in anti-nmdar encephalitis and may be detected in up to 30% of adult. Although not pathognomonic, may support a diagnosis of anti-nmdar encephalitis.

28

29

30

31 Evaluation approach for suspected AE In addition to the above criteria, patients should be carefully examined for other diseases that can mimic autoimmune encephalitis and cause rapidly progressive encephalopathy. The most frequent differential diagnoses are herpes simplex virus encephalitis and other CNS infections. Importantly, CSF herpes simplex virus PCR can be negative if done too early (eg, within 24 h), and this test should be repeated if the clinical suspicion remains high.

32 Evaluation approach for suspected AE The differential diagnosis in pediatric autoimmune encephalitis is broad and includes : CNS infection Epileptic disorders Toxic / Drug ingestion Inborn errors of metabolism Primary psychiatric disease CNS vasculitis Neoplastic disease

33

34 Evaluation approach for suspected AE Existing diagnostic criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy. The diagnosis of definite autoimmune encephalitis greatly depends on the results of autoantibody tests.

35 Evaluation approach for suspected AE Antibody testing is not readily accessible in many institutions and results can take several weeks to obtain. Furthermore, the absence of autoantibodies does not exclude the possibility that a disorder is immune mediated, and a positive test does not always imply an accurate diagnosis. Therefore according to conventional neurological evaluation and standard diagnostic tests (eg, MRI, CSF, or EEG studies) allow the initiation of preliminary treatment while other studies and comprehensive antibody tests are processed and subsequently used to confirm the diagnosis.

36

37 Autoantibody Panels Pediatric autoimmune encephalitides with antibodies targeting neuronal cell surface antigens : Anti-NMDAR encephalitis AMPAR encephalitis Voltage-gated potassium channel complex encephalitides Anti-glycine receptor encephalitis Anti-gamma-aminobutyric acid type A receptor encephalitis Anti-gamma-aminobutyric acid type B receptor encephalitis Anti-dopamine D2 receptor encephalitis Ophelia syndrome

38 Evaluation approach for suspected AE The NMDA receptor is a heterotetramer comprised of two GluN1 subunits and two GluN2 / 3 subunits. Detection of IgG antibodies against the GluN1 subunit is a signature of anti-nmdar encephalitis. By contrast, antibodies against linear epitopes of GluN2 or GluN3 have been reported in many different disorders and their clinical significance is uncertain.

39 Evaluation approach for suspected AE The antibodies associated with autoimmune encephalitis are IgG antibodies. Detection of IgA or IgM antibodies against any of these antigens has unclear significance. For example, IgM or IgA antibodies against the GluN1 subunit of the NMDA receptor have been reported in the serum of 10% of patients with different disorders and in a similar proportion of healthy people.

40 Autoantibody Panels AMPA= α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (non-nmda-type glutamate receptor )

41 Autoantibody Panels VGKC : LGI1=leucine-rich glioma inactivated 1. CASPR2=contactin associated protein 2.

42 GAD=glutamic acid decarboxylase. Autoantibody Panels Pediatric autoimmune encephalitides with autoantibodies targeting intracellular antigens or onconeuronal antibodies : Anti-Hu encephalitis Anti-Ma2 encephalitis Anti-GAD associated encephalitis

43 Evaluation approach for suspected AE The diagnosis of the disorder is established by demonstrating antibodies in CSF or serum. The sensitivity is higher in CSF compared with serum (100% vs 85%), and the levels of antibodies in CSF appear to correlate better with outcome. Antibodies may remain detectable, albeit at lower titers, after patients recover.

44

45

46 CSF analysis shows mild to-moderate lymphocytic pleocytosis (usually less than 100 white blood cells per mm³) in 60 80% of patients, and elevated IgG index or oligoclonal bands in approximately 50% of cases.

47 Autoantibody Panels

48 Autoantibody Panels The mechanisms that trigger the production of the antibodies are unknown. In a small subgroup of adolescent or young adult patients, the presence of a tumor that expresses the target neuronal antigen likely contributes in triggering the immune response. In addition, the high prevalence of prodromal virallike symptoms has suggested that nonspecific viral infections may contribute to breaking immune tolerance and increase the permeability of the blood brain barrier to antibodies.

49

50 Evaluation approach for suspected AE A comprehensive investigation to exclude an underlying neoplasm should be considered in all cases. In adults, autoimmune encephalitis is commonly paraneoplastic, accompanied by the presence of an occult tumor that serves as a stimulus for autoantibody production.

51 Evaluation approach for suspected AE An ovarian teratoma is the most commonly associated tumor and is reported to be present in over half of adult female cases of Anti-NMDAR encephalitis. Testicular teratoma in male patients is rare. Extraovarian tumors can occur but are much more common in older adult cohorts.

52 Evaluation approach for suspected AE In childhood, nonparaneoplastic, antibodyassociated encephalitis is more commonly diagnosed. In pediatric anti-nmdar encephalitis, a unilateral or bilateral ovarian teratoma is discovered in approximately 30% of girls aged 18 years or younger and < 10% in girls less than 14 years.

53 Evaluation approach for suspected AE Because paraneoplastic encephalitis has been reported in children, searching for the neoplasms underlying many of the well-characterized autoimmune encephalitides remains essential and all female patients should undergo MRI of the abdomen and pelvis in search for an ovarian teratoma.

54 Take home message Autoimmune encephalitis is a difficult clinical diagnosis due to the similarities in the clinical, imaging and laboratory findings of many forms of autoimmune and infectious encephalitis.

55 Take home message Encephalitis by way of autoimmunity should be considered in the differential diagnosis of any pediatric patient presenting with unexplained encephalopathy of acute or subacute onset.

56 Take home message Despite a growing knowledge of autoimmune encephalitis (AE), this area remains poorly understood. Because of the Autoimmune encephalitis is a treatable cause of encephalitis, it is important to consider in patients with presenting sign and symptoms of encephalitis.

57 Clinical Scenario

58

59 Thank you For your Attention