AUTOIMMUNE ENCEPHALITIS : CURRENT CONCEPTS

DR. PIYUSH OJHADM RESIDENT

DEPARTMENT OF NEUROLOGYGOVT MEDICAL COLLEGE, KOTA

• Acute encephalitis - debilitating neurological disorder • Develops as a rapidly progressive encephalopathy (usually in less than

6 weeks) caused by brain inflammation.

• Disease with diverse immunologic associations, clinical manifestations, and therapeutic outcomes.

• Estimated incidence of encephalitis ~ 5–10 per 100000 / year

• Affect individuals of all ages • Some syndromes preferentially affect young adults and children

(Armangue et al., 2012).

• Represents a significant burden to patients, families, and society.

HISTORY• Lymphocytic infiltration of the medial temporal lobe (??Limbic

encephalitis) in patients with a remote malignancy (Brierley et al., 1960)

• Brain et al first described Hashimoto’s thyroiditis - 1966 • Pathogenic autoantibodies described in diseases of the PNS

since 1970’s (Autoimmune myasthenia ,LEMS)• Gradual discovery of many antibodies• Vincent et al. 2004 – VGKC antibody complex

INDIAN LITERATURE

NEUROLOGY INDIA 2015;63;687-96

CLUES TO AN AUTOIMMUNE ETIOLOGY• Change in baseline neurologic function• Subacute onset (days to weeks) & Fluctuating course• Personal/family h/o organ- or non-organ-specific autoimmune

disorder• Systemic markers of autoimmunity : eg elevated ANA or TPO

antibodies• History of or concurrent malignancy• CSF studies : elevated WBC (<100 cells/µl), protein

(<100mg/dl), Ig G index, oligoclonal bands, synthesis rate• EEG : Focal abnormalities• MRI : T2/FLAIR abnormalities• PET Brain : areas of hypo/hypermetabolism• Response to immunosuppression• Identification of a neural autoantibody

NEURONAL NUCLEAR, CYTOPLASMIC AND NUCLEOLAR ANTIBODIES

EOM abnormalities – Vertical Gaze Plasy

ANTIBODIES TARGETING NEURAL ION CHANNELS AND RECEPTORS

CLASSIFICATION

• Autoimmune encephalopathies without Malignancy

• Paraneoplastic encephalopathies

NON-PARANEOPLASTIC AUTOIMMUNE ENCEPHALOPATHY

- Females >> Males

- Middle aged (Mean age ~ 59 yrs)

- Onset - Subacute 1-6 weeks

- Majority (91 %) have fluctuations

- Coexisting Systemic autoimmune disorder – 48% cases

• Subacute Dementia - Most common presentation

• Memory loss almost always present

• Seizures -33% cases

• Neuropsychiatric symptoms – 50 % patients

• Other features – Frontotemporal dementia like syndrome, stroke like episdoes

• Tremor and Myoclonus –frequent findings

INVESTIGATIONS :

• Infectious, Toxic/ Metabolic , Vascular , Structural causes are more common - So should be ruled out

• CBC ,ESR, CRP , Thyroid function tests, LFT, RFT, Vit B12

• Screening for Non specific Autoimmunity - ANA , ANCA , TPO• CSF examination – To rule out infectious causes (HSV PCR) ,

Neoplastic causes, 14-3-3 for CJD• CSF - Mild lymphocytic pleocytosis ,oligoclonal bands

IMAGING :• To exclude vascular disease , ICSOLs , other structural causes• In autoimmune encephalopathy – MRI typically normal or

involvement of Mesial temporal lobes• Subcortical white matter abnormalities or cortical ribbon

sign and basal ganglia similar to CJD

EEG :• Diffuse slowing or epileptiform abnormalities in the temporal

lobes • Non convulsive status epilepticus

• Antibody testing- NMDA/ VGKC

• Search for underlying Malignancy even without antibodies

• Patients with subacute or rapidly progressing Dementia should undergo antibody testing and receive a trial of steroids

• Biopsy may be required in some cases

IMAGING

MRI :• Mesial temporal hyperintensities, either unilateral or bilateral

with or without enhancement after gadolinium administration, are classic autoimmune limbic encephalitis findings.

• Normal imaging is common, particularly in the early illness stages

• Extratemporal abnormalities sometimes observed. • If lesions are not in a typical distribution or have avid

enhancement, other inflammatory (eg. neurosarcoidosis) or oncologic (eg. lymphoma) diagnoses should be considered.

FUNCTIONAL IMAGING :

• Global hypometabolism is the most common feature encountered in patients with autoimmune encephalopathies.

• However, focal hypometabolism can also be encountered.

• In instances where the patient has seizures, hypermetabolism can occur.

AUTOIMMUNE LIMBIC ENCEPHALITIS

• Characterised by rapid development of confusion, working memory deficit, mood changes, and often seizures.

• The subacute development of short-term memory loss - considered the hallmark of the disorder

• But can be overlooked because of the presence of other symptoms.

• CSF - mild-to-moderate lymphocytic pleocytosis (usually less than 100 WBCs / mm³) in 60–80% of patients

• CSF – elevated IgG index or oligoclonal bands ( 50% cases)

• Among all immunological subtypes of limbic encephalitis, patients with LGI1 antibodies present with a lower frequency of CSF pleocytosis (41%) or elevated CSF protein concentrations (47%) and rarely have intrathecal IgG synthesis.

• Absence of inflammatory changes in CSF of these patients might initially suggest a non-inflammatory encephalopathy.

• MRI – often shows increased signal on T2w FLAIR in the medial aspect of the temporal lobes.

• Although limbic encephalitis can occur with MRI evidence of unilateral involvement (or be normal), AAN doesnot consider these cases as definite limbic encephalitis unless specific antibodies are subsequently detected.

• Reason - several non-immune disorders may result in similar unilateral MRI abnormalities, including among others, seizures, herpes simplex virus encephalitis, or gliomas.

• MRI findings of immune-compromised patients with HHV-6-associated encephalitis can mimic precisely findings from patients with autoimmune limbic encephalitis, but the clinical setting is different and directs the diagnosis.

• By contrast, the findings in HHV encephalitis are less confined to the limbic system, can occur with haemorrhagic features, and often show restricted diffusion abnormalities and contrast uptake.

• Immunological subtypes established only by measurement of autoantibodies.

• Distinction among immunological subtypes important - those associated with onconeuronal antibodies are much less responsive to immunotherapy than those associated with cell-surface antibodies.

• Onconeuronal antibodies frequently occuring with limbic encephalitis are Hu and Ma2. (seropositive patients almost always have an underlying cancer)

• By contrast, the neuronal cell-surface antibodies more frequently associated with limbic encephalitis - LGI1, GABA B receptor and AMPA receptor antibodies.

• Antibodies against the intracellular antigen Glutamic acid decarboxylase (GAD) occur in a subgroup of patients with limbic encephalitis.

• Mainly young women (median age 23 years) with predominant seizures and no evidence of cancer.

• The risk of cancer, usually SCLC or thymoma, is higher, however, among patients with GAD antibodies and limbic encephalitis who are older than 50 years or have concomitant GABA B receptor antibodies.

ANTI-NMDAR ENCEPHALITIS

• Most frequent antibody-associated encephalitis • 2nd MC immune-mediated encephalitis after ADEM

(Granerod et al., 2010)• MC in young women and children (80% cases) (F>>M)• F>>M less evident in children < 12 years and adults > 45 years. • Highly characteristic , occurs in multiple stages• Acute psychiatric symptoms, seizures, memory deficits,

decreased level of consciousness, and dyskinesias (orofacial, limb, and trunk) (Dalmau et al., 2008).

• Autonomic instability (50% cases - central hypoventilation often requiring mechanical ventilation)

• Many patients initially evaluated by psychiatric services.

• Children – may present with mood and behavioral change at times with new onset seizures, movement disorders, insomnia, or reduction of speech.

• Partial syndromes with predominant psychiatric symptoms or abnormal movements, and less severe phenotypes can occur

• Although almost all patients eventually develop several elements of the syndrome (Kayser et al., 2013)

• Atypical symptoms such as cerebellar ataxia or hemiparesis may occur (children > adults)

• By the end of the first month, 498 (87%) of 571 patients had four or more of the following categories of symptoms (from highest-to-lowest frequency) :– Abnormal behaviour and cognition– Memory deficit– Speech disorder– Seizures– Abnormal movements (orofacial, limb, or trunk dyskinesias) – loss of consciousness or autonomic dysfunction– Central hypoventilation; and – cerebellar ataxia or hemiparesis.

• Only six patients (1%) had one category of symptoms.

Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12: 157–65.

• Approximately 45% of females > 18 years – U/L or B/L ovarian teratomas compared to < 9% of girls < 14 years age.

• Younger children and men only rarely have tumors. • Isolated reported cases - teratoma of the mediastinum, SCLC,

Hodgkin lymphoma, neuroblastoma, Ca breast , and GCT testis

• 80% patients - CSF -> lymphocytic pleocytosis and less commonly, increased proteins and/or oligoclonal bands.

• 35% patients -> increased signal on MRI FLAIR or T2 sequences and less often, faint or transient contrast enhancement of the cerebral cortex, overlaying meninges, basal ganglia, or brainstem

• Abnormal EEG (90%) - generalized slow or disorganized activity without epileptic discharges that may overlap with electrographic seizures.

• 30% patients - unique EEG pattern called extreme delta brush due to its similarity to the delta brush pattern seen in neonatal EEG (Schmitt et al., 2012).

• Diagnosis - demonstration of NMDAR antibodies in CSF and serum

• Antibodies are IgG subtype and target the GluN1 (previously called NR1) subunit of the NMDAR.

BICKERSTAFF BRAINSTEM ENCEPHALITIS• Characterised by subacute onset, < 4 weeks, of progressive

impairment of consciousness along with ataxia and bilateral, mostly symmetrical, ophthalmoparesis.

• Usually preceded by an infectious event, runs a monophasic course, and has a good outcome.

• Additionally, patients frequently develop pupillary abnormalities, bilateral facial palsy, Babinski’s sign, and bulbar palsy.

• Generalised limb weakness can occur, which overlaps with features of GBS.

• CSF pleocytosis occurs in 45% patients.

• Brain MRI usually normal, but brainstem abnormalities on T2w FLAIR imaging present in 23% of patients.

• IgG anti-GQ1b antibodies are highly specific for this entity and related Miller-Fisher syndrome (GQ1b antibody syndrome)

• ~ 32% patients - no detectable antibodies.

ANTI CASPR2 ASSOCIATED ENCEPHALITIS• Contactin-associated protein-like 2 (CASPR2) antibodies • Usually develop Morvan syndrome• Symptoms involving both – CNS - encephalopathy, hallucinations, seizures, insomnia,

autonomic dysfunction) and – PNS - PNH-cramps,myokymia,fasciculations, neuropathy,

allodynia (Lancaster et al., 2011).

• > 50 % complain of neuropathic pain while some develop severe insomnia

• Patients may have other coexisting immune-mediated disorders such as myasthenia gravis with AChR or MuSKantibodies (Fleisher et al., 2013).

• MRI – often normal

• Tumor Screening – Thymoma

• Good response to immunotherapies

ANTI AMPA RECEPTOR ENCEPHALITIS

• Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)

• Predominantly affects middle-aged women (median~ 60 yrs)• Subacute (<8 weeks) symptoms of limbic encephalitis

including confusion, disorientation, and memory loss often associated with prominent psychiatric symptoms – may be confused with Acute Psychosis

• Seizures - < 50 % cases • Syndrome lacks movement disorders, autonomic dysfunction

& hypoventilation

• Approx 70% - underlying tumor in the lung, breast, or thymus.• Antibodies target the GluR1/2 subunits of the AMPAR. • MRI brain - usually shows abnormal FLAIR signal involving the

medial temporal lobesCSF - lymphocytic pleocytosis. • Majority respond to immunotherapy• About 50% have relapses. • Those with relapses usually respond to treatment but these

responses are often partial, resulting in cumulative memory or behavioral deficits.

• Role of chronic immunosuppression in preventing or reducing the risk of relapses – not clear

ANTI LGI1 LIMBIC ENCEPHALITIS• LGI1 - leucine-rich glioma inactivated 1 (Previously described

as targeting the voltage-gated potassium channel (VGKC).• Predominantly Older men (M:F~3:1, median age 60 years)• Develop memory loss, confusion, and temporal lobe seizures. • Approx. 60% - hyponatremia(SIADH) and less often REM

sleep behavior disorders - additional clues in formulating the differential diagnoses (Lai et al., 2010).

• Some patients develop brief tonic or myoclonic-like Faciobrachial dystonic seizures(FBDS) (40%) that precede the memory and cognitive deficits

• Autonomic symptoms ~ 10 %• May develop additional symptoms of peripheral nerve

hyperexcitability (PNH) (Morvan syndrome).

Faciobrachial dystonic seizures in an LGI1 VGKC-complex antibody-mediated encephalitis

• Rapidly progressive memory disturbance along with myoclonic-like movements can lead to the suspicion of rapid onset dementia such as CJD

• Usually no cancer associated and < 10% have an underlying neoplasm(Thymoma)

• MRI shows findings typical of limbic encephalitis. • CSF usually normal, although mild inflammatory changes or

oligoclonal bands may be present• Antibodies almost always detectable in both serum and CSF.• 80% patients - substantial responses to immunotherapy• Mild deficits common• Relapses occur in about 20% of the patients.

ANTI-GABAB ENCEPHALITIS

• Male = female• > 50% cases – associated tumor – almost always SCLC• Presenting features - almost always those of typical limbic

encephalitis -> memory loss, confusion, and prominent seizures (Hoftberger et al., 2013)

• Rarely - ataxia or opsoclonus-myoclonus as presenting complaint – gradually evolve to limbic encephalitis.

• MRI brain - abnormal in 2/3 cases – U/L or B/L medial temporal lobe FLAIR/T2 signal consistent with limbic encephalitis.

• CSF - lymphocytic pleocytosis.

• Majority of patients receiving immunotherapy have full or substantial recoveries, including cases where treatment was delayed by several months.

• For patients with cancer the neurological outcome appears dependent on successful treatment of the tumor.

ANTI-GABAA ENCEPHALITIS

• Rapidly progressive, severe encephalopathy that result in refractory seizures (Petit-Pedrol et al., 2014)

• Extensive MRI abnormalities on FLAIR and T2 imaging with multifocal cortical-subcortical involvement without contrast enhancement.

• Autoimmune encephalitis should be included in the differential diagnosis of any patient, especially if young, with a rapidly progressive encephalopathy of unclear origin.

• Any immunological type of autoimmune encephalitis can have a relapsing course and therefore the diagnosis of these disorders should be considered in patients with a past history of encephalitis or relapsing encephalopathy.

DIFFERENTIAL DIAGNOSIS

DIFFERENTIAL DIAGNOSIS

THANK YOU

REFERENCES

• Bradley’s Neurology in clinical practice 6th edition• Continuum Review Article : Autoimmune

Encephalopathies and dementias : April 2016• Seminars in Neurology : Autoantibody associated

CNS Neurologic Disorders : August 2016• A clinical approach to diagnosis of Autoimmune

Encephalitis : Lancet Neurol 2016;15;391-404

• Susac syndrome - usually have multiple hemispheric white matter lesions involving the corpus callosum, somewhat mimicking multiple sclerosis, but with prominent, extensive leptomeningeal enhancement.

• Rapidly resolving large hemispheric T2 abnormalities - should raise concern for a mitochondrial disorder, such as MELAS.

• Nonenhancing posterior predominant white matter lesions – consider progressive multifocal leukoencephalopathy.

• Cortical ribbon hyperintensities can be observed in some patients (and thus may be misleading for CJD).

ACUTE DISSEMINATED ENCEPHALITIS

• A monophasic, inflammatory disease of the CNS

• Mainly occurs in children and adults < 40 years.

• The disorder can be preceded by an acute systemic infection or vaccination.

• Characterised by a variable extent of encephalopathy , and other neurological signs, such as cranial nerve palsies, ataxia, hemiparesis, myelopathy, or optic neuritis.

• CSF - typically shows mild pleocytosis (less than 50 lymphocytes per mm³), but CSF oligoclonal bands are uncommon (less than 7% of all cases).

• Brain - multiple, large (>2 cm) abnormalities on T2w FLAIR imaging that can be present in the supratentorial white matter, basal ganglia, brainstem, cerebellum, and spinal cord, with or without contrast enhancement.

• No specific biomarkers of ADEM.

• Evidence exists that Myelin oligodendrocyte glycoprotein (MOG) antibodies can transiently occur in almost 50% of children with ADEM.

• At present, the inclusion of MOG antibodies in the diagnostic criteria for ADEM is not considered for two reasons: – The antibodies can be present in demyelinating disorders

with encephalopathy, but without MRI features of ADEM, or in patients with demyelinating disorders without encephalopathy and

– antibody testing remains unavailable at many centres.

SUSAC SYNDROME :-

• A rare, but important, D/D in patients who meet criteria for possible autoimmune encephalitis and have MRI features of demyelination.

• Considered an autoimmune vasculopathy resulting in microvessel thromboses at three levels: the brain, retina, and inner ear.

• In a review of 304 cases, 230 (76%) patients presented with encephalopathy, but simultaneous involvement of the three levels at disease onset occurred in only 31 of 247 (13%) patients.

• Diagnosis based on presence of branch retinal artery occlusions on fluorescein angiography, and MRI findings including snowball-like lesions or holes in the central portion of the corpus callosum and other periventricular white matter abnormalities on T2w FLAIR.

• MRI findings are different from those seen in ADEM and in the setting of encephalopathy are highly suggestive of Susac’s syndrome.