autoimmune encephalitis

AUTOIMMUNE ENCEPHALITIS

WHAT IS AUTOIMMUNE ENCEPHALITIS

• The immune reactions in brain depends on the

interaction between the immune system, innate (glial cells) or adaptive (lymphocytes), and nervous tissue and is modified by blood brain barrier.

• This interaction is seen in many diseases of the nervous system like the multiple sclerosis or neurodegenerative diseases

• A more specific form of autoimmunity in CNS is now recognized in the form of antibodies that bind to neuronal cell surface/synaptic receptors or ion channel related proteins.

• These antibodies are detected in adults as well as the children.

• The antigens, essential for cellular function and neurotransmission, are expressed to different extent in the CNS.

• The clinical signs may depend on the extent of brain regions targeted by the antibodies.

• The effects may be reversible and the patient may frequently recover.

• Some of these disorders may be paraneoplastic. These disorders are often known to be associated with cancer.

• They however differ from paraneoplastic encephalitis because in the latter, the antibodies affect the intracellular proteins such as Hu or CRMP5, and the T cell mechanisms lead to irreversible neuronal dysfunction.

• In contrast to classical paraneoplastic syndromes, these conditions respond to immunotherapy.

WHY IS IT IMPORTANT TO KNOW ABOUT AUTOIMMUNE ENCEPHALITIS

• Large multicentre trials e.g. UK encephalitis

study and California Encephalitis project, have demonstrated that almost one fifths of the acute or subacute encephalitis patients who are not detected to have an infection may be autoimmune encephalitis.

• This and the response to immunotherapy has led to a paradigm shift in approach to autoimmune encephalitis

DETECTION OF AUTOIMMUNE ENCEPHALITIS

• The key clinical features of the autoimmune encephalopathy are – seizures, – altered mental state- confusion, disorientation, – behavioral changes, – cognitive impairment, – movement disorders, – autonomic dysfunctions and – sleep disorders.

• There may be a preceding prodrome of headache and fever suggesting a viral illness.

• The symptoms overlap and the cause may not be apparent from history and examination.

• Seizures suggests a encephalitic process but the inflammation may not be evident in the radiological scans or cerebrospinal fluid. Hence encephalopathy is a more apt term, but may be used interchangeably with autoimmune encephalitis.

• The most specific and appropriate tests are cell based assays. These allow detection of antibodies binding epitopes of neuronal surface antigens in a manner similar to when the antigens are exposed in a circulating fluids.

• The antigen is transfected to a suitable human cell line and the mosaic of such fixed cells expressing different antigens may be used commercially.

• Alternatively, live cell assays can be developed but are much more time consuming.

• Both serum and csf may be used, however csf may yield much more positive results (given the normal ratio of serum to CSF immunoglobulin G levels of around 400). Besides serum is more sticky.

• Other methods such as IHC, immunoblotting and radioimmunoprecipitation assays can be used but have individual limitations.

WHEN TO SUSPECT AUTOIMMUNE ENCEPHALITIS

• Most clinicians rely on algorithm based parameters to support autoimmune or immune causes.

• This is more so since the threshold for considering immunotherapy becomes important.

• Autoimmune encephalitis should be considered in any patient 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.

• The final diagnosis relies upon identification of neuronal antibodies and/or positive response to immunotherapy.

• Attempts have been made to categorize the likelihood of autoimmune cause to definite, probable, or possible.

LIMITATIONS OF THE TESTS

• While the diagnosis is based on demonstration of antibodies, the tests may be negative frequently. One should consider the follows in the situation-

1. The samples are best taken when the patient is symptomatic and maximally affected. Outside the clinical event, the test may be negative. The tests may be repeated on samples previously collected.

2. The immunotherapy, once initiated may influence the results. Where plasmapheresis may result in false tests, use of immunoglobulins may actually yield false positive tests.

3. CSF samples yield a better report than the serum.4. It is possible that the test is negative because the precise

antigenic target has yet to be identified. Thus the absence on identification of a known antibody should not exclude the diagnosis of autoimmune encephalopathy or preclude initiation of treatment

CASE 1

• The patient a 26 year old female presented to the hospital with a history of – Altered speech and behavior,– Gradually increasing drowsiness,– Brief episode of mild fever,– Gradually progressive deterioration of sensorium.

• On examination,– Drowsy– Arousable with difficulty– Moving all 4 limb– Sensory system and cerebellar system could’nt be

examined– Reflexes were brisk.

• MRI Brain showed symmetrical T2/FLAIR

hyperintense signal involving bilateral medial thalamus, caudate, putamen, external and internal capsule, periaqueductal grey white matter, dorsal midbrain, left frontal white matter with patch DWI restriction with swelling of basa ganglia and patchy minimalenhancement suggestive of encephalitis.

• CSf was normal. An autoimmune panel was sent that later came out negative.

• The patient was considered to have possible autoimmune encephalitis.

• A course of steroids was initiated and her sensorium showed improvement.

TREATMENT OPTIONS

The treatment options include1. Removal or suppression of circulating

antibodies via plasma exchange or IvIg.2. Attenuate production of production of

autoimmune antibodies via steroids and other immunosuppressive therapy.

• Concomitant and early use of intravenous steroids and IVIGs and/or plasmapheresis are often effective in achieving control of symptoms and remission.

• There is no data supporting the use of IvIg over plasma exchange.

• Second line therapy with immunosuppresants may yield additional benefits when first line therapy fails e.g. rituximab and/or cyclophosphamide. Prompt initiation of second line drugs is recommended if the first line therapy fails.

• If the patient remains symptomatic despite first- and second-line treatment, repeated and combination therapeutics may help.

• Treatment of tumours, if associated, helps recovery and reduces the risk of relapses

CASE2

• A previously healthy four year old girl presented with – progressive gait instability of two weeks.

• She was clinically diagnosed as viral encephalitis and empirically treated with acyclovir at a centre.

• MRI brain and cerebrospinal fluid (CSF) cell count, biochemical analysis and bacterial culture were normal.

• There was progression of her disease activity. – developed generalized tonic clonic seizures, – choreoathetoid movements, and – aphasia over the next 2 weeks.

• On admission she was – disoriented, – Aphasic– Glasgow coma scale was 8/15– had choreoathtoid movements involving all the limbs, – hypotonia, – quadriparesis – brisk deep tendon reflexes and extensor plantar

response. – had multiple episodes of generalized tonic clonic

seizures.

• Investigations showed– liver and renal function test, serum electrolytes

were normal. – Repeat MRI brain was normal– CSF analysis showed normal protein, lymphocytic

pleocytosis, negative virology and bacterial culture.

– CSF NMDAR antibody was positive confirming the diagnosis of NMDAR encephalitis.

• She was treated with – IV Immunoglobulin (2gm/kg), – IV methyl prednisolone, – anticonvulsants and – supportive measures.

• Her involuntary movements decreased, though she continued to be unresponsive to surroundings with intermittent visual fixation and following. She also started having stereotypic movements. – Given 8 doses of rituximab (375mg/m2) at weekly

intervals.

• Gradually, – her sensorium improved, – involuntary movements decreased in intensity and – seizures were under control. – Child was discharged after 2 months of hospital

stay. • She was on immunosuppression with oral

prednisolone and at one month follow up, child was seizure free with persisting quadriparesis.

BRIEF REVIEW OF THE COMMONEST AUTOIMMUNE ENCEPHALITIS

NMDA receptor encephalitis

• The patient presents with – psychiatric symptoms, – seizures, – memory deficits, – altered sensorium, – dyskinesias, and – autonomic disturbances.

• It affects predominantly the young adults and teenagers with age related association to ovarian teratoma.

• The patients usually recover well with immunotherapy.

LIMBIC encephalitisThe syndrome shows antibodies to different targets

and the symptoms vary according to the site.1.GABA B receptor. • Patients have limbic encephalitis with

predominant seizures. • The patients are usually of advanced age

(approximately 62 years)• Associated SCLC or neuroendocrine tumors. • As many as 75% patients show partial to full

recovery with immunotherapy.

2.AMPA receptor. • The patients show limbic encephalitis with

predominant psychiatric symptoms. • They may have associated breast, lung or

thymus cancer. • Almost 70% patients show recovery with

immunotherapy but relapses are frequent.

3. LG1 receptor. • These patients present with hyponatremia,

REM behavior disorders and seizures- tonic or myoclonic.

• They are infrequently associated with thymoma

• 80% patients recover with immunotherapy but mild residual deficit may persist.

4. mGluR5 and mGluR1 receptor. • The patients are commonly found to have

association with Hodgkin's lymphoma• Recover well with immunotherapy.

GABA A receptor encephalitis

• Rapidly progressive severe encephalopathy with refractory seizures is a common presentation of these patients

• Commonly associated with other autoimmune conditions e.g. TPO and GAD antibodies.

• Patients have good response to treatment.• Medical complications of the status

epilepticus is common and can be fatal.

CASPAR2 receptor encephalitis.

• The patients present with Morvan syndrome and frequently have associated neuropathic pain.

• 70% of the patients show a full or substantial improvement.

TO RECAP, A FLOWCHART TO APPROACH