Autoimmune Encephalitis

Autoimmune ParaneoplasticEncephalitisAntony (MBBS IV)So whats in a name?Paraneoplastic neurological syndromeAssociated with systemic cancer Not related to other mechanismsAutoimmune mediated

Autoimmune neurological syndromeNot necessarily paraneoplasticCan be associated with metabolic, infective etc.So whats in a name?YAutoimmunity? NPara-NeoplasticNot Para-NeoplasticOther stuff.

encephalitis3Clinical Autoimmune Paraneoplastic PhenotypesMyelitissensory/cord associated symptomatology

Limbic Encephalitismood and behavioural changes, cognitive dysfunction

Brainstem encephalitispons and/or medulla PathogenesisPerivascular and interstitial inflammatory infiltrates of T lymphocytes, gliosis, neuronophagic nodules, and loss of neurons

Most frequent neoplasms are cancer of the lung (usually SCLC), seminoma and other testicular tumours, thymoma, breast cancer, and Hodgkin lymphoma.

The most frequently associated antibody is the anti-Hu antibodyPathologic examination usually reveals perivascular and interstitial inflammatory infiltrates of T lymphocytes, gliosis, neuronophagic nodules, and loss of neurons. In addition to T-cell infiltrates, B-cells preferentially cluster around vessels and may be associated with plasma cell infiltrates

The most frequent neoplasms associated with paraneoplastic LE are cancer of the lung (usually SCLC), seminoma and other testicular tumours, thymoma, breast cancer, and Hodgkin lymphoma.

The most frequently associated antibody in AE is the anti-Hu antibody

The most common underlying tumour being small cell lung cancer (SCLC) in approximately 75 percent of paraneoplastic encephalomyelitis (or its variants) patients. This has been confirmed in four large case series comprising over 500 patients.

5Knock knock Hus there?Anti-Hu encephalomyelitis (ANNA-1)EpidemiologyThe median age of 63 years (range 2882 years) M>FSmall Cell Carcinoma Patients. 15% cannot identify a neoplasm.

PresentationMultifocalTemporal lobes, brainstem, cerebellum, dorsal roots, and/or autonomic nervous system Classically Sensory disturbanceAnti-neuronal Nuclear antibody 1 Epi: multifocal, affecting temporal lobes, brainstem, cerebellum, dorsal roots, and/or autonomic nervous system. In many patients, symptoms begin with, and may remain restricted, to the dorsal root ganglia, causing a subacute sensory neuronopathy Pres: Multifocal presentations. In many patients, symptoms begin with, and may remain restricted, to the dorsal root ganglia, causing a subacute sensory neuronopathy

6Anti-Hu encephalomyelitisPathologyHuD is an RNA binding protein only expressed in neuronal cellsTumour expression of Hu antigen = immunoreactivity

ManagementAnti-tumour therapy, Immunomodulation

PrognosisIndividual but prolonged survival can occur with regression of tumourPoor in terms of survival and neurological disabilityPath: HuD is an RNA binding protein only expressed in neuronal cells although reports that it has been found in mammalian pancreas b-islet cells too. Shown to regulate neuronal differentiation, maintenance and plasticity. More recently, insulin translation.Tumour expression of Hu antigen = immunoreactivity

Manag: Report by Shams'ili S

Prog: The prognosis of PEM remains poor in terms of survival and neurological disability. Review by Graus in 2001 of 200 patient suggest median survival of 11.8 months, with a 3-year actuarial survival of 20%

7Ma2 encephalitisEpidemiologyYoung Male patients with Testicular cancer

PresentationIsolated or combined limbic, diencephalic or brainstem encephalopathy Excessive daytime sleepiness and eye movement abnormalitiesAtypical/less common parkinsonism (T.R.A.P. etc.)

Ma2 encephalitisEpi: Pres: Excessive daytime sleepiness and eye movement abnormalities, particularly a vertical gaze paresis that sometimes evolved to total external ophthalmoplegia. Atypical/less common parkinsonism (Trem.Rigid.Ataxi.Postu. etc.) hypokinetic syndrome

Young men with limbic encephalitis and testicular germ cell tumours who stabilise neurologically with long term survival after tumour treatment8Ma2 encephalitisPathologyParaneoplastic antigen Ma2 against the protein Ma2

ManagementOrchidectomy, Immunomodulator,

PrognosisMore responsive to oncologic and immunologic treatment than other types of paraneoplastic encephalomyelitis

Ma2 encephalitisPath: PNM2 Positive regulation of apoptotic process against the protein Ma2. Shares homology to Ma1 a type of uncharacterised phosphoprotein.Manag: oncologic and immunologic managemementProg: Ma2 associated encephalitis is more responsive to oncologic and immunologic treatment than other types of paraneoplastic encephalomyelitis Factor associated with improvement or stabilization included male sex, age 45 years or less, testicular tumour with complete response to treatment, absence of anti-Ma1 antibodies, and limited CNS involvement.9Anti-LGI1 (VGKC) encephalitisPresentationLimbic encephalitis

PathologyUsed to be associated voltage gated potassium channel (VGKC). Now shown to be leucine rich glioma inactivated 1 (LGI1)Secreted neuronal protein

TreatmentTreatment with immunomodulators result in significant improvement in 70 to 80 percent of patients Epi: Present: Limbic encephalitis: short-term memory loss personality change, seizures (especially faciobrachial tonic seizures), depression, anxiety, hallucinations. REM sleep disorder Autonomic instability Hyponatraemia (60%)41 Myotonia (40%)41 Only 20 percent of cases are paraneoplastic; the most common associated tumors are thymoma or SCLC.

Path:Previously attributed to antibodies to voltage gated potassium channel (VGKC). The true target antigen has been shown to be leucine rich glioma inactivated 1 (LGI1) secreted neuronal protein that functions as a ligand for two epilepsy-related proteins, ADAM22 and ADAM23. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series

Treatment:Described in several papers that treatment with glucocorticoids, IVIG, mycophenolate mofetil, and/or plasma exchange result in significant improvement in 70 to 80 percent of patients.10Anti-NMDA encephalitisEpidemiologyChildren as young as eight months have been reported with this syndrome.40% are in the Paediatric population

PresentationDistinct syndromeProdromal headache, fever, or a viral-like process, followed in a few days by a multistage progression of symptoms

ANMDAREpi: Anti-NMDAR encephalitis has only recently been described, often occurring in female patients with associated ovarian teratomas, however, men are affected in 30% of cases. Significant (40%) proportion of anti-NMDAR encephalitis is found in childrenPres: predictable set of symptoms that combine to make up a characteristic syndromeA prodromal syndrome involving headache, low grade fever and non-specific viral illness (nausea, vomiting, upper respiratory tract symptoms) up to 2 weeks prior to presentationcommonly with psychiatric symptomsis found in about 70%Prominent psychiatric manifestations (anxiety, agitation, bizarre behavior, hallucinations, delusions, disorganized thinking); isolated psychiatric episodes may rarely occur at initial onset or at relapse [56]Insomnia Memory deficits Seizures Decreased level of consciousness, stupor with catatonic features Frequent dyskinesias: orofacial, choreoathetoid movements, dystonia, rigidity, opisthotonic postures Autonomic instability Language dysfunction: diminished language output, mutism. Echolalia is often noted in the early stages or in the recovery phase of the disorder

The detection of an ovarian teratoma is age-dependant; approximately 50 percent of female patients older than 18 have uni- or bilateral ovarian teratomas while less than 9 percent of girls younger than 14 years have a teratoma [64,79]. A review of 400 cases showed that African-American patients have a mild predominance

In male patients the detection of a tumor is rare. Cases with associated tumors other than ovarian teratoma include testicular germ cell tumor [45], teratoma of the mediastinum, SCLC [52], Hodgkin's lymphoma [16], ovarian cystadenofibroma [83], and neuroblastoma [84]. The frequency of underlying tumors in older patients (>45 years) is low and when present, tumors are more often carcinomas instead of teratomas [72].

11Anti-NMDA encephalitisPathologyNR1 subunit is the target antigenNR1 down-regulated by selective and reversible decrease in NMDAR surface density and synaptic localizationExcitotoxicity

ManagementImmunomodulatory agents inc. IVIGTreatment is continued until substantial recovery occurs, which may take up to 18 months

PrognosisResection of the tumor, glucocorticoids, intravenous immune globulin, and plasma exchange often result in improvement usually within four weeks Path: NMDA involved in long term potentiation.The NR1 subunit is the target antigen for NMDA receptor antibodies (NMDAR). NR1 is down-regulated causes reduction in GABA release from pre-synaptic neurons that subsequently results in increased glutamate release, dopamine dysregulation and excitotoxicity leading to classical anti-NMDAR encephalitis features.

Man:Continuous immuno therapy of up to a year after initial therapy is reported by a team in the US

Prog:Resection of the tumor, glucocorticoids, intravenous immune globulin, and plasma exchange often result in improvement usually within four weeks Patients who do not improve with these first line therapies (often cases without tumor) may improve with rituximab and/or cyclophosphamide

In one series of 577 patients, 81 percent of patients had a good outcome (modified Rankin scale 0 to 2) at 24 months [67]. Substantive persistent cognitive impairments are more common and more severe when there is a delay to diagnosis and treatment12Other EncephalitidiesIntracellular AntigensAnti-amphiphysin antibodiesAnti-CRMP5

Synaptic AntigensAMPA receptor antibodiesAnti-GABA-A receptorAnti-GABA-B receptor Anti-CASPR-2Anti-IgLON5 Anti- -1 glycine receptor Anti-dipeptidyl-peptidase-like protein-6 More to come13Blood testing

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