TheDiagnosis and Treatment of Autoimmune Encephalitis

Eric Lancaster, MD, PhD Department of Neurology, University of Pennsylvania, 3400 Spruce St., 3 W Gates

Received October 1, 2015Revised October 2, 2015Accepted October 3, 2015

Pendahuluan• Autoimun ensefalitis sulit ditegakkan

dikarenakan persamaan gejala klinis, dan pemeriksaan penunjang– Khas pada autoimun ensefalitis : Penurunan daya ingat

dan kemampuan kognitif beberapa hari hingga beberapa minggu

Jenis &Patofisiologi Autoimmune Encephalitis

• Paraneopastic Antibodi dengan antigen intra sel (anti Hu): meliputi respons dari sel T yang menginvasif sel neuron melalui mekanisme “neuronal killing” yang bersifat ireversibel

Jenis &Patofisiologi Autoimmune Encephalitis

• Autoantibodi ekstraseluler epitopes ion channel, reseptor NMDA & protein lainnya Antibodi pada kelainan ini bersifat patogenik kerusakan reversibel pada celah sinaps & sedikit kematian sel saraf– Anti NMDAR encepahilitis– GAD65

Jenis &Patofisiologi Autoimmune Encephalitis

• Berhubungan Lupus Cerebritis dan ADEM (acute demyeliting Encepahalomyelitis)respons autoimun primer dan sekunder terhadap demam, vaksinasi proses diemelinisasi dan agregasi perivaskuler dari sel imun tanpa disertai adannya virus atau antigen virus

Gejala Sindro Automun Ensefalitis• Muncul hari hingga beberapa minggu

kemudian penurunan kesadaran sering kali naik turun dan penurunan kognitif, ingatan terutama ingatan terbaruKoma – Psikosis– Agregesif– Kelainan sexual– Serangan panik– Kompulsif– Euphoria– Ketakutan

Table 1. Clinical clues in the recognition of particular types of autoimmune encephalitis

Clinical fi Associated autoantibody disorders Psychosis NMDAR, AMPAR, GABA-B-R Dystonia, chorea NMDAR, Sydenham chorea, D2R Hyperekplexia GlyR

Status epilepticus Most characteristic of GABA-B-R and GABA-A-R but NMDAR is much more common;

may occur in other types as well New onset type 1 diabetes GAD65 Fasciobrachial dystonic seizures LGI1 Neuromyotonia, muscle spasms, fasciculations Caspr2

Stiff-person syndrome and/or exaggerated startle GAD65, GlyR, Amphiphysin (with GAD65 being most common in stiff person/stiff limb and

GlyR in PERM, and Amphiphysin in women with breast cancer) CNS (myoclonus, startle, delirium) and gastrointestinal

hyper-excitability DPPX

Cranial neuropathies Ma2, Hu, Miller-Fisher, Bickerstaff (but also infections like Sarcoidosis, Lyme, TB) Cerebellitis GAD65, PCA-1 (Yo), ANNA-1 (Hu), DNER (Tr), mGluR1, VGCC

CNS: central nervous system, TB: tuberculosis.

EKSLKLUSI KELAINAN AUTOIMUN

• Selain dari antibody mediator dan respons paraneoplastik ensefalitis – ADEM Lesi pada otak dan terkadang

meliputi nervus opticus dan spinal cord–MS (Mulitple sclerosis)– Lupus Neuropati, vasculitis, mielitis,

dvt, stroke, kejang, psikosis neurovascular disease

– Bickerstaff dan Miller Fisher Syndrome

EKSKLUSI KELAINAN INFEKSI

Table 2. Risk factors for autoimmune and infectious encephalitis

Risk factor Implications Travel Consider infectious causes of encephalitis in visited region HIV Opportunistic infections, risk depending on CD4 count Transplantation Opportunistic infections (CMV, VZV, HSV1, 6, 7); if recently transplanted, consider infection from donor Systemic autoimmunity Consider lupus cerebritis, vasculitis Cancer Consider specifi paraneoplastic syndromes based on tumor, but also lymphomatous/carcinomatous tumor involvement Prior encephalitis Consider relapse of initial encephalitis, secondary autoimmune causes, and (if immunosuppressed) opportunistic infections

Table 3. Infectious causes of encephalitis

Pathogen Test Notes HSV

PCR

A common cause in both healthy and immune-compromised patients, with particular predilection for the temporal lobes86

Specifi anti-viral therapy may be life-saving Rare cases of secondary anti-NMDAR encephalitis afterwards85

CMV PCR VZV PCR JE PCR Once a leading cause in East Asia, but declining due to vaccination programs

Enterovirus PCR Other, non-polio, strains may also be neurotropic and it is a relatively common

cause of encephalitis

HHV6 PCR Important cause in transplant patients 1% of persons have HHV-6 in their genome, so PCR test can be misleading

HHV7 PCR Rare cause in immune compromised patients

Neuroborreliosis (Lyme disease)

Serology

10-15% of untreated patients have neurological symptoms Manifestations include meningitis, encephalitis, radiculitis, cranial neuritis, and peripheral neuropathy87

WNV (West Nile)

PCR, Serology

Widely distributed mosquito-born fl Most infections asymptomatic or minimally symptomatic Encephalitis is the most common presentation, followed by meningitis and fl

paralysis88

Syphilis

Serologies

Most cases are sexually transmitter. Neurological symptoms may occur years or decades after exposure. Manifestations are protean

Cryptococcus

Latex agglutination antigen test, culture

More often presents with meningitis in patients with AIDS and other immune-compromised states

CSF opening pressure may be marked elevated

Aspergillus fumigatus Culture, biopsy, antigen ELISA

and other methods Disseminated CNS aspergillosus is mostly in immune compromised (transplant

patients), and pathology usually involves basal ganglia and/or thalami89

Mucor Culture, biopsy (ideally

for nasal involvement) May affect both immunocompromised and immune intact persons Prognosis is grim

Tuberculosis

Chest X-ray, PPD, Serology

In one study the second most common cause of infectious temporal lobe encephalitis behind HSV86

May also present with Rhombencephalitis Listeria Culture Rhombencephalitis and meningitis are the two main manifestations Streptococcus Culture Toxoplasmosis Serology Classically, a common cause of brain lesions in patients with AIDS

CNS: central nervous system.

Diagnostik• Tes Autoantibody – NMDAR, LGI1, Caspr2, AMPAR (GluR1,

GluR2 subunits), and GABA-B-R cukup banyak

– GABA- A-R and DPPX agak sulit dilakukan

• NMDAR sangat sensitif dan spsifik terhadap CSF IgA dan IgM Ditemukan pada pasien skizophrenia

• Caspr2 dan LGI1 berhubungan dengan VGKCs. (100–400 pM)

• GAD65 antibodi mempunyai korelasi klinis termasuk SPS serebral degenerasi, epilepsi dibetes tipe 1

• Hashimotos Ensefalopathy: NMDAR GABABR

• Imaging NMDAR, AMPAR, LGI1, Caspr2,and GABA-B antibodies mungkin normal mungkin mengalami peningkatan sinyal T2 terutama lobus temporomedial

EEG

• Bisa mendiagnosis baik autoimun atau infeksius ensefalitis

• Pada antibodi NMDAR terdapat gambaran “extreme delta brush pattern”

• Pada kasus autoimun antibodi NMDAR ensefalitis terdapat abnormal behavior yang tidak disebabkan oleh kejang maka EEG yang dapat membuktikannya

• GABA A dan GABA B biasannya muncul dengan onset kejang jadi membutuhkan EEG

• LG1 antibodies berhubungan dengan FBDS yang biasannya bermanifestasikan kejang kelemahan pada ekstremitas atasgambaran onset kejang multifokal

Biopsi

• Biopsi otak biasannya tidak digunakan untuk diagnoosis dari autoimun ensefalitis

• Keuntungan hanya 8%

Skrining Kanker

• Hu D protein diekspresikan kr dan anker paru, NMDARS pada teratoma ovarium –Mengobati tumor yang disebabkan

kelainan autoimun– Terapi tumor dan imun terapi – Terapi steroid

•

SPESIFIK TIPE AUTOIMUN ENSEFALITIS

• Autoantibody terhadap permukaan antigen:– Anti GABA – Anti NMDAR

• Autoantibody terhadap protein sinaptik intraseluler:– Anti GAD65

• Autoantibody terhadap antigen intraseluler:– Anti HU

Penatalaksanaan

• Steroids • IVIG – IV solumedrol (1 gram daily for 3–5 days

then a taper over several weeks) and– IVIg (0.4 g/kg/day for 5 days).

• Second line therapy– rituximab (often 375 mg/m2 weekly for

4 weeks) – cyclophosphamide (750 mg/m2 IV

monthly)

Keadaaan Penyulit

• Autoimun ensefalitis pada anak• Relapsing autoimun ensefalitis

Kesimpulan

• Diagnosis dan manajemen autoimun ensefalitis harus sesuai algoritma dari penentuan penyebab autoimun ensefalitis

• Evaluai harus diperhatikan dari sejarah dan px fisik dan penyebabnnyaMRI, EEG dan lumbal puncture

• Autoantibody tes berfungsi untuk menentukan diagnosis partikuler penyebab autoimunnya

• Untuk pasien dengan kanker harus diperhatikan selama pemberian terapi awalnnya dan followupnya karena bergantung dengan kelainan autoimun intrasel

Kekurangan Penelitian

• Tidak memaparkan secara jelas patofisiology per penyakit (autoimun)

• Kurangnnya edukasi untuk pencegahan agar tidak terjadinnya autoimun ensefalitis

• Penelitian tidak menjabarkan contoh contoh laporan kasus untuk autoimun meningoensefalitis

• TERIMA KASIH