Table 1.
Main features of childhood neuroimmune diseases of the central nervous system.
| Immune Disorder | Pathology | Clinical features | Neuroimaging | Laboratory features and/or biomarkers | Treatment options |
|---|---|---|---|---|---|
| Acute disseminated encephalo-myelitis (ADEM) | • Presumed immune-cell mediated CNS disease • ADS |
• Polyfocal clinical deficits • Encephalopathy • No new clinical symptoms or MRI abnormalities after 3 months from onset |
• Diffuse, poorly demarcated, large (>1-2-cm) WM lesions • Rare T1-hypointense WM lesions • Deep GM lesions (e.g., basal ganglia, thalamus, or spinal cord) |
• OCBs in CSF in <10% or mirror pattern • Anti-MOG-Abs in ~40% |
• IV MPN • IVIg • PLEX |
| Multiphasic ADEM (MDEM) | • Presumed immune-cell mediated CNS disease • ADS |
• Two clinical event meeting ADEM criteria, separated in time >3 months • No further events |
• New or re-occurrence MRI finings • No clinically-silent new lesions between episodes |
• OCBs in CSF in <10% or mirror pattern • Anti-MOG-Abs in >60% |
• IV MPN • IVIg • PLEX |
| Clinically isolated syndrome (CIS) | • Presumed immune-cell mediated CNS disease • ADS |
• Monofocal or polyfocal clinical deficits • No encephalopathy • Monophasic ON, TM, or brainstem syndrome |
• T2-hyperintense and contrast-enhanced lesions in CNS area causing symptoms • No lesions elsewhere in the CNS |
• None specific | • IV MPN • IVIg • PLEX |
| Pediatric Multiple sclerosis (MS) | • Presumed immune-cell mediated CNS disease • ADS |
• At least 2 non-ADEM-like episodes • Relapsing-remitting course • Monofocal or polyfocal clinical deficits • Cognitive decline in ~30% |
• DIT and DIS • T2-hyperintense, and contrast-enhanced lesions • T1- hypointense multifocal lesions (black holes) • 4 locations: periventricular, cortical or juxtacortical, infratentorial, or spinal cord |
• OCBs in CSF in ~90% • (HLA)-DRB1*1501 • low serum 25(OH) vitamin D |
Acute treatment: • IV MPN • IVIg • PLEX DMDs: • Interferon-β • Glatiramer acetate (ongoing studies) • Teriflunomide • Fingolimod • Dimethyl fumarate • Natalizumab • Ocrelizumab • Rituximab |
| Neuromyelitis optica spectrum disorders (NMOSDs) | • Antibody-mediated CNS disease • ADS |
• Relapsing-remitting course • ON • LETM |
• T2-hyperintense, T1-hypointense, and contrast-enhanced lesions • Long optic nerve • >3 contiguous spinal segments myelitis |
• OCBs in CSF in ~18% • Anti-AQP4-Abs • Anti-MOG-Abs (in AQP4 negative patients) |
I line: • IV MPN • IVIg • PLEX II line: • RTX • CYP Maintenance: • Oral prednisone • AZA • MMF |
| Anti-NMDAR encephalitis | • Antibody-mediated CNS disease | • Prodromal symptoms • Seizures • Movement disorders • Psychiatric behavior • Cognitive and speech dysfunction • Sleep disturbances • Decreased consciousness • Autonomic dysfunction • Relapses ~12% |
• Normal • Transient non-specific T2/ FLAIR hyperintensities in multiple cortical and subcortical regions |
• Anti-NMDAR Abs • Mild pleocytosis, proteinorrachia, or OCBs in CSF |
I line: • IV MPN • IVIg • PLEX • Tumor removal (if any) II line: • RTX • CYP Maintenance: • Oral prednisone • AZA • MMF |
| Anti-VGKCc encephalitides | • Antibody-mediated CNS disease | • Limbic encephalitis • Seizures • Psychiatric symptoms • Movement disorders • Sleep disturbances • Morvan syndrome • Neuromyotonia • Autonomic symptoms • Relapses ~16% |
• Normal • Prominent T2/FLAIR hyperintensities in mesial temporal lobes |
• Anti-LGI1 Abs • Anti-Caspr2 Abs • Double-positivity • Mild pleocytosis, proteinorrachia, or OCBs in CSF |
I line: • IV MPN • IVIg • PLEX II line: • RTX • CYP Maintenance: • Oral prednisone • AZA • MMF |
| Anti-GABAA receptor encephalitis | • Antibody-mediated CNS disease | • Refractory seizures and status epilepticus • Cognitive and memory deficits • Movement disorders • Behavioral disturbances |
• Extensive, multifocal cortical and subcortical T2/FLAIR hyperintensities | • Anti- GABAA Abs • Mild pleocytosis, proteinorrachia, or OCBs in CSF |
I line: • IV MPN • IVIg • PLEX II line: • RTX • CYP |
|
Maintenance: • Oral prednisone • AZA • MMF |
|||||
| Anti-GABAB receptor encephalitis | • Antibody-mediated CNS disease | • Limbic encephalitis • Seizures • Memory deficits • Psychiatric symptoms |
• Normal • T2/ FLAIR hyperintensities in mesial temporal lobes or other regions |
• Anti- GABAB Abs • Mild pleocytosis, proteinorrachia, or OCBs in CSF |
I line: • IV MPN • IVIg • PLEX II line: • RTX • CYP Maintenance: • Oral prednisone • AZA • MMF |
| Anti-AMPAR encephalitis | • Antibody-mediated CNS disease | • Limbic encephalitis • Seizures and status epilepticus • Memory deficits • Behavioral changes |
• Normal • T2/ FLAIR hyperintensities in mesial temporal lobes or other regions |
• Anti-AMPAR Abs • Mild pleocytosis, proteinorrachia, or OCBs in CSF |
I line: • IV MPN • IVIg • PLEX II line: • RTX • CYP Maintenance: • Oral prednisone • AZA • MMF |
| Anti-GlyR encephalitis | • Antibody-mediated CNS disease | • SPS • PERM • Limbic encephalitis • Seizures and status epilepticus • Movement disorders • Brainstem encephalitis |
• Normal • Non-specific cortical and/or subcortical abnormalities |
• Anti-GlyR Abs • Mild pleocytosis, proteinorrachia, or OCBs in CSF |
I line: • IV MPN • IVIg • PLEX II line: • RTX • CYP Maintenance: • Oral prednisone • AZA • MMF |
| Anti-dopamine D2 receptor encephalitis | • Antibody-mediated CNS disease | • Basal Ganglia encephalitis • Lethargy • Psychiatric symptoms • Movement disorders |
• Normal • T2/FLAIR hyperintensities in the basal ganglia |
• Anti-dopamine D2 receptor Abs • Mild pleocytosis, proteinorrachia, or OCBs in CSF |
I line: • IV MPN • IVIg • PLEX II line: • RTX • CYP Maintenance: • Oral prednisone • AZA • MMF |
| Anti-MOG associated disease | • Antibody-mediated CNS disease | • ADEM • MDEM • ON • TM • NMOSD • Non-MS course • Relapsing disease |
• Long optic nerve • >3 spinal segments myelitis • T2-hyperintensities in diencephalon • Multifocal demyelination |
• Anti-MOG Abs • Negative for AQP4 Abs • Typically OCBs negative in CSF |
I line: • IV MPN • IVIg • PLEX II line: • RTX • CYP |
|
Maintenance: • Oral prednisone • IVIg • AZA • MMF |
|||||
| Autoimmune GFAP astrocytopathy | • Antibody-mediated CNS disease | • Meningo-encephalomyelitis • Seizures • Aphasia • Ataxia • Autonomic disfunction • Relapses |
• Periventricular radial/patchy enhancement of diffuse subcortical hyperintensities | • Anti-GFAP Abs • Coexisting anti-NMDAR Abs |
I line: • IV MPN • IVIg • PLEX II line: • RTX • CYP Maintenance: • Oral prednisone |
| • AZA • MMF |
|||||
| Autoimmune encephalitides with intracellular Abs | • Immune-cell mediated CNS disease | • Seizures • Neuropsy-chological deficits • Psychiatric symptoms • Movement disorders • SPS, PERM • Limbic encephalitis • Brainstem encephalitis • Cerebellitis • Encephalo-myelitis • Opsoclonus-myoclonus |
• Normal • Hyperintensity in mesial temporal lobes or other cortical and subcortical regions |
• Cytotoxic T-cell mechanisms predominate • Intracellular Abs as epiphenomenon (GAD65, Hu, CRMP5, amphiphysin, Yo, Ma1, Ma2, Tr) • Tumor surveillance |
I line: • IV MPN • IVIg • PLEX • Tumor removal (if any) II line: • RTX • CYP Maintenance: • Oral prednisone • AZA • MMF |
| Rasmussen encephalitis | • Acquired chronic inflammatory disease | • Refractory focal seizures • EPC • Status epilepticus • Progressive unilateral cortical deficits • Cognitive decline • Aphasia • Hemianopia |
• Progressive hemispheric brain atrophy (cortex and caudate head) • T2/FLAIR hyperintensity in cortex of involved side • Ipsilateral brainstem atrophy • Contralateral cerebellar atrophy |
Brain biopsy • T-cell encephalitis • Activated microglia • Reactive astrogliosis • Neuronal death • Unilateral brain atrophy |
Surgical: • Hemispheric disconnection Immunotherapy: • Corticosteroids • IVIg • PLEX • Monoclonal antibodies • Immuno-suppressants |
| Aicardi Goutières syndrome | • Genetic immune-mediated CNS disease | • Progressive microcephaly • Seizures • Movement disorders • Developmental delay or regression • Chilblain skin lesions |
• Cerebral calcifications • Leukodystrophy • Cerebral atrophy |
• TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR • Increased CSF levels of neopterin, biopterin, and interferons |
• JAK inhibitors • Symptomatic therapies |
| Hemophagocytic Lymphohistiocytosis | • Genetic immune-mediated CNS disease | • Seizures • Impaired consciousness • Meningismus • Focal motor deficits • Fever • Hepatomegaly • Splenomegaly • Lymphadenopathy |
• Symmetric and periventricular WM lesions (T1-hypointensity, and contrast enhancement) | • Pancytopenia • Low fibrinogen • high liver enzymes • High ferritinemia • High triglyceridemia • Hyponatremia • Pleyositosis and proteinorrachia in CSF |
• Immuno-suppression • Bone-marrow transplantation |
CNS, Central Nervous System; ADS, Acquired Demyelinating Syndrome; MRI, Magnetic Resonance Imaging; WM, White Matter; GM, Gray Matterp; OCBs, Oligoclonal Bands; CSF, Cerebrospinal Fluid; Abs, Antibodies; MOG, Myelin Oligodendrocyte Glycoprotein; IV MPN, Intravenous Methylprednisolone; IVIg, Intravenous Immunoglobulins; PLEX, Plasma Exchange; DIT, Dissemination in Time; DIS, Dissemination in Space; DMDs, Disease-Modifying Drugs; ON, Optic Neuritis; TM, Transverse Myelitis; LETM, Longitudinally Extensive Transverse Myelitis; AQP4, Aquaporin-4; RXT, Rituximab; CYP, Cyclophosphamide; AZA, Azathioprine; MMF, Mycophenolate Mofetil; NMDAR, N-methyl-D-aspartate receptor; VGKCc, Voltage-gated potassium channel-complex; LGI1, Leucine-rich glioma inactivated-1; Caspr2, Contactin-associated protein-2 receptor; GABAA, Gamma-aminobutyric acid type A; GABAB, Gamma-aminobutyric acid type B; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; GlyR, Glycine receptor; SPS, Stiff-person syndrome; PERM, Progressive encephalomyelitis with rigidity and myoclonus; GFAP, Glial fibrillary acidic protein; EPC, Epilepsia partialis continua.