The Changing Landscape of Childhood Inflammatory Central Nervous System Disorders

Published:October 06, 2016DOI:
      The past decade has seen significant advances in our knowledge of the etiopathogenesis of inflammatory disorders of the central nervous system (CNS), with a dramatically widening spectrum of disease. Growing recognition of these conditions has come in the wake of increased access to neuroimaging, antibody discovery, and the detection of genetically mediated immune mechanisms in selected patients. Clinical manifestations of childhood inflammatory CNS disorders range from focal neurologic deficits related to discrete lesions (multiple sclerosis [MS], optic neuritis [ON], transverse myelitis [TM], childhood primary angiitis of the CNS [cPACNS]) to decreased level of consciousness and coma with extensive abnormalities on brain magnetic resonance imaging (MRI) (acute disseminated encephalomyelitis [ADEM], myelin oligodendrocyte glycoprotein [MOG]-associated syndromes), to syndromes characterized by seizures and/or selective neuropsychological or behavioral changes in the absence of any visible MRI lesions or cerebrospinal fluid (CSF) abnormality (certain cases of antibody-mediated disorders, Rasmussen encephalitis in its initial stages). In the vast majority of cases, no specific biomarker of disease is known and the final diagnosis is based on recognizable syndromes (clinical features with supportive laboratory investigations and neuroimaging). As such, many of these syndromes carry considerable overlap. By contrast, a rapidly expanding number of disorders are now defined by the presence of pathogenic autoantibodies (eg, neuromyelitis optica spectrum disorders [NMOSDs], N-methyl D-aspartate receptor [NMDAR] encephalitis). In other cases, the inflammatory process may not be limited to the CNS but also target other organs, therefore, broadening the differential diagnosis and prompting additional investigations aiming to characterize fully the condition. In this topical update, we will discuss key clinical and diagnostic findings ( Figure and Table I) in addition to treatment approaches to inflammatory disorders of the CNS ( Table II; available at We present 3 categories of neuroinflammatory conditions: (1) recognizable CNS inflammatory syndromes with no known biomarker, (2) CNS inflammatory conditions identified by a biomarker (antibody-mediated disorders), and (3) systemic inflammatory disorders with secondary CNS involvement. For each category, we have included the most frequent or prototypical diseases to demonstrate their importance in the disease spectrum.
      Figure Approach to the child with an inflammatory condition of the CNS.
      CBC, complete blood and differential white blood cell counts; ESR, erythrocyte sedimentation rate; MR, magnetic resonance; ACE, angiotensin converting enzyme; CT, computed tomography; PET, positron emission tomography.
      Table I Laboratory investigations
      Descriptions Tests Clinical relevance
       Blood chemistry CBC, liver and kidney function tests, folate, B vitamins, lactate dehydrogenase General, organ involvement
      ESR, CRP Systemic inflammatory status/disease activity
      IgA, IgG, IgM, lymphocyte immunophenotyping, C3, C4; in selected cases: CICs, cryoglobulins, total hemolytic complement Immune system function, immunodeficiency, or dysregulated immunity
       Other Calcium, calcium ionized, 24-h urine collection for urinary calcium:creatinine ratio, PTH, calcitonin ACE, sIL2R Sarcoidosis (neurosarcoidosis)
      CBC, liver function tests, fibrinogen, D-dimer, ferritin, fasting triglycerides, LDH, sIL2R, NK cell activity assay Hemophagocytic lymphohistiocytosis
       Hypercoaguable work-up PT, aPTT, fibrinogen, protein C, protein S, activated protein C resistance (factor V gene Leiden mutation), prothrombin gene mutation, factor VIII, antithrombin III, homocysteine, MTHFR gene mutation, APL, haptoglobin, peripheral blood smear, hemoglobin analysis Thrombophilic conditions, hyperhomocysteinemia, sickle-cell disease
       Infection markers Serology; bacterial/mycobacterial, fungal, parasite blood cultures Infection (viral, bacterial, fungal)
       Nonorgan-specific autoantibodies ANA, antibodies to ENAs if ANA positive, p- ANCA/c-ANCA, anti-dsDNA, RF, anticardiolipin Rheumatologic conditions
       Organ-specific autoantibodies Thyroid peroxidase/microsomal Hashimoto encephalopathy
      AQP4 antibodies NMOSD
      GQ1b antibodies. Bickerstaff brainstem encephalitis
      Antibodies against intracellular antigens: Hu (ANNA1), Ma2, GAD Limbic encephalitis (main type of cancer associated: small-cell lung carcinoma, testicular seminoma, thymoma)
      Antibodies against synaptic receptors: NMDA receptor, AMPA receptor, GABA B receptor, GABA A, mGluR5, dopamine-2 receptor Limbic encephalitis, encephalitis, basal ganglia encephalitis (main type of cancer associated: ovarian teratoma, small-cell lung carcinoma, thymoma, Hodgkin lymphoma)
      Antibodies against ion channels: LGI1, CASPR2, DPPX Limbic encephalitis, Morvan syndrome (main type of cancer associated: thymoma, lymphoma)
       Tumor markers Alpha-fetoprotein, carcinoembryonic antigen, HE4, neuron-specific enolase, β-2- microglobulin, β-human chorionic gonadotropin, CA-125, CA-19.9, CA 15-3, HVA/MVA (urine), calcitonin, thyroglobulin, paraproteins Malignancies
      CSF Opening and closing pressures
       Routine chemistry and microbiology Glucose, protein, CSF cell count and differential
      CSF lymphocyte immunophenotyping (in selected cases)
      Oligoclonal banding and IgG index Intrathecal antibody synthesis, CNS inflammation
      CSF cytopathology (in selected cases) Abnormal lymphocytes, malignant cells (intravascular lymphoma, gliomatosis cerebri)
       Infection markers CSF gram stain and culture, CSF PCR studies. Examination for infectious agents (viral, bacterial, fungal)
      CSF ACE Neurosarcoidosis
      ACE, angiotensin converting enzyme; AMPA, alpha-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid; ANA, anti-nuclear antibodies; ANCA, anti-neutrophil cytoplasmic antibodies; ANNA1, type 1 anti-neuronal nuclear antibody; anti-ENAs, antibodies to the (anti-Smith, anti-Ribonuclear protein, anti-Ro, anti-La and others); APL, anti-phospholipid antibodies; aPTT, activated partial thromboplastin time; AQP4, aquaporin-4; CA, cancer antigen; CASPR2, contactin-associated protein-like 2; CBC, complete blood and differential white blood cell counts; CICs, circulating immune complexes; CRP, C-reactive protein; CSF, cerebrospinal fluid; DPPX, dipeptidyl-peptidase-like protein; dsDNA, anti-double-stranded DNA antibodies; ESR, erythrocyte sedimentation rate; GABA, gamma-aminobutyric acid; GAD, glutamic acid decarboxylase; GQ1b, ganglioside Q1b; HE4, Human epididymis protein 4; HVA, homovanillic acid; LGI1, leucine-rich glioma inactivated 1; mGluR5, metabotropic glutamate receptor 5; MOG, myelin oligodendrocyte glycoprotein; MTHFR, methylene tetrahydrofolate reductase; MVA, vanillylmandelic acid; NK, natural killer; NMDA, N-methyl-D-aspartate; NMOSD, neuromyelitis optica spectrum disorders; PCR, polymerase chain reaction; PT, prothrombin time; PTH, parathyroid hormone; RF, rheumatoid factor; sIL2R, interleukin-2 receptor.



      ADEM ( Acute disseminated encephalomyelitis), AQP4 ( Aquaporin-4), CNS ( Central nervous system), cPACNS ( Childhood primary angiitis of the CNS), CSF ( Cerebrospinal fluid), DADA2 ( Deficiency of adenosine deaminase 2), EEG ( Electroencephalography), IVIg ( Intravenous immunoglobulins), LMcPACNS ( Large- and medium-vessel cPACNS), MRI ( Magnetic resonance imaging), MS ( Multiple sclerosis), NMDAR ( N-methyl D-aspartate receptor), NMOSDs ( Neuromyelitis optica spectrum disorders), MOG ( Myelin oligodendrocyte glycoprotein), NPSLE ( Neuropsychiatric SLE), ON ( Optic neuritis), PANDAS ( Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), PANS ( Pediatric acute-onset neuropsychiatric syndromes), POMS ( Pediatric-onset MS), RE ( Rasmussen encephalitis), SLE ( Systemic lupus erythematosus), SVcPACNS ( Small-vessel cPACNS), TM ( Transverse myelitis)
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