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Table 1 Antibodies in acquired demyelinating disorders in children

From: Antibodies in acquired demyelinating disorders in children

 

AQP4 antibodies

MOG antibodies

Kir 4.1 antibodies

NMDAR antibodies

Glycine R antibodies

Syndrome

NMOSD with predominant involvement of optic nerve and spinal cord. Additional manifestations are related to involvement of other areas rich in AQP4, such as area postrema (hiccups or nausea and vomiting), hypothalamus, surrounding the third ventricle (symptomatic narcolepsy or acute diencephalic syndrome), brainstem/cerebral syndrome. Non-CNS involvement: musculoskeletal and hyperCK

Described in all types of ADS; predominant in ADEM, followed by in order of frequency in NMOSD, optic neuritis, and extensive myelitis. Rarely seen and at lower titers in multiple sclerosis

Described in association with adults (47%) and children (57%) with multiple sclerosis; results have not been reproduced by other investigators who showed much lower association (< 1–24%) and positive results in controls including NMOSD patients

Anti-NMDAR encephalitis: psychiatric symptoms, seizures, amnesia, movement disorders, catatonia, autonomic instability, and coma.

Stiff person syndrome in isolation or with concurrent glutamic acid decarboxylase antibodies, progressive encephalomyelitis with rigidity and myoclonus, and rarely in several types of demyelinating syndromes: optic neuritis, multiple sclerosis

Rarely, overlap with clinical and/or radiological ADS, frequently with concomitant MOG and/or AQP4 antibodies: presentation can be sequential or simultaneous

Pathogenesis

Activate complement and disrupt the AQP4 water channel located at astrocyte end-feet

Whether MOG antibodies are pathogenic or serve as surrogate biomarkers of the disease is currently unclear

Clinical significance and existence remains a matter of debate

In vitro and in vivo models show decrease levels of NMDAR

Lack of clinical syndrome specificity and the fact these antibodies are frequently found in patients with ADS concurrent with other more pathogenically relevant antibodies such as MOG and/or AQP4, suggests nonspecific immune activation

Age, Sex

More common in adults (median age 39 years), but the disorder affects patients of all ages with a female predominance

Mostly in children with no sex predominance

No differences were found compared to MS patients without these antibodies

Predominant in children and young adults. Sex and tumor association (teratoma) is agedependent, but no tumor association has been described in patients with overlapping ADS

Predominance depends on the syndrome in which the antibodies are analyzed; in ADS, there are no differences compared to patients without these antibodies.

MRI

Spinal cord lesions extending over ≥ 3 contiguous segments (Fig. 1a, d); area postrema lesions; periependymal brainstem lesions; chiasmatic involvement; and diencephalic lesions. In children, extensive brain lesions similar to that found in ADEM

Typically large, hazy, bilateral lesions in patients with ADEM and MOG antibodies (Fig. 1b, c). Patients with NMOSD can show similar MRI features to those found in patients with AQP4 antibodies

No specific reported data comparing MRI features of patients with or without these antibodies

Normal or T2/FLAIR nonspecific findings in anti-NMDAR encephalitis but can show demyelinating features with overlapping ADS

Depends on the associated clinical syndrome; in ADS very few reported patients but appears to be no differences compared to patients without these antibodies

Relapses

The presence of AQP4 antibodies in NMOSD patients is associated with increased risk of recurrences and increased long-term disability compared to patients without these antibodies. AQP4 antibody titers persist long term.

Frequently monophasic course with good recovery (antibody titers often become negative) (Fig. 1e, f). In some cases, associated with non-MS multiphasic disease; there can be long-term persistence of antibodies. NMOSD patients with MOG antibodies have better prognosis compared to patients with AQP4 antibodies

No differences were found compared to MS patients without these antibodies. One study found higher titers during relapse versus remission in patients with MS

15–25% of patients of anti-NMDAR encephalitis may develop recurrences. Prevalence of NMDAR encephalitis or ADS relapses is unknown in overlapping syndromes

Depends on the associated clinical syndrome; in ADS very few reported patients but appears to be no differences compared to patients without these antibodies

Laboratory Test

Serum CBA (microscopy or flow cytometry-based detection) had a sensitivity of 76.7% in a pooled analysis and 0.1% falsepositive rate in a multiple sclerosis clinic cohort. Indirect immunofluorescence assays and ELISAs have lower sensitivity (63–64% each) and occasionally yield false-positive results (0.5–1.3% for ELISA), especially when the titer is low

Serum CBA (positivity threshold is considered up to 1/160). Some authors use human IgG1 subclass as a secondary antibody to avoid false positive results. ELISA was used in the past with controversial results, and this technique is not recommended

ELISA

Fixed CBA and immunochemistry. Lower sensitivity in serum compared with CSF (85 vs 100%), and false positive results are possible when only serum is tested. Confirmation by two different techniques is preferred when the clinical syndrome does not fit with the lab result or when only serum is tested

Live CBA (positivity threshold is considered up to 1/80)

  1. ADEM acute demyelinating encephalomyelitis; ADS acquired demyelinating disorders; AQP4 aquaporin 4; CBA cell-based assay; CSF cerebrospinal fluid; FLAIR fluid-attenuated inversion recovery; Glycine R glycine receptor; MOG myelin oligodendrocyte glycoprotein; NMDAR N-methyl-d-aspartate receptor; NMOSD neuromyelitis optica spectrum disorders