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Table 1 Recommended indications for MOG-IgG testing in patients presenting with acute CNS demyelination of putative autoimmune etiology

From: MOG encephalomyelitis: international recommendations on diagnosis and antibody testing

1. Monophasic or relapsing acute optic neuritis, myelitis, brainstem encephalitis, encephalitis, or any combination thereof,

and

2. radiological or, only in patients with a history of optic neuritis, electrophysiological (VEP) findings compatible with CNS demyelination,

and

3. at least one of the following findings:

MRI

 a. Longitudinally extensive spinal cord lesion (≥3 VS, contiguous) on MRI (so-called LETM)a,b

 b. Longitudinally extensive spinal cord atrophy (≥3 VS, contiguous) on MRI in patients with a history compatible with acute myelitisa

 c. Conus medullaris lesions, especially if present at onsetc

 d. Longitudinally extensive optic nerve lesion (e.g., >1/2 of the length of the pre-chiasmal optic nerve, T2 or T1/Gd)d

 e. Perioptic Gd enhancement during acute ONe

 f. Normal supratentorial MRI in patients with acute ON, myelitis and/or brainstem encephalitis

 g. Brain MRI abnormal but no lesion adjacent to a lateral ventricle that is ovoid/round or associated with an inferior temporal lobe lesion and no Dawson’s finger-type or juxtacortical U fiber lesion (Matthews-Jurynczyk criteriaf)

 h. Large, confluent T2 brain lesions suggestive of ADEM

Fundoscopy

 i. Prominent papilledema/papillitis/optic disc swelling during acute ON

CSF

 j. Neutrophilic CSF pleocytosisg or CSF WCC > 50/μlh

 k. No CSF-restricted OCB as detected by IEF at first or any follow-up examinationi (applies to continental European patients only)

Histopathology

 l. Primary demyelination with intralesional complement and IgG deposits

 m. Previous diagnosis of “pattern II MS” j

Clinical findings

 n. Simultaneous bilateral acute ON

 o. Unusually high ON frequency or disease mainly characterized by recurrent ON

 p. Particularly severe visual deficit/blindness in one or both eyes during or after acute ON

 q. Particularly severe or frequent episodes of acute myelitis or brainstem encephalitis

 r. Permanent sphincter and/or erectile disorder after myelitis

 s. Patients diagnosed with “ADEM”, “recurrent ADEM”, “multiphasic ADEM” or “ADEM-ON”

 t. Acute respiratory insufficiency, disturbance of consciousness, behavioral changes, or epileptic seizures (radiological signs of demyelination required)

 u. Disease started within 4 days to ~ 4 weeks after vaccination

 v. Otherwise unexplained intractable nausea and vomiting or intractable hiccups (compatible with area postrema syndrome)a

 w. Co-existing teratoma or NMDAR encephalitis (low evidencek)

Treatment response

 x. Frequent flare-ups after IVMP, or steroid-dependent symptomsl (including CRION)

 y. Clear increase in relapse rate following treatment with IFN-beta or natalizumab in patients diagnosed with MS (low evidence)

 
  1. Note that these recommendations are primarily intended for use in adults and adolescents. Indications for MOG-IgG testing in young children need not to be as rigorous as in adults, since MOG-EM is thought to be significantly more frequent among young children with acquired demyelinating disease (up to 70%; frequency declining with age) than among their adult counterparts (≤ 1% in Western countries; probably ≤ 5% in Japan and other Asian countries because of lower MS prevalence), which reduces the risks attached to antibody screening outlined in the Introduction
  2. Abbreviations: ADEM acute disseminated encephalomyelitis, ADEM-ON ADEM with recurrent ON, AQP4 aquaporin-4, CNS central nervous system, CRION chronic relapsing inflammatory optic neuropathy, CSF cerebrospinal fluid, EM encephalomyelitis, Gd gadolinium, IA immunoadsorption, IgG immunoglobulin G, IVMP intravenous methylprednisolone, LE left eye, LETM longitudinally extensive transverse myelitis, MOG myelin oligodendrocyte glycoprotein, MRI magnetic resonance imaging, MS multiple sclerosis, NMDAR N-methyl-D-aspartate receptor, NMO neuromyelitis optica, OCB oligoclonal IgG bands, ON optic neuritis, PEX plasma exchange, RE right eye, RRMS relapsing-remitting MS, VEP visual evoked potentials, VS vertebral segments, WCC white cell count
  3. aIf costs play a role and disease is stable: test AQP4-IgG first, since more frequent in that condition than MOG-IgG. If disease is active, requiring fast decision-making, or if costs play no role: test AQP4-IgG and MOG-IgG in parallel
  4. bLETM is common both in MOG-EM and in AQP4-NMOSD, but rarely if ever occurs in MS; as a caveat, however, non-contiguous lesions may mimic LETM in some patients with MS. N.B.: Short lesions do not per se exclude MOG-EM. MRI shows short lesions at least once over the disease course in around 44–52% of all MOG-EM patients [3, 39] and around 15% of all AQP4-NMOSD patients [40]. Lesion length may also depend on MRI timing issues, with shorter lesions detected when the MRI was performed early in the evolution of acute myelitis or in clinical remission. Both axial and sagittal plane images should be used to judge lesion extent. LETM has also been shown to be frequently present at disease onset in MOG-IgG-positive children with manifestations other than isolated ON (32/40 or 80% of all examined cases) [41]
  5. cPresent in 6/8 patients in [7] (at onset); 4/6 in [8]; 4/11 in [35]; 3/12 in [42]; 5/26 (not all had lumbar MRI) in [3]; and in 13/40 pediatric patients (at onset) with manifestations other than isolated ON [41]
  6. dRamanathan et al. (2015) reported a median optic nerve lesion length of 23.1 mm (IQR 18-33) in MOG-IgG-related ON (N=19); this compares to a median lesion length of 9.9 mm (IQR 6.6-19.8; N=13) in MS-related ON observed in the same study [43] and of 10.5 mm in a second, independent study (N=26) [44]. Recent data suggest that also involvement (T2, T1/Gd or optic nerve swelling) of > 6/12 optic nerve segments (anterior orbital RE/LE, posterior orbital RE/LE, canalicular RE/LE, intracranial RE/LE, chiasm right/left half, optic tract right/left side) may be associated with increased pre-test odds for MOG-IgG (observed in 6/19 [32%] MOG-IgG-positive ON patients but in none of 13 [0%] MS-ON patients) [43]. Longitudinal extensive lesions involving at least 4 of 5 segments (anterior intraorbital segment, posterior intraorbital segment, canalicular, intracranial, chiasmal) were also noted in >=50% of MOG-IgG-positive patients in [45]. By contrast, lesions in MS-related ON extended only over 1 (70%) or 2 (30%) of 9 segments (intraorbital RE/LE, canalicular RE/LE, intracranial RE/LE, chiasmal, optic tract right/left side) in [44], and a mean extension of just 2.2/10 segments (orbital RE/LE, canalicular RE/LE, intracranial RE/LE, chiasma right/left half, optic tract right/left side) was observed in MS-ON in [46]. Longitudinal extensive lesions ranging over more than the half of the distance between the optic nerve head and the chiasm were also reported in 3/3 patients in [47] and in 6/10 (60%) in [3]. Finally, 9/10 MOG-ON Han patients (90%) showed involvement of all three segments of the pre-chiasmal optic nerve (intraorbital, canalicular, intracranial) in [48], in 6 of whom chiasmal and/or optic tract involvement was noted in addition
  7. eObserved in 11/28 patients during acute ON in [3], in 6/18 in [49], and in 6/8 in [48], but not usually in MS. Perioptic T2 hyperintensity alone does not count
  8. fPositive in ≥ 90% of RRMS patients [37, 36, 50]. By contrast, ovoid/round lesions adjacent to a lateral ventricle, lesions adjacent to a lateral ventricle in association with a temporal lobe lesion, and Dawson’s finger-type lesions were absent in 21/21 (100%) MOG-IgG-positive patients in a mixed adult (n = 15) and pediatric (n = 6) cohort [36, 37] and juxtacortical U fiber lesions in 20/21 (95.2%). Recently, a lack of Dawson’s finger-type lesions in MOG-IgG-positive patients has been confirmed in an exclusively pediatric cohort (absent in 68/69 [98.6%]; the only patient positive for Dawson’s finger lesions had typical MS and was negative for MOG-IgG at re-testing); U fiber lesions were absent in 65/69 (94.2%) MOG-IgG-positive pediatric patients in the same study [41]
  9. gPresent at least once in 64% of patients with pleocytosis [3] (median 22% of all white cells; range 3–69%) but typically absent in MS. N.B.: Neutrophilic pleocytosis is also frequently found in AQP4-IgG-positive NMOSD [51]
  10. hObserved in 43% (14/36) of MOG-IgG-positive patients with pleocytosis (peak values) [3], but only rarely in patients with MS (≤ 2% according to [52]; 1/71 patient ≥ 15 years of age [range 15–29] in [53])
  11. iOligoclonal bands (OCB) have been reported in up to 98% of patients with MS in central and Northern Europe [53] but only in around 12–13% of patients with MOG-EM in two recent Central European studies [3, 54]; of note, many MOG-EM patients previously falsely diagnosed with MS were atypical in that they had no OCB in a recent multicenter study [3]. As a caveat, it should be noted that positive OCB do NOT exclude MOG-EM [3] and that the frequency of OCB in MS may be lower in Asian patients (e.g., 40–80% in Japan) as well as in some regions in Europe such as Sardinia (84% in a recent study [55]), possibly depending on genetic factors. “No CSF-restricted OCB” refers to the presence of OCB patterns 1 (no OCB), 4 (mirror pattern without additional IgG bands present exclusively in the CSF), or 5 (monoclonal IgG band present both in the CSF and in the serum) [56]
  12. jSome patients diagnosed with “pattern II MS” lesions, which are characterized by IgG and complement deposits, were shown by independent groups to have in fact MOG-EM, suggesting that the current histopathological criteria may not be sufficiently specific to distinguish between MS and MOG-EM [24, 57, 58]
  13. kPatients with teratoma and positive MOG-IgG serostatus have been identified in two cohorts so far (2/74; 3%) [3, 4, 59]; expression of CNPase, an oligodendrocyte marker, has been described in mature teratomas, and oligodendrogliomas may arise in mature teratomas. Additional testing for NMDAR antibodies is highly recommended in patients with teratoma and neurological symptoms [60]. Recent, though preliminary, reports suggest that MOG-EM and NMDAR encephalitis may occasionally co-exist [61]
  14. lRe-occurrence of symptoms after tapering of oral steroids [3, 18, 20, 22, 62]
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Journal of Neuroinflammation

ISSN: 1742-2094