This presentation contains information about Anti-MOG Ab Demyelinating disorder and Neurological manifestations of IgG4 disease.

1. MOG AND IgG 4 RELATED DISEASE
Presenter: Dr. Kshitij Bansal
Senior Resident
Department of Neurology
Government Medical College, Kota

2. INTRODUCTION
 Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory disorder
of the CNS.
 Characterized by attacks of immune- mediated demyelination predominantly targeting the optic nerves,
brain, and spinal cord.
Phenotype
 ON: 41%-63%
 TM: 30%
 ADEM-like varies based on age (common in paediatric age).
 Brainstem syndromes: up to 30%.

3. PATHOGENESIS
 Myelin oligodendrocyte glycoprotein is a minor myelin component, with a length of 245 amino acids
(AA) and a molecular weight of 26–28 kDa.
 The MOG gene is located at chromosome 6.
 It is exclusively expressed in the central nervous system (CNS) on the surface of myelin sheaths and
oligodendrocyte processes.
 As a member of the immunoglobulin superfamily, it is highly immunogenic.
 The function of MOG has not been fully elucidated, but it may act as a cell adhesion molecule, regulate
microtubule stability, and modulate myelin immune interactions.
PESCHL P, BRADL M, HÖFTBERGER R, BERGER T AND REINDL M (2017) MYELIN OLIGODENDROCYTE GLYCOPROTEIN: DECIPHERING A TARGET IN INFLAMMATORY DEMYELINATING DISEASES. FRONT. IMMUNOL.
8:529.

5. EPIDEMIOLOGY
 As MOG antibody was discovered only in 2007, and widespread testing was not available until years
later, thus the epidemiology reports may have underestimated the frequency of MOG AD.
 Median age: 20 to 30 years.
 Male : Female = 1:1
 Children account for up to 50% of the cases.
 Race / Ethnicity: No predilection has yet been identified.
 Geographic distribution: Variable

6. CLINICAL FEATURES
Characteristic Attacks
 Acute attacks of
 Unilateral or bilateral optic neuritis resulting in severe visual loss.
 ADEM resulting in altered mental status, focal neurologic features, and features of transverse myelitis
 Transverse myelitis, often causing limb weakness, sensory loss, and bowel, bladder, or sexual dysfunction
 MOG AD may have a monophasic or relapsing course.
 Attacks usually develop over days and may plateau with variable recovery over weeks to months.
JURYNCZYK M, MESSINA S, WOODHALL MR, ET AL. CLINICAL PRESENTATION AND PROGNOSIS IN MOG-ANTIBODY DISEASE: A UK STUDY. BRAIN. 2017 DEC 1;140(12):3128-3138.

7. OPTIC NEURITIS
 Most common clinical manifestation of MOG AD is at the onset.
 Even more predominant during relapses.
 Almost always associated with eye pain that worsens with movement.
 Vision loss is bilateral and more severe than in MS but the severity is similar to NMOSD.
 Optic disc edema is found in up to 86% of MOG AD acute ON attacks.
 Longitudinal extensive, anterior part on MRI.
 Good outcome; only 6-14% of patients have residual visual acuity of < 6/60.
CHEN JJ, FLANAGAN EP, JITPRAPAIKULSAN J, ET AL. MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY-POSITIVE OPTIC NEURITIS: CLINICAL CHARACTERISTICS, RADIOLOGIC CLUES, AND OUTCOME. AM J
OPHTHALMOL. 2018 NOV;195:8-15.

8. PRESENTATION AS ADEM
 ADEM is the most common initial presentation of MOGAD in children
 Noted in 68 percent of all MOG-positive pediatric cases.
 A subset of patients develop multiphasic historically, many of these patients may have had MOGAD.
 MOG-IgG is found in 30 to 50 percent of ADEM patients, and its presence may predict a higher
likelihood of recurrence.
 However, patients with MOGAD who have an initial manifestation of ADEM can also have monophasic
disease and never relapse.
ARMANGUE, THAÍS ET AL. “ASSOCIATIONS OF PAEDIATRIC DEMYELINATING AND ENCEPHALITIC SYNDROMES WITH MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODIES: A MULTICENTRE OBSERVATIONAL
STUDY.” THE LANCET. NEUROLOGY VOL. 19,3 (2020): 234-246.

9. TRANSVERSE MYELITIS
 TM may occur as an isolated attack(20%) or in conjunction with involvement in other regions of the CNS
(eg, ADEM, optic neuritis)10-35%.
 80% longitudinally extensive
 Multiple lesions including conus (75%).
 Often confined to grey matter
 Neurogenic bowel and bladder are frequent, and erectile dysfunction in males is also common, possibly
from the frequent involvement of the conus.
 Residual bowel, bladder, and erectile dysfunction are common and often more prominent than residual
motor deficits.
 The severity of the myelitis is more than that seen with MS, and up to one-third will be nonambulatory at
nadir.
CIRON, JONATHAN ET AL. “FREQUENCY AND CHARACTERISTICS OF SHORT VERSUS LONGITUDINALLY EXTENSIVE MYELITIS IN ADULTS WITH MOG ANTIBODIES: A RETROSPECTIVE MULTICENTRIC STUDY.”
MULTIPLE SCLEROSIS (HOUNDMILLS, BASINGSTOKE, ENGLAND) VOL. 26,8 (2020): 936-944.

10. BRAIN STEM AND CEREBELLAR FEATURES
 Isolated brainstem attacks are uncommon when compared with MS / NMO.
 Most often, involvement occurs as a component of multi-focal CNS demyelinating attack involving other
regions.
 Ataxia and diplopia are the most common clinical accompaniments.
 A distinct area postrema syndrome typical of AQP4-IgG NMOSD with isolated intractable nausea,
vomiting, and hiccups is not typically encountered.
BANKS, SAMANTHA A ET AL. “BRAINSTEM AND CEREBELLAR INVOLVEMENT IN MOG-IGG-ASSOCIATED DISORDER VERSUS AQUAPORIN-4-IGG AND MS.” JOURNAL OF NEUROLOGY, NEUROSURGERY, AND
PSYCHIATRY, JNNP-2020-325121. 28 DEC. 2020

11. CLINICAL COURSE
 Monophasic and relapsing,
 50% relapse in first two years after presentation.
 75% relapse by 5 years.
 Titers higher at time of relapse.
 Up to 50% become antibody negative after relapse.
 Persistent positivity indicates higher risk of relapse.
COBO-CALVO, ALVARO ET AL. “CLINICAL FEATURES AND RISK OF RELAPSE IN CHILDREN AND ADULTS WITH MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY-ASSOCIATED DISEASE.” ANNALS OF
NEUROLOGY VOL. 89,1 (2021): 30-41.

12. EVALUATION AND DIAGNOSIS
When to suspect MOG AD
 ON: Bilateral, involves the anterior optic pathway, and is associated with optic disc edema.
 ADEM: ADEM-like presentation accompanied by large, poorly demarcated T2 hyperintense lesions in the
brain and with T2 lesions within the spinal cord.
 Unilateral cortical encephalitis with headache, fever, seizures, encephalopathy, or other focal neurologic
findings with cortical T2 hyperintensity and swelling.
 A complete spinal cord syndrome, especially with prominent bowel, bladder, or erectile dysfunction
symptoms.
MOG-IgG is required for the diagnosis of MOGAD.

13. RED FLAGS

14. DIAGNOSTIC CRITERIA
 Serum positivity for MOG-IgG by cell-based assay.
 A clinical presentation consistent with any of the following central nervous system syndromes:
 ADEM
 Optic neuritis
 Transverse myelitis
 Brain or brainstem demyelinating syndrome
 Any combination of these
 Exclusion of an alternative diagnosis
LÓPEZ-CHIRIBOGA, A SEBASTIAN ET AL. “ASSOCIATION OF MOG-IGG SEROSTATUS WITH RELAPSE AFTER ACUTE DISSEMINATED ENCEPHALOMYELITIS AND PROPOSED DIAGNOSTIC CRITERIA FOR MOG-IGG-
ASSOCIATED DISORDERS.” JAMA NEUROLOGY VOL. 75,11 (2018): 1355-1363.

15. JARIUS, S ET AL. “MOG ENCEPHALOMYELITIS: INTERNATIONAL RECOMMENDATIONS ON DIAGNOSIS AND ANTIBODY TESTING.” JOURNAL OF NEUROINFLAMMATION VOL. 15,1 134. 3 MAY. 2018.

16. INVESTIGATIONS
 MRI
 Orbits
 Brain
 Spinal Cord

17. MRI ORBITS

18. MRI BRAIN

20. MRI SPINE

23. CSF
 CSF OCB are typically absent (positive only in 5-20% of patients).
 50% patients have CSF pleocytosis (lymphocyte predominant).
 Frequency of pleocytosis is higher at the time of attack (55-60%) vs between attack (25-30%).
 Elevated CSF protein is found up to 50% but is non-specific.
 Viral PCR testing is important to assess for alternative diagnosis.

24. MANAGEMENT OF MOG AD
WYNFORD-THOMAS, R., JACOB, A. & TOMASSINI, V. NEUROLOGICAL UPDATE: MOG ANTIBODY DISEASE. J NEUROL 266, 1280–1286 (2019)

25. TREATMENT
Treatment of acute attacks
 Choice of therapy: High dose IV methylprednisolone (1000mg in adults or 20-30mg/kg per day in
children for 5 consecutive days.
Failure of initial acute therapy
 Plasma exchange: One exchange every alternate day for five to seven exchanges in total.
 IVIG: 2 gram/kg divided over 2-5 days.
MARIGNIER, ROMAIN ET AL. “MYELIN-OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY-ASSOCIATED DISEASE.” THE LANCET. NEUROLOGY VOL. 20,9 (2021): 762-772

29. CONTINUUM (MINNEAP MINN) 2019;25(3, MULTIPLE SCLEROSIS AND OTHER CNS INFLAMMATORY DISEASES):815–844.

30. CONTINUUM (MINNEAP MINN) 2019;25(3, MULTIPLE SCLEROSIS AND OTHER CNS INFLAMMATORY DISEASES):815–844.

31. IgG 4 RELATED DISEASE (RD)
 Immunoglobulin G4-related disease is an increasingly recognized immune-mediated condition
comprised of a collection of disorders that share specific pathologic, serologic and clinical features.
 Auto Immune Pancreatitis is considered the prototype IgG4-RD.

32. The commonly shared features include:
 Tumour-like swelling of involved organs.
 A lymphoplasmacytic infiltrate enriched in IgG4- positive plasma cells.
 A variable degree of fibrosis that has a characteristic “storiform” pattern, and obliterative phlebitis.
 Elevated serum concentrations of IgG4 (in 60-70% of the patients)
 Response of glucocorticoids, particularly in the early stage of the disease.
DESHPANDE, VIKRAM ET AL. “CONSENSUS STATEMENT ON THE PATHOLOGY OF IGG4-RELATED DISEASE.” MODERN PATHOLOGY : AN OFFICIAL JOURNAL OF THE UNITED STATES AND CANADIAN ACADEMY OF
PATHOLOGY, INC VOL. 25,9 (2012): 1181-92.

33.  The disease was not recognised as a system systemic condition till 2003 when extra-pancreatic
manifestations were identified in patients of AIP.
 AIP had been linked to elevated serum IgG 4 levels as early as 2001.
 AIP is now considered the prototype IgG4 RD, and the majority of the research regarding these diseases
has been done on AIP.

34.  The hallmarks of IgG4 RD are lymphoplasmacytic tissue infiltration with a predominance of IgG 4
positive plasma cells, usually accompanied by fibrosis, obliterative phlebitis and elevated serum levels of
IgG 4.
 A sizeable minority of patients (less than 40 per cent) have normal serum IgG 4 concentration despite
the presence of the classic histopathological changes in tissue.
 The fibrosis associated with IgG4 RD has a characteristic “storiform” pattern typified by a cartwheel
appearance of the arranged fibroblasts and inflammatory cells. Modest tissue eosinophilia is also
common.
HISTOLOGY
DESHPANDE, VIKRAM ET AL. “CONSENSUS STATEMENT ON THE PATHOLOGY OF IGG4-RELATED DISEASE.” MODERN PATHOLOGY : AN OFFICIAL JOURNAL OF THE UNITED STATES AND CANADIAN ACADEMY OF
PATHOLOGY, INC VOL. 25,9 (2012): 1181-92.

36.  Generally occurs in middle aged and older men.
 Incidence well-studied in Japan= 0.28-1.08 per 100,000 population.
 But, even this prevalence may be underestimated because of lack of experience amongst physicians and
availability of wildly accepted classification criteria.
 No clear-cut risk factors have been identified.
 However, a case-controlled study examining 234 patients with IgG 4 RD and 1170 controls found that
smoking was associated with the increased risk of IgG 4 RD, especially in patients with retroperitoneal
involvement.
EPIDEMIOLOGY
UMEHARA, HISANORI ET AL. “A NOVEL CLINICAL ENTITY, IGG4-RELATED DISEASE (IGG4RD): GENERAL CONCEPT AND DETAILS.” MODERN RHEUMATOLOGY VOL. 22,1 (2012): 1-14.
WALLWORK, RACHEL ET AL. “THE ASSOCIATION OF SMOKING WITH IMMUNOGLOBULIN G4-RELATED DISEASE: A CASE-CONTROL STUDY.” RHEUMATOLOGY (OXFORD, ENGLAND) VOL. 60,11 (2021): 5310-5317.

37.  In a study of 114 patients with IgG4-RD, those with involvement limited to one of several regions (head
and neck, thoracic, hepatopancreatobiliary, and retroperitoneal) and those with systemic involvement
(more than one region) were compared with respect to various demographic and clinical features.
 The ages of patients in all groups were similar, with means from 59 to 68 years (ranges 42 to 79).
 All the groups, other than the patients with head and neck involvement, were predominantly males (75
to 86%),
 But the group with only head and neck disease was divided nearly equally between the sexes (48%
males)
EPIDEMIOLOGY
ZEN, YOH, AND YASUNI NAKANUMA. “IGG4-RELATED DISEASE: A CROSS-SECTIONAL STUDY OF 114 CASES.” THE AMERICAN JOURNAL OF SURGICAL PATHOLOGY VOL. 34,12 (2010): 1812-9.

38.  Natural history of IgG 4 RD is still not clearly defined in sufficient detail.
 A minority of patients improve at least temporarily without treatment but most of these patients relapse.
 IgG 4 RD should be regarded as a chronic disease that progresses at variable rates.

39.  Poorly understood; findings consistent with both an autoimmune disorder and an allergic disorder are
present.
 IgG 4 has been postulated to have a role in tolerance to allergens and in responses to certain infectious
agents, but its physiologic role is poorly understood.
 It is not clear whether the IgG 4 antibodies are pathogenic; may have a anti-inflammatory role.
 IgG 4 antibody may represent a down-regulatory response to another primary process (es).
 Elevations in serum and tissue IgG 4 concentrations are not specific to IgG4 RD; they are also found in
disorders such as Churg-Strauss syndrome and sarcoidosis.
PATHOGENESIS
MAHAJAN, VINAY S ET AL. “IGG4-RELATED DISEASE.” ANNUAL REVIEW OF PATHOLOGY VOL. 9 (2014): 315-47.

40. STONE, JOHN H., YOH ZEN, AND VIKRAM DESHPANDE. "IGG4-RELATED DISEASE." NEW
ENGLAND JOURNAL OF MEDICINE 366.6 (2012): 539-551.

41. CLINICAL
MANIFESTATIONS

42.  IGG 4 RD accounts for 25-50% of all orbital pseudo tumors.
 Patients present with chronic lid swelling, proptosis and variable diplopia with minimal periocular pain.
 Characterized by IgG4-positive lymphoplasmacytic infiltrations.
 Median age: 59 years
 Male to female ratio: 1:1
ORBITAL INFLAMMATORY DISEASE
KUBOTA T, MORITANI S. ORBITAL IGG4-RELATED DISEASE:
CLINICAL FEATURES AND DIAGNOSIS. ISRN RHEUMATOL.
2012;2012:412896.

45.  Median Age: 62 years
 Male : Female: 3:1
 Cases predominantly reported in Asian descent.
 Clinical features depend on the part of the pituitary gland involved.
 Adenohypophysitis (anterior pituitary involvement)
 Hypopituitarism or individual endocrine hormone deficiencies (e.g. hypothyroidism, hypogonadism).
 Mass effects on adjacent structures (e.g. optic chiasm).
 Infundibuloneurohypophysitis (posterior pituitary involvement): diabetes insipidus.
 Panhypophysitis (both anterior and posterior pituitary involvement): all of the above clinical features.
HYPOPHYSITIS
HARANO Y, HONDA K, AKIYAMA Y, KOTAJIMA L, ARIOKA H. A CASE OF IGG4-RELATED HYPOPHYSITIS PRESENTED WITH HYPOPITUITARISM AND DIABETES INSIPIDUS. CLINICAL MEDICINE INSIGHTS. CASE REPORTS.
8: 23-6.

49.  Total 33 patients
 64% Men and 36% Women
 Mean age: 53 years; Range: 32-82 years
 No data on the incidence and prevalence of IgG 4 RD
have been reported to date for specific racial,
geographical or ethnic groups.
HYPERTROPHIC PACHYMENINGITIS

51. UMEHARA, HISANORI ET AL. “COMPREHENSIVE DIAGNOSTIC CRITERIA FOR IGG4-RELATED DISEASE (IGG4-RD), 2011.” MODERN RHEUMATOLOGY VOL. 22,1 (2012): 21-30.
DIAGNOSIS

52. Initial therapy
 The goal is to achieve disease remission.
 Glucocorticoids are the first-line agent for remission induction.
 Inj. MPS 1 gm / day followed by oral steroids is preferred.
 Alternatively, Tab Prednisolone 1 mg / kg (40-60 mg) once daily.
 Continue oral steroid for 2-3 weeks followed by gradual tapering over 2 months period.
TREATMENT APPROACH
ZHANG, W. ET AL. MANAGEMENT OF IGG 4 RELATED DISEASE. LANCET RHEUMATOL. 2019;1:E55.

53. Resistance to initial therapy
 Patients who fail to produce sustained disease control, patients with multi-organ disease or an extremely
high serum IgG 4 (> 5 times ULN) may require additional immunosuppressants.
 Rituximab: Most preferred agent in patients who are resistant to glucocorticoids alone or unable to
reduce their dose below 5 mg / day.
 1 gm IV; 2 doses; 15 days apart.
 Alternatives to Rituximab
 Mycophenoplate Mofetil: up to 2.5 gm / day.
 Azathioprine: 2 mg / kg per day
TREATMENT APPROACH
HART, PHIL A ET AL. “TREATMENT OF RELAPSING AUTOIMMUNE PANCREATITIS WITH IMMUNOMODULATORS AND RITUXIMAB: THE MAYO CLINIC EXPERIENCE.” GUT VOL. 62,11 (2013): 1607-15.

58. Maintenance Therapy
 Maintenance therapy is still under debate
TREATMENT APPROACH

62. THANK YOU