demyelinating Disorders in Children.pptx

Demyelination disorder

1. CNS demyelinating Disorders in Children Prof . ( Dr ) Ariful Islam Department of Pediatric neurology Nins

2. Introduction Neuroimmune disorders of the CNS encompass a wide spectrum of conditions that, collectively, are not uncommon in childhood . Many of these disorders result in acquired demyelination of the brain and/or spinal cord. Neuroimmune demyelinating disorders can manifest in any age, but the clinical phenotypes, radiologic expression, treatment, and prognosis are often distinct in children compared to adults.

3. ACQUIRED DEMYELINATING SYNDROMES (ADS) ADS can be defined as syndromes resulting in single ( monofocal ) or multiple ( polyfocal ) lesions originating in the CNS caused by inflammatory demyelination . May be classified based on the CNS location(s) and extent of involvement ( eg , monofocal versus multifocal). The most common initial monofocal ADS include ON and ATM; multifocal ADS include ADEM.

4. Ads cont …. ADS can be : Monophasic or may represent the initial attack of a multiphasic/chronic demyelinating disorder such as MS . Several clinical, laboratory, and imaging factors can be used to predict the overall risk for relapsing disease.

5. Classification of ADS : A) Monophasic ADS : Optic Neuritis ( ON ) Transverse Myelitis ( TM) ADEM B) Recurrent/Multiphasic ADS : Pediatric MS NMOSD MOG-AD

6. When to suspect ? Any patient with new, subacute focal neurologic deficits occurring after a known infection, and in the absence of trauma, metabolic derangements, or known underlying structural abnormalities, should be suspected of having acquired CNS demyelination. 

7. Ads cont …. Most ADS result in continuous symptoms that exhibit : a subacute course, with gradual onset and worsening over several days to weeks. A hyperacute presentation (reaching maximal severity within a few hours of onset) is less common and could be suggestive of a hemorrhagic/ischemic etiology . Further , neurologic symptoms that come and go ( eg , symptoms lasting for seconds, minutes, or hours and then resolving), are more suggestive of paroxysmal disorders ( eg , migraine, seizure).

8. Approach to a Child with Suspected acquired Demyelination In addition to detailed history and physical examination, the suggested workup includes CSF and serum analysis as well as neuroimaging. The purpose is to secure an accurate diagnosis, & to rule out disease mimics, such as infectious, neoplastic, toxic/metabolic, or genetic etiologies.

9. Ads cont …. Laboratory evaluation: S erum assessment for MOG and AQP-4 IgG antibodies. A rheumatologic evaluation (including antinuclear and extranuclear antibodies) is needed in patients with a history of photosensitivity, oral/nasal ulcers, arthritis, nephritis, or characteristic skin changes. An infectious evaluation may be needed based on seasonality and exposures.

10. Ads cont …. CSF testing include cell counts, protein, glucose, IgG index, and oligoclonal bands (in serum and CSF ). Laboratory features, suggestive of ADS : mild to moderate CSF pleocytosis elevated CSF protein presence of oligoclonal bands (OCBs) increased immunoglobulin G (IgG) index.

11. Ads cont …. MRI features : the presence of multifocal white and gray matter abnormalities presence of spinal cord lesions optic nerve thickening or hyperintensity on T2WI and the presence of enhancement of lesions after the administration of gadolinium.

12. Optic neuritis (on) ON denotes inflammation along the course of the optic nerve accounting for roughly one-fourth of all childhood ADS cases.

13. On cont …. Clinically, manifests as: reduced visual acuity a ltered color vision eye pain that is worsened by eye movement visual field defects an afferent pupillary defect optic disc edema in the acute/subacute setting.

14. On cont …. Unilateral presentation at onset may be followed rapidly by bilateral involvement within a few weeks, or bilateral involvement may occur at onset. Approximately two-thirds of children with ON who are <10 years of age present with bilateral ON, whereas most children >10 years of age present with unilateral ON. Pain with eye movement in approximately 50% of pediatric cases.

15. On cont …. Children also have greater rates of optic disc edema (up to 75%) and more severe vision loss, with more than 50% of children exhibiting a visual acuity of 20/200 or worse acutely . Despite this, long-term visual recovery is greater in children than in adults .

16. On cont …. Evaluation should include: an ophthalmologic examination MRI of the orbits and brain MRI of spine if myelopathic symptoms present VEP and OCT may provide additional quantitative measures of optic nerve and retinal damage, respectively. Serum MOG and AQP4 antibodies (30 % of all cases of pediatric MOG-associated disorders manifest as ON).

17. Optic neuritis This is a MRI with contrast from a patient diagnosed with right optic neuritis. The white arrow points to the normal optic nerve. The red arrow shows the affected optic nerve, which appears white.

18. Optic neuritis . Axial, T2-weighted MRI demonstrating optic nerve sheath dilation (white arrow) and flattening of the posterior aspect of the right globe (asterisk).

19. Management Acute management includes a course of IV steroids and, in refractory cases, IVIg or plasma exchange. Ophthalmologic monitoring and institution of visual aids are important in the management of children with ON.

20. Prognosis Recovery, as measured by visual acuity, is generally good in children with ON. ON may occur in isolation or as an attack (or first attack) of MS, NMOSD, ADEM, or MOG antibody–associated disease. Up to one-third of children with ON will have a second attack, signifying the onset of MS or NMOSD. Some children will have a relapsing MOG antibody–associated disease.

21. Predictors for Multiphasic disease

22. Acute Transverse Myelitis ATM denotes immune-mediated inflammation within the spinal cord and comprises one-fourth of cases of initial pediatric ADS. Bimodal age of distribution, very young ( eg ,<5 yrs of age)and peripubertal ( eg , 10 to 12 years of age ). Although a slight predominance of males exists, a female predominance is seen in adolescents and is associated with relapsing diseases, including MS and NMOSD.

23. Atm cont …. Symptoms can include : weakness numbness urinary incontinence or retention and myelopathic pain Occasionally , respiratory symptoms and autonomic dysfunction

24. Atm cont …. ATM may be idiopathic, which predicts a low risk of recurrence , or it may represent the initial attack of a relapsing neuroinflammatory disorder, such as MS, NMOSD, or MOG-associated disorder.

25. Atm cont …. MRI lesions reveal T1-isointense and T2-hyperintense signals involving the gray matter and neighboring white matter (WM) and may enhance with gadolinium. Lesions may be contiguous or patchy. LETM occurs in 66–85% of ATM in children .

26. Transverse myelitis

27. Atm cont …. Testing should include serum MOG and AQP4 antibodies. CSF protein and white blood cell counts may be normal in up to 50% of children with TM.

28. Atm cont …. Acute treatment includes IV steroids urgently and plasma exchange or IVIg in refractory cases. Bladder ultrasound and catheterization should be considered for urinary retention. Children with acute transverse myelitis have a better outcome than adults, with 50% making a complete recovery by two years.

29. Atm cont …. Mortality is associated with respiratory failure and high cervical cord lesions. Sensory issues and bladder dysfunction (15% to 50%) are the most common sequelae. Approximately one-third of patients require walking aids, and 10% to 20% of children lose mobility or bladder function.

30. Atm cont ….   Potential factors (at onset) that predicts a higher risk of poor outcome : female sex , ASIA scale A to C at presentation , gadolinium enhancement on MRI, absence of CSF pleocytosis .

31. Atm cont …. Approximately 17% to 29% will relapse in the long term . The risk for a future diagnosis of MS following ATM is approximately 14% to 22% and is highest in those of female sex with concurrent demyelinating lesions in the brain and the presence of CSF oligoclonal bands . Compared to adult cohorts, the presence of MOG or AQP4 antibodies is less common in pediatric ATM ( 14% and 3% respectively)

32. Acute Disseminated Encephalomyelitis The clinical hallmark of ADEM is encephalopathy with multifocal neurologic signs and symptoms. Predominantly affects younger pre-pubescent children and is typically monophasic (70-90%), with a median age of onset from 5 to 8 years of age .   More than half report a preceding infection 1 to 3 weeks before clinical onset, typically in the form of a nonspecific upper RTI or GIT illness .

33. Adem cont …. The clinical manifestations include subacute onset of encephalopathy unexplained by fever/illness or postictal symptoms in addition to multifocal neurologic abnormalities that vary based on the CNS area(s) impacted ( eg , paresis with motor tract involvement, truncal or limb ataxia with cerebellar involvement). Cranial neuropathies, including the optic nerve, can be seen, and gray matter involvement is not uncommon.   Seizures are noted in more than one-third of pediatric patients with ADEM.

34. Adem cont …. The differential diagnosis for a child with suspected ADEM is broad but can be significantly narrowed with a good history, neurologic examination, laboratory testing, and imaging.

35. Differential Considerations for Children Presenting With Acquired Demyelinating Syndromes Autoimmune/inflammatory Infectious Genetic Toxic/metabolic Vascular/traumatic Neoplastic ADEM Granulomatous ( eg , sarcoidosis), rheumatologic ( eg , SLE, Sjögren syndrome), neuroinflammatory (MS, NMOSD, MOG-associated disorders) Viral encephalitis ( eg , EBV, herpes simplex virus, HIV) Lyme disease, tuberculosis, Bartonella , Rickettsi Mitochondrial disorders ( eg , polymerase gamma [POLG]-related disorders, MELAS), leukodystrophies , inborn errors of metabolism Carbon monoxide poisoning , neuroleptic malignant syndrome Central nervous system vasculitis, posterior reversible encephalopathy syndrome (PRES) Hemophagocytic lymphohistiocytosis , gliomatosis cerebri , central nervous system lymphoma, infiltrative astrocytoma Optic neuritis Granulomatous (sarcoidosis), rheumatologic (SLE), neuroinflammatory (MS, NMOSD,MOG- associated disorders) Lyme disease, syphilis, Bartonella , tuberculosis, viral infection (HIV,EBV,CMV) Hereditary optic neuropathy ( eg , Leber hereditary optic neuropathy) Vitamin B12 deficiency, biotinidase deficiency Vasculitis (PAN, granulomatosis with polyangiitis ), ischemic optic neuropathy, traumatic optic neuropathy Optic nerve compression, optic glioma Transverse myelitis Granulomatous ( sarcoidosis), rheumatologic ( SLE, Sjögren syndrome), Behçet disease, neuroinflammatory (MS, NMOSD, MOG-associated disorders, GBS) Acute flaccid myelitis, viral ( EBV,VZV enterovirus,HTLV-1, West Nile virus) Mycoplasma, Bartonella , Lyme disease Mitochondrial disorders ( eg , Leigh syndrome, LBSL) Vitamin B12, folate, copper, vitamin E, or biotinidase deficiency; heroin myelopathy, radiation/ chemotherapy-related myelopathy Spinal cord infarction, fibrocartilaginous embolus, AVM, compressive myelopathy Intramedullary tumor ( eg , astrocytoma), extramedullary tumor causing cord compression ( eg , meningioma)

36. Adem cont …. For typical ADEM, the CSF will show mild to moderate lymphocytic and/or monocytic pleocytosis . Intrathecal oligoclonal bands are rare. MOG antibodies are detected in >50% of all pediatric patients with ADEM  and should be tested for in any child presenting with an ADEM phenotype .

37. Adem cont …. In addition to the clinical signs/symptoms MRI shows bilateral large (>1 cm to 2 cm) T2/FLAIR hyperintense lesions that are poorly demarcated and predominantly involve the cerebral white matter . Gray matter involvement is not infrequent, but T1-hypointense lesions should be absent. Gadolinium enhancement is variable, reported in one-third of cases.

38. adem G, H Axial FLAIR images demonstrate multiple, difuse , ‘ fufy ,’ poorly defned hyperintense lesions involving both grey and white matter and both supra- and infratentorial region.

39. Adem cont …. Neuroimaging can be normal early in the course of ADEM; therefore, if clinical suspicion remains high, repeat imaging should be obtained. Following treatment and clinical recovery, the majority of children exhibit complete or partial resolution of previously noted MRI abnormalities.

40. treatment High-dose IV steroids followed by an oral prednisone taper over 4 to 6 weeks. IVIg may also be tried, either concurrent with or following corticosteroid treatment . PE is used for fulminant ADEM or cases that prove refractory to steroids and/or IVIg ( eg , lack of any clinical improvement within 2 to 3 days or lack of marked improvement within 1 to 2 weeks from treatment)

41. prognosis The majority of pediatric patients with ADEM experience a monophasic course with good neurologic outcomes . Repeat imaging at least 3 to 6 months following the initial attack is useful to provide a new imaging baseline for the patient and should demonstrate improvement of prior MRI abnormalities . Less than 10% of children with ADEM will experience a second demyelinating attack more than 3 months after the sentinel attack,and the majority of these patients who relapse exhibit evidence of MOG antibodies.

42. Adem cont …. When a relapse occurs, this may be a second ADEM event (multiphasic ADEM) or isolated optic neuritis (termed ADEM-ON). Rarely , children with ADEM could go on to receive a diagnosis of MS, which requires at least one non-ADEM attack (>3 months from the initial ADEM attack) and meeting 2017 McDonald criteria for dissemination in time and space. In these rare situations, MOG and AQP4 antibodies should be confirmed as negative before making a diagnosis MS .

43. Thank you

44. RELAPSING DEMYELINATING SYNDROMES Multiple Sclerosis Neuromyelitis Optica Spectrum Disorders Myelin Oligodendrocyte Glycoprotein–associated Demyelination

45. Multiple Sclerosis MS is a relapsing neuroinflammatory demyelinating disease. Peak incidence in 20 to 30 years. Onset before the age of 18 in up to 10% of cases. The incidence vary based on geography. The global incidence of pediatric MS is 0.87 per 100,000 individuals per year.

46. EPIDEMIOLOGY - ms

47. EPIDEMIOLOGY - ms

48. EPIDEMIOLOGY - ms

49. EPIDEMIOLOGY - ms

50. EPIDEMIOLOGY - ms

51. Risk factors: Environmental risk factors include: vitamin D deficiency seropositivity for remote EBV infection smoking (passive or active) and obesity Genetic : HLA-DRB1*1501 haplotype

52. Phenotypes Progression of disability in Fulminant, Relapsing-remitting & Progressive MS

53. Phenotypes cont …. MS in childhood is almost exclusively a relapsing-remitting phenotype. The progressive MS phenotype in childhood is very rare.

54. Clinical features Pediatric MS may present with a variety of neurologic attacks including: optic neuritis transverse myelitis and brainstem / cerebellar syndromes followed by relapses.

55. Symptoms developing during the course of disease

56. Ms cont …. Compared to their adult-onset counterparts, pediatric patients with MS exhibit: a more inflammatory disease course, with a clinical relapse rate that is 2 to 3 times greater and significantly higher inflammatory lesion volumes on brain neuroimaging.

57. Diagnosis of POMS and  Diferential Diagnosis An event of ADS, could represent one of many neuroinflammatory diseases including AQP4-NMOSD, MOGSD, or a monophasic disease. Only 20% of pediatric ADS cases are ultimately diagnosed with POMS. The diagnosis of POMS is undertaken through the lens of the adult McDonald MS diagnostic criteria and its latest 2017 revision ( specifcity and sensitivity of 95% and 71%, respectively).

58. Diagnosis of ms cont … When a diagnosis of pediatric MS is considered, a thorough evaluation should include both CSF testing and neuroimaging of the brain and spine. A diagnosis of MS can be made clinically in a child who has two separate clinical attacks that localize to at least two of four critical CNS areas ( eg , cerebellum and spinal cord).

59. Diagnosis of ms cont … Alternatively, a child may meet the criteria for MS after a single attack if imaging provides evidence of both enhancing and nonenhancing typical demyelinating lesions in at least two of four CNS areas ( eg , cortical or juxtacortical , periventricular, infratentorial brain regions, and spinal cord ). For the child who meets dissemination in space criteria but does not yet meet dissemination in time criteria using clinical or radiologic end points, the presence of OCB unique to the intrathecal space can be used to fulfill dissemination in time criteria.

60. POMS A , B Axial FLAIR images demonstrating typical MS-based hyperintensities within the periventricular region, juxtacortical region, and in the posterior fossa (cerebellum).

61. Diagnosis of ms cont … An MS clinical attack is defined as an acute/subacute demyelinating event resulting in focal/multifocal neurologic dysfunction that lasts for at least 24 hours in the absence of fever/infection .

62. Diagnosis of ms cont … All children with a demyelinating syndrome should undergo testing for MOG antibodies (the presence of which would argue against a diagnosis of MS ). Rarely, low-titer and transient MOG antibodies may be detected in typical MS and thus should not exclude a diagnosis of MS, particularly if the clinical history, neuroimaging, and CSF testing are supportive of an MS diagnosis

63. Differential diagnosis to exclude in poms Inflammatory disease – ADEM/MDEM, MOGAD, NMOSD, SLE, PACNS, APS CNS malignancy - Lymphoma, high grade glioma, hemophagocytic lymphohistiocytosis Leukodystrophy - MLD, X-ALD, Alexander disease CNS infection -Acute bacterial or viral infections, Lyme disease, syphilis , HIV Vitamin deficiency- B12, folate Granulomatous disease - Neurosarcoidosis Mitochondrial disease - Leber hereditary optic neuropathy

64. treatment Treatment of an MS relapse is similar to the treatment of other ADS. Once a definite MS is diagnosed and alternative etiologies have been effectively ruled out, an appropriate DMT should be initiated as early as possible. The major goals for treatment include eliminating clinical relapses and the accrual of new lesions on MRI and halting the progression of neurologic disability.

65. Disease-modifying Therapies for Pediatric MS

66. DMT for POMS cont ….

67. Dmt for Poms cont ….

68. DMT for POMS cont ….

69. Treatment of ms cont … The clinical impact and efficacy of DMTs appear to be highly associated with age, with youth with MS deriving the greatest benefits .

70. Treatment of ms cont … Monitoring response  — Both clinical and neuroimaging parameters. The International Pediatric MS Study Group suggests neurologic examinations : at baseline; one , three, and six months after initiating therapy; and every six months thereafter In clinically stable children without attacks, yearly follow-up and neurologic examination may be sufficient.

71. The International Pediatric MS Study Group suggests obtaining repeat brain MRI scans 6 to 12 months after the initiation of a DMT and is compared with the baseline scan performed prior to treatment. For clinically stable patients with no more than one new T2 lesion or lesion with gadolinium enhancement, the MRI can be repeated yearly. For patients with several new T2 lesions and/or several lesions with gadolinium enhancement on follow-up imaging, repeat MRI should be performed again in six months. Changing DMT can be considered if the MRI continues to demonstrate a significantly increasing burden of disease.

72. Treatment failure  —  treatment failure to DMT are considered when one or more of the following conditions are present despite ongoing therapy ( ie , minimum six months on full-dose therapy and fully adherent to treatment) : Two or more relapses in a 12-month period based upon clinical or MRI data Two or more new T2 or contrast-enhancing brain lesions on MRI compared with pre-treatment period For patients with treatment failure, one reasonable strategy is to change therapy: ●Patients who have a poor response to interferon beta drugs or  glatiramer acetate  can be switched to an intermediate efficacy oral DMT, such as  fingolimod  or  dimethyl fumarate , or high efficacy infusion DMT, such as  rituximab

73. Treatment of ms cont … In conjunction with DMT initiation, children with MS and their families should be counseled on modifiable risk factors that may impact their MS, including smoking (passive or active ),vitamin D deficiency,diet quality,obesity or sedentary lifestyle.

74. Treatment of ms cont … Cognitive impairment in children with MS affects up to one-third of patients. For this reason, it is recommended to obtain a full neuropsychologic evaluation on all pediatric patients with MS within the first year of diagnosis . Findings from this testing can be used by the school to implement an individualized education plan to help overcome MS-related cognitive obstacles.

75. Neuromyelitis Optica Spectrum Disorders NMOSD is a CNS inflammatory disorder that preferentially affects the optic nerves and spinal cord but can also involve the area postrema , hypothalamus, and periaqueductal gray matter. Less common in children, pediatric NMOSD account for 2% to 5% of all NMOSD cases. AQP4 antibodies are found in one-half to two-thirds of children with NMOSD, MOG antibodies have been detected in cases of AQP4-negative NMOSD . The median age of onset in pediatric NMOSD ranges from 10 to 14, and a female predominance is seen.

76. Clinical features The first clinical manifestations often include unilateral or bilateral ON, TM and brainstem/cerebellar syndromes. Simultaneous ON and TM in a minority of patients at the initial attack . Hiccups and/or intractable vomiting when the area postrema is involved.

77. Clinical features of nmosd cont … Given that the diencephalon can be affected, more than half of all children with NMOSD may exhibit evidence of endocrinopathies , including hyponatremia, morbid obesity, amenorrhea, and hyperinsulinism . Pediatric NMOSD can coexist with systemic autoimmune disorders, such as SLE, Sjögren syndrome, and Graves disease.

78. investigations Serum MOG and AQP4 antibodies. The majority of children with AQP4-positive NMOSD will have detectable antibodies at presentation. A subgroup may not exhibit evidence of AQP4 IgG until later in the disease course, and thus AQP4 antibodies should be rechecked periodically when a high index of suspicion exists.

79. Investigations NMOSD cont … CSF often shows evidence of a lymphocytic or neutrophilic leukocytosis Protein and IgG index may also be elevated . OCB are seen in less than one-third of pediatric patients.

80. Investigations NMOSD cont … ON in the setting of NMOSD often exhibits longitudinally extensive T2/FLAIR hyperintensities extending posteriorly along the optic tract and into the chiasm. LETM often involves the central cord and extends for at least three spinal cord segments.

81. Distinctive imaging features of ON, myelitis , and brain lesions in AQP4-IgG–positive NMOSD patients versus MOG-IgG–positive NMOSD patients and patients with MS.

82. Typical brain involvement in NMOSD Top : Representative brain MR images show AQP4 antigen distribution (red ). Bottom:FLAIR images show the corresponding lesions. The hyperintense lesions on the FLAIR images have the same distribution as AQP4, reinforcing the involvement of these water channels in NMO

83. NMOSD C, D Sagittal T2 image of the spinal cord and axial FLAIR image demonstrating longitudinal extensive transverse myelitis that involves the brainstem region and extend over the entire cervical portion of the spinal cord.

84. Investigations NMOSD cont … Additionally, T2-hyperintense lesions may be noted within the diencephalon and brainstem, particularly in areas juxtapositioned to the ventricles as these areas have high AQP4 expression. T1- hypointense lesions or gadolinium enhancement, or both, can be noted in a subset of children. Large tumefactive lesions within the cerebral hemispheres may be observed in a small subset of children with AQP4-positive NMOSD .

85. The diagnostic criteria for NMOSD in pediatric patients are the same criteria used for adult patients with NMOSD but with some important considerations. Firstly , LETM is not specific to pediatric NMOSD and can be seen in the setting of ADEM, MOG-associated disorders, and MS. In addition, NMOSD may have features that mimic ADEM, such as the presence of encephalopathy and multifocal demyelination. But c hildren with ADEM should not have AQP4 IgG.

86. tREATMENT Treatment of acute attacks includes high-dose IVMP for 3 to 5 days, although PE should be employed early if little to no neurologic recovery is seen, given the propensity for disability accumulation in NMOSD. The majority of pediatric NMOSD cases (>90%) exhibit a relapsing course, and thus chronic preventive immunotherapy is often required to reduce the risk of future relapses and accumulating neurologic disability.

87. Treatment of nmosd cont …. As of now, there are 3 FDA approved therapies for the treatment of AQP4+ NMOSD. These therapies include eculizumab ( Soliris ; Alexion), inebilizumab ( Uplizna ; Horizon Therapeutics), and satralizumab ( Enspryng ; Genentech). Eculizumab , a complement inhibitor, was the first approved treatment for NMOSD in June 2019. Following that, inebilizumab , an anti-CD19 agent, received approval in June 2020, and then satralizumab , an anti-interleukin-6 receptor, was approved later that year.

88. Treatment of nmosd cont … Retrospective studies have shown benefit with: MMF (titrated over 3 to 4 weeks to goal dosing of 600 mg/m2 2 times a day, maximum of 1 g 2 times a day ), Azathioprine (2 mg/kg/d to 3 mg/kg/d) and Rituximab and a small case series supports the use of tocilizumab (8 mg/kg every 4 weeks, maximum of 800 mg per dose ).

89. prognosis AQP4-positive NMOSD is a highly relapsing disorder that can lead to significant permanent neurologic disability at an early age . The median time to a second attack is 4 to 8 months, and a more aggressive disease course (including a shorter time to second attack) is observed in patients of color.

90. Prognosis of nmosd cont … When followed for up to 4 years : moderate neurologic disability ( ie , EDSS score ≥3) is noted in nearly half of pediatric patients with AQP4-positive NMOSD. One-third of patients exhibit visual acuity of 20/200 or less, and Persistent motor deficits are seen in approximately 20% of patients.

91. Prognosis of nmosd cont … Predictors of poorer neurologic outcomes include: younger age at onset , those with optic neuritis as a first attack and higher EDSS scores at the clinical nadir. Cognitive deficits are noted in one-fourth of patients. Patients who have a younger age at onset and those with brainstem/cerebral attacks are at highest risk for cognitive impairments .

92. Myelin Oligodendrocyte Glycoprotein–associated Demyelination MOG is a protein expressed exclusively in the CNS on the surface of myelin. Anti-MOG antibodies are detected in one-third of all children at the time of initial onset of ADS. The incidence is higher in children than in adults (0.31 versus 0.13 per 100,000) and sex ratio is equal particularly in younger children.

93. clinical PHENOTYPES of MOG-associated demyelination : ADEM ON ATM AQP4- negative NMOSD non-ADEM encephalitis and brainstem syndromes. The phenotype is somewhat age dependent, with younger children presenting with ADEM spectrum disorders, whereas older children (>11 years of age) tend to manifest with ON.

94. MOG-associated demyelination cont … No clinical or radiologic features of MOG-positive ADEM reliably differentiate it from seronegative ADEM; however , MOG positives are more likely to have spinal cord involvement and complete radiologic resolution in long-term follow-up. A higher risk of post-ADEM seizures exists in patients with MOG antibodies. In MOG-positive ON, optic nerve involvement is more likely to be bilateral and longitudinal and preferentially involves the anterior optic pathway as compared to seronegative ON .

95. MOG-associated demyelination cont … Relapsing MOG-AD can occur in <50% and most commonly is restricted to the optic nerve or spinal cord. Risk of relapse is less in children than adult patients. Clinical relapse may occur in one-fourth of children presenting with MOG-positive ON and in less than 10% of patients with MOG-positive ADEM. Children who remain seropositive for MOG antibodies are at higher risk for relapse compared to those who convert to seronegative (38% versus 13%);

96. MOGsd E, F Axial post-contrast FLAIR image demonstrating bilateral optic neuritis with optic nerve edema associated with contrast enhancement of the optic nerve and perineural sheet. Coronal T2 image demonstrating cervical spinal cord lesion spanning over 2.5 vertebral levels

97. treatments : The first-line treatment of an acute attack is similar to that noted above for individual ADS. A subset of patients who are MOG seropositive may exhibit worsening or rebounding symptoms as corticosteroids are weaned and thus may require a slower taper over time.

98. Treatment cont … In most situations, chronic immunotherapy is not used after the first demyelinating attack, given that the majority of pediatric patients with MOG exhibit a monophasic course. Chronic immunotherapy after a first attack is given when the patient exhibits marked residual neurologic impairments following adequate acute treatment and time for recovery.

99. Treatment cont …. For patients who experience a clinical relapse, maintenance immunotherapy is strongly recommended. Monthly IVIg , anti-CD20 therapies (rituximab), MMF, and azathioprine have demonstrated benefits. The duration of maintenance immunotherapy remains unclear(for at least 1 to 3 years following the last relapse).

100. prognosis : Many children with MOG-associated disorders experience a monophasic course (particularly if the presenting phenotype is ADEM) and good functional outcomes. Compared to adults, children exhibit better neurologic recovery, with complete recovery occurring in 75% to 96% of all children. Cognitive concerns are more prominently noted in children who are younger (<10 years of age) with intracranial demyelination ( eg , ADEM ).

101. CONCLUSION ADS is not uncommon in children. Accurately distinguishing monophasic from relapsing disease is of paramount importance. Close longitudinal clinical and radiologic surveillance is needed. Autoantibody testing has helped to define and categorize specific subtypes of demyelinating disorders of childhood.

102. Conclusion cont ….. High-efficacy DMTs appear effective in children, but the long-term safety and impact on future neurologic function and cognitive disability requires further study.

103. Thank you

104. Diagnostic approach to acquired demyelinating syndromes (ADS )