MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome

Abstract

Background

A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).

Objective

To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes.

Methods

Retrospective multicenter study.

Results

The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36%) and markedly impaired ambulation due to paresis or ataxia (25%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in only 13%, and blood-CSF-barrier dysfunction in 32%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9%). Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%, respectively; MS had been suspected in 36%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases.

Conclusion

Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.

Appendix

Due to the novelty and rarity of the disorder, large and comprehensive case series illustrating the broad and heterogeneous spectrum of clinical manifestations, disease courses, and radiological presentations in MOG-IgG-positive encephalomyelitis are lacking. In this appendix, we provide detailed reports on 28 cases of MOG-IgG-positive ON and/or myelitis. We believe that case reports can draw a more vivid ‘real-life’ picture of this rare disorder than statistical analyses alone. For the reader’s convenience, the most important findings are briefly summarized and discussed in a comment at the end of each report. Additional reports are to be found in the “Case reports” section in part 3 of this article series [31].

Contents

I. MOG-IgG-positive NMO without brain involvement (cases 1-5)

II. MOG-IgG-positive NMO with brain involvement (cases 6-10)

III. MOG-IgG-positive recurrent ON (cases 11-18)

IV. MOG-IgG-positive monophasic ON (cases 19-24)

V. MOG-IgG-positive recurrent LETM (case 25)

VI. MOG-IgG-positive monophasic LETM (cases 26-27)

VII. MOG-IgG-positive postvaccinal NMO (case 28)

I. MOG-IgG-positive NMO without brain involvement

Case 1 – Recurrent LETM and ON resulting in persisting unilateral functional blindness and optic nerve atrophy. This Caucasian woman first presented with ON of the right eye in 08/2004 at age 40. Symptoms completely remitted after IVMP treatment. Since then, at least seven relapses of unilateral ON have occurred, which have successively affected both eyes and only partially responded to IVMP or IVMP and PEX. In addition, she experienced two attacks of myelitis, one with paraparesis and bladder and bowel dysfunction (04/2009) and the other with gait ataxia and sensorimotor paraparesis (08/2011); spinal MRI showed LETM lesions extending from C5 to Th2 (04/2009) and at T5 and T11 (08/2011), respectively, with Gd enhancement. Multiple brain MRI examinations were normal or showed only a few non-specific lesions not meeting the Paty or Barkhof criteria for MS; in addition, atrophy of both optic nerves was noted. Electrophysiology revealed prolonged P100 latencies in both eyes; later potentials were lost. While CSF was negative for OCB, very mild pleocytosis (6 cells/μl) was noted. The patient was given AZA (150 mg/d) between 01/2010 and 08/2010, and MTX was commenced in 08/2010. During treatment with AZA, three ON attacks took place; one attack of myelitis and two of ON occurred within 8 months despite treatment with MTX. At last follow-up, the patient had VA of 0.1 in the left eye (and 1.0 in the right eye) but no paresis.

Comment: This case – characterized by ON and LETM, mild pleocytosis, no OCB, and a normal MRI at onset – illustrates how similar the clinical presentation in MOG-IgG-positive patients can be to that of AQP4-IgG-positive NMO. In fact, a substantial proportion of patients in this cohort met Wingerchuk’s 2006 criteria. Of further note, 10 attacks occurred within only 85 months in this patient. Overall, the disease took a relapsing course in 80% of our patients. Moreover, as observed in many cases, acute treatment with IVMP and PEX and long-term immunosuppressive treatment were both only partially effective, resulting in a poor clinical outcome with functional blindness in one eye at last follow-up.

Case 2 – Recurring LETM and IVMP-refractory ON in a young girl, complete recovery after PEX. This young Caucasian woman experienced a first attack of myelitis in 06/2012 at age 17 with hypesthesia ascending from both feet to level T4, followed by predominantly left-sided paraparesis and urinary incontinence. Spinal MRI in 08/2012 demonstrated an LETM lesion extending from T3 to T6 with Gd enhancement (no swelling or necrosis documented). CSF WCC, OCB, QIgG, and total protein were normal. After IVMP (5 × 1000 mg) symptoms remitted except for a mild foot flexor paresis. AQP4 antibodies were negative.

A first relapse of myelitis occurred 1 year later, leading to hemihypesthesia predominantly of the left arm and torso. No MRI was performed. OCB were again negative. 5 × 1000 mg IVMP resulted in only partial recovery (EDSS in remission 3.0). AQP4-IgG was again absent, but MOG-IgG, which had not been previously tested, were positive.

In 07/2014, she suffered a first episode of unilateral ON with painful eye movement, blurred vision, and a small scotoma. VEP demonstrated prolonged P100 latency (amplitudes not reported). IVMP (5 × 1000 mg) resulted in transient full recovery. However, after just 2 weeks symptoms flared up again, with similar VEP results but an enlarged scotoma. Again, symptoms remitted completely after treatment with IVMP (3 x 2000 mg), only to recur after another 2 weeks. In between the first and second re-flare, thrombosis in the patient’s superior sagittal sinus occurred, most likely linked to extensive cortisone pulse therapy. This was associated with two symptomatic epileptic seizures probably due to focal edema. The second re-flare was therefore treated with five cycles of PEX, which resulted in complete remission. While VEP showed a prolonged P100 latency (140 ms) in the affected eye during relapse, VEP were normal at last follow-up in 03/2015.

Comment: As in patient 1, the disease took a severe, recurring course, though in this case final outcome was good. Of particular note, IVMP was effective during the first attack but not or only partially during subsequent attacks. Flare-ups after initial response to IVMP were noted in several other patients, too. In this case, only therapy escalation to PEX resolved the patient’s attack-related symptoms. The occurrence of sinus thrombosis with brain edema and seizures illustrates the risks of extensive cortisone pulse therapy.

Case 3 – Simultaneous bilateral ON and LETM in a patient with rheumatoid arthritis; recurrent myelitis; complete recovery. A 48-year-old woman with an 18-month history of suspected seronegative RA, which had been treated with oral MTX 15 mg per week starting in March 2009, developed bilateral pain on eye movement and severe visual loss in March 2010. Her personal and family history was otherwise unremarkable. A few days later, she additionally developed bilateral weakness of her legs which progressed to severe tetraparesis. Furthermore, she developed numbness of her trunk and legs starting at level T3, severe disturbances of micturition (residual urine 400 mL) and defecation, and severe back pain which was pronounced on head movement. Spinal MRI in an external hospital showed an LETM lesion extending from C2 to T4. Cranial MRI showed no inflammatory lesions but an old right-sided anterior infarction. A detailed search for sources of embolism was negative. CSF analysis revealed 73 leukocytes/μl and moderate blood-CSF barrier dysfunction, while OCB were negative. Both vasculitis screening including antiphospholipid antibodies and AQP4 antibodies were repeatedly negative, as were extensive infectiological investigations. The symptoms gradually improved during initial intravenous treatment with ceftriaxone, ampicillin, and aciclovir. Subsequent high-dose intravenous steroid pulse therapy over 5 days accelerated the remission of symptoms. When the patient first presented to our department 3 weeks after her symptoms had started, vision had normalized and walking was already possible without assistance. VEP amplitudes were reduced bilaterally and the P100 latency was slightly prolonged on the left side (121 ms). Tibialis SSEP were normal and MEP to the tibial anterior muscles showed bilateral slight prolongation of the central conduction time. The patient continued MTX treatment. In August 2010, a detailed neurological examination was unremarkable apart from mild proximal paresis of her right leg, not to be explained by the old anterior infarction on the same side. VEP, SSEP, and MEP were normal. The patient was then seen at half-yearly, later yearly intervals without developing further symptoms until September 2013, when she presented with acute painful numbness of her legs and lower trunk starting at level T10 and a positive Lhermitte’s sign. Cervicothoracic and cranial MRI did not show new or enhancing lesions. CSF analysis revealed 17/mm³ leukocytes and no evidence of a disturbed blood-CSF barrier function; isoelectric focusing again did not show CSF-specific OCB. Somatosensory and visual evoked potentials were normal. High-dose corticosteroid pulse therapy induced full remission of the symptoms. Cranial MRI in 07/2015 still did not show inflammatory lesions; cervicothoracic MRI in 08/2015 was unchanged. The patient was last seen in 08/2015 without having developed further new symptoms. She still continues treatment with MTX.

Comment: This patient’s initial presentation with simultaneous LETM and bilateral ON was considered typical of NMO for many decades. However, recent studies have demonstrated that AQP4-IgG-positive NMO starts with unilateral ON in the majority of cases; by contrast, simultaneous ON and myelitis as well as bilateral ON at onset have been found to be more common among ‘seronegative’ patients with NMO [34]. In the present study, the disease started with simultaneous ON and myelitis (with or without brainstem involvement) in 10%, and the initial attack affected both eyes in 41% of all patients with ON at onset, which corresponded to 30% of all patients. Both the severity of the patient’s presenting symptoms and the promptness as well as the nearly complete remission observed in this case are remarkable. Of particular interest, the patient’s first relapse occurred while on treatment wth MTX for RA. In total, two attacks occurred within 6 years of MTX treatment. Relatively low relapse rates under treatment with MTX were also observed in cases 3, 6, and 13 described here as well as in cases 6 and 12 in part 3 of this series [31].

Case 4 – Simultaneous myelitis and bilateral ON with complete recovery in a child. This 10-year-old Caucasian girl experienced back pain and, within 10 days, developed intention tremor of the upper extremities and complete urinary retention. Neurological examination showed brisk knee jerks without Babinski’s sign and urinary retention, but was otherwise unremarkable. While cranial MRI was normal, axial spinal cord imaging showed two small, non-contrast-enhancing T2-hyperintense lesions in the cervical cord with normal signal in the remaining spinal cord including the conus. Ophthalmological assessment revealed mild bilateral ON with impaired color perception and mild papilledema of the left eye and slightly delayed P100 latencies elicited from both eyes. CSF analysis disclosed 179 cells/μl with a high proportion of neutrophil (69%) and eosinophil granulocytes, mild blood-CSF barrier dysfunction, marginal intrathecal IgM synthesis, and CSF-restricted OCB. Serology and PCR testing ruled out infection with herpes simplex type 1, type 2, and type 6, varicella zoster virus, enterovirus, arbovirus, Borrelia burgdorferi, and Treponema pallidum. CSF cultures for bacterial microorganisms were also negative. The serum tested negative for AQP4-IgG, ANA, and ANCA. CRP was normal. MOG-IgG was present at a titer of Treatment included short-term antibiotics (ceftriaxone) followed by a 5-day pulse of high-dose IVMP and prompted rapid resolution of symptoms. At last follow-up 26 months after onset the patient did not report any residual symptoms; P100 latencies elicited from both eyes were slightly delayed.

Comment: This case – together with cases 8 and 12 as well as case 6 in part 3 of this series [31] – highlights that MOG-IgG-related NMO may begin as early as in childhood or adolescence. As in case 3, the patient presented with bilateral ON at onset and with simultaneous myelitis and ON, two presentations that were previously shown to be more common in AQP4-IgG-negative patients with NMO [34]. Of note, the patient’s spinal cord lesions did not extend over three or more vertebral segments. ‘Non-longitudinally extensive’ lesions have recently been described in two independent studies [34, 93] also in patients with AQP4-IgG-positive NMO; accordingly, LETM lesions are no longer listed among the new, revised 2015 criteria for AQP4-IgG-positive NMOSD [29]. It is of interest that mixed but predominantly neutrophilic pleocytosis was present in this patient; CSF neutrophils were also noted in 21 other patients with CSF pleocytosis and available data. Neutrophil granulocytes were shown to be present also in around 50% of CSF samples in AQP4-IgG-positive NMOSD during acute attacks [76].

Case 5 – Recurrent ON and purely sensory myelitis; good recovery. This Caucasian man developed unilateral ON at age 22 with complete recovery after high-dose IVMP therapy. Lumbar puncture (LP) revealed CSF pleocytosis (128 white cells/μl) and blood-CSF barrier dysfunction. Brain MRI was normal except for optic nerve swelling and Gd enhancement. VEP demonstrated a delayed P100 latency but normal amplitudes. A second ON attack occurred 10 months later but symptoms again remitted completely following IVMP therapy. Over the following 117 months, two more attacks of unilateral ON with complete or almost complete recovery after IVMP occurred, and one attack of myelitis with purely sensory symptoms (including pain/dysesthesia) and bladder bowel dysfunction. Spinal cord MRI showed a short lesion (one vertebral segment) without swelling or Gd enhancement. IVMP treatment resulted in partial recovery. Serum AQP4-IgG was negative, but MOG-IgG was detected at a serum titer of 1:1280. At last follow-up, an EDSS of 1.5 and normal VA was documented. No relapses have occurred so far under treatment with rituximab, which was commenced 2 months before the time of writing.

Comment: This case again illustrates that lesions in MOG-IgG-positive myelitis are not always longitudinally extensive and often exclusively cause sensory symptoms, including pain and dysesthesia. Of note, the latter symptoms were the most common manifestations of myelitis in this cohort, having being present in around 70% of all patients at least once.

II. MOG-IgG-positive NMO with brain involvement

Case 6 – LETM and 13 attacks of ON resulting in unilateral blindness; white matter and callosal lesions. This Caucasian woman had a first, left-sided attack of ON at age 47, with visual loss and retro-orbital pain. MRI showed a longitudinally extensive Gd-enhancing optic nerve lesion on the left side and a clinically inapparent short, Gd-enhancing lesion in the posterior part of the prechiasmatic segment of the optic nerve which extended into the optic chiasm. Symptoms completely remitted following high-dose IVMP treatment. Within 4 months she developed transverse myelitis with thoracic pain, sensory impairment of the abdomen and legs, and urinary incontinence along with blurred vision affecting the other, previously clinically unaffected eye, yet retained high-contrast VA. Spinal MRI revealed two T2 hyperintensities in the thoracic cord; one of these lesions extended over three spinal segments and was accompanied by marked cord swelling and intense contrast enhancement. Cranial MRI showed several non-Gd-enhancing T2-hyperintense lesions in the subcortical supratentorial white matter not involving the corpus callosum. On neurophysiological testing, tibial nerve SSEPs had normal latencies, VEP amplitudes were bilaterally reduced, and P100 latencies were delayed on the left side. The CSF disclosed 14 cells/μl (mostly lymphocytes with a small number of neutrophils) and a normal protein profile without blood-CSF barrier dysfunction and no CSF-restricted oligoclonal IgG bands. The serum tested negative for ANA, anti-ds-DNA-Ab, extractable nuclear antigens (ENA), ANCA, and anti-phospholipid Ab; complement components C3 and C4 were also not altered. High-dose IVMP treatment followed by oral tapering of corticosteroids prompted almost complete recovery of clinical symptoms with mild dysesthesia and restlessness of the lower extremities.

Over the following 12 years, the patient experienced 12 further attacks of mostly unilateral ON, which emerged at a frequency of once or twice per year and were not affected by various long-term immune therapies: 2 of the 12 relapses occurred under treatment with i.m. IFN-beta-1a (1 and 4 months after first injection), 1 under s.c. IFN-beta-1a (less than 2 months after first injection), 1 under s.c. IFN-beta-1b (after 2 months), none under GLAT (6 months), and 1 during a short course of AZA (4 months; no cotreatment with oral steroids). Three PEX cycles (3-5 exchanges each) could also not prevent bilateral deterioration of VA due to recurrent ON with almost complete unilateral blindness and severe contralateral visual loss (0.4 on last follow-up). Of note, two relapses of ON occurred a few weeks after the first and the second infusion of rituximab, respectively. A further relapse of ON took place 12 months after initiation of rituximab therapy and thus probably after reconstitution of B cells. Treatment with IFN-beta-1a, IFN-beta-1b, and GLAT had to be stopped prematurely because of leukopenia; AZA was stopped due to elevated liver enzymes.

Some stabilization of ON frequency was achieved following prolonged therapy with MTX and long-term maintenance treatment with oral corticosteroids (combined with ciclosporin for a period of 7 months); the patient experienced only two further attacks of ON within almost 7 years after implementation of these regimens.

Repeat MRI 2 years after the initial ON revealed numerically stable brain lesions and complete regression of cord hyperintensities; however, after another 2 years, the brain lesion load had increased, with some lesions now involving the corpus callosum and infratentorial white matter tracts. Follow-up laboratory analysis revealed a normal CSF cell count with mildly elevated neutrophils (6%) and protein profile with negative OCB. Serology for AQP4-Ab was negative.

Comment: This case once more illustrates that MOG-IgG-positive NMO is not always a mild and monophasic disease but can take a relapsing course with poor long-term outcome. Here, the disease caused functional blindness in one eye and marked visual loss in the other eye despite IVMP therapy for acute attacks and various immunotherapies. Of particular note and similar to case 12 described below and case 5 in part 3 of this series [31], INF-beta treatment was paralled by several relapses. By contrast, long-term treatment with MTX in combination with oral steroids was followed by significant stabilization.

Case 7 – Recurrent ON and pregnancy-related LETM with permanent functional blindness in one eye; white matter lesions. This female Caucasian patient developed a first episode of unilateral ON in 2005 at age 31 with painful eye movement and blurred vision making reading impossible. Several relapses of unilateral ON occurred up to 2013, all of which responded well to IVMP (5 × 1000 mg) with good partial or full remission of VA. In 04/2013, at which time she was 6 weeks pregnant, she developed numbness of both hands, later accompanied by intense pain of her right arm and shoulder. MRI in 05/2013 revealed an LETM lesion in the cervical spinal cord extending over five vertebral segments. In 12/2013, i.e., only a few weeks after delivery, severe bilateral ON occurred, starting in the left eye and shortly afterwards affecting the right eye. Treatment with IVMP (3 × 1000 mg) and therapy escalation with 2000 mg IVMP 2 weeks later did not result in any significant improvement of the patient’s VA (left eye 0.025 in 02/2014). Following the start of rituximab in 02/2014, very slow subjective improvement of visual function was noted. AQP4-IgG and a broad panel of other anti-neural autoantibodies were negative. MOG-IgG were positive in two samples. Brain MRI was normal at onset but showed inflammatory white matter lesions later. LP revealed pleocytosis (37 cells/μl) but no OCB.

Comment: Of particular note, two attacks in this patient occurred during pregnancy or shortly after delivery, respectively. Similarly, attacks occurred 1.5, 3 and 8 months after delivery in case 12 in part 3 of this series [31] and in cases 23 and 19 described below, respectively. One further patient experienced at least two attacks during pregnancy (see case 13 in part 3 [31]). An increase in relapses post partum has been reported in MS [108], and a negative influence of pregnancy on the disease course has been suggested in NMO as well [85, 86]. On the other hand, disease onset preceded pregnancy by more than 8 years in our patient and several relapses had occurred before the first pregnancy-related attack. A simple coincidence thus cannot be ruled out. Note the poor outcome in this patient: While IVMP was initially effective, both high- and ultra-high-dose IVMP therapy failed to restore vision later on, resulting in permanent visual loss in the left eye.

Case 8 – LETM and recurrent bilateral ON with transient blindness but full recovery in a young boy, ventricular lesion. This young Caucasian male patient first presented in September 2006 at age 12 with an attack of bilateral ON with blurred vision. The symptoms remitted partially after IVMP pulse therapy.

Six weeks later, he developed headaches and tetraparesis. MRI showed a supratentorial lesion at the anterior horn of the right lateral ventricle and a cervical lesion extending from C2 to C6 level with Gd enhancement and swelling. ADEM was suspected. Extensive laboratory examinations did not reveal any infectious or rheumatological cause. Family history was negative for relevant autoimmune diseases. LP showed a normal CSF WCC, normal CSF protein, glucose, and lactate levels, and negative OCB. After IVMP therapy, vision and muscle strength returned to normal.

The third attack occurred in 03/2012 with almost complete loss of vision of the right eye. LP revealed a normal CSF WCC, normal CSF protein concentration, and negative OCB. AQP4 antibodies were negative. Cerebral MRI showed Gd enhancement of the optic chiasm. VEP revealed bilaterally delayed P100 latencies with normal amplitudes. OCT demonstrated bilateral temporal thinning of the retinal nerve fiber layer (RFNL). No clinical signs or symptoms of myelitis were present, but MRI showed a T2 lesion at C3, spanning around one and a half vertebral segments, as well as diffuse lesions extending from level C4 to C7 and from level T7 to T9 with Gd enhancement and swelling. After treatment with IVMP, symptoms remitted completely. MS with an opticospinal focus or NMO was suspected and treatment with GLAT was initiated.

Spinal cord MRI in 09/2013 showed remission of the cervical lesions with a remaining small lesion at C2. At last follow-up in 06/2015, after 36 months of treatment with GLAT, the patient did not report any further clinical relapses and had only mild clinical deficits (EDSS 1).

Comment: While bilateral ON and myelitis did not occur strictly simultaneously in this patient, the interval between the two events was just 6 weeks. Similarly, a very short median time to first relapse (5 months) was found in the total cohort. This suggests that patients presenting with a first attack of MOG-IgG-positive ON or myelitis should be closely monitored and treated early. The severe symptoms noted during acute ON (almost complete unilateral blindness) contrast remarkably with the complete remission achieved after IVMP in this case. Note the young age at onset in this and in three other patients (cases 4 and 12 here and case 6 in part 3 of this article series [31].

Case 9 – Bilateral ON and subsequent LETM with late onset and only partial recovery, callosal lesions on MRI. This Caucasian woman developed bilateral optic neuritis in 11/2009 at age 64 with spontaneous complete remission within 6 weeks but subsequently prolonged P100 latencies. From 01/2011, she complained of increasing dysesthesia in both forearms and impaired ambulation. Spinal MRI in 05/2011 showed two cervical contrast-enhancing lesions. LP revealed identical OCB in CSF and serum (mirror pattern) and a normal cell count. AQP4 antibodies were negative. Except for ANA (1:160), no other concomitant autoantibodies were detected. Treatment with IVMP in 05/2011, 07/2011, and 09/2011 did not result in significant improvement of the still increasing dysesthesia. In 10/2011, spinal MRI showed diffuse hyperintensity ranging from C2 to C6 with Gd enhancement. Cranial MRI revealed numerous non-specific T2 hyperintensities considered to reflect microvascular lesions due to a long history of hypertension. In 12/2011 MOG-IgG was tested for the first time and was positive at a titer of 1:1280. After 11 courses of PEX (12/2011 to 08/2013) and 29 months of treatment with AZA (2 x 50 mg/day, from 01/2012) dysesthesia was still present but not increasing anymore and no further relapses had occurred at last follow-up (06/2014). Follow-up MRI in 02/2013 showed, in addition to the vascular lesions, callosal lesions compatible with focal demyelination and residual discrete T2 hyperintensities in the cervical spinal cord.

Comment: As in 14 further cases, disease started with bilateral ON in this patient. While bilateral ON had traditionally been considered typical for NMO, it was recently shown to be in fact more frequent in AQP4-IgG-negative than in AQP4-IgG-positive patients with NMOSD at disease onset [34]. Of particular interest, LETM was purely sensory, characterized by excruciating dysesthesia, took a protracted or even progressive course, and did not respond to repeat IVMP treatments over a period of 12 months; only PEX and subsequent immunosuppression brought some relief. Surprisingly, 15/19 (78.9%) patients in this cohort reported at least one occurrence of dysesthesia or pain during acute myelitis attacks. Dysesthesia and pain are also common symptoms in AQP4-IgG-positive NMO and are the only symptom in some patients [34]. Both MOG-IgG- and AQP4-IgG-related EM should be considered in the differential diagnosis of patients presenting with purely sensory symptoms compatible with myelitis.

Case 10 – Recurrent attacks of ON and myelitis with good partial recovery; subcortical and callosal lesions. This Asian male patient developed bilateral optic neuritis (VA not documented) in 12/2006 at the age of 35. CSF examination showed a normal cell count and normal protein, glucose, and lactate levels with negative OCB. Brain MRI showed Gd enhancement of both optic nerves, one subcortical lesion in the left cerebral hemisphere, and one lesion in the corpus callosum. Spinal cord MRI was not performed at that time. After IVMP pulse therapy complete remission was documented. Extensive laboratory work-up did not reveal any infectious or rheumatological cause of the symptoms.

A second attack occurred in 10/2007 with clinical symptoms of myelitis (paraparesis, urinary retention, and tingling sensation in the lower extremities). LP revealed an increased cell count (197 cells/μl) with a normal protein level and negative OCB. Spinal MRI showed multifocal myelitis of the upper cervical and thoracic segments (C3-C4, T3-T4) with patchy gadolinium enhancement. After IVMP pulse therapy there was only partial remission and slight unsteadiness of gait remained. MS with an opticospinal focus or neuromyelitis optica was suspected. Treatment with AZA 2 mg/kg (150 mg/day) was initiated and was continued until 07/2008 when treatment was stopped due to clinical stabilization.

The third attack occurred in 03/2010 with unilateral optic neuritis. MRI showed Gd enhancement of the right optic nerve and the previously known T2 lesions with patchy gadolinium enhancement. AQP4 antibodies were tested 4 times during this period and were always negative. Complete remission after IVMP pulse treatment was achieved.

After a fourth attack in 08/2010 with tingling sensation of the lower extremities which was treated with 5 g IVMP with complete remission, treatment with AZA was reinitiated directly after discontinuation of IVMP.

Beginning in 01/2011 (i.e., still within the latency period of AZA) another relapse of myelitis with tingling sensation of the lower extremities and of the right hand (EDSS 2) was treated successfully with IVMP. A VEP examination performed at that time revealed delayed P100 latencies bilaterally with normal amplitudes. OCT showed bilateral thinning of the RFNL. Cerebral and spinal MRI did not show any disease activity. AZA was increased to 200 mg/day and later continued at 150 mg/day. The last MRI of the head and spinal cord was performed in 04/2014 and showed no disease activity. The patient was still relapse-free at last follow-up in 04/2015 with an EDSS of 2.5. In total, this patient has experienced five attacks, comprising two attacks of ON (1 × bilateral) and three of myelitis.

Comment: First, the presence of callosal brain lesions noted in this patient and in others in our study (see cases 6 and 9 here and cases 3 and 8 in part 3 [31]) renders the radiological differential diagnosis of MOG-IgG-positive EM and classical MS more challenging. Callosal lesions have also been observed in AQP4-IgG-positive NMO, where they are typically long (half of the length of the corpus callosum or greater), diffuse, heterogeneous, or edematous [29, 109]. In the present cohort, a longitudinally extensive callosal lesion was noted only in a single patient (see case 3 in part 3 of this series [31]). Second, as a result of ON, RFNL thinning as detected by OCT was present in this as well as in several other patients. Similar findings have previously been reported in AQP4-IgG-positive patients [110, 111]. A detailed OCT analysis of 16 patients with MOG-IgG-positive ON can be found in part 4 of this article series [32].

III. MOG-IgG-positive recurrent ON

Case 11 – Three attacks of ON; no brain lesions; functional blindness in the left eye. A 53-year-old woman first noted reduced vision and pain on moving the right eye in 05/2011. Clinical examination demonstrated a VA of 0.1 in the right eye and 1.0 in the left eye, as well as color desaturation and a relative afferent pupillary defect of the right eye. Cranial MRI showed right optic neuritis, but no parenchymal brain lesions. VEP were slightly delayed in the right eye, but amplitudes were preserved. CSF analysis was normal; in particular, there were no CSF-specific OCB. The patient was treated with high-dose IVMP (2 g/d for 3 days), which resulted in improvement of symptoms. However, about 3 weeks later vision in the right eye deteriorated again.

In 11/2011, she also noted reduced vision in the left eye. She was again administered several courses of IVMP, which did not improve VA, so that she was subsequently treated with four courses of IA. This was associated with almost complete recovery over the next 3 years.

At the end of 11/2014 she again noted reduced VA in the left eye. A cranial MRI performed in 12/2014 showed a left optic neuritis with contrast enhancement as well as hyperintensities in the right optic nerve without contrast enhancement, but no further cerebral lesions. She was again treated with IVMP and four courses of IA, which resulted in only incomplete recovery. In 03/2015, when her VA was finger counting in the left and 0.2 in the right eye, she was admitted to our department. She was tested for serum antibodies to MOG, which were positive both in a live-cell and in a fixed-cell CBA (determined after IA). She was treated with IVMP, five courses of PEX, and rituximab (2 × 1000 mg). However, VA recovered only slightly. At the last follow-up in 05/2015 her vision was 0.2-0.3 in the right and 0.02 in the left eye.

Comment: This case, together with cases 12-18, demonstrates that MOG-IgG-associated ON is not always a monophasic disease but frequently follows a relapsing course. In fact, recurrent ON was noted in 65% of all patients with isolated ON in the present study. Moreover, the disease took a very severe course with partly therapy-refractory attacks, leading to permanent functional blindness in one eye and substantial loss of VA in the other eye. As in other patients in this series, high-dose and even ultra-high-dose IVMP treatment improved the symptoms only transiently or not at all. Although IA was initially effective, it could not restore vision when used to treat a subsequent relapse. While the reason for that discrepancy is unknown, the relatively long time (6 weeks) between attack onset and IA might have played a role. Alternatively, IA as well as PEX might not result in a sufficient decrease in MOG-IgG titers in some patients if not repeated long enough; finally, other pathomechanisms than antibody-related ones, e.g., T cells, might have been involved.

Case 12 – Recurrent ON in a child; no brain lesions; severe permanent visual loss. This Caucasian girl experienced a first episode of ON in 04/2001 at age 6; this attack was bilateral (OD> > OS) with papilledema. VEP showed prolonged P100 latencies. LP demonstrated mild CSF pleocytosis (7 leukocytes/μl). Brain MRI was normal. Symptoms remitted spontaneously. Two years later (04/2003) a second attack of ON occurred, affecting the right eye. Symptoms improved with IVMP. A third attack of ON, again of the right eye, developed 11 months later in 03/2004. CSF was normal. A serum sample drawn in 2004 that was later retrospectively tested was positive for MOG-IgG. When right-sided ON recurred in 08/2008, temporal pallor was noted on fundoscopy bilaterally. In 2009, ocular myositis was suspected, but no additional information is available. In 01/2013 another attack of unilateral ON occurred, associated with contrast enhancement of the right optic nerve; symptoms improved with IVMP. In 04/2013, the patient was started on IFN beta-1a s.c. However, she experienced two more attacks of right-sided ON in 10/2013 and 03/2014, leading to the discontinuation of IFN-beta treatment; both relapses improved after IVMP. MRI still did not show any brain lesions in 10/2013, i.e., 12 years after onset. VA was 0.4 in the right and 0.8 in the left eye at that time. AQP4-IgG antibodies were negative. An OCT examination in 04/2014 showed massive thinning of the RNFL in both eyes (OD > OS). In 07/2014 and again in 01/2015, the patient received two doses of rituximab (2 × 1000 mg, 2 weeks apart). At last follow-up in 03/2015 no further relapses had occurred.

Comment: This is one of the youngest Caucasian patients with MOG-IgG positive ON reported thus far. MOG-IgG autoimmunity is an important differential diagnosis in pediatric patients presenting with NMOSD and other forms of CNS inflammation of unknown cause [107, 112, 113]. The patient’s relapsing disease course confirms that MOG-IgG in pediatric patients with ON is not, as originally thought, limited to monophasic cases [11–13]. Of particular note, the disease has been restricted to the optic nerves in this patient for more than a decade, both clinically and radiologically. As in two other patients (case 6 here and case 4 in part 3 of this series [31]), treatment with IFN-beta was not effective in preventing relapses.

Case 13 – Recurrent ON with late onset; no inflammatory brain lesions; permanent unilateral blindness. This Caucasian woman developed severe bilateral optic neuritis in 12/2003 at age 66 following a gastrointestinal infection with positive Yersinia serology (species not specified). VA at nadir was 0.1 in both eyes. VEP showed no response of the right eye and was delayed on the left side. Symptoms partly responded to IVMP and oral prednisolone. Brain MRI was normal except for numerous vasculopathic lesions due to decades of hypertension. LP showed CSF pleocytosis (80 cells/μl) but no OCB.

The patient was treated with AZA (150 mg/d) and oral steroids from 03/2004 to 11/2004. However, one ON relapse in the right eye occurred at the end of 04/2004 (with a flare-up in mid-05/2004) and a second in 10/2004 after tapering prednisolone to below 10 mg/day. Symptoms did not substantially improve despite several courses of IVMP (VA 1/35). A follow-up CSF examination performed at that time was normal.

In 11/2004, treatment was switched to MTX (15 mg/week). In 01/2006, the patient experienced another attack of unilateral ON, which led to blindness of the right eye. The patient declined IVMP, and symptoms did not improve spontaneously.

No further relapses have occurred under treatment with MTX since then. In 06/2013 VA of 0 on the right and 1.0 on the left side was documented. At last follow-up, in January 2016, the patient was still on MTX (2.5 mg/day). She never experienced any signs or symptoms of myelitis; spinal MRI (11/2004) was normal. Slightly elevated ANA (1:80) were documented on one occasion, but she has no coexisting autoimmune disorders.

Comment: This case is interesting for several reasons: First, disease started after an acute infection, as also seen in at least 10 other patients in our series. Infections have also been reported as a trigger of acute attacks in AQP4-IgG-positive NMOSD [34] and in classic MS [114]. Second, tapering of steroids resulted in recurrence of the patient’s symptoms. Similarly, withdrawal of steroids or reductions in steroid dosage resulted in flare-ups in 20 further patients in our series. Third, disease resulted in permanent blindness in one eye in this patient. Similarly, a decline in VA ≤0.5 occurred in 85% of our patients during relapse and severe visual impairment or functional blindness was present in 37% at last follow-up. This underlines that the notion of MOG-IgG-associated ON being generally mild is incorrect. Fourth, while two attacks occurred under treatment with AZA (and cotreatment with oral steroids) within a period of 9 months in this patient, only one – albeit very severe – relapse occurred under MTX over a period of 10 years. The favorable disease course observed in this and in other MTX-treated patients in this study (see cases 3, 6, and 13 here and cases 6 and 12 in part 3 of this article series [31]) warrants further investigations into the potential efficacy of MTX in MOG-IgG-related autoimmunity.

Case 14 – Recurrent ON starting at age 28; no brain lesions; permanent functional blindness of the left eye. This patient presented with unilateral ON (VA OD 1/35) in 05/2009 at age 28. Symptoms improved following high-dose IVMP (3 × 1 g), but recurred shortly thereafter (VA OD 1/35) and only partly responded to a second IVMP (3 × 1 g) cycle (VA 0.2). Brain MRI was normal.

Five months after onset, the patient developed left-sided ON, which fully responded to IVMP. Brain MRI was again normal, except for enhancement of the left optic nerve and edematous thickening of the right optic nerve. VEP examination revealed bilaterally prolonged P100 latencies (OD > OS) and reduced amplitudes.

Another attack of ON, on the left side, occurred 2 months later with severe visual loss (VA 0.1). Fundoscopy revealed mild papilledema. IVMP and 10 plasma exchanges resulted in partial improvement. The patient was started on AZA 100 mg/day in 10/2009 with 6 months cotreatment with oral steroids. In 02/2012, she experienced another relapse of ON, which partially responded to IVMP. The patient had no other immune disorders except for pollinosis. LP had revealed mild pleocytosis (14 cells/μl) but no CSF-restricted OCB and no blood-CSF barrier dysfunction. A serum sample obtained 2 weeks after IVMP therapy was positive for MOG-IgG at a titer of 1:160 in the live-cell assay. MOG-IgG-seropositivity was confirmed in the fixed-cell assay. AQP4-IgG was negative. At last follow-up VA of 0.1 in the left eye was documented.

Comment: As in many patients in this series, the first high-dose IVMP cycle led only to transient remission of symptoms in this case; moreover, only partial recovery was achieved after a second cycle applied for the same attack as well as during two later attacks. The observation of many cases of partial or complete IVMP failure in this series suggests that additional treatment options should be considered in MOG-IgG-positive patients presenting with acute ON or myelitis. It is unknown why IVMP was effective during some attacks, but not all, in this and other patients. However, timing issues and differences in antibody titers, other immunological parameters (e.g., T cell activation), IVMP dosage, and previous or concomitant treatments might all play a role. Note the poor outcome in this case. Functional blindness in at least one eye was also noted in 9 additional patients at last follow-up.

Case 15 – Three attacks of ON; no brain lesions; full recovery. This 25-year-old woman presented in 10/2010 with bilateral ON accompanied by visual loss and retro-orbital pain on eye movement. Fundoscopy revealed optic papillitis in both eyes. Except for a marginal difference in biceps tendon reflexes the neurological examination was normal. LP showed normal intracranial pressure, slight pleocytosis (6 cells/μl), normal CSF total protein, glucose, and lactate levels, and negative OCB. VEP were lost in both eyes. Cerebral MRI was normal including the optic nerves. Spinal MRI was not performed at that time. AQP4 antibodies were negative as were extensive infectious and rheumatological laboratory diagnostics. After IVMP therapy (1 g/d for 5 days), the patient completely recovered within 2 weeks.

In 11/2010, 4 weeks after onset of the first symptoms, a second attack occurred with complete visual loss in the right eye and a decrease in VA to 60% in the left eye. Ophthalmological examination revealed bilateral optic papillitis. VEP in both eyes could not be elicited. IVMP pulse therapy (2 g for 5 days), followed by oral reduction over 4 weeks, led to rapid and complete recovery.

The patient was clinically stable without any maintenance therapy until 11/2014, when she developed a third attack of ON with a decrease in VA of the right eye to 40% and papillitis of the right optic nerve. The neurological examination was normal. Two cycles of IVMP pulse therapy (1 g/d) for 3 and 5 days, respectively, resulted in complete remission after 2 weeks. In 12/2014 a second brain MRI and a first spinal cord MRI were performed, each with normal findings. SSEP were normal as well.

MOG antibodies were first determined in 03/2015 and were positive. AQP4 antibodies were still negative. At that point the patient was free of symptoms and VEP were normal in both eyes. The patient rejected the idea of commencing any long-term immunosuppressive treatment.

Comment: Despite recurrent disease and severe acute visual impairment with transient blindness and loss of VEP, this patient recovered completely from all attacks following high-dose IVMP (and subsequent oral tapering for one attack). Remarkably, there were no clinical, radiological, or electrophysiological signs of myelitis, brain, brainstem, or cerebellar involvement 3 years after onset; similarly, there was no evidence for spatial dissemination at last follow-up in around a quarter of all MOG-IgG-positive patients in this study.

Case 16 – Recurrent ON; no brain lesions; significant visual loss in both eyes. This patient had a first attack of ON at age 58. At last follow-up, 86 months after onset, eight unilateral ON attacks alternately affecting the left and the right eye (never simultaneously bilateral) had occurred but no brain or spinal cord involvement was noted. MOG-IgG were detected retrospectively in a stored sample taken under treatment with oral steroids. VA was 0.4 in the left and 0.5 in the right eye at the last follow-up visit (during remission). There was no relevant comorbidity, including no concomitant autoimmune diseases, and no autoantibodies other than MOG-IgG were detected.

Comment: This case, which is characterized by high disease activity (ARR 1.2) and poor long-term outcome, again illustrates that MOG-IgG-positive ON is not always a monophasic and mild disease. Disease activity varied substantially among untreated patients with isolated ON. While this patient experienced eight ON attacks within just 86 months, no relapse occurred within 72 months in case 22. This renders decisions about long-term treatment difficult, all the more as reliable long-term prognostic markers are lacking. However, with more than 60% of all patients with isolated ON having developed relapses and around two thirds of those with relapses having been functionally blind or otherwise severely impaired in at least one eye at last follow-up, long-term treatment should be considered in most cases.

Case 17 - Recurrent bilateral ON; transient unilateral blindness; full recovery. This Caucasian woman developed a first episode of bilateral ON at the age of 50, presenting with bi-frontal headache, painful eye movements, and blurred vision. VA was 0.5 in the right and 0.8 in the left eye at first clinical presentation. VEP displayed a prolonged P100 latency (right > left). Brain MRI showed contrast agent enhancement of both optic nerves but was otherwise normal, as was spinal cord MRI. CSF revealed mild pleocytosis (21/μl, lymphomonocytic), elevated total protein (929 mg/l), no OCB, and a normal IgG CSF/serum ratio. No other laboratory abnormalities were noted (ANA, ANCA, cardiolipin, beta2-glycoprotein, ACE, soluble IL2R, borreliosis, syphilis). The patient’s medical history was unremarkable except for arterial hypertension. Following high-dose IVMP, VA initially improved to 0.7 right and 1.0 left; however, a bilateral flare-up of ON occurred within 30 days, resulting in a drop of VA to light perception on the right and 0.5 on the left. The patient received five plasma exchanges which resulted in full recovery.

Three months later another bilateral ON attack with a large scotoma occurred. Full remission (bilateral VA 1.0) was achieved with high-dose IVMP. A further 2.5 years later (10/2012) the patient experienced a mild ON attack with blurred vision but without a drop in VA in the right eye. Following the patient’s preferences, no relapse treatment was given and no preventive immunosuppressive treatment was initiated. Re-testing for serum autoantibodies was unremarkable (NMDA-IgA/IgG, amphiphysin, CV2/CRMP5, Ma2/Ta, Ri, Yo, Hu, LGI1, CASPR2, GABA-B receptors, AMPA receptors, GAD, MAG, c-ANCA, p-ANCA, rheumatoid factor, ganglioside antibodies) except for low-titer ANA (1:160). At last follow-up (11/2015) VA was 1.0 in both eyes and no further relapses had occurred.

Comment: Disease again affected exclusively the optic nerves. The excellent long-term outcome despite large scotoma and near-blindness during acute attacks is remarkable. As in around 44% of all patients, IVMP was only transiently effective when used to treat acute attacks; PEX was required to achieve full remission but, of particular note, could prevent further relapses only for 3 months.

Case 18 – Recurrent ON with late onset; permanent functional blindness; stabilization under rituximab. A 58-year-old woman with a history of hepatitis A two decades previously developed amaurosis in the right eye and headache in 04/2014. Clinical examination revealed a VA of 1/100 in the right eye with global alteration of right visual field and delayed and reduced amplitude of P100 wave at visual evoked potential (VEP). Brain MRI showed T2/FLAIR hyperintensity of the right optic nerve with spotty post-contrast enhancement and non-specific subcortical frontal hyperintense lesions. Spinal MRI and CSF were normal. Routine laboratory examinations were normal except for low-titer ANA (1:80). Despite treatment with high-dose IVMP, almost no improvement was achieved (VA 1/10). Two months later (06/2014) the patient developed left-sided ON. Treatment with oral steroids resulted in only mild improvement (5-6/10). Two and four months later (08/2014 and 10/2014), respectively, further ON attacks affecting the left eye occurred; high-dose IVMP was followed by almost full recovery of VA in this eye. At that time, serum positivity to anti-MOG antibodies was detected. In 10/2014 treatment with rituximab (2 × 1000 mg, 2 weeks apart) and oral steroids was started and was followed by further improvement of VA in the left but not in the right eye. At a follow-up visit 1 year after the last attack, VA was 9/10 on the left (with normal VEP) and 1/10 on the right. Of note, CD19 cells were still undetectable 14 months after the first rituximab infusion in this patient.

Comment: While this patient almost completely recovered from three ON attacks in the left eye, no improvement had been achieved after the initial attack, which had affected the right eye and had left the patient functionally blind. This illustrates that the severity of MOG-IgG-associated attacks varies substantially not only between patients but also intraindividually. Studies investigating risk factors for poor attack outcome in MOG-IgG-positive patients are highly warranted.

IV. MOG-IgG-positive monophasic ON

Case 19 – Single episode of post-infectious bilateral ON 8 months post partum; no brain lesions; partial recovery. A 30-year-old woman who was breastfeeding her 8-month-old healthy daughter noticed bilateral blurred vision, pain when moving the eyes, and moderate frontal headaches in February 2011. During the weeks before symptom onset, she had had common colds with mild fever. Her past medical history was otherwise unremarkable. Ophthalmological examination demonstrated reduced VA of the right (1/25) more than of the left eye (0.5), reduced color vision in the right eye, and papillitis of the right more than of the left eye. Visual field examination revealed bilateral large centrocecal scotomas, again more prominent in the right eye. The patient was admitted to our department, where the rest of the neurological examination was normal. Cranial and orbital MRI demonstrated contrast enhancement in both optic nerves, compatible with bilateral optic neuritis, but no lesions in the brain parenchyma. Spinal MRI and chest radiography were unremarkable. CSF analysis revealed a mildly elevated total cell count of 12 white blood cells per μl (reference range, <5/μl) with 88% lymphocytes and 12% monocytes. CSF protein and lactate were normal and there were no CSF-specific OCB. A complete blood count and C-reactive protein were normal, as were microbiological (Borrelia, Treponema pallidum, Toxoplasma) and virological tests (herpes simplex virus type 1 and 2, varicella zoster virus). ANA were detectable at a titer of 1:320. Screening for ENA, ANCA, and AQP4-IgG was negative. However, antibodies to MOG were detected in the patient’s serum at a titer of 1:1280. The patient was treated with IVMP (1 g/day for 5 days). An ophthalmological follow-up examination in August 2011 showed markedly improved VA of the right (0.7-0.8) and left (0.7) eye. The visual field defects had almost completely resolved. Funduscopy revealed bilateral mild temporal disk pallor consistent with mild partial optic atrophy.

Comment: This patient developed her first relapse in the third trimester post partum. The first 9 months after pregnancy have been previously identified as a risk period for relapses both in AQP4-IgG-positive NMO [85, 86, 115] and in MS [108]. However, systematic studies comparing ARRs before, during, and after pregnancy in MOG-IgG-positive patients are still lacking. Of note, the temporal association between the two events could still be coincidental in the present case, all the more as disease onset was also preceded by feverish infection. Remarkably, almost complete recovery was achieved despite substantial visual loss during an acute attack.

Case 20 – Protracted single episode of bilateral ON; delayed SSP; no brain lesions; complete recovery. This Caucasian man developed a first, bilateral ON at age 70 with severe vision loss (0.5 OD, 0.4 OS), papilledema, scotoma, and delayed P100 latencies (but no or only marginally reduced P100 amplitudes). Treatment with high-dose IV prednisolone (1000 mg 3d) with oral tapering resulted in marked but incomplete short-term recovery with persisting contrast sensitivity impairment and hazy vision. Within 4 weeks from onset of symptoms bilateral visual loss (0.5 OD and OS) and scotoma recurred and improved gradually after a second course of high-dose i.v. prednisolone (1000 mg 3 d) with oral tapering and additional intravenous antibiotics (sobelin, ceftriaxone). Brain MRI revealed slight perineural contrast enhancement around the left optic nerve and signs of ethmoidal cell sinusitis, but was otherwise unremarkable. While spinal MRI did not unequivocally reveal any lesions, tibial nerve SSEP were bilaterally delayed (69 ms on the right; only late components obtainable on the left), suggesting possible subclinical myelitis. Median nerve SSEP were normal except for a side difference in latencies. Transcortical magnetic stimulation to the legs was normal as well. CSF assessment revealed a normal cell profile, mild blood-CSF barrier dysfunction, and no OCB. AQP4-IgG-testing was negative. The patient had been diagnosed with hepatitis B more than 20 years before onset of symptoms; however, Hbs, HBc-IgG, HCV-IgG, and HBE were all negative at the time of ON, as were ANA, ANCA, CRP and rheumatoid factor. Chest radiography did not reveal evidence of sarcoidosis, and serum ACE was normal. At repeated long-term follow-up visits (most recently in 10/2010) complete recovery was confirmed with normal VA and no evidence of scotoma.

Comment: This case, alongside the pediatric cases reported here, illustrates the broad variability in age of onset in MOG-IgG-related disorders. A late onset (>60 years) was also observed in two further patients (66 years in case 13; 64 years in case 9). While MOG-IgG were originally described in pediatric patients with ADEM, these cases demonstrate that MOG-IgG need to be considered also in elderly patients presenting with a first attack of optic neuritis or myelitis. Moreover, this case is one of the few monophasic ones, with no relapse more than 6 years after onset. By contrast, disease followed a relapsing course in 80% of all MOG-IgG-positive patients in this cohort, irrespective of clinical presentation.

Case 21 – Single episode of unilateral ON; no brain lesions; complete recovery. This man presented at age 53 with unilateral retrobulbar ON of the left eye (VA 0/10, peripheral scotoma, intraorbital swelling, and Gd enhancement of the optic nerve with contrast enhancement, VEP delayed and amplitudes reduced; right eye normal). LP was unremarkable with 2 cells/μl, no OCB, and normal CSF/serum ratios of IgG and albumin. MRI revealed no extra-optic nerve brain lesions. MOG-IgG were positive at a titer of 1:1280 prior to treatment. Treatment with high-dose steroids resulted in marked improvement (1 mg/d for 6 days) with complete recovery after some months (VA 10/10). Electrophysiological control examinations 7 and 18 months after onset showed only a residual borderline delay in P100 latency on the left side; brain MRI was still normal 25 months after onset; and at last follow-up at month 75 no new symptoms had occurred. The patient had a history of poliomyelitis during childhood and of brucellosis 12 years prior to ON. Serum AQP4-IgG was absent, but MOG-IgG was present at a titer of 1:1280.

Comment: The favorable attack outcome – with complete recovery following IVMP treatment – and the monophasic disease course – with no new symptoms 75 months after onset – once more illustrate the broad variability in prognosis in MOG-IgG-positive ON.

Case 22 – Single episode of unilateral ON; no brain lesions; persisting visual deficit. A 29-year-old man developed sudden loss of vision and reduced visual field in the right eye. VA was initially 20/200 in the affected eye. Unilateral ON was diagnosed. Brain MRI and intracranial pressure were normal. CSF showed normal leukocyte count, IgG index, and protein level, and no OCB. AQP4-IgG was negative. At follow-up, persisting visual loss (20/60) of the right eye was apparent. So far, no further attacks have occurred. Of note, this patient had psychiatric difficulties in the past (classified as ADHD) and a previous history of central diabetes insipidus of unknown cause with onset at age 7 years.

Comment: It remains unknown whether the patient’s diabetes insipidus and psychiatric symptoms were caused by CNS autoimmunity. Of note, however, psychiatric symptoms (psychomotor slowing, disorientation, and impaired consciousness) were present in two further patients in this series (described in detail in part 3 [31]) and occasionally occur also in AQP4-IgG-positive patients [116–118]. Central diabetes insipidus, which is characterized by a lack of antidiuretic hormone (ADH) in the brain, has been previously reported in a patient with NMO but unknown AQP4-IgG and MOG-IgG serostatus [119], and several AQP4-IgG-positive NMOSD patients with Schwartz-Bartter syndrome (also termed syndrome of inappropriate ADH secretion) due to hypothalamic lesions have been described over the past few years [120–122].

Case 23 – Post-partum episode of ON; possible onset of disease already at age 10; low- rather than high-contrast VA affected. In 1995, at the age of 10 years, this Caucasian patient had suffered from a self-reported “Borrelia-induced meningitis” with headache, diplopia, and bulbar movement pain, with one recurrence 1.5 years later. More than 18 years later, in 07/2015, and 3 months after delivery of her first child, the then 30-year-old woman developed subacute retrobulbar pain and frontal headache on the left side, as well as “focusing deficits” of her left eye. A neurological examination performed 2 weeks after symptom onset was normal including high-contrast VA (1.25 on both sides), but refined vision tests revealed a bilateral reduction of the low-contrast VA (right eye: 0.8; left eye: 0.6). Brain MRI showed a T2-hyperintense left optic nerve lesion and a few bi-frontal non-specific white matter lesions that did not fulfill the diagnostic criteria for MS. MRI of the cervicothoracic spinal cord was unremarkable. LP, performed 3 weeks after symptom onset, revealed slight pleocytosis (9 cells/μl) but was otherwise normal; in particular, OCB were negative. VEP showed normal amplitudes and delayed P100 latencies in the left eye, but only when directly comparing the two eyes with each other (right: 104 ms; left: 112 ms). By contrast, spectral-domain OCT revealed severe bilateral thinning of the RNFL, most prominent in the temporal sectors of both eyes (mean RNFL right: 75 μm, mean RNFL left: 68 μm). Motor, somatosensory, and acoustic evoked potentials were unremarkable. A broad laboratory work-up including ANA, cANCA, pANCA, and AQP4-IgG, was negative. Anti-MOG-IgG antibodies were positive at 1:320. MOG-IgG seropositivity was confirmed by a fixed-cell CBA. While maintaining breastfeeding the patient was treated with IVMP for 5 days (1000 mg once daily), which led to a reduction of the left-sided retrobulbar pain up to the time of the last follow-up in 10/2015. At that time, the patient still refused any long-term immunosuppressant treatment.

Comment: This case is interesting for several reasons. First, the patient presented with unilateral retrobulbar pain and headache but normal VA as detected by Snellen chart and near-normal VEPs. Only additional tests (MRI, OCT, and low-contrast VA testing) revealed marked bilateral optic nerve damage. Similarly, no impairment of high-contrast VA but pathological VEPs were found in cases 25 and 27 here as well as in case 2 in part 3 of this series [31]. These cases indicate that subclinical ON needs to be taken into account also in MOG-IgG-positive patients with apparently normal VA as routinely detected by a Snellen score. Second, symptoms compatible with previous episodes of ON (retrobulbar pain) headache and brainstem encephalitis (diplopia) had occurred 20 and 18.5 years before the present attack in this patient, though it remains unknown whether she was already positive for MOG-IgG at that time. Similarly, disease started with an attack of unilateral ON at age 13 in another patient in this cohort (see case 6 in part 3 of this series [31]), which was followed by a first attack of myelitis only several decades later. Long intervals between first and second attack (up to 17 years) have also been described in AQP4-IgG-positive patients [34]. Third, only OCT, not MRI or VEP, was able to demonstrate damage also of the right optic nerve. Fourth, as in cases 7 and 18 here and in case 12 in part 3 [31], symptoms developed post partum, a period associated with an increased risk for relapse also in MS [108] and in AQP4-IgG-positive NMOSD [115].

Case 24 – Fifteen attacks of ON with poor response to treatment and unfavorable bilateral functional visual outcome. In 2013, this 42-year-old female Caucasian patient experienced for the first time typical clinical signs of left-sided ON, with reduced vision, red color desaturation, and eye pain. Fundoscopic examination showed a hyperemic and swollen papilla of the left eye. The VEP amplitudes were reduced on the left side. Further diagnostic work-up including anti-AQP4 antibodies, onconeural antibodies, and immunological screening was negative. The CSF was normal; in particular, there was no pleocytosis, no OCB, and no disruption of the blood-CSF barrier function. MRI of the brain showed an intense, long-segment gadolinium (Gd) enhancement of the left optic nerve, but only few non-MS-specific T2-hyperintense white matter lesions without subclinical progression or Gd enhancement in follow-up scans. The brainstem was never involved clinically or radiologically. Although the patient reported fluctuating paresthesia of both legs and left arm, there was no further clinical, radiological, or electrophysiological evidence for myelitis.

Due to repeated relapses of isolated ON predominately affecting the left eye and partial response to steroid treatment, diagnosis of a chronic relapsing inflammatory optic neuropathy (CRION) was suggested. After 26 months the patient had experienced altogether 15 relapses of ON, consecutively affecting both eyes, but never with simultaneous bilateral involvement.

Except for two attacks (including the initial one), which both remitted completely, she responded only partially to high-dose IVMP treatment. One relapse was treated with PEX, but to no avail. Successive immunosuppressive treatment with AZA (up to 200 mg per day over 9 months and cotreatment with oral steroids), MTX, mycophenolate, and continuous prednisone failed to prevent further attacks of ON. At the time of the last follow-up, 26 months after onset, she had a residual VA of < 0.2 in both eyes.

Comment: The poor visual outcome after just 26 months and the high number of relapses despite regular IVMP treatment for acute relapses and various IS therapies illustrate that MOG-IgG-positive ON may take a severe, relapsing, and sometimes therapy-refractory course. Testing for MOG-IgG should be considered in all patients with suspected CRION.

V. MOG-IgG-positive recurrent LETM

Case 25 – Recurrent LETM; slightly delayed VEP; no brain lesions; almost complete recovery. This 22-year-old Caucasian woman presented with bilateral dys- and hypesthesia of the lower limbs in 11/2011. The neurological examination additionally revealed very mild foot flexor and extensor paresis bilaterally (5-/5) and saddle anesthesia. MRI of the complete neuroaxis (including brain, cervical, thoracic, and lumbar spine) was unremarkable. CSF showed pleocytosis (58 cells/μl) and slightly elevated protein levels (48.9 mg/dl). After negative viral and microbiological diagnostics, initial treatment with acyclovir and ceftriaxone was changed to 4 × 1 g IVMP and, subsequently, oral steroids with tapered dose reduction. Clinical symptoms receded to slight plantar dysesthesia with good response to pregabalin.

In 03/2012 a relapse with bilateral dys- and hypesthesia occurred, this time affecting the upper limbs (fingertips bilaterally), lower limbs (thighs), and trunk (T4). Cerebral MRI again showed no pathologies; spinal MRI, however, revealed two LETM lesions, one stretching from C1 to C4, the other from C7 to T9; both showed swelling, the latter also Gd enhancement. Diagnostic workup again revealed pleocytosis in the CSF (25 cells/μl) and elevated CSF protein levels (53.2 mg/dl). OCB and AQP4-IgG were negative. Serologically, TPO antibodies were positive, but otherwise there was no indication for another autoimmune disease or vasculitis. Electrophysiology showed marginal P100 delay (117 – 118 ms bilaterally) in VEP and reduced amplitudes in SSEP (pronounced on the right). Again, 4 × 1 g IVMP with tapered dose reduction was applied. With the suspected diagnosis of AQP4-IgG-negative NMO, AZA was started at the end of 03/2012. The neurological symptoms improved under this therapy but the patient developed recurrent genital condyloma, necessitating operative removal.

The patient presented at our hospital for the first time in 11/2014. She had symptoms of slight gait ataxia, mainly at night, slight hypesthesia (inner thighs), and complained of severe fatigue, partly accentuated due to the recurrent operative procedures during the past few weeks. Thus the decision was made to switch the medication to rituximab, and AZA treatment was ended in 12/2014. During the drug-free interval of 3 months, the patient noted a remarkable clinical amelioration of the neurological and neuropsychological symptoms and finally came to be very reserved concerning the initiation of rituximab. Due to the patient´s concerns, it was decided to continue with close clinical and MRI follow-up. At the last two follow-up visits (03/2015 and 06/2015) the patient showed continuous recovery with only slight residual nocturnal gait ataxia (EDSS 1). MRI showed no new lesions and no Gd enhancement. At the first follow-up visit, MOG-IgG were found using a commercial CBA (Euroimmun) and were confirmed in the live-cell CBA.

Comment: The good long-term outcome (EDSS 1.0 at 3.5 years after onset) despite three myelitis attacks and despite the presence of extensive inflammation affecting the spinal cord over a length of 14 vertebral segments is remarkable. MOG-IgG-positive myelitis was longitudinally extensive in most of our patients and involved large parts of or even the entire spinal cord in some cases. Purely sensory attacks, as observed here, occurred in 13 other cases and, as said before, dysesthesia and pain were common symptoms in this cohort. Of note, good response to pregabalin was noted in this patient.

Case 26 – Recurrent LETM; spinal cord biopsy; partial recovery. This Caucasian man developed a first attack of myelitis in 12/2013 at age 41, with tetraparesis. Spinal cord MRI revealed an LETM lesion extending from C3 to C5. Brain MRI showed a right-sided Gd-enhancing T2 lesion adjacent to the posterior horn of the right ventricle. LP demonstrated mild pleocytosis (23 cells/μl) but no OCB. A decompression operation was performed in 01/2014 due to a suspected diagnosis of cervical myelopathy. However, symptoms worsened again in 04/2014 and a biopsy sample was analyzed to rule out neoplasm and vasculitis. Neuropathology revealed T cell infiltration but there was no specific staining for IgG and complement deposition. Follow-up MRI examinations over a period of 1 year persistently showed contrast enhancement in the cervical spinal cord. Two cycles of high-dose IVMP in 10/2014 and 11/2014 with subsequent oral steroid therapy resulted in only transient improvement. Several tests for AQP4-IgG were negative. In 02/2015 MOG-IgG was tested for the first time and was positive at low titer (1:160) in a live-cell assay; the result was confirmed in a commercial fixed-cell assay for MOG-IgG (Euroimmun). Broad differential diagnosis for infectious, (para)neoplastic, and autoimmune conditions was unremarkable. At follow-up in 02/2015 residual paresis (EDSS 4) was present; MOG-IgG were again positive at a titer of 1:160 and were confirmed in a second, commercial fixed-cell CBA (Euroimmun). There was no clinical, MRI, or electrophysiological (normal VEP 03/2015) evidence of optic nerve involvement. In September 2015, just five months after the first infusion of rituximab, the patient developed a relapse of acute myelitis with severe paresis. PEX resulted in only partial recovery. At last follow-up in March 2016, an EDSS of 6 was noted.

Comment: The differential diagnosis of LETM lesions include, among others, tumors, lymphoma, and spinal cord compression. Accordingly, reports on (unnecessary) neurosurgical procedures, including biopsies, exist also in AQP4-IgG-positive LETM patients [123–126]. Except in the case of emergency, AQP4-IgG and MOG-IgG should be excluded using at least two sensitive assays, at least one of which should be a cell-based assay [8, 29, 124], before any such procedure is considered.

VI. MOG-IgG-positive monophasic LETM

Case 27 – Single episode of LETM; no brain lesions; partial recovery at discharge. A 23-year-old Caucasian man presented with a sensory level at T4, local dysesthesia, mildly positive Babinski reaction, and bladder and erectile dysfunction shortly after an unspecified infection. MRI showed an LETM lesion extending from C3 to C7 with swelling. Brain MRI was normal. LP revealed lymphomonocytic pleocytosis (59 cell/μl) and mild blood-CSF barrier dysfunction (QAlb 6.96), but no intrathecal IgG synthesis (no OCB, QIgG normal). Further examinations for infection (Borrelia burgdorferi, Treponema pallidum, HAV, HBV, HCV, HIV, CMV, EBV, HSV1, HSV2, FSME, Mycoplasma pneumoniae) or common autoimmune disorders (ANA, ANCA, rheumatoid factor, CRP, C3d) were negative except for slightly elevated phospholipid/glycoprotein beta2 IgG antibodies (IgM negative). VEP were bilaterally delayed, indicating a history of subclinical ON; MRI of the orbit was unrevealing. MOG-IgG were positive at a titer of 1:10,240. Treatment with rocephine, acyclovir and, subsequently, high-dose steroids and oral tapering was followed by marked improvement. At discharge, residual mild and circumscript paresthesia as well as bladder dysfunction (requiring urinary catheterization) was present.

Comment: In this and two other cases without a history of clinically apparent ON (case 25 here and case 2 in part 3 of this series [31]), delayed P100 latencies were noted, suggesting subclinical optic nerve inflammation. The predictive value of a positive VEP for a future clinical ON relapse in patients with MOG-IgG-positive myelitis is so far unknown. Of note, the current diagnostic criteria for AQP4-IgG-negative NMOSD do not take into account VEP results but only clinical episodes of ON [29].

VII. Postvaccinal ON and myelitis

Case 28 – Recurrent myelitis and ON after vaccination against tetanus, diphtheria and pertussis resulting in functional blindness and tetraparesis; poor outcome. A 47-year-old Caucasian woman presented with acute sensorimotor tetraparesis (upper limbs: BMRC grade 4; lower limbs: BMRC grade 0), transient somnolence, and respiratory distress. Symptoms had started 12 days after vaccination against tetanus, diphtheria, and pertussis (Boostrix®) and had been preceded by a 2- to 3-day episode of fever prior to symptom onset. MRI showed a single parieto-occipital lesion and a longitudinally extensive spinal cord lesion extending over 15 vertebral segments (C2 to T9). CSF examination revealed moderate pleocytosis (210 white cells/μl) and disturbed blood-CSF barrier function but no CSF-restricted OCB. The symptoms responded only partially to IVMP and IA. As MOG-IgG was positive, treatment with rituximab was started. By 11 days after the first infusion, spinal cord T2 hyperintensities had resolved almost completely. However, just 7 weeks after the second infusion of rituximab and 3 months after onset of the first attack, the patient developed an episode of simultaneous myelitis and unilateral optic neuritis leading to severe loss of vision in the right eye. P100 latencies were delayed in both eyes and amplitudes reduced in the right eye. Brain MRI demonstrated an increase in size of the parieto-occipital lesion. Spinal MRI showed T2 hyperintensities from C7 to T8, predominantly in the posterior columns. Treatment with IVMP and IA was followed by incomplete remission of the symptoms. Just 48 days after onset of the second attack, the patient was re-admitted with a new attack of unilateral ON in the left eye resulting in almost complete visual loss (VA 0.05). Treatment with IVMP, IA, and cyclophosphamide led only to partial recovery (VA 0.16 at discharge). At last follow-up, severe spastic paralysis of the lower limbs and an EDSS score of 8 was documented.

Comment: Disease onset in this patient followed vaccination with a polyvalent vaccine against tetanus, diphtheria, and pertussis. Although a causal link between the two events cannot be proved, the close temporal association is highly suggestive of vaccine-mediated immune activation. Of particular note, symptoms also started within 2 weeks after a polyvalent vaccination against tetanus, diphtheria, and pertussis (as well as polio and influenza virus) in a second MOG-IgG-positive patient of this cohort (see case 8 in part 3 [120]). Whether molecular mimicry between vaccine epitopes and neural antigens played a role or whether vaccination only indirectly triggered or promoted the immune reaction against MOG is currently unknown but certainly warrants further investigation.