Appendix
Case 4 – Recurrent NMO starting with simultaneous bilateral ON and LETM followed by an area postrema syndrome; good partial recovery
In January 2012, a 30-year-old woman with no previous personal or family history of autoimmune disease developed sudden loss of vision and reduced visual field in the left eye and 2 days later in the right eye, followed by tetraparesis 2 weeks later. While brain MRI showed no abnormalities, spinal cord MRI revealed an LETM lesion extending from C2 to C7. The patient thus met Wingerchuk’s 2006 criteria for NMO [
35]. LP revealed CSF pleocytosis with 122 leukocytes/μl (97 % mononuclear cells, 3 % granulocytes); OCB were not determined. Treatment with IVMP was followed by partial recovery. Four months later, a relapse of myelitis occurred in the high cervical cord, now associated with brainstem encephalitis. Symptoms included tetraparesis and INV. MRI showed a brainstem lesion adjacent to the fourth ventricle and including the area postrema, which continued into the spinal cord. Brainstem symptoms completely remitted 2 months after IVMP treatment, and spinal symptoms partially remitted with residual paresthesia and mild paraplegia (BMRC 4+) after 3 months.
The patient subsequently had recurrent attacks of isolated ON (3 × full recovery after IVMP) or isolated myelitis (2 × full recovery after IVMP, 1 × partial recovery after IVMP). Six of the eight attacks in this patient occurred during 36 months of treatment with AZA, all of them after discontinuation of co-treatment with oral steroids (given for 3 months). At last follow-up, an EDSS of 3 was documented. MOG-IgG was detected retrospectively in a sample taken during remission by means of a live-cell CBA (1:640) and was confirmed by use of a commercial fixed-cell CBA (Euroimmun). AQP4-IgG was negative. The patient had no previous personal or family history of autoimmune disease.
Case 5 – Recurrent ON, LETM and brainstem attacks, with exacerbation after initiation of interferon-beta treatment; high relapse rate
A 34-year-old Caucasian woman with a positive family history for type 1 diabetes mellitus first presented with paraparesis due to transverse myelitis in 10/2006, which partially remitted after treatment with IVMP. Brain MRI showed asymptomatic lesions adjacent to the lateral ventricles. Five months later a second attack of transverse myelitis with paraparesis occurred, again with partial recovery after IVMP treatment; MR images from that time are unavailable. Later the same year, the patient developed a first attack of unilateral ON. LP revealed CSF pleocytosis but no CSF-restricted OCB. Administration of IVMP was followed by partial recovery. MS was suspected and treatment with intramuscular interferon beta-1a (IFN-beta) was started. However, 3 months later she experienced a brainstem attack with balance difficulties and vertigo. MRI revealed disease exacerbation with new lesions in the pons and in the medulla oblongata as well as multiple cervical and thoracic spinal cord lesions. Symptoms remitted spontaneously. In 01/2009 IFN-beta was discontinued and treatment with natalizumab initiated. During the period of natalizumab treatment (03/2009 – 08/2010), one further attack of brainstem encephalitis with impaired balance and vertigo occurred. In 06/2010, follow-up spinal MRI performed during remission demonstrated an LETM lesion extending from T2 to T6. The findings on brain MRI still did not meet the diagnostic criteria for MS. A diagnosis of relapsing NMO according to Wingerchuk’s 2006 criteria [
35] was made. Over the following 75 months, the patient experienced eight further attacks of myelitis, one of ON, and one of brainstem encephalitis with balance difficulties and dizziness. Four of these episodes, including two of the myelitis attacks and the ON attack (each with full remission after high-dose steroid treatment) as well as the brainstem attack (complete spontaneous remission), occurred while the patient was being treated with AZA for 36 months. Using a live-cell CBA, low-titer MOG-IgG antibodies (1:160) were detected retrospectively in a sample taken during remission. MOG-IgG seropositivity was later confirmed in an independent commercial fixed-cell CBA (Euroimmun). In addition, low-titer serum IgA tissue transglutaminase antibodies and antinuclear antibodies (ANA) were found. Serum AQP4-IgG was negative. At last follow-up, an EDSS of 3 was documented.
Case 6 – ON followed by post-infectious LETM and brainstem encephalitis 40 years later with poor outcome
At the age of 13 years this female patient had severe unilateral ON (visual acuity 10 %) with complete remission. No further neurologic symptoms occurred for 40 years. At age 53 she developed subacute tetraparesis and autonomic bladder and bowel dysfunction after a severe bronchopulmonary infection and a prodromal phase of diffuse tingling in all four extremities. She had been previously diagnosed with rheumatoid arthritis (RA) at the age of 43 years, and long-term treatment with weekly methotrexate (MTX) had been initiated at the age of 48 years. Due to the severe infection her immunosuppressive therapy had been stopped 4 weeks before onset of the neurologic symptoms. Initial MRI workup was inconclusive. Examination of CSF revealed mild pleocytosis with 30 cells/μl and a disturbed BCSFB function (QAlb 21.5) and no OCB. She was treated with empirical antibiotics and aciclovir. As the clinical presentation worsened, the patient became bedridden and lost bladder and bowel control. MRI was repeated and now revealed a longitudinally extensive spinal cord lesion extending centrally from the medulla oblongata to the mid-thoracic level with patchy Gd enhancement; brain MRI revealed no other abnormalities. No symptoms attributable to the medulla oblongata lesion were present. High-dose steroid treatment was initiated and was followed by 5 cycles of therapeutic PEX. She was restarted on her immunosuppressive treatment with MTX and recovered rapidly but only partially. At last follow-up, 1.5 years after this episode, she is ambulatory with no motor deficits but still reports painful dysesthesia and is restricted by severe sensory gait ataxia (EDSS 6.5). Anti-MOG antibodies were retrospectively assessed and found positive in a live-cell CBA of stored serum samples obtained between steroid treatment and the commencement of therapeutic PEX (1:2560) and at a follow-up visit (1:160); both samples were also positive in the fixed-cell CBA. AQP4-antibodies were negative in several samples.
Case 7 – Recurrent LETM and subclinical ON with extensive brainstem and brain involvement; almost full recovery
A Caucasian man experienced a first attack of myelitis with marked paraparesis in February 2012 at the age of 19; this episode remitted fully after IVMP therapy. Spinal cord MRI showed a transverse inflammatory lesion at T9/10 with swelling and Gd enhancement. Brain MRI detected no abnormalities. LP revealed CSF-restricted OCB. Another attack of myelitis with hypesthesia of both legs occurred in May 2012. MRI showed enlargement of the known thoracic lesion, now spanning from T8 to T12, again with swelling and Gd enhancement. At that time, prolonged P100 latency (but with normal amplitudes) was noted on the left side (visual acuity [VA] 0.95 in both eyes). IVMP therapy was again followed by complete remission. AQP4 antibodies were negative, but NMO was suspected and, therefore, treatment with AZA started. A few weeks later, the patient developed severe headache, diplopia, and gait ataxia. MRI performed several times over a period of 4 weeks showed evolving confluent T2-hyperintense lesions in the right temporal lobe, lesions in the periaqueductal grey, the pulvinar bilaterally, and the ventral pons, as well as cervical lesions at C6/7 and an LETM lesion extending from T8 to the conus with Gd enhancement. LP revealed an elevated cell count (22/μl), total CSF protein of 460 mg/l, and positive OCB. VEP showed increased P100 latency on both sides and normal amplitudes. The clinical deficits remitted only partially after one course of IVMP and after therapeutic PEX (five exchanges). B-cell-depleting therapy with rituximab was started in August 2012 and was followed by further slow resolution of symptoms. In May 2013, after repopulation of B cells, mild ON in the right eye occurred but remitted spontaneously. Rituximab therapy was resumed and the patient remained free of disease activity with minor deficits (EDSS of 1.0) until last follow-up in December 2014. MOG-IgG were retrospectively tested using a live-cell CBA and were positive at a titer of 1:1280.
Case 8 – Post-vaccination myelitis and recurrent ON with brainstem and brain involvement; full recovery
A 19-year-old male patient presented with headache, meningism, and photophobia. The patient had received a vaccination (diphtheria, tetanus, pertussis, polio; and influenza) 2 weeks before symptom onset. Examination of the CSF revealed pleocytosis (43 cells/μl; predominantly lymphomonocytic, 3.1 % neutrophils). Brain MRI demonstrated multiple T2 hyperintensities in the pulvinar thalami bilaterally and in the rostral putamen as well as leptomeningeal contrast enhancement. Spinal MRI revealed a lesion at C1 and another one extending from T11 to T12. Pragmatic treatment with ceftriaxone, ampicillin, and acyclovir was started, together with IVMP. After clinical recovery, the patient was discharged to a rehabilitation facility with the diagnosis of suspected viral meningoencephalomyelitis of undetermined origin. However, 1 month later he was readmitted with disorientation, headache, meningism, fever, and fatigue. CSF analysis again revealed pleocytosis (60 white cells/μL; 26 % neutrophils). Brain MRI demonstrated T2-hyperintense lesions in the midbrain, pons, thalamus, basal ganglia, and corpus callosum. Lesions involved the periependymal surfaces of the third ventricle. Spinal cord MRI showed a contrast-enhancing lesion at C5. Shortly thereafter, the patient developed proximal spastic paraparesis, urinary retention, and bilateral visual deficits, accompanied by delayed P100 latencies, MRI-detectable lesions involving the optic chiasm and both optic tracts, and a new T2 hyperintensity at C3. MOG-IgG were positive at a titer of 1:2560. AQP4 antibodies were negative. Treatment with IVMP (1 g/d for 5 days) followed by 5 cycles of PEX led to full clinical and neuroradiologic recovery within 3 months. Long-term immunosuppressive treatment with AZA was initiated. Within the following 20 months, four further attacks of ON (ranging from mild to severe) and presumably one further attack of brainstem encephalitis with hearing loss occurred, with each showing full remission after high-dose steroid treatment (EDSS 0 at last follow-up).
Case 9 – Recurrent ON with subclinical brainstem and spinal cord involvement; almost full recovery
In December 2014, 4 weeks after an ENT infection, a 50-year-old Caucasian man developed a first, left-sided ON (blurred vision, retro-orbital pain, VA OS 30 %, P100 OS delayed) which remitted almost completely after treatment with IVMP. Neurologic examination was otherwise unrevealing except for slightly increased tendon reflexes, in particular of the lower extremities. Brain MRI showed an asymptomatic, median pontine lesion without Gd enhancement; in addition, there was inflammation of the entire optic nerve and parts of its sheath, with extensive Gd enhancement and subtle swelling compared with the other side. Spinal cord MRI demonstrated a possible lesion at C6/7. LP was unrevealing (negative OCB, no pleocytosis, no BCSFB dysfunction). Infectious causes of ON were excluded. Serologically, there was no indication of vasculitis. MOG-IgG antibodies were found to be positive at that time. Due to flaring up of the ON shortly after, the pulse therapy was repeated with 5 × 2 g IVMP, which had no effect. By contrast, PEX treatment (8 cycles) starting 10 days after the last IVMP dose resulted in almost complete recovery.
However, 2 months later a relapse of unilateral ON of the left eye occurred with complete visual loss (VA OS 0 %; Snellen chart), impaired color vision, and retro-orbital pain. Brain MRI showed inflammation of the posterior (pre-chiasmal) part of the optic nerve with Gd enhancement but no significant swelling. Standard VEP findings had worsened (P100 not detectable in left eye); flash VEP revealed a marked P100 prolongation and reduced amplitudes in the left eye. While the pontine lesion had markedly decreased in size, several new dorsolateral and central spinal cord lesions without Gd enhancement had developed (T7/8, T8/9 and T11/12). MOG-IgG were positive at a titer of 1:10,240. PEX treatment (8 cycles) led to almost full clinical recovery, with discretely disturbed color vision and an increased sensitivity to glare as residual symptoms. Standard VEP also improved following PEX treatment, but still showed a delay in latency (159 ms) and reduced amplitudes compared with the right eye. Treatment with rituximab was commenced without complications. At last follow-up (May 2015) the patient had almost fully recovered (VA OS 0.9; EDSS 1.5).
Case 10 – Protracted and recurrent ON with complete visual loss and signs of mild myelitis and brainstem encephalitis; complete recovery
A previously healthy 37-year-old man presented with a 4-day history of bifrontal headache, pain upon eye movement, and bilateral complete visual loss and color desaturation. Ophthalmoscopy revealed bilateral papilledema. Markedly prolonged P100 latencies were noted in both eyes, suggestive of demyelination. Brain MRI showed a bilateral optic nerve lesion with swelling and Gd enhancement but did not reveal any brain lesions. Spinal cord MRI was normal. Serum AQP4-IgG was negative, as were CRP, ANA, ANCA, rheumatoid factor, lupus coagulant, anti-gliadin and anti-transglutaminase, HIV, HTLV-1, and vitamin B12. CSF examination demonstrated mild pleocytosis (5 cells/μl; including 34 % neutrophils and 6 % eosinophils) and identical OCB in CSF and serum but was otherwise normal (including a negative MRZ reaction). Treatment with IVMP (1 g/d for 5 days) was followed by marked improvement in VA. However, only 4 days later the patient was readmitted with new visual impairment; scotoma; hypesthesia of the right lower face and nose, the right hand, and the lateral parts of the right arm; paresthesia in the fingers of both hands and in both legs; and headache. No repeat MRI was performed. VEP and SSEP were normal. AQP4-IgG was still negative. Repeat LP revealed a mild lymphomonocytic pleocytosis (8 cells/μl). The patient’s visual deficits increased (0.6 OS, 0.8 OD) despite a second, prolonged IVMP cycle (1 g/d for 7 days); symptoms stabilized (but did not improve) after PEX (five exchanges). Two days after discharge the patient was again readmitted with further decrease in VA in the left eye (0.3), marked bilateral scotoma (OS> > OD), headache (NAS 3), and vertigo (“like in an elevator moving down”). VEP showed a further increase in P100 latency in the left eye. Treatment with IVMP was followed by complete remission (VA 1.0 in both eyes at discharge). However, follow-up VEP still showed markedly delayed, albeit slightly improved, P100 latencies in both eyes (154 ms compared to 178 ms at previous examination). To prevent further flare-ups after steroid withdrawal, treatment with oral steroids (100 mg/d; tapering to 10 mg/day) was initiated and, taking into consideration the patient’s positive MOG-IgG serostatus, long-term treatment with AZA started. At follow-up 63 days after onset, the patient reported persisting color desaturation and impaired contrast perception, together with paresthesia in the left leg. The patient discontinued AZA after two months.
Six months after onset and one month after the first infusion of rituximab (1000 mg), he developed a relapse of ON, which fully responded to high-dose IVMP treatment, another infusion of rituximab (1000 mg) and subsequent oral steroid treatment. Another two months later, shortly after oral steroids were tapered out, a third attack of ON occurred, which was associated with mild hemiparesis and hemihypesthesia, which fully remitted following treatment with IVMP and, subsequently, oral steroids.
Case 11 – Myelitis and recurrent ON with lesions in the cerebellar peduncle and the frontal lobe; partial remission
A previously healthy 44-year-old Caucasian woman presented in February 2011 with sensorimotor paraparesis and urinary incontinence. Spinal MRI showed a cervicothoracic, longitudinally extensive spinal cord lesion with patchy Gd enhancement and further short, patchy spinal cord lesions. Brain MRI revealed a lesion in the cerebellar peduncle and one small cerebral lesion located in the left frontal lobe with slight Gd enhancement. The myelitis symptoms partially recovered under IVMP (1 g/d for 5 days) with residual detrusor sphincter dyssynergy and slight gait ataxia. Subsequently, the patient suffered recurrent urinary tract infections, which were effectively controlled by use of methionine (3 × 500 mg/d). In May 2011 she developed vision loss in the right eye (VA 0.2) with prolonged P100 latency and reduced P100 amplitudes. VA recovered to 0.75 after IVMP therapy within two months. Two months later, the patient experienced an attack of ON in the previously unaffected left eye (VA reduced to light perception). Partial remission was achieved after 5 PEX cycles; previous treatment with IVMP for 5 days had not resulted in any improvement. In August 2011, immunosuppressive treatment with mitoxantrone was started (10 mg/m2; 4 cycles at 6-week intervals; no relapses). In January 2012, therapy was switched to AZA (2 mg/kg). After at least three attacks of unilateral ON under AZA, the patient’s treatment was changed to rituximab (1000 mg i.v. in February 2015 and March 2015, respectively). Complete B cell suppression was noted 3 months after treatment. In June 2015 she developed bilateral ON with VA of 0.2 in the right eye and 0.05 in the left eye. After IVMP (5 g) and five cycles of PEX, VA improved. At the time of her last follow-up visit in August 2015, VA was 0.8 in both eyes and an EDSS of 2.5 was documented.
Case 12 – Simultaneous ON and LETM with post-partum onset and pontomedullary brainstem encephalitis; full recovery
A 27-year-old woman developed a first, painful attack of ON in July 2012, just 6 weeks after the delivery of her first child. Ophthalmologic assessment revealed VA of 0.8, papilledema, and delayed VEP latencies (but normal amplitudes) in the left eye. Cranial MRI showed swelling as well as intraneural and perineural contrast enhancement extending over the anterior two thirds of the left optic nerve but was otherwise unremarkable. The CSF had normal cell and protein profiles with negative OCB. High-dose intravenous pulse therapy with IVMP (1000 mg/d for 3 days) was followed by complete resolution of symptoms. However, a few days later (and 2 weeks after attack onset) the patient noticed right-sided ocular pain upon eye movements, diplopia, paresthesia around her mouth and her waist, and urge incontinence. On neurologic examination she had a left-sided sixth nerve palsy, gaze-directed horizontal and vertical nystagmus, and a mildly unsteady gait. VA was normal. MRI of the brain and spinal cord now revealed T2-hyperintense lesions extending from the pontomedullary junction throughout the cervical cord as far as C5 as well as an additional T2 hyperintensity located in the juxtacortical insular region on the left side. None of these abnormalities showed Gd enhancement. Repeat lumbar puncture disclosed lymphocytic pleocytosis (59 cells/μl) in the presence of normal lactate and protein levels, including negative OCB. Antineuronal and AQP4 antibodies were negative and there was no evidence of an infectious etiology. The patient was treated with IVMP (1000 mg daily for 5 days) followed by 80 mg orally with subsequent tapering for 7 weeks.
In September 2012, at a maintenance dose of 5 mg methylprednisolone per day and after improvement of symptoms, she experienced right-sided ON leading to a moderate decline in visual acuity (0.6). She received a further course of IVMP (1000 mg daily for 3 days) and oral therapy with decreasing doses of prednisolone (starting with 80 mg) for a total of 4 weeks with a permanent maintenance dose of 10 mg daily. This regimen prompted normalization of visual impairment. AQP4-IgG, tested in a CBA, was again negative. Long-term treatment with AZA and oral corticosteroids was started.
In October 2012 (6 weeks after onset of the last attack), just 4 days after termination of steroid therapy and 1 day following reduction of AZA from 150 mg to 100 mg daily because of elevated liver enzymes, the patient developed a third episode of painful ON with right-sided visual impairment. She received another course of 1000 mg IVMP daily for 5 days followed by oral tapering, which resulted in complete recovery. AZA was stopped in November 2012 and replaced by MTX in February 2013. The patient discontinued MTX in November 2014 because she wanted a second pregnancy. At that time, MRI showed mild residual signal hyperintensity in the left optic nerve, no brain lesions, and a residual short spinal T2 hyperintensity at the C4/5 level. At last follow-up in 09/2015, she had not experience new neurologic symptoms (EDSS 0). Three stored sera obtained in July 2012 were retrospectively tested positive for MOG-IgG at a titer of 1:5120 each.
Case 13 – Recurrent ON and myelitis; hypesthesia of the tongue and cheek; lesions in the medulla oblongata and in the pons; ongoing disease activity during treatment with IFN-beta and GLAT
A 19-year old woman developed acute hypesthesia of both hands and Lhermitte’s sign in 2007. Fifteen months before that event, she had suffered from an episode of extremely painful headache starting 4 weeks after influenza vaccination and lasting for 14 days (no previous history of headache). Brain MRI was normal at the time of attack onset, but spinal cord MRI revealed a single lesion at C2. CSF examination demonstrated lymphocytic pleocytosis (33 cells/μl) and intrathecal IgG and IgM synthesis. VEP, SSEP and MEP were normal. Two months later, she developed unilateral ON. Both attacks were treated with IVMP, which was followed by complete recovery in each case. Over the following 8 years, she developed at least seven more attacks of myelitis and two more attacks of ON despite immunomodulatory or immunosuppressive treatment with IFN-beta 1a s.c., IFN-beta 1a i.m., GLAT, natalizumab or fingolimod for suspected MS, with partial or full recovery following steroid treatment. While most myelitis attacks were characterized by sensory symptoms (including girdle-like or, later, generalized dysesthesia and pain), some resulted in spastic paresis of the lower extremities and impaired ambulation requiring unilateral assistance. Repeat MRI demonstrated both short spinal cord lesions and LETM lesions, partly with swelling of the spinal cord and contrast enhancement. ON attacks were mostly mild, but severe attacks occurred as well (VA 0.25, peripheral scotomas). At least twice, she experienced simultaneous ON and myelitis. Several repeat brain MRIs showed (partly contrast-enhancing) juxtacortical, deep white matter, callosal, and periventricular lesions. While the initial LP had revealed quantitative evidence for intrathecal synthesis of both IgG (33 % of total CSF IgG) and IgM (59 % of total CSF IgM), only intrathecal IgG synthesis was detected at repeat LP during another acute an acute attack 10 months later. Nineteen months after onset, she developed an attack of myelitis with hypesthesia in both legs, Lhermitte’s sign, and lesions at C2, C6, and C7 which was accompanied by hypesthesia of the tongue and facial hypesthesia, dysesthesia and pain, suggesting brainstem encephalitis. However, no brainstem MRI was performed at that time. Two follow-up MRIs showed T2-hyperintense, non-contrast enhancing lesions in the medulla oblongata and in the pons, which remained detectable over a period of at least once year. Additional symptoms attributable to brainstem lesions included impaired coordination, impaired ambulation, and disturbed smooth pursuit. Microbiological examinations for Borrelia burgdoferi, HIV, HBV, HCV and VZV as well as serological examinations for rheumatic diseases were negative. At last follow-up in 2016, an EDSS score of 3.5 was documented.
Case 14 – LETM with pontomedullary brainstem encephalitis and relapsing ON; almost full recovery
A female Caucasian patient developed a first attack of unilateral ON at the age of 17 but recovered fully after IVMP treatment. Brain MRI was normal at onset. CSF examination revealed mild pleocytosis (8 cells/μl) and evidence of BCSFB dysfunction but not of intrathecal IgG synthesis. Seven months later, she developed paraparesis due to an attack of acute myelitis; IVMP treatment was followed by complete recovery. Over the next 56 months, five further attacks of ON occurred (three while on GLAT for suspected MS, one with transient unilateral blindness several weeks after GLAT had been discontinued due to an unplanned pregnancy, and one after 8 months of AZA treatment), all of which responded to IVMP therapy, as well as two further attacks of non-longitudinally extensive transverse myelitis, one of which was associated with internuclear ophthalmoplegia (INO). The latter attack occurred under treatment with IVIG. Previously, AZA had had to be discontinued due to an increase in liver enzymes and a planned pregnancy. During that attack, brain MRI showed a large, Gd-enhancing brainstem lesion affecting the pons bilaterally, both pedunculi cerebelli, and the paramedian pontomedullary junction. Spinal cord MRI showed two separate lesions at C2/3 and C5. In addition, Gd-enhancing supratentorial lesions located peritrigonally and in the corona radiata were noted. PEX was required in addition to IVMP to achieve remission of symptoms. Treatment with rituximab had to be stopped after the first infusion due to an allergic skin reaction. Under subsequent immunosuppression with ofatumumab (18 months so far, 4 cycles) one additional ON attack has occurred (14 months after commencement of therapy). Despite the high number of nine ON attacks and complete blindness during one of those attacks, the patient had almost normal VA (0.9) at last FU. VEP showed prolonged P100 latencies and reduced amplitudes.
Case 15 – Hemihypesthesia including the face; bilateral lesion in the pons and the cerebellar peduncles; myelitis; partial recovery
This 25-year-old Caucasian woman first presented in February 2016 with tingling paresthesias of her left arm and leg, which had developed over the course of 2 days. She had a history of asthma bronchiale and neurodermitis, but except for a bipolar disorder and rare attacks of typical migraine no history of neurological symptoms. She had suffered from fever and fatigue 2 weeks before her neurological symptoms started. Neurological examination revealed paramedian moderate left-sided tactile hemihypesthesia including the face and a pathologically increased left knee-jerk without other pyramidal signs, as well as an unstable Romberg stance with eyes closed, but was otherwise unremarkable. In particular she had no limb ataxia and no further cerebellar signs. Autoimmune serology revealed a strongly increased ANA titer of 1:320 with a speckled/spindle apparatus staining pattern, while no ENA antibodies and no ANCA were detectable. Cranial MRI revealed bilateral lesions of the pons, more marked on the right side, and bilateral lesions in the cerebellar peduncles as well as a single small lesion directly adjacent to the left lateral ventricle, while MRI of the whole spinal cord showed no abnormalities. CSF analysis revealed pleocytosis (150 white cells/μl; 29 % lymphocytes, 45 % monocytes, 26 % granulocytes), total protein of 56.1 mg/dl (<50), and an increased albumin quotient of 11.3 (upper limit of age-corrected normal = 7.0); isoelectric focusing revealed identical OCB in serum and CSF; no intrathecal antibody synthesis against measles, rubella, varicella zoster, and herpes simplex virus was detectable. CSF PCR analyses of a panel of neurotropic viruses were negative. Serology of serum and CSF was negative for Lyme disease and syphilis. Visual, sensory, and motor evoked potentials were normal. Owing to the history of recent fever and CSF pleocytosis including neutrophils, treatment with aciclovir i. v. and ceftriaxone was started, based on a tentative diagnosis of infectious, primarily viral encephalitis on the day of admission. Aciclovir was discontinued after negative viral PCR results became available, while ceftriaxone was continued for 14 days. After an initial worsening of the patient’s hemihypesthesia, occurrence of a mild left-sided hemiparesis, and newly occurring intermittent urinary hesitancy over a few days, the symptoms started to gradually improve. Another lumbar puncture 14 days after admission revealed a cell count of 98/μl. The patient was discharged with partial relief of symptoms. Positive anti-MOG IgG and negative aquaporin-4 antibody results arrived after discharge.
Four weeks later the patient was again admitted to our department with new sensory disturbances affecting her trunk and legs below T10 and stance and gait ataxia. MRI now revealed a lateral spinal cord lesion spanning from T8 to T9 without contrast enhancement. Another spinal tap showed pleocytosis (20 white cells/μl), a now normal albumin quotient of 5.6, and again identical OCB in serum and CSF. Flow cytometric CSF analysis revealed 10 % lymphocytes, all CD3-positive, and a marginally increased CD4/CD8 ratio of 4.4. Visual and sensory evoked potentials were again normal, while the patient rejected analysis of motor evoked potentials. Treatment with IVMP (5 × 1 g/day) induced partial remission of her new symptoms. Cranial MRI after steroid initiation revealed moderate regression of all known brain lesions and no new lesions. After a well-tolerated test dose, secondary prophylactic treatment with azathioprine 150 mg/day was started.
The patient next attended our neuroimmunological outpatient clinic for a routine follow-up appointment in June 2016. She reported that the residual left-sided sensorimotor symptoms from her first attack had intensified in the previous 4 weeks, indicating a potential mild relapse. Two weeks before the beginning of this intensification of symptoms she had had a feverish respiratory infection, for which she had received antibiotic treatment. Based on a peripheral blood lymphocyte count of 2470/μl, the azathioprine dose was increased. An EDSS of 3 was documented.