Kimihiko Kaneko

MRI and retinal abnormalities in isolated optic neuritis with myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies: a comparative study

Acute optic neuritis (ON) typically presents with ocular pain and low visual acuity (VA), and there is a risk of permanent vision loss if ON is not managed properly.1 ON may be the first symptom of inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD). Recently, we reported some distinct characteristics between seropositive anti-aquaporin-4 (anti-AQP4) patients and seropositive antimyelin oligodendrocyte glycoprotein (anti-MOG) patients with NMOSD, using our in-house cell-based assays (CBA). However, patients with a single attack of unilateral ON were not included in our previous study. None of the previous studies of anti-MOG+ patients performed orbital MRI or optical coherence tomography (OCT) segmentation analyses, which may have diagnostic and prognostic implications. To address these issues, we evaluated the diagnostic utility of the anti-MOG assay and compared the MRI and OCT findings of anti-MOG+ and anti-AQP4+ patients with isolated ON. ### Patients We investigated 28 affected ON eyes from 21 consecutive anti-AQP4 seronegative patients aged 12 years or older who presented with isolated ON (4 cases with simultaneous bilateral ON, 3 cases with relapsing unilateral ON, and 14 cases with a single attack of unilateral ON) and were admitted to Tohoku University Hospital between 2011 and 2013. We excluded patients with ON already associated with brain and/or spinal cord MRI lesions. We compared anti-MOG+ ON eyes with nine affected ON eyes from eight anti-AQP4+ patients with isolated ON (one simultaneous bilateral ON). Severe VA loss was set at 0.1 in the decimal Japanese chart (equivalent to 20/200).2 ### Orbital MRI All patients performed orbital imaging using a 1.5 T MRI. We measured the short τ inversion recovery (STIR) and/or T2-weighted image hyperintense lesions …

MOG antibody–positive, benign, unilateral, cerebral cortical encephalitis with epilepsy

Objective: To describe the features of adult patients with benign, unilateral cerebral cortical encephalitis positive for the myelin oligodendrocyte glycoprotein (MOG) antibody. Methods: In this retrospective, cross-sectional study, after we encountered an index case of MOG antibody–positive unilateral cortical encephalitis with epileptic seizure, we tested for MOG antibody using our in-house, cell-based assay in a cohort of 24 consecutive adult patients with steroid-responsive encephalitis of unknown etiology seen at Tohoku University Hospital (2008–2014). We then analyzed the findings in MOG antibody–positive cases. Results: Three more patients, as well as the index case, were MOG antibody–positive, and all were adult men (median age 37 years, range 23–39 years). The main symptom was generalized epileptic seizure with or without abnormal behavior or consciousness disturbance. Two patients also developed unilateral benign optic neuritis (before or after seizure). In all patients, brain MRI demonstrated unilateral cerebral cortical fluid-attenuated inversion recovery hyperintense lesions, which were swollen and corresponded to hyperperfusion on SPECT. CSF studies showed moderate mononuclear pleocytosis with some polymorphonuclear cells and mildly elevated total protein levels, but myelin basic protein was not elevated. A screening of encephalitis-associated autoantibodies, including aquaporin-4, glutamate receptor, and voltage-gated potassium channel antibodies, was negative. All patients received antiepilepsy drugs and fully recovered after high-dose methylprednisolone, and the unilateral cortical MRI lesions subsequently disappeared. No patient experienced relapse. Conclusions: These MOG antibody–positive cases represent unique benign unilateral cortical encephalitis with epileptic seizure. The pathology may be autoimmune, although the findings differ from MOG antibody–associated demyelination and Rasmussen and other known immune-mediated encephalitides.

Myelin injury without astrocytopathy in neuroinflammatory disorders with MOG antibodies

Objective To compare myelin and astrocyte injury in patients with antibodies against myelin oligodendrocyte glycoprotein (anti-MOG) or aquaporin-4 (anti-AQP4), and multiple sclerosis (MS). Methods Myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) levels were measured in the cerebral spinal fluid (CSF) from anti-MOG+ or anti-AQP4+ patients tested in both sera and CSF by cell-based assays with live transfected cells. Results In total, 75.6% (68/90) of the patients were positive for either anti-MOG or anti-AQP4 antibodies in both serum and CSF; 74.2% (23/31) were anti-MOG+, and 76.3% (45/59) were anti-AQP4+. No patients were only CSF positive or were positive for both anti-MOG and anti-AQP4 antibodies, and none of the MS patients or controls had these autoantibodies in the serum or CSF. MBP levels were elevated in the anti-MOG+ cases compared to the multiple sclerosis (MS) patients, and the levels found were similar between anti-MOG+ cases and anti-AQP4+ neuromyelitis optica spectrum disorder (NMOSD) cases. Meanwhile, GFAP was only elevated in the anti-AQP4+ NMOSD. Moreover, CSF pleocytosis, high protein levels, and oligoclonal IgG band negativity distinguished the anti-MOG+ cases from MS patients. Conclusions Myelin injury was more severe in the anti-MOG+ cases than in the MS cases, and anti-MOG+ cases have differences in the CSF characteristics compared to MS. GFAP elevation in anti-AQP4+ cases was absent in anti-MOG+ patients (even in cases with NMOSD phenotype), indicating that immune-mediated astrocytopathy is unique to anti-AQP4+ patients. Our study suggests that anti-MOG+ cases are distinct from MS and anti-AQP4+ NMOSD.

A novel mutation in PNPLA2 causes neutral lipid storage disease with myopathy and triglyceride deposit cardiomyovasculopathy: A case report and literature review

Mutations in PNPLA2 cause neutral lipid storage disease with myopathy (NLSDM) or triglyceride deposit cardiomyovasculopathy (TGCV). We report a 59-year-old patient with NLSDM/TGCV presenting marked asymmetric skeletal myopathy and cardiomyovasculopathy. Skeletal muscle and endomyocardial biopsies showed cytoplasmic vacuoles containing neutral lipid. Gene analysis revealed a novel homozygous mutation (c.576delC) in PNPLA2. We reviewed 37 genetically-proven NLSDM/TGCV cases; median age was 30 years; distribution of myopathy was proximal (69%) and distal predominant (16%); asymmetric myopathy (right>left) was reported in 41% of the patients. Frequently-affected muscles were posterior compartment of leg (75%), shoulder girdle to upper arm (50%), and paraspinal (33%). Skeletal muscle biopsies showed lipid accumulation in 100% and rimmed vacuoles in 22%. Frequent comorbidities were cardiomyopathy (44%), hyperlipidemia (23%), diabetes mellitus (24%), and pancreatitis (14%). PNPLA2 mutations concentrated in Exon 4-7 without apparent genotype-phenotype correlations. To know the characteristic features is essential for the early diagnosis of NLSDM/TGCV.

The clinical spectrum associated with myelin oligodendrocyte glycoprotein antibodies (anti-MOG-Ab) in Thai patients.

Background: Myelin oligodendrocyte glycoprotein (anti-MOG) antibody was reported in anti-aquaporin-4 (anti-AQP4) seronegative neuromyelitis optica spectrum disorders (NMOSD) patients. Objectives: To describe clinical phenotypes associated with anti-MOG. Methods: Seventy consecutive Thai patients with inflammatory idiopathic demyelinating central nervous system disorders (IIDCD) who were previously anti-AQP4 seronegative were tested for anti-MOG. Results: Anti-MOG was positive in six patients, representing 20.7% of the IIDCD anti-AQP4 seronegative patients with a non-multiple sclerosis phenotype, and most had relapses. All first presented with optic neuritis with good visual recovery after treatment. Conclusions: Anti-MOG positive patients may have manifestations that mimic NMOSD but differ in their course and prognosis from anti-AQP4 positive NMOSD.

Different etiologies and prognoses of optic neuritis in demyelinating diseases

We compared the clinical features of optic neuritis (ON) that are frequently observed in various central nervous system demyelinating diseases, including multiple sclerosis (MS), anti-aquaporin 4 (AQP4) antibody- and anti-myelin oligodendrocyte glycoprotein (MOG) autoantibody-related diseases. Almost all the AQP4-ON patients were female, whereas half of the MOG-ON patients were male. The ON-onset age was younger in MS-ON and was older in AQP4-ON. The ON-lesion detected using optic MRI in the acute phase was longer in MOG-ON and showed severe swelling and twisting. The worst visual acuity was similar between the diseases; however, the final visual acuity was significantly worse in AQP4-ON.

Bilateral frontal cortex encephalitis and paraparesis in a patient with anti-MOG antibodies.

Encephalitis seldom causes paraparesis as the initial symptom. Here, we report a case of steroid-responsive bilateral frontal cortical encephalitis involving leg motor areas in a patient who presented with paraparesis on admission. Interestingly, the initial paraparesis evolved into an acute disseminated encephalomyelitis (ADEM)-like illness and optic neuritis, and the patient was found to be positive for anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. A 46-year-old man experienced transient dizziness in early September 2008. Brain MRI retrospectively showed a slight fluid attenuation inversion recovery (FLAIR) high-intensity lesion involving the left frontal cortex (figure 1). One week later, the patient experienced a focal motor seizure in the right leg that subsequently generalised. Thereafter, he gradually developed headache and paraparesis over the course of a week. On admission, he presented with paraparesis without other neurological deficits, but the spinal MRI was normal. An electroencephalogram revealed that there were no epileptic discharges. A cerebrospinal fluid (CSF) examination revealed elevated leucocytes (56 /µL; 93% mononuclear cells, 3% polymorphonuclear leucocytes) and normal protein (36 mg/dL) and glucose (59 mg/dL) levels. The myelin basic protein (MBP) and glial fibrillary acidic protein levels in the CSF were not elevated. Cell-based assays for anti-N-methyl-D-aspartate receptor (NMDAR) antibodies, anti-voltage-gated potassium channel (VGKC) antibodies, anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antibodies and anti-γ-aminobutyric acid-B receptor (GABA(B)R) antibodies in the CSF were negative. Blood and CSF examinations for infectious central nervous system (CNS) CNS diseases, collagen diseases, vasculitis, Behcet disease, sarcoidosis, lymphoma, paraneoplastic syndrome, vitamin B deficiency and Hashimoto encephalopathy were unremarkable. Figure 1 Upper panel: axial fluid attenuation inversion recovery (FLAIR) images (1.5 T; TR 6000 ms, TE 105 ms). (A) Brain MRI at …

Anti–N‐methyl‐D‐aspartate receptor encephalitis with multiphasic demyelination

Titulaer et al recently published a case series of 23 patients with anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis who had brain lesions on magnetic resonance imaging (MRI). Some of their patients had clinical signs of demyelinating syndromes, and antibodies for either myelin oligodendrocyte glycoprotein (MOG) or aquaporin 4 (AQP4). Anti-AQP4 patients predominantly had features resembling neuromyelitis optica, whereas the anti-MOG patients had a broader clinical phenotype. The number of patients was limited, and the study focused on anti-NMDAR, but curiously, none was positive for both anti-MOG and anti-AQP4, confirming the rarity of such cases. However, there are some caveats on this study. The authors confirmed the presence of these antibodies on a single point for the majority of the patients, and the results were mainly based on a retrospective cross-sectional analysis. Followup MRI, antibody titers for anti-NMDAR by the cell-based assay (CBA) performed, and changes in clinical features during the disease course were not reported. We identified a 28-year-old woman who has been followed for 5 years with positivity for both anti-NMDAR and anti-MOG confirmed on samples collected longitudinally associated with brain MRI evaluations (Fig ). She initially presented with symptoms compatible with limbic encephalitis and a normal brain MRI. However, during the disease course, she had some symptoms that are not usually found in anti-NMDAR encephalitis and T2/fluid-attenuated inversion recovery–hyperintense lesions in the cerebral deep gray matter and white matter, sometimes with mild contrast enhancement compatible with acute disseminated encephalomyelitis. These brain lesions resolved after intravenous methylprednisolone (IVMP) treatment. She experienced the reappearance of neuropsychiatric symptoms and new brain MRI lesions when she interrupted the maintenance therapy with oral prednisone. Preand posttreatment paired cerebrospinal fluid (CSF) and sera were available from 1 clinical exacerbation. The anti-MOG titers preversus post-treatment in the sera (1:16,384 vs 1:8,192) and CSF (1:256 vs 1:64) by CBA were reduced shortly after IVMP, whereas the anti-NMDAR titers were unchanged. The anti-MOG titer reduction was also accompanied by reduction of brain MRI lesions after treatment. The CSF:serum ratio for anti-NMDAR (1:1 to 1:10) and anti-MOG (1:32 to 1:128) was different at all time points, so the intrathecal synthesis may be distinct among these 2 antibodies. Anti-MOG is associated with demyelinating diseases and should be suspected in patients with antiNMDAR encephalitis who develop atypical symptoms or brain demyelinating MRI lesions.

Reversible paraspinal muscle hyperintensity in anti-MOG antibody–associated transverse myelitis

Myelin oligodendrocyte glycoprotein immunoglobulin G (anti-MOG-IgG) has been recently found to be associated with some forms of idiopathic inflammatory demyelinating CNS disorders. In a preliminary study from India, recurrent optic neuritis and isolated longitudinally extensive transverse myelitis were identified as the common phenotypes.1 The clinical and radiologic features of this newly discovered subset of autoimmune disorders are only beginning to be understood. In this context, we would like to draw attention to an unusual and hitherto unreported association noticed in a patient with anti-MOG-IgG–associated myelitis.

Subclinical retinal atrophy in the unaffected fellow eyes of multiple sclerosis and neuromyelitis optica

We compared the retinal thickness in the unaffected eyes among the following subtypes of unilateral optic neuritis (ON): multiple sclerosis (MS-ON), neuromyelitis optica spectrum disorder with anti-AQP4 autoantibody (AQP4-ON), patients with serum anti-MOG antibody (MOG-ON), and idiopathic ON. In the chronic phase, macular GCC and circum-papillary RNFL in the unaffected eyes were both atrophied in MS-ON and AQP4-ON, but were not atrophied in the others. Titers of anti-AQP4-Ab was suggested to be associated with such latent neurodegenerative process in AQP4-ON. Long-term follow up of OCT is recommended even in the unaffected side in MS-ON and AQP4-ON.