Repetitive intrathecal injection of human NMO-IgG with complement exacerbates disease severity with NMO pathology in experimental allergic encephalomyelitis mice.

Neuromyelitis optica (NMO) is recognized as a different CNS autoimmune disease from multiple sclerosis (MS). Whether NMO-IgG contributes directly to the pathogenesis of NMO or is just a serologic marker of autoimmune responses of the disease needs to be clarified. We created MOG-induced experimental autoimmune encephalomyelitis (EAE) mice by passively transferring NMO-IgG to model the pathogenic findings in NMO patients. The mice were divided into three groups and administered intrathecal PBS, human complement with IgG from normal subjects, or IgG from AQP4(+) patients on days 8 and 11 after immunization. The EAE scores of EAE mice with intrathecal NMO-IgG injection were significantly elevated 14 days post-immunization. All of the mice were sacrificed for brain and spinal cord pathology analysis on day 21 post-immunization. Compared to mice given normal human IgG, EAE mice injected with NMO-IgG had markedly decreased AQP4 and glial fibrillary acidic protein (GFAP) expression and fluorescent intensity in the brain and spinal cord but more scattered deposition of complement (C9neo). Thus, our studies not only support the pathogenic role of NMO-IgG with complement in NMO disease but also provide a platform for the development of future therapeutics.

Probable sporadic Creutzfeldt-Jakob disease mimicking focal epilepsy.

Creutzfeldt-Jakob disease (CJD) presents with seizures as an early symptom in only approximately 3% of cases. These seizures often present as nonconvulsive status epilepticus (NCSE) or epilepsia partialis continua (EPC). Here, we describe a case of probable sporadic CJD (sCJD) in an 83-year-old man whose manifest an unusual presentation of left-hand tonic seizures without evolution to EPC, as well as brain MRI findings interpreted as peri-ictal changes, which led to an initial misdiagnosis of focal epilepsy.

Functional Remodeling of Both Atria is Associated with Occurrence of Stroke in Patients with Paroxysmal and Persistent Atrial Fibrillation.

BACKGROUND: It is critical to recognize high risk patients who are prone to develop stroke in the management of atrial fibrillation (AF). The purpose of this study was to identify the determinants of AF related stroke by assessing the anatomical and functional remodeling of cardiac chambers. METHODS: We compared the cardiac structure and function of 28 consecutive patients with paroxysmal and persistent AF-related stroke with 69 patients with AF and 21 controls without stroke using contrast-enhanced 64-slice multi-detector computed tomography during sinus rhythm. RESULTS: The volume of left atrium (LA), LA appendage (LAA) and right atrium (RA) were significantly increased across the groups with sinus rhythm (SR), AF and AF-related stroke (p < 0.001 for each, respectively). The emptying fraction and booster-pump function of LA, LAA and RA were decreased across the groups (p < 0.001 for each). In addition, the left ventricular mass index was increased in AF related stroke (p = 0.003). Using multivariate analysis, increased age (p = 0.003), reduced booster-pump function of LA (p = 0.01), LAA (p < 0.001) and RA (p < 0.001) were shown to be independently associated with the occurrence of stroke. CONCLUSIONS: The dilatation and contractile dysfunction of both atria are related to the development of stroke in patients with paroxysmal and persistent AF. Our results suggested that the use of substrate-based assessment may help improve risk stratification of stroke in patients with AF.

The Abundance of Epicardial Adipose Tissue Surrounding Left Atrium Is Associated With the Occurrence of Stroke in Patients With Atrial Fibrillation.

Epicardial adipose tissue (EAT) is positively associated with risk factors for cardiovascular disease, but the role of EAT in the development of atrial fibrillation (AF)-related stroke and its association with the anatomical and functional remodeling of the left atrium (LA) have not been elucidated.This was a comparative cross-sectional study. Twenty-seven patients with paroxysmal or persistent AF and cardioembolic stroke were selected and compared with 68 age- and sex-matched AF patients without stroke. In addition, 20 controls without a history of AF or stroke were included. The periatrial EAT and the structural and functional properties of the LA and left ventricle were evaluated using contrast-enhanced 64-slice multidetector computed tomography during sinus rhythm. Total EAT around the LA was significantly increased across the groups (control vs AF vs AF-related stroke, P < 0.001). The volumes of the LA and the LA appendage (LAA) were also significantly increased across the 3 groups (P < 0.001 for each). The emptying fraction of the LA and LAA and the booster-pump function of the LA and LAA were all reduced across the 3 groups (P < 0.001 for all). In addition, the Hounsfield unit (HU) ratio of the LAA to the ascending aorta (LAA/AA) was also decreased in patients with stroke (P < 0.001). Furthermore, EAT had a negative correlation with the dynamic function of the LA, LAA, and the HU ratio. After a multivariate analysis, increased EAT (P < 0.001) was shown to be independently associated with the occurrence of AF-related stroke.Periatrial EAT was increased and was correlated with atrial dysfunction in patients with AF-related stroke. Hence, EAT assessment may potentially offer an incremental value for grading the risk of cardioembolic stroke in patients with AF.

Poor responses to interferon-beta treatment in patients with neuromyelitis optica and multiple sclerosis with long spinal cord lesions.

Interferon-beta (IFN-ß) treatment may not be effective in neuromyelitis optica (NMO). Whether the poor response to IFN-ß is related to long spinal cord lesions (LSCL) or the NMO disease entity itself is unclear. We evaluated the spinal cord involvement of patients with multiple sclerosis (MS) and NMO, as well as the response after receiving IFN-ß. Forty-nine MS and 21 NMO patients treated with IFN-ß for at least 2 years from 2002-2008 were enrolled in this study and the treatment response was analyzed 2 years post-treatment. In the study, spinal cord lesions were present in 57.1% (28/49) of the MS patients, of which 16.3% (8/49) presented spinal cord lesions longer than 3 vertebral segments (LSCL). Responses to IFN-ß treatment were seen in 69.3% (34/49) of all the MS cases, of which the appropriate response rates were 76.1% (16/21) in MS patients without spinal cord lesions and 37.5% (3/8) in patients with LSCL. Only 14.2% (3/21) of NMO patients responded to IFN-ß treatment. In conclusion, spinal cord lesion is common in MS patients in Taiwan. Both NMO and MS patients with LSCL had a poor response to IFN-ß treatment. NMO patients had a worse response to IFN-ß treatment than MS patients with LSCL, which shows that the crucial structural defect is something other than LSCL such as the elevated serum IL17 level in NMO compared to MS.

α-Lipoic acid enhances endogenous peroxisome-proliferator-activated receptor-γ to ameliorate experimental autoimmune encephalomyelitis in mice.

ALA (α-lipoic acid) is a natural, endogenous antioxidant that acts as a PPAR-γ (peroxisome-proliferator-activated receptor-γ) agonist to counteract oxidative stress. Thus far, the antioxidative and immunomodulatory effects of ALA on EAE (experimental autoimmune encephalomyelitis) are not well understood. In this study, we found that ALA restricts the infiltration of inflammatory cells into the CNS (central nervous system) in MOG (myelin oligodendrocyte glycoprotein)-EAE mice, thus reducing the disease severity. In addition, we revealed that ALA significantly suppresses the number and percentage of encephalitogenic Th1 and Th17 cells and increases splenic Treg-cells (regulatory T-cells). Strikingly, we further demonstrated that ALA induces endogenous PPAR-γ centrally and peripherally but has no effect on HO-1 (haem oxygenase 1). Together, these data suggest that ALA can up-regulate endogenous systemic and central PPAR-γ and enhance systemic Treg-cells to inhibit the inflammatory response and ameliorate MOG-EAE. In conclusion, our data provide the first evidence that ALA can augment the production of PPAR-γ in vivo and modulate adaptive immunity both centrally and peripherally in EAE and may reveal further antioxidative and immunomodulatory mechanisms for the application of ALA in human MS (multiple sclerosis).

Distinct serum cytokine profiles in neuromyelitis optica and multiple sclerosis.

Multiple sclerosis (MS) is the most common prototypic inflammatory demyelinating disease. Neuromyelitis optica (NMO) is another inflammatory demyelinating disease of the central nervous system that exhibits clinical symptoms mainly associated with optic neuritis and myelopathy. The inflammatory reaction in MS is associated with an upregulation of a variety of T helper 1 (Th1)- or Th17-mediated cytokines. However, NMO and MS are intertwined both clinically and pathologically, which complicates their diagnosis and treatment. The aim of this study was to evaluate the differences in serum cytokine levels in patients with NMO and MS. We collected peripheral serum from patients with these central nervous system demyelinating diseases for the study. A cytometric bead array was used to assess the cytokine levels using flow cytometry. We found more inflammatory [interleukin (IL)-2 and interferon-γ) and anti-inflammatory (IL-4 and IL-10) cytokines in NMO than in MS. The differences in the optimal cutoff points of serum cytokines, including IL-2 ≥5 pg/mL, can differentiate NMO from MS. In conclusion, patients with NMO had an increased Th1-mediated inflammatory response, but similar Th17-mediated inflammation changes compared to patients with MS. Serum cytokine studies can differentiate NMO cases from MS.

Prominent brainstem symptoms/signs in patients with neuromyelitis optica in a Taiwanese population.

Neuromyelitis optica (NMO) is a severe demyelinating disease defined principally by its selective effect on the optic nerves and spinal cord. Contemporary diagnostic criteria require an absence of any clinical disease outside the optic nerve or spinal cord. However, we frequently encounter patients with NMO who have previously undetected symptomatic brainstem lesions. We investigated the brainstem symptoms/signs in patients with NMO and their corresponding MRI findings in a Taiwanese population. We evaluated the clinical symptoms/signs, anti-aquaporin-4 antibody titer and corresponding brain MRI of 49 patients with NMO; results were obtained from chart reviews and during clinical visits. A total of 18 (37%) patients with NMO had brainstem symptoms/signs, including diplopia (n=9, 50%), prolonged hiccup and poor appetite (n=9, 50%). For these patients, most of their brainstem events occurred during the first demyelinating attack in their NMO course. A higher percentage (77.8%) of patients with brainstem NMO had brain lesions with specific NMO patterns, including lesions involving the hypothalamus (n=6, 33.3%), midbrain or pons (n=8, 44.4%), periaqueductal regions (n=5, 27.7%), and medulla (n=10, 55.6%). Brainstem symptoms/signs and characteristic NMO imaging findings are common in Taiwanese patients with NMO, and should be considered a part of the illness in addition to optic neuritis and myelitis.

Glatiramer acetate could be a hypothetical therapeutic agent for neuromyelitis optica.

Neuromyelitis optica (NMO) is characterized by concurrence of optic neuritis and transverse myelitis, which is typically associated with a spinal cord lesion extending three or more vertebral segments. NMO is an inflammatory, demyelinating central nervous system disorder, and although it has a relapsing course in more than 90% of patients, it differs from multiple sclerosis in that it is more severe, usually spares the brain, and is associated with a longitudinally extensive lesion on spinal cord magnetic resonance imaging (MRI). Furthermore, NMO is associated with a highly specific serum marker called anti-aquaporin-4 antibody, which is believed to have a central pathogenetic role in NMO. Treatment with B-cell specific monoclonal antibody (rituximab) and plasma exchanges appears to reduce the severity and frequency of attacks in NMO, and therefore, B-cell autoimmunity as well as a humoral mechanism may be involved in the pathogenesis of NMO. Glatiramer acetate (GA; also known as Copaxone, COP-1) is a synthetic copolymer of a pool of peptides composed of random sequences of four amino acids: glutamine, lysine, alanine, and tyrosine. GA-specific T-helper 1- (Th1) and 2-type (Th2) cells produce brain-derived neurotrophic factor (BDNF), which may affect neuronal survival and myelin repair. GA treatment also leads to sustained augmentation of BDNF, neurotrophin (NT)-3, and NT-4 expression in various brain regions as demonstrated by histological analysis of immunostained brain sections and BDNF elevation after GA treatment on both protein and mRNA levels. GA-Th2 activation may also have a neuroprotective role in the course of NMO. Furthermore, B cells from GA-treated mice suppress experimental autoimmune encephalomyelitis. The pathogenesis of NMO is largely unknown. However, there is some evidence that B-cell autoimmunity, activation of eosinophils, and B-cell activating factor play important roles, based on neurotrophic factors, neuroprotection, anti-inflammation, and B-cell modulation, GA is thus a hypothetic potential treatment agent for NMO.

The prevalence of long spinal cord lesions and anti-aquaporin 4 antibodies in neuromyelitis optica patients in Taiwan.

BACKGROUND AND OBJECTIVE: It was the aim of this study to determine the prevalence of anti-aquaporin 4 antibody (anti-AQP4 Ab) and long spinal cord lesions in neuromyelitis optica (NMO) and multiple sclerosis (MS) patients in Taiwan. Asia has a relatively high rate of NMO compared with MS patients. Anti-AQP4 Ab is an important marker for NMO worldwide, but serological data and clinical profiles of NMO patients in Taiwan have not been reported. METHODS: This retrospective study compared the clinical symptoms, demographics, spinal cord lesion length and AQP4 Ab status of 34 patients with NMO with 34 patients diagnosed with conventional MS. RESULTS: Our NMO patients were predominantly middle-aged women (median age 45 years), exhibited many relapses (1.0/year) and displayed a higher Expanded Disability Status Scale score (4.75) than conventional MS patients. NMO patients exhibited long spinal cord lesions as detected by MRI. Forty-one percent of the NMO patients had detectable anti-AQP4 Ab. The Expanded Disability Status Scale score was significantly higher in AQP4 Ab- NMO patients. CONCLUSION: The prevalence of AQP4 Ab in a Taiwanese NMO group was 41%. Long spinal cord lesions and detection of AQP4 Ab helped to differentiate NMO patients from MS patients. Long spinal cord lesions with the anti-AQP4 Ab test may allow for an earlier diagnosis of NMO and improve therapeutic decisions.

The rescue effect of plasma exchange for neuromyelitis optica.

Neuromyelitis optica (NMO) is an uncommon idiopathic demyelinating disease of the central nervous system and is sometimes unresponsive to steroid treatment as compared to multiple sclerosis (MS). There are only a few reports of plasma exchange (PE) as an effective rescue treatment when high-dose steroid therapy fails in exacerbations of NMO. Thus, we aimed to evaluate the efficacy of PE for acute attacks of NMO that failed to respond to high-dose steroid therapy. A retrospective review and clinical follow-up were conducted in two hospitals from January 2001 to January 2008. We recruited patients with NMO who had failed to respond to high-dose steroid treatment, and who then received PE during an acute relapse. We evaluated a global functional assessment of the change in the neurological condition, and the Expanded Disability Status Scale (EDSS) score. All nine patients were middle-aged women (mean age: 48.7 years old), five of whom tested positive for anti-aquaporin (AQP)-4 antibodies in the study. The patients were severely disabled at the initiation of PE (median EDSS score, 8.7; range, 8.5-9.0). Improvement occurred early in the course of PE. At the 2-month post-PE follow-up, eight of nine patients had improved to their pre-attack condition. This study highlights the potential role of PE as a rescue therapy in the management of steroid-unresponsive acute attacks of NMO, especially in patients with auto-antibodies against AQP-4.