NEUROMYELITIS optica spectrum disorder (NMOSD) is an inflammatory disorder that targets the central nervous system. It is characterized by severe inflammation-mediated demyelination, mainly influencing the optic nerve and spinal cord. The prevalence of NMOSD is 0.52-10/100 000[1,2,3,4] in different studies, with a median patient age of 32 to 41 years. The incidence of NMOSD in the Asian population is 3 times higher than that in other areas of the world.[3]
Acute bilateral or consecutive optic neuritis leading to severe loss of vision or transverse myelitis resulting in limb weakness, hypoesthesia or bladder dysfunction are the main characteristics of NMOSD, typically with recurrence. Symptoms of the disease usually appear within a couple of days, and most of the patients can recover to different degrees in the following weeks or months. The detailed etiology of NMOSD remains unclear; however, the important role of aquaporin-4 (AQP4) in the pathophysiology of the disease has been widely acknowledged. AQP4 is the target of the neuromyelitis optica-IgG antibody, and it is distributed in the gray matter of the spinal cord, periaqueductal midbrain and periventricular areas. It is also highly aggregated in the foot processes of astrocytes in the blood-brain barrier. It has been confirmed that neuromyelitis optica-IgG antibody (anti-AQP4 antibody) is a highly specific biomarker in NMOSD patients[5, 6] that plays a direct role in the pathogenesis of the disease.[7, 8]
Huang and colleagues had just investigated NMOSD in China. They found that NMOSD had a great negative impact on the life quality of Chinese patients, including both physical and emotional health. Non-specific oral immunosuppressants were still the most common preventive treatments, and 55.7% of patients were not satisfied with their current treatment option.[9] Pain and depression always comorbid in NMOSD patients, but were often neglected and remain untreated. This article reviews the epidemiology, mechanism, evaluation and treatment of pain-depression comorbidity in NMOSD patients, and hopefully more attention could be paid to this comorbidity.
NMOSD AND PAIN
Epidemiology
The number of patients in cohort studies in the literature is small (11 to 210 patients) due to the low incidence rate of the disease.[9,10,11,12,13,14,15,16,17,18,19,20,21,22] The cohort with the largest sample size comes from the United States. Eaneff and colleagues collected 522 patient data points from an online patient community called PatientsLikeMe.[23] Nevertheless, the data in this study were from voluntary self-reports by patients instead of professional evaluations by physicians, so the reliability of the data was challenged.
Pain is a common symptom of NMOSD. The prevalence of pain in NMOSD patients was as high as 80% in retrospective studies.[10, 15, 21, 22] Qian and colleagues had proved that current pain was more common in NMOSD patients vs. multiple sclerosis patients (86.2% vs. 40.9%), and more severe on a 10-point scale (5.38 vs. 1.85). They also noticed that medication for multiple sclerosis patients to relieve pain was far more effective than for NMOSD patients.[21] Two different types of pain were the most common in NMOSD patients: induced pain caused by muscle spasm and neuropathic pain (NeP). Painful tonic spasms were observed in one fourth of NMOSD cases, and were experienced in unilateral or bilateral limbs.[24] It always emerges during recovery convalescence without accompanying with new neurological deficits or MRI lesions. Muscle spasm could be treated with sodium channel-blocking antiepileptic agents, muscle relaxants, antiparkinsonian drugs and physiotherapy.[25] NeP constitutes 41.6% to 90.9% of pain in NMOSD patients and mostly appears in the thoracolumbar, leg or back areas.[10, 12, 22] NeP in NMOSD patients always manifests as pain accompanied by abnormal pain or thermal sensation, such as allodynia, hyperalgesia, hyperthermesthesia, numbness, and paradoxical heat sensation.
Pain severely influences quality of life in NMOSD patients.[11, 12, 26] Beekman et al.[27] found that NMOSD had a strong negative impact on physical functioning according to Short Form-36 (SF-36) evaluation. Pain imposed the greatest negative physical impact on overall quality of life, whereas the impact of pain on emotional well-being was controversial.[9, 27] Studies also found that dissatisfaction with pain treatment options correlated inversely with quality of life.[27]
Mechanism
Disorder of excitatory glutamate metabolism At the initial stage of disease, the AQP4 antibody combined with AQP4 destroys astrocytes by activating complement or initiating the interaction of effector cells and astrocytes.[28] Damaged astrocytes recruit T cells, and activated macrophages, microglia and granulocytes create and release a series of cytokines, such as interleukin-1β (IL-1β), IL-6, IL-17 and tumor necrosis factor.[25, 29] IL-1β and tumor necrosis factor are able to enhance the signal transduction of glutamate, which can further increase the synaptic transmission between nociceptive C fibers in zones Ⅰ and Ⅱ of the spinal lamina and neurons. The opening of the N-methyl-D-aspartate (NMDA) receptor on glutamate-controlled calcium channels results in long-term potentiation on the synapses of C fibers, which is an important mechanism of hyperalgesia.[30, 31]
Damage to AQP4 leads to water balance disorder. At the same time, the expression of other molecules co-expressed with AQP4 in the lipid raft domain, including excitatory amino acid transporter 2 (EAAT2), is also decreased. EAAT2 plays an important role in glutamate metabolism in astrocytes. A decrease in EAAT2 expression leads to a delay in extracellular elimination of glutamate and results in an elevation of extracellular glutamate concentration in areas damaged by NMOSD. Consequently, abnormal neuronal excitation and excitotoxic tissue injury occur.[32, 33]
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are highly expressed in some inhibitory neurons, and these neurons are very sensitive to high glutamate concentrations. Therefore, these neurons are influenced by the excitotoxicity of glutamate much earlier and more strongly than other neurons.[34] Such damage could destroy the balance between excitatory and inhibitory conduction of noxious stimulation, decrease the excitation threshold, increase neuroexcitability and neurotoxicity, and lead to pain symptoms such as spontaneous pain, hyperalgesia, and allodynia.[25]
Disorder of inhibitory γ-aminobutyric acid and glycine metabolism Pain signaling in the spinal cord includes not only bidirectional excitatory conduction but also a strong inhibitory effect to inhibit pain signals and relieve pain. γ-aminobutyric acid (GABA) and glycine are the two most important inhibitory neurotransmitters in the nociceptive stimulus system.[35] GABA and glycine can prevent the formation of spontaneous pain and allodynia, as well as the regional generalization of hyperalgesia. They can also prevent long-term potentiation formation on the synapses of C fibers to maintain an appropriate reaction for pain stimulation, which plays a significant role in the inhibitory pathway for nociceptive stimuli. After neuronal injury, decreased K+-Cl- exchange channel activity and increased Na+K+-Cl- exchange channel activity can both influence chloride exchange to increase intracellular chloride concentrations and result in enhanced apoptosis of inhibitory interneurons in the spinal cord.[36, 37]
In the central nervous system, glycine is transformed into glutamine and released by astrocytes. Glutamine is then taken up through active transport by GABAergic neurons and transformed back to glycine. Glycine is further transformed into GABA after decarboxylation to take part in the inhibitory process.[38] When neurons are injured, astrocyte death destroys the stabilization of the glycine-glutamine-GABA pathway; as a result, the inhibitory pathway is damaged.
Neurons in the inhibitory pathway are damaged by anti-AQP4 antibody Inhibitory neurons are mainly distributed in the periaqueductal gray.[39] The anti-AQP4 antibody can bind to the AQP4 protein in the periaqueductal gray to directly destroy cells in the inhibitory pathway. Therefore, pain inhibition is decreased, and pain symptoms are aggravated.
NMOSD AND PAIN-DEPRESSION COMORBIDITY
Epidemiology
Pain and depression always coexist, and the concurrence of the two diseases is called pain-depression comorbidity. The prevalence of pain-depression comorbidity is not clear because of the inconsistency among different studies. Rayner and colleagues reported in their research after the investigation of 1204 patients with chronic pain that 60.8% of patients met the criteria for a diagnosis of depression. Moreover, 33.8% of patients even met the diagnostic criteria for severe depression.[40] Consequently, depression should be evaluated in patients with chronic pain. The number of studies on NMOSD accompanied by pain-depression comorbidity is limited due to the low prevalence of the disease. In a study that recruited 71 NMOSD patients, 48% had accompanying NeP, and 28% had moderate to severe depression. Researchers also found that the severity of pain and depression were significantly correlated with each other.[14]
Mechanism
There is no research on the mechanism of pain-depression comorbidity in NMOSD available in the literature. As mentioned above, glutamate and GABA play important roles in the mechanism of pain in NMOSD patients. It is noteworthy that some studies have reviewed whether glutamatergic system hyperfunction[41, 42] and GABAergic system hypofunction[43, 44] are both related to depression.
In animal models, signal enhancement of the excitatory glutamate receptor complex was correlated with allodynia and hyperalgesia, including NMDA receptors and AMPA receptors.[45] Goffer and colleagues indicated that glutamate receptors in the nucleus accumbens are related to chronic pain-related depressive behavior.[46] They found that the GluA1 subunit of the AMPA receptor in the nucleus accumbens was increased, so more AMPA receptors were calcium permeable. Interestingly, this type of receptor could relieve depressive symptoms without reducing pain. As a result, they speculated that this might be a compensatory mechanism of pain-related depression. Consequently, calcium-permeable AMPA receptors might become a new therapeutic target in the future for the treatment of pain-depression comorbidity.
GABAergic system hypofunction was also related to pain-depression comorbidity; however, research in this area was also limited. Sałat and colleagues found in their study that drugs inhibiting the GABA reuptake channel GABA transporter 1 could relieve symptoms of pain and depression in mice. This revealed that the elevation of GABA levels might be effective for the treatment of comorbidities.[47]
Diagnosis, evaluation and treatment
International consensus diagnostic criteria for NMOSD were published in Neurology magazine in 2015 and have been widely used in clinical practice.[48] The classification and severity of pain-depression comorbidity accompanied by NMOSD are always evaluated by multiple assessment scales. These scales are divided into three types: pain assessment scales, depression assessment scales, and quality of life assessment scales. Pain assessment scales can be used to evaluate the type, symptoms, nature, location, and severity of pain and the degree of relief after treatment. Depression assessment scales are used to evaluate the severity of depression. Physicians use quality of life assessment scales to tell how much the disease influences a patient’s quality of life. Here, we summarize the most widely used assessment scales for pain-depression comorbidity evaluation in NMOSD patients, as shown in Table 1.
Table 1 Assessment scales for pain-depression comorbidity evaluation in NMOSD patients and their characteristics
| Name of scales | Characteristics |
|---|---|
| Pain assessment scales | |
| NRS | Pain severity evaluation |
| DN4 | Screening NeP |
| LANSS | Self-reported by patients, screening NeP |
| BPI | Overall assessment of pain, including severity, location, nature, and relief degree after treatment |
| NPSI | NeP symptom evaluation |
| Depression assessment scales | |
| BDI | Most widely used depression evaluation scale |
| PHQ-9 | High sensitivity and specificity in screening depression in patients with chronic pain |
| SDS-Zung | Can be finished within 5 min, easy to use |
| HADS | Used for the evaluation of anxiety and depression |
| Quality of life assessment scales | |
| SF-36 | Most widely used evaluation of HRQoL |
| MSQoL | Specific evaluation scale for HRQoL in MS and NMOSD patients |
| GJCF-NMOSD | Specific evaluation scale for HRQoL in MS and NMOSD patients |
NMOSD: neuromyelitis optica spectrum disorder; NRS: Numerical Rating Scale; DN4: Douleur Neuropathique 4 Questions (Neuropathic Pain Four Questions in French); NeP: Neuropathic Pain; LANSS: Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale; BPI: Brief Pain Inventory; NPSI: Neuropathic Pain Symptom Inventory; BDI: Beck’s Depression Inventory; PHQ: Patient Health Questionnaire; SDS-Zung: Zung Self-rating Depression Scale; HADS: Hospital Anxiety and Depression Scale; SF: Social Functioning; HRQoL: Health-Related Quality of Life; MSQoL: Multiple Sclerosis Quality of Life; MS: multiple sclerosis; GJSF-NMOSD: Guthy-Jackson Charitable Foundation-Neuromyelitis Optica Spectrum Disorder.
Steroids and immunosuppressive drugs have been widely used for NMOSD treatment. Pulsed steroid therapy such as methylprednisolone at a dose of 1 g given intravenously for 3 to 5 days and plasma exchange for 5 to 7 procedures every other day have been proved to be effective in treating severe NMOSD relapse.[49, 50] Intravenous immunoglobulins might also be benefit in NMOSD relapse treatment, but data was limited.[51] With improved understanding of the mechanism of NMOSD, many new therapeutic strategies have recently been evaluated such as Satralizumab and Tocilizumab interfering with IL-6 receptor signalling, Eculizumab preventing complement activation, and Inebilizumab targeting on AQP-4 antibody producing cells, providing realistic hope that NMOSD patients could be treated more effectively.[52]
Other than the treatment of the primary disease, NMOSD, analgesia and depression treatment are the most important ways of controlling symptoms of pain and depression. As one of the symptoms that most severely influences patient quality of life, only a few patients with pain receive analgesic treatment, and the effect of medication is far from satisfactory.[11, 13, 20, 26] It has been proven that, compared with multiple sclerosis patients, NMOSD patients have more accompanying pain symptoms and need higher doses of analgesic drugs but are less sensitive to treatment.[21] Pain-depression comorbidity influences patient quality of life even more severely but attracts insufficient attention. Chavarro and colleagues reported that only 40% of patients with moderate to severe depression received anti-depression treatment among NMOSD patients with comorbidities, and only 50% of the treatment was effective.[14]
Studies suggested that pain and depression were highly intertwined so that some antidepressants also had analgesic effects such as serotonin and norepinephrine antidepressants.[53] Lots of drugs were available to control pain-depression comorbid symptoms including anticonvulsants (gabapentin, pregabalin, carbamazepine, oxcarbazepine), antispasticity medications (baclofen, tizanidine, diazepam), opioids (fentanyl, oxycodone), tricyclic antidepressants (amitriptyline), selective serotonin norepinephrine reuptake inhibitor (SNRI, duloxetine), selective serotonin reuptake inhibitors (SSRI, citalopram), and atypical antidepressants (mirtazapine), et al.[14, 21] Non-drug treatment was also important for pain-depression comorbidity treatment in NMOSD patients. Recently, Mealy and his colleagues proved that Scrambler therapy for 10 consecutive weekdays could significantly release pain and depression symptom safely.[54] The neglect of pain-depression comorbidity in NMOSD patients leads to late treatment for the symptoms. If pain intervention is not provided as early as possible, the effect of drugs will be influenced, especially when the severity of pain and depression reach a certain degree. If preventive intervention is provided for the early treatment of NMOSD, the therapeutic effect will be greatly improved.
CONCLUSIONS
NMOSD patients always suffer from pain, mainly NeP. A large proportion of these patients have pain-depression comorbidity, which influences patients’ quality of life to a great extent and deserves attention. Limited proportion of patients with pain-depression comorbidity receive treatment, and the effectiveness of the current strategy is far from satisfactory. Psychotropic and behavioral therapies usually aimed at treating depression might also be useful for releasing pain symptoms, more drugs targeting specific effective site have been evaluated to better control comorbidity symptoms. What’s more, non-drug therapies also have caught our attention. More studies on the mechanism and therapeutic method of pain-depression comorbidity in NMOSD are required. Early detection, early intervention, and early treatment should be provided, all of which will be significantly important for improving quality of life in NMOSD patients.
Conflicts of Interest Statement
We have no conflicts of interest to declare.
Reference
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PMID:19224310
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Two population-based studies of neuromyelitis optica (NMO) in non-white populations provided prevalence rates of 0.32 and 3.1 per 100,000 population.To estimate NMO prevalence in the multiethnic Cuban population by nation-wide case ascertainment.The study was conducted from October 1, 2003 to November 30, 2004. Ninety percent of general practitioners and all neurologists responded positively to the request for information on cases suspected of optic neuritis (ON), transverse myelitis (TM), multiple sclerosis, or NMO. Among the population of 11,177,743 there were 798 suspected cases, including 89 with possible NMO, relapsing ON (RON) and TM. Of the 89, 87 were examined by two of us (Cabrera JA, Lara R) who selected the NMO cases according to the 1999 Mayo Clinic criteria as well as those with relapsing TM and RON.58 cases provided a prevalence rate of 0.52 per 100,000 (95% CI 0.39-0.67). The 7 males and 51 females gave rates of 0.13 (CI 0.05-0.26) and 0.91 (CI 0.68-1.20). The estimated average annual incidence rate was 0.053 per 100,000 (CI 0.040-0.068). Prevalence rates did not differ significantly among the three ethnic groups. Black NMO cases were significantly older, with more relapses and motor deficit, as well as more abnormalities in brainstem evoked potentials and in brain MRI (not meeting MS criteria). The predominant clinical form was relapsing over monophasic.This Cuban multiethnic population had a prevalence of NMO of 0.52 per 100,000 and an estimated average annual incidence rate of 0.053 per 100,000 with no differences by ethnicity. Black patients were older, with more relapses and motor impairment.
A population-based study of neuromyelitis optica in Caucasians
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PMID:21536639
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Epidemiologic studies have suggested different prevalence of neuromyelitis optica (NMO) in different ethnic groups. However, data on the incidence and prevalence of NMO in Caucasians are scarce.To estimate the incidence and prevalence of NMO in a predominantly Caucasian population based on the Wingerchuk 2006 criteria.The study was a population-based retrospective case series with longitudinal follow-up. Patients with multiple sclerosis (MS), optic neuritis (ON), acute transverse myelitis (TM), and NMO from the 4 neurology and 3 ophthalmology departments in the Region of Southern Denmark having been diagnosed between 1998 and 2008 were investigated. Patients were included based on 1) episodes of ON or TM and 2) an initial brain MRI not diagnostic for MS. An immunofluorescence assay was used to determine aquaporin-4 (AQP-4) antibodies.A total of 477 patients with MS, TM, or ON were evaluated: 163 fulfilled the inclusion criteria, 42 (26%) qualified for the diagnosis of NMO, 26 (62.0%) of these were AQP4 antibody positive. All except one were Caucasian, the female:male ratio was 2.8:1, and mean age at onset was 35.6 years (range 15-64 years). The clinical presentation was heterogeneous including TM, longitudinally extensive TM, ON, and brainstem syndromes. The yearly incidence rate of NMO in the population was estimated to be 0.4 per 10(5) person-years (95% confidence interval [CI] 0.30-0.54) and the prevalence was 4.4 per 10(5) (95% CI 3.1-5.7).Despite being a rare disease, NMO is more common in a Caucasian population than earlier believed.
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Neuromyelitis optica (NMO) and its spectrum disorders (NMOSD) are inflammatory demyelinating diseases (IDDs) with a specific biomarker, aquaporin-4-immunoglobulin G (AQP4-IgG). Prior NMO/NMOSD epidemiological studies have been limited by lack of AQP4-IgG seroprevalence assessment, absence of population-based USA studies, and under-representation of blacks. To overcome these limitations, we sought to compare NMO/NMOSD seroepidemiology across 2 ethnically divergent populations.We performed a population-based comparative study of the incidence (2003-2011) and prevalence (on December 31, 2011) of NMO/NMOSD and AQP4-IgG seroincidence and seroprevalence (sera collected in 80-84% of IDD cases) among patients with IDD diagnosis in Olmsted County, Minnesota (82% white [Caucasian]) and Martinique (90% black [Afro-Caribbean]). AQP4-IgG was measured by M1 isoform fluorescence-activated cell-sorting assays.The age- and sex-adjusted incidence (7.3 vs 0.7/1,000,000 person-years [p < 0.01]) and prevalence (10 vs 3.9/100,000 [p = 0.01]) in Martinique exceeded that in Olmsted County. The AQP4-IgG age- and sex-adjusted seroincidence (6.5 vs 0.7/1,000,000 person-years [p < 0.01]) and seroprevalence (7.9 vs 3.3/100,000 [p = 0.04]) were also higher in Martinique than Olmsted County. The ethnicity-specific prevalence was similar in Martinique and Olmsted County: 11.5 and 13/100,000 in blacks, and 6.1 and 4.0/100,000 in whites, respectively. NMO/NMOSD represented a higher proportion of IDD cases in Martinique than Olmsted County (16% vs 1.4%; p < 0.01). The onset age (median = 35-37 years) and female:male distribution (5-9:1) were similar across both populations; 60% of prevalent cases were either blind in 1 eye, dependent on a gait aid, or both.This study reports the highest prevalence of NMO/NMOSD in any population (10/100,000 in Martinique), estimates it affects 16,000 to 17,000 in the USA (higher than previous predictions), and demonstrates it disproportionately affects blacks. Ann Neurol 2016;79:775-783.© 2016 American Neurological Association.
Incidence and prevalence of NMOSD in Australia and New Zealand
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PMID:28550069
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We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry.NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established.Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases.NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD.NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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PMID:15589308
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Neuromyelitis optica is an inflammatory demyelinating disease with generally poor prognosis that selectively targets optic nerves and spinal cord. It is commonly misdiagnosed as multiple sclerosis. Neither disease has a distinguishing biomarker, but optimum treatments differ. The relation of neuromyelitis optica to optic-spinal multiple sclerosis in Asia is uncertain. We assessed the capacity of a putative marker for neuromyelitis optica (NMO-IgG) to distinguish neuromyelitis optica and related disorders from multiple sclerosis.Indirect immunofluorescence with a composite substrate of mouse tissues identified a distinctive NMO-IgG staining pattern, which we characterised further by dual immunostaining. We tested masked serum samples from 102 North American patients with neuromyelitis optica or with syndromes that suggest high risk of the disorder, and 12 Japanese patients with optic-spinal multiple sclerosis. Control patients had multiple sclerosis, other myelopathies, optic neuropathies, and miscellaneous disorders. We also established clinical diagnoses for 14 patients incidentally shown to have NMO-IgG among 85000 tested for suspected paraneoplastic autoimmunity.NMO-IgG outlines CNS microvessels, pia, subpia, and Virchow-Robin space. It partly colocalises with laminin. Sensitivity and specificity were 73% (95% CI 60-86) and 91% (79-100) for neuromyelitis optica and 58% (30-86) and 100% (66-100) for optic-spinal multiple sclerosis. NMO-IgG was detected in half of patients with high-risk syndromes. Of 14 seropositive cases identified incidentally, 12 had neuromyelitis optica or a high-risk syndrome for the disease.NMO-IgG is a specific marker autoantibody of neuromyelitis optica and binds at or near the blood-brain barrier. It distinguishes neuromyelitis optica from multiple sclerosis. Asian optic-spinal multiple sclerosis seems to be the same as neuromyelitis optica.
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PMID:12076996
[Cited within: 1]
Devic's disease [neuromyelitis optica (NMO)] is an idiopathic inflammatory demyelinating disease of the CNS, characterized by attacks of optic neuritis and myelitis. The mechanisms that result in selective localization of inflammatory demyelinating lesions to the optic nerves and spinal cord are unknown. Serological and clinical evidence of B cell autoimmunity has been observed in a high proportion of patients with NMO. The purpose of this study was to investigate the importance of humoral mechanisms, including complement activation, in producing the necrotizing demyelination seen in the spinal cord and optic nerves. Eighty-two lesions were examined from nine autopsy cases of clinically confirmed Devic's disease. Demyelinating activity in the lesions was immunocytochemically classified as early active (21 lesions), late active (18 lesions), inactive (35 lesions) or remyelinating (eight lesions) by examining the antigenic profile of myelin degradation products within macrophages. The pathology of the lesions was analysed using a broad spectrum of immunological and neurobiological markers, and lesions were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction and the immunopathological evidence of complement activation. The pathology was identical in all nine patients. Extensive demyelination was present across multiple spinal cord levels, associated with cavitation, necrosis and acute axonal pathology (spheroids), in both grey and white matter. There was a pronounced loss of oligodendrocytes within the lesions. The inflammatory infiltrates in active lesions were characterized by extensive macrophage infiltration associated with large numbers of perivascular granulocytes and eosinophils and rare CD3(+) and CD8(+) T cells. There was a pronounced perivascular deposition of immunoglobulins (mainly IgM) and complement C9neo antigen in active lesions associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions. The extent of complement activation, eosinophilic infiltration and vascular fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic multiple sclerosis, and supports a role for humoral immunity in the pathogenesis of NMO. Based on this study, future therapeutic strategies designed to limit the deleterious effects of complement activation, eosinophil degranulation and neutrophil/macrophage/microglial activation are worthy of further investigation.
Synaptic amplifier of inflammatory pain in the spinal dorsal horn
DOI:10.1126/science. 1127233 URL [Cited within: 1]
Induction of synaptic long-term potentiation after opioid withdrawal
DOI:10.1126/science.1171759
PMID:19590003
[Cited within: 1]
mu-Opioid receptor (MOR) agonists represent the gold standard for the treatment of severe pain but may paradoxically also enhance pain sensitivity, that is, lead to opioid-induced hyperalgesia (OIH). We show that abrupt withdrawal from MOR agonists induces long-term potentiation (LTP) at the first synapse in pain pathways. Induction of opioid withdrawal LTP requires postsynaptic activation of heterotrimeric guanine nucleotide-binding proteins and N-methyl-d-aspartate receptors and a rise of postsynaptic calcium concentrations. In contrast, the acute depression by opioids is induced presynaptically at these synapses. Withdrawal LTP can be prevented by tapered withdrawal and shares pharmacology and signal transduction pathways with OIH. These findings provide a previously unrecognized target to selectively combat pro-nociceptive effects of opioids without compromising opioid analgesia.
Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2
DOI:10.1126/science.1171759 URL [Cited within: 1]
Oligodendrocytes are damaged by neuromyelitis optica immunoglobulin G via astrocyte injury
DOI:10.1093/brain/awq177
PMID:20688809
[Cited within: 1]
Devic's neuromyelitis optica is an inflammatory demyelinating disorder normally restricted to the optic nerves and spinal cord. Since the identification of a specific autoantibody directed against aquaporin 4, neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody, neuromyelitis optica has been considered an entity distinct from multiple sclerosis. Recent findings indicate that the neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody has a pathogenic role through complement-dependent astrocyte toxicity. However, the link with demyelination remains elusive. Autoantibodies can act as receptor agonists/antagonists or alter antigen density in their target cells. We hypothesized that the neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody impairs astrocytic function and secondarily leads to demyelination. Rat astrocytes and oligodendrocytes from primary cultures and rat optic nerves were exposed long-term (24 h) to immunoglobulin G in the absence of complement. Immunoglobulin G was purified from the serum of patients with neuromyelitis optica who were either neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody positive or negative, as well as from healthy controls. Flow cytometry analysis showed a reduction of membrane aquaporin 4 and glutamate transporter type 1 on astrocytes following contact with immunoglobulin G purified from neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody positive serum only. The activity of glutamine synthetase, an astrocyte enzyme converting glutamate into glutamine, decreased in parallel, indicating astrocyte dysfunction. Treatment also reduced oligodendrocytic cell processes and approximately 30% oligodendrocytes died. This deleterious effect was confirmed ex vivo; exposed optic nerves showed reduction of myelin basic protein. Immunoglobulin G from neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody seronegative patients and from healthy controls had no similar effect. Neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody did not directly injure oligodendrocytes cultured without astrocytes. A toxic bystander effect of astrocytes damaged by neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody on oligodendrocytes was identified. Progressive accumulation of glutamate in the culture medium of neuromyelitis optica-immunoglobulin G/aquaporin 4-antibody-treated glial cells supported the hypothesis of a glutamate-mediated excitotoxic death of oligodendrocytes in our models. Moreover, co-treatment of glial cultures with neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody and d+2-amino-5-phosphonopentanoic acid, a competitive antagonist at the N-methyl-d-aspartate/glutamate receptor, partially protected oligodendrocytes. Co-immunolabelling of oligodendrocyte markers and neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody showed that astrocytic positive processes were in close contact with oligodendrocytes and myelin in rat optic nerves and spinal cord, but far less so in other parts of the central nervous system. This suggests a bystander effect of neuromyelitis optica-immunoglobulin G-damaged astrocytes on oligodendrocytes in the nervous tissues affected by neuromyelitis optica. In conclusion, in these cell culture models we found a direct, complement-independent effect of neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody on astrocytes, with secondary damage to oligodendrocytes possibly resulting from glutamate-mediated excitotoxicity. These mechanisms could add to the complement-induced damage, particularly the demyelination, seen in vivo.
Parvalbumin-containing interneurons in rat hippocampus have an AMPA receptor profile suggestive of vulnerablility to excitotoxicity
DOI:10.1016/s0891-0618(02)00012-1 URL [Cited within: 1]
Fast synaptic inhibition in spinal sensory processing and pain control
DOI:10.1152/physrev.00043.2010
PMID:22298656
[Cited within: 1]
The two amino acids GABA and glycine mediate fast inhibitory neurotransmission in different CNS areas and serve pivotal roles in the spinal sensory processing. Under healthy conditions, they limit the excitability of spinal terminals of primary sensory nerve fibers and of intrinsic dorsal horn neurons through pre- and postsynaptic mechanisms, and thereby facilitate the spatial and temporal discrimination of sensory stimuli. Removal of fast inhibition not only reduces the fidelity of normal sensory processing but also provokes symptoms very much reminiscent of pathological and chronic pain syndromes. This review summarizes our knowledge of the molecular bases of spinal inhibitory neurotransmission and its organization in dorsal horn sensory circuits. Particular emphasis is placed on the role and mechanisms of spinal inhibitory malfunction in inflammatory and neuropathic chronic pain syndromes.
Differential GABAergic disinhibition during the development of painful peripheral neuropathy
DOI:10.1016/j.neuroscience.2011.03.060
PMID:21496475
[Cited within: 1]
An impaired spinal GABAergic inhibitory function is known to be pivotal in neuropathic pain (NPP). At present, data concerning time-dependent alterations within the GABAergic system itself and post-synaptic GABA(A) receptor-mediated inhibitory transmission are highly controversial, likely related to the experimental NPP model used. Furthermore, it is unknown whether the severity of NPP is determined by the degree of these GABAergic disturbances. In the present study we therefore examined in one experimental animal model whether anatomical changes within the spinal GABAergic system and its GABA(A) receptor-mediated inhibitory function are gradually aggravated during the development of partial sciatic nerve injury (PSNL)-induced NPP and are related to the severity of PSNL-induced hypersensitivity. Three and 16 days after a unilateral PSNL (early and late NPP, respectively), GABA-immunoreactivity (GABA-IR) and the number of GABA-IR neuronal profiles were determined in Rexed laminae 1-3 of lumbar spinal cord cryosections. Additionally, the efficiency of dorsal horn GABA(A) receptor-induced inhibition was examined by cation chloride cotransporter 2 (KCC2) immunoblotting. NPP-induced hypersensitivity was only observed at the ipsilateral side, both at early and late time points. During early NPP, a decrease in ipsilateral dorsal horn GABA-IR was observed without alterations in the number of GABA-IR neuronal profiles or KCC2 protein levels. In contrast, bilateral increases in spinal GABA-IR accompanied by an unchanged number of GABA-IR interneurons were observed during late NPP. This was furthermore attended with decreased ipsilateral KCC2 levels. Moreover, the degree of hypersensitivity was not related to disturbances within the spinal GABAergic system at all time points examined. In conclusion, our anatomical data suggest that a dysfunctional GABA production is likely to be involved in early NPP whereas late NPP is characterized by a combined dysfunctional GABA release and decreased KCC2 levels, the latter suggesting an impaired GABA(A) receptor-mediated inhibition.Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord
DOI:10.1523/JNEUROSCI.22-15-06724.2002 URL [Cited within: 1]
Roles of glutamine in neurotransmission
DOI:10.1017/S1740925X11000093
PMID:22018046
[Cited within: 1]
Glutamine (Gln) is found abundantly in the central nervous system (CNS) where it participates in a variety of metabolic pathways. Its major role in the brain is that of a precursor of the neurotransmitter amino acids: the excitatory amino acids, glutamate (Glu) and aspartate (Asp), and the inhibitory amino acid, γ-amino butyric acid (GABA). The precursor-product relationship between Gln and Glu/GABA in the brain relates to the intercellular compartmentalization of the Gln/Glu(GABA) cycle (GGC). Gln is synthesized from Glu and ammonia in astrocytes, in a reaction catalyzed by Gln synthetase (GS), which, in the CNS, is almost exclusively located in astrocytes (Martinez-Hernandez et al., 1977). Newly synthesized Gln is transferred to neurons and hydrolyzed by phosphate-activated glutaminase (PAG) to give rise to Glu, a portion of which may be decarboxylated to GABA or transaminated to Asp. There is a rich body of evidence which indicates that a significant proportion of the Glu, Asp and GABA derived from Gln feed the synaptic, neurotransmitter pools of the amino acids. Depolarization-induced-, calcium- and PAG activity-dependent releases of Gln-derived Glu, GABA and Asp have been observed in CNS preparations in vitro and in the brain in situ. Immunocytochemical studies in brain slices have documented Gln transfer from astrocytes to neurons as well as the location of Gln-derived Glu, GABA and Asp in the synaptic terminals. Patch-clamp studies in brain slices and astrocyte/neuron co-cultures have provided functional evidence that uninterrupted Gln synthesis in astrocytes and its transport to neurons, as mediated by specific carriers, promotes glutamatergic and GABA-ergic transmission. Gln entry into the neuronal compartment is facilitated by its abundance in the extracellular spaces relative to other amino acids. Gln also appears to affect neurotransmission directly by interacting with the NMDA class of Glu receptors. Transmission may also be modulated by alterations in cell membrane polarity related to the electrogenic nature of Gln transport or to uncoupled ion conductances in the neuronal or glial cell membranes elicited by Gln transporters. In addition, Gln appears to modulate the synthesis of the gaseous messenger, nitric oxide (NO), by controlling the supply to the cells of its precursor, arginine. Disturbances of Gln metabolism and/or transport contribute to changes in Glu-ergic or GABA-ergic transmission associated with different pathological conditions of the brain, which are best recognized in epilepsy, hepatic encephalopathy and manganese encephalopathy.
Cellular and molecular mechanisms of pain
DOI:10.1016/j.cell.2009.09.028
PMID:19837031
[Cited within: 1]
The nervous system detects and interprets a wide range of thermal and mechanical stimuli, as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.
Depression in patients with chronic pain attending a specialised pain treatment centre: prevalence and impact on health care costs
DOI:10.1097/j.pain.0000000000000542 URL [Cited within: 1]
An update on the role of glutamate in the pathophysiology of depression
DOI:10.1111/j.1600-0447.2009.01529.x URL [Cited within: 1]
The role of glutamate on the action of antidepressants
DOI:10.1016/j.pnpbp.2010.06.013 URL [Cited within: 1]
Altered γ-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants
DOI:10.2147/DDDT.S62912 [Cited within: 1]
Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial
DOI:10.1016/S0140-6736(17)31264-3 URL [Cited within: 1]
Biogenic amines and the amino acids GABA and glutamate: relationships with pain and depression
DOI:10.1159/000435933 [Cited within: 1]
Calcium-permeable AMPA receptors in the nucleus accumbens regulate depression-like behaviors in the chronic neuropathic pain state
DOI:10.1523/JNEUROSCI.2454-13.2013 URL [Cited within: 1]
Novel, highly potent and in vivo active inhibitor of GABA transporter subtype 1 with anticonvulsant, anxiolytic, antidepressant and antinociceptive properties
DOI:10.1016/j. neuropharm.2016.10.019 URL [Cited within: 1]
International consensus diagnostic criteria for neuromye- litis optica spectrum disorders
DOI:10.1212/WNL.0000000000001729
PMID:26092914
[Cited within: 1]
Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS. © 2015 American Academy of Neurology.
Treatment of acute relapses in neuromyelitis optica: steroids alone versus steroids plus plasma exchange
DOI:10.1177/1352458515581438 URL [Cited within: 1]
Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica
DOI:10.1177/1352458506071174 URL [Cited within: 1]
Role of intravenous immunoglobin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients
DOI:10.1177/1352458513495938 [Cited within: 1]
Novel emerging treatments for NMOSD
DOI:10.5603/PJNNS.a2019.0049 URL [Cited within: 1]
The triumvirate of co-morbid chronic pain, depression, and cognitive impairment: attacking this “chicken-and-egg” in novel ways
DOI:10.1016/j.sjpain.2017.03.004 URL [Cited within: 1]
Scrambler therapy improves pain in neuromyelitis optica: a randomized controlled trial
DOI:10.1212/WNL.0000000000009370 URL [Cited within: 1]
