Disease characteristics of idiopathic transverse myelitis with serum neuronal and astroglial damage biomarkers.

Despite its close association with CNS inflammatory demyelinating disorders (CIDDs), pathogenic characteristics of idiopathic transverse myelitis (ITM) remain largely unknown. Here, we investigated serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) in patients with ITM to unravel the disease characteristics of ITM. We prospectively recruited 70 patients with ITM, 62 with AQP4 + NMOSD and 85 with RRMS-including 31 patients with acute TM attacks-along with 30 HCs. We measured sNfL and sGFAP levels using single-molecular arrays and compared these levels per lesion volume between the disease groups during attacks. Compared to HCs, ITM patients showed higher sNfL and sGFAP during acute attacks (sNfL: p < 0.001, sGFAP: p = 0.024), while those in remission (sNfL: p = 0.944, sGFAP: p > 0.999) did not, regardless of lesion extents and presence of multiple attacks. ITM patients demonstrated lower sGFAP/volume (p = 0.011) during acute attacks and lower sGFAP (p < 0.001) in remission compared to AQP4 + NMOSD patients. These findings suggest that both neuronal and astroglial damages occur in patients with acute ITM attacks at a similar level to those with RRMS, distinct from AQP4 + NMOSD. However, active neuroinflammatory process was not remarkable during remission in this cohort.

Prognostic factors for relapse and outcome in pediatric acute transverse myelitis.

OBJECTIVE: It may be difficult for clinicians to estimate the prognosis of pediatric acute transverse myelitis (ATM). The aim of this study was to define prognostic factors for relapsing disease and poor outcome in pediatric ATM. METHODS: This prospective cohort study included 49 children, 18 boys and 31 girls (median age 13.1 years, IQR 6.5-16.2) with a first episode of ATM. Factors associated with relapsing disease and poor outcome (Expanded Disability Status Scale (EDSS) ≥ 4) were assessed during a median follow-up of 37 months (IQR 18-75). RESULTS: In total, 14 patients (29%) experienced ≥ 1 relapse(s) and nine patients (18%) had a poor outcome. Factors at onset associated with relapsing disease included higher age (16.1 vs. 11.6 years, p = 0.002), longer time to maximum severity of symptoms (5.5 vs. 3 days, p = 0.01), lower maximum EDSS score (4.0 vs. 6.5, p = 0.003), short lesion on spinal MRI (64 vs. 21%, p = 0.006), abnormalities on brain MRI (93 vs. 44%, p = 0.002) and presence of oligoclonal bands in cerebrospinal fluid (67 vs. 14%, p = 0.004). The only factor associated with poor outcome was presence of a spinal cord lesion on MRI without cervical involvement (56 vs. 14%, p = 0.02). CONCLUSION: Pediatric ATM patients presenting with clinical, radiological and laboratory features associated with multiple sclerosis (MS) are at risk for relapsing disease. In absence of these known MS risk factors at onset of disease these patients are at low risk for relapses. Only a minority of pediatric ATM patients in this cohort have a poor outcome.

A clinico-neurophysiological study of urogenital dysfunction in MOG-antibody transverse myelitis.

OBJECTIVE: To assess the clinical, urodynamic, and neurophysiologic features of patients with persisting bladder, bowel, and sexual dysfunction after transverse myelitis in myelin oligodendrocyte glycoprotein antibody (MOG-Ab) disease. METHODS: Patients with a history of MOG-Ab disease-related transverse myelitis seen prospectively in a tertiary center uro-neurology service between 2017 and 2019 were included. They received cross-sectional clinical assessment; completed standardized questionnaires on bladder, bowel, and sexual symptoms; and underwent urodynamic and pelvic neurophysiologic investigations. RESULTS: Twelve patients (9 male) were included with a total of 17 episodes of transverse myelitis. Mean age at first attack was 26 (SD 9) years, and median follow-up duration was 50 (interquartile range 32-87) months. Acute urinary retention requiring bladder catheterization occurred in 14 episodes and was the first symptom in 10 episodes. Patients with lesions affecting the conus medullaris required catheterization for significantly longer durations than those without a conus lesion (median difference 15.5 days, p = 0.007). At follow-up, all patients had recovered full ambulatory function, but persisting bladder and bowel dysfunction moderately or severely affected quality of life in 55% and 36%, respectively, and 82% had sexual dysfunction. Pelvic neurophysiology demonstrated abnormal residual conus function in 6 patients. Urodynamic findings predominantly showed detrusor overactivity and/or detrusor-sphincter dyssynergia, indicative of a supraconal pattern of lower urinary tract dysfunction. CONCLUSIONS: Persisting urogenital and bowel dysfunction is common despite motor recovery. Although a proportion of patients had neurophysiologic evidence of residual conus abnormalities at follow-up, predominant urodyamic findings suggest that ongoing lower urinary tract dysfunction results from supraconal injury.

Longitudinal extensive transverse myelitis with an abnormal uFLC ratio in a pediatric patient: Case report and literature review.

RATIONALE: The serum and urine-free light chain (sFLC/uFLC) ratios of kappa (κ) to lambda (λ) serve as biomarkers for plasma cell disorders, especially multiple myeloma. However, to our best knowledge, the ratios have not been appropriately assessed for acute transverse myelitis (ATM). PATIENT CONCERNS: We present a 12-year-old boy who had sudden onset low back pain following paralysis of his 4 extremities and disturbance consciousness. Magnetic resonance imaging (MRI) of the brain and spine indicated diffuse hyperintensity in T2-weighted images from the cervical spinal cord to the conus medullaris. An abnormal serum M-peak and uFLC ratio were detected in acute stage. DIAGNOSES: Based on the image findings, laboratory findings, and physical examination results, the diagnosis of acute transverse myelitis was established. INTERVENTIONS AND OUTCOMES: With the treatment of pulse therapy and 5 courses of plasmapheresis, the patient had improvement in expanded disability status scale (EDSS) score from 9 to 5. Besides, the κ/λ ratio was also returned within the normal range. LESSON: The case presented an unusual phenomenon of transient abnormal κ/λ ratio combined with an M-peak in the acute course of longitudinally extensive transverse myelitis (LETM), which revealed FLC ratio recovering accompany with the improvement of disease. Further studies are required to identify the association between ATM and monoclonal gammopathy of undetermined significance (MGUS).

B Cell, Th17, and Neutrophil Related Cerebrospinal Fluid Cytokine/Chemokines Are Elevated in MOG Antibody Associated Demyelination.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody (MOG Ab) associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination. AIM: To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS) and -negative (NEG) groups. METHODS: We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8), transverse myelitis (TM = 2) n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9) demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls. RESULTS: The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19) as well as some of Th17 related cytokines (IL-6 AND G-CSF) compared to MOG Ab NEG group (all p<0.01). In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies. CONCLUSION: Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.

Neuromyelitis optica spectrum disorder as a paraneoplastic manifestation of lung adenocarcinoma expressing aquaporin-4.

BACKGROUND: The observations of neuromyelitis optica spectrum disorders (NMOSD) occurring in the setting of cancer suggest that aquaporin-4 (AQP4) autoimmunity may in some cases be paraneoplastic. RESULTS: We describe a 72-year-old patient who developed a longitudinally extensive transverse myelitis associated with AQP4 autoantibodies in the setting of a lung adenocarcinoma recurrence. AQP4 expression was demonstrated in tumor cells. IgG in patient's cerebrospinal fluid bound to tumor cells co-localizing with AQP4 immunoreactivity. CONCLUSIONS AND RELEVANCE: This case expands the spectrum of paraneoplastic AQP4 autoimmunity highlighting the importance of considering an oncological screening in patients with late-onset NMOSD.

Enhanced IL-6 production in aquaporin-4 antibody positive neuromyelitis optica patients.

Anti-aquaporin-4 (Aqp-4) antibody and complement system have emerged as major pathogenic factors in neuromyelitis optica (NMO). To test the significance of interleukin-6 (IL-6), another important humoral immunity factor, in NMO pathogenesis, we measured serum and cerebrospinal fluid (CSF) IL-6 levels of 23 NMO, 11 transverse myelitis, 16 optic neuritis, 27 relapsing remitting multiple sclerosis patients, and 20 neurologically normal controls. NMO and transverse myelitis patients had higher serum and CSF IL-6 levels than other groups. Particularly, anti-Aqp-4 positive NMO patients (n = 12) had higher serum/CSF IL-6 levels than anti-Aqp-4 negative patients (n = 11) and CSF IL-6 levels correlated with anti-Aqp-4 levels and disease severity of the NMO patients. Our results suggest that IL-6 is involved in NMO pathogenesis presumably via anti-Aqp-4 associated mechanisms.

Common CYP7A1 promoter polymorphism associated with risk of neuromyelitis optica.

Neuromyelitis optica (NMO) is a severe idiopathic inflammatory disease of the central nervous system primarily affecting the optic nerves and spinal cord. In this study, we generated genome-wide SNP data from NMO patients and normal controls (53 cases and 240 controls), and followed up on the association signals with samples from a larger number of inflammatory demyelinating diseases, including NMO (n=93), multiple sclerosis (MS, n=71), idiopathic recurrent transverse myelitis (IRTM, n=57), and normal controls (n=240). Statistical analyses revealed that a common promoter SNP in CYP7A1 has a protective/gene dose-dependent effect on the risk of NMO (P=0.0004). A stronger association between the variables and subsequently, a higher protective effect (lower OR) on the risk of NMO were observed among patients carrying the "G/G" genotype of rs3808607 than those with the "T/G" genotype (OR=0.38/P=0.01 vs. OR=0.12/P=0.0004, respectively). The associations which were only observed in patients with NMO suggest that there are differences in the genetic etiology of the inflammatory demyelinating diseases (NMO, classical MS, and IRTM).

Fluorodeoxyglucose positron emission tomography (FDG-PET) is useful in the diagnosis of neurosarcoidosis.

A 45-year-old man presented with a progressive transverse spinal cord syndrome. MRI scanning revealed bitemporal and multiple spinal lesions with significant enhancement after gadolinium administration mimicking an acute disseminated encephalomyelitis. CSF analyses showed a lymphocytic pleocytosis. After treatment with high dose steroids clinical improvement was observed with a secondary decline shortly thereafter. MRI rescanning showed no remarkable alterations of the lesions. Further diagnostic work-up included a fluorodeoxyglucose positron emission tomography (FDG-PET) of the whole body to search for occult inflammation or neoplasia. The FDG-PET showed hypermetabolic foci corresponding to the lesions on MRI and additionally increased uptake in mediastinal and pulmonary hilar lymph nodes. A mediastinal lymph node was biopsied. Pathology was consistent with the diagnosis of sarcoidosis. The usual diagnostical tools to evaluate a sarcoidosis, such as serum angiotensin converting enzyme (ACE) and computed tomography of the chest were performed initially and revealed no pathological results. Therefore, in this case FDG-PET was crucial for the diagnostic work-up leading to an accessible inflammatory lesion outside the CNS for biopsy and the final diagnosis of sarcoidosis.

Interleukin-17 in transverse myelitis and multiple sclerosis.

CSF IL-6 is elevated in transverse myelitis (TM) and predicts disability. Since IL-17 regulates cytokines (TNFalpha, IL-1beta and IL-6) known to stimulate IL-6 production by astrocytes, we sought to determine whether IL-17 was increased in TM and MS compared to healthy controls (HC) and other neurologic diseases (OND). IL-17 and IL-6 levels were measured in stimulated peripheral blood mononuclear cell (PBMC) supernatants from HC, MS, TM and OND. IL-17 was increased in TM compared to HC, MS, and OND (mean pg/ml+/-standard error; HC: 36.1+/-11.7, MS: 89.4+/-23.3, TM: 302.6+/-152.5, OND: 41.2+/-13.0, p=0.01). IL-6 was increased in TM relative to MS and HC (HC: 2624 pg/ml+/-641, MS: 6129+/-982, TM: 12,536+/-2657, OND: 6920+/-1801, p<0.002). MS patients with early disease (<2 years) also had increased levels of IL-17 (p<0.04) and IL-6 (p<0.05). Cytokine neutralization experiments demonstrated that IL-6 was the main inducer of astrocyte IL-6 production. We conclude that IL-17 and IL-6 production from PBMC in TM and early MS are increased and induce astrocyte IL-6 production through IL-6.

Paraneoplastic myopathy: response to intravenous immunoglobulin.

Necrotizing myopathy is an unusual and severe form of paraneoplastic myopathy in which inflammation is minimal or absent. We report two cases of necrotizing myopathy which demonstrated significant response to intravenous immunoglobulin (IVIG) (one in spite of tumor progression). A third case represents the first association of anti-signal recognition particle (anti-SRP) syndrome with large-cell lung cancer. These cases highlight the role of histopathologic diagnosis in directing the treatment of paraneoplastic myopathy, and the role for IVIG in treatment of the syndrome.

Demyelinating disorders: update on transverse myelitis.

Transverse myelitis (TM) is a focal inflammatory disorder of the spinal cord. Perivascular monocytic and lymphocytic infiltration, demyelination, and axonal injury are prominent histopathogic features of TM. The clinical manifestations of TM are consequent to dysfunction of motor, sensory, and autonomic pathways. At peak deficit, 50% of patients with TM are completely paraplegic (with no volitional movements of legs), virtually all have some degree of bladder dysfunction, and 80% to 94% have numbness, paresthesias, or band-like dysesthesias. Longitudinal case series of TM reveal that approximately one third of patients recover with little to no sequelae, one third are left with a moderate degree of permanent disability, and one third have severe disability. Recent studies have shown that the cytokine interleukin-6 may be a useful biomarker, as the levels of interleukin-6 in the cerebrospinal fluid of acute TM patients strongly correlate with and are highly predictive of disability. Clinical trials testing the efficacy of promising axonoprotective agents in combination with intravenous steroids in the treatment of TM are currently underway.

[Acute transverse myelopathy associated to S. aureus: a difficult differential diagnosis]. / Mielopatía transversa aguda asociada a S. aureus: la dificultad del diagnóstico diferencial.

Acute myelopathy includes a group of diseases with an important associated morbidity, thus early diagnosis and treatment is important. The most frequent etiology is extramedullary compression. Magnetic resonance (MR) is the most suitable procedure in this type of disease since it also offers information on extramedullar lesions and makes it possible to assess spine involvement. We present the case of a 57 year-old man who was admitted because of back pain for several weeks and systemic infection due to S. aureus. Later, he suffered a sudden neurological deficit with spine involvement but without compressive images on the MRI. We discuss the differential diagnosis among intramedullary abscess, epidural abscess, acute transverse myelitis and spondylodiscitis associated to acute myelopathy. We carry out a brief review of the medical literature on diagnosis criteria of those entities.

Elevated 14-3-3 protein and axonal loss in immunoglobulin-responsive, idiopathic acute transverse myelitis.

OBJECTIVES: To report the elevation of the 14-3-3 protein and the complete denervation of hand muscles in idiopathic acute transverse myelitis (IATM) of the cervical cord. CASE DESCRIPTION: In a 29-year-old woman with a 2-week history of neck pain and repeated attenuated flus, subacute quadriplegia, hypaesthesia of both arms, a T3 sensory level, and urinary dysfunction occurred. Based upon the clinical findings, the cervical MRIs, and an elevated 14-3-3 protein in the CSF, IATM C4-C7 was diagnosed. Ten, 17, 28 and 61 days after onset, nerve conduction studies revealed complete denervation of the right abductor pollicis brevis and abductor digiti minimi muscles but gradual improvement of the compound muscle action potential of the left abductor pollicis brevis muscle. F-waves of the right median nerve were absent. Tibial somatosensory evoked potentials showed a prolonged central conduction time. Transcranial magnetic stimulation evoked a response in the left but not the right abductor digiti minimi muscle. CONCLUSION: IATM may cause elevation of the 14-3-3 protein and loss of motor axons originating from affected anterior horn cells.

Immunoreactive myelin proteolipid, protein-like activity in cerebrospinal fluid and serum of neurologically impaired patients.

Two hundred seventy-eight samples of cerebrospinal fluid and 273 samples of sera from a variety of neurological patients were examined by radioimmunoassay for myelin proteolipid protein-like reactivity as an index of structural damage to myelin. Groups of patients with active central nervous system damage could be distinguished easily, although there was a small percentage of false positive reactions. The reactivity was most marked in the demyelinative, encephalitic, and stroke categories. A radioimmunoassay for proteolipid protein of proper sensitivity and specificity may prove to be a useful objective clinical measure of the presence and degree of disease activity in multiple sclerosis and other diseases.

The prognosis of acute and subacute transverse myelopathy based on early signs and symptoms.

Fifty-two patients with acute and subacute transverse myelopathy (TM) were evaluated at the Massachusetts General Hospital between 1955 and 1975 and followed for 1 to 23 years (average, 5). Nineteen had symptoms of a recent acute infectious illness, 3 had cancer, and 1 had undergone a recent operation. There were four types of initial symptom. Twenty-four patients had paresthesias at the onset of the illness, 18 had pain, usually interscapular, 7 had leg weakness, and 3 had urine retention. Prognosis depended on the nature of the onset of TM. An acute catastrophic onset was generally associated with back pain and led to a poor outcome in 7 and a good outcome in only 1 of 11 patients. A subacute progressive onset over several days to four weeks, generally with ascending paresthesias or leg weakness, was associated with a good outcome in 15 and fair outcome in 17 of 37 patients. Preceding febrile illness, treatment with corticosteroids, and the nature of CSF abnormalities had no effect on outcome. Multiple sclerosis evolved in 7 patients during the follow-up period. Because of the frequency with which mass lesions were missed, the need for myelography in the diagnosis of TM is emphasized. The distinguishing clinical characteristics of TM provide guidelines for diagnosis and prognosis.