Objective:
To compare progressive motor impairment onset attributable to a “critical” central nervous system (CNS) demyelinating lesion in patients with highly restricted versus unlimited magnetic ...resonance imaging (MRI) lesion burden.
Methods:
We identified 135 patients with progressive motor impairment for ⩾1 year attributable to a “critical” demyelinating lesion with: MRI burden of 1 lesion (“progressive solitary sclerosis”), 2–5 lesions (“progressive paucisclerosis”), or unrestricted (>5) lesions and “progressive unilateral hemiparesis.” Neuroradiology review of brain and spinal cord MRI documented unequivocally demyelinating lesions.
Results:
A total of 33 (24.4%) patients had progressive solitary sclerosis; 56 (41.5%) patients had progressive paucisclerosis; and 46 (34.1%) patients had progressive unilateral hemiparesis. Median age at onset of progressive motor impairment was younger in progressive solitary sclerosis (49 years; range 24–73) and progressive paucisclerosis (50 years; range 30–64) than in progressive unilateral hemiparesis (54 years; range 39–77; p = 0.02 and p = 0.003, respectively). Within progressive unilateral hemiparesis, motor-progression onset was similar between those with 4–10, 11–20, or >20 brain lesions (55, 54, 53 years of age, respectively; p = 0.44).
Conclusion:
Motor-progression age is similar, but paradoxically earlier, in cohorts with highly restricted CNS lesion burden than in those with unrestricted lesion burden with progressive unilateral hemiparetic MS. The “critical” demyelinating lesion rather than total brain MRI lesion burden is the major contributor to motor-progression onset in these cohorts.
Before the genomics technology revolution allowed us to do genome-wide science, genetics research relied on our limited knowledge about a subject to generate hypothesis and candidate genes to study. ...Despite the level of naiveté, several associations with susceptibility to a complex disease such as multiple sclerosis (MS) were discovered. Of these, HLA-DRB1 and IL7R (1) stand out as being confirmed and refined early by the genome-wide association studies (GWAS) that followed.(2) Despite the expense and gargantuan efforts, these GWAS have successfully led to the discovery of more than 100 additional genes, albeit with smaller effect sizes, that contribute to MS susceptibility.(3) This list keeps growing, but it comes with no surprise that most of these genes identified the immune system as one large candidate for MS susceptibility.
OBJECTIVETo assess whether cervical spinal cord atrophy heralds the onset of progressive MS.
METHODSWe studied 34 individuals with radiologically isolated syndrome (RIS) and 31 patients with ...relapsing-remitting MS (RRMS) age matched to 25 patients within a year of onset of secondary progressive MS (SPMS). Two raters independently measured (twice per rater) the cervical spinal cord average segmental area (CASA) (mm) of axial T2-weighted images between C2 and C7 landmarks. The midsagittal T2-weighted image from the end of C2 to the end of C7 vertebra was used to measure the cervical spine (c-spine) length (mm). Sex, age at cervical MRI, number and location of cervical spinal cord lesions, c-spine length, and diagnoses were analyzed against the outcome measures of CASA and C2 and C7 slice segmental areas.
RESULTSIntrarater and interrater agreement was excellent (intraclass correlation coefficient >0.97). The CASA area (p = 0.03) and C7 area (p = 0.002) were smaller in SPMS compared with RRMS. The C2 area (p = 0.027), CASA (p = 0.004), and C7 area (p = 0.003) were smaller in SPMS compared with RIS. The C2 area did not differ between SPMS and RRMS (p = 0.09). The C2 area (p = 0.349), CASA (p = 0.136), and C7 area (p = 0.228) did not differ between RIS and MS (SPMS and RRMS combined). In the multivariable model, ≥2 cervical spinal cord lesions were associated with the C2 area (p = 0.008), CASA (p = 0.009), and C7 area independent of disease course (p = 0.017). Progressive disease course was associated with the C7 area independent of the cervical spinal cord lesion number (p = 0.004).
CONCLUSIONCervical spinal cord atrophy is evident at the onset of progressive MS and seems partially independent of the number of cervical spinal cord lesions.
CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that MRI cervical spinal cord atrophy distinguishes patients at the onset of progressive MS from those with RIS and RRMS.
ABSTRACT
BACKGROUND AND PURPOSE
Glutamate levels may be informative about the declining neuronal health in the central nervous system. We used an advanced proton MR spectroscopy (1H‐MRS) protocol ...composed of semi‐localization by adiabatic selective refocusing (sLASER) localization and FAST(EST)MAP shimming for detection of alterations in brain glutamate concentrations in patients with amnestic mild cognitive impairment.
METHODS
Participants with amnestic mild cognitive impairment (n = 14; median age = 80) and age‐ and sex‐matched clinically normal controls (n = 32; median age = 79) from the population‐based Mayo Clinic Study of Aging were recruited prospectively to the 3T single‐voxel 1H‐MRS study that examined metabolite changes in the posterior cingulate gyri. To be included, controls had to have low β‐amyloid load on 11C Pittsburgh Compound B (PiB)‐PET (standard uptake value ratio; SUVr < 1.42) and patients with amnestic mild cognitive impairment had to have high β‐amyloid load (SUVr ≥ 1.42).
RESULTS
Glutamate concentration and the glutamate/myo‐inositol ratio were lower in patients with amnestic mild cognitive impairment than clinically normal controls (P < .05). Higher global cortical PiB‐PET SUVr correlated with lower glutamate/myo‐inositol (r = –.3, P = .04).
CONCLUSIONS
The advanced sLASER with FAST(EST)MAP shimming is a promising protocol for identifying glutamate alterations. Advanced 1H‐MRS protocols may add to the understanding of early Alzheimer's disease pathophysiology through detection of glutamate concentration in posterior cingulate gyri of individuals with amnestic mild cognitive impairment.
OBJECTIVETo determine whether basing the decision to initiate immediate vs delayed disease-modifying therapy (DMT) on extent of recovery after initial relapse affects long-term disability ...accumulation in a multiple sclerosis (MS) evidence-based setting.
METHODSWe analyzed the double-blind, placebo-controlled interferon beta-1a 30 mc once a week in clinically isolated syndrome and 10-year-follow-up extension trial. Good recovery after presenting relapse was defined as (1) full early recovery within 28 days of symptom onset (Expanded Disability Status Scale EDSS score of 0 at enrollment maintained ≥6 months) and (2) delayed good recovery (EDSS score > 0 at enrollment and improvement from peak deficit to 6th-month or 1-year visit ≥ median). Time from recovery assignment to future disability (EDSS score ≥ 2.5 or ≥4.0) was studied on a relapse-recovery-stratified age axis and immediate vs 3-year delayed treatment initiation with Kaplan-Meier statistics and hazard ratios (HRs).
RESULTSOne hundred seventy-five/328 patients had good recovery (94 immediate and 81 delayed treatment); 153 did not have good recovery (77 immediate and 76 delayed treatment). HRs for EDSS score ≥2.5 outcome weredelayed treatment without good recovery as reference (HR = 1.0), delayed treatment with good recovery (HR0.67, p = 0.207; HR0.40, p = 0.027), immediate treatment without good recovery (HR0.56, p = 0.061; HR0.40, p = 0.011), and immediate treatment with good recovery (HR0.43, p = 0.014; HR0.48, p = 0.034). Placebo patients were switched to long-term treatment after 3 years, and insufficient EDSS score ≥4.0 outcome events were available to study.
CONCLUSIONSIn patients with MS presenting without good recovery after the initial relapse, immediate DMT initiation favorably influences the likelihood of more ambulatory-benign disease akin to patients with good recovery after the initial relapse.
CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that for patients with MS without good recovery after the initial relapse, immediate DMT initiation increases the likelihood of a benign disease course.
Abstract
Being a woman is one of the strongest risk factors for multiple sclerosis. The natural reproductive period from menarche to natural menopause corresponds to the active inflammatory disease ...period in multiple sclerosis. The fifth decade marks both the peri-menopausal transition in the reproductive aging and a transition from the relapsing-remitting to the progressive phase in multiple sclerosis. A short reproductive period with premature/early menopause and/or low number of pregnancies may be associated with an earlier onset of the progressive multiple sclerosis phase. A cross-sectional study of survey-based reproductive history in a multiple sclerosis clinical series enriched for patients with progressive disease, and a case–control study of multiple sclerosis and age/sex matched controls from a population-based cohort were conducted. Menarche age, number of complete/incomplete pregnancies, menopause type and menopause age were compared between 137 cases and 396 control females. Onset of relapsing-remitting phase of multiple sclerosis, progressive disease onset and reaching severe disability (expanded disability status scale 6) were studied as multiple sclerosis-related outcomes (n = 233). Menarche age was similar between multiple sclerosis and control females (P = 0.306). Females with multiple sclerosis had fewer full-term pregnancies than the controls (P < 0.001). Non-natural menopause was more common in multiple sclerosis (40.7%) than in controls (30.1%) (P = 0.030). Age at natural menopause was similar between multiple sclerosis (median, interquartile range: 50 years, 48–52) and controls (median, interquartile range: 51 years, 49–53) (P = 0.476). Nulliparous females had earlier age at progressive multiple sclerosis onset (mean ± standard deviation: 41.9 ± 12.5 years) than females with ≥1 full-term pregnancies (mean ± standard deviation: 47.1 ± 9.7 years) (P = 0.069) with a pregnancy-dose effect para 0 (mean ± standard deviation: 41.9 ± 12.5 years), para 1–3 (mean ± standard deviation: 46.4 ± 9.2 years), para ≥4 (mean ± standard deviation: 52.6 ± 12.9 years) (P = 0.005). Menopause age was associated with progressive multiple sclerosis onset age (R2 = 0.359, P < 0.001). Duration from onset of relapses to onset of progressive multiple sclerosis was shorter for females with premature/early menopause (n = 26; mean ± standard deviation: 12.9 ± 9.0 years) than for females with normal menopause age (n = 39; mean ± standard deviation: 17.8 ± 10.3 years) but was longer than for males (mean ±standard deviation: 10.0 ± 9.4 years) (P = 0.005). There was a pregnancy-dose effect of age at expanded disability status scale 6 (para 0: 43.0 ± 13.2 years, para 1–3: 51.7 ± 11.3 years, para ≥4: 53.5 ± 4.9 years) (P = 0.013). Age at menopause was associated with age at expanded disability status scale 6 (R2 = 0.229, P < 0.003). Premature/early menopause or nulliparity was associated with earlier onset of progressive multiple sclerosis with a ‘dose effect’ of pregnancies on delaying progressive multiple sclerosis and severe disability. Although causality remains uncertain, our results suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis. If confirmed in prospective studies, our findings have implications for counselling women with multiple sclerosis about pregnancy, surgical menopause and menopausal hormone therapy.
Premature/early menopause or nulliparity was associated with earlier progressive multiple sclerosis onset with a ‘dose effect’ of pregnancies on delaying progressive multiple sclerosis and severe disability. Zeydan et al.’s findings suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis and may have implications for counselling women on reproductive health.
Graphical Abstract
Graphical Abstract
Modulating the immune system does not reverse long-term disability in neurologic disorders. Better neuroregenerative and neuroprotective treatment strategies are needed for neuroinflammatory and ...neurodegenerative diseases.
To review the role of monoclonal, naturally occurring antibodies (NAbs) as novel therapeutic molecules for treatment of neurologic disorders.
Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized clinical trials, and basic science reports, were identified in a PubMed search for articles about NAbs and neurologic disorders that were published from January 1, 1964, through June 30, 2015. We concentrated our review on multiple sclerosis, Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis.
Many insults, including trauma, ischemia, infection, inflammation, and neurodegeneration, result in irreversible damage to the central nervous system. Central nervous system injury often results in a pervasive inhibitory microenvironment that hinders regeneration. A common targeted drug development strategy is to identify molecules with high potency in animal models. Many approaches often fail in the clinical setting owing to a lack of efficacy in human diseases (eg, less than the response demonstrated in animal models) or a high incidence of toxic effects. An alternative approach is to identify NAbs in humans because these therapeutic molecules have potential physiologic function without toxic effects. NAbs of the IgG, IgA, or IgM isotype contain germline or close to germline sequences and are reactive to self-components, altered self-components, or foreign antigens. Our investigative group developed recombinant, autoreactive, natural human IgM antibodies directed against oligodendrocytes or neurons with therapeutic potential for central nervous system repair. One such molecule, recombinant HIgM22, directed against myelin and oligodendrocytes completed a successful phase 1 clinical trial without toxic effects with the goal of promoting remyelination in multiple sclerosis.
Animal studies demonstrate that certain monoclonal NAbs are beneficial as therapeutic agents for neurologic diseases. This class of antibodies represents a unique source from which to develop a new class of disease-modifying therapies.
Abstract There are few reports of cerebellitis in adults and reports of recurrent cerebellitis are extremely rare. This report highlights both the fulminant course that may follow cerebellitis and a ...potentially important association with Crohn's disease. A 41-year-old man presented with headache and cerebellar dysfunction a month after ileo-colonic resection for Crohn's disease. MRI demonstrated T2-signal abnormalities, pial enhancement and cerebellar enlargement. His course was complicated by obstructive hydrocephalus, intraventricular hemorrhage associated with external ventricular drain placement and left transverse sinus venous thrombosis. Treatment with high-dose intravenous steroids and anti-coagulation resulted in improvement. Asymptomatic radiological worsening 13 months after initial presentation occurred during a relapse of Crohn's disease. He was treated with intravenous steroids and maintenance azathioprine for his Crohn's and suspected immune mediated cerebellitis. At last follow-up 4 years after initial presentation his clinical status remained unchanged and radiological changes had stabilized. Adult onset cerebellitis may be fulminant and recurrent. Early immunotherapy in acute relapsing cerebellitis may speed recovery and prevent recurrence. Onset and radiological relapse of cerebellitis during Crohn's disease flare-ups as in our case possibly suggests a shared autoimmune pathogenesis.
Recent studies have better defined the association between the human leukocyte antigen (HLA)-DR, cytotoxic T-lymphocyte antigen-4, interleukin-7 receptor, and interferon-gamma polymorphisms and ...susceptibility to multiple sclerosis (MS), while many more studies have been added to the controversial pool of likely false-positive and false-negative genetic association and linkage studies. Apolipoprotein E alleles may yet play an important role in disease course and cognitive impairment, although largely refuted as being directly associated with ambulatory measures of disease severity. Natural history studies have started to better define the clinical phenotypic heterogeneity of idiopathic inflammatory diseases of the central nervous system, fueling new hypotheses about immunopathogenesis of MS. Our understanding of phenotype measurement tools is improving. However, despite all the ongoing effort, the cause of MS and the determinants of heterogeneity in the clinical phenotype of MS remain largely unknown. As advances in our understanding of the immunobiology of MS start to bridge the gap between pathological and clinical natural history of the disease, biologically relevant phenotypes of MS will hopefully emerge to allow more specific treatment modalities to be developed and brought to practice.
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