Evidence Of White Matter Lesions Research Articles

Allogeneic Hematopoietic Stem Cell Transplantation for Adult Metachromatic Leukodystrophy (MLD): A Case Series

Introduction Adult Metachromatic Leukodystrophy (MLD) is a rare neurological disorder leading to devastating and progressive cognitive impairment and motor impairment with ataxia, spasticity and neuropathy as well as incontinence resulting in complete disability and reduced life expectancy. MLD is caused by autosomal recessive mutations of the ARSA gene, resulting in reduced arylsulfatase A enzyme (ARSA) activity and consecutive accumulation of galactosylceramide-3-0-sulfate in the central nervous system (CNS). Potential therapies in infantile and juvenile MLD include allogeneic hematopoietic stem cell transplantation (allo-HCT), ex-vivo gene therapy (Atidarsagen autotemcel), and (intrathecal) enzyme replacement as tested in ongoing trials. Allo-HCT may slow down or stop MLD progression. However, the outcome in adult patients treated with allo-HCT has been only reported in a few case reports. In this case series, we report our experience of allogeneic transplantation in four patients with adult MLD. Methods Four patients (2 male and 2 female) with a genetically confirmed diagnosis of adult MLD, with enzyme deficiency detectable in peripheral blood (ARSA activity range 0.00-0.06 E514nm/10 -6), evidence of white matter lesions on MRI and demyelinating polyneuropathy in EMG were treated with allo-HCT. One patient was still clinically asymptomatic at the treatment timepoint. Allo-HCT was performed at an age between 18 and 37 years (mean 25.75 years) and within one year after diagnosis. Bone marrow (n=2) or mobilized peripheral blood stem cells (n=2) from 10/10 matched related (n=1) or unrelated (n=3) donors were infused at a dose of 2.2-7.82x10 6 CD34+/kg after a reduced intensity conditioning regime with Fludarabine (150 mg/m²) and Treosulfane (10 or 14 g/m²). Three patients received further infusions with allogeneic mesenchymal stem cells (MSCs) manufactured in the hospital´s own GMP laboratory around day 30 after transplantation. One patient received a second MSC infusion at day 182. MSCs are able to secrete ARSA and were used to consolidate enzyme levels. In case of transplant failure donor lymphocytes (DLI) were given. For posttransplant immunosuppression Tacrolimus, Methotrexate, Mycophenolate mofetil or Anti-thymocyte globulin (ATG, Grafalon®, Neovii 10 mg/kg) were used. Results All patients engrafted 16-21 days after HCT. Platelets regenerated within 14 to 21 days (mean 16 days), neutrophils recovered within 16 to 21 days (mean 18.5 days). In two patients hepatitis and exanthema associated with ATG administration were observed as transient adverse events. Other therapy-associated adverse events were innappetence, hyperkalemia and diarrhea. A mild Graft-versus-host disease of the skin occurred only in one patient with full resolution on a course of steroids and Tacrolimus. After allo-HCT, an increase in ARSA levels reaching normal range values within the first 12 months after treatment was already documented in 3 out of 4 patients; measurements are pending in the 4 th more recently transplanted patient. Three out of four patients developed consistent full donor chimerism within 11 (1-11 ) months after HCT. In the fourth 18-year-old patient autologous chimerism increased to 60-80%, while ARSA activity decreased from 1.05 to 0.61 E514nm/10 -6. Consequently, the patient received DLIs. However, an improvement in chimerism has not be achieved so far. Longer follow-up data will be reported at the meeting. Discussion and Conclusion Allo-HCT in patients with MLD can be used to restore normal range ARSA activity. Donor-derived macrophages with an adequate secretion of ARSA migrate to the central nervous system and release ARSA. To our knowledge, there have been only a few individual case reports on allo-HCT in adult MLD so far. Our case series indicates that allo-HCT can be performed with tolerable risks and evident efficacy in adult patients with MLD. Based on this experience and previously reported cohorts in juvenile and infantile MLD allo-HCT should be thus also considered as a therapeutic option for adult patients with MLD. Longer clinical follow-up, higher patient numbers and ultimately a prospective randomised trial containing an untreated group would be needed to evaluate allo-HCT as a treatment option for adult MLD.

Preventing post-stroke dementia. The MARCH Trial. Protocol and statistical analysis plan of a randomized clinical trial testing the safety and efficacy of Maraviroc in post-stroke cognitive impairment

Background: Current evidence suggest that 25%–33% of stroke-survivors develop post-stroke cognitive impairment (PSCI). The licensed drug Maraviroc, a CCR5-antagonist, is postulated to act via a neuroprotective mechanism that may offer the potential of preventing progression to vascular dementia. Our hypothesis: Maraviroc may have the potential to augment learning skills and cognitive performance by affecting synaptic plasticity, along with neuro-inflammatory modulation in patients with cerebral small vessel disease (SVD) and PSCI. Design: MARCH is a multi-center, double-blind randomized-control Phase-II trial of Maraviroc 150 or 600 mg/day versus placebo for 12-months in five stroke centers in Israel. Included are patients diagnosed with recent (1–24 months) subcortical stroke who experience mild PSCI and have evidence of white matter lesions and SVD on neuroimaging. Outcomes: Primary outcomes: 1. Change in cognitive scores. 2. Drug related adverse events. Secondary outcomes: change in functional and affective scores, MRI-derived measures, inflammatory markers, carotid atherosclerosis, cerebrospinal-fluid biomarkers in a sub-study. A sample size of 60 in each treatment group and 30 in the placebo group (total – 150 participants) provides 80% power between the treatment and the placebo groups. Conclusions: The results of this work could lead to a novel, readily available, therapeutic avenue to reduce PSCI, and possibly other pathologies. This study will test safety and effectiveness of Maraviroc in limiting cognitive deterioration and/or post stroke cognitive impairment in patients with cerebral small vessel disease. Schedule: First-patient first-visit was May 2021. Recruitment to complete in 2023, follow-up to complete in 2024.

Lack of Association of CNS Lesion Number with Cognitive Performance and Cerebral Blood Flow in Sickle Cell Disease

Background: Neurocognitive studies demonstrate a deficit in performance for sickle cell anemia (SCA) patients as compared to age-matched peers. The underlying mechanism for this deficit is not yet understood, but possible contributors include CNS lesion load, perfusion deficits, oxygen deprivation and cerebrovascular autoregulatory impairment. We hypothesized that the number of white matter hyperintensities and the cerebral blood flow (CBF) might contribute to cerebral dysfunction in SCA patients. We sought to examine the relationship between cognition, laboratory parameters and brain perfusion in sickle cell patients as compared to non-sickle cell (AA) controls.Methods: SCA (HbSS/HbSβ0) and AA subjects, ages 18-55 years old, with no evidence of TIA/Stroke, no clotting/bleeding disorders, and not on anticoagulation were recruited. Hydroxyurea use was noted but was neither an inclusion nor exclusion criterion. Evaluation included a routine questionnaire for basic social, educational and health information. Steady state laboratory evaluation was obtained within one week of imaging. Neurocognitive performance was evaluated by the Cogstate battery at the time of the MRI. Cogstate analysis included tests of executive function, recall, social and emotional cognition and learning. Lesion number and CBF were determined using 3T MRI, which included T1w 3D, T2 FLAIR, pseudo-continuous arterial spin labeling, diffusion tensor imaging, and blood oxygen level depending imaging before and during a brief period of hyperoxia. Oxygen saturation and blood pressure were monitored throughout the procedure at 5-minute intervals.Results: To date, we have recruited 15 SCA and 7 AA subjects who answered a tailored questionnaire and underwent 3T MRI, routine laboratory testing and neurocognitive testing. Of the 15 SCA subjects, 6 had no lesions on 3T MRI and 9 had multiple lesions with 8 persons having more than 5. Lesion number correlated only with age (p=0.02). Of the 7 AA patients, 3 had no lesions, 2 had 1, 1 had 4 and 1 patient had >20 lesions. SCA patients fared worse on only one of the cognitive tests, the Groton Maze Learning Test for executive function (GMLT), in which a higher GMLT demonstrates decreased ability (p=0.02). Amongst the SCA subjects, a worse score on GMLT correlated positively with age (p=0.03), ferritin (p=0.02), mean arterial pressure (p=.02) and %HbF (p=0.03) while GMLT correlated negatively with %S (p=0.007), indirect bilirubin (p=0.02) and absolute reticulocyte count (p=0.005). There did not appear to be a relationship of GMLT with LDH, Hb, MCV, MCHC, platelet count, white cell parameters, number of crisis, oxygen saturation, CBF or lesion load. Gray matter CBF in SCA patients was significantly greater than that in AA subjects (164 ml/100g/min vs 113 ml/100g/min in AA, p < 0.007) as was white matter CBF (93 ml/100g/min vs 71 ml/100g/min, p=0.03). Both gray matter and white matter CBF correlated negatively with Hb/Hct levels in SCA patients (p=0.004). SCA patients also had a significantly lower average DP and MAP than the AA patients (p-0.004 and 0.015 respectively).Discussion: This study was undertaken to assess the role of a variety of clinical parameters against neurocognitive performance in SCA patients who had not been diagnosed with prior CVA or stroke. None-the-less, with the use of more powerful 3T MRI technology, there is an increase in the measurement and prevalence of white matter lesions in both SCA and AA subjects and a significant proportion of subjects were found to have evidence of white matter lesions. While white matter hyperintensities have been associated with cognitive outcomes, better detection of these lesions questions these assumptions and the prevailing theory that white matter hyperintensities are a marker of cerebral health and predict cognitive performance. Lesion number did not demonstrate an association with CBF or the GMLT; CBF correlated only with Hb levels and did not correlate with GMLT. There was an association of age with both cognition, as measured by the GMLT, and with lesion number.Conclusion: We suggest that diffuse cerebral dysfunction, rather than discrete infarct quantity, may be the more important mechanism of decreased cognition. We are currently assessing the functional assessments by fMRI to better delineate the nature of this cerebral dysfunction. DisclosuresNo relevant conflicts of interest to declare.

Resistance Training and White Matter Lesion Progression in Older Women: Exploratory Analysis of a 12-Month Randomized Controlled Trial.

To assess whether resistance training (RT) slows the progression of white matter lesions (WMLs) in older women. Secondary analysis of a 52-week randomized controlled trial of RT, the Brain Power Study. Community center and research center. Of 155 community-dwelling women aged 65 to 75 enrolled in the Brain Power Study, 54 who had evidence of WMLs on magnetic resonance imaging (MRI) at baseline were included in this secondary analysis. Participants were randomized to once-weekly RT (1× RT), twice-weekly RT (2× RT), or twice-weekly balance and tone (BAT). Assessors were blinded to participant assignments. WML volume was measured using MRI at baseline and trial completion. At trial completion, the 2× RT group had significantly lower WML volume than the BAT group (P = .03). There was no significant difference between the BAT group and the 1× RT group at trial completion (P = .77). Among participants in the two RT groups, reduced WML progression over 12 months was significantly associated with maintenance of gait speed (correlation coefficient (r) = -0.31, P = .049) but not with executive functions (r = 0.30; P = .06). Engaging in progressive RT may reduce WML progression.

Human Parechovirus 3 Meningitis and Fatal Leukoencephalopathy

Human parechovirus 3 (HPeV3) is a picornavirus associated with neurologic disease in neonates. Human parechovirus 3 infection of preterm and term infants is associated with seizures and destructive periventricular white matter lesions. Despite unremarkable cerebrospinal fluid (CSF), HPeV3 RNA can be amplified from CSF and nasopharyngeal and rectal swabs. We report pathologic findings in 2 autopsy cases of infants with active HPeV3 infection. Both children were born approximately 1 month premature and were neurologically intact but, after a few weeks, developed seizures and radiologic evidence of white matter lesions. Neuropathologic examination demonstrated classic severe periventricular leukomalacia in the absence of an immune response. Human parechovirus 3 sequences were identified in RNA extracted from CSF, sera, and tissues. Human parechovirus 3 in situ hybridization detection of infected cells was limited to meninges and associated blood vessels in addition to smooth muscle of pulmonary vessels. Ultrastructural evaluation of meninges demonstrated dense core structures compatible with picornavirus virions. These findings suggest that encephalopathic changes are secondary to infection of meninges and potential compromise of vascular perfusion. Thus, parechovirus infection of vascular smooth muscle may be a more general pathogenic process.

Exploring the Association between Retinal Nerve Fiber Layer Thickness and Initial Magnetic Resonance Imaging Findings in Patients with Acute Optic Neuritis

Background. Recent studies have shown that OCT-measured retinal nerve fiber layer (RNFL) values may represent a marker for axonal damage in the anterior visual pathway of optic neuritis (ON) and multiple sclerosis (MS) patients. The goal of this study was to determine the link between RNFL values and initial magnetic resonance imaging (MRI) evidence of central nervous system (CNS) inflammation in patients with acute ON. Methods. Fifty patients who experienced ON as a clinically isolated syndrome (CIS) were followed for a mean period of 34 months with OCT testing. RNFL values in affected (ON) eyes and clinically unaffected (non-ON) eyes were compared between patients with MRI evidence of white matter lesions and those with normal baseline MRI findings, over a two year period. Findings. Twenty-one patients (42%) developed clinically definite MS (CDMS) during the study. After two years, temporal RNFL values were thinner (P = .07) in ON patients with MRI lesions at baseline, but the results were not significant. Conclusions. There is no association between RNFL values and baseline MRI status in ON patients at risk for future CDMS over a two year period.

Quality of life in multiple sclerosis is associated with lesion burden and brain volume measures

Health-related quality of life (HRQOL) is reduced in multiple sclerosis (MS). It is unclear whether HRQOL is associated with white matter lesion burden or measures of brain atrophy. A cross-sectional baseline analysis of 507 patients with MS in a prospective cohort study at the University of California, San Francisco was performed. Multivariate linear regression models were used to determine whether MRI measures were associated with the Emotional Well-Being and Thinking/Fatigue subscale scores of the Functional Assessment in Multiple Sclerosis, a validated HRQOL measure in MS. The difference in each MRI metric associated with a minimal clinically important difference in each HRQOL subscale was calculated. Higher T1 lesion load (15 mL; p = 0.024), normalized T1 lesion volume (20 mL; p = 0.016), or T2 lesion load (25 mL; p = 0.028) was associated with worse scores for Emotional Well-Being. Meaningfully lower scores on this subscale were correlated with lower normalized gray matter volume (118 mL; p = 0.037). Reduced Thinking/Fatigue scores were associated with higher normalized T1 lesion volume (21 mL; p = 0.024), or T2 lesion load (22 mL; p = 0.010) and with lower normalized gray matter (87 mL; p = 0.004), white matter (85 mL; p = 0.025), or brain parenchymal (98 mL; p = 0.001) volume. Aspects of health-related quality of life (HRQOL) in multiple sclerosis are associated with MRI evidence of white matter lesions and brain atrophy. These findings strengthen the argument for the use of HRQOL outcome measures in trials and suggest that lesion burden on conventional MRI is important for HRQOL.

The clinical features, MRI findings, and outcome of optic neuritis in children

Optic neuritis (ON) in childhood is thought to be more likely bilateral and less likely to lead to multiple sclerosis (MS) vs ON in adults. The authors evaluated clinical features, maximal visual deficit and recovery, visual evoked potentials (VEPs), neuroimaging, and outcome in a cohort of children with ON. Records of 36 children (female/male ratio 1.6), ages 2.2 to 17.8 (mean 12.2) years, were reviewed. ON was unilateral in 58% and bilateral in 42%. Maximal visual deficit was severe in 69%, but full recovery occurred in 39 of 47 affected eyes (83%). VEPs were abnormal in 88%. Neurologic abnormalities in addition to those associated with ON were documented in 13 children. Neuroimaging studies of the optic nerve were abnormal in 55%. Brain MRI in 35 children demonstrated white matter lesions separate from the optic nerves in 54%. Follow-up is 2.4 years (0.3 to 8.3 years). To date, 13 children (36%) have been diagnosed with MS and 1 has Devic disease. Bilateral ON was more likely to be associated with MS outcome (p = 0.03). All 13 children with MS had white matter lesions on brain MRI. None of the children with a normal brain MRI have developed MS to date. Contrary to expectations, optic neuritis (ON) in childhood was more likely to be unilateral, multiple sclerosis (MS) risk was high (36% at 2 years), and bilateral rather than unilateral ON was associated with a greater likelihood of MS. Clinical findings extrinsic to the visual system on baseline examination (p < 0.0001) and MRI evidence of white matter lesions outside the optic nerves (p < 0.0001) were strongly correlated with MS outcome.

The clinical course of acute disseminated encephalomyelitis

The objective of this review is to describe recent advances in understanding the clinical course of pediatric and adult acute disseminated encephalomyelitis (ADEM), especially the risk of relapse and conversion to multiple sclerosis (MS). The diagnosis of ADEM is reached on clinical grounds, typically in the setting of a post-infectious meningoencephalitic syndrome associated with multifocal neurological symptoms and signs, magnetic resonance imaging (MRI) evidence of white matter lesions and exclusion of other causes. Although typically monophasic, several case series demonstrate 'multiphasic' or 'recurrent' forms of ADEM with clinical relapses occurring within a short interval of disease onset. Furthermore, the estimated risk of developing MS is substantial for both children (0–33%) and adults (∼35%). Advances in neuroimaging have identified some MRI features that have predictive value for a relapsing course but they are not accurate enough for therapeutic decision-making; a diagnosis of monophasic ADEM should be made with caution in all cases, especially those presenting in adulthood. Research in ADEM and related disorders remains hampered by lack of prospective studies, specific and reproducible clinical case definitions and variable follow-up methods. Standardization of these variables would facilitate identification of more accurate diagnostic and prognostic variables, discovery and testing of potential objective biomarkers that would, in turn, allow early prediction of a relapsing course and appropriate therapeutic interventions.

Sudden onset aphasic hemiplegia: an unusual manifestation of disseminated encephalomyelitis

The association of the sudden onset of aphasia with hemiplegia, hemisenosry defect, and facial palsy, with MRI evidence of white matter lesions, requires differentiation between multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM). We have observed eight patients with such a syndrome, all of whom were originally diagnosed as multiple sclerosis, but who, on closer examination, turned out to be instances of disseminated encephalomyelitis. The patterns of demyelination seen in T2-weighted MRI are quite different in both conditions. In two of our patients, MRI reverted to normal after the treatment; in others, the images remained unchanged. A review of the reported cases of multiple sclerosis presenting with the acute onset of aphasia, reveals that the majority of them are, in reality, instances of acute disseminated encephalomyelitis with a much better prognosis. Most of these cases are monophasic and immunomodulatory treatment is inappropriate.

Fetal Brain Injury Following Prolonged Hypoxemia and Placental Insufficiency: A Review

It is well-established that severe, acute episodes of hypoxemia can damage the brain before birth, but the effects of more sustained hypoxemia are less well understood. We have used fetal sheep in a series of studies aimed at determining the effects of prolonged hypoxemia, induced by placental insufficiency of differing severity and duration, on fetal brain structure. Restriction of placental, and hence fetal, growth by carunclectomy caused impaired development of neural processes and connections in the hippocampus, cerebellum, and visual cortex; neuronal migration and neuronal numbers did not appear to be affected. Twenty days of placental insufficiency during late gestation induced by umbilicoplacental embolisation also caused abnormalities in brain structure; the cerebellum, which develops late in gestation, was particularly affected. In the cortex, there was evidence of white matter lesions, an increase in the size of capillaries and a proliferation of astroglia. We also examined the effects of shorter periods of hypoxemia (6–12 hr) near mid-gestation on brain structure; fetuses were allowed to recover for 7 or 35 days after the hypoxemic challenge. The major changes were mild focal damage in the cortical white matter, a reduction in the number of Purkinje cells, a delay in the growth of neural processes in the cerebellum and proliferation of blood vessels. The hippocampus was also affected, in particular the areal density of pyramidal cells was reduced. The use of several classes of pharmacological agents with the potential to protect neurons from hypoxemic injury is discussed in relation to the developing brain.

The effect of white matter low attenuation on cognitive performance in dementia of the Alzheimer type.

The effect of leukoaraiosis or white matter low attenuation (WMLA) on cognitive function is not fully understood. We compared the neuropsychological performance of 37 Alzheimer's disease patients with WMLA on CT brain scans with a similar group of 31 Alzheimer's disease patients with no evidence of white matter lesions. Patients with WMLA performed significantly worse on tests of visuospatial function (Cube Analysis test, p = 0.004), and cognitive speed (Kenrick Digit Copying test, p = 0.05) compared to those with no visible white matter lesions. Patients with widespread WMLA performed generally worse in tests of cognitive function than those with frontal or a mixture of frontal and occipital WMLA. This was most significant in the areas of attention (forward digit span, p = 0.003), visual recognition (p = 0.004), and cognitive speed (p = 0.03). There is an association between impaired cognitive performance and the presence of WMLA in Alzheimer's disease patients, with WMLA probably contributing to the cognitive impairment. This is most evident in patients with widespread white matter lesions.