Metachromatic leukodystrophy: A single-center longitudinal study of 45 patients.

In this study, we characterize the natural course of metachromatic leukodystrophy (MLD), explore intra/inter group differences, and identify biomarkers to monitor disease progression. This is a longitudinal observational study. Genotype and characteristics at disease onset were recorded. Time-to-event analyses were performed to assess time to major disease-related milestones in different subgroups. Longitudinal trajectories of nerve conduction velocities (NCV), brain MRI score, and brainstem auditory evoked responses (BAERs) were described. We recruited 22 late-infantile, 14 early-juvenile, 5 late-juvenile, and 4 adult MLD patients. Thirty-four were prospectively evaluated (median FU time 43 months). In late-infantile patients, the attainment of independent walking was associated with a later age at dysphagia. In early-juvenile, the presence of isolated cognitive impairment at onset was not a favorable prognostic factor. Late-infantile and early-juvenile subjects showed similar rapid loss of ambulation and onset of seizures, but late-infantile displayed earlier loss of trunk control, dysphagia, and death. We found significant differences in all major disease-related milestones (except death) between early-juvenile and late-juvenile patients. Late-juvenile and adult patients both presented with a predominant cognitive impairment, mild/no peripheral neuropathy, lower brain MRI score at plateau compared to LI/EJ, and later cerebellar involvement. NCV and BAER were consistently severely abnormal in late-infantile but not in older subjects, in whom both NCV and BAER were variably affected, with no deterioration over time in some cases. This study clarifies intra/inter group differences between MLD subtypes and provides additional indications regarding reliable clinical and instrumental tools to monitor disease progression and to serve as areference to evaluate the efficacy of future therapeutic interventions inthe different MLD variants.

Optical coherence tomography and visual evoked potentials: which is more sensitive in multiple sclerosis?

OBJECTIVE: To assess the sensitivity of optic coherence tomography (OCT) and visual evoked potentials (VEPs) to visual pathway abnormalities in multiple sclerosis (MS). METHODS: A total of 40 MS subjects, 28 with optic neuritis (ON) at least 3 months before (bilateral in 5), underwent assessment of visual acuity, Expanded Disability Status Scale (EDSS), OCT and VEPs, the latter quantified with a 0-4 conventional score. RESULTS: OCT and VEPs were abnormal in 36% and 56% respectively in all eyes (p=0.11), 68% and 86% in eyes with previous ON (p=0.12), and in 19% versus 40% in eyes without ON history (p=0.007). Combining VEP and OCT increased sensitivity to 89% in ON and 44% in non-ON eyes. Considering all eyes, global retinal nerve fibre layer (RNFL) thickness and VEP score were significantly correlated between them (ρ=-0.63, p<0.001) and with EDSS (RNFL: ρ=0.40, p<0.001; VEP score: ρ=0.47, p<0.001). Disease duration correlated with VEP score (ρ=0.25, p=0.025) and RNFL thickness (ρ=-0.71, p<0.001). CONCLUSIONS: In eyes without ON, VEPs were more frequently abnormal than OCT, while the two techniques showed similar sensitivity in eyes previously affected by ON. The correlation of VEPs and OCT measures with disability prompts further exploration of the two techniques as potential markers of disease burden.

Radio Electric Asymmetric Conveyer Neurobiological Treatments in Non-Specific Neck Pain: A Retrospective Study.

INTRODUCTION: Non-specific neck pain (NSNP) is a rather common symptomatology, and various therapeutic approaches are aimed to treat it, in the field of manual therapy, physiotherapy and pharmacology. METHODS: This retrospective study analyzes 65 subjects treated for NSNP with a neurobiological stimulation administered by medical devices based on radio electric asymmetric conveyer (REAC) technology. Initially, a neuro stimulation treatment called neuro postural optimization (NPO) was administered to improve the coordination of muscle activity and reduce adaptive decompensations. Subsequently, the bio stimulation treatment called tissue optimization (TO) was administered to reduce the algodystrophic and muscle contracture component. The evaluation of the efficacy of these treatments was made through the subjective evaluation of pain by the patients. Data were collected by the use of the numeric pain rating scale (NPRS) and neck pain questionnaire (NPQ), administered before the treatments and at the end of the cycle of therapy. RESULTS: The analysis of the results shows that this type of approach and treatment scheme is effective in reducing the symptoms of NSNP in both male and female subjects, regardless of their age. Other subjective data not quantified in this study but reported by all subjects, during and after the treatment cycle, were a feeling of lower stiffness of neck and shoulder, a reduction in the thickening of the cervicobrachial tissues, and a clear and progressive reduction of pain perception during the skin rolling (SR) maneuver. CONCLUSION: The combination of REAC-NPO neuromodulation and REAC-TO biomodulation treatments used in this study was shown to be effective in NPRS.

In vivo structural and functional assessment of optic nerve damage in neuromyelitis optica spectrum disorders and multiple sclerosis.

Early detection of neuromyelitis optica spectrum disorders (NMOSD), especially after optic neuritis, a presenting manifestation commonly observed also in multiple sclerosis (MS), is crucial for timely treatment and prognosis. Integrated visual pathway assessment with optical coherence tomography (OCT) and visual evoked potentials (VEP) may help in this task, showing in vivo different pathophysiological backgrounds. We evaluated combined VEP and OCT in a cross-sectional, single-centre study assessing 50 consecutive NMOSD patients, 57 MS patients and 52 healthy controls. After optic neuritis, VEP were more frequently absent in NMOSD compared to MS; most NMOSD eyes with recordable VEP showed prolonged latency, but extreme latency delays were less common than in MS. OCT showed predominantly axonal involvement in NMOSD, with 88% eyes (95% CI: 69-97%) displaying retinal nerve fibre layer thickness <60 µm even after first optic neuritis episode. Accuracy of OCT was further enhanced by combination with VEP into a new Z-score derived OCT-VEP index, measuring prevalence of axonal damage or demyelination. Our results suggest that integrated optic nerve assessment may elucidate differences in optic neuritis pathophysiology; conduction slowing with relatively preserved nerve fibre layer suggests MS, while severe neuroaxonal loss after optic neuritis, often hindering VEP response, characterizes NMOSD.

No evidence of disease activity is associated with reduced rate of axonal retinal atrophy in MS.

OBJECTIVE: To explore, in a longitudinal study, the usefulness of optical coherence tomography (OCT) in monitoring people with multiple sclerosis (MS) by testing the association between retinal nerve fiber layer (RNFL) thinning and clinical and brain MRI criteria of no evidence of disease activity (NEDA). METHODS: OCT, visual evoked potentials (VEPs), and disability, using the Expanded Disability Status Scale (EDSS), were tested at baseline and after 2 years in 72 patients, 63 with routine yearly brain MRI. RESULTS: Longitudinal mean binocular RNFL thinning, in absence of optic neuritis during follow-up, was correlated with EDSS worsening, also controlling for baseline EDSS, RNFL, disease duration, and MS subtype (Spearman ρ -0.462, p < 0.001; partial correlation coefficient -0.437, p < 0.001). At follow-up, patients classified as NEDA (20; 31.7%) had RNFL loss of -0.93 µm ± 1.35 SD, while patients with active disease had -2.83 µm ± 2 SD thinning (t test; p < 0.001). At logistic regression, mean RNFL reduction correctly classified 76.2% of patients as NEDA at 2 years (R2 0.355; p = 0.003). A cutoff of -1.25 µm RNFL loss classified NEDA status with specificity 81.4% and sensitivity 80% (receiver operating characteristic curve: area under the curve 0.8; p < 0.001). No significant longitudinal correlations were found between changes in RNFL and in VEP latencies or scores. CONCLUSIONS: NEDA is associated with a relatively preserved RNFL over 2 years. A greater neuroretinal loss was detected even in patients with clinical evidence of disease activity independently from changes in brain MRI lesions, prompting further validation of OCT as an additional tool in MS monitoring.

Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.

Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency.

Click-evoked otoacoustic emissions recorded from untreated congenital hypothyroid newborns.

Thyroid hormone plays an important role in hearing development. Both a genetic or non-genetic hypothyroidism is often associated with congenital hearing loss. The exact incidence of hearing impairment in untreated congenital hypothyroid (CH) patients is unknown. This paper will present the results of measuring of the transient-evoked otoacoustic emissions (TEOAE) in a population of 29 newborns, who tested positive on a screening test for hypothyroidism (CH group) and in 68 well babies (control group) randomly chosen from all the newborns, classified as PASS, included in the Hearing Screening Program of the San Raffaele Hospital in Milan. TEOAE were recorded in all newborns within 1 month after birth and before beginning L-thyroxine treatment with conventional commercial instrumentation. Both temporal and time-frequency analyses of the emitted responses were conducted by means of a wavelet transform. The comparison of the characteristics of the temporal and frequency content of the responses of the two groups (CH and control) showed no statistically significant difference. No correlation was found between outer hair cell dysfunction and hypothyroidism.