Objective: The aim of the study was to report 12-month changes after treatment with nusinersen in a cohort of 85 type I spinal muscular atrophy patients of ages ranging from 2 months to 15 years and 11 months. Methods: All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination-Section 2 (HINE-2). Results: Two of the 85 patients had 1 SMN2 copy, 61 had 2 copies, and 18 had 3 copies. In 4 patients the SMN2 copy number was not available. At baseline, the mean CHOP INTEND scores ranged between 0 and 52 (mean = 15.66, standard deviation [SD] = AE13.48), and the mean HINE-2 score was between 0 and 5 (mean = 0.69, SD = AE1.23). There was a difference between baseline and the 12-month scores on both the CHOP INTEND and the HINE-2 for the whole group (p < 0.001), the subgroups with 2 SMN2 copies (p < 0.001), and those with 3 SMN2 copies (p < 0.001). The difference was found not only in patients younger than 210 days at baseline (p < 0.001) but also in those younger than 5 years on the CHOP INTEND and younger than 2 years on the HINE-2. Interpretation: Our results, expanding the age range and the severity of type I patients treated with nusinersen over 1 year, provide additional data on the range of efficacy of the drug that will be helpful in making an informed decision on whether to start treatment in patients of different ages and severity.

Status dystonicus (SD) is a life threatening disorder that develops in patients with both primary and secondary dystonia, characterized by acute worsening of symptoms with generalized and severe muscle contractions. To date, no information is available on the best way to treat this disorder. We review the previously described cases of SD and two new cases are reported, one of which occurring in a child with static encephalopathy, and the other one in a patient with pantothenate kinase-associated neurodegeneration. Both patients were admitted to an intensive care unit and treated with midazolam and propofol. This approach proved to be useful in the former while the progressive nature of the dystonia of the second patient required the combination of intrathecal baclofen infusion and bilateral pallidal deep brain stimulation. We believe that a rapid and aggressive approach is justified to avoid the great morbidity and mortality which characterize SD. Our experience, combined with the data available in the literature, might permit to establish the best strategies in managing this rare and severe condition.

The increases in IL-1beta and IL-6 expression were correlated with head injury severity and were indicative of poor clinical outcome, reflecting an endogenous neuroinflammatory response after TBI.

Nerve growth factor (NGF), doublecortin (DCX), and neuron-specific enolase concentrations in the CSF are useful markers of brain damage following severe traumatic brain injury (TBI). NGF and DCX upregulation correlates also with better neurologic outcome and could be useful to obtain clinical and prognostic information in children with severe TBI.

Background-Secondary brain damage after traumatic brain injury (TBI) involves neuroinflammatory mechanisms, mainly dependent on the intracerebral production of cytokines. In particular, interleukin 1β (IL-1β) is associated with neuronal damage, while interleukin 6 (IL-6) exerts a neuroprotective role due to its ability to modulate neurotrophins biosynthesis. However, the relationship between these cytokines and neurotrophins with the severity and outcome of TBI remains still controversial.Aims-To determine whether the concentration of IL-1β and IL-6 and neurotrophins (nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF)) in the cerebrospinal fluid (CSF) of children with TBI correlates with the severity of the injury and its neurologic outcome.Methods-Prospective observational clinical study in a university hospital. CSF samples were collected from 27 children at 2h (Time T1) and 48h (Time T2) after severe TBI, and from 21 matched controls. Severity of TBI was evaluated by GCS and neurologic outcome by GOS. CSF concentrations of cytokines and neurotrophins were measured by immunoenzymatic assays.Results-Early NGF and IL-1β concentrations (T1) correlated significantly with the severity of head injury, whereas no correlation was found for IL-6, BDNF, and GDNF. Furthermore, higher NGF and IL-6 and lower IL-1β expression at T2 were associated with better neurologic outcomes. No significant association was found between BDNF or GDNF expression and neurologic outcome.Conclusions-NGF concentration in CSF is a useful marker of brain damage following severe TBI and its up-regulation, in the first 48 h after head injury together with lower IL-1β expression, correlates with a favorable neurologic outcome. Clinical and prognostic information may also be obtained from IL-6 expression.

Secondary brain damage after traumatic brain injury (TBI) involves neuro-inflammatory mechanisms that are mainly dependent on the intracerebral production of cytokines. Interleukin-6 (IL-6) may have a role both in the pathogenesis of neuronal damage and in the recovery mechanisms of injured neurons through the modulation of nerve growth factor (NGF) biosynthesis. However, the relationship between IL-6 and NGF expression and the severity and outcome of TBI remains controversial. We have conducted a prospective observational clinical study to determine whether the concentration of IL-6 and NGF in the cerebrospinal fluid (CSF) of children with TBI correlates with the severity of the injury and neurologic outcome of patients. CSF samples were collected from 29 children at 2 h (time T1) and 48 h (time T2) after severe TBI, and from 31 matched controls. TBI severity was evaluated by Glasgow Coma Scale (GCS) and neurologic outcome by Glasgow Outcome Score (GOS). CSF concentrations of IL-6 and NGF were measured by immunoenzymatic assays. Early NGF concentrations (T1) correlated significantly with head injury severity, whereas no correlation was found between GCS and IL-6. Furthermore, IL-6 and NGF upregulation after injury was associated with better neurologic outcomes. Based on these findings, we posit that NGF expression is a useful marker of brain damage following severe TBI. Moreover, the early upregulation of both IL-6 and NGF, which correlates with a favorable neurologic outcome, may reflect an endogenous attempt at neuroprotection in response to the damaging biochemical and molecular cascades triggered by traumatic insult.

Background/Objectives: To compare the efficacy of a diet rich in natural folate and of two different folic acid supplementation protocols in subjects with “moderate” hyperhomocysteinemia, also taking into account C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. Subjects/Methods: We performed a 13 week open, randomized, double blind clinical trial on 149 free living persons with mild hyperhomocyteinemia, with daily 200 μg from a natural folate-rich diet, 200 μg [6S]5-methyltetrahydrofolate (5-MTHF), 200 μg folic acid or placebo. Participants were stratified according to their MTHFR genotype. Results: Homocysteine (Hcy) levels were reduced after folate enriched diet, 5-MTHF or folic acid supplementation respectively by 20.1% (p < 0.002), 19.4% (p < 0.001) and 21.9% (p < 0.001), as compared to baseline levels and significantly as compared to placebo (p < 0.001, p < 0.002 and p < 0.001, respectively for enriched diet, 5-MTHF and folic acid). After this enriched diet and the folic acid supplementation, Hcy in both genotype groups decreased approximately to the same level, with higher percentage decreases observed for the TT group because of their higher pre-treatment value. Similar results were not seen by genotype for 5-MTHF. A significant increase in RBC folate concentration was observed after folic acid and natural folate-rich food supplementations, as compared to placebo. Conclusions: Supplementation with natural folate-rich foods, folic acid and 5-MTHF reached a similar reduction in Hcy concentrations.

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