Nusinersen injections in adults and children with spinal muscular atrophy: a single-center experience

PurposeNusinersen is a drug approved in December 2016 for treatment of spinal muscular atrophy (SMA). We want to share our initial experience with image-guided, non-image-guided, and port-delivered nusinersen injections in a large single-center SMA patient cohort, treating both pediatric and adult patients with focus on technical considerations and other patient concerns from a combined perspective of patient, neurologist, and radiologist.MethodsAll nusinersen injections between February 2017 and September 2018 were retrospectively reviewed. We obtained age, sex, SMA type and technical details of the injections and postprocedure complications for each procedure.ResultsA total of 52 patients (24 women [46%]; 4 patients with SMA-1 [7.6%]; 30 patients with SMA-2 [57.8%]; 18 patients with SMA-3 [34.6%]; mean age, 25.5 years [7 months to 62 years]) with a total of 265 injections were included. Of the 265 injections, 206 (77.9%) were performed with local anesthetic, 25 (9.4%) with moderate sedation, and 23 (8.6%) under general anesthesia. We performed 65 CT-guided transforaminal injections in 13 patients, 106 fluoroscopy-guided lumbar punctures in 24 patients and 83 lumbar punctures in 16 patients using conventional technique. Only 6 of 265 injections (2.2%) ended up with a post-lumbar puncture headache (PLPH) requiring medical treatment. None required an epidural blood patch. Fourteen PLPH (5.2%) occurred and resolved at the same day without any treatment. After 6 of 265 injections (2.2%), patients reported soreness at the injection site which resolved spontaneously. Three elected to have an intrathecal reservoir placement (2 lumbar, 1 intraventricular) with a total of 11 injections. One patient with lumbar catheter developed infection after surgery with subsequent meningitis and treatment delay. After the resolution of meningitis, a new intraventricular reservoir was placed without any complication in the following injections.ConclusionWith the introduction of nusinersen treatment, neurologists and radiologists play an important role in treatment of SMA patients and therefore should be familiar with different techniques and complications of drug administration. Using good technique, it is possible to have very low complication rates even in this complex patient population, and various image-guided procedures can be a safe alternative to surgical approach, even in the most difficult cases

Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy

<p>Abstract</p> <p>Background</p> <p>Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder characterized by the abnormal beta-oxidation of very long chain fatty acids (VLCFA). In 35-40% of children with ALD, an acute inflammatory process occurs in the central nervous system (CNS) leading to demyelination that is rapidly progressive, debilitating and ultimately fatal. Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease progression in cerebral ALD (C-ALD) if performed early. In contrast, for advanced patients the risk of morbidity and mortality is increased with transplantation. To date there is no means of quantitating neuroinflammation in C-ALD, nor is there an accepted measure to determine prognosis for more advanced patients.</p> <p>Methods</p> <p>As cellular infiltration has been observed in C-ALD, including activation of monocytes and macrophages, we evaluated the activity of chitotriosidase in the plasma and spinal fluid of boys with active C-ALD. Due to genotypic variations in the chitotriosidase gene, these were also evaluated.</p> <p>Results</p> <p>We document elevations in chitotriosidase activity in the plasma of patients with C-ALD (n = 38; median activity 1,576 ng/mL/hr) vs. controls (n = 16, median 765 ng/mL/hr, p = 0.0004), and in the CSF of C-ALD patients (n = 38; median activity 4,330 ng/mL/hr) vs. controls (n = 16, median 0 ng/mL/hr, p < 0.0001). In addition, activity levels of plasma and CSF chitotriosidase prior to transplant correlated with progression as determined by the Moser/Raymond functional score 1 year following transplantation (p = 0.002 and < 0.0001, respectively).</p> <p>Conclusions</p> <p>These findings confirm elevation of chitotriosidase activity in patients with active C-ALD, and suggest that these levels predict prognosis of patients with C-ALD undergoing transplantation.</p

Urea Cycle Disorders: A Neuroimaging Pattern Approach Using Diffusion and FLAIR MRI

BACKGROUND AND PURPOSE This study aimed to assess characteristic regions of MRI involvement utilizing diffusion weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) at urea cycle disorder (UCD) diagnosis to determine the possible association between initial MRI patterns within 10 days of the first hyperammonemia episode, serum ammonia levels, and severity of neurological outcome based on clinical follow-up of >30 days. METHODS Ten patients with UCDs (4 females; median age: 5.4 years, age range: 6 days-54 years) were included who underwent MRI during a first episode of hyperammonemia. The topographical distribution of the DWI and FLAIR abnormalities in the cerebral cortex, deep gray matter, white matter, posterior limb of internal capsule, cerebral peduncle, and cerebellum was evaluated. Possible correlations between the brain injury patterns on DWI/FLAIR images, serum ammonia levels, and severity of neurological outcome were investigated by a trend correlation. RESULTS The UCD cohort (n = 10) involved four ornithine transcarbamoylase deficiencies, four argininosuccinic aciduria, one carbomoylphosphate synthetase deficiency, and one citrullinemia type-1. The observed trend in the distribution of DWI abnormalities as the severity of neurological sequela outcome increased was with diffuse cerebral cortex or corpus striatum involvement. Patients with initial peak serum ammonia >= 450 mu mol/L had a grade 2 to 4 outcome, and those with peak ammonia <450 mu mol/L had a grade 0 or 1 outcome. CONCLUSIONS The presence of more severe neurological outcome could be associated with diffuse cerebral cortex or corpus striatum involvement on DWI and high serum ammonia levels in patients with UCD

Potentially reversible acute cerebellar toxicity associated with Minnelide

Minnelide is an experimental antineoplastic agent that is currently the subject of a phase 1 clinical trial for the treatment of pancreatic and gastrointestinal malignancies. In this study, we documented two cases of reversible acute cerebellar toxicity (REACT) associated with Minnelide and compared its radiological manifestations with other cerebellotoxic agents. Both patients had histories of progressive metastatic cancer and participated in a phase 1 clinical trial with Minnelide. They had an MRI examination including T2WI, FLAIR and SWI, axial and coronal DWI, and ADC map on admission and follow up. In each patient, the initial MRI demonstrated increased signal on FLAIR and restricted diffusion in the cerebellar cortex without involvement of deep cerebellar nuclei or supratentorial areas. The presenting symptoms and the majority of imaging findings resolved on follow up MRI. To our knowledge, Minnelide has shown an uncommon radiologic pattern of isolated cerebellar cortical involvement compared to other causes of cerebellar toxicity. Since this is a new medication, physicians' familiarity with the presenting symptoms and its temporal association with the imaging findings is important

High-fidelity simulation training for nasal bridle placement with a 3D printed model

Background: Nasal bridles help prevent nasoenteric feeding tube dislodgement. If placed incorrectly, nasal bridles can cause injury, epistaxis, skin ulceration, or failure to prevent dislodgment. Training is frequently performed on patients, which can lead to discomfort or complications. To improve training prior to placing nasal bridles in patients, we utilized an anatomically accurate 3D printed simulator for nasal bridle placement training. Methods: The model was modified from a nasopharyngeal swab simulator by BONE 3D, which was developed from imaging data through segmentation, computer-aided design, and 3D printing. Eighteen radiology residents and 3 medical students received a pre-test covering the anatomical knowledge and technique relevant to nasal bridle placement followed by a training session using the model. After training, participants provided feedback on the impact of training with the model on anatomical knowledge, hands-on skills, and confidence via a post-test using a 5-point Likert scale [from 1 (not beneficial/confident) to 5 (extremely beneficial/ confident)]. Results: Twenty participants completed both pre- and post-tests. The group performed significantly better on the post-test (4.8 ± 0.52) than the pre-test (2.6 ± 1.64), and the intervention demonstrated a large effect on knowledge (p < 0.0001; d = 1.82) and confidence level (p < 0.0001, d = 2.45) with mean magnitude of improvement of 2.3 out of 5 points. All respondents requested the 3D printed model be offered in formal training. Conclusions: An anatomically accurate 3D printed model is a feasible and acceptable training aid with the potential to facilitate novice knowledge, proficiency, and confidence for nasal bridle placement

Mosaicism of the UDP-Galactose transporter SLC35A2 in a female causing a congenital disorder of glycosylation: a case report

Abstract Background Congenital disorders of glycosylation are rare conditions caused by genetic defects in glycan synthesis, processing or transport. Most congenital disorders of glycosylation involve defects in the formation or transfer of the lipid-linked oligosaccharide precursor of N-linked glycans. SLC35A2-CDG (previously CDG-IIm) is caused by hemizygous or heterozygous mutations in the X-linked gene SLC35A2 that encodes a UDP-galactose transporter. To date there have only been 10 reported patients with SLC35A2 mutations. Importantly, the patient presented here was not identified in infancy by transferrin isoform analysis, the most common testing to identify patients with a congenital disorder of glycosylation. Case presentation A 27 month old girl with developmental delay, central hypotonia, cerebral atrophy, and failure to thrive with growth retardation was identified by whole exome sequencing to have a mosaic missense variant in SLC35A2 (c.991G > A). This particular variant has been previously reported in a male as a mutation. Comparison of all clinical findings and new information on growth pattern, growth hormone testing and neurodevelopmental evaluation are detailed on the patient presented. Conclusion This patient report increases the clinical and scientific knowledge of SLC35A2-CDG, a rare condition. New information on reduced growth, growth hormone sufficiency, lack of seizures, and neurodevelopmental status are presented. This new information will be helpful to clinicians caring for individuals with SLC35A2-CDG. This report also alerts clinicians that transferrin isoform measurements do not identify all patients with congenital disorders of glycosylation

Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction.

X-linked adrenoleukodystrophy results from mutations in the ABCD1 gene disrupting the metabolism of very-long-chain fatty acids. The most serious form of ALD, cerebral adrenoleukodystrophy (cALD), causes neuroinflammation and demyelination. Neuroimaging in cALD shows inflammatory changes and indicates blood-brain-barrier (BBB) disruption. We hypothesize that disruption may occur through the degradation of the extracellular matrix defining the BBB by matrix metalloproteinases (MMPs). MMPs have not been evaluated in the setting of cALD.We used a multiplex assay to correlate the concentration of MMPs in cerebrospinal fluid and plasma to the severity of brain inflammation as determined by the ALD MRI (Loes) score and the neurologic function score. There were significant elevations of MMP2, MMP9, MMP10, TIMP1, and total protein in the CSF of boys with cALD compared to controls. Levels of MMP10, TIMP1, and total protein in CSF showed significant correlation [p<0.05 for each with pre-transplant MRI Loes Loes scores (R(2) = 0.34, 0.20, 0.55 respectively). Levels of TIMP1 and total protein in CSF significantly correlated with pre-transplant neurologic functional scores (R(2) = 0.22 and 0.48 respectively), and levels of MMP10 and total protein in CSF significantly correlated with one-year post-transplant functional scores (R(2) = 0.38 and 0.69). There was a significant elevation of MMP9 levels in plasma compared to control, but did not correlate with the MRI or neurologic function scores.MMPs were found to be elevated in the CSF of boys with cALD and may mechanistically contribute to the breakdown of the blood-brain-barrier. MMP concentrations directly correlate to radiographic and clinical neurologic severity. Interestingly, increased total protein levels showed superior correlation to MRI score and neurologic function score before and at one year after transplant

Childhood Cerebral Adrenoleukodystrophy: MR Perfusion Measurements and their Use in Predicting Clinical Outcome after Hematopoietic Stem Cell Transplantation

BACKGROUND AND PURPOSE: To prospectively measure MR perfusion (MRP) parameters in patients with cerebral adrenoleukodystrophy (cALD) pre- and post-hematopoietic stem cell transplantation (HSCT), and to correlate those measurements with the clinical outcome. MATERIALS AND METHODS: Ten cALD patients prospectively underwent DSC-MRP at <45 days pre-(baseline), 30–60 days post-, and 1 year post-HSCT. MRP measurements in the 10 patients and 8 controls were obtained from the parietooccipital WM (POWM), callosal splenium (SCC), leading enhancing edge (LEE), and normal-appearing frontal white matter (NAFWM). MR severity (Loes) scores and clinical neurologic function (NFS) and neurocognitive scores were also obtained. MRP values were analyzed in the cALD patients at each time point, and compared to controls. Correlations were calculated between the pre-HSCT MRP values and 1-year clinical scores, with p-value adjustment for multiple comparisons. RESULTS: At baseline in cALD patients, both rCBV and rCBF within the SCC and POWM significantly differed from controls (p=0.005–0.031), and remained so 1 year post-HSCT (p=0.003–0.005). Meanwhile, no MRP parameter within the LEE differed significantly from controls at baseline or at 1 year (p=0.074–0.999), nor significantly changed by 1 year post-HSCT (p=0.142–0.887). Baseline Loes scores correlated with 1 year NFS (r=0.813, p<0.0001), while SCC rCBV also significantly correlated with 1 year NFS, as well as the neurocognitive FSIQ and PIQ scores (r=−0.730–0.815, p=0.007–0.038). CONCLUSION: LEE measurements likely remain normal post-HSCT in cALD, suggesting local disease stabilization. Meanwhile, POWM and SCC rCBV and rCBF values worsen, signifying irreversible injury. Baseline SCC rCBV may predict clinical outcomes following HSCT

Effect of Patient Positioning on Cerebrospinal Fluid Opening Pressure

Background: Prone is the preferred patient position for fluoroscopic-guided lumbar puncture (LP). Normative data for cerebrospinal fluid (CSF) opening pressure (OP) exist for lateral decubitus (LD) positioning only and have not been defined for the prone position. This study compares CSF OP values in the prone and LD positions and examines the effect of body mass index (BMI) on OP. Methods: Patients undergoing diagnostic or therapeutic fluoroscopic-guided LP were recruited prospectively at 2 tertiary care centers from 2009 to 2012. Following prone fluoroscopic-guided LP, patients were rolled to the LD position for repeat CSF OP measurement. In addition to comparing the mean OP in each position, the relationships between OP, body position, and BMI were also explored. Results: Fifty-two patients were enrolled. A mean OP difference of 1.2 cm H2O was observed (prone: 26.5 cm H2O; LD: 27.7 cm H2O; P = 0.07). No correlation between CSF OP and BMI was seen in either position. Conclusions: No statistically or clinically significant difference between prone and LD OP was identified. BMI does not appear to affect CSF OP measurement in either position. (C) 2014 by North American Neuro-Ophthalmology Societ