ALSUntangled #75: Portable neuromodulation stimulator therapy.

Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.

A Comparison of Pediatric- and Adult-Onset Aquaporin-4 Immunoglobulin G-Positive Neuromyelitis Optica Spectrum Disorder: A Review of Clinical and Radiographic Characteristics.

BACKGROUND: The identification of immunoglobulin G antibodies against the aquaporin-4 channel (AQP-IgG) in the majority of adult patients differentiates neuromyelitis optica as a distinct disease entity. The high specificity of AQP4-IgG for neuromyelitis optica has allowed the identification of seropositive patients with atypical presentations of this disease. Neuromyelitis optica spectrum disorder has been increasingly recognized in children who demonstrate patterns of clinical involvement beyond the traditional boundaries of the optic pathways and spinal cord. METHODS: This is a single-center, retrospective review comparing demographic, clinical/paraclinical, and laboratory features of children and adults with a serologically confirmed diagnosis of AQP4-IgG-positive neuromyelitis optica spectrum disorder. RESULTS: Of 151 reviewed patient charts, 12 pediatric-onset and 31 adult-onset patients had AQP4-IgG-positive neuromyelitis optica spectrum disorder. The mean age of pediatric-onset neuromyelitis optica spectrum disorder was 12 ± 3.58 years with a female predilection (3:1). Pediatric patients showed more frequent involvement of the brainstem (6/12 [50%]); P = .008) and diencephalon (3/12 [25%]; P = .018). A preceding infection was identifiable in only 3 of 12 (25%) pediatric-onset patients. Moreover, disability as calculated on the expanded disability status scale was less severe in pediatric-onset cases compared to adult-onset cases in their most recent assessment (0 [0-9]) vs 6.5 [0-10]; P = .005). Pediatric-onset patients were also more likely to respond to treatment of acute episodes with corticosteroids ± intravenous immunoglobulin and/or plasmapheresis (Clinical Global Impression-Change scale: 2.5 [1-4] vs 4 [1-6], P = .009). INTERPRETATION: This retrospective study was able to compare and contrast pediatric- and adult-onset neuromyelitis optica spectrum disorder. Relative to their adult counterparts, pediatric-onset neuromyelitis optica spectrum disorder patients were more likely to respond to treatment and less likely to be disabled from their disease at follow-up. Therefore, pediatric-onset disease may represent a less virulent form of neuromyelitis optica spectrum disorder.

Clinical, electrophysiological, and imaging findings in childhood brachial plexus injury.

AIM: To assess the prognostic capabilities of various diagnostic modalities for childhood brachial plexus injuries (BPIs) and brachial plexus birth injury (BPBI) and postneonatal BPI. METHOD: In this single-center retrospective cross-sectional study, we examined children with BPIs diagnosed or confirmed by electrodiagnostic studies between 2013 and 2020, and compared the prognostic value of various components of the electrophysiologic findings, magnetic resonance imaging (MRI) data, and the Active Movement Scale (AMS). We developed scoring systems for electrodiagnostic studies and MRI findings, including various components of nerve conduction studies and electromyography (EMG) for electrodiagnostic studies. RESULTS: We identified 21 children (10 females and 11 males) aged 8 days to 21 years (mean 8y 6.95mo) who had a total of 30 electrodiagnostic studies, 14 brachial plexus MRI studies, and 10 surgical procedures. Among the diagnostic modalities assessed, brachial plexus MRI scores, EMG denervation scores, and mean total EMG scores were the most valuable in predicting surgical versus non-surgical outcomes. Correspondingly, a combined MRI/mean total EMG score provided prognostic value. INTERPRETATION: Brachial plexus MRI scores and specific electrodiagnostic scores provide the most accurate prognostic information for children with BPI. Our grading scales can assist a multidisciplinary team in quantifying results of these studies and determining prognosis in this setting. WHAT THIS PAPER ADDS: A new scoring system to quantify results of electrodiagnostic and magnetic resonance imaging (MRI) studies is presented. Severity of denervation has good prognostic value for childhood brachial plexus injuries (BPIs). Composite electromyography scores have good prognostic value for childhood BPIs. Brachial plexus MRI has good prognostic value for childhood BPIs.

High altitude is associated with pTau deposition, neuroinflammation, and myelin loss.

Mammals are able to adapt to high altitude (HA) if appropriate acclimation occurs. However, specific occupations (professional climbers, pilots, astronauts and other) can be exposed to HA without acclimation and be at a higher risk of brain consequences. In particular, US Air Force U2-pilots have been shown to develop white matter hyperintensities (WMH) on MRI. Whether WMH are due to hypoxia or hypobaria effects is not understood. We compared swine brains exposed to 5000 feet (1524 m) above sea level (SL) with 21% fraction inspired O2 (FiO2) (Control group [C]; n = 5) vs. 30,000 feet (9144 m) above SL with 100% FiO2 group (hypobaric group [HYPOBAR]; n = 6). We performed neuropathologic assessments, molecular analyses, immunohistochemistry (IHC), Western Blotting (WB), and stereology analyses to detect differences between HYPOBAR vs. Controls. Increased neuronal insoluble hyperphosphorylated-Tau (pTau) accumulation was observed across different brain regions, at histological level, in the HYPOBAR vs. Controls. Stereology-based cell counting demonstrated a significant difference (p < 0.01) in pTau positive neurons between HYPOBAR and C in the Hippocampus. Higher levels of soluble pTau in the Hippocampus of HYPOBAR vs. Controls were also detected by WB analyses. Additionally, WB demonstrated an increase of IBA-1 in the Cerebellum and a decrease of myelin basic protein (MBP) in the Hippocampus and Cerebellum of HYPOBAR vs. Controls. These findings illustrate, for the first time, changes occurring in large mammalian brains after exposure to nonhypoxic-hypobaria and open new pathophysiological views on the interaction among hypobaria, pTau accumulation, neuroinflammation, and myelination in large mammals exposed to HA.

Vitamins are Indeed Vital Amines: A Discussion of 3 Deficiencies With Neurologic Manifestations.

Optimal functioning of the human nervous system depends on a constant supply of nutrients, vitamins, and minerals. In the developed world, nutritional deficiencies are relatively rare and infrequently present with neurologic manifestations. These neurologic disorders can be mistaken for inflammatory and/or autoimmune phenomena. This manuscript describes 2 pediatric cases with neurologic signs/symptoms arising from vitamin deficiencies-(1) optic neuropathy and (2) Wernicke encephalopathy associated with a Guillain-Barre-like pattern of weakness. The 2 cases and the subsequent discussion of vitamin A, B1, and B12 deficiencies underscore the value of taking a thorough dietary history and emphasize risk factors for these 3 nutritional deficiencies.

Apolipoprotein E promoter genotypes are not associated with white matter hyperintensity development in high-altitude careers.

OBJECTIVE: This study sought to determine if there is an association between variants in the apolipoprotein E (ApoE) promoter regions and development of white matter hyperintensities (WMH) in military subjects who have been exposed to high altitude. In an earlier study, we found that ApoE status did not correlate with WMH development, and here we hypothesized that regulation of APOE protein expression may be protective. RESULTS: Our cohort of 92 subjects encountered altitude exposures above 25,000 feet mean sea level through their occupations as pilots or altitude chamber technicians. Using Taqman-style polymerase chain reaction genotyping and t-tests and two-way analyses of variance we found no significant association between ApoE promoter genotypes and the presence, volume, or quantity of WMHs after high altitude exposure. Taken together, the observations that neither ApoE genotype status nor promoter status are associated with WMH properties, we believe that the mechanism of action for developing WMH does not derive from ApoE, nor would therapies for ApoE-mediated neurodegeneration likely benefit high altitude operators.

Acute neurotoxicity following vincristine due to Charcot-Marie-Tooth disease in a young child with medulloblastoma.

Vincristine (VCR), a microtubule inhibitor that arrests the cell cycle by blocking metaphase of mitosis, is unique among the vinca alkaloids for causing polyneuropathy. Patients with increased risk of VCR neurotoxicity include the elderly and those with prior history of neuropathy-prone medical conditions. Identifying such risk factors prior to the development of neurotoxicity should be a goal prior to VCR administration. Clinicians should obtain a thorough medical and family history of neuropathies in any child scheduled to receive neurotoxic medications to avoid exacerbating an underlying disorder. We report a case of a young child with newly diagnosed medulloblastoma who started treatment on a VCR-containing chemotherapy regimen following surgery and craniospinal radiation. She subsequently developed severe peripheral polyneuropathy and new enhancement of the cranial and nerve roots following a relatively low cumulative dose of VCR and was diagnosed with previously unidentified Charcot-Marie-Tooth disease (CMTD) Type 1A. This case highlights that an evaluation of risk factors should be completed prior to initiation of neurotoxic chemotherapies and advocates for testing for inherited neuropathies such as CMTD even in asymptomatic patients when hereditary neuropathy is suspected.

Intravenous Immunoglobulin as a Therapeutic Option for Mycoplasma pneumoniae Encephalitis.

OBJECTIVE: To analyze the outcomes of a cohort of children diagnosed with Mycoplasma pneumoniae encephalitis whose treatment regimens included intravenous immunoglobulin (IVIG). METHODS: A retrospective study was performed at a single center between 2011 and 2016 of children diagnosed with Mycoplasma pneumoniae encephalitis whose acute treatment regimen included IVIG. Details of therapeutic interventions and the clinical course were retrieved from medical records via an institutionally approved protocol. The modified Rankin score was used to quantify outcomes. RESULTS: Four children met inclusion criteria, 3 of whom had prodromal symptoms of infection lasting 5 to 7 days before onset of their neurologic symptoms. One patient presented with neurologic symptoms with no clinical prodrome. The initial treatment regimen included systemic corticosteroids, antibiotics, or both. IVIG was administered for a total dose of 2 g/kg divided over 2 to 4 days to all 4 children. All children showed clinical improvement after IVIG. The 3 children with prodromal symptoms showed immediate and dramatic clinical improvement after IVIG therapy. DISCUSSION: The immediate response to immunomodulatory therapy in the patients with prodrome suggests that the neurologic syndrome may be caused at least in part by an autoimmune process. The child who did not respond to IVIG had no prodrome, and also had normal electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) findings. These cases suggest that early administration of IVIG should be considered in patients suspected of having Mycoplasma encephalitis, particularly in those who have had prodromal symptoms.

Lambert-Eaton myasthenic syndrome and merkel cell carcinoma.

Lambert-Eaton myasthenic syndrome (LEMS) is an antibody-mediated disorder of the neuromuscular junction that is most commonly diagnosed in association with small cell lung carcinoma (SCLC). Small cell lung carcinoma is histologically similar to the aggressive cutaneous neuroendocrine malignancy Merkel cell carcinoma (MCC). We provide a full report and longitudinal clinical follow-up of a case of LEMS occurring with MCC. We also review the literature on paraneoplastic syndromes associated with MCC and other nonpulmonary small cell carcinomas.

White matter and hypoxic hypobaria in humans.

Occupational exposure to hypobaria (low atmospheric pressure) is a risk factor for reduced white matter integrity, increased white matter hyperintensive burden, and decline in cognitive function. We tested the hypothesis that a discrete hypobaric exposure will have a transient impact on cerebral physiology. Cerebral blood flow, fractional anisotropy of water diffusion in cerebral white matter, white matter hyperintensity volume, and concentrations of neurochemicals were measured at baseline and 24 hr and 72 hr postexposure in N = 64 healthy aircrew undergoing standard US Air Force altitude chamber training and compared to N = 60 controls not exposed to hypobaria. We observed that hypobaric exposure led to a significant rise in white matter cerebral blood flow (CBF) 24 hr postexposure that remained elevated, albeit not significantly, at 72 hr. No significant changes were observed in structural measurements or gray matter CBF. Subjects with higher baseline concentrations of neurochemicals associated with neuroprotection and maintenance of normal white matter physiology (glutathione, N-acetylaspartate, glutamate/glutamine) showed proportionally less white matter CBF changes. Our findings suggest that discrete hypobaric exposure may provide a model to study white matter injury associated with occupational hypobaric exposure.

Lumbosacral ventral spinal nerve root atrophy identified on MRI in a case of spinal muscular atrophy type II.

Spinal muscular atrophies are rare genetic disorders most often caused by homozygous deletion mutations in SMN1 that lead to progressive neurodegeneration of anterior horn cells. Ventral spinal root atrophy is a consistent pathological finding in post-mortem examinations of patients who suffered from various subtypes of spinal muscular atrophy; however, corresponding radiographic findings have not been previously reported. We present a patient with hypotonia and weakness who was found to have ventral spinal root atrophy in the lumbosacral region on MRI and was subsequently diagnosed with spinal muscular atrophy. More systematic analyses of imaging studies in spinal muscular atrophy will help determine whether such findings have the potential to serve as reliable diagnostic markers for clinical evaluations or as outcome measure for clinical trials.

Evaluating apolipoprotein E genotype status and neuroprotective effects against white matter hyperintensity development in high-altitude careers.

OBJECTIVE: This study considers the use of a rapid molecular assay to evaluate apolipoprotein E (ApoE) status in military subjects who have been exposed to high altitude. We hypothesize that ApoE status may be protective against developing brain white matter hyperintensities (WMHs) after high altitude exposure. RESULTS: We tested 92 subjects who had been exposed to altitudes above 25,000 ft mean sea level, either as pilots or as altitude chamber technicians. We determined subject genetic status using rapid Taqman-style polymerase chain reaction genotyping and evaluated the association of ApoE subtype versus brain lesions using t-tests and two-way analyses of variance. Our results indicate that there is no significant association between ApoE genotype status and the presence of WMHs after high altitude exposure. We did observe a significantly higher number of hours spent at altitude for subjects with the ApoE E2 allele; however, the mechanism by which this may occur is not determined in this study. To more fully elucidate this effect, larger populations would be required to observe greater numbers of subjects with the E2 and E4 alleles.

Miniature pig magnetic resonance spectroscopy model of normal adolescent brain development.

BACKGROUND: We are developing the miniature pig (Sus scrofa domestica), an in-vivo translational, gyrencephalic model for brain development, as an alternative to laboratory rodents/non-human primates. We analyzed longitudinal changes in adolescent pigs using proton magnetic resonance spectroscopy (1H-MRS) and examined the relationship with white matter (WM) integrity derived from diffusion weighted imaging (DWI). NEW METHOD: Twelve female Sinclair™ pigs underwent three imaging/spectroscopy sessions every 23.95 ± 3.73 days beginning at three months of age using a clinical 3 T scanner. 1H-MRS data were collected using 1.2 × 1.0 × 3.0 cm voxels placed in left and right hemisphere WM using a Point Resolved Spectroscopy sequence (TR = 2000 ms, TE = 30 ms). Concentrations of N-acetylaspartate, myo-inositol (MI), glutamate + glutamine, choline, creatine, and macromolecules (MM) 09 and 14 were averaged from both hemispheres. DWI data were collected using 15 shells of b-values (b = 0-3500 s/mm2) with 32 directions/shell and fit using the WM Tract Integrity model to calculate fractional anisotropy (FA), kurtosis anisotropy (KA) and permeability-diffusivity index. RESULTS: MI and MM09 significantly declined with age. Increased FA and KA significantly correlated with decline in MI and MM09. Correlations lost significance once corrected for age. COMPARISON WITH EXISTING METHODS: MRI scanners/protocols can be used to collect 1H-MRS and DWI data in pigs. Pigs have a larger, more complex, gyrencephalic brain than laboratory rodents but are less complex than non-human primates, thus satisfying the "replacement" principle of animal research. CONCLUSIONS: Longitudinal effects in MRS measurements were similar to those reported in adolescent humans. MRS changes correlated with diffusion measurements indicating ongoing WM myelination/maturation.

Miniature pig model of human adolescent brain white matter development.

BACKGROUND: Neuroscience research in brain development and disorders can benefit from an in vivo animal model that portrays normal white matter (WM) development trajectories and has a sufficiently large cerebrum for imaging with human MRI scanners and protocols. NEW METHOD: Twelve three-month-old Sinclair™ miniature pigs (Sus scrofa domestica) were longitudinally evaluated during adolescent development using advanced diffusion weighted imaging (DWI) focused on cerebral WM. Animals had three MRI scans every 23.95 ±â€¯3.73 days using a 3-T scanner. The DWI imaging protocol closely modeled advanced human structural protocols and consisted of fifteen b-shells (b = 0-3500 s/mm2) with 32-directions/shell. DWI data were analyzed using diffusion kurtosis and bi-exponential modeling that provided measurements that included fractional anisotropy (FA), radial kurtosis, kurtosis anisotropy (KA), axial kurtosis, tortuosity, and permeability-diffusivity index (PDI). RESULTS: Significant longitudinal effects of brain development were observed for whole-brain average FA, KA, and PDI (all p < 0.001). There were expected regional differences in trends, with corpus callosum fibers showing the highest rate of change. COMPARISON WITH EXISTING METHOD(S): Pigs have a large, gyrencephalic brain that can be studied using clinical MRI scanners/protocols. Pigs are less complex than non-human primates thus satisfying the "replacement" principle of animal research. CONCLUSIONS: Longitudinal effects were observed for whole-brain and regional diffusion measurements. The changes in diffusion measurements were interepreted as evidence for ongoing myelination and maturation of cerebral WM. Corpus callosum and superficial cortical WM showed the expected higher rates of change, mirroring results in humans.

Reproducibility of quantitative structural and physiological MRI measurements.

INTRODUCTION: Quantitative longitudinal magnetic resonance imaging and spectroscopy (MRI/S) is used to assess progress of brain disorders and treatment effects. Understanding the significance of MRI/S changes requires knowledge of the inherent technical and physiological consistency of these measurements. This longitudinal study examined the variance and reproducibility of commonly used quantitative MRI/S measurements in healthy subjects while controlling physiological and technical parameters. METHODS: Twenty-five subjects were imaged three times over 5 days on a Siemens 3T Verio scanner equipped with a 32-channel phase array coil. Structural (T1, T2-weighted, and diffusion-weighted imaging) and physiological (pseudocontinuous arterial spin labeling, proton magnetic resonance spectroscopy) data were collected. Consistency of repeated images was evaluated with mean relative difference, mean coefficient of variation, and intraclass correlation (ICC). Finally, a "reproducibility rating" was calculated based on the number of subjects needed for a 3% and 10% difference. RESULTS: Structural measurements generally demonstrated excellent reproducibility (ICCs 0.872-0.998) with a few exceptions. Moderate-to-low reproducibility was observed for fractional anisotropy measurements in fornix and corticospinal tracts, for cortical gray matter thickness in the entorhinal, insula, and medial orbitofrontal regions, and for the count of the periependymal hyperintensive white matter regions. The reproducibility of physiological measurements ranged from excellent for most of the magnetic resonance spectroscopy measurements to moderate for permeability-diffusivity coefficients in cingulate gray matter to low for regional blood flow in gray and white matter. DISCUSSION: This study demonstrates a high degree of longitudinal consistency across structural and physiological measurements in healthy subjects, defining the inherent variability in these commonly used sequences. Additionally, this study identifies those areas where caution should be exercised in interpretation. Understanding this variability can serve as the basis for interpretation of MRI/S data in the assessment of neurological disorders and treatment effects.

White Matter Integrity in High-Altitude Pilots Exposed to Hypobaria.

INTRODUCTION: Nonhypoxic hypobaric (low atmospheric pressure) occupational exposure, such as experienced by U.S. Air Force U-2 pilots and safety personnel operating inside altitude chambers, is associated with increased subcortical white matter hyperintensity (WMH) burden. The pathophysiological mechanisms underlying this discrete WMH change remain unknown. The objectives of this study were to demonstrate that occupational exposure to nonhypoxic hypobaria is associated with altered white matter integrity as quantified by fractional anisotropy (FA) measured using diffusion tensor imaging and relate these findings to WMH burden and neurocognitive ability. METHODS: There were 102 U-2 pilots and 114 age- and gender-controlled, health-matched controls who underwent magnetic resonance imaging. All pilots performed neurocognitive assessment. Whole-brain and tract-wise average FA values were compared between pilots and controls, followed by comparison within pilots separated into high and low WMH burden groups. Neurocognitive measurements were used to help interpret group difference in FA values. RESULTS: Pilots had significantly lower average FA values than controls (0.489/0.500, respectively). Regionally, pilots had higher FA values in the fronto-occipital tract where FA values positively correlated with visual-spatial performance scores (0.603/0.586, respectively). There was a trend for high burden pilots to have lower FA values than low burden pilots. DISCUSSION: Nonhypoxic hypobaric exposure is associated with significantly lower average FA in young, healthy U-2 pilots. This suggests that recurrent hypobaric exposure causes diffuse axonal injury in addition to focal white matter changes.McGuire SA, Boone GRE, Sherman PM, Tate DF, Wood JD, Patel B, Eskandar G, Wijtenburg SA, Rowland LM, Clarke GD, Grogan PM, Sladky JH, Kochunov PV. White matter integrity in high-altitude pilots exposed to hypobaria. Aerosp Med Hum Perform. 2016; 87(12):983-988.