Presenting Symptoms and Disease Severity in Multiple Sclerosis Patients.

INTRODUCTION: The study aims to determine an association between presenting symptoms in multiple sclerosis and measures of disease severity, including the expanded disability status score (EDSS) and MRI based lesion volumes. METHODS: Data was collected as part of a larger 3 year MS study, from 2014 to 2017, to compare Vitamin A levels and MS progression. All data was collected from a single clinical site. Demographic data as well as date of diagnosis and use of disease modifying therapies. Patients not able to obtain MRIs or lab tests and histories of vitamin abnormalities were excluded from the study. 29 patients met inclusion criteria. We chose presenting symptoms of vision, balance, sensory function, and motor function as these represented the most common manifestations of the disease and mirror the domains of the EDSS, which is the most commonly used scale for MS disease severity. We also included neuroimaging based lesion volume as another objective measure for comparison. RESULTS: Although duration of disease was different between comparator groups, no significant difference was found between them when EDSS and lesion volumes were compared. There was a difference in lesion volumes when comparing those patients that had presenting symptoms of visual changes or balance symptoms with those presenting with sensory changes. CONCLUSIONS: This study supports the notion that presenting symptoms are not associated with EDSS independent disease duration. It also verifies that severity of disease is not associated with lesion volumes. However, sensory symptoms as a presenting symptom was associated with less lesion volumes in our study.

Dysphagia and Tongue Deviation: A Rare Case of Collett-Sicard Syndrome after Blunt Head Trauma.

The jugular foramen and the hypoglossal canal are both apertures located at the base of the skull. Multiple lower cranial nerve palsies tend to occur with injuries to these structures. The pattern of injuries tend to correlate with the combination of nerves damaged. Case Report: A 28-year-old male was involved in an AVP injury while crossing the highway. Exam showed a GCS of 15 AAOx3, with dysphagia, tongue deviation to the right, uvula deviation to the left and a depressed palate. Initial imaging showed B/L frontal traumatic Sub-Arachnoid Hemorrhages (tSAH), Left Frontal Epidural Hematoma and a Basilar Skull Fracture. On second look by a trained Neuroradiologist c At 3 month follow up, patient's tongue normalized to midline and his dysphagia resolved. Discussion: Collette-Sicard syndrome is a rare condition/syndrome characterized by unilateral palsy of CN: IX, X, XII. This condition has been rarely described as a consequence of blunt head trauma. In most cases, the condition is self-limiting with patients regaining most to all of their neurological functions within 6 months. Nerve traction injuries and soft tissue edema compressing the cranial nerves are the leading two hypothesis. In conclusion, injuries with focal neurological deficits which were not apparent on initial imaging should be reviewed by relevant experts with concomitant knowledge of the patient's history.

Challenging the Conventional Standard for Thoracic Spine Range of Motion: A Systematic Review.

BACKGROUND: Segmental motion is a fundamental characteristic of the thoracic spine; however, studies of segmental ranges of motion have not been summarized or analyzed. The purpose of the present study was to present a summary of the literature on intact cadaveric thoracic spine segmental range of motion in each anatomical plane. METHODS: A systematic MEDLINE search was performed with use of the terms "thoracic spine," "motion," and "cadaver." Reports that included data on the range of motion of intact thoracic human cadaveric spines were included. Independent variables included experimental details (e.g., specimen age), type of loading (e.g., pure moments), and applied moment. Dependent variables included the ranges of motion in flexion-extension, lateral bending, and axial rotation. RESULTS: Thirty-three unique articles were identified and included. Twenty-three applied pure moments to thoracic spine specimens, with applied moments ranging from 1.5 to 8 Nm. Estimated segmental range of motion pooled means ranged from 1.9° to 3.8° in flexion-extension, from 2.1° to 4.4° in lateral bending, and from 2.4° to 5.2° in axial rotation. The sums of the range of motion pooled means (T1 to T12) were 28° in flexion-extension, 36° in lateral bending, and 45° in axial rotation. CONCLUSIONS: The pooled ranges of motion were similar to reported in vivo motions but were considerably smaller in magnitude than the frequently referenced values reported prior to the widespread use of biomechanical testing standards. Improved reporting of biomechanical testing methods, as well as specimen health, may be beneficial for improving on these estimations of segmental cadaveric thoracic spine range of motion.

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation.

ALS is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and atrophy of distal axon terminals in muscle, resulting in loss of motor function. Motor end plates denervated by axonal retraction of dying motor neurons are partially reinnervated by remaining viable motor neurons; however, this axonal sprouting is insufficient to compensate for motor neuron loss. Activating transcription factor 3 (ATF3) promotes neuronal survival and axonal growth. Here, we reveal that forced expression of ATF3 in motor neurons of transgenic SOD1(G93A) ALS mice delays neuromuscular junction denervation by inducing axonal sprouting and enhancing motor neuron viability. Maintenance of neuromuscular junction innervation during the course of the disease in ATF3/SOD1(G93A) mice is associated with a substantial delay in muscle atrophy and improved motor performance. Although disease onset and mortality are delayed, disease duration is not affected. This study shows that adaptive axonal growth-promoting mechanisms can substantially improve motor function in ALS and importantly, that augmenting viability of the motor neuron soma and maintaining functional neuromuscular junction connections are both essential elements in therapy for motor neuron disease in the SOD1(G93A) mice. Accordingly, effective protection of optimal motor neuron function requires restitution of multiple dysregulated cellular pathways.

Overexpression of the wild-type SPT1 subunit lowers desoxysphingolipid levels and rescues the phenotype of HSAN1.

Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, hereditary sensory, and autonomic neuropathy type I (HSAN1). We previously reported that mice bearing a transgene-expressing mutant SPTLC1 (tgSPTLC1(C133W)) show a reduction in SPT activity and hyperpathia at 10 months of age. Now analyzed at a later age, we find these mice develop sensory loss with a distal small fiber neuropathy and peripheral myelinopathy. This phenotype is largely reversed when these mice are crossed with transgenic mice overexpressing wild-type SPTLC1 showing that the mutant SPTLC1 protein is not inherently toxic. Simple loss of SPT activity also cannot account for the HSAN1 phenotype, since heterozygous SPTLC1 knock-out mice have reduced SPT activity but are otherwise normal. Rather, the presence of two newly identified, potentially deleterious deoxysphingoid bases in the tgSPTLC1(C133W), but not in the wild-type, double-transgenic tgSPTLC1(WT + C133W) or SPTLC1(+/-) mice, suggests that the HSAN1 mutations alter amino acid selectivity of the SPT enzyme such that palmitate is condensed with alanine and glycine, in addition to serine. This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.

Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS.

With a view toward improving delivery of exogenous glial cell line-derived neurotrophic factor (GDNF) to CNS motor neurons in vivo, we evaluated the bioavailability and pharmacological activity of a recombinant GDNF:tetanus toxin C-fragment fusion protein in mouse CNS. Following intramuscular injection, GDNF:TTC but not recombinant GDNF (rGDNF) produced strong GDNF immunostaining within ventral horn cells of the spinal cord. Intrathecal infusion of GDNF:TTC resulted in tissue concentrations of GDNF in lumbar spinal cord that were at least 150-fold higher than those in mice treated with rGDNF. While levels of immunoreactive choline acetyltransferase and GFRalpha-1 in lumbar cord were not altered significantly by intrathecal infusion of rGNDF, GDNF:TTC, or TTC, only rGDNF and GDNF:TTC caused significant weight loss following intracerebroventricular infusion. These studies indicate that insect cell-derived GDNF:TTC retains its bi-functional activity in mammalian CNS in vivo and improves delivery of GDNF to spinal cord following intramuscular- or intrathecal administration.

IGF-1:tetanus toxin fragment C fusion protein improves delivery of IGF-1 to spinal cord but fails to prolong survival of ALS mice.

To improve delivery of human insulin-like growth factor-1 (hIGF-1) to brain and spinal cord, we generated a soluble IGF-1:tetanus toxin fragment C fusion protein (IGF-1:TTC) as a secreted product from insect cells. IGF-1:TTC exhibited IGF-1 and TTC activity in vitro; it increased levels of immunoreactive phosphoAkt in treated MCF-7 cells and bound to immobilized ganglioside GT1b. In mice, the fusion protein underwent retrograde transport by spinal cord motor neurons following intramuscular injection, and exhibited both TTC- and IGF-1 activity in the CNS following intrathecal infusion. Analogous to the case with TTC, intrathecal infusion of the fusion protein resulted in substantial levels of IGF-1:TTC in spinal cord tissue extracts. Tissue concentrations of hIGF-1 in lumbar spinal cords of mice infused with IGF-1:TTC were estimated to be approximately 500-fold higher than those in mice treated with unmodified recombinant hIGF-1 (rhIGF-1). Like rhIGF-1, infusion of IGF-1:TTC reduced levels of IGF-1 receptor immunoreactivity in the same extracts. Despite raising levels of exogenous hIGF-1 in spinal cord, intramuscular- or intrathecal administration of IGF-1:TTC had no significant effect on disease progression or survival of high-expressing SOD1(G93A) transgenic mice. IGF-1:TTC may prove to be neuroprotective in other animal models of CNS disease or injury known to be responsive to unmodified IGF-1.

Recombinant GDNF: tetanus toxin fragment C fusion protein produced from insect cells.

Glial cell line-derived neurotrophic factor (GDNF) has potent survival-promoting effects on CNS motor neurons in experimental animals. Its therapeutic efficacy in humans, however, may have been limited by poor bioavailability to the brain and spinal cord. With a view toward improving delivery of GDNF to CNS motor neurons in vivo, we generated a recombinant fusion protein comprised of rat GDNF linked to the non-toxic, neuron-binding fragment of tetanus toxin. Recombinant GDNF:TTC produced from insect cells was a soluble homodimer like wild-type GDNF and was bi-functional with respect to GDNF and TTC activity. Like recombinant rat GDNF, the fusion protein increased levels of immunoreactive phosphoAkt in treated NB41A3-hGFRalpha-1 neuroblastoma cells. Like TTC, GDNF:TTC bound to immobilized ganglioside GT1b in vitro with high affinity and selectivity. These results support further testing of recombinant GDNF:TTC as a non-viral vector to improve delivery of GDNF to brain and spinal cord in vivo.

Dopaminergic amacrine cells in the inner nuclear layer and ganglion cell layer comprise a single functional retinal mosaic.

Many types of retinal neuron are distributed in an orderly manner across the surface of the retina. Indeed, the existence of such regularity amongst a population of neurons, termed a retinal mosaic, may be a defining feature of functionally independent types of retinal neuron. We have examined the spatial distribution of dopaminergic amacrine cells in the ferret retina both in the inner nuclear layer (INL) and in the ganglion cell layer (GCL) to determine whether the cells in each layer form an independent retinal mosaic as evidence of whether they should be considered as two separate types. Ferret retinas contain approximately 1,900 dopaminergic amacrine cells, of which 27% are located in the GCL, and the rest in the INL. Based on analysis of their Voronoi domains as well as autocorrelation analysis and tests for complete spatial randomness, we found that the distribution of INL cells was statistically regular, while that of the GCL cells was not. However, by using cross-correlation analysis, these two groups of cells were found to be spatially dependent: an exclusion zone was detected in the cross-correlogram of roughly the same size as that found in the autocorrelograms of both INL and GCL cells. Such a pattern would be expected if dopaminergic amacrine cells in the INL and GCL were members of a single regular population differing only in their somatic depth. By using computer simulations, we tested this hypothesis directly, confirming that a random assignment of 27% from the total population produces cross-correlograms that are indistinguishable from those of the biological mosaics. We conclude, therefore, that the cells in the two layers form a single functional population; those in the GCL appear to be misplaced. Somatic positioning with respect to depth within the retina is not, by itself, a reliable guide for functional classification.