Severe Palsy Research Articles

Endovascular Brain-Computer Interface to Restore Motor Control for the Command of Digital Devices in Patients with Severe Quadriparesis (S38.001)

Endovascular Brain-Computer Interface to Restore Motor Control for the Command of Digital Devices in Patients with Severe Quadriparesis (S38.001)

A Case of Botulism After Intramuscular Injection of Botulinum Toxin (P12-7.003)

<h3>Objective:</h3> Case report <h3>Background:</h3> Botulinum toxin is a neurotoxin produced by the bacterium <i>Clostridium botulinum</i> that can result in severe flaccid paralysis. Although its therapeutic applications are well-known, botulism can occur after unintentional intramuscular injections of the toxin. Early diagnosis and management are essential as this condition can be life-threatening when untreated. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 36-year-old female with no significant past medical history presented with 1-week history of generalized weakness. She had botulinum toxin injections into her cheeks and forehead two days prior to symptoms onset. The toxin was obtained off the internet and neither its quality nor the credentials of the administering individual could be verified. She also noticed difficulty chewing and swallowing both liquids and solids limiting her oral intake, followed by worsening lethargy and weakness. On physical exam, she had bilateral ptosis, difficulty resisting eye-opening, dysarthria, and symmetric generalized weakness. Reflexes were present and symmetric, and sensation intact to light touch. Investigations including anti-acetylcholine receptor, muscle-specific kinase, lipoprotein receptor-related protein-4 antibodies, TSH, MRI brain, and EMG were unremarkable. However, her respiratory status worsened requiring non-invasive mechanical ventilation, and she was empirically treated with pyridostigmine. The CDC was contacted, and Botulism antitoxin obtained and administered. Her symptoms then improved significantly, and she was discharged without residual deficits. <h3>Conclusions:</h3> Botulism is a rare but potentially fatal neuroparalytic disease caused by botulinum toxin. It usually occurs after ingestion of contaminated food but can be seen with improper administration of botulinum toxin. EMG is expected to show decremented response to repetitive low frequency and facilitated response to repetitive high frequency nerve stimulation with low compound muscle action potential. This was not the case of our patient whose study was confounded by pyridostigmine’s administration. This case highlights the importance of early diagnosis and treatment with antitoxin as botulism can rapidly progress to respiratory failure if untreated. <b>Disclosure:</b> Dr. Daou has nothing to disclose. Dr. Shnawa has nothing to disclose. Dr. Ariza Hutchinson has nothing to disclose. Dr. Joseph has nothing to disclose. Dr. Yakhkind has nothing to disclose.

Human SCARB2 Acts as a Cellular Associator for Helping Coxsackieviruses A10 Infection.

Coxsackievirus A10 (CVA10) causes hand, foot, and mouth disease (HFMD) and herpangina, which can result in severe neurological symptoms in children. CVA10 does not use the common enterovirus 71 (EV71) receptor, human SCARB2 (hSCARB2, scavenger receptor class B, member 2), for infection but instead uses another receptor, such as KREMEN1. Our research has shown that CVA10 can infect and replicate in mouse cells expressing human SCARB2 (3T3-SCARB2) but not in the parental NIH3T3 cells, which do not express hSCARB2 for CVA10 entry. Knocking down endogenous hSCARB2 and KREMEN1 with specific siRNAs inhibited CVA10 infection in human cells. Co-immunoprecipitation confirmed that VP1, a main capsid protein where virus receptors for attaching to the host cells, could physically interact with hSCARB2 and KREMEN1 during CVA10 infection. It is the efficient virus replication following virus attachment to its cellular receptor. It resulted in severe limb paralysis and a high mortality rate in 12-day-old transgenic mice challenged with CVA10 but not in wild-type mice of the same age. Massive amounts of CVA10 accumulated in the muscles, spinal cords, and brains of the transgenic mice. Formalin inactivated CVA10 vaccine-induced protective immunity against lethal CVA10 challenge and reduced the severity of disease and tissue viral loads. This is the first report to show that hSCARB2 serves as an associate to aid CVA10 infection. hSCARB2-transgenic mice could be useful in evaluating anti-CVA10 medications and studying the pathogenesis induced by CVA10.

Recovery of Patients With Upper Limb Paralysis Due to Stroke Who Underwent Intervention Using Low-Frequency Repetitive Transcranial Magnetic Stimulation Combined With Occupational Therapy: A Retrospective Cohort Study

ObjectivesThe combination of repetitive transcranial magnetic stimulation (rTMS) and motor practice is based on the theory of neuromodulation and use-dependent plasticity. Predictive planning of occupational therapy (OT) is important for patients with rTMS conditioning. Recovery characteristics based on the severity of pretreatment upper extremity paralysis can guide the patient’s practice plan for using the paretic hand. Therefore, we evaluated the recovery of patients with upper limb paralysis due to stroke who underwent a novel intervention of rTMS combined with OT (NEURO) according to the severity of upper limb paralysis based on the scores of the Fugl–Meyer assessment for upper extremity (FMA-UE) with recovery in proximal upper extremity, wrist, hand, and coordination. Materials and MethodsIn this multicenter retrospective cohort study, the recovery of 1397 patients with upper limb paralysis was analyzed by severity at six hospitals that were accredited by the Japanese Stimulation Therapy Society for treatment. The delta values of the FMA-UE scores before and after NEURO were compared among the groups with severe, moderate, and mild paralysis using the generalized linear model. ResultsNEURO significantly improved the FMA-UE total score according to the severity of paralysis (severe = 5.3, moderate = 6.0, and mild = 2.9). However, when the FMA-UE subscores were analyzed separately, the results indicated specific improvements in shoulder/elbow, wrist, fingers, and coordination movements, depending on the severity. ConclusionsThis study had enough patients who were divided according to severity and stratified by lesion location and handedness parameters. Our results suggest that independently of these factors, the extent of recovery of upper limb motor parts after NEURO varies according to the severity of paralysis.

Abstract Number ‐ 13: Endovascular BCI to Restore Motor Control for the Command of Digital Devices in Severe Quadriparesis

Introduction Brain‐computer interfaces (BCIs), functioning as motor neuroprostheses, have the potential to restore the transmission of neural signal from the cerebral cortex to control digital devices and improve functional independence in patients with severe paralysis due to brain, spinal cord, peripheral nerve or muscle dysfunction. Methods COMMAND is an FDA‐approved, NIH‐funded single arm, open‐label, prospective early feasibility study designed to enroll 6 patients with severe quadriparesis to receive an endovascular implantable motor neuroprosthesis (Stentrode, Synchron Inc, Brooklyn, NY). The primary outcome measures include treatment related serious adverse events within 12‐month after device implantation. Secondary outcome measures include restoration of neural signal from the cerebral cortex utilized for neuromuscular control of digital devices, resulting in the successful execution of non‐mechanical digital commands, e.g., for the control of personal computers. The study device comprises of three parts: 1) Endovascular electrode array and lead (StentrodeTM), implanted percutaneously via the jugular vein in the superior sagittal sinus adjacent to the motor cortex using endovascular approach; 2) Implantable Receiver Transmitter Unit (IRTU) implanted in the pectoral region; and 3) Controller, including an External Receiver Transmitter Unit (ERTU), Signal Control Unit (SCU) and Software Application. Results A 67 year‐old patient with complete quadriplegia from amyotrophic lateral sclerosis (ALS) enrolled into the study and completed a screening process, which included CTV and MRV to ascertain normal venous sinus anatomy, with two patent jugular veins and bilateral patent transverse sinuses. Using a right internal jugular vein access, the investigational endovascular Stentrode BCI was implanted in the superior sagittal sinus adjacent to primary motor cortex. Co‐registration to enable accurate anatomical targeting was achieved by fusing structural MRI data with intra‐procedurally acquired 3D‐volume (3D‐DSA). A sub‐clavicular subcutaneous pocket was created to place the IRTU. Then, the lead was tunneled to the pocket and connected to the IRTU. Before closure of the wound, impedance measurement was taken which confirmed functionality of the system. The patient tolerated the procedure very well, was successfully extubated after the procedure and remained neurologically at his baseline. The patient was started on dual antiplatelet therapy 2 weeks prior to the surgery and will be continued on this regimen for 3 months.The participant will undergo machine‐learning‐assisted training to use wirelessly transmitted electrocorticography signals associated with attempted movements to control multiple mouse‐click actions, including zoom and left‐click. Used in combination with an eye‐tracker for cursor navigation, the patient will practice controlling a computer to conduct instrumental activities of daily living (IADL) tasks. Conclusions We describe the first US in‐human experience of a minimally invasive, fully implanted, wireless motor neuroprosthesis using an endovascular stent‐electrode array to transmit electrocorticography signals from the motor cortex for multiple command control of digital devices.

Does the Pathologic Fracture Predict Severe Paralysis in Patients with Metastatic Epidural Spinal Cord Compression (MESCC)?-A Retrospective, Single-Center Cohort Analysis.

Currently, there is uncertainty about the predictive factors for metastatic epidural spinal cord compression (MESCC) and consecutive symptomatology in tumor patients. Prognostic algorithms for identifying patients at risk for paralysis are missing. The influence of the pathologic fracture on the patient's symptoms is widely discussed in the literature and we hypothesize that pathologic fractures contribute to spinal cord compression and are therefore predictive of severe paralysis. We tested this hypothesis in 136 patients who underwent surgery for spinal metastases. The most common primary cancers were prostate (24.3%, n = 33), breast (11.0%, n = 15), lung (10.3%, n = 14), and cancer of unknown primary (10.3%, n = 14). MESCC primarily affected the thoracic (77.2%, n = 105), followed by the lumbar (13.2%, n = 18) and cervical (9.6%, n = 13) spine. Pathologic fractures occurred in 63.2% (n = 86) of patients, mainly in osteolytic metastases. On the American spinal injury association (ASIA) impairment scale (AIS), 63.2% (n = 86) of patients exhibited AIS grade D and 36.8% (n = 50) AIS grade C-A preoperatively. The presence of a pathologic fracture alone did not predict severe paralysis (AIS C-A, p = 0.583). However, the duration of sensorimotor impairments, patient age, spinal instability neoplastic score (SINS), and the epidural spinal cord compression (ESCC) grade together predicted severe paralysis (p = 0.006) as did the ESCC grade 3 alone (p = 0.028). This is in contrast to previous studies that stated no correlation between the degree of spinal cord compression and the severity of neurologic impairments. Furthermore, the high percentage of pathologic fractures found in this study is above previously reported incidences. The risk factors identified can help to predict the development of paralysis and assist in the improvement of follow-up algorithms and the timing of therapeutic interventions.

Mouse Model of Spinal Cord Hypoperfusion with Immediate Paralysis Caused by Endovascular Repair of Thoracic Aortic Aneurysm.

A clinically relevant mouse model of thoracic endovascular aortic repair-induced ischemic spinal cord injury has been lacking since the procedure was first employed in 1991. The hypothesis was that ligation of mouse intercostal arteries would simulate thoracic endovascular aortic repair-induced ischemic spinal cord injury and behavioral deficit. The aim was to create a mouse model of thoracic endovascular aortic repair-induced spinal cord hypoperfusion by ligating five pairs of mouse intercostal vessels. Mice were divided into sham (n = 53) and ligation (n = 60) groups. The procedures called for double ligation of three pairs and single ligation of two pairs of thoracic intercostal arteries in adult C57BL/6 mice. A laser Doppler probe was used in vivo on the spinal cords and intercostal arteries to document the extent of arterial ligation and spinal cord hypoperfusion. The Basso Mouse Scale for Locomotion, histological studies, and electron microscopy demonstrated postligation locomotive and histopathological changes. Ligation induced a significant and instantaneous drop in blood flow in the intercostal arteries (% change; mean = -63.81; 95% CI, -72.28 to -55.34) and the thoracic spinal cord (% change; mean = -68.55; 95% CI, -80.23 to -56.87). Paralysis onset was immediate and of varying degree, with behavioral deficit stratified into three groups: 9.4% exhibited severe paralysis, 37.5% moderate paralysis, and 53.1% mild paralysis at day 1 (n = 32; P < 0.001). Mild and moderate paralysis was transient, gradually improving over time. Severe paralysis showed no improvement and exhibited a higher mortality rate (83%; n = 15 of 18) compared to moderately (33%; n = 6 of 18) and mildly (24%; n = 6 of 25) paralyzed mice (P < 0.001). The overall ligation group survival rate (84%; n = 46 of 55) was significantly lower than the sham group (100%; n = 48 of 48) with P = 0.003. The mouse model generates reproducible spinal cord hypoperfusion and accompanying histopathological ischemic spinal cord damage. The resulting anatomical changes and variable behavioral deficits mimic the variability in radiological and clinical findings in human patients.

Predicting a Favorable (mRS 0–2) or Unfavorable (mRS 3–6) Stroke Outcome by Arterial Spin Labeling and Amide Proton Transfer Imaging in Post-Thrombolysis Stroke Patients

(1) Background: The objective of this study was to determine whether arterial spin labeling (ASL), amide proton transfer (APT), or their combination could distinguish between patients with a low and high modified Rankin Scale (mRS) and forecast the effectiveness of the therapy; (2) Methods: Fifty-eight patients with subacute phase ischemic stroke were included in this study. Based on cerebral blood flow (CBF) and asymmetry magnetic transfer ratio (MTRasym) images, histogram analysis was performed on the ischemic area to acquire imaging biomarkers, and the contralateral area was used as a control. Imaging biomarkers were compared between the low (mRS 0-2) and high (mRS 3-6) mRS score groups using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the potential biomarkers in differentiating between the two groups; (3) Results: The rAPT 50th had an area under the ROC curve (AUC) of 0.728, with a sensitivity of 91.67% and a specificity of 61.76% for differentiating between patients with low and high mRS scores. Moreover, the AUC, sensitivity, and specificity of the rASL max were 0.926, 100%, and 82.4%, respectively. Combining the parameters with logistic regression could further improve the performance in predicting prognosis, leading to an AUC of 0.968, a sensitivity of 100%, and a specificity of 91.2%; (4) Conclusions: The combination of APT and ASL may be a potential imaging biomarker to reflect the effectiveness of thrombolytic therapy for stroke patients, assisting in guiding treatment approaches and identifying high-risk patients such as those with severe disability, paralysis, and cognitive impairment.

Assessment of Safety of a Fully Implanted Endovascular Brain-Computer Interface for Severe Paralysis in 4 Patients

Brain-computer interface (BCI) implants have previously required craniotomy to deliver penetrating or surface electrodes to the brain. Whether a minimally invasive endovascular technique to deliver recording electrodes through the jugular vein to superior sagittal sinus is safe and feasible is unknown. To assess the safety of an endovascular BCI and feasibility of using the system to control a computer by thought. The Stentrode With Thought-Controlled Digital Switch (SWITCH) study, a single-center, prospective, first in-human study, evaluated 5 patients with severe bilateral upper-limb paralysis, with a follow-up of 12 months. From a referred sample, 4 patients with amyotrophic lateral sclerosis and 1 with primary lateral sclerosis met inclusion criteria and were enrolled in the study. Surgical procedures and follow-up visits were performed at the Royal Melbourne Hospital, Parkville, Australia. Training sessions were performed at patients' homes and at a university clinic. The study start date was May 27, 2019, and final follow-up was completed January 9, 2022. Recording devices were delivered via catheter and connected to subcutaneous electronic units. Devices communicated wirelessly to an external device for personal computer control. The primary safety end point was device-related serious adverse events resulting in death or permanent increased disability. Secondary end points were blood vessel occlusion and device migration. Exploratory end points were signal fidelity and stability over 12 months, number of distinct commands created by neuronal activity, and use of system for digital device control. Of 4 patients included in analyses, all were male, and the mean (SD) age was 61 (17) years. Patients with preserved motor cortex activity and suitable venous anatomy were implanted. Each completed 12-month follow-up with no serious adverse events and no vessel occlusion or device migration. Mean (SD) signal bandwidth was 233 (16) Hz and was stable throughout study in all 4 patients (SD range across all sessions, 7-32 Hz). At least 5 attempted movement types were decoded offline, and each patient successfully controlled a computer with the BCI. Endovascular access to the sensorimotor cortex is an alternative to placing BCI electrodes in or on the dura by open-brain surgery. These final safety and feasibility data from the first in-human SWITCH study indicate that it is possible to record neural signals from a blood vessel. The favorable safety profile could promote wider and more rapid translation of BCI to people with paralysis. ClinicalTrials.gov Identifier: NCT03834857.

An Adaptive Brain-Computer Interface to Enhance Motor Recovery After Stroke.

Brain computer interfaces (BCIs) have been demonstrated to have the potential to enhance motor recovery after stroke. However, some stroke patients with severe paralysis have difficulty achieving the BCI performance required for participating in BCI-based rehabilitative interventions, limiting their clinical benefits. To address this issue, we presented a BCI intervention approach that can adapt to patients' BCI performance and reported that adaptive BCI-based functional electrical stimulation (FES) treatment induced clinically significant, long-term improvements in upper extremity motor function after stroke more effectively than FES treatment without BCI intervention. These improvements were accompanied by a more optimized brain functional reorganization. Further comparative analysis revealed that stroke patients with low BCI performance (LBP) had no significant difference from patients with high BCI performance in rehabilitation efficacy improvement. Our findings suggested that the current intervention may be an effective way for LBP patients to engage in BCI-based rehabilitation treatment and may promote lasting motor recovery, thus contributing to expanding the applicability of BCI-based rehabilitation treatments to pave the way for more effective rehabilitation treatments.

A survey on encoding and decoding technology of non-invasive brain-computer interface

A survey on encoding and decoding technology of non-invasive brain-computer interface

Kummell's Disease is Becoming Increasingly Important in an Aging Society: A Review.

Kummell's disease (KD) is referred to as delayed posttraumatic vertebral collapse, avascular necrosis of vertebrae, or ischemic vertebral collapse. KD is no longer rare in an aging society. It is mainly caused by minor trauma, and nonunion occurs secondary to avascular necrosis at the vertebral body fracture site, which can lead to vertebral kyphosis or intravertebral instability. Clinical symptoms of KD range from no symptoms to severe paralysis due to nerve injury. KD is considered a complication of osteoporotic vertebral compression fractures, and conservative treatment, including osteoporosis treatment, is important. Timely interventions such as vertebral augmentation or surgery, with active regular follow-up are necessary before the onset of neurological deficits due to osteonecrotic collapse in patients with suspected KD. In this study, we summarize the pathogenesis, diagnosis, and treatment of KD, which is showing increasing prevalence in an aging society. We have presented a literature review and discussed clinical guidelines and therapeutic strategies to reduce the morbidity and mortality associated with KD.

Clinical Outcome of Hypoglossal-Facial Nerve Anastomosis in Severe Facial Nerve Paralysis: An Experience from Khyber Pakhtunkhwa

Objectives: Facial nerve injury is one of the most devastating complications occurring as a result of any chemical, mechanical or ischemic insult. This study aimed to determine the surgical outcomes of limited experience in lower motor neuron facial palsy in the last decade.&#x0D; Materials and Methods: A Prospective case series was done at Neurosurgery Department, Prime Teaching Hospital, MTI Lady Reading Hospital, and Irfan General Hospital Peshawar Khyber Pakhtunkhwa Pakistan. Patients were diagnosed after thorough clinical examination and radiological findings; conduction studies these as severe facial paralysis (House and Brackmann 4 – 6). Surgical treatment is done with end-to-end hypoglossal-facial nerve anastomosis. Outcomes and complications were documented. Entered data into specifically designed proforma.&#x0D; Results: Out of 13 patients, who underwent a surgical procedure, 8 were male (61.5%) and 5 patients were female (38.5%). The mean age of presentation was 46 years. Patients were labeled on House and Brackmann scale. Improvement was defined as ? 1 grade improvement on the H&amp;B scale, after 1 year of follow-up, 11 patients improved (84.6%) while 2 (15.4%) remained static. The complication was observed as hemiatrophy of the tongue without physiological weakness.&#x0D; Conclusion: Hypoglossal-Facial nerve anastomosis is recommended treatment for severe facial paralysis, during the first year of insult.&#x0D; Keywords: Facial Nerve Paralysis, Hypoglossal-facial nerve, House &amp; Brackmann.

Efficacy of High-Dose Corticosteroid Therapy in Acute Stage Severe Facial Palsy in Children.

To evaluate the efficacy of high-dose corticosteroid for severe acute facial paralysis in children. The present study enrolled 10 pediatric patients with House-Brackmann (H-B) Grade VI facial paralysis who received prednisolone (PSL) 3 to 4 mg/kg/d for 2 to 3 days followed by a 10-day taper (the child high-dose group). Eight pediatric patients who received PSL 0.5 to 1 mg/kg/d were enrolled in a child low-dose group, and nine adult patients (25-64 yr) who received a high-dose PSL 200 mg equivalent for 2 to 3 days followed by a 10-day taper were enrolled in an adult high-dose group. On the initial and follow-up visits, facial movements were evaluated using the H-B grading system. The degree of oral-ocular synkinesis was evaluated by the degree of asymmetry in eye-opening width during mouth movements. The synkinesis index was defined as a percentage of the interpalpebral space width ([normal side - affected side]/normal side). The child high-dose group achieved a significantly better H-B score than the child low-dose group ( p < 0.01). The synkinesis index was significantly lower in the child high-dose group than in the child low-dose group or the adult high-dose group ( p < 0.05). Children receiving PSL 3 to 4 mg/kg/d achieved better recovery and less synkinesis than those treated with low-dose PSL (0.5-1 mg/kg/d).

ODP614 Two cases of Graves Disease Associated Hypokalemic Periodic Paralysis

Abstract Introduction Periodic paralysis (PP) is a rare neuromuscular disorder due to a defect in ion channels in muscle, characterized by episodes of painless muscle weakness or paralysis, which may be precipitated by heavy exercise or high-carbohydrate meals. Hypokalemic PP (HPP) is most common of the periodic paralyses, however is still very rare, with an estimated prevalence of 1 in 100,000. An acquired form of hypokalemic PP can be seen in thyrotoxicosis of any cause. We present 2 cases of HPP due to thyrotoxicosis. Case 1 27 year old Asian male presented to the ED due to sudden onset of acute weakness/near paralysis in lower extremities, with weakness of bilateral upper extremities. He was found to be hypokalemic with a potassium of 2.0 mmol/L (3.5-5.1). At the same time, he was also found to be hyperthyroid with a suppressed TSH of 0.03 uIU/Ml (0.35-5.5) and a free T4 2.2 ng/mL (0.5-1.3), Total T3 225 ng/Dl (70-204), Free T3 5.9 pg/mL (1.5-4.1). TSI antibodies elevated at 1.39 IU/L (&amp;lt;0.10). He was started on potassium supplements and methimazole. At a 3-month follow-up, patient reported no further episodes of weakness or paralysis. Case 2 23 year old White male presented to ED with severe muscle weakness and was found to have hypokalemia of 2 mmol/L (3.5-5.1). On further labs, TSH was undetectable at less than 0.01 uIU/mL (0.35-4.94), Free T4 2.81 ng/dL (0.61-1.82), Total T3 of 451 ng/dL(48-178), TSI antibodies were positive at 178%(&amp;lt;/=122%). Nuclear uptake scan confirmed Graves’ disease with radioactive iodine uptake of 58.1% at 4 hours and 70% at 24 hours with homogenous uptake in the entire gland and no evidence of hot or cold nodules. He was started on methimazole and propranolol for tachycardia and palpitations and potassium supplements. Muscle weakness resolved on treatment methimazole. Discussion and conclusion We present two cases of HPP likely caused by Graves’ disease. Both patients presented with hypokalemia and further workup revealed underlying thyrotoxicosis. The exact mechanism behind HPP due to thyrotoxicosis is not well understood. It is proposed that excess thyroid hormone may predispose to paralytic episodes by increasing the susceptibility to the hypokalemic action of epinephrine or insulin. This condition has been most widely reported in Asian populations, in which the incidence is approximately 2% in contrast to non-asian population with incidence of 0.1 to 0.2%, and is more common in men. Treatment of thyrotoxicosis with restoration and maintenance of euthyroid state ceases attacks. To summarize, few case series report the association of HPP with Graves’ disease. These patients usually present acutely with severe muscle weakness or paralysis. In conclusion, in diagnosis of HPP, possibility of thyrotoxicosis should be considered, especially in the absence of family history of PP. Presentation: No date and time listed

Influence of Zika virus 3′-end sequence and nonstructural protein evolution on the viral replication competence and virulence

ABSTRACT Zika virus (ZIKV) has been circulating in human networks over 70 years since its first appearance in Africa, yet little is known about whether the viral 3′-terminal sequence and nonstructural (NS) protein diverged genetically from ancient ZIKV have different effects on viral replication and virulence in currently prevailing Asian lineage ZIKV. Here we show, by a reverse genetics approach using an infectious cDNA clone for a consensus sequence (Con1) of ZIKV, which represents Asian ZIKV strains, and another clone derived from the MR766 strain isolated in Uganda, Africa in 1947, that the 3′-end sequence –UUUCU-3′ homogeneously present in MR766 genome and the –GUCU-3′ sequence strictly conserved in Asian ZIKV isolates are functionally equivalent in viral replication and gene expression. By gene swapping experiments using the two infectious cDNA clones, we show that the NS1–5 proteins of MR766 enhance replication competence of ZIKV Con1. The Con1, which was less virulent than MR766, acquired severe bilateral hindlimb paralysis when its NS1–5 genes were replaced by the counterparts of MR766 in type I interferon receptor (IFNAR1)-deficient A129 mice. Moreover, MR766 NS5 RNA-dependent RNA polymerase (RdRp) alone also rendered the Con1 virulent, despite there being no difference in RdRp activity between MR766 and Con1 NS5 proteins. By contrast, the Con1 derivatives expressing MR766 Nsps, like Con1, did not develop severe disease in wild-type mice treated with an IFNAR1 blocking antibody. Together, our findings uncover an unprecedented role for ZIKV NS proteins in determining viral pathogenicity in immunocompromised hosts.

Three-Dimensional Printed Mesh-Cage Replacement for a Metastatic Spinal Tumor and a Vertebral Compression Fracture: A Report of Two Cases

Harms mesh cages are commonly used in the treatment of metastatic spinal tumors by spondylectomy with cage insertion and posterior screw fixation. These cages are even useful for the surgical reconstruction of spinal deformities with mesh-cage replacement after vertebral column resection (VCR). Mesh cages can be customized by 3-dimensional (3D) printing based on the angle between the endplates for the requisite weight-bearing capacity and fit. This study reports two cases wherein a 75-year-old man and a 63-year-old woman were treated with reconstructive spondylectomy and mesh-cage replacement, followed by posterior screw fixation. The 75-year-old man was initially diagnosed with an L4 metastatic non–small cell lung carcinoma accompanied by a pathologic fracture and severe paralysis. The 63-year-old woman had slipped 13 years before and sustained a T11-L1 compression fracture that was aggravated 6 months before this admission, with back pain and numbness in both soles. Herein, we describe the treatment approach with instrumentation using a customized 3D-printed mesh cage after total spondylectomy for the metastatic spinal tumor and after VCR for deformity repair surgery in the respective cases. Our application of a 3D-printed mesh cage in surgery for a metastatic tumor is the first report of such treatment in Korea. Although the use of customized 3D-printed cages for a metastatic spinal tumor and a severe compression fracture was effective, challenges remain regarding fitting, manufacturing time, and costs.

FP.38 Linker protein-mediated gene therapy ameliorates muscle and nerve pathology in mouse models for LAMA2-related congenital muscular dystrophy

<i>LAMA2</i>-related muscular dystrophy (LAMA2 MD or MDC1A) is the most frequent form of congenital muscular dystrophies. It is caused by mutations in <i>LAMA2</i>, the gene encoding laminin-α2, one chain of the heterotrimeric extracellular matrix protein laminin-211 (α2β1γ1). The large size of the cDNA encoding laminin-α2 and the heterotrimeric structure of laminin-211 present a challenge for gene replacement or gene editing strategies. Here, we describe the development of an AAV-based gene therapy to functionally replace laminin-211 by two small linker proteins. The two linker proteins, mini-agrin (mag) and αLNNd, are assembled from selected domains of agrin, nidogen-1 and laminin-α1. Previous work from our lab in transgenic mice has demonstrated that this Simultaneous Expression of Artificial Linkers (SEAL) in skeletal muscle of LAMA2 MD mice has a tremendous ameliorative effect on muscle pathology and survival. However, muscle-specific treatment makes the peripheral neuropathy phenotype in aged LAMA2 MD mice very apparent, as they develop a severe hindlimb paralysis. Here, we show in novel transgenic models that ubiquitous expression of linker proteins additionally overcomes this LAMA2-related peripheral neuropathy. We also show that the linker proteins are efficiently expressed upon systemic delivery by AAV9. Expression by a muscle-specific promoter significantly ameliorates the muscle disease phenotype in LAMA2 MD mice, as shown on the level of body- and muscle mass, fiber size, inflammation and muscle function (grip strength and locomotion). These experiments show that AAV-mediated expression of the two linker proteins is possible and they suggest that this functional replacement strategy by the design of small proteins assembled from protein domains present in patients may overcome some of the current challenges of gene therapy trials. Additionally, the linker proteins are secreted and are deposited in the extracellular matrix, which allows their accumulation upon expression by AAV. In summary, this study serves as a proof-of-concept in mice and establishes systemic delivery of AAVs that express the two linkers (SEAL technology) as a promising gene therapy for treating LAMA2 MD. Our current efforts focus on the use of next-generation AAVs with increased tropisms to skeletal muscle but low infection of liver (AAVMYO) and the use of ubiquitous promoters to evaluate the possibility of ameliorating the peripheral neuropathy.

Changes in corticospinal and spinal reflex excitability through functional electrical stimulation with and without observation and imagination of walking.

Functional electrical stimulation (FES), a method for inducing muscle contraction, has been successfully used in gait rehabilitation for patients with deficits after neurological disorders and several clinical studies have found that it can improve gait function after stroke and spinal cord injury. However, FES gait training is not suitable for patients with walking difficulty, such as those with severe motor paralysis of the lower limbs. We have previously shown that action observation combined with motor imagery (AO + MI) of walking induces walking-related cortical activity. Therefore, we combined FES, which alternately generates dorsiflexion and plantar flexion, with AO + MI as an alternative to gait training. The present study investigates the transient effects of 20-min of FES simultaneously with and without AO + MI of walking on corticospinal and spinal reflex excitability in able-bodied participants. We measured motor evoked potentials and Hoffmann-reflexes to assess corticospinal and spinal reflex excitability at rest before and after the 20-min FES with and without the AO + MI. Our results show that FES without AO + MI did not change excitability (p > 0.05), while FES with AO + MI facilitated corticospinal excitability (p < 0.05). This facilitation likely occurred due to the synchronization of sensory inputs from FES and cortical activity during AO + MI. Facilitation was observed only in the dorsiflexor but not the plantar flexor muscle (p < 0.05), suggesting muscle specificity of the facilitation. These results demonstrate the effectiveness of combining FES with AO + MI and pave the way for novel neurorehabilitation strategies for patients with neurological gait deficits.

A Rare Disorder: Hypokalemia Induced Paralysis

Hypokalemic (Induced) Periodic Paralysis is a rare group of disorders that can cause sudden onset of flaccid paralysis. Here we present a case of 41 year old female who presented to the ED complaining of severe flaccid paralysis in both lower &amp; upper limbs since morning. Initially, she was treated as a stroke alert patient and had head scans which showed no acute pathologic changes. Laboratory evaluation revealed a markedly low potassium level. The patient's paralysis resolved after potassium correction and she was discharged with no neurologic deficits. Although rare, Periodic Paralysis must be differentiated from other causes of weakness and paralysis so that the proper treatment can be initiated quickly.