- Pharmacoeconomic Review Report (Resubmission): NUSINERSEN (SPINRAZA): (Biogen Canada Inc.): Indication: Treatment of patients with 5q spinal muscular atrophy [BOOK]
- BOOKCanadian Agency for Drugs and Technologies in Health: Ottawa (ON)
- Spinal muscular atrophy (SMA) is a severe neuromuscular disease and is the leading genetic cause of infant death. It is characterized by the degeneration of alpha motor neurons in the anterior horn o…
Spinal muscular atrophy (SMA) is a severe neuromuscular disease and is the leading genetic cause of infant death. It is characterized by the degeneration of alpha motor neurons in the anterior horn of the spinal cord, leading to progressive muscle weakness. The most common form of SMA, 5q SMA, makes up more than 95% of all cases and is an autosomal recessive disorder caused by homozygous deletion or deletion and mutation of the alleles of the survival motor neuron 1 gene. SMA is a rare disease and estimates of its incidence and prevalence vary between studies. The incidence of SMA is often cited as being approximately 10 in 100,000 live births. Four clinical subtypes of SMA are described: SMA type I makes up about 60% of SMA diagnoses where patients show symptoms before six months of age, never achieve the motor milestone of sitting unsupported, and generally do not survive past two years of age due to respiratory failure. Those with SMA type II achieve the milestone of sitting unsupported, but never walk independently; symptoms generally appear between six and 18 months after birth and most patients will survive past the age of 25, with life expectancy improved by aggressive supportive care. SMA type III makes up approximately 10% to 20% of SMA cases3 and presents between 18 months of age and adulthood. These patients are able to walk independently at some point in their lives and typically have a normal life expectancy. SMA type IV constitutes a very small proportion of SMA cases, has an adult onset, and is the mildest form of the disease. Although muscle weakness is present, these patients retain the ability to walk, have a normal life expectancy, and do not suffer from respiratory or nutritional issues. Nusinersen (Spinraza) is a solution for intrathecal injection, indicated for the treatment of 5q SMA. It is available as a single-use solution in a 5 mL vial size (12 mg) administered intrathecal by lumbar puncture. The recommended dose is initial treatment with four loading doses, with the first three loading doses administered at 14-day intervals (day 0, day 14, and day 28), and a final loading dose approximately 30 days after the third loading dose (day 63); maintenance treatment is 12 mg every four months. At the marketed price of $118,000 per 5 mL vial, the annual cost of treatment with nusinersen ranges from $354,000 for maintenance treatment (three doses) to $708,000 in the first year (six doses). The manufacturer’s listing request is per the Health Canada indication. As part of a resubmission the manufacturer provided new clinical information relating to different subpopulations with SMA (see CADTH Common Drug Review [CDR] Clinical Report). The manufacturer, however, did not provide a revised economic submission nor did it provide any discussion relating to the new clinical information and how this may impact the findings of the economic review based on the original submission. Thus, the CDR economic review remains unchanged with no further data provided to refute the original issues or limitations identified.
- Restless legs syndrome: Clinical changes in nervous system excitability at the spinal cord level. [Review]
- SMSleep Med Rev 2019 May 31; 47:9-17
- Restless legs syndrome (RLS) is a complex multifactorial disorder whose aetiology has yet to be fully elucidated. Some of the features of RLS, such as processing of sensations and activation of movem…
Restless legs syndrome (RLS) is a complex multifactorial disorder whose aetiology has yet to be fully elucidated. Some of the features of RLS, such as processing of sensations and activation of movement, may result from a dysfunction in spinal processing giving rise to a state of spinal hyperexcitability. In the current article we review studies investigating spinal excitability in RLS patients looking specifically at electrophysiological studies of spinal activity, sensory evaluations, and spinal reflex studies. Increased spinal excitability has been shown in RLS patients based on the combined data from electrophysiological studies. Results from studies assessing sensory evaluations in RLS patients show enhanced spinal processing of nociceptive inputs possibly due to central sensitisation. However, not all sensory modalities demonstrate an increase in sensitivity. An increase in nervous system excitability would result in an increase in reflex responses in RLS patients however the data from reflex analyses in RLS patients has failed to consistently show this expected result. Overall changes to RLS spinal excitability have been demonstrated though these changes might be heterogeneous as not all afferent input appears to be affected in the same manner. There may be phase-dependent and modality-dependent alterations in spinal excitability suggesting that the theory of absolute spinal hyperexcitability in RLS patients' needs to be reconsidered.
- Thoracoabdominal Aortic Aneurysm Repair: From an Era of Revolution to an Era of Evolution. [Review]
- STSemin Thorac Cardiovasc Surg 2019 Jun 15
- Thoracoabdominal aortic aneurysm (TAAA) repair has a rich and storied tradition that began in Houston, Texas with great pioneer surgeons such as Drs. Michael E. DeBakey, Denton A. Cooley, and E. Stan…
Thoracoabdominal aortic aneurysm (TAAA) repair has a rich and storied tradition that began in Houston, Texas with great pioneer surgeons such as Drs. Michael E. DeBakey, Denton A. Cooley, and E. Stanley Crawford. Their early attempts to repair TAAA were complicated by the persistent threats of renal and spinal cord ischemia and difficulty in reattaching the branching vessels of the thoracoabdominal aorta. Today, under the tutelage of Dr. Joseph S. Coselli, the Texas Medical Center remains at the forefront of TAAA repair. In this place where great surgeons once walked the halls, their legacy continues.
- Use of in vitro electroporation and slice culture for gene function analysis in the mouse embryonic spinal cord. [Journal Article]
- MDMech Dev 2019 Jun 15; :103558
- The spinal cord is an important part of the central nervous system (CNS). At present, the expression of the exogenous gene in the spinal cord of the embryonic mouse needs in utero spinal cord electro…
The spinal cord is an important part of the central nervous system (CNS). At present, the expression of the exogenous gene in the spinal cord of the embryonic mouse needs in utero spinal cord electroporation, but the success rate of this technique is very low. In this study, we have demonstrated the expression of an exogenous gene on one side of the spinal cord by combining two methods-in vitro electroporation of embryonic mouse spinal cord and organ spinal cord slices culture. We took 12-day embryonic mice, injected the green fluorescent protein (pCAGGS-GFP) plasmid into the spinal cord cavity in vitro, and then electroporated. The spinal cord was cut into 300-μm slices using a vibratory microtome. After cultured for 48 h, GFP-positive neurons were clearly observed on one side of the spinal cord, indicating that the exogenous gene was successfully transferred. The axon projection direction is basically unanimous from the inside to the lateral edge of the spinal cord. Compared to neurons in vivo, a single neuron in the culturing section has more complete neurites and is conducive to studying changes in the structure and behavior of individual neurons. Based on the above results, we have successfully established a convenient and efficient method for expressing the exogenous gene in the spinal cord of the mouse.
- Basal Protrusions Mediate Spatiotemporal Patterns of Spinal Neuron Differentiation. [Journal Article]
- DCDev Cell 2019 Jun 17; 49(6):907-919.e10
- During early spinal cord development, neurons of particular subtypes differentiate with a sparse periodic pattern while later neurons differentiate in the intervening space to eventually produce cont…
During early spinal cord development, neurons of particular subtypes differentiate with a sparse periodic pattern while later neurons differentiate in the intervening space to eventually produce continuous columns of similar neurons. The mechanisms that regulate this spatiotemporal pattern are unknown. In vivo imaging in zebrafish reveals that differentiating spinal neurons transiently extend two long protrusions along the basal surface of the spinal cord before axon initiation. These protrusions express Delta protein, consistent with the hypothesis they influence Notch signaling at a distance of several cell diameters. Experimental reduction of Laminin expression leads to smaller protrusions and shorter distances between differentiating neurons. The experimental data and a theoretical model support the proposal that neuronal differentiation pattern is regulated by transient basal protrusions that deliver temporally controlled lateral inhibition mediated at a distance. This work uncovers a stereotyped protrusive activity of newborn neurons that organize long-distance spatiotemporal patterning of differentiation.
- Novel approach to an early assessment of a patient's potential for neurological remission after acute spinal cord injury: Analysis of hemoglobin concentration dynamics. [Journal Article]
- JSJ Spinal Cord Med 2019 Jun 18; :1-12
- CONCLUSIONS: Elevated Hb concentrations are associated with a higher likelihood of neurological remission. Elevated concentrations of Hb in G1 compared to G0 over time might be linked to both a better initial oxygen supply response and a decreased ECM (extracellular matrix) degradation highlighting the role of Hb as a valuable biomarker for neural regeneration after TSCI.
- Natural history of spinal cord arteriovenous shunts: an observational study. [Journal Article]
- BBrain 2019 Jun 18
- The natural history of intradural spinal cord arteriovenous shunts is unknown. We performed an observational study in a consecutive patient cohort with symptomatic intradural spinal cord arteriovenou…
The natural history of intradural spinal cord arteriovenous shunts is unknown. We performed an observational study in a consecutive patient cohort with symptomatic intradural spinal cord arteriovenous shunts who were admitted to three institutes to investigate the clinical course of this complex disease, which would provide valuable evidence to inform clinical decision-making. The clinical course of patients with symptomatic intradural spinal cord arteriovenous shunts from initial presentation to occurrence of clinical deterioration, initiation of treatment, or last follow-up was analysed. Patients with at least 1 month of observation were included in this study. Clinical onset and deterioration patterns were divided into acute and gradual. Annual and cumulative rates of clinical deterioration as well as their risk factors were analysed using Kaplan-Meier life table analysis and Cox proportional hazards model. To assess risks and benefits of treatment, post-treatment clinical courses were further assessed. Four hundred and sixty-six patients with a mean observational period of 36.9 ± 58.8 months were included; 56.7% of patients presented with acute onset, of whom 77.3% experienced spontaneous recovery. Age of onset older than 28 years, initial modified Aminoff and Logue scale of >3, mid-thoracic lesions and non-ventral lesions were independent predictors of failure for spontaneous recovery. The annual risk of general, acute and gradual clinical deterioration after onset was 30.7%, 9.9% and 17.7%, respectively. Risk of deterioration was highest in the early period after initial onset. Acute onset was the only independent risk factor [hazard ratio 1.957 (95% confidence interval, CI 1.324-2.894); P = 0.0008] of acute deterioration and gradual onset was the strongest predictor [hazard ratio 2.350 (95% CI 1.711-3.229); P < 0.0001] of the gradual deterioration among all the stratifying factors. After invasive treatment, complete obliteration was achieved in 37.9% of patients (138 of 364) and improved or stable clinical status was noted in 80.8% of patients. Forty-two patients (11.5%) experienced permanent complications. Overall post-treatment deterioration rate was 8.4%/year, and 5.3%/year if permanent complications were excluded. The natural history of symptomatic spinal cord arteriovenous shunts is poor, especially in the early period after onset, and early intervention is thus recommended. Initial onset pattern significantly affects the natural history of the lesion, which prompts a differentiated treatment strategy.
- Isolated metastatic dorsal spinal cord compression revealing prostatic adenocarcinoma. [Case Reports]
- UCUrol Case Rep 2019; 24:100863
- Prostate cancer is the second common etiology of cord compression after lung cancer. Its slow natural history justifies an aggressive treatment. The fact that the metastatic lesion precedes the prima…
Prostate cancer is the second common etiology of cord compression after lung cancer. Its slow natural history justifies an aggressive treatment. The fact that the metastatic lesion precedes the primary tumor remains rare. We report the case of a 86 year-old man who was admitted for heaviness of both lower limbs responsible for gait disorder. He had flaccid paraplegia. Spinal MRI showed an epidural lesion. Histology after surgery was compatible for a metastasis of prostatic adenocarcinoma. Spinal cord compression due to prostate cancer is correlated with poor prognosis. The fact that the metastatic lesion precedes the primary tumor remains rare.
- Resection of heterotopic ossification around the hip after trauma. [Review]
- EOEFORT Open Rev 2019; 4(6):263-268
- Traumatic neurological lesions may lead to development of heterotopic ossification. These cases are classified as 'neurogenic heterotopic ossifications' (NHOs). The associated neurological lesions ca…
Traumatic neurological lesions may lead to development of heterotopic ossification. These cases are classified as 'neurogenic heterotopic ossifications' (NHOs). The associated neurological lesions can be caused by cranial trauma or spinal cord injury and may sometimes include a local trauma.NHOs that form around the hip joints are of particular interest because they often cause the patient to avoid the sitting position or the resumption of walking.Whilst NHO can involve the knee, shoulder and elbow joints, hip-involving NHOs are more numerous, and sometimes develop in close contact with vascular or neurological structures.Multi-disciplinary clinical examination is fundamental to evaluate patients for surgical intervention and to define the objectives of the surgery. The best investigation to define an NHO mass is a computerized tomography (CT) scan.Resection is performed to liberate a fused joint to provide functionality, and this need not be exhaustive if it is not necessary to increase the range of motion.While recurrence does occur post-surgery, a partial resection does not pose a greater risk of recurrence and there are no adjuvant treatments available to reduce this risk.The greatest risks associated with NHO surgical resection are infection and haematoma; these risks are very high and must be considered when evaluating patients for surgery. Cite this article: EFORT Open Rev 2019;4 DOI: 10.1302/2058-5241.4.180098.
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- Longitudinally extensive myelitis as first presentation of renal cell carcinoma. [Journal Article]
- IJIran J Neurol 2018 Oct 07; 17(4):197-199