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1.  Intrathecal Baclofen Pump for Spasticity 
Executive Summary
Objective
To conduct an evidence-based analysis of the effectiveness and cost-effectiveness of intrathecal baclofen for spasticity.
The Technology
Spasticity is a motor disorder characterized by tight or stiff muscles that may interfere with voluntary muscle movements and is a problem for many patients with multiple sclerosis (MS), spinal cord injury (SCI), cerebral palsy (CP), and acquired brain injury (ABI).(1). Increased tone and spasm reduces mobility and independence, and interferes with activities of daily living, continence and sleep patterns. Spasticity may also be associated with significant pain or discomfort (e.g., due to poor fit in braces, footwear, or wheelchairs), skin breakdown, contractures, sleep disorders and difficulty in transfer.
Goals of treatment are to decrease spasticity in order to improve range of motion, facilitate movement, reduce energy expenditure and reduce risk of contractures. Existing treatments include physical therapy, oral medications, injections of phenol or botulinum toxin, or surgical intervention.
Baclofen is the oral drug most frequently prescribed for spasticity in cases of SCI and MS.(1) Baclofen is a muscle relaxant and antispasticity drug. In the brain, baclofen delivered orally has some supraspinal activity that may contribute to clinical side effects. The main adverse effects of oral baclofen include sedation, excessive weakness, dizziness, mental confusion, and somnolence.(2) The incidence of adverse effects is reported to range from 10% to 75%.(2) Ochs et al. estimated that approximately 25-30% of SCI and MS patients fail to respond to oral baclofen.(3;4)
Adverse effects appear to be dose-related and may be minimized by initiating treatment at a low dose and gradually titrating upwards.(2) Adverse effects usually appear at doses >60 mg/day.(2) The rate of treatment discontinuation due to intolerable adverse effects has generally been reported to range from 4% to 27%.(2)
When baclofen is administered orally, only a small portion of the original dose crosses the blood brain barrier and enters the central nervous system (CNS) fluid, which is the site of drug action. In order to bypass the oral route, baclofen may be administered intrathecally by infusion directly to the CNS.
Candidates for intrathecal baclofen infusion are patients with spasticity who have intractable spasticity uncontrolled by drug therapy, or who experience intolerable side effects from oral baclofen.
Advantages of intrathecal baclofen infusion are:
Direct drug administration to the cerebrospinal fluid (CSF)
The central side effects of oral baclofen, such as drowsiness or confusion, appear to be minimized with intrathecal administration.
The intrathecal delivery of baclofen concentrates the drug in the CSF at higher levels than those attainable via the oral route.
Intrathecal administration can use concentrations of baclofen of less than one hundredth of those used orally.(5)
Adjustable/programmable continuous infusion makes it possible to finely titrate patients’ doses and to vary the doses over the hours of the day. For example, the dose can be relatively low to give the patients the extensor tone needed for ambulation during the day and increased at night, thereby improving quality of sleep.
Reversible (in contrast to surgery).
A patient who is a candidate for intrathecal baclofen infusion must have no contraindications to the insertion of an intrathecal catheter (e.g., anticoagulant therapy, coagulopathy, local or systemic infection, anatomical abnormality of the spine).
Review Strategy
The Medical Advisory Secretariat reviewed the literature to assess the effectiveness, safety, and cost-effectiveness of intrathecal baclofen to treat patients who have intractable spasticity uncontrolled by drug therapy, or who experience intolerable side effects to oral baclofen.
The Medical Advisory Secretariat used its standard search strategy to retrieve international health technology assessments and English-language journal articles from selected databases.
Summary of Findings
Level 2 evidence supports the effectiveness of intrathecal baclofen infusion for the short-term reduction of severe spasticity in patients who are unresponsive or cannot tolerate oral baclofen
Level 3 evidence supports the effectiveness of intrathecal baclofen for the long-term reduction of severe spasticity in patients who are unresponsive or cannot tolerate oral baclofen
Level 4 qualitative evidence demonstrates functional improvement for patients who are unresponsive or cannot tolerate oral baclofen
Intrathecal baclofen is cost-effective with costs which may or may not be avoided in the Ontario health system
True functional use remains to be determined
PMCID: PMC3382401  PMID: 23074476
2.  Age at spinal cord injury determines muscle strength 
As individuals with spinal cord injury (SCI) age they report noticeable deficits in muscle strength, endurance and functional capacity when performing everyday tasks. These changes begin at ~45 years. Here we present a cross-sectional analysis of paralyzed thenar muscle and motor unit contractile properties in two datasets obtained from different subjects who sustained a cervical SCI at different ages (≤46 years) in relation to data from uninjured age-matched individuals. First, completely paralyzed thenar muscles were weaker when C6 SCI occurred at an older age. Muscles were also significantly weaker if the injury was closer to the thenar motor pools (C6 vs. C4). More muscles were strong (>50% uninjured) in those injured at a younger (≤25 years) vs. young age (>25 years), irrespective of SCI level. There was a reduction in motor unit numbers in all muscles tested. In each C6 SCI, only ~30 units survived vs. 144 units in uninjured subjects. Since intact axons only sprout 4–6 fold, the limits for muscle reinnervation have largely been met in these young individuals. Thus, any further reduction in motor unit numbers with time after these injuries will likely result in chronic denervation, and may explain the late-onset muscle weakness routinely described by people with SCI. In a second dataset, paralyzed thenar motor units were more fatigable than uninjured units. This gap widened with age and will reduce functional reserve. Force declines were not due to electromyographic decrements in either group so the site of failure was beyond excitation of the muscle membrane. Together, these results suggest that age at SCI is an important determinant of long-term muscle strength, and fatigability, both of which influence functional capacity.
doi:10.3389/fnint.2014.00002
PMCID: PMC3899581  PMID: 24478643
motoneuron death; muscle reinnervation; motor axon sprouting; muscle use; muscle fatigue; muscle strength
3.  Selective Effects of Baclofen on Use-Dependent Modulation of GABAB Inhibition after Tetraplegia 
The Journal of Neuroscience  2013;33(31):12898-12907.
Baclofen is a GABAB receptor agonist commonly used to relief spasticity related to motor disorders. The effects of baclofen on voluntary motor output are limited and not yet understood. Using noninvasive transcranial magnetic and electrical stimulation techniques, we examined electrophysiological measures probably involving GABAB (long-interval intracortical inhibition and the cortical silent period) and GABAA (short-interval intracortical inhibition) receptors, which are inhibitory effects mediated by subcortical and cortical mechanisms. We demonstrate increased active long-interval intracortical inhibition and prolonged cortical silent period during voluntary activity of an intrinsic finger muscle in humans with chronic incomplete cervical spinal cord injury (SCI) compared with age-matched controls, whereas resting long-interval intracortical inhibition was unchanged. However, long-term (∼6 years) use of baclofen decreased active long-interval intracortical inhibition to similar levels as controls but did not affect the duration of the cortical silent period. We found a correlation between signs of spasticity and long-interval intracortical inhibition in patients with SCI. Short-interval intracortical inhibition was decreased during voluntary contraction compared with rest but there was no effect of SCI or baclofen use. Together, these results demonstrate that baclofen selectively maintains use-dependent modulation of largely subcortical but not cortical GABAB neuronal pathways after human SCI. Thus, cortical GABAB circuits may be less sensitive to baclofen than spinal GABAB circuits. This may contribute to the limited effects of baclofen on voluntary motor output in subjects with motor disorders affected by spasticity.
doi:10.1523/JNEUROSCI.1552-13.2013
PMCID: PMC3728695  PMID: 23904624
4.  Subcortical Control of Precision Grip after Human Spinal Cord Injury 
The Journal of Neuroscience  2014;34(21):7341-7350.
The motor cortex and the corticospinal system contribute to the control of a precision grip between the thumb and index finger. The involvement of subcortical pathways during human precision grip remains unclear. Using noninvasive cortical and cervicomedullary stimulation, we examined motor evoked potentials (MEPs) and the activity in intracortical and subcortical pathways targeting an intrinsic hand muscle when grasping a small (6 mm) cylinder between the thumb and index finger and during index finger abduction in uninjured humans and in patients with subcortical damage due to incomplete cervical spinal cord injury (SCI). We demonstrate that cortical and cervicomedullary MEP size was reduced during precision grip compared with index finger abduction in uninjured humans, but was unchanged in SCI patients. Regardless of whether cortical and cervicomedullary stimulation was used, suppression of the MEP was only evident 1–3 ms after its onset. Long-term (∼5 years) use of the GABAb receptor agonist baclofen by SCI patients reduced MEP size during precision grip to similar levels as uninjured humans. Index finger sensory function correlated with MEP size during precision grip in SCI patients. Intracortical inhibition decreased during precision grip and spinal motoneuron excitability remained unchanged in all groups. Our results demonstrate that the control of precision grip in humans involves premotoneuronal subcortical mechanisms, likely disynaptic or polysynaptic spinal pathways that are lacking after SCI and restored by long-term use of baclofen. We propose that spinal GABAb-ergic interneuronal circuits, which are sensitive to baclofen, are part of the subcortical premotoneuronal network shaping corticospinal output during human precision grip.
doi:10.1523/JNEUROSCI.0390-14.2014
PMCID: PMC4028504  PMID: 24849366
Baclofen; corticospinal drive; primary motor cortex; spasticity; spinal motoneurons; voluntary drive
5.  Effects of Intrathecal Baclofen on Perceived Sexual Functioning in Men With Spinal Cord Injury 
Background/Objective:
Reports in the literature suggest that administration of intrathecal baclofen to control spasticity may have deleterious effects on erectile function in men with spinal cord injury (SCI). A prospective study was conducted to document any changes in perceived sexual function after implant of a baclofen pump.
Methods:
Seven adult men with SCI (ASIA A or B) who received intrathecal baclofen through an implantable pump for treatment of severe spasticity were followed for an average of 670 days (22.4 months) after implant. Perceived sexual function was assessed using the Brief Sexual Function Inventory. Severity of spasticity and overall health-related quality of life were also assessed.
Results:
Participants reported improvements in spasticity severity and overall health-related quality of life. Two of 7 participants reported some negative changes in perceived sexual function after baclofen pump implant, noted in the areas of reduced sex drive and problems with erections (frequency, rigidity, difficulty in achieving). However, most participants reported minimal effects on sexual function, and 2 participants reported marked improvement in perceived sexual function from pre- to post-implant. Analysis of changes in perceived sexual function over time suggest that problems may be associated with an increase in baclofen dose and may be reversible with a reduction in dose.
Conclusions:
Intrathecal baclofen may impact perceived sexual function particularly at higher doses. However, the effects seem to be reversible with withdrawal or reduction of baclofen administration.
PMCID: PMC2435042  PMID: 18533419
Spinal cord injuries; Baclofen; Spasticity; Sildenafil citrate; Sexual function; Erectile dysfunction
6.  Lasting reduction of severe spasticity after ending chronic treatment with intrathecal baclofen. 
OBJECTIVE--To investigate whether the dose of intrathecal baclofen necessary for a sufficient reduction of muscle tone and spasms changes during treatment of severe spasticity. METHODS--A group of 27 patients received intrathecal baclofen for 61 (SD 18) months. RESULTS--Spasticity remained absent or strongly reduced after stopping the intrathecal baclofen infusion in seven patients. The dose of baclofen could be reduced to 40% of that dose which was originally necessary in 10 patients. The dose remained the same or increased slightly in 10 patients. Possible reasons for the continuing reduction of spasticity after terminating long term intrathecal baclofen infusion in some patients could be: lasting morphological changes in spinal cord neurons by second messenger controlled modulation of gene expression, a toxic effect of baclofen on spinal neurons, muscular atrophy, inflammation due to the catheter, or progression of multiple sclerosis. CONCLUSIONS--A higher initial daily dose of intrathecal baclofen might lead to a faster, lasting suppression of spasticity and the development of spastic symptoms might even be prevented by pre-emptive treatment with baclofen in patients with newly acquired lesions of the spinal cord.
PMCID: PMC1073798  PMID: 8708647
7.  Sustained-release effervescent floating matrix tablets of baclofen: development, optimization and in vitro-in vivo evaluation in healthy human volunteers 
Background and the purpose of the study
Baclofen, a centrally acting skeletal muscle relaxant, is indicated in the long-term treatment of spasticity. It is difficult to formulate baclofen sustained release dosage forms because its absorption on arrival to colon (or even before) is low or nonexistent. In the present investigation efforts were made to improve the bioavailability of baclofen by increasing the residence time of the drug through sustained-release matrix tablet formulation via gastroretentive mechanism.
Methods
Tablets were prepared by wet granulation technique. The influence of gas generating and gel forming agents, amount of baclofen and total weight of tablet on physical properties, in vitro buoyancy, floating lag time, drug release, DSC, X-ray studies were investigated. The release mechanisms were explored and explained by applying zero order, first order, Higuchi and Korsmeyer equations. The selected formulations were subjected to stability study for the period of three months.
Results
For all formulations, kinetics of drug release from tablet followed Higuchi's square root of time kinetic treatment heralding diffusion as predominant mechanism of drug release. Formulations containing 20 mg and 40 mg (F-1 and F-7) showed similar release profiles. There was no significant change in the selected formulations, when subjected to accelerated stability conditions over a period of three months. X-ray imaging in six healthy human volunteers revealed a mean gastric retention period of 5.50±0.7 hrs for the selected formulation.
Conclusion
Stable, sustained release effervescent floating matrix tablets of baclofen could be prepared by wet granulation technique.
PMCID: PMC3232112  PMID: 22615658
Floating tablets; Gastroretentive; Hydrophilic polymers; Mean dissolution time; Sustained release.
8.  Clinical and Neurophysiologic Assessment of Strength and Spasticity During Intrathecal Baclofen Titration in Incomplete Spinal Cord Injury: Single-Subject Design 
Background/Objective:
Spasticity after spinal cord injury (SCI) is commonly managed with oral and intrathecal baclofen (ITB), with less attention to the effects on voluntary motor control. Studies combining clinical and neurophysiologic assessments during dose optimization are rare. Study aims (a) systematically evaluate effects of varied doses of oral and ITB on clinical and neurophysiologic measures of strength and spasticity and (b) relate clinical and neurophysiologic findings.
Methods:
A 41-year-old man with an incomplete T11-ASIA D SCI was studied during ITB titration. Spasticity and strength in the lower extremities were assessed clinically and neurophysiologically at 5 different daily dosages of baclofen: (a) 80 mg oral, (b) 80 mg oral/50 μg ITB, (c) 80 mg oral/125 μg ITB, (d) 30 mg oral/125 μg ITB, and (e) 125 μg ITB only.
Results:
A dose-dependent change in the Ashworth score and lower limb motor score was observed during titration of oral and ITB. Whereas the Hoffman (H)-reflex was abolished after the introduction of ITB, the flexion withdrawal reflex approximated a dose-dependent pattern. Changes in the motor score and EMG during voluntary muscle activation were proportionally smaller than the corresponding changes in clinical and neurophysiologic measures of spasticity. Neurophysiologic assessment largely paralleled clinical findings.
Conclusions:
This single-subject study shows that the control of spasticity can be achieved without detrimental effects on strength in incomplete SCI and suggests the need for including strength testing in comprehensive clinical assessment of spasticity. The study shows convergent validity between clinical and neurophysiologic assessments during ITB dose titration. Adding neurophysiologic assessment to clinical assessment may provide objectivity and sensitivity and facilitate decision-making during ITB titration.
PMCID: PMC2678290  PMID: 19569466
Spinal cord injuries; Paraplegia; Spasticity; Hypertonia; Muscle strength; Baclofen; Intrathecal; Reflexes; Hoffman reflex
9.  Examining the effectiveness of intrathecal baclofen on spasticity in individuals with chronic spinal cord injury: A systematic review 
Objective
To review the available evidence on the effectiveness of intrathecal baclofen in the treatment of spasticity in individuals with spinal cord injuries (SCIs) at least 6 months post-injury or diagnosis.
Data sources
A literature search of multiple databases (Pub Med, CINAHL, EMBASE) was conducted to identify articles published in the English language.
Study selection
Studies were included for review if: (1) more than 50% of the sample size had suffered a traumatic or non-traumatic SCI; (2) there were more than three subjects; (3) subjects received continuous intrathecal baclofen via an implantable pump aimed at improving spasticity; and (4) all subjects were ≥6 months post-SCI, at the time of the intervention.
Data extraction
Data extracted from the studies included patient and treatment characteristics, study design, method of assessment, and outcomes of the intervention.
Data synthesis
Methodological quality was assessed using the PEDro for randomized-controlled trials (RCTs) and the Downs and Black (D&B) tool for non-RCTs. A level of evidence was assigned to each intervention using a modified Sackett scale.
Conclusion
The literature search resulted in 677 articles. No RCTs and eight non-RCTs (D&B scores 13–24) met criteria for inclusion, providing a pooled sample size of 162 individuals. There was substantial level 4 evidence that intrathecal baclofen is effective in reducing spasticity. Mean Ashworth scores reduced from 3.1–4.5 at baseline to 1.0–2.0 (P < 0.005) at follow-up (range 2–41 months). Average dosing increased from 57–187 µg/day at baseline to 218.7–535.9 µg/day at follow-up. Several complications from the use of intrathecal baclofen or pump and catheter malfunction were reported.
doi:10.1179/2045772313Y.0000000102
PMCID: PMC4066544  PMID: 24089997
Baclofen; Muscle spasticity; Spinal cord injuries; Activities of daily living; Ashworth scale
10.  Differential development of tolerance to the functional and behavioral effects of repeated baclofen treatment in rats 
Baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, has been used clinically to treat muscle spasticity, rigidity and pain. More recently, interest in the use of baclofen as an addiction medicine has grown, with promising preclinical cocaine and amphetamine data and demonstrated clinical benefit from alcohol and nicotine studies. Few preclinical investigations, however, have utilized chronic dosing of baclofen, which is important given that tolerance can occur to many of its effects. Thus the question of whether chronic treatment of baclofen maintains the efficacy of acute doses is imperative. The neural substrates that underlie the effects of baclofen, particularly those after chronic treatment, are also not known. In the present study, therefore, rats were treated with either a) vehicle, b) acute baclofen (5 mg/kg) or c) chronic baclofen (5 mg/kg, t.i.d. for 5 days). The effects of acute and chronic baclofen administration, compared to vehicle, were assessed using locomotor activity and changes in brain glucose metabolism (a measure of functional brain activity). Acute baclofen significantly reduced locomotor activity (horizontal and total distance traveled), while chronic baclofen failed to affect locomotor activity. Acute baclofen resulted in significantly lower rates of local cerebral glucose utilization throughout many areas of the brain, including the prefrontal cortex, caudate putamen, septum and hippocampus. The majority of these functional effects, with the exception of the caudate putamen and septum, were absent in animals chronically treated with baclofen. Despite the tolerance to the locomotor and functional effects of baclofen following repeated treatment, these persistent effects on functional activity in the caudate putamen and septum may provide insights into the way in which baclofen alters the reinforcing effects of abused substances such as cocaine, alcohol, and methamphetamine both in humans and animal models.
doi:10.1016/j.pbb.2013.03.001
PMCID: PMC3717556  PMID: 23500188
2-[14C]-deoxyglucose; functional activity; locomotor activity; chronic baclofen; tolerance
11.  Low-dose baclofen therapy raised plasma insulin-like growth factor-1 concentrations, but not into the normal range in a predictable and sustained manner in men with chronic spinal cord injury 
Objective
To evaluate, whether once-daily oral baclofen administration increases and/or sustains plasma insulin-like growth factor-1 (IGF-1) concentration in 11 men with chronic spinal cord injury (SCI) and IGF-1 deficiency (i.e. <250 ng/ml).
Design
Prospective, open-label, dose titration study. Baclofen was administered at 20 mg/day for 8 weeks; then increased to 40 mg/day for another 8 weeks. Plasma IGF-1 and self-reported side effects were measured at baseline and every other week for the duration of the study.
Results
The subjects were 43 ± 12 years old, had duration of injury of 20 ± 12 years; eight subjects had a complete motor injury, and eight had paraplegia. Nine of 11 subjects completed the 20 mg/day treatment and 5 subjects completed the 40 mg/day treatment. Plasma IGF-1 levels improved with each baclofen dose; however, only one subject increased from baseline and remained above the targeted physiological range of 250 ng/ml throughout treatment. A significant increase in IGF-1concentration was observed between baseline and week 2 (154 ± 63 vs. 217 ± 69 ng/ml; P < 0.05), weeks 8 and 10 (188 ± 95 vs. 228 ± 93 ng/ml; P < 0.05), and weeks 8 and 16 (188 ± 95 vs. 259 ± 92 ng/ml; P < 0.05). No serious side effects were observed at 20 mg/day; the 40 mg/day dose was less well tolerated.
Conclusion
Baclofen was not effective at sustaining plasma IGF-1 concentrations in the physiological range in men with chronic SCI.
doi:10.1179/2045772312Y.0000000061
PMCID: PMC3739897  PMID: 23941795
Baclofen; Gamma-aminobutyric acid; Insulin-like growth factor-1; Testosterone; Spinal cord injuries; Paraplegia; Tetraplegia; Spasticity
12.  Automatic classification of motor unit potentials in surface EMG recorded from thenar muscles paralyzed by spinal cord injury 
Journal of Neuroscience Methods  2009;185(1):165-177.
Involuntary electromyographic (EMG) activity has only been analyzed in the paralyzed thenar muscles of spinal cord injured (SCI) subjects for several minutes. It is unknown if this motor unit activity is ongoing. Longer duration EMG recordings can investigate the biological significance of this activity. Since no software is currently capable of classifying 24 hours of EMG data at a single motor unit level, the goal of this research was to devise an algorithm that would automatically classify motor unit potentials by tracking the firing behavior of motor units over 24-hours. Two-channels of thenar muscle surface EMG were recorded over 24-hours from 7 SCI subjects with a chronic cervical level injury using a custom data logging device with custom software. The automatic motor unit classification algorithm developed here employed multiple passes through these 24-hour EMG recordings to segment, cluster, form global templates and classify motor unit potentials, including superimposed potentials. The classification algorithm was able to track an average of 19 global classes in 7 24-hour recordings with a mean (± SE) accuracy of 89.9 % (± 0.98%) and classify potentials from these individual motor units with a mean accuracy of 90.3% (± 0.97%). The algorithm could analyze 24 hours of data in 2–3 weeks with minimal input from a person, while a human operator was estimated to take more than 2 years. This automatic method could be applied clinically to investigate the fasciculation potentials often found in motoneuron disorders such as amyotrophic lateral sclerosis.
doi:10.1016/j.jneumeth.2009.09.012
PMCID: PMC2904617  PMID: 19761794
EMG; long term recording; motor unit classification; spinal cord injury
13.  Extensive Neuronal Differentiation of Human Neural Stem Cell Grafts in Adult Rat Spinal Cord 
PLoS Medicine  2007;4(2):e39.
Background
Effective treatments for degenerative and traumatic diseases of the nervous system are not currently available. The support or replacement of injured neurons with neural grafts, already an established approach in experimental therapeutics, has been recently invigorated with the addition of neural and embryonic stem-derived precursors as inexhaustible, self-propagating alternatives to fetal tissues. The adult spinal cord, i.e., the site of common devastating injuries and motor neuron disease, has been an especially challenging target for stem cell therapies. In most cases, neural stem cell (NSC) transplants have shown either poor differentiation or a preferential choice of glial lineages.
Methods and Findings
In the present investigation, we grafted NSCs from human fetal spinal cord grown in monolayer into the lumbar cord of normal or injured adult nude rats and observed large-scale differentiation of these cells into neurons that formed axons and synapses and established extensive contacts with host motor neurons. Spinal cord microenvironment appeared to influence fate choice, with centrally located cells taking on a predominant neuronal path, and cells located under the pia membrane persisting as NSCs or presenting with astrocytic phenotypes. Slightly fewer than one-tenth of grafted neurons differentiated into oligodendrocytes. The presence of lesions increased the frequency of astrocytic phenotypes in the white matter.
Conclusions
NSC grafts can show substantial neuronal differentiation in the normal and injured adult spinal cord with good potential of integration into host neural circuits. In view of recent similar findings from other laboratories, the extent of neuronal differentiation observed here disputes the notion of a spinal cord that is constitutively unfavorable to neuronal repair. Restoration of spinal cord circuitry in traumatic and degenerative diseases may be more realistic than previously thought, although major challenges remain, especially with respect to the establishment of neuromuscular connections.
When neural stem cells from human fetal spinal cord were grafted into the lumbar cord of normal or injured adult nude rats, substantial neuronal differentiation was found.
Editors' Summary
Background.
Every year, spinal cord injuries, many caused by road traffic accidents, paralyze about 11,000 people in the US. This paralysis occurs because the spinal cord is the main communication highway between the body and the brain. Information from the skin and other sensory organs is transmitted to the brain along the spinal cord by bundles of neurons, nervous system cells that transmit and receive messages. The brain then sends information back down the spinal cord to control movement, breathing, and other bodily functions. The bones of the spine normally protect the spinal cord but, if these are broken or dislocated, the spinal cord can be cut or compressed, which interrupts the information flow. Damage near the top of the spinal cord can paralyze the arms and legs (tetraplegia); damage lower down paralyzes the legs only (paraplegia). Spinal cord injuries also cause many other medical problems, including the loss of bowel and bladder control. Although the deleterious effects of spinal cord injuries can be minimized by quickly immobilizing the patient and using drugs to reduce inflammation, the damaged nerve fibers never regrow. Consequently, spinal cord injury is permanent.
Why Was This Study Done?
Scientists are currently searching for ways to reverse spinal cord damage. One potential approach is to replace the damaged neurons using neural stem cells (NSCs). These cells, which can be isolated from embryos and from some areas of the adult nervous system, are able to develop into all the specialized cells types of the nervous system. However, because most attempts to repair spinal cord damage with NSC transplants have been unsuccessful, many scientists believe that the environment of the spinal cord is unsuitable for nerve regeneration. In this study, the researchers have investigated what happens to NSCs derived from the spinal cord of a human fetus after transplantation into the spinal cord of adult rats.
What Did the Researchers Do and Find?
The researchers injected human NSCs that they had grown in dishes into the spinal cord of intact nude rats (animals that lack a functioning immune system and so do not destroy human cells) and into nude rats whose spinal cord had been damaged at the transplantation site. The survival and fate of the transplanted cells was assessed by staining thin slices of spinal cord with an antibody that binds to a human-specific protein and with antibodies that recognize proteins specific to NSCs, neurons, or other nervous system cells. The researchers report that the human cells survived well in the adult spinal cord of the injured and normal rats and migrated into the gray matter of the spinal cord (which contains neuronal cell bodies) and into the white matter (which contains the long extensions of nerve cells that carry nerve impulses). 75% and 60% of the human cells in the gray and white matter, respectively, contained a neuron-specific protein six months after transplantation but only 10% of those in the membrane surrounding the spinal cord became neurons; the rest developed into astrocytes (another nervous system cell type) or remained as stem cells. Finally, many of the human-derived neurons made the neurotransmitter GABA (one of the chemicals that transfers messages between neurons) and made contacts with host spinal cord neurons.
What Do These Findings Mean?
These findings suggest that human NSC grafts can, after all, develop into neurons (predominantly GABA-producing neurons) in normal and injured adult spinal cord and integrate into the existing spinal cord if the conditions are right. Although these animal experiments suggest that NSC transplants might help people with spinal injuries, they have some important limitations. For example, the spinal cord lesions used here are mild and unlike those seen in human patients. This and the use of nude rats might have reduced the scarring in the damaged spinal cord that is often a major barrier to nerve regeneration. Furthermore, the researchers did not test whether NSC transplants provide functional improvements after spinal cord injury. However, since other researchers have also recently reported that NSCs can grow and develop into neurons in injured adult spinal cord, these new results further strengthen hopes it might eventually be possible to use human NSCs to repair damaged spinal cords.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040039.
The US National Institute of Neurological Disorders and Stroke provides information on spinal cord injury and current spinal cord research
Spinal Research (a UK charity) offers information on spinal cord injury and repair
The US National Spinal Cord Injury Association Web site contains factsheets on spinal cord injuries
MedlinePlus encyclopedia has pages on spinal cord trauma and interactive tutorials on spinal cord injury
The International Society for Stem Cell Research offers information on all sorts of stem cells including NSCs
The US National Human Neural Stem Cell Resource provides information on human NSCs, including the current US government's stance on stem cell research
doi:10.1371/journal.pmed.0040039
PMCID: PMC1796906  PMID: 17298165
14.  Bladder stones – red herring for resurgence of spasticity in a spinal cord injury patient with implantation of Medtronic Synchromed pump for intrathecal delivery of baclofen – a case report 
BMC Urology  2003;3:3.
Background
Increased spasms in spinal cord injury (SCI) patients, whose spasticity was previously well controlled with intrathecal baclofen therapy, are due to (in order of frequency) drug tolerance, increased stimulus, low reservoir volume, catheter malfunction, disease progression, human error, and pump mechanical failure. We present a SCI patient, in whom bladder calculi acted as red herring for increased spasticity whereas the real cause was spontaneous extrusion of catheter from intrathecal space.
Case Presentation
A 44-year-old male sustained a fracture of C5/6 and incomplete tetraplegia at C-8 level. Medtronic Synchromed pump for intrathecal baclofen therapy was implanted 13 months later to control severe spasticity. The tip of catheter was placed at T-10 level. The initial dose of baclofen was 300 micrograms/day of baclofen, administered by a simple continuous infusion. During a nine-month period, he required increasing doses of baclofen (875 micrograms/day) to control spasticity. X-ray of abdomen showed multiple radio opaque shadows in the region of urinary bladder. No malfunction of the pump was detected. Therefore, increased spasticity was attributed to bladder stones. Electrohydraulic lithotripsy of bladder stones was carried out successfully. Even after removal of bladder stones, this patient required further increases in the dose of intrathecal baclofen (950, 1050, 1200 and then 1300 micrograms/day). Careful evaluation of pump-catheter system revealed that the catheter had extruded spontaneously and was lying in the paraspinal space at L-4, where the catheter had been anchored before it entered the subarachnoid space. A new catheter was passed into the subarachnoid space and the tip of catheter was located at T-8 level. The dose of intrathecal baclofen was decreased to 300 micrograms/day.
Conclusion
Vesical calculi acted as red herring for resurgence of spasticity. The real cause for increased spasms was spontaneous extrusion of whole length of catheter from subarachnoid space. Repeated bending forwards and straightening of torso for pressure relief and during transfers from wheel chair probably contributed to spontaneous extrusion of catheter from spinal canal in this patient.
doi:10.1186/1471-2490-3-3
PMCID: PMC155678  PMID: 12659647
15.  Development of AMPA receptor and GABA B receptor-sensitive spinal hyper-reflexia after spinal air embolism in rat: a systematic neurological, electrophysiological and qualitative histopathological study 
Experimental neurology  2012;237(1):26-35.
Decompression sickness results from formation of bubbles in the arterial and venous system, resulting in spinal disseminated neurodegenerative changes and may clinically be presented by motor dysfunction, spinal segmental stretch hyper-reflexia (i.e., spasticity) and muscle rigidity. In our current study, we describe a rat model of spinal air embolism characterized by the development of similar spinal disseminated neurodegenerative changes and functional deficit. In addition, the anti-spastic potency of systemic AMPA receptor antagonist (NGX424) or GABA B receptor agonist (baclofen) treatment was studied. To induce spinal air embolism, animals received an intra-aortic injection of air (50–200 μl/kg). After embolism, the development of spasticity was measured using computer-controlled ankle rotation. Animals receiving 150 or 200 μl of intra-aortic air injections displayed motor dysfunction with developed spastic (50–60% of animals) or flaccid (25–35% of animals) paraplegia at 5–7 days. MRI and spinal histopathological analysis showed disseminated spinal cord infarcts in the lower thoracic to sacral spinal segments. Treatment with NGX424 or baclofen provided a potent anti-spasticity effect (i.e., stretch hyper-reflexia inhibition). This model appears to provide a valuable experimental tool to study the pathophysiology of air embolism-induced spinal injury and permits the assessment of new treatment efficacy targeted to modulate neurological symptoms resulting from spinal air embolism.
doi:10.1016/j.expneurol.2012.06.004
PMCID: PMC3430717  PMID: 22721766
spinal cord; air embolism; paralysis; spinal infarcts; spasticity; Hoffmann reflex; AMPA receptor antagonist; GABA B receptor agonist
16.  Motor unit firing rates during spasms in thenar muscles of spinal cord injured subjects 
Involuntary contractions of paralyzed muscles (spasms) commonly disrupt daily activities and rehabilitation after human spinal cord injury (SCI). Our aim was to examine the recruitment, firing rate modulation, and derecruitment of motor units that underlie spasms of thenar muscles after cervical SCI. Intramuscular electromyographic activity (EMG), surface EMG, and force were recorded during thenar muscle spasms that occurred spontaneously or that were triggered by movement of a shoulder or leg. Most spasms were submaximal (mean: 39%, SD: 33 of the force evoked by median nerve stimulation at 50 Hz) with strong relationships between EMG and force (R2 > 0.69). Unit recruitment occurred over a wide force range (0.2–103% of 50 Hz force). Significant unit rate modulation occurred during spasms (frequency at 25% maximal force: 8.8 Hz, 3.3 SD; at maximal force: 16.1 Hz, 4.1 SD). Mean recruitment frequency (7.1 Hz, 3.2 SD) was significantly higher than derecruitment frequency (5.4 Hz, 2.4 SD). Coactive unit pairs that fired for more than 4 s showed high (R2 > 0.7, n = 4) or low (R2:0.3–0.7, n = 12) rate-rate correlations, and derecruitment reversals (21 pairs, 29%). Later recruited units had higher or lower maximal firing rates than lower threshold units. These discrepant data show that coactive motoneurons are drive both by common inputs and by synaptic inputs from different sources during muscle spasms. Further, thenar motoneurons can still fire at high rates in response to various peripheral inputs after SCI, supporting the idea that low maximal voluntary firing rates and forces in thenar muscles result from reduced descending drive.
doi:10.3389/fnhum.2014.00922
PMCID: PMC4231945  PMID: 25452723
motor unit recruitment; motor unit derecruitment; motor unit firing rate modulation; afferent input; motoneuron; persistent inward current
17.  Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity 
OBJECTIVE—To investigate whether the stiff limb syndrome may be separated from the stiff man syndrome and progressive encephalomyelitis with rigidity on simple clinical grounds, and whether such a distinction has implications for aetiology, treatment, and prognosis.
METHODS— Twenty three patients referred over a 10 year period with rigidity and spasms in association with continuous motor unit activity, but without evidence of neuromyotonia, extrapyramidal or pyramidal dysfunction or focal lesions of the spinal cord were reviewed. The patients were divided into those with an acute or subacute illness, leading to death within 1 year, and those with a chronic course. The latter were divided into those in whom rigidity and spasms dominated in the axial muscles, or in one or more distal limbs, at the time of their first assessment.
RESULTS—This simple division identified three distinct groups of patients. (1) Progressive encephalomyelitis with rigidity: two patients had a rapidly progressive condition characterised by widespread rigidity which resulted in death within 6 and 16 weeks. One patient had negative anti-GAD and anti-neuronal antibodies, but had markedly abnormal CSF and widespread denervation. The principal pathological findings in this case were a subacute encephalomyelitis which primarily affected the grey matter. In the remaining patient anti-GAD antibodies were not tested, and postmortem was refused. (2) Stiff man syndrome: eight patients had rigidity and painful spasms of the lumbar paraspinal, abdominal, and occasionally proximal leg muscles associated with a lumbar hyperlordosis. There was no involvement of the upper limbs, distal lower limbs, sphincters or cranial nerves. Seven had anti-GAD antibodies and most had additional evidence of autoimmune disease. Neurophysiologically there was continuous motor unit activity with abnormal exteroceptive reflexes, but a normal interference pattern during spasms. The patients all responded to baclofen/diazepam and remained ambulant. (3) Stiff limb syndrome: thirteen patients had rigidity, painful spasm, and abnormal postures of the distal limb, usually the leg. About half went on to develop sphincter or brainstem involvement. Generalised myoclonic jerks were not a feature. Only two had truncal rigidity, and another two had anti-GAD antibodies. Most had no evidence of autoimmune disease. Neurophysiologically they had continuous motor unit activity in the affected limb, abnormal exteroceptive reflexes, and abnormally segmented EMG activity during spasms. The disease ran a protracted course, and most patients had only a partial response to baclofen or diazepam. About half became wheelchair bound.
CONCLUSIONS—The stiff limb syndrome seems distinct from the stiff man syndrome or progressive encephalomyelitis with rigidity, and is an important cause of rigidity and spasm in the setting of continuous motor unit activity.


PMCID: PMC2170335  PMID: 9810930
18.  Two Faces of Chondroitin Sulfate Proteoglycan in Spinal Cord Repair: A Role in Microglia/Macrophage Activation 
PLoS Medicine  2008;5(8):e171.
Background
Chondroitin sulfate proteoglycan (CSPG) is a major component of the glial scar. It is considered to be a major obstacle for central nervous system (CNS) recovery after injury, especially in light of its well-known activity in limiting axonal growth. Therefore, its degradation has become a key therapeutic goal in the field of CNS regeneration. Yet, the abundant de novo synthesis of CSPG in response to CNS injury is puzzling. This apparent dichotomy led us to hypothesize that CSPG plays a beneficial role in the repair process, which might have been previously overlooked because of nonoptimal regulation of its levels. This hypothesis is tested in the present study.
Methods and Findings
We inflicted spinal cord injury in adult mice and examined the effects of CSPG on the recovery process. We used xyloside to inhibit CSPG formation at different time points after the injury and analyzed the phenotype acquired by the microglia/macrophages in the lesion site. To distinguish between the resident microglia and infiltrating monocytes, we used chimeric mice whose bone marrow-derived myeloid cells expressed GFP. We found that CSPG plays a key role during the acute recovery stage after spinal cord injury in mice. Inhibition of CSPG synthesis immediately after injury impaired functional motor recovery and increased tissue loss. Using the chimeric mice we found that the immediate inhibition of CSPG production caused a dramatic effect on the spatial organization of the infiltrating myeloid cells around the lesion site, decreased insulin-like growth factor 1 (IGF-1) production by microglia/macrophages, and increased tumor necrosis factor alpha (TNF-α) levels. In contrast, delayed inhibition, allowing CSPG synthesis during the first 2 d following injury, with subsequent inhibition, improved recovery. Using in vitro studies, we showed that CSPG directly activated microglia/macrophages via the CD44 receptor and modulated neurotrophic factor secretion by these cells.
Conclusions
Our results show that CSPG plays a pivotal role in the repair of injured spinal cord and in the recovery of motor function during the acute phase after the injury; CSPG spatially and temporally controls activity of infiltrating blood-borne monocytes and resident microglia. The distinction made in this study between the beneficial role of CSPG during the acute stage and its deleterious effect at later stages emphasizes the need to retain the endogenous potential of this molecule in repair by controlling its levels at different stages of post-injury repair.
Michal Schwartz and colleagues describe the role of chondroitin sulfate proteoglycan in the repair of injured tissue and in the recovery of motor function during the acute phase after spinal cord injury.
Editors' Summary
Background.
Every year, spinal cord injuries paralyze about 10,000 people in the United States. The spinal cord, which contains bundles of nervous system cells called neurons, is the communication superhighway between the brain and the body. Messages from the brain travel down the spinal cord to control movement, breathing, and other bodily functions; messages from the skin and other sensory organs travel up the spinal cord to keep the brain informed about the body. All these messages are transmitted along axons, long extensions on the neurons. The spinal cord is protected by the bones of the spine but if these are displaced or broken, the axons can be compressed or cut, which interrupts the information flow. Damage near the top of the spinal cord paralyzes the arms and legs (tetraplegia); damage lower down paralyzes the legs only (paraplegia). Spinal cord injuries also cause other medical problems, including the loss of bowel and bladder control. Currently there is no effective treatment for spinal cord injuries. Treatment with drugs to reduce inflammation has, at best, only modest effects. Moreover, because damaged axons rarely regrow, most spinal cord injuries are permanent.
Why Was This Study Done?
One barrier to recovery after a spinal cord injury seems to be an inappropriate immune response to the injury. After an injury, microglia (immune system cells that live in the nervous system), and macrophages (blood-borne immune system cells that infiltrate the injury) become activated. Microglia/macrophage activation can be either beneficial (the cells make IGF-1, a protein that stimulates axon growth) or destructive (the cells make TNF-α, a protein that kills neurons), so studies of microglia/macrophage activation might suggest ways to treat spinal cord injuries. Another possible barrier to recovery is “chondroitin sulfate proteoglycan” (CSPG). This is a major component of the scar tissue (the “glial scar”) that forms around spinal cord injuries. CSPG limits axon regrowth, so attempts have been made to improve spinal cord repair by removing CSPG. But if CSPG prevents spinal cord repair, why is so much of it made immediately after an injury? In this study, the researchers investigate this paradox by asking whether CSPG made in the right place and in the right amount might have a beneficial role in spinal cord repair that has been overlooked.
What Did the Researchers Do and Find?
The researchers bruised a small section of the spinal cord of mice to cause hind limb paralysis, and then monitored the recovery of movement in these animals. They also examined the injured tissue microscopically, looked for microglia and infiltrating macrophages at the injury site, and measured the production of IGF-1 and TNF-α by these cells. Inhibition of CSPG synthesis immediately after injury impaired the functional recovery of the mice and increased tissue loss at the injury site. It also altered the spatial organization of infiltrating macrophages at the injury site, reduced IGF-1 production by these microglia/macrophages, and increased TNF-α levels. In contrast, when CSPG synthesis was not inhibited until two days after the injury, the mice recovered well from spinal cord injury. Furthermore, the interaction of CSPG with a cell-surface protein called CD44 activated microglia/macrophages growing in dishes and increased their production of IGF-1 but not of molecules that kill neurons.
What Do These Findings Mean?
These findings suggest that, immediately after a spinal cord injury, CSPG is needed for the repair of injured neurons and the recovery of movement, but that later on the presence of CSPG hinders repair. The findings also indicate that CSPG has these effects, at least in part, because it regulates the activity and localization of microglia and macrophages at the injury site and thus modulates local immune responses to the damage. Results obtained from experiments done in animals do not always accurately reflect the situation in people, so these findings need to be confirmed in patients with spinal cord injuries. However, they suggest that the effect of CSPG on spinal cord repair is not an inappropriate response to the injury, as is widely believed. Consequently, careful manipulation of CSPG levels might improve outcomes for people with spinal cord injuries.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050171.
The MedlinePlus encyclopedia provides information about spinal cord injuries; MedlinePlus provides an interactive tutorial and a list of links to additional information about spinal cord injuries (in English and Spanish)
The US National Institute of Neurological Disorders and Stroke also provides information about spinal cord injury (in English and Spanish)
Wikipedia has a page on glial scars (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050171
PMCID: PMC2517615  PMID: 18715114
19.  Sexual Dysfunction Associated With Intrathecal Baclofen Use: A Report of Two Cases 
Background/Objective:
Intrathecal baclofen is considered standard treatment for severe spasticity of spinal cord and cerebral origin. Recognized side effects include fatigue and constipation. There are few reported findings of sexual dysfunction in men and none in women.
Methods:
Two case reports.
Results:
A male and a female patient with spasticity treated with intrathecal baclofen were recognized to have sexual dysfunction side effects from treatment. On reduction of the intrathecal baclofen dose, complete return to baseline sexual function was achieved for both subjects.
Conclusions:
Intrathecal baclofen can impair sexual function and ejaculation in some patients. Clinicians should be aware of this risk and ask about it during routine clinic follow-up for spasticity. Dosing adjustments need to be considered in these patients.
PMCID: PMC2435028  PMID: 18533420
Baclofen; Intrathecal; Spinal cord injuries; Cerebral palsy; Sexual dysfunction; Spasticity; Gamma-aminobutyric acid-B receptors
20.  Practice Parameter: Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review) 
Neurology  2010;74(4):336-343.
Objective:
To evaluate published evidence of efficacy and safety of pharmacologic treatments for childhood spasticity due to cerebral palsy.
Methods:
A multidisciplinary panel systematically reviewed relevant literature from 1966 to July 2008.
Results:
For localized/segmental spasticity, botulinum toxin type A is established as an effective treatment to reduce spasticity in the upper and lower extremities. There is conflicting evidence regarding functional improvement. Botulinum toxin type A was found to be generally safe in children with cerebral palsy; however, the Food and Drug Administration is presently investigating isolated cases of generalized weakness resulting in poor outcomes. No studies that met criteria are available on the use of phenol, alcohol, or botulinum toxin type B injections. For generalized spasticity, diazepam is probably effective in reducing spasticity, but there are insufficient data on its effect on motor function and its side-effect profile. Tizanidine is possibly effective, but there are insufficient data on its effect on function and its side-effect profile. There were insufficient data on the use of dantrolene, oral baclofen, and intrathecal baclofen, and toxicity was frequently reported.
Recommendations:
For localized/segmental spasticity that warrants treatment, botulinum toxin type A should be offered as an effective and generally safe treatment (Level A). There are insufficient data to support or refute the use of phenol, alcohol, or botulinum toxin type B (Level U). For generalized spasticity that warrants treatment, diazepam should be considered for short-term treatment, with caution regarding toxicity (Level B), and tizanidine may be considered (Level C). There are insufficient data to support or refute use of dantrolene, oral baclofen, or continuous intrathecal baclofen (Level U).
GLOSSARY
= American Academy of Neurology;
= adverse event;
= Ashworth scale;
= botulinum toxin type A;
= botulinum toxin type B;
= cerebral palsy;
= Food and Drug Administration;
= Goal Attainment Scale;
= Gross Motor Function Measure;
= intrathecal baclofen;
= Modified Ashworth scale;
= occupational therapy;
= physiotherapy;
= Quality of Upper Extremity Skills Test;
= Tardieu scale.
doi:10.1212/WNL.0b013e3181cbcd2f
PMCID: PMC3122302  PMID: 20101040
21.  GABA-RECEPTOR ACTIVATION IN THE LUMBOSACRAL SPINAL CORD REDUCES DETRUSOR OVERACTIVITY IN SPINAL CORD INJURED RATS 
The Journal of urology  2008;179(3):1178-1183.
Purpose
We investigated the effects of intrathecal application of GABAA and GABAB receptor agonists on detrusor overactivity in spinal cord injured rats.
Materials and Methods
Adult female Sprague-Dawley rats were used. At 4 weeks after Th9-10 spinal cord transection, awake cystometry and recordings of external urethral sphincter electromyogram were performed to examine the effect of intrathecal application of GABAA and GABAB agonists (muscimol and baclofen, respectively) or GABAA and GABAB antagonists (bicuculline and saclofen, respectively) at the level of L6-S1 spinal cord. Expression of glutamate decarboxylase 67 mRNA in the L6-S1 spinal cord and dorsal root ganglia was also assessed.
Results
Both muscimol and baclofen produced a dose-dependent inhibition of the number (51–73% decrease) and amplitude (35–93% decrease) of nonvoiding bladder contractions, and a decrease in micturition pressure. The effects of muscimol and baclofen were antagonized by bicuculline and saclofen, respectively. Bursting activity of external urethral sphincter electromyogram was inhibited corresponding to the inhibition of bladder activity by muscimol and baclofen. Glutamate decarboxylase 67 mRNA levels in the spinal cord and dorsal root ganglia was decreased (55% and 84%, respectively) after spinal cord transection.
Conclusions
These results indicate that GABAA and GABAB receptor activation in the spinal cord inhibits detrusor overactiivty. The reduction in glutamate decarboxylase 67 mRNA suggests hypofunction of GABAergic inhibitory mechanisms in the spinal cord. Therefore, stimulation of spinal GABAergic mechanisms could be effective for the treatment of detrusor overactivity after spinal cord injury.
doi:10.1016/j.juro.2007.10.030
PMCID: PMC2744108  PMID: 18206170
bladder; urethra; spinal cord injury; GABA; detrusor overactivity
22.  Epidemiology of Vocal Fold Paralyses After Total Thyroidectomy for Well-Differentiated Thyroid Cancer in Medicare Population 
Objectives
Population-level incidence of vocal fold paralysis after thyroidectomy for well-differentiated thyroid carcinoma (WDTC) is not known. This study aimed to measure longitudinal incidence of post-operative vocal fold paralyses and need for directed interventions in the Medicare population undergoing total thyroidectomy for WDTC.
Study Design
Retrospective Cohort Study
Setting
United States Population
Subjects
Medicare Beneficiaries
Methods
SEER-Medicare data (1991 – 2009) were used to identify beneficiaries who underwent total thyroidectomy for WDTC. Incident vocal fold paralyses and directed interventions were identified. Multivariate analyses were used to determine factors associated with odds of developing these surgical complications.
Results
Of 5,670 total thyroidectomies for WDTC, 9.5% were complicated by vocal fold paralysis [8.2% unilateral vocal fold paralysis (UVFP); 1.3% bilateral vocal fold paralysis (BVFP)]. Rate of paralyses decreased 5% annually from 1991 to 2009 (OR 0.95, 95% CI 0.93 – 0.97; p<0.001). Overall, 22% of patients with vocal fold paralysis required surgical intervention (UVFP 21%, BVFP 28%). Multivariate logistic regression revealed odds of post-thyroidectomy paralysis increased with each additional year of age, with non-Caucasian race, particular histologic types, advanced stage, and in particular registry regions.
Conclusions
Annual rates of post-thyroidectomy vocal fold paralyses are decreasing among Medicare beneficiaries with WDTC. High incidence in this aged population is likely due to a preponderance of temporary paralyses, which is supported by the need for directed intervention in less than a quarter of affected patients. Further population-based studies are needed to refine the population incidence and risk factors for paralyses in the aging population.
doi:10.1177/0194599814521381
PMCID: PMC4229384  PMID: 24482349
vocal fold paralysis; unilateral vocal fold paralysis; bilateral vocal fold paralysis; thyroid cancer; thyroidectomy; epidemiology; incidence; Medicare
23.  Efficacy and Safety of Baclofen for Alcohol Dependence: A Randomized, Double-Blind, Placebo-Controlled Trial 
Background
Recent clinical trials and case-reports indicate that baclofen, a GABAB agonist, may have efficacy for alcohol dependence. Baclofen has been shown to enhance abstinence, to reduce drinking quantity, to reduce craving, and to reduce anxiety in alcohol dependent individuals in two placebo-controlled trials in Italy. However, the clinical trial data with baclofen is limited. The purpose of the present study was to test the efficacy and tolerability of baclofen in alcohol dependence in the United States.
Methods
The study was a double-blind, placebo-controlled, randomized study comparing 30 mg per day of baclofen to placebo over 12 weeks of treatment and utilizing eight sessions of BRENDA, a low-intensity psychosocial intervention. 121 subjects were screened to yield 80 randomized subjects (44 male) with randomization balanced for gender. Percent heavy drinking days was the primary outcome measure with other drinking outcomes, anxiety levels, and craving as secondary outcomes. Tolerability was examined.
Results
76% of subjects completed the study. No difference by drug condition was seen in % heavy drinking days where on-average rates were 25.5% (± 23.6%) for placebo and 25.9% (± 23.2%) for baclofen during treatment (t(73)=0.59, p=0.56). Similarly, no differences were seen by drug condition in % days abstinent, time to first drink, or time to relapse to heavy drinking. Baclofen was associated with a significant reduction in state anxiety (F(1,73)=5.39, p=0.02). Baclofen was well tolerated with only two individuals stopping baclofen because of adverse events. There were no serious adverse events.
Conclusions
Baclofen, a GABAB agonist, represents a possible new pharmacotherapeutic approach to alcohol dependence. Despite encouraging preclinical data and prior positive clinical trials with baclofen in Italy, the current trial did not find evidence that baclofen is superior to placebo in the treatment of alcohol dependence. Additional clinical trial work is necessary to establish whether baclofen does or does not have therapeutic efficacy in alcohol dependence and, if it does, what factors are predictive of response.
doi:10.1111/j.1530-0277.2010.01273.x
PMCID: PMC2965272  PMID: 20662805
baclofen; alcoholism; placebo-controlled trial
24.  Control of transient lower oesophageal sphincter relaxations and reflux by the GABAB agonist baclofen in patients with gastro-oesophageal reflux disease 
Gut  2002;50(1):19-24.
Background and aims: Transient lower oesophageal sphincter relaxations (TLOSRs) are the major cause of gastro-oesophageal reflux in normal subjects and in most patients with reflux disease. The gamma aminobutyric acid (GABA) receptor type B agonist, baclofen, is a potent inhibitor of TLOSRs in normal subjects. The aim of this study was to investigate the effect of baclofen on TLOSRs and postprandial gastro-oesophageal reflux in patients with reflux disease.
Methods: In 20 patients with reflux disease, oesophageal motility and pH were measured, with patients in the sitting position, for three hours after a 3000 kJ mixed nutrient meal. On separate days at least one week apart, 40 mg oral baclofen or placebo was given 90 minutes before the meal.
Results: Baclofen reduced the rate of TLOSRs by 40% from 15 (13.8–18.3) to 9 (5.8–13.3) per three hours (p<0.0002) and increased basal lower oesophageal sphincter pressure. Baclofen also significantly reduced the rate of reflux episodes by 43% from 7.0 (4.0–12.0) to 4.0 (1.5–9) per three hours (median (interquartile range); p<0.02). However, baclofen had no effect on oesophageal acid exposure (baclofen 4.9% (1.7–12.4) v placebo 5.0% (2.7–15.5)).
Conclusions: In patients with reflux disease, the GABAB agonist baclofen significantly inhibits gastro-oesophageal reflux episodes by inhibition of TLOSRs. These findings suggest that GABAB agonists may be useful as therapeutic agents for the management of reflux disease.
PMCID: PMC1773078  PMID: 11772961
lower oesophageal sphincter; oesophageal motility; baclofen; gastro-oesophageal reflux disease
25.  Clinical effectiveness of baclofen for the treatment of alcohol dependence: a review 
Baclofen, an agonist at the B subunit of gaba-aminobutyric acid receptor, possesses pharmacologic properties that may confer utility for the treatment of alcohol dependence. Research suggests that not only can it be useful in promoting maintenance of alcohol abstinence but also it may play a key role in decreasing alcohol cravings and anxiety often associated with alcohol dependence. To assess the benefit of baclofen for alcohol dependence, a review of the literature was conducted to identify published data investigating this off-label treatment. Four randomized controlled trials to date have been published and were included in this review. Although primary outcomes differ between studies, patients randomized to baclofen experience higher rates of abstinence from alcohol than those taking placebo in two of the trials. Secondary analyses indicate that baclofen is safe in patients with alcohol dependence, including those with moderate to severe liver cirrhosis, and may provide beneficial anxiolytic effects. Despite some positive data, the largest available randomized controlled trial failed to find any differences between baclofen and placebo. In all studies, individuals with severe medical comorbidities, seizure disorders, and psychiatric disorders were excluded from trials, which may limit external validity. In summary, there may be beneficial effects from using baclofen for the treatment of alcohol dependence; however, limited conclusions can be drawn from the small number of studies currently available for review. Larger well-designed trials are needed to further define baclofen’s role for the treatment of alcohol dependence.
doi:10.2147/CPAA.S32434
PMCID: PMC3706258  PMID: 23869179
baclofen; alcohol; abstinence; relapse; craving; dependence

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