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1.  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.
PMCID: PMC2904617  PMID: 19761794
EMG; long term recording; motor unit classification; spinal cord injury
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.
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.
PMCID: PMC3728695  PMID: 23904624
4.  Intrathecal Baclofen Pump for Spasticity 
Executive Summary
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
5.  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
6.  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.
PMCID: PMC3717556  PMID: 23500188
2-[14C]-deoxyglucose; functional activity; locomotor activity; chronic baclofen; tolerance
7.  Clinical and Neurophysiologic Assessment of Strength and Spasticity During Intrathecal Baclofen Titration in Incomplete Spinal Cord Injury: Single-Subject Design 
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.
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.
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.
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
8.  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.
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.
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.
PMCID: PMC155678  PMID: 12659647
9.  Baclofen Pump Intervention for Spasticity Affecting Pulmonary Function 
Muscle spasticity may adversely affect pulmonary function after spinal cord injury (SCI). However, there is limited information regarding the treatment of spasticity as a determinant of pulmonary function. This study presents the case of a man with C4 tetraplegia who had severe spasticity and difficulty weaning from ventilatory support.
Case presentation.
Severe spasticity likely contributed to respiratory compromise in this patient. Successful and rapid weaning from the ventilator occurred within 3 weeks of baclofen pump placement.
Randomized clinical trials among SCI patients with significant spasticity are needed to determine whether intervention with a baclofen pump facilitates earlier ventilatory weaning.
PMCID: PMC1864906  PMID: 16396387
Spinal cord injuries; Spasticity; Ventilator weaning; Baclofen pump; Respiratory impairment; Tetraplegia
10.  Responses of thenar muscles to transcranial magnetic stimulation of the motor cortex in patients with incomplete spinal cord injury 
OBJECTIVE—To investigate changes in electromyographic (EMG) responses to transcranial magnetic stimulation (TMS) of the motor cortex after incomplete spinal cord injury in humans.
METHODS—A group of 10 patients with incomplete spinal cord injury (motor level C3-C8) was compared with a group of 10 healthy control subjects. Surface EMG recordings were made from the thenar muscles. TMS was applied with a 9 cm circular stimulating coil centred over the vertex. The EMG responses to up to 50 magnetic stimuli were rectified and averaged.
RESULTS—Thresholds for compound motor evoked potentials (cMEPs) and suppression of voluntary contraction (SVC) elicited by TMS were higher (p<0.05) in the patient group. Latency of cMEPs was longer (p<0.05) in the patient group in both relaxed (controls 21.3 (SEM 0.5) ms; patients 27.7 (SEM 1.3) ms) and voluntarily contracted (controls 19.8 (SEM 0.5) ms; patients 27.6 (SEM 1.3) ms) muscles. The latency of SVC was longer (p<0.05) in the patients (51.8 (SEM 1.8) ms) than in the controls (33.4 (SEM 1.9) ms). The latency difference (SVC−cMEP) was longer in the patients (25.3 (SEM 2.4) ms) than in the controls (13.4 (SEM 1.6) ms).
CONCLUSION—The longer latency difference between cMEPs and SVC in the patients may reflect a weak or absent early component of cortical inhibition. Such a change may contribute to the restoration of useful motor function after incomplete spinal cord injury.

PMCID: PMC2170166  PMID: 9667566
11.  Upper-limb muscle responses to epidural, subdural and intraspinal stimulation of the cervical spinal cord 
Journal of neural engineering  2014;11(1):016005.
Electrical stimulation of the spinal cord has potential applications following spinal cord injury for reanimating paralysed limbs and promoting neuroplastic changes that may facilitate motor rehabilitation. Here we systematically compare the efficacy, selectivity and frequency-dependence of different stimulation methods in the cervical enlargement of anaesthetized monkeys.
Stimulating electrodes were positioned at multiple epidural and subdural sites on both dorsal and ventral surfaces, as well as at different depths within the spinal cord. Motor responses were recorded from arm, forearm and hand muscles.
Main results
Stimulation efficacy increased from dorsal to ventral stimulation sites, with the exception of ventral epidural electrodes which had the highest recruitment thresholds. Compared to epidural and intraspinal methods, responses to subdural stimulation were more selective but also more similar between adjacent sites. Trains of stimuli delivered to ventral sites elicited consistent responses at all frequencies whereas from dorsal sites we observed a mixture of short-latency facilitation and long-latency suppression. Finally, paired stimuli delivered to dorsal surface and intraspinal sites exhibited symmetric facilitatory interactions at interstimulus intervals between 2–5 ms whereas on the ventral side interactions tended to be suppressive for near-simultaneous stimuli.
We interpret these results in the context of differential activation of afferent and efferent roots and intraspinal circuit elements. In particular, we propose that distinct direct and indirect actions of spinal cord stimulation on motoneurons may be advantageous for different applications, and this should be taken into consideration when designing neuroprostheses for upper-limb function.
PMCID: PMC4013994  PMID: 24654267
12.  Phrenic Motor Unit Recruitment during Ventilatory and Non-Ventilatory Behaviors 
Phrenic motoneurons are located in the cervical spinal cord and innervate the diaphragm muscle, the main inspiratory muscle in mammals. Similar to other skeletal muscles, phrenic motoneurons and diaphragm muscle fibers form motor units which are the final element of neuromotor control. In addition to their role in sustaining ventilation, phrenic motor units are active in other non-ventilatory behaviors important for airway clearance such as coughing or sneezing. Diaphragm muscle fibers comprise all fiber types and are commonly classified based on expression of contractile proteins including myosin heavy chain isoforms. Although there are differences in contractile and fatigue properties across motor units, there is a matching of properties for the motor neuron and muscle fibers within a motor unit. Motor units are generally recruited in order such that fatigue-resistant motor units are recruited earlier and more often than more fatigable motor units. Thus, in sustaining ventilation, fatigue-resistant motor units are likely required. Based on a series of studies in cats, hamsters and rats, an orderly model of motor unit recruitment was proposed that takes into consideration the maximum forces generated by single type-identified diaphragm muscle fibers as well as the proportion of the different motor unit types. Using this model, eupnea can be accomplished by activation of only slow-twitch diaphragm motor units and only a subset of fast-twitch, fatigue-resistant units. Activation of fast-twitch fatigable motor units only becomes necessary when accomplishing tasks that require greater force generation by the diaphragm muscle, e.g., sneezing and coughing.
PMCID: PMC3183333  PMID: 21763470
13.  The human motor cortex after incomplete spinal cord injury: an investigation using proton magnetic resonance spectroscopy 
OBJECTIVES—(1) A biochemical investigation of the motor cortex in patients with incomplete spinal cord injury and normal control subjects using proton magnetic resonance spectroscopy (MRS). (2) To relate any altered biochemistry with the physiological changes in corticospinal function seen after spinal cord injury.
METHODS—a group of six patients with incomplete spinal cord injury who showed good recovery of motor function were selected. The patients were compared with five healthy control subjects. Electromyographic (EMG) responses of thenar muscles to transcranial magnetic stimulation (TMS) of the motor cortex showed that inhibition of cortical output was weaker in the patients than the controls. Proton MRS data were collected from a plane at the level of the centrum semiovale. Two 4.5 cm3 voxels in the motor cortex and a third voxel in the ipsilateral occipital cortex were examined in the patients and control subjects.
RESULTS—The mean level of N-acetylaspartate (NAA), expressed relative to the creatine (Cr) peak (NAA/Cr), was significantly increased in the motor cortex of the patients compared with their ipsilateral occipital cortex or either cortical area in the controls. No differences between patients and controls were seen for any of the other metabolite peaks (choline (Cho), glutamate/glutamine (Glx) or the aspartate component of NAA (AspNAA)) relative to Cr. Choline relative to Cr (Cho/Cr) was higher in the motor cortex of the control subjects than in their ipsilateral occipital cortex. This difference was not present in the patients.
CONCLUSIONS—Raised NAA/Cr in the motor cortex of the patients probably results from increased NAA rather than a decrease in the more stable Cr. The possible relevance of a raised NAA/Cr ratio is discussed, particularly with regard to the changed corticospinal physiology and the functional recovery seen in the patients.

PMCID: PMC2170339  PMID: 9810950
14.  Effects of Intrathecal Baclofen on Perceived Sexual Functioning in Men With Spinal Cord Injury 
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.
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.
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.
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
15.  Intrathecal baclofen therapy in severe head injury, first time in Nepal, a technique suitable for underdeveloped countries 
Asian Journal of Neurosurgery  2011;6(1):49-51.
Intrathecal baclofen (ITB) has been found to be helpful not only for spasticity but also for unconsciousness in a vegetative patient. This is the first case of ITB in Nepal, and here we discuss the effectiveness of ITB for spasticity in a patient in vegetative state. We also discuss about a simple technique for ITB used in Nepal where baclofen pump is not available. Here, we present a case of a 40-year-old male patient who had severe head injury with diffuse axonal injury treated conservatively. He went on to a vegetative state and subsequently developed severe spasticity of all the limbs. ITB was started under the guidance of one of the authors , Prof. Taira. Baclofen was injected to the spinal intrathecal space through a catheter which is used for spinal anesthesia. Spasticity improved significantly and his higher mental function also showed signs of improvement. He finally became fully conscious and well oriented. ITB is very useful in cases of severe spasticity and vegetative condition, a state of unconsciousness lasting longer than a few weeks. Even with a simple technique in the absence of baclofen pump, ITB can be used with its optimum effect.
PMCID: PMC3205552  PMID: 22059105
Intrathecal baclofen; Nepal; spasticity; vegetative state
16.  Roles of Glycinergic and Gamma-aminobutyric-ergic Mechanisms in the Micturition Reflex in Rats 
Lower urinary tract symptoms  2009;1(S1):S70-S73.
The micturition reflex is one of the autonomic reflexes mediated by the spinobulbospinal reflex pathway that passes through the pontine micturition center. In the central nervous system, glutamate is a major excitatory amino acid, while glycine and gamma-aminobutyric acid (GABA) are major inhibitory neurotransmitters and act to inhibit the micturition reflex at supraspinal and/or spinal sites. Glycine and GABA have additive or synergistic inhibitory effects on bladder activity. Hypofunction of glycinergic/GABAergic mechanisms in the lumbosacral spinal cord induces voiding dysfunctions, such as detrusor overactivity (DO) or detrusor-sphincter dyssynergia (DSD) after spinal cord injury (SCI) or bladder outlet obstruction in rats. Intrathecal, intravenous, or dietary glycine inhibits both bladder and urethral activity in normal and spinal cord injury (SCI) rats. Therefore, glycine might be a useful agent for the treatment of DO. Intrathecal muscimol and baclofen (GABAA and GABAB agonists, respectively) also inhibit non-voiding bladder contractions by suppressing C-fiber bladder afferents in SCI rats. They also improve DSD by suppressing Onuf’s nucleus and C-fiber bladder afferents. Baclofen is approved for the treatment of DO in SCI patients, but this agent has not been widely used because the therapeutic window of the drug is modest and the dose is limited by side-effects. Glutamic acid decraboxylase (GAD), the GABA synthesis enzyme, gene delivery by using non-replicating herpes simplex virus (HSV) vectors inhibits DO by suppressing C-fiber bladder afferents without affecting voiding contraction in SCI rats. Therefore, GAD gene therapy can restore urine storage function without affecting voiding function; it would be more beneficial than drug therapy for the treatment of urinary problems in SCI patients.
PMCID: PMC2910440  PMID: 20676389
gamma-aminobutyric acid; gene therapy; glutamate; glutamic acid decarboxylase; glycine
17.  Neuromuscular adaptations to respiratory muscle inactivity 
Cervical spinal cord injury results in significant functional impairment. It is important to understand the neuroplasticity in response to inactivity of respiratory muscles in order to prevent any associated effects that limit functional recovery. Recent studies have examined the mechanisms involved in inactivity-induced neuroplasticity of diaphragm motor units. Both spinal hemisection at C2 (C2HS) and tetrodotoxin (TTX)-induced phrenic nerve blockade result in diaphragm paralysis and inactivity of axon terminals. However, phrenic motoneurons are inactive with C2HS but remain active after TTX. Diaphragm muscle fibers ipsilateral to C2HS display minimal changes post-injury. Neuromuscular transmission is enhanced following C2HS but impaired following TTX. Synaptic vesicle pool size at diaphragm neuromuscular junctions increases after C2HS, but decreases after TTX. Thus, inactivity-induced neuromuscular plasticity reflects specific adaptations that depend on inactivity at the motoneuron rather than at axon terminals or muscle fibers. Theses results indicate that neuromuscular transmission and functional properties of DIAm fibers can be maintained after spinal cord injury, providing a substrate for functional recovery and/or specific therapeutic approaches such as phrenic pacing.
PMCID: PMC2783688  PMID: 19744580
Fiber Type; Inactivation; Motor Unit; Phrenic; Plasticity; Transmission
18.  Central motor conduction is abnormal in motor neuron disease. 
Conduction in the central motor pathways of the brain and spinal cord was studied in 12 patients with motor neuron disease. Six healthy volunteers served as controls. Transcutaneous electrical stimulation of the cortex, cervical cord, thoracic cord and conus medullaris was used to determine motor latencies to the biceps brachii, thenar eminence and tibialis anterior muscles. Prominent, and often asymmetrical, slowing of central motor conduction was demonstrated in seven of the 12 patients; these findings were most marked in the spinal cord and in most cases correlated with clinical features of corticospinal involvement. In general it was more difficult to excite motor pathways in the central nervous system in the patients with motor neuron disease than in control subjects. Evidence of subclinical involvement of central motor pathways was found in five patients. The central lesion in motor neuron disease may thus contribute more significantly to the clinical deficit than has been realised, since the clinical signs of the upper motor neuron lesion are often masked by the more obvious lower motor neuron features.
PMCID: PMC1031487  PMID: 3572430
19.  Differential effects on KCC2 expression and spasticity of ALS and traumatic injuries to motoneurons 
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease manifested by progressive muscle atrophy and paralysis due to the loss of upper and lower motoneurons (MN). Spasticity appears in ALS patients leading to further disabling consequences. Loss of the inhibitory tone induced by downregulation of the potassium chloride cotransporter 2 (KCC2) in MN has been proposed to importantly contribute to the spastic behavior after spinal cord injury (SCI). The aim of the present study was to test whether the alterations in the expression of KCC2 are linked to the appearance of spasticity in the SODG93A ALS murine model. We compared SODG93A mice to wild type mice subjected to SCI to mimic the spinal MN disconnection from motor descending pathways, and to sciatic nerve lesion to mimic the loss of MN connectivity to muscle. Electrophysiological results show that loss of motor function is observed at presymptomatic stage (8 weeks) in SODG93A mice but hyperreflexia and spasticity do not appear until a late stage (16 weeks). However, KCC2 was not downregulated despite MN suffered disconnection both from muscles and upper MNs. Further experiments revealed decreased gephyrin expression, as a general marker of inhibitory systems, accompanied by a reduction in the number of Renshaw interneurons. Moreover, 5-HT fibers were increased in the ventral horn of the lumbar spinal cord at late stage of disease progression in SOD1G93A mice. Taken together, the present results indicate that spasticity appears late in the ALS model, and may be mediated by a decrease in inhibitory interneurons and an increase of 5-HT transmission, while the absence of down-regulation of KCC2 could rather indicate an inability of MNs to respond to insults.
PMCID: PMC3900854  PMID: 24478630
motoneuron disease; spasticity; hypereflexia; KCC2 transporter; SOD1G93A mice
20.  Pharmacology of Intracisternal or Intrathecal Glycine, Muscimol, and Baclofen in Strychnine-induced Thermal Hyperalgesia of Mice 
Journal of Korean Medical Science  2011;26(10):1371-1377.
Glycine and γ-aminobutyric acid (GABA) are localized and released by the same interneurons in the spinal cord. Although the effects of glycine and GABA on analgesia are well known, little is known about the effect of GABA in strychnine-induced hyperalgesia. To investigate the effect of GABA and the role of the glycine receptor in thermal hyperalgesia, we designed an experiment involving the injection of muscimol (a GABAA receptor agonist), baclofen (a GABAB receptor agonist) or glycine with strychnine (strychnine sensitive glycine receptor antagonist). Glycine, muscimol, or baclofen with strychnine was injected into the cisterna magna or lumbar subarachnoidal spaces of mice. The effects of treatment on strychnine-induced heat hyperalgesia were observed using the pain threshold index via the hot plate test. The dosages of experimental drugs and strychnine we chose had no effects on motor behavior in conscious mice. Intracisternal or intrathecal administration of strychnine produced thermal hyperalgesia in mice. Glycine antagonize the effects of strychnine, whereas, muscimol or baclofen does not. Our results indicate that glycine has anti-thermal hyperalgesic properties in vivo; and GABA receptor agonists may lack the binding abilities of glycine receptor antagonists with their sites in the central nervous system.
PMCID: PMC3192351  PMID: 22022192
Hyperalgesia; Strychnine; Gamma-Aminobutyric Acid; Intracisternal; Intrathecal Drug Delivery
21.  Status Epilepticus After Baclofen Withdrawal 
Baclofen is widely used in the treatment of spasticity of spinal origin. It is relatively free of side effects or toxic actions on the nervous system or other organs. Agitation, personality change, and auditory and visual hallucinations have been described following its abrupt withdrawal. One patient with generalized seizures and one with complex partial seizures after baclofen withdrawal have been reported. This paper presents a patient who developed status epilepticus after baclofen withdrawal, and who sustained hypoxic cerebral injury. This observation further emphasizes the possibility of infrequent complications of baclofen therapy, and the advisability of gradual changes in baclofen dosage.
PMCID: PMC2561766  PMID: 6737510
22.  Intrathecal baclofen: Its effect on symptoms and activities of daily living in severe spasticity due to spinal cord injuries: A pilot study 
Indian Journal of Orthopaedics  2009;43(1):46-49.
Spasticity is a major problem related to spinal cord injuries. Use of intrathecal baclofen with an implanted pump seems a very useful mode of therapy in patients in whom oral antispasmodic agents are either not effective or produce intolerable side-effects.
Materials and Methods:
Twenty-four patients with mean age 50 years (range 32-72 years) had intrathecal baclofen pump implanted for the severe spasticity of spinal origin. One patient died following implantation of pump due to natural causes and was not included in the study. The patients were followed up for mean 22 months (range, one to five years).
All 24 patients showed improvement in their spasm following the procedure. Improvement was noted in pain (12), sleep disturbance (20) and sphincter control (14). Patients had improvement in activities of daily living such as feeding ability (10), self care (10), indoor and outdoor mobility (19), and driving (4). One patient had catheter leakage immediately after the surgery and required change of catheter. The radio telemetry allows very good adjustment of the dose according the individual patients needs.
Intrathecal baclofen pump improves the symptoms of spasm and also the quality of life. It helps the patient to live more independently. It is not an irreversible surgery for the patient and hence it is very useful in the changing the dynamics in this group of patients.
PMCID: PMC2739492  PMID: 19753179
Activities of daily living; intrathecal baclofen; spasticity; spinal cord injury
23.  Sexual Dysfunction Associated With Intrathecal Baclofen Use: A Report of Two Cases 
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.
Two case reports.
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.
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
24.  Degeneration of the Injured Cervical Cord Is Associated with Remote Changes in Corticospinal Tract Integrity and Upper Limb Impairment 
PLoS ONE  2012;7(12):e51729.
Traumatic spinal cord injury (SCI) leads to disruption of axons and macroscopic tissue loss. Using diffusion tensor imaging (DTI), we assessed degeneration of the corticospinal tract (CST) in the cervical cord above a traumatic lesion and explored its relationship with cervical atrophy, remote axonal changes within the cranial CST and upper limb function.
Nine cervical injured volunteers with bilateral motor and sensory impairment and ten controls were studied. DTI of the cervical cord and brain provided measurements of fractional anisotropy (FA), while anatomical MRI assessed cross-sectional spinal cord area (i.e. cord atrophy). Spinal and central regions of interest (ROI) included the bilateral CST in the cervical cord and brain. Regression analysis identified correlations between spinal FA and cranial FA in the CST and disability.
In individuals with SCI, FA was significantly lower in both CSTs throughout the cervical cord and brain when compared with controls (p≤0.05). Reduced FA of the cervical cord in patients with SCI was associated with smaller cord area (p = 0.002) and a lower FA of the cranial CST at the internal capsule level (p = 0.001). Lower FA in the cervical CST also correlated with impaired upper limb function, independent of cord area (p = 0.03).
Axonal degeneration of the CST in the atrophic cervical cord, proximal to the site of injury, parallels cranial CST degeneration and is associated with disability. This DTI protocol can be used in longitudinal assessment of microstructural changes immediately following injury and may be utilised to predict progression and monitor interventions aimed at promoting spinal cord repair.
PMCID: PMC3520920  PMID: 23251612
25.  Intrathecal baclofen and the H-reflex. 
Baclofen was given intrathecally to six patients with severe lower limb spasticity due to traumatic spinal cord injury. The effects of the drug on spasticity and the ratio between the maximum amplitude of the H reflex and the M response from the soleus (Hmax/Mmax ratio) were assessed. In each patient, spasticity was reduced following intrathecal baclofen and in four patients there was a reduction in the amplitude of the H reflex and Hmax/Mmax ratio. These results suggest that the Hmax/Mmax ratio may be helpful in establishing optimum drug dosage, particularly when the drug is used on a chronic basis.
PMCID: PMC1031752  PMID: 2795085

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