Baclofen Solution for Low-Volume Therapeutic Delivery.

OBJECTIVES: Baclofen is a zwitterion molecule where increased ions in the excipient increase the solubility. We developed baclofen in a stable solution similar to cerebrospinal fluid (CSF) without bicarbonate and proteins to improve the solubility of the baclofen and to reduce the potential toxicity to the central nervous system (CNS) and subarachnoid space. The objective is to develop a solution of baclofen wherein baclofen is solubilized in a multivalent physiological ion solution such as artificial cerebrospinal fluid (aCSF) at a concentration from 2 mg/cc to 10 mg/cc. METHODS: First, to determine the solubility of Baclofen in aCSF, solubility was determined at six different pH levels at 37°C, by the addition of aCSF to a known amount of Baclofen. The final concentrations were confirmed by high performance liquid chromatography (HPLC) analysis. Second, the stability of Baclofen at 4 mg/cc investigated in a test manufacturing batch utilizing standard methods of production of 1500 20 cc vials inverted for 18 months at 25°C at 60% humidity. The stability and purity of the baclofen was verified at 18 months by HPLC analysis. RESULTS: Baclofen was initially soluble between pH of 6-8 above 7 mg/cc but fell back to 6.3-5.8 mg/cc level with time. Baclofen produced in vials with inversion were noted to be stable at 4 mg/cc at 18 months with less than 2% breakdown of the baclofen in solution. CONCLUSION: Baclofen is much more soluble in artificial CSF than normal saline. The artificial CSF may also be less toxic to the subarachnoid space than saline.

Phase IIB Randomized Trial on the Use of 4-Aminopyridine in Guillain-Barré Syndrome.

OBJECTIVE: To determine the safety and efficacy of orally delivered 4-aminopyridine (4-AP) in persons with Guillain-Barré Syndrome (GBS) >6 months from initial diagnosis. DESIGN: A randomized, double-blind, placebo-controlled, crossover study. SETTING: Tertiary care clinical outpatient program. PARTICIPANTS: Nineteen participants enrolled (14 male, 5 female; N=19), neurologic impairment secondary to GBS and functional loss on the FIM motor score (stable for ≥12mo) and >3.0 but <5.0 on the American Spinal Injury motor scale. Twelve participants (mean age, 59y; range, 23-77y) completed the study. INTERVENTIONS: A 4-AP dose-escalation study with 8 weeks in each period with a 3-week washout period, followed by 3 months open-label follow-up. MAIN OUTCOME MEASURES: FIM motor score was the primary outcome measure; also evaluated were the American Spinal Injury motor strength score (all limbs), handheld dynamometer, 6-minute walk test, Medical Outcomes Study 12-Item Short Form, Center for Epidemiological Studies Depression scale, Positive and Negative Affect Schedule, pain, GBS disability scale, Jepsen-Taylor Hand Function Test, Minnesota Manual Dexterity Test and Minnesota Rate of Manipulation Test, Get Up and Go Test, McGill Pain Inventory, Craig Handicap Assessment and Reporting Technique, and participant self-evaluation. RESULTS: Seven participants discontinued the study prematurely: 3 because of adverse events, 3 because of travel difficulties or relocation, and 1 because of pretreatment laboratory abnormalities. After removing 3 participants with maximum FIM scores, 4-AP arm trended superior to placebo (P=.065). Patients subjectively could always tell when they were on the active agent usually by tingling sensations or a sense of wellness. No statistically significant differences were found for other outcome measures although there were strong trends. CONCLUSIONS: This study demonstrates the safety of 4-AP in the patient population with GBS as the predominate goal of the study. A trend toward improved function after treatment was noted with most patients electing to stay on the medication after the trial.

Prophylaxis for venous thromboembolism during rehabilitation for traumatic brain injury: a multicenter observational study.

BACKGROUND: Deep venous thrombosis (DVT) is a major cause of mortality and morbidity after traumatic brain injury (TBI). There is no consensus regarding appropriate screening, prophylaxis, or treatment during acute rehabilitation. METHODS: This prospective observational study evaluated prophylactic anticoagulation during rehabilitation in patients with TBI aged 16 years or older admitted to 12 TBI Model Systems rehabilitation centers (July 2004-December 2007). After propensity score stratification within center, the odds ratio associated with incidence of symptomatic DVT or pulmonary embolism (PE) for patients who did and did not receive prophylactic anticoagulation was estimated using conditional logistic regression in patients who were not screened for DVT on rehabilitation admission or who screened negative; the analysis was repeated in these two subgroups. RESULTS: Patients with identified DVTs at rehabilitation admission (n = 266) were excluded, leaving 1,897 patients: 1,002 screened negative, 895 unscreened; 932 received prophylactic anticoagulation, and 965 did not. Symptomatic DVT/PE was detected in 32 patients (15 of 932 [1.6%] with prophylaxis, 17 of 965 [1.8%] without). After propensity score adjustment, the odds ratio (95% confidence interval) for symptomatic DVT/PE with prophylaxis versus no prophylaxis was 0.80 (0.33-1.94) in the full analytic population and 0.46 (0.12-1.84) in the screened-negative subgroup. The only probable venous thromboembolism-related death occurred in the prophylactic anticoagulation group. Fewer new/expanded intracranial hemorrhages occurred among patients who received prophylactic anticoagulation. CONCLUSIONS: Prophylactic anticoagulation during rehabilitation seemed safe for TBI patients whose physicians deemed it appropriate, but did not conclusively reduce venous thromboembolism. Given the number of DVTs present before rehabilitation, screening and prophylaxis during acute care may be more important.

A preliminary assessment of the benefits of the addition of botulinum toxin a to a conventional therapy program on the function of people with longstanding stroke.

OBJECTIVE: To determine if botulinum toxin type A (BTX-A) combined with therapy can facilitate improved upper-extremity (UE) functional status versus therapy alone. DESIGN: Double-blind randomized crossover trial. SETTING: Tertiary care outpatient rehabilitation center. PARTICIPANTS: Convenience sample of 21 men and women (ages 19-80 y) with stroke more than 6 months after insult who had tone greater than 3 on the Ashworth Scale for 2 joints in the involved UE. INTERVENTION: Subjects were consecutively recruited and randomized to a double-blind crossover trial. Subjects received either BTX-A combined with a defined therapy program or placebo injection combined with a therapy program in two 12-week sessions. MAIN OUTCOME MEASURES: The primary functional outcome measure was the Motor Activity Log (MAL). Subjects were also assessed on physiologic measures including tone (Ashworth Scale), range of motion, and motor strength. RESULTS: Improvements were noted in the functional status of the subjects in both arms of the study as measured by the MAL. All subjects had a significant change in functional status on MAL with therapy (P<.05). The use of BTX-A combined with therapy as compared with therapy only improved the functional status of the subjects on the MAL Quality of Movement subscale (P=.0180, t test) and showed a trend toward significance in the Amount of Use subscale (P=.0605, analysis of variance). Six weeks after treatment, the BTX-A combined with therapy decreased the Ashworth score statistically (P=.0271), but the therapy alone group decreased a similar amount at 6 weeks (P=.0117), indicating that most of the physiologic tone change could be attributed to therapy. After each 12-week period, tone had largely returned to baseline (P>.05). CONCLUSION: A focused therapy program showed the most improvement in function in this defined stroke population. BTX-A combined with a focused traditional therapy program slightly enhanced the functional status of stroke subjects beyond that obtained with therapy alone 12 weeks after injection.

Supportive care for patients with Guillain-Barré syndrome.

A multidisciplinary consensus group searched MEDLINE from 1966 to May 2003, extracted relevant references, and prepared recommendations on supportive care for Guillain-Barré syndrome. In the absence of randomized controlled trials, we agreed on recommendations by consensus based on observational studies and expert opinion. In the acute phase in bed-bound adult patients, the group recommended the use of heparin and graduated pressure stockings to prevent deep vein thrombosis, monitoring for blood pressure, pulse, autonomic disturbances, and respiratory failure, and the timely institution of artificial ventilation and tracheostomy. Pain management is difficult, but carbamazepine or gabapentin may help. The cautious use of narcotic analgesics may be needed. Disabled patients should be treated by a multidisciplinary rehabilitation team and should receive an assistive exercise program. Persistent fatigue following Guillain-Barré syndrome is common and may be helped by an exercise program. Because of a very small and possibly only theoretical increase in the risk of recurrence following immunization, the need for immunization should be reviewed on an individual basis. More research is needed to identify optimal methods for all aspects of supportive care.

Cushing's syndrome from epidural methylprednisolone.

Iatrogenic Cushing's syndrome has been reported after the use of nasal, aerosol, oral, and intramuscular steroid preparations. Presented is a case of Cushing's syndrome due to an epidural injection of methylprednisolone. A 24-year-old man had left arm pain after an occupational injury. Electromyography revealed C7 radioculopathy and cervical laminectomy was performed. Postoperatively, the patient noted improvement, however, he had recurrence of his symptoms within 1 month. Significant pain in the left arm, accompanied by swelling, persisted despite non-steroidal anti-inflammatory and anti-depressant medications. Repeat electromyography showed a resolving C7 with increased polyphasic potentials. Reflex sympathetic dystrophy was diagnosed and the patient received 3 stellate ganglion blocks with relief of the swelling, but only temporary relief of pain. He then underwent epidural injection of 60 mg of methylprednisolone. A cushingoid appearance was noted approximately 1 month later. Serum cortisol was undetectable, there was no adrenal response to synthetic ACTH, and urinary-free cortisol was below normal at 12. The patient eventually underwent a second surgical procedure for his pain and required steroid coverage. His pain subsequently showed slow improvement. Urinary-free cortisol normalized 4 months after onset; however, the patient's cushingoid appearance persisted for 12 months.

Impact of early administration of sertraline on depressive symptoms in the first year after traumatic brain injury.

The potential for sertraline administered in the first 3 months after moderate to severe traumatic brain injury (TBI) to decrease the incidence of depression in the first year after injury was assessed in a double-blinded randomized control trial. Subjects were enrolled an average of 21 days after injury (none >8 weeks) followed by oral administration of placebo (50 subjects) or sertraline 50 mg (49 subjects) for 3 months. Subjects were not depressed at the time of study initiation. Outcome was assessed using the Hamilton Depression Rating Scale (HDRS) and the Depression Scale of the Neurobehavioral Functioning Inventory (NFI). Based on intent-to-treat and efficacy subset analyses, those receiving placebo exhibited significantly greater depressive symptoms than those receiving sertraline during the first 3 months after injury while receiving placebo/drug (10% of placebo group achieving a score of 6 or greater on the HDRS, 0% of the sertraline group; p < 0.023.). There was no significant difference in depressive symptoms during the remainder of the year between the two groups. Sertraline is effective in diminishing depressive symptoms even among those not clinically depressed while the medication is being taken. However, the results do not support the idea that administration early in recovery diminishes the expression of depressive symptoms after the drug is stopped. There is no basis from this study to assume that sertraline administered early in recovery after TBI, when neurotransmitter functioning is often altered, has ongoing effects on the serotonin system after sertraline is discontinued.

Constraint-induced movement therapy for recovery of upper-limb function following traumatic brain injury.

A volunteer sample of 22 participants with chronic traumatic brain injury (TBI) (onset >1 year) and relative hemiplegia that revealed moderate disability in the more-affected upper limb (UL) participated. Constraint-induced (CI) movement therapy (CI therapy) was employed for a 2-week period; treatments included massed practice, shaping of the more-affected UL, behavioral contracts, and other behavioral techniques for affecting transfer to a real-world setting. We used the Wolf Motor Function Test, the Fugl-Meyer Motor Performance Assessment, and the Motor Activity Log to measure outcomes. All outcome measures improved significantly as a result of the intervention. More-adherent participants had more improvement compared with less-adherent participants. These preliminary results suggest that CI therapy may be effective for improving UL motor function following chronic TBI.

Cyproheptadine for intrathecal baclofen withdrawal.

OBJECTIVE: To evaluate the efficacy of cyproheptadine in the management of acute intrathecal baclofen (ITB) withdrawal. DESIGN: Descriptive case series. SETTING: University hospital with a comprehensive in- and outpatient rehabilitation center. PARTICIPANTS: Four patients (3 with spinal cord injury, 1 with cerebral palsy) with implanted ITB infusion pumps for treatment of severe spasticity, who had ITB withdrawal syndrome because of interruption of ITB infusion. INTERVENTIONS: Patients were treated with 4 to 8mg of cyproheptadine by mouth every 6 to 8 hours, 5 to 10mg of diazepam by mouth every 6 to 12 hours, 10 to 20mg of baclofen by mouth every 6 hours, and ITB boluses in some cases. MAIN OUTCOME MEASURES: Clinical signs and symptoms of ITB withdrawal of varying severity were assessed by vital signs (temperature, heart rate), physical examination (reflexes, tone, clonus), and patient report of symptoms (itching, nausea, headache, malaise). RESULTS: The patients in our series improved significantly when the serotonin antagonist cyproheptadine was added to their regimens. Fever dropped at least 1.5 degrees C, and heart rate dropped from rates of 120 to 140 to less than 100bpm. Reflexes, tone, and myoclonus also decreased. Patients reported dramatic reduction in itching after cyproheptadine. These changes were associated temporally with cyproheptadine dosing. DISCUSSION: Acute ITB withdrawal syndrome occurs frequently in cases of malfunctioning intrathecal infusion pumps or catheters. The syndrome commonly presents with pruritus and increased muscle tone. It can progress rapidly to high fever, altered mental status, seizures, profound muscle rigidity, rhabdomyolysis, brain injury, and death. Current therapy with oral baclofen and benzodiazepines is useful but has variable success, particularly in severe cases. We note that ITB withdrawal is similar to serotonergic syndromes, such as in overdoses of selective serotonin reuptake inhibitors or the popular drug of abuse 3,4-methylenedioxymethamphetamine (Ecstasy). We postulate that ITB withdrawal may be a form of serotonergic syndrome that occurs from loss of gamma-aminobutyric acid B receptor-mediated presynaptic inhibition of serotonin. CONCLUSION: Cyproheptadine may be a useful adjunct to baclofen and benzodiazepines in the management of acute ITB withdrawal syndrome.

Orally delivered baclofen to control spastic hypertonia in acquired brain injury.

To determine if oral/systemic delivery of baclofen can effectively decrease spastic hypertonia due to acquired brain injury (traumatic brain injury, stroke, anoxia, or encephalopathy). Tertiary care outpatient rehabilitation center directly attached to a university hospital. Patients were a convenience sample recruited consecutively who had been referred for treatment of their spastic hypertonia to our spasticity clinic over a 5-year period. The spastic hypertonia was due to an acquired brain injury by either traumatic brain injury (TBI), stroke, or anoxic brain injury. All patients were more than 6 months postinjury or illness. Retrospective review of patients before and after initiation of treatment with oral baclofen, per standardized clinical data sheets. Thirty-five patients (22 TBI patients) were started on oral baclofen and were reevaluated between 1 to 3 months after initiation of treatment. Data for motor tone (Ashworth scores), spasm scores (Penn spasm frequency score), and deep tendon reflex scores were collected on the affected upper extremity (UE) and lower extremity (LE) side(s). Normal extremities were not assessed. Differences over time were assessed via descriptive statistics and Wilcoxon signed-rank. After 1 to 3 months of treatment when subjects had reached their maximal tolerated dosage, the average LE Ashworth score in the affected lower extremities (LEs) decreased from 3.5 to 3.2 (P =.0003), the reflex score decreased from 2.5 to 2.2 (P =.0274), and there was no statistical difference in the spasm score (P >.05). When the 22 TBI patients are analyzed separately, the average LE Ashworth score decreased from 3.5 to 3.2 (P =.0044) and the reflex score decreased from 2.7 to 2.0 (P =.0003). There was no statistically significant change in UE tone, spasm frequency, or reflexes after 1 to 3 months of treatment (P >.05). The average dosage at follow-up was 57 mg/day of baclofen (range 15-120 mg/day). There was a 17% incidence of somnolence that limited the maximum daily dosage of the medication. The oral delivery of baclofen is capable of reducing LE spastic hypertonia resulting from acquired brain injury. The lack of effect upon the upper extremities may be due to receptor specificity issues. GABA-B receptors may be less involved in the modulation of UE spastic hypertonia.

Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial.

BACKGROUND: Traumatic brain injury (TBI) caused by a high-speed transportation accident results in a mechanism of injury commonly described as diffuse axonal injury (DAI), which is associated with a reduction in dopamine turnover in the brain. Because of its affect on both dopamine and N-methyl-D-aspartate (NMDA) channels, amantadine has been the subject of considerable interest and clinical use in acute TBI. PARTICIPANTS: In this study, 35 subjects, who had a TBI in a transportation accident and were initially seen with a Glasgow Coma Scale score of 10 or less within the first 24 hours after admission, were randomly assigned to a double-blind, placebo-controlled, crossover design trial. MAIN OUTCOME MEASURES: Amantadine, 200 mg, or placebo was each administered for 6 weeks (12 weeks total) to patients who were recruited consecutively. RESULTS: There was an improvement in the Mini-Mental Status (MMSE) scores of 14.3 points (P =.0185), Disability Rating Scale (DRS) score of 9.8 points (P =.0022), Glasgow Outcome Scale (GOS) score of 0.8 points (P =.0077), and in the FIM Cognitive score (FIM-cog) of 15.1 points (P =.0033) in the group that received amantadine during the first 6 weeks (group 1), but there was no improvement in the second 6 weeks on placebo (P >.05). In group 2 (active drug second 6 weeks), there was an improvement in the MMSE of 10.5 points, in the DRS of 9.4 points (P =.0006), in the GOS of 0.5 points (P =.0231), and in the FIM-cog of 11.3 points (P =.0030, Wilcoxon signed rank) spontaneously in the first 6 weeks on placebo (P =.0015). However, group 2 gained a statistically significant additional 6.3 points of recovery in the MMSE (P =.0409), 3.8 points in the DRS (P =.0099), 0.5 points in the GOS (P =.4008), and 5.2 points in the FIM-cog (P =.0173, Wilcoxon signed rank) between the sixth week and the twelfth week of treatment on the active drug. CONCLUSIONS: There was a consistent trend toward a more rapid functional improvement regardless of when a patient with DAI-associated TBI was started on amantadine in the first 3 months after injury.

Screening for venous thromboembolism in traumatic brain injury: limitations of D-dimer assay.

OBJECTIVES: To assess whether 2 different D-dimer fibrin degradation assays-a second-generation latex immunosorbent agglutination (LIA) and an enzyme-linked immunosorbent assay (ELISA)-are predictive for the development of deep venous thrombosis (DVT) at the currently accepted level of 500 microg/L of D-dimer assay during the first weeks after traumatic brain injury (TBI) and to correlate over 8 weeks the second-generation LIA assay with the ELISA assay after acute TBI. DESIGN: A case series of persons with TBI were screened for DVT at 2 weeks (+/-3d) using real-time, spectral Doppler ultrasound, as well as D-dimer fibrin split products. All persons were rescreened at 4, 6, and 8 weeks (+/-3d) after injury using D-dimer LIA and ELISA assays. SETTING: A university hospital with a directly connected comprehensive in- and outpatient rehabilitation center that are part of the Traumatic Brain Injury Model Systems. PARTICIPANTS: Over 3 years, 35 TBI subjects with a mean Glasgow Coma Scale score of 6.5 were consecutively enrolled into the trial while on acute care. Persons were at least 16 years of age with no history of treatment for DVT. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Data were analyzed for the levels of D-dimer and risk as established by a predictive value of 500 microg/L. Changes in D-dimer values over time and within subjects were assessed by analysis of variance (ANOVA) with repeated measures, and the methods were correlated. RESULTS: The mean LIA level at 2 weeks was 4.3mg/L and averaged 1.6 mg/L at 8 weeks from injury (P=.012, ANOVA), and the ELISA dropped from 4,748 microg/L to 1.695 microg/L (P=.0022, ANOVA). Except for 1 ELISA value in 1 patient, D-dimer levels were elevated beyond 500 microg/L at 2 weeks. There was a very good correlation between the LIA and the ELISA at 2, 4, 6, and 8 weeks after TBI (P<.0001). In individual cases, there were only occasional discrepancies between the LIA and ELISA methods. There were no positive DVTs at 2 weeks using ultrasound, so prediction of the sensitivity and the specificity of D-dimer with DVT was not possible. CONCLUSION: Using the currently recommended levels of D-dimer to predict DVT is not clinically useful in the acute TBI population.

Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome.

OBJECTIVE: To suggest guidelines for the prevention, recognition, and management of a life-threatening syndrome (high fever, altered mental status, profound muscular rigidity that sometimes progressed to fatal rhabdomyolysis) in patients who experience the abrupt withdrawal of intrathecal baclofen (ITB) therapy. DESIGN: Retrospective literature and safety-file review. SETTING: Expert panel drawn from physiatry, neurology, and neurosurgery. PARTICIPANTS: Experienced users of ITB therapy in the pediatric and adult populations in the United States. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We reviewed literature reports, MedWatch reports to the US Food and Drug Administration, and our own experiences. We critically analyzed patient management and drug therapy in the context of the pharmacology of baclofen and other antispastic agents. RESULTS: An abrupt reduction in gamma-aminobutyric acid(B) (GABA) agonist activity in the central nervous system can cause the ITB withdrawal syndrome, which is clinically and pathophysiologically distinct from autonomic dysreflexia, malignant hyperthermia, and neuroleptic-malignant syndrome. ITB withdrawal evolves over 1 to 3 days, but may become fulminant if not recognized and treated early. The syndrome can be interrupted by the restoration of ITB therapy. However, supportive measures and high-dose benzodiazepine infusion may be life saving in the interval before ITB therapy is resumed. Dantrolene infusion may relieve muscle rigidity but does not reverse the other manifestations of GABAergic agonist withdrawal. CONCLUSIONS: Most episodes of severe ITB withdrawal were preventable. Patients at risk can be identified and educated prospectively and given medication for emergency use. Treatment with GABAergic agonist drugs may prevent potentially fatal sequelae.