Pharmacology References

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(1970) Diazepam in spasticity. Lancet 1, 1161-1162.

(1973) Baclofen for spasticity. Drug Ther. Bull. 11, 63-64.

(1974) Dantrolene sodium for treatment of spasticity. Med. Lett. Drugs Ther. 16, 61-62.

(1974) A comparative trial of dimethothiazine in spastic conditions. Practitioner 213, 101-105.

(1977) Oestrogens, calcium transport, and coronary spasm. Lancet 1, 229-230.

(1983) Drugs to relieve spasticity. Drug Ther. Bull. 21, 1-3.

(1984) Mantakassa: an epidemic of spastic paraparesis associated with chronic cyanide intoxication in a cassava staple area of Mozambique. 1. Epidemiology and clinical and laboratory findings in patients. Ministry of Health, Mozambique. Bull. World Health Organ 62, 477-484.

(1984) Mantakassa: an epidemic of spastic paraparesis associated with chronic cyanide intoxication in a cassava staple area of Mozambique. 2. Nutritional factors and hydrocyanic acid content of cassava products. Ministry of Health, Mozambique. Bull. World Health Organ 62, 485-492.

(1989) Spasticity. Lancet 2, 1488-1490.

(1991) Consensus conference. Clinical use of botulinum toxin. National Institutes of Health. Conn. Med. 55, 471-477.

(1994) Intrathecal baclofen for spasticity. Med. Lett. Drugs Ther. 36, 21-22.

(1994) A double-blind, placebo-controlled trial of tizanidine in the treatment of spasticity caused by multiple sclerosis. United Kingdom Tizanidine Trial Group. Neurology 44, S70-S78.
Abstract: Tizanidine was evaluated in a prospective, double-blind, randomized, placebo-controlled trial in 187 patients with MS. Taken orally for 9 weeks and preceded by a titration phase for a period of 3 weeks starting at 2 mg daily, tizanidine produced a significant reduction in spastic muscle tone compared with placebo treatment. Within the effective dose range of 24 to 36 mg given daily in three doses, tizanidine achieved a 20% mean reduction in muscle tone. Approximately 75% of patients, with all degrees of spasticity, reported subjective improvement without an increase in muscle weakness, but there was no improvement in activities of daily living depending on movement. Tizanidine achieved its maximum effect on spasticity within 1 week of the start of treatment; the benefit was maintained for at least 1 week after discontinuation of therapy. A variety of adverse events was recorded by patients taking tizanidine, but these were minor and reversible, and rarely limited treatment. Tizanidine is a well- tolerated and effective drug for symptomatic treatment of spasticity

(1997) Marijuana as medicine: how strong is the science? Consum. Rep. 62, 62-63.

(1997) Tizanidine for spasticity. Med. Lett. Drugs Ther. 39, 62-63.

(1998) Spasticity: current and future management. Royal College of Physicians, November 13, 1997. Hosp. Med. 59, 61-69.
Abstract: Tizanidine hydrochloride (Zanaflex), an alpha 2-adrenoreceptor agonist, is the first new antispasticity agent to become available in the UK for more than 20 years. It provides effective reduction of spasticity without affecting muscle strength. The mechanisms of spasticity, its measurement and management, together with the place of tizanidine in its treatment, were discussed at a symposium held at the Royal College of Physicians on November 13 1997

Aarli J.A. (1992) [Treatment with botulinum toxin--a new and effective therapy]. Tidsskr. Nor Laegeforen. 112, 2624.

Abbott R. (1996) Sensory rhizotomy for the treatment of childhood spasticity. J. Child Neurol. 11 Suppl 1, S36-S42.
Abstract: Sensory rhizotomy in the treatment of spasticity has been evolving over the past century since its first use in 1888. This paper reviews its historical evolution, current physiologic basis, range in current surgical technique, and the outcome, along with complications seen over the past decade since its repopularization

Abdel-Salam A., Eyres K.S., and Cleary J. (1992) A new paradiscal injection technique for the relief of back spasm after chemonucleolysis. Br. J. Rheumatol. 31, 491-493.
Abstract: Back spasm, or spasm of the back muscles, is the commonest adverse reaction encountered after chemonucleolysis. In order to overcome this troublesome complication, the authors present a new 'paradiscal injection technique'. After the injection of chymopapain into the affected disc, the needle is withdrawn to just outside the annulus. Bupivacaine is injected into the paradiscal 'space' which acts upon the paravertebral muscles. Eighty consecutive patients have been treated by chemonucleolysis with paradiscal injection for pain relief. All patients were discharged the same day or the following day and no immediate complications occurred. When reviewed 3 weeks later, only three (3.8%) patients complained of back pain (which was different in character to that present before the injection or was exacerbated by the injection). Pain persisted in the same patients until 6 months after the injection but was negligible. None of the remaining patients had developed back pain as a result of chymopapain. The authors suggest that the addition of paradiscal injection of bupivicaine after cymopapain injection can reduce the incidence of spasm of the back muscles. This technique is a major contribution to increasing the efficacy of chemonucleolysis for the treatment of herniated lumbar disc

Abel N.A. and Smith R.A. (1994) Intrathecal baclofen for treatment of intractable spinal spasticity. Arch. Phys. Med. Rehabil. 75, 54-58.
Abstract: This study assessed the safety and efficacy of intrathecal baclofen in the treatment of intractable spasticity caused by spinal cord injury or multiple sclerosis. Twenty-three patients with severe chronic spasticity underwent bolus test dosing with 50, 75, or 100 micrograms of intrathecal baclofen administered by lumbar puncture. All patients were either refractory to oral baclofen at a dose of 120 mg/d or side effects were unacceptable at a lower dose. There was a significant decrease in tone and spasticity in all 23 patients. Nineteen patients underwent implantation of a programmable pump and intrathecal catheter designed to deliver baclofen directly to the spinal cord. Rigidity (tone) was decreased from a mean prebolus Ashworth score of 3.8 to a mean postbolus Ashworth score of 1.5 and spasms from a mean prebolus score of 3.5 to a mean postbolus score of 1.2 for a minimum of 4 hours. Patients have been observed for a mean of 16 months (range 2 to 34 months). Ashworth scores have remained reduced to an acceptable level (< or = 2 with periodic adjustment in dosage in all but three patients. There has been one pump malfunction and four catheter malfunctions; few serious medication and postoperative complications have occurred. There was one death caused by underlying disease, one patient voluntarily withdrew, and three patients developed tolerance to the extent that optimal control of spasticity tone could not be maintained. Although intrathecal baclofen is safe and effective in the majority of patients, three patients required > 1,000 micrograms/d with increasingly higher doses over time and exhibited a poor response

Abramson A.S. (1967) Modern concepts of management of the patient with spinal cord injury. Arch. Phys. Med. Rehabil. 48, 113-121.

Acland R.H. (1993) Intrathecal baclofen for the management of severe spasticity. N. Z. Med. J. 106, 129-130.

Adachi H., Riku S., Fujishiro K., and Kuru S. (1998) [A case of Satoyoshi syndrome with symptoms resembling neuroleptic malignant syndrome]. Rinsho Shinkeigaku 38, 637-640.
Abstract: Satoyoshi syndrome is a rare neurological disorder of unknown etiology characterized by progressive muscle spasms, alopecia, diarrhea and skeletal abnormalities. We here describe a 25-year-old man who developed symptoms similar to neuroleptic malignant syndrome (NMS). He began to have the clinical characteristics of Satoyoshi syndrome at the age of 12 years. He was admitted to hospitals many times with painful muscle spasms and pyrexia in the early stage of the disease. He received steroid pulse therapy and oral prednisone at the age of 19, the extent and frequency of the spells being reduced thereafter. He was admitted to our hospital due to recurrence of his usual muscle spasms. He was treated with midazolam intravenously to relieve severe muscle ache, pain in the left shoulder, and insomnia. About 90 minutes later, he became comatose, with the following manifestations: hyperthermia, low blood pressure, tachycardia, profuse perspiration, acute respiratory failure, and ensuing cardiac arrest. He developed rhabdomyolysis, acute renal failure, hepatic damage, and diffuse intravascular coagulation. Serum creatine kinase level was elevated to 306,910 IU. He died of multiple organ failure 13 days after admission. His symptoms resembled NMS and malignant hyperthermia (MH). None of patients with Satoyoshi syndrome accompanied by NMS or MH have been reported. It remains to be clarified whether midazolam administration induces NMS in Satoyoshi syndrome. Nevertheless, careful attention should be paid when one administers midazolam to patients with this syndrome

Adamcho N.I., Bondar' V.P., and Rusavskii I.V. (1978) [Prevention and treatment of the complications of peridurography]. Vopr. Neirokhir. 43-47.
Abstract: In lumbar peridurography conducted in 117 patients with discogenic radiculitis complications occurred both in the stage of peridural anesthesia and after introduction of the radiocontrast medium. During anesthesia the dura mater was punctured in 4 patients, in another 2 patients dicaine penetrated into the subarachnoid space and caused spinal anesthesia with a high upper level. Peridural anesthesia with paralysis of the respiratory musculature developed in 1 patient. After the injection of the radiocontrast medium, spasm in the lower extremities and trunk of the type of spinal epilepsy developed in 4 patients. The clinical picture, prevention, and treatment of these complications are discussed

Advokat C., Mosser H., and Hutchinson K. (1997) Morphine and dextrorphan lose antinociceptive activity but exhibit an antispastic action in chronic spinal rats. Physiol Behav. 62, 799-804.
Abstract: Within 3-4 weeks after spinal transection, morphine-induced antinociception, assessed with the tail flick reflex in rats, is profoundly reduced. The cause of this decrement is unknown. The present studies were conducted to determine whether this phenomenon reflects a general loss in opiate activity or a selective decline in opiate antinociception. This was accomplished by assessing the effect of morphine on two different responses, the tail flick reflex and the hindlimb spasticity that develops in chronic spinal rats. Because excitatory amino acid antagonists are also antinociceptive in acute spinal rats, the effect of one such drug, dextrorphan, on these two behaviors was also evaluated in chronic spinal animals. The antinociceptive and antispastic effect of subcutaneous (6 mg/kg) and intrathecal (5 micrograms) morphine injections were assessed in intact and chronic (21-28 days) spinal rats, whereas the effect of subcutaneous (25 and 40 mg/kg) and intrathecal (350 micrograms) dextrorphan was assessed in acute (1 day) and chronic spinal rats. The antinociceptive effect of both drugs was significantly reduced in chronic spinal animals, relative to saline controls. However, each drug treatment produced a significant antispastic effect in the same animals, indicating a selective decline in opiate action. This outcome also suggests that excitatory amino acid antagonists may be useful as adjunct antispastic agents

Agar N.S., Irvine S., Davis J.R., and Harley J.D. (1972) Enzymopenic methaemoglobinaemia and spastic diplegia in an Italian- Yugoslavian child. Med. J. Aust. 2, 429-430.

Ahmadi-Abhari S.A., Akhondzadeh S., Assadi S.M., Shabestari O.L., Farzanehgan Z.M., and Kamlipour A. (2001) Baclofen versus clonidine in the treatment of opiates withdrawal, side- effects aspect: a double-blind randomized controlled trial. J. Clin. Pharm. Ther. 26, 67-71.
Abstract: OBJECTIVE: Baclofen is known for the alleviation of signs and symptoms of spasticity. Reports from our previous study have suggested that it may be at least as effective as clonidine in the management of physical symptoms of opiate withdrawal syndromes and superior to clonidine in the management of mental symptoms. We now report on a randomized double- blind comparison of baclofen vs. clonidine in view of side-effects profile. METHODS: A total of 62 opiates addicts were randomly assigned to treatment with baclofen or clonidine during a 14-day, double-blind clinical trial. All patients met the DSM IV criteria for opioid dependence. Maximum daily doses were 40 mg for baclofen and 0.8 mg for clonidine. This trial medication was given three times per day in divided doses. The severity of side-effects was measured in days 0, 1, 2, 3, 4, 7 and 14. RESULTS: There was no significant difference between two treat7ments in terms of retention in treatment (dropout) and overall side-effect. Nevertheless, significantly more problems relating to hypotension were encountered with subjects on clonidine. CONCLUSION: We conclude that, the low incidence of hypotension with baclofen suggests that the drug may be suitable for outpatient ambulatory treatment of withdrawal from opiates

Aicardi J. and Chevrie J.J. (1975) [Neurologic manifestations following pertussis vaccination]. Arch. Fr. Pediatr. 32, 309-317.
Abstract: Twenty cases of acute neurological complications occuring within 7 days of pertussis immunization are reported. Convulsions were present in every case and status epilepticus was observed in five infants. In only 4 cases were neurological or epileptic sequelae lacking. The clustering of neurological complications in the 24 hours following immunization is not consistent with the hypothesis of a mere temporal coincidence. However, the mechanism and incidence of post-immunization encephalopathies remains obscure and epidemiological studies are in order

Aisen M.L., Dietz M.A., Rossi P., Cedarbaum J.M., and Kutt H. (1992) Clinical and pharmacokinetic aspects of high dose oral baclofen therapy. J. Am. Paraplegia Soc. 15, 211-216.
Abstract: Baclofen is a centrally acting muscle relaxant used for treatment of spasticity. Some patients, to experience adequate symptomatic relief, require dosages of baclofen that significantly exceed the conventional 80 mg daily maximum advocated by the 1992 Physicians' Desk Reference. In this pilot study of baclofen kinetics and dynamics in eleven patients, the safety and efficacy of high dose baclofen was confirmed. The data suggest that the pharmacokinetics of high dose baclofen may vary from those described previously. Time-to-peak plasma levels and plasma half-lives were noted to be substantially longer than prior reports indicate. Baclofen blood levels were observed to rise gradually over time in some patients on a stable dosing regimen, probably a result of impaired renal clearance. These findings may indicate that a change in pattern of prescription is warranted and that a reliable and practical measurement of systemic baclofen levels has a useful role in clinical practice, particularly for the patient with neurogenic bladder and potential renal insufficiency

Aisen M.L., Dietz M., McDowell F., and Kutt H. (1994) Baclofen toxicity in a patient with subclinical renal insufficiency. Arch. Phys. Med. Rehabil. 75, 109-111.
Abstract: Baclofen, a centrally acting gamma-aminobutyric acid agonist is a commonly used pharmacotherapy for spasticity of spinal origin. It is primarily excreted by glomerular filtration with a clearance proportional to creatinine clearance. We describe a 39-year-old quadriplegic women who, over a 16-week period, developed clinical signs of baclofen toxicity confirmed by progressively rising serum baclofen levels while on a conventional stable dosing regimen. During this period blood urea nitrogen and creatinine concentrations were normal and stable (9mg/dL and 0.8mg/dL, respectively). However, creatinine clearance values were consistently low (55 to 60m/min), suggesting renal insufficiency as the underlying cause. After a decrease in baclofen dosage, evidence of baclofen toxicity resolved. Clinicians should be alert to signs of evolving baclofen toxicity even in patients on an apparently stable regimen. Baclofen dosage adjustments based on systemic baclofen level may play a role in optimizing the clinical management of spasticity

Akinfieva T.A. and Gerasimova I.L. (1984) [Comparative toxicity of various barium compounds]. Gig. Tr. Prof. Zabol. 45-46.

Akiyama T., Maeda K., and Yamada W. (1971) [Electromyographic studies on muscle tone of the lower extremities in spastic paralysis]. Iryo. 25, 74-90.

Akman M.N., Loubser P.G., Donovan W.H., O'Neill M.E., and Rossi C.D. (1993) Intrathecal baclofen: does tolerance occur? Paraplegia 31, 516-520.
Abstract: Concern over the development of tolerance in patients on continuous intrathecal baclofen therapy has arisen as this new form of treatment for spasticity has gained wider use. We have studied time-dose relationships in 18 spinal cord injured patients who have undergone intrathecal baclofen infusion pump implantation since February 1988 in our facility. Our data show that there was a significant increase in baclofen dosage needed to control spasticity during the first 12 months post implantation. After 12 months, however, no significant changes in dosage requirement was detected. In addition, there was no significant difference between completely and incompletely spinal cord injured patients with regard to both the initial dose and the tolerance trend

Akman M.N., Loubser P.G., Fife C.E., and Donovan W.H. (1994) Hyperbaric oxygen therapy: implications for spinal cord injury patients with intrathecal baclofen infusion pumps. Case report. Paraplegia 32, 281-284.
Abstract: A patient with a cervical spinal cord injury receiving intrathecal baclofen for spasticity control underwent a 7 week course of hyperbaric oxygen therapy to induce healing of an ischial decubitus ulcer. After completion of this treatment and during a routine baclofen infusion pump refill, the actual pump reservoir volume exceeded computer measurements obtained with telemetry. Examination of the physiology of hyperbaric oxygen therapy in relation to infusion pump function revealed that the intraspinal pressures attained during hyperbaric oxygen therapy produced retrograde leakage of cerebrospinal fluid into the infusion pump reservoir

Al Essa M.A., Bakheet S.M., Patay Z.J., Nounou R.M., and Ozand P.T. (1999) Cerebral fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography (FDG PET), MRI, and clinical observations in a patient with infantile G(M1) gangliosidosis. Brain Dev. 21, 559-562.
Abstract: The clinical, biochemical, pathological and neuroradiological findings of a 2-year-old Saudi boy with infantile G(M1) gangliosidosis are reported. The patient had a progressive neurologic deterioration, manifesting with developmental regression, sensorimotor and psychointellectual dysfunction and generalized spasticity that started at 4 months of age. Cherry-red macula, facial dysmorphia, hepatomegaly, exaggerated startle response to sounds, skeletal dysplasia, and vacuolated foamy lymphocytes that contain finely fibrillar material in addition to lamellar membranes and electron-dense rounded bodies were seen. MRI of the brain demonstrated mild diffuse brain atrophy and features of delayed dysmyelination and demyelination. Brain FDG PET scan revealed a mild decrease in the basal ganglia uptake, and moderate to severe decrease in thalamic and visual cortex uptake, and an area of increased glucose uptake in the left frontal lobe, probably representing an active seizure focus. The functional changes indicated by FDG PET scan and the structural abnormalities shown on MRI were found to be complementary in the imaging evaluation of infantile G(M1) gangliosidosis

Al Khodairy A.T., Gobelet C., and Rossier A.B. (1998) Has botulinum toxin type A a place in the treatment of spasticity in spinal cord injury patients? Spinal Cord. 36, 854-858.
Abstract: OBJECTIVE: To present and discuss treatment of severe spasms related to spinal cord injury with botulinum toxin type A. DESIGN: A 2-year follow- up study of an incomplete T12 paraplegic patient, who was reluctant to undergo intrathecal baclofen therapy, presenting severe painful spasms in his lower limbs treated with intramuscular injections of botulinum toxin type A. SETTING: Department of Physical Medicine and Rehabilitation, Hopital de Gravelone, Sion, Switzerland. SUBJECT: Single patient case report. MAIN OUTCOME MEASURE: Spasticity, spasms and pain measured with the modified Ashworth scale, spasm frequency score and visual analogue scale. RESULTS: Treatment of spasticity with selective intramuscular injections of botulinum toxin type A resulted in subjective and objective improvement. CONCLUSION: Botulinum toxin type A has its place in the treatment of spasticity in spinal cord injury patients. This treatment is expensive and its effect is reversible. It can complement intrathecal baclofen in treating upper limb spasticity in tetraplegic patients. Tolerance does occur to the toxin. Although high doses of the product are well tolerated, the quantity should be tailored to the patient's need. The minimal amount necessary to reach clinical effects should be adhered to and booster doses at short period intervals should be avoided

Al Khodairy A.T., Vuagnat H., and Uebelhart D. (1999) Symptoms of recurrent intrathecal baclofen withdrawal resulting from drug delivery failure: a case report. Am. J. Phys. Med. Rehabil. 78, 272-277.
Abstract: A 24-yr-old, completely (T8) paraplegic male patient presenting with severe spasticity had a drug administration device implanted in April 1991 for continuous intrathecal administration of baclofen. After a period of remarkable improvement in both the spasticity level and his quality of life, the patient experienced several short-lasting episodes of increased spasticity, with severe spasms. Among the possible causes of these deleterious episodes were microcrystalluria, obstipation, a decubitus ulcer, a foreign body in the buttocks, drug tolerance to baclofen, electromagnetic interference, and erroneous filling and programing of the pump. The catheter was the most common source of intrathecal baclofen withdrawal symptoms and had to be changed four times in 5 yr. Intrathecal baclofen administered through an implantable drug administration device is a highly effective but complex and expensive procedure that requires careful patient selection and close monitoring by highly qualified and well-trained health professional. Withdrawal symptoms may be related to noncompliance on the part of the patient, erroneous filling or programing of the pump, depletion of the battery, random component failure, concomitant illness, drug tolerance, or advancement of the disease itself. When failure of the device is suspected, substitution with oral baclofen is recommended until a full work-up is performed to determine the defect

Albany K. (1997) Physical and occupational therapy considerations in adult patients receiving botulinum toxin injections for spasticity. Muscle Nerve Suppl 6, S221-S231.
Abstract: Physical and occupational therapists play important roles in the evaluation and management of patients receiving botulinum toxin injections for spasticity. Baseline evaluation includes areas beyond the muscles being injected, since local spasticity reduction may lead to more widespread functional changes. Because the evaluation itself influences tone, a consistent order of muscle evaluation is recommended. The range of preinjection assessments includes evaluation of tone, mobility, strength, balance, endurance, assistive devices, and others. After injection, therapeutic interventions have multiple aims, including strengthening and facilitation, increasing range of motion, retraining of ambulation and gait, improving the fit and tolerance of orthoses, and improved functioning in ADLs

Albright A.L., Cervi A., and Singletary J. (1991) Intrathecal baclofen for spasticity in cerebral palsy. JAMA 265, 1418-1422.
Abstract: Seventeen patients with congenital spastic cerebral palsy and six patients with other forms of spasticity were injected intrathecally with doses of placebo or baclofen, 25 micrograms, 50 micrograms, or 100 micrograms, in a randomized, double-blind manner. Muscle tone in the upper and lower extremities was assessed by Ashworth scores both before the injections and every 2 hours afterward for 8 hours. Function of the upper extremities was evaluated before the injections and 4 hours afterward. Muscle tone in the lower extremities was significantly decreased within 2 hours after baclofen injection and remained lower than baseline 8 hours afterward. Upper extremity tone and function were not significantly affected by these single doses. Confusion and drowsiness occurred in two of the youngest children in the study after the 50-micrograms dose, but cleared within 2 hours. Our findings indicate that intrathecal baclofen reduces spasticity in children with cerebral palsy, as it does in adults with spasticity of spinal origin

Albright A.L. (1992) Neurosurgical treatment of spasticity: selective posterior rhizotomy and intrathecal baclofen. Stereotact. Funct. Neurosurg. 58, 3-13.
Abstract: The pathophysiology of spasticity and the history of posterior rhizotomies are reviewed. The rationale for selective posterior rhizotomies is that electrical stimulation identifies afferent posterior rootlets that terminate on relatively uninhibited alpha motoneurons; if these uninhibited rootlets are divided, spasticity can be alleviated without loss of other posterior root functions. Indications, technique, and results of selective posterior rhizotomies are presented. The use of continuous intrathecal baclofen (CITB) is summarized. CITB at doses of approximately 300 micrograms/day consistently reduces lower extremity spasticity and diminishes or alleviates muscle spasms in adults with spasticity of spinal origin. Single doses of intrathecal baclofen significantly decrease lower extremity muscle tone in children with cerebral palsy, and the effects can be maintained in these patients by CITB infusions which diminish muscle tone not only in the lower extremities, but in the upper extremities as well. CITB is best accomplished via an externally programmable pump that allows titration of the daily dose to attain the desired reduction in spasticity. Factors influencing the decision for rhizotomy or CITB are presented

Albright A.L., Barron W.B., Fasick M.P., Polinko P., and Janosky J. (1993) Continuous intrathecal baclofen infusion for spasticity of cerebral origin. JAMA 270, 2475-2477.
Abstract: OBJECTIVE--To determine if continuous intrathecal baclofen infusion (CIBI) would provide continuous relief of spasticity in patients with spasticity of cerebral origin, especially children with cerebral palsy. DESIGN--Prospective, unblinded trial, before and after CIBI. SETTING-- Children's Hospital of Pittsburgh (Pa). PATIENTS--Thirty-seven patients, 5 to 27 years of age, with spasticity of cerebral origin. INTERVENTION--Continuous intrathecal baclofen infusion for 3 to 48 months. MAIN OUTCOME MEASURES--Muscle tone, range of motion, upper extremity timed tasks, activities of daily living (ADLs). RESULTS--Six and 12 months after CIBI, muscle tone was significantly decreased in the upper (P = .04) and lower (P = .001) extremities. There was a significant relationship between baclofen dosage and muscle tone in the upper (P = .02) and lower (P = .001) extremities. Hamstring motion, upper extremity function, and ADLs were significantly improved in 25 patients who were capable of self-care. CONCLUSION--Spasticity of cerebral origin can be effectively treated with CIBI. Because baclofen dosages can be titrated for the desired clinical response, CIBI is particularly useful for patients who need some spasticity to stand and ambulate

Albright A.L., Barry M.J., and Hoffmann P. (1995) Intrathecal L-baclofen for cerebral spasticity: case report. Neurology 45, 2110-2111.

Albright A.L., Barry M.J., Fasick M.P., and Janosky J. (1995) Effects of continuous intrathecal baclofen infusion and selective posterior rhizotomy on upper extremity spasticity. Pediatr. Neurosurg. 23, 82-85.
Abstract: This study was performed to compare the effects of continuous intrathecal baclofen infusion (CIBI) and selective posterior rhizotomy (SPR) on upper extremity (UE) spasticity and range of motion in children with cerebral palsy. Spasticity was assessed with the Ashworth scale of muscle tone and range of motion was evaluated. Thirty-eight patients who had been treated with CIBI for at least 6 months were paired, according to pretreatment UE muscle tone and functional status, with 38 patients who had undergone SPR. The CIBI dosage had been titrated to reduce over lower extremity spasticity and improve lower extremity function, rather than to improve UE tone. The pretreatment muscle tone in the two groups was virtually identical. The UE tone of children treated with CIBI decreased from 2.07 prior to treatment to 1.66 after 1 year (p < 0.01). The tone of children treated with SPR decreased from 2.03 to 1.70 after 1 year (p = 0.005). In that group, the likelihood of a clinically significant reduction in muscle tone (one point or greater) was greater in children with a higher pretreatment UE muscle tone. There was no correlation between the percentage of posterior lumbar roots divided in SPR and the subsequent reduction in UE tone. There were no significant changes in the range of motion in any UE joint, at either 6 or 12 months, after either CIBI or SPR. We conclude that both CIBI and SPR significantly reduce UE spasticity, in addition to the previously documented reduction in lower extremity spasticity

Albright A.L. (1996) Intrathecal baclofen in cerebral palsy movement disorders. J. Child Neurol. 11 Suppl 1, S29-S35.
Abstract: Intrathecal baclofen reduces spasticity in individuals with cerebral palsy. Intrathecal doses are far lower than oral doses and the effects are considerably greater, and the side effects are fewer. Response to intrathecal baclofen must be confirmed by a screening trial before implantation of a pump for chronic infusion. Intrathecal baclofen reduces spasticity in the upper and lower extremities and is often associated with improved gait and upper extremity function. Quality of life improves for patients and caregivers. The Medtronic pump has been exceedingly reliable and typically functions for 4 or 5 years. The currently available intrathecal catheter is associated with far fewer complications than the initial catheter. Baclofen overdoses are unusual and are usually caused by pump programming errors rather than pump malfunction. Preliminary studies suggest that continuous intrathecal baclofen infusion reduces generalized dystonia in cerebral palsy. Screening to determine response of dystonia to intrathecal baclofen is by continuous infusion. The doses required to reduce dystonia are higher than those for cerebral spasticity. Additional investigations are underway to quantify the effects of continuous intrathecal baclofen infusion on communication, disability, and dystonia

Albright A.L. (1996) Baclofen in the treatment of cerebral palsy. J. Child Neurol. 11, 77-83.
Abstract: Baclofen, a gamma-aminobutyric acid agonist, acts at the spinal cord level to impede the release of excitatory neurotransmitters that cause spasticity. Oral baclofen improves cerebral spasticity mildly, but its activity is limited because of its poor lipid solubility. Cerebrospinal fluid baclofen levels after intrathecal administration are many times higher than those achieved after oral administration. Continuous intrathecal baclofen infusion has been used to treat cerebral spasticity in two patient groups: in older ambulatory children with inadequate underlying leg strength, and in patients with severe spasticity in both the upper and lower extremities. Responsiveness to intrathecal baclofen is confirmed by test injections before insertion of a programmable subcutaneous pump. Continuous intrathecal baclofen infusion dosages vary from 27 to 800 micrograms/day. Continuous intrathecal baclofen infusion reduces spasticity in the upper and lower extremities, and improves upper extremity function and activities of daily living but has no effect on athetosis in the dosages used to treat spasticity. Complications related to the intrathecal catheter occur in approximately 20% of patients, and infection requiring pump removal occurs in approximately 5%. Preliminary studies indicate that continuous intrathecal baclofen infusion alleviates some forms of generalized dystonia associated with cerebral palsy

Albright A.L. and Shultz B.L. (1999) Plasma baclofen levels in children receiving continuous intrathecal baclofen infusion. J. Child Neurol. 14, 408-409.
Abstract: To determine the plasma baclofen concentrations of children undergoing continuous intrathecal baclofen infusion for treatment of cerebral spasticity, we assayed plasma samples from six children, 8 to 18 years of age, who were receiving intrathecal baclofen at constant rates of 77 to 400 micrograms/day. Plasma levels were at or below the limit of quantification (10 ng/mL) in all patients

Alexopoulos K.A. (1973) The importance of breech delivery in the pathogenesis of brain damage. End results of a long-term follow-up. Clin. Pediatr. (Phila) 12, 248-249.

Angelucci L., Lorentz G., Maccari S., Patacchioli F.R., Scaccianoce S., and Taglialatela G. (1990) [Pharmacologic profile of protirelin tartrate]. Ann. Ital. Med. Int. 5, 232-244.
Abstract: Pharmacological interest in the tripeptide thyrotropin-releasing hormone (TRH) is due to the multiple effects it produces. In fact, apart from taking part in regulating the activity of the hypothalamo- pituitary-thyroid axis, TRH produces various neuropharmacological effects which indicate a biological role that is probably more important than that of a releasing hormone. Trials performed in animals have shown, for example, the dose-dependent capacity of TRH to induce analgesia, probably by interacting with the opioid peptide system. Motor activity is affected by TRH. In fact this tripeptide elicits an increase in spontaneous motor and explorative activities by interacting with the dopaminergic neurotransmitter system at the nucleus accumbens level. The neuropharmacological activities of TRH include an interesting arousal effect and an analeptic action on generalized depression of the CNS whether this depression is of natural origin, such as hibernation, or induced pharmacologically (barbiturates, ethanol) or of a traumatic origin (coma). This analeptic action is attributable to stimulation of cholinergic neurons in the septo- hippocampal area and to the presence of terminals containing TRH in the lateral septum and TRH receptors concentrated especially in the medial septum and diagonal band of Broca. It has also been suggested that TRH localized in the pineal gland has a part in activating the neuronal mechanisms of arousal. Associated with the arousal effect and especially evident in variously originated shock conditions are the activating effects of TRH on vegetative functions (body temperature, circulation, the gastrointestinal tract). These stimulatory activities on the CNS were the rationale for therapeutic use of TRH in the initial treatment of coma due to brain trauma and for the treatment of endogenous depression. A most interesting property of TRH is that of counteracting the neurological deficit due to experimental lesion of the spinal cord particularly with regard to spasticity and ataxia. Electrophysiological trials have shown that TRH depolarizes the motoneurons in frog spinal cord thereby increasing the monosynaptic reflex. Furthermore, TRH has recently been shown to have a trophic effect on cultures of rat fetus spinal cord. On this basis TRH has been used successfully for the treatment of amyotropic lateral sclerosis (Charcot's syndrome) and spinocerebellar degeneration. Further support for this therapeutic strategy is given by the demonstration that deafferentiation of rat spinal cord produces an increased density of TRH spinal receptors. Recent studies have also given encouraging results on the possible therapeutic use of TRH for the treatment of Alzheimer's disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Anzai E., Shiozawa Z., Shindo K., Tsunoda S., Koizumi K., and Uchiyama G. (1990) [123I-iodoamphetamine single photon emission computed tomography in three patients with amyotrophic lateral sclerosis]. Kaku Igaku 27, 863-867.
Abstract: We examined the 123I-iodoamphetamine SPECT for 3 patients with ALS, who were clinically diagnosed. Patient 1 was a 31-years-old man, who had bilateral muscle weakness of his upper extremities, and spasticity in lower extremities. Patient 2 was a 51-years-old woman, who had marked weakness of her upper extremities and bulbar sign. Patient 3 was a 68- years-old man, who had severe degree of marked weakness of his upper extremities and mild bulbar signs. Cerebral cognitive function were all normal in three patients. Computed tomographic and magnetic resonance imagings showed moderate degree of cortical atrophy in patient 1, but no abnormalities in patients 2 and 3. In 123I-IMP SPECT, however, hypoperfusion were recognized on the bilateral fronto-parietal border zone areas in these three patients with ALS. It was suggested that patients with ALS showed varying degrees of impaired perfusion in the fronto-parietal border zone areas in spite of normal cognitive functions

Arita J., Hamano S., Nara T., and Maekawa K. (1996) Intravenous gammaglobulin therapy of Satoyoshi syndrome. Brain Dev. 18, 409-411.
Abstract: Satoyoshi syndrome is a very rare disease of unknown etiology, characterized by intermittent painful muscle spasms, alopecia, multiple epiphyseal changes, diarrhea and endocrine disorders. We administered intravenous gammaglobulin to a 7-year-old girl with Satoyoshi syndrome. Frequency of muscle spasms and the titers of antinuclear antibody and anti-DNA antibody decreased. This is the first report of gammaglobulin therapy of Satoyoshi syndrome. We suggest that this illness could be related to an autoimmune mechanism

Arjona V.E. (1974) Sterotactic hypothalamotomy in erethic children. Acta Neurochir. (Wien. ) Suppl 21, 185-191.

Armstrong R.W. (1992) Intrathecal baclofen and spasticity: what do we know and what do we need to know? Dev. Med. Child Neurol. 34, 739-745.

Armstrong R.W., Steinbok P., Cochrane D.D., Kube S.D., Fife S.E., and Farrell K. (1997) Intrathecally administered baclofen for treatment of children with spasticity of cerebral origin. J. Neurosurg. 87, 409-414.
Abstract: Management of severe spasticity in children is often a difficult problem. Orally administered medications generally offer limited benefits. This study examines the value of intrathecally administered baclofen in the treatment of 19 children with severe spasticity of cerebral origin: eight of whom sustained brain injury associated with trauma, near drowning, or cardiac arrest; 10 with cerebral palsy (spastic quadriplegia); and one child with Leigh's disease. At the time of entry into the study, patients ranged from 4 to 19 years of age, and all were completely dependent on caretakers for activities of daily living. Children who responded positively to a trial dose of intrathecal baclofen underwent insertion of a drug delivery system for continuous infusion. This was followed by a double-blind trial of baclofen or placebo and follow-up review at 3 and 6 months, and yearly thereafter. Seven children did not undergo pump implantation because of excess sedation or poor response. The 12 remaining children have been followed for a period of 1 to 5 years. Favorable responses were present in all 12 children as determined by the Ashworth Scale, with the greatest benefit being reduction of lower limb tone. Except in the case of one child who had reduction in lower limb tone that resulted in difficulty with transfers, the caretakers all reported significant benefits from intrathecal baclofen, with improvement in muscle tone, behavior, sitting, and general ease of care being most commonly noted. Central side effects were seen in some children who received continuous intrathecal baclofen infusion and included hypotension (two patients), bradycardia (two), apnea or respiratory depression (two), and sedation (one). During a total of 568 months of pump operation there were 10 mechanical complications, including two related to pump or side port failure and eight related to catheter kinks, extrusions, or dislodgment. Pump pocket effusion occurred in five children and a cerebrospinal fluid fistula was seen in one child. Local infection occurred in three children and meningitis in two children. The results demonstrate the potential value of continuous intrathecal baclofen infusion for treatment of severe spasticity of cerebral origin. However, this treatment can result in significant complications and more experience is required before the long-term benefits can be determined

Ashby P., Burke D., Rao S., and Jones R.F. (1972) Assessment of cyclobenzaprine in the treatment of spasticity. J. Neurol. Neurosurg. Psychiatry 35, 599-605.

Ashby P. and White D.G. (1973) "Presynaptic" inhibition in spasticity and the effect of beta(4- chlorophenyl)GABA. J. Neurol. Sci. 20, 329-338.

Ast D. and Cunha B.A. (1990) Chronic encephalitis caused by leukoencephalopathy. Heart Lung 19, 678-684.
Abstract: As mentioned previously, both MS and PML are demyelinating conditions of the CNS and pose diagnostic difficulties in their differentiation because of similarities in their clinical findings. However, certain features unique to each of these diseases are helpful in clinical diagnosis. MS, unlike PML, is a disease of unknown cause. Polygenetic influences in combination with exposure to an environmental agent and immune-mediated factors may be operative in the pathogenesis of MS. Age of onset peaks in the third to fourth decades with a predominance in women, as contrasted with PML, which peaks in the fifth to sixth decades in most non-AIDS-associated cases with a slight predominance in men. MS is more prevalent in areas farther from the equator: North America, Europe, Australia, and New Zealand. Common initial symptoms seen in MS include bilateral limb weakness (with the legs being affected twice as often as the arms), hyperreflexia, spasticity, optic neuritis, diplopia, incoordination, and paresthesias. (Paresthesias are typically found in the lower limbs in a symmetric pattern, but may follow no obvious anatomic distribution and often do not correspond to the distribution of sensory symptoms. Vibration and position sense are more frequently disturbed than pain and temperature.) Intellectual impairment and mental deterioration are uncommon early in MS, whereas they are a more frequent initial presentation in PML. In addition, the presence of speech impairment and monoparesis or hemiparesis with homonymous hemianopsia is more suggestive of PML. Brain stem involvement is infrequent.(ABSTRACT TRUNCATED AT 250 WORDS)

Aubry M.L., Cowell P., Davey M.J., and Shevde S. (1970) Aspects of the pharmacology of a new anthelmintic: pyrantel. Br. J. Pharmacol. 38, 332-344.

Ault B., Gruenthal M., Armstrong D.R., Nadler J.V., and Wang C.M. (1986) Baclofen suppresses bursting activity induced in hippocampal slices by differing convulsant treatments. Eur. J. Pharmacol. 126, 289-292.
Abstract: Epileptiform activity was induced in area CA3 of hippocampal slices by superfusion of medium containing 50 microM bicuculline and 3.5 mM K, 50 microM bicuculline and 5 mM K, 50 nM kainic acid and 3.5 mM K, or 7 mM K. Burst potentials were recorded at rates between 5 and 44/min, depending on the convulsant treatment. Baclofen reduced the frequency of burst firing in all slices tested in a dose-dependent manner, with little change in the morphology of individual bursts. Thus baclofen primarily affected the initiation of epileptiform discharges. IC50 values varied between 27 and 500 nM and were positively correlated with the rate of bursting. These experiments indicate that baclofen, at concentrations present in the CSF of patients treated for spasticity, has an anticonvulsant-like effect in the hippocampal formation and suggest that its mode of action is to reduce the excitability of pyramidal cells

Autti-Ramo I., Larsen A., Peltonen J., Taimo A., and von Wendt L. (2000) Botulinum toxin injection as an adjunct when planning hand surgery in children with spastic hemiplegia. Neuropediatrics 31, 4-8.
Abstract: The usefulness of botulinum toxin A treatment when planning hand surgery in eight children with spastic hemiplegia was evaluated. The hand function of the children was assessed before and after treatment using a test battery consisting of quantitative and qualitative functional assessment. The results of preoperative botulinum treatment supported surgical intervention in four children and serial botulinum treatment in three children. In one child, the preoperative botulinum treatment provided no additional information. We conclude that preoperative botulinum A treatment in most children with spastic hemiplegia, for whom hand surgery is being considered, identifies the patients who would not benefit from the planned surgery or for whom the functional benefit would probably not outweigh the burden of surgical procedure and postoperative rehabilitation

Avakian G.N., Chukanova E.I., and Nikonov A.A. (2000) [The administration of midocalm in the treatment of vertebrogenic algesic syndromes]. Zh. Nevrol. Psikhiatr. Im S. S. Korsakova 100, 26-31.

Awad I.A. and Barnett G.H. (1990) Neurological deterioration in a patient with a spinal arteriovenous malformation following lumbar puncture. Case report. J. Neurosurg. 72, 650-653.
Abstract: The mechanism of nonhemorrhagic neurological deterioration from spinal arteriovenous malformation (AVM) and the role of acute surgical intervention in this setting are not well understood. The case is described of a 65-year-old man who presented with a 2-year history of mild gait spasticity and vague sensory complaints affecting both lower extremities. Following a diagnostic lumbar puncture, these symptoms progressed painlessly over a 4-day period to total motor paraplegia, urinary retention, and hypesthesia in all modalities with a midthoracic sensory level. Magnetic resonance imaging showed a probable spinal AVM but no evidence of hemorrhage or cord compression. Spinal angiography confirmed the diagnosis of spinal AVM fed by radicular branches of left T-7 and T-8 segmental intercostal arteries. Drainage was via long dorsal veins caudally. Emergency laminectomy with intradural exploration was performed. There was no evidence of prior hemorrhage or focal mass effect, although the cerebrospinal fluid pressure was elevated. The dural component of the spinal AVM was excised, and its communications with the spinal cord were disconnected intradurally. Neurological function started improving within 6 hours of the patient awakening from anesthesia. He had achieved antigravity strength in every muscle group of the lower extremities by the time of discharge to a rehabilitation center 10 days after surgery. Three months postoperatively, he was ambulating with a walker and was continent of urine and stool. Possible pathophysiological mechanisms are discussed in light of the favorable response to timely surgical intervention

Azouvi P., Roby-Brami A., Biraben A., Thiebaut J.B., Thurel C., and Bussel B. (1993) Effect of intrathecal baclofen on the monosynaptic reflex in humans: evidence for a postsynaptic action. J. Neurol. Neurosurg. Psychiatry 56, 515-519.
Abstract: Intrathecal baclofen is a very powerful antispastic agent. Its mechanism of action on the monosynaptic H-reflex in spinal patients was investigated. It could inhibit rapidly and profoundly monosynaptic reflexes in lower limbs, but did not modify Ia vibratory inhibition of the soleus H-reflex. To assess more precisely its effect on Ia afferents, an experimental paradigm using Ia heteronymous facilitation of the soleus H-reflex was used. Intrathecal baclofen did not modify the amount of monosynaptic facilitation of the soleus H-reflex brought about by stimulation of the femoral nerve. This demonstrates that the main part of the inhibitory effect of baclofen on the H-reflex in spinal patients is not due to a presynaptic effect, suggesting a postsynaptic site of action

Azouvi P., Mane M., Thiebaut J.B., Denys P., Remy-Neris O., and Bussel B. (1996) Intrathecal baclofen administration for control of severe spinal spasticity: functional improvement and long-term follow-up. Arch. Phys. Med. Rehabil. 77, 35-39.
Abstract: OBJECTIVES: To assess long-term efficacy and functional benefits of intrathecal baclofen for severe spinal spasticity. DESIGN: A prospective before-after trial. SETTING: A neurological rehabilitation department of a university hospital. Pump implantation was realized in neurosurgery; follow-up was carried out mostly on an outpatient basis. PATIENTS: Eighteen patients with severe and disabling spinal spasticity received intrathecal baclofen by an implantable pump; average follow-up was 37.4 months (range, 9 to 72). MAIN OUTCOME MEASURES: Spasticity (Ashworth and spasms frequency scores); disability (Functional Independence Measure [FIM]). RESULTS: A significant decrease in tone and spasms was observed in all patients. Tolerance appeared during the first 6 to 9 months. Later on, efficacy remained stable, except in cases of mechanical problems of the pump or catheter. Functional assessment found a highly significant (p < .001) increase of FIM score (particularly for bathing, dressing lower body, transfers, and in some cases, locomotion). This was particularly marked in patients with thoracic spinal cord lesion. In cases of severe upper limb dysfunction, FIM was only improved for wheelchair displacements, due to a better sitting position, but nursing became easier and life comfort was enhanced. Severe side effects (overdose) were observed in two cases. CONCLUSION: Efficacy remained stable after 6 to 9 months. Marked improvement of functional independence was observed in paraplegic patients. Improvement was less spectacular in patients with severe upper limb dysfunction, but nevertheless appreciable in terms of life comfort and use of attendants

Azzam F.J. (1987) A simple and effective method for stopping post-anesthetic clonus. Anesthesiology 66, 98.

Backman C., Nystrom A., Backman C., and Bjerle P. (1993) Arterial spasticity and cold intolerance in relation to time after digital replantation. J. Hand Surg. [Br. ] 18, 551-555.
Abstract: Cold induced arterial vasospasm was studied in ten patients with single digit replantation, by measuring finger systolic pressure at different finger temperatures. Each patient was examined three times; within 2 weeks of surgery, after 1 year and after 3 years. The replantations were performed using long arterial and venous grafts. Cold-related vasospasm is established during the first year after trauma, and thereafter seems to be persistent. It is concluded that the subjective cold tolerance, which affects all patients after digital amputation regardless of whether replantation is performed or not, is partly due to vasospasm. It is less pronounced in patients without pathological vasospasm in the replanted digit. Cold intolerance is likely to decrease during the first 2 years after replantation, but not to disappear completely

Backon J. (1989) Inhibiting noradrenergic overactivity by inhibition of thromboxane and concomitant activation of opiate receptors via dietary means. Med. Hypotheses 29, 65-74.
Abstract: A yin-yang hypothesis is presented linking noradrenergic activity, thromboxane, melatonin, left hemisphere functioning, and cyclic AMP on the one hand, and dopamine, beta-endorphin, calcium, right hemisphere functioning, and cyclic GMP on the other. It is further suggested that there is a yoking of NA, TXA2, serotonin and melatonin in the left hemisphere, and a similar yoking of DA, BE, calcium and cGMP in the right. Evidence is presented to support the hypothesis that each element (NA, TXA2, etc.) on one side can modulate or balance a corresponding element (DA, BE, etc.) on the other. It is suggested that thromboxane is the key element in noradrenergic overactivity and that not taking this into consideration has confounded much prior research. This theory takes into account information processing models as well as pharmacological data and neurochemical theory on coupling of adenylate cyclase to its hormone receptors. Inhibiting noradrenergic overactivity can be obtained by inhibiting thromboxane and concomitantly activating opiate receptors. This protocol may have clinical utility in treating a wide range of disorders such as: anxiety, depression, schizophrenia, sleeplessness, withdrawal states, enuresis, Gilles de la Tourette syndrome, Parkinsonism, Alzheimers, dementia, anorexia, infant ruminations, essential tremor, spasticity of spinal cord injury, diarrhoea, ulcerative colitis, extrapyramidal symptoms, akathisia, neuroleptic malignant syndrome, attention deficit disorder, hyperhidrosis, and possibly AIDS

Baikushev S. (1967) [Effect of prostigmine on voluntary and tonic contraction in patients with spastic paralysis. Electromyographic studies]. Folia Med. (Plovdiv. ) 9, 89-98.

Bajd T., Munih M., and Kralj A. (1999) Problems associated with FES-standing in paraplegia. Technol. Health Care 7, 301-308.
Abstract: Prolonged immobilization, such as occurs after the spinal cord injury (SCI), results in several physiological problems. It has been demonstrated that the standing posture can ameliorate many of these problems. Standing exercise can be efficiently performed by the help of functional electrical stimulation (FES). The first application of FES to a paraplegic patient was reported by Kantrowitz in 1963. It was later shown by our group that standing for therapeutic purposes can be achieved by a minimum of two channels of FES delivered to both knee extensors. The properties of the stimulated knee extensors (maximal isometric joint torque, fatiguing, and spasticity) were not found as sufficient conditions for efficient standing exercise. According to our studies, the ankle joint torque during standing is the only parameter which is well correlated to the duration of FES assisted standing. For good standing low values of the ankle joint torque are required. To minimize the ankle joint torque the lever belonging to the vertical reaction force must be decreased. Adequate alignment of the posture appears to be the prerequisite for efficient FES assisted and arm supported standing exercise. Some patients are able to assume such posture by themselves, while many must be aided by additional measures. At present, surface stimulation of knee extensors combined with some appropriately "compliant shoes" looks to be adequate choice

Bakay B., Nissinen E., Sweetman L., Francke U., and Nyhan W.L. (1979) Utilization of purines by an HPRT variant in an intelligent, nonmutilative patient with features of the Lesch-Nyhan syndrome. Pediatr. Res. 13, 1365-1370.
Abstract: The patient, H.Chr.B., was among the first reported with hyperuricemia and central nervous system symptoms. He has been found to have a variant of hypoxanthine guanine phosphoribosyl transferase (HPRT; E.C.2.4.2.8) distinct from the enzyme present in patients with the Lesch-Nyhan syndrome. The patient had chroeoathetosis, spasticity, dysarthric speech, and hyperuricemia. However, his intelligence was normal and he had no evidence of self-mutilation. There was no activity of HPRT in the lysates of erythrocytes and cultured fibroblasts when analyzed in the usual manner. Using a newly developed method for the study of purine metabolism in intact cultured cells, this patient was found to metabolize some 9% of 8-14C-hypoxanthine, and 90% of the isotope utilized was converted to adenine and guanine nucleotides. In contrast, cells from patients with the Lesch-Nyhan syndrome were virtually completely unable to convert hypoxanthine to nucleotides. The patient's fibroblasts were even more efficient in the metabolism of 8- 14C-guanine, which was utilized to the extent of 27%, over 80% of which was converted to guanine and adenine nucleotides. The growth of the cultured fibroblasts of this patient was intermediate in media containing hypoxanthine aminopterin thymidine (HAT), whereas the growth of Lesch-Nyhan cells was inhibited and normal cells grew normally. Similarly in 8-azaguanine, 6-thioguanine, and 8-azahypoxanthine, the growth of the patient's cells was intermediate between normal and Lesch- Nyhan cells. These observations provide further evidence for genetic heterogeneity among patients with disorders in purine metabolism involving the HPRT gene. They document that this famous patient did not have the Lesch-Nyhan syndrome

Baker D., Pryce G., Croxford J.L., Brown P., Pertwee R.G., Huffman J.W., and Layward L. (2000) Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404, 84-87.
Abstract: Chronic relapsing experimental allergic encephalomyelitis (CREAE) is an autoimmune model of multiple sclerosis. Although both these diseases are typified by relapsing-remitting paralytic episodes, after CREAE induction by sensitization to myelin antigens Biozzi ABH mice also develop spasticity and tremor. These symptoms also occur during multiple sclerosis and are difficult to control. This has prompted some patients to find alternative medicines, and to perceive benefit from cannabis use. Although this benefit has been backed up by small clinical studies, mainly with non-quantifiable outcomes, the value of cannabis use in multiple sclerosis remains anecdotal. Here we show that cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, delta9- tetrahydrocannabinol, methanandamide and JWH-133 (ref. 8) quantitatively ameliorated both tremor and spasticity in diseased mice. The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis, and provides a means of evaluating more selective cannabinoids in the future

Baker D., Pryce G., Croxford J.L., Brown P., Pertwee R.G., Makriyannis A., Khanolkar A., Layward L., Fezza F., Bisogno T., and Di M., V (2001) Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 15, 300-302.
Abstract: Spasticity is a complicating sign in multiple sclerosis that also develops in a model of chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice. In areas associated with nerve damage, increased levels of the endocannabinoids, anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG), and of the AEA congener, palmitoylethanolamide (PEA), were detected here, whereas comparable levels of these compounds were found in normal and non-spastic CREAE mice. While exogenously administered endocannabinoids and PEA ameliorate spasticity, selective inhibitors of endocannabinoid re-uptake and hydrolysis-probably through the enhancement of endogenous levels of AEA, and, possibly, 2-arachidonoyl glycerol-significantly ameliorated spasticity to an extent comparable with that observed previously with potent cannabinoid receptor agonists. These studies provide definitive evidence for the tonic control of spasticity by the endocannabinoid system and open new horizons to therapy of multiple sclerosis, and other neuromuscular diseases, based on agents modulating endocannabinoid levels and action, which exhibit little psychotropic activity

Bakheit A.M., Ward C.D., and McLellan D.L. (1997) Generalised botulism-like syndrome after intramuscular injections of botulinum toxin type A: a report of two cases. J. Neurol. Neurosurg. Psychiatry 62, 198.

Bakheit A.M., Thilmann A.F., Ward A.B., Poewe W., Wissel J., Muller J., Benecke R., Collin C., Muller F., Ward C.D., and Neumann C. (2000) A randomized, double-blind, placebo-controlled, dose-ranging study to compare the efficacy and safety of three doses of botulinum toxin type A (Dysport) with placebo in upper limb spasticity after stroke. Stroke 31, 2402-2406.
Abstract: BACKGROUND AND PURPOSE: We sought to define an effective and safe dose of botulinum toxin type A (Dysport) for the treatment of upper limb muscle spasticity due to stroke. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, dose-ranging study. Patients received either a placebo or 1 of 3 doses of Dysport (500, 1000, 1500 U) into 5 muscles of the affected arm. Efficacy was assessed periodically by the Modified Ashworth Scale and a battery of functional outcome measures. RESULTS: Eighty-three patients were recruited, and 82 completed the study. The 4 study groups were comparable at baseline with respect to their demographic characteristics and severity of spasticity. All doses of Dysport studied showed a significant reduction from baseline of muscle tone compared with placebo. However, the effect on functional disability was not statistically significant and was best at a dose of 1000 U. There were no statistically significant differences between the groups in the incidence of adverse events. CONCLUSIONS: The present study suggests that treatment with Dysport reduces muscle tone in patients with poststroke upper limb spasticity. Treatment was effective at doses of Dysport of 500, 1000, and 1500 U. The optimal dose for treatment of patients with residual voluntary movements in the upper limb appears to be 1000 U. Dysport is safe in the doses used in this study

Bakheit A.M., Severa S., Cosgrove A., Morton R., Rousso S.H., Doderlein L., and Lin J.P. (2001) Safety profile and efficacy of botulinum toxin A (Dysport) in children with muscle spasticity. Dev. Med. Child Neurol. 43, 234-238.
Abstract: Botulinum toxin A (BTX-A) is widely used in the management of muscle spasticity in children. However, at present the dose of BTX-A for a given patient is selected empirically. The aim of this study is to provide dosage guidelines that are based on risk/benefit assessment. This was a multicentre retrospective study of the safety profile and efficacy of BTX-A in children with chronic muscle spasticity. Data in 758 patients who received a total of 1594 treatments were analysed (mean age 7.2 years; 429 males, 329 females). Spastic cerebral palsy (CP) was the most common diagnosis (94% of the study sample). Of all treatments 7% resulted in adverse events; incidence was related to the total dose rather than the dose calculated on the basis of body weight. The highest incidence of adverse events was observed in patients who received >1000 IU of BTX-A per treatment session. The odds of an adverse event was 5.1 times greater for this group of patients than for those who had 250 IU or less (p<0.001). A good overall response to treatment was reported in 82% and treatment goals were fully or partially achieved in 3% and 94% of participants respectively. More patients in the highest dose group reported functional deterioration. Interestingly, multilevel treatments resulted in a better response than single-level treatments (odds ratio 1.7, 95% CI 1.3 to 2.2,p=0.001)

Balentine J.D. and Gutsche B.B. (1966) Central nervous system lesions in rats exposed to oxygen at high pressure. Am. J. Pathol. 48, 107-127.

Barolat G., Myklebust J.B., and Wenninger W. (1988) Effects of spinal cord stimulation on spasticity and spasms secondary to myelopathy. Appl. Neurophysiol. 51, 29-44.
Abstract: 16 subjects with severe spasms secondary to traumatic and nontraumatic myelopathy underwent epidural spinal cord stimulation. 4 patients had a complete motor and sensory spinal cord lesion. 6 of the subjects with an incomplete spinal cord lesion were ambulatory. All patients had previously undergone extensive trials with medications and physical therapy. All 14 subjects in whom a satisfactory placement of the electrode could be obtained had a reduction in the severity of the spasms. In 6 patients, the spasms were almost abolished. Extremity, trunkal and abdominal spasms were affected. Clonus in the upper extremities was consistently reduced. Marked improvement in bladder and bowel function was observed in each of 2 subjects. In over 1-year follow-up, 5 subjects show persistence of the results, with less stimulation required to maintain the therapeutic effects. No neurological deterioration occurred following the procedure or after long-term spinal stimulation. 1 patient showed after several months of continuous stimulation increased voluntary motor control present only when spinal cord stimulation was activated. Complications included 1 system infection, 1 electrode migration, 1 wire breakage and skin breakdown at a connector site, development of high impedance in 1 electrode and 1 skin breakdown over the lead

Barolat G. (1988) Surgical management of spasticity and spasms in spinal cord injury: an overview. J. Am. Paraplegia Soc. 11, 9-13.
Abstract: Spasms and spasticity constitute a significant problem in spinal cord injured individuals. Surgical intervention may be indicated when spasms and spasticity cannot be satisfactorily controlled by medications and physical therapy. Surgical procedures carried out on the nervous system include neurotomy, rhizotomy, myelotomy, cordectomy and spinal cord stimulation. The various procedures and their indications will be discussed

Barolat G. (1993) Experience with 509 plate electrodes implanted epidurally from C1 to L1. Stereotact. Funct. Neurosurg. 61, 60-79.
Abstract: This article summarizes the experience gained with implantation of 509 plate electrodes performed by a single neurosurgeon. 350 patients were subjected to implantation of plate electrodes in the dorsal epidural space. 227 patients were implanted for chronic pain management (reflex sympathetic dystrophy, failed back syndrome/arachnoiditis, pain following spinal cord injury, nerve injury pain and other miscellaneous pain conditions), 105 patients for motor disorders (spasms/spasticity following spinal cord or head injury, cerebral palsy, multiple sclerosis, spasmodic torticollis and other miscellaneous conditions) and 18 patients for both. A total of 509 electrodes were implanted in the dorsal epidural space. The electrodes types were: 442 Medtronic Resume, 39 Medtronic Resume-TL and 25 Neuromed Lamitrode. 378 electrodes were implanted for chronic pain management, 106 for motor disorders and 25 in patients presenting with both pain and motor disorders. 192 electrodes were implanted in the cervical area and 317 in the thoracic area. 3.7% of the implanted electrodes became infected and had to be surgically removed. Electrode migration occurred in 1.1% of the patients and electrode breakage in 4 patients. 288 (70%) of the implanted electrodes are still being used. Technical factors relevant to the surgical implantation of plate electrodes at various levels in the spine are presented and discussed

Barolat G., Singh-Sahni K., Staas W.E., Jr., Shatin D., Ketcik B., and Allen K. (1995) Epidural spinal cord stimulation in the management of spasms in spinal cord injury: a prospective study. Stereotact. Funct. Neurosurg. 64, 153-164.
Abstract: Forty-eight spinal cord injury victims were implanted with an epidural spinal cord stimulation system to treat spasms that had not satisfactorily responded to medical therapy. All the patients were at least 6 months after the injury. The protocol included assessment by independent examiners preoperatively and at 3, 6, 12 and 24 months after the implant. Pre- and postoperative data collection included the frequency and severity of the spasms. Combining the frequency and intensity scores into a 'severity' score provided a more accurate clinical picture. No patient observed neurological deterioration following the surgical procedure or the neurostimulation treatment. A statistically significant reduction in the severity of the spasms was observed in the follow-up evaluations, with results that progressively increased in time. It is appears that spinal cord stimulation is an effective and safe alternative in the management of spasms in spinal cord injury victims. Its exact role in relation to intrathecal baclofen infusion and ablative procedures remains to be defined

Barros Filho T.E., Greve J.M., Oliveira R.P., Chiovatto J., and Carnei