Open-label dose-titration safety and efficacy study of tizanidine hydrochloride in the treatment of spasticity associated with chronic stroke.

BACKGROUND AND PURPOSE: Spasticity is a frequently observed motor impairment that develops after stroke; it can cause pain and disability in those affected. The objective of the present study was to evaluate the safety and efficacy of tizanidine, a centrally acting alpha(2)-adrenergic agonist, in the treatment of stroke-related spasticity. METHODS: Forty-seven patients, who were a minimum of 6 months poststroke and had significant spasticity, were studied at 4 centers. Tizanidine was administered in an open-label manner for 16 weeks, beginning at 2 mg/d and slowly titrated to a maximum of 36 mg/d. The Modified Ashworth Scale, muscle strength testing, functional assessments, and Pain and Functional Spasticity Questionnaires were administered at baseline and at 4, 8, 16, and 18 weeks (after 1 week off tizanidine). RESULTS: Spasticity was significantly improved between baseline and week 16, with a decrease in total upper extremity Modified Ashworth Scale score of 2.80+/-0.47 (P<0.0001). No decline in strength was noted. Treatment with tizanidine resulted in a significant improvement in pain intensity (P=0.0375), quality of life (P=0.0001), and physician assessment of disability (P=0.0001). The most frequent side effects were somnolence (62%) and dizziness (32%). No serious adverse events were considered to be drug related. Ten of 47 patients (21%) were able to reach the maximum daily dosage of 36 mg. CONCLUSIONS: Overall, the data suggest that tizanidine is safe and efficacious in the treatment of stroke-related spasticity, preserving muscle strength while reducing muscle tone and painful spasms in affected patients.

Nerve decompression at the wrist in patients with Charcot-Marie-Tooth disease.

Studies evaluating the effects of nerve release in patients with Charcot-Marie-Tooth disease have been extremely limited to date. This series attempts to evaluate the clinical and electrophysiologic effect of nerve release at the wrist in a series of patients with this disease. Five patients with documented Charcot-Marie-Tooth disease of the upper extremity were followed clinically and had nerve conduction testing both before and after surgery. This study shows that there was an improvement in both sensory and motor testing after release in a significant proportion of patients (p < 0.05). All patients documented improvement in their sensory latency response postoperatively (100 percent) and most showed improvement in motor latency responses (87 percent). More importantly, however, there seems to be an even greater clinical improvement in preoperative complaints (e.g., paresthesia and pain) in the majority of the extremities that underwent surgery with all patients experiencing initial relief and the majority showing no recurrence (63 percent) at last follow-up. From these results, this relief can be variable, but has lasted for a significant duration postoperatively in the majority, necessitating careful consideration for surgery as a legitimate option for patients with Charcot-Marie-Tooth.

Aldose reductase inhibitors: the end of an era or the need for different trial designs?

Despite numerous attempts over 16 years, the results of aldose reductase inhibitor (ARI) trials for the treatment of diabetic neuropathy have not proven efficacy. This paper reviews each of the ARI trials, examines confounding factors, and proposes a future course. The confounding factors considered are pharmacokinetics (ARI penetration of human nerve), length of trial (in terms of the natural history of diabetic neuropathy), trial endpoints (reversibility or slowing of progression), reproducibility of clinical measurements (in terms of power calculations), standardization and quality control of endpoints, and clinically meaningful differences in endpoints. We conclude that ARIs are most likely to have a beneficial effect in the management of diabetic distal symmetrical polyneuropathy and autonomic neuropathy but that the clinical role of ARIs is to slow the progression of diabetic neuropathy rather than to reverse it. Future trials should be designed with adequate statistical power, with consideration of the variability of the endpoint measurements for long enough duration, and with rigorous quality control to definitively confirm the utility of ARIs in the treatment of diabetic distal symmetrical polyneuropathy and autonomic neuropathy.

Cardiovascular autonomic nervous system tests: determination of normative values and effect of confounding variables.

OBJECTIVE: To determine normative values for heart rate variation to deep breathing (VAR) and Valsalva ratio (VAL) as well as the effect of various confounding variables on these measures using data from a large group of normal subjects collected from multiple centers. RESEARCH DESIGN AND METHODS: VAR and VAL were measured on 611 normal subjects, age range 9-79, from 63 centers and was analyzed at a single Autonomic Nervous System Reading Center. Using simple and stepwise logistic regression the effect of age, gender, height, weight, mean arterial blood pressure (MAP) and body mass index (BMI), on VAR and VAL was evaluated. RESULTS: The 95% normative values range (values at 2.5 to 97.5 percentile) for VAR (n = 580) was 12.8-103.5 (mean 49.7) and for VAL (n = 425) was 1.31-2.97 (mean 1.97). No gender effect was found for either VAR or VAL (p > 0.05). VAR correlated inversely with both age and MAP, while VAL correlated inversely with both age and BMI. Since age is the principal confounding variable for both VAR and VAL, normative values are also presented stratified by age. CONCLUSION: Normative values for VAR and VAL based on a large population sample are presented. However, the values presented may not be valid in patients with morbid obesity or malignant hypertension. These data are applicable for either individual patients or for use in multicenter research trials.

Components of variance for vibratory and thermal threshold testing in normal and diabetic subjects.

Quantitative sensory testing (QST) is commonly used in the assessment of diabetic neuropathy. However, little data are available on the reliability of tactile and thermal testing devices. Reproducibility of QST measures between centers has not been previously reported. This study was designed to validate QST testing procedures and determine if these devices are suitable for large scale multicenter clinical trials. Finger and toe vibratory (Vf, Vt) and thermal (Tf, Tt) thresholds were determined for ten normal individuals by a two-alternative forced-choice procedure using the Optacon Tactile Tester (OTT) and Thermal Sensitivity Tester (TST). Threshold measurements were reproducible between technologists and had a day-to-day coefficient of variation of Vf 20%, Vt 23%, Tf 41%, and Tt 95%. Thresholds were determined for 140 normal individuals at six centers. Mean threshold values between centers were not significantly different. Center-to-center coefficients of variation (CV) were Vf 44%, Vt 45%, Tf 47%, and Tt 87%. There was no significant difference in threshold measures with regard to sex, side studied, presence of calluses, or skin temperature. Vf thresholds significantly correlated with age (p < 0.01). There was no correlation between either vibratory or thermal thresholds in normal individuals, and nerve conduction velocities (NCV). Thermal and vibratory thresholds were determined for 98 diabetic patients. Diabetic subjects without clinical evidence of neuropathy were not significantly different from normal individuals, but diabetic patients with neuropathy had increased thresholds compared to normals (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

A highly successful and novel model for treatment of chronic painful diabetic peripheral neuropathy.

OBJECTIVE: To investigate why, in spite of a vast variety of treatment agents, the alleviation of pain in patients with diabetic neuropathy is difficult. Previous studies have not used a treatment algorithm based on anatomic site and neuropathophysiological source of the neuropathic pain. RESEARCH DESIGN AND METHODS: A model that categorizes the types of pain into three groups (superficial, deep, and muscular) was applied in 75 diabetic patients with chronic (> 12 mo) painful distal symmetrical polyneuropathy in a controlled case series. Twenty-two patients were untreated and 53 patients were treated with imipramine +/- mexiletine for deep pain, capsaicin for superficial pain, and stretching exercises and metaxalone +/- piroxican for muscular pain. Each type of pain was scored separately on a scale of 0 (none) to 19 (worst), and the total of all three types was used as an index of overall pain. Ability to sleep through the night was scored by a scale of 1 (never) to 5 (always). RESULTS: No significant differences were observed in initial pain scores, sleep scores, demographics, biochemistries, or physical findings between the two groups. After 3 mo a significant improvement in scores was noted in the treated but not the untreated patients. In addition, a significant difference was found in the change of scores between the treated and untreated patients: total pain (-18 +/- 2 vs. 0 +/- 2), deep pain (-7 +/- 1 vs. 0 +/- 1), superficial pain (-5 +/- 1 vs. 0 +/- 1), muscular pain (-6 +/- 1 vs. 0 +/- 1), and sleep (1.2 +/- 0.2 vs. 0.2 +/- 0.2), all P < 0.0001. In treated patients 21% became pain-free (total pain < 2), 66% had improvement (decrease in total pain > 5, but not total elimination of painful symptoms), and 13% were considered treatment failures (a decrease in total pain of < or = 5). This compares with 0 (P < 0.02), 10 (P < 0.0001), and 90% (P < 0.0001), respectively, in the untreated patients. CONCLUSIONS: This study presents a new rationale and hypothesis for the successful treatment of chronic painful diabetic peripheral neuropathy. It uniquely bases the treatment algorithm on the types and sources of the pain.

Causes of urinary incontinence after acute hemispheric stroke.

BACKGROUND AND PURPOSE: We prospectively studied bladder function in stroke patients to determine the mechanisms responsible for poststroke urinary incontinence. METHODS: Fifty-one patients with recent unilateral ischemic hemispheric stroke admitted to a neurorehabilitation unit were enrolled. The presence of urinary incontinence was correlated with infarct location, neurological deficits, and functional status. Urodynamic studies were performed on all incontinent patients. RESULTS: Nineteen patients (37%) were incontinent. Incontinence was associated with large infarcts, aphasia, cognitive impairment, and functional disability (p < 0.05) but not with age, sex, side of stroke, or time from stroke to entry in the study. Urodynamic studies, performed on all 19 incontinent patients, revealed bladder hyperreflexia in 37%, normal studies in 37%, bladder hyporeflexia in 21%, and detrusor-sphincter dyssynergia in 5%. All of the patients with normal urodynamic studies were aphasic, demented, or severely functionally impaired. All of the patients with hyporeflexic bladders had underlying diabetes or were taking anticholinergic medications. Forty-six percent of incontinent patients treated with scheduled voiding alone were continent at discharge compared with 17% of patients treated pharmacologically. CONCLUSIONS: There are three major mechanisms responsible for poststroke urinary incontinence: 1) disruption of the neuromicturition pathways, resulting in bladder hyperreflexia and urgency incontinence; 2) incontinence due to stroke-related cognitive and language deficits, with normal bladder function; and 3) concurrent neuropathy or medication use, resulting in bladder hyporeflexia and overflow incontinence. Urodynamic studies are of benefit in establishing the cause of incontinence. Scheduled voiding is a useful first-line treatment in many cases of incontinence.