David A. Gelber

Sleep-Disordered Breathing and Poor Functional Outcome After Stroke

BACKGROUND AND PURPOSE We objectively evaluated patients with recent stroke to determine the prevalence of sleep-disordered breathing (SDB) and whether SDB was associated with unfavorable clinical outcomes. METHODS Forty-seven patients with recent ischemic stroke (median, 13 days) were studied with computerized overnight oximetry for evidence of arterial oxyhemoglobin desaturation (SaO2). Polysomnography was also performed on 19 patients. Medical history, sleep history, location of stroke, and severity of neurological deficit were recorded, and patients were observed by staff for evidence of snoring and excessive daytime sleepiness. Functional abilities were measured with the use of the Barthel Index (BI). Outcome variables included ability to return home at discharge, continued residence at home at 3 and 12 months, BI at discharge, BI at 3 and 12 months, and death from any cause at 12 months. RESULTS Mean SaO2 during oximetry was 94.0 +/- 1.7%, and percentage of recording time spent at < 90% SaO2 was 4.3 +/- 5.7%. The number of desaturation events per hour of recording time (desaturation index [DI]) was 9.5 +/- 9.67, with 15 of 47 (32%) having DI > 10 and 6 of 47 (13%) having DI > 20. Oximetry measures of SDB correlated with lower BI scores at discharge and lower BI at 3- and 12-month follow-ups (P < or = .05, Pearson coefficients). Oximetry measures correlated with return home after discharge, but the association between oximetry measures and living at home was lost at 12 months. Two oximetry variables correlated with death at 1 year. Brain stem location correlated with higher DI and time at < 90% SaO2, but patients with hemispheric stroke and oximetry abnormalities also had worse functional outcome. No correlation was found between oximetry values and sex, age, preexisting medical conditions (except previous stroke), or severity of neurological deficit. Oximetry abnormalities were associated with a history of snoring. Polysomnography on 19 patients confirmed oximetry evidence of severe SDB. Eighteen of 19 patients (95%) had an apnea-hypopnea index (AHI) of > 10 events per hour of recording, 13 of 19 (68%) had an AHI > 20, and 10 of 19 (53%) had an AHI > 30. Desaturation events were largely due to obstructive apneas. CONCLUSIONS SDB accompanied by arterial oxyhemoglobin desaturation is common in patients undergoing rehabilitation after stroke and is associated with higher mortality at 1 year and lower BI scores at discharge and at 3 and 12 months after stroke. SDB may be an independent predictor of worse functional outcome. Obstructive sleep apnea appeared to be the most common form of SDB, and the frequent history of snoring suggests that SDB preceded the stroke in most patients.

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.

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 neurore-habilitation 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.

Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone

Purpose: To characterize the clinical features and perform linkage analysis of candidate loci in a large Illinois family with autosomal dominant limb-girdle muscular dystrophy (LGMD) and Paget disease of bone (PDB).Methods: The family includes 11 affected individuals (8 M, 3 F). Clinical, biochemical and radiologic evaluations were performed to delineate clinical features of the disorder. Linkage analysis with polymorphic markers was performed for previously identified LGMD, PDB and cardiomyopathy loci.Results: Onset of PDB is early, at a mean age of 35 y, with classic distribution involving the spine, pelvis, and skull. Muscle weakness and atrophy is progressive with mildly elevated to normal creatine phosphokinase levels. Muscle biopsy in the oldest male revealed vacuolated fibers, however, in others revealed nonspecific myopathy. Affected individuals die from progressive muscle weakness, and respiratory and cardiac failure in their 40s-60s. Linkage analysis excluded autosomal dominant and recessive LGMD, PDB, and cardiomyopathy loci.Conclusion: Autosomal dominant LGMD associated with PDB is an unusual disorder. Linkage analysis indicates a unique locus in this family.

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.

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 Unique Point Mutation in the PMP22 Gene Is Associated with Charcot-Marie-Tooth Disease and Deafness

Charcot-Marie-Tooth disease (CMT) with deafness is clinically distinct among the genetically heterogeneous group of CMT disorders. Molecular studies in a large family with autosomal dominant CMT and deafness have not been reported. The present molecular study involves a family with progressive features of CMT and deafness, originally reported by Kousseff et al. Genetic analysis of 70 individuals (31 affected, 28 unaffected, and 11 spouses) revealed linkage to markers on chromosome 17p11.2-p12, with a maximum LOD score of 9.01 for marker D17S1357 at a recombination fraction of .03. Haplotype analysis placed the CMT-deafness locus between markers D17S839 and D17S122, a approximately 0.6-Mb interval. This critical region lies within the CMT type 1A duplication region and excludes MYO15, a gene coding an unconventional myosin that causes a form of autosomal recessive deafness called DFNB3. Affected individuals from this family do not have the common 1.5-Mb duplication of CMT type 1A. Direct sequencing of the candidate peripheral myelin protein 22 (PMP22) gene detected a unique G-->C transversion in the heterozygous state in all affected individuals, at position 248 in coding exon 3, predicted to result in an Ala67Pro substitution in the second transmembrane domain of PMP22.

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 &agr;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.

Comparison of Two Therapy Approaches in the Rehabilitation of the Pure Motor Hemiparetic Stroke Patient

Although there are a variety of therapeutic philosophies applied in stroke rehabilitation, it has not been determined whether one approach is superior to another. We prospectively evaluated twenty-seven patients with pure motor hemiparetic strokes admitted to an acute neurorehabilitation unit and randomized them to treatment with either a traditional functional retraining approach (TFR) or neurodevelopmental techniques (NDT). NDT and TFR treated patients did not differ with regard to age, gender, side of stroke, or days from stroke to study entry. Other than an increased gait velocity in NDT treated patients at hospital discharge (p = 0.04), there was no significant difference in gait measures, upper extremity motor skills, or Functional Independence Measure (FIM) scores at hospital discharge, six month, or twelve month follow-up. Rehab length of stay did not differ significantly between the two treatment groups. This data suggests that TFR and NDT approaches are equally efficacious in treating pure motor hemiparetic strokes in terms of functional outcomes, gait measures, and upper extremity motor skills. Key Words: Stroke—Rehabilitation—Physical therapy— Neurodevelopmental technique.

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.