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.

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.

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.

Anticipation in a unique family with Charcot-Marie-Tooth syndrome and deafness: delineation of the clinical features and review of the literature.

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of polyneuropathies characterized by degeneration of peripheral nerves, resulting in distal muscle atrophy, sensory loss, and deformities of hands and feet. We have studied 34 individuals in a large 84-member four-generation central Illinois family with autosomal dominant Charcot-Marie-Tooth and deafness. Nerve conduction velocities are consistent with type 1 CMT. Audiological evaluation revealed both auditory neuropathy and cochlear involvement in affected individuals. There is increasing clinical severity and younger age of onset of CMT and deafness with each progressive generation, suggestive of anticipation (P < 0.05). The proband, a female diagnosed at birth with hypotonia, bilateral vocal cord palsy, swallowing incoordination, and hearing impairment, died at age 18 months. Another individual died at the age of 3 months from hypotonia later attributed to CMT. Genetic analysis indicated that affected individuals in this family do not have the common 1.4 Mb duplication associated with type 1A CMT; however, all affected individuals have a unique G to C transversion at position 248 in coding exon 3 of the peripheral myelin PMP22 gene located on chromosome 17p11.2-p12. This mutation is predicted to cause an Ala67Pro substitution in the second transmembrane domain of PMP22, consistent with the molecular cause of the CMT phenotype. However, it does not explain the cochlear component of the deafness, the clinical observation of anticipation, and other features in this family.

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)

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.

Clinical evaluation of prior suicide attempts and suicide risk in psychiatric inpatients.

BACKGROUND: In practice psychiatrists rely on their own experience and intuition to evaluate the suicide potential of individual patients, but the algorithms for the decision-making process remain unclear. OBJECTIVES: (1) to establish models for the decision making process for evaluating suicide risk; (2) to simulate the impact of information concerning the number of previous suicide attempts on the clinician's ability to detect patients who performed medically serious suicide attempts (MSSAs). METHODS: Four decision models (linear, dichotomized, hyperbolic, and undifferentiated) depicting the influence of the number of previous suicide attempts on the clinician's recognition of MSSAs in 250 psychiatric inpatients were elicited and tested by a series of discriminant analyses. RESULTS: The dichotomized model ("all or none") was found to be the most efficient in detecting medically serious suicide attempts. CONCLUSION: The "all or none" paradigm seems to be the most appropriate way to evaluate the weight of previous suicide attempts in the decision-making process identifying medically serious suicide attempt patients.

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.

Effect of inositol on bulimia nervosa and binge eating.

OBJECTIVES: This study aimed to determine whether inositol has therapeutic value in patients with bulimia nervosa and binge eating. METHOD: A double-blind crossover trial using 18 g inositol versus placebo was performed in 12 patients for 6 weeks in each arm. RESULTS: Inositol was significantly better than placebo on the Global Clinical Impression, the Visual Analogue Scale, and the Eating Disorders Inventory. DISCUSSION: Inositol is as therapeutic in patients with bulimia nervosa and binge eating as it is in patients with depression and panic and obsessive-compulsive disorders. This increases its parallelism with serotonin selective reuptake inhibitors.

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.

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.

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 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.

Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.

Autosomal dominant myopathy, Paget disease of bone, and dementia constitute a unique disorder (MIM 605382). Here we describe the clinical, biochemical, radiological, and pathological characteristics of 49 affected (23 male, 26 female) individuals from four unrelated United States families. Among these affected individuals 90% have myopathy, 43% have Paget disease of bone, and 37% have premature frontotemporal dementia. EMG shows myopathic changes and muscle biopsy reveals nonspecific myopathic changes or blue-rimmed vacuoles. After candidate loci were excluded, a genome-wide screen in the large Illinois family showed linkage to chromosome 9 (maximum LOD score 3.64 with marker D9S301). Linkage analysis with a high density of chromosome 9 markers generated a maximum two-point LOD score of 9.29 for D9S1791, with a maximum multipoint LOD score of 12.24 between D9S304 and D9S1788. Subsequent evaluation of three additional families demonstrating similar clinical characteristics confirmed this locus, refined the critical region, and further delineated clinical features of this unique disorder. Hence, autosomal dominant inclusion body myopathy (HIBM), Paget disease of bone (PDB), and frontotemporal dementia (FTD) localizes to a 1.08-6.46 cM critical interval on 9p13.3-12 in the region of autosomal recessive IBM2.