Role of Basal Forebrain Neurons in Adrenomyeloneuropathy in Mice and Humans.

OBJECTIVE: X-linked adrenoleukodystrophy is caused by mutations in the peroxisomal half-transporter ABCD1. The most common manifestation is adrenomyeloneuropathy, a hereditary spastic paraplegia of adulthood. The present study set out to understand the role of neuronal ABCD1 in mice and humans with adrenomyeloneuropathy. METHODS: Neuronal expression of ABCD1 during development was assessed in mice and humans. ABCD1-deficient mice and human brain tissues were examined for corresponding pathology. Next, we silenced ABCD1 in cholinergic Sh-sy5y neurons to investigate its impact on neuronal function. Finally, we tested adeno-associated virus vector-mediated ABCD1 delivery to the brain in mice with adrenomyeloneuropathy. RESULTS: ABCD1 is highly expressed in neurons located in the periaqueductal gray matter, basal forebrain and hypothalamus. In ABCD1-deficient mice (Abcd1-/y), these structures showed mild accumulations of α-synuclein. Similarly, healthy human controls had high expression of ABCD1 in deep gray nuclei, whereas X-ALD patients showed increased levels of phosphorylated tau, gliosis, and complement activation in those same regions, albeit not to the degree seen in neurodegenerative tauopathies. Silencing ABCD1 in Sh-sy5y neurons impaired expression of functional proteins and decreased acetylcholine levels, similar to observations in plasma of Abcd1-/y mice. Notably, hind limb clasping in Abcd1-/y mice was corrected through transduction of ABCD1 in basal forebrain neurons following intracerebroventricular gene delivery. INTERPRETATION: Our study suggests that the basal forebrain-cortical cholinergic pathway may contribute to dysfunction in adrenomyeloneuropathy. Rescuing peroxisomal transport activity in basal forebrain neurons and supporting glial cells might represent a viable therapeutic strategy. ANN NEUROL 2024;95:442-458.

Multimodal pre-screening can predict BCI performance variability: A novel subject-specific experimental scheme.

BACKGROUND: Brain-computer interface (BCI) systems currently lack the required robustness for long-term daily use due to inter- and intra-subject performance variability. In this study, we propose a novel personalized scheme for a multimodal BCI system, primarily using functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG), to identify, predict, and compensate for factors affecting competence-related and interfering factors associated with performance. METHOD: 11 (out of 13 recruited) participants, including five participants with motor deficits, completed four sessions on average. During the training sessions, the subjects performed a short pre-screening phase, followed by three variations of a novel visou-mental (VM) protocol. Features extracted from the pre-screening phase were used to construct predictive platforms using stepwise multivariate linear regression (MLR) models. In the test sessions, we employed a task-correction phase where our predictive models were used to predict the ideal task variation to maximize performance, followed by an interference-correction phase. We then investigated the associations between predicted and actual performances and evaluated the outcome of correction strategies. RESULT: The predictive models resulted in respective adjusted R-squared values of 0.942, 0.724, and 0.939 for the first, second, and third variation of the task, respectively. The statistical analyses showed significant associations between the performances predicted by predictive models and the actual performances for the first two task variations, with rhos of 0.7289 (p-value = 0.011) and 0.6970 (p-value = 0.017), respectively. For 81.82 % of the subjects, the task/workload correction stage correctly determined which task variation provided the highest accuracy, with an average performance gain of 5.18 % when applying the correction strategies. CONCLUSION: Our proposed method can lead to an integrated multimodal predictive framework to compensate for BCI performance variability, particularly, for people with severe motor deficits.

Hereditary Neuropathies.

OBJECTIVE: This article provides an overview of hereditary neuropathies, describes the different hereditary neuropathy subtypes and the clinical approach to differentiating between them, and summarizes their clinical management. LATEST DEVELOPMENTS: Increasingly available clinical genetic testing has broadened the clinical spectrum of hereditary neuropathy subtypes and demonstrated a significant overlap of phenotypes associated with a single gene. New subtypes such as SORD -related neuropathy and CANVAS (cerebellar ataxia, neuropathy, vestibular areflexia syndrome) have emerged. The optimization of clinical management has improved gait and motor function in the adult and pediatric populations. Novel therapeutic approaches are entering clinical trials. ESSENTIAL POINTS: Hereditary neuropathies constitute a spectrum of peripheral nerve disorders with variable degrees of motor and sensory symptoms, patterns of involvement, and clinical courses.

Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants.

Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.

Psychometric evaluation of modified spinal muscular atrophy functional rating scale (SMAFRS) in adult patients using Rasch analysis.

INTRODUCTION/AIMS: The Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) was first developed as a secondary functional outcome measure to detect changes over time in patients with spinal muscular atrophy (SMA) in clinical trials. Its modified version evaluates 10 activities of daily living. The aim of the study was to analyze modified SMAFRS data using item response theory psychometric models. METHODS: A total of 253 responses from 41 adult patients with ambulatory and non-ambulatory SMA types 2, 3, and 4 were analyzed. Rasch analysis was used to explore item-person targeting, fit statistics, category response functioning, dimensionality, and differential item functioning. RESULTS: Most items had good fitting with the exception of "toileting" and "respiratory." There were no major floor or ceiling effects, and most items covered a good range of disability with only a negligible breech of uni-dimensionality from eating, dressing, and respiratory items. Differential item function highlighted differences in toileting, turning, transferring, walking, and respiratory items between ambulatory and non-ambulatory populations. DISCUSSION: Despite subtle misfitting of certain items, mainly related to respiratory and bulbar function, overall modified SMAFRS remained a psychometrically stable and unidimensional outcome measure. There were some differences in measuring properties of certain functional items between ambulatory and non-ambulatory items that need to be taken into consideration in clinical trial design. Overall, the modified SMAFRS is a psychometrically reliable tool in assessment of adult patients with SMA.

SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia.

Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive. Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia. The effect of these variants on the catalytic activity and homeostatic regulation of serine palmitoyltransferase was investigated in human embryonic kidney cells, patient fibroblasts and Drosophila. Our results showed that two different pathogenic variants in SPTSSA caused a hereditary spastic paraplegia resulting in progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction in three individuals. The variants in SPTSSA impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila. These findings support the pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function.

Disease Progression in Charcot-Marie-Tooth Disease Related to MPZ Mutations: A Longitudinal Study.

OBJECTIVE: The paucity of longitudinal natural history studies in MPZ neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ neuropathies across 13 sites of the Inherited Neuropathies Consortium. METHODS: Change in Charcot-Marie-Tooth Examination Score (CMTES) and Rasch modified CMTES (CMTES-R) were evaluated using longitudinal regression over a 5-year period in subjects with MPZ neuropathy. Data from 139 patients with MPZ neuropathy were examined. RESULTS: The average baseline CMTES and CMTES-R were 10.84 (standard deviation [SD] = 6.0, range = 0-28) and 14.60 (SD = 7.56, range = 0-32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 (mean change from baseline of 0.87 points at 2 years, p = 0.008). Subgroup analysis revealed greater change in CMTES at 2 years in subjects with axonal as compared to demyelinating neuropathy (mean change of 1.30 points [p = 0.016] vs 0.06 points [p = 0.889]). Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy (mean 2-year change of 1.14 for baseline CMTES 8-14 [p = 0.025] vs -0.03 for baseline CMTES 0-7 [p = 0.958] and 0.25 for baseline CMTES ≥ 15 [p = 0.6897]). The progression in patients harboring specific MPZ mutations was highly variable. INTERPRETATION: CMTES is sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ neuropathies. ANN NEUROL 2023;93:563-576.

Peroxisome Metabolism Contributes to PIEZO2-Mediated Mechanical Allodynia.

Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodystrophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive neurodegeneration and an associated pain syndrome that is poorly understood. In the nervous system of mice, we found ABCD1 expression to be highest in dorsal root ganglia (DRG), with satellite glial cells (SGCs) displaying higher expression than neurons. We subsequently examined sensory behavior and DRG pathophysiology in mice deficient in ABCD1 compared to wild-type mice. Beginning at 8 months of age, Abcd1-/y mice developed persistent mechanical allodynia. DRG had a greater number of IB4-positive nociceptive neurons expressing PIEZO2, the mechanosensitive ion channel. Blocking PIEZO2 partially rescued the mechanical allodynia. Beyond affecting neurons, ABCD1 deficiency impacted SGCs, as demonstrated by high levels of VLCFA, increased glial fibrillary acidic protein (GFAP), as well as genes disrupting neuron-SGC connectivity. These findings suggest that lack of the peroxisomal half-transporter ABCD1 leads to PIEZO2-mediated mechanical allodynia as well as SGC dysfunction. Given the known supportive role of SGCs to neurons, this elucidates a novel mechanism underlying pain in X-linked adrenoleukodystrophy.

Feasibility of simultaneous high-resolution anatomical and quantitative magnetic resonance imaging of sciatic nerves in patients with Charcot-Marie-Tooth type 1A (CMT1A) at 7T.

INTRODUCTION/AIMS: Magnetic resonance imaging (MRI) of peripheral nerves can provide image-based anatomical information and quantitative measurement. The aim of this pilot study was to investigate the feasibility of high-resolution anatomical and quantitative MRI assessment of sciatic nerve fascicles in patients with Charcot-Marie-Tooth (CMT) 1A using 7T field strength. METHODS: Six patients with CMT1A underwent imaging on a high-gradient 7T MRI scanner using a 28-channel knee coil. Two high-resolution axial images were simultaneously acquired using a quantitative double-echo in steady-state (DESS) sequence. By comparing the two DESS echoes, T2 and apparent diffusion coefficient (ADC) maps were calculated. The cross-sectional areas and mean T2 and ADC were measured in individual fascicles of the tibial and fibular (peroneal) portions of the sciatic nerve at its bifurcation and 10 mm distally. Disease severity was measured using Charcot-Marie-Tooth Examination Score (CMTES) version 2 and compared to imaging findings. RESULTS: We demonstrated the feasibility of 7T MRI of the proximal sciatic nerve in patients with CMT1A. Using the higher field, it was possible to measure individual bundles in the tibial and fibular divisions of the sciatic nerve. There was no apparent correlation between diffusion measures and disease severity in this small cohort. DISCUSSION: This pilot study indicated that high-resolution MRI that allows for combined anatomical and quantitative imaging in one scan is feasible at 7T field strengths and can be used to investigate the microstructure of individual nerve fascicles.

Longitudinal dysphagia assessment in adult patients with nephropathic cystinosis using the Modified Barium Swallow Impairment Profile.

INTRODUCTION/AIMS: Nephropathic cystinosis is a lysosomal storage disorder with known myopathic features, including dysphagia. Evaluation of oropharyngeal swallowing physiology can be standardized using the Modified Barium Swallow Impairment Profile (MBSImP), a validated assessment tool used to analyze and rate swallowing across 17 distinct physiologic domains. Our objective was to better characterize swallowing impairments in nephropathic cystinosis using MBSImP analysis. METHODS: We retrospectively evaluated 40 video fluoroscopic swallowing studies performed at two time points over 1 y in patients with nephropathic cystinosis with various levels of oral and pharyngeal stage dysphagia. Patients completed two self-administered dysphagia outcome measures (the M. D. Anderson Dysphagia Inventory [MDADI] and the 10-item Eating Assessment Tool [EAT-10]). RESULTS: We demonstrated oral stage and pharyngeal stage dysphagia across domains that impacted bolus control, transit, and clearance through both the oral cavity and pharyngeal lumen. Also captured were deficits related to onset and completeness of laryngeal closure that impact airway protection during swallow. There were significant correlations between pharyngeal total score and EAT-10 (r = 0.5, p < 0.001) and between oral total score and EAT-10 (r = 0.7, p < 0.001), MDADI-e (r = -0.6, p < 0.001), MDADI-p (r = -0.5, p < 0.001) and MDADI-c (r = -0.6, p < 0.001). There were no differences in oral or pharyngeal total scores across the 1-y time span. DISCUSSION: This study identifies oral and pharyngeal stage dysphagia as crucial to patients with nephropathic cystinosis and paves the path for future studies of treatment targets.

Restless Legs Syndrome in X-linked adrenoleukodystrophy.

OBJECTIVE/BACKGROUND: X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that causes progressive gait and balance problems. Leg discomfort, sleep disturbances, and pain contribute to daily disability. We sought to investigate the prevalence and severity of Restless Legs Syndrome (RLS) in patients with ALD. PATIENTS/METHODS: We administered questionnaires and conducted diagnostic telephone interviews to assess RLS severity. We retrospectively extracted data from neurological examinations, functional gait measures, and laboratory assessments. RESULTS AND CONCLUSIONS: Thirty-two adults with ALD (21 female, 11 male) were recruited to participate. Thirteen patients (40.6%) had RLS (10/21 females and 3/11 males). The median age of RLS onset was 35 years [IQR = 22-54]. Patients with RLS had more signs and symptoms related to myelopathy, but not the brain demyelination seen in ALD. This pilot study suggests a high prevalence of RLS in adults with ALD, which may contribute to sleep problems and impair quality of life.

The Adverse Event Unit (AEU): A novel metric to measure the burden of treatment adverse events.

OBJECTIVE: To design a physician and patient derived tool, the Adverse Event Unit (AEU), akin to currency (e.g. U.S. Dollar), to improve AE burden measurement independent of any particular disease or medication class. PATIENTS/METHODS: A Research Electronic Data Capture (REDCap) online survey was administered to United States physicians with board certification or board eligibility in general neurology, subspecialty neurology, primary care internal medicine or family medicine, subspecialty internal medicine, general pediatrics, and subspecialty pediatrics. Physicians assigned value to 73 AE categories chosen from the Common Terminology Criteria of Adverse Events (CTCAE) relevant to neurologic disorder treatments. An online forced choice survey was administered to non-physician, potential patients, through Amazon Mechanical Turk (MTurK) to weight the severity of the same AE categories. Physician and non-physician data was combined to assign value to the AEU. Surveys completed between 1/2017 and 3/2019. RESULTS: 363 physicians rated the 73 AE categories derived from CTCAE. 660 non-physicians completed forced choice experiments comparing AEs. The AEU provides 0-10, weighted values for the AE categories studied that differ from the ordinal 1-4 CTCAE scale. For example, CTCAE severe diabetes (category 4) is assigned an AEU score of 9. Although non-physician input changed physician assigned AEU values, there was general agreement among physicians and non-physicians about severity of AEs. CONCLUSION: The AEU has promise to be a useful, practical tool to add precision to AE burden measurement in the clinic and in comparative efficacy research with neurology patients. AEU utility will be assessed in planned comparative efficacy clinical trials.

Effect of medetomidine on left ventricular outflow tract velocity in cats: A Doppler echocardiography study.

The purpose of the present study was to evaluate effects of medetomidine on left ventricular outflow tract (LVOT) velocity in domestic short-haired cats. Eighteen healthy adult male domestic short-haired cats were used for this study. All animals were client-owned. Echocardiography machine with 7.50 MHz transducer was used. Specific veterinary two-dimensional and pulse-waved echocardiogram images in apical five chamber right parasternal view were obtained and blood velocity in LVOT was calculated. After baseline echocardiographic recordings, 0.04 mg kg-1 of medetomidine was intramuscularly administered to each animal and LVOT velocity was calculated after 15 (T15), 50 (T30) and 80 (T80) min following drug administration. The LVOT velocity values (mean SEM) of cats in baseline were 1.06 0.04 m sec-1. There were significant differences between baseline and T15 and T30 regarding mean LVOT values. Age and weight had no significant effect on LVOT velocity values. The LVOT velocity values of T15, T50 and T80 were 0.77 0.04, 0.80 0.02 and 0.960.03 m sec-1, respectively. Our findings revealed significant decrease in mean LVOT velocity up to 50 min following medetomidine administration. The present study determined normal LVOT velocity range for a small population of cats before and after intra-muscular medetomidine administration.

Facial Palsy, Radiographic and Other Workup Negative: FROWN.

OBJECTIVES: Slow-onset peripheral facial palsy is far less common than acute-onset peripheral facial palsy and necessitates diagnostic evaluation for benign or malignant tumors or other less common etiologies. In the rare scenario in which no clarifying etiology is discovered following long-term evaluation (no radiographic or hematologic abnormalities and an otherwise unremarkable evaluation), a diagnostic and management dilemma occurs. We present a series of patients with this possible new clinical entity: Facial palsy, Radiographic and Other Workup Negative (FROWN) and propose a management strategy for this diagnosis of exclusion. METHODS: A series of 3,849 patients presenting with facial palsy to a tertiary facial nerve center was retrospectively assessed to identify those with progressive loss of facial function over at least 1 month. Exclusion criteria were history, physical or hematologic findings indicative of known diseases associated with facial palsy, and radiographic studies demonstrating a benign or malignant tumor. RESULTS: Patients with slow-onset facial palsy constituted 5% (190 patients) of the cohort and were ultimately diagnosed with either a benign or malignant neoplasm or other facial nerve pathology. Fourteen patients with slow-onset facial palsy remained without a diagnosis following long-term evaluation and serial imaging. Eleven patients underwent dynamic facial reanimation surgery and facial nerve and muscle biopsy, with no clear histopathologic diagnosis. CONCLUSION: Patients with slow-onset facial palsy with negative radiographic and medical evaluations over several years may be characterized as having FROWN, an idiopathic and as yet poorly understood condition, which appears to be amenable to facial reanimation but requires further investigation as to its pathophysiology.

Gait Difficulties and Postural Instability in Adrenoleukodystrophy.

Background: Gait and balance difficulties are among the most common clinical manifestations in adults with X-linked adrenoleukodystrophy, but little is known about the contributions of sensory loss, motor dysfunction, and postural control to gait dysfunction and fall risk. Objective: To quantify gait and balance deficits in both males and females with adrenoleukodystrophy and evaluate how environmental perturbations (moving surfaces and visual surrounds) affect balance and fall risk. Methods: We assessed sensory and motor contributions to gait and postural instability in 44 adult patients with adrenoleukodystrophy and 17 healthy controls using three different functional gait assessments (25 Foot Walk test, Timed Up and Go, and 6 Minute Walk test) and computerized dynamic posturography. Results: The median Expanded Disability Status Scale score for the patient cohort was 3.0 (range 0.0-6.5). Both males and females with adrenoleukodystrophy showed impairments on all three functional gait assessments relative to controls (P < 0.001). Performance on walking tests and Expanded Disability Status Scale scores correlated with incidence of falls on computerized dynamic posturography, with the 25 Foot Walk being a moderately reliable predictor of fall risk (area under the ROC curve = 0.7675, P = 0.0038). Conclusion: We demonstrate that gait difficulties and postural control deficits occur in patients with adrenoleukodystrophy, albeit at an older age in females. Postural deficits were aggravated by eyes closed and dynamic conditions that rely on vestibular input, revealing challenges to the interplay of motor, sensory and vestibular circuitry in adrenoleukodystrophy.

Beyond gait and balance: urinary and bowel dysfunction in X-linked adrenoleukodystrophy.

OBJECTIVE: To characterize the prevalence, onset, and burden of urinary and bowel dysfunction in adult patients with adrenoleukodystrophy (ALD) and to evaluate any sex differences in symptom presentation. METHODS: In this retrospective and prospective study, we performed medical record review (n = 103), analyzed the results of clinically indicated urodynamic testing (n = 11), and developed and distributed a symptom and quality of life (QOL) survey (n = 59). RESULTS: Urinary and bowel symptoms are highly prevalent in both males (75.0%) and females (78.8%) in this population, most commonly urinary urgency, often leading to incontinence. Time to onset of first urinary or bowel symptom occurs approximately a decade earlier in males. Seventy-two percent of symptomatic patients report a limitation to QOL. Urodynamic evaluation provides evidence of three distinct mechanisms underlying lower urinary tract dysfunction: involuntary detrusor contractions (indicating uncontrolled neuronal stimulation with or without leakage), motor underactivity of the bladder, and asynergy between detrusor contraction and sphincter relaxation. CONCLUSIONS: Beyond gait and balance difficulties, urinary and bowel symptoms are common in adults with ALD and impair QOL. Males are affected at a younger age but both sexes experience a higher symptom burden with age. As this population also experiences gait and balance impairment, patients with ALD are more vulnerable to urinary urgency leading to incontinence. Urodynamic evaluation may help better elucidate the pathophysiologic mechanisms underlying neurogenic lower urinary tract dysfunction, which can allow more targeted treatment.

Psychometric longitudinal evaluation of the Chronic Acquired Polyneuropathy Patient-Reported Index (CAPPRI) in patients with chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: We studied the performance of a 15-item, health-related quality-of-life polyneuropathy scale in a longitudinal study of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Sixty-one patients with CIDP completed the Chronic Acquired Polyneuropathy Patient-Reported Index (CAPPRI) scale and Patient Impression of Change (PIC) at baseline and follow-up visits. Clinicians completed Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores at baseline and follow-up visits. Conventional and modern psychometric analyses were performed on the completed forms. RESULTS: CAPPRI was psychometrically stable between visits without significant difference in response pattern between visits 1 and 2 (paired t-test P = .72). There was strong correlation between changes in INCAT and changes in CAPPRI scores between two visits (rho = 0.6, P < .001). In addition, we showed robust CAPPRI effect sizes between PIC categories. CONCLUSIONS: We demonstrated psychometric stability and construct longitudinal validity of CAPPRI.

Clinical trial readiness study of distal myopathy and dysphagia in nephropathic cystinosis.

BACKGROUND: Nephropathic cystinosis is a lysosomal storage disorder with late-onset systemic complications, such as myopathy and dysphagia. Currently employed outcome measures lack sensitivity and responsiveness for dysphagia and myopathy, a limitation to clinical trial readiness. METHODS: We evaluated 20 patients with nephropathic cystinosis in two visits over the course of a year to identify outcomes sensitive to detect changes over time. Patients also underwent an expiratory muscle strength training program to assess any effects on aspiration and dysphagia. RESULTS: There were significant differences in the Timed Up and Go Test (TUG) and Timed 25-Foot Walk (25-FW) between baseline and 1-y follow-up (P < .05). Maximum expiratory pressure (MEP) and peak cough flow (PCF) significantly improved following respiratory training (P < .05). CONCLUSIONS: Improved respiratory outcomes may enhance patients ability to expel aspirated material from the airway, stave off pulmonary sequelae associated with chronic aspiration, and yield an overall improvement in physical health and well-being.