Evaluation of the Walking Index for Spinal Cord Injury II (WISCI-II) in children with Spinal Cord Injury (SCI).

STUDY DESIGN: Mixed methods were used in this study. The appropriateness of the levels of the Walking Index for Spinal Cord Injury II (WISCI-II) for application in children was critically reviewed by physical therapists using the Modified Delphi Technique, and the inter- and intra-rater reliability of the WISCI-II in children was evaluated. OBJECTIVES: To examine the construct validity, and to establish reliability of the WISCI-II related to its use in children with spinal cord injury (SCI). SETTING: United States of America. METHODS: Using a Modified Delphi Technique, physical therapists critically reviewed the WISCI-II levels for pediatric utilization. Concurrently, ambulatory children under age 18 years with SCI were evaluated using the WISCI-II on two occasions by the same therapist to establish intra-rater reliability. One trial was photographed and de-identified. Each photograph was reviewed by four different physical therapists who gave WISCI-II scores to establish inter-rater reliability. Summary and descriptive statistics were used to calculate the frequency of yes/no responses for each WISCI-II level question and to determine the percent agreement for each question. Inter- and intra-rater reliability was calculated using interclass correlation coefficients (ICCs) with 95% confidence intervals (CI). RESULTS: Construct validity was confirmed after one Delphi round during which at least 80% agreement was established by 51 physical therapists on the appropriateness of the WISCI-II levels for children. Fifty-two children with SCI aged 2-17 years completed repeated WISCI-II assessments and 40 de-identified photographs were scored by four physical therapists. Intra- and inter-rater reliability was high (ICC=0.997, CI=0.995-0.998 and ICC=0.97, CI=0.95-0.98, respectively). CONCLUSION: This study demonstrates support for the use of the WISCI-II in ambulatory children with SCI. SPONSORSHIP: This study was funded by the Craig H Neilsen Foundation, Spinal Cord Injury Research on the Translation Spectrum, Senior Research Award #282592 (Mulcahey, PI).

Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study.

This study was designed to evaluate whether subjects with amyloid beta (Aß) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than subjects without Aß pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aß+) or negative (Aß-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aß+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aß+ MCI subjects demonstrated greater worsening compared with Aß- subjects on the ADAS-Cog over 36 months (5.66 ± 1.47 vs -0.71 ± 1.09, P = 0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P < 0.05). Similar to MCI subjects, Aß+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aß+ AD patients showed greater declines in verbal fluency and the MMSE (P < 0.05). Aß+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aß+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aß+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aß- subjects do.

Rivastigmine transdermal system for the treatment of mild to moderate Alzheimer's disease.

Today patients with mild to moderate Alzhiemer's disease (AD) have a treatment approach choice: oral or transdermal delivery. The aim of this review was to provide a concise, comprehensive overview of the clinically relevant safety, tolerability and efficacy information available for the rivastigmine transdermal system. Relevant articles were identified through a MEDLINE search of publications in the past 3 years using the terms 'rivastigmine' and 'transdermal' or 'patch'. Efficacy, safety and tolerability of the rivastigmine patch vs. placebo were established in a large, international, 24-week, double-blind, randomised clinical trial and subsequent 28-week open-label extension study. Drug exposure with the 9.5 mg/24 h rivastigmine patch was not significantly different to that provided by an oral capsule dose of 12 mg/day. Most frequently observed adverse events were gastrointestinal. In the primary study, incidences of nausea, vomiting and diarrhoea were: 5%, 3% and 3% respectively in the placebo group; 7%, 6% and 6% in the 9.5 mg/24 h rivastigmine patch group; and 23%, 17% and 5% in the 12 mg/day capsule group. Most patients experienced no, slight or mild application-site skin reactions. De novo patients or those taking oral rivastigmine or donepezil may tolerate a switch to rivastigmine patch. By providing drug exposure that is not significantly different to the highest recommended rivastigmine capsule dose (12 mg/day), with less fluctuation over 24 h, rivastigmine patch offers similar efficacy with an improved tolerability profile. The rivastigmine patch provides a viable treatment option for patients with mild to moderate AD.

Safety and tolerability of rivastigmine transdermal patch compared with rivastigmine capsules in patients switched from donepezil: data from three clinical trials.

OBJECTIVES: To compare the safety and tolerability of switching patients with mild-to-moderate Alzheimer's disease from donepezil to either rivastigmine capsule or transdermal patch. METHODS: Three studies investigated the switch from donepezil to rivastigmine; study US13 was a 26-week, single-arm, immediate-switch study; US18 was a 26-week, sequential cohort study (both studies evaluated rivastigmine capsules 3-12 mg/day); study US38 was a 25-week, randomised, parallel-group, open-label study which investigated switch (immediate or after 7 days' withdrawal) from donepezil to rivastigmine transdermal patch (4.6 mg/24 hr). Safety outcomes included adverse events (AEs), discontinuations caused by AEs and serious AEs (SAEs). RESULTS: Patient groups receiving rivastigmine patch (n = 261) or capsules (n = 331) had mean +/- SD ages of 77.3 +/- 8.0 and 78.1 +/- 7.8 years, dementia durations of 3.9 +/- 2.6 and 3.6 +/- 2.2 years and Mini-Mental State Examination scores of 18.3 +/- 4.00 and 17.9 +/- 4.4 respectively. Overall, 184 (70.5%) and 276 (83.4%) patients experienced at least one AE, and 23 (8.8%) and 55 (16.6%) patients experienced an SAE with the rivastigmine patch and capsules respectively. Of the patients who experienced an AE, 10 (3.8%) and 109 (32.9%) experienced nausea, and 11 (4.2%) and 80 (24.1%) experienced vomiting with the rivastigmine patch and capsules respectively. Discontinuations because of AEs occurred in 64 (19.3%) patients receiving capsules and 38 (14.6%) patients in the transdermal patch group. The most common reasons for discontinuation with the transdermal patch were application site reaction and disease progression, and nausea and vomiting with the capsules. CONCLUSIONS: The rivastigmine transdermal patch appears to have better tolerability than rivastigmine capsules, with fewer gastrointestinal AEs and discontinuations because of these AEs. Simple daily rotation of patch location will likely reduce the frequency of skin reactions. This post hoc analysis was carried out by Novartis Pharmaceuticals Corporation. Data for the analysis were collected from the US13 study (CENA713B US13), the US18 study (CENA713B US18) and the US38 study (CENA713D US38).

Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer's Disease Suggest Disease Modification Potential.

BACKGROUND: Alzheimer's Disease (AD) patients homozygous for the APOE4 allele (APOE4/4) have a distinct clinical and biological phenotype with high levels of beta amyloid (Aß) pathology and toxic Aß oligomers. Tramiprosate, an oral agent that inhibits Aß monomer aggregation into toxic oligomers, was evaluated in two Phase 3 Mild to Moderate AD studies which did not show efficacy in the overall population. Re-analyses of these trials showed the most consistent clinical benefits in APOE4/4 patients. We analyzed efficacy in the APOE4/4 patients with Mild disease. OBJECTIVES: To determine the optimal stage of AD for future trials in APOE4/4 homozygotes. DESIGN: Two randomized, double-blind, placebo-controlled parallel-arm multi-center studies of 78-weeks duration. SETTING: Academic Alzheimer's disease centers, community-based memory clinics, and neuropsychiatric research sites. PARTICIPANTS: Participants included 2,025 AD patients with MMSE 16-26. Approximately 13-15% had APOE4/4 genotype (N= 147 and 110 per study), mean age 71.1 years, 56% females. Almost all were on stable symptomatic drugs. INTERVENTION: Randomized subjects received oral placebo, 100mg BID, or 150mg BID of tramiprosate. MEASUREMENTS: Co-primary outcomes were change from baseline in the ADAS-cog11 and CDR-SB. Disability assessment for dementia (DAD) was a secondary outcome. RESULTS: In APOE4/4 homozygotes receiving 150mg BID tramiprosate, efficacy in the traditional Mild AD patients (MMSE 20-26) was higher than the overall group (MMSE 16-26) and efficacy in the Mild patients (MMSE 22-26) was highest. Tramiprosate benefits compared to placebo on ADAS-cog, CDR-SB, and DAD were 125%, 81% and 71%, respectively (p<0.02). The Mild subgroup (MMSE 22-26) showed cognitive stabilization with no decline over 78 weeks, both ADAS-cog and DAD effects increased over time. Tramiprosate safety in APOE4/4 patients was favorable. Most common adverse events were nausea, vomiting, depression and decreased weight. CONCLUSIONS: The Mild subgroup of APOE4/4 AD patients (MMSE 22-26) showed larger benefits on the high dose of tramiprosate than the overall Mild and Moderate group. Consistent with its preclinical effects on Aß oligomers, tramiprosate seemed to stabilize cognitive performance, supporting its disease modification potential. Confirmatory studies using ALZ-801, an improved pro-drug formulation of tramiprosate, will target APOE4/4 patients with Mild AD.

Tract-Specific Diffusion Tensor Imaging in Cervical Spondylotic Myelopathy Before and After Decompressive Spinal Surgery: Preliminary Results.

PURPOSE: Diffusion tensor imaging (DTI) metrics of the cervical spinal cord in patients with cervical spondylotic myelopathy (CSM) were compared to those measured in healthy volunteers, using tract-specific region of interests (ROIs) across all cervical intervertebral disc levels. METHODS: Magnetic resonance (MR) imaging of the cervical spinal cord was performed in four patients with CSM and in five healthy volunteers on a 3-T MR scanner. Region-specific fractional anisotropy (FA) and mean diffusivity (MD) were calculated on axial imaging with ROI placement in the anterior, lateral, and posterior regions of the spinal cord. FA and MD were also calculated on sagittal acquisitions. Nonparametric statistical tests were used to compare controls and patients before and after surgery. RESULTS: FA values were significantly lower (p = 0.050) and MD values were significantly higher (p = 0.014) in CSM patients measured at level of maximal compression before surgery than in healthy controls in lateral and posterior ROIs, respectively. In posterior ROIs, MD values were significantly higher in patients before surgery compared to controls at all levels except C7-T1. CONCLUSION: Patients with CSM may demonstrate region-specific changes in DTI metrics when compared to healthy controls. Changes in DTI metrics may also occur at levels remote from site of compression.

Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Individuals with Early Alzheimer's Disease: Amyloid Imaging Positron Emission Tomography and Safety Results from a Phase 2 Study.

BACKGROUND: ACC-001 is an investigational therapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease. OBJECTIVES: To evaluate safety, immunogenicity, impact on brain amyloid, and other exploratory endpoints in participants receiving ACC-001. DESIGN: Randomized, phase 2, interventional study. TRIAL REGISTRATION: Clinicaltrials.gov ID NCT01227564. PARTICIPANTS: Individuals with early Alzheimer's disease (Mini-Mental State Examination scores ≥25, a global Clinical Dementia Rating of 0.5, and evidence of elevated baseline brain amyloid burden). INTERVENTION: Participants were randomized to ACC-001 3 µg or 10 µg with QS-21 adjuvant (50 µg), or placebo. MEASUREMENTS: The primary endpoint was change in brain amyloid burden by 18F-florbetapir positron emission tomography in composite cortical standard uptake value ratio. RESULTS: A total of 63 participants were randomized and 51 completed the study. At week 104, no significant differences were observed in 18F-florbetapir positron emission tomography composite cortical standard uptake value ratio between either ACC-001 dose compared with placebo. In both ACC-001 + QS-21 treatment groups, following the initial immunization, the anti-amyloid-beta geometric mean titers increased after each subsequent vaccination and then declined, with less apparent decline after the later compared with earlier immunizations. The majority of treatment-emergent adverse events in the ACC-001 + QS-21 groups were injection site reactions, which occurred at a greater rate in active treatment groups than in the placebo group. No amyloid-related imaging abnormalities of edema or effusion were reported. CONCLUSION: No statistically significant differences were observed between groups in the change from baseline brain amyloid burden despite apparently robust systemically measured anti-amyloid-beta antibody response at both dose levels. Insufficient antibody titers, poor quality immune response, short duration of treatment, or small sample size may have resulted in these findings. The safety and tolerability profile was acceptable.

Agenesis of the corpus callosum with hypothermia.

A patient with episodic hypothermia and agenesis of the corpus callosum had no direct evidence of hypothalamic-pituitary dysfunction. However, it is speculated on the basis of a recent clinicopathologic case study that selective hypothalamic involvement is the cause of the hypothermia. Electroencephalograms and treatment with antiseizure medication did not support an epileptic genesis for the episodic hypothermia. Double, simultaneous, tachistoscopic stimulation studies revealed an asymmetry of response that can be explained by either a functional disconnection of the cerebral hemispheres or bilateral independent and asymmetrical representation of speech mechanisms.

Postradiation motor neuron syndrome.

We report an unusual case of selective lower motor neuron syndrome (MNS) complicating whole neuraxis radiation therapy. Only three well-documented similar cases have been found in a thorough review of the literature. The syndrome has a stereotyped time course and is self-limited. We discuss here possible pathogenetic mechanisms and their relationship to motor neuron disease.

Effect of tacrine on language, praxis, and noncognitive behavioral problems in Alzheimer disease.

OBJECTIVE: To examine the effects of tacrine hydrochloride in patients with Alzheimer disease (AD) and detectable baseline deficits in discrete cognitive and noncognitive parameters who are enrolled in a previously reported multicenter, double-blind, 30-week trial. DESIGN: An exploratory analysis using last observation carried forward. The study population included a placebo group (n = 181) and all patients randomized to treatment within 160 mg/d of tacrine hydrochloride (n = 234), regardless of highest dose achieved or duration of tacrine therapy. STUDY POPULATION: Male and female subjects, at least 50 years of age, with mild to moderate AD and detectable baseline deficits in discrete cognitive and noncognitive parameters. MAIN OUTCOME MEASURES: Change from baseline to last observation carried forward in discrete subscale scores of the Alzheimer's Disease Assessment Scale (ADAS): cognitive (memory, language, praxis) and noncognitive (mood, behavior). Improvement was defined as a decrease of at least 1 point from baseline; stabilization was defined as no change or a decrease from baseline. RESULTS: Compared with the placebo group, the percentage of patients receiving tacrine whose conditions improved or stabilized was significantly greater for 8 of 11 ADAS-cognitive items (word recall, word recognition, orientation, language production, comprehension, word finding, following commands, ideational praxis) and for the ADAS-noncognitive items: cooperation, delusions, and pacing. CONCLUSIONS: Tacrine stabilizes or improves specific behavioral deficits and symptoms in AD. The previous demonstration of tacrine's effect on global cognitive function has been extended by suggesting an association between tacrine therapy and improvements in individual cognitive and noncognitive items of the ADAS. Effects of tacrine in clinical practice might be more accurately and efficiently assessed by measuring individual ADAS cognitive and noncognitive items relevant to individual patient pretreatment clinical status.

Alexia without agraphia, hemianopia, or color-naming defect: a disconnection syndrome.

A patient with alexia without agraphia, hemianopia, or color-naming defect was found at operation to have a meningioma arising from the tentorium cerebelli that compressed the inferior aspect of the left temporal-occipital junction. It is presumed to have involved only the left ventral visual association cortex and its inferior outflow tracts to the angular gyrus. The input from the right occipital area also was disconnected from the visual language verbal association area by involvement of the ventral outflow of the splenium of the corpus callosum. Preservation of color naming and matching suggests that these functions are dependent on the integrity of more dorsal occipital association systems.

Timing of temporomandibular joint sounds in orthodontic patients.

The consistency of occurrence and also the timing of TMJ sounds during jaw opening and closing were studied by means of an audio-visual sound recording system in an attempt to address the possible causes of temporomandibular joint (TMJ) sounds. From a group of 347 orthodontic patients, 104 were found to have medium- or high-amplitude TMJ sounds during jaw opening or closing. Most patients (53%) had reciprocal clicking--that is, a single sound on opening and on closing; another 12% had multiple sounds on opening or closing; 22% had a single closing sound; and 13% had a single opening sound. Sounds occurred at all degrees of jaw opening throughout this sample, but in most patients opening sounds tended to be closer to maximum opening, whereas closing sounds tended to occur in the middle of the closing movement. No statistically significant association was found between the timing of the opening and closing sounds. In 42.3% of patients, the sound was inconsistent in its occurrence on successive opening and closing cycles. Twenty-three percent of patients reported pain, jaw locking, or limitation of movement, but these were not associated with the timing of the opening sound. The findings suggest that the reciprocal click, widely associated with anterior disc displacement with reduction, was relatively common, but that other explanations for the joint sounds should also be considered. Conversely, a large variation may exist in the timing and the occurrence of sounds in patients with anterior disc displacement in the absence of pain and limitation of movement.

Temporomandibular joint sounds related to orthodontic therapy.

A cross-sectional survey for temporomandibular joint (TMJ) sounds was conducted on 347 orthodontic patients before, during, and after treatment. Those patients who reported joint sounds, or in whom sounds were noted on clinical examination, were subjected to an audiovisual evaluation which was recorded on videotape to identify more precisely the character of the sounds during jaw opening and closing. TMJ sounds were quite common before, during, and after orthodontic treatment. There was a significant association among three variables: joint sounds, age, and treatment. It is not clear, however, whether joint sounds increased due to orthodontic treatment, age, or both. No significant associations were found between TMJ sounds and functional occlusal factors. Significantly more sounds were noted by the examiners than were reported by the patients. Medium or high amplitude sounds were evident in 32.6% of the 135 subjects who underwent the audiovisual examination.

Electrical stimulation in spinal cord injury.

The use of electricity to stimulate nerves or muscles is nothing new. In the 18th century Galvani recognized that electricity could be converted into "nerve force". Numerous applications of electrical stimulation have been explored, most notably cardiac pacing, cochlear implants or transcutaneous electrical nerve stimulation (TENS) units for pain control. Spinal cord injury (SCI), with its "transecting lesion" that leaves intact nervous system below the injury completely disconnected from the centers that exert motor control provides the ideal opportunity for electrical stimulation use. Multiple applications are being investigated, including those for aerobic conditioning/cardiovascular exercise, cough and breathing assistance, improving bowel and bladder control, erection and ejaculation, hand grasp, spasticity management, neuro-muscular reeducation, standing and walking, etc. This review will focus on innovative and technologically advanced applications of electrical stimulation in the management of patients with spinal cord injury.

Spinal cord injury.

PURPOSE: This article is an overview of the newer therapeutic interventions employed in the care of the spinal cord injured individual and the theoretical rationale supporting them. ISSUE: Spinal Cord Injury (SCI) care was, until recently, a maintenance type treatment, addressing systems mostly affected by complications of the original injury (e.g. bladder, skin, spasiticity). CONCLUSION: With the recent advances in the neuroscience field, more aggressive interventions geared at secondary injury prevention, neuronal regeneration and functional restoration are emerging.

Occlusal contacts following orthodontic treatment: a follow-up study.

Occlusal contacts in maximum intercuspation were examined in a sample of 40 patients at the end of active orthodontic treatment and again an average of 21 months later. An increase in the total number of contacts was due to more actual and near contacts on all posterior teeth and more near contacts on anterior teeth. When the results were compared to a previous short term study, continued settling of the occlusion occurred beyond an initial three months of retention. Few contacts changed their location between the occlusal inclined planes and central grooves, suggesting minimal settling of the occlusion in a buccolingual direction.

Long-term stability of dental relationships after orthodontic treatment.

Adult changes in selected occlusal parameters are measured, with the study sample limited to 72 subjects with a history of malocclusion treated orthodontically 12 to 35 years previously. Variations were large. Most of the corrections were retained, with mean changes tending toward pretreatment values.

Methodologies for evaluating long-term stability of dental relationships after orthodontic treatment.

A comprehensive review of literature which considers methodologies for studying long-term occlusal stability is presented. This article focuses on the evaluation of plaster study models because occlusal changes are best reflected in longitudinal casts. Of particular interest is the assessment of crowding in the dentition and the various physical and mathematical procedures used to evaluate the measurement of space available. Indices used to assess the overall occlusal results of treatment are also presented.

Switching from oral cholinesterase inhibitors to the rivastigmine transdermal patch.

Oral cholinesterase inhibitors (ChEIs) are associated with side effects such as nausea and vomiting. The use of transdermal patches for ChEI delivery may help to minimize these problems. The objective of this review was to consider available data from patients switching from oral ChEIs to transdermal rivastigmine treatment, and to suggest practical guidelines for patients wishing to do this. Literature database and reference list searches were performed to identify suitable publications. Data from two clinical trials and a series of open observational studies, in which patients were switched to the rivastigmine patch from oral rivastigmine, donepezil tablets, or galantamine, were evaluated. Adverse events were tabulated. In the studies reported here, nausea was reported in up to 3.2% and vomiting in up to 1.9% of patients switching to the rivastigmine patch from oral rivastigmine. Similar rates (up to 3.8% of patients for nausea and 0.8% of patients for vomiting) were reported when switching to the rivastigmine patch from donepezil tablets, and no nausea or vomiting was reported in a case study of patients switching to the rivastigmine patch from galantamine tablets. Switching regimes used in clinical trials appeared well tolerated. Data support recommendations for patients on high rivastigmine capsule doses to switch directly to the 9.5 mg/24 h rivastigmine patch, while those on lower oral rivastigmine doses should start on the 4.6 mg/24 h patch for 4 weeks before increasing to the 9.5 mg/24 h patch. This latter regimen is recommended for patients on other oral cholinesterase inhibitors if switching is medically indicated or requested by the patient or the caregiver.