Estimating motor unit numbers from a CMAP scan: Repeatability study on three muscles at 15 centres.

OBJECTIVE: To assess the repeatability and suitability for multicentre studies of MScanFit motor unit number estimation (MUNE), which involves modelling compound muscle action potential (CMAP) scans. METHODS: Fifteen groups in 9 countries recorded CMAP scans twice, 1-2 weeks apart in healthy subjects from abductor pollicis brevis (APB), abductor digiti minimi (ADM) and tibialis anterior (TA) muscles. The original MScanFit program (MScanFit-1) was compared with a revised version (MScanFit-2), designed to accommodate different muscles and recording conditions by setting the minimal motor unit size as a function of maximum CMAP. RESULTS: Complete sets of 6 recordings were obtained from 148 subjects. CMAP amplitudes differed significantly between centres for all muscles, and the same was true for MScanFit-1 MUNE. With MScanFit-2, MUNE differed less between centres but remained significantly different for APB. Coefficients of variation between repeats were 18.0% for ADM, 16.8% for APB, and 12.1% for TA. CONCLUSIONS: It is recommended for multicentre studies to use MScanFit-2 for analysis. TA provided the least variable MUNE values between subjects and the most repeatable within subjects. SIGNIFICANCE: MScanFit was primarily devised to model the discontinuities in CMAP scans in patients and is less suitable for healthy subjects with smooth scans.

The neuropathological signature of bulbar-onset ALS: A systematic review.

ALS is a multisystem disorder affecting motor and cognitive functions. Bulbar-onset ALS (bALS) may be preferentially associated with cognitive and language impairments, compared with spinal-onset ALS (sALS), stemming from a potentially unique neuropathology. The objective of this systematic review was to compare neuropathology findings reported for bALS and sALS subtypes in studies of cadaveric brains. Using Cochrane guidelines, we reviewed articles in MEDLINE, Embase, and PsycINFO databases using standardized search terms for ALS and neuropathology, from inception until July 16th 2016. 17 studies were accepted for analysis. The analysis revealed that both subtypes presented with involvement in motor and frontotemporal cortices, deep cortical structures, and cerebellum and were characterized by neuronal loss, spongiosis, myelin pallor, and ubiquitin+ and TDP43+ inclusion bodies. Changes in Broca and Wernicke areas - regions associated with speech and language processing - were noted exclusively in bALS. Further, some bALS cases presented with atypical pathology such as neurofibrillary tangles and basophilic inclusions, which were not found in sALS cases. Given the limited number of studies, all with methodological biases, further work is required to better understand neuropathology of ALS subtypes.

Assessing cognitive functioning in ALS: A focus on frontal lobe processes.

OBJECTIVE: It is generally acknowledged that at least 50% of individuals with amyotrophic lateral sclerosis (ALS) will exhibit cognitive deficits outside of the characteristic motor neuron involvement. However, a specific cognitive profile has been difficult to ascertain due to disease-related testing barriers and limitations in the sensitivity and specificity of available assessment methods. This study assessed the level of functioning of extramotor frontal cognitive processes in ALS, and the amount of change in the functioning in these processes over time as disease progresses. METHODS: Empirical tests validated for a model of frontal lobe functioning were modified into an assessment battery appropriate for individuals with ALS in a clinical setting (the ALS-CFB, Computerised Frontal Battery). Twenty ALS participants and 36 age- and education-matched neurologically healthy controls were tested, and a sub-sample of each group (11 ALS and 20 controls) re-tested after approximately nine months. RESULTS AND CONCLUSIONS: Compared to standard neuropsychological screening tests that did not show a difference between ALS participants and healthy controls, the ALS-CFB illustrated a profile of extramotor frontal dysfunction involving energisation (preparing the neural system to respond) and executive functions, a profile that may be indicative of the nature of neurodegeneration in ALS.

Establishing a Canadian registry of patients with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating cause of progressive weakness, respiratory failure and death. To date there is no effective therapy to meaningfully extend survival but continuously emerging targets and putative treatments are studied in clinical trials. Canadian epidemiological data on ALS is scarce and the socioeconomic impact of ALS on Canadian society is unclear. The Canadian Neuromuscular Disease Registry (CNDR) is a national clinic-based registry of patients with neuromuscular diseases with the goal of facilitating the design and execution of clinical research. METHODS: We conducted a national stakeholder survey to assess interest for a Canadian ALS registry and an assessment of expected case ascertainment. A dataset derivation meeting was held to establish the registry medical dataset. RESULTS: We report the results of the national stakeholder survey, case ascertainment assessment, and the derived dataset that have resulted in the current implementation of a Canadian registry of patients with ALS. CONCLUSIONS: The development of this long sought-after resource is a significant step forward for the Canadian ALS patient and research communities that will result in more efficient clinical trial recruitment and advancements in our understanding of ALS in Canada.

A novel double mutation in FUS gene causing sporadic ALS.

It has been shown that mutations in the Fused in Sarcoma gene (FUS) could explain up to 5% of cases with familial amyotrophic lateral sclerosis (ALS). Our mutation analysis of FUS in a Canadian ALS patient of Chinese origin revealed an unusual novel heterozygous double point mutation (R514S/E516V) confirming that exon 15 is a mutation hot-spot. The substitutions are in cis position to each other and affect highly conserved codons in the RGG-rich region of the FUS protein. The absence of clinical signs of ALS in the relatives of the affected carrier could indicate that this mutation is incompletely penetrant or de novo. The pathologic significance of the R514S/E516V mutation was confirmed by immunohistochemistry. FUS-positive cytoplasmic inclusions were noted in a moderate number in neurons and abundantly in glial cells in the motor cortex and the brainstem. Of interest, a significant number of neuronal and glial FUS-positive inclusions were found in the tegmentum of the brainstem. Importantly, some neurons with inclusions showed retention of the normal nuclear FUS immunostaining.

A mechanism for low penetrance in an ALS family with a novel SOD1 deletion.

BACKGROUND: About 20% of familial amyotrophic lateral sclerosis (ALS) is caused by mutations in SOD1 and is typically transmitted as an autosomal dominant trait. However, due to reduced mutation penetrance, the disease may present in a recessive or sporadic manner. OBJECTIVE: To determine the factors responsible for the low penetrance of the SOD1 mutation. METHODS: Twelve members of a Canadian ALS family of Filipino origin were recruited for the study. SOD1 was sequenced in the proband. SOD1 expression was assessed by real-time-PCR and immunoblotting. RESULTS: The proband was a homozygous carrier of a novel 6 bp deletion in exon 2 (DeltaG27/P28), the pathologic significance of which was confirmed by immunohistochemistry. Eight living family members are heterozygotes and remain unaffected at ages ranging between 48 and 85 years. Haplotype analysis showed that the deletion is a single founder mutation likely common in the Cagayan province (Philippines). The low penetrance of the mutation is explained by the fact that it enhances the naturally occurring alternative splicing of exon 2 of the SOD1 mRNA, leading to reduced transcription of the mutant allele. Indeed, Western blot analysis demonstrated the low level of SOD1 protein in carriers of the DeltaG27/P28 compared to wild-type individuals or a carrier of the A4V SOD1 mutation. CONCLUSION: The enhanced splicing of exon 2 acts as a natural knock-down of the mutant SOD1 allele in the Filipino amyotrophic lateral sclerosis (ALS) family. There is a need for careful investigation of splicing isoforms of SOD1 and other ALS genes as factors influencing the severity of disease.

The use of prophylactic anticonvulsants in patients with brain tumours-a systematic review.

QUESTIONS: Should patients with newly diagnosed brain tumours receive prophylactic anticonvulsants to reduce seizure risk? What is the best practice for patients with brain tumours who are taking anticonvulsant medications but who have never had a seizure? PERSPECTIVES: Patients with primary or metastatic brain tumours who have never had a seizure still have a 20% risk of experiencing a seizure over the course of their disease. Because considerable practice variation exists in regard to the management of patients with brain tumours who have never had a seizure, and because conflicting evidence has been reported, the Neuro-oncology Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-based Care felt that a systematic review of the evidence was warranted. OUTCOMES: Outcomes of interest were incidence of seizures and adverse effects of prophylactic anticonvulsant therapy. METHODOLOGY: The medline and Cochrane Library databases were systematically searched for relevant evidence. The review included fully published reports or abstracts of randomized controlled trials (rcts), systematic reviews, meta-analyses, and practice guidelines. The present systematic review was reviewed and approved by the Neuro-oncology dsg, which comprises medical and radiation oncologists, surgeons, neurologists, a nurse, and a patient representative. QUALITY OF EVIDENCE: The literature search located one evidence-based practice guideline, one systematic review, and five rcts that addressed prophylactic anticonvulsants for patients with brain tumours. Evidence for the best management of seizure-naïve patients who are already taking anticonvulsants was limited to one retrospective study and exploratory analyses within several rcts. BENEFITS AND HARMS: Pooled results of the five rcts suggest that the incidence of seizures in patients who receive prophylactic anticonvulsants is not significantly different from that in patients who do not receive anticonvulsants (relative risk: 1.04; 95% confidence interval: 0.70 to 1.54; p = 0.84). This analysis accords with results from a published meta-analysis. Evidence is insufficient to determine whether patients who are currently taking anticonvulsants but who have never had a seizure should taper the anticonvulsants. Patients who received anticonvulsants reported adverse effects, including rash, nausea, and hypotension, but whether these effects are a result of the anticonvulsants or of other treatments could not be determined. CONCLUSIONS: Based on the available evidence, the routine use of postoperative anticonvulsants is not recommended in seizure-naïve patients with newly diagnosed primary or secondary brain tumours, especially in light of a significant risk of serious adverse effects and problematic drug interactions. Because data are insufficient to recommend whether anticonvulsants should be tapered in patients who are already taking anticonvulsants but who have never had a seizure, treatment must be individualized.

A pilot study to compare the use of the Excorim staphylococcal protein immunoadsorption system and IVIG in chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune mediated neuropathy responding to immunomodulation with IVIG or plasma exchange (PE). We tested the efficacy and safety of selective immunoglobulin removal by Excorim immunoadsorption (IA) in a pilot trial in CIDP patients randomized to monthly IA or IVIG treatments for 6 months. Response rates at 2 and 6 months were greater with IA due to longer disease duration and greater disability at baseline in the patients receiving IVIG. IA appears to be a safe and efficacious therapy for patients with CIDP, but an appropriately powered clinical trial with stratification for disease duration is required.

Q-flap reconstruction of panurethral strictures.

OBJECTIVE: To review our experience with an extended Q-shaped penile skin flap for the reconstruction of panurethral strictures. PATIENTS AND METHODS: Between 1991 and 1999, 15 men with extensive strictures underwent a single-stage urethral reconstruction with a distal circumferential penile skin flap incorporating a ventral midline extension (Q-flap). None had undergone previous urethroplasty nor had any been circumcised. RESULTS: The Q-flap provided a pedicled strip of penile skin with a mean (range) length of 17 (15-24) cm; no additional graft materials were necessary. Excellent results were obtained in 10 patients; in the remainder, complications included recurrent stricture (in two) and (in one patient each) a cerebral vascular accident, urethrocutaneous fistula, meatal stenosis, femoral neuropathy and prolonged catheterization for focal extravasation. CONCLUSION: The Q-flap provides an abundant hairless penile skin flap that enables single-stage panurethral reconstruction while eliminating the additional time and morbidity of harvesting further grafts.

Optimal management of the 3- to 6-centimeter anterior urethral stricture.

The optimal management of anterior urethral stricture that does not respond to an endoscopic urethrotomy or is found to be unsuitable for excision and anastomotic repair remains controversial. Genital skin island onlay flaps or buccal mucosal grafts are presently the most dependable single stage procedures used for strictures more than 3 cm in length. Nonhirsute penile island fasciocutaneous flaps constitute the most durable substitution technique for pendulous stricture disease, with long-term studies reporting 90% to 96% success. The complex proximal bulb and bulbomenbraneous stricture with a compromised proximal fibrous avascular bed is ideally managed with either a penile or scrotal island flap or some combination of partial urethral excision with a dorsally placed genital skin island. The buccal mucosal onlay graft is a promising addition to this reconstructive paradigm, and early outcomes have been favorable. The graft is presently used for bulbar strictures, avoiding the transsphincteric on pendulous location, or a compromised recipient bed. The present standard of care for proximal bulb strictures is wide bulbospongiosal mobilization, partial urethral excision, a floor strip anastomosis, and placement of an augmenting flap on the graft in a dorsal location.

Radiolabeled monoclonal antibody indium 111-labeled CYT-356 localizes extraprostatic recurrent carcinoma after prostatectomy.

OBJECTIVES: The sites of recurrent carcinoma of the prostate were localized with radiolabeled monoclonal antibody, and these sites were correlated with the response of patients treated with pelvic radiation after prostatectomy. METHODS: Radionuclide scans were performed with indium 111-labeled CYT-356, a monoclonal antibody that binds to prostate epithelial cells, in 48 men diagnosed with recurrent carcinoma detected by prostate-specific antigen (PSA) screening after radical retropubic prostatectomy. RESULTS: In 48 patients with recurrent carcinoma detected by PSA screening following radical retropubic prostatectomy, 73% had monoclonal antibody activity beyond the prostatic fossa, and only 3 patients (6%) had activity in the prostatic fossa alone; 65% had monoclonal antibody activity in pelvic lymph nodes despite the fact that lymph node dissections were pathologically negative at the time of prostatectomy in 90% of the patients; and 23% of patients had monoclonal antibody activity in abdominal and extrapelvic retroperitoneal nodes. Of 48 patients, 13 underwent external beam radiation therapy after monoclonal antibody scans. Six patients had scans showing activity beyond the field of radiation, and radiation therapy failed in 4 of these patients. Seven patients had scans with no activity beyond the field of radiation therapy, and radiation therapy failed in only 2 of these patients. CONCLUSIONS: The scans frequently show monoclonal antibody uptake in pelvic, abdominal, and extrapelvic retroperitoneal sites beyond the region of limited obturator node dissections and may account for the understaging and subsequent failure of radical prostatectomy in some patients. The monoclonal antibody scan seems to be a good predictor of which patients will respond to radiation therapy after radical prostatectomy, but because these patients often have nodal activity beyond the radiated field, this initial response may not be curative.

[Reconstruction of the posterior urethra]. / Rekonstruktion der hinteren Urethra.

The posterior prostatomembranous urethral stricture or distraction defect has historically been the most formidable challenge of stricture surgery. This uncommon lesion occurs most often as the sequelae of pelvic fracture injuries, or straddle trauma, and is associated with serious urethral disruption and separation--an injury that is often complicated by inappropriate initial management using substitution skin flap techniques with the development of recurrent stenosis, irreversible impotence, and occasional incontinence. Management by endoscopic techniques may be possible in patients with short strictures or in those after prostatectomy, but they rarely play a role in resolving the complex obliterated urethra with a significant defect [1]. Resolution of post-traumatic posterior urethral distraction defects and other posterior urethral pathologic conditions has dramatically improved over the past two decades despite an inaccessible subpublic location involving exposed sphincter-active and erectile neurovascular anatomy. The contemporary, perineal, one-stage bulboprostatic anastomotic operation as popularized by Turner-Warwick [20] with selective scar excision is a versatile procedure with a high patent lumen success. Patients undergoing anastomotic urethroplasty have a substained patent urethral lumen success rate approaching 100% versus those who have undergone urethral skin flap or patch repair, where the restricture rate in 5 and 10 years increases twofold to threefold [1, 20]. A patent urethra after an anastomotic urethroplasty at 6 months is free from further recurrent stricture and gives credence to Mr. Turner-Warwick's admonition that "urethra is the best substitute for urethra".

Collaborative and reciprocal effects of ciliary neurotrophic factor and nerve growth factor on the neuronal phenotype of human neuroblastoma cells.

We have probed the molecular basis of functional effects of ciliary neurotrophic factor (CNTF) and nerve growth factor (NGF) on aspects of the neuronal differentiation of LA-N-2 neuroblastoma cells. The influence of CNTF on the cholinergic phenotype can be accounted for by transcriptional/translational effects without implicating posttranslational mechanisms. Although both NGF receptors are expressed constitutively by LA-N-2 cells, CNTF has a marked stimulatory effect on trkA mRNA and protein. The NGF receptors are functional in serum-free conditions where they mitigate CNTF effects on cell adhesion but do not support process extension. Following priming by CNTF, NGF and CNTF have synergistic influences on process formation but not on choline acetyltransferase-specific activity.

Stomal construction, complications, and reconstruction.

This article reviews stomal complications and their management. To accomplish this goal, the authors review techniques used for planning and creating the stomas for both continent reservoirs and incontinent conduits.

Extragenital muscular myocutaneous and fasciocutaneous flaps in urethral reconstruction.

Urethral strictures are fibrotic sequelae of inflammatory or traumatic injuries of the urethral epithelium and corpus spongiosa that result in a variety of obstructive lesions. To help resolve these difficult and challenging strictures, fistulas, and obliterative defects of the urethra, the author has borrowed many flaps from the ubiquitous bank of extragenital axial flaps presently in use for trunk and limb reconstruction, alone or in combination with free skin grafts. This article discusses and describes five extragenital flap techniques used in a variety of high-risk urethral strictures.

Management of invasive squamous cell carcinoma of the bulbomembranous male urethra with co-ordinated chemo-radiotherapy and genital preservation.

OBJECTIVE: To determine the success of chemo-radiotherapy for squamous cell carcinoma (SCC) of the bulbar male urethra, an uncommon but aggressive cancer usually treated by radical deforming surgery. PATIENTS AND METHODS: Two men, aged 42 and 49 years, with locally advanced SCC of the proximal deep urethra were treated with a modified Nigro chemo-radiation protocol. The initial treatment was by suprapublic cystotomy urinary diversion followed by 45 Gy in 25 fractions over 5 weeks to the penis, perineum and regional lymphatics. Chemotherapy consisted of a single intravenous dose of mitomycin C (10 mg/m2) and an intravenous infusion of 5-fluorouracil (1 g/m2/day) for 96 h starting on the first day of radiation therapy and repeated 28 days later. RESULTS: Follow-up evaluation with urethral biopsies, retrograde urethrography, computed tomography of the pelvis and cysto-urethroscopy under anaesthesia showed no residual tumour in either patient but the development of a proximal urethral stricture at 1.5 and 4 years, respectively. CONCLUSION: This report presents the first evidence of a successful reduction of tumour stage with the local eradication of invasive SCC and penile preservation with no recurrence of the tumour or the need to excise the urethra.

Regression of large pelvic desmoid tumor by tamoxifen and sulindac.

A 54-year-old man was evaluated for symptoms of bladder outlet obstruction. Evaluation revealed a 10 by 9.8-cm tumor composed of bland, fibroblastic, poorly cellular material adjacent to the prostate. Administration of a course of antiestrogen (tamoxifen) and a nonsteroidal anti-inflammatory agent (sulindac) resulted in prompt relief of symptoms and a slow decrease in the size of the tumor as measured by computed tomography. After 54 months of therapy, the tumor was undetectable clinically and dramatically reduced in size as seen on computed tomography. Data on the natural history of desmoid tumors and the efficacy of various therapeutic strategies are reviewed.