PLS Patients Research Articles

Progressive lacunar strokes behave differently from stable ones even at one year—An observational study

Background and aimsSmall fraction of lacunar stroke patients have an early fluctuating course, described as progressive lacunar syndrome [PLS].We studied the predictors and short term outcome of progressive lacunar strokes in comparison with those with an early stable course. Materials and methodsSingle centre retrospective study where patients with lacunar strokes from 2016 to 2020 were included in the study. Progression was defined as increase in stroke severity [NIHSS] by ≥2 points from baseline without imaging evidence of new infarcts or haemorrhagic transformation. We compared the clinical variables, risk factors, imaging, treatment received and 1 year outcome of subjects with PLS with those with a stable course, with modified Rankin score 0–2 taken as good outcome. ResultsOf the 216 patients with a mean age 63.17 years, progressive course was noted in 56 subjects [26 %].Majority of the fluctuations occurred within 24 h of onset of symptoms. Though stroke severity at admission was comparable between the 2 groups, discharge and 1 year outcome was poorer in those with an early progressive course. We found that presentation as pure motor syndrome, hypertriglyceridemia and thrombolytic therapy were predictors of poor outcome in progressive lacunar strokes, while age, risk factors, infarct location or leukoaraiosis failed to show an association. Thalamic infarcts and atypical lacunar syndromes were associated with a stable course. ConclusionProgressive course is seen in a quarter of lacunar strokes and they have poorer outcome at 1 year. Our finding of thrombolysis being associated with worse outcome in PLS patients, should alert physicians regarding need for more definitive therapies for this condition.

Advantages of routine next-generation sequencing over standard genetic testing in the amyotrophic lateral sclerosis clinic.

Next-generation sequencing has enhanced our understanding of amyotrophic lateral sclerosis (ALS) and its genetic epidemiology. Outside the research setting, testing is often restricted to those who report a family history. The aim of this study was to explore the added benefit of offering routine genetic testing to all patients in a regional ALS centre. C9ORF72 expansion testing and exome sequencing was offered to consecutive patients (150 with ALS and 12 with primary lateral sclerosis [PLS]) attending the Oxford Motor Neuron Disease Clinic within a defined time period. A total of 17 (11.3%) highly penetrant pathogenic variants in C9ORF72, SOD1, TARDBP, FUS and TBK1 were detected, of which 10 were also found through standard clinical genetic testing pathways. The systematic approach resulted in five additional diagnoses of a C9ORF72 expansion (number needed to test [NNT] = 28), and two further missense variants in TARDBP and SOD1 (NNT = 69). Additionally, 3 patients were found to carry pathogenic risk variants in NEK1, and 13 patients harboured common missense variants in CFAP410 and KIF5A, also associated with an increased risk of ALS. We report two novel non-coding loss-of-function splice variants in TBK1 and OPTN. No relevant variants were found in the PLS patients. Patients were offered double-blinded participation, but >80% requested disclosure of the results. This study provides evidence that expanding genetic testing to all patients with a clinical diagnosis of ALS enhances the potential for recruitment to clinical trials, but will have direct resource implications for genetic counselling.

Genetic characterization of primary lateral sclerosis

Background and objectivesPrimary lateral sclerosis (PLS) is a motor neuron disease characterised by loss of the upper motor neurons. Most patients present with slowly progressive spasticity of the legs, which may also spread to the arms or bulbar regions. It is challenging to distinguish between PLS, early-stage amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). The current diagnostic criteria advise against extensive genetic testing. This recommendation is, however, based on limited data.MethodsWe aim to genetically characterize a PLS cohort using whole exome sequencing (WES) for genes associated with ALS, HSP, ataxia and movement disorders (364 genes) and C9orf72 repeat expansions. Patients fulfilling the definite PLS criteria by Turner et al. and with available DNA samples of sufficient quality were recruited from an on-going, population-based epidemiological study. Genetic variants were classified according to the ACMG criteria and assigned to groups based on disease association.ResultsWES was performed in 139 patients and the presence of repeat expansions in C9orf72 was analysed separately in 129 patients. This resulted in 31 variants of which 11 were (likely) pathogenic. (Likely) pathogenic variants resulted in 3 groups based on disease association: ALS-FTD (C9orf72, TBK1), pure HSP (SPAST, SPG7), “ALS-HSP-CMT overlap” (FIG4, NEFL, SPG11).DiscussionIn a cohort of 139 PLS patients, genetic analyses resulted in 31 variants (22%) of which 10 (7%) (likely) pathogenic associated with different diseases (predominantly ALS and HSP). Based on these results and the literature, we advise to consider genetic analyses in the diagnostic work-up for PLS.

Abnormal profiles of cathepsin C secreted in urine of Papillon Lefevre syndrome patients

BackgroundPapillon Lefevre syndrome (PLS) is an autosomal recessive disorder that results from a mutated gene that encodes a lysosomal peptidase known as cathepsin C (CTSC). The clinical presentation of PLS involves mainly palmoplantar keratosis and periodontitis with a variable degree of severity. Subjectsand methods: Our study included ten patients with a broad spectrum of palmoplantar keratosis and periodontitis severity. CTSC variants were detected by Sanger sequencing. CTSC protein secreted in urine was detected by western blotting. ResultsFive patients have missense variants, Four have nonsense variants, and one has splice variants in CTSC. The activation products of cathepsin C protein (Heavy and light chains) were absent in all patients’ urine samples except one with a significantly reduced level compared to the controls. The dimeric form of CTSC protein was found in all the studied cases. The monomeric form was found in five cases. The products of proteolytic activation of CTSC by other cathepsins (L and S) were found in the urine samples of five of the patients. Each patient had a characteristic pattern of accumulated CTSC protein maturation/activation substrates, intermediates, and products. 40% of the patients had the activation products of other lysosomal cathepsins. ConclusionUrinary CTSC in PLS patients could be used as a diagnostic biomarker for the biochemical screening of the disease. Different variants in CTSC result in different profiles of CTSC secreted in the urine of PLS patients. The profiles of secreted CTSC in urine could be correlated to the severity of palmoplantar keratosis.

Outcomes of surgically managed primary lung sarcomas: a National Cancer Database analysis.

BackgroundPrimary lung sarcoma (PLS) represents a rare form of lung cancer with outcomes that are poorly defined by small datasets. We sought to characterize clinical and pathological characteristics and associated survival within the surgically managed subgroup of these unusual pulmonary malignancies.MethodsWe performed a retrospective analysis of the National Cancer Database (NCDB), which was queried for cases of surgically managed PLS diagnosed between 2004–2014. Adjusted mortality was evaluated in a multivariable Cox proportional hazards model and compared to surgically manage non-small cell lung cancer (NSCLC) patients from the same time period.ResultsA total of 695 patients with surgically managed PLS were identified with 37 different histologic subtypes. The mean age of diagnosis was 57.7 years (range, 18–90 years). A majority of patients underwent surgical resection alone (64.3%) with an estimated 5-year overall survival (OS) of 51%. The multivariable Cox model identified increasing age, Charlson-Deyo score ≥2, high tumor grade, tumor size >5 cm, positive margins, and positive lymph nodes to be associated with higher risk for mortality (P<0.05). Compared to 101,428 surgically managed patients with adenocarcinoma, PLS patients were younger with fewer comorbidities but had larger tumors, higher grade tumors, and were more likely node negative (P<0.001). Surgery with adjuvant chemotherapy was associated with worse survival than surgery alone (HR 1.41, 95% CI: 1.05–1.88). The extent of parenchymal resection (lobar vs. sublobar) was not predictive for survival. Five-year OS was lower for patients with PLS (44%) than adenocarcinoma (53.6%, P<0.001).ConclusionsThe survival of surgically managed PLS is reasonable and impacted by tumor attributes and the completeness of surgical resection. Further study to define the role of multimodal therapy is indicated.

Utility of intrathecal baclofen pump in primary lateral sclerosis

Primary lateral sclerosis is a disorder categorized by insidious onset of progressive upper motor neuron dysfunction without lower motor neuron involvement. PLS often presents with gradual-onset, progressive lower extremity stiffness and pain due to muscle spasticity. Intrathecal Baclofen pumps (ITB) have been used to effectively treat spasticity in several neurologic conditions including MS and spinal cord injury. This study aimed at reviewing a cohort of PLS patients with spasticity requiring ITB to assess the clinical course, benefits, and complications in these patients. A series of 5 patients were identified who were diagnosed with PLS and received ITB as treatment for spasticity. The average age of the patients at the time of ITB insertion was 56.4 years. The average length of treatment was 10.4 years with a range of 4–15 years. All patients reported improvement in spasticity as measured by clinical examinations and Ashworth scores; 1/5 had complications with the pump related to migration of catheter. No patients required permanent removal of the ITB. ITB is a safe and effective treatment for spasticity in PLS and should be considered in other patients.

MRI data confirm the selective involvement of thalamic and amygdalar nuclei in amyotrophic lateral sclerosis and primary lateral sclerosis.

A standardised imaging protocol was implemented to evaluate disease burden in specific thalamic and amygdalar nuclei in 133 carefully phenotyped and genotyped motor neuron disease patients. “Switchboard malfunction in motor neuron diseases: selective pathology of thalamic nuclei in amyotrophic lateral sclerosis and primary lateral sclerosis” [1] “Amygdala pathology in amyotrophic lateral sclerosis and primary lateral sclerosis” [2] Raw volumetric data, group comparisons, effect sizes and percentage change are presented. Both ALS and PLS patients exhibited focal thalamus atrophy in ventral lateral and ventral anterior regions revealing extrapyramidal motor degeneration. Reduced accessory basal nucleus and cortical nucleus volumes were noted in the amygdala of C9orf72 negative ALS patients compared to healthy controls. ALS patients carrying the GGGGCC hexanucleotide repeats in C9orf72 exhibited preferential pathology in the mediodorsal-paratenial-reuniens thalamic nuclei and in the lateral nucleus and cortico-amygdaloid transition area of the amygdala. Considerable thalamic atrophy was observed in the sensory nuclei and lateral geniculate region of PLS patients. Our data demonstrate genotype-specific patterns of thalamus and amygdala involvement in ALS and a distinct disease-burden pattern in PLS. The dataset may be utilised for validation purposes, meta-analyses and the interpretation of thalamic and amygdalar profiles from other ALS genotypes.

Evolving diagnostic criteria in primary lateral sclerosis: The clinical and radiological basis of “probable PLS”

IntroductionPrimary lateral sclerosis is a rare neurodegenerative disorder of the upper motor neurons. Diagnostic criteria have changed considerably over the years, and the recent consensus criteria introduced ‘probable PLS’ for patients with a symptom duration of 2–4 years. The objective of this study is the systematic evaluation of clinical and neuroimaging characteristics in early PLS by studying a group of ‘probable PLS patients’ in comparison to a cohort of established PLS patients. MethodsIn a prospective neuroimaging study, thirty-nine patients were stratified by the new consensus criteria into ‘probable’ (symptom duration 2–4 years) or ‘definite’ PLS (symptom duration >4 years). Patients were evaluated with a standardised battery of clinical instruments (ALSFRS-r, Penn upper motor neuron score, the modified Ashworth spasticity scale), whole genome sequencing, and underwent structural and diffusion MRI. The imaging profile of the two PLS cohorts were contrasted to a dataset of 100 healthy controls. All ‘probable PLS’ patients subsequently fulfilled criteria for ‘definite’ PLS on longitudinal follow-up and none transitioned to develop ALS. ResultsPLS patients tested negative for known ALS- or HSP-associated mutations on whole genome sequencing. Despite their shorter symptom duration, ‘probable PLS’ patients already exhibited considerable functional disability, upper motor neuron disease burden and the majority of them required walking aids for safe ambulation. Their ALSFRS-r, UMN and modified Ashworth score means were 83%, 98% and 85% of the ‘definite’ group respectively. Motor cortex thickness was significantly reduced in both PLS groups in comparison to controls, but cortical changes were less widespread in ‘probable’ PLS on morphometric analyses. Corticospinal tract and corpus callosum metrics were relatively well preserved in the ‘probable’ group in contrast to the widespread white matter degeneration observed in the ‘definite’ group. ConclusionsOur clinical and radiological analyses support the recent introduction of the ‘probable’ PLS category, as this cohort already exhibits considerable disability and cerebral changes consistent with established PLS. Before the publication of the new consensus criteria, these patients would have not been diagnosed with PLS on the basis of their symptom duration despite their significant functional impairment and motor cortex atrophy. The introduction of this new category will facilitate earlier recruitment into clinical trials, and shorten the protracted diagnostic uncertainty the majority of PLS patients face.

“Switchboard” malfunction in motor neuron diseases: Selective pathology of thalamic nuclei in amyotrophic lateral sclerosis and primary lateral sclerosis

The thalamus is a key cerebral hub relaying a multitude of corticoefferent and corticoafferent connections and mediating distinct extrapyramidal, sensory, cognitive and behavioural functions. While the thalamus consists of dozens of anatomically well-defined nuclei with distinctive physiological roles, existing imaging studies in motor neuron diseases typically evaluate the thalamus as a single structure. Based on the unique cortical signatures observed in ALS and PLS, we hypothesised that similarly focal thalamic involvement may be observed if the nuclei are individually evaluated. A prospective imaging study was undertaken with 100 patients with ALS, 33 patients with PLS and 117 healthy controls to characterise the integrity of thalamic nuclei. ALS patients were further stratified for the presence of GGGGCC hexanucleotide repeat expansions in C9orf72. The thalamus was segmented into individual nuclei to examine their volumetric profile. Additionally, thalamic shape deformations were evaluated by vertex analyses and focal density alterations were examined by region-of-interest morphometry. Our data indicate that C9orf72 negative ALS patients and PLS patients exhibit ventral lateral and ventral anterior involvement, consistent with the ‘motor’ thalamus. Degeneration of the sensory nuclei was also detected in C9orf72 negative ALS and PLS. Both ALS groups and the PLS cohort showed focal changes in the mediodorsal-paratenial-reuniens nuclei, which mediate memory and executive functions. PLS patients exhibited distinctive thalamic changes with marked pulvinar and lateral geniculate atrophy compared to both controls and C9orf72 negative ALS. The considerable ventral lateral and ventral anterior pathology detected in both ALS and PLS support the emerging literature of extrapyramidal dysfunction in MND. The involvement of sensory nuclei is consistent with sporadic reports of sensory impairment in MND. The unique thalamic signature of PLS is in line with the distinctive clinical features of the phenotype. Our data confirm phenotype-specific patterns of thalamus involvement in motor neuron diseases with the preferential involvement of nuclei mediating motor and cognitive functions. Given the selective involvement of thalamic nuclei in ALS and PLS, future biomarker and natural history studies in MND should evaluate individual thalamic regions instead overall thalamic changes.

217. Impact of previous lumbar spine surgery on outcome of lumbar total disc replacement: analysis of prospective five-year follow up study data

BACKGROUND CONTEXT FDA-regulated prospective trials evaluating lumbar total disc replacement (LTDR) have included patients with previous lumbar surgeries. Unitedhealth care, one of the largest insurers in the United States recently issued a positive coverage policy for LTDR that disqualifies patients with previous lumbar surgeries of any kind from treatment with LTDR. However, such patients were included in FDA IDE trials that led to approval of these devices. PURPOSE The purpose of this study was to compare LTDR outcomes in patients with prior lumbar spine surgery to outcomes in those without prior surgery. STUDY DESIGN/SETTING The study was a post hoc analysis of data collected prospectively as part of an FDA-regulated trial with 5-year follow-up. PATIENT SAMPLE The study was based on 376 patients from the activL® IDE study population. All patients were treated for single-level symptomatic degenerative disc disease at L4-L5 or L5-S1 unresponsive to at least 6 months of nonoperative care. OUTCOME MEASURES Clinical outcome measures used in the study included Oswestry Disability Index (ODI), Visual analog scales (VAS) assessing back and leg pain, SF-36, adverse events and reoperations. Radiographic outcome evaluations were based on flexion/extension range of motion (ROM) and translation of the operated segment. METHODS Patients were divided into two groups: prior lumbar surgery (PLS, n=92) and no prior lumbar surgery (NPLS, n=284). PLS patients had undergone one or more of the following procedures: intradiscal electrothermal annuloplasty (IDET) (n=5), percutaneous nucleoplasty (n=4), microdiscectomy (n=81), hemilaminectomy (n=17), laminotomy (n=36) or other (n=1) prior to receiving a LTDR. Patients with prior lumbar fusion were excluded from the IDE study. Baseline characteristics, functional and pain outcomes, serious adverse events and reoperations were statistically compared between the groups preoperatively and postoperatively at 6 weeks, 3 and 6 months and 1, 2, 3, 4 and 5 years. RESULTS Patient baseline demographics were very similar between the two groups. When comparing pre- to postoperative scores, ODI, VAS back pain and leg pain and the SF-36 Physical Component Score improved significantly (p CONCLUSIONS Prior lumbar spine surgery was not related to compromised outcomes among patients undergoing LTDR. There were no statistically significant differences in ODI, SF-36, pain scores or safety rates between PLS and NPLS patients. These results are in line with findings from earlier studies that prior surgery is not a contraindication for LTDR provided that other selection criteria are met. These results do not support the denial by an insurer to give patients and providers the option of receiving LTDR for DDD unresponsive to nonoperative care as described in the FDA approved device usage labeling. FDA DEVICE/DRUG STATUS activL (Approved for this indication), ProDisc-L (Approved for this indication), Charite (Approved for this indication)

The clinical and radiological profile of primary lateral sclerosis: a population-based study.

Primary lateral sclerosis is a progressive upper-motor-neuron disorder associated with markedly longer survival than ALS. In contrast to ALS, the genetic susceptibility, histopathological profile and imaging signature of PLS are poorly characterised. Suspected PLS patients often face considerable diagnostic delay and prognostic uncertainty. To characterise the distinguishing clinical, genetic and imaging features of PLS in contrast to ALS and healthy controls. A prospective population-based study was conducted with 49 PLS patients, 100 ALS patients and 100 healthy controls using genetic profiling, standardised clinical assessments and neuroimaging. Whole-brain and region-of-interest analyses were undertaken to evaluate patterns of grey and white matter degeneration. In PLS, disease burden in the motor cortex is more medial than in ALS consistent with its lower limb symptom-predominance. PLS is associated with considerable cerebellar white and grey matter degeneration and the extra-motor profile of PLS includes marked insular, inferior frontal and left pars opercularis pathology. Contrary to ALS, PLS spares the postcentral gyrus. The body and splenium of the corpus callosum are preferentially affected in PLS, in contrast to the genu involvement observed in ALS. Clinical measures show anatomically meaningful correlations with imaging metrics in a somatotopic distribution. PLS patients tested negative for C9orf72 repeat expansions, known ALS and HSP-associated genes. Multiparametric imaging in PLS highlights disease-specific motor and extra-motor involvement distinct from ALS. In a condition where limited post-mortem data are available, imaging offers invaluable pathological insights. Anatomical correlations with clinical metrics confirm the biomarker potential of quantitative neuroimaging in PLS.

Longitudinal analysis of sniff nasal inspiratory pressure assessed using occluded and un-occluded measurement techniques in amyotrophic lateral sclerosis and primary lateral sclerosis

Objective: Sniff nasal inspiratory pressure (SNIP) is a commonly used clinical measure of respiratory impairment in amyotrophic lateral sclerosis (ALS), which is used to guide the initiation of noninvasive ventilation (NIV). SNIP can be completed with either an occluded or an un-occluded contralateral nostril. The aim of this study was to compare occluded and un-occluded SNIP measurements and to examine the decline in occluded SNIP over time compared to the ALSFRS-R respiratory subscore. Methods: This was a prospective longitudinal study examining occluded and un-occluded SNIP scores in ALS and PLS patients recorded between 2001 and 2018. Bland and Altman graphs were plotted for occluded vs. un-occluded SNIP measurements taking account of the repeated measures nature of the data. Longitudinal models were constructed as linear mixed effects multi-level models with follow-up in ALS limited to 6 years. Results: SNIP measured with an occluded contralateral nostril was systematically higher than with an un-occluded nostril. SNIP measured using both methods declined non-linearly, particularly after 2–3 years. The best fit model for decline in occluded SNIP included a main effect and interaction between site of onset and time, with age and diagnostic delay as independent variables. This showed a linear decline in spinal onset with a floor effect in bulbar-onset ALS. Conclusion: SNIP measured with an occluded and un-occluded contralateral nostril is not interchangeable, which is relevant in interpreting thresholds for initiation of NIV. SNIP declines non-linearly, which is explained in spinal onset ALS by age and diagnostic delay, but an apparent floor effect remains in bulbar onset.

Cross-sectional and longitudinal assessment of the upper cervical spinal cord in motor neuron disease.

BackgroundAmyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease characterized by both upper and lower motor neuron degeneration. While neuroimaging studies of the brain can detect upper motor neuron degeneration, these brain MRI scans also include the upper part of the cervical spinal cord, which offers the possibility to expand the focus also towards lower motor neuron degeneration. Here, we set out to investigate cross-sectional and longitudinal disease effects in the upper cervical spinal cord in patients with ALS, progressive muscular atrophy (PMA: primarily lower motor neuron involvement) and primary lateral sclerosis (PLS: primarily upper motor neuron involvement), and their relation to disease severity and grey and white matter brain measurements.MethodsWe enrolled 108 ALS patients without C9orf72 repeat expansion (ALS C9–), 26 ALS patients with C9orf72 repeat expansion (ALS C9+), 28 PLS patients, 56 PMA patients and 114 controls. During up to five visits, longitudinal T1-weighted brain MRI data were acquired and used to segment the upper cervical spinal cord (UCSC, up to C3) and individual cervical segments (C1 to C4) to calculate cross-sectional areas (CSA). Using linear (mixed-effects) models, the CSA differences were assessed between groups and correlated with disease severity. Furthermore, a relationship between CSA and brain measurements was examined in terms of cortical thickness of the precentral gyrus and white matter integrity of the corticospinal tract.ResultsCompared to controls, CSAs at baseline showed significantly thinner UCSC in all groups in the MND spectrum. Over time, ALS C9– patients demonstrated significant thinning of the UCSC and, more specifically, of segment C3 compared to controls. Progressive thinning over time was also observed in C1 of PMA patients, while ALS C9+ and PLS patients did not show any longitudinal changes. Longitudinal spinal cord measurements showed a significant relationship with disease severity and we found a significant correlation between spinal cord and motor cortex thickness or corticospinal tract integrity for PLS and PMA, but not for ALS patients.DiscussionOur findings demonstrate atrophy of the upper cervical spinal cord in the motor neuron disease spectrum, which was progressive over time for all but PLS patients. Cervical spinal cord imaging in ALS seems to capture different disease effects than brain neuroimaging. Atrophy of the cervical spinal cord is therefore a promising additional biomarker for both diagnosis and disease progression and could help in the monitoring of treatment effects in future clinical trials.

Brainstem pathology in amyotrophic lateral sclerosis and primary lateral sclerosis: A longitudinal neuroimaging study.

Brainstem pathology is a hallmark feature of ALS, yet most imaging studies focus on cortical grey matter alterations and internal capsule white matter pathology. Brainstem imaging in ALS provides a unique opportunity to appraise descending motor tract degeneration and bulbar lower motor neuron involvement. A prospective longitudinal imaging study has been undertaken with 100 patients with ALS, 33 patients with PLS, 30 patients with FTD and 100 healthy controls. Volumetric, vertex and morphometric analyses were conducted correcting for demographic factors to characterise disease-specific patterns of brainstem pathology. Using a Bayesian segmentation algorithm, the brainstem was segmented into the medulla, pons and mesencephalon to measure regional volume reductions, shape analyses were performed to ascertain the atrophy profile of each study group and region-of-interest morphometry was used to evaluate focal density alterations. ALS and PLS patients exhibit considerable brainstem atrophy compared to both disease- and healthy controls. Volume reductions in ALS and PLS are dominated by medulla oblongata pathology, but pontine atrophy can also be detected. In ALS, vertex analyses confirm the flattening of the medullary pyramids bilaterally in comparison to healthy controls and widespread pontine shape deformations in contrast to PLS. The ALS cohort exhibit bilateral density reductions in the mesencephalic crura in contrast to healthy controls, central pontine atrophy compared to disease controls, peri-aqueduct mesencephalic and posterior pontine changes in comparison to PLS patients. CONCLUS: ions: Computational brainstem imaging captures the degeneration of both white and grey matter components in ALS. Our longitudinal data indicate progressive brainstem atrophy over time, underlining the biomarker potential of quantitative brainstem measures in ALS. At a time when a multitude of clinical trials are underway worldwide, there is an unprecedented need for accurate biomarkers to monitor disease progression and detect response to therapy. Brainstem imaging is a promising addition to candidate biomarkers of ALS and PLS.

Eye-tracking in amyotrophic lateral sclerosis: A longitudinal study of saccadic and cognitive tasks

A relative preservation of eye movements is notable in ALS, but saccadic functions have not been studied longitudinally. ALS overlaps with FTD, typically involving executive dysfunction, and eye-tracking offers additional potential for the assessment of extramotor pathology where writing and speaking are both impaired. Eye-tracking measures (including anti-saccade, trail-making and visual search tasks) were assessed at six-monthly intervals for up to two years in a group of ALS (n = 61) and primary lateral sclerosis (n = 7) patients, compared to healthy age-matched controls (n = 39) assessed on a single occasion. Task performance was explored speculatively in relation to resting-state functional MRI (R-FMRI) network connectivity. Results showed that ALS patients were impaired on executive and visual search tasks despite normal basic saccadic function, and impairments in the PLS patients were unexpectedly often more severe. No significant progression was detected longitudinally in either group. No changes in R-FMRI network connectivity were identified in relation to patient performance. In conclusion, eye-tracking offers an objective means to assess extramotor cerebral involvement in ALS. The relative resistance of pure oculomotor function is confirmed, and higher-level executive impairments do not follow the same rate of decline as physical disability. PLS patients may have more cortical dysfunction than has been previously appreciated.

Seminal, clinical and colour‐Doppler ultrasound correlations of prostatitis‐like symptoms in males of infertile couples

'Prostatitis-like symptoms' (PLS) are a cluster of bothersome conditions defined as 'perineal and/or ejaculatory pain or discomfort and National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) pain subdomain score ≥4' (Nickel's criteria). PLS may originate from the prostate or from other portions of the male genital tract. Although PLS could be associated with 'prostatitis', they should not be confused. The NIH-CPSI is considered the gold-standard for assessing PLS severity. Although previous studies investigated the impact of prostatitis, vesiculitis or epididymitis on semen parameters, correlations between their related symptoms and seminal or scrotal/transrectal colour-Doppler ultrasound (CDU) characteristics have not been carefully determined. And no previous study evaluated the CDU features of PLS in infertile men. This study was aimed at investigating possible associations among NIH-CPSI (total and subdomain) scores and PLS, with seminal, clinical and scrotal/transrectal CDU parameters in a cohort of males of infertile couples. PLS of 400 men (35.8±7.2years) with a suspected male factor were assessed by the NIH-CPSI. All patients underwent, during the same day, semen analysis, seminal plasma interleukin 8 (sIL-8, a marker of male genital tract inflammation), biochemical evaluation, urine/seminal cultures, scrotal/transrectal CDU. PLS was detected in 39 (9.8%) subjects. After adjusting for age, waist and total testosterone (TT), no association among NIH-CPSI (total or subdomain) scores or PLS and sperm parameters was observed. However, we found a positive association with current positive urine and/or seminal cultures, sIL-8 levels and CDU features suggestive of inflammation of the epididymis, seminal vesicles, prostate, but not of the testis. The aforementioned significant associations of PLS were further confirmed by comparing PLS patients with age-, waist- and TT-matched PLS-free patients (1:3 ratio). In conclusion, NIH-CPSI scores and PLS evaluated in males of infertile couples, are not related to sperm parameters, but mainly to clinical and CDU signs of infection/inflammation.

Clinical evolution of pure upper motor neuron disease/dysfunction (PUMMD)

PLS is defined as pure upper motor neuron disease/dysfunction (PUMND) beyond 48 months after symptom onset. We know little about its early stages, but such knowledge would help to identify the mechanisms underlying PLS and ALS and determine why PLS patients seem to be protected against lower MND (LMND). We reviewed 622 MND cases during a 4-year period and identified 34 patients with PUMND (5.4%). Among 23 cases with follow-up data/electromyograms (EMGs; 2 had only 1 EMG), 13 (57%) remained classified as PUMND, and 8 (35%) developed LMND (mean, 51.4 months after onset). Of these 8, LMND developed in 3 after 48 months from symptom onset. Patients with PUMND and LMND were more functionally impaired (P = 0.02). Separately, we identified 5 patients with PUMND who developed LMND long after 48 months (range, 50-127 months). PLS belongs to the ALS spectrum, and perhaps all cases eventually develop LMND.

Isolation and Characterization of Dental Pulp Stem Cells from a Patient with Papillon–Lefèvre Syndrome

IntroductionPapillon–Lefèvre syndrome (PLS) is a rare autosomal recessive disorder characterized by immune dysregulation because of a mutation in cathepsin c gene, resulting in hyperkeratosis of the palms, soles, elbows, and knees combined with premature loss of the primary and permanent dentitions. Periodontal tissue abnormalities in PLS patients were reported previously. However, less is known about dental pulp tissue derived cells of PLS patients. This study aimed to show stem cell potential of PLS dental pulp stem cells (DPSCs) and provide new evidence regarding the pathophysiology of the disease. MethodsDPSCs were characterized by using flow cytometry and immunocytochemistry. They were also induced to differentiate into adipogenic, osteogenic, chondrogenic, odontogenic, and myogenic cells. ResultsThe results revealed that PLS DPSCs are stained positive for mesenchymal stem cells surface markers CD29, CD73, CD90, CD105, and CD166. PLS DPSCs were able to differentiate into adipogenic, osteogenic, chondrogenic, and odontogenic cell types properly. PLS DPSCs expressed embryonic stem cell markers Oct4, Sox2, cMYc, and Klf4 and showed similar proliferation rate compared with DPSCs isolated from healthy young controls. Interestingly, it was found that unlike the healthy DPSCs, PLS DPSCs are not able to form myotubes with correct morphology. ConclusionsThese data are being reported for the first time; therefore, they might provide new insights to the pathology of the disease. Our results suggest that the PLS DPSCs might be an autologous stem cell source for PLS patients for cellular therapy of alveolar bone defects and other dental tissue abnormalities observed in PLS.

169 Antisaccade task as a biomarker in MND

BackgroundMND is a multiple system neurodegenerative disorder sharing clinicopathological features with frontotemporal dementia. The normal saccade generating network has overlap with cortical regions consistently involved in MND, and the relative...

Red, purple, and brown skin lesions in a 2-month-old boy

While the CTSC gene mutation is generally diagnostic for PLS (along with periodontitis), it can also be found in HaimeMunk syndrome (HMS), a type of PPK that presents similarly to PLS. Patients with HMS have findings such as arachnodactyly, acroosteolysis, onychogryphosis, and pes planus. Our patient’s normal radiographic results rule out HMS. PLS is diagnosed by PPK and periodontitis clinically in addition to genetic studies for the CTSC mutation. Radiographs of the hands and feet are necessary to differentiate PLS from HMS, because these diseases have overlapping clinical manifestations. Oral retinoids are the treatment of choice for this syndrome and most other types of PPK. Early treatment and monitoring of PLS patients at disease onset may help with tooth retention. For this series, the recommended choices are: 6, a; 7, b; 8, d; 9, c; 10, b.