Sleep apnea in end-stage renal disease patients: Impact on cardiovascular and neurological outcomes.

INTRODUCTION: Sleep apnea (SA) is an important comorbidity in end-stage renal disease (ESRD) patients. The association between SA and cardiac and neurological disease is known. This study investigates the relationship between SA and cardiovascular and cerebrovascular outcomes in the ESRD population. METHODS: In a retrospective cohort study, the United States Renal Data System was queried to identify ESRD patients aged 18-100 years in whom hemodialysis had been initiated between 2005 and 2013. Diagnoses of SA and clinical comorbidities were determined from International Classification of Disease-9 codes. Demographic variables were obtained from Centers for Medicare and Medicaid Services Form-2728. Logistic regression was used to examine the association of SA with myocardial infarction (MI) or with stroke, controlling for demographic and clinical variables. RESULTS: Of 858,131 subjects meeting the inclusion criteria, 587 had central SA, and 22,724 had obstructive SA. The SA cohort was younger, more likely to be male and Caucasian compared to the non-SA cohort. Patients with SA also had more tobacco and alcohol use, hypertension, heart failure, and diabetes. Central SA (aRR = 1.69, 95% CI = 1.28-2.23) and obstructive SA (aRR = 1.15, 95% CI = 1.09-1.21) were associated with an increased risk of stroke but not MI. CONCLUSION: In the ESRD population, a diagnosis of central SA or obstructive SA increased the risk of stroke, but not MI. Early identification and treatment of SA in the ESRD population may help reduce the risk of stroke in these patients.

Drug-resistant generalized epilepsies: Revisiting the frontiers of idiopathic generalized epilepsies.

The 2017 International League Against Epilepsy (ILAE) classification suggested that the term "genetic generalized epilepsies" (GGEs) should be used for the broad group of epilepsies with so-called "generalized" seizure types and "generalized" spike-wave activity on EEG, based on a presumed genetic etiology. Within this framework, idiopathic generalized epilepsies (IGEs) are described as a subset of GGEs and include only four epileptic syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. The recent 2022 ILAE definition of IGEs is based on the current state of knowledge and reflects a community consensus and is designed to evolve as knowledge advances. The term "frontiers of IGEs" refers to the actual limits of our understanding of these four syndromes. Indeed, among patients presenting with a syndrome compatible with the 2022 definition of IGEs, we still observe a significant proportion of patients presenting with specific clinical features, refractory seizures, or drug-resistant epilepsies. This leads to the discussion of the boundaries of IGEs and GGEs, or what is accepted within a clinical spectrum of a definite IGE. Here, we discuss several entities that have been described in the literature for many years and that may either constitute rare features of IGEs or a distinct differential diagnosis. Their recognition by clinicians may allow a more individualized approach and improve the management of patients presenting with such entities.

Pathways to epilepsy surgery in children with tuberous sclerosis complex-associated epilepsy.

BACKGROUND: Previous studies showed the efficacy of epilepsy surgery in carefully selected children with epilepsy associated with tuberous sclerosis complex. However, how this selection is conducted, and the characteristics of the patients brought to surgery are still poorly described. By conducting a multicentric retrospective cohort study covering the practice of the last twenty years, we describe the paths leading to epilepsy surgery in children with epilepsy associated with tuberous sclerosis complex. METHODS: We identified 84 children diagnosed with tuberous sclerosis complex and epilepsy by matching two exhaustive registries of genetic diseases and subsequent medical records reviews within two French neuropediatric and epilepsy centers. Demographic, clinical, longitudinal, and diagnostic and surgical procedures data were collected. RESULTS: Forty-six percent of the children were initially drug-resistant and 19% underwent resective surgery, most often before the age of four. Stereotactic electroencephalography was performed prior to surgery in 44% of cases. Fifty-seven and 43% of patients remained seizure-free one and ten years after surgery, respectively. In addition, 52% of initially drug-resistant patients who did not undergo surgery were seizure-free at the last follow-up. The number of anti-seizure medications required decreased in 50% of cases after surgery. Infantile spasms, intellectual disability, autism spectrum disorder or severe behavioral disorders were not contraindications to surgery but were associated with a higher rate of complications and a lower rate of seizure freedom after surgery. CONCLUSION: Despite the assumption of complex multifocal epilepsy and practical difficulties in young children with tuberous sclerosis complex, successful surgery results are comparable with other populations of patients with drug-resistant epilepsy, and a spontaneous evolution to drug-sensitive epilepsy may occur in non-operated patients.

Hashimoto's thyroiditis and renal transplant rejection.

PURPOSE: Hashimoto's thyroiditis (HT) is a common autoimmune thyroid disorder that can disrupt thyroid function and homeostasis. As HT results from a dysregulated immune system, we hypothesized that these patients might be more susceptible to transplant failure; however, literature on this association is limited. The purpose of this study is to examine the association of HT with the risk of renal transplant failure. METHODS: We utilized the United States Renal Database System dataset collected from 2005 to 2014 and compared the time from first renal transplant to transplant failure in end-stage renal disease (ESRD) patients with a HT diagnosis to ESRD patients without a HT diagnosis that underwent renal transplant. RESULTS: A total of 144 ESRD patients had International Classification of Disease-9 claim codes for HT prior to renal transplant, amongst a total cohort of 90,301 renal transplant patients aged 18-100 and meeting criteria. Patients with HT were significantly more likely to be female, white, and to have a diagnosis of cytomegalovirus compared to patients without. ESRD patients with a HT diagnosis that underwent renal transplant had a significantly increased risk of renal transplant failure compared to those ESRD renal transplant patients without an HT diagnosis. There was a significantly increased adjusted hazard ratio for graft failure in patients with a HT diagnosis compared to those without. CONCLUSION: Thyroid health and HT may play a significant role in the development of the increased risk of renal transplant failure observed in this study. Additional studies are needed to investigate the underlying mechanisms for this association.

IL11RA-related Crouzon-like autosomal recessive craniosynostosis in 10 new patients: Resemblances and differences.

By describing 10 new patients recruited in centres for Human Genetics, we further delineate the clinical spectrum of a Crouzon-like craniosynostosis disorder, officially termed craniosynostosis and dental anomalies (MIM614188). Singularly, it is inherited according to an autosomal recessive mode of inheritance. We identified six missense mutations in IL11RA, a gene encoding the alpha subunit of interleukin 11 receptor, 4 of them being novel, including 2 in the Ig-like C2-type domain. A subset of patients had an associated connective tissue disorder with joint hypermobility and intervertebral discs fragility. A smaller number of teeth anomalies than that previously reported in the two large series of patients evaluated in dental institutes points toward an ascertainment bias.

Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.

Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

Slow Passage Through a Hopf Bifurcation in Excitable Nerve Cables: Spatial Delays and Spatial Memory Effects.

It is well established that in problems featuring slow passage through a Hopf bifurcation (dynamic Hopf bifurcation) the transition to large-amplitude oscillations may not occur until the slowly changing parameter considerably exceeds the value predicted from the static Hopf bifurcation analysis (temporal delay effect), with the length of the delay depending upon the initial value of the slowly changing parameter (temporal memory effect). In this paper we introduce new delay and memory effect phenomena using both analytic (WKB method) and numerical methods. We present a reaction-diffusion system for which slowly ramping a stimulus parameter (injected current) through a Hopf bifurcation elicits large-amplitude oscillations confined to a location a significant distance from the injection site (spatial delay effect). Furthermore, if the initial current value changes, this location may change (spatial memory effect). Our reaction-diffusion system is Baer and Rinzel's continuum model of a spiny dendritic cable; this system consists of a passive dendritic cable weakly coupled to excitable dendritic spines. We compare results for this system with those for nerve cable models in which there is stronger coupling between the reactive and diffusive portions of the system. Finally, we show mathematically that Hodgkin and Huxley were correct in their assertion that for a sufficiently slow current ramp and a sufficiently large cable length, no value of injected current would cause their model of an excitable cable to fire; we call this phenomenon "complete accommodation."

The neuropsychological profile of patients with 3-methylglutaconic aciduria type III, Costeff syndrome.

Costeff syndrome is a rare genetic neuro-ophthalmological syndrome consisting of early-onset bilateral optic atrophy along with a progressive complex motor disorder with elevated levels of urinary 3-methylglutaconic acid and 3-methylglutaric acid. While borderline to mild cognitive deficits have been considered to be common in patients with this syndrome, a comprehensive cognitive assessment has never been performed. The aim of the current study was to explore the cognitive profile associated with Costeff syndrome. Sixteen adult patients diagnosed with Costeff syndrome were administered a neuropsychological test battery that was composed of standardized verbal tests adapted for the blind. General intelligence ranged from average to borderline, with a group mean consistent with intact general cognitive functioning (VIQmean = 85, z = -1) in the low-average range of the general population. The auditory immediate and delayed memory indexes were in the average range and were significantly higher than the general cognitive functioning, whereas the working memory index was significantly lower than the general cognitive functioning. Adult patients with Costeff syndrome have intact global cognition and learning abilities and strong auditory memory performance. © 2015 Wiley Periodicals, Inc.

Features of the metabolic syndrome and subclinical atherosclerosis in patients with cerebrotendinous xanthomatosis: An augmented risk for premature cardiovascular disease.

Background: Cerebrotendinous xanthomatosis (CTX) is a rare lipid storage disease, caused by deficiency of sterol-27-hydroxylase. Xanthomatous lesions in numerous tissues, and an elevation of cholestanol levels, characterize the disease. Its natural course is progressive neurologic deterioration, leading to premature death. Chronic treatment with oral chenodeoxycholic acid (CDCA) reduces cholestanol levels. Occurrence of premature atherosclerosis has been described in CTX in an unknown mechanism. Aim: The aim of the current work was to evaluate the potential metabolic abnormalities and preclinical vascular changes in Israeli CTX patients. Methods: Ten subjects with CTX were studied. Features of the metabolic syndrome were evaluated, and carotid intima media thickness (cIMT) was measured in the common carotid arteries. Results: All patients were diagnosed with CTX, and all received treatment with CDCA, which resulted in normalization of their plasma cholestanol levels. At the conclusion of the follow up, risk factors for CVD and features of MS were present in all the patients and in three patients, cIMT was higher compared to control subjects. Conclusion: Cardiovascular risk factors and premature vascular changes exist in young CTX patients and proper assessment should be implemented with preventive measures to reduce the risk of atherosclerotic cardiovascular disease in CTX patients.

High prevalence of malignant melanoma in Israeli patients with Parkinson's disease.

The risk of melanoma is higher in patients with Parkinson's disease (PD) than in the general population. Whether the association is disease related or treatment related is unclear. The objective of this study was to assess melanoma prevalence in PD patients in Israel using active dermatologic screening. Consecutive patients with idiopathic PD were recruited by 12 Israeli centers. A movement disorder specialist assessed the severity of PD and obtained a medical, neurological, and medication history. Subsequently, a dermatologist assessed melanoma risk factors, recorded a dermatologic history, proactively performed a whole-body skin examination, and biopsied suspicious skin lesions. Of the enrolled patients (n = 1,395, mean age 69.5 ± 10.6 years, mean PD duration 7.3 ± 6.0 years), 95.3% were treated with dopaminergic agents. Biopsies revealed 8 patients with melanoma in situ and 1 with invasive malignant melanoma; 14 patients reported a melanoma prior to enrollment. The observed 5-year limited duration prevalence of melanoma in PD patients was 4.4 times greater (95% CI 2.6-7.6) than expected from melanoma prevalence in an age- and sex-matched cohort from the Israel National Cancer Registry. The increase was accounted for by an elevated prevalence of melanoma in situ [relative risk 12.5 (95% CI 6.7-23.2)]. Occurrence of melanoma did not correlate with levodopa therapy or time of onset of PD. Melanoma prevalence in PD patients was higher than expected in the general Israeli population. This was not related to levodopa treatment. PD patients should be actively screened for melanoma on a routine basis.

The role of apolipoprotein E polymorphisms in levodopa-induced dyskinesia.

OBJECTIVES: To determine the relationship between apolipoprotein E (APOE) polymorphisms to the time to appearance of levodopa-induced dyskinesia (LID) in patients with Parkinson's disease. METHODS: The APOE genotype of 155 consecutive patients treated with levodopa was determined and its effect on the time of onset of LID was examined using Cox regression model, controlling for gender, age of disease onset, time to initiation of levodopa treatment and history of smoking. RESULTS: Two patients were homozygous for the APOE ε2 allele, 7 had ε2/ε3, 1 had ε2/ε4, 130 had ε3/ε3, 12 had ε3/ε4 and 3 had ε4/ε4; LID appeared in 57.4% of the patients, appearing 4.1 ± 3.5 years after the initiation of levodopa treatment. The survival curve for LID was not affected by the APOE genotype (P = 0.34). CONCLUSION: APOE polymorphisms were found not to be associated with either the occurrence or the time to development of LID.

Diagnostic and severity scores for Cockayne syndrome.

BACKGROUND: Cockayne syndrome is a progressive multisystem genetic disorder linked to defective DNA repair and transcription. This rare condition encompasses a very wide spectrum of clinical severity levels ranging from severe prenatal onset to mild adult-onset subtypes. The rarity, complexity and variability of the disease make early diagnosis and severity assessment difficult. Based on similar approaches in other neurodegenerative disorders, we propose to validate diagnostic and severity scores for Cockayne syndrome. METHODS: Clinical, imaging and genetic data were retrospectively collected from 69 molecularly confirmed CS patients. A clinical diagnostic score and a clinical-radiological diagnostic score for CS were built using a multivariable logistic regression model with a stepwise variable selection procedure. A severity score for CS was designed on five items (head circumference, growth failure, neurosensorial signs, motor autonomy, communication skills) and validated by comparison with classical predefined severity subtypes of CS. RESULTS: Short stature, enophtalmos, hearing loss, cataracts, cutaneous photosensitivity, frequent dental caries, enamel hypoplasia, morphological abnormalities of the teeth, areflexia and spasticity were included in the clinical diagnostic score as being the most statistically relevant criteria. Appropriate weights and thresholds were assigned to obtain optimal sensitivity and specificity (95.7% and 86.4% respectively). The severity score was shown to be able to quantitatively differentiate classical predefined subtypes of CS and confirmed the continuous distribution of the clinical presentations in CS. Longitudinal follow-up of the severity score was able to reflect the natural course of the disease. CONCLUSION: The diagnostic and severity scores for CS will facilitate early diagnosis and longitudinal evaluation of future therapeutic interventions. Prospective studies will be needed to confirm these findings.

Phagocytosis by zippers and triggers.

Two mechanisms have been considered for particle phagocytosis. According to the zipper mechanism, ingestion occurs by sequential engagement of a phagocyte's membrane against the particle surface, and pseudopod advance proceeds no further than receptor-ligand interactions permit. In contrast, in the trigger mechanism particle binding initiates an all-or-none phagocytic response. Although the weight of experimental evidence has favoured the zipper mechanism, recent observations of bacterial entry into epithelial cells and macrophages indicate an indiscriminate, triggered response. This prompts a reconsideration of the underlying mechanisms.

Cryptococcal disease presenting as necrotizing cellulitis in transplant recipients.

Disseminated cryptococcosis uncommonly presents with skin lesions in immunocompromised hosts. Necrotizing fasciitis, necrotizing vasculitis, myositis, or necrotizing soft tissue infection are even more rare presentations. We report 3 cases of cryptococcal necrotizing soft tissue infection, 2 in renal transplant patients, and 1 in a heart transplant patient, and discuss similar cases from the literature. Cryptococcus neoformans should be considered in the differential diagnosis of cellulitis or necrotizing soft tissue infections in immunocompromised patients.

Localized myofascial pain responds better than referring myofascial pain to botulinum toxin injections.

Myofascial pain of the muscles of mastication is a common temporomandibular disorder. Patients unresponsive to conservative treatment modalities pose a therapeutic challenge to the treating clinician. The efficacy of intramuscular botulinum toxin injections for recalcitrant cases is still not well established due to mixed results from clinical trials. The Diagnostic Criteria of Temporomandibular Disorders (DC/TMD) classified chronic muscle pain broadly into a localized pattern (when pain is localized to the site of palpation or the muscle palpated) and a referring pattern (when the pain spreads beyond the boundary of the muscle being palpated). The medical records of 25 consecutive patients treated with botulinum were analysed retrospectively. Significant pain reduction was achieved in 69.2% of the patients with localized myofascial pain and 16.7% of the patients with referring myofascial pain (P=0.015). Seventy-seven per cent of the patients with localized myofascial pain reported using less analgesic throughout the follow-up period, whereas only 25% of the patients with referring myofascial pain (P=0.017). The effects of botulinum toxin in responsive patients subsided after a mean of 3.21 months. Patients with localized myofascial pain benefited from botulinum toxin injections, but patients with referring myofascial pain responded poorly to this treatment.

Benign mucous membrane pemphigoid of the upper aero-digestive tract: rare paraneoplastic syndrome presentation in renal cell carcinoma.

Benign mucous membrane pemphigoid is a rare autoimmune disorder affecting the upper aero-digestive tract and conjunctivae. This is a case presentation of benign mucous membrane pemphigoid affecting the oral mucosa, pharynx, oesophagus and larynx, leading to cicatricial lesions in the pharynx and larynx, causing dysphagia, hoarseness and stridor. The alternative forms of management for laryngeal scarring due to this disease are explained. The patient was later diagnosed with advanced renal cell carcinoma, raising the possibility of cicatricial pemphigoid manifesting as a paraneoplastic syndrome of underlying renal cell carcinoma.

Progressive decreases in nuclear retinoid receptors during skin squamous carcinogenesis.

Retinoids are essential for normal skin growth, differentiation, and apoptosis and are active pharmacologically in the prevention and treatment of skin cancers and other lesions. Retinoid effects are mediated mainly by retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which act as transcription factors to alter gene expression. Using in situ hybridization, we analyzed the expression of RARs and RXRs in normal sun-exposed skin (n = 85), squamous cell carcinoma (SCC; n = 28), and actinic keratosis [AK (a precursor to SCC); n = 38]. The expressions of five receptors (RAR-alpha and -gamma and RXR-alpha, -beta, and -gamma) were moderate to very strong in normal skin, with higher expressions in spinous and granular layers than in the basal layer. RAR-beta expression was weak or absent in normal and lesion samples. All five receptors expressed in the skin were suppressed progressively from normal skin to premalignant skin (AK) to invasive skin SCC. Specific receptor decreases in lesions relative to normal skin ranged from 75% (RXR-beta) to 96% (RAR-alpha) in SCC and from 37% (RAR-gamma) to 68% (RXR-beta) in AK. The degree of suppression of RXR-alpha and RAR-gamma, the two predominant retinoid receptors in skin, was relatively less for RXR-alpha (58% versus 86%; P = 0.015) and relatively greater for RAR-gamma (37% versus 89%; P = 0.0001) between AK and SCC, suggesting that suppression of RXR-alpha may be an earlier event and expression of RAR-gamma may be a later event of multistep squamous skin carcinogenesis. Our results indicate that suppressed expression of retinoid receptors occurs early (in AK) and is associated with progression of squamous skin carcinogenesis to SCC.

Decreased dopaminergic treatment of hospitalized Parkinson's disease patients during infectious diseases is associated with poor outcomes.

A retrospective analysis of consecutive Parkinson's disease (PD) patients hospitalized in internal medicine wards during the years 2008 to 2013 due to infectious disease was performed. PD patients are prone to infections, often leading to hospitalization in internal medicine wards. We observed that during these hospitalizations, chronic anti-Parkinson's medications are frequently overlooked and withdrawn, their reintroduction is delayed and dosages are decreased. Only patients on chronic therapy with at least one anti-Parkinson's medication were included in this study. Multivariate analyses established the association between medication dose reductions on short-term clinical outcomes, including in-hospital mortality and change in discharge destination. Medical records from 528 PD patients were analyzed and 430 were excluded. Of the 98 included, 53 had pneumonia and 58 had urinary tract infections. The overall in-hospital mortality rate was 11.2%. 56.1% of patients' dopaminergic medications were decreased in dose upon admission (22.5% mean decrease in levodopa equivalent daily dose [LEDD]; p<0.001). Both absolute and relative LEDD reductions were associated with significantly increased in-hospital mortality (mean reduction of 394.5 mg versus 188.4 mg; p=0.035 by analysis of variance adjusted to age, sex and renal function) and was also associated with worse discharge destination relative to original place of arrival (mean reduction of 377.8 mg versus 150.7 mg; p=0.014). Decreased dopaminergic medication dosing upon admission of PD patients due to infection is widespread and potentially associated with worse clinical outcomes.

Exploring determinants of progression in Parkinson's disease. Is there a difference among Jewish ethnic groups?

INTRODUCTION: Parkinson's disease (PD) displays an individually variable rate of progression, of which the underlying mechanisms are largely unknown, but may involve genetic factors. In this study, we aimed to explore the effect of ethnic origin on PD progression rate in Israeli Jews, as expressed by time from onset until reaching Hoehn and Yahr stage 3 (HY3). METHODS: Consecutive patients with PD followed bi-annually at the Movement Disorders Institute at Sheba Medical Center, were included. Demographic data and clinical information, including age at PD onset (AO), H&Y staging, and family history of PD, were collected. Ethnicity was determined based on the parents' origin and was categorized as Ashkenazi Jews (AJ), Yemenite Jews (YJ), North African Jews (NAJ) and Oriental Jews (OJ) excluding YJ. Associations between the above variables and the time to HY3 were determined using Cox proportional hazards model. Survival curves were derived from the model. RESULTS: Of 707 patients [430 males, AJ: 458, YJ: 37, NAJ: 75 and OJ: 137] included in the analysis, 343 had reached HY3. In a multivariate analysis, a longer time to HY3 was significantly associated with a younger AO (HR = 1.07, p < 0.001). YJ showed a significantly shorter time to HY3 compared to AJ and OJ, but not compared to NAJ. Time to HY3 was significantly shorter for NAJ than for OJ. CONCLUSION: Jewish PD patients of Yemenite and North African origin may have a more rapid progression of PD, compared to those of Ashkenazi and Oriental origin, suggesting distinctive genetic influences.