Polysomnography findings in pediatric spinal muscular atrophy types 1–3

BackgroundSleep disordered breathing (SDB) causes sleep disturbance and daytime symptoms in children with neuromuscular disorders. Although polysomnography (PSG) findings are well described in many neuromuscular disorders, there are limited reports from children with spinal muscular atrophy (SMA). The aim of this study was to determine the sleep architecture and breathing characteristics and non-invasive ventilation (NIV) use in our pediatric SMA cohort.MethodsWe conducted a cross-sectional cohort study of all children with SMA in Queensland, Australia. Children were Nusinersen naïve and had a full diagnostic PSG in 2018. The PSG was scored and reported by a single pediatric sleep physician in accordance with American Academy of Sleep Medicine Criteria (2012).ResultsIn sum, 31 children (18 males), Six with Type 1, 16 with Type 2 and nine with Type 3, aged 0.25–18.8 years old were studied. SDB was seen in each SMA type and was more pronounced during rapid eye movement (REM) sleep. Type 1: all patients exhibited SDB, three (50%) with central sleep apnea (CSA) and three (50%) with mixed disease. Type 2: five (31%) had CSA, one (6%) mixed disease, seven (44%) had early SDB and three (19%) had normal sleep breathing. Type 3: four (44%) children had CSA and five had early SDB. No child exhibited obstructive sleep apnea (OSA) alone.Starting NIV significantly reduced mean total PSG Apnea-Hypopnea Index (AHI) scores from a grouped mean of 15.4 events per hour (SD ± 14.6; 95% CI 6.1–24.7) to 4.0 events per hour (SD ± 4.2, 95% CI 1.2–6.5, p = 0.01).ConclusionSDB is common in children with SMA and was present in all types. CSA was the most common disorder; with mixed SDB also present in type 1 and 2 SMA.     

Clinical and radiological Comparison of treatment of atlantoaxial instability by posterior C1–C2 transarticular screw fixation or C1 lateral mass-C2 pedicle screw fixation

We compared the clinical and radiological results of posterior atlantoaxial fixation surgery using transarticular screws to those using a polyaxial screw–rod system in 55 patients with symptomatic atlantoaxial instability. Patients underwent posterior C1–C2 fixation: 28 patients (group 1) underwent C1–C2 transarticular screw fixation and 27 patients (group 2) underwent C1 lateral mass–C2 pedicle screw fixation. Patients were followed-up for at least 24 months. The clinical and radiological results were evaluated in the early postoperative period and at 3, 6, 12 and 24 months after surgery. Long-term postoperative stability and bone fusion were examined. After surgery, 93% of patients in group 1 and 96% of patients in group 2 were free of neck pain. The solid fusion rates were 82% for group 1 patients and 96% for group 2 patients at 12 months (p < 0.092). In group 1, three patients showed fibrous union. Four patients had hardware failure due to a screw malposition (one in group 1) and pseudoarthrodesis (two in group 1 and one in group 2). One patient in group 1 had cerebrospinal fluid leakage. One patient in group 2 had occipital neuralgia. One vertebral artery injury occurred during the screw placement in group 1 and another in group 2 during the muscle dissection. C1–C2 transarticular screw fixation and C1 lateral mass–C2 pedicle screw fixation both produced excellent results for stabilization of the atlantoaxial complex, but the radiological outcome tended to be superior in C1 lateral mass–C2 pedicle screw fixation.     

C1 dome-like laminotomy and posterior C1–C2 polyaxial screw-rod fixation for a patient with cervical myelopathy due to a retro-odontoid pseudotumor

A 49-year-old man presented with progressive cervical myelopathy caused by a retro-odontoid mass, with associated developmental canal stenosis at C1, and C1–C2 instability. Surgery was scheduled for a dome-like laminotomy at C1, posterior C1–C2 fixation using C1 lateral mass screws and C2 pedicle screws, and structural bone grafting between C1 and C2. Prior to surgery, we produced a 3-dimensional full-scale model of the patient’s cervical spine and performed a simulation of the scheduled surgery. Through the simulation, we accurately evaluated the laminotomy sites and the screw insertion points. During the actual surgery, all procedures were successful. After surgery, the patient’s neurological deficits markedly improved. Successful C1–C2 fusion, adequate decompression of the spinal cord, and spontaneous regression of the retro-odontoid mass were achieved by this procedure without any apparent restriction in neck movement.     

Simultaneous Guillain-Barré syndrome and acute disseminated encephalomyelitis in the pediatric population

Few cases of simultaneous acute demyelination of the peripheral and central nervous systems are reported. Four patients diagnosed as having Guillain-Barré syndrome and acute disseminated encephalomyelitis during the same hospitalization are described herein. Two patients manifest an atypical form of Guillain-Barré syndrome, with magnetic resonance imaging of the head showing acute disseminated encephalomyelitis. A third patient has acute disseminated encephalomyelitis and develops Guillain-Barré syndrome during his hospitalization. A fourth patient demonstrates transverse myelitis that evolves into Guillain-Barré syndrome, with demyelination seen on brain magnetic resonance imaging. All patients are treated with intravenous immunoglobulins or corticosteroids. Three patients have a favorable outcome; 1 patient has a chronic inflammatory demyelinating polyradiculoneuropathy. Guillain-Barré syndrome and acute disseminated encephalomyelitis can occur simultaneously in the pediatric population. This may be explained by a shared epitope between peripheral and central nervous system myelin. Further research is necessary to better describe this entity and its prognosis.     

Clinical outcome of posterior C1–C2 pedicle screw fixation and fusion for atlantoaxial instability: A retrospective study of 86 patients

We retrospectively studied the clinical results of posterior C1–C2 pedicle screw fixation and fusion for 86 patients diagnosed with atlantoaxial instability from January 2002 to January 2013. The study population included 48 men and 38 women, with an average age of 42.6 (range, 16–69 years old). The causes of atlantoaxial instability could be divided into traumatic fracture (44 patients), congenital malformation (17 patients), rheumatoid arthritis (15 patients), and other causes (nine patients). The mean follow-up duration was 33.9 months (range, 13–72 months). The average operative time was 133.0 min (range, 90–290 min), and the mean blood loss during the operation was 185.7 ml (range, 110–750 ml). No patient experienced neurological function worsening related to the surgical procedure. In addition, 63% of the patients who presented with neurological symptoms reported improvement after surgery. Screw placement and reduction was achieved satisfactorily in all the patients and their neck pain was greatly relieved. Plain radiography and CT scans indicated solid fusion after 12 months in all the patients. We suggest that C1–C2 pedicle screw internal fixation is a reliable method for treating atlantoaxial instability.     

Electroretinogram changes in a pediatric population with epilepsy: is vigabatrin acting alone?

Vigabatrin, a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), is widely used as initial monotherapy in infantile spasms and add on therapy in partial onset seizures. Vigabatrin is associated with retinal toxicity causing constriction of the visual field. Our aim was to assess what effect add-on antiepileptic drug therapy has on the incidence of retinal toxicity in patients being treated with vigabatrin. Medication dosages, duration of treatment, and electroretinogram results were examined in a single center retrospective study. Retinal toxicity was detected in 18 of 160 patients (11.25%) over a 10-year period. A total of 14 (77%) were in the group treated with additional antiepileptic drugs, the other 4 received vigabatrin as monotherapy. We detected a significantly higher percentage of toxicity in the group of patients treated with vigabatrin and additional antiepileptic drugs. Our numbers were not sufficient to detect which drug or combination of drugs might be associated with higher risk.     

Subclinical autism spectrum symptoms in pediatric obsessive–compulsive disorder

The literature on subclinical autism spectrum (ASD) symptoms in pediatric obsessive–compulsive disorder (OCD) is scarce, and it remains unclear whether ASD symptoms are related to OCD severity. The aims of the present study were to assess the prevalence of ASD symptoms and age and sex differences in children and adolescents with OCD, and to explore the relation between ASD symptoms and OCD severity. This is the largest study of ASD symptoms in an OCD population to date, and the first directly aimed at elucidating sex and age differences in this matter. The study used baseline data from the Nordic Long-term OCD Treatment Study in which parents of 257 children and adolescents with OCD aged 7–17 completed the Autism Spectrum Screening Questionnaire. OCD severity was assessed with the Children’s Yale–Brown Obsessive Compulsive Scale. Pediatric OCD patients were found to exhibit elevated rates of ASD symptoms compared to a norm group of school-age children. ASD symptoms were concentrated in a subgroup with a prevalence of 10–17 %. This subgroup was characterized by a male preponderance with a sex ratio of approximately 2.6:1, while children versus adolescents with OCD exhibited similar rates. Autism-specific social and communication difficulties were not related to OCD severity, while restricted repetitive behavior was positively related to OCD severity. The results indicate that clinicians need to be aware of ASD symptoms in children and adolescents with OCD since one out of ten exhibits such symptoms at a clinical sub-threshold.     

DSM–IV pain disorder in the general population

BACKGROUND: Despite an abundance of questionnaire data, the prevalence of clinically significant and medically unexplained pain syndromes in the general population has rarely been examined with a rigid personal-interview methodology. OBJECTIVE: To examine the prevalence of pain syndromes and DSM-IV pain disorder in the general population and the association with other mental disorders, as well as effects on disability and health-care utilization. METHODS: Analyses were based on a community sample of 4.181 participants 18-65 years old; diagnostic variables were assessed with a standardized diagnostic interview (M-CIDI). RESULTS: The 12-month prevalence for DSM-IV pain disorder in the general population was 8.1%; more than 53% showed concurrent anxiety and mood disorders. Subjects with pain disorder revealed significantly poorer quality of life, greater disability, and higher health-care utilization rates compared to cases with pain below the diagnostic threshold. The majority had more than one type of pain, with excessive headache being the most frequent type. CONCLUSIONS: Even when stringent diagnostic criteria are used, pain disorder ranks among the most prevalent conditions in the community. The joint effects of high prevalence in all age groups, substantial disability, and increased health services utilization result in a substantial total burden, exceeding that of depression and anxiety.     

5HT–2C receptor polymorphism in suicide victims

Abstract. Sustainable observations suggest that suicidal behaviour by itself may have biological correlates, among which those related to the serotonergic synapse hold the key position. Based on the association of suicide and serotonergic dysfunction, it was proposed that genetic mechanisms affecting suicidal behaviour could be related to the alterations of the genes encoding the elements of 5HT synapse. The present study tested the association of the polymorphism in the serotonin 2C (5HT-2C) receptor coding region (Cys23Ser) with suicide commitment. Study was based on two independent samples, one of German (284 suicide victims versus 297 controls) and other of Slavic/Croatian (118 suicide victims versus 275 controls) ethnicity. No significant differences in allele or genotype frequencies between victims and controls were demonstrated. Results did not provide supporting evidence for the potential involvement of the investigated variants of 5HT-2C receptor in the susceptibility to suicide.     

Dynamic expression of Slit1–3 and Robo1–2 in the mouse peripheral nervous system after injury

The Slit family of axon guidance cues act as repulsive molecules for precise axon pathfinding and neuronal migration during nervous system development through interactions with specific Robo receptors.Although we previously reported that Slit1–3 and their receptors Robo1 and Robo2 are highly expressed in the adult mouse peripheral nervous system,how this expression changes after injury has not been well studied.Herein,we constructed a peripheral nerve injury mouse model by transecting the right sciatic nerve.At 14 days after injury,quantitative real-time polymerase chain reaction was used to detect mRNA expression of Slit1–3 and Robo1–2 in L4–5 spinal cord and dorsal root ganglia,as well as the sciatic nerve.Immunohistochemical analysis was performed to examine Slit1–3,Robo1–2,neurofilament heavy chain,F4/80,and vimentin in L4–5 spinal cord,L4 dorsal root ganglia,and the sciatic nerve.Co-expression of Slit1–3 and Robo1–2 in L4 dorsal root ganglia was detected by in situ hybridization.In addition,Slit1–3 and Robo1–2 protein expression in L4–5 spinal cord,L4 dorsal root ganglia,and sciatic nerve were detected by western blot assay.The results showed no significant changes of Slit1–3 or Robo1–2 mRNA expression in the spinal cord within 14 days after injury.In the dorsal root ganglion,Slit1–3 and Robo1–2 mRNA expression were initially downregulated within 4 days after injury;however,Robo1–2 mRNA expression returned to the control level,while Slit1–3 mRNA expression remained upregulated during regeneration from 4–14 days after injury.In the sciatic nerve,Slit1–3 and their receptors Robo1–2 were all expressed in the proximal nerve stump;however,Slit1,Slit2,and Robo2 were barely detectable in the nerve bridge and distal nerve stump within 14 days after injury.Slit3 was highly ex-pressed in macrophages surrounding the nerve bridge and slightly downregulated in the distal nerve stump within 14 days after injury.Robo1 was upregulated in vimentin-positive cells and migrating Schwann cells inside the nerve bridge.Robo1 was also upregulated in Schwann cells of the distal nerve stump within 14 days after injury.Our findings indicate that Slit3 is the major ligand expressed in the nerve bridge and distal nerve stump during peripheral nerve regeneration,and Slit3/Robo signaling could play a key role in peripheral nerve repair after injury.This study was approved by Plymouth University Animal Welfare Ethical Review Board (approval No.30/3203) on April 12,2014.     

Charcot–Marie–Tooth disease: genetic subtypes in the Sardinian population

Charcot–Marie–Tooth disease (CMT) is characterised by great variability of genetic subtypes. This study aimed to assess the genetic subtypes of CMT disease in the Sardinian population. Genetic screening was performed for CMT cases (CMT1, CMT2, and hereditary neuropathy with susceptibility to pressure palsies [HNPP]). A total of 1,043 subjects (119 index cases) were evaluated. In CMT1 index cases (69/119; 58%), PMP22 duplication at 17p11.2 was the most frequent genetic diagnosis (60/69; 87%), followed by mutations in the GJB1 gene (5/69; 7.2%), in the SH3TC2 gene (3/69; 4.4%) and PMP22 Gly107Val point mutation (1/69; 1.4%). The CMT2 group (24/119; 20.1%) comprised 10/24 (41.6%) patients carrying MPZ gene Ser44Phe mutation, 6/24 (25%) with mutations in MFN2 and HSPB1, and 1/24 (4.2%) in GJB1 and LRSAM1. In the HNPP group (26/119; 21.9%), the majority of patients reported the PMP22 deletion (25/26; 96.2%). Further studies are needed to comprehend the overall picture of the disease in Mediterranean area.     

Lateral C1–C2 dislocation complicating a type II odontoid fracture

We describe a unique C1–C2 lateral dislocation complicating a displaced type II odontoid fracture. We report a 63-year-old female pedestrian involved in a motor vehicle accident who required posterior open reduction and segmental C1–C2 instrumentation and fusion. Radiological examination of the cervical spine demonstrated a lateral dislocation of the atlantoaxial joint with a displaced type II fracture of the odontoid, fracture of the right lateral mass of C1 and left superior articular facet of C2. Neurological examination revealed the patient to be myelopathic and closed halo traction failed to achieve reduction. Due to the irreducible nature of the dislocation, posterior open reduction and segmental C1–C2 instrumentation and fusion was performed. The dislocated C1–C2 articulation was successfully reduced surgically with subsequent bony fusion and resolution of all neurological symptoms and signs at final follow-up. To our knowledge, this the first report of this type of injury. We also review the related literature on this unique injury pattern.     

Adrenomedullin 2/Intermedin in the Hypothalamo–Pituitary–Adrenal Axis

Adrenomedullin 2/intermedin (AM2/IMD) is a new member of the calcitonin/calcitonin gene-related peptide (CGRP) family. CGRP, adrenomedullin (AM), and AM2/IMD share the receptor system consisting of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMP). The CRLR/RAMP2 or CRLR/RAMP3 complex forms the AM receptor, whereas the CRLR/RAMP1 forms the CGRP receptor. AM2/IMD binds non-selectively to all three CRLR/RAMP complexes. AM2/IMD has various actions, such as a potent vasodilator action and a protective action against oxidative stress, like AM and CGRP. When administered intracerebroventricularly, AM2/IMD stimulates the sympathetic nervous system and increases blood pressure. In human hypothalamus, AM2/IMD is expressed in the paraventricular and supraoptic nuclei and colocalized with arginine vasopressin. Anterior pituitary cells were diffusely immunostained for AM2/IMD. AM2/IMD stimulates the release of ACTH, prolactin, and oxytocin, but suppresses GH release. Some of these pituitary actions of AM2/IMD have been supposed to be mediated by an unidentified unique receptor for AM2/IMD. In the adrenal gland, immunoreactive (IR)-AM2/IMD and IR-AM were detected in the medulla, while the degree of IR-AM2/IMD and IR-AM in the cortex was relatively weak or undetectable. Furthermore, AM2/IMD and AM were expressed in adrenocortical tumors, such as aldosterone-secreting adenomas, and pheochromocytomas. CRLR and RAMPs are expressed in the hypothalamus, pituitaries, adrenal glands, and adrenal tumors. Thus, AM2/IMD is expressed in every endocrine organ of the hypothalamo–pituitary–adrenal axis together with its receptor. AM2/IMD may act as a neurotransmitter or modulator in the brain and as a paracrine/autocrine regulator in the hypothalamo–pituitary–adrenal axis.     

Cytochrome P450 2E1 gene polymorphisms/haplotypes and Parkinson’s disease in a Swedish population

Cytochrome P450 2E1 (CYP2E1), which inter alia is located in dopamine containing neurons in the substantia nigra, has been hypothesized to be of importance for the pathophysiology of Parkinson’s disease (PD), either by its production of reactive oxygen species (ROS) or by its capability to detoxify putative neurotoxins. Numerous polymorphisms in the coding and non-coding regions of the gene for this enzyme have been reported. Different variants may account for inter-individual differences in the activity of the enzyme or production of ROS. In this study, the CYP2E1 gene was examined in a control population (n = 272) and a population with PD (n = 347), using a tag-single nucleotide polymorphism (tSNP) approach founded on HapMap Data. Six tSNPs were used in the analysis and haplotype block data were obtained. In case of significance, the SNP was further examined regarding early/late age of disease onset and presence of relatives with PD. We found an association between allele and genotype frequencies of the C/G polymorphism at intron 7 (rs2070676) of this gene and PD (P value of 0.026 and 0.027, respectively). Furthermore, analysis of the rs2070676 polymorphism in subgroups of patients with age of disease onset higher than 50 years and those not having a relative with PD also demonstrated a significant difference with controls. This was seen in both genotype (corresponding to P value = 0.039 and 0.032) and allele (P = 0.027 and 0.017 respectively) frequency. As a representative of many polymorphisms or in possible linkage disequilibrium with other functional variants, it is possible that rs2070676 could influence the regulation of the enzyme. In conclusion, our results display an association between the rs2070676 polymorphism and PD. Additional investigations are needed to elucidate the importance of this polymorphism for the activity of CYP2E1 and PD susceptibility.     

Orbital frontal cortex in treatment-naïve pediatric obsessive–compulsive disorder

The orbital frontal cortex (OFC) has been implicated in obsessive–compulsive disorder (OCD). Participants comprised 28 treatment-naïve pediatric OCD patients and 21 controls, who were examined using magnetic resonance imaging. OCD patients had larger right but not left OFC white matter volume than controls. This is fresh evidence implicating white matter in OCD.     

Genotype–phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations

Merosin deficient congenital muscular dystrophy 1A (MDC1A) results from mutations in the LAMA2 gene. We report 51 patients with MDC1A and examine the relationship between degree of merosin expression, genotype and clinical features. Thirty-three patients had absence of merosin and 13 showed some residual merosin. Compared to the residual merosin group, patients with absent merosin had an earlier presentation (<7 days) (P = 0.0073), were more likely to lack independent ambulation (P = 0.0215), or require enteral feeding (P = 0.0099) and ventilatory support (P = 0.0354). We identified 33 novel LAMA2 mutations; these were distributed throughout the gene in patients with absent merosin, with minor clusters in exon 27, 14, 25 and 26 (55% of mutations). Patients with residual merosin often carried at least one splice site mutation and less frequently frameshift mutations. This large study identified novel LAMA2 mutations and highlights the role of immunohistochemical studies for merosin status in predicting clinical severity of MDC1A.     

Lack of association between monocyte protein-1 (MCP-1) –2518 A > G chemoattractant and C–C chemokine receptor 2 (CCR2) Val64Ile polymorphisms and multiple sclerosis in a Tunisian population

Chemokines and their receptors are known to mediate inflammation and tissue damage in autoimmune disorders such as multiple sclerosis (MS). Multiple sclerosis is an inflammatory disease of the central nervous system, characterized by myelin damage and neurological complications. Monocyte chemoattractant protein-1 (MCP-1) interacts with the C–C chemokine receptor 2 (CCR2) and plays a role in the migration of leukocytes into the central nervous system, thus contributing to the T cell-mediated pathogenesis of MS. Genomic DNA obtained from 58 MS patients and 72 healthy controls was tested for the MCP-1 –2518 A > G and CCR2 Val64Ile polymorphisms using polymerase chain reaction–restriction fragment length polymorphism analysis. Neither the MCP-1 –2518G (p = 0.43) nor the CCR2 64Ile (p = 0.52) variant contributed to the risk of MS in Tunisians.     

C1 lateral mass screw insertion from the caudal–dorsal to the cranial–ventral direction as an alternate method for C1 fixation: A quantitative anatomical and morphometric evaluation

ObjectC1 lateral mass screw has been widely used for fixation of the upper cervical spine. However, traditional fixation methods are not without complication. Morphometric measurement of an alternative approach is conducted.MethodsThree-dimensional CT scans of the cervical spine obtained in 100 adults were evaluated, and key measurements were determined for screw entry points, trajectories, and screw lengths for placement of a C1 screw via this alternate approach. Additional measures were included to account for relevant anatomic variation, including the size of the dangerous lateral zone of the C1 entry point and depth of the atlantooccipital joint surface. Twenty dried atlantal specimens were evaluated to determine corresponding ex vivo measurements.ResultsThe mean maximum angle of medialization was 20.8° ± 2.8° (right) and 21.1° ± 2.8° (left), as measured in the axial CT images. Sagittal CT images show the mean maximum superior angulation was 24.7° ± 4.3° (right) and 24° ± 4.0° (left), and the mean minimum superior angulation was 13.6° ± 4.4° (right) and 13.6° ± 3.9° (left). The mean screw length within the lateral mass was 21.2 ± 1.9 mm (right) and 21.3 ± 2.0 mm (left). Given an additional 10–15 mm needed for rod adaptation, an ideal screw length of 30–35 mm was determined.ConclusionThe C1 insertion caudally from the C2 nerve root may become an alternate method. Preoperative consideration of the ideal screw insertion point, trajectory, and length are vital for safe and effective surgical intervention.