Asperger syndrome and “non-verbal learning problems” in a longitudinal perspective: Neuropsychological and social adaptive outcome in early adult life

Co-existence of Asperger syndrome (AS) and non-verbal learning disability (NLD) has been proposed based on the observation that people with AS tend to have significantly higher verbal than performance IQ (VIQ>PIQ by ≥15 points), one of the core features of NLD. In the present study we examined neuropsychological and social adaptive profiles with “non-verbal learning problems” associated with NLD in a group of individuals with AS followed from childhood into early adult life. The group was divided into three subgroups: (i) persistent NLD (P-NLD), i.e. NLD (VIQ>PIQ) both in childhood and early adulthood occasions, (ii) childhood NLD (CO-NLD), i.e. NLD (VIQ>PIQ) only at original diagnosis, or (iii) No NLD (VIQ>PIQ) ever (NO-NLD). All three subgroups were followed prospectively from childhood into adolescence and young adult life. One in four to one in five of the whole group of males with AS had P-NLD. The P-NLD subgroup had poorer neuropsychological outcome in early adult life than did those with CO-NLD and those with NO-NLD. There were no unequivocal markers in early childhood that predicted subgroup status in early adult life, but early motor delay and a history of early speech-language problems tended to be associated with P-NLD.     

Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults

OBJECTIVES: To study the occurrence of relapse of herpes simplex encephalitis (HSE) and to find out whether soluble activity markers in cerebrospinal fluid (CSF) indicate direct viral or immune- mediated events. METHODS: A consecutive series of 32 adult survivors of HSE were followed to determine the incidence of clinical relapse of HSE. Four patients had neurological deterioration interpreted as relapsing HSE. Four non-relapsing HSE cases were selected as matched controls. Fifty nine batched, paired CSF and serum samples from the eight HSE patients were analysed for soluble activity markers, predominantly cytokines and mediators (interferon-gamma, soluble CD8, tumour necrosis factor-alpha, and interleukin-10), amount of HSV-DNA and markers of glial and neuronal destruction (neurofilament protein, glial fibrillary acidic protein, S-100-beta, and neuron specific enolase). RESULTS: Relapse of HSE was diagnosed in 3 of 26 (12 %) acyclovir-treated patients (5 episodes during 6.1 years of followup) and in 1 of 6 vidarabine-recipients. All relapses occurred from 1 to 4 months after acute HSE, except for a second relapse after 3.3 years in one patient. Computer tomography at relapses revealed few abnormalities apart from those found during the primary disease. Intravenous acyclovir and corticosteroids were given for 7-21 days in all the relapse patients. All relapse patients seemed to recover to the pre-relapse condition. HSV-DNA was demonstrated in CSF in all patients during the acute stage but not in any of 13 CSF samples taken during relapse phases. The HSV viral load during the acute stage of HSE was not higher or of longer duration in the relapsing patients than in the non-relapsing HSE controls. The levels of sCD8 were increased in nearly all CSF samples tested with peaks of sCD8 at one month of acute HSE. In all episodes of relapse, sCD8 peaks were detected during the first week at high levels. CSF levels of neuron-specific enolase, S-100 and glial fibrillary acidic protein were markedly lower at relapse than at the acute stage of HSV-1 encephalitis. CONCLUSION: The lack of demonstrable HSV DNA in CSF, the lack of acute CSF signs and the lack of signs of neural and glia cells destruction indicate that a direct viral cytotoxicity is not the major pathogenic mechanism in relapse. Instead, the pronounced CSF proinflammatory immunological response and the relative lack of CSF anti-inflammatory cytokine IL-10 response suggest immunologically-mediated pathogenicity.     

Enhanced levels of urokinase plasminogen activator and its soluble receptor in common variable immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by defective immunoglobulin production and high frequency of bacterial infections, autoimmunity and manifestations of chronic inflammation.The urokinase plasminogen activator (uPA), its cell bound and soluble receptor (uPAR, suPAR) have complex biological functions involving innate immune defense mechanisms and regulation of inflammation. Based on this dual role, we hypothesized that the uPA system could be affected in CVID, and examined expression of components of the uPA system in subgroups of CVID. All CVID-patients had increased plasma levels of suPAR with particularly high levels in those with splenomegaly and thrombocytopenia. Plasma uPA levels were also raised in these patients, and both suPAR and uPA levels correlated with the monocyte activation marker neopterin. Monocytes from CVID patients had increased expression of uPAR. We show an increased activation of the uPA system possibly contributing to the inflammatory phenotype seen in subgroups of CVID patients.     

MECP2 mutation screening in Swedish classical Rett syndrome females

Rett syndrome (RS) is a neurodevelopmental disorder almost exclusively affecting females. We have studied the mutation spectrum of the responsible gene MECP2, encoding methyl-CpG-binding protein 2 (MeCP2), in 16 sporadic classical RS females from Sweden. In 13 of 16 patients (81%) we detected nonsense or missense mutations in the coding parts of MECP2. This mutation rate is in agreement with other reports (65-80%). In all, 12 different mutations and one polymorphism were found; three of the mutations have not been reported previously. The missense mutations were restricted to highly conserved regions of the gene. None of the mutations was detected in parents; thus, they had probably arisen de novo. In contrast, two normal variants, one intron deletion and one silent mutation, were seen singly only in two patients' mothers; neither has been reported previously. One patient showed two different mutations closely located, i.e. 802C > T (R268W) together with 808C > T (R270X). Another patient had a mutation in the stop codon 1459T > C (X487R), leading to a gene product prolonged with 27 amino acids. In conclusion, our results indicate that the majority of Swedish RS patients (81%) have mutations in MECP2 that are sporadic cases with de novo mutations. Moreover, both missense and nonsense mutations occur, but in different parts of the gene, probably reflecting the function of the domains in MeCP2. This study has improved our ability to offer these families an early confirmation of Rett diagnoses.     

Microglial MyD88 signaling regulates acute neuronal toxicity of LPS-stimulated microglia in vitro

Although the role of microglial activation in neural injury remains controversial, there is increasing evidence for a detrimental effect in the immature brain, which may occur in response to release of neurotoxic substances including pro-inflammatory cytokines. However, the signaling mechanisms involved in microglial-induced neuronal cell death are unclear. Microglia isolated from the brains of wild-type (WT) or MyD88 knockout (KO) mice were exposed to PBS or the TLR4-ligand LPS (100 ng/mL) for 2, 6, 14, or 24 h, and the microglia-conditioned medium (MCM) collected. Detection of multiple inflammatory molecules in MCM was performed using a mouse 22-plex cytokine microbead array kit. Primary neuronal cultures were supplemented with the 14 or 24 h MCM, and the degree of neuronal apoptosis examined after exposure for 24 h. Results showed a rapid and sustained elevation in multiple inflammatory mediators in the MCM of WT microglia exposed to LPS, which was largely inhibited in MyD88 KO microglia. There was a significant increase in apoptotic death measured at 24 h in cultured neurons exposed to CM from either 14 or 24 h LPS-stimulated WT microglia (p < .05 vs. WT control). By contrast, there was no increase in apoptotic death in cultured neurons exposed to CM from 14 or 24 h LPS-stimulated MyD88 KO microglia (p = .15 vs. MyD88 KO control). These data suggest that MyD88-dependent activation of microglia by LPS causes release of factors directly toxic to neurons.     

Long‐term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease

We report the 5 to 6 year follow‐up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinson's disease (PD) patients. Thirty‐five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinson's Disease Rating Scale (UPDRS) assessed with a prospective cross‐over double‐blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off‐ and on‐medication states with and without stimulation, activities of daily living (ADL), anti‐PD medications, and dyskinesias. In double‐blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off‐stimulation, regardless of the sequence of stimulation. In open assessment, both STN‐ and GPi‐DBS significantly improved the off‐medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti‐PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long‐term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN‐DBS patients and fewer adverse events in the GPi‐DBS group. © 2010 Movement Disorder Society     

Accurate determination of blood–brain barrier permeability using dynamic contrast-enhanced T1-weighted MRI: a simulation and in vivo study on healthy subjects and multiple sclerosis patients

Dynamic contrast-enhanced magnetic resonance imaging (DCE–MRI) is increasingly used to estimate permeability in situations with subtle blood–brain barrier (BBB) leakage. However, the method''s ability to differentiate such low values from zero is unknown, and no consensus exists on optimal selection of total measurement duration, temporal resolution, and modeling approach under varying physiologic circumstances. To estimate accuracy and precision of the DCE–MRI method we generated simulated data using a two-compartment model and progressively down-sampled and truncated the data to mimic low temporal resolution and short total measurement duration. Model fit was performed with the Patlak, the extended Tofts, and the Tikhonov two-compartment (Tik-2CM) models. Overall, 17 healthy controls were scanned to obtain in vivo data. Long total measurement duration (15 minutes) and high temporal resolution (1.25 seconds) greatly improved accuracy and precision for all three models, enabling us to differentiate values of permeability as low as 0.1 ml/100 g/min from zero. The Patlak model yielded highest accuracy and precision for permeability values <0.3 ml/100 g/min, but for higher values the Tik-2CM performed best. Our results emphasize the importance of optimal parameter setup and model selection when characterizing low BBB permeability.     

Ankle torque steadiness is related to muscle activation variability and coactivation in children with cerebral palsy

The aims of this study were to: (1) investigate the significance of muscle activation variability and coactivation for the ability to perform steady submaximal ankle torque (torque steadiness) in healthy children and those with cerebral palsy (CP), and (2) assess ankle function during isometric contractions in those children. Fourteen children with CP who walked with equinus foot deformity and 14 healthy (control) children performed maximal and steady submaximal ankle dorsi‐ and plantarflexions. Dorsiflexion torque steadiness was related to agonist and antagonist muscle activation variability as well as the plantarflexor coactivation level in children with CP (r > 0.624, P < 0.03). Moreover, children with CP displayed reduced maximal torque and submaximal torque steadiness of both dorsi‐ and plantarflexion compared with controls (P < 0.05). Both muscle groups may benefit from strength training, as they exhibit poor submaximal control and weakness in children with CP. Muscle Nerve, 2009