Relationship between Spectral Characteristics of Spontaneous Postural Sway and Motion Sickness Susceptibility.

Motion sickness (MS) usually occurs for a narrow band of frequencies of the imposed oscillation. It happens that this frequency band is close to that which are spontaneously produced by postural sway during natural stance. This study examined the relationship between reported susceptibility to motion sickness and postural control. The hypothesis is that the level of MS can be inferred from the shape of the Power Spectral Density (PSD) profile of spontaneous sway, as measured by the displacement of the center of mass during stationary, upright stance. In Experiment 1, postural fluctuations while standing quietly were related to MS history for inertial motion. In Experiment 2, postural stability measures registered before the onset of a visual roll movement were related to MS symptoms following the visual stimulation. Study of spectral characteristics in postural control showed differences in the distribution of energy along the power spectrum of the antero-posterior sway signal. Participants with MS history provoked by exposure to inertial motion showed a stronger contribution of the high frequency components of the sway signal. When MS was visually triggered, sick participants showed more postural sway in the low frequency range. The results suggest that subject-specific PSD details may be a predictor of the MS level. Furthermore, the analysis of the sway frequency spectrum provided insight into the intersubject differences in the use of postural control subsystems. The relationship observed between MS susceptibility and spontaneous posture is discussed in terms of postural sensory weighting and in relation to the nature of the provocative stimulus.

Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under L-DOPA, 5-HTP and BH4 Trials.

UNLABELLED: Objective/context: We describe the second patient presenting the combination of two homoallelic homozygous nonsense mutations in two genes distant from 1.8 Mb in the chromosome 2p13-3, the methylmalonyl-CoA epimerase gene (MCEE) and the sepiapterin reductase gene (SPR). CASE REPORT: The patient was born from consanguineous parents. He has presented a moderate but constant methylmalonic acid (MMA) excretion in urine associated with a mental retardation. The first homozygous mutation was identified in the MCEE gene (c.139C>T; p.Arg47*). Progressive dystonia and cataplexy narcolepsy led to diagnose the second homozygous mutation in the SPR gene: c.751A>T; p.Lys251*. Sepiapterin reductase deficiency (SRD) was characterized by a defect in tetrahydrobiopterin (BH4), the cofactor of several hydroxylases needed for the synthesis of neurotransmitters. A treatment with L-DOPA/carbidopa and 5-HTP dramatically improved the dystonic posture, the mood and the hypersomnia, proving that the pathogenesis was due to SRD. A supplementation with BH4 did not induce additional clinical benefit, although HVA and HIAA increased in CSF. The polyunsaturated fatty acids were measured in CSF as the markers of the neuronal stress. We have shown that DHA and its precursor EPA were high before and during the time course of the different treatments. IN CONCLUSION: The patient has inherited two copies of the two mutations from his consanguineous parents in the MCEE and SPR genes in the chromosome 2p13-3. DHA and EPA increased in CSF as a response to the neuronal stress induced by the defect in neurotransmitters or the altered metabolism of the odd-chain fatty acids and cholesterol.

An ion channel chip for diagnosis and prognosis of autoimmune neurological disorders.

Autoantibodies directed against ion channels and ionotropic receptors are associated with neuromuscular and neurological disorders. Their detection has proven to be useful for diagnosis, prognosis and treatment of these autoimmune syndromes. We have designed an ion channel chip for the systematic and rapid screening of antibodies directed against tens of different ion channels. The chip has been validated by confirming the presence of autoantibodies in patients with anti-NMDA receptor encephalitis. Such a chip will be useful for the diagnosis of already documented disorders, but also to identify new targets of autoimmunity and classification of the corresponding diseases. The article presents some promising patents on the Ion Channel Chip.

Functional and electrophysiological characterization of four non-truncating mutations responsible for creatine transporter (SLC6A8) deficiency syndrome.

Intellectual disability coupled with epilepsy are clinical hallmarks of the creatine (Cr) transporter deficiency syndrome resulting from mutations in the SLC6A8 gene. So far characterization of pathogenic mutations of SLC6A8 has been limited to Cr uptake. The aim of our study was to characterize the electrogenic and pharmacological properties of non truncating SLC6A8 mutations identified in patients presenting variable clinical severity. Electrophysiological and pharmacological properties of four mutants (including two novel ones) were studied in X. laevis oocyte expression system. Creatine uptake was assessed with [(14)C]-Cr in X. laevis and patients' fibroblasts. Subcellular localization was determined by immunofluorescence and western blot. All mutants were properly targeted to the plasma membrane in both systems. Mutations led to the complete loss of both electrogenic and transport activities in X. laevis and Cr uptake in patients' fibroblasts. Among the Cr analogs tested, guanidinopropionate induced an electrogenic activity with the normal SLC6A8 transporter similar to creatine whereas a phosphocreatine derivative, PCr-Mg-CPLX, resulted in partial activity. SLC6A8 mutants displayed no electrogenic activity with all Cr analogs tested in X. laevis oocytes. Although the mutations altered various domains of SLC6A8 Cr uptake and electrogenic properties were completely inhibited and could not be dissociated. Besides the metabolic functions of Cr, the loss of SLC6A8 electrogenic activity, demonstrated here for the first time, may also play a role in the altered brain functions of the patients.

Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy.

OBJECTIVE: Sepiapterin reductase deficiency (SRD) is an under-recognized levodopa-responsive disorder. We describe clinical, biochemical, and molecular findings in a cohort of patients with this treatable condition. We aim to improve awareness of the phenotype and available diagnostic and therapeutic strategies to reduce delayed diagnosis or misdiagnosis, optimize management, and improve understanding of pathophysiologic mechanisms. METHODS: Forty-three individuals with SRD were identified from 23 international medical centers. The phenotype and treatment response were assessed by chart review using a detailed standardized instrument and by literature review for cases for which records were unavailable. RESULTS: In most cases, motor and language delays, axial hypotonia, dystonia, weakness, oculogyric crises, and diurnal fluctuation of symptoms with sleep benefit become evident in infancy or childhood. Average age of onset is 7 months, with delay to diagnosis of 9.1 years. Misdiagnoses of cerebral palsy (CP) are common. Most patients benefit dramatically from levodopa/carbidopa, often with further improvement with the addition of 5-hydroxytryptophan. Cerebrospinal fluid findings are distinctive. Diagnosis is confirmed by mutation analysis and/or enzyme activity measurement in cultured fibroblasts. INTERPRETATION: Common, clinical findings of SRD, aside from oculogyric crises and diurnal fluctuation, are nonspecific and mimic CP with hypotonia or dystonia. Patients usually improve dramatically with treatment. Consequently, we recommend consideration of SRD not only in patients with levodopa-responsive motor disorders, but also in patients with developmental delays with axial hypotonia, and patients with unexplained or atypical presumed CP. Biochemical investigation of cerebrospinal fluid is the preferred method of initial investigation. Early diagnosis and treatment are recommended to prevent ongoing brain dysfunction.

Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect.

BACKGROUND: X-linked cerebral creatine deficiency is caused by the deficiency of the creatine transporter (CTP) encoded by the SLC6A8 gene. PATIENTS AND METHODS: We report here a series of six patients with severe CTP deficiency, four males and two females; clinical presentations include mild to severe mental retardation (6/6), associated with psychiatric symptoms (5/6: autistic behaviour, chronic hallucinatory psychosis), seizures (2/6) and muscular symptoms (2/4 males). Diagnosis was suspected upon elevated urinary creatine/creatinine (except in one of the female patients) and on a markedly decreased creatine peak on magnetic resonance spectroscopy (MRS). Diagnosis was confirmed by molecular analysis that identified four novel mutations not reported so far, including a mutation found twice in two male patients. All patients were treated successively and according to the same protocol by creatine alone then combined to its precursors, L-glycine and L-arginine for 42 months. RESULTS AND CONCLUSION: In our patients, creatine supplementation alone or with its precursors L-glycine and L-arginine showed benefit only in the muscular symptoms of the disease and no improvement in the cognitive and psychiatric manifestations and did not modify brain creatine content on MRS of male and female CTP deficient patients. New treatment strategies are required including creatine derivatives transported independently from CTP or using alternative pathways and transporters.

Newborn Analgesia Mediated by Oxytocin during Delivery.

The mechanisms controlling pain in newborns during delivery are poorly understood. We explored the hypothesis that oxytocin, an essential hormone for labor and a powerful neuromodulator, exerts analgesic actions on newborns during delivery. Using a thermal tail-flick assay, we report that pain sensitivity is two-fold lower in rat pups immediately after birth than 2 days later. Oxytocin receptor antagonists strongly enhanced pain sensitivity in newborn, but not in 2-day-old rats, whereas oxytocin reduced pain at both ages suggesting an endogenous analgesia by oxytocin during delivery. Similar analgesic effects of oxytocin, measured as attenuation of pain-vocalization induced by electrical whisker pad stimulation, were also observed in decerebrated newborns. Oxytocin reduced GABA-evoked calcium responses and depolarizing GABA driving force in isolated neonatal trigeminal neurons suggesting that oxytocin effects are mediated by alterations of intracellular chloride. Unlike GABA signaling, oxytocin did not affect responses mediated by P2X3 and TRPV1 receptors. In keeping with a GABAergic mechanism, reduction of intracellular chloride by the diuretic NKCC1 chloride co-transporter antagonist bumetanide mimicked the analgesic actions of oxytocin and its effects on GABA responses in nociceptive neurons. Therefore, endogenous oxytocin exerts an analgesic action in newborn pups that involves a reduction of the depolarizing action of GABA on nociceptive neurons. Therefore, the same hormone that triggers delivery also acts as a natural pain killer revealing a novel facet of the protective actions of oxytocin in the fetus at birth.

18F-FDG PET reveals frontotemporal dysfunction in children with fever-induced refractory epileptic encephalopathy.

UNLABELLED: Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a recently described epileptic entity whose etiology remains unknown. Brain abnormalities shown by MRI are usually limited to mesial-temporal structures and do not account for the catastrophic neuropsychologic findings. METHODS: We conducted FIRES studies in 8 patients, aged 6-13 y, using 18F-FDG PET to disclose eventual neocortical dysfunction. Voxel-based analyses of cerebral glucose metabolism were performed using statistical parametric mapping and an age-matched control group. RESULTS: Group analysis revealed a widespread interictal hypometabolic network including the temporoparietal and orbitofrontal cortices bilaterally. The individual analyses in patients identified hypometabolic areas corresponding to the predominant electroencephalograph foci and neuropsychologic deficits involving language, behavior, and memory. CONCLUSION: Despite clinical heterogeneity, 18F-FDG PET reveals a common network dysfunction in patients with sequelae due to fever-induced refractory epileptic encephalopathy.

Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).

PURPOSE: Fever induced refractory epileptic encephalopathy in school age children (FIRES) is a devastating condition initiated by prolonged perisylvian refractory status epilepticus (SE) triggered by fever of unknown cause. SE may last more than 1 month, and this condition may evolve into pharmacoresistant epilepsy associated with severe cognitive impairment. We aimed to report the effect of ketogenic diet (KD) in this condition. METHODS: Over the last 12 years we collected data of nine patients with FIRES who received a 4:1 ratio of fat to combined protein and carbohydrate KD. They presented with SE refractory to conventional antiepileptic treatment. RESULTS: In seven patients, KD was efficacious within 2-4 days (mean 2 days) following the onset of ketonuria and 4-6 days (mean 4.8 days) following the onset of the diet. In one responder, early disruption of the diet was followed by relapse of intractable SE, and the patient died. Epilepsy affected the other six responders within a few months. DISCUSSION: KD may be an alternative therapy for refractory SE in FIRES and might be proposed in other types of refractory SE in childhood.

Self-induced stretch syncope of adolescence: a video-EEG documentation.

We present the first video-EEG documentation, with ECG and EMG features, of stretch syncope of adolescence in a young, healthy 16-year-old boy. Stretch syncope of adolescence is a rarely reported, benign cause of fainting in young patients, which can be confused with epileptic seizures. In our patient, syncopes were self-induced to avoid school. Dynamic transcranial Doppler showed evidence of blood flow decrease in both posterior cerebral arteries mimicking effects of a Valsalva manoeuvre. Dynamic angiogram of the vertebral arteries was normal. Hypotheses concerning the physiopathology are discussed. [Published with video sequences].

A tarantula peptide against pain via ASIC1a channels and opioid mechanisms.

Psalmotoxin 1, a peptide extracted from the South American tarantula Psalmopoeus cambridgei, has very potent analgesic properties against thermal, mechanical, chemical, inflammatory and neuropathic pain in rodents. It exerts its action by blocking acid-sensing ion channel 1a, and this blockade results in an activation of the endogenous enkephalin pathway. The analgesic properties of the peptide are suppressed by antagonists of the mu and delta-opioid receptors and are lost in Penk1-/- mice.

Membrane potential-regulated transcription of the resting K+ conductance TASK-3 via the calcineurin pathway.

The 2P domain K(+) channel TASK-3 is highly expressed in cerebellar granule neurons where it has been proposed to underlie the K(+) leak conductance, IKso. In a previous work we showed that expression of TASK-3 increases in cerebellar granule neurons as they mature in culture. Here we show that within the cerebellum, levels of TASK-3 mRNA increase as granule neurons migrate to their adult positions and receive excitatory mossy fiber input. To understand the mechanism of this increase in TASK-3 expression we used an in vitro model culturing the neurons in either depolarizing conditions mimicking neuronal activity (25K, 25 mm KCl) or in conditions which approach deafferentation (5K, 5 mm KCl). An important increase in TASK-3 mRNA is uniquely observed in 25K and is specific since other background K(+) channel levels remain unchanged or decrease. The rise in TASK-3 mRNA leads to an increase in TASK-3 protein and the IKso conductance resulting in hyperpolarization. Blocking L-type calcium channels or their downstream effector calcineurin, abrogates TASK-3 expression and IKso, leading to hyperexcitability. This is the first study demonstrating that depolarization-induced Ca(2+) entry can directly regulate cellular excitability by dynamically regulating the transcription of a resting K(+) conductance. The appearance of this conductance may play an important role in the transition of depolarized immature neurons to their mature hyperpolarized state during neuronal development.