Magnetic resonance spectroscopy in MELAS syndrome: correlation with CSF and plasma metabolite levels and change after glutamine supplementation.

PURPOSE: MELAS syndrome is a genetic disorder caused by mitochondrial DNA mutations. We previously described that MELAS patients had increased CSF glutamate and decreased CSF glutamine levels and that oral glutamine supplementation restores these values. Proton magnetic resonance spectroscopy (1H-MRS) allows the in vivo evaluation of brain metabolism. We aimed to compare 1H-MRS of MELAS patients with controls, the 1H-MRS after glutamine supplementation in the MELAS group, and investigate the association between 1H-MRS and CSF lactate, glutamate, and glutamine levels. METHODS: We conducted an observational case-control study and an open-label, single-cohort study with single-voxel MRS (TE 144/35 ms). We assessed the brain metabolism changes in the prefrontal (PFC) and parieto-occipital) cortex (POC) after oral glutamine supplementation in MELAS patients. MR spectra were analyzed with jMRUI software. RESULTS: Nine patients with MELAS syndrome (35.8 ± 3.2 years) and nine sex- and age-matched controls were recruited. Lactate/creatine levels were increased in MELAS patients in both PFC and POC (0.40 ± 0.05 vs. 0, p < 0.001; 0.32 ± 0.03 vs. 0, p < 0.001, respectively). No differences were observed between groups in glutamate and glutamine (Glx/creatine), either in PFC (p = 0.930) or POC (p = 0.310). No differences were observed after glutamine supplementation. A positive correlation was found between CSF lactate and lactate/creatine only in POC (0.85, p = 0.003). CONCLUSION: No significant metabolite changes were observed in the brains of MELAS patients after glutamine supplementation. While we found a positive correlation between lactate levels in CSF and 1H-MRS in MELAS patients, we could not monitor treatment response over short periods with this tool. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04948138; initial release 24/06/2021; first patient enrolled on 1/07/2021. https://clinicaltrials.gov/ct2/show/NCT04948138.

Elevated glutamate and decreased glutamine levels in the cerebrospinal fluid of patients with MELAS syndrome.

BACKGROUND: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA (mtDNA) mutations in the MT-TL1 gene. The pathophysiology of neurological manifestations is still unclear, but neuronal hyperexcitability and neuron-astrocyte uncoupling have been suggested. Glutamatergic neurotransmission is linked to glucose oxidation and mitochondrial metabolism in astrocytes and neurons. Given the relevance of neuron-astrocyte metabolic coupling and astrocyte function regulating energetic metabolism, we aimed to assess glutamate and glutamine CSF levels in MELAS patients. METHODS: This prospective observational case-control study determined glutamate and glutamine CSF levels in patients with MELAS syndrome and compared them with controls. The plasma and CSF levels of the remaining amino acids and lactate were also determined. RESULTS: Nine adult patients with MELAS syndrome (66.7% females mean age 35.8 ± 3.2 years) and 19 controls (63.2% females mean age 42.7 ± 3.8 years) were included. The CSF glutamate levels were significantly higher in patients with MELAS than in controls (18.48 ± 1.34 vs. 5.31 ± 1.09 µmol/L, p < 0.001). Significantly lower glutamine concentrations in patients with MELAS than controls were shown in CSF (336.31 ± 12.92 vs. 407.06 ± 15.74 µmol/L, p = 0.017). Moreover, the CSF levels of alanine, the branched-chain amino acids (BCAAs) and lactate were significantly higher in patients with MELAS. CONCLUSIONS: Our results suggest the glutamate-glutamine cycle is altered probably due to metabolic imbalance, and as a result, the lactate-alanine and BCAA-glutamate cycles are upregulated. These findings might have therapeutic implications in MELAS syndrome.

Early-Onset Dementia Associated with a Heterozygous, Nonsense, and de novo Variant in the MBD5 Gene.

The haploinsufficiency of the methyl-binding domain protein 5 (MBD5) gene has been identified as the determinant cause of the neuropsychiatric disorders grouped under the name MBD5-neurodevelopment disorders (MAND). MAND includes patients with intellectual disability, behavioral problems, and seizures with a static clinical course. However, a few reports have suggested regression. We describe a non-intellectually disabled female, with previous epilepsy and personality disorder, who developed early-onset dementia. The extensive etiologic study revealed a heterozygous nonsense de novo pathogenic variant in the MBD5 gene. This finding could support including the MBD5 gene in the study of patients with atypical early-onset dementia.

Antisaccades and memory-guided saccades in genetic generalized epilepsy and temporal lobe epilepsy.

OBJECTIVE: Oculomotor tasks can be used to measure volitional control of behavior sensitive to frontal dysfunction. This study aimed to examine the saccadic eye movement in Genetic Generalized Epilepsy (GGE) which could correlate with the abnormality of the frontal lobe or the thalamo-frontal network. METHODS: Twenty-one patients with GGE were compared with 22 patients with Temporal Lobe Epilepsy (TLE) and 39 healthy controls. Visual-guided saccades, Antisaccades, and Memory-guided saccades as oculomotor tasks were performed using a novel gaze-tracker designed for clinical practice use. RESULTS: Patients with epilepsy (either GEE or TLE) had similar latency, accuracy, and velocity in visual-guided saccades and memory-guided saccades. Patients with epilepsy had similar latencies and correct antisaccade number. However, healthy volunteers, matched by age, had faster responses and more accurate results than patients with epilepsy. CONCLUSIONS: Our investigations did not reveal differences between TLE and GGE patients' groups in visually guided saccades, antisaccades, and memory-guided saccades, thus suggesting that the frontal cortical mechanisms responsible for them are not explicitly impaired in patients with GGE.

Clinical, genetic and quality-of-life study of a cohort of adult patients with tuberous sclerosis.

BACKGROUND AND OBJECTIVE: Tuberous sclerosis (TS) is a condition whose manifestations in childhood have been extensively described, but whose presentation in adults is less well known. This study describes the clinical and genetic characteristics, therapeutic management and quality of life of a cohort of adult patients with TS. A comparative study of the characteristics of patients diagnosed in childhood and adulthood is also carried out. MATERIAL AND METHODS: This observational, retrospective, cross-sectional study included a large cohort of adult patients (≥ 16 years old) followed for 5 years in a specific rare diseases unit. RESULTS: Fifty-seven patients with a diagnosis of tuberous sclerosis were included, more than 50% of whom were diagnosed as adults. The mean age of the patients was 42 years (20-86). The central nervous system was the main area affected (97%), followed by the skin (80.7%) and kidneys (73%). The most frequent genetic alteration was a mutation in the TSC2 gene (47.7%). Among patients diagnosed in adulthood, there was less neurological involvement, with less frequency of epileptic seizures (30.8% vs 60.79% of patients diagnosed in childhood) and astrocytomas (3.8% vs 53.6%), less intellectual disability (11.5% vs 71.4%) and less expressiveness of the condition. 42% of patients were treated with mTOR pathway inhibitors, and presence of an angiomyolipoma was the main indication. In a quality-of-life analysis, the means of the summary indices were below the scores of the average Spanish population: (47.42 (SD ± 9.82) on the physical health scale, 45.61 (SD ± 7.99) on the mental health scale) versus 50 (SD ± 10) for the general population. CONCLUSIONS: Up to 50% of adult patients with TS were diagnosed in adulthood, and the condition is less severe with less frequent epileptic seizures and intellectual disability. 42% require treatment with mTOR inhibitors, in most cases due to the presence of AMLs. The quality of life of adult patients with TS is diminished compared to the general population.

Accelerated forgetting in temporal lobe epilepsy: When does it occur?

OBJECTIVE: The main goal of the study was to analyse differences in the forgetting rates of Temporal Lobe Epilepsy (TLE) patients at different intervals (30 sec, 10 min, 1 day and 1 week) compared with those of healthy controls. A secondary aim of this research was to provide an assessment of the relationship between clinical epilepsy-related variables and forgetting rates in TLE patients. METHOD: The sample was composed of 14 TLE patients and 14 healthy matched controls. All participants underwent a full standardised neuropsychological assessment including general intelligence, executive functioning, memory, language and other variables, such as depression, anxiety or everyday memory failures. Two specific memory tasks, consisting of cued recall of 4 short stories and 4 routes, were carried out at four different intervals. RESULTS: There was a significant difference between groups at 10-min interval on the stories task, with the TLE group displaying greater forgetting than healthy controls. None of the other intervals on either task showed significant group differences. No differences were found when controlling for clinical epilepsy-related variables. CONCLUSION: Forgetting of verbal information at 10 min was greater in patients with TLE compared with controls, but accelerated longer term forgetting was not found. This study suggests that a late consolidation process is not necessarily impaired in TLE patients.

Acute hypokinetic-rigid syndrome following SARS-CoV-2 infection.

OBJECTIVE: To report a case of a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who acutely developed a hypokinetic-rigid syndrome. METHODS: Patient data were obtained from medical records from the Hospital Universitario 12 de Octubre in Madrid, Spain. [123I]-ioflupane dopamine transporter (DaT) SPECT images were acquired 4 hours after a single dose of 185 MBq of 123I-FP-CIT. Quantitative analysis was performed with DaTQUANT software providing the specific binding ratio and z score values of the striatum. RESULTS: We report a previously healthy 58-year-old man who developed hyposmia, generalized myoclonus, fluctuating and transient changes in level of consciousness, opsoclonus, and an asymmetric hypokinetic-rigid syndrome with ocular abnormalities after a severe SARS-CoV-2 infection. DaT-SPECT confirmed a bilateral decrease in presynaptic dopamine uptake asymmetrically involving both putamina. Significant improvement in the parkinsonian symptoms was observed without any specific treatment. CONCLUSION: This case study provides clinical and functional neuroimaging evidence to support that SARS-CoV-2 can gain access to the CNS, affecting midbrain structures and leading to neurologic signs and symptoms.

Generalized myoclonus in COVID-19.

OBJECTIVE: To report 3 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who developed generalized myoclonus. METHODS: Patient data were obtained from medical records from the University Hospital "12 de Octubre," Madrid, Spain. RESULTS: Three patients (2 men and 1 woman, aged 63-88 years) presented with mild hypersomnia and generalized myoclonus following the onset of the so-called inflammatory phase of coronavirus disease 2019 (COVID-19). All of them had presented previously with anosmia. Myoclonus was generalized with both positive and negative jerks, predominantly involving the facial, trapezius, sternocleidomastoid, and upper extremities muscles. These myoclonic jerks occurred spontaneously and were extremely sensitive to multisensory stimuli (auditive and tactile) or voluntary movements, with an exaggerated startle response. Other causes of myoclonus were ruled out, and none of the patients had undergone respiratory arrest or significant prolonged hypoxia. All of them improved, at least partially, with immunotherapy. CONCLUSIONS: Our 3 cases highlight the occurrence of myoclonus during the COVID-19 pandemic as a post- or para-infectious immune-mediated disorder. However, we cannot rule out that SARS-CoV-2 may spread transneuronally to first- and second-order structures connected with the olfactory bulb. Further investigation is required to clarify the full clinical spectrum of neurologic symptoms and optimal treatment.

Mechanical vibration does not systematically reduce the tremor in essential tremor patients.

Essential tremor (ET) is a major cause of disability and is not effectively managed in half of the patients. We investigated whether mechanical vibration could reduce tremor in ET by selectively recruiting afferent pathways. We used piezoelectric actuators to deliver vibratory stimuli to the hand and forearm during long trials (4 min), while we monitored the tremor using inertial sensors. We analyzed the effect of four stimulation strategies, including different constant and variable vibration frequencies, in 18 ET patients. Although there was not a clear homogeneous response to vibration across patients and strategies, in most cases (50-72%) mechanical vibration was associated with an increase in the amplitude of their tremor. In contrast, the tremor was reduced in 5-22% of the patients, depending on the strategy. However, these results are hard to interpret given the intrinsic variability of the tremor: during equally long trials without vibration, the tremor changed significantly in 67% of the patients (increased in 45%; decreased in 22%). We conclude that mechanical vibration of the limb does not have a systematic effect on tremor in ET. Moreover, the observed intrinsic variability of the tremor should be taken into account when designing future experiments to assess tremor in ET and how it responds to any intervention.

Peripapillary retinal nerve fibre layer thinning in genetic generalized epilepsy.

PURPOSE: The purpose of this study was to compare the peripapillary retinal nerve fibre layer (RNFL) between patients with genetic generalized epilepsy (GGE) and healthy controls. METHODS: This prospective observational study was conducted on adults aged 18-60 years. The study group comprised 26 consecutive patients who met the inclusion criteria and 26 healthy age- and sex-matched healthy adults. Peripapillary RNFL thickness was measured by spectral domain optical coherence tomography. RESULTS: The average peripapillary RNFL thickness was significantly thinner for GGE patients (98.61 µm) than for healthy controls (104.77 µm) (p = 0.016). Similar results were obtained for the left eye. The peripapillary RFNL thickness of all quadrants was lower for GGE patients than for healthy controls, but it was significant only in the superior (p = 0.009) and inferior (p = 0.024) quadrants for both eyes. CONCLUSIONS: Our results suggest that the peripapillary RNFL is significantly thinner in GGE patients than in healthy participants. We concluded that this microstructural feature might be an intrinsic feature of GGE.

A new MR radiological sign in HaNDL syndrome. A case report.

BACKGROUND: One of the classical diagnostic criteria of the syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL syndrome) is the normality of imaging studies except from some reversible alterations as leptomeningeal enhancement or focal hypoperfusion. CASE: We present a 41 year-old man who abruptly started with a set of right parietal symptoms, meeting the diagnostic criteria for HaNDL syndrome. An electroencephalographic record showed a slowing of the right hemisphere. MR susceptibility weighted sequences demonstrated a reduced venous signal in the symptomatic hemisphere, unlike other transient disorders as migraine aura where an opposite pattern with prominence of the venous structures in the symptomatic hemisphere has been reported. This sign could reflect a decrease in metabolic demands or a fail in oxygen employment by the affected tissue. CONCLUSION: To our knowledge, this finding has not been described yet, and it may provide a new insight on the pathogenesis of HaNDL syndrome.

Long-term forgetting in temporal lobe epilepsy: Is this phenomenon a norm?

OBJECTIVES: This research investigated forgetting rates of patients with temporal lobe epilepsy (TLE) at brief and longer intervals. METHODS: The sample is formed by 5 patients with TLE and 10 healthy individuals. One of the patients received the diagnosis of transient epileptic amnesia (TEA). All patients underwent a standardized clinical protocol for diagnosis including a comprehensive neuropsychological assessment. In addition, two experimental tasks were used to assess the forgetting rates at 4 intervals (30s, 10min, 1day, and 1week): a story task to evaluate verbal cued recall and a route task to assess visuospatial cued recall. RESULTS: There were no significant differences between groups in forgetting rates. CONCLUSIONS: These findings suggest that forgetting patterns in patients with TLE may be heterogeneous, and the presence of accelerated long-term forgetting is not universal.

NEOPLASM study: Real-life use of lacosamide in patients with brain tumor-related epilepsy.

BACKGROUND: The choice of antiepileptic drug (AED) therapy in patients with brain tumor-related epilepsy (BTRE) is complicated, and there are a lack of robust clinical trial data to date. METHODS: The NEOPLASM (Neuroncologic Patients treated with LAcoSaMide) study was a 6-month, multicenter, retrospective, observational study in patients with BTRE treated with lacosamide. Patients were started on lacosamide because of a lack of efficacy or adverse events (AEs) with prior AEDs or suitability versus other AEDs, according to clinical practice. The primary efficacy variable was the seizure-free rate at 6months. Safety variables included the proportion of patients with an AE and the proportion with an AE that led to discontinuation. RESULTS: Overall, 105 patients from 14 hospital centers were included in the analysis. Treatment with lacosamide for 6months resulted in a 30.8% seizure-free rate, and 66.3% of patients had a ≥50% seizure reduction (responders). In the subset of patients included because of a lack of efficacy with prior AEDs, seizure-free rates were 28.0%, and 66.7% of patients were responders. No statistically significant differences in efficacy were observed according to the mechanism of action or enzyme-inducing properties of concomitant AEDs. Adverse events were reported by 41.9% of patients at 6months, and 4.7% of them led to discontinuation. The most common AEs were somnolence/fatigue and dizziness. Notably, 57.1% of the patients who were switched to lacosamide because of AEs with their previous therapy did not report any AE at 6-month follow-up. CONCLUSIONS: In this open-label, observational study, lacosamide appeared to be effective and well tolerated in a large population of patients with BTRE. Lacosamide may therefore be a promising option for the treatment of patients with BTRE.

Análisis del estado nutricional y composición corporal de personas con discapacidad intelectual / Analysis of the nutritional status and body composition of persons with intellectual disability

Introducción. La discapacidad intelectual, definida como limitaciones sustanciales en el funcionamiento intelectual, afecta al 0,7-1,5% de la población. Estas personas presentan mayores tasas de obesidad, y sus valores calóricos y estado nutricional son deficientes. Objetivos. Conocer los hábitos nutricionales, analizar la eficacia de la educación nutricional y evaluar la posible mejora, introduciendo talleres de ejercicio físico y nutrición, en la discapacidad intelectual. Pacientes y métodos. Se realizó una valoración clínica, nutricional y antropométrica (peso, talla, índice de masa corporal, grasa corporal, perímetro de la cintura) a 47 sujetos con discapacidad intelectual. Se registraron los hábitos deportivos, la historia clínica y la historia dietética mediante un registro alimentario y un cuestionario de adhesión a la dieta mediterránea (KidMed). Los talleres de nutrición y ejercicio físico contaron con una estructura de explicación teórica, práctica y juegos. Resultados. El 76,1% presentaba exceso ponderal en el inicio del estudio. Tras la intervención, los valores de grasa corporal (-0,94 ± 4,4%) y grasa visceral (-0,86 ± 2%), así como el peso (-0,4 ± 3,3 kg) y el índice de masa corporal (-0,2 ± 1,6 kg/m2), disminuyeron, más en las mujeres que en los hombres. El 60,5% no cumplía con una alta adhesión a la dieta mediterránea. Tras la intervención, se observó una diferencia significativa (p ≤ 0,001) en la puntuación del KidMed. El taller de actividad física tuvo efectos positivos sobre la antropometría. Conclusiones. La alimentación fue inadecuada en la mayoría de los individuos. La prevalencia de obesidad fue elevada. Los talleres de educación nutricional y de ejercicio son una herramienta útil para trabajar con este colectivo, y consiguen cambios significativos para prevenir la obesidad y mejorar su salud (AU)

Introduction. Intellectual disability refers to substantial limitations in intellectual functioning, affecting 0.7-1.5% of the population. People with intellectual disability have higher rates of obesity, since caloric values and nutritional status, are deficient. Aims. To determine the nutritional habits, analyze the effectiveness of nutritional education and evaluate the possible effect of improvement introducing exercise and nutrition workshops, in a group of people with intellectual disability. Patients and methods. Clinical, nutritional and anthropometric (weight, height, body mass index, body fat, waist circumference) assessment was conducted in 47 patients. An ad hoc survey was designed in which exercise habits, medical and dietary history, record of 72 hours (including 2 weekdays and 1 weekend) and the adherence to Mediterranean diet data were collected. The workshops of exercise and nutrition counted with a structure of theoretical-practical explanation and games. Results. 76.1% presented weight excess at baseline. After the intervention values of total body fat (-0.94 ± 4.4%) and visceral fat (-0.86 ± 2%), weight (-0.4 ± 3.3 kg) and body mass index (-0.2 ± 1.6 kg/m2) decreased, more in women than in men. 60.5% of subjects did not meet a high adherence to the Mediterranean diet. After nutritional intervention, a significant difference (p ≤ 0,001) was observed in the KidMed score. The workshop of physical activity had positive effects on the anthropometry of subjects. Conclusions. Both the intake and the prevalence of obesity in this group of people are inadequate. Nutritional education and physical exercise workshops are useful for working with this group, achieving significant changes to prevent obesity and improve their health (AU)