Respiratory phenotypes in amyotrophic lateral sclerosis as determined by respiratory questions on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised and their relation to respiratory tests

Background and purpose

Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). Respiratory symptoms are scored in questions Q10 (dyspnoea) and Q11 (orthopnoea) of the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The association of respiratory test alterations with respiratory symptoms is unclear.

Methods

Patients with ALS and progressive muscular atrophy were included. We retrospectively recorded demographic data, ALSFRS-R, forced vital capacity (FVC), maximal inspiratory (MIP) and expiratory (MEP) pressures, mouth occlusion pressure at 100 ms, nocturnal oximetry (SpO₂mean), arterial blood gases, and phrenic nerve amplitude (PhrenAmpl). Three groups were categorized: G1, normal Q10 and Q11; G2, abnormal Q10; and G3, abnormal Q10 and Q11 or only abnormal Q11. A binary logistic regression model explored independent predictors.

Results

We included 276 patients (153 men, onset age = 62.6 ± 11.0 years, disease duration = 13.0 ± 9.6 months, spinal onset in 182) with mean survival of 40.1 ± 26.0 months. Gender, onset region, and disease duration were similar in G1 (n = 149), G2 (n = 78), and G3 (n = 49). Time to noninvasive ventilation (NIV) was shorter in G3 (p < 0.001), but survival was similar. ALSFRS-R subscores were significantly different (G1 > G2 > G3, p < 0.001), except for lower limb subscore (p = 0.077). G2 and G3 patients were older than G1 (p < 0.001), and had lower FVC, MIP, MEP, PhrenAmpl, and SpO₂mean. Independent predictors for G2 were MIP and SpO₂mean; for G3, the only independent predictor was PhrenAmpl.

Conclusions

These three distinct ALS phenotypic respiratory categories represent progressive stages of ventilatory dysfunction, supporting ALSFRS-R clinical relevance. Orthopnoea is a severe symptom that should prompt NIV, phrenic nerve response being an independent predictor. Early NIV promotes similar survival for G2 and G3.     

Effect of stimulation intensity on assessment of voluntary activation

Introduction: Although it is known that continuous noninvasive ventilation (CNIV) can prolong life in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), in this study we explore similar claims for diaphragm pacing (DP). Methods: NIV and DP users' vital capacities (VCs) over time and duration of NIV and CNIV dependence were analyzed for 354 non‐DP and 8 DP ALS/MND patients. Results: Patients had a higher rate of monthly VC decline before NIV use (5.1 ± 7.6%) than during NIV use (2.5 ± 3.6%) (P < 0.01, 95% CI 0.84–4.5); the decline for 4 DP users was 3.7–20%. Fifty‐five ALS/MND patients used part‐time NIV for 19.9 ± 27.6 months until tracheostomy/death, whereas 113 others used it for 10.9 ± 10.5 months until CNIV dependence for another 12.8 ± 16.2 months. After placement, 7 DP users were CNIV dependent in 8.0 ± 7.0 months, whereas 6 underwent tracheostomy/died in 18.2 ± 13.7 months. Conclusions: CNIV prolonged the survival of 113 of the 354 non‐DP and 6 DP ALS/MND patients by 12.8 and 10.2 months, respectively. DP provided no benefit on VC or mechanical ventilation–free survival. Muscle Nerve, 2012     

Pulmonary function tests and diaphragmatic compound muscle action potential in patients with sporadic amyotrophic lateral sclerosis

Sathyaprabha TN, Pradhan C, Nalini A, Thennarasu K, Raju TR. Pulmonary function tests and diaphragmatic compound muscle action potential in patients with sporadic amyotrophic lateral sclerosis.
Acta Neurol Scand: 2010: 121: 400–405.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Background – Respiratory failure is the primary cause of death in patients with amyotrophic lateral sclerosis (ALS). Diaphragmatic compound muscle action potentials (DCMAP) are valid parameters to assess the respiratory muscle innervation. Aim – In this study we propose to establish evidence of pulmonary dysfunction in patients with ALS and its relation to DCMAP parameters among patients with sporadic ALS. Materials and methods – Twenty nine patients (M‐20, F‐9) diagnosed to have sporadic ALS by El. Escorial criteria, without symptoms of pulmonary dysfunction, and able to perform the PFT satisfactorily, were studied. Thirty controls (M‐20, F‐10) were selected from patient’s relatives. Forced vital capacity (FVC), forced expiratory volume in one second (FEV₁), peak expiratory flow rate (PEFR) and maximum voluntary ventilation (MVV) were measured by spirometry. Maximum expiratory pressure (MEP) was measured by digital peak pressure monitor. Right phrenic nerve conductions (DCMAP) were performed and the latencies and amplitude of diaphragmatic com‐pound action potential (DCMAP) was recorded in controls and ALS patients. Results – The mean age of patients was 51.41 ± 10.72 years (37–82) and control was 53.57 ± 8.85 years (30–68). None of the patients had symptoms or clinical evidence of respiratory dysfunction. The FVC, FEV1, PEFR, MVV, MIP and MEP were significantly (P < 0.001) reduced in ALS. The mean DCMAP amplitude was reduced among patients (610 ± 506.231 μv) as compared to controls (1303.33 ± 584.56, P < 0.001) and mean latency was increased in patients (9.73 ± 2.57 ms) compared to controls (7.69 ± 0.87, P = 0.001). There was significant negative correlation between PFTs and latencies of DCMAP. Amplitude of DCMAP did not correlate with PFTs. Conclusion – There is significant negative correlation between DCMAP latencies and PFTs suggesting early loss of myelinated fibres and diaphragmatic dysfunction. DCMAP latencies may be a good indicator of early respiratory muscle involvement and also of disease progression in ALS.     

Pressure support versus assisted controlled noninvasive ventilation in neuromuscular disease

Introduction: Noninvasive ventilation (NIV) is being increasingly used in patients with chronic neuromuscular disorders, but the optimal ventilation mode remains unknown. We compared physiological short-term effects of assist/controlled ventilation (ACV) and two pressure-limited modes (pressure-support ventilation [PSV] and assist pressure-controlled ventilation [ACPV]) in patients with neuromuscular disease who needed NIV. Methods: Tidal volume was 10 to 12 mL/kg. The ACPV mode used the same respiratory cycle timing as the volume-limited mode. The level of inspiratory support was set to achieve the same tidal volume during the other ventilatory modes. Results: Thirteen patients with neuromuscular disease who met international criteria for NIV were included. The three ventilatory modes increased alveolar ventilation and decreased respiratory effort indices. However, no difference in breathing or respiratory effort was found among the three modes, with the exception that inspiratory peak flow and percentage of triggered cycles were higher during PSV than volume-limited ventilation. Interestingly, no relationship was observed between subjective patient preference and inspiratory effort indices or percentage of triggered cycles. Conclusion: In chronic, stable patients with neuromuscular disease, both noninvasive ACV, ACPV, and PSV had similar effects on alveolar ventilation and respiratory muscle unloading, despite some differences in the pattern of breathing and percentage of triggered cycles.     

Relationship between respiratory failure and plasma noradrenaline levels in amyotrophic lateral sclerosis

We evaluated plasma noradrenaline (NA) levels at rest and during head-up tilt test in 20 patients with sporadic amyotrophic lateral sclerosis (ALS). Their fasting plasma NA levels ranged from 195 to 4227 pg/ml. The average plasma NA level was 483 pg/ml in five ambulatory patients, 341 in two wheelchair-bound patients, 1264 in 11 bedridden patients, and 208 in two respirator-dependent patients whose disability grading was the worst among the four groups. Arterial carbon dioxide (PCO₂) was evaluated as a measure of respiratory function. The coefficient of correlation between PCO₂ and plasma NA wasr=0.654 (p<0.01). Either respiratory failure or lower motor neuron dysfunction may relate to the elevation of plasma NA levels. In the two bedridden patients, plasma NA levels and heart rate at rest increased significantly as the disease progressed. Cardiovascular responses to head-up tilting were normal. These data suggest that the elevation of plasma NA levels may be related to progression of respiratory failure and lower motor neuron dysfunction. In conclusion, sympathetic hyperactivity in ALS is considered to be not primary, but secondary to somatic motor disabilities and respiratory failure.     

Noninvasive and invasive ventilation and enteral nutrition for ALS in Italy

Introduction: We performed a population‐based study to assess amyotrophic lateral sclerosis (ALS) survival after noninvasive ventilation (NIV), invasive ventilation (IV), and enteral nutrition (EN). Methods: We included patients diagnosed from 2000 to 2009 in Modena, where a prospective registry and a Motor Neuron Diseases Centre have been active since 2000. Results: Of the 193 incident cases, 47.7% received NIV, 24.3% received tracheostomy, and 49.2% received EN. A total of 10.4% of the patients refused NIV, 31.6% refused IV, and 8.7% refused EN. The median survival times after NIV, IV, and EN were 15, 19, and 9 months, respectively. Of the tracheostomized patients, 79.7% were discharged from the hospital; 73.0% were discharged to home. The median survival times for tracheostomized patients who were cared for at home and in nursing homes were 43 and 2 months, respectively. The multivariate analysis demonstrated that the place of discharge was the only independent prognostic factor after IV (P < 0.01). Conclusions: Service organizations may promote adherence to NIV, IV, EN, and influence postprocedure survival. These data may be useful in defining health plans regarding advanced ALS care and in patient counseling. Muscle Nerve 50: 508–516, 2014     

Predictors of noninvasive ventilation tolerance in patients with amyotrophic lateral sclerosis

Noninvasive ventilation (NIV) appears to improve survival and quality of life in patients with amyotrophic lateral sclerosis (ALS), but little is known about predictors of NIV tolerance. NIV use was assessed and clinical predictors of tolerance were investigated, using predictive modeling, in ALS patients diagnosed and followed in our clinic until death over a 4-year time period. Patients were prescribed NIV based on current practice parameters when respiratory symptoms were present or forced vital capacity was less than 50%. We prescribed NIV in 52% (72) of patients. For those prescribed NIV, information regarding tolerance was available for 50 patients, with 72% (36) tolerant to its use. Tolerance was six times more likely in limb-onset than bulbar-onset ALS patients, with a trend toward reduced tolerance in those with lower forced vital capacity at NIV initiation. Age, gender, and duration of disease were not predictors of NIV tolerance. We conclude that a majority of ALS patients who are prescribed NIV can successfully become tolerant to its use.     

Respiratory therapies for amyotrophic lateral sclerosis: A primer

Respiratory complications are a common cause of morbidity and mortality in amyotrophic lateral sclerosis (ALS). Treatment of respiratory insufficiency with noninvasive ventilation (NIV) improves ALS patients' quality of life and survival. Evidence-based practice guidelines for the management of ALS patients recommend treatment of respiratory insufficiency with NIV as well as consideration of insufflation/exsufflation to improve clearance of airway secretions. Despite these recommendations respiratory therapies remain underused. In this review we provide a practical guide for the clinician to prescribe and manage respiratory therapies for the patient with ALS. Muscle Nerve 46: 313-331, 2012.     

Pulmonary evaluation and prevalence of non-invasive ventilation in patients with amyotrophic lateral sclerosis: a multicenter survey and proposal of a pulmonary protocol.

In order to evaluate the current standard of care for the management of respiratory failure in patients with amyotrophic lateral sclerosis (ALS), a questionaire was mailed to the Medical Directors of 48 multidisciplinary ALS centers in the United States. Twenty centers reported information on 2357 patients, mean of 124 patients per center. Pulmonary function tests were performed at each visit in 17/20 institutions. Arterial blood gases, maximal expiratory pressures and maximal inspiratory pressures were followed in three centers and serum chloride was monitored in only four centers. The use of non-invasive ventilation (NIV) was extremely variable (range 0-50%) and included 360 patients (15%). The majority of centers used symptoms/signs of hypoventilation and worsening forced vital capacity (FVC) to initiate NIV with no established protocol. A FVC between 20 and 40% was used by most centers to initiate NIV. Due to great variability in the approach to monitoring pulmonary function among ALS centers and the modest effects of current medications to slow disease progression, we propose the use of a structured protocol which can prospectively study the role of NIV in prolonging survival and improving quality of life.     

Modification in swallowing and ventilation co‐ordination during hypercapnia,hypoxia, and tachypnea in unrestrained animals

Background It has been demonstrated that aspirations could occur during respiratory failure, explained by a lack of co‐ordination between swallowing and ventilation. To test this hypothesis, we examined the co‐ordination of ventilation and swallowing in a completely unrestrained rat model during different level of hypercapnia, during hypoxia, and during tachypnea. Methods A total of 50 male Wistar rats (250–350 g) were studied in a barometric plethysmograph to analyze swallowing and ventilation during swallowing, at different gas concentration [room air (G1), 10% of O₂ and 0% of CO₂ (G2), 21% of O₂ and 5% of CO₂ (G3), 21% of O₂ and 10% of CO₂ (G4), tachypnea (G5)]. Key Results During hypoxia, there was no difference between G2 and G1 regarding the swallowing parameters and ventilatory parameters. During hypercapnia, there was an increase in swallowing during inspiration in G4 (16 ± 20%P < 0.01) compared with G1. The analysis of ventilatory parameters during swallowing showed an increase in tidal volume (VT) and mean inspiratory time (VT/TI) (P < 0.001) with no change in respiratory cycle duration (TTOT), inspiratory time (TI), and expiratory time (TE) when compared with G1. During tachypnea (G5), the VT decreased (P < 0.05) without any change in VT/TI. Conclusions & Inferences Our results on animal demonstrated that hypercapnia increased swallowing during inspiration, which was not the case for tachypnea or hypoxia, and could explain some aspirations during respiratory failure.     

Soluble VEGFR1 (sVEGFR1) as a novel marker of amyotrophic lateral sclerosis (ALS) in the North Indian ALS patients

Background and purpose: North Indian patients with amyotrophic lateral sclerosis (ALS) exhibit substantially extended survival time after onset of the disease as compared to their Western counterparts. Earlier, we found that vascular endothelial growth factor‐A (VEGF‐A) may be associated with increased survival of these patients. We now measured soluble vascular endothelial growth factor receptor‐1 (sVEGFR1), an inhibitor receptor for VEGF‐A, in these patients with ALS. Methods: Patients with sporadic ALS (n = 36) attending the Neurology Outpatient at Post Graduate Institute of Medical Education and Research (PGIMER) at Chandigarh were included on the basis of El Escorial criteria. The sVEGFR1 levels were analyzed in serum of these patients using enzyme‐linked immunosorbent assay (ELISA) and compared with normal controls (n = 36). Results: Soluble vascular endothelial growth factor receptor‐1 was found to be decreased significantly in serum of patients with ALS. Serum obtained from definite ALS revealed significantly lower sVEGFR1 as compared to probable ALS. However, there was no difference in serum sVEGFR1 levels between male and female patients with ALS. Conclusions: Soluble vascular endothelial growth factor receptor‐1 downregulation may result in increased serum VEGF‐A reported previously in our patients with ALS and may indicate the activation of compensatory mechanism in response to neurodegeneration. The lower serum sVEGFR1 levels may have a possible clinicopathological association, if not causal, to the extended survival of North Indian patients with ALS; however, the result needs further investigations particularly in comparable Caucasian ALS population.     

Amyotrophic lateral sclerosis: gender differences in the use of mechanical ventilation

Background and purpose: Invasive and non‐invasive mechanical ventilation are therapeutic options in patients with amyotrophic lateral sclerosis (ALS). Related to known national ALS incidence figures, the study aims to examine gender aspects versus physiological data in patients with ALS commencing mechanical ventilation. Methods: Data from two nationwide registers involving all patients with ALS in Norway and Sweden who started invasive and non‐invasive mechanical ventilation during 2002–2007. Results: The total ALS population on invasive and non‐invasive mechanical ventilation comprised n = 308 subjects [Norway n = 96 (72% men), Sweden n = 212 (69% men)]. Compared to Swedish ALS incidence figures, our finding of a male/female ratio of 2.3/1 in patients with ALS on invasive and non‐invasive mechanical ventilation shows a statistically significant male predominance in the use of mechanical ventilation (P‐value 0.0084 Chi square). Only 6.7% of men and 3.8% of women had invasive (via tracheotomy) ventilation (P = 0.344). Initiation of mechanical ventilation was acute (not planned) in 18% of patients (no gender difference). Age distribution (mean age 62), pulmonary function tests (FVC%pred, FEV₁%pred), daytime blood gas analyses (PaO₂, PaCO₂) and survival revealed no statistically significant gender differences. Conclusion: In Norwegian and Swedish patients with ALS on invasive and non‐invasive mechanical ventilation, two‐thirds were men. Associated with known national ALS male/female incidence figures, our finding shows that statistically significantly more men than women with ALS are using mechanical ventilation. Physiological data and survival were equal in both genders. This may indicate the need for a more aggressive approach to stimulate mechanical ventilation in female patients with ALS.     

UK physicians’ attitudes and practices in long-term non-invasive ventilation of Duchenne Muscular Dystrophy

Previous studies have shown that long-term non-invasive ventilation (NIV) is not always routinely offered by all physicians in Duchenne Muscular Dystrophy (DMD), despite evidence that this treatment improves quality of life and survival. This study examined UK physicians’ practices related to respiratory follow-up and DMD ventilation. A mailed questionnaire was used. Thirty-eight of the 59 (64%) UK physicians identified via the Muscular Dystrophy Campaign (MDC) responded. Eighty-one per cent of respondents felt ethically obliged to discuss NIV with families while 13% believed that NIV results in poor quality of life. Forty-seven per cent of physicians discuss in-depth the use of NIV when the patient is in respiratory failure. Eighty-four ventilated DMD patients in the respondents’ practice use NIV (via Bi-Pap Nasal mask). Nearly 66% of physicians do not consider the public cost to be an impediment to offering NIV, despite significant problems with resources’ allocation in their area. While the majority of UK physicians have comparable attitudes and practices regarding NIV, the questionnaire highlighted that not all specialists were aware of the existence of consensus guidelines regarding respiratory monitoring. In addition, different practices of disclosure of life-prolonging ventilation options were used by different physicians. Seventy-one per cent of physicians wished for national consensus guidelines for different DMD age groups.

Estudios previos han demostrado que la ventilación no invasiva a largo plazo (NIV) no siempre es ofrecida en forma rutinaria por todos los médicos a los pacientes con Distrofia Muscular de Duchenne (DMD), a pesar de existir evidencia de que este tratamiento mejora la calidad de vida y la sobrevivencia. Examinamos las prácticas de los médicos del Reino Unido en relación al control y el seguimiento de la respiración y la ventilación en pacientes con DMD. Se utilizó un cuestionario por correo. Solo 38 de los 59 (64%) médicos del Reino Unido, identificados a través de la Campaña de Distrofia Muscular (MDC), respondieron. 81% de los que respondieron se sintieron obligados éticamente a discutir NIV con las familias, mientras que el 13% creían que la NIV daba como resultado una pobre calidad de vida. 47% de los médicos discutieron a profundidad el uso de la NIV cuando el paciente se encuentra en falla respiratoria. 84 pacientes con DMD y con asistencia ventilatoria en la consulta de los médicos que respondieron, usaban NIV (a través de una mascara nasal Bi-Pap). Casi el 66% de los médicos no consideraban el costo al público como un impedimento para ofrecer a la NIV, a pesar de haber problemas significativos en la asignación de recursos en el área. A pesar de que la mayoría de los médicos del Reino Unido tenían practicas y actitudes comparables en relación al NIV, el cuestionario resaltó que no todos los especialistas estaban conscientes de la existencia de guías consensuadas en relación al monitoreo respiratorio. Además diferentes médicos usaban formas diferentes de brindar la información acerca de las opciones de ventilación para prolongar la vida. 71% de los médicos expresaban su deseo por guías consensuadas a nivel nacional para los diferentes grupos de edades con DMD.

Palabras clave: ventilación mecánica, creencias médicas, Distrofia Muscular de Duchenne.

Abreviaturas: DMD: Distrofia Muscular de Duchenne, LTV: Ventilación a largo plazo, NIV: Ventilación no invasiva, MDC: Campaña de Distrofia Muscular, FUC: Capacidad vital forzada.     

Electrical and mechanical properties of skeletal muscle underlying increased fatigue in patients with amyotrophic lateral sclerosis

To investigate the mechanical efficiency of surviving motor units of anterior tibial muscle in patients with amyotrophic lateral sclerosis (ALS), we studied motor unit action potentials, muscle force, and muscle fatigability in patients with ALS and controls using 25 min of low to moderate intensity voluntary isometric exercise. During exercise, tetanic force (TF) and maximum voluntary contraction declined more in patients than in controls. The mean motor unit action potential duration, amplitude, and polyphasia were increased in patients compared to controls but did not change during 9 months of disease progression. The enlarged motor units in patients were negatively correlated to the muscle force and positively correlated to muscle fatigability. Furthermore, after a mean follow-up period of 9 months, the decline in force-generating capacity of the anterior tibial muscle in patients (twitch tension by 37.5 ± 11.2%, TF by 30.6 ± 7.4%) was greater than the decline in the amplitude of the compound muscle action potential (21.1 ± 8.8%, P < 0.05), suggesting a relative dissociation between electrical and mechanical properties. In conclusion, the enlarged motor units in patients with ALS are mechanically less efficient and fatigue relatively more than in healthy muscles, possibly due to an abnormality that is primarily distal to the muscle membrane. © 1996 John Wiley & Sons, Inc.     

The Role of Non-invasive Ventilation and Factors Predicting Extubation Outcome in Myasthenic Crisis

Introduction  Myasthenic crisis is a great threat to patients with myasthenia gravis. Usage of non-invasive ventilation (NIV) to prevent intubation and timing of extubating of patients in myasthenic crisis are important issues though not well documented. Methods  To explore the factors predicting NIV success and extubation outcome in myasthenic crisis, we reviewed the records of 41 episodes of myasthenia crisis. Results  NIV was applied to 14 episodes of myasthenic crisis and eight (57.1%) of them were successfully prevented from intubation. An Acute Physiology and Chronic Health Evaluation (APACHE) II score of <6 and a serum bicarbonate level of <30 mmol/l were independent predictors of NIV success. For patients undergoing invasive mechanical ventilation, extubation failure was observed in 13 (39.4%) of 33 episodes, and the most common cause was sputum impaction due to a poor cough strength (61.5%). A maximal expiratory pressure (Pemax) of ≥40 cmH₂O was a good predictor of extubation success. Extubation failure led to poorer outcomes. Conclusions  NIV may be applied to those patients with a low APACHE II score and a lesser degree of metabolic compensation for respiratory acidosis. For patients undergoing invasive mechanical ventilation, extubation failure is associated with significant in-hospital morbidity in myasthenic crisis. Adequate levels of Pemax and cough strength correlate significantly with extubation success.     

Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive cell death of upper and lower motor neurons. In this study, we measured monocyte chemotactic protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) levels in cerebrospinal fluid (CSF) and serum by enzyme-linked immunosorbent assay (ELISA) in 42 ALS patients, and compared these levels with those of control subjects with other neurodegenerative disorders or with those of normal controls. MCP-1 levels in CSF were significantly higher in ALS patients than in the control group. VEGF levels in CSF tended to be lower in ALS patients than in the control group, but not significantly. A positive correlation was found between MCP-1 levels in CSF of ALS patients and the total Norris scale. The elevation of MCP-1/VEGF ratio in CSF was more specific to ALS patients compared to other neurological diseases such as Parkinson's disease (PD) and spinocerebellar ataxia (SCA) and to controls. Our data suggested that both MCP-1 levels and MCP-1/VEGF ratio in CSF may be useful markers for the clinical diagnosis of ALS.     

Hyperhomocysteinemia and schizophrenia: case control study

Objectives

Homocysteine (Hcys) is a sulphur-containing amino acid that has been widely investigated for its putative role in neuropsychiatric disorders. Elevated plasma homocysteine levels have been associated with schizophrenia. Among other factors, low folate and vitamin B12 levels have been implicated in the increase in homocysteine. The aim of the study was to determine plasma Hcys, folate and vitamin B12, and the frequency and severity of hyperhomocysteinemia in patients with schizophrenia, and to investigate the association between Hcys and clinical features and its relationship with folate and vitamin B12 levels.

Methods

This was a case-control study carried out on 61 (54 males and seven females, mean age = 33.3 ± 9.2) inpatients with chronic schizophrenia according to DSM-IV criteria and 46 (25 males and 21 females, mean age = 45.9 ± 14.2) healthy controls. Most of patients (90.2%) were treated by first generation antipsychotics with a mean daily dosage of 401.6 mg chlorpromazine equivalents. Total homocysteine serum levels were determined quantitatively by fluorescence-polarization immunoassay (FPIA) with an AxSYM analyzer™ (Abbott). Quantitative vitamin B12 and folate serum levels were measured with an Elecsys 2010 analyzer™ (Roche Diagnostics). Differences between patients and controls were examined using a two-way Ancova with gender and diagnosis as independent variables, adjusting for age.

Results

Patients with schizophrenia showed higher plasma Hycs and lower plasma folate than controls (mean = 16.1 μmol/L in patients versus 10.9 μmol/L in controls; P = 0.028 for Hycs and 4.2 μg/L in patients versus 8.2 μg/L in controls; P < 0.001 for folate). Patients and controls did not differ in vitamin B12 levels. Both male and female patients had increased plasma Hcys compared to controls. Hyperhomocysteinemia (Hcys levels > 15 μmol/L) was present in 34.4% of the patients versus 15.2% in controls. The prevalence of moderate hyperhomocysteinemia (Hcys levels: 15–29 μmo/L) was 26.2% and that of intermediate hyperhomocysteinemia (Hcys levels: 30–100 μmol/L) was 8.2%. In patients with schizophrenia, plasma Hcys was not correlated with age (r = 0.07; P = 0.56), duration of illness (r = –0.04; P = 0.78) and did not differ with gender and clinical sub-types. Moreover, plasma Hcys was higher in patients without family history of psychiatric disorders (19.2 μmol/L) versus 12.7 μmol/L in patients with family history of psychiatric disorders (P = 0.032). Concerning therapeutic features, plasma Hcys did not differ with type of antipsychotic and was not related to daily dosage of antipsychotics. A negative correlation was found between plasma Hcys and vitamin B12 levels (r = –0.26; P = 0.04).

Conclusion

These results confirm an increase of Hcys levels in schizophrenic patients and suggest that it is associated with absence of family history of psychiatric disorders and with low vitamin B12 levels. Hyperhomocyteinemia could be related to the pathophysiology of aspects of this illness. Homocysteine should be considered as a factor to consider in monitoring and management of patients with schizophrenia.     

Zinc transporters ZnT3 and ZnT6 are downregulated in the spinal cords of patients with sporadic amyotrophic lateral sclerosis

The loss of homeostasis of essential metals is associated with various diseases, including neurodegenerative diseases. Previous studies have shown that the levels of zinc (Zn) are significantly higher in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Zn transporters and metallothioneins tightly control intracellular and extracellular Zn levels. This study investigated the protein levels of ZnT, a Zn transporter family, in ALS patients and model mice. The mRNA expression of ZnT1, −3, −4, −5, −6, −7, and −10 was assessed in the spinal cords of human control subjects. ZnT3 and ZnT6 protein levels were significantly diminished in the spinal cords of sporadic ALS patients compared with controls. Furthermore, immunohistochemical staining demonstrated decreased ZnT3 and ZnT6 immunoreactivity in the ventral horn of the spinal cords in ALS patients. Moreover, immunohistochemical analysis revealed that all ZnTs expressed in the spinal cords were localized in a distinct subset of motor neurons. In addition, ZnT3 and ZnT6 protein levels were not altered in SOD1 (G93A) mutant transgenic mice before or after the onset of ALS symptoms compared with controls. These results suggest that ZnT3 and ZnT6 protein levels are decreased in the spinal cords of sporadic ALS patients; however, this did not occur merely via loss of motor neurons. © 2014 Wiley Periodicals, Inc.     

Toenail mercury Levels are associated with amyotrophic lateral sclerosis risk

Introduction: Mercury is a neurotoxic metal that is potentially a risk factor for amyotrophic lateral sclerosis (ALS). Consumption of methylmercury contaminated fish is the primary source of US population exposure to mercury. Methods: We used inductively coupled plasma mass spectrometry to measure levels of mercury in toenail samples from patients with ALS (n = 46) and from controls (n = 66) as a biomarker of mercury exposure. Results: Patients with ALS had higher toenail mercury levels (odds ratio 2.49, 95% confidence interval 1.18–5.80, P = 0.024) compared with controls, adjusted for age and sex. We also estimated the amount of mercury consumed from finfish and shellfish and found toenail mercury levels elevated overall among patients with ALS and controls in the top quartile for consumption (P = 0.018). Discussion: Biomarker data show that ALS is associated with increased with mercury levels, which were related to estimated methylmercury intake via fish. Replication of these associations in additional populations is warranted. Muscle Nerve 58 : 36–41, 2018     

Effects of the Serotonin Synthesis Inhibitor p-CPA on the Expression of the Crossed Phrenic Phenomenon 4 h Following C2 Spinal Cord Hemisection

The present study assesses the effects of para-chlorophenylalanine (p-CPA), a serotonin-depleting drug, on the recovery of respiratory-related activity in the phrenic nerve induced by asphyxia 4 h following ipsilateral C2 hemisection in young adult rats. HPLC analysis was used to quantify levels of serotonin (5-HT), dopamine (DA), norepinephrine, and the 5-HT metabolite, 5-hydroxyindoleacetic acid, in the C4 segment of the spinal cord, all of which were significantly lower in p-CPA-treated hemisected rats compared to hemisected controls receiving saline. Hemisection alone was found to significantly increase 5-HT levels and significantly decrease DA levels compared to normal controls. Eight of eight saline-injected rats expressed recovery of respiratory-related activity in the ipsilateral phrenic nerve during asphyxia 4 h following hemisection, while only 4/8 rats in the p-CPA-treated group expressed recovery in the ipsilateral nerve. Quantification of integrated phrenic nerve waveforms indicated that the mean amplitude of respiratory-related activity in the ipsilateral phrenic nerve was significantly lower in p-CPA-treated rats than in saline controls. In addition, saline controls demonstrated significant increases in mean respiratory frequency and mean amplitude of contralateral phrenic nerve activity during asphyxia, compared to normocapnia. However, p-CPA-treated rats did not express significant differences in either mean respiratory frequency or mean amplitude of integrated respiratory waveforms during asphyxia, compared to normocapnia. The results suggest that p-CPA treatment attenuates the recovery of respiratory-related activity in the phrenic nerve 4 h following ipsilateral C2 hemisection and attenuates asphyxia-induced increases in respiratory frequency and respiratory burst amplitude recorded from the contralateral phrenic nerve.