Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades.

Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006-2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989-2018) were identified by NBS and treated with natural protein restriction (1.0-1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973-2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p < .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.

Molecular and biochemical study of glutaric aciduria type 1 in 49 Russian families: nine novel mutations in the GCDH gene.

Glutaric aciduria type 1 (GA1, deficiency of glutaryl CoA dehydrogenase, glutaric acidemia type 1) (ICD-10 code: E72.3; MIM 231670) is an autosomal recessive disease caused by mutations in the gene encoding the enzyme glutaryl CoA dehydrogenase (GCDH). Herein, we present the biochemical and molecular genetic characteristics of 51 patients diagnosed with GA1 from 49 unrelated families in Russia. We identified a total of 21 variants, 9 of which were novel: c.127 + 1G > T, с.471_473delCGA, c.161 T > C (p.Leu54Pro), c.531C > A (р.Phe177Leu), c.647C > T (p.Ser216Leu), c.705G > A (р.Gly235Asp), c.898 G > A (р.Gly300Ser), c.1205G > C (р.Arg402Pro), c.1178G > A (р.Gly393Glu). The most commonly detected missense variants were c.1204C > T (p.Arg402Trp) and с.1262C > T (р.Ala421Val), which were identified in 56.38% and 11.7% of mutated alleles. A heterozygous microdeletion of the short arm (p) of chromosome 19 from position 12,994,984-13,003,217 (8233 b.p.) and from position 12,991,506-13,003,217 (11,711 b.p.) were detected in two patients. Genes located in the area of imbalance were KLF1, DNASE2, and GCDH. Patients presented typical GA1 biochemical changes in the biological fluids, except one patient with the homozygous mutation p.Val400Met. No correlation was found between the GCDH genotype and glutaric acid (GA) concentration in the cohort of our patients.

Occurrence of subdural hematomas in Dutch glutaric aciduria type 1 patients.

UNLABELLED: Patients with glutaric aciduria type 1 (GA1), a rare inherited metabolic disorder, have an increased risk for subdural hematomas (SDHs). GA1 is therefore generally included in the differential diagnosis of children presenting with SDHs. This retrospective cohort study reviews all 25 registered, in the Dutch Diagnosis Registration for Metabolic Disorders, GA1 patients in the Netherlands. This was done between May 2014 and November 2014 to determine the lifetime incidence of SDHs in this population. Seventeen patients were diagnosed either due to clinical symptoms or because of family members with GA1. One out of these 17 had a SDH. This patient showed widened Sylvian fissures on MRI, characteristic for GA1. Eight patients were diagnosed by newborn screening. Three of them had neuroimaging results, and none of them had SDHs. This study shows an overall lower incidence (4.0 %) of SDHs in patients with GA1 than reported in the literature (20-30 %). CONCLUSION: This finding, in combination with the fact that SDHs in GA1 appear to occur only in the presence of characteristic brain abnormalities on imaging, we recommend that GA1 should not routinely be a part of the differential diagnosis of children with unexplained SDHs in the absence of imaging characteristics suggestive of GA1. WHAT IS KNOWN: • Glutaric aciduria type 1 is a rare metabolic disorder predisposing children to subdural hematoma development due to brain abnormalities. • Because of these subdural hematomas, glutaric aciduria type 1 testing is part of abusive head trauma work-up. What is new: • The overall subdural hematoma incidence in glutaric aciduria type 1 patients is much lower than previously reported and only occurs in case of predisposing brain abnormalities.

Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases.

Many newborn screening programmes now use tandem mass spectrometry in order to screen for a variety of diseases. However, countries have embraced this technology with a differing pace of change and for different conditions. This has been facilitated by the ability of this diagnostic method to limit analysis to specific metabolites of interest, enabling targeted screening for particular conditions. MS/MS was introduced in 2009 in England to implement newborn bloodspot screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) raising the possibility of screening for other inherited metabolic disorders. Recently, a pilot screening programme was conducted in order to evaluate the health and economic consequences of screening for five additional inherited metabolic disorders in England. As part of this study we conducted a systematic review and meta-analysis to estimate the birth prevalence of these conditions: maple syrup urine disease, homocystinuria (pyridoxine unresponsive), glutaric aciduria type I, isovaleric acidaemia and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency including trifunctional protein deficiency. We identified a total of 99 studies that were able to provide information on the prevalence of one or more of the disorders. The vast majority of studies were of screening programmes with some reporting on clinically detected cases.

Neurological symptoms in hospitalised patients: do we assess hyponatraemia with sufficient care?

AIM: To review the incidence of hyponatraemic encephalopathy in children treated in a tertiary care centre hospital, together with the clinical setting and clinical management of these cases. METHODS: Retrospective descriptive study by chart review of patients admitted to hospital during 2000-2010. Patients older than 1 month were included who had severe hyponatraemia (sodium concentration <125 mmol/L) on admission or during their hospital stay and co-incidental neurological symptoms. Epidemiological, clinical, laboratory and therapeutic data were collected. RESULTS: We analysed 41 cases of severe hypotonic hyponatraemia and neurological symptoms compatible with hyponatraemic encephalopathy. Boys accounted for 56.1% patients, and the median age was 1 year. Hyponatraemia was acquired in hospital by 61% of the patients, and 88% of those patients were receiving intravenous hypotonic fluids. The most frequent neurological symptom was seizures. The most common therapeutic strategy was sodium supplementation and antiepileptic drugs. Hypertonic fluids were only used in the initial treatment of 16 patients. There were two deaths related to hyponatraemic encephalopathy. CONCLUSION: Hyponatraemia should always be considered a cause of neurological symptoms in hospitalised patients. Treatment should be prompt to prevent neurological sequelae and death. Current recommendations for fluid management in hospitalised children should be reviewed.

Resuscitation intensity at birth is associated with changes in brain metabolic development in preterm neonates.

INTRODUCTION: Intensive resuscitation at birth has been linked to intraventricular haemorrhage (IVH) in the preterm neonate. However, the impact of less intensive resuscitation on more subtle alterations in brain metabolic development is largely unknown. Our objective was to determine the relationship between the intensity of neonatal resuscitation following preterm birth on brain metabolic development. METHODS: One hundred thirty-three very preterm-born neonates (median gestational age [GA] 27 ± 2 weeks) underwent MR spectroscopic imaging early in life (median postmenstrual age 32 weeks) and again at term-equivalent age (median 40 weeks). Severity of white matter injury, IVH and cerebellar haemorrhage on magnetic resonance imaging were scored. Ratios of N-acetylaspartate (NAA) and lactate to choline (Cho) were calculated in eight regions of interest and were assessed in relation to intensiveness of resuscitation strategy (bag and mask, continuous positive airway pressure [CPAP], intubation, cardiopulmonary resuscitation [CPR]). RESULTS: Within the first hour of life, 14 newborns had no intervention, 3 received bag and mask, 30 had CPAP, 79 were intubated and 7 had CPR. Resuscitated infants were more likely to have IVH (p = 0.02). More intensive resuscitation was associated with decreased NAA/Cho maturation (p < 0.001, adjusting for birth GA). Metabolic development was similar in neonates requiring CPAP in comparison to those receiving no intervention. The change in lactate/Cho did not differ across resuscitation categories (p = 0.8). CONCLUSIONS: Intensity of resuscitation at birth is related to changes in metabolic brain development from early in life to term-equivalent age. Results suggest that preventing the need for intensive neonatal resuscitation may provide an opportunity to improve brain development in preterm neonates.

Biochemical and molecular features of chinese patients with glutaric acidemia type 1 from Fujian Province, southeastern China.

BACKGROUND: Glutaric acidemia type 1 (GA1) is a rare autosomal recessive inherited metabolic disorder caused by variants in the gene encoding the enzyme glutaryl-CoA dehydrogenase (GCDH). The estimated prevalence of GA1 and the mutational spectrum of the GCDH gene vary widely according to race and region. The aim of this study was to assess the acylcarnitine profiles and genetic characteristics of patients with GA1 in Fujian Province, southeastern China. RESULTS: From January 2014 to December 2022, a total of 1,151,069 newborns (631,016 males and 520,053 females) were screened using MS/MS in six newborn screening (NBS) centers in Fujian Province and recruited for this study. Through NBS, 18 newborns (13 females and 5 males) were diagnosed with GA1. Thus, the estimated incidence of GA1 was 1 in 63,948 newborns in Fujian province. In addition, 17 patients with GA1 were recruited after clinical diagnosis. All but one patient with GA1 had a remarkable increase in glutarylcarnitine (C5DC) concentrations. The results of urinary organic acid analyses in 33 patients showed that the concentration of glutaric acid (GA) increased in all patients. The levels of C5DC and GA in patients identified via NBS were higher than those in patients identified via clinical diagnosis (P < 0.05). A total of 71 variants of 70 alleles were detected in patients with GA1, with 19 different pathogenic variants identified. The three most prevalent variants represented 73.23% of the total and were c.1244-2 A > C, p.(?) (63.38%), c.1261G > A, p.Ala421Thr (5.63%), and c.406G > T, p.Gly136Cys (4.22%). The most abundant genotype observed was c.[1244-2 A > C]; [1244-2 A > C] (18/35, 52.43%) and its phenotype corresponded to high excretors (HE, GA > 100 mmol/mol Cr). CONCLUSIONS: In conclusion, we investigated the biochemical and molecular features of 35 unrelated patients with GA1. C5DC concentrations in dried blood spots and urinary GA are effective indicators for a GA1 diagnosis. Our study also identified a GCDH variant spectrum in patients with GA1 from Fujian Province, southeastern China. Correlation analysis between genotypes and phenotypes provides preliminary and valuable information for genetic counseling and management.

Early cerebral metabolic crisis after TBI influences outcome despite adequate hemodynamic resuscitation.

BACKGROUND: Optimal resuscitation after traumatic brain injury (TBI) remains uncertain. We hypothesize that cerebral metabolic crisis is frequent despite adequate resuscitation of the TBI patient and that metabolic crisis negatively influences outcome. METHODS: We assessed the effectiveness of a standardized trauma resuscitation protocol in 89 patients with moderate to severe TBI, and determined the frequency of adequate resuscitation. Prospective hourly values of heart rate, blood pressure, pulse oximetry, intracranial pressure (ICP), respiratory rate, jugular venous oximetry, and brain extracellular values of glucose, lactate, pyruvate, glycerol, and glutamate were obtained. The incidence during the initial 72 h after injury of low brain glucose <0.8 mmol/L, elevated lactate/pyruvate ratio (LPR) >25, and metabolic crisis, defined as the simultaneous occurrence of both low glucose and high LPR, were determined for the group. RESULTS: 5 patients were inadequately resuscitated and eight patients had intractable ICP. In patients with successful resuscitation and controlled ICP (n = 76), within 72 h of trauma, 76% had low glucose, 93% had elevated LPR, and 74% were in metabolic crisis. The duration of metabolic crisis was longer in those patients with unfavorable (GOSe ≤ 6) versus favorable (GOSe ≥ 7) outcome at 6 months (P = 0.011). In four multivariate models the burden of metabolic crisis was a powerful independent predictor of poor outcome. CONCLUSIONS: Metabolic crisis occurs frequently after TBI despite adequate resuscitation and controlled ICP, and is a strong independent predictor of poor outcome at 6 months.

Diagnosis, treatment and outcome of glutaric aciduria type I in Zhejiang Province, China.

BACKGROUND: Glutaric aciduria type I (GA I; MIM 231670) is a rare autosomal recessive disorder resulting from glutaryl-CoA dehydrogenase deficiency. This article reports our experience in the diagnosis, treatment and outcome of GA I patients in Zhejiang Province, China. MATERIAL/METHODS: A total of 129,415 newborns (accounting for approximately one-tenth of the annual births in Zhejiang Province) and 9640 high-risk infants were screened for inborn errors of metabolism in the Neonatal Screening Center of Zhejiang Province during a 3-year period. Tandem mass spectrometry and gas chromatography-mass spectrometry were used for diagnosis of the patients. Dietary modification, carnitine supplementation and aggressive treatment of intercurrent illnesses were adapted for GA I patients. RESULTS: Three infants were diagnosed with GA I by high-risk screening (detection rate: 1/3,213) and 2 were diagnosed by newborn screening (incidence: 1/64,708). Four patients (3 by high-risk screening and 1 by neonatal screening) undergoing MRI examination showed remarkable changes on T2-weighted image. Four patients accepted timely treatment, and in the patient diagnosed by neonatal screening, treatment was delayed until hypotonia appeared 3 months later. Neuropsychological assessment showed mental and motor retardation in 3 patients after treatment, including the patient diagnosed by neonatal screening. CONCLUSIONS: Individualized timely treatment and close monitoring of GA I patients needs to be optimized in China. Appropriate communication with parents may help to achieve successful management of GA I patients.

Symptom Prevalence and Genotype-Phenotype Correlations in Patients With TANGO2-Related Metabolic Encephalopathy and Arrhythmias (TRMEA).

BACKGROUND: TANGO2-related metabolic encephalopathy and arrhythmias (TRMEA) is a rare, phenotypically heterogeneous, neurological disease affecting children. METHODS: We conducted a chart review of five children with molecularly confirmed TRMEA diagnosed at our institution and compiled pathogenic variant frequency and symptom prevalence from cases previously reported in the literature. RESULTS: Including those patients in our case series, 76 patients with TRMEA have been described. Developmental delay (93%) and/or regression (71%), spasticity (78%), and seizures (57%) are common in TRMEA and frequently precede life-threatening symptoms such as metabolic decompensation with lactic acidosis (83%), cardiomyopathy (38%), and cardiac arrhythmias (68%). Deletion of exons 3 to 9 is the most common pathogenic variant (39% of alleles). The majority of reported intragenic variants (17 of 27) result in disruption of the reading frame, and no clear genotype-phenotype correlations could be identified for those variants wherein the reading frame is maintained, highlighting instead the variable expressivity of the disease. CONCLUSIONS: Patients with TRMEA frequently experience life-threatening complications that are preceded by common neurological symptoms underscoring the need for pediatric neurologists to be familiar with this condition. Additional work pertaining to disease pathophysiology and potential therapeutics is needed.

Glutaric aciduria type 1 in South Africa-high incidence of glutaryl-CoA dehydrogenase deficiency in black South Africans.

Glutaric Aciduria type 1 (GA 1) is an inherited disorder of lysine and tryptophan catabolism that typically manifests in infants with acute cerebral injury associated with intercurrent illness. We investigated the clinical, biochemical and molecular features in 14 known GA 1 patients in South Africa, most of whom were recently confirmed following the implementation of sensitive urine organic acid screening at our laboratory. Age at diagnosis ranged from 3days to 5years and poor clinical outcome reflected the delay in diagnosis in all but one patient. Twelve patients were unrelated black South Africans of whom all those tested (n=11) were found homozygous for the same A293T mutation in the glutaryl-CoA dehydrogenase (GCDH) gene. Excretion of 3-hydroxyglutarate (3-OHGA) was >30.1µmol/mmol creatinine (reference range <2.5) in all cases but glutarate excretion varied with 5 patients considered low excretors (glutarate <50µmol/mmol creatinine). Fibroblast GCDH activity was very low or absent in all of five cases tested. Heterozygosity for the A293T mutation was found 1 in 36 (95% CI; 1/54 - 1/24) unrelated black South African newborns (n=750) giving a predicted prevalence rate for GA 1 of 1 in 5184 (95% CI; 1/11664 - 1/2304) in this population. GA 1 is a treatable but often missed inherited disorder with a previously unrecognised high carrier frequency of a single mutation in the South African black population.

Limbic metabolic abnormalities in remote traumatic brain injury and correlation with psychiatric morbidity and social functioning.

The aim of this study was to investigate limbic metabolic abnormalities in remote traumatic brain injury (TBI) and their psychiatric correlates. Twenty patients and 13 age-matched comparison subjects received complete psychiatric evaluation and brain MRI and MR spectroscopy at 3 Tesla. Patients had reduced NAA to creatine ratio in the left hippocampus relative to comparison subjects (mean=1.3 [SD=0.21] compared with mean=1.55 [SD=0.21]; F=10.73, df=1, 30, p=0.003), which correlated with the Social Functioning Examination scores (r(s)=-0.502, p=0.034). Furthermore, patients with mood disorders had reduced NAA to creatine ratio in the left cingulate relative to patients without mood disorders (1.47 compared with 1.68; F=3.393, df=3, 19, p=0.044). Remote TBI displays limbic metabolic abnormalities, which correlate to social outcome and psychiatric status.

Iron deficiency in children with mitochondrial disease.

Mitochondrial disease is an energy metabolic disorder with various organ involvement. Iron is widely known to be one of the most important nutriments required for normal brain development and several essential metabolic functions. We retrospectively studied the laboratory data on iron deficiency (ID) in 69 children with mitochondrial respiratory chain complex (MRC) defects by biochemical enzyme assay using muscle tissue. We analyzed the differences between groups of mitochondrial disease based on the presence of ID. ID has higher prevalence in children with mitochondrial disease than in the normal population. There were 6 (9%) patients with low hemoglobin, 12 (17%) with low serum ferrtin, and 22 (32%) with low transferrin saturation levels among children with MRC defects. In comparisons between the ID and the non-ID group of MRC-defect patients, the frequency of MRC I defect was significantly higher in the ID group while that of MRC IV defect was higher in the non-ID group. Abnormal brain magnetic resonance imaging (MRI) findings were more frequently detected in the ID group. The incidence of failure to thrive and gastrointestinal symptoms were significantly higher in the ID group. Early diagnosis and proper treatment of ID are recommended. Especially in cases with risk factors such as failure to thrive or gastrointestinal manifestation, active evaluation of ID should be encouraged.

Incidence of newborn screening disorders among 56632 infants in Central Saudi Arabia. A 6-year study.

OBJECTIVES: To determine the incidence of newborn screening (NBS) disorders and to study the key performance indicators of the program. METHODS: This retrospective single-center study enrolled all infants who underwent NBS from January 2012 to December 2017 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. We screened 17 NBS disorders. Blood samples were collected 24 hours after birth. If the initial result was positive, a second sample was collected. True positive cases were immediately referred for medical management. Data were extracted from laboratory computerized and non-computerized records using case report forms. RESULTS: During the study period, 56632 infants underwent NBS with a coverage rate of 100%. Thirty-eight cases were confirmed. The incidence of congenital hypothyroidism was 1:3775. The positive predictive value for the detection of congenital hypothyroidism was 11.8%. Propionic aciduria was the most common metabolic disorder, with an incidence of 1:14158. Very long-chain acyl CoA dehydrogenase deficiency and glutaric aciduria type 1 had an incidence of 1:18877 each. Phenylketonuria, biotinidase deficiency, maple syrup urine disease, and citrullinemia had an incidence of 1:28316 each. However, galactosemia and 3-methyl crotonyl carboxylase deficiency had the lowest incidence of 1:56632. CONCLUSION: The NBS coverage rate at our facility was 100%. Congenital hypothyroidism was the most frequently detected disorder with an incidence that matches worldwide figures. The incidence of other inherited disorders was consistent with regional figures.

[Metabolic encephalopathies]. / Encéphalopathies métaboliques.

Metabolic encephalopathies (ME) are a common cause of admission to emergency rooms, to hospitalization wards or to intensive care units. They could account for 10 to 20% of causes of comatose states in ICU and could be associated to a poor outcome especially in older patients. Nevertheless, they are often reversible and are associated with a favorable outcome when diagnosed and rapidly treated. They correspond to an altered brain functioning secondary to the deficiency of a substance that is mandatory for the normal brain functioning or to the accumulation of a substance that can be either endogenous or exogenous. It preferably occurs in co-morbid patients, complicating its diagnosis and its management. Altered brain functioning, going from mild neuropsychological impairment to coma, movement disorders especially myoclonus and the absence of any obvious differential diagnosis are highly suggestive of the diagnosis. Whereas some biological samplings and brain MRI are essential to rule out differential diagnosis, some others, such as electroencephalogram, may be able to propose important clues in favor of the diagnosis. Once simple symptomatic measures are introduced, the treatment consists mainly in the correction of the cause. Specific treatment options are only seldom available for ME; this is the case for hepatic encephalopathy and some drug-induced encephalopathies. We will successively describe in this review the main pathophysiological mechanisms, the main causes, favoring circumstances of ME, the differential diagnosis to rule out and the etiological work-up for the diagnosis. Finally, a diagnostic and therapeutic strategy for the care of patients with ME will be proposed.

The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy.

OBJECTIVES: This study was undertaken to investigate the relationship among maternal intrapartum fever, neonatal acidosis, and the risk of neonatal encephalopathy. STUDY DESIGN: Cohort study of pregnancies at term. Logistic regression was used to estimate the effect of maternal fever and acidosis on the risk of neonatal encephalopathy. The potential interaction between maternal fever and acidosis was included in the models. RESULTS: Of 8299 women, 25 neonates (0.3%) had encephalopathy develop. These were more often born acidotic (adjusted odds ratio 11.5; 95% CI, 5.0-26.5) or after a maternal intrapartum fever (adjusted odds ratio 8.1; 95% CI, 3.5-18.6). Where both risk factors coexisted, the risk was 12.5% (adjusted odds ratio 93.9; 95% CI, 28.7-307.2). Although this effect is multiplicative, there was no evidence of statistical interaction (P = .93); the effect of maternal fever on the risk of encephalopathy was similar in infants with (adjusted odds ratio 8.7; 95% CI, 2.4-31.7) and without acidosis (adjusted odds ratio 7.4; 95% CI, 2.4-21.9). CONCLUSION: The combination of a maternal fever with cord acidosis greatly increases the risk of neonatal encephalopathy, but there is evidence against interaction between them, suggesting that they represent 2 separate causal pathways.

Movement disorders at a university hospital emergency room. An analysis of clinical pattern and etiology.

We prospectively evaluated the clinical features and etiologies of all common categories of movement disorder seen in the emergency room (ER) of an urban university hospital over a period of 12 months. We divided movement disorders according to the presenting phenomenology likely to dominate the clinical presentation, that is, gait disorder, tremor, dystonia, myoclonus, and acute akinetic crisis and classified a specific etiology in the individual phenomenology. In one year, there were 60,002 ER visits; of these, 58 (0.09 %) were diagnosed as a primary movement disorder. The most common clinical presentation was gait disorder (n = 21, 36.2 %), followed by myoclonus (n = 16, 27.6 %), dystonia (n = 10, 17.2 %), tremor (n = 8, 13.8 %), and acute akinetic crisis (n = 3, 5.2 %). Comparing the movement disorders, the mean age of the patients with dystonia was significantly lower than that of patients with other movement disorders (P < 0.001). Of the patients, 37 (63.8 %) had drug-related movement disorders. The contribution of drugs was significantly higher in patients with dystonia compared with the other movement disorders (P < 0.01). Our study showed that a large proportion of the movement disorders seen in the ER are drug-related. Careful selection of drugs while prescribing would decrease movement disorder-related visits to the ER.

Peripheral and central neurologic complications in type 2 diabetes mellitus: no association in individual patients.

Diabetes mellitus is associated with end-organ complications in the peripheral and central nervous system. It is unknown if these complications share a common aetiology, and if they co-occur in the same patient. The aim of the present study was to relate different measures of peripheral neuropathy in patients with type 2 diabetes mellitus (DM2) to cognition and brain MRI. A standardized neurological examination and questionnaire, neuropsychological examination and brain MRI were performed in 122 patients with DM2 and 56 matched controls. Measures of peripheral neuropathy were vibration threshold, a sensory examination sum score and the Toronto Clinical Neuropathy Scoring System. Neuropsychological test scores were expressed in standardized z-values across five predetermined cognitive domains. White matter lesions and cortical and subcortical atrophy were rated on MRI. Overall 38% of the patients with DM2 and 12% of the controls were classified as having any neuropathy (p<0.001). Patients with DM2 had a lower performance on the neuropsychological tests, more white matter lesions (p<0.01) and more atrophy (p<0.01) than controls. Within the DM2 group none of the measures of peripheral neuropathy was related to MRI abnormalities or cognitive dysfunction (linear regression analyses, adjusted for age, education, sex). We conclude that peripheral neuropathy in patients with DM2 is not related to cognitive dysfunction and brain abnormalities. This indicates that central and peripheral neurological complications of DM2 might have different etiologies.

Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children.

The objective of the study was to assess acute neurotoxicity associated with triple intrathecal therapy (TIT)+/-high-dose methotrexate (HD MTX) in children with acute lymphoblastic leukemia (ALL). 1395 children were enrolled on FRALLE 93 protocol from 1993 to 1999. Lower-risk group (LR, n=182) were randomized to weekly low-dose MTX at 25 mg/m(2)/week (LD MTX, n=81) or HD MTX at 1.5 g/m(2)/2 weeks x 6 (n=77). Intermediate-risk group (IR, n=672) were randomized to LD MTX (n=290) or HD MTX at 8 g/m(2)/2 weeks x 4 (n=316). Higher-risk group (HR, n=541) prednisone-responder patients received LD MTX and cranial radiotherapy. HR group steroid resistant cases were grafted (autologous or allogenic). TIT (MTX, cytarabine and methylprednisolone) was given every 2 weeks during 16-18 weeks and every 3 months during maintenance therapy in LR and IR patients. 52 patients (3.7%) developed neurotoxicity. Isolated seizures: n=15 (1.1%), peripheral and spinal neuropathy: n=17 (1.2%) and encephalopathy: n=20 (1.4%). Age >10 years was significantly associated with neurotoxicity (P=0.01) and use of HD MTX is associated with encephalopathy (P=0.03). Sequels are reported respectively in 60 and 33% of spinal neuropathy and encephalopathy cases. Current strategies tailoring risk of neurological sequels has to be defined.

Renal failure is a risk factor for cefepime-induced encephalopathy.

BACKGROUND: Cefepime is a widely used antibiotic. However, it can cause encephalopathy, which has been increasingly described in the literature, occurring mainly in patients with impaired renal function. The primary objective in this study was to measure the incidence of cefepime-induced encephalopathy and determine potential risk factors for its occurrence. METHODS: In the period from February 2005 to February 2006, a prospective cohort study was conducted, which followed 498 patients using cefepime. Other metabolic problems were ruled out for all patients with clinical suspicion of encephalopathy and, when cefepime was the probable cause, electroencephalographic (EEG) tests were performed to assist in the diagnosis, with the first performed during cefepime use and another performed at least 48 hours following drug discontinuation and/or clinical improvement. RESULTS: Among patients selected for this study (n=498), 5 were diagnosed with cefepime-induced encephalopathy, thus indicating a cumulative incidence of approximately 1% (0.01), 387 had glomerular filtration rate (GFR) >or=60 ml/min and 111 had GFR <60 ml/min. Among the latter, 5 patients developed cefepime-induced encephalopathy. Mean GFR value in patients with encephalopathy (n=5) was 17.20 ml/min (SD +/-10.75 ml/min) and, in patients without encephalopathy (n=106) it was 32.59 ml/min (SD +/-14.89 ml/min) (p=0.025). CONCLUSION: The development of cefepime-induced encephalopathy seems to be related to the severity of impairment in glomerular filtration.