The pathogenetic basis for a disease continuum in early- and late-onset ataxia-dystonia supports a unified genetic diagnostic approach.

INTRODUCTION: Genetically inherited ataxic disorders are classified by their age of disease presentation into early- and late-onset ataxia (EOA and LOA, presenting before or after the 25th year-of-life). In both disease groups, comorbid dystonia co-occurs frequently. Despite overlapping genes and pathogenetic features, EOA, LOA and dystonia are considered as different genetic entities with a separate diagnostic approach. This often leads to diagnostic delay. So far, the possibility of a disease continuum between EOA, LOA and mixed ataxia-dystonia has not been explored in silico. In the present study, we analyzed the pathogenetic mechanisms underlying EOA, LOA and mixed ataxia-dystonia. METHODS: We analyzed the association of 267 ataxia genes with comorbid dystonia and anatomical MRI lesions in literature. We compared anatomical damage, biological pathways, and temporal cerebellar gene expression between EOA, LOA and mixed ataxia-dystonia. RESULTS: The majority (≈65%) of ataxia genes were associated with comorbid dystonia in literature. Both EOA and LOA gene groups with comorbid dystonia were significantly associated with lesions in the cortico-basal-ganglia-pontocerebellar network. EOA, LOA and mixed ataxia-dystonia gene groups were enriched for biological pathways related to nervous system development, neural signaling and cellular processes. All genes revealed similar cerebellar gene expression levels before and after 25 years of age and during cerebellar development. CONCLUSION: In EOA, LOA and mixed ataxia-dystonia gene groups, our findings show similar anatomical damage, underlying biological pathways and temporal cerebellar gene expression patterns. These findings may suggest the existence of a disease continuum, supporting the diagnostic use of a unified genetic approach.

Application of the Scale for Assessment and Rating of Ataxia in toddlers.

INTRODUCTION: In young children with early onset ataxia (EOA), quantitative rating of ataxia by the Scale for Assessment and Rating of Ataxia (SARA) is longitudinally influenced by the physiological age effect on motor coordination. To enable longitudinal quantitative interpretation of ataxia by SARA in children with EOA, the EPNS ataxia working group has previously determined SARA-scores in typically developing children (4-16 years of age). In toddlers, this information is still lacking. We therefore aimed to investigate the feasibility and reliability of SARA-scores in typically developing toddlers. METHODS: In 57 typically developing toddlers (2-4 years), we aimed to determine the: 1. feasibility of SARA-scores, 2. age-related pre-requisites to obtain SARA-scores in toddlers over all domains, 3. SARA-score reliability, 4. mathematical age connection of SARA-scores in toddlers and older children. RESULTS: In typically developing toddlers, the feasibility of SARA is strongly age-dependent (p < .000). After computing compensations for two age-related, unfeasible and therefore un-assessable kinetic subtasks and after allowing the videotaping of non-kinetic SARA sub-task performances at home, the SARA was fully reliably assessable in all (n = 57) toddlers (ICC = 0.732). From two to 16 years of age, SARA-scores were mathematically represented by one continuous, exponentially decreasing trend line approaching the adult-optimum at 16 years of age. CONCLUSION: In toddlers, SARA-scores are reliably assessable, by using two age-compensations and allowing the videotaping of SARA-performances partly at home. In children with EOA, these data enable longitudinal quantification and interpretation of quantitative ataxia-scores by SARA from 2 years of age throughout childhood.

Instrumented classification of patients with early onset ataxia or developmental coordination disorder and healthy control children combining information from three upper limb SARA tests.

BACKGROUND: Early Onset Ataxia (EOA) and Developmental Coordination Disorder (DCD) share several phenotypical characteristics, which can be clinically hard to distinguish. AIM: To combine quantified movement information from three tests obtained from inertial measurements units (IMUs), to improve the classification of EOA and DCD patients and healthy controls compared to using a single test. METHODS: Using IMUs attached to the upper limbs, we collected data from EOA, DCD and healthy control children while they performed the three upper limb tests (finger to nose, finger chasing and fast alternating movements) from the Scale for the Assessment and Rating of Ataxia (SARA) test. The most relevant features for classification were extracted. A random forest classifier with 300 trees was used for classification. The area under the receiver operating curve (ROC-AUC) and precision-recall plots were used for classification performance assessment. RESULTS: The most relevant discerning features concerned smoothness and velocity of movements. Classification accuracy on group level was 85.6% for EOA, 63.5% for DCD and 91.2% for healthy control children. In comparison, using only the finger to nose test for classification 73.7% of EOA and 53.4% of DCD patients and 87.2% of healthy controls were accurately classified. For the ROC/precision recall plots the AUC was 0.96/0.89 for EOA, 0.92/0.81 for DCD and 0.97/0.94 for healthy control children. DISCUSSION: Using quantified movement information from all three SARA-kinetic upper limb tests improved the classification of all diagnostic groups, and in particular of the DCD group compared to using only the finger to nose test.

Dyskinesia Impairment Scale scores in Dutch pre-school children after neonatal therapeutic hypothermia.

BACKGROUND: Neonatal therapeutic hypothermia (TH) can ameliorate or prevent the development of dyskinetic cerebral palsy (CP) after hypoxic-ischemic encephalopathy (HIE). The Dyskinesia Impairment Scale (DIS) was recently launched to quantify dyskinetic (dystonic and choreatic) motor features in patients with CP. In TH treated children, who are at risk of developing dyskinetic CP, we aimed to determine DIS-scores at pre-school age. METHOD: In 21 Dutch pre-school children (3-6 years of age) who had received TH according to the Dutch-Flemish treatment protocol, we determined DIS-scores. We associated DIS-scores with 1. age-matched control values (Kuiper et al., 2018) [1], and 2. previously reported DIS-score range in dyskinetic CP (Monbaliu E et al., 2015). RESULTS: The motor phenotype was determined as: normal (n = 18/21), mildly impaired (reduced coordination (n = 2/21)) and abnormal (dyskinetic CP; n = 1/21). In absence of CP (n = 20/21), DIS-scores were lower (more favorable) than in dyskinetic CP, without any overlapping group scores (mean difference: 71 points; p < .05). However, the obtained DIS-scores were still higher than previously reported in healthy age-matched controls (mean difference: 14 points; p < .05). There was an association between DIS-scores and retrospective neonatal MRI (basal ganglia and thalamus injury on diffusion weighted imaging (DWI)) and (a)EEG parameters (p < .05). CONCLUSION: In the vast majority (95%) of Dutch TH-HIE treated pre-school children, the phenotypic motor outcome was favorable. However, DIS-scores were moderately increased compared with healthy age-matched controls. Future studies may elucidate the significance of moderately increased DIS-scores should to further extent.

A clinical diagnostic algorithm for early onset cerebellar ataxia.

Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases.

Instrumented finger-to-nose test classification in children with ataxia or developmental coordination disorder and controls.

BACKGROUND: During childhood, many conditions may impact coordination. Examples are physiological age-related development and pathological conditions, such as early onset ataxia and developmental coordination disorder. These conditions are generally diagnosed by clinical specialists. However, in absence of a gold phenotypic standard, objective reproducibility among specialists appears limited. METHODS: We investigated whether quantitative analysis of an upper limb coordination task (the finger-to-nose test) could discriminate between physiological and pathological conditions impacting coordination. We used inertial measurement units to estimate movement trajectories of the participants while they executed the finger-to-nose test. We employed random forests to classify each participant in one category. FINDINGS: On average, 87.4% of controls, 74.4% of early onset ataxia and 24.8% of developmental coordination disorder patients were correctly classified. The relatively good classification of early onset ataxia patients and controls contrasts with the poor classification of developmental coordination disorder patients. INTERPRETATION: In absence of a gold phenotypic standard for developmental coordination disorder recognition, it remains elusive whether the finger-to-nose test in these patients represents a sufficiently accurate entity to reflect symptoms distinctive of this disorder. Based on the relatively good results in early onset ataxia patients and controls, we conclude that quantitative analysis of the finger-to-nose test can provide a reliable support tool during the assessment of phenotypic early onset ataxia.

Physiological movement disorder-like features during typical motor development.

AIM: To compare physiological age-relatedness between dyskinesia (dystonia/choreoathetosis), dystonia and ataxia rating scale scores in healthy children. METHOD: Three movement disorders specialists quantified dyskinetic-like features in healthy children (n = 52; 4-16 years) using the Dyskinesia Impairment Scale (DIS = DIS-choreoathetosis (DIS-C) + DIS-dystonia (DIS-D)). We compared the age-related regression coefficients of the DIS with data processed from previous studies on dystonia and ataxia rating scales (Burke-Fahn-Marsden Movement and Disability Scales (BFMMS and BFMDS) and Scale for Assessment and Rating of Ataxia (SARA), International Cooperative Ataxia Rating Scale (ICARS) and Brief Ataxia Rating Scale (BARS)). RESULTS: Dyskinetic scores were obtained in 79% (DIS); 65% (DIS-D) and 17% (DIS-C) versus dystonic and ataxic scores in 98% (BFMMS) and 89% (SARA/ICARS/BARS) of the children. Age-related DIS and DIS-D scores (B = -0.90 and 0.77; p < 0.001) were correlated with age-related BFMMS scores (B = -0.49; p < 0.001; r = 0.87; p < 0.001), whereas DIS-C scores were age-independent. Ataxic scores revealed stronger age-related regression coefficients than dyskinetic and dystonic scores (4-8 years; p < 0.05). INTERPRETATION: In healthy children, comparison between physiological dyskinesia, dystonia and ataxia rating scale scores revealed: 1. inverse age-relatedness for dystonic and ataxic scores, but not for choreoathetotic scores, 2. interrelated dystonic DIS-D and BFMMS scores, 3. the strongest age-related expression by ataxic scores. In healthy children, these physiological movement disorder-like features are interpreted as an expression of the developing underlying motor centres.

Amplitude-Integrated EEG and Cerebral Near-Infrared Spectroscopy in Cooled, Asphyxiated Infants.

OBJECTIVE: To assess the predictive value of amplitude-integrated electroencephalography EEG (aEEG) and near-infrared spectroscopy (NIRS) during therapeutic hypothermia. PATIENTS AND METHODS: We studied 39 cooled, asphyxiated infants. We assessed aEEG and calculated mean regional cerebral oxygen saturation (rcSO2) during and after treatment. At 30 months, we performed a neurological examination and administered the Bayley Scales of Infant and Toddler Development, 3rd edition. We calculated the odds ratios (ORs) of abnormal aEEG and rcSO2 for severely abnormal outcome. RESULTS: At 6 and 12 hours, severely abnormal aEEGs predicted severely abnormal outcomes (OR, 7.7 [95% confidence interval, CI, 1.39-42.6] and 24.4 [95% CI 4.2-143] respectively), as did epileptic activity (OR 28.9, 4.6-183). During the first 48 hours, rcSO2 was not associated with outcome, but at 72 hours after birth and after rewarming it was, with ORs for severely abnormal outcomes of 12.8 (1.31-124) and 21.6 (1.05-189), respectively. In multivariate analyses, aEEG and rcSO2 remained independently predictive in the model at 48 hours and significantly from 72 hours after birth onward. CONCLUSION: aEEG was a strong predictor of adverse outcome. After 48 hours of cooling, a higher rcSO2 was associated with a severely abnormal outcome, adding to the predictive value of aEEG in cooled, asphyxiated infants.

De novo variants in KLF7 are a potential novel cause of developmental delay/intellectual disability, neuromuscular and psychiatric symptoms.

Due to small numbers of reported patients with pathogenic variants in single genes, the phenotypic spectrum associated with genes causing neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder is expanding. Among these genes is KLF7 (Krüppel-like factor 7), which is located at 2q33.3 and has been implicated in several developmental processes. KLF7 has been proposed to be a candidate gene for the phenotype of autism features seen in patients with a 2q33.3q34 deletion. Herein, we report 4 unrelated individuals with de novo KLF7 missense variants who share similar clinical features of developmental delay/ID, hypotonia, feeding/swallowing issues, psychiatric features and neuromuscular symptoms, and add to the knowledge about the phenotypic spectrum associated with KLF7 haploinsufficiency.

Clinical Pearls - how my patients taught me: The fainting lark symptom.

BACKGROUND: Compulsive movements, complex tics and stereotypies are frequent, especially among patients with autism or psychomotor retardation. These movements can be difficult to characterize and can mimic other conditions like epileptic seizures or paroxysmal dystonia, particularly when abnormal breathing and cerebral hypoxia are induced. CASE PRESENTATION: We describe an 18-year-old patient with Asperger syndrome who presented with attacks of tonic posturing of the trunk and neck. The attacks consisted of self-induced stereotypic stretching of the neck combined with a compulsive Valsalva-like maneuver. This induced cerebral hypoperfusion and subsequently dysautonomia and some involuntary movements of the arms. CONCLUSION: This patient suffered from a complex tic with compulsive respiratory stereotypies. His symptoms contain aspects of a phenomenon described in early literature as 'the fainting lark'.

An external validation of the ETVSS for both short-term and long-term predictive adequacy in 104 pediatric patients.

PURPOSE: This study aims to provide external validation of the "Endoscopic Third Ventriculostomy Success Score (ETVSS)" for both short-term and long-term predictive adequacy. METHODS: Between 1998 and 2007, we collected clinical follow-up data (after 6 and 36 months) of all 104 hydrocephalic children (<18 years of age) treated by endoscopic third ventriculostomy (ETV) in our hospital. Predictive adequacy of ETVSS for 6- and 36-month periods was tested by means of an unpaired t test, Hosmer-Lemeshow "goodness-of- fit" test, and area under the receiver operating characteristic curve. RESULTS: Mean follow-up was 73.4 months. For both the short-term (6 months) and the long-term (36 months) periods, the mean predicted probability of ETV for the patients with successful ETV treatment was significantly higher than in the patients with failed ETV treatment. The areas under the curve for the short- and long-term periods were, respectively, 0.82 (95% CI 0.71-0.92) and 0.73 (95% CI 0.62-0.84). For patients with moderate ETVSS (50-70), the median age at first ETV was significantly higher for patients with successful ETV for both short- and long-term periods. CONCLUSION: In hydrocephalic children, the ETVSS is a useful tool for prediction of outcome after ETV treatment. The ETVSS is more adequate in predicting short-term than long-term success. In our population, it is suggested that success rate for patients with moderate ETVSS could be improved if more weight is attributed to age at first ETV.

Sprengel's deformity and spinal dysraphism: connecting the shoulder and the spine.

BACKGROUND AND PURPOSE: Sprengel's deformity, a rare congenital malformation of the scapula, may be observed in combination with spinal dysraphism. The co-occurrence of these malformations suggests an unknown shared etiology. Therefore, we reviewed the medical records of eight children presenting with both malformations and performed a review of the literature. PATIENTS AND METHODS: Databases from four university medical centers were searched for children presenting between 1992 and 2012 with spinal dysraphism and a Sprengel's deformity. CONCLUSION: The combination of spinal dysraphism and Sprengel's deformity is rare, and is associated with segmentation defects of the spine and ribs. Although the etiology of both spinal dysraphism and Sprengel's deformity remains unclear, all deformities of the spine, ribs, and shoulder might result from a common genetic defect affecting somitogenesis.

In spina bifida aperta, muscle ultrasound can quantify the "second hit of damage".

PURPOSE: In spina bifida aperta (SBA), the "second-hit hypothesis" addresses consequences by delayed neurological damage superimposed upon the congenital myelomeningocele (MMC). This secondary damage is postulated to underlie the disappearance of leg movements shortly after birth. Innovative fetal surgery might prevent this, but results are methodologically hard to prove in small and heterogeneous treatment groups. We reasoned that delayed postnatal alterations in muscle ultrasound density (MUD = muscle echogenicity) could quantitatively reflect consequences by "the second hit" of damage. In the present study, we investigated whether delayed postnatal leg-MUD alterations are associated with postnatal muscle function loss. METHODS: We cross-sectionally assessed leg-MUD in 16 postnatally operated SBA children (MMC-L5; at 0, 6, and 12 months; in n = 11/16; 11/16, and 15/16 children, respectively) and compared outcomes with 13 healthy control children. Additionally, we assessed SBA MUD caudal and cranial to the MMC and calculated MMC-L5 impact by: dMUD((MMC-L5)) = [MUD(calf muscle/S1-2)] - [MUD(quadriceps muscle/L2-4)] and associated outcomes with leg muscle function caudal to the MMC. RESULTS: At 0 month, clinically discernible dMUD was more often increased in SBA than in control newborns (p < .05), but a relationship between absolute quantitative differences and leg muscle dysfunction was still lacking. At 6-12 months, additionally increased dMUD outcomes coincided with SBA leg muscle dysfunction (p < .05). CONCLUSIONS: In post-neonatal SBA, secondarily increased dMUD (i.e., MMC impact) coincides with leg muscle dysfunction. This may implicate that muscle ultrasound could provide a quantitative tool to assess the neuromuscular impact by the second hit of damage.

Low-pressure valves in hydrocephalic children: a retrospective analysis.

PURPOSE: A series of 100 children under 2 years of age treated for hydrocephalus is described. All patients received a standard differential low-pressure (SD low) valve as the first cerebrospinal fluid (CSF) shunt treatment. The performance of this group during follow-up is analysed. METHODS: A retrospective cohort study was performed using the intern electronic health record from our hospital. Children younger than 2 years who underwent initial CSF shunt treatment with a SD low valve between 1998 and 2008 were eligible. RESULTS: Mean follow-up was 7 years. The majority of 81% (81 of 100) of the children did not receive an upgrade of pressure profile throughout follow-up. The first revision was done after a mean of 456 days (median, 64 days; min, 3; and max, 4,183). The 1-year survival rate of the CSF shunt in this cohort was 42%. In the relatively large group of myelomeningocele patients (37 of 100), only one patient developed symptomatic overdrainage. A total of 9% (9 of 100) of the children presented with symptoms of overdrainage. In 3% (3 out of 100) of these children, symptoms of overdrainage persisted, in spite of multiple valve mutations. During the total follow-up, 26% (26 of 100) of the patients had never received shunt revision surgery. Fifteen percent (15 of 100) of the children developed a shunt infection within the first year. CONCLUSIONS: The use of SD low valves in the youngest age group is effective in the majority of children. The aetiology of myelomeningocele appears to protect the patient from symptomatic overdrainage.

Neurophysiological evaluation in children with Friedreich's ataxia.

INTRODUCTION: In children with Friedreich's ataxia (FRDA children), clinical ataxia outcomes are hardly substantiated by underlying neurophysiological parameters. In young FRDA children, some reports (based upon International Cooperative Ataxia Rating Scale scores (ICARS)) mention transient neurological improvement upon idebenone treatment. However, these outcomes are obtained with adult instead of pediatric reference values. It is unknown whether age-related neurophysiological parameters can really substantiate neurologic improvement. AIM: In young FRDA children, we aimed to determine longitudinal neurophysiological parameters during idebenone treatment. METHODS: During a two-year study period, 6 genetically proven FRDA children with cardiomyopathy (6-18years) were longitudinally assessed for neurophysiological parameters [sensory evoked potentials (SEPs), F response, peripheral nerve conduction and dynamometry] in association with age-matched ICARS-scores. RESULTS: In all FRDA children, SEPs remained absent during the two-year study period. Peroneal nerve conduction velocity declined (from -1SD to -2SD; p<.05), whereas F responses remained essentially unaltered. Total muscle force and leg muscle force decreased (from -2 to -3SD and -2.5 to -3.5SD; both p<.05) and age-related ICARS-scores deteriorated (median increase +41%; p<.05). CONCLUSION: In FRDA children, age-related neurophysiological and ataxia parameters deteriorate during idebenone treatment. Although we cannot exclude some (subjective) disease stabilization, age-related neurophysiological parameters do not substantiate neurologic improvement.

Intraspinal dermoid and epidermoid tumors: report of 18 cases and reappraisal of the literature.

Intraspinal dermoid and epidermoid tumors are two histopathological subtypes of cutaneous inclusion tumors of the spine. This classification is based on obsolete embryological knowledge. In fact, according to current embryology, both tumor types consist of ectodermal derivatives. Therefore, we hypothesized that dermoid and epidermoid tumors do not differ in clinical practice. To explore this hypothesis, we studied the clinical, radiological and intraoperative findings of 18 patients, and related these findings to the histopathological characteristics of the tumor. No differences were found between dermoid and epidermoid tumors regarding clinical presentation, radiological examination and outcome, while intraoperative diagnosis by the surgeon correlated with the histopathological diagnosis in only 8 of 18 cases. Therefore, the histopathological difference between intraspinal dermoid and epidermoid tumors is not important in clinical practice and should be avoided. A new nomenclature is proposed in which both tumor types are referred to as 'spinal cutaneous inclusion tumors'.

Muscle ultrasound density in human fetuses with spina bifida aperta.

BACKGROUND: In fetal spina bifida aperta (SBA), leg movements caudal to the meningomyelocele (MMC) are transiently present, but they disappear shortly after birth. Insight in the underlying mechanism could help to improve treatment strategies. In fetal SBA, the pathogenesis of neuromuscular damage prior to movement loss is still unknown. We reasoned that prenatal assessment of muscle ultrasound density (fetal-MUD) could help to reveal whether progressive neuromuscular damage is present in fetal SBA, or not. AIM: To reveal whether prenatal neuromuscular damage is progressively present in SBA. PATIENTS/METHODS: In SBA fetuses (n=6; 22-37 weeks gestational age), we assessed fetal-MUD in myotomes caudal to the MMC and compared measurements between myotomes cranial to the MMC and controls (n=11; 17-36 weeks gestational age). Furthermore, we intra-individually compared MUD and muscle histology between the pre- and postnatal period. RESULTS: Despite persistently present fetal leg movements caudal to the MMC, fetal-MUD was higher caudal to the MMC than in controls (p<0.05). Fetal-MUD caudal to the MMC did not increase with gestational age, whereas fetal-MUD in controls and cranial to the MMC increased with gestational age (p<0.05). In 5 of 6 patients assessed, comparison between pre- and postnatal MUD and/or muscle histology indicated consistent findings. CONCLUSIONS: In fetal SBA, persistent leg movements concur with stable, non-progressively increased fetal-MUD. These data may implicate that early postnatal loss of leg movements is associated with the impact of additional neuromuscular damage after the prenatal period.

Spinal hemorrhages are associated with early neonatal motor function loss in human spina bifida aperta.

BACKGROUND: In spina bifida aperta (SBA), leg movements caudal to the meningomyelocele are present in utero, but they disappear shortly after birth. It is unclear whether leg movements disappear by impact of the neuro-developmental malformation or by superimposed traumatic damage. If superimposed traumatic damage is involved, targeted fetal intervention could improve motor outcome. AIM: To characterize neuromuscular pathology in association with perinatal motor function loss in SBA. PATIENTS/METHODS: In fetal SBA (n=8; 16-40 weeks GA), the median time interval between ultrasound registrations of fetal motor behavior and post-mortem histology was 1 week. Histology was assessed cranial, at and caudal to the meningomyelocele and compared with findings in fetal controls (n=4). RESULTS: Despite fetal movements caudal to the meningomyelocele (5/6), histology indicated muscle fiber alterations (6/6) that concurred with neuro-developmental and traumatic spinal defects [Neuro-developmental defects: spinal ependymal denudation (3/8), reduced amount of (caspase3-negative) lower motor neurons (LMNs; 8/8), aberrant spinal vascularization (8/8). Traumatic defects: gliosis (7/8), acute/fresh spinal hemorrhages near LMNs (8/8)]. CONCLUSION: In all delivered SBA patients, recent spinal hemorrhages were superimposed upon pre-existing defects. If early therapeutic strategies can prevent these superimposed secondary spinal hemorrhages, motor outcome may improve.

Pyridoxine induces non-specific EEG alterations in infants with therapy resistant seizures.

PURPOSE: In infants with frequent therapy resistant seizures (TRS-infants), clinical detection of pyridoxine-dependency (PD) or -responsiveness (PR) occurs by empirical intravenous (IV) pyridoxine administration during recording of the EEG. However, in undiagnosed TRS-infants it is still unclear to what extent EEG alterations by pyridoxine-IV are attributable to PD/PR or to non-specific responses. Before EEG alterations by pyridoxine-IV can be ascribed to PD/PR, these non-specific responses should be excluded first. METHODS: In 10 TRS-infants under 1 year of age, we determined the EEG effect by pyridoxine-IV on the EEG-recording. RESULTS: After pyridoxine-IV administration, our data indicate declined (10-15%; p<0.05) EEG-amplitudes and total power (magnitude/frequency-band) at frontal, central and centro-temporal electrodes. CONCLUSION: In TRS-infants, pyridoxine-IV affects EEG-amplitude and -total power in a non-specific way, which does not identify PD/PR.