Aromatic L-Amino-Acid Decarboxylase Deficiency Screening by Analysis of 3-O-Methyldopa in Dried Blood Spots: Results of a Multicentric Study in Neurodevelopmental Disorders.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human DDC gene injected into the putamen is available. The typical presentation is characterized by early-onset hypotonia, severe developmental delay, movement disorders, and dysautonomia. Recently, mild and even atypical phenotypes have been reported, increasing the diagnostic challenge. The aim of this multicentric study is to identify the prevalence of AADCd in a population of patients with phenotypic clusters characterized by neurodevelopmental disorders (developmental delay/intellectual disability, and/or autism) by 3-O-methyldopa (3-OMD) detection in dried blood spots (DBS). It is essential to identify AADCd promptly, especially within non-typical phenotypic clusters, because better results are obtained when therapy is quickly started in mild-moderate phenotypes. Between 2021 and 2023, 390 patients with non-specific phenotypes possibly associated with AADCd were tested; none resulted in a positive result. This result highlights that the population to be investigated for AADCd should have more defined clinical characteristics: association with common signs (hypotonia) and/or pathognomonic symptoms (oculogyric crisis and dysautonomia). It is necessary to continue to screen selected clusters for reaching diagnosis and improving long-term outcomes through treatment initiation. This underscores the role of newborn screening in identifying AADCd.

Clinical profiles of acute arterial ischemic neonatal stroke.

INTRODUCTION: Perinatal stroke includes a heterogeneous group of early focal neurological injuries affecting subsequent brain development, often resulting in motor sequelae, symptomatic epilepsies, and cognitive, language and behavioral impairment. The incidence of perinatal stroke is about 1/3500 live birth. EVIDENCE ACQUISITION: A PubMed and SCOPUS search strategy included the entries "neonatal ischemic stroke" OR "perinatal ischemic stroke" and the age of the filter under 18 years and January 2000-August 2022. EVIDENCE SYNTHESIS: The cumulative literature analysis highlighted 3880 published patients (from 98 articles) with stroke, mainly presenting with clinical or electro-graphical seizures (2083 patients). The mean age at presentation was 2,5±2,4 days (data available for 1182 patients). Stroke occurred in the first week of life in 1164 newborns. The mainly involved ischemic areas were within the territories of the middle cerebral artery (1403 patients). Predisposing risk factors included fetal/newborn factors (1908 patients), dystocial birth (759 patients), maternal (678 patients), and placental factors (63 patients). No thrombolysis and/or endovascular treatments were performed, while data about other pharmacological treatments were restricted to a single article. The death occurred in 29 newborns. Motor, neurocognitive and language impairment were cumulatively reported in 875 patients. Epileptic seizures during the follow-up were reported in 238 cases. CONCLUSIONS: The literature analysis highlighted that every term newborn presenting with acute neurological signs and symptoms during the first week of life should always be considered for the identification of an ischemic stroke.

Atypical presentation of juvenile multiple sclerosis in a patient with COVID-19.

PURPOSE: To report our experience with a case of a very atypical clinical onset of multiple sclerosis in a young boy during a COVID-19 infection. CASE REPORT: A 16-year-old boy was referred to our ophthalmology clinic with a complete isolated bilateral horizontal gaze palsy. The condition had onset suddenly 2 weeks prior and he had no associated symptoms, as well as no significant medical history. His corrected visual acuity was 0.0 logMAR in both eyes. While hospitalized, he was found infected with COVID-19. Subsequent brain MRI showed multiple lesions typical of a yet undiagnosed MS, as well as an active pontine plaque which was highly probable the cause of the horizontal gaze palsy. High-dose steroid treatment was initiated 1 week later, after the patient exhibited negative COVID-19 test results. CONCLUSION: Clinical manifestations of MS are rarely seen in male teenagers and only a few cases of isolated bilateral horizontal gaze palsy have been reported as the initial manifestation, but never during concomitant COVID-19 infection. We presume that the presence of COVID-19 may have been a neuroinflammatory trigger of underlying MS.

Early Immunotherapy and Longer Corticosteroid Treatment Are Associated With Lower Risk of Relapsing Disease Course in Pediatric MOGAD.

BACKGROUND AND OBJECTIVES: We sought to identify early factors associated with relapse and outcome in paediatric-onset myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD). METHODS: In a multicenter retrospective cohort of pediatric MOGAD (≤18 years), onset features and treatment were compared in patients with monophasic vs relapsing disease (including cases with follow-up ≥12 months after onset or relapse at any time) and in patients with final Expanded Disability Status Scale (EDSS) 0 vs ≥1 at last follow-up (including cases with follow-up >3 months after last event or EDSS0 at any time). Multivariable logistic regression models were used to evaluate factors associated with relapsing disease course and EDSS ≥ 1 at final follow-up. RESULTS: Seventy-five children were included (median onset age 7 years; median 30 months of follow-up). Presentation with acute disseminated encephalomyelitis was more frequent in children aged 8 years or younger (66.7%, 28/42) than in older patients (30.3%, 10/33) (p = 0.002), whereas presentation with optic neuritis was more common in children older than 8 years (57.6%, 19/33) than in younger patients (21.4%, 9/42) (p = 0.001). 40.0% (26/65) of patients relapsed. Time to first relapse was longer in children aged 8 years or younger than in older patients (median 18 vs 4 months) (p = 0.013). Factors at first event independently associated with lower risk of relapsing disease course were immunotherapy <7 days from onset (6.7-fold reduced odds of relapsing course, OR 0.15, 95% CI 0.03-0.61, p = 0.009), corticosteroid treatment for ≥5 weeks (6.7-fold reduced odds of relapse, OR 0.15, 95% CI 0.03-0.80, p = 0.026), and abnormal optic nerves on onset MRI (12.5-fold reduced odds of relapse, OR 0.08, 95% CI 0.01-0.50, p = 0.007). 21.1% (15/71) had EDSS ≥ 1 at final follow-up. Patients with a relapsing course had a higher proportion of final EDSS ≥ 1 (37.5%, 9/24) than children with monophasic disease (12.8%, 5/39) (p = 0.022, univariate analysis). Each 1-point increment in worst EDSS at onset was independently associated with 6.7-fold increased odds of final EDSS ≥ 1 (OR 6.65, 95% CI 1.33-33.26, p = 0.021). DISCUSSION: At first attack of pediatric MOGAD, early immunotherapy, longer duration of corticosteroid treatment, and abnormal optic nerves on MRI seem associated with lower risk of relapse, whereas higher disease severity is associated with greater risk of final disability (EDSS ≥ 1).

Prognostic relevance of quantitative and longitudinal MOG antibody testing in patients with MOGAD: a multicentre retrospective study.

BACKGROUND: IgG antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) define a subset of associated disorders (myelin oligodendrocyte glycoprotein associated disorders (MOGAD)) that can have a relapsing course. However, information on relapse predictors is scarce. The utility of retesting MOG-IgG over time and measuring their titres is uncertain. We aimed to evaluate the clinical relevance of longitudinal MOG-IgG titre measurement to predict relapses in patients with MOGAD. METHODS: In this retrospective multicentre Italian cohort study, we recruited patients with MOGAD and available longitudinal samples (at least one >3 months after disease onset) and tested them with a live cell-based assay with endpoint titration (1:160 cut-off). Samples were classified as 'attack' (within 30 days since a disease attack (n=59, 17%)) and 'remission' (≥31 days after attack (n=295, 83%)). RESULTS: We included 102 patients with MOGAD (57% adult and 43% paediatric) with a total of 354 samples (83% from remission and 17% from attack). Median titres were higher during attacks (1:1280 vs 1:640, p=0.001). Median onset titres did not correlate with attack-related disability, age or relapses. Remission titres were higher in relapsing patients (p=0.02). When considering the first remission sample available for each patient, titres >1:2560 were predictors of relapsing course in survival (log rank, p<0.001) and multivariate analysis (p<0.001, HR: 10.9, 95% CI 3.4 to 35.2). MOG-IgG seroconversion to negative was associated with a 95% relapse incidence rate reduction (incidence rate ratio: 0.05, p<0.001). CONCLUSIONS: Persistent MOG-IgG positivity and high remission titres are associated with an increased relapse risk. Longitudinal MOG-IgG titres could be useful to stratify patients to be treated with long term immunosuppression.

The duration of successive epileptic seizures is monotonically correlated in neonates.

OBJECTIVE: Prolonged neonatal seizures are often due to severe acute brain injuries and are known to be harmful to the brain. No predictors have yet been identified to distinguish at an early time-point between brief and long seizures. We investigated the duration of seizures in neonates to determine the relationship between the duration of a seizure and that of subsequent seizures. METHODS: We retrospectively reviewed video-electroencephalogram confirmed seizures of 30 preterm and 36 full-term neonates selected from patients admitted to the neonatal intensive care unit of Parma University Hospital. The duration and relationship between successive seizures were investigated. Statistical models were performed to evaluate the risk of long-lasting ictal events among neonates with seizures. RESULTS: A positive monotonic relationship between the duration of successive seizures was identified. Most seizures were brief. No significant differences in seizure duration were found between preterm and full-term neonates, although a borderline significance emerged. CONCLUSION: Neonatal seizures are usually brief, and as the seizure duration increases, the duration of the subsequent seizures tends to increase. We also suggest that full-term neonates could be at higher risk of experiencing long seizures compared to preterm neonates. In summary, estimating the seizure duration is critical to evaluating the optimal timing of therapeutic interventions and can help to predict how seizures evolve.

Herpes zoster preceding neuromyelitis optica spectrum disorder: casual or causal relationship? A systematic literature review.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe, inflammatory, immune-mediated astrocytopathy of the central nervous system, characterized by recurrent inflammatory events primarily involving optic nerves and the spinal cord. Recently, a triggering role of infectious events in the development of NMOSD has been suggested. Varicella zoster virus (VZV) is the agent most involved, although the linkage with anti-aquaporin-4 antibodies is so far unknown. A review of the literature on the association between NMOSD and VZV infection was carried out by searching PUBMED and EMBASE from 1975 to July 2020. A total of 13 articles concerning Herpes zoster preceding NMOSD were identified. All patients were female and the median age at NMOSD presentation was 28.5 (range 5-63) years. Four NMOSD cases occurred after chicken pox while the remaining ten after HZ. Full recovery occurred in 5/14 patients. From the review of the literature, we can infer that VZV seems to trigger LETM attacks and not the disease itself. The strict temporal relationship between VZV infection and NMOSD seems to exceed the pure chance and represents an unusual clinical scenario posing several diagnostic and management challenges.

Epilepsy, electroclinical features, and long-term outcomes in Pitt-Hopkins syndrome due to pathogenic variants in the TCF4 gene.

BACKGROUND AND PURPOSE: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by deletions/variants in the TCF4 gene. Seizures may be present in up to half of the patients, leading to a more severe disease burden. This study aims to analyse the electroclinical phenotype, treatment options, and long-term outcomes of epilepsy in PTHS. METHODS: A multicentre observational cohort study was performed, and the electroclinical data of PTHS individuals affected by epileptic seizures were retrospectively reviewed and analysed. RESULTS: The series includes 21 patients (11 female) with a median age at seizure onset of 2 years (range = 0.5-8). The median time of follow-up was 7.9 years (range = 2-27). Both generalized and focal epilepsies were present at the same prevalence (42.8%), whereas a minority of patients presented developmental and epileptic encephalopathies (14.4%). At the long-term follow-up, 42.8% achieved seizure freedom, whereas 42.8% developed drug-resistant epilepsy (DRE). The age at seizure onset was found to be an independent predictor for seizure outcome; in this regard, patients having seizure onset after the age of 2 years were more prone to achieve seizure freedom (odds ratio = 0.04, 95% confidence interval = 0.003-0.53; p = 0.01). During evolution, seizures tended to settle down, and even in patients with DRE, seizures tended to persist at a lower frequency and appeared to be more easily manageable over time. CONCLUSIONS: This study provides new insight into the natural history of epilepsy in PTHS. Better characterization of epileptic phenotype and prompt tailored treatment improve overall management and quality of life.

Psychiatric Emergency in Children and Adolescents: A Retrospective Study in Parma Local Health Unit.

The mental health care system in Italy is based on Law 180/70 which leaves great regional autonomy about the management of adolescent patients suffering from psychiatric diseases. The aim of this study is the evaluation of demographic, social, and clinical features of minors admitted to psychiatric wards, as starting point to improve individualized services for them. Data about all under 18s consecutively admitted to Parma's psychiatric wards from 2013 to 2015 were retrospectively collected from medical records. Diagnoses were classified according to ICD-10 criteria, and statistical analysis was performed using SPSS statistical software (IBM SPSS Statistics 22.0) for Windows. Clinical samples include 51 cases, 30 males (mean age: 15.5 years, ranging from 12 to 17 years) and 21 females (mean age: 15.9, ranging from 14 to 17 years). The most frequent diagnosis is conduct disorder (39.2%), with higher prevalence among males. Following this, 23.5% of the patients present comorbidity issues and 9.8% suffer from personality disorders, which is more frequent among females. High percentages of foreigners (31.4%), adopted minors (15.7%), and drug users (40%) are reported. Furthermore, data reveal that unprotective family environment, registered in 80.4% of cases, plays an important role as risk factor for the development of mental disease, readmissions in psychiatric wards, and discharge to residential facilities. Readmissions, as well as compulsory treatments (11 cases), are mainly required in case of conduct disorders and comorbidity diagnosis. Lastly, in contrast with the situation before hospital admission, most patients (63.3%) are discharged and sent to community residential facilities. Findings can be useful to improve the management of psychiatric emergencies in minors, focusing on their specific needs, such as conduct disorders and substance abuse, and to face emerging challenges, for example, mental health disease associated with the growing phenomenon of immigration.

Nystagmus in Infantile Pompe Disease: a new feature?

We describe a 3 month-old female floppy infant with hypertrophic cardiomyopathy, serum enzyme levels, which were characterized by an aspartate aminotransferase level of 144 U/l, alanine transaminase 240 U/L and creatine kinase level of 543 U/l. On the basis of the clinical signs and laboratory results,  acid α-glucosidase activity was determined from dried blood spots resulting lower than the normal range (0.2 mmol/L/h: normal reference range: 1,86-21,9 mmol/L/h) and leading to a diagnosis of infantile Pompe disease. She also showed multi-directional nystagmus. Refractive errors, ptosis and strabismus are described in infantile Pompe Disease, while nystagmus is rarely reported before. Therefore with this paper we highlight an atypical ocular symptom, whose uncertain pathogenesis, to be taken into consideration, because by now, with increasing survival with ERT, new phenotypes of Pompe disease are taking shape.

Neuromyelitis Optica Spectrum Disorder Attack Triggered by Herpes Zoster Infection.

Neuromyelitis optica spectrum disorder is a severe autoimmune disease of the central nervous system characterized by recurrent inflammatory events primarily involving the optic nerves and spinal cord. Recently, a triggering role of infectious events in the development of NMOSD has been suggested. Varicella zoster virus is the most common viral infection involved, though the linkage with anti-aquaporin-4 antibodies is so far unknown. We report, to the best of our knowledge, the first pediatric case report about NMOSD relapse triggered by herpes zoster infection. The strict temporal relationship between VZV infection and NMO attacks seems to be more than simply due to chance; however, further reports are needed to be confirmed.

Incidence of Epilepsy after Neonatal Seizures: A Population-Based Study.

BACKGROUND: The incidence of childhood and adolescence epilepsy varies in different areas and over time. Published reports in the Italian pediatric population are few and there is no information on the incidence of epilepsy using the new clinical definition of the disease signed by the International League Against Epilepsy. An increased risk of epilepsy is reported in subjects who presented with neonatal seizures (NS), but few population-based studies are available that compare incidence and age at onset of epilepsy in children with and without NS. OBJECTIVES: Ascertain the incidence of epilepsy in children in the province of Parma by applying the new practical clinical definition of epilepsy, and compare incidence and age of epilepsy onset in children with and without previous NS. METHODS: The study was carried out in the province of Parma, Emilia-Romagna Region, Northern Italy, using different data sources (clinical records and administrative data), and considered all the children born in the province of Parma between January 2002 and December 2014 and developing epilepsy by December 2016. We calculated the incidence of epilepsy in patients up to 14 years of age, incidence of epilepsy after NS and cumulative incidence of epilepsy at 1, 5, and 10 years' follow-up. To evaluate age at onset of epilepsy, we divided patients into 3 groups (epilepsy onset within 1 month, between 1 and 12 months, and after 1 year of life) and we compared age at onset of epilepsy between patients who had had previous NS and those who had not. RESULTS: The incidence of epilepsy was 78.6/100,000 persons-years (boys 88.1/100,000, girls 68.6/100,000). The incidence of epilepsy after NS was 15.2% (8.2% for male, 23.5% for female; 16.3% in born at term, 14.3% in pre-term). The incidence of epilepsy at 1, 5, and 10 years' follow-up was higher in patients with previous NS than in others. The age at onset of epilepsy was significantly different in the 2 groups, and was younger in those with history of NS: mean age at onset was 10.5 months in those with NS and of 61.8 months in the others. CONCLUSIONS: The incidence rate of epilepsy in the Parma district was higher than that reported in other Italian areas studied, probably due to the different methodology used and the application of the most recent definition of epilepsy. Children with NS were at higher risk of epilepsy and develop the disease at a younger age.

Tap seizures in infancy: A critical review.

Tap seizure is a type of reflex myoclonic epilepsy in which seizures are evoked mainly by unexpected tactile stimuli and which is classified among the electroclinical syndromes of infancy. This condition, whose onset is in the first two years of life, is characterized by excellent prognosis and is extremely rare. We reviewed all published articles and case reports on Reflex Myoclonic Epilepsies focusing on touch-induced seizures in order to clarify clinical and electroencephalographic findings. Our aim is to increase knowledge about this specific disorder in order to help pediatricians avoid extensive investigations when making their diagnosis and reassure parents regarding absence of long-term complications.

A novel temporal pattern of childhood cerebral X-linked adrenoleukodystrophy.

We report a 9-year-old boy, with childhood cerebral X-linked adrenoleukodystrophy (CCALD), presenting with an episode of loss of consciousness, fixed gaze, hypotonia and vomit with spontaneous resolution and post-ictal sleep. Behavioural impairment has been observed since the previous five months. Magnetic Resonance Images (MRI) revealed isolated bilateral, symmetric, confluent temporal white matter lesions involving also corticospinal tracts, with sparing of the parieto-occipital and frontal white matter. This report outlines an atypical neuroradiological localization of X-linked adrenoleukodystrophy and neuropsychological findings not specifically related to the brain involvement seen at the MRI.

Reflex Myoclonic Epilepsy of Infancy: Seizures Induced by Tactile Stimulation.

Myoclonic epilepsy with reflex seizures in infancy is an extremely rare condition, in which seizures are provoked mainly by auditory or auditory-tactile stimuli. To increase the awareness of pediatricians regarding this underrecognized condition, we describe a child with seizures provoked only by the tactile stimulation of specific areas of the head and face.

Hereditary Hemorrhagic Telangiectasia presenting as migraine: a case report.

BACKGROUND: Hemorrhagic Hereditary Telangiectasia (HHT) is an autosomal dominant disease characterized by the presence of multiple arteriovenous malformations (AVMs). Migraine is described in association with HHT in adulthood, while only few paediatric cases are reported in the literature. AIM: In this paper, we describe an atypical case of HHT in a 7-year-old boy, who presented severe and recurrent episodes of migraine-like headache as the first symptom of the disease. METHODS: The patient was accurately investigated both clinically (general, neurological and dermatological examinations), instrumentally (electroencephalogram, brain magnetic resonance, transcranic Eco-color-Doppler, contrast echocardiography and enhanced chest computed tomography) and genetically. RESULTS: Familial history was positive for HHT in the paternal line. Both general and neurological examination were normal. Brain magnetic resonance imaging showed a minor old infarct in the right parietal and occipital lobes. Transcranic Eco-color-Doppler, contrast echocardiography and enhanced chest computed tomography revealed a pulmonary AVM. Cephalalgia resolved after transcatheter embolotherapy. A genetic test, identifying the mutation in endoglin gene both in the patient and in the father, confirmed the suspected diagnosis of HHT. CONCLUSIONS: Although headache is rarely reported in children as the first symptom of HHT, we warn clinicians on this possible link, as a promptly diagnosis is advisable in order to prevent potential complications.

Clinical and polygraphic improvement of breathing abnormalities after valproate in a case of Pitt-Hopkins syndrome.

Pitt-Hopkins syndrome is a rare genetic form of severe psychomotor delay, caused by mutations in transcription cell factor-4 gene and characterized by distinctive dysmorphic features and abnormal breathing pattern. The current report describes the polygraphic features of the syndrome's typical breathing pattern in a patient both in wakefulness and in sleep. The control of these breathing alterations is important to prevent the neurological sequelae linked to chronic cerebral hypoxemia in early ages. No data are available on effective treatment options for breathing abnormalities of Pitt-Hopkins syndrome. The authors polygraphically documented a reduction of apneic and hypopneic phenomena, with a significant improvement in saturation values, after the introduction of sodium valproate.

Mortality risk after neonatal seizures in very preterm newborns.

We analyzed clinical and instrumental data of 403 consecutive newborns with gestational age from 24 to 32 weeks, admitted to the University-Hospital of Parma between January 2000 and December 2007, to evaluate the possible relationship between neonatal mortality and occurrence of neonatal seizures in very preterm newborns. Seventy-four subjects died during hospital stay. Seizures were present in 35 neonates, in whom the mortality rate was 37.1%. Multivariate analysis revealed that birth-weight <1000 g (odds ratio: 4.48; 95% confidence interval: 1.47-13.68; P < .01), cardiopulmonary resuscitation (odds ratio: 5.35; 95% confidence interval: 1.19-23.98; P = .02), and moderately and severely abnormal cerebral ultrasound scan findings (odds ratio: 2.48; 95% confidence interval: 1.02-6.05; P < .04; odds ratio: 9.56; 95% confidence interval: 3.45-26.51; P < .01, respectively) were related to the in-hospital mortality but not the presence of neonatal seizures. Our study suggests that neonatal seizures alone are not an independent risk factor for early death in very preterm newborns.