[Movement disorders]. / Trastornos del movimiento.

Thanks to the application of modern techniques such as next-generation sequencing in the study of apparently non-inherited encephalopathies it has become possible to describe de novo pathogenic mutations in unsuspected genes and to define the phenotypes of these mutations. Interestingly, in most cases, their clinical signs and symptoms show a spectrum in which epileptic encephalopathy, neurodevelopmental disorder and hyperkinetic abnormal movement disorders overlap. Their pathophysiology is located in synapses (synaptopathies). This article offers a brief summary of these disorders and also includes a simple note, in honour of Dr Natalio Fejerman (1934-2018), on the so-called «benign polymorphic disorder of infancy¼.

TITLE: Trastornos del movimiento.Gracias a la aplicacion de modernas tecnicas como la siguiente secuenciacion (next-generation sequencing) en el estudio de encefalopatias aparentemente no heredadas ha sido posible descubrir mutaciones patogenas de novo en genes insospechados y definir los fenotipos de estas mutaciones. Es interesante que, en la mayoria de los casos, sus cuadros clinicos muestran un espectro en el que se solapan encefalopatia epileptica, trastorno del neurodesarrollo y movimientos anormales de tipo hipercinetico. Su fisiopatologia se localiza en la sinapsis (sinaptopatias). En este articulo se hace una breve sintesis de estos trastornos y se añade una sencilla nota, en honor al Dr. Natalio Fejerman (1934-2018), sobre la base del denominado «trastorno polimorfo benigno del lactante¼.

Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency.

Tyrosine hydroxylase (TH) deficiency is an inborn error of dopamine biosynthesis and a cause of early parkinsonism. Two clinical phenotypes have been described. Type "B": early onset severe encephalopathy; type "A": later onset, less severe and better response to L-dopa. We aimed to study the expression of several key dopaminergic and gabaergic synaptic proteins in the cerebrospinal fluid (CSF) of a series of patients with TH deficiency and their possible relation with the clinical phenotype and response to L-DOPA. Dopamine transporter (DAT), D2-receptor and vesicular monoamine transporter (VMAT2) were measured in the CSF of 10 subjects with TH deficiency by Western blot analysis. In 3 patients, data of pre- and post-treatment with L-DOPA were available, and in one of them, GABA vesicular transporter was determined. Results were compared to an age-matched control population. The concentration of D2-receptors in CSF was significantly higher in patients with TH deficiency than in controls. Similarly, DAT and vesicular monoamine transporter type 2 were up-regulated. Studies performed before L-DOPA, and on L-DOPA therapy showed a paradoxical response with D2 receptor expression increase as L-Dopa doses and homovanillic concentration gradually raised in a B phenotype patient. The opposite results were found in two patients with A phenotype. However, this is a very small sample, and further studies are needed to conclude robust differences between phenotypes. Synaptic proteins are detectable in the CSF and their quantification can be useful for understanding the pathophysiology of neurotransmitter defects and potentially to adjust and personalize treatments in the future.

Treatment for dystonia in childhood.

Management of childhood dystonia differs in certain respects from that of adult dystonia: (i) childhood dystonia is more often secondary than primary; (ii) mixed motor disorders are frequent; (iii) in children, the course of dystonia may be influenced by ongoing brain maturation and by the remarkable plasticity of the young brain; (iv) drug tolerability and effectiveness can be different in children; (v) the therapeutic strategy must be discussed with both the patient and his or her parents; and (vi) the child's education must be taken into account. Based on a systematic review of the literature through June 2011 and on our personal experience, we propose a therapeutic approach to childhood dystonia. After a detailed clinical evaluation and a comprehensive work-up to rule out a treatable cause of dystonia, symptomatic treatment may include various drugs, local botulinum toxin injections, and deep brain stimulation, in addition to rehabilitation.

Hypokinetic-rigid syndrome in children and inborn errors of metabolism.

Hypokinetic-rigid syndrome (HRS) or "parkinsonism" is rare in children. From a clinical point of view it is characterised by a group of signs in which hypokinesia (decreased number of movements), bradykinesia (slowness of movements), rigidity and rest tremor are the fundamental traits. Nervous system infections, immunomediated encephalitis, hypoxia and some drugs have been described as acquired or secondary causes of HRS in the paediatric age. Inborn errors of metabolism (IEM) comprise and important group regarding genetic causes. Main diseases causing HRS in children are neurotransmitter (biogenic amines) defects, metal storage diseases, energy metabolism disorders and lysosomal diseases. In general, in IEM, the HRS is associated to other neurological signs such as dykinesias, pyramidal signs, and psychomotor delay, is very rare in the neonatal period, tends to be more frequent in advanced stages of progressive diseases, and may respond to specific therapies. In particular, l-dopa + carbidopa can be a very effective treatment in neurotransmitter defects, whereas other disorders such as Wilson disease and some particular lysosomal disorders have different therapeutic possibilities. Furthermore, other genetic conditions in dopa-responsive and non-responsive HRS should be also considered, especially in juvenile parkinsonism. Through this review, a practical orientation for paediatric neurologists concerning clinical clues, diagnostic procedure and treatment of metabolic HRS will be provided.

Dystonia. The paediatric perspective.

BACKGROUND AND AIMS: This review focuses on some paediatric dystonias such as transient dystonias, new primary paediatric-onset dystonias, dopamine biosynthesis defects and new paroxysmal disorders. It is designed to provide practical help for neurologists and neuropediatricians to make appropriate diagnoses and plan the management of these disorders. MATERIAL AND METHODS: Literature searches were performed and original papers, meta-analyses and review papers were reviewed. CONCLUSION: Paediatric onset dystonia is an increasingly interesting group of conditions that provides an expanding area of neuroscientific knowledge. Given the long life expectancy of children, appropriate treatment at the correct moment will have an important, lasting effect on the personal, social and healthcare domains.

Inborn errors of metabolism and motor disturbances in children.

Motor disturbances are very common in paediatric neurology. Often families can be reassured that these are just variants of normal development. However, abnormal movements can also be the hallmark of severe brain dysfunction of different and complex origins. This review concentrates on motor disturbances as frequent and important symptoms of inborn errors of metabolism. A structured diagnostic approach is developed taking into account age-dependent physiological developments and pathophysiological responses of gross and fine motor functions. A series of investigations are presented with the primary aim of early diagnosis of treatable conditions. The correct recognition and differentiation of movement disorders (ataxia, rigid akinetic syndrome (Fparkinsonism_), dystonia, athetosis, tremor,and others), spasticity, and neuromuscular disorders, requires profound neurological expertise. A high level of suspicion and close interaction between paediatric neurologists and specialists in inborn errors of metabolism are indispensable to effectively and timely identify patients in whom motor disturbances are the presenting and/or main symptom of an inborn error.

[Pharmacological preconditioning with sildenafil of warm ischemic kidneys]. / Precondicionamiento farmacológico con sildenafilo del riñón con isquemia normotérmica.

OBJECTIVES: To evaluate the preconditioning effect of sildenafil administered preoperatively in kidneys subjected to a period of warm ischemia (WI), hypothermic perfusion (HP) or cold storage (CS) and finally, autotransplant (AT). MATERIAL AND METHOD: We studied 6 groups of autotransplanted kidneys: no-WI-inmediate AT (Group A); 45 min of WI + immediate AT (Group B); 45 min of WI + 60 min of HP + autotransplant (Group C); 45 min of WI + 60 min of CS + autotransplant (Group D); 100 mg of oral sildenafil preoperatively + 45 min of WI + autotransplant (Group E); 100 mg of oral sildenafil preoperatively + 45 min of WI+60 min of HP + autotransplant (Group F). Belzer solution was used for HP; UW-Viaspan for CS. Inmediately after the autotransplant (reperfusion period), we recorded in real time for 60 min the values of Renal vascular Flow (RVF) and Renal Vascular Resistance (RVR). Nitric Oxide levels in the cava and renal graft vein were recorded every 15 min during the 60 min of the reperfusion-study period. Conventional & Electronic microscopy were completed after the process. RESULTS: We obtained significant higher values of RVF and lower values of RVR in sildenafil groups (E and F) in comparison to the other groups (A-D) (Table 1). NO levels were also significantly higher in groups E and F (Fig. 1). Groups A, B, E and F showed integrity of tubule and endothelium in comparison to groups C and D in the microscopic study. CONCLUSIONS: We showed a beneficious effect of sildenafil in inmediate post-transplant reperfusion hemodynamic and biochemical parameters of kidneys subjected to a critical period of warm-ischemia.

Secondary abnormalities of neurotransmitters in infants with neurological disorders.

Neurotransmitters are essential in young children for differentiation and neuronal growth of the developing nervous system. We aimed to identify possible factors related to secondary neurotransmitter abnormalities in pediatric patients with neurological disorders. We analyzed cerebrospinal fluid (CSF) and biogenic amine metabolites in 56 infants (33 males, 23 females; mean age 5.8mo [SD 4.1mo] range 1d-1y) with neurological disorders whose aetiology was initially unknown. Patients were classified into three clinical phenotypes: epileptic encephalopathy, severe motor impairment, and non-specific manifestations. All patients showed normal results for screening of inborn errors of metabolism. We report clinical, neuroimaging, and follow-up data. Among the patients studied, 10 had low homovanillic acid (HVA) levels and in four patients, 5-hydroxyindoleacetic acid (5-HIAA) was also reduced. Patients with neonatal onset had significantly lower levels of HVA than a comparison group. HVA deficiency was also associated with severe motor impairment and the final diagnosis related to neurodegenerative disorders. 5-HIAA values tended to be decreased in patients with brain cortical atrophy. The possibility of treating patients with L-Dopa and 5-hydroxytryptophan, in order to improve their neurological function and maturation, may be considered.

Palatal tremor in childhood: clinical and therapeutic considerations.

Palatal tremor (PT) is a rhythmic movement of the soft palate that often causes an ear click. PT can be symptomatic (SPT) or essential (EPT). The symptomatic form usually occurs in adults and the essential form mainly occurs in children. Several different treatments for EPT in children appear in the literature with variable reported efficacy. This report details four paediatric patients with EPT (three males, one female; mean age 6y 4mo [SD 6mo]; age at onset 6-7y) treated with piracetam (2-oxo-1-pyrrolidine acetamide). Piracetam was used to treat EPT because of its antimyoclonic properties. All children showed a good response to doses of 100 to 300mg/kg/day. EPT relapsed on withdrawal of piracetam and remitted on reintroduction. Piracetam's effect on EPT was sustained. It is concluded that piracetam is an effective drug for the treatment of EPT in children.

GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis.

BACKGROUND: Guanidinoactetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine synthesis. The authors analyzed clinical, biochemical, and molecular findings in 27 patients. METHODS: The authors collected data from questionnaires and literature reports. A score including degree of intellectual disability, epileptic seizures, and movement disorder was developed and used to classify clinical phenotype as severe, moderate, or mild. Score and biochemical data were assessed before and during treatment with oral creatine substitution alone or with additional dietary arginine restriction and ornithine supplementation. RESULTS: Intellectual disability, epileptic seizures, guanidinoacetate accumulation in body fluids, and deficiency of brain creatine were common in all 27 patients. Twelve patients had severe, 12 patients had moderate, and three patients had mild clinical phenotype. Twenty-one of 27 (78%) patients had severe intellectual disability (estimated IQ 20 to 34). There was no obvious correlation between severity of the clinical phenotype, guanidinoacetate accumulation in body fluids, and GAMT mutations. Treatment resulted in almost normalized cerebral creatine levels, reduced guanidinoacetate accumulation, and in improvement of epilepsy and movement disorder, whereas the degree of intellectual disability remained unchanged. CONCLUSION: Guanidinoactetate methyltransferase deficiency should be considered in patients with unexplained intellectual disability, and urinary guanidinoacetate should be determined as an initial diagnostic approach.

A systematic review on the diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS/MDS-ES Task Force.

To review the literature on primary dystonia and dystonia plus and to provide evidence-based recommendations. Primary dystonia and dystonia plus are chronic and often disabling conditions with a widespread spectrum mainly in young people. Computerized MEDLINE and EMBASE literature reviews (1966-1967 February 2005) were conducted. The Cochrane Library was searched for relevant citations. Diagnosis and classification of dystonia are highly relevant for providing appropriate management and prognostic information, and genetic counselling. Expert observation is suggested. DYT-1 gene testing in conjunction with genetic counselling is recommended for patients with primary dystonia with onset before age 30 years and in those with an affected relative with early onset. Positive genetic testing for dystonia (e.g. DYT-1) is not sufficient to make diagnosis of dystonia. Individuals with myoclonus should be tested for the epsilon-sarcoglycan gene (DYT-11). A levodopa trial is warranted in every patient with early onset dystonia without an alternative diagnosis. Brain imaging is not routinely required when there is a confident diagnosis of primary dystonia in adult patients, whereas it is necessary in the paediatric population. Botulinum toxin (BoNT) type A (or type B if there is resistance to type A) can be regarded as first line treatment for primary cranial (excluding oromandibular) or cervical dystonia and can be effective in writing dystonia. Actual evidence is lacking on direct comparison of the clinical efficacy and safety of BoNT-A vs. BoNT-B. Pallidal deep brain stimulation (DBS) is considered a good option, particularly for generalized or cervical dystonia, after medication or BoNT have failed to provide adequate improvement. Selective peripheral denervation is a safe procedure that is indicated exclusively in cervical dystonia. Intrathecal baclofen can be indicated in patients where secondary dystonia is combined with spasticity. The absolute and comparative efficacy and tolerability of drugs in dystonia, including anticholinergic and antidopaminergic drugs, is poorly documented and no evidence-based recommendations can be made to guide prescribing.

[Inborn errors of neurotransmitters in neuropaediatrics]. / Errores congénitos de los neurotransmisores en Neuropediatría.

AIMS: The aim of this work is to describe the clinical, biochemical and genetic characteristics of neurotransmitter diseases at the paediatric age, together with possible forms of treatment. We also sought to determine the diagnostic methodology of these disorders (collection and analysis of samples). DEVELOPMENT: These diseases essentially consist of a deficit of biogenic amines and alterations in GABA metabolism (gamma-aminobutyric acid). Disorders affecting the neurotransmission of biogenic amines often present in the form of hypokinesia, trunk hypotonia with increased limb tone, oculogyric crises, ptosis, faulty temperature regulation or abnormal movements. Defects in GABA metabolism give rise to epileptic encephalopathies and unspecific mental retardation, sometimes associated to signs of cerebellar dysfunction, convulsions and alterations in neuroimaging studies. Overall incidence of these diseases is low but they are unquestionably under-diagnosed, since they cannot be detected by conventional studies in plasma and urine, and require extraction and directed analysis of cerebrospinal fluid (CSF) for their detection. Additionally, the CSF study must be carried out in specific standardised conditions. Segawa's disease, or dopa-responsive dystonia, responds extremely well to therapy, whereas the other entities respond in varying ways to the different therapeutic alternatives. CONCLUSIONS: It is important for the paediatrician to know about these entities as a group of treatable neurometabolic diseases. Moreover, their detection would allow prenatal diagnosis in the vast majority of cases.

[Movement disorders of functional origin (psychogenic) in children]. / Trastornos del movimiento de origen funcional (psicogénicos) en el niño.

PATIENTS AND METHODS: Sixteen cases of functional (psychogenic) pediatric movement disorders (PMD) have been analyzed. They represents 2.4% of a PMD personal series (age of onset less than 18). RESULTS: Apart from a case, age of onset was older than 10 years. 81% (13/16 cases) were females. Tremor (68%) was the predominant abnormal movement followed by mioclonus. These facts are according with the scarce studies reported of functional PMD. We emphasize the diagnostic difficulties of this kind of conditions. CONCLUSIONS: Diagnostic clues are age of onset older than 10 years, female gender, clinical inconsistency of the movement, increasing or decreasing of the movements with attention to the movements or distraction, normality of the exams including neurophysiological studies. However in some cases a follow-up is necessary to confirm the diagnosis.

[Primary versus secondary stereotypic movements]. / Estereotipias primarias frente a estereotipias secundarias.

Stereotypic movements are repetitive patterns of movements whose physiopathology and relations to other neurobehavioural disorders are still only poorly understood. In this paper our aim is to distinguish between primary stereotypic movements, which are the sole manifestation of an anomaly, while the complementary examinations, except for those involving molecular genetics, are normal; associated stereotypic movements, when they meet primary disorder criteria but there are other coexisting independent neurological signs, that is to say, they are neither the cause nor the consequence of the movement disorder; and secondary stereotypic movements, when they are the consequence of a lesion or acquired neurological dysfunction. Examples of primary stereotypic movements include episodes of parasomnia, such as head rocking, in subjects who are otherwise normal, and stereotypic movements due to emotional disorders, severe environmental deprivation or in institutionalised infants. Examples of associated stereotypic movements are those observed in Rett syndrome, in subjects with sensory defects or with mental retardation due to a variety of causes. And as instances of secondary stereotypic movements we have those that can be seen in infinite like syndrome caused by congenital cerebellar lesions. The purpose of the classification is to lay the foundations for the identification of new syndromes, which would without a doubt facilitate research into their physiopathology, their aetiology and the possible therapeutic attitude to be adopted.

[Incidence, air pollution and risk factors of acute otitis media in the first year of life: a prospective study]. / Incidencia, contaminación ambiental y factores de riesgo de otitis media aguda en el primer año de vida: estudio prospectivo.

BACKGROUND: Epidemiological studies of acute otitis media (AOM) are scarce and no prospective studies have been performed in Spain. OBJECTIVES: To describe the incidence of AOM in the first year of life and its associated risk factors, with special focus on air pollution. METHODS: We performed a prospective cohort study of 229 newborn infants during the first year of life stratified by pollution zones, and followed-up by their pediatricians in their health center. AOM was defined on clinical grounds. A questionnaire on risk/protective factors included items on the following: sex, older siblings, smoking, breastfeeding, socioeconomic status, parental education and the mother's occupational status. RESULTS: The incidence of AOM episodes during the first year of life was 45 % and the proportion of children who experienced at least one episode was 32 %. Independent risk factors were male gender (aOR: 2.03; 95 % CI: 1.09-3.7) and living in a polluted area (aOR: 2.01; 95 % CI: 1.05-3.84). Independent protective factors were being born in spring (aOR: 0.41; 95 % CI: 0.19-0.88) and having a mother with at least primary school education (aOR: 0,53; 95 % CI: 0.24-1.15). Socioeconomic markers indicated a lower mean level among families whose children had at least one AOM episode. CONCLUSIONS: Air pollution and low socioeconomic status are greater risk factors for AOM than having siblings or parents who smoke. A minimum educational level reduces the risk of AOM. The incidence of AOM could be reduced by modifying certain environmental factors.

Electrophysiological approach to the study of essential tremor in children and adolescents.

Surface electromyography and accelerometry provide essential information on the neurophysiological characteristics of essential tremor. There are many reports on neurophysiological features in adult-onset essential tremor, but to our knowledge there have been no similar investigations of essential tremor in children. We conducted a neurophysiological study of nine children, six males and three females, with definite essential tremor. They were subdivided into two groups according to age: a 'children's group', consisting of four patients aged from 7 to 12 years, and an 'adolescent group', consisting of five patients aged from 14 to 16 years. Finger tremor as opposed to hand tremor was studied. In children the mean tremor frequency was 5.3 Hz (SD 0.5) with arms extended, which increased to 8.2 Hz (SD 1.5) when we added a mass of 300 g. In adolescents the mean tremor frequency was 9.0 Hz (SD 1.4) with arms extended, and 7.2 Hz (SD 1.8) with added mass. We discuss several hypotheses to find an explanation for these results.

[Stereotypic movements]. / Estereotipias.

Stereotypic movements are repetitive patterns of movement with certain peculiar features that make them especially interesting. Their physiopathology and their relationship with the neurobehavioural disorders they are frequently associated with are unknown. In this paper our aim is to offer a simple analysis of their dominant characteristics, their differentiation from other processes and a hypothesis of the properties of stereotypic movements, which could all set the foundations for research work into their physiopathology.

Neonatal dopa-responsive extrapyramidal syndrome in twins with recessive GTPCH deficiency.

The authors report two twin sisters, age 15 years, with recessive GTP cyclohydrolase deficiency, who presented with neonatal onset of rigidity, tremor, and dystonia but with no other symptoms suggestive of a diffuse CNS involvement. The plasma phenylalanine levels were normal. Treatment with L-dopa/carbidopa, started at age 1 year, was associated with sustained recovery from all neurologic signs. The patients were homozygous for a new recessive mutation in the GHI gene.

[Comorbid disorders associated with tics]. / Trastornos comórbidos relacionados con los tics.

INTRODUCTION: Tics are the most frequent abnormal movements in children. This is one reason for their importance. Another reason is their relationship to fascinating disturbances of human behaviour such as compulsion and obsessions. Several 'behavioural disorders', mainly attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), are more frequent in patients with tics than in the general population. These associated disorders (named 'comorbid') are probably of more consequence than the tics. Relationship between tics and comorbid disorders is not well known. This review considers data, consequences, hypothesis and management of comorbid disorders associated to tics. DEVELOPMENT: From the personal series of children with tics, data of comorbid disorders associated to tics was analysed. Of 340 cases of tics, 132 (39%) cases have ADHD, 135 (40%) cases have OCD, obsessive compulsive symptoms (OCS) or obsessive-compulsive behaviour (OCB). 68 (20%) cases have both ADHD and OCD. Considering only Tourette cases (219) the figures are only slight higher: ADHD (42%), OCD (45%) and ADHD plus OCD (24%) suggesting that all the spectrum of tics has a common basis. CONCLUSIONS: Familial studies shows that 44 percent of the patients with tics have a positive familial history of tics and 30 percent positive familial history of obsessive compulsive signs. The data of the literature on the tics and comorbid disorders relationship is also revised.