#Neuropädiatrie
In recent years, pediatric neurology has undergone a change from a predominantly diagnostic discipline to a field with a variety of therapeutic developments. The increasing understanding of the pathophysiology and molecular biology of neurological diseases has led to the introduction of new therapies that directly intervene in the pathomechanism. The coming years will see the further establishment of already approved therapies and the introduction of new, targeted therapies such as gene therapy, enzyme replacement therapy or new, seizure-suppressing therapies. Individual illnesses that were considered a death sentence 10 years ago can now be successfully treated if they are detected early enough. For other diseases, a “watch and wait” approach has previously applied, which must be partially revised with the new treatment options. The initiation, choice, or discontinuation of seizure-suppressing medications has also changed as understanding of the pathophysiology of genetic epilepsies has led to personalization of therapy. The development of genetic diagnostics means that new diseases/syndromes are discovered almost every day, with increasing therapeutic implications, so that a “genetic first approach” now applies to many clinical pictures.
This article presents important developments in neuropediatrics that are relevant for pediatricians in practice and clinic.
Spinale Muskelatrophie – “The old, the new and the latest”
Spinal muscular atrophy (SMA) is a genetic disorder caused by a homozygous deletion of exon 7 of the SMN1 (survival motor neuron) gene. This results in a loss of alpha motor neurons in the anterior horn of the spinal cord, which leads to progressive muscle weakness with slowing and loss of motor skills and development with preserved cognition(1). Humans have an almost identical variant of this gene (SMN2), which, however, only leads to a very low production of the SMN protein due to small changes (including splice variants influencing the inclusion of exon 7). Depending on the number of copies of the SMN2 gene (1, 2, 3 and more copies), the age of clinical presentation and the severity of the disease vary(1). Patients with only a few SMN2 copies present before the 6th month of life with pronounced muscle weakness in a very awake infant, lack of intrinsic muscle reflexes and slowing or loss of motor skills (no learning to sit freely, approx. 50% of SMA patients ). If left untreated, bulbar symptoms and respiratory insufficiency quickly develop. Until a few years ago, these children usually died before their first birthday. However, if there are more copies of the SMN2 gene, the children only become symptomatic later: in some cases they learn to sit but not to walk freely (approx. 30%) or they learn to walk freely and only later lose existing motor skills (approx. 10 %)(1).
In 2017, the first therapy for SMA was approved in Switzerland (Nusinersen, Spinraza®), in 2021 the first gene therapy (Onasemnogene abeparvovec, Zolgensma®) and the orally available exon skipping therapy (Risdiplam, Evrysdi®)(2, 3). All 3 therapies (Figure 1) are effective and lead to a change in the clinical picture, but in the vast majority of cases not to a cure. The reason for this is that at the onset of symptoms there has already been a relevant loss of alpha motor neurons (2-5). This was demonstrated by a study of presymptomatic patients who showed a significant improvement in motor development when therapy was initiated before the onset of symptoms(6). In many countries, this circumstance led to the inclusion of SMA in newborn screening in 2020-2021(7); in Switzerland, SMA will be included in newborn screening in March 2024. In this screening, almost 5% of the cases that can be traced back to point mutations are not detected. If there is clinical suspicion, rapid referral for clarification is still necessary. After the introduction of newborn screening, the big challenge will now be to inform the families of the newborns as quickly as possible and to obtain approval for costs in order to treat the children as quickly as possible – the experiences from countries that already use SMA in newborn screening recorded show that every day counts until the start of therapy (7).
Illustration 1.
The SMN protein is produced by two paralogous genes on chromosome 5q – SMN1 and SMN2. The SMN1 gene consists of 9 exons and produces most of the complete and functional SMN protein. The SMN2 gene, which differs from SMN1 by only a few nucleotides and is present in different copy numbers (1 to >4), leads to 90% of the truncated, non-functional form of the SMN protein (SMNΔ7) and only 10% to the SMN2 gene normal SMN protein. Risdiplam and nusinersen are splice-modifying therapies that improve the inclusion of exon 7 during splicing of the SMN2 gene, thereby increasing the production of the complete and functional SMA protein. Onasemnogen, on the other hand, is a gene addition therapy in which a copy of the SMN1 gene is introduced via a viral vector primarily into the cell nuclei of alpha motor neurons (2, 8, 25). The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.
Neurofibromatose Typ 1 – “The old made new and the new”
Neurofibromatosis, one of the most common genetic diseases, was first described in 1881 by Friedrich Daniel von Recklinghausen. It is a tumor predisposition syndrome with multisystem involvement of the skin, brain, peripheral nerves, kidneys, bones, etc., which is caused by a heterozygous (autosomal dominant) mutation in the NF1 gene. This leads to an inactivation of the tumor suppressor gene NF1, which leads to abnormal RAS activation and thus abnormal regulation of cell growth (9). The incidence is approximately 1:3000 to 1:2500, with approximately 50% of cases being inherited in families and 50% being caused by new mutations. In 2021, revised diagnostic criteria for neurofibromatosis type I were published (9). What is particularly new is that genetics has been included as a diagnostic criterion; thus, the presence of a pathogenic variant in the NF1 gene is considered the main diagnostic criterion (Figure 2).
The typical presentation in infancy and toddlerhood is characterized by muscular hypotonia and slow motor development, relative macrocephaly and café-au-lait spots. Up to 60% of children show difficulty concentrating and schooling (10).
Tumors of the central nervous system and the visual pathways, plexiform neurofibromas, bone anomalies (bending of the long bones and scoliosis) or vasculopathies (e.g. Moyamoya syndrome) occur much less frequently (11). Benign tumors of the skin (cutaneous neurofibromas) and plexiform neurofibromas can also occur. Plexiform neurofibromas are congenital, benign but sometimes rapidly growing and locally infiltrating tumors that develop along peripheral nerves and can cause significant morbidity and impairment of quality of life. Due to their local infiltration, they often cannot be completely removed surgically(9,11). They differ from cutaneous neurofibromas in that they are often significantly larger, grow quickly, are not located in the cutaneous/subcutaneous tissue and can sometimes spread over a large area. It is not uncommon for the skin in this area to be thickened, darker and may be hairy. These tumors are also often sensitive to pressure (9,11).
Since July 2023, a new therapy for the treatment of inoperable plexiform neurofibroma has been approved for a limited period in Switzerland. This therapy (Selumetinib®) works in molecular biology as a MEK pathway inhibitor. In the phase II study, this therapy led to a global reduction in tumor volume and a reduction in additional symptoms (including local pain) in patients with inoperable plexiform neurofibromas (12). Patients with a suspected diagnosis of NF1 or suspected plexiform neurofibroma should therefore be referred to a specialized center (depending on where they live, neuropediatrics, oncology or dermatology).
Figure 2. Revised Diagnostic Criteria for NF-1(9)
Childhood migraines – “The old and the new”
Migraine in children is a leading cause of repeated school absences and affects approximately 10% of school-age children(13). In adulthood, migraines affect 30% of women and 19% of men(13). Most patients develop the first symptoms of migraine in the first or second decade of life, making this a pediatric disease. Family history is often positive. The clinical presentation of migraine is very diverse and some migraine episodes are difficult to differentiate from other acute, severe neurological diseases. A rare form of migraine, familial hemiplegic migraine, is inherited in a monogenic autosomal dominant manner (14). Migraines can be divided into 2 subtypes, with or without aura. Additionally, depending on the frequency of attacks, it can be divided into episodic or chronic. The diagnostic criteria for migraine are shown in Table 1, further details can be found in the ICHD-3 (International headache society classification)(15, 16).
Table 1. Diagnostic criteria for tension headaches and migraines in children and adolescents (15)
Migraine therapy is essentially based on 2 pillars: The first goal is to control migraine attacks as well as possible. In this regard, it is currently still recommended that children and teenagers take non-steroidal anti-inflammatory drugs quickly (Table 2). From 12 years of age, triptans can also be administered intranasally for severe migraine attacks; however, these are contraindicated during the aura. Nausea can usually be controlled well with this therapy. However, if nausea and vomiting are the main symptoms, ondansetron may also be administered (16). The second pillar of migraine treatment is basic therapy with the aim of reducing the frequency of migraine attacks. The basic therapy consists, on the one hand, of non-drug measures: Good information for patients and parents as well as advice (e.g. understanding triggering factors: keeping a headache diary. Lifestyle measures: regular drinking of at least 2 liters per day and, if necessary, regular physical activity. Therapies: relaxation procedures according to Jacobson, possibly physiotherapy, yoga exercises and, depending on the situation, psychological/social support). TENS devices can also be used. If the non-drug measures are not sufficient, basic drug therapy can also be carried out. Primarily, magnesium can be used in a dosage of 5-20 mmol/d depending on tolerability. If episodes continue to be frequent, flunarizine (5-10 mg in the evening, CAVE contraindication, including depressive mood/depression, high BMI) or propranolol 1-2 mg/kg body weight per day (CAVE contraindication, including bronchial asthma, arterial hypotension) can be used (13 , 16).
Table 2. Acute medication for migraines in children. If necessary, an increased single dose can be taken in certain acute situations, but the 24-hour dose should not be exceeded (adapted from (16)).
The understanding of the pathophysiology of migraine attacks has increased significantly in recent years. In summary, it is an abnormal activation of the trigeminovascular system, with the neuropeptide calcitonin gene-related peptide (CGRP) playing a central role (17). Based on this new knowledge, targeted therapies have been developed, some of which have already been approved for adult patients and show very good effectiveness (17). Anti-CGRP antibodies and CGRP inhibitors, among others, are currently being investigated in clinical studies in children. Based on this, it can be assumed that new treatment options will also be available for children in the next few years (18).
Epilepsie – “The old made new”
Epilepsy or a first epileptic seizure is one of the most important reasons for referral in neuropediatrics(19). The classification of seizure forms and epilepsies was revised in 2017 and the epilepsy syndromes were renamed in 2022 (ILAE classification)(20). New additions include the causes of epilepsy (including genetic, structural, etc.). The distinction between focal and generalized forms of seizures remains; The beginning of the seizure is particularly important here. The purpose of the new classification is to improve etiological clarification and subclassification to improve the therapeutic attitude. The classic epilepsy syndromes were also reclassified and named, also with regard to common etiology and common therapeutic approach (21). What has also been new in epileptology in recent years is the increasing understanding of the pathophysiology of genetically determined epilepsies (19).
Until about 10 years ago, the treatment of epilepsy was mostly based on 2 main pillars: 1. seizure-specific therapy: focal or generalized and 2. according to epilepsy syndromes (e.g. absence epilepsy). “Precision medicine” is currently growing. Among other things, ion channel diseases (gene mutations of various ion channels) are currently of great importance both in research and in everyday clinical practice (19); For example:
- Variant in a sodium channel-encoding gene: Depending on the type of variant in SCN2A (“loss of function” or “gain of function”), a sodium channel blocker (oxcarbazepine) is indicated or contraindicated (22).
- Early/childhood absence epilepsy is usually treated with ethosuximide or valproate. If the epilepsy is due to a glucose transporter defect (glut-1 defect, variant in SLC2A1), however, the ketogenic diet is the primary therapy (19).
- In tuberous sclerosis, everolimus (blockade of the mTOR pathway, which is abnormally activated in this disease) is a therapeutic option (23).
When a severe epilepsy syndrome or epileptic encephalopathy is suspected without a clear etiology on imaging, trio-exome analysis (examination of the exome of the patient and the parents) is increasingly being used to adapt seizure-suppressive therapy depending on the underlying etiology. In addition, gene or RNA therapies are expected in the future(24).
outlook
The new findings and developments in neuropediatrics have led to a paradigm shift from primarily diagnostic and symptom-treating to increasingly specific and disease-modifying therapies. This makes the work very interesting and leads to the need for subspecialization into subfields. Furthermore, for some symptom complexes, the molecular biological cause of the disease must be diagnosed quickly so as not to miss available treatment options.
A big thank you goes to Prof. Andrea Klein for her scientific contribution and review of the manuscript, to PD Dr. med. Iciar Sanchez for her contribution about Chanelopathies and epilepsy, to Robin Münger for reviewing the manuscript and the fruitful exchange and to Daniel Brechbühl for help with the design of the graphics.
