Identification of New Antiseizure Medication Candidates in Preclinical Animal Studies.

Epilepsy is a multifactorial neurologic disease that often leads to many devastating disabilities and an enormous burden on the healthcare system. Until now, drug-resistant epilepsy has presented a major challenge for approximately 30% of the epileptic population. The present article summarizes the validated rodent models of seizures employed in pharmacological researches and comprehensively reviews updated advances of novel antiseizure candidates in the preclinical phase. Newly discovered compounds that demonstrate antiseizure efficacy in preclinical trials will be discussed in the review. It is inspiring that several candidates exert promising antiseizure activities in drug-resistant seizure models. The representative compounds consist of derivatives of hybrid compounds that integrate multiple approved antiseizure medications, novel positive allosteric modulators targeting subtype-selective γ-Aminobutyric acid type A receptors, and a derivative of cinnamamide. Although the precise molecular mechanism, pharmacokinetic properties, and safety are not yet fully clear in every novel antiseizure candidate, the adapted approaches to design novel antiseizure medications provide new insights to overcome drug-resistant epilepsy.

Zingerone Modulates Neuronal Voltage-Gated Na+ and L-Type Ca2+ Currents.

Zingerone (ZO), a nontoxic methoxyphenol, has been demonstrated to exert various important biological effects. However, its action on varying types of ionic currents and how they concert in neuronal cells remain incompletely understood. With the aid of patch clamp technology, we investigated the effects of ZO on the amplitude, gating, and hysteresis of plasmalemmal ionic currents from both pituitary tumor (GH3) cells and hippocampal (mHippoE-14) neurons. The exposure of the GH3 cells to ZO differentially diminished the peak and late components of the INa. Using a double ramp pulse, the amplitude of the INa(P) was measured, and the appearance of a hysteresis loop was observed. Moreover, ZO reversed the tefluthrin-mediated augmentation of the hysteretic strength of the INa(P) and led to a reduction in the ICa,L. As a double ramp pulse was applied, two types of voltage-dependent hysteresis loops were identified in the ICa,L, and the replacement with BaCl2-attenuated hysteresis of the ICa,L enhanced the ICa,L amplitude along with the current amplitude (i.e., the IBa). The hysteretic magnitude of the ICa,L activated by the double pulse was attenuated by ZO. The peak and late INa in the hippocampal mHippoE-14 neurons was also differentially inhibited by ZO. In addition to acting on the production of reactive oxygen species, ZO produced effects on multiple ionic currents demonstrated herein that, considered together, may significantly impact the functional activities of neuronal cells.

Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents.

Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH3 lactotrophs. RFM increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) in pituitary GH3 lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca2+-activated K+ channels (BKCa channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BKCa channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na+ current (INa) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of KCa1.1 channels with amino acid residues, thereby functionally affecting BKCa channels' activity. This study is the first to present evidence that, in addition to inhibiting the INa, RFM effectively modifies the IK(Ca), which suggests that it has an impact on neuronal function and excitability.

Immunity, Ion Channels and Epilepsy.

Epilepsy is a common chronic neurological disorder in modern society. One of the major unmet challenges is that current antiseizure medications are basically not disease-modifying. Among the multifaceted etiologies of epilepsy, the role of the immune system has attracted considerable attention in recent years. It is known that both innate and adaptive immunity can be activated in response to insults to the central nervous system, leading to seizures. Moreover, the interaction between ion channels, which have a well-established role in epileptogenesis and epilepsy, and the immune system is complex and is being actively investigated. Some examples, including the interaction between ion channels and mTOR pathways, will be discussed in this paper. Furthermore, there has been substantial progress in our understanding of the pathophysiology of epilepsy associated with autoimmune encephalitis, and numerous neural-specific autoantibodies have been found and documented. Early recognition of immune-mediated epilepsy is important, especially in cases of pharmacoresistant epilepsy and in the presence of signs of autoimmune encephalitis, as early intervention with immunotherapy shows promise.

The Specific Effects of OD-1, a Peptide Activator, on Voltage-Gated Sodium Current and Seizure Susceptibility.

OD-1, a scorpion toxin, has been previously recognized as an activator of voltage-gated Na+ currents. To what extent this agent can alter hippocampal neuronal Na+ currents and network excitability and how it can be applied to neuronal hyperexcitability research remains unclear. With the aid of patch-clamp technology, it was revealed that, in mHippoE-14 hippocampal neurons, OD-1 produced a concentration-, time-, and state-dependent rise in the peak amplitude of INa. It shifted the INa inactivation curve to a less negative potential and increased the frequency of spontaneous action currents. Further characterization of neuronal excitability revealed higher excitability in the hippocampal slices treated with OD-1 as compared with the control slices. A stereotaxic intrahippocampal injection of OD-1 generated a significantly higher frequency of spontaneous seizures and epileptiform discharges compared with intraperitoneal injection of lithium-pilocarpine- or kainic acid-induced epilepsy, with comparable pathological changes. Carbamazepine significantly attenuated OD-1 induced seizures and epileptiform discharges. The OD-1-mediated modifications of INa altered the electrical activity of neurons in vivo and OD-1 could potentially serve as a novel seizure and excitotoxicity model.

Characterization of the Inhibitory Effect of Gastrodigenin and Gastrodin on M-type K+ Currents in Pituitary Cells and Hippocampal Neurons.

Gastrodigenin (HBA) and gastrodin (GAS) are phenolic ingredients found in Gastrodia elata Blume (GEB), a traditional Chinese herbal medicine. These compounds have been previously used to treat cognitive dysfunction, convulsion, and dizziness. However, at present, there is no available information regarding their potential ionic effects in electrically excitable cells. In the current study, the possible effects of HBA and GAS on different ionic currents in pituitary GH3 cells and hippocampal mHippoE-14 neurons were investigated using the patch-clamp technique. The addition of HBA or GAS resulted in the differential inhibition of the M-type K+ current (IK(M)) density in a concentration-dependent manner in GH3 cells. HBA resulted in a slowing of the activation time course of IK(M), while GAS elevated it. HBA also mildly suppressed the density of erg-mediated or the delayed-rectifier K+ current in GH3 cells. Neither GAS nor HBA (10 µM) modified the voltage-gated Na+ current density, although they suppressed the L-type Ca2+ current density at the same concentration. In hippocampal mHippoE-14 neurons, HBA was effective at inhibiting IK(M) density as well as slowing the activation time course. Taken together, the present study provided the first evidence that HBA or GAS could act on cellular mechanisms, and could therefore potentially have a functional influence in various neurologic disorders.

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures.

BACKGROUND/AIMS: Immunological mechanisms can be triggered as a response to central nervous system insults and can lead to seizures. In this study an investigation was made to determine if glatiramer acetate (GA), an immunomodulator currently used in the treatment of multiple sclerosis, could protect rats from pilocarpine-induced seizures and chronic epilepsy. METHODS: Two groups of adult male Sprague-Dawley rats, experimental (GA) and control, were used in the study. The systemic IL-1α and IL-1ß levels at baseline were checked as well as status epilepticus (SE), and the spontaneous recurrent seizure (SRS) stage by enzyme-linked immunosorbent assay. The GA group was given GA (150 µg/kg, ip) and the control group was given a saline injection prior to pilocarpine-induced seizures. Seizure susceptibility, severity and mortality were evaluated, using Racine seizure classification and hippocampal damage was evaluated by Nissl staining. The GA group received GA (150 µg/kg/day, ip) daily after SE, and the chronic spontaneous seizures were evaluated by long-term video recording, and mossy fiber sprouting was evaluated by Timm staining. The IL-1α and IL-1ß levels were correlated with seizure activities. The TNF-α level in the hippocampus was determined at the SRS stage by immunohistochemistry. The effect of GA on ionic currents and action potentials (APs) in NG108-15 differentiated neurons was investigated using patch-clamp technology. RESULTS: It was found that latency to severe seizures was significantly longer in the GA (p < 0.01) group, which also had SE of shorter duration and less frequent SRS (p < 0.01). GA attenuated acute hippocampal neuron loss and chronic mossy fiber sprouting in the CA3 and the SRS-reduction correlated with the reduction of IL-1α, but not with IL-1ß or TNF-α levels. Mechanistically, GA reduced the peak amplitude of voltage-gated Na+ current (INa), with a negative shift in the inactivation curve of INa and reduced the amplitude of APs along with decreased firing of APs. CONCLUSION: GA might serve as a neuroexcitability modulator which attenuates pilocarpine-induced acute and chronic excitotoxicity. Sodium channel attenuation was partially independent of the immunomodulatory effect.

Stimulatory actions of a novel thiourea derivative on large-conductance, calcium-activated potassium channels.

In this study, we examine whether an anti-inflammatory thiourea derivative, compound #326, actions on ion channels. The effects of compound #326 on Ca2+ -activated K+ channels were evaluated by patch-clamp recordings obtained in cell-attached, inside-out or whole-cell configuration. In pituitary GH3 cells, compound #326 increased the amplitude of Ca2+ -activated K+ currents (IK(Ca) ) with an EC50 value of 11.6 µM, which was reversed by verruculogen, but not tolbutamide or TRAM-34. Under inside-out configuration, a bath application of compound #326 raised the probability of large-conductance Ca2+ -activated K+ (BKCa ) channels. The activation curve of BKCa channels was shifted to less depolarised potential with no modification of the gating charge of the curve; consequently, the difference of free energy was reduced in the presence of this compound. Compound #326-stimulated activity of BKCa channels is explained by a shortening of mean closed time, despite its inability to alter single-channel conductance. Neither delayed-rectifier nor erg-mediated K+ currents was modified. Compound #326 decreased the peak amplitude of voltage-gated Na+ current with no clear change in the overall current-voltage relationship of this current. In HEK293T cells expressing α-hSlo, compound #326 enhanced BKCa channels effectively. Intriguingly, the inhibitory actions of compound #326 on interleukin 1ß in lipopolysaccharide-activated microglia were significantly reversed by verruculogen, whereas BKCa channel inhibitors suppressed the expressions of inducible nitric oxide synthase. The BKCa channels could be an important target for compound #326 if similar in vivo results occur, and the multi-functionality of BKCa channels in modulating microglial immunity merit further investigation.

The Roles of Glutamate Receptors and Their Antagonists in Status Epilepticus, Refractory Status Epilepticus, and Super-Refractory Status Epilepticus.

Status epilepticus (SE) is a neurological emergency with a high mortality rate. When compared to chronic epilepsy, it is distinguished by the durability of seizures and frequent resistance to benzodiazepine (BZD). The Receptor Trafficking Hypothesis, which suggests that the downregulation of γ-Aminobutyric acid type A (GABAA) receptors, and upregulation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors play major roles in the establishment of SE is the most widely accepted hypothesis underlying BZD resistance. NMDA and AMPA are ionotropic glutamate receptor families that have important excitatory roles in the central nervous system (CNS). They are both essential in maintaining the normal function of the brain and are involved in a variety of neuropsychiatric diseases, including epilepsy. Based on animal and human studies, antagonists of NMDA and AMPA receptors have a significant impact in ending SE; albeit most of them are not yet approved to be in clinically therapeutic guidelines, due to their psychomimetic adverse effects. Although there is still a dearth of randomized, prospective research, NMDA antagonists such as ketamine, magnesium sulfate, and the AMPA antagonist, perampanel, are regarded to be reasonable optional adjuvant therapies in controlling SE, refractory SE (RSE) or super-refractory SE (SRSE), though there are still a lack of randomized, prospective studies. This review seeks to summarize and update knowledge on the SE development hypothesis, as well as clinical trials using NMDA and AMPA antagonists in animal and human studies of SE investigations.

The Role of Glutamate Receptors in Epilepsy.

Glutamate is an essential excitatory neurotransmitter in the central nervous system, playing an indispensable role in neuronal development and memory formation. The dysregulation of glutamate receptors and the glutamatergic system is involved in numerous neurological and psychiatric disorders, especially epilepsy. There are two main classes of glutamate receptor, namely ionotropic and metabotropic (mGluRs) receptors. The former stimulate fast excitatory neurotransmission, are N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate; while the latter are G-protein-coupled receptors that mediate glutamatergic activity via intracellular messenger systems. Glutamate, glutamate receptors, and regulation of astrocytes are significantly involved in the pathogenesis of acute seizure and chronic epilepsy. Some glutamate receptor antagonists have been shown to be effective for the treatment of epilepsy, and research and clinical trials are ongoing.

Unilateral non-lesional temporal lobe epilepsy presenting as isolated ictal vertigo: a case report.

Temporal lobe epilepsy is the most common focal epilepsy syndrome and has a broad spectrum of presentations. Nevertheless, isolated vestibular symptoms without other symptoms typical of temporal lobe seizures are relatively rare. Here, we report one female patient who suffered from chronic refractory vertigo and had inappropriate pharmacotherapy for several years. Eventually, epileptic vertigo and dizziness (ictal vertigo) were accurately diagnosed by detailed history taking and serial examinations assisted by sphenoid electroencephalography. Awareness of this unique syndrome is important in the diagnosis of patients with epileptic vertigo and dizziness.

The Primary Prevention of Poststroke Epilepsy in Patients With Middle Cerebral Artery Infarct: Protocol for a Randomized Controlled Trial.

BACKGROUND: Poststroke epilepsy poses a significant clinical challenge for individuals recovering from strokes, leading to a less favorable long-term outlook and increased mortality rates. Existing studies have primarily concentrated on administering antiseizure or anticonvulsant treatments only after the onset of late-onset seizures, without intervening during the epileptogenesis phase following a stroke. OBJECTIVE: This research protocol is designed to conduct a randomized controlled trial to assess whether the early, preventive introduction of low-dose antiepileptic drug therapy (levetiracetam [LEV] or perampanel [PER]) in patients who have experienced middle cerebral artery (MCA) infarction can reduce the risk of developing poststroke epilepsy (primary prevention). METHODS: Participants with MCA infarction, either with or without reperfusion treatments, will be recruited and promptly receive preventive intervention within 72 hours of the stroke occurrence. These participants will be randomly assigned to receive either PER (4 mg per day), LEV (1000 mg per day), or a placebo that matches the active drugs. This treatment will continue for 12 weeks after allocation. Brain magnetic resonance imaging will be used to confirm the presence of MCA territory infarction, and an electroencephalography will be used to ensure the absence of epileptiform discharges or electrographic seizures at the time of the stroke. All participants will undergo follow-up assessments for 72 weeks after allocation. RESULTS: The primary outcome under evaluation will be the incidence of poststroke epilepsy in the 3 groups following the 18-month study period. Secondary outcomes will encompass the time to the occurrence of the first seizure, the severity of seizures, any treatment-related adverse events, and the modified Rankin scale score at 3 and 18 months. Exploratory outcomes will involve comparing the effectiveness and safety of PER and LEV. CONCLUSIONS: We anticipate that the intervention groups will experience a lower incidence and reduced severity of poststroke epilepsy compared to the control group after 18 months. We aim to establish evidence supporting the potential preventive effects of LEV and PER on poststroke seizures and epilepsy in patients with MCA infarction, as well as to explore the antiepileptogenic potential of both LEV and PER in patients with major ischemic strokes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04858841; https://clinicaltrials.gov/study/NCT04858841. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/49412.

Effectiveness and Safety of Lacosamide, A Third-generation Anti-seizure Medication, for Poststroke Seizure and Epilepsy: A Literature Review.

Advances in stroke treatment have resulted in a dramatic reduction in stroke mortality. Nevertheless, poststroke seizures and epilepsy are issues of clinical importance affecting survivors. Additionally, stroke is the most common cause of epilepsy in older adults. Although numerous antiseizure medications exist, studies are needed to provide robust evidence of the efficacy and tolerability of these medicines for treating poststroke seizures and epilepsy. Crucially, the newer generations of antiseizure medications require testing. Lacosamide, a third-generation antiseizure medication approved for treating localization-related epilepsy, has a novel mechanism of selectively enhancing the slow inactivation of sodium channels. This literature review evaluated whether lacosamide is effective and safe for the treatment of poststroke seizures and epilepsy. This review critically analyzed studies published in major academic databases (Pubmed, Embase, and Cochrane Library) from inception through June 2022 regarding the interaction of lacosamide with poststroke seizures and epilepsy. We included clinical prospective, retrospective, and case studies on patients with poststroke seizure and epilepsy, lacosamide as a treatment for seizures, neuroprotection in animal models of seizures, and the safety of lacosamide when coadministering anticoagulants. Clinical studies revealed lacosamide to be an effective antiseizure medication with high efficacy and tolerability in patients with poststroke seizures and epilepsy. In animal models, lacosamide proved effective at seizure reduction and neuroprotection. Pharmacokinetic studies demonstrated the safety of lacosamide when coadministering conventional and new anticoagulants. The literature suggests that Lacosamide is a promising candidate antiseizure medication for patients with poststroke seizures and epilepsy.

Neonatal seizures: dialogues between clinic and bench.

Neonatal seizures are common and often reflect a severe underlying neurologic dysfunction in neonates. Phenobarbital remains the mainstay of treatment of neonatal seizures, however, but it is ineffective in many patients and has adverse profiles in cognition. Furthermore, gamma-aminobutyric acid is excitatory early in brain development; therefore, treatment of neonatal seizures with phenobarbital must be cautious. In this review, we highlight the substantial progress that has been made in animal studies, and translate these results to the treatment of seizures in human neonates.

Interventions for Body Composition and Upper and Lower Extremity Muscle Strength in Older Adults in Rural Taiwan: A Horizontal Case Study.

The purpose of this study was to understand the effects of a physical activity program and high-protein supplementation on body composition and upper and lower extremity muscle strength in male older adults in rural areas. In this study, 60 healthy male older adults (mean age 77.5 ± 4.6 years) from rural areas were recruited and randomly assigned to experimental group A (intervention of the physical activity program and high-protein supplementation), experimental group B (daily routine, with only intervention of high-protein supplementation), or control group C (daily routine). Experimental group A (EGa) carried out a physical activity plan three times a week, with an exercise intensity and calorie consumption of 250 kcal (5METs × â…”hr × 75) for 3 months and drank a high-protein supplement (1.3 g/kg BW/day) after each exercise; experimental group B (EGb) followed only the intervention of high-protein supplementation. All the participants underwent pre- and post-tests for body composition, waist-hip circumference (WC, HC), handgrip strength (HS), 30 s dominant arm curl, 30 s sit to stand, and 2 min step tests. The results of the study showed that EGa significantly decreased body mass index (BMI), body fat mass (BFM), body fat percentage (BFP), WC, HC, and waist-to-hip ratio (WHR) and increased basal metabolic rate and muscle mass. Although both EGa and EGb used high-protein supplementation, EGa's added three-month intervention of a physical activity program made it easier for that group to increase muscle mass and muscle strength. The WHR decreased from 1.015 to 0.931, representing a decrease of 8.28%, and an obvious weight loss effect was achieved. Thus, we concluded that the best way to maintain muscle strength in older adults is through physical activity with resistance and protein supplementation, which can reduce muscle loss in older adults.

Brain Imaging in Epilepsy-Focus on Diffusion-Weighted Imaging.

Epilepsy is a common neurological disorder; 1% of people worldwide have epilepsy. Differentiating epileptic seizures from other acute neurological disorders in a clinical setting can be challenging. Approximately one-third of patients have drug-resistant epilepsy that is not well controlled by current antiepileptic drug therapy. Surgical treatment is potentially curative if the epileptogenic focus is accurately localized. Diffusion-weighted imaging (DWI) is an advanced magnetic resonance imaging technique that is sensitive to the diffusion of water molecules and provides additional information on the microstructure of tissue. Qualitative and quantitative analysis of peri-ictal, postictal, and interictal diffusion images can aid the differential diagnosis of seizures and seizure foci localization. This review focused on the fundamentals of DWI and its associated techniques, such as apparent diffusion coefficient, diffusion tensor imaging, and tractography, as well as their impact on epilepsy in terms of differential diagnosis, epileptic foci determination, and prognosis prediction.

Perinatal hypoxic-ischemic encephalopathy.

Perinatal hypoxic-ischemic encephalopathy (HIE) is an important cause of brain injury in the newborn and can result in long-term devastating consequences. Perinatal hypoxia is a vital cause of long-term neurologic complications varying from mild behavioural deficits to severe seizure, mental retardation, and/or cerebral palsy in the newborn. In the mammalian developing brain, ongoing research into pathophysiological mechanism of neuronal injury and therapeutic strategy after perinatal hypoxia is still limited. With the advent of promising therapy of hypothermia in HIE, this paper reviews the pathophysiology of HIE and the future potential neuroprotective strategies for clinical potential for hypoxia sufferers.

The Discordance between Network Excitability and Cognitive Performance Following Vigabatrin Treatment during Epileptogenesis.

Vigabatrin (VGB), a potent selective γ-aminobutyric acid transaminase (GABA-T) inhibitor, is an approved non-traditional anti-seizure drug for patients with intractable epilepsy. Nevertheless, its effect on epileptogenesis, and whether this effect is correlated with post-epileptogenic cognitive function remain unclear. Based on lithium-pilocarpine-induced seizure modeling, we evaluated the effect of VGB on epileptogenesis and neuronal damage following status epilepticus in Sprague-Dawley rats. Cognitive evaluations were performed with the aid of inhibitory avoidance testing. We found that VGB could interrupt epileptogenesis by reducing spontaneous recurrent seizures, hippocampal neuronal damage, and chronic mossy fiber sprouting. Nevertheless, VGB did not help with the retention of cognitive performance. Our findings suggest that further research into the role of VGB in epileptogenesis and the treatment of epilepsy in clinical practice is warranted.

Status Epilepticus Mortality Risk Factors and a Correlation Survey with the Newly Modified STESS.

BACKGROUND: Status epilepticus (SE) is a neurological emergency and is usually associated with significant morbidity and mortality rates. Several clinical scales have been proposed to predict the clinical outcome of such incidents, including the Status Epilepticus Severity Score (STESS), the modified STESS (mSTESS), and the Encephalitis-Nonconvulsive Status Epilepticus-Diazepam Resistance-Image Abnormalities-Tracheal intubation (END-IT). Nevertheless, there is still a need for a more practical and precise predictive scale. METHODS: This is a retrospective cohort study which examines data from patients with SE in our Department of Neurology between 2009 and 2020. Based on the outcome of each case, the patients were divided into survivor and non-survivor groups. We analyzed the independent factors and adjusted the STESS to achieve a better prediction of prognosis. The predictive accuracy of our new STESS scale was then compared with that of the mSTESS and the END-IT. RESULTS: Data on a total of 59 patients were collected, with 6 of them classified as non-survivors. The effects of the variables of age, sex, underlying disease(s), and type(s) of antiepileptic drug (AED) use showed no significant differences between the survivor and non-survivor groups. Importantly, the number of AEDs used in the first week and the use of thiobarbiturates predicted non-survival. We adjusted the STESS to create the newly modified STESS (nSTESS), which showed a better predictive capacity than the STESS, the mSTESS, and the END-IT. CONCLUSIONS: Our adjustment of the STESS with the addition of the factors "number of AEDs within the first week" and "use of thiobarbiturates", could have a positive impact on the prediction of mortality rates compared with currently used scales. This nSTESS could potentially be useful in clinical practices, for the early prediction of outcomes for patients with SE.

Prevalence and Initial Diagnosis of Cerebral Palsy in Preterm and Term-Born Children in Taiwan: A Nationwide, Population-Based Cohort Study.

The aim of this long-term longitudinal study in Taiwan was to estimate and compare the prevalence of cerebral palsy (CP) and to identify the age of CP diagnosis of term-born and preterm children with different birthweights. Records of 1494 extremely low birth weight (ELBW, <1000 g), 3961 very low birth weight (VLBW, 1000-1499 g), 19,612 low birth weight (LBW, 1500-2499 g) preterm, and 100,268 matched term-born children were retrieved from Taiwan's National Health Insurance Research Database. According to a 12-year retrospective data review, the results showed the highest prevalence of CP in preterm ELBW children (147.3 cases per 1000 neonatal survivors), followed by preterm VLBW (97.2 cases), preterm LBW (27.7 cases), with the lowest prevalence in term-born children (2.5 cases). Regardless of the birthweight group, 90% of preterm children with CP were diagnosed by 4 years of age, but it was 7 years before 90% of term-born children with CP were diagnosed. After removing the children whose CP was caused by brain infections, injuries, or cerebrovascular accidents after 4 months of age, there were similar mean ages at the initial CP diagnosis (1.58-1.64 years of age) across birthweight groups born prematurely, but initial diagnosis occurred at an older age (2.41 years of age) in term-born children. The results indicate that birthweight is reversely correlated with the prevalence of CP in preterm children. Although the three preterm birthweight groups received different types of developmental follow-up programs after birth, it did not influence their age at the initial diagnosis of CP. Furthermore, we suggest that follow-up for at least 4 years after birth for preterm children, and 7 years for term-born children, is optimal for estimating CP prevalence. In order to identify and provide early intervention for term-born children with CP earlier, it is suggested that parents routinely fill out a self-reported motor developmental screening questionnaire and pediatricians conduct a motor developmental examination on term-born children at each time of scheduled vaccination injections.