Hippocampal malrotation is an anatomic variant and has no clinical significance in MRI-negative temporal lobe epilepsy
There is considerable difficulty in diagnosing hippocampal malrotation (HIMAL), with different criteria of variable reliability. Here we assess qualitative and quantitative criteria in HIMAL diagnosis and explore the role of HIMAL in magnetic resonance imaging (MRI)–negative temporal lobe epilepsy (TLE).Methods
We studied the MRI of 155 adult patients with MRI-negative TLE and 103 healthy volunteers, and we asked (1) what are the qualitative and quantitative features that allow a reliable diagnosis of HIMAL, (2) how common is HIMAL in a normal control population, and (3) is HIMAL congruent with the epileptogenic side in MRI-negative TLE.Results
We found that the features that are most correlated with the expert diagnosis of HIMAL are hippocampal shape change with hippocampal diameter ratio > 0.8, lack of normal lateral convex margin, and a deep dominant inferior temporal sulcus (DITS) with DITS height ratio > 0.6. In a blinded analysis, a consensus diagnosis of unilateral or bilateral HIMAL was made in 25 of 103 controls (24.3% of people, 14.6% of hippocampi—14 left, six right, 10 bilateral) that did not differ from 155 lesion-negative TLE patients where 25 had HIMAL (16.1% of patients, 11.6% of hippocampi—12 left, two right, 11 bilateral). Of the 12 with left HIMAL only, 9 had seizures arising from the left temporal lobe, whereas 3 had right-sided seizures. Of the two with right HIMAL only, both had seizures arising from the left temporal lobe.Significance
HIMAL is an anatomic variant commonly found in controls. HIMAL is also an incidental nonpathologic finding in adult MRI-negative TLE and should not influence surgical decision making.
A prospective study contrasting the psychiatric outcome in drug-resistant epilepsy between patients who underwent surgery and a control group
Psychiatric morbidity in drug-resistant epilepsy is frequent and has a negative influence on quality of life. Surgery is proven to be the best therapeutic alternative for treating seizures. However, it is inconclusive with the current evidence whether surgery, per se, is a risk factor or promotes amelioration of psychiatric disorders. Until now, most studies have been cross-sectional with small or heterogeneous groups. In addition, the few prospective studies did not have an identical control group. The present study aims to clarify the role of surgery in psychopathologic alterations.Methods
We analyzed, through a prospective case-control study, the psychopathologic outcomes of patients with drug-resistant epilepsy, comparing those who underwent surgery and those who continued with pharmacologic treatment due to not being suitable for surgery. The assessments were performed during presurgical evaluation and 6 months after surgery. We studied psychiatric changes for each group, compared differences between groups, and also analyzed de novo and remission cases. Finally, we determined associated factors for postsurgical psychiatric disturbances.Results
The surgical group experienced a significant decrease in psychopathologic alterations in comparison with the control group. In addition, distress perception of surgical patients also improved, whereas it did not decrease in the control group. Patients who underwent surgery presented a decrease in depressive and anxiety symptoms, whereas the nonsurgical group increased its anxiety levels. De novo disturbances that appeared after surgery were less frequent than in nonsurgical patients. We observed significant favorable outcomes considering de novo versus remission cases for anxiety, depression, and total symptoms only in the surgical group. The two main predictors for psychiatric disorders after surgery were presurgical psychiatric functioning and surgery.Significance
Provides evidence that surgery improves psychiatric functioning in drug-resistant epilepsy through a prospective controlled study.
Pathologic increases in excitability levels of cortical tissue commonly underlie the initiation and spread of seizure activity in patients with epilepsy. By reducing the excitability levels in neural tissue, antiepileptic drug (AED) pharmacotherapy aims to reduce seizure severity and frequency. However, AEDs may also bring about adverse effects, which have been reported to increase with higher AED load. Measures that monitor the dose-dependent effects of AEDs on cortical tissue and quantify its excitability level are therefore of prime importance for efficient clinical care and treatment but have been difficult to identify. Here, we systematically analyze continuous multiday electrocorticography (ECoG) data from 10 patients under different levels of AED load and derive the recently proposed intrinsic excitability measures (IEMs) from different brain regions and across different frequency bands. We find that IEMs are significantly negatively correlated with AED load (prescribed daily dose/defined daily dose). Furthermore, we demonstrate that IEMs derived from different brain regions can robustly capture global changes in the degree of excitability. These results provide a step toward the ultimate goal of developing a reliable quantitative measure of central physiologic effects of AEDs in patients with epilepsy.
A new study, published in the scientific journal Epilepsy and Behavior, shows that irritable bowel syndrome (IBS) is more common in people with epilepsy than in the ‘general’ population.
The research also suggests that, although IBS itself doesn’t have a negative impact on health-related quality of life in people with epilepsy, it is associated with a greater likelihood of depression/anxiety symptoms and insomnia.
During the study, scientists, led by Dr Marco A. Díaz-Torres, at Universidad Autónoma de Nuevo León in Monterrey, Mexico, recruited 65 people with epilepsy and a group of people with similar characteristics, e.g. age, social demographic, who did not have epilepsy.
The team was interested in finding out how common (how prevalent) IBS and another bowel condition called functional dyspepsia were in each group. They also investigated the subjects’ sleep, symptoms of depression/anxiety and health-related quality of life.
The results showed that the prevalence of IBS was significantly higher in people with epilepsy than in those without epilepsy; but that the prevalence of functional dyspepsia was similar in the two groups.
Particpiants with both epilepsy and IBS had higher rates of insomnia (inability to sleep) and symptoms of depression/anxiety than those with epilepsy who did not have IBS; however, the presence of IBS itself in people with epilepsy did not appear to have a negative effect on health-related quality of life scores.
People with epilepsy are not routinely screened for IBS. This means that treatment may be delayed or withheld altogether. Moreover, gastrointestinal complaints may be wrongly attributed to antiepileptic drugs (AEDs), leading to unnecessary treatment changes. The authors therefore concluded that clinicians should screen for the presence of IBS in people with epilepsy complaining of gastrointestinal (bowel) symptoms.
Author: Dr Özge Özkaya
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Researchers in Sweden and France have developed a tiny device that can detect epileptic seizures at the exact point in which they arise, and deliver, to that precise point, a substance that can stop them before they spread to other areas of the brain.
The device, called a bioelectronic neural pixel, is 20×20 μm* in size (approximately the size of a human hair follicle) and combines recording electrodes with a pump mechanism to administer treatment.
If it can be safely applied in humans, this technology could potentially be used to locally record brain activity and regulate the targeted release of specific therapeutic agents; minimising side effects. It “creates a range of opportunities,” write the authors, whose results are published in the leading scientific journal Proceedings of the National Academy of Sciences (PNAS).
These findings come from work in animal brain tissue, in which the scientists chemically induced seizure-like activity. They used the device to first locate the origin of the seizures and then deliver a substance called GABA, which dampens neuronal activity, to try and stop them.
The team found that the GABA was able to stop seizure activity on the spot, whilst a recording at that point was being taken.
Antiepileptic drugs (AEDs), which are taken orally or injected into the blood stream, spread throughout the body and often cause unpleasant side effects. Therefore, being able to deliver a therapeutic compound to the exact place where it is needed could minimise or completely eliminate its side effects.
Dr Daniel T. Simon, Senior Author of the study, said in a press release: “Our technology makes it possible to interact with both healthy and sick neurons. We can now start investigating opportunities for finding therapies for neurological illnesses so rapidly and so locally that the patient doesn’t notice them.”
Author: Dr Özge Özkaya
*1 μm is one millionth of a metre
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Rapid advances in genetic research and increased use of genetic testing have increased the emphasis on genetic causes of epilepsy in patient encounters. Research in other disorders suggests that genetic causal attributions can influence patients' psychological responses and coping strategies, but little is known about how epilepsy patients and their relatives will respond to genetic attributions of epilepsy. We investigated the possibility that among members of families containing multiple individuals with epilepsy, depression, the most frequent psychiatric comorbidity in the epilepsies, might be related to the perception that epilepsy has a genetic cause.Methods
A self-administered survey was completed by 417 individuals in 104 families averaging 4 individuals with epilepsy per family. Current depression was measured with the Patient Health Questionnaire. Genetic causal attribution was assessed by three questions addressing the following: perceived likelihood of having an epilepsy-related mutation, perceived role of genetics in causing epilepsy in the family, and (in individuals with epilepsy) perceived influence of genetics in causing the individual's epilepsy. Relatives without epilepsy were asked about their perceived chance of developing epilepsy in the future, compared with the average person.Results
Prevalence of current depression was 14.8% in 182 individuals with epilepsy, 6.5% in 184 biologic relatives without epilepsy, and 3.9% in 51 individuals married into the families. Among individuals with epilepsy, depression was unrelated to genetic attribution. Among biologic relatives without epilepsy, however, prevalence of depression increased with increasing perceived chance of having an epilepsy-related mutation (p = 0.02). This association was not mediated by perceived future epilepsy risk among relatives without epilepsy.Significance
Depression is associated with perceived likelihood of carrying an epilepsy-related mutation among individuals without epilepsy in families containing multiple affected individuals. This association should be considered when addressing mental health issues in such families.
Early cardiac electrographic and molecular remodeling in a model of status epilepticus and acquired epilepsy
A myriad of acute and chronic cardiac alterations are associated with status epilepticus (SE) including increased sympathetic tone, rhythm and ventricular repolarization disturbances. Despite these observations, the molecular processes underlying SE-associated myocardial remodeling remain to be identified. Here we determined early SE-associated myocardial electrical and molecular alterations using a model of SE and acquired epilepsy.Methods
We performed electrocardiography (ECG) assessments in rats beginning at 2 weeks following kainate-induced SE, and calculated short-term variability (STV) of the corrected QT intervals (QTc) as a marker of ventricular stability. Using western blotting, we quantified myocardial β1-adrenergic receptors (β1-AR) and ventricular gap junction protein connexin 43 (Cx43) levels as makers of increased sympathetic tone. We determined the activation status of three kinases associated with sympathetic stimulation and their downstream ion channel targets: extracellular signal-regulated kinase (ERK), protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CamKII), hyperpolarization-activated cyclic nucleotide-gated channel subunit 2 (HCN2), and voltage-gated potassium channels 4.2 (Kv4.2). We investigated whether SE was associated with altered Ca2+ homeostasis by determining select Ca2+-handling protein levels using western blotting.Results
Compared with the sham group, SE animals exhibited higher heart rate, longer QTc interval, and higher STV beginning at 2 weeks following SE. Concurrently, the myocardium of SE rats showed lower β1-AR and higher Cx43 protein levels, higher levels of phosphorylated ERK, PKA, and CamKII along with decreased HCN2 and Kv4.2 channel levels. In addition, the SE rats had altered proteins levels of Ca2+-handling proteins, with decreased Na+/Ca2+ exchanger-1 and increased calreticulin.Significance
SE triggers early molecular alterations in the myocardium consistent with increased sympathetic tone and altered Ca2+ homeostasis. These changes, coupled with early and persistent ECG abnormalities, suggest that the observed molecular alterations may contribute to SE-associated cardiac remodeling. Additional mechanistic studies are needed to determine potential causal roles.
We investigated the prevalence of post–epilepsy surgery psychogenic nonepileptic seizures (PNES) in patients with drug-resistant epilepsy and the possible influence of risk factors on these seizures.Methods
In this retrospective study, we examined data from all patients with a clinical diagnosis of drug-resistant epilepsy who underwent epilepsy surgery at Graduate Hospital and the Jefferson Comprehensive Epilepsy Center between 1986 and 2016. Postsurgical outcome was identified for up to 15 years after surgery. Diagnosis of PNES was verified in the epilepsy monitoring unit with video–electroencephalography (EEG) ictal recording. Potential associated factors were assessed by comparing patients with or without postoperative PNES.Results
A total of 1,105 patients were studied; 697 patients had postoperative seizures, and, of these, 27 patients (3.9%) had documented PNES after surgery. A full-scale intelligence quotient (IQ) <80 was significantly associated with post-epilepsy surgery PNES (odds ratio [OR] 2.89, p = 0.007, 95% confidence interval [CI] 1.33–6.29). A history of a preoperative psychiatric diagnosis was also significantly associated with post–epilepsy surgery PNES (OR 4.67, p = 0.0001, 95% CI 2.01–10.82). Other factors were not significantly associated with post–epilepsy surgery PNES.Significance
Post–epilepsy surgery PNES should be considered when patients report recurrent seizures after epilepsy surgery. Although these seizures probably occur relatively infrequently, attention to factors such as appearance of new ictal behaviors, a preoperative history of a psychiatric disorder, and a low full-scale IQ should raise suspicion and lead to appropriate diagnostic measures.
Phenobarbital hypersensitivity is one of the common drug hypersensitivity syndromes in children. Clinical symptoms of phenobarbital hypersensitivity vary from maculopapular rashes (MPs) to severe cutaneous adverse drug reactions (SCARs) including drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Drug hypersensitivity has been demonstrated to be associated with variations in the HLA genotypes. This study was to investigate the association between the variations of HLA genotypes and phenobarbital hypersensitivity in Thai children.Methods
The cases were Thai children, between 0 and 18 years of age, who were diagnosed with phenobarbital hypersensitivity, which included SCARs and MPs. The control patients were Thai children of a corresponding age who had taken phenobarbital for at least 12 weeks without any hypersensitivity reaction. Blood samples were collected for HLA genotyping by using a reverse-sequence-specific oligonucleotide (SSO) probes method. The carrier rates of HLA alleles were compared between 47 cases (27 SCARs and 20 MPs) and 54 controls.Results
The carrier rates of HLA-A*01:01 and HLA-B*13:01 were significantly higher in the phenobarbital-induced SCARs than in the tolerant controls (18.5% vs. 1.85%, p = 0.01, odds ratio [OR] 11.66, 95% confidence interval [CI] 1.21–578.19; 37.04% vs. 11.11%, p = 0.009, OR 4.60, 95%CI 1.29–17.98). There was a trend of a higher carrier rate of HLA-C*06:02 in the phenobarbital-induced SCARs when compared with those in the tolerant controls (29.63% vs. 11.11%, p = 0.059, OR 3.31, 95% CI 0.88–13.31). In contrast to the phenobarbital-induced SCARs, only the HLA-A*01:01 carrier rate in the phenobarbital-induced MPs was significantly higher than those in the tolerant controls (20% vs. 1.85%, p = 0.017, OR 12.69, 95% CI 1.15–661.62).Significance
An association between phenobarbital hypersensitivity and HLA-A*01:01 and HLA-B*13:01 has been demonstrated in Thai children.
Regional and global connectivity disturbances in focal epilepsy, related neurocognitive sequelae, and potential mechanistic underpinnings
Epilepsy is among the most common brain network disorders, and it is associated with substantial morbidity and increased mortality. Although focal epilepsy was traditionally considered a regional brain disorder, growing evidence has demonstrated widespread network alterations in this disorder that extend beyond the epileptogenic zone from which seizures originate. The goal of this review is to summarize recent investigations examining functional and structural connectivity alterations in focal epilepsy, including neuroimaging and electrophysiologic studies utilizing model-based or data-driven analytic methods. A significant subset of studies in both mesial temporal lobe epilepsy and focal neocortical epilepsy have demonstrated patterns of increased connectivity related to the epileptogenic zone, coupled with decreased connectivity in widespread distal networks. Connectivity patterns appear to be related to the duration and severity of disease, suggesting progressive connectivity reorganization in the setting of recurrent seizures over time. Global resting-state connectivity disturbances in focal epilepsy have been linked to neurocognitive problems, including memory and language disturbances. Although it is possible that increased connectivity in a particular brain region may enhance the propensity for seizure generation, it is not clear if global reductions in connectivity represent the damaging consequences of recurrent seizures, or an adaptive mechanism to prevent seizure propagation away from the epileptogenic zone. Overall, studying the connectome in focal epilepsy is a critical endeavor that may lead to improved strategies for epileptogenic-zone localization, surgical outcome prediction, and a better understanding of the neuropsychological implications of recurrent seizures.
Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review
We performed a systematic review of the clinical, molecular, and biochemical features of polymerase gamma (POLG)–related epilepsy and current evidence on seizure management. Patients were identified from a combined electronic search of articles using Ovid Medline and Scopus databases, published from January 2000 to January 2015. Only patients with a confirmed genetic diagnosis of POLG mutations were considered. Seventy-two articles were included for analysis. We identified 128 pathogenic variants in 372 patients who had POLG-related epilepsy. Among these, 84% of the cases harbored at least one of these pathogenic variants: p.Ala467Thr, p.Trp748Ser, and p.Gly848Ser. A bimodal distribution of disease onset was present in early childhood (<5 years) and adolescence; female patients had a later presentation than male patients (median age 4.00 vs. 1.83 years, p-value = 0.041). Focal-onset seizure including convulsive, myoclonus, and occipital seizures was common at the outset and was refractory to pharmacotherapy. We confirmed that homozygous pathogenic variants located in the linker region of POLG were associated with later age of onset and longer survival compared to compound heterozygous variants. In addition, biochemical and molecular heterogeneities in different tissues were frequently observed. POLG-related epilepsy is clinically heterogeneous, and the prognosis is, in part, influenced by the location of the variants in the gene and the presence of hepatic involvement. Normal muscle and fibroblast studies do no exclude the diagnosis of POLG-related mitochondrial disease and direct sequencing of the POLG gene should be the gold standard when investigating suspected cases.
The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations
The coincidence of autism with epilepsy is 27% in those individuals with intellectual disability.1 Individuals with loss-of-function mutations in SHANK3 have intellectual disability, autism, and variably, epilepsy.2-5 The spectrum of seizure semiologies and electroencephalography (EEG) abnormalities has never been investigated in detail. With the recent report that SHANK3 mutations are present in approximately 2% of individuals with moderate to severe intellectual disabilities and 1% of individuals with autism, determining the spectrum of seizure semiologies and electrographic abnormalities will be critical for medical practitioners to appropriately counsel the families of patients with SHANK3 mutations.Methods
A retrospective chart review was performed of all individuals treated at the Blue Bird Circle Clinic for Child Neurology who have been identified as having either a chromosome 22q13 microdeletion encompassing SHANK3 or a loss-of-function mutation in SHANK3 identified through whole-exome sequencing. For each subject, the presence or absence of seizures, seizure semiology, frequency, age of onset, and efficacy of therapy were determined. Electroencephalography studies were reviewed by a board certified neurophysiologist. Neuroimaging was reviewed by both a board certified pediatric neuroradiologist and child neurologist.Results
There is a wide spectrum of seizure semiologies, frequencies, and severity in individuals with SHANK3 mutations. There are no specific EEG abnormalities found in our cohort, and EEG abnormalities were present in individuals diagnosed with epilepsy and those without history of a clinical seizure.Significance
All individuals with a mutation in SHANK3 should be evaluated for epilepsy due to the high prevalence of seizures in this population. The most common semiology is atypical absence seizure, which can be challenging to identify due to comorbid intellectual disability in individuals with SHANK3 mutations; however, no consistent seizure semiology, neuroimaging findings, or EEG findings were present in the majority of individuals with SHANK3 mutations.
These are the findings of an Epilepsy Research UK (ERUK) grant, which was awarded to Dr Rachel Charlton, at the University of Bath, in 2014.
For women with epilepsy pregnancy requires very careful planning, because exposure to some anti-epileptic drugs (AEDs) in the womb, valproate in particular, has been linked to an increased chance of birth defects, behavioural problems and delayed cognitive development.
Traditional methods for assessing the risk of behavioural and developmental issues in unborn babies (i.e. face-to-face interviews) require a lot of work and they are very expensive. In recent years, databases that contain routinely-collected electronic medical records have been increasingly used for research; however, whilst this approach offers many advantages, including lower cost and access to larger numbers of exposed children, it is not clear whether it is a reliable way of detecting developmental and behavioural problems. This is important to know, because if the risks of exposure to an AED in the womb are overestimated via a database, the drug may not be recommended by doctors when it is in fact safe. Conversely, if the risks are underestimated, doctors may recommend an AED that could inadvertently cause harm.
Here, Dr Charlton and colleagues aimed to compare the two methods, looking at the risk of specific neurodevelopmental disorders – autism, attention deficit hyperactivity disorder (ADHD) and dyspraxia (coordination difficulties) – associated with different types of AED exposure in the womb.
The researchers used an electronic database, called the Clinical Practice Research Datalink, to collect anonymised information about 7,066 mother-child pairs. Pairs were classified into three groups: 1) in which the mother had epilepsy and received AED treatment during pregnancy (546) 2) in which the mother had epilepsy but did not receive AED treatment during pregnancy (472) and 3) in which the mother did not have epilepsy and had not taken an AED (6,048).
The investigators used the data to identify all of the children in each group who had developed a neurodevelopmental disorder, and they were then able to calculate risk estimates. Risk in the ‘AED-treated group’ was broken down according to the different AEDs/combinations of AEDs taken by the mothers. Finally, the scientists compared their results with those obtained in an earlier UK study that used traditional methods.
Both studies found an increased risk of neurodevelopmental disorders in children born to women with epilepsy than in those born to women without epilepsy; however the database study produced risk estimates that were much lower. Moreover, the risk found amongst the children born to women without epilepsy was lower than that seen in the general population.
In the database study, neurodevelopmental disorders were found in a small number of children born to women with epilepsy who appeared not to have taken any medication during pregnancy. However, on closer examination, it was discovered that these women may still have been coming off their AEDs in the early stages of pregnancy. To look at the impact of this, the team adjusted the groups so that the ‘treated’ mothers also included women who had taken AEDs in the six months before pregnancy.
In both studies, the risk of neurodevelopmental disorders differed between AED exposure groups. Although the database study showed a higher risk with valproate monotherapy (valproate taken alone), it was a) a lot lower than that seen in the traditional study and b) not statistically significant, even when the exposure groups were modified to include the six months before pregnancy. This means that, according to recognised statistical rules, the chance that the finding could have occurred by chance was too high for it to be conclusive. Valproate polytherapy (taken with other AEDs), however, was associated with a significantly increased risk of neurodevelopmental disorders, although this risk was slightly lower than that reported in the traditional study.
These results suggest that neurodevelopmental disorders in children exposed to AEDs before birth are under-recorded in the Clinical Practice Research Datalink. This in turn means that some databases might not be as reliable as traditional methods for assessing the risks associated with AED exposure in the womb. Future research must take the findings of this study into consideration, so that women with epilepsy can be offered the most accurate pregnancy advice possible.
Earlier this year, the Medicines and Healthcare Products Regulatory Authority (MHRA) issued important new guidance about the risks of valproate in pregnancy. Click here to find out more.
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Paediatric researchers from Taiwan, who compared the effects of old and new antiepileptic drugs (AEDs) on bone health, found that new AEDs may be safer and better tolerated. They note, however, that further research is needed to fully understand the effects of newer AEDs on bone health and growth.
According to the scientists, whose study is published in the International Journal of Molecular Sciences, their analysis “emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities.”
There have been some conflicting findings to date regarding the effects of AEDs on bone health. This prompted Dr Ching-Shiang Chi and colleagues, at Tungs’ Taichung Metroharbor Hospital, to conduct a review of past studies, which involved almost 69,000 people with epilepsy.
The results of their analysis suggest that taking AEDs is associated with a decrease in bone mass density and an increased risk of fractures.
The team found strong evidence that older or classical AEDs, such as benzodiazepines carbamazepine, phenytoin, phenobarbital and valproic acid, cause vitamin D deficiency and have a negative impact on bone health. Newer AEDs, such as levetiracetam, oxcarbazepine, lamotrigine, topiramate, gabapentin, and vigabatrin, were found to be safer and better tolerated; although more research is required to determine their effect on bone health.
The authors conclude: “Proper use of a new medication may avoid serious disabilities in users. In addition, supplementation of calcium and vitamin D are still recommended to epileptic patients on AEDs.”
AEDs are the ﬁrst choice of treatment for epilepsy and approximately two thirds of people respond to them. However, they do carry a risk of side effects, including dizziness, drowsiness and weight gain.
Previous research has shown that AEDs may also have a negative impact on bone health, especially if used long-term. In fact, more than half of people with epilepsy who take AEDs are reported to have bone abnormalities. This is a cause for concern, especially in younger children who are at a critical stage of growth.
Author: Dr Özge Özkaya
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