Psychiatric symptoms of children and adolescents with juvenile neuronal ceroid lipofuscinosis

Background Juvenile neuronal ceroid lipofuscinosis (JNCL) is one of the most common neurodegenerative disorders in childhood and adolescence. The clinical picture includes diverse and complex psychiatric symptoms that are difficult to treat. Only symptomatic treatment is available. To improve symptomatic therapy, it is important to recognize the symptoms. The purpose of this study was to identify predominant psychiatric symptoms in patients with JNCL. Methods The study included 27 patients with JNCL with and without psychotropic treatment. The mean age was 15.2 (range 9–21) years. Characteristic psychiatric symptoms in this patient group were clarified by using the following standardized questionnaires filled in by parents, teachers and the patients themselves: Child Behavior Checklist (CBCL), Teacher Report Form (TRF) and Children's Depression Inventory (CDI). The symptoms were recorded for the entire study group and compared between patients with and without psychotropic treatment and between genders. Results The patients had a large number of psychiatric symptoms according to the CBCL and TRF. The most commonly reported symptoms were social, thought, attention problems, somatic complaints and aggressive behaviour. Patients receiving psychotropic medication had more psychiatric symptoms according to the CBCL and TRF. Moreover, female patients had more problems than male patients according to the CBCL. The total psychiatric symptom score was at clinical or borderline range for psychiatric disturbance in 74% of patients. The number of depressive symptoms reported by the patients themselves was low. Conclusions JNCL patients suffer from a multitude of psychiatric symptoms. To improve drug choice and dosage, a thorough evaluation of these symptoms by standardized methods is needed before initiating treatment. Progress and possible adverse effects of treatment should be monitored on a regular basis.     

青少年型神经元蜡样质脂褐素沉积病6例的临床特点和基因分析

目的报告6例经病理诊断为青少年型神经元蜡样质脂褐素沉积病(juvenlie neuronal ceroid lipofus-cinosis,JNCL)患者的临床特点以及部分患者的基因研究结果。方法总结分析6例JNCL患者的临床特点,并对其中3例患者进行CLN3基因检查。结果 6例患者,发病年龄为2~7岁,首发症状4例主要为癫痫,2例为视力下降。主要临床表现包括癫痫、视力下降、智能减退。基因检查3例患者均没有发现国外常见的CLN3基因的大片断缺失,在1例患者发现位于第一外显子的c3G→T杂合突变。结论国人JNCL具有自己的特点,在CLN3基因的突变类型方面和其他地区的病例可能不完全相同,也可能存在新的基因。     

Neuropsychological test battery in the follow-up of patients with juvenile neuronal ceroid lipofuscinosis

The aim of the present study was to develop a neuropsychological test battery for patients with juvenile neuronal ceroid lipofuscinosis (JNCL) and to study the development of cognitive functions during the first 5 years after diagnosis. Fourteen patients with JNCL entered the study. Nine patients were homozygous for the major mutation, whereas five were compound heterozygotes. All patients were studied annually with a special neuropsychological test battery (NEPSY) adapted from Luria's neuropsychological test, and modified for the visually handicapped; the Wechsler Intelligence Scale for Children – Revised (WISC‐R) was also included. The neurological examinations were scored. Furthermore, 1.OT magnetic resonance imaging scan was performed at the beginning of follow‐up and after a mean of 5 years. A decline in verbal IQ (WISC‐R) during the follow‐up period was found in all subjects except one compound heterozygous male. Short‐term memory and digit memory span were already impaired at an early stage of the disease. Orientation to time was found to decline more than orientation to person and place. Motor speed usually became impaired after 10 years of age. Spatial orientation was impaired only in the patients homozygous for the major mutation. The test battery was found to be reliable and easy to use, and offered valuable information on the progress of the disease. It also provided important guidelines for rehabilitation.     

Current trends in antiepileptic drug therapy

Summary: Over the last two decades, drug therapy for epilepsy has improved substantially. This can be ascribed to a large extent to three factors, including the demonstration of the advantages of monotherapy; the realization of the need for dosage tailoring, coupled [for some antiepileptic drugs (AEDs)] with control of pharmacokinetic variability through therapeutic drug monitoring; and the introduction of newer agents with improved tolerability profiles. What further advances should we expect for the future? Current trends that are expected to increasingly affect our prescribing patterns include greater reliance on evidence‐based medicine and treatment guidelines, a trend that will be facilitated by completion of therapeutically meaningful randomized trials (including cost‐effectiveness studies) and high‐quality observational studies (including multinational pregnancy registries), as well as initiatives from scientific societies and government organizations aimed at condensing the most relevant information into therapeutic guidelines. The explosion in communication technology will accelerate dissemination of this information and its application to clinical practice. Other factors include a more rational patient‐tailored AED selection and dose individualization, aided by characterization of predictors of outcome as defined by clinical parameters (sex, age, epilepsy syndrome, and etiology), pathophysiological mechanisms, and newly discovered genetic markers of outcome; improved definition of the role of new AEDs, resulting in their increased use in newly diagnosed epilepsy; and reappraisal of the value of combination therapy in refractory epilepsies, based on evidence produced by experimental and clinical studies designed to identify favorable pharmacodynamic interactions. Additional important developments may come from the discovery of novel, more efficacious AEDs and from exploration of potential new targets, such as prevention of epileptogenesis.     

Quantifying antiepileptic drug effects using intrinsic excitability measures

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.     

Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis

Purpose:   Long-term antiepileptic drug (AED) therapy has been associated with an increase in risk of atherosclerosis. At issue is whether this risk is related to the duration of AED therapy. We evaluated the hypothesis that the cumulative effect of long-term exposure to AEDs plays a pivotal role in the pathogenesis of atherosclerosis in patients with epilepsy.
Methods:   One hundred ninety-five patients under long-term AED therapy and 195 healthy age- and sex-matched control subjects received measurement of intima media thickness (IMT) at the far wall of the common carotid artery (CCA) by B-mode ultrasonography to assess the extent of atherosclerosis. Other measurements included body mass index (BMI) and blood lipid profile or homocysteine, folic acid, uric acid, fasting blood sugar, high sensitivity C-reactive protein (hs-CRP), thiobarbituric acid reactive substances (TBARS), and total reduced thiols.
Results:   CCA IMT was significantly increased in patients with epilepsy, with male subjects exhibiting thicker IMT than their female counterparts. Whereas BMI, homocysteine, hs-CRP, and TBARS were significantly elevated, folic acid and thiols were significantly reduced in patients with epilepsy. Multiple linear regression analysis further revealed that duration of AED therapy, age, gender, and TBARS level (index for oxidative stress) were independently associated with CCA IMT. In addition, the log-transformed CCA IMT increased linearly with duration of AED therapy after adjustments for age, gender, and TBARS level.
Discussion:   The duration of AED therapy is significantly associated with the acceleration of atherosclerosis in patients with epilepsy, alongside independent contributions of age, gender, and oxidative stress to the atherosclerotic process.     

Treatment Strategies for Myoclonic Seizures and Epilepsy Syndromes with Myoclonic Seizures

Summary:   Despite the availability of numerous treatment options, the diagnosis and treatment of myoclonic seizures continue to be challenging. Based on clinical experience, valproate and benzodiazepines have historically been used to treat myoclonic seizures. However, many more treatment options exist today, and the clinician must match the appropriate treatment with the patient's epilepsy syndrome and its underlying etiology. Comorbidities and other medications must also be considered when making decisions regarding treatment. Rarely, some antiepileptic drugs may exacerbate myoclonic seizures. Most epileptic myoclonus can be treated pharmacologically, but some cases respond better to surgery, the ketogenic diet, or vagus nerve stimulation. Because myoclonic seizures can be difficult to treat, clinicians should be flexible in their approach and tailor therapy to each patient.     

A novel in-frame mutation in CLN3 leads to Juvenile neuronal ceroid lipofuscinosis in a large Pakistani family

Abstract

Aim: Neuronal ceroid lipofuscinosis (NCLs) are the most common neurodegenerative disorders, with global incidence of 1 in 100,000 live births. NCLs affect central nervous system, primarily cerebellar and cerebral cortices. Juvenile neuronal ceroid lipofuscinosis (JNCL), also known as Batten disease, is the most common form of NCLs. JNCL is primarily caused by pathogenic mutations in CLN3 gene, which encodes a transporter transmembrane protein of uncertain function. The 1.02?kb deletion is the most common mutation in CLN3 that results in frame shift and a premature termination leading to nonfunctional protein. Here, we invetigated a large consanguineous family consisting of four affected individuals with clincal symptoms suggestive of Juvenile neuronal ceroid lipofuscinosis.

Materials and methods: We conducted clinial and radilogical investigation of the family and performed NGS based Gene Panel sequencing comprising of five hundred and forty five candidate genes to characterize it at genetic level.

Results: We identified a novel homozygous c.181_183delGAC mutation in the CLN3 gene seggregating witht the disorder in the family. The mutation induces in-frame deletion, deleting one amino acid (p.Asp61del) in CLN3 protein. The deleted amino acid aspartic acid plays an important role as general acid in enzymes active centers as well as in maintaining the ionic character of proteins.

Conclusion: Our finding adds to genetic variability of Juvenile neuronal ceroid lipofuscinosis associated with CLN3 gene and a predicted CLN3 protein interacting domain site.     

The pharmacologic basis of antiepileptic drug action

The development of medications used in the treatment of epilepsy has accelerated over the past decade, and has benefited from a parallel growth in our knowledge of the basic mechanisms underlying neuronal excitability and synchronization. This understanding of the pharmacologic basis of antiepileptic drug (AED) action has, in large part, arisen from recent advances in cellular and molecular biology, coupled with avenues of drug discovery that have departed somewhat from the largely empiric approaches of the past. Physicians now have available to them an ever-growing armentarium of AEDs, necessitating a firmer appreciation of their mechanisms of action if more rational approaches toward both clinical application and research are to be adopted. An important example in this regard is the concept of rational polypharmacy for patients with epilepsy who are refractory to monotherapy. This review summarizes our current understanding of the molecular targets of clinically significant AEDs, comparing and contrasting their differing mechanisms of action.     

Antiepileptic drug therapy and its management in sudden unexpected death in epilepsy: a case-control study

PURPOSE: Because frequent seizures constitute a major risk factor for sudden unexpected death in epilepsy (SUDEP), the treatment with antiepileptic drugs (AEDs) may play a role for the occurrence of SUDEP. We used data from routine therapeutic drug monitoring (TDM) to study the association between various aspects of AED treatment and the risk of SUDEP. METHODS: A nested case-control study was based on a cohort consisting of 6,880 patients registered in the Stockholm County In Ward Care Register with a diagnosis of epilepsy. Fifty-seven SUDEP cases, and 171 controls, living epilepsy patients, were selected from the cohort. Clinical data including data on TDM were collected through medical record review. RESULTS: The relative risk (RR) of SUDEP was 3.7 (95% CI, 1.0-13.1) for outpatients who had no TDM compared with those who had one to three TDMs during the 2 years of observation. RR was 9.5 (1.4-66.0) if carbamazepine (CBZ) plasma levels at the last TDM were above and not within the common target range (20-40 microM). High CBZ levels were associated with a higher risk in patients receiving polytherapy and in those with frequent dose changes. Although the subgroup of patients with high CBZ levels was small (six cases of 33 with CBZ therapy), and the result should be interpreted with caution, no similar associations were demonstrated for phenytoin plasma levels and risk of SUDEP. No association was found between SUDEP risk and within-patient variation in AED levels over time. CONCLUSIONS: Polytherapy, frequent dose changes, and high CBZ levels as identified risk factors for SUDEP all point to the risks associated with an unstable severe epilepsy. It is unclear whether high CBZ levels per se represent a risk factor or just reflect other unidentified aspects of a severe epilepsy. Our results, however, prompt further detailed analyses of the possible role of AEDs in SUDEP in larger cohorts and suggest that reasonable monitoring of the drug therapy may be useful to reduce risks.     

Felbamate Levels in Patients with Epilepsy

The usefulness of felbamate (FBM) levels in managing epilepsy patients has not been determined. The purpose of the present study was to determine if FBM levels obtained at routine office visits correlated with side effects reported by patients. We determined FBM levels by high-pressure liquid chromatography (HPLC) of 46 epilepsy patient plasma specimens (41 patients) and assessed medication toxicity and seizure frequency by a questionnaire. Thirty-six patients were treated with other antiepileptic drugs (AEDs); concomitant AED levels not in ranges believed to cause toxicity. FBM levels ranged from 9 to 134 pg/ml, and were divided into three groups for analysis, resulting in low-range (9–36 pg/ml), mid-range (37–54 μg/ml), and high-level (44–134 pg/ml) groups. Anorexia and complaints of severe side effects were reported significantly more often in the high-level group as compared with the low- and midrange groups. Significantly more patients in the high-level group (1043) reported decreased seizure frequency, as compared with 12 of 30 of patients in the low-and midrange groups combined. FBM levels correlated linearly with doses overall, but most closely in FBM monotherapy patients.     

A favorable response to antiparkinsonian treatment in juvenile neuronal ceroid lipofuscinosis

To study the effect of dopaminergic drugs on the parkinsonism in juvenile neuronal ceroid lipofuscinosis, the authors conducted an open study of 21 patients. According to the motor Unified PD Rating Scale (UPDRS) score, treatment was initiated with either levodopa (n = 10) or selegiline (n = 6). Five patients served as a control group. The UPDRS score after 1 year was compared with the score at onset. Both in the control group and in the selegiline group, the mean UPDRS score increased, whereas in the levodopa group, the mean UPDRS score decreased. The difference between the levodopa group and the control group was significant.     

Epilepsy and antiepileptic drug use in elderly people as risk factors for dementia

OBJECTIVE: To assess the role of epilepsy and antiepileptic drugs (AEDs) as risk factors for probable Alzheimer's disease (AD) and for all dementias in the Canadian Study of Health and Aging (CSHA). A secondary objective was to isolate the effect of the AED phenytoin on the development of dementia and AD. METHODS: The cohort consists of 5376 participants aged 65 years or older with no evidence of dementia, defined as Modified Mini-Mental State (3MS) score > or =78. Primary exposure was self-report or clinical diagnosis of epilepsy at baseline (n=39), or self-report of AED therapy (n=67). Primary outcomes were development of dementia, defined as 3MS<78, or AD, determined by clinical examination using standard criteria, during a 5-year follow-up period. People whose 3MS score remained > or =78 served as the comparison group. RESULTS: People reporting AED use at baseline had an age, sex and baseline 3MS adjusted odds ratio (OR) of 2.11 (95% CI 1.11 to 4.01) for developing dementia compared to those not taking AEDs at baseline. The association remained significant using only phenytoin as the exposure. No significant association was found between AED use and development of AD, nor between epilepsy and development of either AD or dementia. CONCLUSIONS: Older adults taking AEDs are at a significantly higher relative risk of developing dementia than those not taking AEDs. Further investigation of this finding is warranted.     

Blood lymphocytes in neuronal ceroid lipofuscinosis

Ultrastructural examination of white blood cells of 8 patients with neuronal ceroid lipofuscinosis showed the characteristic cytosomes, i.e. curvilinear bodies, fingerprint profiles, osmiophilic bodies, as seen in nerve cells. The reliability of this simple technique in the diagnostic work-up of this progressive neurodegenerative disorder is emphasized.

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Sommario Vengono presentati i risultati dell'indagine ultrastrutturale dei linfociti circolanti in 8 pazienti affetti da Ceroido-Lipofuscinosi Neuronale. Nel citoplasma delle cellule ematiche sono stati osservati i medesimi citosomi (corpi curvilinei, processi ad impronte digitate, corpi osmiofili), che si riscontrano nei neuroni. Vengono sottolineati i vantaggi di questa semplice metodica nell'iter diagnostico di questa encefalopatia degenerativa a carattere progressivo.

     

Effect of dosage failed of first antiepileptic drug on subsequent outcome

Purpose: The recent definition of drug‐resistant epilepsy proposed by the International League Against Epilepsy (ILAE) stipulated failure of an adequate trial of two tolerated, appropriately chosen and used antiepileptic drug (AED) schedules to achieve seizure freedom. Doses failed were not specifically discussed. We explored the effect of the doses at which the first and second AED regimens failed on subsequent outcomes in a population of adults with newly diagnosed epilepsy followed for up to 20 years. Methods: Patients in whom epilepsy was diagnosed and the first AED prescribed between July 1, 1982 and April 1, 2006, were followed until March 31, 2008. Dosage at which an AED failed was categorized according to the World Health Organization’s defined daily dose (DDD) for each drug. Cumulative incidence curves for time to final seizure freedom (no seizure for at least 1 year on unchanged dosage at last follow up) were stratified by whether the first regimen was failed at doses above or below the 25%, 50%, or 75% cutoffs for the DDD of each AED. Key Findings: Among patients who had taken a second regimen (n = 327), those in whom the first AED failed at doses above the various cutoffs (particularly 50% and 75% DDD) had lower probability of becoming seizure‐free at last follow‐up (p = 0.06 for 25% DDD, p < 0.001 for both 50% and 75% DDD). The same difference was observed for patients who had taken a third regimen (n = 141; p = 0.23 for 25% DDD, p < 0.01 for 50% DDD; and p = 0.002 for 75% DDD). A trend to higher seizure‐free rate was observed in patients who had taken the third regimen when both the first and second regimens failed at <75% DDD. The difference remained significant after adjusting for covariates when using 50% DDD as the cutoff for patients who took a second regimen (hazard ratio 1.60, 95% confidence interval 1.08–2.37). Significance: Higher failure dosage of the first AED predicts poorer subsequent outcome. This methodology could be used to refine further the ILAE definition of drug‐resistant epilepsy by exploring the doses need to fail to provide an adequate AED trial.     

Long-term seizure outcome and antiepileptic drug treatment in surgically treated temporal lobe epilepsy patients: a controlled study

PURPOSE: To evaluate the long-term impact of surgical treatment on seizure outcome and antiepileptic drug (AED) use in patients with pharmacoresistant temporal lobe epilepsy (TLE). METHODS: Comparison of seizure outcome and AED us in operated-on TLE patients (n=148) and nonsurgically treated TLE patients (n=94) at a baseline visit and a follow-up visit after a mean period of 4.8 years. RESULTS: At follow-up, 44.6% of the surgical patients and 4.3% of the nonsurgical patients had been continuously seizure- free since the baseline visit (including the immediate postoperative period). A further 17.6% of the operated-on and 3.2% of the not operated-on patients had been seizure-free for at least the previous year; 37.8% of the surgical and 92.5% of the nonsurgical patients had had seizures during the previous 12 months (p < 0.001). Of the surgical patients, 8.8% versus none of the nonsurgical patients were AED free at follow-up; 55.4% versus 20.2% were receiving monotherapy, and 35.8% versus 79.8% were receiving polytherapy (p < 0.001). Mean number of AEDs and mean change in number of AEDs were significantly more favorable in operated-on than in non-operated-on patients. Further subgroup analysis revealed that not only the continuously seizure-free surgical patients, but also the operated-on patients with ongoing seizures took fewer AEDs than their respective non-operated-on counterparts. CONCLUSIONS: This controlled study for the first time provides comprehensive information on long-term seizure outcome and AED use in surgical TLE patients. It shows a more favorable seizure outcome and AED use in the surgically treated patients. The latter holds true even for the not seizure-free patient subgroup.