Review of pharmacogenetics of antiseizure medications: focusing on genetic variants of mechanistic targets.

Antiseizure medications (ASMs) play a central role in seizure management, however, unpredictability in the response to treatment persists, even among patients with similar seizure manifestations and clinical backgrounds. An objective biomarker capable of reliably predicting the response to ASMs would profoundly impact epilepsy treatment. Presently, clinicians rely on a trial-and-error approach when selecting ASMs, a time-consuming process that can result in delays in receiving alternative non-pharmacological therapies such as a ketogenetic diet, epilepsy surgery, and neuromodulation therapies. Pharmacogenetic studies investigating the correlation between ASMs and genetic variants regarding their mechanistic targets offer promise in predicting the response to treatment. Sodium channel subunit genes have been extensively studied along with other ion channels and receptors as targets, however, the results have been conflicting, possibly due to methodological disparities including inconsistent definitions of drug response, variations in ASM combinations, and diversity of genetic variants/genes studied. Nonetheless, these studies underscore the potential effect of genetic variants on the mechanism of ASMs and consequently the prediction of treatment response. Recent advances in sequencing technology have led to the generation of large genetic datasets, which may be able to enhance the predictive accuracy of the response to ASMs.

The Genetics of Primary Familial Brain Calcification: A Literature Review.

Primary familial brain calcification (PFBC), also known as Fahr's disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes (SLC20A2, PDGFRB, PDGFB, and XPR1) and three recessive inherited genes (MYORG, JAM2, and CMPK2). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to be identified. The function of currently known genes suggests that PFBC could be caused by the dysfunction of the neurovascular unit, the dysregulation of phosphate homeostasis, or mitochondrial dysfunction. An improved understanding of the underlying pathogenic mechanisms for PFBC may facilitate the development of novel therapies.

Risk factors for seizures after cranioplasty.

PURPOSE: Cranioplasty can improve a patient's psychosocial and cognitive functions after decompressive craniectomy, however seizures are a common complication after cranioplasty. The risk factors for early and late seizures after cranioplasty are unclear. This study is to evaluate the risk factors for early and late seizure after cranioplasty. METHODS: Two hundred and thirty-eight patients who received cranioplasty following craniectomy between January 2012 and December 2014 were included in this study. The risk factors of the patients with early and late post-cranioplasty seizures were compared to those with no post-cranioplasty seizures. RESULTS: Seizures (73/238, 30.3%) were the most common complication after cranioplasty. Of these 73 patients, 17 (7.1%) had early post-cranioplasty seizures and 56 (23.5%) had late post-cranioplasty seizures. Early post-cranioplasty seizures were related to a longer interval between craniectomy and cranioplasty (P = 0.006), artificial materials (P < 0.001), and patients with late post-craniectomy seizures (P = 0.001). Late post-cranioplasty seizures were related to the presence of neurological deficits (P = 0.042). After stepwise logistic regression analysis, a longer interval between craniectomy and cranioplasty (P = 0.012; OR: 1.004, 95% CI: 1.001-1.007) and late post-craniectomy seizures (P = 0.033; OR: 4.335, 95% CI: 1.127-16.675) were independently associated with early post-cranioplasty seizures. CONCLUSION: Delayed cranioplasty procedures and seizures before cranioplasty were significantly associated with early post-cranioplasty seizures. Further studies are warranted to investigate whether early surgery after craniectomy can reduce the risk of early post-cranioplasty seizures.

Conformational switch of polyglutamine-expanded huntingtin into benign aggregates leads to neuroprotective effect.

The abundant accumulation of inclusion bodies containing polyglutamine-expanded mutant huntingtin (mHTT) aggregates is considered as the key pathological event in Huntington's disease (HD). Here, we demonstrate that FKBP12, an isomerase that exhibits reduced expression in HD, decreases the amyloidogenicity of mHTT, interrupts its oligomerization process, and structurally promotes the formation of amorphous deposits. By combining fluorescence-activated cell sorting with multiple biophysical techniques, we confirm that FKBP12 reduces the amyloid property of these ultrastructural-distinct mHTT aggregates within cells. Moreover, the neuroprotective effect of FKBP12 is demonstrated in both cellular and nematode models. Finally, we show that FKBP12 also inhibit the fibrillization process of other disease-related and aggregation-prone peptides. Our results suggest a novel function of FKBP12 in ameliorating the proteotoxicity in mHTT, which may shed light on unraveling the roles of FKBP12 in different neurodegenerative diseases and developing possible therapeutic strategies.

Central nervous system involvement in hepatocellular carcinoma: clinical characteristics and comparison of intracranial and spinal metastatic groups.

From January 1993 to December 2006 we analyzed the clinical characteristics of patients with hepatocellular carcinoma (HCC) with central nervous system (CNS) metastasis at the Kaohsiung Chang Gung Memorial Hospital, Taiwan. Forty-six patients with HCC and CNS metastasis were identified, of whom 36 had intracranial metastasis and 10 had spinal metastasis. The clinical presentations, laboratory data and imaging studies were collected and analyzed. The age at the time of HCC diagnosis ranged from 34 to 78 years; CNS metastasis occurred between 0 and 85 months after diagnosis and death followed between 0 and 93 months later. The Glasgow Coma Scale (GCS) score at the time of CNS metastasis ranged from 7 to 15 and the Child-Pugh score at diagnosis of HCC ranged from 5 to 15. Patients with spinal metastasis had a higher GCS score and lower Child-Pugh score at diagnosis. None of the serum biochemical studies showed unique abnormalities. From the data currently available, intracranial metastasis is the most common site of CNS metastasis of HCC. Advances in treating and diagnosing HCC have improved patient outcomes remarkably; however, CNS metastasis continues to have a grave prognosis. Without a specific biomarker for predicting CNS involvement in HCC, a high index of suspicion for the diagnosis should be maintained, particularly in HCC hyperendemic areas such as Taiwan.

Idiopathic hypereosinophilia syndrome with loeffler endocarditis, embolic cerebral infarction, and left hydranencephaly: a case report.

PURPOSE: Idiopathic hypereosinophilia syndrome (iHES) is classically defined as prolonged peripheral eosinophilia and multiple organ involvement. The involvement of the heart can lead to intraventricular thrombus because of infiltration of the endomyocardium by eosinophils. Cerebral infarction has been ascribed to thromboembolic events originating from intraventricular thrombus. CASE REPORT: A 67 year-old woman with hypereosinophilia for 6 months presented acute weakness of the right limbs. Left hydranencephaly and absence of the left internal carotid artery were found on brain computed tomography. Brain magnetic resonance imaging (MRI) showed multiple infarctions at bilateral hemispheres. An intraventricular thrombus was detected both in transesophageal echocardiography and in heart MRI. Hypereosinophilia responded well to steroid use and warfarin was used for stroke prevention. CONCLUSIONS: Complete evaluation of systemic involvement in iHES is mandatory and early intervention may prevent deterioration of this disease. Both cardiogenic embolism and endothelial damage related to circulating eosinophils may contribute to the occurrence of stroke in this patient.

Clinical characteristics of spinal involvement in hepatocellular carcinoma.

PURPOSE: To analyze the clinical characteristics of hepatocellular carcinoma (HCC) with spinal metastasis. METHODS: During a period of 14 years, 42 HCC patients with cranial and/or spinal metastasis were identified. Among them, 12 had spinal involvement and thus were included for study. The clinical, laboratory and neuroimaging data of these 12 cases were analyzed. RESULTS: The 12 cases were all male, aged 36-65 years. The time interval from the diagnosis of HCC to the finding of spinal involvement was 0-38 months. Among these 12 cases, four had the features of spinal involvement in the initial presentation of their HCC. Low back pain was the most common symptom followed by weakness and numbness in the lower limbs. A serum biochemical study did not show unique findings. All 12 cases died within nine months after the diagnosis of the HCC spinal involvement. CONCLUSIONS: 28.6% (12/42) of the HCC patients with nervous system metastasis had spinal involvement and the exact incidence rate can be increased by more extensive neuroimaging studies. Viral hepatitis and liver cirrhosis are common preceding events in patients with HCC with spinal involvement. T- and L-spine are the most commonly involved segments and back pain is the most common complaint in patients with HCC with spinal metastasis. The prognosis in this group of patients is grave and most of the patients died soon after the development the HCC's spinal involvement. No specific biomarker can predict the development of spinal involvement in HCC patients and diagnostic consideration can only be emphasized, especially in HCC hyperendemic areas such as Taiwan.