Epigenetics of neurological diseases.

Higher-order DNA structure and gene expression are governed by epigenetic processes like DNA methylation and histone modifications. Abnormal epigenetic mechanisms are known to contribute to the emergence of numerous diseases, including cancer. Historically, the chromatin abnormalities were only considered to be limited to discrete DNA sequences and were thought to be associated with rare genetic syndrome however, recent discoveries have pointed to genome-wide level changes in the epigenetic machinery which has contributed to a better knowledge of the mechanisms underlying developmental and degenerative neuronal problems associated with diseases such as Parkinson's disease, Huntington's disease, Epilepsy, Multiple sclerosis, etc. In the given chapter we describe the epigenetic alterations seen in various neurological disorders and further discuss the influence of these epigenetic changes on developing novel therapies.

Correlation of age at seizure onset with GABAA receptor subunit and chloride Co-transporter configuration in Focal cortical dysplasia (FCD).

Focal cortical dysplasia (FCD) represents a group of malformations of cortical development, which are speculated to be related to early developmental defects in the cerebral cortex. According to dysmature cerebral development hypothesis of FCD altered GABAA receptor function is known to contribute to abnormal neuronal network. Here, we studied the possible association between age at seizure onset in FCD with the subunit configuration of GABAA receptors in resected brain specimens obtained from patients with FCD. We observed a significantly higher ratio of α4/α1 subunit-containing GABAA receptors in patients with early onset (EO) FCD as compared to those with late onset (LO) FCD as is seen during the course of development where α4-containing GABAA receptors expression is high as compared to α1-containing GABAA receptors expression. Likewise, the influx to efflux chloride co-transporter expression of NKCC1/KCC2 was also increased in patients with EO FCD as seen during brain development. In addition, we observed that the ratio of GABA/Glutamate neurotransmitters was lower in patients with EO FCD as compared to that in patients with LO FCD. Our findings suggest altered configuration of GABAA receptors in FCD which could be contributing to aberrant depolarizing GABAergic activity. In particular, we observed a correlation of age at seizure onset in FCD with subunit configuration of GABAA receptors, levels of NKCC1/KCC2 and the ratio of GABA/Glutamate neurotransmitters such that the patients with EO FCD exhibited a more critically modulated GABAergic network.

Upregulation of breast cancer resistance protein and major vault protein in drug resistant epilepsy.

PURPOSE: Identifying factors involved in the development of drug resistant epilepsy (DRE) remains a challenge. Candidate gene studies have shown modulation of resistance to drugs by various multidrug resistance proteins in DRE. However the resistance to drugs in DRE could be more complex and multifactorial involving molecules in different pharmacokinetic processes. In this study for the first time we have analyzed the relative expression of four molecules with different drug resistance mechanisms in two most common DRE pathologies, mesial temporal lobe epilepsy (MTLE) and focal cortical dysplasia (FCD) with respect to each other and also with different non-epileptic controls. METHODS: Brain tissues resected from MTLE (n=16) and FCD type I and II (n=12) patients who had undergone surgery were analysed for mRNA levels of multidrug resistance-associated protein 1(MRP1), major vault protein (MVP), breast cancer resistance protein (BCRP), and one drug metabolising enzyme (UGT1A4) as compared to non-epileptic controls which were tissues resected from tumor periphery (n=6) and autopsy tissues (n=4) by quantitative PCR. RESULTS: We found significant upregulation of MVP and BCRP whereas MRP1 and UGT1A4 were unaltered in both pathologies. While upregulation of BCRP was significantly higher in MTLE (9.34±0.45; p<0.05), upregulation of MVP was significantly higher in FCD (2.94±0.65; p<0.01). CONCLUSION: We propose that upregulation of BCRP and MVP is associated with MTLE and FCD and these molecules not only may have the potential to predict pathology specific phenotypes but may also have therapeutic potential as adjunct treatment in these pathologies.

Role of inflammation and its miRNA based regulation in epilepsy: Implications for therapy.

There is a need to develop innovative therapeutic strategies to counteract epilepsy, a common disabling neurological disorder. Despite the recent advent of additional antiepileptic drugs and respective surgery, the treatment of epilepsy remains a major challenge. The available therapies are largely based on symptoms, and these approaches do not affect the underlying disease processes and are also associated frequently with severe side effects. This is mainly because of the lack of well-defined targets in epilepsy. The discovery that inflammatory mediators significantly contribute to the onset and recurrence of seizures in experimental seizure models, as well as the presence of inflammatory molecules in human epileptogenic tissue, highlights the possibility of targeting specific inflammation related pathways to control seizures that are otherwise resistant to the available AEDs. Emerging studies suggest that miRNAs have a significant role in regulating inflammatory pathways shown to be involved in epilepsy. These miRNAs can possibly be used as novel therapeutic targets in the treatment of epilepsy as well as serve as diagnostic biomarkers of epileptogenesis. This review highlights the immunological features underlying the pathogenesis of epileptic seizures and the possible miRNA mediated approaches for drug resistant epilepsies that modulate the immune-mediated pathogenesis.

Initial experience of using high field strength intraoperative MRI for neurosurgical procedures.

We report our initial experience to optimize neurosurgical procedures using high field strength intraoperative magnetic resonance imaging (IOMRI) in 300 consecutive patients as high field strength IOMRI rapidly becomes the standard of care for neurosurgical procedures. Three sequential groups (groups A, B, C; n=100 each) were compared with respect to time management, complications and technical difficulties to assess improvement in these parameters with experience. We observed a reduction in the number of technical difficulties (p<0.001), time to induction (p<0.001) and total anesthesia time (p=0.007) in sequential groups. IOMRI was performed for neuronavigation guidance (n=252) and intraoperative validation of extent of resection (EOR; n=67). Performing IOMRI increased the EOR over and beyond the primary surgical attempt in 20.5% (29/141) and 18% (11/61) of patients undergoing glioma and pituitary surgery, respectively. Overall, EOR improved in 59.7% of patients undergoing IOMRI (40/67). Intraoperative tractography and real time navigation using re-uploaded IOMRI images (accounting for brain shift) helps in intraoperative planning to reduce complications. IOMRI is an asset to neurosurgeons, helping to augment the EOR, especially in glioma and pituitary surgery, with no significant increase in morbidity to the patient.

Ten years' experience in the management of spinal intramedullary tumors in a single institution.

We retrospectively reviewed the outcomes of 195 patients with intramedullary tumors who underwent surgery between January 2001 and December 2010 at a single institution. The symptomatology, neurological and neuroradiological findings, operative details, perioperative and postoperative complications, histopathological data and follow-up examinations of the 137 (70.2%) males and 58 (29.7%) females were studied and analyzed. Epidermoid was the most common intramedullary tumour in children (23%), whereas in adults, ependymomas were more common (46%). Ependymomas were more amenable to resection (total excision in 57.7% and near-total excision in 39.4%) as compared to astrocytomas (total excision in 29%; near total excision in 60.5%). At the final clinical follow-up, 24 patients (16.4%) had improved in McCormick grade, 112 patients (76.7%) remained unchanged and 11 patients (7.5%) had worsened. Complete removal of the lesion is the primary goal of surgery. We conclude that the strongest predictor of functional outcome was the preoperative neurological condition, beyond the histological differentiation of the intramedullary tumor.

Outcome following surgery for ophthalmic segment aneurysms.

Ophthalmic segment aneurysms account for about 5% of all intracranial aneurysms. Anatomical complexity of the paraclinoid region makes surgical management of aneurysms arising from the ophthalmic segment challenging. This study was carried out to assess the presenting features, complications and outcomes after surgical treatment of ophthalmic segment aneurysms. The authors retrospectively analysed the clinical records of patients with ophthalmic aneurysms treated at our Institute from January 2001 to September 2008, which constituted about 9% (78/850) of all intracranial aneurysms. Of the 78 ophthalmic segment aneurysms, six patients (8%) had giant aneurysms and 19 (24%) patients had multiple aneurysms. Fifty-six patients underwent microsurgery, with direct clipping in most. The mean age was 42 years (range 12-75 years) and the mean follow-up was 8 months (range, 2-93 months). A good outcome was achieved in 46 (83%) patients (Glasgow Outcome Scale [GOS] score 4-5) and 17% had a poor outcome (GOS score 1-3) at last follow-up. The overall complication rate was 21% (12/56), most of which were transient complications, with 3.5% (2/56) mortality. Direct microsurgical clipping remains our preferred treatment approach, whenever possible, for ophthalmic segment aneurysms. This surgery has an acceptable complication rate and leads to a good outcome in more than 80% of patients with ophthalmic aneurysms. Use of modern microsurgical instrumentation and endovascular adjuncts can further reduce the surgical morbidity associated with these vascular lesions.

Expression of CD34 as a novel marker for glioneuronal lesions associated with chronic intractable epilepsy.

The spectrum of glioneuronal lesions underlying intractable epilepsies includes malformative pathologies like focal cortical dysplasia (FCD); and neoplastic lesions like gangliogliomas (GG) and dysembryoplastic neuroepithelial tumours (DNT). These may occur either singly or as dual lesions, having simultaneous presence of both elements. Currently, the relationship between the malformative and neoplastic glioneuronal lesions is poorly understood. Recently, CD34, a stem cell marker transiently expressed during early neurulation, has been identified in these tumours. This study was undertaken to (i) evaluate the role of CD34 as a diagnostic marker for glioneuronal lesions of epilepsy, namely, GG, DNT and FCD, and (ii) attempt to define the relationship among these lesions, using CD34 as a marker. Tissues resected from 47 patients with intractable epilepsy due to glioneuronal lesions (GG, FCD, DNT) were studied. These were evaluated for CD34 expression, using immunohistochemistry. Dysplastic or atypically differentiated neural precursors which could not be identified on routine haematoxylin and eosin (H&E) staining were highlighted by CD34 immunostaining. The pattern of immunostaining was diffuse in GGs, unlike FCDs, wherein cells were present singly or in small clusters. However, cases of DNT and control tissue were largely CD34-immunonegative. Based on these findings, we propose a possible common origin of GG and FCD, from a bipotent precursor that undergoes abnormal glioneuronal development, while DNTs possibly have a different origin. The CD34-immunoreactive cells represent dysplastic or undifferentiated neural precursors, which may signify a valuable marker for the diagnostic evaluation of neoplastic and/or malformative pathologies in patients with intractable epilepsy.

Primary lumbosacral Wilms tumor associated with diastematomyelia and occult spinal dysraphism. A report of a rare case and a short review of literature.

BACKGROUND: The occurrence of an extrarenal Wilms tumor in the lumbosacral region is an extremely uncommon condition. CASE REPORT: We report a case of Wilms tumor in the lumbosacral region that was associated with diastematomyelia and occult spina bifida. An 18-month-old girl presented with a swelling over the lower back with a tuft of hair on it, which she had had since birth. Imaging of the spine revealed spina bifida, bony diastematomyelia, and tethered cord. Excision of the bony spur and detethering of the cord was done. After a year, she had recurrence of swelling at the same site, weakness of both lower limbs, and incontinence of bladder and bowel. Excision of the mass and bony spur and detethering of the spinal cord were done. Histopathological examination showed features of a Wilms tumor.

Foramen magnum tumors: a series of 30 cases.

BACKGROUND AND AIMS: Foramen magnum tumors, especially those located ventrally, are surgically challenging. We studied clinical and surgical details of extramedullary tumors located in the region of the foramen magnum. MATERIAL AND METHODS: A series of 30 cases of extramedullary tumors at the foramen magnum, operated over a period of 8 years is presented. RESULTS: There were 10 neurofibromas, 8 meningiomas, 6 chordomas, 2 tuberculomas and 4 miscellaneous tumors. The clinical profile consisted of sensory symptoms in all the patients, quadriparesis in 24, lower cranial nerve affection in 8 and sphincter disturbances in 6 patients. The surgical approaches consisted of an extreme lateral approach in 10, a posterior or posterolateral approach in 18 and a per-oral route in 2 cases. Total excision of the tumor was performed in 24 and a subtotal excision of the tumor was done in 6 cases. Two patients died, one due to meningitis and the other due to chest infection. Eight other patients had complications like CSF leak, meningitis, pseudomeningocele, laryngeal edema, and transient worsening of neurological deficits. CONCLUSIONS: Foramen magnum tumors have long been regarded as difficult lesions both in terms of diagnosis and management. However, with the availability of MR imaging, newer surgical techniques and skull basal exposures, the excision of these lesions is becoming easier and safer.

Intrasellar tuberculoma--an enigmatic pituitary infection: a series of 18 cases.

OBJECTIVE: Intrasellar tuberculomas are rare and only few case reports have been described in the literature. We report a series of 18 cases of histologically proven intrasellar tuberculomas, which, to the best of our knowledge, is the largest series in the English literature. METHODS: A total of 1143 pituitary lesions, between 1984 and June 1999, were operated for various reasons in our institute. Of these, 18 cases were histopathologically proven intrasellar tuberculomas. The clinical profile was reviewed in detail. Radiological data and histopathological slides were also reviewed. RESULTS: The age ranged from 8 to 43 years (average 23.6 years) with a female preponderance. The duration of symptoms varied from 15 days to 2 years (average 4 months), the most common symptoms being headache followed by decrease or loss of vision. Five patients had features of pan-hypopituitarism whereas three had raised prolactin (PRL) levels. In six patients, both sella as well as sphenoid sinus were involved. In one patient the lesion was extending from the sella over the clivus. Clinically as well as radiologically, these lesions were mistaken for pituitary adenomas except for one case where tuberculoma was suspected on imaging. In three patients, there was past history of pulmonary tuberculosis, in one patient of tuberculous meningitis, and in one patient, of spondilytis of the spine. In one patient there was cervical lymphadenopathy along with features of acromegaly (also proved by high levels of serum growth hormone) and radiology revealed a pituitary pathology. Microscopic examination of the excised lesion revealed a composite lesion consisting of a pituitary adenoma and tuberculoma, which has not been documented in literature to date. One patient died during the hospital stay. All the other patients were put on antitubercular chemotherapy following surgery and had good outcomes. CONCLUSION: Intrasellar tuberculomas are rare. These may be suspected in female patients especially if radiological imaging shows involvement of paranasal sinuses and pituitary fossa along with thickening of pituitary stalk. Simultaneous involvement of clivus may also be an additional feature. The incidence of pituitary tuberculosis is likely to increase with a rise in the incidence of AIDS.