Recent Advances in Delivery of Peptide and Protein Therapeutics to the Brain.

The classes of neuropharmaceuticals known as proteins and peptides serve as diagnostic tools and are involved in specific communication in the peripheral and central nervous systems. However, due to tight junctions resembling epithelial cells found in the blood-brain barrier (BBB) in vivo, they are typically excluded from transport from the blood to the brain. The drugs having molecular weight of less than 400 Dalton are able to cross the BBB via lipid-mediated free diffusion. However, large molecule therapeutics are devoid of these characteristics. As an alternative, these substances may be carried via chimeric peptide drug delivery systems, and assist in transcytosis through BBB with the aid of linker strategies. With their recent developments, several forms of nanoparticles, including poly (ethylene glycol)-poly(ε-caprolactone) copolymers, nanogels, liposomes, nanostructured lipid carriers, poly (D, L-lactide-co-glycolide) nanoparticles, chitosan, and solid lipid nanoparticles, have also been considered for their therapeutic applications. Moreover, the necessity for physiologic optimization of current drug delivery methods and their carriers to deliver therapeutic doses of medication into the brain for the treatment of various neurologic illnesses has also been emphasized. Therapeutic use of proteins and peptides has no neuroprotective impact in the absence of all these methods. Each tactic, however, has unique drawbacks and considerations. In this review, we discuss different drug delivery methods for therapeutic distribution of pharmaceuticals, primarily neuroproteins and neuropeptides, through endothelial capillaries via blood-brain barrier. Finally, we have also discussed the challenges and future perspective of protein and peptide therapeutics delivery to the brain. SIGNIFICANCE STATEMENT: Very few reports on the delivery of therapeutic protein and peptide nanoformulations are available in the literature. Herein, we attempted to discuss these nanoformulations of protein and peptide therapeutics used to treat brain diseases.

Multimetal exposure: Challenges in diagnostics, prevention, and treatment.

Extensive use of heavy metals has posed a serious concern for ecosystem and human too. Heavy metals are toxic in nature and their accumulation in human body causes serious disorders such as neurological disease, cardiac disease, gastrointestinal problems, skin disorders, reproductive disease, lungs diseases, and so on. Furthermore, heavy metals not only affect the human health but also have a negative impact on the economy. In the current review, we have elaborated the impact of heavy metal exposure on human health and socioeconomics. We have discussed the molecular mechanism involved in the heavy metal-induced human disorders such as oxidative stress, neuroinflammation, and protein misfolding. Finally, we discussed the preventive measure and treatment strategy that could counter the negative effects of heavy metal intoxications. In conclusion, there is a substantial correlation between heavy metals and the onset and advancement of several health issues. Chelation treatment could be a useful tactic to lessen the toxic metal load and the difficulties that come with it.

Pituitary Dysfunction in Idiopathic Intracranial Hypertension: An Analysis of 80 Patients.

BACKGROUND: Empty sella is a commonly described imaging entity in patients with idiopathic intracranial hypertension (IIH). Though menstrual and hormonal disturbances have been associated with IIH, available literature lacks systematic analysis of pituitary hormonal disturbances in IIH. More so, the contribution of empty sella in causing pituitary hormonal abnormalities in patients of IIH has not been described. We carried out this study to systematically assess the pituitary hormonal abnormalities in patients with IIH and its relation to empty sella. METHODS: Eighty treatment naïve patients of IIH were recruited as per a predefined criterion. Magnetic resonance imaging (MRI) brain with detailed sella imaging and pituitary hormonal profile were done in all patients. RESULTS: Partial empty sella was seen in 55 patients (68.8%). Hormonal abnormalities were detected in 30 patients (37.5%), reduced cortisol levels in 20%, raised prolactin levels in 13.8%, low thyroid-stimulating hormone (TSH) levels in 3.8%, hypogonadism in 1.25%, and elevated levels of gonadotropins were found in 6.25% of participants. Hormonal disturbances were independent and were not associated with the presence of empty sella (p = 0.493). CONCLUSION: Hormonal abnormalities were observed in 37.5% patients with IIH. These abnormalities did not correlate with the presence or absence of empty sella. Pituitary dysfunction appears to be subclinical in IIH and responds to intracranial pressure reduction, not requiring specific hormonal therapies.

The Neuro-Ophthalmology of Tuberculosis.

Tuberculosis (TB) is a global health concern and central nervous system (CNS) TB leads to high mortality and morbidity. CNS TB can manifest as tubercular meningitis, tuberculoma, myelitis, and arachnoiditis. Neuro-ophthalmological involvement by TB can lead to permanent blindness, ocular nerve palsies and gaze restriction. Visual impairment is a dreaded complication of tubercular meningitis (TBM), which can result from visual pathway involvement at different levels with varying pathogenesis. Efferent pathway involvement includes cranial nerve palsies and disorders of gaze. The purpose of this review is to outline the various neuro-ophthalmological manifestations of TB along with a description of their unique pathogenesis and management. Optochiasmatic arachnoiditis and tuberculomas are the most common causes of vision loss followed by chronic papilloedema. Abducens nerve palsy is the most commonly seen ocular nerve palsy in TBM. Gaze palsies with deficits in saccades and pursuits can occur due to brainstem tuberculomas. Corticosteroids are the cornerstone in the management of paradoxical reactions, but other immunomodulators such as thalidomide and infliximab are being explored. Toxic optic neuropathy caused by ethambutol necessitates careful monitoring and immediate drug discontinuation. Cerebrospinal fluid diversion through ventriculo-peritoneal shunting may be required in patients with hydrocephalus in stage I and II of TBM to prevent visual impairment. Early diagnosis and prompt management are crucial to prevent permanent disability. Prevention strategies, public health initiatives, regular follow-up and timely intervention are essential in reducing the burden of CNS TB and its neuro-ophthalmological complications.

MR vessel wall imaging in cerebral bacterial and fungal infections.

PURPOSE: Central nervous system (CNS) bacterial and fungal infections can cause secondary vasculitis which worsens the prognosis due to development of complications like infarctions or hemorrhages. In this prospective study, we aim to study intracranial vessel wall imaging findings in bacterial and fungal infections. METHODS: We included 12 cases of nontubercular bacterial and fungal CNS infections each, in whom definitive microbiological diagnosis could be made. High-resolution vessel wall imaging (VWI) and time of flight MR angiography (TOF MRA) were incorporated in the routine imaging protocol. All cases were evaluated for the presence of vascular enhancement, pattern of enhancement, and stenosis on VWI. Statistical analysis was done to evaluate association between findings of vessel wall imaging and infarctions. RESULTS: We found infarctions in 5 out of 12 cases (41.7%) of the bacterial group and 7 out of 12 cases (58.3%) of the fungal group. Vessel wall enhancement was seen in 5 cases (41.7%) of the bacterial group and 9 cases (75%) of the fungal group. There was a significant association between infarctions and vessel wall enhancement in the fungal group. However, pattern of enhancement or stenosis on VWI was not significantly associated with presence of infarction. VWI detected more cases of vascular involvement than TOF MRA. CONCLUSION: Secondary infectious vasculitis in bacterial and fungal infections can be detected by VWI, which can play an important role in better patient management as detection of vascular involvement can prompt early treatment to prevent complications like infarctions or hemorrhages.

Seronegative panencephalitis complicated by viral encephalomyelitis in a case of Good's syndrome - a neuropathological report.

BACKGROUND: The role of thymus in the immune cascade of the body is still under active clinical scrutiny. Meanwhile, there is an unravelling of myriad presentations of thymoma with effects on various organ systems. These effects arise both due to autoimmunity or a paraneoplastic process secondary to thymoma. However, an occasional patient can be a conundrum and may give no clue regarding the pathogenesis and etiology of its clinical profile. MATERIAL AND METHODS: We present an enigmatic case of a 30-year-old male presenting with superficial fungal infections followed by multiaxial neurological involvement against a background of thymoma. Extensive workup for bacterial, viral, autoimmune and paraneoplastic etiologies were negative. Thymectomy confirmed thymoma (Type AB) but failed to ameliorate the progression of symptoms. He developed recurrent episodes of severe sepsis which remitted with sensitive antibiotics only to reappear again. Immunological profile showed complete absence of peripheral circulating B-cells with reversal of CD4/CD8 ratio, findings compatible with Good's syndrome. Radiological findings showed only progressive brain atrophy without any hyperintensity. He was also treated with intravenous immunoglobulins but failed to respond with the same. RESULTS: Autopsy revealed features of panencephalitis (neuronophagia, neuronal loss, perivascular lymphocytic cuffing and microglial nodules) with virus particles detected ultrastructurally. Although the distinction between seronegative autoimmune encephalitis versus a viral encephalomyelitis often blurs histologically, we speculated viral encephalomyelitis to have happened toward the latter part of his long illness. To our knowledge, this is a case of Good's syndrome presenting with seronegative autoimmune panencephalitis superimposed with a viral infection.

Computational Design, Synthesis, and Pharmacological Evaluation of Naproxen-Guaiacol Chimera for Gastro-Sparing Anti-Inflammatory Response by Selective COX2 Inhibition.

The 4-allyl guaiacol is a natural phenolic molecule that has been widely studied for its antioxidant capacity against reactive-oxygen-species-mediated cellular damage. Therefore, we hypothesized that concomitant use of an antioxidant and NSAID may decrease the risk of gastrointestinal toxicity and make the therapy safer. To address the gastrointestinal toxicity of conventional NSAIDs, a new S-naproxen-4-allyl guaiacol chimera (MAS-1696) was computationally developed, chemically synthesized, and tested for anti-inflammatory effectiveness and gastrointestinal safety. The inhibitory potency of MAS-1696 tested against cyclooxygenase-2 (COX2), 15-lipoxygenase-2 (15-LOX2), and lipoxygenase-5 (5-LOX) in vitro revealed a stronger inhibition of COX2. Furthermore, the MAS-1696 chimera increased the COX selectivity index by 23% as compared to the parent compound naproxen, implying higher efficacy and gastric safety. In vivo data showed that MAS-1696 was less likely to cause gastrointestinal harm than naproxen while also exerting anti-inflammatory and analgesic effects equivalent to or superior to naproxen. In conclusion, MAS-1696 is orally active, bio-labile, and crystalline, making it a medication that may be administered orally.

Carbamazepine versus levetiracetam in epilepsy due to neurocysticercosis.

BACKGROUND: The choice of antiepileptic drug (AED) in newly diagnosed neurocysticercosis (NCC) patients with epilepsy continues to be arbitrary. We compared efficacy and side effect profile of levetiracetam (LEV) and carbamazepine (CBZ) for the treatment of seizures in newly diagnosed patients with NCC. PATIENTS AND METHODS: This was an open-labeled randomized comparative monotherapy study including newly diagnosed drug naïve patients of NCC (n = 99) presenting with seizures who were randomized in 1:1 ratio using computed generated numbers. All patients were followed up for at least six months after start of treatment. The primary outcome measure was seizure control over six months following start of AEDs. RESULTS: Fifteen (15.2%) patients [CBZ- 4(8.2%); LEV- 11(22%)] developed recurrence of seizures. A trend (p = 0.09) was found toward better control of seizures in CBZ compared to LEV. Two (4%) patients in LEV group and 17 (34.6%) patients in CBZ group developed drug-related minor side effects (p < 0.0001). Three patients in CBZ group needed discontinuation of therapy due to skin rash. Eleven patients who relapsed while on LEV did not have any recurrence of seizures after switching over to CBZ. Out of 3 patients who relapsed while receiving CBZ and were changed to LEV, two developed seizures during follow-up. CONCLUSION: CBZ and LEV could be used as alternatives in newly diagnosed patients of NCC at the behest of minor side effects in the CBZ group.

MR vessel wall imaging in tubercular meningitis.

PURPOSE: Tubercular meningitis (TBM) has the propensity to cause secondary vasculitis through various mechanisms leading to development of cerebrovascular complications. These vascular involvements can be detected by vessel wall imaging (VWI). In this study, we aimed to study detailed findings of vessel wall imaging in cases of tubercular meningitis. METHODS: All consecutive patients of suspected tubercular meningitis in whom diagnosis of TBM could be made according to diagnostic criteria given by Ahuja et al. were included in the study. High-resolution MR VWI and time of flight (TOF) magnetic resonance angiography (MRA) were done along with routine MRI sequences. Arteries up to second-order branches were studied, and statistical analyses were done with respect to stage of tubercular meningitis, infarctions and TOF MRA findings. RESULTS: Out of all 101 cases of TBM, infarctions were found in 49 cases (48.5%), and vessel wall enhancement was seen in 67 cases (66.3%). With increasing severity of disease, more severe vascular involvement was seen on VWI. There was significant association between enhancement of individual arteries and infarctions in their territories. VWI had better sensitivity than the MRA, while MRA had better specificity than VWI for detection of vascular complications. CONCLUSION: Tubercular vasculitis can be detected by VWI in the form of nodular or smooth segmental enhancement of vessel wall with or without stenosis. Incorporation of VWI in routine MR imaging can play a greater role in early detection and management of cerebrovascular complications which can help to improve prognosis of the disease.

Magnetic bead flocculation test: Improving the diagnosis of tuberculous meningitis (TBM) in low-resource settings.

BACKGROUND: Despite several recent advances in detection techniques, there is still an unmet need for simple tests for the diagnosis of tuberculous meningitis (TBM). Therefore, in an effort towards developing a simple and rapid diagnostic test for resource-poor settings, we designed an assay in which magnetic bead flocculation test (MBF) was used to detect the amplified DNA. Multi-targeted (using two multicopy gene targets IS6110 and IS1081) loop-mediated isothermal amplification (MLAMP) was used for amplification. METHODS: MLAMP-MBF assay was performed on CSF samples of 600 patients, out of which 120 were definite TBM (culture confirmed), 280 were probable TBM and 200 were non-TB controls, based on Marais's criteria. The performance of assay was evaluated by comparing the result of definite TBM with culture and that of probable TBM with composite reference standard consisting of clinical, microbiological(smear/culture) and radiological parameters. RESULTS: The overall sensitivity of MLAMP-MBF (using any of the two gene targets) was 89.5% and specificity was 100%. The sensitivity was 96.6% (116/120) in diagnosing definite TBM and 86.4% (242/280) in diagnosing probable TBM. The sensitivity of IS1081 was 88% and that of IS6110 was 83% in diagnosing TBM. Specificity of both the gene targets was 100%. There were 20 cases positive only by IS1081 LAMP and 6 cases positive only by IS6110; thus 26 of 400 (6.5%) TBM cases could be additionally detected following multi-targeted approach. CONCLUSION: MLAMP-MBF is a sensitive, robust, cost-effective and promising technique for diagnosis of TBM in low-resource high-endemic settings.

Atypical neurological manifestations of dengue fever: a case series and mini review.

BACKGROUND: In this mini review, we discuss some of the atypical neurological manifestations of dengue virus and attempt to bring them to attention to highlight the neurotropic property of the dengue virus. METHODS: Cases were chosen from retrospective hospital and outpatient records of all patients seropositive for dengue who attended the neurology referral. Seven patients have been chosen as illustrative examples of dengue-associated neurological involvement. We discuss the various central and peripheral nervous system involvement of patients and discuss the relevant findings in them. CONCLUSION: Through this case series, we wish to highlight that the dengue virus can affect the nervous system at various targets, using multiple mechanisms of pathogenesis to generate a plethora of presentations. Hence, it is vital to be aware of its presentations to be able to diagnose dengue and treat it accordingly.

Non-Arteritic Anterior Ischaemic Optic Neuropathy - Myths and Misconceptions: Experience from a Tertiary Care Centre in North India.

We prospectively evaluated 22 consecutive patients (24 eyes) suffering from non-arteritic anterior ischaemic optic neuropathy (NAION) at a tertiary care centre in Northern India. The mean age was 51.7 years. Visual loss on awakening was noticed only in three (12.5%) eyes. Six (27.3%) patients had headache while three (9.7%) patients had retro-orbital pain at the onset of visual loss. Peripapillary haemorrhages were seen in two (8.3%) eyes. At follow up, only one eye showed improvement in visual acuity. The results of our study suggest that NAION may not always present with the classic clinical picture. Accordingly, a high index of suspicion remains the key to correct diagnosis.

A prospective single-center observational study to assess the efficacy of the second-generation supraglottic airway device I-gel in laparoscopic surgeries in children.

BACKGROUND AND AIMS: Supraglottic airways used in pediatric surgeries are associated with a lesser number of postanesthesia respiratory complications. However, there is limited literature on the use of i-gel for pediatric laparoscopic surgery. The aim of this study is to assess the adequacy of ventilation of i-gel for pediatric laparoscopic surgery and note any associated adverse event. MATERIAL AND METHODS: This is a single-centered prospective observational study including 119 children, aged 6 months to 18 years, scheduled for laparoscopic surgery, during a 9-month period, in a tertiary care center. I-gel was used for positive pressure ventilation, and if the post-insertion oropharyngeal seal pressure was <25 cm H2O, it was replaced with a tracheal tube. Adequacy of ventilation and adverse events were noted. RESULTS: Data from 102 cases were analyzed (17 cases excluded: tracheal intubation in 11; missing data in 6 cases). The mean oropharyngeal seal pressure was 34.2 ± 5.2 cm H2O and mean airway pressure was 16.1 ± 2.4 cm H2O. The adverse events included transient cough (10.7%), sore throat (4.9%), and desaturation (3.9%). There was no sign of respiratory distress during the recovery and no intervention was required in any child postoperatively. CONCLUSION: I-gel provided adequate ventilation of the lungs in children undergoing laparoscopic surgery with no major adverse event.

Progressive multifocal leukoencephalopathy in idiopathic CD4+ lymphocytopenia: A case report and review of literature.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease due to a lytic infection of oligodendrocytes caused by polyoma virus (JC virus) infection. PML usually occurs in a setting of severe immunosuppression and is most commonly associated with human immunodeficiency virus (HIV) infection. Idiopathic CD4+ lymphocytopenia is a very rare cause of PML and only a few cases have been reported in the literature. We present a case of a 45-year-old man who presented with behavioral alteration followed by progressive weakness of right side of the body. Contrast-enhanced magnetic resonance imaging of the brain revealed confluent irregular areas of T2-weighted/fluid-attenuated inversion recovery hyperintensities in left frontoparietal and right temporoparietal regions. His hematological work up showed a decreased absolute CD4+ count of 217 per microliter, but was negative for HIV serology. Keeping a differential diagnoses of central nervous system lymphoma, brain biopsy was performed. Histopathology revealed demyelination with presence of intranuclear inclusions in the oligodendrocytes, which were positive for SV40 immunostain. Adjacent areas showed reactive gliosis with hypertrophic astrocytes, hence a diagnosis of PML was made. The patient died due to aspiration pneumonia. PML can occur very rarely in association with idiopathic CD4+ lymphocytopenia in the absence of other immunosuppressive illnesses. This report highlights the importance of high index of clinical suspicion and need for a careful histological examination for diagnosis of PML to facilitate adequate patient management.

PGIMER, Chandigarh: A temple of holistic Neurology.

History helps us to become better students, judge wisely, understand change, and most importantly, it tells us who we are. It helps us to understand what happened, why it happened and what its ramifications are. Winston Churchill once said: "Study history, study history. In history lie all the secrets of statecraft." Here, we take this opportunity to pay our gratitude to our esteemed teachers who worked relentlessly for uplifting of the department of Neurology, PGIMER, Chandigarh; and, narrate chronicles of all those people who made this department reach the heights where it stands today.

Tuberculous meningitis: Challenges in diagnosis and management: Lessons learnt from Prof. Dastur's article published in 1970.

It has been approximately five decades since Dastur et al., published their seminal work on pathology of tuberculous meningitis (TBM). Though most of their findings find relevance in today's era, there is an important difference; these findings can now be replicated during life using modern day technology. In this article, we review the seminal words of Professor Dastur and colleagues, analyse their findings, interpret how these revolutionized our understanding of TBM and highlight their relevance in today's era. We also discuss challenges in the management of TBM, which we continue to face today and the various options required to overcome these challenges.

The Eye Opener: Finding and Targeting the Midbrain Lesion.

Lesions of the central nucleus of the third cranial nerve in midbrain leads to bilateral ptosis. We present a case of a 14 year old boy, who was found to have B/L non-correctable ptosis and medial rectus palsy. There was a ring enhancing lesion in the midbrain in contrast MRI which resolved with treatment. The case exemplifies that bilateral ptosis results from the central nucleus involvement of third nerve which has bilateral innervation.

Clinical and Neuro-ophthalmologic Predictors of Visual Outcome in Idiopathic Intracranial Hypertension.

Despite the potential of Idiopathic Intracranial Hypertension (IIH) to cause visual morbidity, limited literature is available focussing on predictors of visual outcome in IIH. This study was planned to assess visual morbidity in patients of IIH in terms of clinical and neuro-ophthalmo- logical parameters. In this prospective study of 40 patients of IIH, neuro-ophthalmological parameters were noted in the form of visual acuity, visual field, contrast sensitivity, Retinal Nerve Fibre Layer thickness, and visual evoked potential. Visual outcome was defined in using specific criteria. Final visual outcome of patients was compared with clinical and neuro-ophthalmologic para- meters to determine any correlation. The most common presenting clinical symptoms were headache (85%) and Transient visual obscurations (TVOs) (52.5%). In univariate analysis severity of visual loss, Cerebro Spinal Fluid (CSF) pressures and abnormal Visual evoked potential (VEP) were associated with worse visual outcome or need of aggressive management. When adjusted for severity of visual loss no independent clinical/neuroophthalmic predictor could be established. High CSF opening pressure, worsening vision/papilledema, greater Retinal Nerve Fiber Layer (RNFL) thickness and abnormal VEPs may be some of the alarming signs for physicians, but none of these parameters can be used as an independent predictor for visual outcome in isolation. Visual loss at presentation is probably the most important predictor of the final visual outcome in these patients. This may also suggest that patients presenting in an advanced disease course (with worse visual status) fair badly despite best medical/surgical management. Early diagnosis and prompt management is the cornerstone of management.

Understanding and Appraising Systematic Reviews and Meta-Analysis.

Systematic reviews and meta-analysis seek to answer a pre-framed research question to lead to a valid answer through a systematic, explicit and reproducible method of locating; identifying, including and appraising appropriate trials. The results are synthesized considering the methodological rigor of included trials. While the meta-analysis quantitatively pools the results from individual included studies, the systematic review summarizes the findings as qualitative conclusions. These reviews are crux of evidence based dentistry for various stake-holders, i.e., clinicians, researchers and policy-makers. Although the meticulous methodology of systematic review and meta-analysis minimizes the elements of bias, yet the validity and reliability of their findings should be explored prior to translating their conclusions to practice. The goal of this paper is to familiarize readers with rationale, conduct and appraisal of systematic review and meta-analysis. Further, guidance is provided on tracing potential elements of bias in the review to enable readers to judge the quality of evidence generated from the review.

Infiltrative Optic Neuropathies: Opening Doors to Sinister Pathologies.

Optic disc edema may be caused by a number of conditions. A commonly ignored but important aspect is the presence of "infiltration" of disc; that may closely mimic disc edema. Disc edema, optic nerve dysfunction and a normal appearing disc in any combination may occur in infiltrative optic neuropathies. Identifying disc infiltration can aid in diagnosis of many sinister pathologies even in the absence of other specific clinical features. We describe two patients presenting with optic nerve dysfunction and infiltrated disc appearance, which on investigations were found to have underlying malignancies thereby underscoring the importance of detecting infiltrative optic neurpathies.