Clinical and radiological spectrum of acquired inflammatory demyelinating diseases of the central nervous system in a tertiary care center.

Objectives: Demyelinating diseases of central nervous system (CNS) are a broad spectrum of conditions with autoimmune process against myelin. In a resource limited country like India, it is imperative to perform proper clinical evaluation, neuroimaging to differentiate among various categories of CNS demyelinating diseases to decide regarding further workup and treatment. The objective of our study was to determine clinical presentation, imaging findings, serology results, diagnosis, and treatment outcome of primary demyelinating disorders of CNS. Materials and Methods: In this prospective study, a total of 44 patients were enrolled over a period of 1 year. After proper evaluation, patients were categorized into different groups applying newer diagnostic criteria. Patients were treated with steroids, appropriate immunomodulatory therapy, and outcomes were analyzed. Results: The majority of cases were of neuromyelitis optica spectrum disorder (NMOSD) (45.5%) with an overall female-to-male ratio of 3.4:1 and mean age of presentation was 30.5 ± 11.15. Myelitis (52.3%) followed by optic neuritis (45.5%) was the most common initial presentation. The most common site of involvement on magnetic resonance imaging was the spinal cord (particularly the cervicodorsal cord). The majority showed good response to therapy (77.27%) and two patients did not survive. Conclusion: Higher disability observed among seropositive NMOSD patients warrants aggressive treatment during the first attack itself. It is important to suspect myelin oligodendrocyte glycoprotein antibody disease in patients with preceding viral infection. A good outcome in the majority is likely due to the availability of serological assays and aggressive immunomodulatory therapy.

Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab.

OBJECTIVES: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer's disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab results were consistent across studies with non-significant differences versus placebo that were intermediate to the high-dose arm in EMERGE. The present investigation examined data from EMERGE and ENGAGE through post-hoc analyses to determine factors that contributed to discordant results between the high-dose arms of the two studies. DESIGN: EMERGE and ENGAGE were 2 phase 3, randomized, double-blind, placebo-controlled, parallel-group studies. SETTING: EMERGE and ENGAGE were 2 global multicenter studies involving 348 sites in 20 countries. PARTICIPANTS: Participants in EMERGE and ENGAGE were aged 50 to 85 years and had mild cognitive impairment or mild AD dementia with confirmed amyloid pathology. The randomized and dosed population (all randomized patients who received at least one dose of study treatment) included 1638 patients in EMERGE and 1647 in ENGAGE. INTERVENTION: In EMERGE and ENGAGE, participants were randomized to receive low- or high-dose aducanumab or placebo (1:1:1) once every 4 weeks. MEASUREMENTS: In this paper, 4 areas were investigated through post-hoc analyses to understand the discordance in the high-dose arms of the EMERGE and ENGAGE studies: baseline characteristics, amyloid-related imaging abnormalities, non-normality of the data, and dosing/exposure to aducanumab. RESULTS: Post-hoc analyses showed that outcomes in the ENGAGE high-dose group were affected by an imbalance in a small number of patients with extremely rapid progression and by lower exposure to the target dose of 10 mg/kg. These factors were confounded and present in early enrolled patients but were not present in later-enrolled patients who were randomized to the target dosing regimen of 10 mg/kg after titration. Neither baseline characteristics nor amyloid-related imaging abnormalities contributed to the difference in results between the high-dose arms. CONCLUSIONS: Results were consistent across studies in later enrolled patients in which the incidence of rapidly progressing patients was balanced across treatment arms.

AMAN with Ophthalmoparesis: A Rare Presentation.

Acute motor axonal neuropathy (AMAN) is a variant of Guillain-Barré syndrome (GBS), characterized by acute areflexic flaccid quadriparesis with motor axonal changes and absence of demyelinating findings in electrophysiological studies. A 30-year-old man presented with acute onset flaccid type of weakness involving all four limbs, along with drooping of eyelids. Examination revealed ptosis with restricted horizontal and vertical eye movements. Spinomotor system examination revealed acute flaccid areflexic quadriparesis. Nerve conduction studies (NCS) showed features suggestive of motor axonal neuropathy changes. Cerebrospinal fluid (CSF) revealed albuminocytological dissociation. The diagnosis of AMAN was made, and the patient was treated with intravenous immunoglobulin (IVIg). His weakness gradually improved over 1 month, with partial improvement in ptosis and eye movements. This case highlights the occurrence of ophthalmoparesis in the AMAN variant of GBS. The presence of ophthalmoparesis and areflexia makes it necessary to exclude Miller-Fisher syndrome. But, the presence of axonal changes in nerve conduction study and the profound weakness with negative serum anti-GQ1b antibody profile, supports the diagnosis of AMAN. How to cite this article: Budumuru U, Muralidharan K, Sowmini PR, et al. AMAN with Ophthalmoparesis: A Rare Presentation. J Assoc Physicians India 2023;71(11):103-104.

Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. OBJECTIVES: We evaluated the efficacy and safety of aducanumab in early Alzheimer's disease. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer's disease. SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50-85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. RESULTS: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. CONCLUSIONS: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose- and time-dependent reduction in pathophysiological markers of Alzheimer's disease was observed in both trials.

Utility of bilateral inferior petrosal sinus sampling for diagnosis and lateralization of Cushing's disease in the pediatric population: case series and review of the literature.

OBJECTS: Cushing's disease (CD) is the most common cause of ACTH-dependent hypercortisolism in children age ≥ 7. The utility of bilateral inferior petrosal sinus sampling (BIPSS), an important test in adults, is less defined in children. We present a case series of children with ACTH-dependent hypercortisolemia and review the literature to assess the utility of BIPSS in the diagnosis and localization of CD. METHODS: We performed an IRB-approved chart review of patients aged ≤ 18 with ACTH-dependent hypercortisolism at MGH between 2000 and 2019 and collected clinical, laboratory, radiographic, BIPSS, surgical, and outcomes data. RESULTS: In our cohort (n = 21), BIPSS had a sensitivity of 93% and specificity of 100% for diagnosis of CD. Compared to surgery, successful BIPSS correctly predicted adenoma laterality in 69% of cases vs. 70% by MRI. Among patients with lesions ≥ 4 mm (n = 9), BIPSS correctly lateralized in 50% vs. 100% by MRI. In patients with subtle lesions (< 4 mm, n = 7), BIPSS correctly lateralized in 80% vs. 71% by MRI. In patients (n = 4) with CD and negative MRIs, BIPSS correctly lateralized in 75% cases. Surgical cure was achieved in 90% of patients and 95% of patients had long-term disease control. CONCLUSIONS: In our cohort (n = 21; n = 20 CD, n = 1 ectopic ACTH secretion), BIPSS was sensitive and specific for the diagnosis of CD. Compared to MRI, BIPSS was not additionally helpful for lateralization in patients with lesions ≥ 4 mm on MRI. BIPSS was helpful in guiding surgical exploration and achieving immediate postoperative remission among patients with subtle and negative MRI findings.

FOLFIRINOX for advanced pancreatic cancer: the Princess Margaret Cancer Centre experience.

BACKGROUND: FOLFIRINOX has been shown to significantly increase both overall survival (OS) and progression-free survival (PFS) in metastatic pancreas cancer. There is limited data regarding the treatment of locally advanced pancreatic cancer. We present a retrospective study of patients with both locally advanced and metastatic pancreas cancer using FOLFIRINOX as first-line therapy in our centre. METHODS: This is a retrospective review of patients treated with FOLFIRINOX for pancreatic cancer at Princess Margaret Cancer Centre, between December 2011 and July 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications. RESULTS: One hundred two patients were identified; 66 metastatic and 36 locally advanced. Sixty-eight per cent of patients initiated treatment with a dose reduction. The median (95% CI) OS in the metastatic group was 13.1 (6.3-16.1) months with full dose and 12.9 (10.3-30.1) months with modified dose. The median (95% CI) OS in the locally advanced group was 11.1 (6.1-not reached) months with full dose and 23 (not reached-not reached) months with modified dose. The median (95% CI) PFS in the metastatic group was 6.2 (4.9-15.2) months with full dose and 8.7 (5.7-12.9) months with modified dose. The median (95% CI) PFS in the locally advanced group was 11.1 (3.1-not reached) months with full dose and 10.4 (6.8-not reached) months with modified dose. Grade 3/4 haematologic adverse events were observed in 43% of patients. Grade 3/4 non-haematologic adverse events were observed in 28% of patients. Patient well-being significantly improved from baseline to cycle 4 (P=0.002). CONCLUSIONS: Efficacy was achievable with dose-modified FOLFIRINOX in daily setting. The safety of FOLFIRINOX remains a concern with a high rate of grades 3 and 4 neutropaenia despite dose reduction.

Childhood maltreatment and corpus callosum volume in recently diagnosed patients with bipolar I disorder: data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM).

Childhood trauma (CT) has been associated with abnormalities in the corpus callosum (CC). Decreased CC volumes have been reported in children and adolescents with trauma as well as adults with CT compared to healthy controls. CC morphology is potentially susceptible to the effects of Bipolar Disorder (BD) itself. Therefore, we evaluated the relationship between CT and CC morphology in BD. We using magnetic resonance imaging in 53 adults with BD recently recovered from their first manic episode, with (n = 23) and without (n = 30) CT, defined using the Childhood Trauma Questionnaire (CTQ) and 16 healthy controls without trauma. ANCOVA was performed with age, gender and intracranial volume as covariates in order to evaluate group differences in CC volume. The total CC volume was found to be smaller in BD patients with trauma compared to BD patients without trauma (p < .05). The differences were more pronounced in the anterior region of the CC. There was a significant negative correlation between CTQ scores and total CC volume in BD patients with trauma (p = .01). We did not find significant differences in the CC volume of patients with/without trauma compared to the healthy subjects. Our sample consists of patients recovered from a first episode of mania and are early in the course of illness and reductions in CC volume may occur late in the course of BD. It might mean there may be two sources of CC volume reduction in these patients: the reduction due to trauma, and the further reduction due to the illness.

Phase-controlling phononic crystals: realization of acoustic Boolean logic gates.

A phononic crystal (PC) consisting of a square array of cylindrical polyvinylchloride inclusions in air is used to construct a variety of acoustic logic gates. In a certain range of operating frequencies, the PC band structure shows square-like equi-frequency contours centered off the gamma point. This attribute allows for the realization of non-collinear wave and group velocity vectors in the PC wave vector space. This feature can be utilized to control with great precision, the relative phase between propagating acoustic waves in the PC. By altering the incidence angle of the impinging acoustic beams or varying the PC thickness, interferences occur between acoustic wave pairs. It is recognized that information can be encoded with this mechanism (e.g., wave amplitudes/interference patterns) and accordingly to construct a series of logic gates emulating Boolean functions. The NAND, XOR, and NOT gates are demonstrated with finite-difference time-domain simulations of acoustic waves impinging upon the PC.

Delayed onset, protracted delirium and aspiration pneumonitis associated with a combination of clozapine and electroconvulsive therapy.

Few studies reported the efficacy and safety in combination of clozapine and electroconvulsive therapy (ECT) in schizophrenia; systematic studies are lacking. Side effects like seizure, and confusional state are reported. Authors report two cases of delayed onset/protracted delirium with ECT and clozapine in schizophrenia, one of whom developed aspiration pneumonitis possibly due to clozapine hyper-salivation. Delirium improved with stopping of ECT and clozapine. Clozapine monotherapy restarted to previous dosages in both cases without recurrence of delirium. Authors recommend for careful monitoring for delirium in ECT augmentation on high dose clozapine. Unilateral ECT may be preferred for augmenting clozapine.

Bifrontal ECT for drug-induced psychosis in Parkinson's disease.

Psychosis has been documented to occur during treatment for idiopathic Parkinson's disease (PD). This case report describes an elderly male who developed psychosis during the course of treatment for idiopathic PD. He was treated with clozapine but experienced significant adverse effects without clinical improvement. He was prescribed bifrontal electroconvulsive therapy (BF-ECT). Here, we report the efficacy of BF-ECT in treating psychosis and motor symptoms in PD, without producing cognitive side effects in an elderly male.

Experimental and theoretical evidence for subwavelength imaging in phononic crystals.

We show experimentally and theoretically that super resolution can be achieved while imaging with a flat lens consisting of a phononic crystal exhibiting negative refraction. This phenomenon is related to the coupling between the incident evanescent waves and a bound slab mode of the phononic crystal lens, leading to amplification of evanescent waves by the slab mode. Super resolution is only observed when the source is located very near to the lens, and is very sensitive to the location of the source parallel to the lens surface as well as to site disorder in the phononic crystal lattice.

Detection of Aspergillus spp. and aflatoxin B1 in rice in India.

Twelve hundred rice samples consisting of paddy (675) and milled rice (525) were collected from 20 states across India. These samples were assessed for Aspergillus spp. infection on selective medium and aflatoxin B(1) (AFB1) by indirect competitive ELISA. In this investigation, Aspergillus flavus contamination dominated in all the seed samples. The other major contaminants were Aspergillus niger, Aspergillus ochraceus and Aspergillus parasiticus. Out of 1200 rice samples, 67.8% showed AFB1 ranging from 0.1 to 308.0 microg/kg. All the paddy samples from Chattishgarh, Meghalaya and Tamil Nadu showed AFB1 contamination. Milled rice grains from different states showed below the permissible levels of AFB1 (average 0.5-3.5 microg/kg). Eighty-two percent of samples from open storage that were exposed to rain showed AFB1 contamination followed by one-year-old seed. Out of 1200 samples, 2% showed AFB1 contamination above the permissible limits (>30 microg/kg). This is the first comprehensive report of aflatoxin contamination in rice across 20 states in India.

Primary mediastinal pleomorphic rhabdomyosarcoma: a case report.

OBJECTIVE: To report a rare case of pleomorphic rhabdomyosarcoma which occurred in the mediastinum of a 34-year-old man. CLINICAL PRESENTATION AND INTERVENTION: A young male labourer presented with dyspnoea on exertion. A large mediastinal mass was detected on chest CT scan. The chest surgeons advised against open biopsy. His alpha-fetoprotein was 22,000 IU/l; based on this the diagnosis of a germ cell tumour was made and the patient was treated with a bleomycin/etoposide/cisplatin regimen. He left for his native country where an open biopsy from the mediastinum was taken and reported as pleomorphic rhabdomyosarcoma. He was given five courses of chemotherapy with doxorubicin, etoposide, and ifosfamide with mesna protection without much relief. The inoperable disease occupied the whole of the right chest and mediastinum. The enormous size of the radiation field made radiotherapy prohibitive. Finally, the patient opted for symptomatic treatment and left for his native place. CONCLUSION: This case is presented because of its difficulty in management and rarity.

High energy density materials from azido cyclophosphazenes.

Azido substituted cyclophosphazenes were prepared and their standard heats of formation were calculated based on experimentally determined heats of combustion.

Preparation of the first examples of ansa-spiro substituted fluorophosphazenes and their structural studies: analysis of C-H...F-P weak interactions in substituted fluorophosphazenes.

The reactions of fluorophosphazenes, endo ansa FcCH(2)P(S)(CH(2)O)(2)[P(F)N](2)(F(2)PN) (1) (Fc = ferrocenyl) and spiro [RCH(2)P(S)(CH(2)O)(2)PN](F(2)PN)(2) (R = Fc (2), C(6)H(5) (3)], with dilithiated diols have been explored. The study resulted in the formation of the first examples of ansa-spiro substituted fluorinated cyclophosphazenes as well as a bisansa substituted fluorophosphazene. The bisansa compound [1,3-[FcCH(2)P(S)(CH(2)O)(2)]][1,5-[CH(2)(CH(2)O)(2)]]N(3)P(3)F(2) (4) was found to be nongeminaly substituted with both the ansa rings in cis configuration, which is in stark contrast to the observations on cyclic chlorophosphazenes where geminal bisansa formation has been observed. The ansa-spiro compounds (5-7) underwent the ansa to spiro transformation leading to dispiro compounds in the presence of catalytic amounts of CsF at room temperature. Two of the ansa-spiro compounds, endo-[3,5-[FcCH(2)P(S)(CH(2)O)(2)]][1,1-[CH(2)(CH(2)O)(2)]]N(3)P(3)F(2) (5) and endo-[3,5-[FcCH(2)P(S)(CH(2)O)(2)]][1,1-[FcCH(2)P(S)(CH(2)O)(2)]]N(3)P(3)F(2) (6), were structurally characterized, and the crystal structures indicate boat-chair conformation as well as crown conformation for the eight-membered ansa rings. Weak C-H.F-P interactions observed in the crystal structures of the ansa-spiro substituted fluorophosphazene derivatives have been analyzed and compared with C-H.F-P interactions of other fluorinated phosphazenes and thionyl phosphazenes.

Ansa versus spiro substitution of cyclophosphazenes: is fluorination essential for ansa to spiro transformation of cyclophosphazenes?

Fluorinated ansa substituted cyclophosphazenes endo-FcCH(2)P(S)(CH(2)O)(2)[P(F)N](2)(F(2)PN) [Fc = ferrocenyl] (1) and exo-FcCH(2)P(S)(CH(2)O)(2)[P(F)N](2)(F(2)PN) (2) readily transform to the spirocyclic compound [FcCH(2)P(S)(CH(2)O)(2)PN](F(2)PN)(2) (3) not only in the presence of CsF but also with non-fluorinated bases such as Cs(2)CO(3), K(2)CO(3), KOBu(t), Et(3)N, DABCO, DBN, and DBU. The analogous tetrachloro ansa compound exo-FcCH(2)P(S)(CH(2)O)(2)[P(Cl)N](2)(Cl(2)PN) (5), however, did not transform to the chlorinated spiro compound (6) in the presence of these bases. With excess of CsF, P-Cl bonds of 5 were found to undergo fluorination leading to the formation of 2, which transformed to spirocyclic compound 3. Time dependent (31)P NMR spectroscopy was used to monitor this transformation. Crystal structure studies on the ansa substituted compounds 4 and 5 have shown weak bonding interactions involving C-H...Cl, C-H...O, and C-H...S interactions.

Radiotherapy for early stage of Hodgkin's disease at Kuwait Cancer Control Center, Kuwait.

OBJECTIVE: To evaluate the outcome of using radiotherapy (RT) alone to treat patients with early-stage Hodgkin's disease (HD). METHOD: The records of 28 patients with HD treated with RT alone at Kuwait Cancer Control Center between 1980 and 1998 were reviewed. RESULTS: Twenty-three patients had stage I HD and 5 stage II. Two patients had B symptoms, 12 (42.9%) patients lymphocyte-predominant histology, 9 (32.1%) nodular sclerosis and 7 (25%) mixed cellularity. Overall survival and relapse-free survival at 10 years were 100 and 83%, respectively. CONCLUSION: Our data indicate that the use of RT alone for treatment of early stages of HD appears to be effective.

Phylogeography of the asian elephant (Elephas maximus) based on mitochondrial DNA.

Populations of the Asian elephant (Elephas maximus) have been reduced in size and become highly fragmented during the past 3,000 to 4,000 years. Historical records reveal elephant dispersal by humans via trade and war. How have these anthropogenic impacts affected genetic variation and structure of Asian elephant populations? We sequenced mitochondrial DNA (mtDNA) to assay genetic variation and phylogeography across much of the Asian elephant's range. Initially we compare cytochrome b sequences (cyt b) between nine Asian and five African elephants and use the fossil-based age of their separation (approximately 5 million years ago) to obtain a rate of about 0.013 (95% CI = 0.011-0.018) corrected sequence divergence per million years. We also assess variation in part of the mtDNA control region (CR) and adjacent tRNA genes in 57 Asian elephants from seven countries (Sri Lanka, India, Nepal, Myanmar, Thailand, Malaysia, and Indonesia). Asian elephants have typical levels of mtDNA variation, and coalescence analyses suggest their populations were growing in the late Pleistocene. Reconstructed phylogenies reveal two major clades (A and B) differing on average by HKY85/gamma-corrected distances of 0.020 for cyt b and 0.050 for the CR segment (corresponding to a coalescence time based on our cyt b rate of approximately 1.2 million years). Individuals of both major clades exist in all locations but Indonesia and Malaysia. Most elephants from Malaysia and all from Indonesia are in well-supported, basal clades within clade A. thus supporting their status as evolutionarily significant units (ESUs). The proportion of clade A individuals decreases to the north, which could result from retention and subsequent loss of ancient lineages in long-term stable populations or, perhaps more likely, via recent mixing of two expanding populations that were isolated in the mid-Pleistocene. The distribution of clade A individuals appears to have been impacted by human trade in elephants among Myanmar, Sri Lanka, and India, and the subspecies and ESU statuses of Sri Lankan elephants are not supported by molecular data.