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The aim of this article is to review recent developments in the areas of the disease features and treatment of Wilson disease, and survey disorders that share its pathophysiology or clinical symptoms.Knowledge of the clinical spectrum of Wilson disease has expanded with recognition of patients who present in atypical age groups - patients with very early onset (5 years) and those in whom symptoms present in mid-to-late adulthood. A disease phenotype with dominant psychiatric features and increased risk of cardiac problems and various sleep disorders have been identified.In addition to a better understanding of the phenotype of Wilson disease itself, features of some related disorders ('Wilson disease-mimics') have been described leading to a better understanding of copper homeostasis in humans. These disorders include diseases of copper disposition, such as mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratoderma syndrome, Niemann-Pick type C, and certain congenital disorders of glycosylation, as well as analogous disorders of iron and manganese metabolism.Outcomes for existing treatments, including in certain patient subpopulations of interest, are better known. Novel treatment strategies being studied include testing of bis-choline tetrathiomolybdate in phase 2 clinical trial as well as various preclinical explorations of new copper chelators and ways to restore ATP7B function or repair the causative gene.Recent studies have expanded the phenotype of Wilson disease, identified rare inherited metal-related disorders that resemble Wilson disease, and studied long-term outcomes of existing treatments. These developments can be expected to have an immediate as well as a long-term impact on the clinical management of the disease, and point to promising avenues for future research.

South Asia, encompassing many populous countries including India, Pakistan, and Bangladesh, is home to a wide variety of infectious diseases several of which are disproportionately prevalent, endemic or distinctive to the region. These result in considerable morbidity and mortality, which can be greatly reduced through public-health measures, timely diagnosis and treatment. Some of these infectious diseases have neurological manifestations including movement disorders either due to the pathogen being neuroinvasive or via an immune-mediated response. For diseases such as Japanese encephalitis, movement disorders are the primary manifestation while for others, they can be a presenting feature. Thus, recognizing these movement disorders is often crucial to the diagnosis of the particular infection, and/or to exclude infection as a cause and arrive at the correct alternate diagnosis. Once diagnosed, the infection-related movement disorders are treated by targeting the infectious agent, or symptomatically. In this article, we describe and illustrate a variety of movement disorders that are seen in patients infected by viruses, bacteria and parasites in South Asia. This would be of value to neurologists practicing in the region and, with the increasing ease in movement of people and pathogens, those practicing elsewhere.

The present study contributes to literature by investigating the impact of corporate governance practices on earnings management. To achieve the objectives of this study, we analysed a sample of 50 large capitalization companies from 10 different sectors viz. automotive, oil and gas, pharmaceuticals, cement/construction, chemical, real estate/ retail, food and beverage, technology, engineering and metals and mining listed on BSE for the period 2005–06 to 2015–16. Corporate governance has been quantified through its different attributes, i.e., board size, board committee meeting frequency, board independence, role duality (CEO/chairman), audit committee meeting frequency and audit committee independence. Earnings management is measured by discretionary accruals calculated using modified Jones model developed by Dechow, Sloan and Sweeney (1995). Empirical findings of overall analysis reveal that board size and earnings management are negatively associated whereas board meeting frequency is positively associated with earnings management. In the sector-wise analysis, impact of corporate governance in constraining earnings management was found to be relatively higher and consistent in Oil and Gas sector and Technology sector as compared to other sectors. The findings of the study have important policy implications as they encourage adopting corporate governance practices in firms in order to mitigate earnings management.

Wilson disease (WD) is an autosomal recessive disease caused by mutations in the ATP7B gene that lead to impaired hepatic disposition of copper. It manifests with overlapping phenotypes of hepatic and neurological impairment. Neurological WD is characterized by movement disorders as well as cognitive and behavioral problems, and it is seen in children and young adults. With early diagnosis and treatment, good neurological outcomes can be expected in most patients. However, both diagnosis and treatment are challenging and neurological WD is often associated with considerable morbidity and mortality. In this review, we outline the clinical spectrum and the steps to identify the syndrome of neurological WD. We also highlight the neuroimaging features of the disease. Additionally, we discuss the principles of decoppering, symptomatic (adjunctive) treatment, and the particular problems faced in treating patients with neurological WD.

India’s growth performance has been diverse yet fascinating over a period of time. While agriculture and manufacturing were the dominant sectors during the pre-industrialisation and industrialisation period respectively, more recently, the services sector has emerged as the most important sector in terms of its contribution to GDP. The growing demands of service sector and its importance in the economy has led to a concern about the situation of India’s manufacturing sector. This study analyses the ‘Make in India’ initiative of the present government launched in September 2014, with the twin objectives of developing India as hub of business and manufacturing and generating massive employment opportunities for India’s teeming young population. The analysis indicates that Indian economy is gaining momentum slowly, and growth estimates are in line with projections made. India also has the best prospects for the growth opportunities in coming decade. Since this concept is new, it will take some years before analysts can effectively measure the success of this campaign.

COVID-19 has a wide-ranging and multimodal neurological impact. First, several neurological symptoms and complications are commonly observed in patients with COVID-19. Second, medications and vaccinations used to counter the disease can have secondary neurological effects. Third, patients with pre-existing neurological disorders bear an increased health-risk due to COVID-19. And finally, the pandemic has disrupted the delivery of neurological and vaccination services, and associated educational and research programs. In this article we review the various channels through which the pandemic is known or projected to effect individual patients or the practice of neurology. We also provide recommendations to manage its immediate effects and prepare for the longer-term fall-out.

Summary Wilson disease (WD) is an autosomal recessive disorder resulting from mutations in the ATP7B gene, with over 600 mutations described. Identification of mutations has made genetic diagnosis of WD feasible in many countries. The heterogeneity of ATP7B mutants is, however, yet to be identified in the Indian population. We analyzed the mutational pattern of WD in a large region of Western India. We studied patients (n = 52) for ATP7B gene mutations in a cohort of families with WD and also in first-degree relatives (n = 126). All 21 exon‐intron boundaries of the WD gene were amplified and directly sequenced. We identified 36 different disease-causing mutations (31 exonic and five intronic splice site variants). Fourteen novel mutations were identified. Exons 2, 8, 13, 14, and 18 accounted for the majority of mutations (86.4%). A previously recognized mutation, p.C271 ∗ , and the novel mutation p.E122fs, were the most common mutations with allelic frequencies of 20.2% and 10.6%, respectively. Frequent homozygous mutations (58.9%) and disease severity assessments allowed analysis of genotype‐phenotype correlations. Our study significantly adds to the emerging data from other parts of India suggesting that p.C271 ∗ may be the most frequent mutation across India, and may harbor a moderate to severely disabling phenotype with limited variability.

Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype-genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation.

We report on a young woman who survived acute liver failure (ALF) without liver transplant. During the ALF, she developed a disabling, levodopa-unresponsive, symmetrical Parkinsonism. This was characterized by severe bradykinesia, mild rigidity, mutism, and prominent gait impairment. Magnetic resonance imaging (MRI) showed bilateral T1W pallidal hyperintensities. Parkinsonism and MRI changes remitted in parallel with normalization of hepatic function. We implicate excessive pallidal manganese deposition secondary to ALF in the pathogenesis of this neuroradiological syndrome. Though hitherto unreported, we propose that Parkinsonism with T1W pallidal hyperintensities may not be uncommon in ALF.

Mutations in the copper (Cu) transporter gene ATP7B, the primary cause of Wilson disease (WD), result in high liver Cu and death of hepatocytes. Cu chelators and zinc salts are the two most important drugs used in the treatment of WD patients; however, the molecular mechanisms of the drugs with regard to ATP7B expression have not been determined. A targeted knockout of ATP7B (KO) was established in the most widely used human hepatoma cell line, HepG2 for molecular studies of the pathogenesis and treatment of the disease. KO cells showed similar growth, Cu uptake, release, and gene expression as compared to parental cells. However, in the presence of Cu, morphological changes, oxidative stress, apoptosis, and loss of viability were observed. Induction of metallothionein (MT1X) after Cu exposure was significantly reduced in KO cells. Following zinc treatment, MT1X expression was strongly induced and a high percentage of KO cells could be rescued from Cu induced toxicity. D-penicillamine treatment had a minor effect on the viability of KO cells whereas the parental cell line showed a pronounced improvement. Combined treatment displayed a highly synergistic effect in KO cells. The data suggest that zinc has a previously unrecognized effect on the viability of hepatocytes that lack ATP7B due to a high induction of MT1X expression that compensates low gene expression after Cu exposure. A combination therapy that simultaneously targets at MT1X induction and Cu chelation improves the overall survival of hepatocytes for most efficient therapy of patients having WD.

This chapter reviews the spectrum and mechanisms of neurologic adverse effects of commonly used gastrointestinal drugs including antiemetics, promotility drugs, laxatives, antimotility drugs, and drugs for acid-related disorders. The commonly used gastrointestinal drugs as a group are considered safe and are widely used. A range of neurologic complications are reported following use of various gastrointestinal drugs. Acute neurotoxicities, including transient akathisias, oculogyric crisis, delirium, seizures, and strokes, can develop after use of certain gastrointestinal medications, while disabling and pervasive tardive syndromes are described following long-term and often unsupervised use of phenothiazines, metoclopramide, and other drugs. In rare instances, some of the antiemetics can precipitate life-threatening extrapyramidal reactions, neuroleptic malignant syndrome, or serotonin syndrome. In contrast, concerns about the cardiovascular toxicity of drugs such as cisapride and tegaserod have been grave enough to lead to their withdrawal from many world markets. Awareness and recognition of the neurotoxicity of gastrointestinal drugs is essential to help weigh the benefit of their use against possible adverse effects, even if uncommon. Furthermore, as far as possible, drugs such as metoclopramide and others that can lead to tardive dyskinesias should be used for as short time as possible, with close clinical monitoring and patient education.

This chapter reviews the spectrum and mechanisms of neurologic adverse effects of commonly used gastrointestinal drugs including antiemetics, promotility drugs, laxatives, antimotility drugs, and drugs for acid-related disorders. The commonly used gastrointestinal drugs as a group are considered safe and are widely used. A range of neurologic complications are reported following use of various gastrointestinal drugs. Acute neurotoxicities, including transient akathisias, oculogyric crisis, delirium, seizures, and strokes, can develop after use of certain gastrointestinal medications, while disabling and pervasive tardive syndromes are described following long-term and often unsupervised use of phenothiazines, metoclopramide, and other drugs. In rare instances, some of the antiemetics can precipitate life-threatening extrapyramidal reactions, neuroleptic malignant syndrome, or serotonin syndrome. In contrast, concerns about the cardiovascular toxicity of drugs such as cisapride and tegaserod have been grave enough to lead to their withdrawal from many world markets. Awareness and recognition of the neurotoxicity of gastrointestinal drugs is essential to help weigh the benefit of their use against possible adverse effects, even if uncommon. Furthermore, as far as possible, drugs such as metoclopramide and others that can lead to tardive dyskinesias should be used for as short time as possible, with close clinical monitoring and patient education.

Wilson's disease (WD) is a potentially fatal disorder of chronic copper toxicity, primarily affecting the liver and the brain. Judicious treatment can restore health and longevity, even in patients with severe neurological impairment. However, the disease is associated with considerable morbidity and mortality resulting from delay in diagnosis, and difficulty in pacing the medical treatment. In this article, we briefly review the diagnosis and treatment options for WD and share our experience in managing patients with WD. We focus on decoppering (copper chelation) treatment of WD and outline pragmatic strategies for patient management designed to recognize and minimize adverse effects while ensuring treatment compliance and effectiveness.

Wilson disease (WD) is an inherited disorder of chronic copper toxicosis characterized by excessive copper deposition in the body, primarily in the liver and the brain. It is a progressive disease and fatal if untreated. Excessive copper accumulation results from the inability of liver to excrete copper in bile. Copper is an essential trace metal and has a crucial role in many metabolic processes. Almost all of the body copper is protein bound. In WD, the slow but relentless copper accumulation overwhelms the copper chaperones (copper-binding proteins), resulting in high levels of free copper and copper-induced tissue injury. Liver is the central organ for copper metabolism, and copper is initially accumulated in the liver but over time spills to other tissues. WD has protean clinical manifestations mainly attributable to liver, brain, and osseomuscular impairment. Diagnosis of WD is challenging and based on combination of clinical features and laboratory tests. Identification of various high-frequency mutations identified in different population studies across the world has revived interest in developing DNA chips for rapid genetic diagnosis of WD. All symptomatic and all presymptomatic patients require lifelong decoppering with careful clinical tracking. Decoppering ensures that presymptomatic individuals remain symptom free. With judicious decoppering, given time, even patients with severe neurological disability improve and can return to normal life and resume school or work at par with their peers. Treatment regimens and tracking patients using the WD-specific Global Assessment Scale for WD (GAS for WD) are discussed.

Wilson disease (WD) is an inherited disorder of chronic copper toxicosis characterized by excessive copper deposition in the body, primarily in the liver and the brain. It is a progressive disease and fatal if untreated. Excessive copper accumulation results from the inability of liver to excrete copper in bile. Copper is an essential trace metal and has a crucial role in many metabolic processes. Almost all of the body copper is protein bound. In WD, the slow but relentless copper accumulation overwhelms the copper chaperones (copper-binding proteins), resulting in high levels of free copper and copper-induced tissue injury. Liver is the central organ for copper metabolism, and copper is initially accumulated in the liver but over time spills to other tissues. WD has protean clinical manifestations mainly attributable to liver, brain, and osseomuscular impairment. Diagnosis of WD is challenging and based on combination of clinical features and laboratory tests. Identification of various high-frequency mutations identified in different population studies across the world has revived interest in developing DNA chips for rapid genetic diagnosis of WD. All symptomatic and all presymptomatic patients require lifelong decoppering with careful clinical tracking. Decoppering ensures that presymptomatic individuals remain symptom free. With judicious decoppering, given time, even patients with severe neurological disability improve and can return to normal life and resume school or work at par with their peers. Treatment regimens and tracking patients using the WD-specific Global Assessment Scale for WD (GAS for WD) are discussed.

Wilson disease (WD) is an autosomal recessive disorder resulting from mutations in the ATP7B gene, with over 600 mutations described. Identification of mutations has made genetic diagnosis of WD feasible in many countries. The heterogeneity of ATP7B mutants is, however, yet to be identified in the Indian population. We analyzed the mutational pattern of WD in a large region of Western India. We studied patients (n = 52) for ATP7B gene mutations in a cohort of families with WD and also in first-degree relatives (n = 126). All 21 exon-intron boundaries of the WD gene were amplified and directly sequenced. We identified 36 different disease-causing mutations (31 exonic and five intronic splice site variants). Fourteen novel mutations were identified. Exons 2, 8, 13, 14, and 18 accounted for the majority of mutations (86.4%). A previously recognized mutation, p.C271*, and the novel mutation p.E122fs, were the most common mutations with allelic frequencies of 20.2% and 10.6%, respectively. Frequent homozygous mutations (58.9%) and disease severity assessments allowed analysis of genotype-phenotype correlations. Our study significantly adds to the emerging data from other parts of India suggesting that p.C271* may be the most frequent mutation across India, and may harbor a moderate to severely disabling phenotype with limited variability.

This chapter reviews focal dyskinesias that affect a restricted region of the body in isolation. Focal dyskinesias often affect body parts not commonly involved in isolation by movement disorders and are not readily classified into one of the major categories of movement disorders or peripheral nerve excitability syndromes. The clinical features and phenomenology of these "unusual focal dyskinesias" are discussed according to the region affected (ear, lip, chin, jaw, tongue, abdomen, and diaphragm (belly dancer's dyskinesias), back, scapula, and limbs). The phenomenology and origin of the unusual focal dyskinesias remain the subject of debate. Most are characterized by slow semirhythmic jerky movements at variable (usually slow) frequencies superimposed on sustained postures, consistent with dystonic movements. However, the body parts affected and pattern of occurrence (in repose rather than during action) are different to those usually seen in primary dystonia. Many of the unusual focal dyskinesias are associated with trauma and pain to the affected region, prompting the suggestion that the movements follow central sensorimotor reorganization occurring spontaneously or secondary to changes in the peripheral nervous system. In other cases, inconsistent signs and spontaneous recovery suggest a psychogenic origin.

This chapter reviews focal dyskinesias that affect a restricted region of the body in isolation. Focal dyskinesias often affect body parts not commonly involved in isolation by movement disorders and are not readily classified into one of the major categories of movement disorders or peripheral nerve excitability syndromes. The clinical features and phenomenology of these "unusual focal dyskinesias" are discussed according to the region affected (ear, lip, chin, jaw, tongue, abdomen, and diaphragm (belly dancer's dyskinesias), back, scapula, and limbs). The phenomenology and origin of the unusual focal dyskinesias remain the subject of debate. Most are characterized by slow semirhythmic jerky movements at variable (usually slow) frequencies superimposed on sustained postures, consistent with dystonic movements. However, the body parts affected and pattern of occurrence (in repose rather than during action) are different to those usually seen in primary dystonia. Many of the unusual focal dyskinesias are associated with trauma and pain to the affected region, prompting the suggestion that the movements follow central sensorimotor reorganization occurring spontaneously or secondary to changes in the peripheral nervous system. In other cases, inconsistent signs and spontaneous recovery suggest a psychogenic origin.

Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype-genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379CT, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation.

Wilson's disease (WD) is an inherited disorder of copper metabolism. Despite being treatable, patients with WD suffer severe disabilities due to delay in initiation and difficulty in monitoring treatment. We propose a two tier, Global Assessment Scale for Wilson's Disease (GAS for WD) that grades the multisystemic manifestations of the disease. Tier 1 scores the global disability in four domains: Liver, Cognition and behavior, Motor, and Osseomuscular. Tier 2 is multidimensional scale for a fine grained evaluation of the neurological dysfunction. We prospectively validated this scale in 30 patients with WD. Both tiers had a high inter-rater reliability (Intraclass correlation coefficient ICC (A, 2) = 0.96-1.0). Tier 2 items were internally consistent (Cronbach's alpha = 0.89) and factorial analysis showed that 90.3% of the Tier 2 total score variance was determined by seven factors. Scores of both tiers were commensurate with the disease burden as assessed by standard disability scales (Child Pugh, UPDRS, SS3, and CGI) and satisfied criteria for validity. Longitudinal follow-up over 1.5 years showed that the scale was sensitive to clinical change. This suggests that GAS for WD is a practical tool with potential applications in management of patients, and in testing and comparison of treatment regimens.

To study the effect of anti-copper treatment for survival of hepatic cells expressing different ATP7B mutations in cell culture.The most common Wilson disease (WD) mutations p.H1069Q, p.R778L and p.C271*, found in the ATP7B gene encoding a liver copper transporter, were studied. The mutations represent major genotypes of the United States and Europe, China, and India, respectively. A human hepatoma cell line previously established to carry a knockout of ATP7B was used to stably express WD mutants. mRNA and protein expression of mutant ATP7B, survival of cells, apoptosis, and protein trafficking were determined.Low temperature increased ATP7B protein expression in several mutants. Intracellular ATP7B localization was significantly impaired in the mutants. Mutants were classified as high, moderate, and no survival based on their viability on exposure to toxic copper. Survival of mutant p.H1069Q and to a lesser extent p.C271* improved by D-penicillamine (DPA) treatment, while mutant p.R778L showed a pronounced response to zinc (Zn) treatment. Overall, DPA treatment resulted in higher cell survival as compared to Zn treatment; however, only combined Zn + DPA treatment fully restored cell viability.The data indicate that the basic impact of a genotype might be characterized by analysis of mutant hepatic cell lines.

Background: There is dismal rate of recanalization following intravenous thrombolysis of large vessel occlusive ischemic stroke. Trials on use of mechanical clot retrievers in acute ischemic stroke have used time from onset and clinical deficit at presentation as the main indications for intervention. Materials and Methods: Retrospective analysis of case records of acute stroke seen between May 2009 and October 2011 was done. It revealed 23 patients with acute ischemic stroke treated by mechanical thrombectomy using Penumbra system (PS). We used magnetic resonance (MR) imaging in correlation with clinical presentation to determine patients likely to benefit from recanalization and accordingly offered or at times deferred revascularization. A comparison of approach and outcomes was done with other relevant trials/reports. Results: Recanalization was achieved in all but one patient. Median modified Rankin Scale (mRS) score at 90 days was 2. Good clinical outcome (mRS ≤ 2) was achieved in 56.5% compared with 25% in Penumbra pivotal trial and 36% in multi Mechanical Embolus Removal in Cerebral Ischemia (multi MERCI) trial. All cause mortality was 13.04%. Symptomatic intracerebral hemorrhage (ICH) occurred in two patients (8.6%). Conclusion: Analysis of our results suggests that PS is safe and effective (91.3%) in recanalizing cerebral vessels without concomitant thrombolytics.

An 18 year old man presented after developing progressive dysarthria and abnormal limb postures. From the age of 15 he had been increasingly irritable, belligerent, and difficult to discipline. He played truant from school, wandered aimlessly around the city claiming to be a dynamic entrepreneur, and heard voices plotting against him. Examination revealed psychosis, severe dysarthria, and generalised dystonia with prominent oromandibular involvement. A diagnostic eye sign was noted (fig 1⇓). Treatment for 18 months led to considerable clinical improvement and regression of the abnormality in the eye. Fig 1 Diagnostic eye sign ### Short answers Fig 2 Kayser-Fleischer rings, visible as a greenish ring at the outer corneal surface (arrow)