Axonal Growth Abnormalities Underlying Ocular Cranial Nerve Disorders.

Abnormalities in cranial motor nerve development cause paralytic strabismus syndromes, collectively referred to as congenital cranial dysinnervation disorders, in which patients cannot fully move their eyes. These disorders can arise through one of two mechanisms: (a) defective motor neuron specification, usually by loss of a transcription factor necessary for brainstem patterning, or (b) axon growth and guidance abnormalities of the oculomotor, trochlear, and abducens nerves. This review focuses on our current understanding of axon guidance mechanisms in the cranial motor nerves and how disease-causing mutations disrupt axon targeting. Abnormalities of axon growth and guidance are often limited to a single nerve or subdivision, even when the causative gene is ubiquitously expressed. Additionally, when one nerve is absent, its normal target muscles attract other motor neurons. Study of these disorders highlights the complexities of axon guidance and how each population of neurons uses a unique but overlapping set of axon guidance pathways.

Neurocan is a New Substrate for the ADAMTS12 Metalloprotease: Potential Implications in Neuropathies.

BACKGROUND/AIMS: The composition of the extracellular matrix (ECM) in the central nervous system (CNS) has several features that make it unique. For instance, it is remarkable for the presence of proteoglycans such as versican, brevican, and neurocan, some of which have been identified as substrates of different members of the ADAMTS family of secreted metalloproteases. Previous studies have associated ADAMTSs with the repair of the CNS, including recovery following degradation of glial scar tissue and the stimulation of axonal growth after brain injury. However, the involvement of ADAMTSs in diseases of the CNS is complex and not understood fully, and a current challenge is unraveling the precise roles of these metalloproteases in the brain. METHODS: ADAMTS12 and neurocan gene expression was examined by quantitative PCR. Western blot analysis was employed to detect ADAMTS12 and neurocan protein expression in cell lines, and immunostaining techniques were used to detect neurocan in mouse brain tissues. Neurocan cleavage using recombinant ADAMTS1, ADAMTS4, ADAMTS5, and ADAMTS12 metalloproteases was evaluated by western blotting. Cell adhesion and migration were assessed using uncoated culture dishes or dishes coated with Matrigel or ECM components. RESULTS: We identified neurocan as a novel component of brain ECM that can be cleaved by ADAMTS12. In addition, we showed that neurocan cleavage by ADAMTS12 altered the adhesive properties of the human neuroglioma H4 cell line. Moreover, immunohistochemical analysis of Adamts12-deficient mice revealed the significant accumulation of neurocan in the brain of neonatal mice. CONCLUSION: Overall, our results suggest that ADAMTS12 could be involved in the repair of the CNS through its ability to degrade neurocan. Moreover, it can be inferred that alterations in neurocan degradation processes could be associated with the pathogenesis of neurological disorders.

Long-term outcome in neuroZika: When biological diagnosis matters.

OBJECTIVE: To characterize the full spectrum, relative frequency, and prognosis of the neurologic manifestations in Zika virus (ZIKV) postnatal infection. METHODS: We conducted an observational study in consecutive ZIKV-infected patients presenting with neurologic manifestations during the French West Indies 2016 outbreak. RESULTS: Eighty-seven patients, including 6 children, were enrolled. Ninety-five percent of all cases required hospitalization. Guillain-Barré syndrome was the most frequent manifestation (46.0%) followed by encephalitis or encephalomyelitis (20.7%), isolated single or multiple cranial nerve palsies (9.2%), other peripheral manifestations (6.9%), and stroke (1.1%). Fourteen patients (16.1%), including one child, developed a mixed disorder involving both the central and peripheral nervous system. Mechanical ventilation was required in 21 cases, all of whom had ZIKV RNA in at least one biological fluid. Two adult patients died due to neuroZika. Clinical follow-up (median 14 months; interquartile range, 13-17 months) was available for 76 patients. Residual disability (modified Rankin Scale score ≥2) was identified in 19 (25.0%) patients; in 6 cases (7.9%), disability was severe (modified Rankin Scale score ≥4). Among patients with ZIKV RNA detected in one biological fluid, the risk of residual disability or death was higher (odds ratio 9.19; confidence interval 1.12-75.22; p = 0.039). CONCLUSIONS: NeuroZika spectrum represents a heterogeneous group of clinical neurologic manifestations. During an outbreak, clinicians should consider neuroZika in patients presenting with cranial nerve palsies and a mixed neurologic disorder. Long-term sequelae are frequent in NeuroZika. ZIKV reverse-transcription PCR status at admission can inform prognosis and should therefore be taken into consideration in the management of hospitalized patients.

MAPKs and NF-κB-mediated acrylamide-induced neuropathy in rat striatum and human neuroblastoma cells SY5Y.

Acrylamide (ACR) is a potent neurotoxin that can be produced during high-temperature food processing, but the underlying toxicological mechanism remains unclear. In this study, the detrimental effects of ACR on the striatal dopaminergic neurons and the roles of mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NF-κB) in ACR-induced neuronal apoptosis were investigated. Acute ACR exposure caused dopaminergic neurons loss and apoptosis as revealed by decreased tyrosine hydroxylase (TH)-positive cells and TH protein level and increased terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in the striatum. ACR-decreased glutathione content, increased levels of malondialdehyde, proinflammatory cytokines tumor necrosis factor α, and interleukin 6. In addition, nuclear NF-κB and MAPKs signaling pathway with c-Jun N-terminal kinase (JNK) and p38 were activated by ACR. Specific inhibitors were used to explore the roles of MAPKs and NF-κB pathways in ACR-induced apoptosis in SH-SY5Y cells. Pretreatment with JNK-specific inhibitors SP600125 markedly upregulated the reduced B-cell lymphoma 2 (Bcl-2) content and downregulated the increased Bcl-2-associated X protein (Bax) level and thereby eventually reduced the proportions of early and late apoptotic cells induced by ACR, while p38 suppression by SB202190 only reversed the decrease in Bcl-2 expression. Inhibition of NF-κB by BAY 11-7082 markedly upregulated Bax level and decreased Bcl-2 expression, and eventually increasing the proportions of neuronal apoptosis compared with that in ACR alone. These results suggested that JNK contributed to ACR-induced apoptosis, while NF-κB acted as a protective regulator in response to ACR-induced neuropathy. This study helps to offer a deeper insight into the mechanism of ACR-induced neuropathy.

Spatiotemporal control of mitochondrial network dynamics in astroglial cells.

Mitochondria are increasingly recognized for playing important roles in regulating the evolving metabolic state of mammalian cells. This is particularly true for nerve cells, as dysregulation of mitochondrial dynamics is invariably associated with a number of neuropathies. Accumulating evidence now reveals that changes in mitochondrial dynamics and structure may play equally important roles also in the cell biology of astroglial cells. Astroglial cells display significant heterogeneity in their morphology and specialized functions across different brain regions, however besides fundamental differences they seem to share a surprisingly complex meshwork of mitochondria, which is highly suggestive of tightly regulated mechanisms that contribute to maintain this unique architecture. Here, we summarize recent work performed in astrocytes in situ indicating that this may indeed be the case, with astrocytic mitochondrial networks shown to experience rapid dynamic changes in response to defined external cues. Although the mechanisms underlying this degree of mitochondrial re-shaping are far from being understood, recent data suggest that they may contribute to demarcate astrocyte territories undergoing key signalling and metabolic functions.

Bilateral Alterations in Corneal Nerves, Dendritic Cells, and Tear Cytokine Levels in Ocular Surface Disease.

This review summarizes the recent literature regarding corneal imaging in human subjects using in vivo confocal microscopy. It also covers the recent literature on corneal immune cells, nerves, and tear cytokine levels in ocular surface diseases as well as corneal immune privilege. The significance of interactions between corneal immune cells and nerves in health, neurotrophic keratopathy, and infectious keratitis is discussed. Furthermore, bilateral alterations of immune cells and nerves in clinically unilateral corneal diseases and the link to changes of tear cytokines or neuropeptide levels in contralateral eyes are described. Recent studies reported increased density and morphologic changes of corneal dendritic cells in ocular surface disease that correlated with a decrease in subbasal nerve and corneal nerve density, suggesting potential interactions between the immune and nervous systems in the cornea. Although the relevance of tear cytokines is poorly understood, tear cytokines might have an important role in the pathogenesis of ocular surface diseases. In humans and experimental animal models, alterations in immune cells, cytokines, and immunomodulatory neuropeptide levels in contralateral eyes might mediate the incidence of bilateral infectious keratitis and loss of immune privilege of the cornea in bilateral corneal transplantation or neurotrophic keratopathy cases. The discovery of bilateral alterations of immune cells and nerves in ocular surface diseases is considered the missing link between the immune and nervous systems in the cornea, and demonstrates how studies of animal models and humans aid our understanding of human corneal disease phenomena.

Long-term Effects of LASIK on Corneal Innervation and Tear Neuropeptides and the Associations With Dry Eye.

PURPOSE: To investigate the associations between dry eye, corneal nerves, and tear neuroptides in dry eye after LASIK. METHODS: A single visit cross-sectional study was performed. Twenty participants who had LASIK more than 12 months prior and 20 healthy participants were recruited. Ocular comfort, tear functions, ocular surface sensitivity, basal tear collection, and corneal nerve morphology assessments were conducted. Tear substance P and calcitonin gene-related peptide (CGRP) concentrations were determined using ELISAs. Differences in variables between groups were examined using an independent t test or Mann-Whitney U test, as appropriate. Associations between variables in the post-LASIK group were examined using a Spearman's correlation test. A P value of less than .05 was considered significant. RESULTS: Central corneal nerve morphology parameters were all altered in the post-LASIK group (P < .05). Higher ocular discomfort (P = .01), tear CGRP concentration (P = .001), and conjunctival sensitivity (P < .009) were found in the post-LASIK group. There was a positive association between dry eye symptoms and superior corneal sensitivity (P = .51, P = .02) and tear substance P concentration (P = .52, P < .03). CONCLUSIONS: This study provides evidence of the association between tear neuropeptides, conjunctival sensitivity, and symptoms in symptomatic patients after LASIK. The differences in nerve morphology, neuropeptide, and ocular surface sensitivity between symptomatic and asymptomatic patients after LASIK are required to better understand the mechanism of dry eye after LASIK. [J Refract Surg. 2016;32(8):518-524.].

Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases.

OBJECTIVES: To systematically review literature about the structure and function of nucleotide-binding oligomerization domain containing 2 (NOD2) and its disease association. METHODS: The English literature was searched using keywords "NOD2" and "disease". Relevant original and review articles were reviewed. RESULTS: NOD2 is an intracellular protein and shares similar molecular structure with NOD1, pyrin, and cryopyrin. There are more than 100 NOD2 gene mutations, some of which have been linked to diseases such as Crohn disease, Blau syndrome, and NOD2-associated autoinflammatory disease (NAID). The NOD2 variants located in the leucine-rich repeat (LRR) region are susceptible to Crohn disease, and the variants in the nucleotide-binding domain (NBD) and in between the NBD and LRR are associated with Blau syndrome and NAID, respectively. No disease association with the gene variants has been found in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis/psoriatic arthritis, adult sarcoidosis, granulomatous polyangiitis, or multiple sclerosis. The potential association of the NOD2 variants with graft-versus-host-disease remains controversial. NOD2 functions mainly through RICK or RIP2 to activate p38 mitogen-activated protein kinases and NF-κB, resulting in inflammatory response, and enhanced autophagic activity. Biologic therapy may be beneficial for NOD2-associated diseases, and new drug development may be realized based upon the signaling pathways. CONCLUSIONS: NOD2 gene mutations are associated with several diseases, and some of the mutations are of diagnostic value in Blau disease and NAID. To understand the NOD2 function, disease association, and its pathogenesis is important given the ever increasing clinical significance of NOD2.

Capsaicin-induced corneal sensory denervation and healing impairment are reversed by NGF treatment.

PURPOSE: We aimed to evaluate the nerve growth factor (NGF) pathway and its influence on corneal healing mechanisms in normal conditions and in an animal model of corneal denervation induced by capsaicin. METHODS: Peripheral sensory damage was induced in rat pups by subcutaneous injection of capsaicin and the effects evaluated by hot-plate test, corneal nerve count, and tear secretion. Corneal damage was induced in capsaicin-treated and -untreated rats by epithelial scraping. Healing rate; NGF pathway (NGF, tyrosine kinase A [TrkA], p75); and the stem cell marker p63 were evaluated by RT-PCR, ELISA, Western blot, and immunohistochemistry. The effects of exogenous NGF administration as eye drop formulation were also tested. RESULTS: Capsaicin treatment induced a significant reduction of peripheral sensitivity, corneal innervation, tear secretion, and corneal healing rate. The ocular effects of capsaicin treatment were associated with an NGF pathway alteration. NGF eye drop treatment aided corneal healing mechanisms through a significant increase in the NGF receptors TrkA and p75, and in the stem cell marker p63. CONCLUSIONS: In this study, we show that an alteration in the NGF pathway is responsible for a delay in corneal healing in an animal model of sensory denervation. Moreover, we show that NGF eye drop administration modulates corneal innervation, epithelial cell healing, and corneal stem cells. These findings may trigger further research on the role of the NGF pathway in limbal stem cell deficiency.

Morphologic and immunohistochemical characterization of granulomas in the nucleotide oligomerization domain 2-related disorders Blau syndrome and Crohn disease.

BACKGROUND: Blau syndrome (BS) and Crohn disease (CD) are both characterized by granulomatous inflammation and related to nucleotide oligomerization domain 2 (NOD2) mutations. OBJECTIVE: This study aimed to define the morphologic and immunohistochemical characteristics of granulomas in patients with NOD2-related BS and CD. METHODS: Granuloma-containing biopsy specimens from 6 patients with BS and 7 pediatric patients with CD carrying NOD2 mutations or single nucleotide polymorphisms were studied for morphology, cellular composition, and cytokine expression by using hematoxylin and eosin staining and immunohistochemistry. RESULTS: Biopsy specimens from patients with BS typically showed polycyclic granulomas with large lymphocytic coronas, extensive emperipolesis of lymphocytes within multinucleated giant cells (MGCs), MGC death, and fibrinoid necrosis and fibrosis. In contrast, biopsy specimens from patients with CD showed simple granulomas with subtle/absent lymphocytic coronas, sclerosis of the surrounding tissue, and polymorphonuclear cells. Findings found to be similar in all granulomas were as follows: CD68 and HLA-DR expression by epithelioid cells, monocyte-macrophage lineage cells and MGCs, increased lymphocytic HLA-DR expression, increased CD4(+)/CD8(+) T-cell ratio, and CD20(+) B lymphocytes evenly distributed within and around granulomas. In both patient groups prominent IFN-γ expression was found in and around granulomas, and TNF-α and IL-23 receptor expression was moderate. IL-6, IL-17, and TGF-ß expression was prominent in granulomas from patients with BS but sporadic in granulomas from patients with CD. IL-10 expression was absent. CONCLUSION: Granulomas from patients with BS and granulomas from patients with NOD2-associated CD show distinct morphologic features and cytokine expression patterns, suggesting that the T(H)17 axis might be involved in the pathogenesis of BS, whereas T(H)1 is important in both patients with BS and patients with CD.

Decreased corneal sensitivity and abnormal corneal nerves in Fuchs endothelial dystrophy.

PURPOSE: To determine corneal sensitivity and evaluate corneal nerves before and after keratoplasty for Fuchs endothelial dystrophy. METHODS: Central corneal sensitivity, measured by using a Cochet-Bonnet esthesiometer in 69 eyes before and after different keratoplasty procedures for Fuchs dystrophy, was compared with that of 35 age-matched normal corneas. Corneal nerves were qualitatively examined by confocal microscopy in 42 eyes before and after Descemet stripping endothelial keratoplasty (DSEK). RESULTS: Corneal sensitivity in Fuchs dystrophy (4.61 ± 1.42 cm) was lower than that of age-matched controls (5.74 ± 0.48 cm, P < 0.001). Sensitivity decreased by 1 month after DSEK (2.98 ± 2.01 cm, P < 0.001), returned to preoperative sensitivity by 24 months (4.50 ± 1.63 cm, n = 33, P = 0.99), but remained lower than controls at 36 months (4.50 ± 1.48 cm, n = 15, P < 0.001). Sensitivity at 36 months after penetrating keratoplasty (1.46 ± 1.98 cm) remained decreased compared with preoperative sensitivity (P < 0.001). Subbasal nerves appeared sparse with abnormal branching before and through 36 months after DSEK. Sensitivity was lower in corneas without visible subbasal nerves by confocal microscopy at 12 months after DSEK (P < 0.005) than in corneas with visible nerves. Stromal nerves were frequently tortuous and formed loops in Fuchs dystrophy, and this appearance persisted in some eyes at 36 months after DSEK. CONCLUSION: Corneal sensitivity is decreased in Fuchs dystrophy compared with normal and remains subnormal even at 3 years after endothelial keratoplasty. Decreased sensitivity is likely to be related to loss of subbasal nerves and abnormal nerve morphology, which persist after endothelial keratoplasty.

Blau syndrome revisited.

PURPOSE OF REVIEW: Blau syndrome is a monogenic disease resulting from mutations in nucleotide oligomerization domain 2 (NOD2) and is phenotypically characterized by granulomatous polyarthritis and uveitis. Not only there has been significant progress in disease characterization but also the biological pathways associated with NOD2 and related proteins of the innate immunity are better understood. RECENT FINDINGS: The phenotype of Blau syndrome has proven to be more complex than initially thought. A discussion on those manifestations will be provided in the clinical sections of this review. As more patients and pedigrees are found new mutations in the NOD2 gene have emerged and we discuss them in some detail. Due to its importance in Crohn's disease NOD2 has become the focus of intense research. A brief review of more recent advances in relevant pathways is presented and published reviews referenced for the interested reader. The granulomatous character of Blau syndrome provides an opportunity to look at possible pathogenic effects of NOD2 'gain of function'. New immunohistochemical data are briefly reviewed as well. SUMMARY: Elucidation of downstream effects of NOD2 mutations could provide valuable clues to mechanisms of arthritis and uveitis in general as well as granulomatous diseases in particular.

Differential anti-neuropathic pain effects of tetrodotoxin in sciatic nerve- versus infraorbital nerve-ligated rats--behavioral, pharmacological and immunohistochemical investigations.

Several voltage-gated sodium channels are expressed in primary sensory neurons where they control excitability and participate in the generation and propagation of action potentials. Peripheral nerve injury-induced alterations in both tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels have been proposed to contribute to neuropathic pain caused by such lesion. We herein investigated whether the blockade of TTX-sensitive channels could reduce pain-related behaviors and evoked c-Fos immunoreactivity in rats with neuropathic pain produced by chronic unilateral constriction injury to either the sciatic nerve or the infraorbital nerve. Acute as well as subchronic administration of TTX (1-6 mug/kg s.c.) was found to suppress for up to 3 h allodynia and hyperalgesia in sciatic nerve-ligated rats. In contrast, TTX was only moderately effective in rats with ligated infraorbital nerve. In sciatic nerve-ligated rats, TTX administration prevented the increased c-Fos immunoreactivity occurring in the dorsal horn of the lumbar cord and some supraspinal areas in response to light mechanical stimulation of the nerve-injured hindpaw. The anti-allodynia/antihyperalgesia caused by TTX in these neuropathic rats was promoted by combined treatment with naloxone (0.5 mg/kg s.c.) but unaffected by the 5-HT(1B) receptor antagonist F11648 (0.5 mg/kg s.c.) and the alpha(2)-adrenergic receptor antagonist idazoxan (0.5 mg/kg i.v.). In contrast, the anti-allodynic and anti-hyperalgesic effects of TTX were significantly attenuated by co-administration of morphine (3 mg/kg s.c.) or the cholecystokinin(2)-receptor antagonist CI-1015 (0.1 mg/kg i.p.). These results indicate that TTX alleviates pain-related behaviors in sciatic nerve-lesioned rats through mechanisms that involve complex interactions with opioidergic systems.

Pigment epithelium-derived factor (PEDF) attenuated capsaicin-induced neurotrophic keratouveitis.

PURPOSE: To reveal the influence of retrobulbar capsaicin treatment on rats' eyes and to test the protective effects of PEDF, a known neurotrophic and antiangiogenic substance, against neurotrophic keratouveitis. METHODS: A single retrobulbar injection of capsaicin (50 mg/kg) was performed in young rats, and the effect of subsequent retrobulbar injections of PEDF 3.2 or 6.4 microg was recorded. Tear fluid alterations were evaluated with the Schirmer test and corneal alterations with slit lamp biomicroscopy. Histopathologic alterations were studied with light and electron microscopy. The number of leukocytes (myeloid cells) in the anterior and posterior chambers, peripheral retina, and vitreous were quantitatively evaluated. RESULTS: Reduced tear secretion was found in capsaicin-treated rats compared with the control, but this effect was significantly attenuated by PEDF. Corneal ulceration developed and was followed by scar formation and neovascularization in the capsaicin-treated, and it was also significantly attenuated by PEDF treatment. Leukocyte infiltration of the anterior and posterior chambers, as well as the peripheral retina and vitreous, was also observed in capsaicin-treated eyes and was significantly reduced by PEDF treatment. The protective effects of PEDF were dose dependent for each parameter, even if the treatment was initiated at day 14 after the challenge. CONCLUSIONS: PEDF accelerated the recovery of tear secretion and also prevented capsaicin-induced neurotrophic keratouveitis and peripheral vitreoretinal inflammation. These effects of PEDF, described herein for the first time, may have a clinical application in inflammatory and neovascular diseases of the eye.

Chronic constriction injury of the infraorbital nerve in the rat using modified syringe needle.

Here we report a method for performing a chronic constriction injury (CCI) of the infraorbital nerve (ION) in the rat as a component of a chronic pain model. The surgical approach to the ION is described together with the use of a modified dental syringe needle that simplifies placing two chromic gut ligatures around the ION. This method makes the surgical procedure easier, the nerve injury more consistent across animals and reduces secondary damage to the ION and surrounding tissue. Pain behavior testing together with immunostaining for markers of nerve injury in the spinal trigeminal nucleus show the suitability of this procedure as a model of orofacial pain.

Cranial neuropathies after intracranial Photofrin-photodynamic therapy for malignant supratentorial gliomas-a report on 3 cases.

BACKGROUND: In an RCT of PDT in the treatment of malignant gliomas, 3 patients developed cranial neuropathies after photoillumination. We are aware of no previous reports on cranial neuropathy after intracranial PDT. METHODS: In a cohort of 80 patients, there were 41 men and 39 women; 47 were newly diagnosed and 33 had recurrent tumors. All patients underwent surgical tumor extirpation. There were 77 malignant gliomas, 2 meningiomas, and 1 metastatic tumor. The tumor locations were as follows: 39 frontal, 25 temporal, 12 parietal, and 4 occipital. Of the 25 patients with temporal lobe tumors, 18 received PDT. RESULTS: Three of the 18 patients with temporal lobe tumors developed cranial neuropathies after PDT. The floor of the middle fossa received photoillumination in all 3 patients. This complication was not seen in any other patient with tumors in the frontal, parietal, or occipital regions, or patients with temporal lobe tumors who did not receive PDT. The first patient developed seventh nerve paresis and hypoesthesia in fifth nerve distribution, which resolved only partially. The second patient developed a seventh nerve paresis that resolved completely. The third patient developed transient neuralgic pain in the trigeminal nerve distribution. CONCLUSIONS: Cranial neuropathies could be the result of photoillumination of fifth and seventh cranial nerves during PDT of the temporal fossa. We recommend shielding of the middle fossa floor during PDT.

Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocal microscopy.

PURPOSE: To define the alterations of corneal nerves in aqueous tear deficiency dry eye patients with or without Sjögren syndrome and to identify the relationship between the morphologic changes of corneal nerves and the extent of dry eye. METHODS: Confocal microscopy was used to examine 38 consecutive aqueous tear deficiency patients (8 Sjögren syndrome and 30 non-Sjögren syndrome) and 30 age- and gender-matched normal controls. Images taken by Confocal2 slit-scanning microscope at subbasal epithelial cell layer of central cornea were analyzed. The number and density of corneal nerves and their size, beads, tortuosity, and branching pattern were compared. These data were correlated with age and the degree of dry eye. RESULTS: Sjögren syndrome patients showed a significant increase in average nerve number and tortuosity as compared with normal controls (P = 0.031 and 0.021, respectively). Severe nerve tortuosity (grade 4) and nerve branching appeared more frequently in aqueous tear deficiency than in normal subjects (P = 0.024 and 0.042, respectively). A decreased nerve number was observed with age in the normal controls (P = 0.002). However, such a correlation did not exist in aqueous tear deficiency. In aqueous tear deficiency, rose bengal staining score correlated positively with nerve density (P = 0.048) and nerve number (P = 0.001). Corneal fluorescein staining score was also positively correlated with nerve number (P = 0.027). CONCLUSIONS: Abnormal morphologic changes are observed in aqueous tear deficiency that are more severe in Sjögren syndrome. The distinct changes of corneal nerves include increased nerve number, tortuosity, and chances of branching, suggesting an attempted nerve regeneration. A strong correlation exists between the changes of nerve morphology and the degree of dry eye. These results provide some possible evidence for the abnormal corneal sensation in dry eye.

Ocular surface changes in laser in situ keratomileusis-induced neurotrophic epitheliopathy.

PURPOSE: To evaluate the ocular surface changes in patients with laser in situ keratomileusis (LASIK)-induced neurotrophic epitheliopathy. METHODS: Seven consecutive patients with LASIK-induced neurotrophic epitheliopathy were studied prospectively and compared to a control group (seven consecutive patients who had LASIK- but without neurotrophic epitheliopathy). Bilateral sequential LASIK was performed at a 1-week interval; the first operated eye of each patient was considered for statistical analysis. Blinking, corneal sensitivity, tear break-up time, tear secretion and clearance were measured preoperatively (T0) and postoperatively at 1 week after surgery on the first eye (T1), and 1 week (T2), 1 month (T3), and 3 months (T4) after surgery was performed on the second eye. RESULTS: Laser in situ keratomileusis-induced neurotrophic epitheliopathy occurred bilaterally in all patients. During follow-up, patients with LASIK-induced neurotrophic epitheliopathy showed a significant decrease in blinking (P = .0002), which was not observed in cases without LASIK-induced neurotrophic epitheliopathy [corrected] Compared to eyes without LASIK-induced neurotrophic epitheliopathy, those with LASIK-induced neurotrophic epitheliopathy revealed lower values of sensitivity in the central cornea preoperatively and early postoperatively (T0, P = .004; T1, P = .003; T2, P = .003). A trend towards reduced sensitivity was also detected in the central cornea in late follow-up and in the superior, temporal, and nasal sectors of the flap at all examinations. No significant differences were observed in break-up time, tear secretion, or clearance within or between the two groups. CONCLUSION: Decreased blinking seems to be involved in the pathogenesis of LASIK-induced neurotrophic epitheliopathy. The reduction probably depends on the lower levels of corneal sensitivity and induces the epitheliopathy by increasing the ocular surface exposure.