Central retinal vein occlusion in patients with metastatic solid tumors on tyrosine kinase inhibitors: a report of case series and literature review.

Background: Central retinal vein occlusion (CRVO) is a rare adverse effect related to the use of tyrosine kinase inhibitors (TKIs) in patients with metastatic malignancies, which has only been reported in several case reports. Case presentation: We reported the case series of three CRVO patients on regular regimens of TKIs as part of targeted therapies for metastatic malignancies, all of whom were otherwise healthy with no or well-controlled systemic conditions. All these patients received injections of intravitreal dexamethasone implant (IDI) and achieved a fluid-free macula at the end of the visit. In addition, we reviewed the existing literature on this subject and present here an updated analysis of the related TKIs, ocular presentation, treatment, and prognosis. Conclusion: All patients diagnosed with CRVO on TKIs received dexamethasone implant treatment and obtained a fluid-free macula. We would like to raise awareness among our colleague oncologists about the possibility of CRVO related to TKI use and the necessity for patients to be screened regularly by a retinal specialist.

Atopic Dermatitis Associated Retinal Detachment and Retinal Vasculitis: A Case Report.

Atopic dermatitis is usually associated with various ocular complications. We report a 21-year-old Chinese male who presented to our ophthalmology clinic with bilateral retinal detachment and cataracts. The patient had a clear medical history of atopic dermatitis, which had been diagnosed eight years earlier and had been treated with loratadine and pimecrolimus. Cataract surgery was performed for both eyes, combined with scleral buckling for the right eye and pars plana vitrectomy for the left eye. During postoperative follow-up, fundus fluorescein angiography showed retinal vasculitis in both eyes and macular edema in the left eye, which coincided with an exacerbation of atopic dermatitis. Macular edema improved after four months of regular dupilumab treatment in the dermatology department. The ocular condition remained stable three years postoperatively.

Retinal Vasculitis as an Ocular Manifestation in Atopic Dermatitis-Associated Retinal Detachment: A Case Report.

Atopic dermatitis is usually associated with various ocular complications. We report a 21-year-old Chinese male who presented to our ophthalmology clinic with bilateral retinal detachment and cataracts. The patient had a clear medical history of atopic dermatitis, which had been diagnosed eight years earlier and had been treated with loratadine and pimecrolimus. Cataract surgery was performed in both eyes, combined with scleral buckling in the right eye and pars plana vitrectomy in the left eye. During postoperative follow-up, fundus fluorescein angiography indicated retinal vasculitis in both eyes and macular edema in the left eye, which coincided with an exacerbation of atopic dermatitis. Macular edema improved after four months of regular dupilumab treatment in the dermatology department. The ocular condition remained stable three years postoperatively.

Iridociliary Body Metastasis of Atypical Carcinoid: Case Management with Intravitreal Anti-Vascular Endothelial Growth Factor Injections.

We report a rare case involving a 52-year-old female diagnosed with an atypical bronchial carcinoid tumor with metastases to the mediastinum, hilar lymph nodes, breast, and pancreas. In additional, the patient had metastases to the iris and ciliary body, resulting in progressive vision loss in her left eye. Treatment was successful by intravitreal injections of anti-vascular endothelial growth factor.

Development of Diagnostic Recommendations for Vitreoretinal Lymphoma.

PURPOSE: To develop diagnostic recommendations for diffuse large B-cell vitreoretinal lymphoma (VRL) in Chinese patients. METHODS: Retrospective observational case series. Seventy-three eyes of 40 VRL patients and 8 control patients were analyzed. Eighteen patients from Beijing Tongren Hospital and 46 patients from literature were involved as validations. RESULTS: Diagnostic methods included (1) typical clinical manifestations; (2) vitreous cytology; (3) immunohistochemical examination of vitreous or choroid/retina; (4) aqueous humor or vitreous cytokine; (5) vitreous cell gene rearrangement; (6) vitreous flow cytometry. If patients meet (1)+(2)+(3), or if they meet (1), and two of (4), (5), (6) are positive, they can be diagnosed as VRL. The sensitivity and specificity values for accurate diagnosis were 0.975 and 1.00. One hundred percent eyes from Beijing Tongren Hospital and 92.7% eyes from literature can be diagnosed. CONCLUSION: We developed diagnostic recommendations for diffuse large B-cell VRL through vitreous cytology combined with multiple auxiliary examinations.

Cerebrospinal Fluid Interleukin-10 Biomarker for Vitreoretinal Lymphoma.

PURPOSE: To analyze the correlation between cerebrospinal fluid (CSF) interleukin-10 (IL-10) levels and the clinical characteristics in patients with vitreoretinal lymphoma (VRL). DESIGN: Retrospective observational case series. METHODS: Forty-one patients were diagnosed as VRL and underwent lumbar puncture for CSF examination. Aqueous humor cytokine detection, vitreous cytopathologic analysis, monoclonal gene rearrangement, and flow cytometry were performed. The CSF was assessed through biochemical and cytologic examination, flow cytometry, and cytokine detection. RESULTS: The median levels of aqueous humor IL-10 and IL-6 were 415.0 and 40.7 pg/mL. The median CSF levels of IL-10 and IL-6 were 35.7 and 3.5 pg/mL, respectively. IL-10 levels in CSF were higher than normal in 37 patients (90.2%) and higher in patients with intracranial lesions. The level of CSF IL-10 decreased after systemic treatment, and it rose before intracranial lesion onset or recurrence. The level of IL-10 in CSF was related to the duration of ocular symptoms, but was not related to the level of IL-10 in aqueous humor. There was no significant difference in CSF IL-10 levels between patients with and without anterior chamber inflammation or retinal lesions. In eyes with recurrent vitreoretinal lymphoma, the level of IL-10 in aqueous humor increased significantly, but there was no corresponding increase in the level of IL-10 in CSF. CONCLUSION: CSF IL-10 is a potentially important biomarker in VRL, especially in the monitoring of intracranial lesions.

Long-term efficacy and safety of sirolimus for retinal astrocytic hamartoma associated with tuberous sclerosis complex.

Mammalian target of rapamycin (mTOR) inhibitors (sirolimus or everolimus) have been demonstrated effective in reducing the size of tuberous sclerosis complex (TSC)-associated retinal astrocytic hamartoma (RAH) in short term. To investigate the long-term efficacy and safety of sirolimus on TSC-associated RAH, 13 TSC-associated RAH patients (59 RAH lesions) who received sirolimus therapy for at least 2 years were retrospectively enrolled in this study. Changes in the maximal thickness (MT) of RAH on optical coherence tomography and the longest base diameter (LBD) of RAH on color fundus photography were assessed. The results showed that for a mean follow-up of 39 months, sirolimus was associated with a mean reduction of 14.6% in MT and 6.8% in LBD of RAHs. The main impacts of sirolimus occurred within the first 6-12 months, with 14.8% reduction in MT and 4.7% reduction in LBD. Mouth ulceration (10 [76.9%]) and acne (9 [69.2%]) were the most common adverse events. These follow-up data support the long-term use of sirolimus in TSC-associated RAH patients, and persistent use of sirolimus possibly prevents tumor regrowth.

Recurrent vitreous opacity caused by intraocular Toxocara larva: a case report and literature review.

BACKGROUND: Toxocara larva entity has seldom been reported on the surface of the retina. We report on an unusual case of recurrent vitreous opacity caused by intraocular Toxocara larva after vitrectomy. CASE PRESENTATION: A 34-year-old male was referred to our clinic with a 6-month history of decreased visual acuity in the right eye characterized as red, painless, and progressive. Optos fundus photograph showed optic disc elevation with granuloma, and proliferative membrane starting from the optic disc and running towards the superior temporal retina due to the movement of a Toxocara larva, which was covered by the proliferative membrane in the superior temporal retina. Since it adhered closely to the retina, the lesion in the superior temporal retina was not removed to avoid induction of an iatrogenic retinal break and the larva was not found during the first diagnostic pars plana vitrectomy. Intraocular Anti-Toxocara IgG was 45.53U (< 3, enzyme-linked immunosorbent assay (ELISA)), and the Goldmann-Witmer coefficient was 8.55, confirming the diagnosis of ocular toxocariasis. After this operation, visual acuity improved to 20/200. However, vitreous opacity worsened again, and the proliferative membrane expanded around the Toxocara larva three weeks after the operation. Toxocara larva was found and removed in the superior temporal region during the second operation. His visual acuity improved to 20/100, vitreous opacity disappeared, and the retina was stable two months after the second operation. CONCLUSION: It is advisable to remove suspected Toxocara larva to prevent the reoccurrence of ocular toxocariasis.

Apnea caused by retrobulbar anesthesia: A case report.

BACKGROUND: Apnea caused by retrobulbar anesthesia is a very rare but severe complication during ophthalmic surgery. CASE SUMMARY: We report a rare case of apnea caused by retrobulbar anesthesia, and emergency resuscitation was used. A 74-year-old female patient was diagnosed with rhegmatogenous retinal detachment in the right eye and planned to undergo vitrectomy under retrobulbar anesthesia. After the retrobulbar anesthesia in her right eye, she became unconscious and apneic. It was suggested that she had developed brainstem anesthesia. Assisted ventilation was initiated. Atropine 0.5 mg, epinephrine 1 mg, ephedrine 30 mg, and lipid emulsion were given. Five minutes later, her consciousness and breathing gradually returned, but with uncertain light perception in her right eye. Alprostadil 20 µg was given, and after 2 h her visual acuity resumed to the preoperative level. CONCLUSION: Brainstem anesthesia is a serious complication secondary to retrobulbar anesthesia. Medical staff should pay attention to the identification of brainstem anesthesia and be familiar with the emergency treatment for this complication.

Case Report: Intraocular Hemorrhage in a Primary Vitreoretinal Lymphoma Patient Treated With Zanubrutinib.

Purpose: To report a case of primary vitreoretinal lymphoma (PVRL) treated with oral zanubrutinib, who had bilateral intraocular hemorrhage after intravitreal injection of methotrexate (MTX). Case report: A 69-year-old Chinese female presented with vision decrease in both eyes. After diagnostic vitrectomy, the patient was diagnosed as PVRL in both eyes, and was treated with intravenous rituximab, oral zanubrutinib and bilateral intravitreal MTX. There were bilateral anterior chamber and vitreous hemorrhage after the fourth intravitreal MTX combined with paracentesis. After discontinuation of zanubrutinib, vitrectomy and silicon oil tamponade were performed on the left eye, and the blood in the right eye was absorbed. Conclusion: Bleeding is a major concern in the use of zanubrutinib. It is suggested that drugs be held for a few days prior to procedures and surgeries.

Application of a 3D-printed eye model for teaching direct ophthalmoscopy to undergraduates.

PURPOSE: This study aims to design an eye model that can simulate the fundus for teaching direct ophthalmoscopy and to evaluate its effectiveness. METHODS: We first used 3D printing materials to make an eye model and then randomly assigned 92 undergraduates into group A (model-assisted training group) and group B (traditional training group) to test our model. After the same training time, real patients were used to test the students, with 120 s as the examination time limit. We recorded the students' ability to clearly see the optic disk, the time to determine the cup-to-disk ratio, and whether they were correct. RESULTS: Forty-three students in group A (93.48%) successfully saw the fundus, while 21 in group B (45.65%) succeeded. The difference between the two groups was 47.83% (95% confidence interval, 29.59-66.07%, P < 0.0001). The median time to see the fundus was 29s (95% confidence interval 23-45 s) in group A, while an estimated minimum time in group B was 80 s, indicating that group A was significantly faster than group B (P < 0.0001). CONCLUSIONS: This 3D-printed eye model significantly improved the students' study interest, study efficiency, and study results and is worthy of being promoted.

The influence of delayed treatment due to COVID-19 on patients with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

PURPOSE: To explore the impact of coronavirus disease 2019 (COVID-19) on the prognosis of patients with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV), and share the experience in managing them during pandemics. METHOD: This is a retrospective study of nAMD and PCV patients treated at Peking Union Medical College Hospital from 31 December 2019 to 1 August 2020. Baseline demographic and clinical characteristics, best corrected visual acuity (BCVA), optical coherence tomography (OCT) features, duration of delayed treatment and number of anti-vascular endothelial growth factor (VEGF) injections were analyzed. RESULTS: A total of 130 nAMD patients (155 eyes) and 76 PCV patients (89 eyes) were identified. Compared to the conditions before COVID-19, the BCVA of delayed cases decreased significantly, and the proportion of patients presenting with sub-macular scar was significantly greater in the delayed treatment group (p < 0.05). The BCVA of non-delayed cases remained stable, with the percentage of patients with disease activity sub-retinal fluid and hemorrhage at the fovea decreasing significantly (p < 0.05). The stable cases who did not require anti-VEGF treatment had significantly worse baseline and final BCVA, these patients were likely to be chronic and 'burnt out' cases with significantly worse anatomical structures (p < 0.05). CONCLUSIONS: The delayed cases due to the pandemic suffered compromised visual function and a higher rate of sub-macular scar formation, while the visual function of non-delayed cases remained stable with favorable anatomical outcomes, suggesting the importance of regular follow-up for nAMD and PCV patients. Besides, effective measures of hospitals during pandemics are crucial to provide timely treatment for chronic disease.

Ring lymphoma: highly indicative ultrasound biomicroscopy findings of ciliary body lymphoma.

BACKGROUND: To describe the ultrasound biomicroscopy (UBM) findings of extremely rare ciliary body lymphoma. METHODS: This was a retrospective noncomparative case series study. Five patients (8 affected eyes) diagnosed with ciliary body lymphoma at Peking Union Medical College Hospital from 2008 to 2019 were included. The UBM findings, including the location, height, and acoustic features, were documented to assess the tumour characteristics. RESULTS: UBM in all 8 (100%) affected eyes revealed 360° ring-like, solid infiltration of the ciliary body with low and homogeneous internal reflectivity. The continuity of the tumours could be most vividly demonstrated by transverse sections. CONCLUSIONS: Ciliary body lymphoma tends to grow in a characteristic circumferential 360° pattern, and the name "ring lymphoma of the ciliary body" is proposed.

Reliability of optic disc edema area in estimating the severity of papilledema in patients with POEMS syndrome.

BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome is a rare paraneoplastic syndrome involving multisystem. Optic disc edema (ODE) is the most common ocular manifestation in patients with POEMS syndrome and serves as an independent prognostic factor. However, parameters previously used to estimate its severity were inconvenient and costly. This study was designed to bring forward a novel and practical parameter, optic disc edema area, to evaluate ODE in patients with this disease and applied it to assess effectiveness of lenalidomide combined with dexamethasone in respect of ODE. RESULTS: Forty-one treatment-naive patients with POEMS syndrome were enrolled in this single-center prospective study and treated with lenalidomide combined with dexamethasone. They received ocular examination to determine optic disc edema (ODE) area and other optic manifestations. Meanwhile, serum VEGF was measured before and after treatment. Among 41 enrolled patients, 38 received complete ocular examinations, and 25 of which had ODE at initial visit. Binocular mean ODE area of patients with ODE was significantly related to ODE grade (r = 0.620, p = 0.003) and peripapillary retinal thickness (r = 0.760, p < 0.001) before treatment. Serum VEGF was significantly higher in patients with ODE than their counterparts (p = 0.025) and positively correlated with binocular mean ODE area (r = 0.460, p = 0.036). After treatment, ODE area, along with serum VEGF, decreased markedly (p < 0.001). CONCLUSION: ODE area was a reliable index to evaluate ODE severity and could precisely reflect ODE improvement through systemic treatment. Additionally, it was related to serum VEGF, a key factor in disease pathogenesis, suggesting its potential as an indicator of the overall severity of this disease. TRIAL REGISTRATION: Clinicaltrials, NCT01816620. Registered March 222,013.

Comparison of choriocapillary flow density between fellow eyes of polypoidal choroidal vasculopathy and neovascular age-related macular degeneration.

BACKGROUND: To compare the choriocapillary flow density (CFD) among the fellow eyes of polypoidal choroidal vasculopathy (PCV), neovascular age-related macular degeneration (nAMD), and healthy controls using spectral-domain optical coherence angiography tomography (SD-OCTA). METHODS: This is a cross-sectional study that includes the fellow eyes of 38 patients with unilateral PCV, 36 patients with unilateral nAMD, and 36 eyes from 36 healthy volunteers. The PCV group was further classified into polypoidal CNV (P-CNV) and typical PCV (T-PCV) for subgroup analysis. The age, subfoveal choroidal thickness (SFCT), Age-Related Eye Disease Study (AREDS) classification, and fellow eye diagnosis were acquired. All subjects underwent SD-OCTA with a 6.0-mm scan pattern. Circles with radius of 1.00, 1.50, and 3.00 mm were manually selected in the choriocapillaris (CC) slab, and the CFD was calculated as the percentage of the flow area to the whole selected area as CFD-1.00, 1.50, and 3.00, respectively. Univariate and multivariate analysis were performed to study the correlation between the aforementioned factors with CFD. RESULTS: The mean CFD-1.00, 1.50, and 3.00 of the nAMD group were 61.51, 63.18, and 66.20, respectively; these were significantly lower than those of the PCV group (65.90, 66.89, and 67.94; P < 0.001, P < 0.001, and P = 0.010; respectively) and control group (66.28, 66.96, and 68.42; P < 0.001, P < 0.001, and P = 0.001, respectively), and no difference was detected between the PCV and control group or between PCV subtypes. The AREDS classification and fellow eye diagnosis were correlated with CFD in univariate analysis; however, only the fellow eye diagnosis showed a significant correlation after multiple linear regression. CONCLUSIONS: The CFD of nAMD fellow eyes was significantly lower than that of PCV and control eyes, and no difference was detected between PCV and control group, indicating that CC loss plays a different role in the early pathogenesis of nAMD and PCV.

Diagnosis of bilateral diffuse uveal melanocytic proliferation unveils primary gastric adenocarcinoma: a case report.

BACKGROUND: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is an extremely rare paraneoplastic syndrome, with most cases reported as secondary to female urogenital and male lung malignancies. We reported this case of BDUMP patient whose primary malignancy was gastric adenocarcinoma verified with gastroscopy and subsequent pathological test. CASE PRESENTATION: A patient complaining blurred vision was suspected of bilateral diffuse uveal melanocytic proliferation (BDUMP), due to bilateral round oval patches at the posterior pole and cardinal signs in retinal angiography. Malignancy screening was suggested, and pathological report from gastroscopy confirmed the primary lesion as gastric adenocarcinoma. The patient chose palliative care due to late stage and unresectable nature of the malignancy. CONCLUSIONS: Identifying BDUMP warrants further investigation of a primary malignancy. Our case provided evidence for the link between gastric adenocarcinoma and BDUMP.

Comparison of aqueous humor levels of PlGF and VEGF in proliferative diabetic retinopathy before and after intravitreal conbercept injection.

AIMS: The aim of this paper is to observe the change of aqueous humor levels of placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF) in proliferative diabetic retinopathy (PDR) patients before and one week after intravitreal conbercept injection. METHODS: A prospective case series study was conducted in 24 active PDR patients (24 eyes). All the patients had received 0.5 mg of intravitreal conbercept followed by vitrectomy one week later. The aqueous humor was collected before conbercept injection and at the beginning of vitrectomy. RESULTS: Before conbercept injection, the aqueous humor median levels of VEGF-A, VEGF-B and PlGF were457.0pg/mL(IQRfrom392.9to860.6pg/mL), 43.6pg/mL(IQRfrom33.6to81.6pg/mL), 37.5pg/mL(IQRfrom25.0to53.6pg/mL), respectively. One week after conbercept injection, the aqueous humor levels of VEGF-A, VEGF-B and PiGF decreased significantly. The aqueous humor VEGF-A levels in PDR patients with fibrovascular membranes were lower than those without them. There was positive correlation between aqueous humor VEGF-B and PiGF levels (P = 0.007). No significant correlation was found between VEGF-A and PiGF levels. No ocular and systemic adverse events were observed. CONCLUSIONS: The aqueous humor levels of PlGF was correlated with VEGF-B, and levels of VEGF-A, VEGF-B, and PlGF decreased after intravitreal conbercept injection in active PDR patients.

Clinical features and optical coherence tomography findings of retinal astrocytic hamartomas in Chinese patients with tuberous sclerosis complex.

PURPOSE: To investigate the clinical features and spectral-domain optical coherence tomography (SD-OCT) findings of retinal astrocytic hamartoma (RAH) in Chinese patients with tuberous sclerosis complex (TSC). METHODS: The medical records of 91 consecutive patients with established TSC diagnosis were retrospectively reviewed. Fundus findings regarding RAH documented by fundus photography and SD-OCT at presentation were collected and analyzed. RESULTS: RAHs were seen in 69 of the 91 patients (75.8%); 50.7% of these patients showed bilateral retinal involvement. Type 1 RAH was found the most common type with a prevalence of 94.2%, while type 2 and type 3 RAH with 7.2% and 18.8% respectively. A significant correlation between age and RAH types was shown by Fisher's exact test (p < 0.001). By SD-OCT, non-calcified RAHs featured in hyperreflective thickening of the retinal nerve fiber layer with some degree of retinal disorganization, while multinodular calcified RAHs characterized with moth-eaten appearances representing intraretinal calcification with posterior dense optical shadowing. CONCLUSION: A higher prevalence of TSC-associated RAH but an unexpected lower prevalence of calcified RAHs was shown in Chinese compared with that of Caucasians. SD-OCT can be used to facilitate the detection and follow-up of RAHs.

OCULAR MANIFESTATIONS AND TREATMENT OUTCOMES IN CHINESE PATIENTS WITH POEMS SYNDROME.

PURPOSE: To evaluate the relationship of serum vascular endothelial growth factor (VEGF) levels and ocular manifestations in Chinese patients with POEMS syndrome. METHODS: This is a prospective study. Forty-one treatment-naive patients were enrolled from April 2014 to November 2014. Among the 41 patients, 40 had complete ocular examination, spectral domain optical coherence tomography scan, and serum VEGF measurement before treatment and every 3-month interval after lenalidomide and dexamethasone treatment. RESULTS: Twenty-seven (67.5%) patients had optic disk edema (ODE) at baseline. Retinal manifestations included retinal hemorrhage, subretinal fluid, macular edema, and cotton wool spot. The difference in mean serum VEGF concentrations between patients with and without ODE was significant (P = 0.017). Among patients with ODE, there was a significant positive correlation between mean serum VEGF levels and the binocular mean retinal nerve fiber layer thickness (P = 0.008), as well as mean peripapillary retinal thickness (P = 0.020) before treatment. After 3 months to 17 months treatment, mean serum VEGF concentrations decreased significantly (P < 0.001). Mean retinal nerve fiber layer thickness and mean peripapillary retinal thickness decreased significantly (P < 0.001). The remission rate of ODE was 87.5%, and complete remission rate was 58.3%. CONCLUSION: The ODE is a common manifestation in POEMS syndrome, and raised VEGF might explain the development and mechanism. Systemic treatment could lead to decrease in serum VEGF levels accompanied by regression of ODE.

Natural course of vitreomacular traction syndrome observed by spectral-domain optical coherence tomography.

OBJECTIVE: Our study aimed to characterize the natural course of vitreomacular traction (VMT) syndrome, on which discrepancies have been reported in previous publications, by spectral-domain optical coherence tomography (SD-OCT). DESIGN: Retrospective chart review. PARTICIPANTS: A total of 23 eyes of 23 patients with idiopathic symptomatic VMT syndrome diagnosed and followed up in Peking Union Medical College Hospital from 2008 to 2013. METHODS: Clinical records of all patients who underwent SD-OCT examination and were diagnosed and followed up as idiopathic VMT syndrome were reviewed. Those who had at least 2 visits were included. The median observation period of the patients was 8.2 ± 7.9 months. RESULTS: The 23 eyes were categorized into 3 groups based on the follow-up results of SD-OCT: the posterior vitreous detachment (PVD) group comprised 4 eyes that developed complete PVD, the full-thickness macular hole (FMH) group included 4 eyes that formed FMH, and the persisted VMT (PVMT) group comprised the other 15 eyes with PVMT. Epiretinal membrane (ERM) persisted in all 5 eyes in the PVMT group. FMH occurred in 3 of 7 eyes with outer lamellar macular hole (LMH) at the first visit. CONCLUSIONS: Spontaneous development of complete PVD in VMT syndrome during follow-up appeared to be more common in our study than in previous reports without SD-OCT. Persistence of ERM might be an unfavourable prognostic factor in the natural course of VMT syndrome. The outer LMH might be a risk factor for FMH formation.