Cobb’s Tufts: A Systematic Review

Cobb's tufts, also known as iris vascular tufts (IVT) and iris microhemangiomas (IMH), are coils of tightly clustered, minute blood vessels at the iris pupillary border. This study aimed to analyze previous literature and provide an update on Cobb’s tufts. A systematic literature review was carried out by interrogating PubMed, Google Scholar, Cochrane, and Embase databases. Full-text English language articles of any year were included in this study. A total of 38 articles fulfilled our inclusion criteria. A total of 115 reported cases of Cobb’s tufts were incorporated into our review. The age of the patients ranged between 36 and 86 years. No sex or racial predisposition was noted. Most patients had no history of trauma, surgery, or blood dyscrasia. The majority of cases are asymptomatic and bilateral unless a spontaneous hyphema occurs, which most commonly presents as blurred vision. The etiology of this condition remains uncertain; however, a higher incidence has been shown in systemic conditions such as myotonic dystrophy and diabetes. Fluorescein angiography can be utilized to investigate tufts. Management includes treatment of raised intraocular pressure, observation for single bleeds, laser therapy for recurrent hyphemas, and lastly, iridectomy, which is considered in cases of recurrence following laser treatment.


Introduction And Background
Cobb's tufts, also known as iris vascular tufts (IVT) and iris microhemangiomas (IMH), are true hamartomas of the iris stromal blood vessels [1]. The first case of a spontaneous hyphema with iris microhemangioma was reported by Tyson in 1932, according to Fechner's article in 1958 [2]. In 1969, Cobb provided an observational study providing a detailed description of the condition [3]. This led to them being eponymously named Cobb's tufts. Cobb noted that these lesions protruded forward from the iris in single or multiple loops, were vascularized, adjacent to pupillary ruff, and were separate from each other. In a later publication, he also associated the occurrence of vascular tufts in patients with myotonic dystrophy and diabetes [4]. They can uncommonly present as spontaneous hyphemas, which can lead to high intraocular pressure (IOP) and may potentially cause irreversible damage to the optic nerve [5]. There is a lack of good quality evidence as to the management of this condition. To our knowledge, the last review of the literature was in 2013 [6]. The purpose of this study was to analyze current literature and provide a comprehensive update on all aspects of this condition.

Review Methods
We present a systematic review of the literature on Cobb's tufts following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [7]. The PRISMA statement and checklist were used to critically analyze articles and structure this review [7]. Our literature search extends from 1958 to February 2020. The systematic search was conducted through PubMed, Embase, Google Scholar, Cochrane, and the reference lists of the articles. We utilized the following terms in our search: Cobb's tufts, iris microhemangiomas, iris vascular tufts, and neovascular tufts.
Studies published from any year in the English language were included. Studies that reported spontaneous hyphemas without evidence of IVT and iris neovascularization (rubeosis iridis) were excluded. Moreover, editorials and correspondences were also included. The study identification and selection process are demonstrated in Figure 1   Full texts were obtained for articles that met inclusion criteria. Data were extracted and information was expressed according to data points as shown in Table 1.

Results
This review compiled 38 articles based on the selection criteria including one case-control study, two crosssectional studies, five case series, and 30 case reports, describing a total of 115 cases of iris vascular tufts. Since the last literature review in 2013, there have been 10 new articles reporting 26 new cases of IVTs. One article was a retrospective observational case series on 14 patients [8].

Patient Characteristics
Patients' ages ranged from 36 to 86 years with a mean of 65 years and median of 67 years. No sex or racial predisposition was noted. There was no case of prior intra-ocular trauma or surgery. Only one case of blood dyscrasia was reported with the patient being on warfarin [5]. Hypertension (48%), ischemic heart disease (18%), and diabetes (12%) were common among those with co-morbidities. Previous medical and ocular history is summarized in Table 1. The lesions appear as very small and nodular hemangioma on the iris and range from 15 to 150 microns in size [2,3]. They can be single or multiple and are most commonly bilateral [2,3]. The onset is usually in the sixth decade or older [3,4]. Meades et al. provided an electron microscopic description of IVT, indicating the nature of a true hamartoma of the iris stromal blood vessels [1].

Etiology and Other Associations
The exact cause of IVT remains unclear. Initially, these lesions were assumed to be congenital [2]. However, as there are no reported cases in children, these lesions are believed to be acquired [9]. Literature suggests a higher incidence of this lesion in those with systemic and other ocular conditions. Mason (1979) and Cobb et al. (1970) provided evidence that IVT can be associated with myotonic dystrophy and diabetes mellitus [3,4,10]. Mason's investigation demonstrates an incidence of tufts in 6.7% of adult-onset diabetics and in 12.5% of patients with myotonic dystrophy. Tufts were not seen in 14 patients with juvenile-onset diabetes [10]. There appeared to be increased pancreatic B cell responsiveness in patients with myotonic dystrophy in response to glucose, thus causing high endogenous insulin levels. This study hypothesized that the higher levels of serum insulin might participate in the development of iris neovascularization by immunologic or other unknown mechanisms [10]. Cobb et al. (1969) hypothesized that tufts may proliferate in response to biochemical changes in the aqueous as in cataracts, diabetes, respiratory failure, and ocular hypotony [4]. Blanksma and Hooijmans (1979) also suggested that there seems to be a connection between the development of IVT and cardiovascular and pulmonary disease [11]. Systemically, they could also be associated with hypertension [12], congenital cyanotic heart disease [13], and congenital hemangiomatosis [6]. Nuova et al. (2020) presented a study of a patient with poorly controlled hypertension who presented with a spontaneous hyphema and hypertensive crisis [12]. Krarup (1977) reported a case of two years of bilateral IVT and recurrent microhyphema with the background of congenital cyanotic heart disease. The study summarized that a prolonged stasis with subsequent hypoxia of the iris tissue is a common factor in those conditions where a local or systemic disease is known to be present [13].
Cobb's tufts have also presented simultaneously with other ocular manifestations. Elgohary and Sheldrick (2004) presented a case of spontaneous hyphema from IVT in the context of acute branch retinal vein occlusion. The authors concluded that hyphema from IVT may indicate a recent retinal vein occlusion and that their presence can be a risk factor for the development of hyphema during the acute stage of an ischemic retinal vein occlusion [14]. There has been a report of idiopathic juxtafoveolar retinal telangiectasis presenting concurrently with IVT, although no association could be identified [9]. Acute glaucoma has presented simultaneously with spontaneous hyphema secondary to IVT; however, their association cannot be accurately determined based on the lack of reports. Perry et al. (1977) felt the attack of glaucoma could be precipitated by the occurrence of the hyphema [15]. IVT may also present similar to amaurosis fugax as the tufts bleed occasionally and resolve rapidly. Care must be taken to avoid this misdiagnosis [16].

Investigations
The external ocular examination is usually normal. VA ranges from normal to light perception based on the degree of hyphema. Tonometry commonly reveals raised IOP when there is an observable hyphema [9]. If there was a hyphema, gonioscopy can reveal a trace of blood, otherwise, this part of the examination is usually normal [16]. There has been a case where the patient presented with acute angle-closure on gonioscopy, as well as a spontaneous hyphema secondary to IVT [15]. Fundoscopy is also largely unremarkable; however, Akram et al. provide a case demonstrating a hyperemic disc with a splinter hemorrhage and venous congestion. These changes did resolve within six weeks of topical therapy [30]. Similar retinal nerve fiber changes can also be seen if there is a simultaneous branch retinal vein occlusion [14]. A slit-lamp examination can demonstrate vascular abnormalities at the pupillary border and may reveal active bleeding or a blood clot; only a third of IVT were revealed by slit-lamp microscopy that was later demonstrated on iris fluorescein angiography (IFA) [22]. These changes can be subtle and further assessment with IFA is recommended to delineate the full extent of these lesions [22]. IVT appears as coils of tightly clustered, minute blood vessels at the pupillary margin and demonstrate early hyperfluorescence with late staining [22]. Photographic/videographic documentation is recommended to assess changes over time [19,29]. The fellow eye should also be imaged as IVT is most commonly bilateral [3,22]. Meades et al. (1986) provided the first electron microscopic description of an iris microhemangioma, indicating it to be a true hamartoma of the iris stromal blood vessels [1]. Histopathology illustrates endothelial cells surrounded by pericytes and loose connective tissue and electron microscopic evidence of normal cell thickness with no fenestrations [1]. Another valuable tool that has recently been reported is the anterior segment optical coherence tomography (OCT) of IVT. Its advantages include shorter acquisition time, no need for intravenous dye injection, and three-dimensional visualization of ocular tissue permitting segmental analysis of microvascular anatomy [32]. However, IFA remains the more commonly used mode of investigation supplements clinical examination. In addition to all the above, a full blood count, clotting screen, and urine analysis should be carried out, which are normal in the vast majority of cases. A fasting blood glucose and oral glucose tolerance test is also recommended due to the incidence of IVT in diabetics [3,10].

Differential Diagnosis
When trauma is excluded, clinicians should be vigilant of the following conditions. Uveal melanoma is the most vital differential diagnosis to exclude and this can be detected by IFA and serial examinations with photographic surveillance [1,6]. Hereditary hemorrhagic telangiectasis (HHT) is another differential that is a rare autosomal dominant disorder. It is characterized by multiple dilatations of capillaries and venules of skin, mucous membranes, and viscera that may cause bleeding. Conjunctival and eyelid involvement is common, which is not present in IVT [33]. Gonioscopy can be valuable in differentiating IVT from iris neovascularization [25]. Rubeosis can appear similar to IVT; however, the major morphological difference is IVT are elevated, not flat, and they are confined to the pupillary border [10]. Other differentials include inflamed iris vessels and iris hemangiomas [6].

Conservative
Cobb's tufts do not produce symptoms unless the patients develop a hyphema [17]. Most patients with IVT rarely develop bleeding and rarely re-bleed [21,27]. Studies have shown that most hyphemas resolve without requiring intervention, thus they are initially treated with time and bed rest [2,15,26,29,30]. There has been a case of spontaneous hyphema from IVT secondary to over-anticoagulation with warfarin and intravenous vitamin K was part of the management plan [5].
Raised IOP commonly presents with hyphemas and is a vital part of acute management. Prolonged elevation in IOP may lead to optic nerve damage. There have been many studies showing successful responses to acetazolamide and/or topical beta-blockers such as Timoptol [5,6,15,16,20,27,30,34]. Topical steroids and mydriatics/cycloplegics should also be considered and help to decrease light sensitivity and intraocular inflammation [5,8,20,26,27,29,34,35]. Conservative management is sufficient even if there is active bleeding or hyphema is recurrent or pronounced [34].

Laser Photocoagulation
There have been numerous studies documenting the treatment of hyphema caused by IVT with serial argon laser photocoagulation (ALP) [6,8,14,18,20,21,24,27,31,[34][35][36]. Variable laser parameters are shown in literature, in terms of spot size, laser power, duration, and the number of spots targeted ( Table 2). IFA prior to ALP or surgical treatment is necessary [6]. Dharmasena and Wallis (2013) employed a laser with neodymium-doped yttrium aluminum garnet (Nd:YAG) with YAG Pi settings with a good outcome and no recurrence within six months. The laser was aimed at an angle to reduce the risk of inadvertent macular burn. The parameters used were 500 um spot size, 100 mW power, 0.5 seconds, and eight confluent burns [6]. ALP was utilized for a single episode of active bleeding in four studies [21,27,28,36]. Williams et al. (2018) recently published a retrospective observational case series reporting a good outcome from the use of ALP in two cases of active bleeding despite medical therapy with topical steroids and atropine [8]. There have also been three reports of its use in single episodes of hyphema [20,24,31]. Only one of these five studies suffered a recurrence years later, which was managed conservatively [27]. Bandello et al.'s (1993) study demonstrated no further bleeding but showed angiographic evidence of new IVT, leading to two further treatments with ALP [31]. The rationale behind the use of ALP in single episodes of hyphema is unclear, especially since these have shown good outcomes with conservative management alone. Two cases have been documented of ALP use in recurrent hyphema prior to cataract surgery and have shown good outcomes [18,35]. The risk of bleeding from cataract surgery is unknown. Winnick et al. (2003) utilized parameters of 200 mW power for the 0.1-second duration on 50 spots of 200 um size [35]. It was theorized that closure of IVT would reduce the intra-operative risk of bleeding during surgery. Only minimal bleeding from the iris was observed and no further hyphema was documented in the postoperative period [35]. Interestingly, Goetz and Cosgrave (2015) report a case of cataract surgery without prior laser photocoagulation three months after a hyphema occurred in a patient with IVT. The procedure was carried out successfully without intra-or postoperative bleeding [37]. The follow-up periods post-procedure were variable and ranged from two to 228 months, with a mean of 42 and a median of 16 months (

Surgery
Iridectomy offers the benefits of no recurrence and clinically excludes a malignant lesion. Good outcomes have been shown from the procedure. The literature recommends that this should be considered in patients who are still symptomatic despite laser treatment or in case of suspicion regarding a malignant lesion [6].

Discussion
Cobb's tufts are coils of tightly clustered, minute blood vessels at the iris pupillary margin [22]. The etiology and pathogenesis of this condition are largely unknown. To date, there is no literature based on these aspects. As there are no reported cases in children, these tufts are believed to be acquired [9]. Moreover, there is a higher incidence of Cobb's tufts in patients with systemic conditions such as myotonic dystrophy and diabetes mellitus [3,4,10]. IVT also seems to occur more in patients with cardiovascular, respiratory disease, and hypertension [11,12]. There are also single reports of IVT presenting as spontaneous hyphemas in patients with congenital heart disease, congenital hemangiomatosis, and hereditary hemorrhagic telangiectasia, respectively [6,13,33]. Clinicians should also be aware of possible ocular associations. Interestingly, these lesions have presented as hyphemas in the context of acute branch retinal vein occlusion, idiopathic juxtafoveolar retinal telangiectasis, and acute glaucoma [9,14,15]. The authors would recommend considering the possibility of the aforementioned systemic and ocular associations when assessing patients with spontaneous hyphemas and/or IVT.
IFA is helpful to investigate the full extent of these lesions. They are commonly found to be bilateral, more numerous, and demonstrate early hyperfluorescence with late staining [22]. IFA can be combined with serial examinations to exclude iris melanoma. The authors would recommend considering differential diagnoses such as rubeosis, iris neovascularization, iris hemangiomas, HHT, and inflamed iris vessels [6,10,25,33]. However, there is a weak level of evidence surrounding differential diagnosis for IVT.
Prior to treatment, it is commonly reported that IFA is performed [6]. The majority of spontaneous hyphemas secondary to Cobb's tufts can be treated conservatively. Conservative modalities include bed rest and topical therapy including IOP-reducing drugs such as beta-blockers, steroids, and mydriatics/cycloplegics [2,15,26,29,30]. Literature has shown the successful use of ALP in active bleeding, single episodes of bleeding, and recurrent hyphemas [6,8,14,18,20,21,24,27,31,[34][35][36]. The indication for laser treatment in single episodes of bleeding remains unclear due to the very good outcomes of conservative management. Therefore, we would recommend that ALP is reserved for cases of hyphema recurrence or failure of medical therapy.
The benefit of ALP prior to intraocular surgery is unknown. There have been two studies of ALP prior to cataract surgery, one of which resulted in minimal bleeding intra-operatively [18,35]. On the other hand, Goetz and Cosgrave (2016) reported a case of cataract surgery in a patient with IVT and reported no complications or bleeding [37]. Iridectomy can be considered in patients who are still symptomatic despite ALP or if there is suspicion of malignancy.
Dharmasena and Wallis provided us with the last literature review on this topic in 2013, there have been 10 new articles reporting 26 new cases of IVT. One issue is the majority of these studies are case reports and consist of a very small sample size (one to four). Some studies also add further evidence of known knowledge regarding Cobb's tufts but lack any new breakthroughs [12,21,25,26,39]. These articles reiterate that conservative management is recommended initially, the importance of controlling IOP and blood pressure and that ALP should be reserved for recurrent hyphemas. Blanco et al. (2019) provided rare video documentation of the course of this condition. They utilized repeat digital compression of the superior eyelid as part of conservative management [19]. The authors feel this is unlikely to be of many benefits since the majority of such hyphemas settle with bed rest and time. Another study highlighted the risk of anticoagulation therapy as a predisposing factor for spontaneous hyphema and this should factor into management considerations [5].
Recent updates in literature, such as Williams et al.'s (2018) observational study of 14 patients (22 eyes), further confirm that IFA is a diagnostic modality and that ALP should be reserved for recurrence [8]. This was the second recent article to mention optical coherence tomography angiography (OCTA) as an alternative to IFA [32]. The non-invasive nature and depth-localizing strengths of this new development are appealing but require further studies before it would surpass IFA. Another recent study by Goetz and Cosgrave makes us rethink the use of ALP prior to intraocular surgery in eyes containing IVT [37]. The authors feel that further studies are required surrounding ALP prior to intraocular surgery in the context of IVT as conflicting results have been shown in the very few studies available.

Limitations
The sum of this systematic review is limited by the published literature due to the relative scarcity of the condition. Most papers are case discussions or small number case series. There has been limited research into etiology and much remains to be investigated.

Conclusions
Cobb's tufts are benign true hamartomas of the iris stromal vessels at the pupillary border. They cause no symptoms unless a hyphema develops, which most commonly presents as blurred vision. A single episode of bleeding is rare and re-bleeding is also a rare occurrence. Recent literature provides further evidence to support conservative treatment of a spontaneous hyphema in the first instance, given the reports of great resolution rates and low recurrence. Laser photocoagulation has a role in cases of hyphema recurrence despite medical therapy. A large array of settings is employed resulting in uncertainty regarding the optimal settings for laser photocoagulation. Current literature largely consists of case reports/series making for weak evidence regarding etiology, laser photocoagulation, and surgical treatment. OCTA has recently emerged as an alternative imaging modality for these lesions and demonstrates favorable initial advantages over IFA. However, larger prospective studies are needed to research this imaging modality, in addition to the optimal management strategy to use with laser photocoagulation and iridectomy for these lesions.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.