Background: Retinoblastoma is the most common intraocular tumor in the pediatric population. Its main therapeutic objectives are to avoid fatal outcomes and preserve vision as much as possible. Intra-arterial chemotherapy (IAC) improves drug delivery and reduces possible systemic adverse effects. This modality allows direct administration of chemotherapeutic agents to intraocular malignancies via the ophthalmic artery (OA), proving to be a feasible and effective method for globe salvage. Most side effects of IAC are local, including eyelash loss of the nasal portion of the eyelid. Summary: We performed a comprehensive review to analyze data regarding ciliary madarosis in patients diagnosed with retinoblastoma treated with IAC. We describe 9 studies with a total of 637 eyes with retinoblastoma that underwent IAC, of which 45 cases presented madarosis. In chemotherapy-induced alopecia, there is hair shaft thinning and breakage. On trichoscopy, the remaining end of the fractured hair will be observed as black dots. Differential diagnoses must include alopecia areata and trichotillomania. Key Messages: Ciliary madarosis secondary to IAC, although transitional, may cause discomfort in patients and family members. Physical examination, as well as a trichoscopic evaluation of the affected area, can help in reaching a prompt diagnosis and prognosis for this particular alopecia.

Worldwide, retinoblastoma is the most common intraocular malignancy in children, with a fatal outcome if left untreated. Although enucleation is the standard treatment for advanced cases, novel techniques to salvage the globe have been proposed [1]. The technique known as intra-arterial chemotherapy (IAC) consists of a direct infusion of a chemotherapeutic agent into the ostium of the ophthalmic artery (OA), allowing the delivery of high drug concentrations to the tumor, with less risk of systemic exposure and toxicity [2]. Although few dermatological adverse effects have been associated with this procedure, a characteristic medial eyelash loss pattern has been reported in a small percentage of patients treated [3]. The purpose of this comprehensive review was to analyze data regarding ciliary madarosis in patients diagnosed with retinoblastoma treated with IAC. We performed a literature search via PubMed, ScienceDirect, and Cochrane Library using the following keywords: madarosis, cilia loss, eyelash loss, lash loss, intra-arterial chemotherapy, and retinoblastoma.

A two-year-old Hispanic girl was referred to the Ocular Oncology Service for left eye (OS) leukocoria. On examination, the right eye (OD) was normal; however, OS was positive for a white intraocular tumor compatible with group E retinoblastoma. Magnetic resonance imaging revealed an intact optic nerve and the absence of brain lesions. She underwent IAC with melphalan (Alkeran®) 7.5 mg. Unfortunately, vitreous hemorrhage was evidenced in the following days, prompting management with enucleation instead. One month later, ciliary madarosis was observed and referred to the dermatology department for assessment. She presented with mild edema and inner and middle third eyelash loss in her left upper eyelid (Fig. 1). With trichoscopy (Dermlite®PRO HR), yellow black dots and upright regrowing hairs were seen (Fig. 2).

Fig. 1.

Ciliary madarosis is observed on a 2-year-old girl’s left eye after IAC administration, with melphalan. She presented mild edema with inner and middle third eyelash loss in her left upper eyelid.

Fig. 1.

Ciliary madarosis is observed on a 2-year-old girl’s left eye after IAC administration, with melphalan. She presented mild edema with inner and middle third eyelash loss in her left upper eyelid.

Close modal
Fig. 2.

Trichoscopy of the upper left eyelid shows yellow and black dots as well as upright regrowing hairs.

Fig. 2.

Trichoscopy of the upper left eyelid shows yellow and black dots as well as upright regrowing hairs.

Close modal

IAC is a supraselective procedure developed to successfully treat advanced cases of intraocular retinoblastoma [1]. The endovascular technique includes general anesthesia, usually through a femoral artery approach by the Seldinger technique. Digital subtraction angiography (DSA) is performed to define the OA and its anatomical disposition. The traditional technique includes placing a low-profile guide catheter in the internal carotid artery (ICA) and using a flow microcatheter to cannulate the ostium of the OA. Through pulsed infusion, various chemotherapy agents are administered, mainly melphalan; stability of the OA is corroborated during the procedure, and reflux of the ICA should be avoided. When safe cannulation of the OA is not possible, the SOAI system developed by Yamane et al. [2] can be used, which consists of placing a balloon distal to the origin of the OA and administering the chemotherapy agent while the ICA is temporarily occluded. Other alternative routes have been used through extra-intracranial communications from branches of the external carotid artery to the OA. Special care must be taken in using these alternative routes because of the risk of reflux into the ICA and subsequent chemotherapy administration to the cerebral arteries. Once the chemotherapy has been administered, final controls are performed to observe adequate flow in the OA and the rest of the distal cerebral arteries.

Side effects of IAC, although infrequent, include eyelid ptosis, transient palpebral redness, periocular edema, intraocular vascular events, and cataract development [1‒3]. Ciliary madarosis is an unusual finding, with few cases reported in the literature (Table 1). From the 9 studies included in this review, a total of 45 (7%) cases of madarosis were described, out of 637 eyes with retinoblastoma that underwent IAC.

Table 1.

Studies reporting madarosis after IAC

ReferenceEyes treated with IAC, nEyes with madarosis after IAC, nEvent details
Marr et al. [4] (2010) 69 Ciliary madarosis was always associated with periocular erythema 
Madarosis resolved spontaneously after 3 months 
Abramson et al. [5] (2010) 28 NA Nasal loss of lashes was transiently noted, although not a specific number of cases was described 
Gobin et al. [6] (2011) 95 12 Ciliary madarosis was a temporal side effect 
Shields et al. [7] (2011) 17 The only patient with cilia loss had also associated eyelid edema 
Did not specify madarosis location along the eyelid 
Venturi et al. [8] (2013) 41 Nasal ciliary madarosis was associated with lid edema 
Bracco et al. [9] (2013) 48 Madarosis was associated with periorbital edema 
No distinction between ciliary or supraciliary madarosis was made 
Abramson et al. [10] (2016) 112 10 Did not specify madarosis location along the eyelid 
Michaels et al. [11] (2016) 19 No distinction between ciliary or supraciliary madarosis was made 
Stacey et al. [12] (2020) 208 Transient madarosis was present only in 1 case treated with melphalan plus topotecan 
No distinction between ciliary or supraciliary madarosis was made 
Total 637 45 (7%)  
ReferenceEyes treated with IAC, nEyes with madarosis after IAC, nEvent details
Marr et al. [4] (2010) 69 Ciliary madarosis was always associated with periocular erythema 
Madarosis resolved spontaneously after 3 months 
Abramson et al. [5] (2010) 28 NA Nasal loss of lashes was transiently noted, although not a specific number of cases was described 
Gobin et al. [6] (2011) 95 12 Ciliary madarosis was a temporal side effect 
Shields et al. [7] (2011) 17 The only patient with cilia loss had also associated eyelid edema 
Did not specify madarosis location along the eyelid 
Venturi et al. [8] (2013) 41 Nasal ciliary madarosis was associated with lid edema 
Bracco et al. [9] (2013) 48 Madarosis was associated with periorbital edema 
No distinction between ciliary or supraciliary madarosis was made 
Abramson et al. [10] (2016) 112 10 Did not specify madarosis location along the eyelid 
Michaels et al. [11] (2016) 19 No distinction between ciliary or supraciliary madarosis was made 
Stacey et al. [12] (2020) 208 Transient madarosis was present only in 1 case treated with melphalan plus topotecan 
No distinction between ciliary or supraciliary madarosis was made 
Total 637 45 (7%)  

Ciliary madarosis secondary to IAC was first reported in 2010 by Marr et al. [4] in 63 patients with retinoblastoma. Of the 69 eyes treated, eight (11.6%) had associated eyelash loss of the medial third of the upper eyelid. In this study, ciliary madarosis was always associated with periocular erythema and was not seen in the other 58 eyes without this cutaneous finding. In all of the eyes treated, eyelash loss resolved spontaneously within 3 months after completion of IAC. That same year, Abramson and colleagues [5] reported, in their clinical trial of 28 eyes that underwent IAC, a transitional nasal loss of lashes. However, they did not specify the exact number of cases with this ocular complication.

In 2011, in a prospective study by Gobin et al. [6], where 95 eyes with retinoblastoma of 78 patients received IA chemotherapy, twelve (12.6%) eyes had temporary ciliary thinning or loss along the nasal upper eyelid. That same year, Shields and colleagues [7] reported eyelash loss just in one eye (5.9%) of the 17 eyes treated with IAC in their retrospective interventional series.

In Italy, Venturi et al. [8] reported the only 2 (4.9%) out of 41 eyes were treated, who had medial loss of eyelashes associated with lid edema in 2013. The Italian study by Bracco and colleagues [9] reported that 38 out of the 48 eyes were treated with IAC presented periorbital edema. Two (4.2%) out of those 38 had unspecified madarosis.

In the retrospective study by Abramson et al. [10], of the 112 eyes treated, 10 (9%) presented ciliary madarosis, without specifying location along the eyelid. Michaels et al. [11] reported a larger percentage of madarosis in 7 (36.8%) out of 19 eyes with either eyebrow or eyelash loss. Stacy et al. [12] reported transient madarosis only in 1 case (0.05%) out of the 208 eyes treated with melphalan plus topotecan.

Chemotherapy-induced alopecia occurs when the mitotic activity of the follicle is rapidly suppressed. The hair shafts become thinner locally and tend to break at the thinned points. In this case, the fracture occurs at the eyelid level. The remaining end of the fractured hair shaft appears on trichoscopy as black dots, as shown in Figure 2. The evidence of yellow dots represents empty hair follicles [13].

Alopecia areata and trichotillomania must be considered as differential diagnoses in madarosis. Trichoscopy represents a diagnostic tool ally; however, clinical diagnosis remains challenging. The presence of eyelashes broken at different lengths and black dots may indicate trichotillomania but does not exclude alopecia areata [14]. A biopsy might be required, but the history of IAC, such as in this case, may be useful to rule out these former conditions.

Permanent madarosis was not reported in the studies reviewed. It is important to consider the increasing reports of permanent chemotherapy-induced alopecia, which are mostly related to taxanes or epidermal growth factor (EGFR) inhibitors. In approximately 5% of the cases with eyebrow or eyelash loss related to systemic chemotherapy has been permanent [15]. The most common chemotherapeutic agent used in IAC to treat retinoblastoma is melphalan, alone or combined with carboplatin and/or topotecan [2]. Both melphalan and carboplatin are alkylating agents, which have a genotoxic mechanism toward cancer cells. Systemically, alkylating agents can cause diffuse non-scarring alopecia in more than 60% of the cases [16]. Topotecan is a topoisomerase inhibitor, which generates DNA breaks leading to apoptotic cell death. Diffuse alopecia has been reported with this agent when administered systemically, with a frequency of 60–100% [16]. In IAC, the hair loss is not diffuse and is limited to the eyebrow and/or eyelash portions. It seems the intra-arterial route affects more strongly the hair follicles when the chemicals are infused directly into the artery. We believe the type of chemotherapy agent, the exposure time, and the administration route impact the extension and the temporality of the alopecia.

In systemic chemotherapy, the timing of the onset of madarosis usually appears weeks or months after scalp alopecia, which usually occurs within 1–2 weeks of starting treatment [17]. As in our case, the patient developed partial ciliary madarosis in the expected time frame, a month after IAC. The onset of eyelash loss varies for other types of chemotherapy-induced alopecia due to its shorter anagen phase and longer telogen phase [15].

Ciliary madarosis appears to be a self-limited side effect that occurs in a small percentage of cases. However, the characteristic hair loss pattern along the medial portion of the upper eyelid is striking. The nasal portion of the upper eyelid is irrigated by the superior medial palpebral artery, which arises from the ophthalmic artery.

We theorize that a direct toxic insult to the matrix cells in this arterial branch may cause the characteristic hair loss pattern. Also, it would be valuable to consider the presence of periorbital edema as a predictor of madarosis since a great percentage of the studies that report eyelash loss mention an association with edema. Further studies would be optimal to determine whether the vascular anatomy or infusion techniques contribute to this finding.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the parent/legal guardian of the patient for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

No funding source was used.

Watts-Santos: investigation (equal) and writing – original draft preparation (lead). Ancona-Lezama: visualization (lead) and conceptualization (supporting). Figueroa-Sánchez: visualization (supporting), supervision (supporting), and writing – review and editing (supporting). Mares-Custodio: investigation (supporting) and writing – original draft preparation (supporting). Garza-Rodríguez: conceptualization (lead), investigation (equal), supervision (lead), and writing – review and editing (lead).

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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