Nomenclature

Despite the presence of numerous other descriptive names for the condition (including hole-in-the-head disease, lateral line erosion, head and lateral line erosion syndrome, chronic ulcerative dermatopathy, and chronic erosive dermatopathy), the authors of 2 reports^5,13 have proposed that LLD be adopted as an apt term for 3 reasons. First, some LLD lesions are not erosive or ulcerative but hyperplastic on histologic examination.^5,13 Second, LLD is a more accurate description of the definitive diagnostic lesion found in all affected fish.^5,13 Finally, and most importantly, LLD should be considered a clinical observation rather than a specific disease or syndrome.^5,13

Epidemiological features

Lateral line depigmentation has been reported globally in ex situ marine and freshwater fish populations in Asia,¹¹ Australia,^6,15 Europe,^7,9,10,14 and North America.^{8,12,13,20,a,b} It is frequently observed in the ornamental marine fish families Acanthuridae (surgeon-fishes, tangs, and unicornfishes) and Pomacentridae (angelfishes) as well as the tropical freshwater fish families Anabantidae (climbing gouramies), Belontidae (gouramies) and Cichlidae (cichlids, discus, and oscars).⁵ Lateral line depigmentation has also been observed in the marine and freshwater food fish families Gadidae (cods), Sparidae (sea breams and porgies), and Percichthyidae (temperate perches), particularly the Murray cod (Maccullochella peelii).^5–7 It is unclear whether the increased prevalence of LLD in these families is attributable to their overrepresentation in ex situ settings or if they have a greater inherent susceptibility than other families. To our knowledge, formal morbidity and mortality statistics for LLD have not been reported, but anecdotally, LLD has resulted in variable morbidity rates and low mortality rates.⁵ Similarly, analysis of associations between sex, life stage, or other demographic features and LLD was not documented in the reviewed reports, but anecdotally LLD affects larger, older fish.⁵

Etiopathogenesis

Despite the global prevalence of LLD, a consensus regarding a common underlying cause is lacking. Although the authors of 1 report⁸ cite an unpublished 2009 survey of 100 advanced aquarists in which > 25 potential causes for LLD in marine fish were identified, we synthesized the potential causes of LLD that were formally investigated in the reviewed reports into 4 broad categories: infectious agents, water quality, nutrition, and activated carbon.

Infectious agents—Lateral line depigmentation has historically been attributed to diplomonad flagel-late protozoa, specifically of the genus Spironucleus.⁹ Diplomonad flagellates are considered commensal intestinal protozoa of many fish species, including angelfish, discus, oscars, and African cichlids.²¹ However, a heavy intestinal burden of Spironucleus spp may lead to severe enteritis and has the potential to invade host tissues and cause systemic infection.²² A possible association between systemic infection with Spironucleus vortens and development of LLD was reported⁹ after the parasites were recovered from skin lesions of diseased fish with an infection that presumably originated from the intestinal tract, from which trophozoites were isolated. The presence of LLD has also been associated with a reovirus-like agent isolated from a liver-spleen homogenate from 1 moribund marine angelfish (Pomacanthus semicirculatus)¹⁰ as well as with Aeromonas hydrophila, which was isolated from lesions on the head of an affected oscar (Astronotus ocellatus).¹¹ Whereas multiple records with level III or V evidence suggest possible infectious causes, the preponderance of records with level I or II evidence indicate that no infectious agent contributes to LLD.^6,7,12–14 In 1 experimental study, the presence of diplomonad flagellates in the gastrointestinal tract of 4 discus fish did not result in clinical signs, lesions, or the development of LLD.¹⁴ These discrepancies in the literature imply that secondary opportunistic infections are likely to develop in fish that have LLD lesions.

Water quality—Lateral line depigmentation, particularly in marine and freshwater food fish, has been linked to poor water quality. Murray cod and sharp-snout sea bream (Diplodus puntazzo) in 2 studies^6,7 developed LLD when reared in pools of groundwater from specific sources, and the lesions spontaneously resolved when the fish were transferred pools of fresh river water or seawater, respectively. Although groundwater has multiple physicochemical properties that could contribute to the development of LLD, heavy metals have been suggested to be the most likely causative factor.⁶ Chloride salts of heavy metals, specifically copper, zinc, and cadmium, were shown to damage the epithelium of the head and lateral lines in mummichog (Fundulus heteroclitus).²³ Groundwater is often poorly buffered, resulting in high concentrations of carbon dioxide and low pH,⁷ both of which can be responsible for the development of skin lesions in fish.²⁴ Skin damage caused by mild decreases in pH may be exacerbated by greater concentrations of catecholamines in blood that are induced by hypercapnia and hyperglycemia resulting from aquaculture conditions or toxicants such as heavy metals.²⁴ Interestingly, the concentrations of copper, lead, nickel, and zinc found in the groundwater used in 1 of the aforementioned studies⁷ were within acceptable limits for aquaculture, suggesting that chronic exposure and the lower pH of groundwater may potentiate heavy metal toxicosis. In another experimental study,¹⁵ the preconditioning of groundwater in vegetated earthen ponds or in the presence of artificial macrophytes was found to substantially reduce the incidence and severity of LLD in Murray cod, compared with findings for conspecifics in similar systems that used unpreconditioned groundwater. Preconditioning is any treatment, filtration, or processing performed for water prior to its use in an aquaculture or aquarium system.

Nutrition—Inadequate nutrition, including vita-min deficiencies, has also been linked to LLD, particularly in surgeonfish and tangs. Channel catfish that had food withheld for 12 months uniformly developed LLD.¹³ In the earliest experimental study¹⁶ and most widely cited report found in our review, a group of blue tangs (Acanthurus coeruleus) fed a commercial dry flake diet developed LLD after 3 weeks, whereas a control group fed the same diet but also allowed to graze on benthic algae remained unaffected. The LLD in affected fish of the treatment group resolved when they were fed green algae supplemented with vitamin C.¹⁶ In an unpublished preliminary study cited by the authors of 1 record,^a blue tangs and ocean surgeonfish (Acanthurus bahianus), were divided into 3 treatment groups that were fed washed green algae (Ulva sp) or 1 of 2 commercially available foods (flaked or pelleted diet) marketed for marine reef fish; 27% of fish fed the flaked diet developed LLD, whereas no lesions were identified in fish fed the pelleted diet or green algae. The main nutritional difference between the 2 commercial foods was that the pelleted diet had approximately 8 times the amount of measured vita-min A (287,210 U/kg) found in the flaked diet (35,433 U/kg).^a A larger-scale follow-up study^a in which the control group was fed the aforementioned pelleted diet (control) and 3 treatment groups were fed a commercial finfish food containing modified concentrations of vitamin A (1,907.2, 50,231.1, and 133,404 U/ kg) supported the hypothesis that low dietary concentrations of vitamin A may cause captive ocean surgeonfish, particularly A bahianus, to develop LLD as early as 12 weeks after beginning the modified diet. Although some nutritional imbalances may cause or contribute to LLD, not all have been shown to induce LLD under experimental conditions. No significant differences in the proportions of fish that developed LLD were noted among groups of ocean surgeon-fish fed diets that contained various concentrations of vitamin C (ranging from 0 to ≥ 1,000 ppm) for 16 weeks,^b and an unfavorable calcium-to-phosphorus ratio (0.03) in the diet of discus fish for a similar duration did not cause LLD.¹⁴

Activated carbon—Once the carbon cycle in a system reaches steady-state, dissolved organic carbon compounds accumulate, ultimately changing the appearance of water in an aquarium from clear to a yellow tint. Activated carbon is often used to remove dissolved organic carbons, providing better water clarity. However, some aquarists have speculated that excessive use of activated carbon may result in the circulation of carbon dust or fines, which may be irritating to fish and result in LLD. Results of 1 experimental study¹⁷ revealed that filtering of aquarium water with extruded activated carbon derived from coconut shells at a full-stream rate was associated with development of LLD in ocean surgeonfish, with LLD appearing and progressing exponentially over 15 days. After the use of activated carbon was discontinued and the fish were placed in untreated water, the LLD improved and lesions resolved within 49 days.¹⁷ A similar experimental study⁸ found that ocean surgeonfish housed in systems filtered with lignite carbon developed severe LLD in ≤ 3 months, and ocean surgeonfish exposed to extruded carbon developed histologic lesions consistent with LLD but did not have gross lesions detectable after 4 months. In the previously described study^a of potential associations between dietary vitamin A content and LLD in Atlantic surgeonfish, activated carbon was added to the water systems of all treatment groups to clarify the water after 14 weeks of observation, and within 2 weeks, LLD became apparent in all blue tangs and ocean surgeonfish across all treatment groups. In a study⁷ of sharpsnout sea bream, LLD attributed to poor water quality was exacerbated by the use of activated carbon, with an increase in the size of lesions on the head and flank as well as extensive erosion of the fins. Although multiple reports^7,8,17,a indicate that activated carbon use can cause LLD, the quality of the activated carbon used and filter flow rates are likely meaningful factors, because the proportions of affected fish and severity of signs vary among investigations.

Clinical signs

Across species, the classic appearance of LLD comprises mild to severe, focal to coalescing areas of grossly depigmented skin along the lateral lines of affected fish.⁵ Gross lesions usually begin on the lateral lines of the head as shallow, pinpoint foci that can expand in size, depth, and surface area over time.⁵ Affected fish often behave normally, but many eventually become anorexic, lethargic, or both as LLD worsens.⁵ No hematologic or plasma biochemical abnormalities were found in Murray cod with LLD, even in fish that had advanced signs.^15,18 The presence of LLD may be detected in individual fish or entire schools in systems or tanks. A presumptive diagnosis of LLD can be made solely on the observance of depigmented, often pitted, symmetrical lesions associated with the head, lateral lines, or both⁵; a postmortem example is provided (Figure 2). Additional images depicting LLD in several species are available in records^5–7 included in our review.

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Representative postmortem photographs depicting gross lesions characteristic of LLD in an affected tang. Notice the focal to coalescing areas of grossly ulcerated, depigmented skin along the head and lateral line. © Shedd Aquarium. Reproduced with permission.

Citation: Journal of the American Veterinary Medical Association 259, 6; 10.2460/javma.259.6.617

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Histopathologic findings

Although the gross presentation of LLD is highly similar among species, the histopathologic features of lesions can be highly variable. We found comprehensive histopathologic descriptions of LLD in 5 species: blue tang, Murray cod, Nile tilapia, channel catfish, and sharpsnout sea bream.^6,7,12,13,16 Across these species, the lateral line system and epidermis overlying the lateral line canals were affected, and no microorganisms were found to be directly associated with the lesions. However, pathological changes of the epidermis overlying the lateral line canals varied among species. In some species, such as blue tang, channel catfish, and sharpsnout sea bream, thickness of the epidermis was often reduced to a single cell layer over the canals, and there was no inflammation present.^7,13,16 In other species, marked epithelial hyperplasia, including hyperplasia of mucous-producing cells, as well as inflammation characterized by granular cells and lymphocytes, were observed in the epithelium overlying the canals in Murray cod and Nile tilapia.^6,12

Rodlet cells are an enigmatic cell type found in teleost fish that have been implicated as having some role in the host's response to disease or the environment.¹⁹ One investigation identified a significantly higher number of rodlet cells in the gills and collecting ducts of the kidneys in LLD-affected Murray cod than in unaffected conspecifics when both groups were reared in groundwater. However, rodlet cells were present in the gills, kidneys, and intestines of Murray cod with and without LLD, suggesting that rodlet cells may more likely be a response to the poor water quality of groundwater rather than a result of LLD.¹⁹ Results of another study¹⁸ showed that, although Na+, K+-ATPase activity in the gills of Murray cod with severe LLD was significantly higher in than that in unaffected conspecifics, LLD-affected Murray cod were able to osmoregulate effectively, perhaps at an increased energetic cost. Channel catfish and blue tang with LLD were described as having reduced numbers of expanded melanocytes at the dermo-epidermal junction, with melanocytes forming aggregates of contracted cells in the epidermis.^13,16 Expanded melanocytes are responsible for the gross dark appearance of the skin of fish, and contracted melanocytes produce a blanched (depigmented) gross appearance¹³; thus, the gross depigmentation of lateral lines in affected fish may result from the loss of expanded melanocytes at the dermo-epidermal junction.

The anatomic distribution of LLD lesions (ie, the intimate association with the lateral lines) has led some authors to suggest that it might be linked to changes in the function of the lateral line system. A change in intercellular signaling from neuromast cells to epidermal cells might result in the regional thinning of skin due to a lack of nerve input, and therefore, the decreased epidermal thickness in some LLD lesions might result from atrophy rather than erosion.¹³ However, evidence of neuromast degeneration and subsequent changes in the function of the lateral line system varies across species. The condition of exposed neuromasts of LLD-affected sharpsnout sea bream were found to vary from apparently healthy to completely necrotic.⁷ No evidence of neuromast degeneration was found in Murray cod or Oranges-potted sunfish.^1,6 However, vacuolation and degeneration of superficial neuromasts were observed in LLD-affected goldfish exposed to groundwater.⁶

Treatment

In addition to supportive care that may benefit any ill fish, current evidence-based treatment of LLD in individual fish consists of source control, topical application of 0.01% becaplermin gel,^h and if warranted, antimicrobial treatment. In the context of LLD, source control consists of moving affected fish from the system or tank where lesions were first observed to a different system or tank. Moving affected fish to a different system or tank alone has been shown to be therapeutic and curative in Murray cod and sharpsnout sea bream.^6,7 The LLD-affected fish treated in the system or tank where lesions were first observed continued to develop LLD lesions despite targeted treatment.²⁰ Similarly, treating fish and returning them to the same system in which they developed LLD was shown to be of little clinical value.²⁰

The LLD lesions in multiple species of fish treated topically with 0.01% becaplermin gel were found to heal significantly more and faster than those in control fish with untreated LLD lesions or untreated LLD lesions on the contralateral side of the same fish.^20,c–e Becaplermin (recombinant human platelet-derived growth factor BB suspended in a nonsterile water-soluble gel) is a treatment approved for human use that stimulates blood vessel growth in vertebrates, ultimately assisting in the development of granulation tissue and then healthy epithelial tissue in wounds.^c It is currently cost-prohibitive for many veterinary practices; however, a single treatment of 0.01% becaplermin diluted with 0.9% sodium chloride in a 1:3 ratio applied with no minimum contact time was subjectively found to have results similar to those achieved with the full-strength product in LLD-affected fish.^20,d Applying a single treatment of becaplermin gel at the described dilution can help to reduce the cost of treatment, staff labor, and potential stress to the fish. One quasi-experimental preliminary study^e suggested that combining topical becaplermin treatment with low-level laser treatment may further improve the healing of LLD lesions, but more research is needed before this can be recommended. It is advisable to culture LLD lesions for bacteria to guide judicious antimicrobial treatment, given the risk of opportunistic infection^9,14 and an anecdotal finding that LLD-affected fish seemed to improve faster when treated with antimicrobials.⁵