How I approach... Demodicosis

Introduction 

The diagnosis and treatment of demodicosis has evolved since it was first described in 1842 1. Indeed, as recently as 1979 one publication 2 noted: “Demodectic mange, particularly in the generalized form, may be one of the most persistent of diseases and often responds poorly to treatment,” but times have changed; a recent dermatology textbook states “the prognosis for generalized demodicosis has improved dramatically since the mid-’90s…..with intense treatment, most cases, probably near 90%, can be cured, but it may take nearly a year” 3.

Over the past few years, newly identified mites and new shapes of old mites have been reported. Before you can identify the mite, however, you first need to find it; missing the mite will certainly decrease your success rate! Knowing where to look is therefore critical. Appropriate treatment recommendations and prognosis will vary with the clinical presentation, the Demodex species and the life stages identified. As in all therapies, one must consider the risks associated with treatment; some former recommendations have been found to have no effect on speed of resolution, whilst adjunctive therapies may be helpful and necessary – but some could lead to fatal drug interactions. This article therefore reviews the various presentations of demodicosis and discusses the most effective diagnostic techniques, as well as considering treatment options and potential pitfalls.

Presentation 

Localized versus generalized 

Demodicosis in both dogs and cats can present as either a localized or a generalized form. The differentiation is important, as most localized cases generally have a very favorable prognosis and will usually resolve without specific miticidal treatment. There is no universally accepted definition that clearly specifies the differences between the two, but localized demodicosis has been defined as one where there are “6 or fewer lesions that are less than 2.5 cm in diameter” 3. Generalized demodicosis can be defined as one where there are more than 12 affected areas, or a presentation where a whole body region (e.g., head and face) is affected 3. Pododemodicosis falls into the generalized category 3.

Unfortunately, this leaves a grey area between localized and generalized that requires clinical judgement (is it “multifocal localized” or generalized?) and it would be useful to have a diagnostic test that would separate the two. A recent paper looked at acute phase response in dogs with generalized versus localized demodicosis and found that the generalized form does indeed have biomarker changes which do not seem occur in the localized form 4.

The parameters tended to normalize after treatment, and it has been suggested that measurements of serum C-reactive protein and haptoglobin may help to differentiate generalized from localized cases – and indeed that they may be used in future to monitor treatment efficacy, as the return to normal reference values could indicate a good response.

Juvenile versus adult onset

Demodicosis is also defined by the age of onset; I define “juvenile onset” where the disease presents at under 12 months in small breed dogs, 18 months in large breeds and 2 years in giant breeds. Many cases diagnosed between 2-4 years of age have had ongoing problems since puppyhood and so the time of onset may be less clear. Adult onset demodicosis (i.e., no skin problems before 4 years of age) carries a poorer prognosis.

Clinical appearance 

Successful treatment is dependent on recognizing that an animal could have Demodex in the first place; this is not always easy, as affected patients may present in a variety of guises: for example;

• Papulopustular dermatitis – easily confused with bacterial skin disease (Figure 1).

• “Moth eaten” appearance of the coat (alopecic macules or patches) – especially in short-haired dogs, and easily confused with bacterial skin disease, dermatophytosis and hair follicle abnormalities.

• Erythematous dermatitis – previously known as “red mange” (Figure 2).

• Hyperpigmented patches/comedones – owners sometimes complain that the skin is “turning blue” (Figure 3).

• Scales – easily confused with a scaling dermatosis or infection (Figure 4).

• Pododemodicosis – Demodex can be particularly challenging to diagnose in these cases. 

Dogs with Demodex injai may present differently; such patients commonly present with a seborrheic dermatitis on the dorso-lumbar area (Figure 5). Dogs older than two years and Terrier breeds appear to be over-represented, although the parasite has been identified in other breeds including the Dachshund and Lhasa Apso. Excessive glucocorticoid therapy and hypothyroidism have been reported as predisposing causes, and secondary bacterial folliculitis and Malassezia dermatitis may also be present 5 6.

In the cat, localized Demodex cati is rare; signs are most often seen in the peri-ocular region, head, neck and eyelids, and the problem presents as a variably pruritic, patchy alopecia with scaling and crusting 3; it can also present as a ceruminous otitis externa. Localized lesions can self-heal, especially if an underlying cause can be identified and treated. Siamese and Burmese cats may be predisposed to the generalized form, although it is usually associated with a significant underlying disease such as diabetes, hyperadrenocorticism, FIV or FeLV 6. D. cati infestation has been identified in lesions of multi-centric squamous cell carcinoma 3 7.

Differential diagnosis includes dermatophytosis (which can occur simultaneously), bacterial pyoderma, and allergic skin disease, although in fact all causes of seborrhea and crusting in cats should be considered 6.

Demodex gatoi dermatitis is a pruritic skin disease usually seen in young, short-haired cats with alopecia or broken hairs, erythema, scaling, excoriations and crusting, particularly on the head, neck, elbows and/or flanks, the ventrum and rear limbs. Hyperpigmentation can occur, and the disease may be symmetrical 3. This form of Demodex is contagious to other cats in the home. Note this parasite seems to be regional – I have only diagnosed three cases – so the case history may be suggestive; verify if the pet has lived in a geographical region that has reported the mite (e.g., southern USA) and/or if there is a history of contagion. There may be also an association with allergic skin disease, although the reason for the link is as yet uncertain. 

Pathophysiology 

The parasite is a normal resident of the dog’s skin, as shown by PCR studies demonstrating that small populations of the mite colonize most parts of the skin of healthy dogs 8. The mites transfer to the neonate by nursing contact with the mother within the first 2-3 days of life 3; puppies removed from the bitch by cesarean section and raised away from her do not have mites The immune system of the host usually keeps mite numbers under control 9; dogs with generalized demodicosis have a genetic cell-mediated immunodeficiency associated with depressed T-cell function (actual T-cell numbers are typically normal) 3 and it is recommended that these dogs are not used in any breeding program. One paper notes that generalized juvenile demodicosis with Demodex injai has not been reported to date; it is postulated that the suspected genetic defect in the control of Demodex populations may be specific for D. canis 1.

It is assumed that the mite colonizes the skin of healthy cats too, but to date there are no PCR studies to confirm this.

Important factors in the pathogenesis include cutaneous barrier rupture, inflammation, secondary bacterial infections and a type IV hypersensitivity reaction, which may explain the alopecia, pruritus, erythema and comedone formation associated with this disease 9.

Diagnostic testing 

In humans, the prevalence of Demodex is close to 100% with a mean of 0.7 mites per cm² of facial skin, especially the chin 8. However, it seems that mites are more difficult to find in dogs and even very small numbers of mites found on scrape should be viewed as suspicious. If a single D. canis is found, this should not be considered as indicative of normality, and additional examinations are recommended before excluding demodicosis 10. Note that scrapes should always be considered before initiating corticosteroid treatment; one of the main causes of demodicosis in adult dogs is hyperadrenocorticism.

Skin scraping and trichograms (hair pluckings) are the traditional tests performed to diagnose demodicosis. Hair plucking is considered less sensitive than skin scraping when the number of mites is low (70% relative sensitivity) 11. However, one study found that there was no significant difference between skin scraping and hair plucking in the proportion of positive samples taken from 161 dogs suffering either from localized or generalized demodicosis. Squeezing the skin prior to scraping significantly improved the number of positive samples, but hair plucks should not be squeezed prior to sample collection to reduce extrusion of the follicular keratin during the procedure 12.

One diagnostic technique using acetate tape has been reported; tape is applied to the test area and the skin squeezed before lifting the tape (Figure 6). The study reported the technique allowed a significant increase in mite detection compared to deep skin scraping, both in the total number of mites and in the number of larvae and adults detected (P < 0.05) 13. No significant difference between the two methods was observed for the number of eggs or nymphs. Nevertheless, I still find that scraping and squeezing yields the greatest number of mites when compared to trichograms or the “tape and squeeze” collection technique, although tape is a great option in “hard-to-scrape” areas.

In general skin biopsy is not considered an appropriate diagnostic test to exclude demodicosis. The sample collected is generally small and the mites tend to shrink during histological preparations, making detection difficult 10. One exception may be pododemodicosis, where good scrapings are difficult to obtain (Figure 7). No matter what technique is employed, the following tips can increase the likelihood of a positive test:

Choosing the test site: 

• Take your time; look closely at the skin and choose the most appropriate sites (and choose a technique suitable for the chosen area). Good places to test include:

- red scaly areas 
- comedones/hyperpigmented regions (these can look “blue” but with magnification nearly coalescing comedones are apparent) 
- regions of follicular casts (these can also be good for hair plucks in hard-to-reach areas such as the inter-digital region)

• Cats may ingest the mites due to overgrooming, which can make identification difficult; however D. gatoi may be found at the base of neck on superficial scrapings (as the cat cannot reach this area); sometimes the parasite can be found on tape preps, or it can be worthwhile scraping another cat in the household that is less affected.

• D. cati is most commonly found around the head and neck, whilst superficial interscapular scrapings may identify D. gatoi, but do deep scrapes as well – it is possible to have dual D. cati/gatoi infections.

• Deep skin scrapings under sedation or biopsy may be needed with pododemodicosis.

When scraping: 

• Advise the owner that the lesion may look worse after sampling than before. 
• Dull the blade (e.g., by using a tongue depressor) before scraping; experience is required to get the correct degree of sharpness. 
• Squeeze the skin before and during the procedure. 
• Hold the blade at right angles to the skin; this reduces the likelihood of cutting the pet. 
• Scrape deep enough to get a significant amount of capillary bleeding and collect samples from multiple sites. 
• The sample needs to be of sufficient quantity to make the procedure worthwhile. 

When taping: 

• Use tape that will not be visible under the microscope.
• Place the tape on a suitable lesion and squeeze the skin under the tape. 
• Remove the tape and apply to a microscope slide. 

Trichogram (hair plucks) 

• Pluck in the direction of hair growth to increase the likelihood that the base of the hairs are included in the sample. 
• Do not squeeze; aim for 100 hairs per sample. 

Examining the slides 

• Smear the sample onto a microscope slide, add enough mineral oil and a cover slip to minimize oil slicks and aid visualization. 
• Lower the condenser to help look for motility and aid identification of mite skeletons. 
• Be sure to look at all fields using 10x power. 
• Look for all the different life stages and record the number of mite and life stages. This will allow comparison with future scrapings, and assist assessment of response to therapy.

Ancillary tests

Localized demodicosis 

Demodex mites (and also Cheyletiella, scabies mites and fleas) can be found on SAF* fecal exams. It may be wise to remind the lab to report external as well as internal parasites! Anecdotally a higher success rate in diagnosing D. gatoi in fecal exams compared with skin scrapings has been reported.

Close scrutiny of adult onset cases may be indicated as this presentation may be a harbinger of things to come. Factors to consider include verifying any concurrent medication (e.g., steroids, including chronic use of potent topical steroids) and hematological and biochemical profiles, including a heartworm test if indicated. Endocrine studies may be indicated (based on results and patient’s history). In all cases dietary assessment (to ensure that the pet is on a complete and balanced diet) is essential.

*SAF: Sodium acetate-acetic acid-formalin solution

Generalized demodicosis 

In juvenile onset generalized Demodex cases both good nutrition and parasite control play very important roles in recovery, and a general health assessment (including hematological and biochemical profiles and a urinalysis) is warranted to rule out congenital disease. Heartworm testing (in endemic areas) is indicated before avermectin treatment and an MDR1 screening test should be performed in breeds known to be predisposed to this genetic problem (see below).

For the adult dog with generalized demodicosis all the preceding considerations should be part of the standard workup. In addition, a detailed hunt for a possible sinister disease affecting the immune system is recommended, including thyroid evaluation, hyperadrenocorticism tests, and screening for tumors using abdominal ultrasound and thoracic radiography.

Workup in the cat for generalized demodicosis is similar, paying special attention to the possibility of steroid-induced disease. Hematological and biochemical profiles should be performed to assess for diabetes and FIV/FeLV tests are certainly indicated.

The “Players” – identifying the “cigars with legs” 

Demodex in the dog 

1. Demodex canis inhabits the hair follicle. The cigar- shaped adult measures approximately 170-225 μm and has 4 pairs of legs 5. D. canis nymphs have a shorter body but the same number of legs. Larvae only have 3 pairs of stubby legs and the eggs look like “pregnant bananas”.

2. Demodex injai is a relative newcomer (Figure 8). It can be found most commonly in the sebaceous glands, and all life stages are much longer than the equivalent D. canis stages – the adult is 330-370 μm long (approximately twice the size of D. canis) 5.

A short-bodied Demodex mite that may be more of a surface (stratum corneum) dweller, similar to D. gatoi in cats, has been described in the dog 6 and has been unofficially named Demodex cornei. It measures half the length of D. canis and is often found at the same time 14. However, recent studies have questioned the novel nature of this mite. The relationship between D. canis, D. injai, D. cornei and the human mite, D. folliculorum, has been assessed using mitochondrial rDNA 1. This study concluded that D. canis and D. injai are two different species, but that the short-bodied mite D. cornei is a morphological variant of D. canis. D. injai appeared to be closer to D. folliculorum than to D. canis.

Demodex in the cat 

1. Demodex cati is similar to D. canis – the adult mite is about 200 μm in length 6. The ova are more oval than the eggs of D. canis. 
2. Demodex gatoi is the short-bodied Demodex mite of cats (Figure 9).

Unlike the situation in the dog, D. cati and D. gatoi have been shown to be different species 15.

Treatment 

Localized demodicosis 

Systemic antiparasitic therapy is not appropriate for localized demodicosis. There is no evidence that failure to treat localized cases results in generalized ones and in fact this treatment may fail to identify the patients that become generalized. That is not to say that there are no treatments. In juvenile dogs with localized demodicosis, it is essential to ensure a “stress-free” lifestyle. Poor nutrition will certainly play a role in the pet’s immune competence, and close evaluation of the diet and proper dietary recommendations are important factors; I typically recommend balanced, high quality, commercial diets from reputable companies. Fecal evaluation and appropriate deworming is also important. Products containing benzoyl peroxide are often recommended by dermatologists as they are said to aid “follicular flushing” – although the owner should be advised that manipulation of the lesion could initially increase loss of hairs that were about to be shed. Benzoyl peroxide does dry the skin and should be followed with a moisturizer.

Generalized demodicosis 

The owner must be aware that once treatment for generalized demodicosis is commenced, the pet should be monitored by repeat scraping every 4 weeks. The life stages and numbers of parasites should be recorded to monitor progress, and advise the owners that treatment will continue for two months after a negative scrape – typically 3-7 months in total. If one form of treatment is unsuccessful, try a different one, but some patients are “control versus cure” (especially the adult onset cases).

Amitraz is licensed in many countries for the treatment of demodicosis. There is good evidence of efficacy using the drug at 250-500 ppm every 7-14 days (possibly better with shorter time intervals) 16. Long- and medium-haired dogs should be clipped before application, and treatment should only be performed in a well-ventilated area (respiratory problems have been observed in humans) by veterinary personnel wearing protective clothing; dogs should remain in the veterinary hospital until dry and should not become wet between rinses. Treated animals should not be subjected to stress for a period of at least 24 hours post-treatment 1617. Amitraz is a monoamine oxidase (MAO) inhibitor and it is important to remember the potential for drug interactions; as an α2-adrenergic agonist, side effects can be treated (pre- or post-treatment) with yohimbine or atipamezole.

Avermectins (ivermectin, doramectin) are macrocyclic lactones. They bind selectively and with high affinity to glutamate-gated chloride channels resulting in increased cell permeability and neuromuscular blocking resulting in paralysis and death of the parasite. They interact with gamma-aminobutyric acid (GABA) sites 17. GABA is a CNS neurotransmitter and these drugs are kept out of the nervous system by the P-glycoprotein pumps of the brain capillary endothelial cells (blood-brain barrier). It is important to remind the owners that using such products at the doses recommended for demodicosis is considered off-label use.

Numerous breeds have members that are homozygous mutants for the MDR1 (multi-drug resistant) gene which are very sensitive to the effects of ivermectin. Although Collies have the highest allelic frequency for the mutant, other affected breeds include the Longhaired Whippet, Shetland Sheepdog, Miniature Australian Shepherd, Silken Windhound, McNab, Australian Shepherd, Wäller, White Swiss Shepherd, Old English Sheepdog, English Shepherd, German Shepherd and Border Collie 18. Since this genetic defect has been identified in many mixed breed dogs testing could be recommended in all dogs before using an avermectin.

Remember that some other drugs (e.g., ketoconazole, erythromycin) can also tie up P-glycoprotein and increase risk of neurotoxicosis when co-administered with a macrocyclic lactone.

Ivermectin (the injectable product given orally) is the most common treatment for generalized demodicosis used in my practice. I routinely recommend a slowly increasing dosage protocol with the drug given with food. A suggested schedule is to start at a trial dose of 0.05 mg/kg daily, then increase to 0.1 mg/kg for the next week. If all is well, increase to 0.2 mg/kg the next day, and 0.3 mg/kg the following day, and finally maintain on 0.4 mg/kg daily, although some patients may require doses as high as 0.6 mg/kg. Continue treatment for two months past negative scrapings. Advise the owner to discontinue immediately if there is evidence of toxicosis (especially lethargy, ataxia, mydriasis and gastrointestinal signs); in this situation, I will usually revert to a lower dose – typically 0.3 mg/kg – on an alternate day treatment schedule (if the dog does not show adverse signs at this dose), while monitoring closely for adverse events.

Note that ivermectin has a relatively long half-life and with daily administration serum concentrations continue to increase for weeks before reaching equilibrium; adverse effects have been reported as long as 10 weeks following institution of treatment 17. Neurotoxicosis can be induced in “normal” (i.e., MDR1(-/-)) dogs after administration of ivermectin or doramectin equal to or greater than 100 μg/kg 18. Clinical signs are dose-dependent and can range from mild depression and ataxia, as well as disorientation and mydriasis within 12 hours of dosing (at 0.1-0.12 mg/kg), to more severe ataxia, stupor, recumbency, head bobbing, apparent blindness, facial twitches, hypersalivation, episodes of hyperventilation and bradycardia (at doses up to 0.17 mg/ kg). Severe neurotoxicosis signs can be seen with doses around 0.2-0.25 mg/kg or more, and include depression, ataxia and apparent blindness as early onset symptoms, as well as vomiting, paddling movements, tremor and excessive salivation, followed by stupor, feeble attempts to crawl, recumbency, and finally non-responsiveness and coma within 30-50 hours after application, often resulting in death 18.

Doramectin has been recommended with apparent efficacy for the treatment of demodicosis in MDR1 (+/+) dogs at weekly subcutaneous injections of 0.6 mg/kg 14, although the author has no personal experience with this product and further investigation has been recommended 17.

Milbemycins can be successful in treating demodicosis. Milbemycin oxime given orally (0.5-2 mg/kg q24H) is reported, with a better success rate at the higher dose 1718. I usually do not suggest “step-up” dosing of these cases but there will be the rare “sensitive” patient that develops neurological adverse effects. Moxidectin has also been evaluated for canine generalized demodicosis (0.2-0.5 mg/kg q24H PO) and again careful monitoring is recommended 19. Moxidectin is available in some countries as a 2.5% spot-on formulation (in combination with 10% imidacloprid) and can be used to treat demodicosis when applied weekly; the spot-on formulation has a markedly higher success rate in dogs with milder disease.

Lime sulfur dips (2%) used weekly for 4-6 weeks can be useful in treating feline demodicosis 6. They are very safe, and may be used as a parasiticide response trial to rule out D. gatoi in a pruritic cat; most affected cats will improve after three treatments. All in-contact cats should be treated when following this regime, and owners must be cautioned that this product can turn white cats yellow and may discolor jewelry; they should also be warned about the odor associated with treatment. A protective collar should be applied to the cat until it is dry, as many cats will vomit if allowed to groom while the product is wet.

Finally, follicular demodicosis is associated with bacterial furunculosis, and I have significantly reduced the population of Demodex using benzoyl peroxide (BPO) shampoos (followed by a conditioner) and antibiotics without antiparasitic drugs. Clipping the animal may improve contact with the shampoo. It is important to treat concurrent pyoderma/furunculosis as bacteria have been implicated in the immunosuppression of affected patients; however, the infection is considered secondary. Recent studies have shown that the use of systemic antibiotics did not change the treatment duration of dogs with generalized demodicosis when administered in addition to oral ivermectin and BPO shampoo; there was no significant difference in duration until the first negative scraping. One can presume that antibiotics can be discontinued once the pyoderma is clinically resolved 20.

In summary, one can conclude that with appropriate diagnostic skills and aggressive therapy, the success rate for this most challenging disease can be quite good. The response to treatment can be dramatic and very satisfying (Figure 10).