Demodex Mites and Elastotic Degeneration

[Mistica]

Originally Posted by Michael_V

OMG, that just gave me the heebie-jeebies!

Yes, and they are all armed to explode!

[Mistica]

Originally Posted by Wistar

I started D3 at 10,000 iu/d at beginning of October. Right at the time I stopped using the acaricides. It could be the D3 is helping keep me clear. Not sure how I can know if D3 is working or not.

On the first day, after taking the D3, I had a hot head, like a fever that lasted about 6 hours with intense tingling in my cheeks and ears. My forehead was really hot. After the second dose of D3, it came back but less intense. It certainly felt like something was happening.

I am still taking the D3 everyday at the same dose. I don't get the hot head effect any more. Something is definitely working as no relapse for 4 weeks is a new record for me.

Hi Wistar,

Yes, it sounds like something is happening. Remember, it takes months to increase your 25(OH)D levels. I would continue to supplement even if you do get another outbreak, as eventually they should stop.

I seem to get two types of outbreaks. Topical ivermectin worked on one type. I still have some of the solution in the fridge and if my current random outbreaks shown a definite trend, I might do another course.


Good luck!

[Wistar]

Originally Posted by Michael_V

... and now I'm motivated for another round of acaricidals!

I just ordered some Origins Youthtopia Skin Firming Lotion that contains benzyl benzoate (and some other interesting ingredients), although I'm not sure in what concentration.

Wistar, where does one obtain benzyl benzoate 25% lotion?

I bought the Benzyl Benzoate from an online pharmacy in the UK. Like this one here that sells it. It comes in a big 500ml (heavy) glass bottle.

This paper has a review of BB. It is written by the same author, Dr Forton, as the link Mistica posted earlier. Full version below:

Br J Dermatol. 1998 Mar;138(3):461-6.
Demodex folliculorum and topical treatment: acaricidal action evaluated by standardized skin surface biopsy.

Forton F, Seys B, Marchal JL, Song AM.

Clinic of Dermatology, Saint Pierre University Hospital, Université Libre de Bruxelles, Belgium.

A standardized skin surface biopsy was performed in 34 patients suffering from skin diseases with high Demodex folliculorum density (Dd) > 5 D/cm2 before, during and after topical treatment. The patients were randomized into six comparable groups to study six topical treatments: metronidazole 2%, permethrin 1%, sublimed sulphur 10%, lindane 1%, crotamiton 10% and benzyl benzoate (BB) 10%. Their acaricidal activity was measured according to three criteria: (i) for each treatment, decrease of Dd to under the normal threshold (<= 5 D/cm2); (ii) for each treatment, a significant decrease in Dd; and (iii) comparison of the relative difference in Dd between treatments. These three criteria converged to establish the acaricidal activity of BB on D. folliculorum; the efficacy of crotamiton was demonstrated by the second criterion. An important irritating effect was observed with BB and sulphur.

Demodex folliculorum is a 0.3 mm long transparent mite which asymptomatically parasitizes the human pilosebaceous follicles. The prevalence of the mite is 100%. It is considered to play a pathogenic role when, rarely, it penetrates the dermis, and when, much more frequently, it multiplies: its density (Dd), measured by standardized skin surface biopsy (SSSB), is therefore abnormally high (> 5 D/cm2).

In 1961, Spickett succeeded in culturing D. folliculorum in human sebum to study its life cycle. In 1970, Norn studied the survival periods of D. folliculorum in vitro (n = 592) in contact with 45 different drugs and observed a marked killing effect of several substances on the mite. However, mass culture in vitro has not yet been performed successfully.

We therefore found it useful to evaluate on D. folliculorum in vivo the acaricidal efficacy treatments (in their own form and application regimen) which produced, upon topical application, either clinical results in rosacea (metronidazole) or a sporadic acaricidal efficacy (permethrin, sulphur compound, lindane, crotamiton, and benzyl benzoate (BB)).

The aim of the present study was to select direct acaricide treatments which were most likely to be subjected to a clinical trial.

Patients and methods Go to: Sampling method: standardized skin surface biopsy

Skin surface biopsy is a non-invasive sampling method by which it is possible to collect the superficial part of the horny layer and of the follicle content. It consists of placing a drop of cyanoacrylic adhesive (Loctite®) on a microscope slide, applying the adhesive-bearing surface of the slide to the skin, and removing it gently after it has been allowed to dry (about 1 min). Initially, a standard surface area of 1 cm2 had been drawn on the other side of the slide with a waterproof marker, traced after putting the slide down on a sheet of standard square paper. The area of 1 cm2 was divided into four equal squares in order to make counting of parasites easier. After removal from the skin, each sample was clarified with two to three drops of immersion oil, and then covered with a coverslip. The samples were studied microscopically at standard magnifications (× 40, ×100). A maximum of 4 h elapsed between the time of sampling and the examination of specimens.

The site used for SSSB was the clinically affected zone. During successive clinical examinations for the same patient the site was always the same. However, samples from the same patient were taken in a rotation in order to avoid sampling at exactly the same place. The sampling sites were the cheek (n = 27), the forehead (n = 3), the nasolabial folds (n = 2) and the chin (n = 2). The clinical and microscopic examinations were performed by the same investigator.

Topical treatments tested

The treatments were metronidazole 2% twice daily, permethrin 1% for 10 min once every 2 days, sublimed sulphur 10% (mixed with violet essence in order to mask its smell) once every 2 days, lindane 1% once every 2 days, crotamiton 10% once daily, and BB 10% twice daily. All were mixed into Carbomerum gel (Pannoc Chemie S.A., Lammerdries, Belgium), except for permethrin which was used as a specialty (Nix® rinse cream, Warner-Lambert S.C.A., Excelsiorlaan, Belgium). Carbomerum gel is composed of carbomer-lauromacrogol-propyleneglycol-neutrol TE-aqua conservans.

The attribution of the acaricide was made by randomization in groups of three patients. The tubes of cream were prepared by Pannoc (except for Nix®) and were provided to the patients without masking the composition of the product. One tube of Ictyane® moisturizing cream (Ducray-Pierre Fabre Benelux S.A., Bruxelles, Belgium) was also provided to each patient; this cream was to be used as required in the case of skin drying or skin irritation. The topical substances were applied for 45 days except for lindane, for which, owing to its potential risks of intoxication, we had to stop treatment at day 15, whatever the result.

Patients

All patients in the study gave their informed consent. They had been recruited between January 1995 and March 1996. Any patient presenting a skin condition likely to be correlated with an abnormally high density of D. folliculorum (see below) was asked to participate in the study. The inclusion criterion was Dd > 5 D/cm2. The exclusion criteria were: Dd <= 5 D/cm2, skin which was too irritated, pregnant women, children, topical medicinal substance applied during the previous month or during the study, oral treatment (antibiotic, isotretinoin, metronidazole) or other factor (inhalation, peeling) likely to interfere with Dd. Among the 50 patients recruited for the study, 16 (32%) were excluded. The reasons for exclusion were: important skin irritation (n = 6), therapeutic interference (n = 5), lack of compliance (n = 4) and unforeseen hospitalization (n = 1). We initially intended to enrol six patients for each acaricide tested, but in the groups tested with BB and sulphur there were only five patients. These topical substances proved to be so irritating that we gave up in the course of the study and failed to complete our series for ethical reasons.

The conditions of the 34 participating patients were as follows: 14 had pityriasis folliculorum Demodex (PFD), 13 had papulopustular rosacea (PPR), three had 'squamous demodicidosis' (fine white non-follicular scales, without the typical frosted appearance of PFD), two had erythematotelangiectatic rosacea, one had 'dilated follicular orifices', giving her an orange peel aspect, and one had folliculitis. Two patients with PPR, one patient with PFD and the patient with follicular dilated ostia had an associated seborrheic dermatitis.

Statistical analysis

The six groups of patients were matched at baseline (day 0) for sex, age, relevant clinical parameters and Dd. The acaricidal activity of the treatments was assessed according to three criteria at the evaluation date. This date was day 15 for lindane and day 45 for the other treatments.

Clinician's criterion An efficient treatment was a treatment able to bring down the Dd to normal values in all cases. The threshold was fixed at 5 D/cm2 because it had been observed that 98% of patients in the control group of our previous study had fewer than 5 D/cm2.3 No statistical test was performed.

A second qualitative criterion This was the proportion of cases in which Dd was reduced at the evaluation date with regard to day 0. Bonnar et al. observed that Dd remains stable over the course of time, and this was confirmed in our experience. The probabilities that a parasite density increases or decreases were thus equal: in the absence of an efficient treatment, the density would increase in half of patients, whereas it would decrease in the other half. This was the null hypothesis of the binomial test applied to each treatment. The alternative hypothesis was that if a treatment were efficient, it would reduce the Dd in more than half of the patients. Only observations of five decreases/five patients and six decreases/six patients were statistically significant, with P = 0.031 and P = 0.016, respectively.

Quantitative criterion This is the relative difference of Dd computed for each patient. It is calculated by the following formula: 100 (Dde ? Dd0)/Dd0, where Dd0 and Dde, respectively, correspond to the Dd measurements made at day 0 and at the evaluation date. The Kruskal–Wallis rank test was used for global comparison of the index distributions of the six groups. Multiple comparisons were then carried out using a corrected level of significance ? in order to identify which treatments differed from the others, as indicated by Siegel and Castellan and according to the method of Scheffé. The tests performed were unilateral for the second criterion and bilateral for the third. The global significance level ? was equal to 0.05. The analyses were performed with Epi-Info software.

Results Go to: The treated groups were comparable at day 0 for all variables, due to randomization. The mean and median Dd at day 0 were, respectively, 53 and 27 for metronidazole, 82 and 88 for permethrin, 71 and 30 for sulphur, 42 and 30 for lindane, 61 and 43 for crotamiton, 64 and 30 for BB, and 62 and 39 for the whole sample.

According to the first criterion (the clinician's), only BB was efficient: the Dd was normal (? 5 D/cm2) at day 45 in all patients treated (five of five patients). According to the second criterion, BB and crotamiton were efficient: the Dd decreased statistically significantly in more than half of the patients with BB (five of five patients; P = 0.031) and with crotamiton (six of six patients; P = 0.016) at the evaluation date. The third criterion, based on the relative difference, showed that Dd decreased by an average of 98.2% from its initial value with BB, and by 64.4% with crotamiton. It decreased to a lesser extent with permethrin (20.3%) and sulphur (6.4%). It increased with metronidazole (12.9%) and lindane (34.9%). The comparison of the six treatments revealed that one of them, at least, had an efficacy different from the others (P = 0.038). Multiple comparisons showed that only the difference between BB and lindane was statistically significant (P < 0.05).

The three criteria converged to establish the acaricidal activity of BB. The efficacy of crotamiton was demonstrated according to the second criterion. Six patients were excluded for important skin irritation, three of them in the sulphur group and three in the BB group. Other, more moderate irritations, which did not necessitate stopping treatment, were observed: three patients with sulphur, two patients with BB. One case of irritation was reported with Nix® and one case with crotamiton. Approximately one patient in two (59% at day 45) used the moisturizing cream Ictyane® that had been provided at the beginning of the treatment, irrespective of the treatment group.

Discussion Go to: The fact that D. folliculorum becomes pathogenic when it multiplies is probably linked to the amplification of its individual irritating action, which then becomes sufficient to induce a perifollicular inflammation and to be clinically observed. Several compounds have proved their efficacy in rosacea or other demodicidoses but their mode of action remains hypothetical and their efficacy against Demodex is not proved. In our study, metronidazole did not show any acaricidal activity on D. folliculorum. We observed that the mean relative difference oscillated around the initial value, combined with a large standard deviation throughout the whole study. This means that the response was not homogeneous. At day 45, a mean Dd increase of 13% was observed.

Permethrin was tested in the form of 1% rinse cream, because it was successfully used like this by Dominey et al. Although the mean of relative differences showed a Dd decrease, no acaricidal action on Demodex could be demonstrated in a statistically significant way. Perhaps the vehicle or the concentration used was not adapted to kill Demodex; therefore, it would be useful to study, for example, 5% permethrin cream in a future study.

Sublimed sulphur frequently showed an important irritant effect in the course of our study. Moreover, its acaricidal activity could not be demonstrated: the mean relative differences showed an important Dd decrease at day 15 in the group of patients treated with sulphur, but this decrease was not maintained and became non-significant at day 45. This is perhaps attributable to an unconfessed lack of compliance by the patients resulting from the irritating effect of the sulphur gel, to a chemical instability of the preparation, or to the limited number of patients that could be tested. Based on the results of previous studies, however, we think that sulphur deserves to be included in a later study, in the form of 2.5% selenium sulphide shampoo once daily or at 10% in Diprobase® cream three times per week.

Lindane (gamma benzene hexachloride) did not have any statistically significant acaricidal effect on Dd. Perhaps this is due to the fact that this substance was only tested for 15 days; however, we do not suggest testing lindane in a higher concentration or for a longer time, owing to its well-known potential toxicity to the central nervous system.

The efficacy of crotamiton on Demodex was confirmed: the Dd was normalized after 6 weeks treatment in only one of six patients, but it decreased on average by 64% in all patients (P = 0.016). The acaricidal activity of crotamiton seems to be lower than that of BB in our study: we therefore suggest that in a future study crotamiton should be applied twice daily instead of once daily.

According to the literature, BB has not often been used in demodicidosis but nevertheless, we observed an important acaricidal action of BB: Dd decreased in all cases, by an average of 98%, and became normal in all patients (five of five) at day 45. No statistical test was applied to confirm the performance of BB according to the first criterion; however, based on the results obtained for the other treatments, if the study were to be conducted on a larger number of patients, the probability that one of the other treatments tested would be able to give such a result is low. Regarding the third criterion, which is a quantitative one, only the difference in activity between BB and lindane, reaching 133%, was statistically significant (P < 0.05). However, even a difference as high as 111.1% (as observed between BB and metronidazole) could not guarantee statistical significance owing to the low number of patients. These multiple comparisons are known to be statistically insensitive in detecting differences that truly exist. We observed an important irritant action of this substance. Certain changes could therefore be made in a further study: BB might be less concentrated and applied once instead of twice daily.

The SSSB collects the superficial part of the follicle content, so the acaricidal action demonstrated in this study concerns only the mites of the superficial part of the follicle, and not the population of the entire follicle. However, an acaricidal action at the opening of the follicle would probably impair the reproduction of the mite because copulation occurs at this level. The acaricidal action that has been demonstrated in this study results from a global evaluation: it only takes the final results into account (only the disappearance of Demodex), without knowing whether the acaricidal action is direct or indirect.

Our experimental method was suited to select treatments which are most effective against Demodex: to demonstrate an important activity of a treatment on the Dd (in the case of the first two evaluation criteria), or an important difference in efficacy between the treatments considered (in the case of the third evaluation criterion). Owing to the limited number of patients, the activity of certain substances might elude the statistical tests and could appear only in larger samples.

The importance of the quantitative aspect in the pathogenic role of D. folliculorum is that it supports the usefulness of finding effective treatments against this mite in order to combine them with the current treatments for rosacea and other demodicidosis. Further studies will have to confirm if this role can be played by BB or crotamiton, whose acaricidal activity against Demodex is demonstrated in this study.

[Spav]

Wistar Thanks for sticking around and giving us the benefit of your research. I'm sure i have a demodex component to my rosacea. I actually seem to have cured my forehead and checks of pustules with ZZ cream and invermectin. However the nose and eye areas are proving to be very stubborn. So i've ordered some BB to give it a go.

[Wistar]

Another new article featuring a case of demodicosis, titled Demodicidosis (November 5, 2009). The woman in the picture doesn't seem to have any papules visible. Just red cheeks. Cleared with ivermectin.