Pathophysiology

Pruritus is a specific cutaneous sensation that is quite distinct from the other cutaneous sensations of heat, cold, touch and pain. Pruritus and pain are closely related sensations and both are thought to arise in the extensive network of undifferentiated nerve endings located at the dermo-epidermal junction. The impulses are then carried by the small nonmyelinated slow conducting C fibres and to a lesser extent A delta fibres. Whilst not conclusively proven, it would appear that separate nerves carry pruritus and pain sensations centrally where the signals may be modified.

Multiple chemical mediators have been considered potential initiators of pruritus and include: histamine, peptides, neuropeptides (including proteinases, endopeptidases, bradykinin, Substance P, calcitonin gene related peptide (CGRP), vasoactive intestinal peptide (VIP), proteases (including trypsin, chymotrypsin, fibrinolysin), prostaglandins (PGE₁), leukotrienes (esp. LTB₄) and opioid peptides. Proteolytic enzymes are currently thought to be the most important mediators, although the importance of the role of leukotrienes seems to increasing. Many of these mediators and others may also be found from exogenous sources such as bacteria, yeast, fungi, parasites and venom. No one single mediator is responsible for the initiation of the sensation and it is most likely that the additive effect of multiple mediators summate to produce pruritus. This is highlighted by the fact that no single blocking agent is consistently effective in the elimination of pruritus in any mammalian species yet studied.

Modulation of Pruritus

'Gate theory' has been proposed to explain how central factors may modulate the sensation of itch, which may occur at or above the level of the spinal cord. Stress, anxiety, boredom, pain, touch and temperature may all affect it. For example, in humans the itch threshold may be reduced at night when other sensory inputs are reduced. Whilst anecdotal, clients often comment that their pets seem to be worse at night when the household has settled for the night and on the reverse side, few patients itch in the consult room, when a host of new stimuli bombard the animal. Maybe this represents a similar phenomenon in animals?

Environmental factors may increase skin sensitivity such that the response to a specific stimulus is increased. For example, low humidity leads to drying of the skin, high humidity leads to sweat retention both then resulting in high body temperature and vasodilation.

'Threshold phenomenon' proposes that a certain pruritic load may be tolerated without causing any clinical signs. A small increase in the stimuli, however, may push the individual over the threshold, leading to the development of clinical signs. While some factors initiate pruritus, others may simply lower this threshold. Connected with this is the 'Summation effect,' whereby pruritic stimuli from different mediators or coexistent skin diseases may add together to produce moderate to severe pruritus, where any individual factor would only produce mild or no effect at all.

Clinical Aspects

Clinical Manifestations

Pruritus is a sensation and is synonymous with itch. Animals generally display the sensation of itch clinically by scratching. However, it may also be manifested by licking, sucking, biting, chewing, rubbing, or rolling. All just mean that the individual is itchy and has chosen one or a combination of the previous to relieve this itch. It is important to list all of the manifestations to the client when trying to determine the history, severity and distribution of irritation, as frequently the client may not associate some of these (particularly licking) as a symptom of itch.

Pruritus may be seen with a variety of diseases and pathologic changes. It may be caused by primary diseases, but may also be affected by modulating and/or amplifying factors. The relative importance of all of these must be sorted out in each individual if successful management is to be achieved. Unfortunately, it doesn't always play by the rules. Sometimes it may be present associated with traditionally nonpruritic diseases and other times absent in disease where it is usually present!

Causative factors of pruritus

Successful management involves determination of the following:

1.  What is the specific diagnosis or diagnoses?

2.  Are modulating or amplifying factors present (which may either increase pruritic load or lower pruritic threshold)?

3.  What will the diagnostic and management plan involve?

4.  Are the clients aware of the investigative and treatment plan? Are they compliant?

Client education and compliance are critical if these animals are to be managed successfully long term, and should be the most time-consuming portion of the initial consult or second only after the history. Remember, pruritus is a symptom, not a disease, and the most successful treatment involves identifying and treating the cause.

Investigation

History and clinical signs are used to determine the differential diagnosis. The goal is to establish a chronology of the disease progression. At what age did it begin, what were the clinical signs initially versus now? Have they changed, is it getting worse?

Is it seasonal or non-seasonal - food adverse reactions may mimic atopy, but is generally nonseasonal. Atopy, insect bite hypersensitivity are more frequently seasonal.

Response to therapy? This will often give clues as to amplifying or modulating factors. For example, failure of antibiotics or steroids, when they were previously effective, may signal Malassezia infection. Failure of steroids may indicate pyoderma, bacterial overgrowth or Malassezia.

Recurrent otitis may indicate either atopy or food allergy. In fact, up to 30% of atopic or food allergic animals may present with otitis as the initial and sometimes only clinical sign.

Clinical Examination

Rule out the obvious: are ectoparasites present? Fleas, lice, ticks? Treatment and elimination will allow determination of their significance.

Pruritus and Lesions Present (Diagram 1)

Diagram 1

Alopecia, scaling and hyperpigmentation may indicate Demodex and scaling, crusting and papules (particularly on the pinnal margin, periocularly, elbows or ventrally) may indicate scabies. Scabies also generally causes severe pruritus, such that the animal will scratch madly during the consult. It is one of the few diseases where the animals will continue to scratch in this fashion in the consult room. Cheyletiella is a pruritic disease that causes scaling which may be severe particularly along the dorsum. It is also described as 'walking dandruff' because in severe infestation, the specks in the coat (the mites) may be seen to move.

Skin scrapes need to be collected to rule out these parasites. If Demodex is suspected, deep scrapes in a number of areas, until there is capillary oozing, is necessary. Scabies requires a much more extensive, superficial scrape including as much crusted area as possible to identify the mites. Despite this, the yield rate for scabies on skin scrapes has been reported as low as 20–40%. So if scabies is suspected, trial therapy with ivermectin, milbemycin or topicals may be necessary. Cheyletiella requires collection of the scale using tape preparations, combing and scraping. A technique to concentrate the mites and increase the chance of identification has been described. This involves collecting the scale material digesting it in potassium hydroxide (KOH) and suspending the resultant material in faecal floatation medium. The yield rate despite this may only be up to 65%. Therefore, if Cheyletiella is suspected, trial therapy (ivermectin, topicals) should be used if the skin scrape is negative. If in doubt, skin scrape - there is no lesion that "couldn't possibly be mites" or "just doesn't look like mites."

Are other lesions present (e.g., erythema, lichenification, hyperpigmentation, greasiness, scaling, crusting, papules, pustules, epidermal collarettes, annular areas of hyper or hypopigmentation, 'footprint' lesions). 'Moth-eaten' alopecia more commonly suggests bacterial involvement. Lichenification, hyperpigmentation, erythematous plaques, yellow greasy crusts, waxy follicular casts (particularly in the fold regions) and scaly mild paronychia may all suggest Malassezia.

Cytology is critical. I don't think it is much of an overstatement to say that it should be performed in areas of irritation on every animal regardless of the presence of lesions. Cytology must also be collected from several sites, as the infection present may be quite regional in its distribution.

If abnormal numbers of organisms are identified, trial treatment is necessary to determine to what extent (if any) the infections are contributing to (amplifying) the itch. A clear distinction must be made to the client between resolution of the lesions and resolution of the itch. For example, it may be that treatment with antibiotics will lead to resolution of lesions but no or minimal change in pruritus in one animal, yet lead to both a resolution of lesions and near complete resolution of pruritus in another - despite the fact that clinically and cytologically the two animals were similar.

Oral or topical medications, or a combination of both, may be used in eliminating the organisms identified on cytology.

Once the infection has been eliminated, the animal is reassessed for its remaining level of pruritus.

1. Lesions Resolve, Pruritus Remains

Any reduction in pruritus allows a determination of the contribution of the infection. The differentials thus are narrowed to insect bite hypersensitivity, food adverse reaction and atopy. Insect bite hypersensitivity is diagnosed on the basis of appropriate clinical signs along with a positive response to an insect elimination trial.

The 4 products I use for an insect elimination trial are: 1. Comfortis (Spinosad) at 0, 2 and 4 weeks (dogs only); 2. Frontline (fipronyl) spray applied at 0, 2 weeks and 4 weeks; 3. Capstar (nitenpyram) daily (dogs) or every second day (cats) for 4 weeks; 4. Permoxin (permethrin) applied daily (to saturation) for 3–4 weeks (NB dogs only). Response to the trial is made at a 4-week recheck.

A food elimination trial involves the feeding of a novel (i.e., not fed before) protein in combination with carbohydrate - usually potato. I do not use pasta, as wheat is a component of many commercial products, or rice, as it is commonly fed. In addition, the diet is supplemented with a balanced calcium source, safflower oil (to increase the energy density) and a multivitamin and thiamine. This should be fed for at least 6 weeks. If there is an improvement at this time the diagnosis is made by relapse on re-challenge with the old diet. A smorgasbord of all of the old diet is fed for 7–10 days. If the animal is sensitive to anything in the diet it will react within this time, most in the first 3 days. If a flare in itch is seen, a sequential rechallenge is performed to determine precisely what component of the diet the animal is sensitive to. It must be stressed that improvement on a food elimination diet is not a diagnosis of food adverse reaction, unless there is a flare on rechallenge.

If there is no response to the food elimination trial or insect elimination trial, and the animal has clinical signs consistent with atopy, a diagnosis of atopy can be made. There is some debate on the criteria required for the definitive diagnosis of atopy. The requirement for historical and clinical features is agreed but the importance of intradermal or serological tests to detect antigen specific IgE is disputed. The criteria put forward by Willemse in 1986 does not require a positive skin test or blood test before a diagnosis of atopy can be made. This system requires that 3 major and 3 minor clinical signs be present for a diagnosis.

Griffin (1998) suggests a diagnosis may be made on the basis of appropriate historical and clinical findings, elimination of all other differentials, and a positive intradermal test to at least one aeroallergen.

Favrot (2010) proposed the following criteria should be used to establish the diagnosis:

1.  Onset of signs < 3 years of age

2.  Dog living mostly indoors

3.  Glucocorticoid-responsive pruritus

4.  Pruritus sine materia at onset (i.e., alesional pruritus)

5.  Affected front feet

6.  Affect ear pinnae

7.  Non-affected ear margins

8.  Non-affected dorsolumbar area

A combination of 5 criteria has a sensitivity of 85% and specificity of 79%, although completing a previous elimination process would increase this.

If a diagnosis of atopy is made, the long-term treatment needs to be discussed with the client. If they wish to pursue desensitising vaccine, then intradermal skin testing or, if that is not available, in vitro testing (using a test that detects individual antigen sensitivity) is the next step. If they do not want to use vaccine, there is little to be gained with either of these tests, as one cannot use the test to determine what antigens to eliminate from the environment to control the animal's symptoms.

2. Lesions Resolve and Itch Resolves

The reason that the animal developed secondary infections needs to be identified. In older dogs, endocrinopathies, most commonly hypothyroidism or hyperadrenocorticism, are responsible and need to be investigated with appropriate tests. In younger dogs (or old dogs with a longstanding history dating from a younger animal), atopy may present as chronic or chronic relapsing pyoderma. In some breeds, e.g., the British Bulldog, atopy is not generally pruritic, but presents as erythema in classic areas (e.g., intradigital, axiallae, groin, face, pinnae).

Pruritus Present, No Lesions Present (Diagram 2)

Diagram 2

The differential list includes Sarcoptes 'incognito,' atopy, food adverse reaction, insect bite hypersensitivity, intestinal parasite hypersensitivity, contact hypersensitivity, contact irritant reaction, and neoplasia. Investigation involves trial therapy and elimination trials as previously described. Particularly in older dogs, investigation for neoplasia should be done.

A biopsy may allow the identification of contact reactions, neoplasia, and vasculitis and a nonspecific reaction pattern suggestive of hypersensitivity.

Once a diagnosis has been made and the importance of both modulating factors and amplifying factors has been determined, a treatment plan can be formulated and implemented.

References

1.  Bernhard JD. Clinical aspects of pruritus. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al., eds. Dermatology in General Medicine. 4th ed. New York: McGraw Hill; 1993.

2.  Favrot C, et al. Vet Dermatol. 2010;21:23–30.

3.  Griffin CE. Diagnosis and management of pruritus in the dog. In: 14th Proceedings of the AAVD/ACVD meeting. San Antonio, TX; 1998:5–10.

4.  Ihrke PJ. Pruritus. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 4th ed. Philadelphia, PA: WB Saunders; 1995:214–218.

5.  Shanley KJ. Pathophysiology of pruritus. Vet Clin North Am. 1988;18:971.