25 - nikolskiy sign and related signs

Clinical signs to elicit characteristics of blisters are a crucial part of the examination of patients with vesiculobullous disorders. It is therefore essential for dermatologists to be familiar with, or rather be expert at eliciting these signs, which include Nikolskiy sign, bulla spread sign, Sheklakov sign/false-Nikolskiy sign, and pseudo-Nikolskiy sign/epidermal peeling sign.

Nikolskiy sign

This sign is named after the Russian dermatologist Piotr Vasiliyevich Nikolskiy who described it in 1894¹. A positive Nikolskiy sign indicates intraepidermal cleavage and differentiates intraepidermal blisters from subepidermal blisters.² It is pathognomonic of pemphigus and staphylococcal scalded skin syndrome. The sign may also be elicitable in the rare ichthyosis bullosa of Siemens, where it is termed the `mauserung phenomenon'.³

The sign is best elicited by applying lateral pressure with the thumb or fingerpad on skin over a bony prominence. This results in a shearing force that dislodges the upper layers of epidermis from the lower epidermis.^4,5 A rubber eraser or any blunt object that grips the skin well may also be used. Nikolskiy sign can also be elicited on the intact oral mucosa with the help of a rubber eraser or a cotton-tipped swab.

Nikolskiy sign may be elicited over the normal looking skin of a pemphigus patient either close to existing lesions (marginal Nikolskiy sign) or over normal looking skin at a distant site (direct Nikolskiy sign).⁶ A positive direct Nikolskiy sign indicates severe activity of the disease in pemphigus. It is the first sign to disappear as the disease responds to therapy; the marginal Nikolskiy sign may persist for some time.

The Nikolskiy sign is positive in the active or progressive stage of pemphigus. When it becomes negative in a patient receiving immunosuppressive therapy, it indicates the end of acute stage disease. However, its reappearance during the course of treatment signals a flare up. Such a patient would require an increase in the dosage of immunosuppressants or the introduction of new drugs.

The term "Nikolskiy phenomenon" is applied when the superficial layer of the epidermis is felt to move over the deeper layer, and instead of immediately forming an erosion as in Nikolskiy's sign, a blister develops after some time. ⁶

Bullae may also be induced in pemphigus patients by application of suction. Unlike the usual suction-induced subepidermal blisters, these are due to intraepidermal acantholysis. Occasionally, cantharidin has also been used to induce blisters. Such induced blisters may be required for histological diagnosis in pemphigus patients with no blisters and a negative Nikolskiy sign.

The "modified Nikolskiy" sign⁷ is the peripheral extension of blisters on applying pressure to their surface. This is helpful in patients in whom a new vesicle or bulla is not available for biopsy.⁸ The advantage here is that the artificially extended blister cannot show epithelial regeneration, which is sometimes seen in the floor of older subepidermal blisters making them appear as intraepidermal.

Bulla spread sign

In the traditional "bulla spread" sign or Lutz sign, the margin of an intact bulla is first marked by a pen. Slow, careful and unidirectional pressure applied by a finger to the bulla causes peripheral extension of the bulla beyond the marked margin. The bulla thus extended has an irregular angulated border in pemphigus vulgaris, while a regular rounded border is observed in bullous pemphigoid or other subepidermal blistering disorders.⁶

The sign may also be elicited on a burst blister if a substantial portion of the roof is intact. The Asboe-Hansen sign is a variation of the bulla spread sign. It applies to smaller, intact, tense bullae where the pressure is applied to the centre of the blister.⁹

This sign is positive in all varieties of pemphigus and many cases of subepidermal blisters, including bullous pemphigoid, dermatitis herpetiformis, epidermolysis bullosa acquisita, cicatricial pemphigoid, dystrophic epidermolysis bullosa, Stevens-Johnson syndrome and toxic epidermal necrolysis. Due to fragility of the roof of the blister it is usually negative in Hailey-Hailey disease and staphylococcal scalded skin syndrome.

Sheklakov sign/False Nikolskiy sign

This sign is positive in subepidermal blistering disorders, like bullous pemphigoid, cicatricial pemphigoid, herpes gestationis, dermatitis herpetiformis, linear IgA bullous dermatotis, epidermolysis bullosa acquisita, junctional and dystrophic epidermolysis bullosa, porphyrias and bullous SLE.

This involves pulling the peripheral remnant of a roof of a ruptured blister, thereby extending the erosion on the surrounding normal appearing skin. It is called the "false Nikolskiy" sign because it is a subepidermal cleavage occurring in the perilesional skin.⁶ The erosions thus induced are limited in size, do not exhibit tendency to subsequent spontaneous extension and heal rapidly.

Pseudo-Nikolskiy sign/Epidermal peeling sign

This sign is positive in Stevens-Johnson syndrome, toxic epidermal necrolysis and in some cases of burns and bullous ichthyosiform erythroderma. The method and mechanism of elicitation is the same as for Nikolskiy sign. However, it can be elicited only on the involved or erythematous areas. This phenomenon has been described as Nikolskiy sign in most textbooks.^10-12 However, the underlying mechanism here is the necrosis of epidermal cells and not acantholysis as in true Nikolskiy sign.