Nikolsky's sign - A clinical method to evaluate damage at epidermal-dermal junction

Abstract

Soft tissues of the oral cavity are often affected by various mucocutaneous disorders of variable etiology, affecting both the skin and mucosae, with severe clinical manifestations such as blisters involving the tissues; and therefore their appropriate management relies on their correct diagnosis. Clinical signs to elicit characteristics of blisters are a crucial part of the examination of patients with such disorders. It is therefore essential for clinicians to be familiar with, or rather be expert at eliciting these signs to frame an accurate diagnosis, since proper treatment and follow-up will depend on which disease is involved. The Nikolsky's sign is one such sign that can be helpful in the clinical diagnosis of pemphigus group of disease and differentiating it from other blistering dermatoses. This review gives an overview of sign of Nikolsky and other related sign, its clinical presentation and their diagnostic implications, using PubMed and Medline databases searching for articles written in English. Peer-reviewed articles were targeted using the keywords “Nikolsky's sign”, “mucocutaneous disorders” and “pemphigus”. Available full-text articles were read, and related articles were also scrutinized and finally the search was subsequently refined to articles concerning to “Nikolsky's sign”. It was concluded that early recognition of these signs are necessary to prevent delayed diagnosis and for early institution of appropriate treatment of these potentially serious mucosal and dermatological diseases.

Full text

© 2018 Journal of Indian Academy of Oral Medicine & Radiology | Published by Wolters Kluwer - Medknow
68
Review Article
IntroductIon
Theautoimmunemucocutaneousdisordersarethegroupof
diseases,sometimes characterized by acantholysisand in
whichcomponentsoftheepidermisandbasementmembrane
zonearetargetedresultingintheformationofmucosaland
cutaneousblisters.[1]Clinical identicationoftheseblisters
arenecessarytointerpretthepathologyaccurately.Clinical
signsare the well‑known mechanical signs evolved by
cliniciansand are considered animportant part of clinical
examinationinpatientwiththesedisorders.TheNikolsky’s
signisdenedasawell‑describedclinicalsignwhichmanifest
asdislodgementofintactsupercialepidermisbyashearing
force,indicatingaplane of cleavageintheepidermis.The
defectmaybeduetoepidermalantibodiesasinpemphigus
orstaphylococcal toxin asin staphylococcal scalded skin
syndrome.[2]Itischaracteristicallyassociatedwithpemphigus
vulgaris.[3]The presence of Nikolsky’ssign is a signicant
indicatorofactiveacantholysisandalteredstructuralintegrity
withintheepidermis,[4]whichallowsaphysiciantodetermine
thelevelofthesplitintheskinsoastodistinguishbetween
intraepidermaland subepidermal blistering diseasesin the
clinicalsettings.[5,6,7]
Literatureoftencoversclinicalobservationsandindividualcase
reportsinrelationtothesediseasesbutlittleattentionhasbeen
paidtotheimportanceandclinicalutilityofNikolsky’ssignand
otherrelatedsigninthediagnosisofthesedisorders.Thisclinical
paperisanattempttoillustratetheusefulnessofNikolsky’ssign
andotherrelatedsignsalongwiththeirdiagnosticandprognostic
signicanceintheclinicaldiagnosisofvariousmucocutaneous
blisteringdiseasesaffectingtheskinandoralcavity.
Methods
Togetup‑to‑dateinformation,aweb‑basedsearchwasinitiated
usingPubMed/Medlinedatabasesearchingforarticleswritten
Nikolsky’s Sign ‑ A Clinical Method to Evaluate Damage at
Epidermal‑Dermal Junction
Abhishek G. Soni
Department of Oral Medicine and Radiology, Modern Dental College and Research Center, Indore, Madhya Pradesh, India
Softtissuesoftheoralcavityareoftenaffectedbyvariousmucocutaneousdisordersofvariableetiology,affectingboththeskinandmucosae,
withsevereclinicalmanifestationssuchasblistersinvolvingthetissues;andthereforetheirappropriatemanagementreliesontheircorrect
diagnosis.Clinicalsignstoelicitcharacteristicsofblistersareacrucialpartoftheexaminationofpatientswithsuchdisorders.Itistherefore
essentialforclinicianstobefamiliarwith,orratherbeexpertatelicitingthesesignstoframeanaccuratediagnosis,sincepropertreatment
andfollow‑upwilldependonwhichdiseaseisinvolved.TheNikolsky’ssignisonesuchsignthatcanbehelpfulintheclinicaldiagnosisof
pemphigusgroupofdiseaseanddifferentiatingitfromotherblisteringdermatoses.ThisreviewgivesanoverviewofsignofNikolskyandother
relatedsign,itsclinicalpresentationandtheirdiagnosticimplications,usingPubMedandMedlinedatabasessearchingforarticleswrittenin
English.Peer‑reviewedarticlesweretargetedusingthekeywords“Nikolsky’ssign”,“mucocutaneousdisorders”and“pemphigus”.Available
full‑textarticleswereread,andrelatedarticleswerealsoscrutinizedandnallythesearchwassubsequentlyrenedtoarticlesconcerningto
“Nikolsky’ssign”.Itwasconcludedthatearlyrecognitionofthesesignsarenecessarytopreventdelayeddiagnosisandforearlyinstitution
ofappropriatetreatmentofthesepotentiallyseriousmucosalanddermatologicaldiseases.
Keywords:Dermis,epidermis,mucocutaneousdisorders,Nikolsky’ssign,pemphigus
Address for correspondence: Dr. Abhishek G. Soni,
Department of Oral Medicine and Radiology, Modern Dental College
and Research Center, Indore ‑ 453 112, Madhya Pradesh, India.
E‑mail: drabhishek_soni@rediffmail.com
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DOI:
10.4103/jiaomr.jiaomr_95_17
Abstract
How to cite this article:SoniAG.Nikolsky'ssign‑Aclinicalmethodto
evaluatedamageat epidermal‑dermal junction.JIndianAcadOral Med
Radiol2018;30:68‑72.
Received: 05‑10‑2017Accepted:04‑03‑2018Published:23‑04‑2018
This is an open access journal, and arcles are distributed under the terms of the Creave
Commons Aribuon-NonCommercial-ShareAlike 4.0 License, which allows others to remix,
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Soni: Nikolsky’s sign
Journal of Indian Academy of Oral Medicine & Radiology ¦ Volume 30 ¦ Issue 1 ¦ January‑March 2018 69
inEnglish. Peer‑reviewed articles were targetedusingthe
keyterms “Nikolsky’ssign”, “mucocutaneous disorders”
and“pemphigus” to determine the scope of coveragein
well‑documentedarticles.The search was subsequently
renedtoarticlesconcerningto“Nikolsky’ssign”.Thesites
ofspecialized scientic journals inthe areas of oraland
maxillofacialpathology,dermatology,and other relevant
journalswerealsoused.Thebibliographieswerealsoreviewed
toidentify additional relevant studies.Available full‑text
articleswereread,andrelatedarticleswerealsoscrutinized.
Historical Perspective
Nikolsky’ssignwasrstdescribedbyaRussiandermatologist,
Piotr Vasiliyevich Nikolsky(1858‑1940).[5]Althoughhisname
wasspelt Nikolskiy, the signis better known asNikolsky’s
sign.[8]Herelatedhow,afterrubbingtheskinofpatientswho
hadpemphigusfoliaceus,therewasablisteringordenudation
oftheepidermiswithaglistening,moistsurfaceunderneath.[9]
Accordingtohisexplanation,theskinshowedaweakrelationship
andcontactamongtheepidermallayers(betweenthecorneal
andgranular cell layers) onall surfaces and evenin places
betweenlesions(e.g.,blistersandexcoriations)onseemingly
unaffectedskin.[10]
Thecredit of the finding “Nikolsky’ssign” should also
goto his teacher ProfessorM.I. Stukovenkov [(a Russian
Dermatologist (1847-1897), at the University of Kiev)]who
pointedoutthisobservationinpemphigusfoliaceus.However,
thesignwaswelldescribedbyP.V.Nikolskiyinhisthesisand
popularlycametobeknownasNikolsky’ssign.Nikolsky’s
observationswere later conrmed byLyellin1956, who
describedaNikolsky’ssigninpatientswithtoxicepidermal
necrolysis.[9]
Pathophysiology
Thepathophysiologyassociated withNikolsky’ssignisthe
acantholysis[8]i.e.,lossofcoherencebetweenepidermalcells
duetothebreakdownoftheirintercellularbridges.[11,12,13]In
acantholysis,thecellsremainintactbutarenolongerattached
toeachother;theytendtoacquirethesmallestpossiblesurface
areaand become rounded up, resulting in intra‑epidermal
clefts,vesicles andbullae.[11]Thesigncanbeelicitedinthe
affectedareasaswellasinareaswithintact,normal‑appearing
skinandalso on the oral mucosalsurface.[8,14]However,in
theoralcavityidenticationofintactvesicleandbullareally
posedchallengetotheclinicianbecauseoffriablenatureof
oralmucosa and also due to the constantexposure of oral
mucosato the frictional irritation. Furthermore, rupture of
theselesionsleadstoerosionsorulcerationsonthemucosal
surface,hence making thediagnosis of such lesionseven
moredifficult because the lesionsoften resemble each
otherclinicallyandsometimesitisdifcult to differentiate
betweenthem.Theprimaryhistologicndinginpatientswith
pemphigusisacantholysiswiththeoccurrenceofsuprabasal
epidermal/intraepidermalsplits;[15,16]theseeventspresumably
contributeto the epidermal separation characteristic of a
positiveNikolsky’ssign.[7]Nikolsky’ssignisusuallypositive
indiseases with intraepidermal acantholysisand typically
negativeindiseaseswithdermo‑epidermalseparation,[8]thus
helpingtodistinguishpemphigusfrombullouspemphigoid.[7]
Elicitation of Nikolsky’s sign
Tilltodaythere is no absoluteconsensus available inthe
literatureonastandardmethodtoelicittheNikolsky’ssign.
However,Nikolskiyoriginallydescribedthree methods to
elicitthesign:[5,15,17]
(1) Hornylayercan be detached for a longdistance,even
onnormal‑appearingskin,by pulling a remnant of the
rupturedwalloftheblister;
(2) Hornylayercanbedislodgedonvisiblynormalskinareas
attheperipheryofexistinglesionsbylateralpressurewith
anger;and
(3) Normal‑appearingskincanbedenudedleavingthemoist
surfaceofthegranularlayerbyrubbingtheepidermis.
Althoughthe classic Nikolsky’s sign is seen on the skin,
therehave been two case reports showing itsappearance
onmucous membranes of othertissues. In one instance, a
Nikolsky’ssignwaselicitedintheesophageal mucosa ofa
patientwithpemphigus vulgaris.[18]Intheother,Nikolsky’s
signwaselicitedinthemucosaoftheuterinecervixin13of
16patientswithpemphigus.[19]However,these occurrences
areexceedinglyrare.
Conditions associated with Nikolsky’s sign
PositiveNikolsky’ssignisthe hallmark of pemphigus
vulgaris,[4]andishelpfulintheclinicaldiagnosisofpemphigus
groupof diseases.[15] Uzun andDurdu[5] in theirstudy on
123consecutive patients withvarious cutaneous diseases
presentingas intact blistersand/or erosions concluded that
Nikolsky’ssign offers a moderately sensitivebut highly
specictoolforthediagnosisofpemphigus.Otherblistering
conditions,which are known toexhibit Nikolsky’ssign
includepemphigus foliaceous, paraneoplastic pemphigus,
Stevens‑Johnsonsyndrome, staphylococcal scalded skin
syndrome(SSSS), toxic epidermalnecrolysis (TEN), oral
lichenplanus, benign mucous membrane pemphigoid,and
epidermolysisbullosa.[20,21]
Variants of Nikolsky’s sign
Clinical Nikolsky’s sign
Whenthe tangential pressure isapplied on apparently
normalskin/mucosa, or on peri‑lesionalskin/mucosa
oron affected skin/mucosa withthe thumb or ngerpad
resultis ashearingforcethat dislodgestheupperlayersof
epidermisfromthelowerepidermisresultinginformation
ofblisters, a phenomenon isknown as Nikolsky’s sign
(Clinical Nikolsky’s sign).[4,6,10,15,17,22]
Microscopic Nikolsky’s sign
MicroscopicNikolsky’ssignis the subclinical counterpart
ofNikolsky’ssign.[11]Whentangentialpressureisexertedon
apparentlynormalskin/mucosa,sameasinelicitingclinical
Nikolsky’ssign, resultin weakening of theintercellular
adhesion.Thismayproduceminimaldamageatthecellular
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Soni: Nikolsky’s sign
Journal of Indian Academy of Oral Medicine & Radiology ¦ Volume 30 ¦ Issue 1 ¦ January‑March 2018
70
levelwhichcan bedemonstratedonlymicroscopically.The
pathologicalchangesthatareinducedafterapplyingtearing
tangentialpressuretoskin/mucosaatthesubclinicallevel,is
denedasmicroscopicNikolsky’ssign.[4,11,16]
Ithasbeen proposed that microscopicNikolsky’ssign may
beabetterandmoresensitivemethodofrapiddiagnosisand
canincreasethesensitivityofthehistopathologicalstudies.[18]
HameedandKhan[16] intheirstudydemonstrated apositive
microscopicNikolsky’ssignin73.9%ofpemphiguspatients
whowerebiopsiedafterapplyingtangentialpressure.There
wereno changes in thebiopsies of healthy controls.They
suggestedthatthistechniquecouldbeofvalueinareaswhere
immunouorescenceisnotreadilyavailable.Inanotherstudy
byBarzegari M et al.,[4] they suggestedthat microscopic
Nikolsky’ssign wassignicantly higher in patientswith
generalizeddisease. Pemphigus vulgaris patients with
mucocutaneousinvolvement have both desmoglein (Dsg3)
andDsg1antibodies.[23,24]Presenceofthegeneralizeddisease
isprobablyduetomuchhigherpemphigus antibodylevels,
makingthedevelopmentofmicroscopicNikolsky’ssignmore
frequent.Thustheyconcluded that microscopic Nikolsky’s
signcan increase thesensitivity of histologic diagnosis of
pemphigusvulgaris.[4]
Marginal and Direct Nikolsky’s sign
“MarginalNikolsky’ssign”canbedescribedastheextension
ofthe erosion on thesurrounding normal‑appearing skin
byrubbing the skin surrounding existing lesions; while
“DirectNikolsky’ssign”is the induction ofan erosion on
normal‑appearingskin,distantfromthelesions.[6,11]Apositive
directNikolsky’ssignindicatessevereactivityofthedisease
inpemphigus.It istherstsign todisappearasthedisease
respondstotherapy;themarginalNikolsky’ssignmaypersist
forsometime.[25]
UzunandDurdu[5]determinetheusefulnessoftheNikolsky’s
signontheclinicaldiagnosisofpemphigusin123consecutive
patientsandfoundthatthesensitivityof“direct”Nikolsky’s
sign(38.4%)waslessthanthatofthe“marginal”form(69.2%),
butthe specicity of “direct”Nikolsky’ssign(100%)was
higherthanthatofthe“marginal”form(93.8%).Basedonthe
resultofthestudytheyconcludedthatapositiveNikolsky’s
sign,whenelicitedespeciallywith‘‘direct’’modication,is
moderatelysensitivebuthighlyspecicforclinicaldiagnosis
ofpemphigus,particularlyforpemphigusvulgaris.
Wet and Dry Nikolsky’s sign
Nikolsky’ssignis furthercharacterizedas“wet”and“dry”.
Afterapplyingpressureontheskinororalmucosalsurface,
whentheerodedbaseisfoundtobemoistandglistening,the
Nikolsky’ssignisconsideredas“wet”;while“dry”Nikolsky’s
signcan bedescribedas those,inwhichthebaseoferoded
skinororalmucosalsurfaceisdry.[7,11]
Modified Nikolsky’s sign
The“modiedNikolsky’s”signisdescribedas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.Theadvantagehereisthatthearticially
extendedblistercannot show epithelialregeneration,which
issometimesseenintheoorofoldersubepidermalblisters
makingthemappearasintraepidermal.[25,26,27]
Implications of Nikolsky’s sign
Diagnostic implication
• Nikolsky’s sign ispathognomonic of pemphigus
andcanbeusedas a preliminary test for theclinical
diagnosisofpemphigus inclinicalsettings.Although
questionshave been raised aboutits sensitivity and
specificity,[28,29]it appearsto be a highlyspecific
techniqueintheoralsetting(96.3%)andmaybevery
usefulinthe fundamentaldiagnosisoforalblistering
diseases.[30]Although the Nikolsky’ssign is highly
specic,it only offers moderate sensitivityfor the
diagnosisofpemphigusvulgaris[5]
• Nikolsky’ssignisalsousefulindifferentiating various
blisteringdiseases.Itisusuallypositiveinintraepidermal
blisteringdiseasewhileinsubepidermalblisteringdisease
suchasbullouspemphigoid,thesignisusuallyabsent.[7]
Prognostic implication
• Nikolsky’ssignmayalsobeconsideredasasuggestive
signfor the prognosis ofpemphigus by indicating
activediseaseorclinicalexacerbation.[5]TheNikolsky’s
signis positive in the active or progressivestage of
pemphigus.It becomes negative when patientreceives
immunosuppressivetherapyanditindicatestheendof
acutestagedisease.However,itsreappearanceduringthe
courseoftreatmentsignalsaareup.Suchapatientwould
requireanincreaseinthedosageofimmunosuppressant
ortheintroductionofnewdrugs[25]
• Inpatientswith active pemphigus vulgaris,a wet
signis expected, whereasthe dry sign indicates
re‑epithelializationbeneath a pemphigus blisterwhich
wouldsignifyinghealingandthusafavorablending.[21]
Nikolsky’s phenomenon
Theterm “Nikolsky’sphenomenon” is applied whenthe
superciallayer of the epidermisis felt tomove over the
deeperlayer,andinsteadofimmediatelyformingerosionas
inNikolsky’ssign,ablisterdevelopsaftersometime.[25]
Mauserung phenomenon
TheNikolsky’ssignmayalsobeelicitableintherareichthyosis
bullosaof Siemens, where itis termed the “Mauserung
phenomenon”.[31]
False Nikolsky’s sign
FalseNikolsky’ssign,alsoknown as Sheklakov’s sign, is
describedaspullingtheperipheralremnantroofofaruptured
blister,therebyextendingthe erosion on thesurrounding
normalskin.Theerosionsthusinducedarelimitedinsize,lack
thetendencytoextendspontaneously,andhealrapidly.[11,25]Itis
calledthe“falseNikolsky’ssign”becauseitisasubepidermal
cleavageoccurringintheperilesionalskin.[6]
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Journal of Indian Academy of Oral Medicine & Radiology ¦ Volume 30 ¦ Issue 1 ¦ January‑March 2018 71
FalseNikolsky’ssignispositiveinsub‑epidermalblistering
disordersthat includes bullous pemphigoid, cicatricial
pemphigoid,pemphigoidgestationis,dermatitisherpetiformis,
linearimmunoglobulinA(IgA) bullous dermatosis,
epidermolysisbullosa acquisita, junctional and dystrophic
epidermolysisbullosa,porphyriasandbulloussystemiclupus
erythematosus(SLE).[25]
Pseudo Nikolsky’s sign
PseudoNikolsky’ssignor epidermal peeling signcan be
elicitedinthesamewayasfortrueNikolsky’ssign,butthis
couldbeelicitedonlyintheinvolvederythematousareas.Here,
theunderlyingmechanismisnecrosisofepidermalcellsin
contrasttoacantholysisintrueNikolsky’ssign.[11,14,25]
PseudoNikolsky’ssignis positive in Stevens‑Johnson
syndrome,toxicepidermalnecrolysis,insomecasesofburns
andbullousichthyosiformerythroderma.[25]
Other related signs
Bulla spread sign
The“bullaspreadsign”,alsoknownasLutzsign,[14,25]refers
totheextensionofablistertoadjacentunblisteredskinwhen
pressureisputonthetopofthebulla.[32]
Inthetraditional“bullaspread”sign,themarginofanintact
bullaisrstmarkedbyapen.Slowandcarefulunidirectional
pressureapplied by a nger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.The
signmay also be elicited on a burstblister if an adequate
portionoftheroofisintact.[14,25]
Thebullaspreadsignispositiveinallvarietiesofblistering
diseaseslike the pemphigusgroupof diseases and many
casesofsubepidermalblisters,includingbullouspemphigoid,
dermatitisherpetiformis, epidermolysis bullosaacquisita,
cicatricialpemphigoid, dystrophic epidermolysis bullosa,
bullousdrugeruptions,Stevens‑Johnsonsyndromeandtoxic
epidermalnecrolysis.[14,25]
Asboe-Hansen sign
TheAsboe‑Hansensign,namedbyaDanishphysician,Gustav
Asboe‑Hansen(1917‑1989),[14,33]isconsideredasavariationof
thebullaspreadsign.However,itappliestosmaller,intact,tense
bullaewherethepressureisappliedtothecentreoftheblister.[34]
BothAsboe Hansen and Nikolsky’s sign have been
demonstratedinacutebullouslichenplanus.[35]Duetofragility
oftheroofoftheblisterAsboeHansensignisusuallynegative
inHailey‑Hailey disease andstaphylococcal scalded skin
syndrome.[25]
conclusIon
Despitethenumerousinvestigationmethodsthatareusedinthe
diagnosisofautoimmuneblisteringdiseases,Nikolsky’ssign,
ifperformedcorrectlyandinterpretedproperly,canstillserve
asausefulandrapiddiagnostictooltoassistinpreliminary
chairsidediagnosisofthepemphigusgroupofdiseaseandalso
differentiatingitfromotherblisteringdiseases.Also,inthose
areaswherefacilitiesforimmunouorescencearelimitedand
appropriatelesionsforobtainingmeaningfulresultsbyroutine
histopathologyarenotreadilyavailable,theseclinicalsigns
couldbeusedasanadjunctivediagnosticmeasure.Insummary,
itappearsreasonabletoconcludethateveryclinicianshould
beawareabout theseclinicalsignswhichare imperativein
earlydiagnosisandprompttreatmentofthesepotentiallyfatal
mucocutaneousdiseasesinclinicalsettings.Althoughthelack
ofstandardizationregardinghowexactlytoelicitthesignhas
limitedits usefulness, but it remains an interestingsign to
observeandinterpret.
Financial support and sponsorship
Nil.
Conflicts of interest
Therearenoconictsofinterest.
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Journal of Indian Academy of Oral Medicine & Radiology ¦ Volume 30 ¦ Issue 1 ¦ January‑March 2018
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