Gisela Heyer

Recent Studies of Cutaneous Nociception in Atopic and Non-Atopic Subjects

Itching reflects a distinct quality of cutaneous nociception elicited by chemical or other stimuli to neuronal receptors at the superficial layers of the skin and muco‐cutaneous orifices. Although recent experimental studies of the conduction and perception of itch have yielded deeper insight into the physiology of this sensory quality, little is known about the neuromechanisms involved in pruritus accompanying many inflammatory skin diseases, in particular, in atopic eczema.

Effect of topical capsaicin on the cutaneous reactions and itching to histamine in atopic eczema compared to healthy skin

Abstract Capsaicin ( trans -8-methyl- N -vanillyl-6-nonenamide) is thought to produce analgesic and possibly also antipruritic effects when applied topically. Capsaicin 0.05% was applied three times daily over a 5-day period to the same infrascapular region. The effects of the pretreatment upon the pruritogenic and wheal and flare reactions to subsequent histamine iontophoresis (20 mC) were evaluated on the following day. The antipruritic effects of the pretreatment were compared with the effects of placebo pretreatment and no pretreatment. Wheal and flare areas were evaluated planimetrically. Itch or pain were rated every minute over a 24-min period. The areas of alloknesis, i.e. the induction of perifocal itch sensation by usually nonitching (e.g. mechanical) stimuli, were also evaluated. In control subjects, but not in atopic eczema (AE) patients, capsaicin pretreatment significantly reduced the flare area. Compared with control subjects, AE patients showed a lack of alloknesis or significantly smaller areas of alloknesis in pretreated and nonpretreated skin. In control subjects, capsaicin pretreatment significantly reduced itch sensations compared with nonpretreated skin, whereas in AE patients no differences were seen. Itch sensations in capsaicin-pretreated skin were significantly lower in control subjects than in AE patients. We conclude that capsaicin does effectively suppress histamine-induced itching in healthy skin but has less effect in AE. The diminished itch sensations and the absence of alloknesis in atopic individuals indicate that histamine is not the key factor in itching in AE.

Acetylcholine is an inducer of itching in patients with atopic eczema.

As previous experimental studies disproved histamine as the main mediator of eliciting pruritus in atopic eczema (AE), we examined the neurocutaneous sensations in 15 patients with AE and in 15 age‐ and sex‐matched non‐atopic controls after i.c. injection of acetylcholine (Ach, 0.5 M, 20 μl) or buffered saline. The sensory perceptions were rated by the participants of the study with regard to their quality and intensity using a visual analogue scale. Simultaneously, the vascular reactions to Ach were recorded by the examinators via laser Doppler fluxmetry as well as flare and wheal planimetry. In contrast to the approximately equal flare and wheal extensions in either group, the cutaneous sensations differed significantly. The patients complained of ‘pure’ itching that developed shortly after Ach injection, whereas the control subjects reported only burning pain. Moreover, the patients perceived their sensations significantly earlier and significantly longer than did the controls. The study provides evidence that Ach plays an important role in the pathogeny of pruritus in patients with AE. Further investigations of the neuronal mechanisms involved in this atopy‐related effect of Ach have to be performed.

Experimentally induced pruritus and cutaneous reactions with topical antihistamine and local analgesics in atopic eczema

We investigated the antipruritic effect of a 15-min application of dimethindene maleate (Fenistil gel) and other local analgesics (Optiderm, EMLA, Xylocain ointment 5%) on subsequent focal histamine stimulus (20 mC) given by iontophoresis in 12 patients suffering from acute atopic eczema (AE). The results were compared to histamine after pretreatment with the respective placebo and to non-pretreated skin. Wheal and flare areas were planimetrically evaluated. Itch or pain ratings were performed over a 24-min period using a rating scale. The examination also comprised alloknesis, i.e. induction of a perifocal itch sensation by a non-itching mechanical stimulus. None of the antihistaminic and anaesthetic agents reduced the itch intensity significantly. Three of the AE patients had a total lack of alloknesis. We conclude that these substances, when applied for 15 min, are not sufficiently effective in atopic skin suppressing histamine-induced reactions under experimental conditions. The diminished elicitation of alloknesis in these patients may be a result of central nervous system alteration.

Cutaneous reactions and sensations after intracutaneous injection of vasoactive intestinal polypeptide and acetylcholine in atopic eczema patients and healthy controls.

Abstract We analysed vasoreactions and sensations of atopic eczema (AE) patients and healthy controls after intracutaneous (i.c.) injection of vasoactive intestinal polypeptide (VIP) and acetylcholine (ACh). Blood flow was measured by laser Doppler flowmetry (LDF). Plasma extravasation and flare size were evaluated planimetrically, and sensations were recorded using visual analog scales. Three groups of subjects (controls, AE patients suffering from acute eczema and AE patients during a symptom-free period) were investigated. We administered VIP separately at concentrations of 1.5 × 10 –7 , 1.5 × 10 –6 and 1.5 × 10 –5 M and in combination with ACh (5.5 × 10 –6 M ) into the volar forearm of the subjects. Both substances led to an increase in LDF measurements and induced a wheal and flare reaction. Blood flow was elevated as a function of dose after a single VIP application in all groups. Compared with healthy controls, a significant increase in blood flow was measured after combined VIP and ACh administration in AE patients suffering from acute AE, whereas flare area and plasma extravasation were significantly reduced after single VIP and combined VIP and ACh injections, respectively. In all groups, VIP induced dose-dependent pruritus. Compared with a control stimulus (0.9% sodium chloride and ACh), combined injections of VIP and ACh had no additional effect on the magnitude of the sensation. In AE patients, the intensity was similar to that experienced by the control subjects, but the quality of sensation was different: ACh induced pain in the control subjects, pruritus in AE patients, and a mixture of pain and itching in AE patients showing no symptoms. Our results suggest that VIP- and ACh-induced skin reactions and the quality of the sensations depend on the activity of the atopic eczema. Confirming our former studies, AE patients develop a different quality of sensation after ACh administration and also after administration of VIP combined with ACh. Therefore, we suggest that ACh might be involved in the pathomechanisms of pruritus in AE.

Antipruritugener Effekt antihistaminerger und lokalanästhetischer Externa nach iontophoretischem Histaminreiz

ZusammenfassungNachdem die pathophysiologischen Mechanismen des Pruritus noch weitgehend ungeklärt sind, gestaltet sich die antipruriginöse Therapie bei juckenden Dermatosen häufig unspezifisch und somit unbefriedigend. Ziel der bei 12 Hautgesunden durchgeführten Studie war es, die antipruriginösen Effekte eines Antihistaminikums (Fenistil®-Gel) und verschiedener Lokalanästhetika (Optiderm®, EMLA®, Xylocain®-Salbe 5%) nach 15minütiger Einwirkzeit auf iontophoretische Applikation von Histamin (20 mC) zu untersuchen. Als Vergleich diente Histaminreiz ohne bzw. mit Vorbehandlung mit der jeweiligen wirkstoffreien Basissubstanz. Untersucht wurden Juckempfindung, kutane Vasoreaktionen und Alloknesis, d.h. Auslösung von Jucken durch einen normalerweise nicht pruritugenen Reiz, hier provoziert durch mechanischen Stimulus. Es zeigte sich, daß sowohl wirkstoffhaltige als auch wirkstoffreie Substanzen die Alloknesis unterdrücken, was auf verminderte Erregung kutaner Mechanorezeptoren zurückgeführt wird. Das Juckempfinden wurde durch alle wirkstoffhaltigen Substanzen und durch die polidocanolfreie Basissubstanz von Optiderm®signifikant reduziert. Dieser Effekt der Basissubstanz von Optiderm®ist sehr wahrscheinlich auf den Harnstoffgehalt zurückzuführen.SummaryNo adequate topical therapy is available for pruritus. As little is known about the local influence of antihistamines and topical anaesthetics on the pruritic effect of histamine, we studied these agents in 12 volunteers. The antipruritic effect of 15-min topical application of dimethindene maleate (Fenistil gel) and different agents (Optiderm, EMLA, Xylocaine-Salbe 5%) on subsequent focal histamine stimulus (20 mC) given by iontophoresis was evaluated. The results were compared with those of pretreatment with the corresponding placebo creams and observations on skin. Wheal and flare areas were evaluated planimetrically. Itch or pain ratings were entered on a scale every minute over a 24-min period. The examination also comprised alloknesis, i.e. elicitation of perifocal itch sensation by usually non-itch-inducing (e.g. mechanical) stimuli. Remarkably, all topically applied substances, regardless of antihistaminic or anaesthetic potential, reduced the area of alloknesis significantly. This is likely to be a result of diminished excitability of the cutaneous mechanoreceptors. Itching was significantly reduced by all active substances, including the placebo cream corresponding to Optiderm, which might be due to the presence of urea.

Flare responses of atopic eczema patients analysed with true colour images

Abstract.Objective and Design: Attenuated flare responses of atopic eczema (AE) patients to histamine are well documented, but their origin is still unknown.¶Subjects and Methods: Here we studied the development of erythema after histamine iontophoresis in 12 AE patients and 12 healthy volunteers by means of a RGB-camera for recording true colour images.¶Treatment: 10 mg cetirizine or placebo was administered orally 3 h before the experiment in a crossover design.¶Results: The flare reaction was found to develop after termination of histamine iontophoresis in two phases: a first phase lasting 1–2 min in which the flare increased by about 10 mm2/s and a second phase lasting another 10–15 min characterized by a slower growth in the range of 1 mm2/s.¶Conclusions: Flare size was diminished in AE patients, mainly due to a slower or absent growth in the second phase. Oral application of the H1-antagonist cetirizine (Zyrtec®) reduced the flare reaction in both groups of volunteers significantly, indicating that the reaction is dependent on the activation of chemosensitive nerve fibres via H1-receptors.

Abnormal cutaneous vasoreactions in atopics during and after acute eczema

In atopic eczema patients the well-known abnormal cutaneous reactivity of the blood vessels (white dermographism, delayed blanch after acetylcholine, paradoxical blanching after nicotinic acid application and diminished erythema after histamine injection) were observed during acute eczematous episodes and later in an eczema-free state in comparison with controls. In this follow-up study the use of different stimuli allowed us to demonstrate abnormal cutaneous vascular reactions in the patients depending on the severity of their atopic eczema. Severely affected patients showed persistence of the paradoxical vascular reactions even in an eczema-free cutaneous state.Zusammenfassung. Bei atopischen Ekzematikern wurden die bekannten paradoxen kutanen Gefäßreaktionen (weißer Dermographismus, delayed blanch Phänomen nach Acetylcholin-Injektion, paradoxe Abblassung nach Nikotinsäureester-Applikation und vermindertes Axon-Reflex-Erythem nach Histamin-Injektion) im Vergleich zu Hautgesunden während des akuten Krankheitsschubes und nach Abheilung beurteilt. Durch diese Längsschnittstudien konnte erstmals gezeigt werden, daß die nach Applikation verschiedener Reize beobachteten abnormen Gefäßreaktionen bei atopischen Ekzematikern in Abhängigkeit von der Schwere des Ekzems sich im erscheinungsfreien Intervall bessern oder normalisieren, bei schweren Ekzemformen aber persistieren.Abstract. In atopic eczema patients the well-known abnormal cutaneous reactivity of the blood vessels (white dermographism, delayed blanch after acetylcholine, paradoxical blanching after nicotinic acid application and diminished erythema after histamine injection) were observed during acute eczematous episodes and later in an eczema-free state in comparison with controls. In this follow-up study the use of different stimuli allowed us to demonstrate abnormal cutaneous vascular reactions in the patients depending on the severity of their atopic eczema. Severely affected patients showed persistence of the paradoxical vascular reactions even in an eczema-free cutaneous state.

Dosisabhängige pellagroide Hautreaktion durch Carbamazepin

ZusammenfassungEs wird über ein 11 Jahre altes Mädchen berichtet, welches wegen Grand-mal-Anfällen antikonvulsiv mit Carbamazepin behandelt wurde. Nach einjähriger Therapie erfolgte aufgrund Größenwachstums und Gewichtszunahme eine Dosissteigerung, woraufhin sich zunächst an den Händen, anschließend an Fußrücken, Fersen, Gesicht, Rumpf, Knieregion, Axillae und Leistenregion relativ scharf begrenzte, bräunlich-rote, makulöse Herde mit koleretteartiger Schuppung und Hyperkeratosen an Palmae bzw. Plantae entwickelten, die klinisch und histologisch an eine Pellagra erinnerten. Klinische und laborchemische Untersuchungen waren bis auf anfangs erhöhte Carbamazpin-, Nikotinsäureamid- und Vitamin-B6-Werte im Serum normwertig. Parallel zur Carbamazepindosisreduktion mit Absinken des Serumspiegels innerhalb des therapeutischen Bereichs kam es zu einem kontinuierlichen Rückgang der Hautveränderungen. Die hier beobachteten, dosisabhängigen Carbamazepin-induzierten Hautveränderungen erinnern klinisch wie histologisch an eine Pellagra und unterscheiden sich jedoch von bisher bekannten Carbamazepin-induzierten Hautreaktionen (systemischer Lupus erythematodes, Erythema multiforme, exfoliative Dermatitis, lichenoide Eruptionen etc.). Unseres Wissens wurde bisher kein pellagroides Exanthem durch Carbamazepin beschrieben.SummaryA 11-year-old girl suffering from grand mal epilepsy underwent antiepileptic therapy with carbamazepine (600 mg/daily). Two weeks after increasing the dose (900 mg/day) she suddenly developed relatively sharply limited, sunburn-like brown reddish macular lesions with central scaling and partly hyperkeratotic areas on the hands, feet, face, knees, gluteal and axillar regions. Otherwise no health disorders were found; in particular no neurological or gastrointestinal symptoms occurred. After reduction of the dosis (450 mg/day) these skin lesions faded away. With exception of elevated serum levels of carbamazepine, nicotinamide and vitamin B6, all blood tests were in normal range. Interactions of carbamazepine with the vitamin B6- nicotinamide metabolism are the reason for these previously undescribed cutaneous side effects in connection with carbamazepine therapy. The present case demonstrates a toxic, non-allergic reaction during carbamazepine treatment with pellagroid skin symptoms.