Biopsia di cute. Maria Nolano

Transcript

1 Biopsia di cute Maria Nolano Palermo, Marzo 2010

2 La cute - organo più esteso del corpo - 1,5-2 m 2 di superficie con uno spessore di 0,5 fino a 3-6 mm

3 Epidermide Derma papillare Derma reticolare Ipoderma

4 Epidermide - epitelio squamoso s. s. basale pluristratificato - Cheratinociti 90% - Melanociti - C. di Langerhans - C. di Merkel s. s. spinoso s. s. granuloso s. s. corneo

5 La cute Barriera vs vs insulti: --meccanici --fisici --chimici --biologici

6 La cute -Funzione immunitaria

7 La cute -barriera ma anche interfaccia

8 La cute -Funzione sensitiva: terminazioni libere e corpuscolate -Funzione autonomica: fibre simpatiche destinate a vasi, ghiandole e muscolo erettore del pelo

9 PGP COL IV ULEX

10 La cute Importante estroflessione del sistema nervoso periferico

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14 COSCIA GAMBA

15 CUOIO CAPELLUTO TRIGEMINO V1 TRIGEMINO V2 COSCIA POLPASTRELLO GAMBA ALLUCE

16 Basi molecolari della sensibilità termica: I canali ionici Heat transduction -TRP (transient receptor potential) family TRPV1 (molecular target of capsaicin) >42 C TRPV2 >52 C TRPV C TRPV C

17 Cold transduction - TRP-M8 >32 C mentolo etc - TRP-A1<20 C - Non-TRP ion channels

18 Mechanotransduction Strectch-sensitive channels gated by forces in the membrane bilayer, activated by pressure Strectch-sensitive channels gated by tethers to the cytoskeletron, directly or indirectly activated by pressure Channels coupled to mechanically sensitive proteins trough signalling intermediates

19 Epidermide Solo supporto fisico e trofico per le terminazioni nervose?

20 Possibile ruolo dell epidermide nella percezione di stimoli fisici e chimici Linee di evidenza: - Due sottopopolazioni di fibre terminano in strati distinti dell epidermide - I keratinociti secernano numerose molecole chimiche capaci di modulare, attivare o inibire i neuroni sensitivi - espressione di vari recettori implicati nella percezione di stimoli dolorosi o termici.

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24 100 mm PGP MBP PGP S100 PGP MBP 100 mm 25 mm

25 PGP S100

26 Rosso = MBP Verde = PGP Blu = Ulex

27 PGP Sub P PGP CGRP

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30 PGP MBP PGP-MBP

31 PGP MBP PGP-MBP

32 S100 PGP

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34 03 Merkel VIP PGP and ULEX.JPG

35 PGP COL IV

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37 PGP COL IV

38 COL IV PGP ULEX

39 PGP MBP ULEX

40 A B C D E

41 CGRP PGP ULEX

42 B

43 MBP

44 PGP MBP

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47 PGP MBP

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49 Distribuzione percentuale per calibro delle fibre mieliniche a livello del ramo digitale (A) e della cute del polpastrello (B) del III dito Modificato da G. Caruso et al., Brain ,00% % 8,00% 8 % 6,00% 6 % 4,00% 4 % 2,00% 2 % 0,00% 0 % 0,5 1,5 2,5 3,5 4,5 5,5 6,5 7,5 8,5 9,5 10, ,5 12,5 13,5 14,5 15,5 16,5 17,5 18,5 A 30,00% % 25,00% % 20,00% % 15,00% 15 % 10,00% 10 % 5,00% 5 % 0,00% 0 % 0,5 2,0 3,5 5,0 6,5 8,0 9, ,0 12,5 14,0 15,5 17,0 B 18,5

50 Terminal branches of A-delta fibers can be unmyelinated in their most distal portion so indistinguishable from cutaneous terminations of C fibers. The classic criteria based on fiber size, used to distinguish myelinated fibers populations in sensory nerves, are not suitable to identify myelinated terminations in the skin. The definition cutaneous myelinated terminations better describes this population of fibers.

51 Il Il 25-50% dei neuroni simpatici dei gangli paravertebrali è coinvolto nel controllo autonomico cutaneo

52 ULEX PGP

53 VIP PGP ULEX

54 DbH PGP ULEX

55 PGP COL IV ULEX

56 DbH PGP ULEX

57 VIP PGP ULEX

58 DbH VIP ULEX

59 DbH VIP ULEX

60 Role in in neuropathic pain?

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62 Congenital insensitivity to pain with anhidrosis (CIPA or HSAN IV) Selective lack of unmyelinated and small myelinated nerve fibers. Trk A (Nerve growth factor receptor) disorder

63 NORMAL CIPA 100 µm 100 µm 100 µm 100 µm

64 PGP COL IV ULEX

65 PGP COL IV ULEX

66 Capsaicin application Selective loss of nociceptors?

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71 Quantitative sensory testing and epidermal nerve fibers during and after capsaicin treatment 1000 capsaicin after 100 Touch Pin Prick Cold Heat ENFs/mm 10 Time 0 3 days 1 week 2 weeks 3 weeks 1 week 2 weeks 3 weeks 6 weeks

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73 Capsaicin produced a rapid decrease in the number of ENFs, with nearly complete disappearance after 3 days of treatment. Heat pain evoked by the small, but not the large, thermode decreased dramatically after capsaicin treatment. Regression analysis indicated that heat pain sensation evoked by the small thermode correlated much better with the number of ENFs than heat pain sensation evoked by the large thermode.

74 ENF and QST IENF density inversely correlates: with warm and heat-pain thresholds (Chiang et al., 2002; Pan et al., 2001; Pan et al., 2003; Pittenger et al., 2004; Scherens et al., 2009; Shun et al., 2004; Tseng et al., 2006; Vlckova- Moravcova et al., 2008) with both cold and warm/heat detection thresholds (Devigili et al., 2008; Loseth et al., 2008; Quattrini et al., 2007) with cold threshold (Holland et al., 1997; Novak et al., 2001; Periquet et al., 1999) with cold and heat detection (Sorensen et al., 2006; Zhou et al., 2007).

75 IENF density correlates with quantitative sensory testing. Correlation with a specific sensory modality (e.g. cooling, warm, heat-pain) remains uncertain

76 Loss of epidermal nerve fibers = loss of pain

77 painful neuropathies epidermal nerve fiber loss

78 Periquet MI, et al Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology. 1999;53: Lauria G et al., Trigeminal small-fiber sensory neuropathy causes burning mouth syndrome. Pain. 2005;115:332-7 Devigili G et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain [Epub ahead of print] Laaksonen SM et al. Neuropathic symptoms and findings in women with Fabry disease. Clin Neurophysiol Jun;119(6): Oaklander AL. The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles. Pain. 2001;92:

79 IENF density is lower in diabetic neuropathy patients with pain compared to those without pain (Quattrini et al., 2007; Sorensen et al., 2006; Vlckova Moravcova et al., 2008) IENF density inversely correlates with pain severity in HIVassociated sensory neuropathy (Zhou et al., 2007). In patients with pure SFN of mixed aetiology, IENF density is lower in those with pure spontaneous pain than those with pure evoked pain, but it did not correlate with its intensity (Devigili et al., 2008).

80 A reduction of pain parallels the increase in intraepidermal nerve-fiber density during the improvement of a neuropathy

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82 The relationship between IENF density and neuropathic pain is complex. An increase in ENF density can induce improvement of pain. Lower IENF density may be associated with the presence of neuropathic pain, but it does not correlate with the intensity of pain.

83 The distal degeneration of C fibers induces multiple events, including among others: 1. Increased ectopic and spontaneous firing of primary afferents 2. transmission of painful signals along large myelinated nerves that do not normally transmit pain 3. neurochemical and structural change in the dorsal root ganglion and dorsal horn of the spinal cord 4. altered brain processing and inhibition of painful sensation

84 Additional factors: Inflammatory mediators through the activation of resident immuno-cells can play a role in sensitizing C fibers and inducing spontaneous discharge. Macrophage derived nerve growth factor (NGF) induces mast cell degranulation with the release of prostaglandins, bradykinin, histamine and serotonin.

85 43 patients with burning feet (unpublished data) 27 M 16 F mean age 55 ±10.3 Disease duration 1-10 years -21 idiopathic small fiber neuropathy -22 glucose dysmetabolism

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87 PGP COL IV

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89 PGP COL IV

90 COL IV PGP ULEX

91 ULEX PGP COL IV PGP ULEX

92 COL IV PGP ULEX

93 100,0 90,0 80,0 70,0 60,0 50,0 40,0 30,0 20,0 10,0 0,0 Thigh 1 Leg 2 FT 3 4 MCs 5 MyE 6 ENFs Occurrence (%) of reduced density of ENFs, Meissner corpuscles and MyE in patients with painful sensory neuropathy

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98 PGP VIP

99 Sensory deficit in Parkinson s disease: evidence of a cutaneous denervation 2008

100 Cutaneous innervation role in neuropathic pain??? - Epidermal nerve fiber density (C fibers) - Myelinated nerve ending density (A-beta fibers) - C fiber - A-beta fiber interaction - Morphological abnormalities (clusters, varicosities )

101 Skin biopsy is a window on peripheral nervous system that allows exploration of last endings of unmyelinated and myelinated endings

102 In Conclusions: - A better assessment of C and A Beta fibers could give more insight in the study of neuropathic pain - The correlation with sensory function requires appropriate tools

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