scalp. Cutis 2013;92:291-6. 50. Garza I. The trigeminal trophic syndrome: an unusual cause of face .... Neurocutaneous disease: Neurocutaneous dysesthesias.
Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Steinhoff M, Schmelz M, Szabó IL, Oaklander AL. Clinical presentation, management, and pathophysiology of neuropathic itch. Lancet Neurol 2018; 17: 709–20.
Peripheral neuropathic itch from length-dependent small-fiber polyneuropathy
A woman developed widespread itch in her arms and legs without evident cause at age 50. Dermatological evaluation and treatments were non-productive. Results of electromyography and nerve conduction study, quantitative sensory testing and electroencephalography were normal. At age 60, she presented with scratch-related excoriations and scars (stocking-and-glove distribution) suggesting length-dependent small-fiber polyneuropathy (SFPN). Both of two skin biopsies from the standard distal-leg site showed 44 neurites/mm2 skin surface area, less than the 1st centile of predicted age-, sex-, and ethnic group-specific norms and thus pathologically diagnostic for small-fiber polyneuropathy. No amyloid birefringence was noted. Blood-test elimination of other causes (e.g., diabetes) and the patient’s history of a brother with mild pain and itch in his legs labeled as fibromyalgia raised the possibility of autoimmune SFPN, and a trial of immunotherapy was suggested but she was lost to follow-up.1
Central neuropathic itch from spinal-cord cavernous hemangioma
A man presented with disabling dermatomal neuropathic itch (NI) and scratching initiated by hemorrhage of his left C3-4 dorsal-horn cavernous hemangioma 2 years earlier. Ultra-high resolution 7T spinal MRI revealed at-level hyposignal (black arrowhead) indicating hemosiderin deposition. This was hypothesized to excite his spared dorsal-horn itch circuits. The long delay before onset of his NI was attributed to slow Wallerian degeneration of ascending itch projection neurons (open arrowheads). Wallerian degeneration had not been visualized on earlier posthemorrhage pre-itch MRIs (not shown). The ascending degeneration was more evident in his dorsal columns than in his anterolateral spinothalamic tract. Reprinted with permission from 2.
Table 1 Differences Between Normal Itch and Neuropathic Itch
Itch in inflamed skin
Neuropathic itch (non-inflamed skin)
Initiated by exogenous or endogenous mechanical and/or chemical stimulation of normal sensory neurons Pathophysiological concept focuses on pruritic mediators (H1 histamine receptor as prototype) Dermatological evaluation usually identifies the diagnosis Firing of itch neurons is proportional to stimulus strength (normal stimulus response curve) Onset of itch is time-coupled to causal condition, subsides rapidly after pruritogen is removed and inflammation improves
No direct mechanical or chemical pruritogens but sensory fibers themselves fire abnormally
Itch is the major sensory symptom, can be associated with inflammatory dermatological signs (hives, erythema, eczema) Scratching usually stops when it becomes painful (e.g. atopic eczema) Dermatological treatment (antihistamines, anti-inflammatories) usually effective
Pathophysiological concept focuses on central neuronal circuits and pathology (similarities to neuropathic pain, epileptogenesis) Dermatological evaluation usually non-productive, requires neurological evaluation Firing of itch neurons becomes uncoupled from stimulus (spontaneous, excessively prolonged) Onset of itch can be delayed (up to 18 mo after CNS injury) due to axon degeneration, or can persist for years until regeneration sufficient (eg, postherpetic itch) Itch can occur alone or with other neurological signs and symptom , e.g. co-localizing neuropathic pain Painless scratching can be continued until injurious Dermatological treatment usually ineffective, requires treatment directed at neurons
Table 2: Differences Between Neuropathic Itch and Neuropathic Pain
Both
Neuropathic pain
Transduced only from tissues accessible to scratching–skin and adjacent mucosa
Neuropathic itch
Nocifensive sensations trigger reflex and volitional movements to distance threat and marshal internal inflammatory response
Transduced from most tissues, although internal visceral pain less localized and modality-specific
Ectopic firing of individual damaged C-fibers produces itch percept Alloknesis refers to pain induced by normally nonpainful stimuli, hyperknesis refers to excess pain from normally painful stimulus Decreased by axonal degeneration, but scratching can trigger sprouting Brachioradial pruritus, notalgia paresthetica
Peripheral sensitization and unprovoked firing
Wider firing of damaged Cfibers produces pain percept
Transduced by C-fibers and A-delta fibers, undergo central sensitization
Allodynia refers to pain induced by normally nonpainful stimuli, hyperalgesia refers to excess pain from normally painful stimulus Decreased by axonal degeneration
Often felt at border of innervated and denervated skin where isolated afferents fire spontaneously Mu-opioids potentiate itch, myelopathic itch particularly associated with cavernous hemangiomas Triggers reflex and volitional scratching and rubbing to remove small attached threat
Spinal and trigeminal root syndromes
Opioids worsen itch, local anesthetics appear more effective even in longstanding cases
Most therapies effective for both
Epidermal nerve fiber density
Peripheral nerve syndromes
Meralgia paresthetica, Cheiralgia paresthetica etc.
In spinal cord, peripheral signals modulated in dorsal horn and transmitted to brain mostly via anterior spinothalamic tract, kappaopioids suppress both
Mu-opioids suppress pain
In the brain, most transmission and processing areas colocalize
Triggers reflex and volitional withdrawal movements to move away from unattached external threat Opioids often but not always improve neuropathic pain, topical local anesthetics not often effective
Table 3 Case management suggestions for managing localized NI Management General considerations For every patients with chronic itch, nail trimming, cotton gloves at night. Reduce impediments to nerve healing (eg diabetes, nutritional) TOPICAL THERAPIES Calcineurin inhibitor tacrolimus ointment BID Capsaicin 0·025-0·1% ointment 3-5 times daily
8% patch 1hr, after EMLA pretreatment, single aplication
Topical amitriptyline (1-2%) or ketamine (0·5%) alone or as combination cream/gel (2-3x daily) Topical amitriptyline (5%) – ketamine (5-10%)lidocaine(5%) combination cream Botulinum A toxin intradermal injection
Local anaesthetics Prilocaine ointment Lidocaine (2·5%) and Pirlocaine (2·5%) cream (EMLA) Paravertebral or epidural blockade Bupivacaine (0·75%) or lidocaine (40mg) methylprednisolone (40-80mg) Epidural catheter with infusion of clonidine (1 µg/mL) and bupivacaine 0·05% Ganglion stellate block Bupivacaine (0·25%) or ropivacaine (0·2%)
Peripheral nerve block 4% tetracaine + 0·5% bupivacaine
Notalgia Paraesthetica (NP) Exercises and stretches (12 patients, mean VAS 5·7 reduced to 2·4.3 Osteopathic treatment in one case (VAS 6-7 reduced to 3).4
Brachioradial pruritus (BP)
Post-herpetic itch (PHI)
Sun protection,5 avoiding hot ambient temperature; local cooling
Patient education and training,6 wound bandaging and management (e.g. alginate, negative pressure wound therapy, thermoplastic mesh).7
Reduces itch frequency and/or intensity (6 of 7 patients, VAS 6·6 reduced to 4·6).8 Widely used, mild to moderate effect, itch recurrence after cessation. Vehicle-controlled double-blind crossover study: 3-5x daily: (14 (70%) of 20 patients improved)10 Ineffective in one case report.11 More effective, in some patients, fast and long-lasting effect achieved.12-14
Insignificant reduction of itch (8·6 decreased to 5·1) in 3 patients as a part of a retrospective study.22 Double-blind, randomized, controlled study with long-term follow-up (5 patients): No statistically significant effect.23,24 Open pilot study: Effective in 2 (33%) of 6 patients (mean VAS reduction 2·8).25 Ineffective in a case report.11 3 (100%) of 3 patients improved in a case series.27
Case report: Symptom-free for 12 months after injection (1 patient).11 Case report: “nearly complete resolution” of symptoms.28
Trigeminal trophic syndrome (TTS)
Single case report, augmented with gabapentin; relapse after discontinuation.9 Widely used alone or in combination. Open-label trial: Significant improvement in 10 (77%) of 13 patients.15 Effective in two patients in a case series16 Resolved pain and itch in 5 (100%) of 5 patients.17 Complete remission in 5 (100%) of 5 patients with therapy-refractory itch.14 Effective in astrocytoma-caused BRP in a bicentric retrospective study.18 Ineffective in 1/1 report.18 Complete relief in case report19. Complete resolution or improvement (6 (55%) of 11 patients).20 Significant reduction of itch (NRS 8·4 to 3·5) in 9 BRP patients in a retrospective study.22 Complete cure for 5-6 months in a case report.26
Topical capsaicin contraindicated for use on the face, near eyes or on mucosa
Modest control of itch when combined with gabapentin in a case.21
2 (10%) of 20 patients improved, others not mentioned20
Effective in a case report, effect lasts for more than 6 months,29
Case report: relief from otherwise intractable itch for up to 2 days. Catheter infusion controlled itch for 4 weeks than became ineffective.30
Relief of itch, reduction of lancinating pain attacks.31 Case report in 1 child: Severe and refractory itching significantly improved after 3 sequential treatments.32
Case report: 6 months relief in therapy-refractory patient.33
SYSTEMIC THERAPIES
Notalgia Paraesthetica (NP)
Improvement in 1/1 patient.20
Anticonvulsants Carbamazepine (1x100 mg up to 3x200 mg daily)
Oxcarbazepine (starting with 300 mg BID, up to 900 mg BID).
Gabapentin (most widely used systemic drug in NI,34 starting with 300 mg daily, up to 3600 mg/d).
Pregabalin (100-600mg daily)
Brachioradial pruritus (BP)
In an open pilot study, mean VAS of 5 patients receiving oxcarbazepine decreased from 8·75 to 6, also moderate effect for paraesthesia or pain.35 Ineffective in 2 patients.23 Non-randomized, parallel, nonblinded study of 10 patients recieving 300 mg daily had a moderate effect, mean VAS reduction of 4·5 (9·5 to 5).34
Various efficacy in case reports.8,36-38 Additional burning sensation may occur as side effect.39
Post-herpetic itch (PHI) Itch resolution in single case report.45
Trigeminal trophic syndrome (TTS) Significant improvement after gabapentin ineffective.46 Effective in 3 other cases.47,48
Partial response in a patient with 3X600mg daily oxcarbazepine after Pregabalin failed in maximal dose.40
3 patients responded to 900 mg daily.40 1/1 responded very well for 900 mg daily.41 5 (91%) of 7 patients collected in a cross-sectional study achieved “good or excellent” itch reduction.42 Resolution of itch in 1/1 with recurrence a few days after cessation.43 Complete itch reduction (mean VAS decreased from 7-9 to 0) (100-225mg daily).44 Case report: 2 (67%) of 3 patients improved or itch-free.20
A patient responded well to 300 mg gabapentine daily, after 2 months ulcer and tenderness resolved, 4-5 weeks after cessation of therapy ulceration recurred, after restarting gabapentin it healed again.49 Partial relief in two casest.50 Some relief in combination with 25mg Doxepin at night.51
Ineffective when combinaed with carbamazepine.52
Tricyclics Clomipramin
One patient had partial relief from symptoms.28
Amitriptyline 10-100 mg
One patient improved after 3 months (VAS: 7 to 4).39
20 (91%) of 22 patients in a cross-sectional study had “good or excellent” itch reduction.42 Ineffective in 1/1.29 In 1/1, 60 mg daily caused replacement of pain by itch, at 120 mg itch also disappeared.36 Quickly and effectively reduces itch in a case report, itch returns after discontinuation.53
Phototherapy narrow-band UVB therapy
Effective in 5 (100%) of 5 patients; mean VAS reduction: 7·3 to 2).37
Contraindicated: Sunlight can trigger BRP. Until offending wavelength is identified, avoid UV.
Other
Electrical stimulation (of serratus anterior).36
Surgery
Surgical decompression.57
SNRIs Duloxetine 60-120 mg Neurokinin Receptor 1 antagonist Aprepitant (120 then 80mg/d) Other modalities
Single-center randomized controlled trial: local thiamine injection caused improvement in 14 (70%) of 20 patients.54 Prevention: Subunit vaccine almost eliminated shingles in patients over 50 (phase 3 trials).55,56 Surgical decompression.58
Regional flaps with nerve and blood supply.59
Abbreviations. BID: bis in die (twice a day), VAS: visual analogue score (scale 1-10, NRS numerical rating scale (segmented numeric version of VAS), EMLA: eutectic mixture of local anaesthetics, HZ: herpes zoster, TCA: tricyclic antidepressant, SNRI: serotonin–norepinephrine reuptake inhibitors, UVB: ultraviolet –B,
Focal Point: History of Neuropathic Itch
Before electromyography and nerve conduction study were developed, neurologists were equally interested in sensory as in motor symptoms and signs. Itch, defined in 1660 by Samuel Hafenreffer,60 was studied by neurological and neurosurgical pioneers. Neurological interest waned only after until Rieveschl’s 1943 discovery of diphenhydramine, the first histamine receptor blocker. In early 20th century studies by Denny-Brown, Eccles, and Sherrington helped delineate the spinal dermatomes by establishing that cutting a dorsal root caused some monkeys to scratch and injure the denervated bands of skin.61 The trigeminal trophic syndrome (TTS) came to prominence when Harvey Cushing’s signature operation, the suboccipital Gasserian ganglionectomy he developed to treat trigeminal neuralgia (TN), inadvertently left thousands of people with trigeminal neuropathic itch (NI).62-67 Since this was before the pharmaceutical era, ganglionectomy was the only effective treatment for TN, and it was widely performed; in one paper alone Walter Dandy reported more than 2,000 surgeries.68 The name “trigeminal trophic syndrome” reflected the initial erroneous theory that these post-operative ulcers were caused by deprivation of nutritive “trophic factors’ from the trigeminal nerve. In the 1930’s, the correct cause was recognized as neuropathic itch triggering excessive and often-painless scratching, and the trigeminal rhizotomy that replaced ganglionectomy caused less TTS. After medications and non-ablative suboccipital decompression replaced rhizotomy for treating TN, lower facial TTS was primarily reported after other procedures or lesions of the lower trigeminal ganglion or roots or central trigeminal pathways (e.g. Wallenberg’s syndrome).69-71 In the mid-20th century, fewer neurologists remembered post-surgical TTS, and it was often attributed to psychiatric causes during the Freudian era.6,48,49,52,69,72-84 Modern cases are often misattributed to dermatological causes.85,86 Neurological diagnosis and management remain the keys to effective treatment.
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