Neurogenic Rosacea: a Distinct Than BT-A

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tial effect, 3.0 (2.8) days (range, 1-7 days) for BT-B vs cal, and material support: Brigo, Acler, and Vicentini. Study 14.3 (6.7) days (range, 7-20 days) for BT-A. Anhidrotic supervision: Frasson and Bertolasi. areas developed earlier in the BT-B side. Patients re- Financial Disclosure: None reported. ported longer-lasting subjective benefit from BT-B than 1. Guttmann L. The management of the quinizarin sweat test (Q.S.T.). Postgrad BT-A: 17.3 (7.4) weeks vs 12.9 (8.4) weeks. Med J. 1927;23(262):353-366. All patients tolerated intradermally injected BT-A and 2. Naumann M, Lowe NJ. Botulinum toxin type A in treatment of bilateral pri- BT-B well, although some experienced mild pain, espe- mary axillary hyperhidrosis: randomised, parallel group, double blind, pla- cebo controlled trial. BMJ. 2001;323(7313):596-599. cially during BT-B injections. No hematomas developed 3. Dressler D, Adib Saberi F, Benecke R. Botulinum toxin type B for treatment at the injection site, nor did any participant report sys- of axillar hyperhidrosis. J Neurol. 2002;249(12):1729-1732. temic adverse effects. 4. Birklein F, Eisenbarth G, Erbguth F, Winterholler M. Botulinum toxin type B blocks sudomotor function effectively: a 6 month follow up. J Invest Dermatol. 2003;121(6):1312-1316. Comment. In all patients, although both toxins im- 5. Schlereth T, Mouka I, Eisenbarth G, Winterholler M, Birklein F. Botulinum proved axillary hyperhidrosis, BT-B proved more effec- toxin A (Botox) and sweating-dose efficacy and comparison to other BoNT tive than BT-A in reducing sweat production and area. preparations. Auton Neurosci. 2005;117(2):120-126. We therefore provide objective evidence that BT-B is safe and effective for treating bilateral axillary hyperhidrosis.3,4 When administered at the same dose ratio of 1:50 used for the motor system, BT-B blocks sweating better Neurogenic Rosacea: A Distinct than BT-A. The subjective outcome measures, includ- Clinical Subtype Requiring ing the beginning and duration of benefit and treatment a Modified Approach to Treatment satisfaction scores, were also higher for BT-B than for BT-A treatment. osacea is generally categorized into 4 distinct Our finding that BT-B effectively reduces axillary hy- clinical subtypes: erythematotelangiectatic, perhidrosis differs from other studies probably because R papulopustular, phymatous, and ocular.1 the other studies used lower toxin ratios (1:40 or 1:20) Granulomatous rosacea, rosacea fulminans, and perioral and higher dilutions.3,4 Botulinum toxin type B might dermatitis have been described as additional variants.2 strongly reduce hyperhidrosis because it specifically tar- Herein we describe 14 patients with rosacea and promi- gets the autonomic nervous system, as happens in botu- nent neurologic symptoms, who represent another dis- lism type B.5 tinct subset of rosacea meriting a unique approach to Botulinum toxin type B merits increasing use in pal- management. mar hyperhidrosis to guarantee long-lasting benefit without hand muscle weakening. Future research should com- Methods. Patients with prominent neurologic symp- pare how BT-A and BT-B affect the autonomic and motor toms in addition to classic features of rosacea were iden- nervous systems and how long their action on both sys- tified during routine appointments at a major teaching tems lasts. hospital. Details regarding medical history, disease symptoms and triggers, and response to treatments were ob- Emma Frasson, MD tained via clinic visits and telephone interviews. The study Francesco Brigo, MD was approved by the institutional review board of the Uni- Michele Acler, MD versity of California, San Francisco. Giuseppe Didonè, MD Silvana Vicentini, MS Results. Twelve of the 14 patients were women, and 12 Laura Bertolasi, MD were white. Mean age at disease onset was 38 years. Promi- nent symptoms included burning or stinging pain (100% Accepted for Publication: July 21, 2010. [14 of 14]), erythema (100% [14 of 14]), and flushing Author Affiliations: Department of Neurology, Cit- (93% [13 of 14]), sometimes accompanied by facial edema tadella Hospital, Padua, Italy (Drs Frasson and Didonè); (50% [7 of 14]), telangiectasias (50% [7 of 14]), pruri- and Department of Neurological Sciences and Vision, Sec- tus (43% [6 of 14]), and papules (36% [5 of 14]). Im- tion of Clinical Neurology, University of Verona, Ve- portant symptom triggers included heat (93% [13 of 14]), rona, Italy (Drs Brigo, Acler, Vicentini, and Bertolasi). sunlight (93%[13 of 14]), hot showers (79% [11 of 14]), Correspondence: Dr Frasson, Department of Neurol- stress (71% [10 of 14]), exercise (64% [9 of 14]), and ogy, Cittadella Hospital, Via Casa di Ricovero 40, Padua alcohol consumption (57% [8 of 14]). Use of makeup 35013, Italy ([email protected]). (50% [7 of 14]), eating spicy foods (43% [6 of 14]), touch- Author Contributions: All authors had full access to all ing skin (36% [5 of 14]), drinking hot beverages (29% the data in the study and take responsibility for the in- [4 of 14]), cold weather (21% [3 of 13]), and humidity tegrity of the data and the accuracy of the data analysis. (14% [2 of 13]) were less reliable triggers. Notably, 71% Study concept and design: Frasson and Bertolasi. Acquisi- of patients experienced relief from cooling via fans or cold tion of data: Frasson, Brigo, Acler, and Vicentini. Analy- compresses or ice applied to the face or held in the mouth sis and interpretation of data: Frasson, Brigo, Acler, and (10 of 14). Figure 1 depicts typical examination find- Didonè. Drafting of the manuscript: Frasson, Brigo, Acler, ings in these patients. and Vicentini. Critical revision of the manuscript for im- A notably high percentage of patients had neurologic portant intellectual content: Frasson, Didonè, and Berto- (43% [6 of 14]) or neuropsychiatric (50% [7 of 14]) con- lasi. Statistical analysis: Didonè. Administrative, techni- ditions, including complex regional pain syndrome, es-

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 innate immunity.3 We believe neuronal dysregulation is equally integral to rosacea pathogenesis. It may contrib- ute to disease via various mechanisms, such as vasomotor instability, release of proinflammatory neuro- peptides, and neuronal injury leading to perceived dysesthesias.4,5 In an individual patient, the relative im- portance of each of the mechanisms may differ, influ- encing both the spectrum of clinical symptoms and the optimal treatment strategy. We propose the diagnostic and treatment algorithm illustrated in Figure 2 as a guide for clinicians in man- aging a patient with suspected neurogenic rosacea. Pa- tients with prominent vasomotor symptoms, defined clini- cally by flushing and telangiectasias, may respond to vasoactive medications, including ␤-blockers, alpha-1 adrenergic blockers, and calcium channel blockers. In addition, laser- and light-based therapies seem to be more effective in this subset of patients. Patients with inflammatory features such as papules, pustules, or edema may respond, if symptoms are mild, to traditional topical therapies such as metronidazole, azelaic acid, or sulfur. Systemic antibiotics and antimalarial agents used for their anti-inflammatory effect may be useful for nonresponders. Figure 1. Facial erythema is seen in most patients at baseline and uniformly Finally, patients with dysesthesia out of proportion during flares. Inflammatory papules and pustules and rhinophymatous to flushing or inflammation can be difficult to treat and change are unusual in this subset of patients. require a unique approach first used to treat disorders such as complex regional pain syndrome and neuro- sential tremor, depression, and obsessive-compulsive dis- pathic itch. In our experience, neuroleptic agents (eg, gab- order. Neurovascular disorders, including headaches (71% apentin, pregabalin), tricyclic antidepressants, and pain- [10 of 14]) and Raynaud phenomenon (29% [4 of 14]), modifying antidepressants (eg, duloxetine) are the most as well as rheumatologic disorders (36% [5 of 14]), ineffective. N-methyl-D-aspartic acid receptor antagonists cluding lupus, rheumatoid arthritis, fibromyalgia, mixed (eg, memantine), systemic antibiotics, and other topi- connective tissue disease, and psoriatic arthritis, were also cally formulated medications (eg, ketamine, glycopyr- common. rolate, capsaicin) may be helpful in certain cases. Be- Many patients had tried the following treatments with cause of the associated heightened sensitivity to heat and limited success: topical metronidazole (0 of 12 were sunlight, laser- and light-based interventions should be helped), topical steroids (1 of 8), and oral antibiotics, usu- used with caution. ally tetracyclines (4 of 8). Most patients benefitted from Because our understanding of this enigmatic sub- neurologically focused treatments (9 of 12), including class of rosacea is extremely limited, further research is gabapentin (5 of 11), duloxetine (4 of 6), pregabalin (1 clearly needed to better describe the underlying patho- of 4), tricyclic antidepressants (2 of 3), and memantine physiologic characteristics and to identify additional ef- (2 of 2). Topically formulated neuroleptic agents, in- fective treatment methods. cluding doxepin, glycopyrrolate, amitriptyline, capsaicin, and ketamine, were occasionally effective (3 of 7). Tiffany C. Scharschmidt, MD Hydroxychloroquine (3 of 5), an antimalarial agent with John M. Yost, MD, MPH neuromodulatory effects, and vasoactive agents includ- Sam V. Truong, MD ing ␤-blockers and alpha-1 adrenergic receptors (2 of 5) Martin Steinhoff, MD, PhD were each effective in a subset of patients. Comorbidi- Kevin C. Wang, MD, PhD ties, demographic data, and individual treatment re- Timothy G. Berger, MD sponses are summarized in the Table. Accepted for Publication: July 13, 2010. Comment. We propose that this group of patients with Author Affiliations: Department of Dermatology, Uni- strikingly prominent neurologic symptoms represents an versity of California, San Francisco (Drs Scharschmidt, underrecognized subgroup of rosacea that we term neu- Truong, Steinhoff, Wang, and Berger); School of Medi- rogenic rosacea. By highlighting and formally naming this cine, University of Michigan, Ann Arbor (Dr Yost); Los subgroup, we hope to increase awareness and recogni- Angeles Medical Center, Kaiser Permanente, Los Ange- tion of these patients and aid the practicing dermatolo- les, California (Dr Truong); and Program in Epithelial gist in their therapeutic management. Biology, Stanford University School of Medicine, Stan- The cause of rosacea is complex, poorly understood, ford, California (Dr Wang). and likely multifactorial, with significant proposed con- Correspondence: Dr Wang, Department of Dermatol- tributions from dysfunctional cutaneous vasculature and ogy, Stanford Medicine Outpatient Center, 450 Broad-

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Patient No./Sex/ Age at Onset, y/ Therapies With at Least Symptom Duration, y Pertinent Medical History Previous Ineffective Therapies Partial Efficacy 1/F/38/9 Depression, chronic pain, cervical Topical steroids, topical clindamycin Gabapentin, combination cream of stenosis, fibromyalgia, migraines, ketamine, 15%/amitriptyline, essential tremor, Raynaud 5%/clonidine, 0.2%/ketoprofen, 10% phenomenon 2/F/45/15 Depression, migraines Topical capsaicin, pregabalin, tramadol Gabapentin, duloxetine 3/F/25/10 Acne vulgaris, migraines, allergic Oral tetracyclines, topical metronidazole, Amoxicillin, desonide for itch contact dermatitis nadolol, gabapentin, amitriptyline 4/F/50/10 Carpal tunnel syndrome, autoimmune NA Gabapentin, duloxetine thyroiditis, chronic pain, neurogenic itch, spondylolisthesis 5/F/36/8 Complex regional pain syndrome, Oral antibiotics, topical steroids Pregabalin, duloxetine positive ANA without other known autoimmune disease 6/F/29/8 Mixed connective tissue disease, Topical metronidazole, Gabapentin, minocycline Raynaud phenomenon, hydroxychloroquine depression, bulimia 7/M/37/13 Scrotal dysesthesia, psoriasis, C3-6 Topical metronidazole Minocycline, doxycycline degenerative joint disease 8/F/41/17 Rheumatoid arthritis Topical metronidazole, topical steroids, Nortriptyline oral antibiotics, ␤-blockers, gabapentin, hydroxychloroquine, amitriptyline 9/M/15/10 Psoriatic arthritis, irritable bowel Topical metronidazole, topical steroids, Topical glycopyrrolate, 3%; prazosin, syndrome, obsessive compulsive gabapentin, topiramate, botulinum memantine NMDA-receptor disorder toxin type A, laser therapy, thoracic antagonist sympathectomy, clonidine, propranolol 10/F/53/5 Oral lichen planus, headaches Topical sulfa Amoxicillin 11/F/32/12 Headaches Topical metronidazole, topical steroids, Topical capsaicin, duloxetine gabapentin, pregabalin 12/F/60/2 Complex regional pain syndrome, Topical metronidazole, topical steroids, Gabapentin, hydroxychloroquine Raynaud phenomenon, topical doxepin depression, esophageal dysmotility, positive ANA without other known autoimmune disease 13/F/37/8 Anxiety, depression, headaches, Topical sulfasalazine, topical Titanium dioxide, hydroxychloroquine, Raynaud phenomenon metronidazole, azelaic acid, amitriptyline, propranolol doxycycline, gabapentin, intense pulsed light, topical amitriptyline, topical ketamine 14/F/22/9 Systemic lupus erythematosus, Topical metronidazole, oral tetracyclines, Hydroxychloroquine, memantine Raynaud phenomenon gabapentin, pregabalin, ␤-blockers, vascular laser therapy, topical doxepin, topical ketamine

Abbreviations: ANA, antinuclear antibody; NA, not applicable; NMDA, N-methyl-D-aspartic acid.

way, Pavillion B, Fourth Floor, Redwood City, CA 94063 ([email protected]). Neural dysregulation Author Contributions: Drs Scharschmidt, Wang, and Berger had full access to all the data in the study and take responsibility for the integrity of the data and the accu- Vasomotor Inflammatory Neuropathic racy of the data analysis. Drs Scharschmidt and Yost con- tributed equally to this work. Study concept and design: Flushing, Edema, papules, Dysesthesia, telangiectasia pustules pruritus Scharschmidt, Yost, Wang, and Berger. Acquisition of data: Scharschmidt, Yost, Truong, and Steinhoff. Analysis and interpretation of data: Scharschmidt, Yost, Steinhoff, and β-Blockers, Antibiotics, Neuroleptics vascular lasers immune modulators Wang. Drafting of the manuscript: Scharschmidt, Truong, and Steinhoff. Critical revision of the manuscript for important intellectual content: Steinhoff, Wang, and Berger. Figure 2. Proposed diagnostic and treatment algorithm for a patient with Statistical analysis: Yost. Administrative, technical, and ma- rosacea based on clinical-pathologic correlation. In any given patient, more than 1 pathway and treatment method might be important, but identifying terial support: Scharschmidt, Truong, and Steinhoff. Study individual components can help guide management. supervision: Scharschmidt, Steinhoff, Wang, and Berger.

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Financial Disclosure: Dr Steinhoff serves as a consultant croscopy. In addition, a moderate neutrophilic infiltrate for and holds a research grant and patent with Galderma. was present throughout the dermis and superficial sub- Dr Berger is a consultant for Prescription Solutions and cutis, suggestive of cellulitis. Direct immunofluores- serves as a nonsalaried principal investigator in other re- cence showed IgG and ␭ light chains in the papillary der- search studies involving GlaxoSmithKline, Clinsys Clini- mis but no IgA, IgM, ␬ light chains, or C3. cal Research Inc, Merz Pharmaceuticals, and Pharmanet. A diagnosis of bullous amyloidosis complicated by cel- Additional Contributions: Elaine Yu, BA, Susan McGuire, lulitis was made. Blood cultures were positive for Esch- BA, and Chris Walker, JD, provided technical assistance erichia coli. It was believed that the source of the pa- and support. tient’s bacteremia was cutaneous breakdown in the groin. The patient responded well to antibiotic therapy and was 1. Wilkin J, Dahl M, Detmar M, et al; National Rosacea Society Expert Com- mittee. Standard grading system for rosacea: report of the National Rosacea discharged after 1 week. Society Expert Committee on the classification and staging of rosacea. JAm Acad Dermatol. 2004;50(6):907-912. Comment. Amyloidosis typically occurs in the setting of 2. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004;51(3):327-341. multiple myeloma and occurs less commonly with Wal- 3. Yamasaki K, Gallo RL. The molecular pathology of rosacea. J Dermatol Sci. denstrom macroglobulinemia. Twenty-five percent of pa- 2009;55(2):77-81. tients with amyloidosis exhibit cutaneous involvement, 4. Wang K, Berger T. Dermatological neurological interactions. In: Aminoff MJ, ed. Neurology and General Medicine. 4th ed. Philadelphia, PA: Churchill Liv- with lesions ranging from petechiae and ecchymoses to ingstone; 2008. papules, plaques, nodules, alopecia, or sclerodermatous 5. Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuro- changes.1 Mucous membrane involvement rarely oc- nal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol 2 Rev. 2006;86(4):1309-1379. curs. Bullous lesions are rare, with fewer than 40 cases reported. The eruption is often intertriginous, likely ex- acerbated by friction. Hemorrhage is likely secondary to VIGNETTES fragility of vessel walls, which contain amyloid.3 Amyloidosis related to multiple myeloma is usually due to immunoglobulin light chain deposition. Few cases of heavy chain amyloidosis have been reported.4 Of in- Bullous Amyloidosis Complicated terest, our case showed positive direct immunofluores- by Cellulitis and Sepsis: A Case Report cence findings for IgG and ␭ light chains in the papillary dermis where amyloid deposition was seen, indicating Report of a Case. A 78-year-old African American man that this might be the first case of mixed heavy chain and was seen with a history of easy bruising for 1 year. Workup light chain bullous amyloidosis reported in the literature. revealed free ␭ light chains in the serum and urine. Af- Another interesting feature of this case was the de- ter bone marrow biopsy, the patient was diagnosed as velopment of septic shock. Our patient was immuno- having multiple myeloma. He underwent chemotherapy compromised due to his underlying malignant neo- with cyclophosphamide, bortezomib, and dexametha- plasm as well as by recent chemotherapy, and he exhibited sone along with prophylaxis with sulfamethoxazole-tri- E coli sepsis. Bullous amyloidosis complicated by sec- methoprim, fluconazole, and acyclovir and began to ondary infection and gram-negative rod septicemia (with show improvement. E coli and Enterococcus faecalis) has only once been re- However, 3 months into treatment, he was seen in the ported in the literature, to our knowledge.5 The predomi- emergency department for septic shock. No source of in- nantly intertriginous localization of bullous amyloid le- fection was initially evident. Dermatology was con- sions is likely a contributing factor. sulted for evaluation of bullous skin lesions, which had been present for 2 weeks prior to admission. Although Kalpana Reddy, MD the patient had been seen by a physician during this time, Syed Hoda, MD no diagnostic studies or therapeutic measures to ad- Adam Penstein, MD dress his skin lesions were undertaken. His last chemo- Tarun Wasil, MD therapy treatment was 2 days prior to admission. Sheng Chen, MD, PhD Dermatologic examination revealed tender, erythem- atous patches with hemorrhagic bullae and few ero- Author Affiliations: Department of Dermatology, State sions in an intertriginous distribution, with lesions in the University of New York (SUNY) Downstate Medical Cen- axillae, groin including the penis, and medial thighs ter, Brooklyn (Dr Reddy); and Departments of Pathol- (Figure). Nikolsky and Asboe-Hansen signs were nega- ogy (Drs Hoda and Chen) and Medicine (Drs Penstein tive. One or 2 superficial erosions were present on the and Wasil), North Shore–LIJ Health System, New York, dorsal aspects of the hands and feet. Mucous mem- New York. branes were clear. No macroglossia or lymphadenopa- Correspondence: Dr Reddy, Department of Dermatol- thy was found. ogy, SUNY Downstate Medical Center, 450 Clarkson Ave, A punch biopsy specimen from the medial thigh re- Box 46, Brooklyn, NY 11203 ([email protected]). vealed hemorrhage and intradermal vesicle formation Financial Disclosure: None reported. (cleavage plane in the papillary dermis). A fine granular Additional Contributions: Saul Teichberg, MD, helped eosinophilic material in the papillary dermis was con- with electron microscopy. firmed to be amyloid by electron microscopy and Congo 1. Bayer-Garner IB, Smoller BR. The spectrum of cutaneous disease in multiple red stain with apple green birefringence on polarized mi- myeloma. J Am Acad Dermatol. 2003;48(4):497-507.

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