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Chronic Pain in Gaucher Disease: Skeletal Or Neuropathic Origin?

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Chronic Pain in Gaucher Disease: Skeletal Or Neuropathic Origin? Devigili et al. Orphanet Journal of Rare Diseases (2017) 12:148 DOI 10.1186/s13023-017-0700-7 RESEARCH Open Access Chronic pain in Gaucher disease: skeletal or neuropathic origin? Grazia Devigili1†, Michele De Filippo2, Giovanni Ciana2, Andrea Dardis2, Christian Lettieri1, Sara Rinaldo1, Daniela Macor2, Alessandro Moro2, Roberto Eleopra1 and Bruno Bembi2*† Abstract Backgound: Pain is one of the most disabling symptoms of Gaucher disease. It is referred by the majority of Gaucher patients and often persists despite long-term enzyme replacementtreatment.Ithasbeenmainlyconsideredasnociceptive pain secondary to skeletal involvement but it is described even in the absence of bone disease without a clear explanation. In the last years an increasing number of reports have described the presence of neurological manifestation in Gaucher type 1 patients, including subclinical large fibre neuropathy. In our Gaucher clinic we have observed the recurrence of painful symptoms in a group of type 1 Gaucher patients even after a long-term enzyme replacement therapy. Methods: A cross-sectional study was designed to investigate the pathophysiology of pain in a cohort of 25 Gaucher patients (13 females, 12 males). Twenty-two patients received enzyme replacement therapy for a period of time ranging from 10 to >20 years, while three were new diagnosis. Pain was classified as bone or neurologic related on the basis of anamnestic data, clinical and electrophysilogical examinations. Intensity and quality of pain were recorded by Douleur Neuropathique en 4 questionnaire and Neuropathic Pain Symptom Inventory. Neuroalgological evaluation, quantitative sensory testing, nerve conduction studies and evaluation of epidermal nerve fibres density were performed. Comorbidities for peripheral neuropathy were excluded. Results: Thirteen patients complained of pain suggestive of neuropathic origin with proximal patchy distribution, six manifested severe pain paroxysmal, nine pinprick hypoesthesia and 17 thermal hypoesthesia. At quantitative sensory testing, all of them showed high cold thresholds with errata sensation (burning instead of cold), paradoxical heat sensation and mechanic hypoesthesia; three patients showed pressure pain hyperalgesia. Epidermal denervation was present in 19 patients, 12 of them with non-length dependent pattern. Conclusions: These results confirm the role of peripheral neuropathy in Gaucher pain and demonstrate that skin denervation is as a constitutive feature of the disorder. In addition, they further confirm the existence of a continuum Gaucher phenotype, and provide a new interpretation of pain origin that should be considered for an appropriate disease management and to avoid unnecessary dose escalations of enzyme therapy. Keywords: Gaucher type 1 disease, Bone pain, Neuropathic pain, Small fibre neuropathy, Peripheral neuropathy Background (GD2) and the chronic late-onset neurological form Gaucher disease is a lysosomal storage disorder due to the (GD3) [1, 2]. Although this classification helps in describ- deficient activity of the acid β-glucosidase enzyme [1]. ing disease progression and prognosis, studies of GD clin- Based on the presence of neurological involvement, three ical history showed the existence of a continuum of phenotypes have been described: the non-neuropathic phenotypes, ranging from the severe GD2 to the asymp- form (GD1), the acute, early fatal, neuropathic form tomatic GD1 form [3]. In accordance with this concept, different authors have described signs of neurological in- * Correspondence: [email protected] volvement in GD1 patients [4–9]. In particular, Biegstraa- † Equal contributors ten M et al. showed a high prevalence of peripheral 2Regional Coordinator Centre for Rare Diseases, AMC Hospital of Udine, Building 16; Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy neuropathy (16.5%) in a cohort of GD1 patients followed Full list of author information is available at the end of the article for 2 years [9]. © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Devigili et al. Orphanet Journal of Rare Diseases (2017) 12:148 Page 2 of 10 A relevant manifestation of GD is pain, usually related neurotoxic drugs; alcohol abuse; causes of monoclonal to skeletal involvement [1, 10]. In general, bone pain is gammopathy not GD related. described as a dull pain mainly localized to joints, legs and the back. The most severe expression of bone pain Bone pain is bone crisis, reported in 30 to 65% of untreated pa- Anamnestic data on the presence of recurrent or chronic tients and characterized by warmth and swelling of the dull pain, (not movement related, localized to joint, legs affected site, often accompanied by systemic inflamma- or vertebral column) as well as on the presence of bone tory signs [10–12]. Bone pain and particularly bone cri- crisis were collected through patients’ diary consultation sis are generally reported as well responsive to enzyme and direct interrogation. In presence of a positive feed- replacement therapy (ERT) [12]. back, pain was classified as of bone origin. However, we have recently observed pain recurrence or sensory dysesthesias with neuropathic features in a Neuroalgologic evaluations group of GD1 patients who had received long-term ERT Neurological examination included extensive sensory (up to >20 years). Neuropathic pain is considered conse- evaluation according to the European Federation Neuro- quent to a primary lesion in somatosensory nervous sys- logical Society (EFNS) Guideline [15, 16]. Intensity of tem, in particular to the damage of small nerve fibers ongoing or shooting spontaneous pain, allodynia (static [13, 14]. However, small nerve fibers function has not mechanical [pressure], dynamic mechanical [brush], heat been properly investigated in GD1. or cold [thermal]), and hyperalgesia were graded with the 11-point numerical rate scale (NRS). The Douleur Methods Neuropathique en 4 questionnaire (DN4) was prelimin- Patients ary assessed [17], if the DN4 score was at least 1/10 the This is a cross-sectional study that enrolled 25 GD1 pa- Italian version of Neuropathic Pain Symptom Inventory tients (13 females, 12 males, aged 18 to 63 years) (NPSI) was performed [18]. Presence and distribution followed for 10 to >20 years by the Regional Coordinator (e.g. length or non-length dependent) of sensory loss Centre for Rare Diseases of the Academic Medical and pain were recorded. Centre Hospital (AMCH) of Udine. Twenty-nine GD1 patients who came to the annual follow-up visit from 1st Nerve conduction studies tests April 2016 to 31st December 2016 were asked to partici- Sensory and motor nerve conduction studies (NCS) pate in the study, regardless of the presence of painful were performed using surface recording electrodes and symptoms. Twenty-five patients accepted to participate standard placement. Compound muscle action potential and signed the informed consent. The study was ap- (CMAP), motor nerve conduction velocity (MCV), distal proved by the Ethical Committee of the Regione Friuli motor latency (DL) and F wave latencies were recorded Venezia Giulia. for median, ulnar, peroneal, and tibial nerves. Sensory The diagnosis of Gaucher disease was based on the as- nerve conduction velocity (SNCV) and sensory nerve ac- sessment of residual leukocytes β-glucosidase activity tion potential (SNAP) were assessed for median, ulnar, and the molecular analysis of the GBA gene. Twenty- lateral femoral-cutaneous and sural nerves. two patients received alglucerase/imiglucerase therapy or substrate reduction therapy (SRT) with miglustat (1 Quantitative sensory testing patient) for a mean of 15.0 (±6.4) years, while 3 patients QST was performed using calibrated device and stand- were naïve for any treatment. ard procedure [19, 20]. Warm (WDT) and cold (CDT) The follow-up protocol included: yearly clinical examin- thresholds as well as pain thresholds for cold (CPT) and ation, laboratory tests (Hb, platelets, leucocytes, ferritin, hot (HPT) stimuli were assessed by the MedocTM de- AST, ALT, GGT, ALP, direct and conjugated bilirubin, vice (MedocTM Thermal Sensory Analyser, TSA-2001, serum protein, gammaglobulins, lipid pattern) and bi- Israel), using a 30 × 30 mm probe with the method of annual imaging study (liver and spleen volume measure- limits. Abnormal sensations including paradoxical heat ment by echography and nuclear magnetic resonance, sensation (PHT) during alternating cold and warm NMR; NMR bone marrow analysis; L1-L4 bone mineral stimulation, errata sensation, thermal allodynia or hyper- density, BMD, by DEXA). Therapy efficacy was evaluated algesia, and aftersensation were recorded. by Zimran-severity score index (Zimran-SSI). The mechanical detection threshold (MDT) was mea- Other causes of somatic and/or autonomic neur- sured with a standardized set of modified von Frey hairs, opathy were excluded: diabetes mellitus; renal, liver or from 0.26mN to 490mN using the method of limits thyroid dysfunction;
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