Chronic pain in Gaucher disease: skeletal or neuropathic origin?

Grazia Devigili†,
Michele De Filippo,
Giovanni Ciana,
Andrea Dardis,
Christian Lettieri,
Sara Rinaldo,
Daniela Macor,
Alessandro Moro,
Roberto Eleopra and
Bruno Bembi†Email author View ORCID ID profile

†Contributed equally

Orphanet Journal of Rare Diseases201712:148

https://doi.org/10.1186/s13023-017-0700-7

Received: 8 June 2017

Accepted: 22 August 2017

Published: 31 August 2017

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 replacement treatment. It has been mainly considered as nociceptive 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.