Chronic pain in Gaucher disease: skeletal or neuropathic origin?

Gaucher disease is a lysosomal storage disorder due to the deficient activity of the acid β-glucosidase enzyme [1]. Based on the presence of neurological involvement, three phenotypes have been described: the non-neuropathic form (GD1), the acute, early fatal, neuropathic form (GD2) and the chronic late-onset neurological form (GD3) [1, 2]. Although this classification helps in describing disease progression and prognosis, studies of GD clinical history showed the existence of a continuum of phenotypes, ranging from the severe GD2 to the asymptomatic GD1 form [3]. In accordance with this concept, different authors have described signs of neurological involvement in GD1 patients [4‐9]. In particular, Biegstraaten M et al. showed a high prevalence of peripheral neuropathy (16.5%) in a cohort of GD1 patients followed for 2 years [9].

A relevant manifestation of GD is pain, usually related to skeletal involvement [1, 10]. In general, bone pain is described as a dull pain mainly localized to joints, legs and the back. The most severe expression of bone pain is bone crisis, reported in 30 to 65% of untreated patients and characterized by warmth and swelling of the affected site, often accompanied by systemic inflammatory signs [10‐12]. Bone pain and particularly bone crisis are generally reported as well responsive to enzyme replacement therapy (ERT) [12].

However, we have recently observed pain recurrence or sensory dysesthesias with neuropathic features in a group of GD1 patients who had received long-term ERT (up to >20 years). Neuropathic pain is considered consequent to a primary lesion in somatosensory nervous system, in particular to the damage of small nerve fibers [13, 14]. However, small nerve fibers function has not been properly investigated in GD1.

Patients’ demographic characteristics and a summary of therapeutic outcomes are reported in Table 1. At therapy beginning (T0), patients’ mean age was 27.2 (±14.6) years with seven patients starting therapy during pediatric age (≤16 years). Twenty-one out of 25 patients received exclusively ERT, one received a ERT/SRT combination (patient 20) and three were naïve patients (patients: 2, 16, 24). The mean ERT period was 15.0 years (±6.4) with a mean initial dosage of 35.3 (±14.2) IU/kg/b.w., increased to 66.5 (±22.5) IU/kg/b.w. at last visit (Tx).

At T0, β-glucosidase activity was significantly reduced in all patients (data not shown), while the molecular analysis of the GBA gene showed the presence of the common N370S mutation in 21 patients (four homozygous and 17 compound heterozygous) while different mutations were identified in four patients, Table 2. In course of ERT we observed a significant reduction of liver and spleen volume (p < 0.01) and a progressive normalization of laboratory parameters: mean Hb value increased from 11.9 to 14.3 g/dl (p = <0.01) while platelets count increased from 155.7 × 10³/mm³ to 214.3 × 10³/mm³ (p = <0.05). Elevated serum levels of IgG were present in ten patients (patients: 5, 6, 7, 8, 10, 15, 16, 17, 21, 25) at T0 and persisted in two of them (patients 7 and 8) at Tx, with a mean value decreasing from 1632.5 to 1164.5 g/dl (p = <0.01).

Bone mineral density showed a mean Z-score of −1.0 at T0 that increased to −0.26 at last visit. Only three patients (patients: 7, 8, 20) had a Z-score in the range of osteoporosis (−2.0, −2.3 and −3.4 respectively) that after ERT normalized in patients 7 and remained pathological in the other 2 (8 and 20): −2.0 and -2.8 respectively.

Zimran-SSI was calculated in 21 patients both a T0 and Tx, showing a reduction to the milder severity group (score 0–10) in all of them.

Due to the severe osteoporosis, patient 20 received exclusive SRT with miglustat for 3 years, then he switched to combined SRT/ERT for 1 year and finally switched to ERT exclusively. He never complained of bone crisis or symptoms secondary to miglustat treatment (diahrrea, abdominal pain, tremors).

Data of patients’ therapy duration, genotyping and pain history are reported in Table 2. At T0 a history of bone pain was reported in 13 of the 22 treated patients, 59.1%, (patients: 5, 6, 7, 8, 9, 10, 11, 13, 15, 17, 20, 22, 23), including two siblings (patients 7 and 8) who suffered also from pathological fractures before ERT start. Seven patients, 31.8%, presented recurrent bone crisis episodes (patients: 5, 7, 8, 10, 15, 22, 23). In course of ERT both bone crises and severe joint pain disappeared in all patients, while attenuated painful symptoms involving joints, legs and the back remained still present in 4 patients, 18.1% (patients: 7, 8, 13, 22).

However, at Tx a group of 13 patients (patients: 1, 5, 7, 8, 12, 13, 15, 16, 17, 18, 20, 21, 24) referred the presence of painful symptoms, described as a persistent cold pain with proximal distribution, in six with paroxysmal cold sensation. Among them: eight had referred bone pain at T0 (patients: 5, 7, 8, 13, 15, 17, 20, 21), three developed pain over time (patients: 1, 12, 18) and two were new diagnosed patients, naïve to any treatment (patients 16 and 24). At NRS, pain intensity resulted >4/10 in all. Only one patient (17) experienced a severe chronic pain (mean NRS of 8) with pins paroxysmal (NRS of 10), Table 3. All patients described this cold painful sensation as completely different from the pain at T0. Aching sensation in the limbs and joints was also reported by patients 7, 8, 22.

Clinical evaluation showed pinprick hypoesthesia at lower limb, usually in patchy fashion, in nine patients (patients: 8, 9, 12, 15, 16, 17, 18, 20, 21), in two of them (patients 8 and 18) with a stocking pattern involving also the hands, Fig. 1. In four patients (patients: 8, 9, 13, 17) distal tactile hypoesthesia was found while ankle reflexes were reduced in three patients (patients: 12, 13, 20). Neither static or dynamic mechanical allodynia nor hypopallesthesia were observed.

In all 13 patients with chronic pain at Tx, the DN4 score was ≥4/10, Table 2. The data of NPSI questionnaire (Table 3) showed spontaneous cooling-pain (Q1) in a group of 11 patients (NRS > 4; mean NRS 6.1 ± 1.6) and evoked pain (Q10) in another group of 11 patients (NRS > 4; mean NRS 7.2 ± 1.1). Cold evoked burning pain (Q10) was present in 9 (mean NRS 4.2 ± 1.8), pain evoked by pressure (Q9) in 2 (patients 15 and 21; mean NRS 4.5; data not shown in Table 3) whereas two groups of patients, composed by six patients each (Q11 and Q12), showed pins evoked sensation (mean NRS 5.5 ± 1.6) and tingling paraesthesia (mean NRS 5.6 ± 1.2), Table 3.

Seventeen patients performed the multimodal QST, Fig. 1. The sensory profile showed a stereotypical pattern with high cold thresholds (CDT) with errata sensation (burning or pins instead of cold), presence of paradoxycal heat sensation (PHS) and mechanical hypoestesia (MDT), Table 3. Finally, six patients presented pressure pain hyperalgesia (PPT), Table 3. Sensory and motor nerve conduction studies were normal in 22 patients. One patient (13) had carpal tunnel syndrome and 2 patients (patients 5 and 13) showed L5-S1 radiculopathy not related to GD.

Skin biopsy performed in 21 patients, showed abnormal IENF density in 19 of them (patients: 1, 3, 4, 5, 8, 9, 10, 11, 12, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25), Table 3. Seven patients presented a length-dependent loss of fibers (patients: 3, 5, 9, 16, 19, 22, 24), whereas 12 patients (patients: 1, 4, 8, 10, 11, 12, 15, 17, 20, 21, 23, 25) showed a not length-dependent pattern of epidermal denervation, Fig. 2. Skin denervation was found in nine patients only at proximal site, Table 3. We found a significant inverse correlation between IENF density and CDT at both the distal and proximal site (Pearson coefficient = 0.7 at distal leg and 0.77 at proximal site). No correlation between pain intensity and IENF density or GBA genotype was observed.

Despite affecting a considerable number of patients and representing one of the most disabling symptoms, pain per se has been poorly studied in GD. It has been generally associated with skeletal involvement, particularly with its most severe form, the bone crisis [1, 24]. Moreover, this association has been reinforced by the positive effect of ERT on bone symptoms. However, patients seldom refer also abdominal pain or a discomfort sensation due to hepatosplenomegaly and only recently pain has been related to peripheral neuropathy [5‐7, 9, 25, 26].

Muscoskeletal pain is defined by the presence of acute or chronic pain that arises from actual or threatened damage to non-neural tissue, and is due to the activation of nociceptors by several noxius stimuli such as chemical mediators release or mechanical stress [27]. The skeletal pain in GD patients is generally a localized joint pain often referred as a chronic deep penetrating pain and tenderness sensation. However, some patients may experience severe and dramatic acute pain (bone crisis) usually related to ischemic insult to the bone tissue [10].

The persistence of pain symptoms in several patients after long-term ERT, even after they had reached the therapeutic goals [28], with modified sensation (i.e. widespread burning-cold, pins sensation on leg and back regions) and negative signs as hypoesthesia or hypoalgesia, prompted us to investigate its possible neuropathic origin. In the past decade the presence of sensory symptoms in GD1 has been reported in different studies in almost 30% of patients: cold sensation (13%–28.4%), pins and needle (15%–25%) and on-going burning sensation (11%–33%) [6, 7, 9, 29, 30]. However, a systematic evaluation of small sensory nerves has not been performed. Only one previous study analyzed small nerve function using an obsolete and not adequate system: the Current Perception Threshold test [5]. This study for the first time provides a comprehensive analysis of the pain symptomatology in a cohort of 25 GD1 patients.

In our cohort ERT showed to be effective in controlling bone involvement and bone pain in nine out of the 13 who presented bone pain at T0. Only a group of four patients showed a persistence of attenuated joint pain during treatment (patients: 7, 8, 13, 22). However, an evolution of painful symptoms was observed after long-time ERT, with the presence of pain features suggestive of neuropathic origin with a quite stereotypical pattern of sensory profile in 13 patients. Four of them belonged to the group in which bone pain was resolved in course of ERT (patients: 5, 15, 17. 20,), 3 were patients with persisting bone symptoms (patients: 7, 8, 13), 4 were previously asymptomatic (patients: 1, 12, 18, 21) and 2 were new diagnosed (patients: 16 and 24). The pattern mostly showed thermal-hypoesthesia affecting lower limbs with prevalent involvement of cold than warm perception, similar to pain features observed in Fabry patients [31, 32].

These functional data were confirmed by histopathology, showing the presence of IENF denervation in 19/21 patients, both symptomatic and asymptomatic ones. Interestingly a denervation pattern was observed also in the three naïve asymptomatic patients (patients: 2, 16 and 24), excluding a correlation with ERT.

The presence of a severe SFN is a well-known feature in Fabry disease and has recently been described also in a patient affected by Pompe disease [33‐35]. Despite the hystopathological evidences, the molecular mechanisms underlying painful perception in patients affected by these lysosomal diseases are still poorly understood. However, evidences of a direct link between substrate accumulation and pain have been provided. Indeed, the administration of lyso-Gb3 to healthy mice caused mechanical allodynia and evoked an increase in intracellular Ca²⁺ levels associated with the functional up-regulation of voltage-activated Ca²⁺ channels in DRG neurons [36] These data suggest that the lipids species that accumulate in Fabry disease may cause pain through a direct action on sensory neurons, being a Ca²⁺-dependent excitability of nociceptors a possible mechanism. In addition, a direct effect of lipid accumulation on small nerve fibers damage has been hypothesized, since Ca²⁺ influx promoted by lyso-Gb3 may cause Ca²⁺-dependent excitotoxicity [37].

Whether a similar mechanism plays a role in painful perception in Gaucher patients needs to be investigated. However, it has been well documented that increased levels of glucosyceramide, the main lipid accumulating in GD, leads to an overactivation of the endoplasmic reticulum (ER) calcium channel, the ryanodine receptor, with the consequent increase of agonist-inducted Ca2+ release from this compartment [38, 39]. Furthermore, it has been suggested that the Ca²⁺ release from ryanodine-sensitive intracellular stores can induce neuronal cell death [38]. In light of these data it is reasonable to hypothesize a direct link between lipid storage and pain also in GD. Further experiments are needed to confirm this hypothesis.

The results of our study suggest that SNF is a constitutive feature of the disease in GD. This result stresses the concept of the existence of a phenotypic continuum already evidenced by previous studies [3]. Therefore, pain might be considered as a “late-onset” complication of the disease that can manifest even after long-term ERT as a consequence of a structural damage of peripheral nervous system. These results suggest the need to differentiate between bone and neurological pain in GD1 in order to provide an appropriate anti-pain therapy and to avoid unnecessary ERT dose escalation with the consequent unjustified increase of health costs. Future follow-up studies might also help to understand the natural progression of SNF in Gaucher disease.