Abstract
Background: Primary erythromelalgia (PE) is a rare disorder characterized by thermalgia. It is caused by mutations in voltage-gated Na channel (Nav) 1.7, which increase neuron excitability. The symptom of salt aversion in PE has not yet been reported. Case presentation: A 72-year-old woman had experienced severe frostbite since childhood. The patient developed redness as she warmed up at the age of 40 years and thermalgia as well as a salt aversion due to hypersensitivity to saltiness at the age of 70 years. She was diagnosed with PE. At the age of 72 years, we initiated treatment with stellate ganglion blocks (SGB) and epidural blocks. The symptom of salt aversion and pain in fingertips disappeared after treatment with SGB. Bilateral lumbar sympathetic ganglion blocks were performed to further attenuate pain in the tips of the toes, which disappeared after 2 months. Conclusions: We herein report the successful treatment of PE with hypersensitivity to saltiness.
I Background
Erythromelalgia is a rare disorder characterized by thermalgia at the extremities1). It is classified as primary or secondary1). Secondary erythromelalgia is caused by polycythemia and myeloproliferative diseases. The amelioration of symptoms is achieved by treatment of the underlying disease and aspirin may be therapeutically beneficial1). Primary erythromelalgia (PE) is caused by gain-of-mutations in voltage-gated Na channel (Nav) 1.7 that increase neuron excitability1). The clinical onset of PE often occurs in the first decade of life, but may range from congenital to the early 60s1). The diagnosis of PE depends on the clinical history and a physical examination1). Treatment often involves Na channel blockers or pregabalin. However, most cases of PE are intractable to pharmacotherapy1). Previous studies reported the effectiveness of sympathetic blocks2,3).
We herein describe the successful treatment of PE with the symptom of salt aversion by the combination of a stellate ganglion block (SGB), lumbar epidural block (LEB), and lumbar sympathetic ganglion block (LSGB).
Written informed consent was obtained from the patient for the publication of this case report.
II Case Presentation
A 72-year-old woman had experienced severe frostbite in the winter since childhood. At the age of 40 years, she developed pain in her fingertips. She was diagnosed with contact dermatitis and treatment was initiated; however, her symptoms persisted. She developed redness in her cheeks and auricles as she warmed up in the sun and was diagnosed with sun sensitivity, which persisted without improvement. At the age of 70 years, redness and a tingling sensation in the toes, fingertips, cheeks, auricles, and tongue were noted. The patient reported a burning pain upon bathing that was attenuated by elevation and cooling. Furthermore, even though she already had a preference for lighter tasting food, sensitivity to saltiness increased; salt in food tasted very bitter and, thus, she was unable to eat it. Based on these findings, the patient was diagnosed with a taste disorder. She reported pain on her tongue when eating mustard and hot peppers, which she was unable to eat. Although food with a high salt content did not cause pain, she was unable to eat it due to its bitter taste. Her medical history included migraine (occasionally treated with ibuprofen) and cataracts. Her family history revealed a daughter with similar symptoms; severe frostbite, contact dermatitis at the age of 40 years, and a preference for lighter tasting food.
After consulting with a dermatologist and orthopedic surgeon, the patient was referred to a neurologist with a diagnosis of peripheral neuropathy. While nerve conduction velocity was normal, current perception thresholds indicated small fiber neuropathy. Serological and cerebrospinal fluid examinations were normal. Skin biopsy, gastric biopsy, and echocardiography were performed and were normal. A CT scan revealed lung cancer in the right lower lobe and suspected cancerous neuropathy. Therefore, thoracoscopic lobectomy was performed. The postoperative pathology finding was “adenocarcinoma in situ”. After surgery, her symptoms persisted. There were no causative findings. The heat exposure test was positive. The patient was diagnosed with PE, and pregabalin and aspirin were administered. Genetic screening was not performed at her request.
Treatment at a pain clinic
At the age of 72 years, the patient was referred to a pain clinic because pain persisted despite the administration of 250 mg/day of pregabalin. The numerical rating scale (NRS) was 10 during these episodes. There was no pain or redness in the interval between episodes (Figure 1A), and thermography showed a decreased skin temperature in the toes, indicating excessive vasoconstriction (Figure 1B). The administration of aspirin was stopped. We treated pain in the toes with LEB (using 6 ml of 1％ mepivacaine) at 8 days. This treatment was performed 8 times over 9 weeks. Pain in the toes decreased to NRS 4. Therefore, bilateral LSGB at L2 and L3 each with 2 ml of 99.9％ ethanol, a neuroleptic, were performed at 64 and 83 days, respectively. LEB was repeated 3 times over 26 weeks, with the disappearance of pain, after which LEB was no longer necessary. The degree of the thermographic skin temperature elevation was more significant after LSGB (Figure 1D) than after LEB (Figure 1C). The patient felt warmth, but no pain (NRS 0–1).
Regarding pain in both cheeks, auricles, fingertips, and tongue, we performed SGB (using 3 ml of 1％ mepivacaine) at 15 days. We performed SGB 12 times (six each on the right and left) over 18 weeks. After SGB 7 times, her pain level decreased to NRS 2. SGB is currently conducted once a month. The patient is taking 125 mg/day of pregabalin.
Hypersensitivity to saltiness
The symptom of salt aversion disappeared after SGB had been performed 4 times. The patient was able to consume salt concentrations ranging between 0.8–0.9 and 14.5–16％ and expressed her satisfaction.
III Discussion
PE, primary Raynaud's disease, and migraine may have an unstable vascular tone in common4). Patients with PE show no symptoms during vasospasms between episodes, but have severe burning and warming of the extremities during the return of flow, the so-called reactive hyperemic phase4). Thermography shows increased temperatures in the affected areas during these episodes5). Between episodes, the limb may be normal or cyanotic with cold skin5). PE is caused by mutations in Nav1.7 which is expressed in pain-related nerves, such as trigeminal nerves, the dorsal root ganglion (DRG), and sympathetic ganglion (SG) neurons, as well as in nociceptive nerve endings1). In human skin, Nav1.7 is expressed in vascular myocytes, endothelium, and in both sensory and sympathetic nerves that converge and terminate on the intracutaneous vasculature6). Mutations in Nav1.7 in DRG increase neuron excitability and cause thermalgia2). Unless Nav1.8 is co-expressed, mutations in Nav1.7 result in reduced excitability7). DRG neurons co-express Nav1.8, whereas SG neurons do not7). In SG, Nav1.7 mutations produce hypoexcitability7). SG dysfunction may contribute to skin redness in PE7).
It currently remains unclear why a sympathetic ganglion block is effective in PE patients whose SG nerve becomes hypoexcitable following mutations in Nav1.7. Nav1.7 in vascular myocytes and the endothelium may be a contributing factor6). Vascular myocytes and the endothelium do not express Nav1.86). Therefore, Nav1.7 mutations may result in the hypoexcitability of vascular myocytes, which causes vasodilation due to the release nitric oxide by endothelial cells6). A recent study showed that the administration of nitroglycerin attenuated the symptoms of PE8). The mitigation of vasospasms between episodes by vasodilators or a sympathetic ganglion block may ameliorate PE symptoms. In the present case, thermography revealed lower temperatures in the interval between episodes. Sympathetic blocks attenuated vasoconstriction between episodes. As the degree of vasodilation during episodes was mild, pain during these episodes may have been reduced. In the present case, the degree of the thermographic skin temperature elevation was significantly greater after LSGB than after LEG. Therefore, LSGB may be more effective than LEG.
Pain, smell, and taste share common features as protective warning systems9). Nav1.7 is expressed on olfactory neurons and has been detected in taste cells receptive to salt in mice10–12). PE exhibits high olfactory sensitivity10). Hypersensitivity to salt in PE has not yet been reported. A high salt intake may increase blood pressure and the risks of heart disease and stroke13). A salty taste is unique in that an increasing salt concentration fundamentally transforms an innately appetitive stimulus into an aversive one12). This appetitive-aversive balance helps to maintain appropriate salt consumption12). High salt avoidance behavior begins at a salt concentration of 0.8％ and becomes prominent at 3.5％14). In mice, high salt concentrations recruited the two primary aversive taste pathways by activating bitter- and sour-taste receptor cells12). Furthermore, bitter-taste receptor cells were found to express Nav1.711). Hypersensitivity to salt may be a novel clinical feature of PE and was attenuated by SGB. Since genetic screening was not performed, we were unable to identify the Nav1.7 mutation in this patient. Further research is warranted.
Acknowledgements: We would like to thank Mizuko Ikeda, a professor at the Department of Anesthesiology and Management, Fukuoka Dental College.
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