High frequency dorsal column spinal cord stimulation for management of erythromelalgia

Abstract

Erythromelalgia is a rare hereditary channelopathy affecting the Nav1.7 sodium channel. Patients afflicted with this condition suffer from pain in their hands and feet, with vasomotor changes including flushing and redness to the distal upper and lower extremities. Current treatment modalities for this condition include pharmacological therapies (neuropathic medications), behavioural interventions, lumbar epidural infusions with local anaesthetics and sympathetic nerve blocks. Despite these treatments, many patients may have refractory pain. In these situations, there may be a role for dorsal column spinal cord stimulation for management of their pain. Here, we present the case of a 21-year-old man with 9-year history of refractory erythromelalgia successfully treated with paresthesia-free dorsal column spinal cord stimulation.

Background

Erythromelalgia (EM) is a rare disorder first described by Weir Mitchell in 1878.¹ It is characterised by episodic symptoms of red, hot, hyperperfused, painful skin areas associated with the upper and lower distal extremities.² Triggers for these symptoms include increases in environmental temperatures, exposure to heated surfaces or physical exercise while paroxysmal and circadian rhythm related episodes also occur.² Previously, EM has been a diagnosis of exclusion; however, diagnostic criteria have been proposed by Thompson et al to include burning extremity pain, pain aggravated by warming, pain relieved by cooling, erythema of the affected skin and increased temperature of the affected skin.³

There are predominantly two forms of EM. Primary EM is caused by an autosomal dominant mutation of the SCN9A gene, the alpha subunit of the human Nav1.7 sodium channel in the dorsal root and sympathetic ganglia.⁴ SCN9A is a highly polymorphic gene with over 70 mutations in this region associated with various phenotypes, of which over 20 have been identified and found to be associated with alterations to the Nav1.7 channel resulting in 100% penetrance. Mechanistically, these mutated sodium channels behave with increased neuronal excitability due to namely hyperpolarised shifts to activation, but also depolarised shifts in steady-state inactivation, slowed deactivation and enhanced ramp currents.⁴ Ultimately, this sensitises the sensory neurons resulting in increased blood flow to the distal extremities. Secondary EM is a condition not associated with any specific genetic mutations but is associated with various disease states including haematological conditions, infections, myeloproliferative disorders, neoplastic diseases, metabolic diseases and medications.¹

Early studies indicated a predominant presence of this condition in females with a mean onset age of 11.6 for those with syndromic presentation, 43.4 years in those with primary EM and 49.1 with secondary EM.⁵ In the paediatric population, the age of onset ranged from 1.2 to 14 years.⁶ Interestingly, this study classified syndromic presentation in familial cases independently from primary, though we now would classify both as primary with current definitions. The true incidence of this condition is not known. However, a study of incidence in a single centre in Sweden estimated the incidence as being 0.36 per 100 000 persons per year while an earlier Norwegian study noted an incidence of 0.25 per 100 000 person per year.^{2 7} In the USA, a population-based study in Olmsted County, Minnesota, USA, reported an incidence of 2.0 per 100 000 women and 0.6 per 1 00 000 men.⁸

EM is difficult to treat as most cases are refractory to traditional pharmacologic modalities.⁹ Similarly, nerve blocks may have limited efficacy since the mutation affects a sodium channel subunit that may be involved in local anaesthetic binding, reducing the efficacy of local anaesthetic.¹⁰ Currently, work is underway to develop Nav1.7 selective agents using viral delivery of anti-Nav1.7 sequences for treatment of EM.^{11 12} As it stands, there are not many options for treatment of this channelopathy with resultant neuropathic pain. In this vacuum, there may be a role for spinal cord stimulation (SCS).

SCS has been widely adopted for treatment of neuropathic pain conditions including failed back syndrome, refractory radiculopathy and complex regional pain syndrome.^13–17 Recently, studies indicate SCS may have a role in successful treatment of painful diabetic neuropathy.^{18 19} Further, several case reports have been published detailing successful use of SCS for management of nerve-associated pain conditions including multiple sclerosis, while animal models have shown promise for SCS in management of chemotherapy-induced neuropathic pain.^20–22 Given its ever-expanding role in the algorithm for management of chronic pain conditions, SCS may provide a means of management for EM. Here, we present a case of EM treated with dorsal column SCS.

Case presentation

A 12-year-old boy presented for evaluation of left foot pain in 2011 after hitting his foot while walking down the stairs resulting in persistent severe pain. At the time, imaging studies and surgical consultation determined that there was no structural damage. He was started on gabapentin and tiagabine, which were unsuccessful in managing his pain. The medications were stopped due to development of significant side effects including sedation and abnormal behaviours. His pain persisted, requiring several hospital admissions for epidural analgesic to address his pain. During this time, he was diagnosed with complex regional pain syndrome type 1. The patient was referred to physical therapy, hypnotherapy and pain psychology with minimal improvements; he was subsequently lost to follow-up.

Five years later, the patient presented in clinic for follow-up after being newly diagnosed with primary EM by his primary care physician. His symptoms evolved to include both his feet and hands with new positional flushing of his extremities (figure 1). During his time away, the patient had tried various other pain regimens including ketamine infusion, lidocaine infusion, lumbar sympathetic blocks, stellate ganglion blocks, cannabidiol (CBD) oil, pregabalin (300 mg two times per day), tramadol (50 mg daily) and duloxetine (30 mg daily) without significant improvement. Given his refractory case, SCS was offered and the patient and his parents agreed to a trial.

Figure 1.

Hands of patient with erythromelalgia. (A) pooling of blood away from hand when elevated. (B) cutaneous flushing and pooling of blood when hand is in gravity dependent position.

Treatment

The patient was trialled with 10 kHz frequency HF10 therapy (Nevro, Redwood City, California, USA) through a percutaneously placed split lead trial with the superior lead terminating at C2–3 space and the inferior lead placed at the top of T10 (figure 2). He was trialled for 8 days and reported significant relief. He had 85% relief of pain in his feet and 75% of pain in his hands. Given his experiences with the trial, the patient opted to pursue implantation. During implantation, the leads were placed at the top of C2 and top of T9 (figure 3).

Figure 2.

Post-trial imaging. (A) Cervical lead imaging prior to trial lead removal. (B) Thoracic lead imaging prior to trial lead removal.

Figure 3.

Intraoperative imaging. (A) Placement of cervical lead (C2). (B) Placement of thoracic lead (T9).

Outcome and follow-up

By 1-week follow-up after initiation of therapy, he noted some improvement of both areas. At 1-month follow-up, he lost efficacy of the hand relief and the device was reprogrammed to improve his upper extremity coverage. When last assessed at 5 months and 12 months follow-up, he had excellent relief in his hands and continues to work with programming to optimise his overall pain relief. Additionally, he noted functional improvement as he was able to participate in light simple exercises, something he was unable to do in the past due to his pain from EM. He was also able to perform tasks with his hands and began working again.

Discussion

Neuromodulation has been employed for treatment of EM as early as 1993 when Graziotti and Goucke successfully used a transcutaneous electrical nerve stimulation for management of EM in a 69-year-old patient with a 20-year history of secondary EM from a history of chronic deep vein thrombosis (DVT).²³ Since then, a few studies have been published on the topic (table 1). Patel et al published a case report of a 15-year-old girl with EM who had a paresthesia-based system at T12–L1 that successfully managed her pressure pain, but she continued to experience burning pain. This led the authors to report that two types of pain exist in patients with EM: pressure and burning. The patient was followed for 2 years and had beneficial analgesia with the device compared with mexiletine alone.²⁴ Matzke et al subsequently described a case of an 80-year-old woman with secondary EM treated with SCS with lead placement at T11 guided by pain mapping. Relief was noted up to 18 months after implant with significant decrease in her daily oral morphine equivalent usage.²⁵ Aside from pain improvement, the patient also noted improved vasomotor symptoms with decreased flushing of her feet. Fan et al later published the successful management of a 12-year-old girl with primary EM of her bilateral feet using a paresthesia-based system with leads at T11. She had complete resolution of her symptoms at 12-month follow-up as well as cessation of all pain medication.²⁶

Table 1.

Case reports published to date regarding percutaneous neuromodulation for management of erythromelalgia

Authors	Demographic	EM type	Pain site	Modality	Lead location	Outcome
Fan et al26	12-year-old girl	Primary	Bilateral feet	Paresthesia-based dual lead (eight contacts)	T11	Complete resolution of pain and symptoms at 12 months with cessation of pain medication use.
Matzke et al25	80-year-old woman	Secondary; type 2 diabetes	Bilateral lower extremities	Paresthesia-based dual lead (eight contacts)	T11	18 months relief with decrease in narcotic usage
Eckmann et al29	20-year-old man	Primary	Bilateral upper and lower extremity	Two paresthesia-based dual lead (eight contact) systems	C3 and T8	6 months relief, stopped all pain medications
Graziotti and Goucke23	69-year-old woman	Secondary; DVT	Bilateral feet	Paresthesia-based single lead (four contact) dorsal column stimulation	T9–10	Pain relief up to 18 months
Patel et al24	15-year-old girl	Primary	Bilateral feet	Paresthesia-based dual lead (eight contacts)	T12	Pain relief up to 24 months
Hagedorn et al28	70-year-old foman	Primary	Bilateral feet	DRG	Bilateral S1	Great relief similar to trial relief (80% improvement) at 3 months follow-up

DRG, dorsal root ganglion; EM, erythromelalgia.

The exact cause of pain from EM is unknown. In their case report in which a patient with EM was successfully managed with a course of epidural local anaesthetic infusion, Chinn and Guan theorised that it may be associated with dorsal root ganglion (DRG) dysfunction combined with sympathetic system dysfunction.²⁷ Recently, a case report by Hagedorn et al detailed the successful management of a patient with primary EM with bilateral S1 DRG stimulation with great relief 3 months postimplant, further validating the thought that DRG dysfunction may play a role in the symptomatology of EM.²⁸ In a literature review by Chinn and Guan, eight reports were found where epidural infusions were successful in managing EM symptoms and seven reported cases where lumbar sympathetic blocks were successful. However, they note that advanced interventions may be warranted in refractory cases. Though the mechanism for the relief by SCS for EM is unknown, it is thought to be due to inhibition of sympathetic tone, allowing for improved oxygen delivery through vasodilation for ischaemic pain while modulating dorsal horn signalling to improve neuropathic pain.²⁷

Similarly, our patient reported significant pain relief with SCS. Unique to our patient was the utilisation of paresthesia-free SCS and a split lead, single generator system for management of bilateral hand and foot pain. Eckmann et al had previously published a case report for successful management of upper and lower extremity pain from EM. However, in their scenario, they used paresthesia-based therapies through a two generator system (two cervical and two thoracic leads).²⁹ Like previously published case reports, our patient presented at an early age with a medically refractory course of treatment for their EM. Despite a variety of pharmacologic agents, injections, and epidural/intravenous infusions, he continued to experience debilitating pain. Eventually, he was able to obtain some relief by SCS and continues to work to improve his functional status. Utilisation of a paresthesia-free SCS modality in managing his EM is unique to this case, as previous reports were mostly paresthesia-based dorsal column systems. Further, this is the first reported case to our knowledge of a split cervical and thoracic lead single generator configuration for management of bilateral hand and foot pain for EM.

Care should be expressed when using SCS for EM treatment. Compared with other modalities, SCS is associated with a higher risk compared to pharmacological therapies and injection-based therapies for management of EM as it requires a surgically placed device with associated perioperative morbidities including the risk of anaesthesia exposure, wound dehiscence and perioperative infections. Once implanted, lead migration may complicate the healing process and decrease the therapeutic efficacy. Further, certain SCS devices are MRI compatible but certain restrictions on magnet strength may need to be exercised if they are to obtain future MRIs. Lastly, most devices will need to have the implantable pulse generator replaced in the future. Patients need to be comfortable with the idea of an implanted battery and the need for future battery replacements to be eligible for this therapy.

Our case report suggests that patients with medically refractory EM may benefit from SCS for management of their pain. Further, given the success experienced by our patient using a single generator split lead system, this configuration may provide benefit for patients with bilateral hand and foot pain from EM. To date, there are no large randomised clinical trials that compare SCS to the current treatment methods for EM. Future studies may help delineate the true efficacy of SCS in management of this condition, which may provide evidence for an earlier role for neuromodulation in the treatment algorithm. With new programming modalities including paresthesia-free high-frequency algorithms, there may be an increased role of SCS in management of unique and rare neuropathic conditions including EM.

Learning points.

• High frequency paresthesia free dorsal column spinal cord stimulation may be used for management of patients with extremity pain from type 1 erythromelalgia (EM).

• In patients with upper and lower extremity pain, a single unit, split lead configuration may be used instead of the previously published two system, quad lead configurations.

• There may be a role for high frequency paresthesia free dorsal column spinal cord stimulation for management of type 2 EM.

• Paresthesia mapping may not be needed for lead placement for management of EM-associated pain.

Ethics statements

Patient consent for publication

Obtained.