Imaging the neural correlates of neuropathic pain and pleasurable relief associated with inherited erythromelalgia in a single subject with quantitative arterial spin labelling

Abstract

We identified a patient with severe inherited erythromelalgia secondary to an L858F mutation in the voltage-gated sodium channel Na(v)1.7. The patient reported severe ongoing foot pain, which was exquisitely sensitive to limb cooling. We confirmed this heat hypersensitivity using quantitative sensory testing. Additionally, we employed a novel perfusion imaging technique in a simple block design to assess her baseline erythromelalgia pain vs cooling relief. Robust activations of key pain, pain-affect, and reward-related centres were observed. This combined approach allowed us to confirm the presence of a temperature-sensitive channelopathy of peripheral neurons and to investigate the neural correlates of tonic neuropathic pain and relief in a single subject.

Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1

Graphic representation of the erythromelalgia psychophysical paradigm. For clarity, each coloured block represents the temperature of water continuously perfusing over the subject’s feet: “BASE” (mean temperature = 35.5°F, SE = 0.72; light gray) vs “cool” (mean temperature = 13.9, SE = 0.86; dark gray). The bottom panel shows the arterial spin labelling scan paradigm used. A 10-minute resting-state (RSN) was acquired at the beginning and end of the paradigm. Five-minute blocks of continuous erythromelalgia-associated pain (BASE, light blue) vs pain-relief (cool, dark gray) were repeated 3 times per scan session. Each scan was separated by approximately 3 minutes. Two separate scan sessions were acquired for this subject. Black bars show when the pain intensity and unpleasantness ratings were taken (verbal report, NRS).

Fig. 2

Photograph of the patient’s legs showing erythema up to the level of the mid calf.

Fig. 3

Quantitative sensory test results. Quantitative sensory tests were performed on both hands and feet. These same tests have been repeated in normal healthy controls to comprise an extensive database as generated and held by the German Neuropathic Pain Network (DFNS) (8). These normal data are distributed within the shaded area (mean at 0 ± 2 SDs). Data from our subject are reported as z-score profiles for each sensory test as depicted here. z Score is defined as the SD of the recorded result from the mean normal data result. Each data point is discrete, however, they are connected for graphical illustration as a z profile. Quantitative sensory tests included: CDT (cold detection threshold), WDT (warm detection threshold), TSL (thermal sensory limen), CPT (cold pain threshold), HPT (heat pain threshold), PPT (pressure pain threshold), MPT (mechanical pain threshold), MPS (mechanical pain sensitivity), WUR (wind up ratio), MDT (medical detection threshold), and VDT (vibration detection threshold). All tests to the control site were within normal limits. Hypersensitivity to heat pain is demonstrated by a lowered HPT in the feet. Hyposensitivity to deep pressure (PPT) and vibration (VDT) is also seen in the feet. These abnormal sensitivities may be attributable to thickening of the skin at the test site. Additionally, the presence of paradoxical heat sensations was tested using TSL. Three paradoxical heat sensations were recorded in the feet (an abnormally high number), whilst there were none in the hands.

Fig. 4

(A) Psychophysical data. Verbally reported pain intensity (solid) and unpleasantness (opaque) ratings averaged over the 5-minute blocks of erythromelalgia-associated heat pain (purple) and blocks of pain relief (blue) across both sessions. Error bars represent SD from the mean. (B) Brain perfusion data from the erythromelalgia case study acquired with the multi-TI whole brain pseudo-continuous arterial spin labelling sequence. Averaged zstat maps (n = 1) of perfusion activation superimposed on the MNI152 standard template brain (fixed effects, cluster corrected; z: 2.3–5.0, P < 0.05). Perfusion maps represent the contrast of the subject’s erythromelalgia-associated pain vs blocks of cooling pain relief. The sagittal slice shows the column of activation across the whole brain. Axial slices (one slice every 10 mm in ascending order) correspond to the plane indicated in the sagittal slice.