Abstract
Background
Trigeminal autonomic cephalalgias and complex regional pain syndrome are rare conditions, and their co-occurrence has not been reported previously.
Conclusions
These findings suggest some overlap in the pathophysiology of complex regional pain syndrome and trigeminal autonomic cephalalgias. Specifically, central sensitization and/or disruption of inhibitory pain modulation on the affected side of the body in complex regional pain syndrome might trigger ipsilateral cranial symptoms and increase vulnerability to trigeminal autonomic cephalalgias.
Keywords
Introduction
Trigeminal autonomic cephalalgias (TACs) encompass headaches associated with cranial autonomic disturbances. The prototypical TAC, cluster headache, is linked with activation of the ipsilateral posterior hypothalamus during attacks (1). This activation may disrupt trigeminal pain processing and drive trigeminal-parasympathetic reflexes that generate lacrimation and rhinorrhoea.
In this report, we describe a novel association between TAC and complex regional pain syndrome (CRPS), an uncommon chronic pain syndrome that may develop after limb injury (2,3). Like cluster headache, CRPS is associated with autonomic disturbances in the painful region (4) and with a probable deficit in descending inhibitory pain controls (5–7). We sought to clarify whether the co-occurrence of TAC and CRPS in two patients was due to shared pathophysiology.
Methods
Ethics.
Both patients provided their informed consent for the procedures (8–10), which were approved by the university’s Human Research Ethics Committee.
Psychophysical assessments.
Sensitivity to pressure, pinprick, brushing, cold and warmth was assessed on the dorsum of the affected and contralateral upper limbs and the lower limbs, and on each side of the forehead (9,10). In addition, the visual discomfort threshold and pupil diameter were assessed (9).
Forehead cooling.
The 1.5 cm end of a metal bar, cooled to 2°C, was applied to each side of the forehead for 30 s while the patient rated limb pain at 5-s intervals (0 corresponding to “no pain” and 10 to “extremely intense pain”) (8).
Case reports
When examined 33 months after the injury, CR1 reported aching, stabbing and burning pain in the left fourth and fifth fingers, the left forearm and upper arm to the shoulder, associated with numbness and pins-and-needles. The fourth and fifth fingers were swollen and cyanotic, felt numb, were difficult to move voluntarily, and resting tremor was observed. When measured with an infrared thermometer, the temperature of the dorsal proximal segment of each finger was 2.3 to 4.5°C cooler on the left side than the right (mean ± standard deviation 24.1 ± 1.1°C versus 27.6 ± .8°C).
CR1 was sensitive to mechanical and thermal stimulation not only in his affected hand but also in the ipsilateral lower limb and forehead (Table 1). An acoustic startle stimulus (1 kHz, 92 dBA, 0.5 s) sounded more uncomfortable in his left ear than right. In addition, cooling the left side of his forehead aggravated pain in his left forearm whereas pain remained unchanged when the right forehead was cooled.
Sensory assessment.
CR1 had been free from headaches until approximately one year after he injured his hand. Since then, extremely severe left-sided headaches lasting around 30 minutes had recurred once or more/day without significant periods of remission despite treatment of CRPS and TAC with duloxetine, pregabalin, tapentadol and verapamil. They spread from the left occipital region to behind his left eye and cheek. The headaches were associated with left-sided lacrimation and conjunctival injection, and the left eyelid drooped. A typical attack developed during an assessment of photophobia. The visual discomfort threshold was 804 lux on the left and 1,133 lux on the right, the left eye watered and the left eyelid drooped (Figure 1A). The headache lasted approximately 40 minutes. On another occasion, an attack developed shortly after examination of sensitive scars in the left hand and persisted for 23 minutes when treated with 100% oxygen.
A. Pupillometry in CR1 during an attack of cluster headache. Both in bright light (500 lux, 1) and dim light (5 lux, 2), the palpebral fissure was smaller on the left (affected) side than the right. Photographs of the pupils were taken with a Nikon D7000 camera (Nikon Corporation, Tokyo, Japan), modified to extend into the infrared range to enhance the contrast between the pupil and iris. B. MRI angiography in CR2 of an anomalous loop of a vessel arising from the basilar artery abutting the VII and VIII cranial nerve root entry zone at the left pontomedullary junction (arrows). C. Pupillometry in CR2 after several minutes of dim light (5 lux, image 1) and the first 6 s of exposure to bright light (500 lux, images 2–7). This was followed by several minutes of exposure to bright light (image 8), then 6 s of exposure to dim light (images 9–14). Note the progressive decrease in the width of the left palpebral fissure over the course of the exposure, even in dim light. Note also that the left pupil was slightly smaller than the right pupil in most images.
Starting 55 months after the injury, CR1 recorded headaches and hand pain for 14 consecutive days. During this time, CR1 experienced 31 moderately or intensely painful left-sided headaches (1–3/day lasting 10–45 minutes, mean duration 24 ± 9 minutes). Hand pain increased from 5.3 ± 1.2 (± standard deviation on a 0–10 pain intensity scale) before the headache to 6.7 ± 1.1 during the headache (p < .001).
When examined 38 months after the injury, CR2 described burning pain and pins-and-needles around her left elbow and in her left forearm and hand. The fingers of her left hand were swollen and cyanotic. She had lost power in her left hand and the fingers occasionally assumed a fixed flexed posture. The temperature of the dorsal proximal segment of each finger was 2.7 to 4.1°C cooler on the left side than the right (22.7 ± .3°C versus 26.3 ± .6°C).
CR2 was sensitive to mechanical and thermal stimulation of her left hand, and this sensitivity extended to her ipsilateral forehead and foot (Table 1). An acoustic startle stimulus sounded more uncomfortable in her left ear than right, and upper limb pain increased slightly when the startle stimulus was presented on the left. Cooling either side of the forehead aggravated tingling sensations and pain in her left forearm and triggered a burning sensation around her left eye; this developed more quickly and intensely when the left forehead was cooled. The visual discomfort threshold was 680 lux on the left and 876 lux on the right. Headache intensified during an assessment of the pupillary light reflex in association with progressive eyelid closure and persistent left-sided miosis (Figure 1C).
Local anaesthetic block of the stellate ganglion alleviated limb pain, headaches and associated symptoms, apart from facial tingling, for approximately two weeks. Similar but more persistent effects were achieved for limb pain and facial symptoms after radiofrequency block of the stellate ganglion.
Starting eight weeks after the radiofrequency block, CR2 rated pain and other symptoms for 22 consecutive days. Pain in her hand and face cycled together, peaking in the afternoon and evenings (Figure 2). Treatment with indomethacin was then initiated. Facial pain averaged 4.0 ± 1.2 (± standard deviation) for 22 days before and 1.5 ± 1.3 for 15 days during 75–100 mg indomethacin treatment daily (p < .001). When followed up two months later, CR2 reported recurrence of facial tingling and mild headaches with an occasional stronger flare while taking 100 mg indomethacin daily.
Association between pain in the face and hand in CR2, rated between 0 (no pain) and 10 (extremely severe pain) over 22 consecutive days. Each day is represented by a separate data point; however, fewer than 22 points are shown in each graph because of data overlap. Note the close association between pain in the face and hand from day to day, and that pain generally worsened as the day wore on.
Discussion
In both patients, CRPS preceded the onset of TAC by many months. Importantly, TAC was ipsilateral to upper limb CRPS, and hyperalgesia extended beyond the upper limb to encompass the ipsilateral forehead and special senses. In addition, photophobia was greater on the affected than contralateral side, and bright light appeared to aggravate symptoms. Facial and upper limb pain cycled together in both patients. Furthermore, in one patient, stellate ganglion blockade inhibited pain for an extended period not only in the affected limb but also the face (perhaps by reducing secondary central sensitization). Together, these findings suggest some overlap in the pathophysiology of CRPS and TAC.
CR1 presented with features of cluster headache whereas symptoms in CR2 were consistent with indomethacin-responsive hemicrania continua possibly linked with vascular impingement on the left facial nerve root. Secondary TAC can arise from displacement of brainstem structures or cranial nerves by tumours or blood vessels (11). Although it is difficult to draw cause-and-effect conclusions from just one case, we speculate that vascular irritation of the facial nerve generated paraesthesiae and aggravated parasympathetic signs, peri-ocular muscle spasm and facial droop during severe attacks. Sensory disturbances associated with this putative vascular irritation might have resembled hemicrania continua due to CRPS-linked sensitization of nociceptive inputs.
In CR2, squinting to bright light appeared to exacerbate eyelid closure. Like other patients with CRPS, the visual discomfort threshold for monocular stimulation of each eye (but particularly on the affected side) was well below the normal range for monocular stimulation in pain-free controls (normal visual discomfort threshold >2,400 lux) (9). Photophobia was accompanied by hyperalgesia in the ipsilateral forehead, consistent with aberrant processing of nociceptive and visual inputs in the trigeminal-medullary region of the brainstem.
CRPS pathology likely disrupts inhibitory influences on noxious sensations evoked by visual, auditory and cutaneous stimuli, more so on the affected than contralateral side of the body (5,8–10,12). Specifically, disruption in the trigeminocervical complex and/or thalamus might account for ipsilateral cranial symptoms (9,12). Descending inhibitory pain controls appear to be impaired during bouts of cluster headache (6), and this may increase activity in the trigeminocervical system during attacks. It is difficult to draw firm conclusions based on only two cases. However, it is tempting to speculate that spread of CRPS pathology within the brainstem and/or thalamus triggers expansion of symptoms to include the head and neck, and increases vulnerability to TAC. The association between CRPS and TAC came to our attention because, in our two cases, examination of the CRPS-affected limb and/or visual stimulation was a consistent trigger for TAC. The low incidence of TAC (1) and CRPS (3) might explain why this association has not been reported before.
The mechanism proposed here for co-morbidity of CRPS and TAC is not proven and could be wrong. However, further investigation seems warranted as similar mechanisms might apply for other forms of chronic pain (e.g., fibromyalgia) and headache (e.g., migraine). If so, treatments that target chronic pain could decrease symptoms in a variety of headache syndromes.
Clinical implications
In two patients, upper limb CRPS preceded the onset of ipsilateral TAC by many months. Hyperalgesia extended beyond the upper limb to encompass the ipsilateral forehead and special senses. CRPS-associated disruption of inhibitory pain modulation might trigger ipsilateral cranial symptoms and increase vulnerability to TAC.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
