The challenge of recognizing severe pain and autonomic abnormalities for early diagnosis of CRPS

Patient material

A large number of patients were referred to the Department of Neurology, Section of Clinical Neurophysiology, Oslo University Hospital (OUS), Rikshospitalet in the period 2004 to present (2019), as part of an assessment of a chronic pain condition secondary to trauma or primary surgical treatment and for determination of degree of medical disability (insurance cases). Of these, a total of 52 patients diagnosed with CRPS (34 patients with type 1 and 18 patients with type 2) were selected for participation in this study. Current information is based on 1. a retrospective report from the patients on the development of pain and autonomic abnormalities from the time of the precipitating injury (interviews with the patients when examined at OUS-Rikshospitalet) 2. Reports of pain and autonomic changes from review of previous medical records, specialist statements from the time of the injury and 3. results from examination at OUS-Rikshospitalet (symptoms and clinical findings).

The patient material in this study is to some degree overlapping, but not entirely identical with the patient material reported previously, where patients were examined up to 2015 [20]. We have excluded patients from our previous material where we did not have accurate information of intensity of pain from time of injury, and we have included more new patients, investigated as late as in 2019.

Ethical considerations

The publication of results was considered by the Regional Ethical Committee as part of a quality improvement of a clinical material with no actual necessity of an ethical approval. We chose anyhow to obtain informed consent from the patients. All patients were investigated according to ethical guidelines and the Helsinki declaration and are anonymous in the present study.

Diagnosis of CRPS

When examined at OUS-Rikshospitalet, CRPS was diagnosed using two different guidelines/diagnostic criteria, depending on the time period of examination. Patients examined in the period 2004–2010 were diagnosed according to the IASP criteria Table 1 [6]. After 2010, new and current criteria were used, the so-called Budapest criteria [5] which are described in detail in Table 2 above

Patients’ retrospective reports of pain and autonomic abnormalities, when examined at OUS-Rikshospitalet

The patients were asked about both pain and symptoms of autonomic abnormalities (oedema, vasomotor and sudomotor changes, and trophic changes in the injured extremity), from the debut after the actual injury as well as the development of such symptoms. It was explicitly asked for the debut of pain and its intensity on a numeric rating scale (NRS) from 0 to 10, where 0 represents no pain and 10 worst imaginable pain.

Regarding the time course of autonomic dysfunction, we (retrospectively) explicitly asked for the onset and development over time of oedema, discoloration of skin, altered skin temperature, altered sweat pattern and trophic changes.

The onset/debut of autonomic abnormalities was classified as follows; (1) immediately after primary injury, (2) within one week, (3) within 2–4 weeks and (4) after one month.

We further defined the time period for development of autonomic changes as the time from onset/debut until a stable clinical picture was achieved. The distribution of type of autonomic signs and symptoms at both onset and at the time of a stable clinical picture was evaluated.

We also obtained a detailed description of both loss and/or addition of the type of signs and symptoms of autonomic dysfunction over time.

Clinical examination at Oslo University Hospital

Clinical examination was performed of all patients at OUS-Rikshospitalet, including a thorough neurological examination. An evaluation of anamnestic details of both symptoms and signs of autonomic abnormalities was performed in all patients. The following symptoms and signs were asked for: swelling/oedema, discoloration of the skin, altered skin temperature, trophic changes (changes in hair and nail growth, as well as thin and/or gleaming skin) and altered sweat production (increased/decreased).

Furthermore, a detailed patient history of the intensity of pain in the days following the actual injury as well as a detailed assessment of later pain profile was obtained, with description of the following variables; pain character, localization, spontaneous ongoing pain, paroxysmal pain and provoked pain (hyperalgesia and/or allodynia).

All patients were clinically examined for possible motor dysfunction in terms of possible palsy, as well as dystonia and tremor (results not reported here). A clinical assessment of sensory profile, including the presence of hyposensitivity and hypersensitivity, was performed for different modalities. Allodynia to light touch was tested with a cotton swab and hyperalgesia to pin-prick/pressure. EMG/neurography with Dantec counterpoint or Keypoint was performed in most patients (not possible in all patients due to pain) in order to ascertain the diagnosis of CRPS 1 vs. 2. Quantitative sensory testing (assessment of thermal thresholds) was also performed in all patients, but the results are not presented here and the methods not described.

Patient history as obtained from medical records

We obtained detailed information regarding past medical history from the time of the actual injury and until examination at OUS-Rikshospitalet from a complete overview of the patients’ medical records sent to the principal investigator (Dr. Jorum) (from primary care physicians as well as specialists (orthopedic surgeons, specialists in pain medicine, specialists in “physical medicine”, neurologists) before examination at OUS-Rikshospitalet). All information about pain (debut and development of pain, eventual intensity of pain) as well as the description of autonomic abnormalities from the time of the injury until examination at OUS-Rikshospitalet was noted.

Comparison of reports of symptoms and actual signs of autonomic abnormalities

Diagnosis of CRPS is based on a total clinical picture, requiring a combination of both symptoms and clinical signs. We wanted to evaluate if the clinical signs during examination at OUS-Rikshospitalet coincided with the patient’s reported symptoms on the day of investigation, or if there existed a discrepancy.

Autonomic dysfunction according to eliciting events

For all patients the mechanism of injury/eliciting event was noted. The following groups were described and classified; (1) Soft tissue damage without fracture, (2) Fractures and (3) Primary surgery. Soft tissue injury (gr. 1) was composed of patients with contusions, squeeze injuries, crushing injuries, stretch injuries and cut/penetrating injuries.

We also included patients with soft tissue injuries and fractures, who had also undergone secondary surgery with exacerbation of pain and often with development of additional signs and symptoms. Group 4 (tissue injuries) and 5 (fractures) therefore represent patients with a secondary triggering event (i.e., secondary surgery).

The distribution of symptoms and signs of autonomic dysfunction at examination at OUS-Rikshospitalet was evaluated for these five groups of eliciting events. We investigated for possible correlations between type of autonomic dysfunction and type of eliciting events. Analyzes were performed only for CRPS 1 and 2 merged, as the numerical data for CRPS 1 and 2 separately were too small, and could have resulted in unreliable results.

Statistical analyses

In this study, we investigated for significant differences between CRPS type 1 and 2. A student Mann–Whitney U-test was used to compare the following variables: (1) mean time for development of a stable clinical picture, (2) mean difference in skin temperature between healthy and affected side and (3) mean pain intensity (numeric rating scale-NRS).

Furthermore, we used a two-sided chi-square test (non-parametric test) to compare (1) debut/onset of autonomic dysfunction, (2) distribution of the type of signs and symptoms of autonomic dysfunction at examination at OUS-Rikshospitalet and (3) distribution of allodynia, hyperalgesia and paroxysmal pain.

We also investigated for significant differences (using a two-sided chi-square test) between the defined groups of eliciting events and the distribution of autonomic dysfunction at examination at OUS-Rikshospitalet, but it was not possible to conduct a more detailed analysis separately for CRPS 1 and 2 due to an insufficient number of patients in each group. For all described analyzes a p-value of less than 0.05 (5%) was defined as being statistically significant.

Limitations of the study

We include retrospective reports of the patients’ intensity of pain from the time following the injury as well as reports of time debut and development of autonomic abnormalities. A retrospective analysis will always be encumbered with possible errors.

Furthermore, we removed five patients with CRPS type 1 and three patients with CRPS type 2 in an analysis of data from previous medical reports, because it was uncertain whether we had the complete set of medical records for evaluation of autonomic abnormalities.

Pain profile

All patients reported spontaneous pain immediately or within the first days of the eliciting event. Mean pain intensity was 7.27 (SD 1.7) (CRPS1 and 2) 7.2 (SD 1.8) (CRPS1) and 7.3 (SD 1.6) (CRPS2).

A detailed presentation of stimulus dependent and independent pain from the investigation at OUS-Rikshospitalet is presented in Table 3.

We found no significant differences between CRPS1 and 2. Correlation analysis between pain variables (Table 3) and autonomic symptoms was not possible to perform.

Report of early pain (less than four months following injury) in medical reports

For patients with verified CRPS type 1 (n=34), there were reports of intense pain (described as strong, intense, increasing) in at total of 10 patients (29.4%). In the remaining patients, there were either no notifications of pain or only pain, with no evaluation of intensity. Pain in the early phase was not assessed by VAS (visual analogue scale) nor NRS (numeric rating scale). For patients with CRPS type 2 (n=18), intense pain (described as strong, intense, unbearable) was reported in a total of 8 patients (44.4%).

Early onset of autonomic dysfunction, as reported retrospectively by the patients

Of a total of 52 patients, merged for CRPS 1 and 2, we found the following distribution of onset of autonomic dysfunction: 16 patients (30.8%) with immediate onset, 19 (36.5%) with onset within 1 week, 13 (25%) within 2–4 weeks and three patients (5.8%) with onset after one month. Subsequent to the eliciting event/injury, we found that autonomic dysfunction was present in 67.3 and 94.2% of the patients within 1 week and 1 month, respectively. We found similar figures separately for CRPS type 1 and 2, without any significant differences. The distribution of various autonomic failures within the first month is presented in Table 4A.

Development of autonomic symptoms and signs over time, as reported retrospectively by the patients

Mean time from onset until a stable clinical picture (symptoms and signs of autonomic dysfunction) was achieved were 1.02 years for CRPS 1 and 2 merged, 1.05 for CRPS 1 and 0.96 years for CRPS 2 (no significant difference).

The distribution of symptoms and signs of autonomic failure changed over time (Table 4B). The main trend was that over time, patients developed additional symptoms and signs of autonomic abnormalities. The exception was a continuous reduction in both self-reported and objective detection of oedema, from 86.5% (88.2 and 83.3% of patients with CRPS type 1 and 2, respectively), to 73.1% (82.3 and 55.5% for CRPS 1 and 2, respectively). For all other variables of autonomic dysfunction, an increase was seen over time (Table 4B).

Skin discoloration was the most common type of autonomic dysfunction, present in 46 patients (88.5%), followed by alteration in skin temperature, oedema, and altered sweat patterns, while trophic change was least frequent (Table 4B) (no significant difference between CRPS1 and 2).

A total of 92.3% of the patients experienced a change (loss or addition of symptoms and signs), 88.5% of patients (CRPS 1 and 2) experienced an overall increase in symptoms and signs, while only 3.8% (CRPS 1 and 2 merged) experienced an overall loss of symptoms and signs. Alteration in skin temperature was the most frequent additional symptom/sign, accounting for 57.7% for CRPS 1 and 2 merged. Oedema very rarely developed over time, only in 3.8%. The remaining symptoms and signs were evenly distributed and present in just under 50% of the patients. We tested for possible statistical differences between CRPS 1 and 2 and found that the development of both trophic changes (p-value = 0.032) and altered sweat patterns (p-value = 0.006) was significantly higher in patients with CRPS 1 (Table 5).

Of the various autonomic changes, we found that oedema was the most frequent feature that lapsed over time, both for CRPS overall (19.2%) and for types 1 and 2 separately.

Apart from oedema, loss of autonomic changes was relatively rare over time. For the other variables, we found the following distribution for loss of autonomic dysfunction, merged for CRPS 1 and 2, 7.7% of patients with skin discoloration, 1.9% of altered skin temperature, 1.9% of trophic changes and 3.8% of altered sweat pattern. We found similar patterns for CRPS 1 and 2 separately, without any statistical differences between CRPS 1 and 2.

Assessment of autonomic symptoms and signs from medical records

We report from 29 (of 34) patients with CRPS 1 and 15 (of 18) patients with CRPS 2. It was not possible to evaluate presentation of autonomic dysfunction from the first week post-injury, so we chose to present reports of symptoms/signs of autonomic abnormalities within the first four months following injury, and then symptoms and signs in the following months and years. The results are presented in Table 6, separately for CRPS 1 (Table 6A) and CRPS 2 (Table 6B). As apparent from the results, descriptions of autonomic abnormalities were far inferior to what reported by the patients. In a total of 10 patients with CRPS 1, no symptom or sign of autonomic abnormalities was reported.

Diagnosis of CRPS prior to or during examination at OUS-Rikshospitalet

CRPS was diagnosed in 35 patients prior to investigation at OUS-Rikshospitalet and only by specialists, primarily specialists in orthopedic surgery or in pain medicine, and by no primary care physician (although autonomic abnormalities were described by some physicians). A total of 20 patients were diagnosed in the time period of IASP criteria and 32 patients by Budapest criteria. However, the exact criteria were seldom mentioned, it was noted “diagnosis according to criteria” or also with no mentioning of any criteria. Budapest criteria was mentioned in the case of three patients. When the diagnosis of CRPS was decided, also in the time period of Budapest criteria, there was seldom mentioning of more than one or two types of autonomic abnormalities, see next section. Diagnosis in the time period of Budapest criteria, was seldom based on a combination of both symptoms and clinical findings (as required).

For the whole material (n=52): in a total of 10 patients with CRPS type 1, there was no report of any autonomic abnormalities during the first four months following injury, seven patients with injury after 2010 (time period of Budapest criteria with more specific demands of autonomic failures) and three patients in the time period of former IASP-criteria. Four of these patients were diagnosed from 13 to 21 months post-injury. The remaining six (as also included in section below) from 51 to 126 months after injury. There was no significant difference in delay of diagnosis from the use of Budapest (38.2 months [SD 37.9 min 2 max 139]) or IASP (28.2 months [SD 22.7 min three max 75]) criteria.

A total of 10 patients (six patients also from section above) were diagnosed with CRPS type 1 as late as greater than four years (range 50–139 months), two patients with injuries before 2010 and eight patients after 2010 (Budapest-criteria). Intense pain was only reported in one patient, and autonomic changes only for two patients (oedema in one case, discolored skin in one patient). On the other hand. a total of eight patients, six with CRPS type 1 and two patients with CRPS 2, were diagnosed by specialists (orthopedic surgeons and pain specialists) within four months following injury. In these patients, intense pain was described in four patients with CRPS type 1 and in both patients with CRPS type 2 (recognizing the risk factor of intense pain). Autonomic abnormalities were also described in more detail. Details of time intervals for diagnosis are presented in Table 7.

Distribution and correlation of clinical signs and self-reported symptoms of autonomic dysfunction during investigation at OUS

At examination at OUS-Rikshospitalet, we assessed whether symptoms of autonomic failure coincided with the actual clinical findings. We found an equal distribution only for altered skin temperature in the affected limb (Table 8, around 85% of the patients). For all other modalities, there was a higher degree of self-reported symptoms compared to what was objectively found (Table 8). This discrepancy was most prominent for oedema, which was reported by 38 (73.1%) and demonstrated in 17 (32.7%), a difference of 40.4% (p<0.001) and for alteration in sweating (primarily hyperhidrosis) reported in 26 (50% and demonstrated only in 3 (5.8%) (p<0.001) (and with no significant difference between CRPS 1 and 2). Also, with regard to discoloration of skin and trophic changes, there were larger percentages of reported symptoms than clinically shown, but with lesser differences.

The eliciting injuries/events

Isolated soft tissue injuries were the most frequent eliciting cause in our patient material, both overall (38.5%) (CRPS 1 [41.2%] and CRPS 2 [33.3%]), followed by fractures/skeletal injury 23.1% (26.5% in CRPS 1, 16.7% CRPS 2), primary surgery 7.7% (8.8% CRPS1 and 5.6% CRPS 2). Merged for CRPS 1 and 2, exacerbation after subsequent surgery was seen in 19.2% of patients with primary soft tissue injury, and in 11.5% of patients with primary skeletal injury (fractures). In our patient material we found that 30.7% of patients (CRPS 1 and 2 merged) experienced exacerbation after subsequent surgery. These figures are presented in Table 9.