Pain and small-fiber affection in hereditary neuropathy with liability to pressure palsies (HNPP)

2.1 Material

Nineteen patients above 18 years with genetically verified HNPP were included in the study. None of the patients suffered from other diseases likely to induce neuropathy. The study was approved by the Regional Ethical Committee and the patients have signed informed consents.

2.2 Clinical examination

The patients underwent a clinical neurological examination included testing of motor and sensory function, including reflexes. They were asked about the presence of ongoing, paroxysmal and evoked pain, the distribution and intensity of pain (if present).

2.3 Nerve conduction study (NCS)

The patients were examined with a Keypoint Dantec (Skovlunde, Denmark) with measurements of motor amplitude, distal latency and nerve conduction velocity in the median and ulnar nerve in the upper extremity and the peroneal and tibial nerve in the lower extremities. Sensory amplitudes, distal latency as well NCV were established from the median, ulnar, radial, superficial peroneal as well the sural nerves. All values were compared to normal values in the Keypoint equipment.

2.4 Quantitative sensory testing

Threshold temperatures for the sensation of warmth, cold, heat pain and cold pain were determined using a computerized Thermotest (SENSElab, Somedic A/B, Hörby, Sweden) with a thermode size of 5×2.5 cm. Warmth detection threshold (WD), cold detection threshold (CD), heat pain detection threshold (HP) and cold pain detection threshold (CP) were determined from a baseline temperature of 32 °C with a 1 °C/s rate of change. The subjects were instructed to push a signal-button when the relevant sensation was perceived. When this happened or if cut-off temperature (50 °C and 10 °C) was obtained, the temperature returned to baseline. WD, CD, HP, CP were determined from the right thenar eminence (within the innervation territory of the median nerve) and the dorsum of both feet in all patients (within the innervation territory of the peroneal nerve) as well as the lateral part of both legs, below the knee. For calculations of thresholds, an average of five recordings for WD and CD and the average of three recordings for HP and CP were used. The values were compared with values from age- and sex matched healthy individuals. For individual evaluation of thermal thresholds, these were judged pathological when like or above 95 percentile of normal controls for warmth (41.1 °C) and like or below 25 percentile for cold (26.8 °C).

2.5 QSART

Evoked sweat response at rest from the dorsum of the feet was measured by the Quantitative sudomotor axon reflex tester (WR medical electronics co, Stillwater, OK, USA).

To evoke axon reflex sweating, iontophoresis (2 mA for 5 min) of 10% acetylcholine (ACh) was started after a stable baseline sweating level had been obtained. A commercially available device (Iontophor ll, Life-Tech Inc., Stafford, TX, USA) was used for this purpose. Axon reflex sweat output during the 5 min of iontophoresis and additional 10 min was recorded via a sweat capsule with an area of 0.767 cm² attached to the skin of the dorsum of both feet.

Values were compared with normal values form previous investigations of healthy persons.

2.6 Statistics

Non-parametric statistical methods were used (IBM SPSS Statistics 25), the median as a measure of location and the interquartile range as a measure of distribution, except for age where mean (SD) are reported. Mann-Whitney U test was used to calculate significant differences between patients and normal controls and between patients with and without pain. Values of p<0.05 were considered statistically significant.

3.1 Material

Nineteen patients were included, eight men and 11 women (mean age 40.4, median 41.5). Eleven patients were related, from different families (Table 1). All patients had a verified mutation 17p 11.2 PMP22. Clinical findings and results of neurophysiological testing are presented in Tables 1 and 2.

3.2 Results of clinical findings

A total of 10 patients reported numbness in some extremity, most in the arms. The results of clinical examination revealed reduced sensibility to light touch distally in the legs and to some extension also in the hands in nine patients. Absent or weakened reflexes (at the level of the knee or ankle) were found in four of these patients. The clinical findings were compatible with a clinical polyneuropathy, corresponding to the findings of a more generalized neuropathy on NCS, either pure sensory or combined motor/sensory.

In these 10 patients, NCS (Table 1) showed findings of entrapment of several nerves, predominantly the median and ulnar nerve in the arm, peroneal nerve in one patient as well as a more generalized neuropathy in nine and normal results of NCS in one patient. In three patients who reported a combination of both numbness (arms) as well as pain in the feet, NCS showed findings of a general neuropathy in addition to small fiber affection. NCS also showed abnormalities in four patients with no numbness but with pain.

3.3 Results of nerve conduction studies (NCS)

Results of NCS were missing in two of the patients. In the remaining 17 patients, there were pathological findings as indicated in Table 1, either with findings compatible with entrapment of individual nerves alone (n=2) or in combination with a more general neuropathy (n=13). Two patients had only findings of a general polyneuropathy.

Of a total of 15 patients with a general neuropathy (with and without pain), NCS showed sural nerve abnormality (n=8), or a combined motor/sensory neuropathy (n=7). Twelve of these patients had elevated thermal thresholds, either with elevated both cold – and warm detection thresholds (n=7), or only cold detection thresholds (n=5) (Table 1).

Only two patients had a general large fiber sensory neuropathy with normal temperature detection thresholds.

3.4 Patients with pain and small fiber affection

A total of 8/19 patients suffered from pain, mainly distal pain in both feet (7/8). The pain was described as burning, aching, shooting. Six of the seven patients with pain in feet had a severe damage to small nerve fibers, all with elevated cold detection thresholds, but also four patients with elevated thresholds to warmth (Table 2). One of the seven patients had only borderline cold detection thresholds. Four of the patients with pain in the feet had signs of a severe sensory neuropathy on NCV, with no sural nerve findings. Only one of the patients had signs compatible with an entrapment of the peroneal nerve. One patient with only pain in the arms, had only minor changes on NCS and normal QST-values. Mean age of patients with pain was 40.4 years (SD 12, 3) at the time of investigation. We have not sufficient information as to conclude on the start of painful symptoms.

When comparing QST values between patients with pain and patients without pain, there were no significant difference at group levels (Table 3).

3.5 QST values of patients compared to healthy subjects

Cold detection thresholds (CD) were significantly elevated (reduced sensibility) on the dorsum of the foot (mean of two feet), in patients [26.0 °C (19.7–28.0)] as compared with healthy subjects [28.6 °C (27.4–29.6) p=0.000]. Warm detection thresholds were also elevated in patients [39.5 °C (36.4–42.9)] as compared with healthy subjects [37.7 °C (36.1–39.4)] p=0.048. Also warmth detection threshold in the hand was elevated in patients [34.7 °C (33.9–35.3)] as compared to healthy subjects [33.9 °C (33.3–34.4) (p=0.013)]. Cold pain threshold was also reduced (higher temperature) on the thenar eminence in patients 15.5 (11.8–16.8) compared to heathy subjects [10.0 (10.0–12.5) (p=0.001)] compatible with a relative cold allodynia in the patients. There were no significant differences in other thresholds (Table 4).

3.6 QST-changes related to entrapment of individual nerves

QST was performed on the thenar eminence, within the innervation of the median nerve, and on the dorsum of the feet, within the innervation territory of the peroneal nerve. A total of 14 patients had NCS findings showing affection of the median nerve (only sensory for some patients, but combined motor and sensory in most patients), but only four of these patients had pathological QST values, two patients with elevated cold detection thresholds, one patient with borderline cold detection threshold, and one patient with elevated warmth detection threshold.

Several patients had NCS findings of peroneal nerve affection (in a general neuropathy), but only one patient had a verified entrapment of the peroneal nerve at the level of the knee (Table 1).

3.7 The effect of age

Comparing patients with and without pain, the mean age was [40.4 (SD 12.33)] in patients with pain and [39.2 (SD 12.7)] in patients without pain, but the difference was not significant (p=0.78).

3.8 Autonomic findings

Seven patients had reduced QSART volumes from the dorsum of the feet, absent responses in five patients, reduced on the dorsum of the feet in one patient, and only reduced on one foot in one patient indicative of a damage of autonomic efferent sudomotor small unmyelinated C-fibers. Five of these patients had a general motor-sensory polyneuropathy. In one patient NCS was missing and in one of the patients with absent response, NCS was normal. Only two of these patients had elevated thermal thresholds on both feet. Only one patient with absent response and elevated thermal thresholds suffered from pain. There were no report of abnormal or reduced sweating.