5. Congenital indifference to pain
With these insights into the basis of pain insensitivity, stoics will patiently await the unravelling of the genetic basis of the clinically less pressing, but philosophically more interesting problem of congenital indifference to pain. – John Wood, 1996
Congenital indifference to pain, also referred to as congenital universal insensitivity to pain, has been reported since the early 1930s (Dearborn; Ford; Boyd; McMurray; Ogden; Landrieu and Davis). These individuals typically have painless injuries beginning in infancy, but normal sensory responses on examination. Perception of passive movement, joint position, and vibration is normal, as are tactile thresholds and light touch perception. The ability to distinguish sharp and dull stimuli and detect differences in temperature seems to be intact ( McMurray and Ogden). Reflexes and autonomic responses are also normal.
Peripheral nerve samples were obtained from several of the earlier cases of congenital indifference to pain, and no abnormalities were observed (Ogden et al., 1959). Because of their seemingly normal neurologic examinations, these individuals were considered to have a deficit in the affective response to pain rather than in the sensory discrimination of painful stimuli. However, because morphometric analysis of nerve fiber size density had not been performed, it is unclear whether selective loss of nerve fibers was present. There have been mixed results with some biopsies reported as abnormal ( Low and Dyck) and it is possible that some cases are HSAN V. Because of the possibility of peripheral neuropathy, these cases are therefore not considered definitive examples of indifference to pain ( Dyck and Thomas).
A case of congenital indifference to pain with normal nerve morphology has been described by Landrieu et al. (1990). The patient was a 5-year-old girl with painless fractures and indifference to ‘casual injuries’. Withdrawal reflexes and grimacing were present to pinprick and hot water (43°C), but she was indifferent to prolonged or repeated application of the painful stimuli anywhere on her body. Subcutaneous injection of histamine yielded normal results. She had an otherwise normal neurological examination. She detected pinprick, heat, and cold, and responded normally to light touch, joint position, vibration, and pressure. Her reflexes were normal, no autonomic abnormalities were observed, and cortical sensory evoked potentials were normal. A sural nerve biopsy appeared normal using electron microscopy, and the size density distributions appeared normal for both myelinated and unmyelinated fibers. In addition, she was reported to have normal psychomotor development.
The normal electron microscopic nerve morphometry rules out the possibility of a selective absence of unmyelinated nociceptors, although it does not exclude the possibility of other structural or neurochemical abnormalities. This patient demonstrates that congenital indifference to pain does not require the same type of peripheral nerve abnormalities associated with the hereditary sensory neuropathies. As Thomas (1993) has suggested, such patients ‘could represent a disturbance affecting neurotransmitters that did not involve loss of nerve fibers, or … the differences could be due to an abnormality of the central sensory pathways or processing’. Additionally, the case suggests that abnormal pain responses can occur even though pain discrimination, affect, and withdrawal responses appear preserved.
Davis et al. (1998) described a subject with normal perception of pinprick, light touch, and vibration. In addition to lifelong lack of pain perception with accompanying painless injuries, she had gait disturbance and spasticity. Sural nerve biopsy and electrophysiologic studies were normal. At age 56, she had progressive decline in cognitive abilities. Autopsy conducted at age 62 showed evidence of Alzheimer's disease and thalamic gliosis at multiple levels, including both ventral and midline nuclei. The amount of gliosis exceeded that found in age-matched normal brains and in an Alzheimer's disease control brain. Other family members were reported to have similar symptoms, including a lack of response to painful stimuli. Although complicated by the presence of other neurologic symptoms, this report suggests that deficits present in hereditary pain insensitivity and indifference disorders can have central as well as peripheral origins.
6. Asymbolia for pain and related conditions
When lesions occur in the areas of the brain that subserve the processing of painful stimuli, deficits in one or more of the components of pain perception can occur, and disorders similar to congenital pain insensitivity can result. Lesions in the anterior cingulate cortex or insular cortex impact the medial pain system and, thus, might be expected to cause a loss of the affective-motivational component. Lesions in the primary and secondary somatosensory cortex affect the lateral pain system; their expected major effect would be loss of sensory-discriminative components of pain.
Loss of the affective-motivational component of pain has been called ‘asymbolia for pain’. An early report described a patient who showed a lack of responsiveness to strong electrical currents and physically threatening gestures (Schilder and Stengel, 1931). Although there was some reaction to pain, no withdrawal responses occurred, and the patient at times ‘even seemed to derive some pleasure’ from the painful stimuli. The authors described both the ‘pain reaction’ and the ‘appreciation of pain’ as inadequate, and attributed pain asymbolia to findings of parietal lobe lesions in this patient and two others who were studied.
Later authors restricted use of the term ‘asymbolia for pain’ to patients with deficits in the affective-motivational component of pain but preserved sensory discrimination. Such patients perceive painful stimuli but lack emotional responses and withdrawal movements (Berthier et al., 1988). As in the earlier descriptions, some patients reportedly smiled or laughed in response to noxious stimuli. Computed tomography demonstrated insular cortex lesions in all patients in a series of six such patients ( Berthier et al., 1988). Lesions in the secondary somatosensory cortex could have explained a lack of response to painful stimuli, but no such abnormalities were found in two of these patients.
It is also possible that central lesions could impair the sensory-discriminative components of pain while sparing affective-motivational components. Ploner et al. (1999) describe a patient with a lesion in the primary and secondary somatosensory areas subserving the left hand. He had normal heat pain thresholds in the right hand, but did not perceive pain in the left hand, even at temperatures much higher than those used on his unaffected side. He showed deficits in the assessment of both stimulus localization and quality in the left hand. When offered a list of prompts including both painful and non-painful thermal descriptors, the patient would not use any of them to describe the stimulus, nor could he locate the stimulus more specifically than ‘between fingertips and shoulder’.
However, when stimulus intensities equal to and greater than what he considered painful on the unaffected side were administered to the left hand, the patient described a ‘clearly unpleasant’ feeling that he wanted to avoid. This finding suggests that the affective-motivational component of pain was intact and is consistent with the lateral pain system, which includes the somatosensory cortex, being more involved in the sensory-discriminative component of pain than in pain affect. This case also illustrates that it is possible for pain responses to occur without an intact sensory-discriminative system.
The deficits present in the different pain insensitivity syndromes provide insight into the complex anatomical and physiological nature of pain perception. Reports of pain asymbolia and related cortical conditions illustrate that there can be losses that independently involve either the sensory-discriminative component or the affective-motivational component of pain perception, thus highlighting their different anatomical localization. The presentations of congenital indifference to pain and pain asymbolia overlap, which suggests that indifference to pain – whether congenital or acquired – may involve one or more deficits preferentially affecting the components of the medial pain system, which includes the anterior cingulate cortex.
By affecting both the lateral and medial pain systems, the peripheral nerve abnormalities observed in individuals with the various types of HSAN cause deficits in both components of pain perception. The case of Ploner et al. (1999) demonstrates that the affective-motivational component can be retained even in the absence of the sensory-discriminative component. Importantly, this suggests that the absence of affective responses in individuals with HSAN is not simply a consequence of loss of sensory discrimination but also involves loss of input to the medial pain system caused by the peripheral neuropathy.
It has been proposed that the affective component of pain is not unitary and consists of at least two stages, an immediate primary stage and a cognitively-mediated second stage (Price, 1999). In the cases reviewed, it is unclear at which stage the observed deficits originate. Careful assessment of the separate components of pain sensory intensity and unpleasantness in patients with various congenital pain insensitivity and indifference disorders will help to further clarify the pathways underlying the different components of pain perception. In addition, mapping genetic defects in HSAN patients will provide important clues about molecular mechanisms of pain, and the promise of new, more effective and selective therapies.
Categories: Congenital insensitivity to pain