Congenital insensitivity to pain (CIP) is a rare clinical syndrome characterized by dramatic impairment of pain perception since birth (for a recent review, see Nagasako et al., 2003). As they lack the protective function of pain against dangerous stimuli, patients with this syndrome are prone to potentially life-threatening painless injuries and unnoticed illnesses, especially during childhood. Most often, CIP is a manifestation of hereditary sensory and autonomic neuropathy (HSAN) involving the small-calibre (A-delta and C) nerve fibres, which normally transmit nociceptive inputs along sensory nerves. The sensory loss for pain in HSAN may be either generalized or restricted to some body parts. In many cases, the nociceptive fibres gradually degenerate in a length-dependent manner and sensation is partly preserved proximally. At present, five types of HSANs with different underlying genetic abnormalities have been identified as potential causes of CIP (Dyck et al., 1983 and Thomas, 1993). HSAN I usually begins after the first decade with a distal loss of pain and thermal sensitivity that can progress to impairment across all sensory modalities and ulcerations of extremities. This disease has been shown to be caused by a mutation in the SPTLC1 gene encoding a subunit of serine palmitoyltransferase (Bejaoui et al., 2001 and Dawkins et al., 2001). HSAN II presents with diffuse impairment of discriminative touch and pressure sensation with variable impairment of other sensory modalities in a glove-and-stocking pattern, leading to trophic ulcers in infancy. Mutations of a novel gene termed HSN2 have been identified recently in patients with HSAN II (Riviere et al., 2004 and Lafreniere et al., 2004). Patients with HSAN III (familial dysautonomia or Riley–Day syndrome) show widespread autonomic dysfunction and a severe pansensory disturbance caused by a mutation in the I?B kinase complex associated protein, IKBKAP, gene (Anderson et al., 2001 and Slaugenhaupt et al., 2001). The clinical picture of HSAN IV includes diffuse thermal and pain insensitivity, self-mutilation, anhidrosis and recurrent fevers with preservation of other sensory modalities. Mutations in the nerve growth factor receptor gene TRKA have been found in all cases of HSAN IV analysed so far, implicating the NGF/TRKA pathway in the pathogenesis (Indo et al., 1996 and Indo, 2001). The presentation of HSAN V may be similar to HSAN IV, except for variable autonomic involvement (Donaghy et al., 1987, Dyck et al., 1983 and Low et al., 1978). Recently, a mutation in the NGF beta gene has been identified in a Swedish family with a similar clinical picture (Einarsdottir et al., 2004).
Despite partial or total sensory loss for pain, many patients with CIP can experience pain during their life, especially in HSAN I (Dyck, 1993, p. 1069). Such patients can have phantom pain in amputated extremities, lancinating pains due to inflammation within nerves containing actively degenerating fibres, mechanical allodynia in partially denervated areas and stimulus-independent pain that may be of central origin (anonymous reviewer, personal communication). We report the case of a 32-year-old woman with a severe and generalized congenital insensitivity to pain caused by HSAN, who experienced physical pain for the first and unique time in her life shortly after the sudden loss of her brother.
The patient was an intelligent and communicative woman who worked as a shop assistant. Her parents were algerians and the incidence of CIP in the family suggested an autosomic recessive mode of transmission. The patient had sustained innumerable painless injuries during childhood, including fractures of the nose and of the left radius, severe burns of both buttocks after sitting on a radiator and of the scalp after a hot shower. She had also had her teeth drilled several times at the dentists without anaesthesia, without any pain. At the age of 13, appendicitis was revealed by vomiting and diarrhea without pain. Deliveries of her two children (at the age of 27 and 31) were completely painless despite the lack of anaesthesia. She had no history of self-mutilation, osteomyelitis or joint disease. Unexplained episodes of hyperthermia up to 40 °C were first noted at the age of 12 and recurred during periods of hot weather. The patient had always been anosmic. She was ticklish and remembered having felt intense itch after nettle contact. Sweating was reported to be normal.
When systematically asked about possible previous experiences of physical pain, the patient reported that the only pain she had ever felt consisted of an episode of intense headache, which had taken place 2 years before the interview but, fortunately, had been well documented by her general practitioner. This inaugural headache occurred in a context of strong emotional overload and anxiety, 3 weeks after her younger brother died suddenly in a car accident. She had the sensation of carrying an enormous weight bilaterally on top of her head, which hurt so much that she was no more able to concentrate on her work. The pain was not associated with focal neurological symptoms, photophobia, phonophobia, nausea or vomiting, and was not aggravated by routine physical activity. There was no family history of headache. Standard clinical examination was normal, as was a brain CT scan. Paracetamol and aspirin were ineffective. The pain spontaneously waned after a few days and completely disappeared 2 weeks later. The general practitioner concluded in favor of an episode of tension-type headache as part of an anxious reaction to the loss of her brother.
The clinical picture of this patient, which includes a history of innumerable painless injuries during childhood, deficient pain and temperature sensitivity and autonomic abnormalities, is typical of CIP (Nagasako et al., 2003). The association between CIP, anosmia and ageusia has been described previously in several case reports (Jewsbury, 1951, Losa et al., 1989, Madonick, 1954, Ogden et al., 1959 and Thrush, 1973). Although the lack of neuropathological and genetic data does not allow a definitive classification of the present case, both clinical features and neurophysiological data suggest a selective defect of small-calibre nerve fibres with preserved sweating and with intact large-diameter nerve fibres, which best fit with the diagnosis of HSAN V (Donaghy et al., 1987, Dyck et al., 1983, Low et al., 1978 and Minde et al., 2004). Indeed, the abnormality of the nociceptive flexion reflex indicates a marked loss of A-delta-afferent fibres (Willer and Albe-Fessard, 1983), while the complete lack of neurogenic inflammation after intradermal injection of capsaicin strongly suggests a defect of C-fibre function (Culp et al., 1989, Koltzenburg et al., 1992, Torebjörk et al., 1992 and Schmelz et al., 2000). Moreover, preservation of the sympathetic skin response eliminates the diagnosis of HSAN IV, which is always associated with anhidrosis (Hilz et al., 1999 and Shorer et al., 2001). Altogether, these data clearly demonstrate that the pain insensitivity of this patient is associated with a marked impairment of peripheral (i.e. primary afferent) nociceptive mechanisms. Thus, this patient must be diagnosed as a case of congenital insensitivity to pain, not congenital indifference to pain (for a clear distinction between these terms, see Dyck et al., 1983, Kunkle, 1961 and Landrieu et al., 1990
The patient's report of a single episode of intense headache should be interpreted cautiously. First, as noted previously by Thrush (1973), “there are many semantic difficulties in discussing pain with patients who have no experience of it”. For example, patients with CIP may adopt the same pain language as normal people to avoid being regarded as ‘strange’ or ‘abnormal’ (Losa et al., 1989 and Thrush, 1973). Moreover, there is evidence that the memory for a past pain is often inaccurate and that numerous factors may affect its recall (Brodie and Niven, 2000, Erskine et al., 1990 and Feine et al., 1998). One must also consider that our patient might have re-interpreted afterwards the distressing experience of her brother's death as a physically painful event. However, the clinical data suggest that the episode of headache reported by our patient corresponded to a genuine pain experience: the quality of the pain and its localization were precisely described and fulfilled the diagnostic criteria of episodic tension-type headache (Headache Classification Committee of The International Headache Society, 2004); most importantly, the patient's complain of intense headache had been well documented by her general practitioner, who corroborated her own description.
Interestingly, a few previous case reports mentioned that headache could be the sole (or almost the sole) manifestation of pain in patients with CIP (Cohen et al., 1955, Comings and Amromim, 1974, Dearborn, 1932, Jewsbury, 1951 and Magee et al., 1961). The patient reported by Dearborn could not recall any pain except occasional headaches, which unfortunately were not described in detail (Dearborn, 1932). Jewesbury's case n°3 (aged 76) recalled a single unexplained attack of severe headache and vomiting which had occurred 50 years before (Jewsbury, 1951). Of particular interest is Jewesbury's case n°2: this 38-yo man, who was liable to frontal headaches of 24-h duration, developed no headache after intravenous injection of a high dose of histamine diphosphate (though his face flushed within the first minute) (Jewsbury, 1951). However, this same patient developed a severe and prolonged headache after a lumbar puncture, just like another CIP patient reported by Cohen et al. (1955). Histamine headache has been shown to be caused by dilatation of intracranial vessels (Wolff, 1963), while post-lumbar puncture headache is probably caused by continued leakage of cerebrospinal fluid from the subarachnoid space, leading to lowering of intracranial pressure, withdrawing support for the brain and thus causing traction upon intracranial vessels (Lance and Goadsby, 1998, p. 258). Overall, such occurrence of headache in CIP patients suggests that some forms of headache might bypass peripheral nociceptive mechanisms and be generated directly in the central nervous system. Such a mechanism of centrally generated headache has been demonstrated previously. Indeed, Raskin et al., 1987 and Veloso et al., 1998 have shown that a substantial number of patients treated surgically for uncontrollable chronic pain developed recurrent headaches for the first time after electrodes had been inserted in their periaqueductal gray area. On the other hand, one could postulate that residual intact peripheral nociceptors might also contribute to the triggering of trigeminal pain in some CIP patients. As a matter of fact, toothaches have been reported in a few cases (Comings and Amromim, 1975 (patients DW and WW); Landrieu et al., 1990 (patient 2)). Our patient never experienced dental pain, however, although she had had her teeth drilled several times without anaesthesia. Moreover, she once severely burnt herself on the scalp without feeling any pain. Such a complete lack of trigeminal pain evoked by noxious stimuli suggests a profound loss of peripheral trigeminal nociceptive innervation and pleads in favor of the central origin of her headache.
The originality of the present case lies in the fact that our patient's pain was closely related to an event with strong emotional impact. One could argue that the occurrence of this inaugural headache soon after her brother's death might be coincidental. However, it is well known that psychological factors may play a central role in certain pain syndromes such as tension-type headache (Lance and Goadsby, 1998), and that physical pain may be precipitated or revived by a current emotional illness or event, including bereavement (Merskey, 1975 and Zisook et al., 1982). As a matter of fact, previous studies have underlined the contribution of bereavement to the development of tension-type headache (Kaiser and Primavera, 1993 and Abu-Arafeh, 2001). In this perspective, the inaugural episode of headache in this patient with CIP who had never experienced pain before, strongly suggests that the transcription of the grief of bereavement into physical pain may sometimes occur independently of the peripheral mechanisms of nociception. This observation fits nicely with Sigmund Freud's postulate that “the intense, ever-increasing cathexis of the absent (lost) object (…) creates exactly the same economic conditions as does the pain-generated cathexis of an injured part of the body, and makes it possible for the absence of the usual prerequisite of physical pain - an attack somewhere in the periphery—to be disregarded” (Freud, 2003). In agreement with such a psychodynamic view, experimental data suggest that the same neural mechanisms that regulate physical pain may also control the expression of separation distress in mammals. Some of the brain areas, which are the most responsive during separation distress, such as the anterior cingulate cortex, the dorsomedial thalamus and the periaqueductal gray area (Herman and Panksepp, 1981 and Panksepp, 2003), are also involved in pain processing and modulation (Peyron et al., 2000, Tracey et al., 2002 and Craig, 2003). Moreover, a recent fMRI study performed in human volunteers showed that activity in the dorsal anterior cingulate cortex—which is known to be linked to pain unpleasantness (Tolle et al., 1999)—was associated with increased distress after social exclusion, providing further evidence that the experience of social and physical pain share a common neuroanatomical basis (Eisenberger et al., 2003). These results have led to the challenging hypothesis that the social attachment system of mammals may have adopted the neural computations of the physical pain system to promote survival (Panksepp, 1998 and Panksepp, 2003). Such an evolutionary perspective may indeed help to understand why some patients may feel physically hurt after the loss of someone they love.