Allodynias in Neuropathic Pain Patients

Spectrum of cutaneous hyperalgesias/ allodynias in neuropathic pain patients

Verdugo RJ, Bell LA, Campero M, Salvat F, Tripplett B, Sonnad J, R. J. Verdugo1,2, L. A. Bell1, Ochoa JL. Spectrum of cutaneous hyperalgesias/allodynias in M. Campero1,2, F. Salvat3, neuropathic pain patients. B. Tripplett1, J. Sonnad1, Acta Neurol Scand 2004: 110: 368–376. Blackwell Munksgaard 2004. J. L. Ochoa1 1Oregon Nerve Center at Legacy Good Samaritan Objectives – The aim of this study was to discern the pathophysio- Medical Center, Departments of Neurology and logical bases for neuropathic hyperalgesias. Methods – In this study, Neurosurgery, Oregon Health and Science University, neurological and neurophysiological evaluation of 132 consecutive Portland, OR, USA; 2Department of Neurology, Faculty hyperalgesia patients using rigorous clinical and laboratory protocols of Medicine, Universidad de Chile, Santiago, Chile; were carried out. Results – Two discrete semeiologic entities emerged: 3Department of Neurology, Raul Carrea Institute for classic neurological vs atypical, fulfilling taxonomically complex Neurological Research, FLENI, Buenos Aires, Argentina regional pain syndrome (CRPS) II and I, respectively. The classic group (34.9%) exhibited sensorimotor patterns restricted to nerve distribution and documented nerve fiber dysfunction. Among them four (3.03%) had sensitization of C-nociceptors, seven (5.3%) had central release of nociceptive input, and 35 (26.52%) probable ectopic nerve impulse generation. The atypical group (65.1%) displayed weakness with interrupted effort; non-anatomical hypoesthesia and hyperalgesia; hypoesthesia or paresis reversed by placebo, or atypical Key words: neuropathic pain; complex regional pain abnormal movements, and physiological normality of motor and syndrome; hyperalgesia; allodynia; somatization sensory pathways. Conclusions – Spatiotemporal features of Jos L. Ochoa, The Oregon Nerve Center, Good neuropathic hyperalgesia constitute key criteria for differential Samaritan Medical Center, 1040 NW 22nd Ave., diagnosis between CRPS II and I and, together with other behavioral Suite 600, Portland, Oregon 97210, USA sensorimotor features, signal psychogenic pseudoneurological e-mail: [email protected] dysfunction vs structural neuropathology. ÔNeuropathicÕ hyperalgesias may reflect neuropathological or psychopathological disorders. Accepted for publication July 22, 2004

There is increasing awareness that the pathophys- abolished clinically. Controversy surrounds the iological basis for neuropathic pains following medical nature of the second group, which, in peripheral injury is multifactorial (1, 2) and both descriptive terminology, is labeled complex regio- peripheral and central determinants are recog- nal pain syndrome type I (CRPS I). Given its nized. There has been little recognition of the fact atypical neurological features, underlying conver- that the apparent uniform clinical profile of Ôneur- sion–somatization is intuited (3). Alternatively, opathicÕ patients is actually bisected into discrete based on impressive secondary structural and groups after formal neurological evaluation. In one functional changes documented in the spinal cord 1group, anatomical, physiological and pathological or thalamus following experimental primary nerve analyses of the nervous system predict the clinical injury or inflammation, a central neuronal disorder features, prognosis, and response to management. is indicated by many. Critics of the psychoneuro- The other group departs from the anatomical logical viewpoint fear that the persistent pain principles; symptoms often worsen paradoxically might be incorrectly dismissed as being of psycho- with time, rather than improve with natural repair; logical origin and pointedly remind that inability become refractory to all therapeutic measures; and to discern an ÔorganicÕ explanation does not prove when tested through objective neurophysiological psychological causation (4). The counterargument methods, the motor and sensory pathways function emphasizes the inexistence of anatomophysiologi- normally even when voluntary movement and cal tests to specifically diagnose CRPS I and the reported sensation may appear defective or even absence of a valid animal model for it; what are

368 Hyperalgesias in neuropathic pain available are models of peripheral nerve injury, consent, all patients underwent a standard clinical which CRPS I patients lack. These contrasting protocol for the evaluation of the function of theories, however, indicate a central nervous motor, sensory and autonomic systems. Depending system disorder in common, differing only in its on the emerging profile, the evaluation was fol- hypothetical location: sensory nuclei vs cerebrum. lowed by conventional nerve conduction tests Here we focus on hyperalgesia/allodynia, a (130 patients), needle electromyography (105 prevalent psychophysical feature of neuropathic patients), measurement of somatosensory evoked pain patients that has become a favorite subject in potentials (57 patients), transcranial magnetic sti- somatosensory research. Hyperalgesia is defined as mulation of motor pathways (81 patients), quan- Ôan increased response to a stimulus which is titative somatosensory thermotest (QST) (127 normally painfulÕ, while allodynia is defined as patients), infrared telethermography (103 patients), Ôpain due to a stimulus which does not normally placebo-controlled somatic nerve blocks (60 provoke painÕ (5). The term allodynia is rejected by patients) and placebo-controlled (inert and active) some investigators (6) while others suggest that the sympathetic blocks (62 patients). Thus, the vast term hyperalgesia should embrace both allodynia majority of patients were tested using standard and hyperalgesia proper (2). In the present paper, electrophysiological and psychophysical methods the term hyperalgesia is used to refer to both for detecting peripheral nerve fiber dysfunction. allodynia and hyperalgesia, as defined by the Additional methods to detect central motor and International Association for the Study of Pain sensory dysfunction were reserved for patients (IASP) (5). without peripheral pathology. The present neurological and physiological study The types of cutaneous hyperalgesias were: of a large cohort of patients with chronic neuro- dynamic mechanical hyperalgesia, 74 patients; pathic pain, reveals that in the clinic it is possible to static mechanical hyperalgesia, 53; punctate hyper- explicitly ascertain equivalents of structural pathol- algesia, 35; cold hyperalgesia, 55; and heat hyper- ogy as well as the presence of psychogenic dys- algesia, 37 patients. Many patients expressed more function behind neuropathic hyperalgesias. than one kind of cutaneous hyperalgesia.

Patients and methods Results The present series was extracted from an overall Dynamic mechanical hyperalgesia population of 376 consecutive patients referred to the Oregon Nerve Center between January 1998 Dynamic mechanical hyperalgesia (Ôbrush-inducedÕ and December 2000 for evaluation of chronic allodynia) was found in 74 of 132 (56.06%) painful complaints with neuropathic characteris- patients. In 20 of the 74 patients (27.03%), tics. All patients underwent a uniform evaluation comprehensive clinical and laboratory evaluation protocol as described previously (7–9). Inclusion documented some peripheral nerve pathology that criterion was the presence, on neurological explained the symptom. This group included six examination or laboratory testing, of cutaneous cases with peripheral painful polyneuropathy, in hyperalgesia to mechanical (dynamic, static or whom dynamic hyperalgesia was present in bilat- punctate), cold, or heat stimuli. Dynamic mechan- eral stocking distribution. The remainder had ical hyperalgesia was defined as an unpleasant, not single peripheral nerve injury (nine patients), rad- necessarily painful, sensation evoked by light iculopathy (three patients), mononeuropathy mul- stroking of the skin. Static mechanical hyperalgesia tiplex (one case) and multifocal motor neuropathy was defined as a painful sensation in response to (one patient). In all 20 patients, the areas of sustained gentle pressure on the skin (10). Punctate dynamic mechanical hyperalgesia remained con- hyperalgesia was defined as an exaggerated painful fined to the peripheral nerves affected, without sensation elicited by pinprick. Cold hyperalgesia expansion into other territories. was defined as an exaggerated painful sensation In 46 (62.6%) patients with dynamic mechanical evoked by low-temperature stimulation during hyperalgesia, clinical and laboratory evaluation quantitative somatosensory thermal test [Marstock not only disclosed a normal function of peripheral method; (11)]. Heat hyperalgesia was defined as an and central sensory and motor pathways but also exaggerated painful response evoked by elevation positive signs recognized as non-organic [Ôpsycho- of the stimulus temperature (12). genicÕ; Table 1; (13)], including give-way weakness A total of 132 patients fulfilled the inclusion without significant pain (7, 14, 15), tremor, Ôshaki- criteria. There were 81 females and 51 males (mean nessÕ and muscle spasms of ostensibly non-organic age 45.7 years, range 18–85). After informed semeiology (16), extensive non-anatomical areas of

369 Verdugo et al.

Table 1 Signs of non-organic dysfunction in patients with physiological evidence of normality of peripheral and central sensory and motor pathways

Dynamic mechanical Static mechanical Punctate Cold Heat

No nerve Minor nerve No nerve Minor nerve No nerve Minor nerve No nerve Minor nerve No nerve Minor nerve Type of hyperalgesia injury injury injury injury injury injury injury injury injury injury

Give-way weakness without pain 29 4 20 4 15 1 21 4 17 2 Abnormal psychogenic movements 11 11 4 8 2 5 1 Non-anatomical cutaneous hypoesthesia 24 4 15 2 11 1 21 1 18 1 Normal two-point discr. threshold with 1294471 severe hypoesthesia Reversal of hypoesthesia after placebo 9 3 6 1 5 9 8 1 Reversal of weakness after placebo 9 4 8 2 8 8 2 6

Table 2 Distribution of types of cutaneous hyperalgesia among patients with and without nerve injury, with and without expansion beyond anatomical nerve territories

Patients with nerve injury Patients without nerve injury Patients with very minor nerve injuries

Type of hyperalgesia Expanded Not expanded Expanded Not expanded Expanded Not expanded

Dynamic mechanical 0 20 33 13 8 0 Static mechanical 0 15 26 7 5 1 Punctate 0 11 23 0 1 0 Cold 0 14 18 19 4 0 Heat 0 8 15 12 2 0 cutaneous hypoesthesia to pinprick and/or light post-polio syndrome also. Like the group with touch (13, 17, 18), normal two-point discrimin- neurological normality, these patients also exhib- ation threshold in areas of profound psychophys- ited positive signs of non-organic pseudoneuro- ical hypoesthesia, reversal of severe cutaneous pathic dysfunction (Table 1). hypoesthesia after inert placebo or active drug administration during local anaesthetic or sympa- Static mechanical hyperalgesia thetic block (9), dramatic improvement of weakness, or motor paralysis after placebo or any Static mechanical hyperalgesia was detected in irrelevant active drug administration. Three of 54 (40.91%) of the 132 patients. Only 15 (27.78%) these patients were known to be substance abusers patients with static hyperalgesia had evidence of and another two were found to be malingerers by a peripheral nerve pathology accounting for the secret video surveillance. In 33 (71.74%) patients neuropathic syndrome featuring static mechanical with positive evidence of non-organic components, hyperalgesia. In this group, there were six patients the areas of dynamic mechanical hyperalgesia with painful polyneuropathy, ﬁve of whom expanded with time to involve extensive territories expressed additional heat hyperalgesia. These are without recognizable peripheral dermatomal dis- characteristics of the ABC syndrome due to the tribution (Table 2). Additionally, eight patients sensitization of C-nociceptors (19, 20). One patient showed striking variation of intensity of the expressed cold hyperalgesia and sympathetic den- hyperalgesia with distraction, or upon repetition ervation supersensitivity in the feet, as described in of the neurological examination. the Ôtriple cold syndromeÕ (21). In all these patients Eight patients had minor peripheral nerve with painful polyneuropathy, static mechanical pathology that could not account for the extensive hyperalgesia was detected in bilateral stocking or distant neuropathic display. This group included distribution and was not associated with dynamic one patient with a minor C6 radiculopathy, one mechanical hyperalgesia. In nine patients, there with a mild ulnar nerve lesion and one with mild was focal pathology including one case of cervical entrapment of the median nerve: all three exhibited radiculopathy. In all these 15 patients, the area of extensive areas of mechanical hyperalgesia invol- static mechanical hyperalgesia was restricted to the ving the entire upper extremity, including the normal anatomical territory of the affected nerve shoulder. Four patients had a minor nerve lesion trunk or root. In three of these cases, static in remote body segments. One patient who com- mechanical hyperalgesia was associated with plained of severe pain in the entire left dynamic or punctate hyperalgesia, plus heat hyper- upper extremity after a minor work injury, had a algesia in one and cold hyperalgesia in another.

370 Hyperalgesias in neuropathic pain

In 33 (61.11%) patients with static mechanical hyperalgesia, there was evidence of peripheral hyperalgesia, there was evidence of normality of nerve pathology behind the neuropathic syndrome. function of peripheral and central sensory and Nine of them were found to have a polyneuropa- motor pathways and positive evidence of non- thy. In these patients, cold hyperalgesia was organic dysfunction (Table 1). Anecdotally, two frequently associated with paradoxical hot burning patients displayed a nocebo effect, developing sensation [Ôtriple cold syndromeÕ; (21)]. In all nine atypical muscle spasms during saline administra- patients, the cold hyperalgesia was present distally tion. Moreover, in 26 (78.79%) patients with in both lower extremities. In six patients, there was positive evidence of psychogenic dysfunction, the a focal peripheral nerve lesion-caused cold hyper- areas of static mechanical hyperalgesia expanded algesia. One of them also had paradoxical hot with time far beyond the territory of a peripheral burning sensation and impaired vasomotor reflex nerve trunk or root. activity, as described in the triple cold syndrome. Six patients with static mechanical hyperalgesia Only two among these 14 patients expressed harbored a minor nerve injury that could not concurrent cold and heat hyperalgesia. account for the expansive neuropathic symptom Thirty-seven patients with cold hyperalgesia had complex. These patients also had a positive normal functioning of afferent and efferent path- evidence of non-organic dysfunction (Table 1). ways, associated with non-organic phenomena Five of these six patients exhibited extensive non- (Table 1). In one of these 37 patients, who had dermatomal distribution of static hyperalgesia. undergone several surgical interventions to treat his painful syndrome, a factitious disorder was suspected. In 26 patients there was coexistent Punctate mechanical hyperalgesia mechanical hyperalgesia, with a non-dermatomal Punctate mechanical hyperalgesia was present in 35 pattern of distribution in 20. In 18 cases, cold (26.52%) of 132 patients. In 11 (31.43%) patients 2hyperalgesia was present in an extensive area that with punctate hyperalgesia, there was documented did not follow anatomical peripheral nerve or root peripheral nerve pathology determining the hyper- territories. This is likely an underestimate consid- algesia. In seven of these patients, punctate hyper- 3ering that many patients underwent QST in algesia was associated with dynamic and/or static restricted body segments. Furthermore, three mechanical hyperalgesia, in two cases punctate patients showed gross variability in the severity hyperalgesia coexisted with cold hyperalgesia and of cold hyperalgesia and one additional patient in one with heat hyperalgesia. Only one patient had reported a threshold for cold pain at a warmer a painful polyneuropathy, expressing punctate temperature than the threshold for specific cold hyperalgesia in stocking distribution. In nine sensation. Strikingly, 23 (62.16%) patients with patients, the cause of the neuropathic painful cold hyperalgesia with evidence of psychogenic syndrome was a focal peripheral nerve injury and disorder expressed simultaneous cold and heat in one a post-surgical thoracic radiculopathy. In all hyperalgesia, a rare finding in patients with these 11 cases, punctate hyperalgesia remained organically based neuropathy. confined to the normal anatomical territory of the A minor peripheral disorder, that could not affected nerves or root. explain the severe chronic neuropathic painful In 23 (65.71%) patients with punctate hyperal- syndrome was found in four patients. They all gesia, the symptom occurred in the realm of had evidence of non-organic dysfunction (Table 1). normal function of peripheral and central afferent and efferent pathways and positive evidence of Heat hyperalgesia non-organic (psychogenic) dysfunction (Table 1). One woman with punctate mechanical hyperal- Heat hyperalgesia was present in 37 (28.03%) of gesia had a minor sensory polyneuropathy detected 132 patients. In eight (21.62%) patients with heat electrophysiologically. She complained of incapa- hyperalgesia, peripheral nerve pathology was docu- citating pain in the entire right lower extremity mented. Four of these had a painful peripheral after a minor injury at work. She exhibited give- polyneuropathy. Sensitization of peripheral noci- way weakness and total loss of cold and warm ceptors was likely in three of these polyneuropathic sensation in stocking distribution in the right leg. patients as they exhibited bilateral hyperthermia of the feet despite available vasomotor sympathetic reflex activity. Two polyneuropathic patients had Cold hyperalgesia associated punctate mechanical hyperalgesia, and Cold hyperalgesia was found in 55 (41.67%) of one had static mechanical hyperalgesia. The 132 patients. In 14 (25.45%) patients with cold remaining four patients had a defined focal nerve

371 Verdugo et al.

injury as a cause of the painful neuropathic neuropathic patients who altogether reported five syndrome. Two of these had combined cold and descriptive types of cutaneous hyperalgesia/allody- heat hyperalgesia. nia in response to dynamic mechanical, static Heat hyperalgesia in a background of normal mechanical, punctate mechanical, cold and heat peripheral and central sensory and motor function, stimuli. Two contrasting clinical profiles were plus positive evidence of psychogenic dysfunction discerned. As to the descriptive IASP denomina- was found in 27 (72.97%) patients with heat tions (5) the classic group of patients qualifies for hyperalgesia (Table 1). Twenty-one patients CRPS type II (causalgia) while the second qualifies had associated mechanical hyperalgesia, which in for CRPS type I (reflex sympathetic dystrophy). 13 was of non-anatomical distribution. Like cold The five types of cutaneous hyperalgesia presented hyperalgesia, heat hyperalgesia frequently covered in varied combinations and with the same fre- a broad and non-anatomical distribution in quency in both groups of patients, with the 15 patients. The frequent association of cold and exception of the combined pattern of cold and heat hyperalgesia in this group of patients was heat hyperalgesia which was more common in the mentioned earlier. atypical group. The remaining two patients with heat hyperalgesia had a minor nerve injury distant from the Neuropathological meaning of the present populations painful area. These two also displayed several signs of psychogenic dysfunction (Table 1). Neurological pain may be the natural expression of various primary structural pathologies of the central nervous system (CNS) affecting the spino- Summary of findings thalamic pathway (22, 23). This is not the subject Results yielded two discrete semeiologic entities: of the present study. When the evaluation of classic neurological vs. atypical. They are each seemingly PNS-based Ôneuropathic painÕ patients other’s antithesis and fulfill criteria for the des- abides to a formal neurological protocol, the criptive entities CRPS II and I, respectively. The detection of cardinal subgroups is inescapable. group of classic (CRPS II) patients (34.9%) The two emerging categories carry explicit mean- exhibited a coherent positive and negative sensory ing: (i) peripheral pathology causing commensur- and motor pattern, invariably restricted to the ate pathophysiology (CRPS II), constrasting with anatomical distribution of nerve trunks and spinal (ii) a pseudoneurological health disorder with roots. In them, known equivalents of peripheral absence of analogues of peripheral pathology nerve pathology were documented objectively (CRPS I). When in CRPS I patients, the presumed through neurological examination and physiologi- central pathological basis for puzzling negative cal tests. Among these patients, there were four motor and sensory phenomena (paralysis and (3.03%) with evidence of sensitization of C-noci- sensory loss), associated to pain and hyperalgesia, ceptors (20), seven (5.3%) had a central release of was investigated through direct electrophysiologi- primary nociceptive input (21), and 35 (26.52%) cal means, the evidence negated it (see also 24). had signs reflecting ectopic nerve impulse generation. Patients in the atypical (CRPS I) group Classic ÔCRPS IIÕ 4(65.2%) departed from the laws of anatomy, physiology and pathology of the nervous system. Several pathophysiological mechanisms were iden- They displayed muscle weakness because of inter- tified among the classic group of patients in this rupted voluntary effort; extensive and fluctuating series. Sensitization of peripheral nociceptors as cutaneous hypoesthesia and hyperalgesia not con- the cause of cutaneous hyperalgesia has been forming to nerve or spinal root territories; hypoes- documented in clinical (25, 26) and experimental thesia reversed by inert or active placebo conditions (see 27). Sensitization is one pathophys- intervention; atypical abnormal movements; or iological response of cutaneous nociceptors to recovery of muscle weakness in response to noxious stimuli (28). In this series, several patients placebo. These patients had physiologically displayed the characteristic profile of pathological normal motor and sensory pathways both in the nociceptor sensitization, including spontaneous peripheral and central nervous systems (Table 2). burning pain and redness of the skin caused by antidromically induced cutaneous vasodilatation (20). Patients with sensitized nociceptors express Discussion relief of symptoms with exposure to low tempera- We describe neurological and multiple neurophys- ture and worsening with higher temperatures iological characteristics of a vast population of (29). Experimentally the entire clinical picture is

372 Hyperalgesias in neuropathic pain replicated by cutaneous application of capsaicin in should expansion of hyperalgesia in ÔneuropathicÕ humans (30) and recent studies on the vanilloid pain occur only when the hypothetical primary receptor, involved in the activation of nociceptors nerve pathology, taken in theory to induce, main- by capsaicin, indicate that its responsiveness to tain and expand hyperalgesia through a secondary mechanical stimulation is facilitated by increased central mechanism, does not exist? Our findings temperature (see 31). The few patients with docu- also challenge the evidential power of the aphorism mented sensitization of peripheral nociceptors had that touch-induced pain must signal central sensi- no evidence of neuronal sensitization within the tization in the spinal cord. spinal cord or higher centers. These patients showed a strict correlation between discharge of Psychogenic ÔCRPS IÕ peripheral C-nociceptors and intensity of pain and experienced no expansion of the areas of hyperal- The pseudoneuropathic atypical group of patients gesia (25). A group of patients with cold hyperal- is explicitly recognizable as psychoneurological in gesia associated with cold hypoesthesia displayed origin (3). This diagnosis is not based purely on the the Ôtriple cold syndromeÕ (21). In them, dynamic absence of evidence of nerve damage, nor on afferent interactions in the CNS explained cold presence of psychopathology, nor even on the hyperalgesia and paradoxical hot burning sensa- record of normal function of afferent and efferent tion. These phenomena develop experimentally central and peripheral pathways. The diagnosis after selective blockade of myelinated fibers, inclu- largely rests on evidence of pseudoneurological ding A-delta afferents specific for cold sensation dysfunction of brain origin, including: (a) subject- (32). Ectopic generation of impulses (or ephaptic ive cutaneous hypoesthesia or hyperalgesia which transmission?) is another mechanism in undeter- do not follow nerve trunk or spinal root territories mined patients from this group. It is also likely that (13, 17) in patients with normal peripheral and further primary abnormal biophysical mechanisms central electrophysiological parameters, (b) punc- will be identified in the future. Occasionally, tual denial while blindfolded of each tactile stimu- ectopic impulse generation leading to multiplica- lus within a reportedly anaesthetic area (9), tion of the afferent barrage may be associated with (c) normal report of two-point touch discrimin- sensitization of C-nociceptors (26). ation within areas of reportedly profound tactile hypoesthesia, (d) hypoesthesia reversed by inert or active placebo intervention (9), (e) muscle weak- Differential significance of the sensory profiles ness with interrupted voluntary upper motor drive, Although superficially similar, when examined in the absence of significant pain (7, 14, 15), formally the clinical features of patients with (f) atypical abnormal movements with erratic chronic neuropathic pain caused by peripheral worsening, and relieved with placebo and distrac- nerve pathology, compared with those of Ôneuro- tion (16) and (g) recovery of profound muscle pathicÕ patients with evidence of absence of nerve weakness with placebo. injury, signal cardinally different pathogeneses. Noordenbos and Wall (36) rejected the psycho- When there is clear peripheral nerve injury, the genic alternative in patients with chronic neuro- areas of cutaneous mechanical and thermal hyper- pathic pain unresponsive to nerve grafting: Ôwe do algesia never extend to areas of other nerves or not accept this easy way out as an explanation of roots (33). In all patients with nerve injury, the the pain of our patients particularly the four who pain was restricted to the affected nerves with no were continuing active work and successful private tendency to spread beyond the innervation terri- lives… these patients, unlike psychiatric patients, tory (34). This finding also matches optimally did respond to therapies such as local nerve block, Moore and Schady’s (35) demonstration that transcutaneous stimulation and sympathetic blocks intraneural microstimulation of fascicles of severed but for periods too brief for useful therapy.Õ nerves in patients always evokes painful and non- However, in the early 1980s, Noordenbos and painful sensations projected to the normal distri- Wall (36) had not come to appreciate today’s bution of the affected nerve, even years after universally acknowledged placebo bias (37). More- injury, at a time when spinal and supraspinal over, whether ÔpsychiatricÕ or not, all sorts of centers must presumably be fully reorganized ÔneuropathicÕ pain patients often respond in the through neuronal plasticity. Conversely, large and short term to the placebo effect of blocks, and often bizarre areas of mechanical and thermal neurostimulation (see results, 38). Regrettably, hyperalgesia are invariably seen in CRPS I patients psychogenic dysfunction as a potential primary with clinically and physiologically intact peripheral mechanism of causation and maintenance of chro- and central afferent and efferent systems. Why nic neuropathic pain is often denied, by taboo,

373 Verdugo et al. even when it is acknowledged that for CRPS I Ôthe predominance of sensory symptoms: chronic pain mechanism remains unknownÕ (39). The fact that, and chronic fatigue in particular.Õ Ja¨nig (45) states in somatization, the brain generates the clinical that ÔCRPS-I can only be understood as a pain appearance of a neurological syndrome is often syndrome or disease that is actively generated by misleading. Psychopathology has become disguised the brainÕ. For this type of brain-generated syn- as neuropathology (40). Malingerers who fake drome, no animal model is available (43). Func- CRPS I may pass undetected, as we spotted only tional imaging of the brain of patients with three in this series. Classic neurologists knew diagnosed hysterical (motor and sensory) dysfunc- about, and accepted, abnormal psychoneurological tion and pain, have revealed intromission of limbic processes in atypical Ôneuropathic patientsÕ (22). As circuit activation during impaired motor or sensory Mitchell (41) points out Ôin hysteria, the centers are tasks. Studies with positron emission tomography affected, and in many cases of causalgia, when the 6(PET) scan show that in hysterical paralysis the constitutional disturbance is at its height, these are areas of brain activation when attempting to move so excitable that a touch of the skin anywhere, the the paralyzed extremity include the premotor area, sound of a step or the rustle of paper, is felt to be as in normal movements, but not the primary unpleasant, and even at times exquisitely painfulÕ motor area. Instead, activation of the orbitofrontal (p. 180). and cingulate cortex is observed (46). In hysterical Regarding other studies on patients of this kind, motor and sensory loss and pain, Vuilleumier et al. one drawback of many published Ôneuropathic (47) describe reduction in regional cerebral blood painÕ series that form the basis for current theories flow in the contralateral thalamus and basal and inspire animal models of painful nerve injury, ganglia, suggesting that Ôhysterical conversion def- is their meager clinical evaluation. Motor and icits may entail a functional disorder in striato- sensory phenomena that are so revealing of the thalamocortical circuits controlling sensory-motor nature of the patients are frequently ignored. function and voluntary motor behavior.Õ Studies in Among the 123 patients with ÔCRPSÕ pooled from patients with chronic atypical neuropathic pain recognized centers, the only criterion used to Ôwith predominant affective componentÕ also show distinguish between CRPS I and II was a limited abnormal cortical activation in response to painful electromyogram (EMG)/nerve conduction study. stimulation, particularly in the anterior cingulate No information is given on other laboratory tests, and prefrontal cortex (48). Iadarola et al. (49) let alone neurological examination (42). Indeed, describe diminution of metabolism in the contra- management of chronic Ôneuropathic pain patientsÕ lateral thalamus of atypical patients with chronic is often conducted without prior neurological ÔneuropathicÕ pain without nerve injury and Apk- differential diagnosis (43). The refractoriness of a arian et al. (50) report prefrontal hyperactivity in large fraction of ÔneuropathicÕ pain patients to similar patients they descriptively label CRPS I and hypothesis-driven, invasive or addictive therapy, empirically adjudicate as being Ôsympathetically betrays current misinterpretation of their authentic maintainedÕ. Mailis-Gagnon et al. (51) report neuropathological and psychopathological origins, abnormal forebrain and limbic activation in while highlighting the iatrogenic impact of the patients with intractable pain and the diagnosis current paradigm. of conversion disorder. Further cerebral studies, coupled with comprehensive neurological and psychiatric evaluation will lead to a better under- The neuronal cerebral bases of pseudoneurological profiles standing and treatment of patients with The distribution of classic neuropathic and pseu- somatization disorders (52, 53). doneuropathic patients found in this series matches the incidence of organically based neuropathic and Acknowledgement psychogenic painful syndromes previously described (8). Livingston (44), working with a similar This study was supported by NIH grant NS 39761. patient population, from the same country and state as the present series, had reported the References abundance of atypical profiles eventually labeled Ôpseudoneurologic illnessÕ. Shorter (3) wrote: 1. Ochoa JL. Pain mechanisms in neuropathy. Curr Opin Neurol 1994;7:407–14. Ôalthough hysteria has been downplayed in official 2. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, nosology, it remains a robust category…Historical symptoms, mechanisms, and management. Lancet change gives pseudoneurologic illness its plasti- 1999;353:1959–64. city…in the history of changing symptoms 3. Shorter E. The borderland between neurology and history. what characterizes the twentieth century is the Conversion reactions. Neurol Clin 1995;13:229–39.

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