Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome

In addition to the debilitating fatigue, the majority of patients with chronic fatigue syndrome (CFS) experience chronic widespread pain. These pain complaints show the greatest overlap between CFS and fibromyalgia (FM). Although the literature provides evidence for central sensitization as cause for the musculoskeletal pain in FM, in CFS this evidence is currently lacking, despite the observed similarities in both diseases. The knowledge concerning the physiological mechanism of central sensitization, the pathophysiology and the pain processing in FM, and the knowledge on the pathophysiology of CFS lead to the hypothesis that central sensitization is also responsible for the sustaining pain complaints in CFS. This hypothesis is based on the hyperalgesia and allodynia reported in CFS, on the elevated concentrations of nitric oxide presented in the blood of CFS patients, on the typical personality styles seen in CFS and on the brain abnormalities shown on brain images. To examine the present hypothesis more research is required. Further investigations could use similar protocols to those already used in studies on pain in FM like, for example, studies on temporal summation, spatial summation, the role of psychosocial aspects in chronic pain, etc.
Introduction
Chronic fatigue syndrome (CFS), as defined by the Centers for Disease Control and Prevention (CDCP), is a complex illness characterized by prolonged debilitating fatigue and multiple non-specific symptoms including headaches, recurrent sore throats, fever, muscle and joint pain, and neurocognitive complaints [1, 2]. In addition to the chronic fatigue, widespread and persistent pain is common in individuals with CFS [3–5]. A population-based study revealed that 94% of the persons diagnosed with CFS report muscle aches and pain and 84% report joint pain [6]. Nishikai et al. [7] reported muscle pain in 85 CFS patients of 114 patients (74.6%). Seventy-four patients (64.9%) complained of arthralgia. In another study, 24 of 44 patients suffered from chronic widespread pain [8]. Chronic fatigue accompanied by chronic musculoskeletal impairments such as myalgias and arthralgias could be considered an important subclass of CFS [9]. Evidence supportive of the clinical importance of widespread pain in CFS has been provided [10]: chronic pain accounts for up to 34% of the CFS patients’ self-reported activity limitations and participation restrictions. Chronic pain is more disabling than chronic fatigue [10].
Given these facts, it may be surprising that the etiology of these pain complaints has not been studied extensively in patients with CFS. The systematic literature review by Meeus et al. [11] shows that only little progress has been made in understanding chronic widespread pain in patients with CFS. A few hypotheses have been proposed, but they have not been studied in depth or relatively little work has been performed to test these hypotheses. In contrast, a large body of scientific literature regarding the etiology of chronic pain complaints in fibromyalgia (FM) is currently available. The diagnosis of FM is based on the 1990 American College of Rheumatology criteria. Following these criteria, FM patients present with 11 of 18 positive tender points and with widespread pain [12]. Validity of both the definition for CFS and FM has been shown [12, 13].
Especially, investigations focusing on the phenomenon “central sensitization” are presented in force in FM. In CFS, the theory of central sensitization has only been suggested, to our knowledge [14]. Given the great overlap between CFS and FM [15] and given the dearth of studies focusing on the explanation for the chronic widespread pain in patients with CFS, it would be interesting to propose a theoretical model for the chronic pain in CFS based on the current knowledge of CFS and on the evidence for central sensitization in FM, giving rise to further research on that matter. Besides the knowledge on chronic pain in FM, it is necessary to gather knowledge on musculoskeletal pain in CFS.
The syndromes may overlap, but despite the similarities between the two syndromes, there are also differences. For example, immunological dysregulations such as the abnormal 2–5A synthetase/RNase L pathway [16] have been revealed in CFS but have never been detected in FM patients. Furthermore, there is not yet any good evidence for similar pain mechanisms in CFS and FM. Some authors already found evidence suggesting differences in pain processing. For example, patterns of functional brain activity in patients with FM are quite different from those in patients with CFS.
Patients with CFS, relative to controls, showed significantly lower blood perfusion in the brain stem [17, 18]. Patients with FM exhibited significantly lower rCBF levels, during rest, in the thalamus and the caudate nucleus [19]. Furthermore, Substance P has been found to be elevated in CSF of FM patients [20] and not in patients with CFS [21]. Therefore, the knowledge on pain in FM cannot be applied on CFS patients without further study. Based on the similarities and differences between the two syndromes, further research on pain in CFS is advised to get an image of pain processing in the two diseases.
The goal of this article is to provide a rational basis for future investigations. First, the concept of central sensitisation as a cause of chronic pain will be explained. This theoretical background will then be applied to FM and an overview of the evidence for central sensitization in FM will follow. Finally, based on the theoretical background and the findings in FM, the hypothesis concerning central sensitization in CFS will be unfolded, supported with the present knowledge on CFS.
Central sensitization
Introduction Pain is a complex perception that is influenced by prior experience and by the context within which the noxious stimulus occurs; “nociception” is the physiologic response to tissue damage or prior tissue damage [22]. The definition of pain is endorsed by the International Association for the Study of Pain: “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” [23]. There are a host of physiologic mechanisms by which injuries lead to nociceptive responses and ultimately to pain [22]. However, not all nociceptive signals are perceived as pain and vice versa, not every pain sensation originates from nociception. Nevertheless, acute pain almost always originates from nociceptors in somatic or visceral tissue. Mainly two types of pain receptors are activated by nociceptive input. These include low-threshold nociceptors that are connected to fast conducting A-delta pain fibers, and high-threshold nociceptors that conduct impulses in slow (unmyelinated) C fibers. Within the dorsal horn of the spinal cord, these pain fibers synapse with spinal neurons via synaptic transmission. Many neurotransmitters (i.e., glutamate, substance P, etc.) are able to modulate the postsynaptic responses with further transmission to supraspinal sites (thalamus, anterior cingulated cortex, insular cortex, and somatosensory cortex) via the ascending pathways [22, 24, 25].The simplest form of plasticity in nervous systems is that repeated noxious stimulation may lead to habituation (decreased response) or sensitization (increased response) [26]. Prolonged or strong activity of dorsal horn neurons caused by repeated or sustained noxious stimulation may subsequently lead to increased neuronal responsiveness or central sensitization [25, 27]. Neuroplasticity and subsequent CNS sensitization include altered function of chemical, electrophysiological, and pharmacological systems [22, 28, 29]. These changes cause exaggerated perception of painful stimuli (hyperalgesia), a perception of innocuous stimuli as painful (allodynia) and may be involved in the generation of referred pain and hyperalgesia across multiple spinal segments [25, 30–33].While the exact mechanism by which the spinal cord becomes sensitized or in “hyperexcitable” state currently remains somewhat unknown, some contributing factors have been proposed.
Temporal summation or wind-up “Wind up” refers to a central spinal mechanism in which repetitive noxious stimulation results in a slow temporal summation that is experienced in humans as increased pain [34]. In 1965, animal experiments showed for the first time that repetitive C-fiber stimulation could result in a progressive increase of electrical discharges from the second-order neuron in the spinal cord [35]. This mechanism of pain amplification in the spinal cord is related to temporal summation of second pain or wind-up. Second pain, which is more dull and strongly related to chronic pain states, is transmitted through unmyelinated C fibers to dorsal horn nociceptive neurons. During the C-fibres transmitted stimuli, N-methyl-d-aspartate (NMDA) receptors of second-order neurons become activated.It is well-known that NMDA activation induces calcium entry into the dorsal horn neurons [36]. Calcium entry into sensory neurons in the dorsal horn induces activation of nitric oxide (NO) synthase, leading to the synthesis of NO [37]. NO can affect the nociceptor terminals and enhance the release of sensory neuropeptides (in particular, substance P) from presynaptic neurons, therefore contributing to the development of hyperalgesia and maintenance of central sensitization [38]. Substance P (SP) is an important nociceptive neurotransmitter. It lowers the threshold of synaptic excitability, resulting in the unmasking of normally silent interspinal synapses and the sensitization of second-order spinal neurons [39].Furthermore, SP can extend for long distances in the spinal cord and sensitize dorsal horn neurons at a distance from the initial input locus. This results in an expansion of receptive fields and the activation of wide dynamic neurons by non-nociceptive afferent impulses [24].Wind-up can be elicited in human patients if identical nociceptive stimuli are applied to the skin or muscles more often than once every 3 s. The resulting progressive increase of pain sensations represents wind-up and has been demonstrated to result from a central rather than a peripheral nervous system mechanism, because the input from C nociceptors has been shown to decline or stay the same with stimulus repetition [40].
Endogenous pain modulatory systems The presence of several pain inhibitory and facilitatory centers in the brainstem is well recognized. The dorsolateral funiculus appears to be a preferred pathway for descending pain inhibitory systems [41]. Experimental evidence for the existence of descending inhibitory pathways, and their connection with central sensitization, include the observations that bilateral lesions of the dorsolateral funiculus in the rat led to a significant decrease in latency for paw withdrawal to noxious stimulus [42]. Similarly, temporary spinal cord block (lidocaine) caused dorsal horn nociceptive neurons to expand their receptive fields and their responsiveness to afferent input [43]. In addition, selective chemical lesion of serotonergic inhibitory neurons in experimentally “inflamed” animals resulted in demonstrable behavioral “pain” hypersensitivity [42].The foregoing investigations suggest that disruption of one or more of the elements of the inhibitory system can result in, among other things, the equivalent of central sensitization [44]. One function of the descending inhibitory pathway is to “focus” the excitation of the dorsal horn neurons. The effect is to generate a more urgent, localized, and rapid pain signal by suppressing surrounding neuronal activity [45]. This role is attributed to the “diffuse noxious inhibitory controls” (DNIC) phenomenon [46]. According to this model, descending pathways effectively enhance the biologically valuable pain signal by reducing the level of irrelevant “noise” in the system.Facilitatory pathways leading from the brainstem have also been identified. There is now behavioral evidence that forebrain centers are capable of exerting powerful clinically significant influences on various nuclei of the brainstem, including the nuclei identified as the origin of the descending facilitatory pathway [44]. The activity in descending pathways is not constant but can be modulated, for example, by the level of vigilance or attention and by stress [47]. Brosschot [48] refers to it as cognitive emotional sensitization. Forebrain products such as cognitions, emotions, attention, and motivation have influence on the clinical pain experience [44].Dubner and Ren [41] rewarded subjects for responding to a randomly delivered transient tissue threatening peripheral stimulus. It was found that sensitization of second-order pain pathway neurons was directly related to the strength of attention. The evidence suggests that selective attention to relevant stimuli activated descending pain modulatory systems, turning the balance in favor of facilitation. The dominance of descending facilitation then led to sensitization of second-order neurons [44]. Behavioral variables such as attention to a potentially threatening stimulus result in sensitization of dorsal horns spinal cord neurons. Moreover, behavioral modulation associated with selective attention to a perceived threat utilizes the same forebrain and brainstem structures and mechanisms as are involved in the development, amplification, and maintenance of persistent pain after actual tissue damage and inflammation [41].Certain cognitive styles and personality traits have been associated with amplification of pain and its extension in the absence of tissue damage. These include somatization, catastrophizing, and hypervigilance [49–52]. Thus, via descending pathways behavioral and cognitive therapies might also effect synaptic transmission in the spinal cord and thereby have the capacity to prevent or reverse long-term changes of synaptic strength in pain pathways [47].
Evidence in FM
Exaggerated pain is common in whiplash and FM patients. Theoretically, peripheral mechanisms can account for the pain hypersensitivity. In FM, however, there is no evidence for peripheral sensitization as the cause of hyperalgesia, given the absence of real tissue damage. Peripheral sensitization is defined as a reduction in the threshold of nociceptive afferent receptors caused by a local change in the sensitivity of sensory fibers initiated by tissue damage [53]. Peripheral sensitization almost always depends on local inflammation, which may lead to decreased nociceptor thresholds. Despite extensive investigations, no tissue pathology, structural abnormalities, or evidence for a source of chronic stimulation of pain afferents have been detected in fibromyalgic patients [54].
Furthermore, FM pain lacks a distinct spatial localization [55]. This suggests that pathophysiological central mechanisms contribute to or are responsible for FM pain [56]. This has led to the hypothesis that the central nervous system is hyperexcitable in these patients. Central hypersensitivity could explain exaggerated pain in the presence of minimal and undetectable tissue damage, in that the nociceptive signal is amplified by the hyperexcitable neurons [57].
Pain measurements Studies in patients with chronic pain after whiplash injury and with FM have demonstrated exaggerated pain responses after sensory stimulation of healthy tissues [55, 58–63]. For example, at same level of thermal stimulation, FM patients perceived pain as 49 and 52% more intense than healthy controls and patients with low-back pain [61]. After-sensations at 15 s after heat taps were regarded as painful on 83% of FM patients, compared to 37% pain reports of healthy controls. The late after-sensations (2 min after heat stimulation) were rated as painful in 55 and 5% of FM and control subjects, respectively [55]. It was not mentioned in the results if all FM patients were subject to increased sensitivity, but there were always significant differences between the FM patients and the healthy controls.Although most comparisons were made to pain-free subjects, some researchers, like Julien et al. [61], even compared the pain responses of FM patients to other pain patients, such as patients with chronic low-back pain. They could also report significant differences. Despite the lack of research into the contribution of psychological factors in wind-up, these results suggest that input to central nociceptive pathways is abnormally processed in patients with FM. Intramuscular electrical stimulation has been used to assess the efficacy of temporal summation of painful muscle stimuli. Temporal stimulation was found to be more pronounced and to cause stronger pain and larger referred areas in FM patients compared to controls [60].The increased efficacy of temporal summation in FM has even so been reproduced with cutaneous heat stimulation [55] and with cold and heat taps [59]. Facilitated temporal summation in patients with pain suggests that the efficacy of central processing is increased (central sensitization) in these patients [64]. In addition, after-sensation was greater in magnitude, lasted longer, and was more frequently painful in patients with FM [55]. The prolonged decay together with the augmentation provides evidence for the presence of central sensitization [24, 25]. Immersion of the arm in circulating noxious cold water resulted in a 49% more intense pain in FM patients compared to healthy controls [61]. Further evidence of central sensitization in FM is seen by enlarged referred pain areas. Sörensen et al. [60] found that fibromyalgic patients experienced stronger pain and larger referred areas after intramuscular injection of hypertonic saline.Moreover, spatial summation effect during increase of the stimulation area was found only in patients with FM and not in healthy controls or in patients with chronic low-back pain [61]. This indicates that pain inhibitory systems are not optimally recruited in patients with FM. FM patients perceived pain at the same intensities and unpleasantness during the ascending and the descending sessions (fingertip to shoulder and shoulder to fingertip immersion). In healthy controls and patients with low-back pain, the noxious stimulation of a large surface area results in an activation of a large population of nociceptive afferents that induce endogenous inhibitory responses, resulting in a decreased response in the dorsal horn neurons, and subsequently leads to lower pain intensities afterward.Given that FM patients experience similar pain intensities in the descending session after noxious stimulation of the whole arm, this study clearly demonstrated that FM patients present with a lack of activation of endogenous inhibitory systems [61]. Secondly, Lautenbacher and Rollman [65] showed that tonic painful and non-painful thermal stimulation of the foot increased the pain thresholds to electrical stimulation applied to a non-tender point (inner forearm) in healthy controls but had no effect on patients with FM. Kosek and Hansson [66] found that tourniquet ischemic pain in an arm increased the pressure pain threshold in healthy controls but not in FM patients, suggesting once more a deficiency in the latter of a pain-inhibitory phenomenon termed “diffuse noxious inhibitory control” (DNIC) [66, 67]. Similarly, aerobic exercise has been shown to decrease wind-up pain in normal subjects but increased it in FM patients, suggesting the possibility of reduced endogenous analgesic mechanisms [68]. Also, isometric exercise (i.e., hand-grip exercise) resulted in increased thermal pain ratings and decreased pain thresholds, both ipsilateral and contralateral to the exercised extremity [69]. These investigations support a general hypothesis that FM reflects a disorder affecting modulation of pain sensitivity [66, 67]. In one such scenario, tonic DNIC is present in the normal situation, and its pathological absence results in the spontaneous pain and evoked pain sensitivity associated with FM [34].
Measurements of excitability The results of the above-mentioned studies, however, are based on pain reports of the patients and thus subjective in nature, and it was not clear whether this hypersensitivity was the result of central mechanisms or whether the hypersensitivity was the cause of hypervigilance. Banic et al. [57] could provide objective evidence by quantifying the minimal intensity of transcutaneous electrical stimulation of the sural nerve required to evoke flexion reflex in the biceps femoris. This study clearly demonstrates that spinal cord neurons are sensitized in chronic pain after whiplash and in patients with FM; because the stimuli were delivered at random time intervals and the latency of EMG response was measured, voluntary symptom amplification could be ruled out. Moreover, the electrical stimulation bypasses peripheral receptors.
Cognitive emotional sensitization Patients with FM or other pain disorders often receive the message that it is “all in their head”. One construct that has been hypothesized to explain the pain amplification in FM is that of hypervigilance [34]. This hypothesis of hypervigilance has been argued by McDermid et al. [70]. FM showed an increased aversiveness to non-painful stimuli such as loud noise. Also, Crombez et al. [71] reported significant correlations between hypervigilance and pain intensity in FM patients. Furthermore, exposure to stressful situations, including noise, lights, and weather, is known to exacerbate symptoms of FM, including pain [72].In addition, FM patients with catastrophic thoughts report increased pain intensities [73–75]. Hassett et al. [74] found catastrophizing (27% of the variance) and depression (30% of the variance) to be significant predictors of pain. Finally, kinesiophobia and fear of pain are related to pain severity in patients with FM [76].The foregoing relations between emotions or cognitions and reported pain severity support the hypothesis of cognitive emotional sensitization in FM.
Central abnormalities in FM FM patients differ from healthy persons in regional cerebral blood flow (rCBF) distribution in several brain structures involved in pain processing and pain modulation both at rest and during experimental pain induction. Patients with FM exhibited significantly lower rCBF levels, during rest, in the thalamus and the caudate nucleus [17]. Dysregulation of thalamic activity and hypoperfusion of the caudate nucleus may contribute to the abnormal pain modulation, given the results of previous investigations [77–79]. In addition to nociceptive transmission, the thalamus also plays an important role in pain modulation. Animal studies proved that thalamic stimulation induces analgesia and lesions of the thalamus cause hyperalgesia [77, 78].Similarly, stimulating the caudate nucleus decreases pain behavior [79]. During pain induction in patients with FM, the absence of significant thalamic activation and a bilateral activation of the somatosensory cortices and the right anterior cingulated cortex was seen [80]. The patterns of cortical activation may be characteristic of patients with allodynia, and pain-induced activation of the right anterior cingulated cortex is associated with the use of maladaptive coping strategies [81]. Patients recruited by Bradley et al. [80] indeed reported significantly greater use of emotion-focused coping strategies (e.g., praying and hoping) during pressure stimulation. In addition, increased right frontal brain activity seemed related to increased pain sensitivity [82].Furthermore, FM patients are characterized by relatively high cerebrospinal fluid levels of substance P [20]. This finding indicates that abnormal brain activity in persons with FM is associated with abnormal CSF levels of a neuropeptide involved in pain transmission [80]. In addition, it is shown that a subgroup of FM patients present with mycoplasma infections [83]. Infection triggers the release of the pro-inflammatory cytokine interleukin-1β, which is known to play a major role in inducing cyclooxygenase-2 (COX-2) and prostaglandin E2 expression in the central nervous system [84].Peripheral nerve terminals can be sensitized by elevated COX-2 amounts and prostaglandin E2. Peripheral infections are even able to activate spinal cord glia, leading to the release of NO and proinflammatory cytokines, enhancing the pain response [85]. Physiological symptoms, such as pain, can be explained by these mechanisms (“sickness response”).
Central sensitization in CFS?
Direct evidence supporting the central sensitization hypothesis in CFS patients is currently lacking. But the present knowledge concerning CFS is suggestive of a central process similar to that seen in FM, given the great overlap between the two diseases and the observed similarities.
First, lower pain thresholds at different sites (hyperalgesia) are reported in patients with CFS, compared to controls [86, 87]. Similar to FM, the lack of peripheral tissue damage and the lack of a distinct localization of the pain complaints are suggestive of a central abnormality responsible for the chronic widespread pain. To our knowledge, there are no investigations that focused on abnormal wind-up, temporal summation, or spatial summation in CFS, to collect evidence for central sensitization in CFS. Yet, evidence of a dysfunctional central anti-nociceptive mechanism in CFS has been proved by Whiteside et al. [88]. They reported a decrease of pain threshold in patients with CFS after graded exercise, while healthy controls present an increased pain threshold. These findings are similar to those of Vierck et al. [68] in FM patients.
Secondly, the frequently reported opportunistic infections [89, 90] may lead to the “sickness response” and complies with the central sensitization hypothesis, as explained above. Indeed, elevated NO levels have been documented in CFS patients [91]. As earlier mentioned, NO plays an important role in the history of central sensitization and, therefore, central sensitization caused by NO would be likely in patients with CFS. The release of excessive amounts of Substance P in the CSF, however, could not be documented in patients with CFS, in contrast to FM patients [21]. The CFS patients in this study, however, did not experience chronic widespread pain, and it is not clear if they fulfilled the 1994 CDC criteria [2]. Given that 70% of the CFS patients do fulfill the ACR criteria for widespread pain [12], it is striking that the patients included in the investigation of Evengard et al. [21] (focused on the source of pain) did not report these pain complaints. Further research on that matter should analyze the CSF of CFS patients (fulfilling the Fukuda criteria) suffering from chronic widespread pain.
A third important argument in the central sensitization theory for CFS concerns the cognitive, psychological, and behavioral changes in patients diagnosed with CFS. CFS patients often present with depression [6, 92], catastrophizing [93, 94], somatization [95, 96], and kinesiophobia or fear avoidance [97–99]. In CFS, it is known that these psychosocial aspects are important factors in maintaining the complaints of CFS. These cognitions and emotions are able to influence pain perception via modulation of the descending pathways [44]. Furthermore, these “cognitive styles” and “personality traits” have earlier been mentioned to be associated with the amplification and the extension of pain [49–52].
Finally, brain imaging already provided evidence for altered brain activity in CFS. Patterns of functional brain activity in patients with FM are quite different from those in patients with CFS. Patients with CFS, relative to controls, showed significantly lower blood perfusion in the brain stem [17, 18]. Patients with FM exhibited significantly lower rCBF levels, during rest, in the thalamus and the caudate nucleus [19]. However, the areas are different in FM and in CFS; both the affected areas could be related to central pain processing. Low brain stem rCBF levels may contribute to abnormal function of the locus ceruleus in patients with CFS. The locus ceruleus is involved in controlling descending anti-nociceptive pathways from the brain to the spinal dorsal horn [56]. In consequence, pain experiences of patients with CFS may be related to low resting state levels of functional activity in the brain stem [80].
Conclusion
Chronic widespread pain can be the consequence of central sensitization. Central sensitization is known as an increased central neuronal responsiveness and causes hyperalgesia, allodynia, and referred pain and hyperalgesia across multiple spinal segments, leading to chronic widespread pain. Possible triggers for sensitization of the spinal cord have extensively been discussed, such as wind-up or temporal summation, dysregulated descending inhibitory pathways, and upregulated facilitatory modulation. Wind-up or temporal summation is the result of repetitive noxious stimuli, leading to an increase in electrical discharges in the dorsal horn. Inhibitory modulation can be impaired by abnormalities in the central nervous system and the facilitatory pain pathways can be stimulated by certain behavioral and cognitive factors.
This theoretical background can be applied to FM. In FM, studies already provided evidence for central sensitization as the cause of chronic pain. Temporal summation was found to be more facilitated, and the inhibitory pain modulation seemed impaired in FM patients. These findings can explain the chronic spontaneous pain in FM. Furthermore, some central abnormalities could be examined/objectified in FM: 1) hyperexcitability of the spinal cord, 2) decreased perfusion of pain-related brain structures, and 3) high levels of substance P in CSF. In addition, FM patients often present with pain hypervigilance, maladaptive coping strategies, and catastrophic thoughts, leading to cognitive central sensitization.
Based on the knowledge on central sensitization, on FM and on CFS, it is suggested that chronic widespread pain in CFS is the consequence of central sensitization. There are arguments and probable mechanisms that could explain this phenomenon in CFS. Also, in other chronic pain populations, central sensitization may play a key role. In fact, there are many similarities between CFS patients and other chronic pain populations such as patients with chronic low-back pain, whiplash, FM, etc. The psychosocial factors, for example, have been proved to contribute to pain perception in these different pain populations. But the specific nature of CFS such as the immunological abnormalities, elevated NO amounts, preceding infections etc., invites further research, in particular, on the possible contributory role of these abnormalities to pain processing in CFS.
In FM, many researches have been conducted to prove the theory of central sensitization. In CFS, however, it sticks to “supposing.” To give a scientific basis to the theory, the protocols applied in FM investigations could be used for patients with CFS. It would, for example, be interesting to test the efficacy of temporal summation in CFS. The inhibitory control of pain could be another point of interest. The influence of exercise on pain tolerance has already been studied in CFS [88], however, on a relatively small sample. On the contrary, spatial summation has, to our knowledge, never been investigated in CFS. Furthermore, the role of depression, hypervigilance, kinesiophobia, catastrophising, etc. on chronic pain in CFS requires further research. To obtain more direct and objective information on central sensitization, the protocol described by Banic et al. [57] could be used to test the sensitivity of the central nervous system. Clearly, there are many possible research areas to test the hypothesis, but there is still a long way to go to elucidate the nature of the chronic pain in CFS.

central sensitization
fibromyalgia
chronic fatigue syndrome
chronic pain


Benefits and entitlements in the Hungarian health care system

This contribution considers entitlements and benefits in the Hungarian health care system. After a brief introduction to the organizational structure of the system the decision-making processes are discussed in detail, including the most important actors, types and pieces of legislation, formal structures, decision-making criteria, and outputs in terms of benefit catalogues. Within the two main public financing systems (social insurance and tax-funded services) there are four types of regulatory regimes: (a) traditional political decision making, (b) price negotiations, (c) updating of classification systems for payment purposes, and (d) the procedure for the inclusion of registered medicines in the scope of the social health insurance system. As an example we discuss the benefit regulations and benefit catalogues in the category of services of curative care (HC.1) of the OECD classification of health services.
With the crisis and the collapse of the communist dictatorship Hungary witnessed the beginning of a thorough health sector reform. Replacing the tax-based financing of the state-socialist system, Hungary reverted to the earlier Bismarckian model of compulsory social insurance in 1990. New performance-based provider payment methods were introduced (capitation in primary care, fee-for-service for outpatient specialist services, and diagnosis-related groups (DRGs) in the acute inpatient care sector) together with cost-containment mechanisms to ensure that the preset budgets were not exceeded. Ownership of the majority of hospitals and other health care facilities was transferred to local governments. The vast majority of medical doctors and other health workers remained salaried public employees, with the only exception of primary care, where the bulk of family physicians work as contracted private entrepreneurs. The minimum salary for public employee physicians is determined by law, whereas the average salary in the health sector has remained among the lowest in the economy [1].
Entitlement to health care is based mainly on the participation in the social insurance scheme (with compulsory membership, opting out is not permitted), and to a few services on citizenship. The national Health Insurance Fund (HIF) provides a virtually universal population coverage with an almost comprehensive benefit package, which applies to the whole country (i.e., there are no variations by region or by payer). Nevertheless, the HIF covers only the recurrent costs of services. The owners of health care facilities, mainly local governments, are obliged to cover the capital costs of services, which usually come from general and local taxation. Tax revenues are also used for covering the deficit of the HIF [1997 Act LXXX on Those Entitled for the Services of Social Insurance and Private Pensions and the Funding of these Services, Sect. 3(2)], certain special services (e.g., public health, catastrophe medicine, experimental medical technologies, family planning and maternal care), which are financed entirely from the central government budget [1997 Act LXXXIII on the Services of Compulsory Health Insurance, Sect. 18(5)a–d, h; 1997 Act CLIV on Health, Sects. 141(2)b, 142(2)], and the copayment for certain medicines and therapeutic devices for socially disadvantaged (1993 Act III of on Social Services). In addition to informal payments to health workers, copayments for medicines and therapeutic devices constitute the most important private source of health care financing, which are almost exclusively out-of-pocket, as private health insurance is still insignificant in Hungary [1].
Decision-making processes and actors
Entitlement to publicly financed health services is regulated by various types of regulatory instruments (Table 1). These represent the decisions of various decision-making actors, with varying decision-making rules/processes and power. There is a hierarchy of regulations with the constitution on top, followed by governmental and then ministerial decrees. In the case of conflicting provisions the higher level regulation precedes the lower one, but the provisions of lower regulations are usually more detailed.Table 1 Main types of regulations in Hungary [1949 Act XX on the Constitution of the Republic of Hungary; 1987 Act XI on Codification; Resolution No. 1088/1994 (IX.21) on the Decision-Making Procedures of the Government; 1990 Act LXV on Local Governments]Type of regulationDecision makerMethod of decision makingConsultationLegal regulations, laws  ConstitutionNational AssemblyTwo-thirds majority voteRequired  Fundamental actsNational AssemblyTwo-thirds majority voteRequired  ActsNational AssemblySimple majority voteRequired  Governmental decreesCentral governmentSimple majority vote of the government or exceptionally the prime minister (one person)Required  Ministerial decreesMinistersOne personRequired  Local government decreesLocal government assembliesSimple majority voteRequiredRulings of the Constitutional CourtConstitutional CourtSimple majority vote–Other means of state control  ResolutionNational Assembly, central government, governmental committees, local governmentsAccording to decision maker–  OrderMinisters, heads of organizations with national scope of authorityOne person–  PolicyNational Assembly, central government, ministers, heads of national organizationsAccording to decision makerRequired  Statement of interpretation of legislationsNational Assembly, central governmentAccording to decision maker?  Announcement, communicationMinisters, heads of organizations with national scope of authorityOne person–
The National Assembly (Parliament) and the central government (and Ministry of Health, MOH) are the key actors in national-level decision making. Parliament determines, for instance, the scope of publicly funded services, the benefit package, and the budget of the HIF. While most decisions of Parliament require a simple majority, the constitution and other fundamental acts (e.g., on local governments) can be changed only with a two-third majority vote. Passed bills are promulgated as acts, on the basis of which governmental and ministerial decrees are issued, which regulate the implementation of acts in detail [1].
In addition to acts, governmental, ministerial, and local government decrees, which represent generally valid and obligatory behavioral norms and are called “legal regulations” or “laws,” there are lower level regulations, which are categorized as “other means of state control,” such as resolutions, orders, policies, statements, and announcements (1987 Act XI on Codification, Sects. 46–56) as well as organizational operational rules and procedures of various organizations and decision-making bodies. Resolutions, for instance, can be issued by the Parliament, the government, governmental committees, local governments, and their organs to regulate the tasks of organizations controlled by them, the rules of their own operation and plans within their scope of authority, while orders can be issued by ministers and the heads of organizations with national scope of authority to regulate the activities of the organizations under their control [1987 Act XI on Codification, Sect. 46(1)].
The process of decision making and the content of the benefit basket are usually regulated at least in ministerial decrees with only a few cases, when the decision on benefits has been decentralized to other organizations (Table 2). This does not mean that the decision making has no input from a wide range of actors in the health care arena. The most important actors are as follows: (a) National Health Insurance Fund Administration (NHIFA), which administers the HIF, in particular its Department of Payment Informatics (formerly the Information Center for Health Care of MOH, (GYÓGYINFOK)) which is responsible for the provider payment and performance measurement; (b) various advisory bodies and organizations of the MOH, including the national institutes of health and the professional colleges, which provide an expert input concerning a particular medical specialty; (c) professional organizations (e.g., Hungarian Medical Chamber, HMC; Hungarian Chamber of Pharmacists, HCP), unions, and provider and patient associations [1].Table 2 Regulations of entitlements and benefits in HungaryRegulation (type according to Table 1)What is regulated?C/PAct XX of 1949 (1)Right to healthCAct CLIV of 1997 (3)Right to health services; scope and broad content of health servicesCAct LXXX of 1997 (3)Participation in and contribution to the social insurance scheme (who is covered)–Act LXXXIII of 1997 (3)Framework for benefits of social insuranceC, PGovernment Decree No. No. 217/1997. (XII. 1 Korm (4)Executive order of Act LXXIII of 1997P, CDecree No. 46/1997. (XII. 17) NM of the Minister of Welfare (5)Services excluded from public financingCGovernment Decree No. 284/1997 (XII. 23) Korm (4)Copayments; exclusions (full fee)CAct XCIII of 1993 (3)Occupational health servicesCGovernment Decree No. 89/1995. (VII. 14) Korm (4)Occupational health servicesCDecree No. 27/1995. (VII. 25) NM of the Minister of Welfare (5)Occupational health servicesCDecree No. 5/2004. (XI. 9) EüM of the Minister of Health (5)Benefit catalogue of balneotherapyCDecree No. 20/1995. (VI. 17) NM of the Minister of Welfare (5)Benefit catalogue of treatment in sanatoriaCDecree No. 48/1997. (XII. 17) NM of the Minister of Welfare (5)Benefit catalogue of dental careCDecree No. 49/1997. (XII. 17) NM of the Minister of Welfare (5)Benefit catalogue of infertility treatmentsCDecree No. 47/1997. (XII. 17) NM of the Minister of Welfare (5)Eligibility for free breast milkCDecree No. 50/1997. (XII. 17) NM of the Minister of Welfare (5)Eligibility for patient transportationCDecree No. 51/1997. (XII. 18) NM of Minister of Welfare (5)Benefit catalogue of screeningCDecree No. 56/2003. (IX. 19) ESzCsM of the Minister of Health, Social and Family Affairs (5)Benefit catalogue of balneotherapyCDecree No. 19/2003. (IV. 29) ESzCsM of the Minister of Health, Social and Family Affairs (5)Benefit catalogue of medical aids and prostheses (therapeutic devices)CGovernment Decree No. 43/1999. (III. 3) Korm (Annex 8) (4)Benefit catalogue of chronic careCDecree No. 9/1993. (IV. 2) NM of the Minister of Welfare (5)Benefit catalogue of outpatient specialist services; acute inpatient care; dental care; day cases of curative care; dialysis; chronic outpatient care;CDecree No. 1/2003. (I. 21) ESzCsM of the Minister of Health, Social and Family Affairs (valid until 1 July 2005 then NHIFA announcement) (5, 12)Benefit catalogue of medicinesCDecree No. 20/1996. (VII. 26) NM of the Minister of Welfare (5)Benefit catalogue of home careCDecree No. 49/2004. (V. 21) ESzCsM of the Minister of Health, Social and Family Affairs (5)Tasks of MCH nursesCDecree No. 26/1997. (IX. 3) NM of the Minister of Welfare (5)Tasks of school health services (physician, MCH, dentist, assistant)CGovernment decree No. 168/2004. (V. 25) Korm (4)Regulatory regime (price negotiations for special medicines)PDecree No. 6/1998. (III. 11) NM of the Minister of Welfare (5)Regulatory regime (payment)PGovernment Decree No. 112/2000. (VI. 29) Korm (4)Regulatory regime (price negotiation)PDecree No. 32/2003. (IV. 26) ESzCsM of the Minister of Health, Social and Family Affairs (5)Regulatory regime (medicines)POrder No. 6/2005. (Eb. K. 3) OEP of the Chief Executive Officer of the National Health Insurance Fund Administration (9)Regulatory regime (medicines)PC content regulation,
P Process regulation
The 1987 Act XI on Codification explicitly requires relevant nongovernmental and interest representation organizations to be consulted in the phase of preparation of laws (Sects. 27–32).
Given that the existing benefit catalogues are almost exclusively incorporated into acts, governmental decrees and ministerial decrees, the general features of the decision-making processes (regulatory regimes) on benefits are common, as described above. While in these cases it is straightforward who makes the decision on the basis of what method, the real issue is who is consulted in what form in the preparatory phase of the decision making process, for which the acts discussed so far only provide a very general and vague guidance.
In many cases the decision support mechanisms have not yet been formalized in lower level regulations, and therefore that the process of preparation and codification is based on tradition. For instance, the need for the creation of a ministerial decree can originate from the provision of an act or governmental decree—in this case the MOH Legal Department initiates the codification process at the relevant professional department—or it can be initiated internally or by an external actor/stakeholder. Although each department must work on the basis of specific regulations on issue handling, in what cases, who is to be consulted, and how are usually not specified in these regulations but passed from one civil servant on the other (Zs. Kovácsy, personal communication, 2005).
This traditional regulatory regime is the most commonly used decision-making mechanism regarding entitlements and benefits (Fig. 1). The two key acts in the center of the definition of the benefit package are 1997 Act CLIV on Health and 1997 Act LXXXIII on the Services of Compulsory Health Insurance. These acts define only a general framework in which both exclusions and inclusions are usually stipulated only at the level of broad functional categories. According to the 1997 Act CLIV, the right to health services is unconditional only for emergency life-saving services, services, which prevent serious or permanent health damage, and for the reduction in pain and suffering (Sect. 6). Patients have a right to other health services only within the limits set by another legislation (Sect. 7). The Act states that the state is responsible for the operation of the social insurance scheme to enable the individuals to exercise their right to health, and then lists the services, which must be financed from the central government’s budget (Sects. 141, 142). The 1997 Act LXXXIII defines health services which are free of charge (Sects. 10–17), covered with copayment (Sects. 23–25), or excluded [Sect. 18(5–6)]. The starting point of the Act is that all health services are fully covered and exclusions are stipulated. In the frame of social insurance all professionally justified treatments can be used [Sect. 18(4)], but diagnostic and treatment protocols issued by the MOH can further specify the actual services for which the patients are entitled to [Sect. 19(1)]. Physicians are allowed not to adhere to the protocols if the deviation is justified by the status of the patient and by therapeutic considerations. It must be noted, however, that broad functional areas are also listed (i.e., there is a scope for implicit exclusions) in the Act in three main categories: (a) services for the prevention and early detection of diseases (Sect. 10), (b) curative services, including family physician services, dental care, outpatient specialist, and inpatient care (Sects. 11–14), and (c) other services including deliveries, medical rehabilitation, patient transport and emergency ambulance services (Sects. 15–17, 22).Fig. 1 Traditional regulatory regime for entitlements and benefits in Hungary
These laws were passed by Parliament with a simple majority vote but are not updated or modified on a regular basis. Their modification can be initiated by the government (Minister of Health), the President of the Republic, Members of Parliament, Parliamentary Committees, or other stakeholders through these actors [Resolution No. 46/1994 (IX. 30) OGY of the National Assembly].
The above acts contain a large number of clauses, which call the government, the Minister of Health, or both of them to further specify certain functional areas. There are two main types of ministerial decrees. The 1997 Act CLIV calls on the Minister of Health to regulate the professional requirements, including minimum standards and procedures of certain service categories, and these decrees may include provisions related to the benefit package. For instance, these types of ministerial decrees can specify the tasks which must be fulfilled in the framework of a particular service (e.g., school health services Decree No. 26/1997 (IX. 3) NM of the Minister of Welfare on School Health Services) and what service can be ordered for what patients’ conditions (e.g., rehabilitative treatments in sanatoria Decree No. 20/1995 (VI. 17) NM of the Minister of Welfare on the Treatment in Sanatoria in the Frame of Medical Rehabilitation) and define who is allowed to provide specific services [e.g., home care; Decree No. 20/1996 (VII. 26) NM of the Minister Welfare on Home Care)].
On the other hand, the 1997 Act LXXXIII authorizes ministerial (and governmental) decrees to specify entitlements and benefits within a particular service category [e.g., dental care; Decree No. 48/1997 (XII. 17) NM of the Minister of Dental Services which Can Be Utilized in the Frame of the Compulsory Health Insurance]. In certain cases it is not the service concerned specified but the criteria of eligibility [e.g., the supply of breast milk; Decree No. 47/1997 (XII. 17) NM of the Minister of Welfare on the Supply of Breast Milk in the Frame of the Compulsory Health Insurance]. The updating of these decrees is made on an ad hoc basis as the need arises. Benefits are uniform throughout the country and explicitly defined, although services are usually not detailed.
Nevertheless, there are certain areas, such as pharmaceuticals and therapeutic devices, where various factors such as the presence of powerful suppliers (manufacturers of medical goods) have led to more formalized decision making. These developments received a new impetus in Hungary as a result of the country’s integration into the European Union, as the requirements of EU directives, for instance, in the case of pharmaceuticals, have had to be incorporated into Hungarian regulations. The decision-making process for the inclusion of a particular medicine in the benefit package of the social insurance scheme has been regulated down to the details of decision-making criteria.
Furthermore, the introduction of new payment mechanisms created indirect means of defining benefits through the classification of cases and services for the purpose of provider reimbursement (Fig. 2). In the case of outpatient care there is a list of services with the World Health Organization International Classification of Procedures in Medicine (ICPM) codes and point values, while acute inpatient cases are categorized into one of the 786 DRGs on the basis of the diagnosis (coded on the basis of the 10th edition of the International Classification of Diseases) and the procedures performed [Decree No. 9/1993 (IV. 2) NM of the Minister of Welfare of the Social Insurance Financing of Specialist Services]. While the 1997 Act LXXXIII of declares that all professionally justified curative services are included in compulsory social health insurance financing, there is no incentive for the providers to provide services which are not reimbursed. Therefore these classification systems can be regarded as indirect benefit catalogues, with the updating procedure being their indirect modification. Since the introduction of the new payment mechanisms they have been regularly updated and the process of instituting changes has been formalized since 1998 [Decree No. 6/1998 (III. 11) NM of the Minister of Welfare on the Regulation of Updating Professional Classification Systems and Financing Parameters Used in Health Care]. The updating process includes the modification and extension of the two fundamental classification systems as well as the various payment catalogues. The extension of the ICPM has special relevance for the benefit package, since those health care interventions, which are not listed in the Hungarian version of the ICPM have been excluded from public financing (1997 Act LXXXIII on the Services of Compulsory Health Insurance).Fig. 2 Updated Classification Systems for Payment Purposes. [Decree No. 6/1998. (III. 11) NM of the Minister of Welfare; Procedure of the Payment Codes Updating Committee]
The key actors in the process are the GYÓGYINFOK and the so-called Payment Codes Updating Committee (PCUC), which is an advisory body of the minister of health [Decree No. 6/1998 (III. 11) NM of the Minister of Welfare on the Regulation of Updating Professional Classification Systems and Financing Parameters Used in Health Care]. The former is responsible for preparing decision support documents, including the collection and the analysis of the necessary financing data, while the PCUC makes the decisions formulated as proposals, guided by the criteria of public health impact and of the efficient allocation of resources [Procedure of the Payment Codes Updating Committee (Working Committee), December 2003, Sect. 2.5]. The ultimate decisions rest with the MOH. The list of outpatient specialist services, DRGs, day cases of curative care, chronic care services, and the various forms of dialysis (as well as their modifications) are always issued as ministerial decrees. Various announcements, communications, and guidelines are also published to promote the lawful use of payment catalogues [Decree No. 6/1998 (III. 11) NM of the Minister of Welfare on the Regulation of Updating Professional Classification Systems and Financing Parameters Used in Health Care Sects. 2(2–4), 7(1)].
The PCUC has 15 permanent members, delegated by the MOH (2), CEO of the NHIFA (2), GYÓGYINFOK (2), Hungarian Hospital Association (2), and HMC (1), while the Minister of Health appoints six medical experts and the head of the PCUC [Procedure of the Payment Codes Updating Committee (Working Committee), December 2003, Sect. 3]. The committee prepares its procedure, a yearly workplan and a methodological document as the basis of the updating process [Decree No. 6/1998 (III. 11) NM of the Minister of Welfare on the Regulation of Updating Professional Classification Systems and Financing Parameters Used in Health Care Sect. 5(4)].
The updating process can be initiated in two ways. Regular updates are planned in the workplan of PCUC, while all the relevant stakeholders are allowed to ask for unscheduled updates which must then be evaluated and answered within 30 days [Decree No. 6/1998 (III. 11) NM of the Minister of Welfare on the Regulation of Updating Professional Classification Systems and Financing Parameters Used in Health Care, Sect. 1(2)]; Procedure of the Payment Codes Updating Committee (Working Committee), December 2003, Sect. 2.4]. First, the latter proposals must be submitted to the head of the relevant national institute or directly to the Committee if there is no national institute concerned. The relevant professional college(s) then provides an expert opinion, and the GYÓGYINFOK then prepares a cost estimation and budget impact analysis usually on the basis of data provided by a sample of health care institutions. The PCUC has at least one meeting per month, whose proceedings are to be submitted to the MOH in the form of a proposal for changes at least once in a year [Decree No. 6/1998 (III. 11) NM of the Minister of Welfare on the Regulation of Updating Professional Classification Systems and Financing Parameters Used in Health Care, Sect. 5(6–7); Procedure of the Payment Codes Updating Committee (Working Committee), December 2003, Sect. 4.4].
In summary, there are four main regulatory regimes for the definition and modification of entitlements and benefits: (a) the traditional decision-making process, guided by the general rules of codification with less formalized preparatory phase, for services such as primary care and home care, (b) formalized as “price negotiations” for therapeutic devices and balneotherapy, (c) formalized as the “procedure for the inclusion of registered medicines in the scope of the social health insurance system” in line with the provisions of Council Directive 89/105/EEC (21 December 1988), and (d) formalized as the “procedure of updating professional classification systems and payment parameters” for outpatient specialist and inpatient care services.
As a result of the various regulatory regimes, universal benefit catalogues exist for almost all service areas.
Entitlements and benefits: services of curative care
Table 3 summarizes entitlements and benefits in the category of services of curative care (HC.1) of the International Classification for Health Accounts (ICHA) taxonomy [2].Table 3 Entitlements and benefits: services of curative care (HC.1)HCFunctional categoryRegulatory regimeaBenefit catalogue (regulation no. from Table 2, method of classification, date passed, last updateda), taxonomy1.1Inpatient curative careUpdating of classification systems for payment purposes (4)Acute inpatient care–somatic, intensive care, mental special area: transplantation21, Annex 3 (and Annex 8 for high cost high tech interventions; Annex 10 for course-type treatments); itemized by case (linked to diagnosis and therapy); 2 April 1993, 6 August 2004. 26 main groups (major diagnostic categories), altogether with 786 items (DRGs)1.2Day cases of curative careSpecialist outpatient care—day surgery21, Annex 9; itemized by service; 2 April 1993, 6 August 2004.227 items in two lists: (a) 194 elective surgical procedures (Sect. I), (b) 33 other (“clinical”) interventions (Sect. III)Special area: hemodialysis21, Annex 11; itemized by service; 2 April 1993, 2 March 2001.6 items: (a) hemodialysis, hemofiltration, hemodiafiltration; (b) same for patients under 18 years old; (c) peritoneal dialysis, (d) hemoperfusion, (e) hemodialysis with reusable dialysator, (f) mobile treatment1.3Outpatient care1.3.1Basic medical and diagnostic services(Curative) primary careTraditional (2, 4)–1.3.2Outpatient dental careDental prophylaxis, care, surgeryTraditional (2, 4)13; itemized by service; 17 December 1997, 1 November 2001.3 main groups: (a) dental screening, with 7 items in three subgroups; (b) dental emergency services with 10 items; (c) dental primary and secondary care, defined as the payment list, detailed in a separate decree (no. 21)Updating of classification systems for payment purposes (4)21, Annex 12; itemized by service; 2 April 1993, 11 March 2003.125 items in 10 groups: (a) examinations, documentations, 9; (b) prevention, 5; (c) radiography, 5; (d) anesthesia and drug prescription, 5; (e) tooth preserving services and endodontia, 12; (f) oral diseases and parodontology, 11; (g) dental surgery, 24; (h) dental prosthetics, 26; (i) child, school, and youth dental services, 13; (j) orthodontia, 151.3.3All other specialized health careSpecialist outpatient care–somaticUpdating of classification systems for payment purposes (4)21, Annex 2; itemized by service; 2 April 1993, 27 August 2004.List contains 3,166 (and together with the dispensary specific services 3,204) items (based on the 1978 ICPM of WHO)Specialist outpatient care–mental; special area: psychoanalysis, -therapy21, Annex 15; itemized by service; 11 May 2004.Altogether 120 items (82 items overlap with Annex 2) in five main groups: (a) skin and STD, 29 items; (b) oncology, 26 items; (c) pulmonology, 25 items; (d) psychiatry, 19 items; (e) addictology, 21 items1.3.9All other outpatient curative careOutpatient care by other professionalsUpdating of payment classification systems (4)As with 1.3.3, which are included (e.g., logopedia, physiotherapy, dietetics, optometry, acupuncture); the rest are implicitly excluded (e.g., chiropody, bioenergy treatments, iris diagnostics, hydrotherapy)Alternative and complementary medicineSpecial area: balneotherapy and physiotherapyTraditional (4)11 (definition of entitlements, regulation of prescription, utilization, and professional requirements); itemized by service; indications and contraindications; 9 November 2004.Annex 1, balneotherapy services, 10 items; Annex 4, physiotherapy services, 13 items; Annexes 5 and 6, indications and contraindicationsPrice negotiations (4)18; itemized by service; 19 September 2003.3 groups with the same 10 items; copayment is different for spas, which have national, regional, and local qualification1.4Services of curative home careTraditional (4)23, Annex 1 (specifies professional requirements); itemized by service; 26 July 1996, 9 June 1999.13 service categories, 22 items (includes hospice at home)a Benefit catalogues with the traditional regulatory regime are updated on an ad hoc basis, while the updating of payment lists is regular. All benefit catalogues are issued as ministerial decrees.
The general framework for these services is set by the 1997 Acts CLIV and LXXXIII, as discussed above, but all health services in this category are considered within the frame of the social insurance scheme. Although the 1997 Act LXXXIII states that all professionally justified services are included, in most cases the detailed payment catalogues imply implicit exclusions, such as most services of alternative medicine. With the exception of family physician services (primary care), there are benefit catalogues for each service category, either as a list of cases/services for payment purposes (1.1, 1.2, partly 1.3.2, 1.3.3, and partly 1.3.9) or for further specification of broad functional categories enumerated in the Act (partly 1.3.2, partly balneotherapy) or for the specification of professional requirements (1.4, partly balneotherapy).
These nationally valid benefit catalogues are the output of either the traditional decision-making process or the process of updating classification systems for payment purposes. They are issued as a ministerial decree in both cases, with the MOH being the final decision maker. Updating is ad hoc in the case of the former and regular in the case of the latter, where the preparatory phase is much more formalized and even a few decision-making criteria are defined (budget and public health impact), as discussed above.
Undoubtedly the two most detailed benefit catalogues are the lists of DRGs for inpatient curative care (1.1), and the so-called WHO point, or German point system for outpatient specialist care (1.3.3, partly 1.3.9). The essence of the DRG based hospital payment is that it pays a standard fee for discharged acute hospital cases and not for any individual service items such as laboratory tests, hospital days, drugs, and procedures. The DRG system classifies cases into a manageable number of categories, which are more or less medically meaningful and in which resource use is the same or at least similar (homogeneous resource use) [3]. The DRG system was introduced countrywide in Hungary in 1993 after a pilot project that began in 1987. The DRG system in the United States was adapted to the local situation using the cost data collected [4]. The current version of the Hungarian adaptation of DRGs (homogeneous disease groups, HDGs) is 5.0, which contains 786 groups in 26 main diagnostic categories [Decree No. 9/1993 (IV. 2) NM of the Minister of Welfare of the Social Insurance Financing of Specialist Services]. The first step of classifying patients is to determine the major diagnostic category, in which the main diagnosis and/or the interventions can be a principal classification criterion, which is to be further modified by comorbidity and age. For instance there are three groups of classifying factors in the major diagnostic category 14 (pregnancy, birth and childbed): the type of pregnancy (without complications, pathological pregnancy), the type of delivery (cesarean, vaginal, vaginal with operation, vaginal with epidural anesthesia) and the conditions of delivery (high risk, other comorbidity; Fig. 3). While in principle inpatient cases are sorted into HDGs primarily on the basis of diagnosis, which leaves hospital physicians to select treatment options freely, several treatment modalities are costly enough to be a principal classification criterion.Fig. 3 Examples of the homogeneous disease groups in Hungary. [Decree No. 9/1993. (IV. 2) NM of the Minister of Welfare on the Social Insurance Financing of Specialist Services]
The WHO point system, however, is entirely itemized by service. It is based on the 1978 ICPM, but the original list has been modified frequently ever since it has been introduced as the basis of payment in the outpatient specialist setting. Along with the chronic outpatient care items, the current catalogue contains 3,204 service items and has been in effect since 27 August 2004. Each service has a five-digit identification code and the services are listed in numerical order, from item 110011 (first aid) to 97550 (ambulatory developmental-neurology follow-up care of infants with spina bifida) and the list closes with 12 items of “complementary” points for special transfusion (two items) for noncompliant patients who threaten or attack attending medical staff (one item), for supervision of patients after treatment (five items), for drug loading (one item), and for patients of young age (three items). The list in the ministerial decree is not structured in groups or subgroups, but it is generally service (e.g., ultrasound examinations) and organ-oriented [e.g., eye-examinations; Decree No. 9/1993 (IV. 2) NM of the Minister of Welfare of the Social Insurance Financing of Specialist Services].
Discussion
The provision of universal and comprehensive coverage was the founding principle of the previous, state-socialist health care system. The tension between the changing and increasing needs and the available resources created shortages which have not been acknowledged and explicitly dealt with. Rationing effectively occurred through queuing, implicit waiting lists, the dilution of services, and informal payments [1].
The social insurance and payment reforms have brought about little change in this respect. Successive governments have faced the chronic deficit of the HIF, but measures to balance the budget have almost exclusively targeted the revenue side of the system, and only minor modifications have been implemented in the almost comprehensive benefit package [1]. Although entitlements are in principle linked to paying the contribution, the coverage is universal in practice since entitlement is not checked by the providers [5]. Despite payment catalogues the benefit package is defined rather negatively. While services financed by the HIF should be provided according to treatment protocols issued by the MOH, no such protocols have yet come into effect.
The general opinion in Hungary is that more explicit priority setting with more exclusions or more significant copayments would not be accepted by the majority of the population, and therefore politicians are reluctant to touch the issue of priority setting in a more systematic manner. On the other hand, the financial pressure on the system is high, and indirect, implicit rationing does occur, for instance, through informal payments. It is a question of how long this schism can be uphold, especially in the light of the challenges by joining the EU.
The plan of the current government is to revise entitlements to health care by expanding the scope of services to all emergency care for which all citizens are eligible [6]. The rest of the health services will be provided on the basis of participation in the social insurance scheme, but it will be checked whether the patient is in fact entitled to services. Furthermore, the government plans to revitalize the system of treatment protocols, which is obviously a means to exclude certain interventions. It is not yet known whether this is only a first step towards a more explicit priority setting, or whether the benefit package remains essentially unchanged.

hungary
health services
health benefit plans
health priorities
national health programs


Interpreting scan data acquired from multiple scanners: A study with Alzheimer's disease

Large, multi-site studies utilizing MRI-derived measures from multiple scanners present an opportunity to advance research by pooling data. On the other hand, it remains unclear whether or not the potential confound introduced by different scanners and upgrades will devalue the integrity of any results. Although there are studies of scanner differences for the purpose of calibration and quality control, the current literature is devoid of studies that describe the analysis of multi-scanner data with regard to the interaction of scanner(s) with effects of interest. We investigated a data-set of 136 subjects, 62 patients with mild to moderate Alzheimer's disease and 74 cognitively normal elderly controls, with MRI scans from one center that were acquired over 10 years with 6 different scanners and multiple upgrades over time. We used a whole-brain voxel-wise analysis to evaluate the effect of scanner, effect of disease, and the interaction of scanner and disease for the 6 different scanners. The effect of disease in patients showed the expected significant reduction of grey matter in the medial temporal lobe. Scanner differences were substantially less than the group differences and only significant in the thalamus. There was no significant interaction of scanner with disease group. We describe the rationale for concluding that our results were not confounded by scanner differences. Similar analyses in other multi-scanner data-sets could be used to justify the pooling of data when needed, such as in studies of rare disorders or in multi-center designs.
Introduction
Techniques utilizing in vivo MRI-derived measures of brain tissue morphometrics show increasing promise for aiding clinicians in assessment and diagnosis of disease. Studies that use longitudinal and/or multi-site data-sets, such as the Alzheimer's Disease Neuroimaging Initiative (Mueller et al., 2005), have the potential to provide a wealth of information. The large numbers of subjects resulting from pooling multi-scanner data-sets has numerous advantages. It increases sensitivity thus allowing detection of subtle effects and enables the analysis of subgroups within a cohort. Additionally, pooling offers increased reliability and confidence about the size of effect by averaging out unforeseen confounds and hence a method for carrying out meta-analyses or analyses of rare subjects with orphan-diseases scanned at home rather than in distant centers. Any one study may have unforeseen bias which is lessened by pooling. However, one important confound of combining images gathered from different scanners is the potential for scanner effects to introduce systematic error, thus making the interpretation of results difficult. Partial volume effects and image intensity inhomogeneity can introduce error into automatic segmentation with any given scanner (Li et al., 2005). Noise of the electronics of the MRI system, subject-specific physiological noise and imaging gradient non-linearities also contribute to image intensity variability (Jovicich et al., 2006; Littmann et al., 2006). Furthermore, differences in subject positioning between sites add to the variability in distortion fields (Jovicich et al., 2006) and images can vary as a function of protocol differences between a baseline and a later scan or with drifts in instrument signal to noise over time (Preboske et al., 2006). The interaction of scanner differences with segmentation remains a particular concern and potential cause of varied measures of regional tissue volume in the brain (Ashburner and Friston, 2000). It is therefore vital to confirm that there is no important interaction between scanner and effect of interest and/or account for the effects of different scanners in a principled manner before pooling from different scanners can be recommended as a routine.
The use of phantoms to calibrate different scanners and account for scanner drift or upgrades is well established (Tofts, 1998; Van Haren et al., 2003; Schnack et al., 2004; Jovicich et al., 2006) and a useful way to guarantee quality. Studies using a small number of healthy subjects repeatedly scanned on different scanners or after upgrades are also recommended to test reliability (Tofts, 1998; Han et al., 2006; Jovicich et al., 2006). However, it is not clear that the extra calibration efforts can actually correct for the majority of these sources of variability (Jovicich et al., 2006), or are even necessary. Also, it has yet to be established how confidently the results from multi-scanner data-sets can be interpreted irrespective of up-front calibration.
Multi-scanner studies, though not common, are increasing. A longitudinal aging study by Raz and colleagues, one of the few which discussed the analysis of images derived from multiple scanners, concluded that using different scanners in 4 subjects did not affect measured intracranial volume with a manual tracing method (Raz et al., 2005). Likewise, manual hippocampal measurements performed on both 1.5 T and 3.0 T scanners in 8 healthy controls were not affected by field strength (Breillmann et al., 2001). We are not aware of any study that has described an automated analysis of a large, multi-scanner data-set with the aim of assessing whether scanner-associated biases are significant.
We set out to investigate scanner effects in an automatically preprocessed data-set of subjects with mild to moderate AD and cognitively normal elderly people whose MRI scans had been collected over a period of 10 years with multiple scanners and upgrades on a consistent platform and repeated calibrations. Even though the concern has been raised that segmentation errors are a particular problem in atrophic brains (Good et al., 2002), we did not find this to be an issue in our sample, possibly because the disease was early. We hypothesized that the changes due to AD pathology are large compared to scanner induced distortions and that there would be no interaction of scanner with case and/or control groups. In this paper, we report the results in our data-set and outline a method by which multi-scanner data-sets might be pooled with confidence.
Methods and results
Our data-set included a total of 6 scanners and 136 subjects scanned over a 10-year period. None of the subjects were scanned more than once. All scans were done on the same platform, General Electric Signa 1.5 T scanners (slice thickness 1.6, matrix dimensions 256 × 192). There were minor variations in the TR, TE, and flip angle (see Table 1). Scanners also underwent upgrades over time. Importantly, all scanners were monitored with daily phantom quality checks which calibrated the gradients to within ± 1 mm over a 200-mm volume centered at iso-center, monitored signal to noise and radio frequency (RF) transmit gain. The major hardware elements (body resonance module gradient coil and birdcage head transmit–receive volume coil) were unchanged throughout time and across scanners, except that for the oldest scanner (scanner 2), the wiring in the resistive shim set was not cooled to super conducting temperatures, whereas for the other 5 scanners, the shim coils were inside the dewar and were cooled to the superconducting range.
We used voxel-based morphometry (VBM) to evaluate the interaction of scanner and grey matter segmented modulated images for the 6 different scanners. VBM has the advantage of assessing the whole brain and not being biased to one particular region or structure. It entails a voxel-wise comparison of local volume of grey matter between groups after the images are spatially normalized into the same space, segmented, modulated, and smoothed. Voxel-wise statistical parametric maps result from statistically thresholded contrasts after corrections for multiple comparisons (Ashburner and Friston, 2000) using false discovery rate (FDR) (Benjamini and Hochberg, 1995).
Images were visually inspected for artifacts or structural abnormalities unrelated to AD. They were firstly segmented into white (WM) and grey matter (GM) using SPM5 (Wellcome Trust Centre for Neuroimaging, Institute of Neurology, UCL, London UK – http://www.fil.ion.ucl.ac.uk/spm). Then, WM and GM segments were further normalized to a population template generated from the complete image set using a diffeomorphic registration algorithm. This non-linear warping technique minimizes structural variation between subjects (Ashburner, 2007). For comparison, we also repeated the analysis using the more widely used standard SPM5 segmentation code (Ashburner and Friston, 2005) instead of the diffeomorphic registration algorithm. Resolution before normalization was − .9, .9, 1.6 and after normalization was − 1.5, 1.5, 1.5 for the diffeomorphic registration algorithm and − 2.0, 2.0, 2.0 with the standard SPM5 procedure. A separate ‘modulation’ step (Ashburner and Friston, 2000) was used to ensure that the overall amount of each tissue class was not altered by the spatial normalization procedure. Modulation was performed by multiplying the warped tissue probability maps by the Jacobian determinant of the warp on a voxel-by-voxel basis, which represents the relative volume ratio before and after warping, thus allowing voxel intensities in the segmented grey matter map, together with the size of the voxels, to reflect regional volume and preserve total grey matter volume from before the warp. Modulated grey matter scans were smoothed using a 6-mm full-width at half-maximum Gaussian kernel.
The smoothed grey matter images were analyzed in a factorial design, with the 6 different scanners as one factor (SCANNER) with 6 levels and the presence of AD (GROUP) as the second factor with two levels (present and absent). Age, gender, and total intracranial volume were entered as covariates (Fig. 1). We performed F-tests correcting for multiple comparisons across the brain (FDR correction). The degrees of freedom was 121 for all comparisons. The effect of group revealed strong effects (p < 0.001) in the left medial temporal lobe (− 29, − 24, − 9 [x, y, z]; F = 100.34) and right medial temporal lobe (30, − 27, − 9 [x, y, z]; F = 91.44) (Fig. 2). The effect of scanner showed significant differences (p < 0.05) in the right (9, − 30, 0 [x, y, z]; F = 11.93) and left (− 9, − 11, 8 [x, y, z]; F = 9.69) thalami (Fig. 3), but this effect was less than the effect of group. T-tests contrasting each scanner against the others revealed the scanner effect in the thalamus was mostly due to the oldest scanner (scanner 2). One newer scanner (scanner 6) revealed an effect that did not survive FDR correction in the right thalamus (8, − 5, − 3 [x, y, z]; T = 4.03), whereas the oldest scanner contrasted with the others revealed a significant effect (p < 0.05) in the left thalamus (− 9, − 11, 6 [x, y, z]; T = 5.94). Despite the effect of scanner, there was no significant interaction of scanner with group, the highest Z-score being 3.82 with a corrected p value of 0.942. We performed F-tests for each possible combination of scanners and found no significant interaction with any of these groupings. When using the standard VBM procedure implemented in SPM5 for normalization and segmentation, the results of the various contrasts followed the same patterns as when using the diffeomorphic normalization/segmentation procedure. We failed to find an interaction of scanner with group; the highest Z-score was 3.78 with an FDR corrected p value of 0.954. The effect of scanner showed significant differences (p < 0.05) in the left thalamus (− 10, − 10, 6 [x, y, z]; F = 9.49) and the right thalamus (8, − 28, − 4 [x, y, z]; F = 9.41). The effect of group also showed strong effects (p < 0.001) in the left medial temporal lobe (− 26, − 14, − 20 [x, y, z]; F = 101.46) and right medial temporal lobe (26, − 8, − 18 [x, y, z]; F = 77.98).
Importantly, we found no significant scanner effects in the medial temporal lobe cluster (− 29,− 24, − 9 [x, y, z]; F = 0.01) and the disease effect size in the thalamus was minimal compared to the effect size in the medial temporal lobe (9, − 30, 0 [x, y, z]; F = 1.06), suggesting minimal scanner effects in the areas that are most affected by AD and minimal disease effects in the areas showing scanner differences. Confidence intervals, which are reflective of the standard deviations, for the contrast estimates are shown in Fig. 4. At the voxel of greatest effect of group, the confidence interval is small relative to the effect size for the main effect of group. The opposite is true for the effect of scanner at the area of greatest disease, which is further evidence of lack of effect. For the main effect of scanner, confidence intervals are similar between the different scanner contrasts (see Fig. 4A), indirectly suggestive of relatively little variance across scanners.
Because there were 4 software upgrades, we also analyzed the interaction of software version and disease. Using the same basic design matrix as described for the interaction with scanners, this time the contrasts included cases and controls from each software version, covaried with age, gender and intracranial volume. As with the effect of scanner, there was no significant interaction of software version with group, the highest Z-score being 3.65 with a corrected p value of 0.880.
Discussion
In our data-set, we found the effect of disease to be substantially larger than the effect of scanner and failed to find a significant interaction of disease with scanner or software upgrades. In general, the effect of disease in AD is liable to be larger than the effect of scanner, which is supported by our result of no important interaction between scanner and effect of interest. Ideally, further studies with an even larger data set to better calculate the effect sizes and quantify the distance between the scanner effect cluster and group effect cluster could be done to validate our findings. However, comparison of the magnitude of the scanner effect versus disease effect in the medial temporal lobe cluster in our data-set demonstrates that scanner differences had minimal effects in the areas that are important in the study of AD. Furthermore, even though there are likely to be some differences among data from different scanners, our experiments were explicitly designed to detect scanner-related differences. By modeling appropriate confounds in the design matrix, it appears possible to remove these small effects. We were able to model this interaction easily because relatively homogeneous cases and controls were scanned in each machine. We are unable to say whether lesser or more subtle and distributed changes would be as resistant to scanner effects.
Though we did not detect a significant interaction of scanner with disease, we cannot be absolutely certain it is indeed due to the absence of such effect. The lack of significance may be a reflection of the lack of statistical power, e.g., insufficient number of scans. Other causes such as a high average residual variance or residual variance inhomogeneities could also under-power the detection of the effects. However, the variance inhomogeneity was considered in our analysis by assuming unequal variance for the different levels of each of the two factors in our full factorial design (the two factors are the scanner and group). In a post-hoc manner, we explored the residual variance across scanners to assess whether that explained the lack of sensitivity in the results. In the area of greatest disease effect, the variance was low and did not reflect significant inhomogeneity, but in the area of greatest scanner effect there was lower average residual variance and more variability. Though our tests for variance inhomogeneity across the 6 scanners was not voxel-by-voxel over the whole brain volume, our findings seem to support that the variance inhomogeneity is location-dependent and should be accounted for when analyzing data acquired from different scanners as we attempted to do in our analysis.
The greatest effect of scanner was in the thalamus. The effect of the thalamus was largely driven by the scanner with the resistive shim set that was not cooled to superconducting temperatures, which suggests an impact of such hardware differences on thalamic segmentation. The composition of the thalamus is an issue of debate as it is not completely grey matter receiving numerous white matter tracts from other parts of the brain. Additionally, the grey matter intensity value of the thalamus is different from that of cortical grey matter. The intrinsically poor intensity contrast in the thalamus renders it susceptible to small differences in image contrast due to scanner differences. There is also less variability in this part of the brain, so tests will be more sensitive to such differences. These factors may contribute to the difficulty of accurate segmentation of the thalamus in addition to scanner effects.
The relatively small effect of scanner is potentially attributable to quality control measures during data acquisition and/or the robustness of the segmentation method. The SPM5 algorithm, by using spatial information together with intensity information, should be more robust to such differences than a segmentation algorithm that is purely intensity-based. However, this study did not directly investigate which forms of preprocessing are most affected by scanner parameters. It is important to note, though, that the effect was not due to the diffeomorphic normalization procedure, since we obtained similar patterns to those with the standard SPM5 normalization. Presumably, the use of daily scanner calibrations allows for a relatively constant intensity contrast between grey and white matter voxels between scans. Routine procedures designed to minimize image intensity differences over time are useful, particularly since it has been demonstrated that several common scan functions can potentially introduce measurement errors as high as 100% (i.e., much greater than the disease effect of AD), without appropriate quality control measures in place (Preboske et al., 2006). Even though it is common experience that current generation scanners are remarkably stable over time, they do still drift in a way that is correctable with judicious calibration. Though we collected no data to determine the frequency and level of sophistication necessary, basic calibration akin to the current standard in most major centers is likely sufficient. Furthermore, while it can be useful to collect data on inter-subject variability by scanning the same subjects in different scanners, such efforts would not directly answer the question of whether data from different subjects on different scanners can be pooled.
The unified segmentation method of SPM5 (Ashburner and Friston, 2005) produces an estimate of the tissue class intensities from a fitting of spatial priors to the image, which allows for differences in image intensities between scans. Additionally, any image intensity differences due to subject to subject variation in coupling of the RF coil to the head that may be introduced by different head shapes and sizes are likely to be well-accounted for by bias corrections in the unified segmentation algorithm.
As long as provision for different scanners and/or upgrades is made within an analysis, the effect of scanner regardless of magnitude is not likely to devalue the integrity of results. However, if there is a true physical interaction of the biological effect of interest with the method of measurement, perfect calibration or even using a single scanner would not prevent bias. On the other hand, any unusually large effect from one scanner would be attenuated by the totality of scans from different scanners that make up the template, which averages the different scanner effects for normalization.
To date, methodological differences between individual studies have prevented comprehensive pooling of data in meta-analyses of AD MRI studies (Zakzanis et al., 2003; Whitwell and Jack, 2005; Wahlund et al., 2005). To the extent that data pooling was possible, the meta-analysis compared regional volume between disease groups (Zakzanis et al., 2003). Although there may be concern about error introduced by the variability inherent in preprocessing many individuals across studies, automated VBM methods successfully overcome the problems to combine information from multiple scans and studies. VBM meta-analyses of pooled scans permit the usual range of analyses beyond simple categorical comparisons (e.g., regression, age interaction, subgroup, nonlinear, etc.).
Our results suggest that for Alzheimer's disease, particularly if the imaging platform remains constant, variations attributable to individual scanners and upgrades may have negligible effects on segmented grey matter images. We expect, though do not yet have the data, that the approach is robust enough to accommodate using both 1.5 T and 3 T scans in the same meta-analysis. A principled approach to test the validity of a meta-analysis is to carry out an a priori interaction analysis of scanner by biological effect to be studied to exclude scanner-specific compromising effects. Additional comfort can be gained by finding that the biological effect is of greater magnitude than any effect of scanner. An alternative approach is to model each scanner's effects separately, thereby permitting a principled meta-analysis on pooled data. That data can be pooled from different scanners without corroding the integrity of results is reassuring for large multi-site studies.

alzheimer's disease
multi-scanner
magnetic resonance imaging (mri)
voxel based morphometry