From acute to long-term alterations in pain processing and modulation after spinal cord injury: mechanisms related to chronification of central neuropathic pain.

ABSTRACT: A severe and debilitating consequence of a spinal cord injury (SCI) is central neuropathic pain (CNP). Our aim was to investigate the processes leading to CNP emergence and chronification by analyzing causal relationship over time between spinothalamic function, pain excitability, and pain inhibition after SCI. This longitudinal follow-up study included 53 patients with acute SCI and 20 healthy controls. Spinothalamic, pain excitability, and intrasegmental and extrasegmental pain inhibition indices were repeatedly evaluated at 1.5, 3, and 6 months post-SCI. Between- and within-group analyses were conducted among those patients who eventually developed CNP and those who did not. Healthy controls were evaluated twice for repeatability analysis. Patients who developed CNP, compared with those who did not, exhibited increased thermal thresholds (P < 0.05), reduced pain adaptation (P < 0.01), and conditioned pain modulation (P < 0.05), early post-injury, and the CNP group's manifestations remained worse throughout the follow-up. By contrast, allodynia frequency was initially similar across SCI groups, but gradually increased in the subacute phase onward only among the CNP group (P < 0.001), along with CNP emergence. Early worse spinothalamic and pain inhibition preceded CNP and predicted its occurrence, and early worse pain inhibition mediated the link between spinothalamic function and CNP. Crossover associations were observed between early and late pain inhibition and excitability. Inefficient intrasegmental and extrasegmental inhibition, possibly resulting from spinothalamic deafferentation, seems to ignite CNP chronification. Pain excitability probably contributes to CNP maintenance, possibly via further exhaustion of the inhibitory control. Preemptive treatment promoting antinociception early post-SCI may mitigate or prevent CNP.

Biomarkers for predicting central neuropathic pain occurrence and severity after spinal cord injury: results of a long-term longitudinal study.

Central neuropathic pain (CNP) after spinal cord injury (SCI) is debilitating and immensely impacts the individual. Central neuropathic pain is relatively resistant to treatment administered after it develops, perhaps owing to irreversible pathological processes. Although preemptive treatment may overcome this shortcoming, its administration necessitates screening patients with clinically relevant biomarkers that could predict CNP early post-SCI. The aim was to search for such biomarkers by measuring pronociceptive and for the first time, antinociceptive indices early post-SCI. Participants were 47 patients with acute SCI and 20 healthy controls. Pain adaptation, conditioned pain modulation (CPM), pain temporal summation, wind-up pain, and allodynia were measured above, at, and below the injury level, at 1.5 months after SCI. Healthy control were tested at corresponding regions. Spinal cord injury patients were monitored for CNP emergence and characteristics at 3 to 4, 6 to 7, and 24 months post-SCI. Central neuropathic pain prevalence was 57.4%. Central neuropathic pain severity, quality, and aggravating factors but not location somewhat changed over 24 months. Spinal cord injury patients who eventually developed CNP exhibited early, reduced at-level pain adaptation and CPM magnitudes than those who did not. The best predictor for CNP emergence at 3 to 4 and 7 to 8 months was at-level pain adaptation with odds ratios of 3.17 and 2.83, respectively (∼77% probability) and a cutoff value with 90% sensitivity. Allodynia and at-level CPM predicted CNP severity at 3 to 4 and 24 months, respectively. Reduced pain inhibition capacity precedes, and may lead to CNP. At-level pain adaptation is an early CNP biomarker with which individuals at risk can be identified to initiate preemptive treatment.

Increased psychological distress among individuals with spinal cord injury is associated with central neuropathic pain rather than the injury characteristics.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: Central neuropathic pain (CNP) is common after spinal cord injury (SCI). The psychological impact of CNP is not clear. Previous studies reported depression and pain catastrophizing among patients with SCI and CNP; however, the lack of control groups prevented discerning whether these were attributed to CNP or to the SCI itself. The aim was to examine the psychological distress among individuals with SCI with and without CNP and controls to evaluate its impact and possible source. SETTING: Outpatient clinic of a large rehabilitation center. METHODS: Individuals with SCI and CNP (n = 27) and without CNP (n = 23), and able-bodied controls (n = 20) participated. Data collection included sociodemographics, SCI characteristics, and level of post-traumatic stress disorder (PTSD), anxiety, stress, depression, and pain catastrophizing. The sensory, affective, and cognitive dimensions of CNP were analyzed. RESULTS: Individuals with SCI and CNP exhibited elevated levels of PTSD, anxiety, stress, depression, and pain catastrophizing compared to the two control groups, which presented similar levels. The psychological variables among the CNP group correlated positively only with the affective dimension of CNP. Neither CNP nor the psychological variables correlated with SCI characteristics. CONCLUSIONS: Irrespective of CNP intensity, the affective dimension (suffering) is associated with increased psychological distress. Perhaps individual differences in the response to SCI and/or individual traits rather than the mere exposure to SCI may have a role in the emergence of CNP and psychological distress/mood dysfunction. Rehabilitation programs should prioritize stress management and prevention among individuals with SCI and CNP.

Differential pain modulation properties in central neuropathic pain after spinal cord injury.

It seems that central neuropathic pain (CNP) is associated with altered abilities to modulate pain; whereas dysfunction in descending pain inhibition is associated with the extent of chronic pain distribution, enhanced pain excitation is associated with the intensity of chronic pain. We investigated the hypothesis that CNP is associated with decreased descending pain inhibition along with increased neuronal excitability and that both traits are associated with spinothalamic tract (STT) damage. Chronic spinal cord injury subjects with CNP (n = 27) and without CNP (n = 23) and healthy controls (n = 20) underwent the measurement of pain adaptation, conditioned pain modulation (CPM), tonic suprathreshold pain (TSP), and spatial summation of pain above injury level. Central neuropathic pain subjects also underwent at and below-lesion STT evaluation and completed the questionnaires. Central neuropathic pain subjects showed decreased CPM and increased enhancement of TSP compared with controls. Among CNP subjects, the dysfunction of CPM and pain adaptation correlated positively with the number of painful body regions. The magnitude of TSP and spatial summation of pain correlated positively with CNP intensity. STT scores correlated with CNP intensity and with TSP, so that the more affected the STT below injury level, the greater the CNP and TSP magnitude. It seems that CNP is associated with altered abilities to modulate pain, whereas dysfunction in descending pain inhibition is associated with the extent of chronic pain distribution and enhanced pain excitation is associated with the intensity of chronic pain. Thus, top-down processes may determine the spread of CNP, whereas bottom-up processes may determine CNP intensity. It also seems that the mechanisms of CNP may involve STT-induced hyperexcitability. Future, longitudinal studies may investigate the timeline of this scenario.

A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation.

OBJECTIVE: Distal hereditary motor neuropathies (dHMN) form a clinically and genetically heterogeneous group of disorders, characterized by muscle weakness and atrophy predominating at the distal part of the limbs, due to the progressive degeneration of motor neurons in the spinal cord. We report here a novel rare variant of dHMN with autosomal recessive inheritance in a large Jewish family originating from Morocco. The disease is characterized by a predominance of paralysis at the lower limbs and an early adulthood onset. We performed a genetic study in this family to identify and characterized the causing mutation. METHODS: Homozygosity mapping strategy and sequencing of the candidate genes were performed. Expression studies were made on patient fibroblasts. Functional experiments were performed on a cellular model of motor neuron disease. RESULTS: We mapped the disease to the 2q34-q36.1 chromosomal region and identified a homozygous splice mutation in the gene HSJ1 (DNAJB2) decreasing the expression of the 2 main isoforms HSJ1a and HSJ1b. Overexpression of both HSJ1a and HSJ1b reduced inclusion formation induced by the mutated SOD1-A4V in a neuronal cellular model. INTERPRETATION: HSJ1 is a neuronal enriched member of the HSP40/DNAJ co-chaperone family. Previous studies have shown that HSP40 proteins play a crucial role in protein aggregation and neurodegeneration in several neuronal types, in animal models and human diseases. Interestingly, this mutation causing a loss-of-function of HSJ1 is linked to a pure lower motor neuron disease, strongly suggesting that HSJ1 also plays an important and specific role in motor neurons.

Heterotopic ossification in Guillain-Barré syndrome: incidence and effects on functional outcome with long-term follow-up.

OBJECTIVE: To define the incidence, effects on functional abilities, and possible causation of heterotopic ossification (HO) in Guillain-Barré syndrome (GBS) patients admitted for inpatient rehabilitation. DESIGN: Long-term prospective study on neurologic and functional outcome of GBS patients admitted for rehabilitation. SETTING: Rehabilitation department, inpatient and outpatient, within a university-affiliated medical center. PARTICIPANTS: All GBS patients admitted for rehabilitation and followed for a minimum of 3 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Presence of HO, factors that may be etiologically significant, and effects on functionality. Data included: medical interventions, Disability Grading Scale, need for assisted ventilation, electrodiagnostic findings, autonomic function, standard neuro-musculo-skeletal evaluation, and hospital length of stay. RESULTS: Four (6%) of 65 patients had HO, 24 of whom required mechanical ventilation. All had decreased range of motion in the involved hips that affected mobility. CONCLUSIONS: Even though it has been rarely reported, HO does occur in GBS and affects functional outcome.

From the philosophy auditorium to the neurophysiology laboratory and back: from Bergson to Damasio.

Henri Bergson (1859-1941) was probably the most influential French philosopher at the turn of the twentieth century. In 1927 he was awarded the Nobel Prize for literature. Far beyond the restricted academic philosophical milieu, the impact of his thinking reached personalities as diverse as Claude Debussy, Marcel Proust, George Bemard Shaw, and the impressionists. His essay The Laughter (Le Rire) is one of the most profound and original ever written on the sense of humor. Bergson's opinions, with their emphasis on life, instinct and intuition, represented a deviation from the rationalist mainstream of western philosophical tradition. In some circles he was received with skepticism and irony, as in Bertrand Russel's History of Western Philosophy. Today, unbiased by theoretical "bergsonism," neurophysiologic research--as undertaken mainly by Antonio Damasio's team at Iowa University--confirms many of his hypotheses and elucidates their mechanisms. In this new light, intuition and "recognition by the body" should not be seen as the personal fantasy of an original thinker but as fundamental cognitive tools.

Sensory determinants of thermal pain.

It is still unclear whether the quality of painful thermal sensation is determined only by conduction in specific, dedicated nociceptive channels (i.e. C or Adelta nociceptors) or whether it is a result of integrated activity in both nociceptive and non-nociceptive systems. To evaluate this question, we conducted quantitative and qualitative somatosensory testing in spinal cord injury subjects who suffered from partial or complete loss of thermal sensibility. Testing was performed in skin areas, below the level of the lesion, which were either lacking any thermal sensibility, lacking only one thermal sensation (either heat or cold) or having normal thermal sensations. We found that, in areas lacking any thermal sensibility, warm and cold stimuli produced a sensation of pricking pain, which had no thermal quality and was detected at significantly higher thresholds than in normal controls (48.5 +/- 1.8 and 9.7 +/- 5.1 degrees C for noxious heat- and noxious cold-induced pricking pain, respectively). Normal thermal pain sensations, consisting of normal perception of thermal quality and normal mean pain thresholds, were present both in normal skin areas (42.1 +/- 1.9 and 27.6 +/- 2.25 degrees C for heat and cold pain, respectively) and in areas in which only one thermal modality remained intact, when tested for that modality. Thus, testing for heat pain in areas in which only warm sensation was intact, or cold pain when only cold was intact produced normal qualities and thresholds of pain (42.8 +/- 3.4 and 24.4 +/- 6.2 degrees C for heat and cold pain, respectively). No spatial summation of pricking pain was observed, in contrast to the marked summation of heat pain in normal areas. In areas with only a single intact thermal modality, the quality of the perceived non-painful sensation was not determined by the thermal stimulus but by the intact modality (paradoxical sensation). Cold stimuli were perceived as warm in areas in which only warm sensation was preserved, and vice versa. A similar pattern was also seen for pain perception in areas with intact warm sensation. In these areas, both noxious heat and cold elicited a sensation of heat pain. No consistent pattern of heat-elicited pain was observed in areas in which only cold sensation was intact. These data suggest that the integrity of non-noxious thermal systems is essential for the normal perception of thermal pain, and that the subjective sensation of pain depends on the integration of information from nociceptive and non-nociceptive channels.