Annina B. Schmid

Paradigm shift in manual therapy? Evidence for a central nervous system component in the response to passive cervical joint mobilisation.

Segmental neurological modulation, neural hysteresis and biomechanical effects have been proposed as mechanisms underpinning the effects of manual therapy. An increasing number of studies hypothesise activation of the central nervous system resulting in a non-segmental hypoalgesic effect with concurrent activation of other neural pathways as a potential mechanism of action. Whether this model is consistent with the current literature is unknown. This systematic review aims to assess the consistency of evidence supporting an involvement of supraspinal systems in mediating the effects of passive cervical joint mobilisation. We searched randomised trials in three electronic databases from inception to November 2007, without language restriction, and checked reference lists of included studies. We assessed study validity and extracted salient features in duplicate. Fifteen studies met our inclusion criteria. The overall quality was high. We found consistency for concurrent hypoalgesia, sympathetic nervous system excitation and changes in motor function. Pooling of data suggested that joint mobilisation improved outcomes by approximately 20% relative to controls. This specific pattern suggests that descending pathways might play a key role in manual therapy induced hypoalgesia. Our review supports the existence of an alternative neurophysiological model, in which passive joint mobilisation stimulates areas within the central nervous system.

Biphosphonates for the therapy of complex regional pain syndrome I--systematic review.

Objectives: Several studies found that biphosphonates counteract locally increased bone resorption and associated pain in patients with complex regional pain syndrome I (CRPS I). We performed a systematic review of all randomised controlled trials to assess the benefit of biphosphonates in the treatment of CRPS I patients with bone loss.

Local and remote immune-mediated inflammation after mild peripheral nerve compression in rats.

After experimental nerve injuries that extensively disrupt axons, such as chronic constriction injury, immune cells invade the nerve, related dorsal root ganglia (DRGs), and spinal cord, leading to hyperexcitability, raised sensitivity, and pain. Entrapment neuropathies, such as carpal tunnel syndrome, involve minimal axon damage, but patients often report widespread symptoms. To understand the underlying pathology, a tube was placed around the sciatic nerve in 8-week-old rats, leading to progressive mild compression as the animals grew. Immunofluorescence was used to examine myelin and axonal integrity, glia, macrophages, and T lymphocytes in the nerve, L5 DRGs, and spinal cord after 12 weeks. Tubes that did not constrict the nerve when applied caused extensive and ongoing loss of myelin, together with compromise of small-, but not large-, diameter axons. Macrophages and T lymphocytes infiltrated the nerve and DRGs. Activated glia proliferated in DRGs but not in spinal cord. Histologic findings were supported by clinical hyperalgesia to blunt pressure and cold allodynia. Tubes that did not compress the nerve induced only minor local inflammation. Thus, progressive mild nerve compression resulted in chronic local and remote immune-mediated inflammation depending on the degree of compression. Such neuroinflammation may explain the widespread symptoms in patients with entrapment neuropathies.

Transcriptional regulator PRDM12 is essential for human pain perception

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

Effect of splinting and exercise on intraneural edema of the median nerve in carpal tunnel syndrome—an MRI study to reveal therapeutic mechanisms

Splinting and nerve and tendon gliding exercises are commonly used to treat carpal tunnel syndrome (CTS). It has been postulated that both modalities reduce intraneural edema. To test this hypothesis, 20 patients with mild to moderate CTS were randomly allocated to either night splinting or a home program of nerve and tendon gliding exercises. Magnetic resonance images of the wrist were taken at baseline, immediately after 10 min of splinting or exercise, and following 1 week of intervention. Primary outcome measures were signal intensity of the median nerve at the wrist as a measure of intraneural edema and palmar bowing of the carpal ligament. Secondary outcome measures were changes in symptom severity and function. Following 1 week of intervention, but not immediately after 10 min, signal intensity of the median nerve was reduced by ∼11% at the radioulnar level for both interventions (p = 0.03). This was accompanied by a mild improvement in symptoms and function (p < 0.004). A similar reduction in signal intensity is not observed in patients who only receive advice to remain active. No changes in signal intensity were identified further distally (p > 0.28). Ligament bowing remained unchanged (p > 0.08). Intraneural edema reduction is a likely therapeutic mechanism of splinting and exercise.

The relationship of nerve fibre pathology to sensory function in entrapment neuropathy

The impact of peripheral entrapment neuropathies on target innervation remains unknown. Using quantitative sensory testing, neurophysiology and skin biopsies, Schmid et al. demonstrate that carpal tunnel syndrome affects large fibres and their nodal complexes, but is also associated with a reduction in the number and functioning of small sensory axons.

The double crush syndrome revisited--a Delphi study to reveal current expert views on mechanisms underlying dual nerve disorders.

A high prevalence of dual nerve disorders is frequently reported. How a secondary nerve disorder may develop following a primary nerve disorder remains largely unknown. Although still frequently cited, most explanatory theories were formulated many years ago. Considering recent advances in neuroscience, it is uncertain whether these theories still reflect current expert opinion. A Delphi study was conducted to update views on potential mechanisms underlying dual nerve disorders. In three rounds, seventeen international experts in the field of peripheral nerve disorders were asked to list possible mechanisms and rate their plausibility. Mechanisms with a median plausibility rating of ≥7 out of 10 were considered highly plausible. The experts identified fourteen mechanisms associated with a first nerve disorder that may predispose to the development of another nerve disorder. Of these fourteen mechanisms, nine have not previously been linked to double crush. Four mechanisms were considered highly plausible (impaired axonal transport, ion channel up or downregulation, inflammation in the dorsal root ganglia and neuroma-in-continuity). Eight additional mechanisms were listed which are not triggered by a primary nerve disorder, but may render the nervous system more vulnerable to multiple nerve disorders, such as systemic diseases and neurotoxic medication. Even though many mechanisms were classified as plausible or highly plausible, overall plausibility ratings varied widely. Experts indicated that a wide range of mechanisms has to be considered to better understand dual nerve disorders. Previously listed theories cannot be discarded, but may be insufficient to explain the high prevalence of dual nerve disorders.

Reappraising entrapment neuropathies-Mechanisms, diagnosis and management

The diagnosis of entrapment neuropathies can be difficult because symptoms and signs often do not follow textbook descriptions and vary significantly between patients with the same diagnosis. Signs and symptoms which spread outside of the innervation territory of the affected nerve or nerve root are common. This Masterclass provides insight into relevant mechanisms that may account for this extraterritorial spread in patients with entrapment neuropathies, with an emphasis on neuroinflammation at the level of the dorsal root ganglia and spinal cord, as well as changes in subcortical and cortical regions. Furthermore, we describe how clinical tests and technical investigations may identify these mechanisms if interpreted in the context of gain or loss of function. The management of neuropathies also remains challenging. Common treatment strategies such as joint mobilisation, neurodynamic exercises, education, and medications are discussed in terms of their potential to influence certain mechanisms at the site of nerve injury or in the central nervous system. The mechanism-oriented approach for this Masterclass seems warranted given the limitations in the current evidence for the diagnosis and management of entrapment neuropathies.

Multifidus Muscle Changes After Back Injury Are Characterized by Structural Remodeling of Muscle, Adipose and Connective Tissue, but Not Muscle Atrophy: Molecular and Morphological Evidence.

Study Design. Longitudinal case-controlled animal study. Objective. To investigate putative cellular mechanisms to explain structural changes in muscle and adipose and connective tissues of the back muscles after intervertebral disc (IVD) injury. Summary of Background Data. Structural back muscle changes are ubiquitous with back pain/injury and considered relevant for outcome, but their exact nature, time course, and cellular mechanisms remain elusive. We used an animal model that produces phenotypic back muscle changes after IVD injury to study these issues at the cellular/molecular level. Methods. Multifidus muscle was harvested from both sides of the spine at L1–L2 and L3–L4 IVDs in 27 castrated male sheep at 3 (n = 10) or 6 (n = 17) months after a surgical anterolateral IVD injury at both levels. Ten control sheep underwent no surgery (3 mo, n = 4; 6 mo, n = 6). Tissue was harvested at L4 for histological analysis of cross-sectional area of muscle and adipose and connective tissue (whole muscle), plus immunohistochemistry to identify proportion and cross-sectional area of individual muscle fiber types in the deepest fascicle. Quantitative polymerase chain reaction measured gene expression of typical cytokines/signaling molecules at L2. Results. Contrary to predictions, there was no multifidus muscle atrophy (whole muscle or individual fiber). There was increased adipose and connective tissue (fibrotic proliferation) cross-sectional area and slow-to-fast muscle fiber transition at 6 but not 3 months. Within the multifidus muscle, increases in the expression of several cytokines (tumor necrosis factor &agr; and interleukin-1&bgr;) and molecules that signal trophic/atrophic processes for the 3 tissue types (e.g., growth factor pathway [IGF-1, PI3k, Akt1, mTOR], potent tissue modifiers [calcineurin, PCG-1&agr;, and myostatin]) were present. Conclusion. This study provides cellular evidence that refutes the presence of multifidus muscle atrophy accompanying IVD degeneration at this intermediate time point. Instead, adipose/connective tissue increased in parallel with the expression of the genes that provide putative mechanisms for multifidus structural remodeling. This provides novel targets for pharmacological and physical interventions. Level of Evidence: N/A

A crossover study on the effect of cervical mobilization on motor function and pressure pain threshold in pain-free individuals.

OBJECTIVE Cervical mobilization has been shown to elicit effects on pain perception, autonomic function, and motor function in subjects who experience musculoskeletal pain. The improvement in motor function may be a direct effect of the treatment or secondary to a hypoalgesic effect. This study tested whether it is possible to alter motor function following joint mobilization in situations where motor performance is not impaired by pain. METHODS Twenty-four asymptomatic subjects participated in this double-blind, controlled, within-subjects crossover study. Pressure pain thresholds and electromyographic activity of the superficial neck flexor muscles were compared with repeated-measures analysis of variance between a posteroanterior cervical mobilization, manual contact, and noncontact condition. RESULTS The results indicate no significant change in the pressure pain threshold (P =.846) after posteroanterior cervical mobilization. There was no significant difference in superficial neck flexor muscle activity during the craniocervical flexion test (P =.713). Post hoc power analysis demonstrated the ability to detect a 15% difference in electromyographic activity with 70% power. CONCLUSION The improvement in motor function demonstrated in previous studies was not replicated, suggesting that either it is only possible to produce an effect when motor function is impaired or the change in motor function is secondary to the pain inhibitory effect of the treatment.