Novel imaging techniques in refractory pituitary adenomas.

Accurate localization of the site(s) of active disease is key to informing decision-making in the management of refractory pituitary adenomas when autonomous hormone secretion and/or continued tumor growth challenge conventional therapeutic approaches. In this context, the use of non-standard MR sequences, alternative post-acquisition image processing, or molecular (functional) imaging may provide valuable additional information to inform patient management.

Spinal navigation for minimally invasive thoracic and lumbosacral spine fixation: implications for radiation exposure, operative time, and accuracy of pedicle screw placement.

PURPOSE: Navigation is emerging as a useful adjunct in percutaneous, minimally invasive spinal surgery (MIS). The aim of this study was to compare C-Arm navigated, O-Arm navigated and conventional 2D-fluoroscopy assisted MIS thoracic and lumbosacral spine fixation techniques in terms of operating time, radiation exposure and accuracy of pedicle screw (PS) placement. METHODS: Retrospective observational study of 152 consecutive adults who underwent MIS fixations for spinal instability: 96 2D-fluoroscopy assisted, 39 3D-C-Arm navigated and 27 using O-Arm navigated. RESULTS: O-Arm navigation significantly reduced PS misplacement (1.23%, p) compared to 3D-C-Arm navigation (7.29%, p = 0.0082) and 2D-fluoro guided placement (5.16%, p = 0379). 3D-C-Arm navigation was associated with lower procedural radiation exposure of the patient (0.4 mSv) than O-Arm navigation (3.24 mSv) or 2D-fluoro guidance (1.5 mSv). Operative time was comparable between three modalities. CONCLUSIONS: O-Arm navigation provides greater accuracy of percutaneous instrumentation placement with an acceptable procedural radiation dose delivered to the patients and comparable operative times. These slides can be retrieved under Electronic Supplementary material.

The surgical management of metastatic spinal disease: prospective assessment and long-term follow-up.

The last decade has witnessed a resurgence of interest in the surgical treatment of metastatic spinal disease to compliment radiotherapy. A recent randomized controlled trial looking directly at this issue concluded strongly in favour of a combination of surgical decompression and radiotherapy, and there is now growing enthusiasm for surgery to play a role in the management of these patients. We present a prospective cohort study of 62 patients who presented with metastatic cord or cauda equina compression, and were treated with surgical decompression and fixation where necessary. Patients were treated by one surgeon working in a single unit. They were followed-up long term and were assessed objectively, by clinical assessment and prospective questionnaires that included SF36, visual analogue pain scores and Roland Morris back pain scores. Sixty-two patients with a median age of 62 (22-79 years, 27 male) were included in the study. The commonest primary tumours were breast (26%) and lymphoma (13%). The majority of patients had involvement of thoracic vertebrae (58%). 56% of patients were alive at 1 year and 28% at 3 years, with significant improvements observed in both walking and continence. Similarly, significant improvements were seen in SF36 quality of life scores as well as pain. With careful patient selection, long-term survival and good quality of life can be achieved. However, not every patient is suitable or appropriate for surgery, and the discussion focuses on where the surgical threshold should be set.

Pain mechanisms and management: a central perspective.

Although pain is always intense and unpleasant, the capacity to experience this sensation is, under normal circumstances, fundamental to the preservation of bodily integrity. Clinically, however, after injury to peripheral tissue or directly to the nervous system, spontaneous and evoked pain manifest that serve no physiologic function, are crippling to patients, and are difficult to treat. Here, we review the specific role of the dorsal horn of the spinal cord in the mechanisms of nociceptive protective pain and the spinal plasticity that occurs after nerve and tissue injury. This spinal neuronal plasticity is shown to be a key contributor to pathologic pain hypersensitivity. The potential for the molecular mechanisms responsible for the spinal plasticity in revealing new targets for future treatment is also discussed.

Diversity of expression of the sensory neuron-specific TTX-resistant voltage-gated sodium ion channels SNS and SNS2.

The differential distribution of two tetrodotoxin resistant (TTXr) voltage-gated sodium channels SNS (PN3) and SNS2 (NaN) in rat primary sensory neurons has been investigated. Both channels are sensory neuron specific with SNS2 restricted entirely to those small dorsal root ganglion (DRG) cells with unmyelinated axons (C-fibers). SNS, in contrast, is expressed both in small C-fiber DRG cells and in 10% of cells with myelinated axons (A-fibers). All SNS expressing A-fiber cells are Trk-A positive and many express the vanilloid-like receptor VRL1. About half of C-fiber DRG neurons express either SNS or SNS2, and in most, the channels are colocalized. SNS and SNS2 are found both in NGF-responsive and GDNF-responsive C-fibers and many of these cells also express the capsaicin receptor VR1. A very small proportion of small DRG cells express either only SNS or only SNS2. At least four different classes of A- and C-fiber DRG neurons exist, therefore, with respect to expression of these sodium channels.

A role for HSP27 in sensory neuron survival.

Peripheral nerve injury in neonatal rats results in the death of the majority of the axotomized sensory neurons by 7 d after injury. In adult animals, however, all sensory neurons survive for at least 4 months after axotomy. How sensory neurons acquire the capacity to survive axonal injury is not known. Here we describe how the expression of the small heat shock protein 27 (HSP27) is correlated with neuronal survival after axotomy in vivo and after NGF withdrawal in vitro. The number of HSP27-immunoreactive neurons in the L4 DRG is low at birth and does not change significantly for 21 d after postnatal day 0 (P0) sciatic nerve axotomy. In contrast, in the adult all axotomized neurons begin to express HSP27. One week after P0 sciatic nerve section the total number of neurons in the L4 DRG is dramatically reduced, but all surviving axotomized neurons, as identified by c-jun immunoreactivity, are immunoreactive for HSP27. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling reveals that very few HSP27-expressing neurons are dying 48 hr after neonatal axotomy. In vitro, a similar correlation exists between HSP27 expression and survival; in P0 DRG cultures, neurons that express HSP27 preferentially survive NGF withdrawal. Finally, overexpression of human HSP27 in neonatal rat sensory and sympathetic neurons significantly increases survival after NGF withdrawal, with nearly twice as many neurons surviving at 48 hr. Together these results suggest that HSP27 in sensory neurons plays a role in promoting survival after axotomy or neurotrophin withdrawal.

Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity.

Brain-derived neurotrophic factor (BDNF) is expressed in nociceptive sensory neurons and transported anterogradely to the dorsal horn of the spinal cord where it is located in dense core vesicles in C-fiber terminals. Peripheral inflammation substantially up-regulates BDNF mRNA and protein in the dorsal root ganglion (DRG) in a nerve growth factor-dependent fashion and results in novel expression of BDNF by DRG neurons with myelinated axons. C-fiber electrical activity also increases BDNF expression in the DRG, and both inflammation and activity increase full-length TrkB receptor levels in the dorsal horn. Sequestration of endogenous BDNF/neurotrophin 4 by intraspinal TrkB-Fc fusion protein administration does not, in noninflamed animals, change basal pain sensitivity nor the mechanical hypersensitivity induced by peripheral capsaicin administration, a measure of C fiber-mediated central sensitization. TrkB-Fc administration also does not modify basal inflammatory pain hypersensitivity, but does block the progressive hypersensitivity elicited by low-intensity tactile stimulation of inflamed tissue. BDNF, by virtue of its nerve growth factor regulation in sensory neurons including novel expression in A fibers, has a role as a central modulator of tactile stimulus-induced inflammatory pain hypersensitivity.

Neuropathic pain: aetiology, symptoms, mechanisms, and management.

We highlight current theories about peripheral neuropathic pain and show that progress in management is contingent on targeting treatment not at the aetiological factors or the symptoms but at the mechanisms that operate to produce the symptoms. This approach will require substantial progress in our understanding of the pathophysiology of neuropathic pain, the development of accurate diagnostic tools to discover what mechanisms contribute to the pain syndrome in an individual, and effective treatments aimed specifically at the mechanisms.

Heat shock protein 27: developmental regulation and expression after peripheral nerve injury.

The heat shock protein (HSP) 27 is constitutively expressed at low levels in medium-sized lumbar dorsal root ganglion (DRG) cells in adult rats. Transection of the sciatic nerve results in a ninefold upregulation of HSP27 mRNA and protein in axotomized neurons in the ipsilateral DRG at 48 hr, without equivalent changes in the mRNAs encoding HSP56, HSP60, HSP70, and HSP90. Dorsal rhizotomy, injuring the central axon of the DRG neuron, does not upregulate HSP27 mRNA levels. After peripheral axotomy, HSP27 mRNA and protein are present in small, medium, and large DRG neurons, and HSP27 protein is transported anterogradely, accumulating in the dorsal horn and dorsal columns of the spinal cord, where it persists for several months. Axotomized motor neurons also upregulate HSP27. Only a minority of cultured adult DRG neurons are HSP27-immunoreactive soon after dissociation, but all express HSP27 after 24 hr in culture with prominent label throughout the neuron, including the growth cone. HSP27 differs from most axonal injury-regulated and growth-associated genes, which are typically present at high levels in early development and downregulated on innervation of their targets, in that its mRNA is first detectable in the DRG late in development and only approaches adult levels by postnatal day 21. In non-neuronal cells, HSP27 has been shown to be involved both in actin filament dynamics and in protection against necrotic and apoptotic cell death. Therefore, its upregulation after adult peripheral nerve injury may both promote survival of the injured neurons and contribute to alterations in the cytoskeleton associated with axonal growth.

Deafferentation is insufficient to induce sprouting of A-fibre central terminals in the rat dorsal horn.

The mechanism by which A-fibres sprout into lamina II of the dorsal horn of the adult rat after peripheral nerve injury, a region which normally receives input from noci- and thermoreceptive C-fibres alone, is not known. Recent findings indicating that selective C-fibre injury and subsequent degenerative changes in this region are sufficient to induce sprouting of uninjured A-fibres have raised the possibility that the structural reorganisation of A-fibre terminals is an example of collateral sprouting, in that deafferentation of C-fibre terminals alone in lamina II may be sufficient to cause A-fibre sprouting. Primary afferents of the sciatic nerve have their cell bodies located predominantly in the L4 and L5 dorsal root ganglia (DRGs), and the A-fibres of each DRG have central termination fields that show an extensive rostrocaudal overlap in lamina III in the L4 and L5 spinal segments. In this study, we have found that C-fibres from either DRG have central terminal fields that overlap much less in lamina II than A-fibres in lamina III. We have exploited this differential terminal organisation to produce deafferentation in lamina II of the L5 spinal segment, by an L5 rhizotomy, and then test whether A-fibres of the intact L4 dorsal root ganglion, which terminate within the L5 segment, sprout into the denervated lamina II in the L5 spinal segment. Neither intact nor peripherally injured A-fibres were seen to sprout into denervated lamina II after L5 rhizotomy. Sprouting was only ever seen into regions of lamina II containing the terminals of peripherally injured C-fibres. Therefore, it seems that the creation of synaptic space within lamina II is not the explanation for A-fibre sprouting after peripheral nerve section or crush, emphasising that injury-induced changes in C-fibres and subsequent chemotrophic effects in the superficial dorsal horn are the likely explanation.

Intact sciatic myelinated primary afferent terminals collaterally sprout in the adult rat dorsal horn following section of a neighbouring peripheral nerve.

Peripheral nerve section induces sprouting of the central terminals of axotomized myelinated primary afferents outside their normal dorsoventral termination zones in lamina I, III, and IV of the dorsal horn into lamina II, an area that normally only receives unmyelinated C-fiber input. This axotomy-induced regenerative sprouting is confined to the somatotopic boundaries of the injured nerve in the spinal cord. We examined whether intact myelinated sciatic afferents are able to sprout novel terminals into neighbouring areas of the dorsal horn in the adult rat following axotomy of two test nerves, either the posterior cutaneous nerve of the thigh or the saphenous nerve. These peripheral nerves have somatotopically organized terminal areas in the dorsal horn that overlap in some areas and are contiguous in others, with that of the sciatic central terminal field. Two weeks after cutting either the posterior cutaneous or the saphenous nerve, intact sciatic myelinated fibers labelled with the B fragment of cholera toxin conjugated to horseradish peroxidase (B-HRP) sprouted into an area of lamina II normally only innervated by the adjacent injured test nerve. This collateral sprouting was strictly limited, however, to those particular areas of the dorsal horn where the A-fiber terminal field of the control sciatic and the C-fiber terminal field of the injured test nerve overlapped in the dorsoventral plane. No mediolateral sprouting was seen into those areas of neuropil solely innervated by the test nerve. We conclude that intact myelinated primary afferents do have the capacity to collaterally sprout, but that any resultant somatotopic reorganization of central projections is limited to the dorsoventral plane. These changes may contribute to sensory hypersensitivity at the edges of denervated skin.

Collateral sprouting of uninjured primary afferent A-fibers into the superficial dorsal horn of the adult rat spinal cord after topical capsaicin treatment to the sciatic nerve.

That terminals of uninjured primary sensory neurons terminating in the dorsal horn of the spinal cord can collaterally sprout was first suggested by Liu and Chambers (1958), but this has since been disputed. Recently, horseradish peroxidase conjugated to the B subunit of cholera toxin (B-HRP) and intracellular HRP injections have shown that sciatic nerve section or crush produces a long-lasting rearrangement in the organization of primary afferent central terminals, with A-fibers sprouting into lamina II, a region that normally receives only C-fiber input (Woolf et al., 1992). The mechanism of this A-fiber sprouting has been thought to involve injury-induced C-fiber transganglionic degeneration combined with myelinated A-fibers being conditioned into a regenerative growth state. In this study, we ask whether C-fiber degeneration and A-fiber conditioning are both necessary for the sprouting of A-fibers into lamina II. Local application of the C-fiber-specific neurotoxin capsaicin to the sciatic nerve has previously been shown to result in C-fiber damage and degenerative atrophy in lamina II. We have used B-HRP to transganglionically label A-fiber central terminals and have shown that 2 weeks after topical capsaicin treatment to the sciatic nerve, the pattern of B-HRP staining in the dorsal horn is indistinguishable from that seen after axotomy, with lamina II displaying novel staining in the identical region containing capsaicin-treated C-fiber central terminals. These results suggest that after C-fiber injury, uninjured A-fiber central terminals can collaterally sprout into lamina II of the dorsal horn. This phenomenon may help to explain the pain associated with C-fiber neuropathy.