Treatment of 213 Patients with Symptomatic Tarlov Cysts by CT-Guided Percutaneous Injection of Fibrin Sealant.

BACKGROUND AND PURPOSE: There has been a steady progression of case reports and a small surgical series that report successful surgical treatment of Tarlov cysts with concomitant relief of patients' symptoms and improvement in their neurological dysfunction, yet patients are still told that these lesions are asymptomatic by physicians. The purpose of this study was to analyze the efficacy and safety of intervention in 213 consecutive patients with symptomatic Tarlov cysts treated by CT-guided 2-needle cyst aspiration and fibrin sealing. MATERIALS AND METHODS: This study was designed to assess outcomes in patients who underwent CT-guided aspiration and injection of ≥1 sacral Tarlov cyst at Johns Hopkins Hospital between 2003 and 2013. In all, 289 cysts were treated in 213 consecutive patients. All these patients were followed for at least 6 months, 90% were followed for 1 year, and 83% were followed for 3-6 years. The aspiration-injection procedure used 2 needles and was performed with the patients under local anesthesia and intravenous anesthesia. In the fibrin-injection stage of the procedure, a commercially available fibrin sealant was injected into the cyst through the deep needle (Tisseel VH). RESULTS: One year postprocedure, excellent results were obtained in 104 patients (54.2% of patients followed), and good or satisfactory results were obtained in 53 patients (27.6%). Thus, 157 patients (81.8%) in all were initially satisfied with the outcome of treatment. At 3-6 years postprocedure, 74.0% of patients followed were satisfied with treatment. There were no clinically significant complications. CONCLUSIONS: The aspiration-injection technique described herein constitutes a safe and efficacious treatment option that holds promise for relieving cyst-related symptoms in many patients with very little risk.

Validation of the composite autonomic symptom scale 31 (COMPASS-31) in patients with and without small fiber polyneuropathy.

BACKGROUND AND PURPOSE: The recently developed composite autonomic symptom score 31 (COMPASS-31) is a questionnaire that assess symptoms of dysautonomia. It was distilled from the well-established Autonomic Symptom Profile questionnaire. COMPASS-31 has not yet been externally validated. To do so, its psychometric properties and convergent validity in patients with and without objective diagnosis of small fiber polyneuropathy (SFPN) were assessed. METHODS: Internal validity and reliability of COMPASS-31 were assessed in participants with or without SFPN spanning the full range of severity of autonomic symptoms. Convergent validity was assessed by comparing results of the COMPASS-31 with the "gold standard" autonomic function testing that measures cardiovagal, adrenergic and sudomotor functions. Additionally, relationships between COMPASS-31 and the Short Form McGill Pain Questionnaire, Short Form Health Survey and 0-10 numeric pain scale were measured. COMPASS-31 and all other questionnaire results were compared between patients with or without evidence of SFPN, objectively confirmed by distal-leg PGP9.5-immunolabeled skin biopsy. RESULTS: Amongst 66 participants (28 SFPN+, 38 SFPN-), COMPASS-31 total scores had excellent internal validity (Cronbach's α = 0.919), test-retest reliability (r(s) = 0.886; P < 0.001) and good convergent validity (r(s) = 0.474; P < 0.001). COMPASS-31 scores differed between subjects with or without SFPN (Z = -3.296, P < 0.001) and demonstrated fair diagnostic accuracy. Area under the Receiver Operating Characteristic curve was 0.749 (P = 0.01, 95% confidence interval 0.627-0.871). CONCLUSIONS: COMPASS-31 has good psychometric properties in the population of patients being evaluated for SFPN and thus it might be useful as an initial screening tool for the more expensive SFPN objective tests.

Endoneurial pathology of the needlestick-nerve-injury model of Complex Regional Pain Syndrome, including rats with and without pain behaviors.

Current rodent models of neuropathic pain produce pain hypersensitivity in almost all lesioned animals and not all identified experimental effects are pain specific. 18G needlestick-nerve-injury (NNI) to one tibial nerve of outbred Sprague-Dawley rats models the phenotype of Complex Regional Pain Syndrome (CRPS), a post-traumatic neuropathic pain syndrome, leaving roughly half of NNI rats with hyperalgesia. We compared endoneurial data from these divergent endophenotypes searching for pathological changes specifically associated with pain-behaviors. Tibial, sural, and common sciatic nerves from 12 NNI rats plus 10 nerves from sham-operated controls were removed 14 days post-surgery for morphometric analysis. PGP9.5(+) unmyelinated-fibers were quantitated in plantar hindpaw skin. Distal tibial nerves of NNI rats had endoneurial edema, 30% fewer axons, twice as many mast cells, and thicker blood-vessel walls than uninjured tibial nerves. However the only significant difference between nerves from hyperalgesic versus non-hyperalgesic NNI rats was greater endoneurial edema in hyperalgesic rats (p < 0.01). We also discovered significant axonal losses in uninjured ipsilateral sural nerves of NNI rats, demonstrating spread of neuropathy to nearby nerves formerly thought spared. Tibial and sural nerves contralateral to NNI had significant changes in endoneurial blood-vessels. Similar pathological changes have been identified in CRPS-I patients. The current findings suggest that severity of endoneurial vasculopathy and inflammation may correlate better with neuropathic pain behaviors than degree of axonal loss. Spread of pathological changes to nearby ipsilateral and contralateral nerves might potentially contribute to extraterritorial pain in CRPS.

Nucleotide signaling and cutaneous mechanisms of pain transduction.

Sensory neurons that innervate the skin provide critical information about physical contact between the organism and the environment, including information about potentially-damaging stimuli that give rise to the sensation of pain. These afferents also contribute to the maintenance of tissue homeostasis, inflammation and wound healing, while sensitization of sensory afferents after injury results in painful hypersensitivity and protective behavior. In contrast to the traditional view of primary afferent terminals as the sole site of sensory transduction, recent reports have lead to the intriguing idea that cells of the skin play an active role in the transduction of sensory stimuli. The search for molecules that transduce different types of sensory stimuli (mechanical, heat, chemical) at the axon terminal has yielded a wide range of potential effectors, many of which are expressed by keratinocytes as well as neurons. Emerging evidence underscores the importance of nucleotide signaling through P2X ionotropic and P2Y metabotropic receptors in pain processing, and implicates nucleotide signaling as a critical form of communication between cells of the skin, immune cells and sensory neurons. It is of great interest to determine whether pathological changes in these mechanisms contribute to chronic pain in human disease states such as complex regional pain syndrome (CRPS). This review discusses recent advances in our understanding of communication mechanisms between cells of the skin and sensory axons in the transduction of sensory input leading to pain.

Effects of distal nerve injuries on dorsal-horn neurons and glia: relationships between lesion size and mechanical hyperalgesia.

Penetrating limb injuries are common and usually heal without long-lasting effects, even when nerves are cut. However, rare nerve-injury patients develop prolonged and disabling chronic pain (neuralgia). When pain severity is disproportionate to severity of the inciting injury, physicians and insurers may suspect exaggeration and limit care or benefits, although the nature of the relationship between lesion-size and the development and persistence of neuralgia remains largely unknown. We compared cellular changes in the spinal dorsal-horn (the initial CNS pain-processing area) after partial or total tibial-nerve axotomies in male Sprague-Dawley rats to determine if these changes are proportional to the numbers of peripheral axons cut. Unoperated rats provided controls. Plantar hind-paw responses to touch, pin, and cold were quantitated bilaterally to identify hyperalgesic rats. We also compared data from nerve-injured rats with or without hyperalgesic responses to mechanical hind-paw stimulation to evaluate concordance between pain behaviors and dorsal-horn cellular changes. Hyperalgesia was no less prevalent or severe after partial than after total axotomy. L(5) spinal-cord sections from rats killed 7 days postoperatively were labeled for markers of primary afferents (substance P calcitonin gene-related peptide isolectin B4, gamma aminobutyric acid, and glial fibrillary acidic protein), then labeled cells were stereologically quantitated in somatotopically defined dorsal-horn regions. Total axotomy reduced markers of primary afferents more than partial axotomy. In contrast, GABA-immunoreactive profiles were similarly reduced after both lesions, and in rats with sensory loss versus hyperalgesia. Numbers of GFAP-immunoreactive astrocytes increased independently of lesion size and pain status. Small nerve injuries can thus have magnified and disproportionate effects on dorsal-horn neurons and glia, perhaps providing a biological correlate for the disproportionate pain of post-traumatic neuralgias (including complex regional pain syndrome-I) that follow seemingly minor nerve injuries. However, the presence of similar dorsal-horn changes in rats without pain behaviors suggests that not all transcellular responses to axotomy are pain-specific.

The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles.

The mechanisms of chronic neuropathic pain are not well understood. Postherpetic neuralgia (PHN), which occurs in some patients after shingles (herpes zoster), was used to investigate the neural determinants of chronic pain. Skin biopsies were obtained from 38 adults with or without PHN at least 3 months after healing of shingles on the torso. Vertical sections were immunolabeled against PGP9.5, a pan-axonal marker, to measure the density of remaining nerve endings in skin previously affected by shingles. All axons that end in the epidermis are nociceptors, neurons that transmit pain messages. The densities ranged between 2 and 3976 neurites/mm2 skin surface, but the overlap between subjects and without PHN was small. Of 19 subjects without PHN, 17 had more than 670 neurites/mm2 skin surface area (mean +/- SEM = 1569 +/- 230), and 18 of 19 subjects with PHN had 640 or fewer neurites/mm2 (mean +/- SEM = 367 +/- 92). PHN may be a 'phantom-skin' pain associated with loss of nociceptors. This threshold of approximately 650 neurites/mm2 skin surface was not detected in previous studies that used summary statistics. It implies that the absence of pain after shingles may require the preservation of a minimum density of primary nociceptive neurons, and that the density of epidermal innervation may provide an objective correlate for the presence or absence of PHN pain.

Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms.

BACKGROUND: Postherpetic neuralgia (PHN) is considered by some investigators to be predominantly a deafferentation-type central pain syndrome; others suggest that activity of remaining peripheral nociceptors plays a critical role. The authors investigated the sensory dysfunction in subjects with PHN of varying duration and at different sites to gain further insight into the mechanisms responsible for the clinical features of neuropathic pain. In addition, the relationships between ongoing pain and pain evoked by mechanical and thermal stimuli were compared in patients with trigeminal and truncal PHN, to determine if the pathophysiologic mechanisms differed among subjects. METHODS: In 63 subjects with PHN, quantitative sensory testing was performed in the region of maximum allodynia or ongoing pain and the corresponding contralateral site. The intensity of ongoing pain was recorded. Sensory thresholds for warmth, coolness, heat pain, and cold pain were determined. Pain induced by various mechanical stimuli (dynamic, static, punctate) was rated using a numerical rating scale of 0-10. RESULTS: The mean rating of ongoing PHN pain was 7.3 +/- 2.0 (mean +/- SD). Allodynia induced by one or more mechanical stimuli was observed in 78% of subjects. A smaller subset (40%) had hyperalgesia to heat or cold stimuli. In subjects with duration of PHN of < or = 1 yr duration, but not in those with duration of > 1 yr, the intensity of ongoing pain correlated with intensity of allodynia induced by dynamic stimuli. Deficits in thresholds for heat and cold pain were observed in the affected region of subjects with PHN in the thoracic dermatomes (P < 0.005), but not in the trigeminal distribution. No relationship was observed between the thermal deficits and ongoing pain or mechanical allodynia in the groups of subjects with either trigeminal or thoracic PHN. CONCLUSION: Despite a common cause, the patterns of sensory abnormalities differ between subjects. Particular differences were noted between groups with facial or truncal PHN and between groups with recent or more chronic PHN. The observations suggest that the relative contributions of peripheral and central mechanisms to the pathophysiology of pain differ among subjects and may vary over the course of PHN.

The pathology of shingles: Head and Campbell's 1900 monograph.

Shingles (herpes zoster) and postherpetic neuralgia, a chronic neuropathic pain syndrome that can persist after the shingles lesions heal, were studied by eminent neurologists of the 19th century. Autopsy studies were used to establish sensory neural pathways in the peripheral and central nervous systems. More recently, zoster and postherpetic neuralgia have served as models for the study of the pathogenesis and treatment of neuropathic pain. Postherpetic neuralgia has the cardinal clinical features of all neuropathic pain syndromes, including sensory abnormalities, ongoing pain, and allodynia (touch-induced pain). Unlike most other neuropathic pain syndromes, such as trigeminal neuralgia or nerve root compressions, shingles has a well-defined pathogenesis and onset, as well as visible lesions, and is therefore uniquely suitable for study.

Unilateral postherpetic neuralgia is associated with bilateral sensory neuron damage.

Shingles can cause chronic neuropathic pain (postherpetic neuralgia) long after skin lesions heal. To investigate its causes, we quantitated immunolabeled sensory neurites in skin biopsies from 18 subjects with and 16 subjects without postherpetic neuralgia after unilateral shingles. Subjects rated the intensity of their pain. Punch skin biopsies were evaluated from the site of maximum pain or shingles involvement, the homologous contralateral location, and a site on the back, distant from shingles involvement. Sections were immunostained with anti-PGP9.5 antibody, a pan-axonal marker, and the density of epidermal and dermal neurites determined. The group with postherpetic neuralgia had a mean density of 339 +/- 97 neurites/mm2 in shingles-affected epidermis compared with a density of 1,661 +/- 262 neurites/mm2 for subjects without pain. Neurite loss was more severe in epidermis than dermis. Unexpectedly, the group with pain had also lost half of the neurites in contralateral epidermis. Contralateral damage occurred despite the lack of contralateral shingles eruptions or pain, correlated with the presence and severity of ongoing pain at the shingles site, and did not extend to the distant site. Thus, the pathophysiology of postherpetic neuralgia pain may involve a new bilateral mechanism.

Unilateral nerve injury down-regulates mRNA for Na+ channel SCN10A bilaterally in rat dorsal root ganglia.

Injury makes sensory neurons abnormally excitable and triggers coincident alterations in relative levels of different types of voltage-gated sodium channels that they express. We report that nerve injury depress levels of SCN10A-specific mRNA in contralateral as well as ipsilateral dorsal root ganglia of rats, suggesting a possible peripheral mechanism for the contralateral 'mirror-image' hyperalgesia described in nerve-injured humans and experimental animals.

Small-scale magnetic isolation of mRNA and synthesis of cDNA in 96-well plates.

Multiple small biological samples can be simultaneously prepared for RT-PCR by magnetically isolating mRNA and synthesizing cDNA in 96-well plates. The resulting accuracy, high throughput and ease of use facilitate commercial and clinical applications.

Cold blockade of axonal transport activates premitotic activity of Schwann cells and wallerian degeneration.

Between 3 and 4 days after transection of cat sciatic nerve, Schwann cell-associated premitotic activity spreads anterogradely along degenerating distal nerve stumps at a rate of approximately 200 mm/day. We investigated whether fast anterograde axonal transport contributes to the initiation of this component of Wallerian degeneration. Axonal transport was blocked in intact and transected cat sciatic nerves by focally chilling a proximal segment to temperatures below 11 degrees C for 24 hr. Incorporation of [3H]thymidine (a marker of premitotic DNA synthesis) was then measured 3 and 4 days posttransection in cold blocked- and control-degenerating nerves. Effects of cold block prior to and concomitant with nerve transection were studied. Results failed to support the hypothesis that Schwann-cell premitotic activity after axotomy is associated with entry into the axon of mitogenic substances and their anterograde fast transport along the distal stump. Instead, data suggested that progressive anterograde failure of fast anterograde transport distal to transection serves to effect the Schwann-cell premitotic response to axotomy.

Early changes in degenerating mouse sciatic nerve are associated with endothelial cells.

This study determines the earliest reproducible biochemical change in nerves undergoing Wallerian degeneration by assessing the timing, magnitude, and specificity of changes in markers of cellular function in distal stumps of transected mouse sciatic nerves. Analysis of temporal changes in synthesis of DNA, RNA, protein, and in activity of ornithine decarboxylase in transected and sham-operated nerves 0-5 days postoperatively indicated that incorporation of [3H]thymidine, a marker of premitotic activity, was the earliest and only specific marker of early Wallerian degeneration. Although the 3-4 day peak in [3H]thymidine incorporation in distal stumps at the onset of the [3H]thymidine response (1 day post-transection) revealed preferential labeling of endothelial cells lining intrafascicular capillaries.

Rapid anterograde spread of premitotic activity along degenerating cat sciatic nerve.

Peripheral nerve transection triggers a series of phenotypic alterations in Schwann cells distal to the site of injury. Mitosis is one of the earliest and best characterized of these responses, although the mechanism by which axonal damage triggers this critical event is unknown. This study examines the appearance and spatio-temporal spread of premitotic activity in distal stumps of transected cat tibial nerves. Premitotic activity was determined by measuring incorporation of [3H]thymidine (a marker of DNA synthesis during the S-phase of the cell cycle) into consecutive segments of desheathed tibial nerve. Incorporation of [3H]thymidine spread proximo-distally within distal nerve stumps between 3 and 4 days posttransection with an apparent velocity of at least 199 +/- 67 mm/day. This suggests that anterograde fast axonal transport may directly or indirectly be associated with the Schwann cell mitotic response to axon transection.

Saxitoxin binding to central and peripheral nervous tissue of the myelin deficiency (md) mutant rat.

Tritium-labeled saxitoxin binding was assayed in the CNS and PNS of normal and of 'myelin deficiency' (md) mutant rat pups. This mutant in the Wistar rat is characterized by a virtually complete amyelination of the CNS, the PNS being normal. No significant difference was found in the saxitoxin binding capacity of md and normal brain, spinal cord, or sciatic nerves. This suggests that the presence or absence of myelin does not influence the number of voltage-sensitive sodium channels in the rat.

Reactive glial protein synthesis and early disappearance of saxitoxin binding in degenerating rat optic nerve.

The biochemistry of gliotic CNS tissue was assessed by monotoring changes in de novo protein synthesis distal to site of crush in the rat optic nerve between 3 and 20 days post-operatively. Radioactivity profiles on 12% polyacrylamide SDS gels showed reproducible peaks associated with protein(s) with dissociated molecular weights of 57K, 51K, 42K, 40K, 37K and 23K. Differences between crush and control nerves were observed with respect to the latter two peaks. De novo synthesis of 23K protein (comigrant with myelin proteolipid protein) was evident in control but not crushed nerves. Synthesis of 37K protein (identity unknown) was evident at 7, 10 and (to a lesser extent) 20 days post-operatively in crushed nerves, but not in crushed nerves at 3 days post-operatively or in unoperated nerves at any time point. The appearance of the synthesis of the 37K protein coincides with a drop in the level of functional axolemma (assessed by [3H]saxitoxin binding) in crushed nerves from 78% to 36% of control levels between 3 and 7 days post-operatively.