Tri-partite complex for axonal transport drug delivery achieves pharmacological effect.

BACKGROUND: Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. RESULTS: We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. CONCLUSION: Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.

Diagnosis and treatment of pudendal nerve entrapment syndrome subtypes: imaging, injections, and minimal access surgery.

OBJECT: To improve diagnostic accuracy and achieve high levels of treatment success in patients with pudendal nerve entrapment (PNE) syndromes, the author of this study applied advanced technology diagnostics in distinguishing the various syndrome types according to the different entrapment locations and evaluated new minimal access surgical techniques to treat each subtype. METHODS: Two hundred cases were prospectively evaluated using a standardized set of patient-completed functional and symptom assessments, a collection of new physical examination maneuvers, MR neurography, open MR image-guided injections, intraoperative neurophysiology, minimal access surgery, and formal outcome assessment with the Oswestry Disability Index, pain diagrams, and analog pain scales. RESULTS: Four primary types of PNE syndromes were identified based on the different locations of entrapment: Type I, entrapment at the exit of the greater sciatic notch in concert with piriformis muscle spasm; Type II, entrapment at the level of the ischial spine, sacrotuberous ligament, and lesser sciatic notch entrance; Type III, entrapment in association with obturator internus muscle spasm at the entrance of the Alcock canal; and Type IV, distal entrapment of terminal branches. The application of new, targeted minimal access surgical techniques led to sustained good to excellent outcomes (50-100% improvement in the pain score or functional score) in 87% of patients. Most of these patients obtained most of their improvement within 4 weeks of surgery, although some continued to experience progressive improvements up to 12 months after surgery. CONCLUSIONS: The application of advanced diagnostics to categorize PNE syndrome origins into 4 major subtypes and the subsequent treatment of each subtype with a tailored strategy greatly improved therapeutic outcomes as compared with those reported when only a single treatment paradigm was applied to all patients.

Piriformis and related entrapment syndromes: diagnosis & management.

Highly reliable evidence for piriformis syndrome and other pelvic sciatic syndromes arises from three major categories of data: magnetic resonance neurography diagnostic imaging, open magnetic resonance-guided injection studies, and patient treatment outcome studies. This article reviews the evidence in each category. This is part of a Point-Counterpoint discussion with Dr. Robert Tiel's presentation of "Myth and Fallacy".

A historical hypothesis of the first recorded neurosurgical operation: Isis, Osiris, Thoth, and the origin of the djed cross.

A new textual analysis of the central religious aspect of the ancient Egyptian creation myth reveals what appears to be a description of the oldest recorded neurosurgical operation, occurring circa 3000 BC. The analysis results in a hypothesis suggesting that traction reduction was used successfully to reverse a paralyzing cervical spine injury of an early Egyptian leader (Osiris), which inspired the story of his resurrection. The Egyptian mother god Isis, working with the god Thoth (the inventor of medicine), resurrects Osiris by treating his damaged cervical spine. Numerous references in the Papyrus of Ani (Book of the Dead) to Osiris regaining the strength and control of his legs are linked textually to the treatment of his spine. The connection between the intact spine and the ability to rise and stand is used as a distinct metaphor for life and death by the spinal representation of the "djed column" painted on the back of the numerous Egyptian sarcophagi for thousands of years. Controversy over the translation of the vertebral references in Egyptian texts is clarified by considering the specific neurosurgical meanings of hieroglyphs appearing in both the Edwin Smith medical papyrus and in the Papyrus of Ani, and in light of recent scholarly reassessments of those hieroglyphs in the Egyptological literature.

Emergence and optimization of upright posture among hominiform hominoids and the evolutionary pathophysiology of back pain.

The lordotic region of the lumbar spine is a significant focus of pain and dysfunction in the human body, and its susceptibility to disorders may reflect its substantial reconfiguration during the course of human evolution. The basic anatomy of the lumbar vertebra in Old World Monkeys and Early Miocene apes, or proconsulids, retains typical mammalian architecture. The lumbar vertebra in humans is different in the repositioning of the lumbar transverse process dorsal to the vertebral body rather than originating on the body itself and in the loss of the styloid process that is adjacent to the facets in other primates. These two features appeared in Morotopithecus bishopi 21.6 million years ago, suggesting that this ape is the founder of an upright hominiform lineage. The iliocostalis lumborum muscles migrated onto the iliac crest approximately 18 million years ago, becoming a powerful lateral flexor muscle of the trunk. The posterior superior iliac spine shifted far dorsal to the longissimus insertion in the genus Homo between 1 and 2 million years ago, making this muscle a powerful extensor of the lumbar spine. Functionally, the establishment of strong muscular flexors and extensors adds dynamic compressive stresses to the lumbar disks and also makes these muscles susceptible to strain.

Homeotic evolution in the mammalia: diversification of therian axial seriation and the morphogenetic basis of human origins.

BACKGROUND: Despite the rising interest in homeotic genes, little has been known about the course and pattern of evolution of homeotic traits across the mammalian radiation. An array of emerging and diversifying homeotic gradients revealed by this study appear to generate new body plans and drive evolution at a large scale. METHODOLOGY/PRINCIPAL FINDINGS: This study identifies and evaluates a set of homeotic gradients across 250 extant and fossil mammalian species and their antecedents over a period of 220 million years. These traits are generally expressed as co-linear gradients along the body axis rather than as distinct segmental identities. Relative position or occurrence sequence vary independently and are subject to polarity reversal and mirroring. Five major gradient modification sets are identified: (1)--quantitative changes of primary segmental identity pattern that appeared at the origin of the tetrapods ; (2)--frame shift relation of costal and vertebral identity which diversifies from the time of amniote origins; (3)--duplication, mirroring, splitting and diversification of the neomorphic laminar process first commencing at the dawn of mammals; (4)--emergence of homologically variable lumbar lateral processes upon commencement of the radiation of therian mammals and ; (5)--inflexions and transpositions of the relative position of the horizontal septum of the body and the neuraxis at the emergence of various orders of therian mammals. Convergent functional changes under homeotic control include laminar articular engagement with septo-neural transposition and ventrally arrayed lumbar transverse process support systems. CONCLUSION/SIGNIFICANCE: Clusters of homeotic transformations mark the emergence point of mammals in the Triassic and the radiation of therians in the Cretaceous. A cluster of homeotic changes in the Miocene hominoid Morotopithecus that are still seen in humans supports establishment of a new "hominiform" clade and suggests a homeotic origin for the human upright body plan.

Sciatica of nondisc origin and piriformis syndrome: diagnosis by magnetic resonance neurography and interventional magnetic resonance imaging with outcome study of resulting treatment.

OBJECT: Because lumbar magnetic resonance (MR) imaging fails to identify a treatable cause of chronic sciatica in nearly 1 million patients annually, the authors conducted MR neurography and interventional MR imaging in 239 consecutive patients with sciatica in whom standard diagnosis and treatment failed to effect improvement. METHODS: After performing MR neurography and interventional MR imaging, the final rediagnoses included the following: piriformis syndrome (67.8%), distal foraminal nerve root entrapment (6%), ischial tunnel syndrome (4.7%), discogenic pain with referred leg pain (3.4%), pudendal nerve entrapment with referred pain (3%), distal sciatic entrapment (2.1%), sciatic tumor (1.7%), lumbosacral plexus entrapment (1.3%), unappreciated lateral disc herniation (1.3%), nerve root injury due to spinal surgery (1.3%), inadequate spinal nerve root decompression (0.8%), lumbar stenosis (0.8%), sacroiliac joint inflammation (0.8%), lumbosacral plexus tumor (0.4%), sacral fracture (0.4%), and no diagnosis (4.2%). Open MR-guided Marcaine injection into the piriformis muscle produced the following results: no response (15.7%), relief of greater than 8 months (14.9%), relief lasting 2 to 4 months with continuing relief after second injection (7.5%), relief for 2 to 4 months with subsequent recurrence (36.6%), and relief for 1 to 14 days with full recurrence (25.4%). Piriformis surgery (62 operations; 3-cm incision, transgluteal approach, 55% outpatient; 40% with local or epidural anesthesia) resulted in excellent outcome in 58.5%, good outcome in 22.6%, limited benefit in 13.2%, no benefit in 3.8%, and worsened symptoms in 1.9%. CONCLUSIONS: This Class A quality evaluation of MR neurography's diagnostic efficacy revealed that piriformis muscle asymmetry and sciatic nerve hyperintensity at the sciatic notch exhibited a 93% specificity and 64% sensitivity in distinguishing patients with piriformis syndrome from those without who had similar symptoms (p < 0.01). Evaluation of the nerve beyond the proximal foramen provided eight additional diagnostic categories affecting 96% of these patients. More than 80% of the population good or excellent functional outcome was achieved.

MR neurography and muscle MR imaging for image diagnosis of disorders affecting the peripheral nerves and musculature.

Recent advances in the technology of MR imaging are beginning to transform the fundamental methodology of diagnostic evaluations in neuromuscular disorders. When properly implemented, MR neurography is capable of providing high-quality information about nerve compression, nerve inflammation, nerve trauma, systemic neuropathies, nerve tumors, and recovery of nerve from pathologic states. Muscle MR imaging can identify denervation on a precise anatomic basis, document the progression of various conditions causing myopathy and myositis; and even provide insight into abnormal patterns of muscle activation. There is an essential role for the neurologist as well as for the specialist radiologist that requires a high level of familiarity of the various new types of image findings in this steadily advancing field.