Neurologic Complications of Paget Disease of Bone

ObjectiveTo review the epidemiology, evaluation, and management of the neurologic complications associated with Paget disease of bone (PDB).MethodsWe reviewed the English-language medical literature using MEDLINE data sources from 1950 to August 2008 and manually searched cross-references from original articles and reviews. Search terms included “Paget* disease of bone” and “neurologic* complications,” “cranial nerve,” “spinal cord,” or “peripheral nerve.”ResultsSeveral neurologic problems in the central and peripheral nervous systems may complicate PDB. Up to 76% of patients may have some form of neurologic involvement. Neurologic complications can occur in patients with a long history of PDB as well as in patients with previously unrecognized disease. The primary mechanisms of nerve damage in PDB involving the spine are ischemic myelitis and compression due to bone hypertrophy. Evaluation includes determining the serum alkaline phosphatase level and imaging by radiography, bone scintigraphy, computed tomographic scanning, and, for lesions of the central nervous system, magnetic resonance imaging. If a soft-tissue mass is found, biopsy should be considered to exclude the presence of sarcoma. Treatment strategies include calcium, vitamin D, bisphosphonates, and possibly surgical intervention for refractory cases.ConclusionNeurologic sequelae of PDB may be underappreciated. Despite the paucity of data guiding treatment, zoledronic acid is a reasonable first-line therapy. Lack of response to treatment or relapse should prompt diagnostic reevaluation with a heightened suspicion for tumor. (Endocr Pract. 2009;15:158-166)     

Carcinomatous Neuromyopathy—The Non-Metastatic Effects of Cancer on the Nervous System

Cancer can produce a variety of effects on the nervous system either by direct compression or invasion, or remotely by some as yet unknown metabolic, toxic, viral or immunologic effect on the nervous system. The neurologic effects associated with cancer that does not directly involve neural tissue have distinctive features that can give the first clue to a previously undiagnosed neoplasm. Physicians who see patients with neurologic illness should be aware that there may be an underlying malignant lesion giving rise to the neurologic syndrome; and conversely they should be on the alert for neurologic complications in patients with known cancer even though the lesion does not directly press upon or invade nerve tissue.     

Adaptive changes of locomotion after central and peripheral lesions

This paper reviews findings on the adaptive changes of locomotion in cats after spinal cord or peripheral nerve lesions. From the results obtained after lesions of the ventral/ventrolateral pathways or the dorsal/dorsolateral pathways, we conclude that with extensive but partial spinal lesions, cats can regain voluntary quadrupedal locomotion on a treadmill. Although tract-specific deficits remain after such lesions, intact descending tracts can compensate for the lesioned tracts and access the spinal network to generate voluntary locomotion. Such neuroplasticity of locomotor control mechanisms is also demonstrated after peripheral nerve lesions in cats with intact or lesioned spinal cords. Some models have shown that recovery from such peripheral nerve lesions probably involves changes at the supra spinal and spinal levels. In the case of somesthesic denervation of the hindpaws, we demonstrated that cats with a complete spinal section need some cutaneous inputs to walk with a plantigrade locomotion, and that even in this spinal state, cats can adapt their locomotion to partial cutaneous denervation. Altogether, these results suggest that there is significant plasticity in spinal and supraspinal locomotor controls to justify the beneficial effects of early proactive and sustained locomotor training after central (Rossignol and Barbeau 1995; Barbeau et al. 1998) or peripheral lesions.     

Bilateral amaurosis caused by Salmonella enteritidis infection

The aim of this paper was to show the potential of Salmonella enteritidis infection to eventually result in visual impairment. A case of salmonellosis in a 6-year-old boy, caused by intake of a cake made from eggs infected with Salmonella enteritidis, is presented. Prolonged duration of the disease was followed by complete remission of neurologic complications and persistent amaurosis with bilateral optic nerve atrophy. A severe form of Salmonella enterocolitis with neurologic involvement can lead to optic nerve lesion with consequential loss of vision.     

Lumbar spinal stenosis.

Lumbar spinal stenosis, the results of congenital and degenerative constriction of the neural canal and foramina leading to lumbosacral nerve root or cauda equina compression, is a common cause of disability in middle-aged and elderly patients. Advanced neuroradiologic imaging techniques have improved our ability to localize the site of nerve root entrapment in patients presenting with neurogenic claudication or painful radiculopathy. Although conservative medical management may be successful initially, surgical decompression by wide laminectomy or an intralaminar approach should be done in patients with serious or progressive pain or neurologic dysfunction. Because the early diagnosis and treatment of lumbar spinal stenosis may prevent intractable pain and the permanent neurologic sequelae of chronic nerve root entrapment, all physicians should be aware of the different neurologic presentations and the treatment options for patients with spinal stenosis.     

Functional assessment of neurologic impairment: track analysis in diabetic and compression neuropathies

A laboratory approach to measuring neurologic impairment has been developed that is applicable to systemic disease as well as localized nerve injury. This approach compares individual parameters of the experimental rat hind footprint (walking track) with weight- and sex-matched control track parameters; classic mathematical indexing is not utilized. The normal track data obtained for the Sprague-Dawley rat showed a significant increase in print length (PL), toe spread (TS), and intermediate toe spread (ITS) with increasing rat weight. A significant difference between male and female rats above 400 gm also was noted. For a localized injury (sciatic nerve cut), this approach demonstrated that the contralateral hind footprint was a "compensated" rather than a normal track. This approach to track analysis also was capable of demonstrating progressive neurologic impairment for a sciatic nerve compression model and a systemic disease such as diabetes, as well as demonstrating reversal of these abnormal patterns when the "disease state" was treated.     

Neurologic complications of lightning injuries.

Over the past ten years, we have cared for 13 patients who suffered serious neurologic complications after being struck by lightning. The spectrum of neurologic lesions includes the entire neuraxis from the cerebral hemispheres to the peripheral nerves. We describe these various neurologic disorders with regard to the site of the lesion, severity of the deficit, and the outcome. Damage to the nervous system can be a serious problem for patients struck by lightning. Fatalities are associated with hypoxic encephalopathy in patients who suffered cardiac arrests. Patients with spinal cord lesions are likely to have permanent sequelae and paralysis. New technology for detecting lightning with wideband magnetic direction finders is useful in establishing lightning-flash densities in each state. Florida and the Gulf Coast states have the highest densities. Colorado and the Rocky Mountain states have the next highest.     

Diagnosis and treatment of brainstem mass lesions by CT-guided stereotactic surgery

Current neuroradiographic techniques including computed tomographic scanning (CT) and magnetic resonance imaging (MRI) when added to the clinical neurologic examination can localize precisely even small lesions within the brainstem. While the clinical-radiographic diagnosis is accurate with respect to locale, it is often in error with respect to the pathologic nature of the solitary brainstem lesion. Therefore, empiric treatment without the benefit of a tissue diagnosis will often be inappropriate. CT-guided stereotactic surgery can safely and reliably provide a tissue diagnosis in such cases. Furthermore, in selected cases, therapeutic interventions can be of substantial and lasting benefit to the patient.     

Nerve fiber planimetry in acute and chronic nerve lesions and in nerve lesions in continuity

The level of resection of damaged nerve tissue in acute and chronic nerve lesions was determined on the basis of the vascular structure, the consistency of the nerve during palpation, the amount of interfascicular connective tissue, and the mushroom formation of the fascicles. Intraoperative electrophysiologic recordings were performed on the cut nerve ends to determine the function of the axons. Postoperative planimetric analyses of cross sections made through the resected nerve stumps were performed to measure axonal and endoneural tube diameters and to correlate these results with the clinical criteria used through the operating microscope. Axons in the proximal nerve ends of acute and chronic nerve lesions displayed a similar mean diameter. Endoneural tubes in chronic nerve lesions shrunk significantly as nerve repair was delayed. In several nerve lesions in continuity, axons remained present across the injured site despite absence of electrical conduction. When comparing the results of axonal or endoneural tube diameters of chronic nerve lesions to the results of other studies or acute nerve lesions, we demonstrated that careful examination through the operating microscope provided valid information about the proper management and resection level of chronic nerve lesions. Electrophysiologic evaluation aided the surgical management but was not useful for the resection of the distal damaged nerve segment. The presence of an evoked potential in the proximal nerve ends guaranteed a nearly normal nerve fiber diameter distribution, while the absence of such a potential in the distal nerve ends indicated an abnormal, absent, or disturbed endoneural tube diameter histogram.     

Occupational neurology

The nervous system is vulnerable to the effects of certain chemicals and physical conditions found in the work environment. The activities of an occupational neurologist focus on the evaluation of patients with neurological disorders caused by occupational or environmental conditions. When one is making a differential diagnosis in patients with neurological disorders, the possibility of toxic exposure or encounters with physical factors in the workplace must not be overlooked. Central to an accurate clinical diagnosis is the patient's history. A diagnosis of an occupational or environmental neurological problem requires a careful assessment of the clinical abnormalities and confirmation of these disabilities by objective tests such as nerve conduction velocity, evoked potentials, electroencephalogram, neuropsychological batteries, or nerve biopsy. On the basis of information about hazards in the workplace, safety standards and environmental and biological monitoring can be implemented in the workplace to reduce the risks of undue injury. Clinical manifestations of headache, memory disturbance, and peripheral neuropathy are commonly encountered presentations of the effects of occupational hazards. Physicians in everyday clinical practice must be aware of the signs and symptoms associated with exposure to possible neurotoxins and work methods. Occupational and environmental circumstances must be explored when evaluating patients with neurologic disorders.     

NERVE LESIONS IN INDUSTRY—Atrophy of Disuse as a Confusing Element in Diagnosis; The Value of Electromyography

Traumatic peripheral nerve lesions characteristically result in denervation muscular atrophy. Atrophy of disuse may take place concomitantly, either proximal, adjacent to or distal to the denervation muscular atrophy. The degree of atrophy of disuse depends upon the severity of the nerve lesion. Clinically, it is difficult to determine where true denervation muscular atrophy ends and accompanying atrophy of disuse begins. In such circumstances a clinician may be misled into belief that the cause of so apparently extensive a lesion is elsewhere. The patient then is often submitted to other complex diagnostic procedures and treatments. This difficulty can usually be dissipated by the use of electromyography, for each specific type of muscular atrophy produces its own characteristic electromyographic changes. Disuse atrophy produces no changes in electrical activity, whereas denervation atrophy manifests itself by typical denervation activity. Moreover it is possible to determine what part of muscular atrophy in a given area is owing to damage to a nerve and what part is owing only to disuse without denervation.     

Allergy and the atomic age

Traumatic peripheral nerve lesions characteristically result in denervation muscular atrophy. Atrophy of disuse may take place concomitantly, either proximal, adjacent to or distal to the denervation muscular atrophy. The degree of atrophy of disuse depends upon the severity of the nerve lesion. Clinically, it is difficult to determine where true denervation muscular atrophy ends and accompanying atrophy of disuse begins. In such circumstances a clinician may be misled into belief that the cause of so apparently extensive a lesion is elsewhere. The patient then is often submitted to other complex diagnostic procedures and treatments. This difficulty can usually be dissipated by the use of electromyography, for each specific type of muscular atrophy produces its own characteristic electromyographic changes. Disuse atrophy produces no changes in electrical activity, whereas denervation atrophy manifests itself by typical denervation activity. Moreover it is possible to determine what part of muscular atrophy in a given area is owing to damage to a nerve and what part is owing only to disuse without denervation.     

Somatosensory evoked potentials (SEPs) elicited by magnetic nerve stimulation

Magnetic stimulation of peripheral nerves at distal and proximal sites of the upper and lower extremities and at the midlumbar level were used to elicit cortical somatosensory evoked potentials. Evidence is provided that peripheral nerve trunks, rather than distal receptor afferents, are the anatomical structures stimulated by the electromagnetic fields. Magnetic stimulation of peripheral nerves is considered to be useful for an evaluation of the integrity of proximal nerves, nerve roots and central conduction along sensory pathways. In contrast to electrical nerve stimulation, magnetic stimulation is painless and can be applied to proximal nerves and plexus. By means of proximal nerve stimulation central sensory conduction can be tested even in patients with peripheral nerve lesions or polyneuropathy.     

Adaptive mechanisms of spinal locomotion in cats

This paper reviews some aspects of locomotor plasticity afterspinalisation and after peripheral nerve lesions. Adult catscan recover spontaneous hindlimb locomotion on a treadmill severaldays or weeks after a complete section of the spinal cord atT13. The kinematics as well as the electromyographic activityare compared in the same animal before and after the spinalsection to highlight the resemblance of locomotor characteristicsin the two conditions. To study further the mechanisms of spinalplasticity potentially underlying such locomotor recovery, wealso summarize the locomotor adaptation of cats submitted tovarious types of peripheral nerve section of either ankle flexoror extensor muscles or after denervation of the hindpaws' cutaneousinputs. It is argued that, even in the spinal state, cats havethe ability to compensate for such lesions of the peripheralnervous system suggesting that the spinal cord has a significantpotential for adaptive plasticity that could be used in rehabilitationstrategies to restore locomotion after spinal cord injury.     

Kinin-mediated inflammation in neurodegenerative disorders

The mediatory role of kinins in both acute and chronic inflammation within nervous tissues has been widely described. Bradykinin, the major representative of these bioactive peptides, is one of a few mediators of inflammation that directly stimulates afferent nerves due to the broad expression of specific kinin receptors in cell types in these tissues. Moreover, kinins may be delivered to a site of injury not only after their production at the endothelium surface but also following their local production through the enzymatic degradation of kininogens at the surface of nerve cells. A strong correlation between inflammatory processes and neurodegeneration has been established. The activation of nerve cells, particularly microglia, in response to injury, trauma or infection initiates a number of reactions in the neuronal neighborhood that can lead to cell death after the prolonged action of inflammatory substances. In recent years, there has been a growing interest in the effects of kinins on neuronal destruction. In these studies, the overexpression of proteins involved in kinin generation or of kinin receptors has been observed in several neurologic disorders including neurodegenerative diseases such Alzheimer's disease and multiple sclerosis as well as disorders associated with a deficiency in cell communication such as epilepsy. This review is focused on recent findings that provide reliable evidence of the mediatory role of kinins in the inflammatory responses associated with different neurological disorders. A deeper understanding of the role of kinins in neurodegenerative diseases is likely to promote the future development of new therapeutic strategies for the control of these disorders. An example of this could be the prospective use of kinin receptor antagonists.     

Neurotrophic factors and neurologic disease.

Discovered only 40 years ago, nerve growth factor is the prototypic neurotrophic factor. By binding to specific receptors on certain neurons in the peripheral nervous system and brain, nerve growth factor acts to enhance their survival, differentiation, and maintenance. In recent years, many additional neurotrophic factors have been discovered; some are structurally related to nerve growth factor while others are distinct from it. The robust actions of neurotrophic factors have suggested their use in preventing or lessening the dysfunction and death of neurons in neurologic disorders. We review the progress in defining neurotrophic factors and their receptors and in characterizing their actions. We also discuss some of the uses of neurotrophic factors in animal models of disease. Finally, we discuss how neurotrophic factors could be implicated in the pathogenesis of neurologic disorders.     

Oxidative Stress Contributes to Status Epilepticus Associated Mortality

Status epilepticus is a common manifestation of nerve agent toxicity and represents a serious medical emergency with high rates of mortality and neurologic injury in those that survive. The aim of the current study was to determine if targeting oxidative stress with the catalytic antioxidant, AEOL10150, would reduce pilocarpine-induced mortality and attenuate neuronal death and neuroinflammation. We found that treatment with AEOL10150 in conjunction with scopolamine and diazepam following pilocarpine-induced SE was able to significantly reduce mortality compared to treatment with just scopolamine and diazepam. Mortality was further reduced when AEOL10150 was used in conjunction with atropine and diazepam which is considered the standard of care for nerve agent exposures. Both treatment paradigms offered significant protection against SE-induced oxidative stress. Additionally, treatment with scopolamine, AEOL10150 and diazepam attenuated SE-induced neuronal loss and neuroinflammation. Taken together, the data suggest that pharmacological targeting of oxidative stress can improve survival and attenuate secondary neurological damage following SE induced by the nerve agent surrogate pilocarpine.     

Experimental nerve imaging at 1.5-T

Experimental lesions of the peripheral nerve system can be visualized in vivo by magnetic resonance imaging (MRI). Many studies of the rat peripheral nervous systems were performed on dedicated animal MR scanners with a high magnetic field strength for good spatial resolution. Here, we present an MR protocol to study experimental lesions of the rat nervous system with clinical 1.5-T MR scanners and commercially available coils. Using a three-sequence approach (T1-weighted imaging, fat-saturated T2-weighted imaging and fat-saturated T1-weighted imaging with Gd-DTPA in the same plane), the relevant signal changes of the lesioned nerve can be visualized and separated from other structures, e.g., blood vessels. Furthermore, we give an overview on different types of contrast agents used for peripheral nerve MR imaging and MR findings in selected experimental models of rat peripheral nerve injury.     

Proteomic signature of Temporomandibular Joint Disorders (TMD): Toward diagnostically predictive biomarkers

The temporomandibular joint (TMJ) articulates the mandible with the maxilla. Temporomandibular joint disorders (TMD) are dysfunctions of this joint, which range from acute to chronic inflammation, trauma and dislocations, developmental anomalies and neoplasia. TMD manifest as signs and symptoms that involve the surrounding muscles, ligaments, bones, synovial capsule, connective tissue, teeth and innervations proximal and distal to this joint. TMD induce proximal and distal, chronic and acute, dull or intense pain and discomfort, muscle spasm, clicking/popping sounds upon opening and closing of the mouth, and chewing or speaking difficulties. The trigeminal cranial nerve V, and its branches provide the primary sensory innervation to the TMJ. Our clinical work suggests that the auriculotemporal (AT) nerve, a branch of the mandibular nerve, the largest of the three divisions of the trigeminal nerve, plays a critical role in TMD sequelae. The AT nerve provides the somatosensory fibers that supply the joint, the middle ear, and the temporal region. By projecting fibers toward the otic ganglion, the AT nerve establishes an important bridge to the sympathetic system. As it courses posteriorly to the condylar head of the TMJ, compression, injury or irritation of the AT nerve can lead to significant neurologic and neuro-muscular disorders, including Tourette's syndrome,Torticolli, gait or balance disorders and Parkinson's disease. Here, we propose that a proteomic signature of TMD can be obtained by assessing certain biomarkers in local (e.g., synovial fluid at the joint) and distal body fluids (e.g., saliva, cerebrospinal fluid), which can aid TMD diagnosis and prognosis.