Peripheral Nervous System Lesions Research Articles

Cervical dystonia: Etiology and pathophysiology

Etiological and pathophysiological aspects of cervical dystonia Dystonias present in many different ways and can vary widely in the number of body areas and systems involved, as well as in clinical features, age of onset, natural history, and etiology. Cervical dystonia (CD) may be isolated or a part of more complex dystonias, be they primary or secondary. The majority of CDs are primary and focal, that is, they have no other associated clinical or neuroimaging features and they remain restricted to the neck and shoulder girdle muscles. Secondary CD can be drug induced or caused by a peripheral or central nervous system (CNS) lesion or genetic metabolic defects. We will provide an overview of data derived from genetic, posttraumatic, and tardive etiologies of CD. This will be followed by a more in-depth discussion of potential loci of pathological changes within the CNS and discussion of the motor and sensory features that result will follow. The evidence presented will focus on studies of CD and will be complemented with studies from other dystonias. For an expanded discussion of the epidemiology, clinical presentation, and classification of CD, see Dr. Stacy's article in this supplement.

Differential astroglial responses in the spinal cord of rats submitted to a sciatic nerve double crush treated with local injection of cultured Schwann cell suspension or lesioned spinal cord extract: implications on cell therapy for nerve repair

Reactive astrocytes are implicated in several mechanisms after central or peripheral nervous system lesion, including neuroprotection, neuronal sprouting, neurotransmission and neuropathic pain. Schwann cells (SC), a peripheral glia, also react after nerve lesion favoring wound/repair, fiber outgrowth and neuronal regeneration. We investigated herein whether cell therapy for repair of lesioned sciatic nerve may change the pattern of astroglial activation in the spinal cord ventral or dorsal horn of the rat. Injections of a cultured SC suspension or a lesioned spinal cord homogenized extract were made in a reservoir promoted by a contiguous double crush of the rat sciatic nerve. Local injection of phosphate buffered saline (PBS) served as control. One week later, rats were euthanized and spinal cord astrocytes were labeled by immunohistochemistry and quantified by means of quantitative image analysis. In the ipsilateral ventral horn, slight astroglial activations were seen after PBS or SC injections, however, a substantial activation was achieved after cord extract injection in the sciatic nerve reservoir. Moreover, SC suspension and cord extract injections were able to promote astroglial reaction in the spinal cord dorsal horn bilaterally. Spinal cord astrocytes react according to repair processes of axotomized nerve, which may influence the functional outcome. The event should be considered during the neurosurgery strategies.

Pharmacokinetics of eugenol and its effects on thermal hypersensitivity in rats

Neuropathic pain is a type of chronic pain following central or peripheral nervous system lesions that cause allodynia (pain initiated by a non-painful stimulus) and hyperalgesia (increased pain sensation following a painful stimulus). The first objective of the study was to evaluate the pharmacokinetics of eugenol, the principle chemical constituent of clove oil, following a gavage administration (40 mg/kg) in male Sprague–Dawley rats. The second objective was to evaluate the effect of repeated oral administrations of eugenol on hyperalgesia and allodynia using an experimental model of neuropathic pain in rats. Thermal and mechanical sensitivity (Hargreave's test and von Frey filaments) were determined in sciatic nerve cuff-implanted rats. Sensitivities were assessed following repeated oral administrations of 40 mg/kg of eugenol or saline for 5 days ( n = 6 per group). Pharmacokinetic parameters were calculated using noncompartmental methods. Serial blood samples were collected over 24 h. Concentrations of eugenol in blood and plasma peaked rapidly following oral administration. Mean T 1/2 values of eugenol in plasma and blood were long (14.0 and 18.3 h, respectively), suggesting a potential accumulation of the drug following repeated administrations. Reaction time to thermal stimuli appeared to increase constantly following repeated administrations of eugenol. On the last day of treatment, eugenol treatments resulted in a statistically significant prolongation of the reaction time to thermal stimuli in rats compared to the saline group (Mean ± S.E.M.: 11.4 ± 1.23 vs. 6.1 ± 0.53 s, P < 0.01). These results support the hypothesis that eugenol may alleviate neuropathic pain and that the cumulative effect of the drug may be in part responsible for this effect following repeated daily administrations.

Peripheral nervous system lesion syndromes and the mechanisms of their formation in connective tissue diseases

Systemic rheumatological diseases are often accompanied by the development of central and peripheral nervous system pathology. Data providing evidence of the high incidence of peripheral nervous system lesions in systemic lupus erythematosus and systemic scleroderma are presented. These diseases in particular are characterized by polyneuropathies and tunnel syndromes. Our own observations, along with published data, revealed the following major pathogenetic mechanisms of peripheral nervous system lesions in diffuse connective tissue diseases - ischemic, immunological, and metabolic. Consideration of these mechanisms will lead to pathogenetically based treatment and improved therapeutic outcomes.

Clinical Decision Making and Oral Motor Treatments

Clinical Decision Making and Oral Motor Treatments

Damage of cutaneous peripheral nervous system evolves differently according to the disease phase and subset of systemic sclerosis

Evidence shows that peripheral nervous system (PNS) is involved in systemic sclerosis (SSc), but few morphological studies have assessed the ultrastructural pathological modifications. The aim was to study ultrastructural modifications of skin PNS fibres in SSc according to subsets [limited SSc (lSSc) and diffuse SSc (dSSc)] and phases (early and advanced) of the disease. Skin biopsies were taken from the forearms of 23 SSc patients (11 lSSc and 12 dSSc) and 10 controls. Each biopsy was processed for transmission electron microscopy (TEM). At TEM, observation in skin from early lSSc, signs of inflammation were evident, while PNS fibres were not damaged. The microvascular wall showed hypertrophic endothelial cells bulging into the lumen. In advanced lSSc, fibrosis prevailed on inflammation and slight ultrastructural alterations of PNS fibres were evident in the papillary derma. In early dSSc, ultrastructural alterations of PNS fibres, similar to those observed in the advanced phase of lSSc, were found together with signs of inflammation and fibrosis. In advanced dSSc, in the papillary and reticular dermis PNS fibres were reduced and showed relevant ultrastructural alterations. In SSc, PNS ultrastructure damage is linked to the progression and severity of skin involvement. The alterations evolve from the early to the advanced phase mainly in the diffuse subset. In particular, the severe PNS lesions found in advanced lSSc are already present and widely diffuse in early dSSc and the microvascular involvement in early lSSc seems to precede the modification of the PNS in the skin. Thus, an early therapeutic approach can be useful to reduce the progression of PNS and skin damage in SSc patients.

Critical reappraisal of referrals to electromyography and nerve conduction studies*

A large number of examinees referred to electromyographic (EMG) laboratories do not have symptoms or signs suggestive of a peripheral nervous system disorder, and the aim of the present study was to check this. All examinees evaluated by the author in a "general" EMG laboratory in the first 4 months of 2002 were included. Data on examinees, referral physicians and diagnoses, clinical symptoms and signs, and electrodiagnostic findings were statistically evaluated. Three hundred examinees, 42% men, were included. A neurological diagnosis was provided in 55% of referrals. Electrodiagnostic abnormalities were found in 45% of examinees. Using multivariate statistics, a positive effect of neurological referral diagnosis, history of paraesthesias and of weakness and sensory loss on examination, and a negative effect of history of pain on pathological electrodiagnostic findings were found. Except 20 patients with carpal tunnel syndrome, no patient with normal clinical examination had abnormal electrodiagnostic findings. Our study confirmed the inappropriateness of referrals to electrodiagnostic examination to screen patients for peripheral nervous disorders. We propose electrodiagnostic examination mainly of patients with unequivocal clinical signs of a peripheral nervous system lesion and of patients with typical symptoms of the carpal tunnel syndrome.

Occupational and sport related traumatic neuropathy.

Sport and occupation related traumatic nerve injury is a common problem in the United States. While the physical requirements of each pursuit place participants at risk for injury to certain peripheral nervous system structures, the vast numbers of professional and recreational pursuits limits the ability to become familiar with nerve injuries specific to each. A more pragmatic approach is to apply knowledge of mechanisms of injury, physiology of nerve injury, regional anatomy, and at-risk peripheral nervous system structures to the routine neurologic history and physical assessment to arrive at a localizing and etiologic diagnosis. The authors discuss potential mechanisms of nerve injury, the role of electrodiagnostic testing, regional peripheral nervous system anatomic considerations and lesion localization. Despite the wide variety of professionally and recreationally induced peripheral nerve injuries, application of anatomic, physiologic and mechanistic considerations allow the neurologist to make an etiologic and localizing diagnosis.

Neurofisiologia e plasticidade no córtex cerebral pela estimulação magnética transcraniana repetitiva

Um velho dogma da biologia afirma que só existiria capacidade de reorganização cortical (neuroplasticidade) em animais muito jovens; no adulto, tal capacidade seria pequena ou mesmo inexistente. Aqui, revisamos estudos realizados em animais e em humanos que demonstram uma capacidade de reorganização cortical nos sistemas sensoriais e motores em indivíduos adultos. Destacamos os estudos realizados com a técnica de estimulação magnética transcraniana. O córtex cerebral asulto é capaz de reorganização após lesões do sistema nervoso periférico ou central ou no contexto do aprendizado.

Purification of Schwann cells by selection of p75 low affinity nerve growth factor receptor expressing cells from adult peripheral nerve

The intrinsic capacity of Schwann cells to promote regeneration after limited peripheral nerve lesions has been successfully transferred to extensive peripheral nerve injuries and central nervous system lesions by autologous transplantation strategies. However, both the intrinsic ability of axotomized neurons to regenerate and the permissiveness of the parenchyma surrounding the acute injury site diminish over time. Therefore, the autologous transplantation mode requires a fast and effective method to isolate Schwann cells from peripheral nerve biopsies. Here, we report a method to purify p75 low affinity nerve growth factor receptor (p75LNGFr) expressing Schwann cells from peripheral nerve biopsies in adult rats using magnetic-activated cell separation (MACS). After 1 week of nerve degeneration in culture, nerve fragments were dissociated resulting in mixed cultures containing Schwann cells and fibroblasts. After incubation with specific anti-p75LNGFr antibodies and secondary magnetic bead conjugated antibodies followed by one cycle of MACS, 95% pure Schwann cell cultures were generated as confirmed by flow-cytometry and immunocytochemistry. In contrast to established methods, MACS separation of p75LNGFr expressing cells allows the reliable purification of Schwann cells within 9 days after biopsy employing direct selection of Schwann cells rather than fibroblast depletion assays. Therefore, this method represents an effective and fast means to generate autologous Schwann cells for clinical transplantation strategies aiming for axon repair and remyelination.

Tissue culture methods to study neurological disorders: establishment of immortalized Schwann cells from murine disease models.

Previously, the authors have established spontaneously immortalized cell lines from long-term cultures of normal adult mouse Schwann cells. Establishment of such Schwann cell lines derived from murine disease models may greatly facilitate studies of the cellular mechanisms of their peripheral nervous system lesions in the relevant diseases. Recently, the authors have established immortalized Schwann cell lines derived from Niemann-Pick disease type C mice (NPC; spm/spm) and globoid cell leukodystrophy mice (twitcher). In the present study, long-term cultures were maintained of Schwann cells derived from dorsal root ganglia and consecutive peripheral nerves of another NPC mouse (npc(nih)/npc(nih), npc(nih)/+), myelin P0 protein-deficient mice (P0-/-, P0+/-) with their wild-type littermates (P0+/+), and neurofibromatosis type 1 gene (NF1)-deficient mice (Nf1(FCr)/+) for 8-10 months, and immortalized cell lines from all these animals established spontaneously. These cell lines had spindle-shaped Schwann cell morphology and distinct Schwann cell phenotypes and retained genomic and biochemical abnormalities, sufficiently representing the in vivo pathological features of the mutant mice. These immortalized Schwann cell lines can be useful in studies of nervous system lesions in these mutant mice and relevant human disorders.

Changes of non-affected upper limb cortical representation in paraplegic patients as assessed by fMRI.

Peripheral and central nervous system lesions can induce reorganization within central somatosensory and motor body representations. We report changes in brain activation patterns during movements of non-affected body parts in paraplegic patients with spinal cord injury (SCI). Nine SCI patients and 12 healthy controls underwent blood oxygen level dependent signal functional MRI during sequential finger-to-thumb opposition, flexion and extension of wrist and of elbow, and horizontal movements of the tongue. Single subject and group analyses were performed, and the activation volumes, maximum t values and centres of gravity were calculated. The somatotopical upper limb and tongue representations in the contralateral primary motor cortex (M1) in the SCI patients were preserved without any shift of activation towards the deefferented and deafferented M1 foot area. During finger movements, however, the SCI patients showed an increased volume in M1 activation. Increased activation was also found in non-primary motor and parietal areas, as well as in the cerebellum during movements of the fingers, wrist and elbow, whereas no changes were present during tongue movements. These results document that, in paraplegic patients, the representation of the non-impaired upper limb muscles is modified, though without any topographical reorganization in M1. The extensive changes in primary and non-primary motor areas, and in subcortical regions demonstrate that even distant neuronal damage has impact upon the activation of the whole sensorimotor system.

Osteopontin: a novel axon-regulated Schwann cell gene.

Osteopontin (OPN) is a RGD-containing glycoprotein with cytokine-like, chemotactic, and pro-adhesive properties. During wound healing, OPN is abundantly expressed by infiltrating macrophages and has been implicated in posttraumatic tissue repair. To delineate a role in the regenerative response to axotomy we examined the expression of OPN in Wallerian degeneration of the sciatic nerve in rats. Unexpectedly, we found high constitutive expression of OPN by myelinating Schwann cells (SCs) in uninjured control nerves. OPN mRNA expression was confirmed in primary cultures of rat SCs. Upon axotomy, SC-expressed OPN in the degenerating distal nerve stump transiently increased during the first days after injury, but was continuously downregulated thereafter, reaching its minimum at Day 14. Macrophages invading axotomized nerves were OPN-negative. During late stages after axotomy, SC-OPN was reexpressed in regenerating but not permanently transected nerves. We also found OPN expression by myelinating SCs in human sural nerves with a dramatic reduction in severe axonal polyneuropathies. Taken together, our study identifies OPN as a novel Schwann cell gene regulated by axon-derived signals. The lack of OPN induction in infiltrating macrophages indicates fundamental differences in tissue repair between axonal injury in the peripheral nervous system and structural lesions in other organ systems.

Median nerve somatosensory evoked potentials recorded with cephalic and noncephalic references in central and peripheral nervous system lesions.

Somatosensory evoked potentials (SSEP) to electrical stimulation of the median nerve by using cephalic and noncephalic references were studied to detect the generator sources of short latency evoked potentials in 29 patients with cerebral, brainstem, spinal and peripheral nerve lesions. Patients were divided into six groups according to the localization of their lesions: group 1: cortical and subcortical lesions, group 2: basal ganglion lesions, group 3: pons and mesencephalon lesions, group 4: diffuse cerebral lesions, group 5: cervical cord lesions, group 6: brachial plexus lesions. Potentials were recorded using cephalic and noncephalic references after median nerve stimulation. Evidence obtained from patients suggested the following origins for these short latency SSEPs: P9 may arise in brachial plexus, P11 in dorsal basal ganglions or dorsal column, P13 and P14 in the nucleus cuneatus and lemniscal pathways, N16 in subthalamic structures and most likely mid and lower pons, N18 from the thalamus and thalamocortical tract, and N20 from primary somatosensory cortex.

What Is the Cell Death Mechanism in Vasculitic Neuropathy

Patients with systemic infectious or immune-mediated vasculitis may develop peripheral nervous system (PNS) lesions along with involvement of other

Pain-Related somatosensory evoked potentials.

The authors reviewed basic and clinical reports of pain-related somatosensory evoked potentials (SSEP) after high-intensity electrical stimulation [pain SSEP(E)] and painful laser stimulation [pain SSEP(L)]. The conduction velocity of peripheral nerves for both pain SSEP(E) and pain SSEP(L) is approximately 10 to 15 m/second, in a range of Adelta fibers. The generator sources are considered to be the secondary somatosensory cortex and insula, and the limbic system, including the cingulate cortex, amygdala, or hippocampus of the bilateral hemispheres. The latencies and amplitudes are clearly affected by vigilance, attention-distraction, and various kinds of stimulation applied simultaneously with pain. Abnormalities of pain SSEP(L) reflect an impairment of pain-temperature sensation, probably relating to dysfunction of A5 fibers of the peripheral nerve and spinothalamic tract. In contrast, conventional SSEP after nonpainful electrical stimulation reflects an impairment of tactile, vibratory, and deep sensation, probably relating to dysfunction of Aalpha or Abeta fibers of the peripheral nerve and dorsal column. Therefore, combining the study of pain SSEP(L) and conventional SSEP is useful to detect physiologic abnormalities, and sometimes subclinical abnormalities, of patients with peripheral and central nervous system lesions.

DISTURBANCE OF VIBRATION SENSITIVITY DURING RHEUMATOID ARTHRITIS. CLINICAL ASPECTS

Summary Aim of study: To study the vibration sensitivity (VS) in rheumatoid arthritis (RA) depending on the clinical peculiarities of the disease. Material and methods: The study included 67pts (M:F=7:60) with reliable RA (ARA criteria, 1987). 55 out of 67 pts were positive on rheumatoid factor (RF), 20 pts had the 1st stage of activity, 32 - 2nd, 15 - 3d, corticosteroids were taken by 21 pts. Study of vibration sensitivity was done by electronic biotensiometer (EG Electronic, USA) in three points of lower extremities: dorsal foot surface, front al crural surface in the area of tibia bone crest in medial tertiary> level, knee calycle. Results: Frequency of VS disturbance was measured in parallel with clinical and laboratory indices and was in case of the 1st stage of activity 40%, in 2nd - 75% and in 3d - 93.3%. It was found that VS changing in great majority of cases allows to diagnose the lesion of peripheral nervous system as compared with other clinical changes. Assessing VS dynamics in the course of the therapy on the clinical stage and using NSAIDs and intraarticular injections of corticosteroids was not accompanied by the reliable dynamics of the index understudy. Clinical improvement of articular syndrome and disappearing of systemic manifestations was not associated with the improvement of VS indices. Conclusion: VS disturbance in RA pts is associated with the stage of activity and severity of the disease. Association of VS disturbance with systemic manifestations enables us to study VS in RA as an additional diagnostical test of revealing of systemic symptoms.

Intraoperative Diagnosis of Nervous System Lesions

To determine the accuracy of comparative cytologic and frozen section intraoperative diagnosis in neuropathology and the relevance of diagnostic accuracy during both craniotomic and stereotactic biopsies and to provide further data on rare and/or diagnostically controversial lesions. Both cytologic and frozen section preparations were employed in the intraoperative diagnosis of 85 consecutive central and peripheral nervous system lesions obtained from classical surgery (70 samples, 4 of which were intramedullary) and stereotactic biopsies (15 samples). Combining cytologic and frozen section details allowed a fair diagnosis in 81 cases (95.29%), confirmed on paraffin sections. In the remaining cases intraoperative misdiagnosis was due to technical-staining defects (1 case); absence of tumor differentiation, resolved only by ultrastructural examination (2 cases); and marked tumor heterogeneity, resolved by wide tissue sampling and immunohistochemistry (1 case). Besides providing a general description of cytologic and frozen section criteria useful in intraoperative diagnostic neuropathology and adding further details about some problematic and/or rare entities, our work confirmed: (1) the usefulness of comparative cytologic and frozen section examination in the intraoperative diagnosis of central nervous system lesions, (2) the relevance of the accuracy of intraoperative diagnosis during both craniotomy and stereotaxis, including intramedullary samples; and (3) the importance of fair "conduct" in intraoperative neuropathology, always comparatively considering morphologic and clinicoradiologic data.

C-Jun expression in adult rat dorsal root ganglion neurons: differential response after central or peripheral axotomy.

The response of the mature central nervous system (CNS) to injury differs significantly from the response of the peripheral nervous system (PNS). Axotomized PNS neurons generally regenerate following injury, while CNS neurons do not. The mechanisms that are responsible for these differences are not completely known, but both intrinsic neuronal and extrinsic environmental influences are likely to contribute to regenerative success or failure. One intrinsic factor that may contribute to successful axonal regeneration is the induction of specific genes in the injured neurons. In the present study, we have evaluated the hypothesis that expression of the immediate early gene c-jun is involved in a successful regenerative response. We have compared c-Jun expression in dorsal root ganglion (DRG) neurons following central or peripheral axotomy. We prepared animals that received either a sciatic nerve (peripheral) lesion or a dorsal rhizotomy in combination with spinal cord hemisection (central lesion). In a third group of animals, several dorsal roots were placed into the hemisection site along with a fetal spinal cord transplant. This intervention has been demonstrated to promote regrowth of severed axons and provides a model to examine DRG neurons during regenerative growth after central lesion. Our results indicated that c-Jun was upregulated substantially in DRG neurons following a peripheral axotomy, but following a central axotomy, only 18% of the neurons expressed c-Jun. Following dorsal rhizotomy and transplantation, however, c-Jun expression was upregulated dramatically; under those experimental conditions, 63% of the DRG neurons were c-Jun-positive. These data indicate that c-Jun expression may be related to successful regenerative growth following both PNS and CNS lesions.

Diagnostic significance of electroneuromyographic (enmg) indices in diphtheria polyneuropathy

There studied changes of electroneuiomyographical indices for evaluation of incidence and dynamics of lesion of peripheral nervous system during diphtheria. For this purpose 37 patients with diphtheria polyneuropathy at the age of 214 years at different terms of disease were examined. It was shown that during diphtheria most often the nerves of lower extremities are damaged: fibular and tibial. Information of ENMG indices of the latter is more significant. For revealing the initial symptoms of the nervous system lesion it is useful to investigate the state of myelinization of proximal parts of peripheral nerves according to F-wave latency.