Michel Kliot

Assessing disease onset and progression in the SOD1 mouse model of ALS.

&NA; SOD1 transgenic mice are the most widely used animal model of amyotrophic lateral sclerosis (ALS). In addition to providing valuable insights into the pathogenesis of ALS, these animals are used intensively in many laboratories as an in vivomodel for investigating novel therapeutic interventions towards this devastating motorneuron disease. Such pre‐clinical studies require objective and reliable quantification of the clinical phenotype of individual mice, most importantly of the neuromuscular abnormalities. Here we compare four parameters of the clinical phenotype: motor signs, body weight, rotarod performance and paw grip endurance for their usefulness in monitoring the SOD1 mouse model. We found that paw grip endurance is a sensitive and inexpensive alternative to the widely used rotarod test.

Magnetic Resonance Imaging Signal Changes in Denervated Muscles after Peripheral Nerve Injury

The evaluation of peripheral nerve disorders has traditionally relied on a clinical history, physical examination, and electrodiagnostic studies. Recent studies have used magnetic resonance imaging (MRI) to evaluate a variety of both nerve and muscle disorders. In this article, we describe the use of MRI, using short-tau inversion recovery (STIR) sequences, to evaluate muscle signal characteristics in a variety of peripheral nerve disorders. A total of 32 patients were studied, and 12 representative cases are discussed in detail. Increased STIR signal in muscle was seen in cases of severe axonotmetic injuries involving the transection of axons producing severe denervation changes on electromyography. The increased STIR signal in denervated muscles was seen as early as 4 days after the onset of clinical symptoms, which is significantly earlier than changes detected on electromyography. The MRI signal changes were reversible when the recovery of motor function occurred as a result of further muscle innervation. In cases of neurapraxic nerve injuries, characterized by conduction block without axonal loss, the STIR signal in muscle was normal. These findings show that MRI using STIR sequences provides a panoramic visual representation of denervated muscles useful in localizing and grading the severity of peripheral nerve injury secondary to either disease or trauma. MRI using STIR sequences may therefore play an important role in the prediction of clinical outcome and the formulation of appropriate therapy early after peripheral nerve injury.

Differential Macrophage Responses in the Peripheral and Central Nervous System during Wallerian Degeneration of Axons

We characterized quantitatively the macrophage response following axonal injury in both the peripheral (PNS) and central nervous system (CNS) of adult mammals. A monoclonal antibody (ED-1) which stains monocytes, macrophages, and activated microglia was employed. In one model, Wallerian degeneration of the sciatic nerve was studied. An increase in the number of macrophages was seen as early as 1 day following nerve transection. Macrophage number increased synchronously along the length of degenerating nerve over a 21-day period. In a second model, transection of a spinal dorsal sensory root allowed us to compare and contrast the macrophage response along the PNS and CNS portions of a single axonal pathway. An increased number of macrophages restricted to the PNS portion of this pathway was seen by 3 days and continued to increase over a 14-day period. Myelin breakdown occurred in association with an increase in the number of macrophages by 3 days in the PNS but not the CNS portion of the degenerating dorsal root axon pathway. Low-affinity nerve growth factor receptor immunohistochemical staining increased by Day 1 in the PNS but not the CNS portion of this pathway, occurring prior to the invasion of macrophages. In both models, the morphology of infiltrating macrophages changed over time from small slender ramified cells to large elongated multivacuolated cells. In conclusion, our results demonstrate that the macrophage response during Wallerian degeneration of axons in adult mammals is much more rapid and robust in the PNS, where axonal regeneration occurs, than in the CNS, where axonal regeneration is far more limited.

Ulnar nerve entrapment at the elbow: Correlation of magnetic resonance imaging, clinical, electrodiagnostic, and intraoperative findings

The diagnosis of ulnar nerve entrapment at the elbow has relied primarily on clinical and electrodiagnostic findings. Recently, magnetic resonance imaging (MRI) has been used in the evaluation of peripheral nerve entrapment disorders to document signal and configuration changes in nerves. We performed a prospective study on a population of 31 elbows in 27 patients with ulnar nerve entrapment at the elbow. The study correlated MRI findings with clinical, electrodiagnostic, and operative findings. A control population consisting of 10 asymptomatic subjects also was studied by MRI. Electrodiagnostic evaluation confirmed ulnar neuropathy in 24 (77%) elbows of the 31, with localization to the elbow region in 21 (68%). MRI, using a short tau inversion recovery sequence, demonstrated increased signal of the ulnar nerve in 30 (97%) elbows of the 31 and enlargement of the ulnar nerve in 23 (74%). No MRI abnormalities were found in the control population. MRI signal increase of the ulnar nerve occurred an average of 27 mm proximal to the distal humerus and extended distally an average of 4 mm below the distal humerus. The mean total length of increased ulnar nerve signal was 34 mm. Ulnar nerve enlargement occurred an average of 19 mm proximal to the distal humerus and extended distally an average of 8 mm above the distal humerus. The mean total length of ulnar nerve enlargement was 12 mm. The 12 patients who underwent a surgical procedure for ulnar nerve entrapment were found to have ulnar nerve compression, with 9 (75%) having excellent and 3 (25%) having good postoperative results. In this study, MRI was both sensitive and specific in diagnosing ulnar nerve entrapment at the elbow as defined by clinical, electrodiagnostic, and operative findings.

The utility of magnetic resonance imaging in evaluating peripheral nerve disorders

The evaluation of peripheral nerve injuries has traditionally relied primarily on information gained from the clinical history, physical examination, and electrodiagnostic testing. Taken together, all of this clinical and diagnostic information often allows one to determine the location and severity of the underlying peripheral nerve problem. However, it may not be sufficient in diagnosing a focal entrapment neuropathy superimposed upon a more generalized peripheral neuropathy; localizing a focal lesion along a long segment of nerve which may be difficult to assess accurately with electrodiagnostic sutdies; distinguishing early between an axonotmetic grade of injury, which can recover through axonal regeneration, and a neurotmetic grade which cannot and therefore may benefit from a surgical exploration and repair procedure; and noninvasively diagnosing and determining the surgical resectability of peripheral nerve mass lesions such as tumors. The goal of this review is to illustrate how standard and evolving magnetic resonance imaging techniques can provide additional information in dealing with some of these problems.

MR nerve imaging in a prospective cohort of patients with suspected carpal tunnel syndrome

Objectives To evaluate the reliability and diagnostic accuracy of high-resolution MRI of the median nerve in a prospectively assembled cohort of subjects with clinically suspected carpal tunnel syndrome (CTS). Methods The authors prospectively identified 120 subjects with clinically suspected CTS from five Seattle-area clinics. All subjects completed a hand-pain diagram and underwent a standardized nerve conduction study (NCS). The reference standard for determining CTS status was a classic or probable hand pain diagram and NCS with a difference >0.3 ms between the 8-cm median and ulnar peak latencies. Readers graded multiple imaging parameters of the MRI on four-point scales. The authors also performed quantitative measurements of both the median nerve and carpal tunnel cross-sectional areas. NCS and MRI were interpreted without knowledge of the other study or the hand pain diagram. Results Intrareader reliability was substantial to near perfect (kappa = 0.76 to 0.88). Interreader agreement was lower but still substantial (kappa = 0.60 to 0.67). Sensitivity of MRI was greatest for the overall impression of the images (96%) followed by increased median nerve signal (91%); however, specificities were low (33 to 38%). The length of abnormal signal on T2-weighted images was significantly correlated with nerve conduction latency, and median nerve area was larger at the distal radioulnar joint (15.8 vs 11.8 mm2) in patients with CTS. A logistic regression model combining these two MR variables had a receiver operating characteristic area under the curve of 0.85. Conclusions The reliability of MRI is high but the diagnostic accuracy is only moderate compared with a research-definition reference standard.

Surgery versus non-surgical therapy for carpal tunnel syndrome: a randomised parallel-group trial

BACKGROUND A previous randomised controlled trial reported greater efficacy of surgery than of splinting for patients with carpal tunnel syndrome. Our aim was to compare surgical versus multi-modality, non-surgical treatment for patients with carpal tunnel syndrome without denervation. We hypothesised that surgery would result in improved functional and symptom outcomes. METHODS In this parallel-group randomised controlled trial, we randomly assigned 116 patients from eight academic and private practice centres, using computer-generated random allocation stratified by site, to carpal tunnel surgery (n=57) or to a well-defined, non-surgical treatment (including hand therapy and ultrasound; n=59). The primary outcome was hand function measured by the Carpal Tunnel Syndrome Assessment Questionnaire (CTSAQ) at 12 months assessed by research personnel unaware of group assignment. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00032227. FINDINGS 44 (77%) patients assigned to surgery underwent surgery. At 12 months, 101 (87%) completed follow-up and were analysed (49 of 57 assigned to surgery and 52 of 59 assigned to non-surgical treatment). Analyses showed a significant 12-month adjusted advantage for surgery in function (CTSAQ function score: Delta -0.40, 95% CI 0.11-0.70, p=0.0081) and symptoms (CTSAQ symptom score: 0.34, 0.02-0.65, p=0.0357). There were no clinically important adverse events and no surgical complications. INTERPRETATION Symptoms in both groups improved, but surgical treatment led to better outcome than did non-surgical treatment. However, the clinical relevance of this difference was modest. Overall, our study confirms that surgery is useful for patients with carpal tunnel syndrome without denervation. FUNDING NIH/NIAMS 5P60AR048093 and the Intramural Research Program of the NIH Clinical Center.

Complement Depletion Reduces Macrophage Infiltration and Activation during Wallerian Degeneration and Axonal Regeneration

After peripheral nerve injury, macrophages infiltrate the degenerating nerve and participate in the removal of myelin and axonal debris, in Schwann cell proliferation, and in axonal regeneration.In vitro studies have demonstrated the role serum complement plays in both macrophage invasion and activation during Wallerian degeneration of peripheral nerve. To determine its rolein vivo, we depleted serum complement for 1 week in adult Lewis rats, using intravenously administered cobra venom factor. At 1 d after complement depletion the right sciatic nerve was crushed, and the animals were sacrificed 4 and 7 d later. Macrophage identification with ED-1 and CD11a monoclonal antibodies revealed a significant reduction in their recruitment into distal degenerating nerve in complement-depleted animals. Complement depletion also decreased macrophage activation, as indicated by their failure to become large and multivacuolated and their reduced capacity to clear myelin, which was evident at both light and electron microscopic levels. Axonal regeneration was delayed in complement-depleted animals. These findings support a role for serum complement in both the recruitment and activation of macrophages during peripheral nerve degeneration as well as a role for macrophages in promoting axonal regeneration.

Evaluation and surgical management of peripheral nerve problems.

OBJECTIVE To illustrate how an understanding of the basic biological responses of peripheral nerves to injury is important in formulating a rational treatment plan. METHODS Peripheral nerve anatomy and physiology are described in a context that is relevant to understanding the different grades of peripheral nerve injury. Methods of evaluating and treating peripheral nerve injuries both medically and surgically are reviewed. Relevant scientific studies with potential clinical impact are also discussed. RESULTS The clinical symptoms, physical findings, and electrodiagnostic and imaging test results relevant to the diagnosis of peripheral nerve problems are reviewed. Conventional and new medical or surgical strategies in the management of peripheral nerve injuries and mass lesions are described. CONCLUSION The diagnosis and treatment of peripheral nerve injuries follow logically from an understanding of the biological responses of peripheral nerves after injury and during recovery.

Astrocyte-polymer implants promote regeneration of dorsal root fibers into the adult mammalian spinal cord

To overcome obstacles to the regeneration of crushed dorsal root fibers at the dorsal root entry zone, we have employed specially designed Millipore implants coated with embryonic astrocytes to serve as a substrate for axonal growth. This strategy was successful in promoting the growth of crushed dorsal root axons into the grey matter of the adult mammalian spinal cord in a small number of animals. Fiber ingrowth into the spinal cord was closely associated with the surface of the polymer implant. In addition, unique terminal arbor malformations, not normally present, were seen in several animals. A consistent finding was the presence of a limited inflammatory response in regions immediately adjacent to the implant where axons penetrate the spinal cord. Our findings suggest that providing the dorsal root entry zone with an embryonic milieu can stimulate a limited amount of axonal regeneration into the adult mammalian spinal cord.