Sports Related Neuromuscular Disorders

Anthony E. Chiodo, MD Lawrence W. Frank, MD Andrew H. Dubin, MD, MS Francis P. Lagattuta, MD

2008 COURSE G AANEM 55th Annual Meeting Providence, Rhode Island

Copyright © September 2008 American Association of Neuromuscular & Electrodiagnostic Medicine 2621 Superior Drive NW Rochester, MN 55901 Printed by Johnson Printing Company, Inc. ii iii iii Sports Related Neuromuscular Disorders

Faculty

Anthony E. Chiodo, MD Andrew H. Dubin, MD,MS Associate Professor Associate Professor Department of Physical Medicine and Rehabilitation Albany Medical Center Hospital Director of Spinal Cord Injury Medicine Department of Physical Medicine and Rehabilitation University of Michigan Medical Center Albany, New York Ann Arbor, Michigan Dr. Dubin is currently an associate professor of physical medicine and After completing his medical school training in his home state at the rehabilitation at Albany Medical College. He received his medical degree University of Connecticut Health Center, Dr. Chiodo started his physi- from Albany Medical College, and completed his residency at Thomas atric career at the University of Michigan Hospital where he completed Jefferson University Hospital in Philadelphia. He is board certified by his residency and neuromuscular fellowship. He had a private prac- the American Board of Physical Medicine and Rehabilitation and the tice in Pediatric Rehabilitation at Methodist Hospital in Indianapolis American Board of Electrodiagnostic Medicine. His particular interests and was Medical Director of Physical Medicine and Rehabilitation in include the areas of spasticity and treatment of neuropathic pain. Farmington, New Mexico on the border of the Navajo reservation. Dr. Chiodo returned to the University of Michigan in 1998. His academic areas of interest include anatomic localization in electromyography, Francis P. Lagattuta, MD lumbosacral plexopathy after pelvic trauma, and clinical electrodiagnostics. Director He is board certified in pain medicine and spinal cord injury, applying his LAGS Spine and Sportscare research emphasis in electrodiagnostics to those areas of specialty as well. Santa Maria, California He has continued his work in the care for the disabled in underserved areas that he started in New Mexico by working on sustainable medical Dr. Lagattuta is one of the pioneer pain interventionalists. He is board rehabilitation program development in Ghana, West Africa. certified in pain medicine, physical medicine and rehabilitation, and electrodiagnostic medicine. He originally had a practice in Chicago and was involved in sports medicine serving as the team doctor for the Naperville Lawrence W. Frank, MD and Wheaton high schools, and the Chicago Bulls. He now has his offices in Santa Barbara, Santa Maria, Atascadero, and Lompoc, California with a Assistant Professor surgical center in Santa Maria. He is the Current Procedural Terminology Department of Physical Medicine and Rehabilitation (CPT) representative for the American Academy of Physical Medicine and Department of Neurological Surgery Rehabilitation (AAPMR) from 2004 to present. He was the CPT repre- Rush Medical College sentative for the North American Spine Society (NASS) from 2000-2004. Chicago, Illinois Dr. Lagattuta has been a board member for the American Association Dr. Frank received his BS in Electrical Engineering from the University of Neuromuscular and Electrodiagnostic Medicine (AANEM) and the of Illinois in Urbana-Champaign and his medical degree from the Physiatrist Association of Spine, Sports Medicine, and Occupational University of Illinois at Chicago. He completed his residency in Physical Medicine in addition to serving on multiple committees for AANEM, Medicine and Rehabilitation at the Rehabilitation Institute of Chicago AAPMR, and NASS. He has written numerous articles and given many at Northwestern University followed by a fellowship in Spine and Sports national presentations. Medicine at Illinois Spine and SportsCare in Bloomingdale, IL. Dr. Frank is the founder and medical director of Spine & Sports Physiatrists in Elmhurst, IL. He has extensive sports medicine experience including team physician positions with high school athletic teams, the Chicago Fire Professional Soccer Club and the FIFA Women’s World Cup. He is a guest examiner for the American Board of Physical Medicine and Rehabilitation and the American Board of Electrodiagnostic Medicine. He is Past- President of the Illinois Society of Physical Medicine and Rehabilitation and has served as a board member of the Physiatric Association of Spine Sports and Occupational Rehabilitation.

Authors had nothing to disclose.

Course Chair: Anthony E. Chiodo, MD

The ideas and opinions expressed in this publication are solely those of the specific authors and do not necessarily represent those of the AANEM. iv Sports Related Neuromuscular Disorders

Please be aware that some of the medical devices or pharmaceuticals discussed in this handout may not be cleared by the FDA or cleared by the FDA for the specific use described by the authors and are “off-label” (i.e., a use not described on the product’s label). “Off-label” devices or pharmaceuticals may be used if, in the judgement of the treating physician, such use is medically indicated to treat a patient’s condition. Information regarding the FDA clearance status of a particular device or pharmaceutical may be obtained by reading the product’s package labeling, by contacting a sales representative or legal counsel of the manufacturer of the device or pharmaceutical, or by contacting the FDA at 1-800-638-2041. v Sports Related Neuromuscular Disorders

Contents

Faculty iii

Objectives v

Course Committee vi

Sciatica in Athletes 1 Anthony E. Chiodo, MD

Stingers and Burners 5 Lawrence W. Frank, MD

Upper Extremity Mononeuropathies 9 Andrew H. Dubin, MD, MS

Mononeuropathies of the Lower Extremities in Sports 15 Francis P. Lagattuta, MD

CME Activity and Faculty Evaluation 25

O b j e c t i v e s —After attending this session, participants will be able to (1) list the diagnoses associated with the presentation of sciatica in athletes, (2) distinguish on-the-field clinical characteristics of cervical radiculopathy versus brachial plexopathy, (3) understand return-to-play criteria for burner - stinger injuries, (4) formulate a differential diagnosis for nerve injuries from sports, (5) formulate an electrodiagnostic test to determine the exact nerve injury, and (6) prescribe a treatment program for the specific nerve problem. P rerequisite —This course is designed as an educational opportunity for physicians. A c c r e d i t a t i o n St a t e m e n t —The AANEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. CME Cr e d i t —The AANEM is accredited by the ACCME to provide continuing medical education (CME) for physicians. The AANEM designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s) TM. Each physician should only claim credit commensurate with the extent of their participation in the activity. This event is an Accredited Group Learning Activity as defined by the Maintenance of Certification Program of The Royal College of Physicians and Surgeons of Canada. CME for this activity is available 9/08 - 9/11. vi

2007-2008 AANEM COURSE COMMITTEE Anthony E. Chiodo, MD, Chair Ann Arbor, Michigan

Shawn J. Bird, MD Erick A. Grana, MD Simon Zimnowodzki, MD Philadelphia, Pennsylvania Tampa, Florida Chicago, Illinois

Kevin B. Boylan, MD Thomas Y.C. Pang, MD Sasa Zivkovic, MD Jacksonville, Florida Chicago, Illinois Pittsburgh, Pennsylvania

Gary L. Branch, DO David Bryan Shuster, MD Owosso, Michigan Dayton, Ohio

2007-2008 AANEM PRESIDENT Peter D. Donofrio, MD Nashville, Tennessee 1

Sciatica in Athletes

Anthony E. Chiodo, MD Associate Professor Department of Physical Medicine and Rehabilitation Director of Spinal Cord Injury Medicine University of Michigan Medical Center Ann Arbor, Michigan

INTRODUCTION important role that the disc and vertebral body play in the stability of the trunk in all activities that put it at risk. Under normal Lumbar spine dysfunction among athletes presents a particular conditions, the intervertebral disc carries 80% to 85% of the challenge to the treating physician because these patients have a axial load, while the two facet joints collectively carry the remain- high-activity level and want a swift return to their sport. Traditional ing 15% to 20%. With forward flexion, the disc is placed at the treatment plans that include activity modification must consider load with the resultant torque created by the head and by objects the need for continued physical conditioning to sustain the athlete’s carried increasing intradiscal pressures as high as 7 times more conditioning results from months of previous sport-specific exercise. than in static standing. With spine extension, there is an increased Although the long-term outcome of treatment is important, a quick percentage of weight carried by the facet joints. Degeneration return to the athlete’s activity is critical. A quick return may or may of the discs or of the facet joints can result in changes in these not be the fastest path to the completion of treatment; shorter term percentages due to mechanical malalignment, pain avoidance, treatments that will return the athlete to activity and keep them going or instability.39 through the season may be preferred by the athlete to a definitive treatment plan that might require more lengthy activity restrictions. The timing of the injury with respect to the specific sport season will PRESENTATION be a critical factor in determining the type of treatment best suited to the athlete. The importance of returning the athlete to the activity, Changes in training methods or intensity, inflexibility, poor along with the sport and the athlete’s position, mean that each injury technique, or poor equipment can lead to undue stress and failure is unique and challenging to the treating physician, requiring expert of an athlete’s spine-disc unit.15 Torsional stresses and combined knowledge, keen understanding, and creativity. motions (i.e., forward flexion and rotation) are the most injurious.34 Because combined motions are commonly encountered in sports, The young athlete differs significantly from the adult athlete. Forty- the supporting structures (i.e., muscles and connective fascia) must eight percent of patients with back pain have discogenic pain. In be of sufficient strength to offset some of the forces on the spine or the adolescent and young adult athlete, 47% of patients present with the disc and facet joint complex will be vulnerable to injury. The stress fractures, and 25% present with hyperlordosis. These presenta- consequences of such injury include the potential for development of tions in young athletes may be due to several factors including the facet synovitis, breakdown of the annulus, and migration of nuclear high level of mechanical stress applied to the lumbar spine in athletes, material beyond the confines of the disc and surrounding ligaments the relatively lordotic lumbar spine seen especially in young women, leading to mechanical or chemical irritation of nerve roots or the the immaturity of the pars interarticularis, and the relative flexibility spinal cord. Kawakami demonstrated in a rat model that chromic of ligamentous structures including the annulus fibrosis. gut as a chemical irrigant caused hyperalgesia, not compression.19,20 This demonstrates that although spinal nerve compression may be However, sciatica occurs in the adolescent and young adult athlete the primary reason for motor loss, the presence of inflammation just as it does in the adult athlete. Normal anatomy indicates the might be the pathophysiology of pain.12,13 Similarly, an annular 2 Sciatica in Athletes AANEM Course sprain or annular tear without disc herniation might create a chemi- Differential Diagnosis cal environment where sciatica could occur. Myofascial pain with trigger points can cause referred pain that For example, a 22-year-old football running back presented with mimics sciatica. The use of trigger point injection with local a 9-month history of right buttock pain. He had dropped from anesthetic can clarify the diagnosis. In addition, trochanteric second to fifth on his position depth chart. Physical examina- bursitis can result in lateral hip and posterior thigh pain.31 tion revealed right L5 motor weakness in the hip, knee, and foot. Treatment would include ultrasound with myofascial treatment or Lumbar magnetic resonance imaging (MRI) scan revealed right intra-bursal steroid and local anesthetic injection. The facet joint L4 - L5 facet arthropathy with lateral recess stenosis and a right has been shown to cause limb pain. The mechanism of injury eccentric L5 - S1 disc herniation. Right L5 - S1 transforaminal could include referred pain in segments with similar innervation epidural injection and L4 - L5 facet block relieved his pain and or compression due to neuroforaminal stenosis, lateral recess improved his strength, allowing a return to rehabilitation. When stenosis, synovial cyst, or degenerative arthritis.11 Intra-articular injury to another player allowed him an opportunity to play in the injection can clarify the diagnosis, and result in effective treatment of third week of the season, he was the team’s most valuable player, synovitis or the synovial cyst. scoring two touchdowns in the victory. Referred pain from other sources including the sacroiliac (SI) joint Young athletes that have no spine degeneration, disc space narrow- may also occur.32 The pathophysiology is referred pain in the ing, facet hypertrophy, or ligamentous hypertrophy have a stable L5 - S4 distributions or lumbosacral plexus irritability.7 Additionally, segment with a wide open spinal canal. A small central or lateral disc SI joint hypo-mobility with sacral torsion can result in nerve herniation or protrusion might lead to fairly subtle symptoms rather root irritability due to rotation of the L5 - S1 segment, further than the classical signs and symptoms of disc herniation and sciatica irritated by the ballistic movements demanded by athletic training commonly seen in older adults. A 20-year-old gymnast presented and competition.7 Clinical testing of the SI joint has a low with bilateral lower extremity pain with uneven bar and floor exercise sensitivity and specificity. Radiological testing also has low sensitiv- routines. A normal neurological examination was noted. A lumbar ity and specificity. Although its validity is questioned, intra-articular MRI scan revealed a broad-based eccentric disc bulge at L5 - S1 with injection is an important diagnostic and therapeutic intervention. no stenosis. Caudal epidural injection relieved her symptoms and Intra-articular injection,23 medial branch blocks, and medial branch allowed her training and competition schedule to resume. radio frequency ablation38 are available treatment options

Athletes presenting with classic sciatica symptoms may not have Treatment a readily identifiable disc herniation that corresponds with the neuroanatomic level of their symptoms.16 This may be due to In a Cochrane review, there was no apparent benefit of bed rest complete annular tear without disc herniation, referred pain from over general activity.17 Early treatment with spine manipulation discogenic causes, or nerve root injury or dysfunction that occurs is not recommended. There is no proven efficacy for lumbar due to insult from ligament or annular trauma during a ballistic traction in the treatment of acute low back pain.9 The McKenzie activity that does not result in ligament or annular failure. Sensory approach for acute disc herniation has demonstrated efficacy loss and weakness can be insidious and unrealized, as in the in selective patients with centralizing symptoms with lumbar example of the 22-year-old running back, resulting in significant extension.6 This study gives credence to the concept for posture dysfunction in high-demand athletic activities. training for a postero-lateral disc herniation in extension and a central disc herniation in mild flexion or neutral position. The In adult populations, the type of activity14,27 and history of patient learns how to control trunk and hip musculature to reduce trauma27 are risk factors for sciatica and disability resulting from forces on the supportive muscles and ligaments of the spine. The the sciatica. The increased risk in noncontact sports such as diving, ability to maintain these correct postures may require correction of golf, gymnastics, racquet sports, rowing, and weight lifting might tightness in the hamstrings, hip flexors, and hip rotators. Attending be accounted for on the basis of activity with strain on the lumbar to weakness of the hip extensor and abdominal muscles is also needed disc unit. This increased risk may explain the higher incidences to teach proper biomechanics for activities of daily living as well as of low-back pain and sciatica in contact sports such as basketball, sports activities.39 hockey, football, rugby, and wrestling. Managing pain is key in achieving a rapid progression in the Long-term follow-up studies indicate that approximately one-third exercise program. This can be accomplished via medications and/ of primary care acute back pain patients continue to experience or judicious use of pain-relieving modalities. Pain medication back pain for at least half of the time during the first 2 years.35 This treatment with acetaminophen or nonsteroidal anti-inflammatory suggests that with the initial insult to the spine, changes occur that drugs is recommended. Narcotic pain medication and tra- render the spine damaged from the standpoint of strength, flex- madol is effective.8 Caution should be used when prescribing ibility, stability, and fatigue, with resultant mechanical dysfunction narcotic pain medication early in the treatment. A study found and vulnerability to further injury. For the athlete, the distinction that when controlling for demographic data and severity of between the absence of symptoms and an absence of dysfunction is presentation, narcotic pain medication is associated with longer particularly important. disability and increased cost of care.36 AANEM Course Sports Related Neuromuscular Disorders 3

The effectiveness of transforaminal epidural steroid injections has Treatments such as nucleoplasty coblation24,26 and endoscopic been noted in a previous study. Lee stated that the time course microdiscectomy18 showed efficacy in a clinical series. However, of improvement of pain was over 2 weeks.22 A study of 224 no controlled trials with a comparable control group have been patients treated with epidural steroids after a disc herniation showed conducted. In the series published, the outcomes were comparable improvement in the measures of the Oswestry low back pain to conservative care or traditional treatments without demonstrating disability questionnaire for up to 3 weeks post-procedure.2 In any distinct advantages. Osterman demonstrated this in a 2-year consideration of the number of days of complete health achieved, prospective controlled trial that compared microdiscectomy and the cost benefit analysis for epidural steroids was not favorable, conservative management. There were no clinically significant although benefits for loss of pain, improved function, and partial differences in leg or back pain intensity, subjective disability, or return to activity were not factored into the interpretation of the health-related quality of life, although discectomy seemed to be results.30 The use of epidural steroid injections as part of a total associated with a more rapid initial recovery.28 Peul noted similar rehabilitation program rather than as a stand-alone therapy makes results in a controlled trial of 283 patients with sciatica. Although sense in light of its limitations. 39% of the control group went on to surgery at a mean time of 18 weeks,7 the perceived recovery and disability scores were no differ- Cauda equina remains a disorder that requires emergent manage- ent when comparing the surgical and nonsurgical groups.29 ment. A recent study of 56 adults indicated that acute onset of bowel or bladder symptoms in relation to the time of operation Studies have demonstrated a reduction in size of the disc herniation did not influence the neurological outcome. However, bowel over time. A study of 69 conservatively treated patients re-imaged dysfunction at the time of presentation correlated with long-term with MRI at an average of 11 months showed that 63% of the sexual function outcome.25 This finding contradicts previous subjects demonstrated a reduction in herniation size by more than studies showing that management within 48 hours is associated 30%, and 48% showed a reduction of more than 70%. The largest with better bowel, bladder, and sexual function outcome.1 Up herniations showed the most dramatic decrease in size.5 Jensen to 83% of cases with delayed intervention were caregiver related, noted no correlation between the degree of MRI improvement indicating to physicians the importance of early recognition and clinical outcome after an episode of sciatica.21 Autio noted and management.33 that a decrease in clinical symptoms correlated with the rate of disc herniation reduction.4 Outcome

Long-term outcome studies consistently report no significant CONCLUSION differences between surgical and nonsurgical care. A prospective 10-year cohort study of nearly 500 patients showed improvement Sciatica in athletes is a common occurrence and has many causes. rates that were not significantly different for the surgical group A careful review of a patient’s history and physical examination, (69%) than from the nonsurgical group (61%). At a 10-year coupled with appropriate diagnostic testing is required to diagnosis follow-up visit, a larger percentage of surgical patients reported that sciatica. Treatment is focused on pain management to allow for their low back and leg pain was much better or completely gone rehabilitation and a return to activity. Long-term surgical and (56% versus 40%), and were reportedly more satisfied with their nonsurgical outcomes are not significantly different. It is reason- status (71% versus 56%). However, work and disability status at able to consider early surgical treatment in athletes with persistent 10 years was comparable between the two groups. Over the course neurological symptoms and for those with poor pain control during of the study, 25% of surgical patients required at least one ad- conservative treatment. The time delay for return to activity with ditional lumbar spine operation, and 25% of nonsurgical patients surgical treatment and the lack of difference in long-term outcome had at least one lumbar spine operation.3 The re-operation rate was between surgical and nonsurgical patients leaves open the possibil- consistent with findings in other studies.10 ity of using conservative measures to manage an athlete through a season, if pain and neurological status can be managed. Cauda The Spine Patients Outcomes Research Trial was a nonrandom- equine syndrome, however requires rapid intervention to prevent ized trial that examined 743 patients prospectively managed with long term sequelae. conservative therapy or open surgery. It noted significant differences in pain, as measured by the Medical Outcomes 36 Item Short Form Health Survey (SF-36) bodily pain scale, and func- REFERENCES tional outcome, as measured by the modified Oswestry Disability Index, in favor of the surgical group over a 2-year follow-up 1. Ahn UM. Ahn NU. Buchowsk JM. Et al. Cauda equina syndrome period. Pain showed a mean change of 40.9 in the surgical group secondary to lumbar disc herniation: met-analysis of surgical out- and 26.0 in the nonoperative group at 3 months, decreasing to comes. Spine 2000;25(12):1515-22. 42.6 and 32.4, respectively, at 2 years. Disability index scores 2. Arden NK. Price C. Reading I. Stubbing J. Hazelgrove J. Dunne C. decreased to 36.1 for the surgical group, and to 20.9 in the Michel M. Rogers P. Cooper C. A multicentre randomized controlled nonoperative group, then decreased to 37.6 and 24.2 at 2 years. trial of epidural corticosteroid injections for sciatica. Rheumatology All treatment effects fell within the 95% confidence intervals and 2005;44(11):1399-406. were statistically significant.37 4 Sciatica in Athletes AANEM Course

3. Atlas SJ. Keller RB. Wu YA. Deyo RA. Singer DE. Long-term out- 21. Jensen TS. Albert HB. Soerensen JS. Manniche C. Leboeuf-Y de C. comes of surgical and nonsurgical management of sciatica secondary Natural course of disc morphology in patients with sciatica: an MRI to a lumbar disc herniation: 10 year results from the Maine lumbar study using a standardized qualitative classification system. Spine spine study. Spine 2005;30(8):927-35. 2006;31(14):1605-12. 4. Autio RA. Karppinen J. Niinimaki J. Ojala R. Kurunlahti M. Haapea 22. Lee JW. Kim SH. Lee IS. Choi JA. Choi JY. Hong SH. Kang HS. M. Vanharanta H. Tervonen O. Determinants of spontaneous Therapeutic effect and outcome predictors of sciatica treated using resorption of intervertebral disc herniations. Spine 2006;31(11):1247- transforaminal epidural steroid injection. American Journal of 52. Roentgenology 2006;187(6):1427-31. 5. Bozzao A. Gallucci M. Masciocchi C. Aprile I. Barile A. Passariello R. 23. Maigne JY. Aivaliklis A. Pfefer F. Results of sacroiliac joint double Lumbar disk herniation: MR imaging assessment of natural history block and value of sacroiliac pain provocation tests in 54 patients in patients treated without surgery. Radiology 1992;185:135-141. with low back pain. Spine 1996;21(16):1889-92. 6. Browder DA. Childs JD. Cleland JA. Fritz JM. Effectiveness of 24. Masala S. Massari F. Fabiano S. Ursone A. Fiori R. Pastore F. an extension-oriented treatment approach in a subgroup of subjects Simonetti G. Nucleoplasty in the treatment of lumbar diskogenic with low back pain: a randomized clinical trial. Physical Therapy back pain: one year follow-up.Cardiovascular & Interventional 2007;87(12):1608-18. Radiology 2007;30(3):426-32. 7. Buijs E. Visser L. Groen G. Sciatica and the sacroiliac joint: a forgot- 25. McCarthy MJ. Aylott CE. Grevitt MP. Hegarty J. Cauda equina ten concept. Br J Anaesthesia 2007;99(5):713-6. syndrome: factors affecting long-term functional and sphincteric 8. Chou R. Huffman LH. Medications for acute and chronic low outcome. Spine 2007;32(2):207-16. back pain: a review of the evidence for an American Pain Society/ 26. Mirzai H. Tekin I. Yaman O. Bursali A. The results of nucleoplasty American College of Physicians clinical practice guideline. Annals of in patients with lumbar herniated disc: a prospective clinical study of Internal Medicine 2007;147(7):505-14. 52 consecutive patients. Spine Journal 2007;7(1):88-92. 9. Chou R. Huffman LH. Nonpharmacologic therapies for acute and 27. Nurminem M. Reanalysis for the occurrence of back pain among chronic low back pain: a review of the evidence for an American Pain construction workders: modeling for the interdependent effects of Society/American College of Physicians clinical practice guideline. heavy physical work , earlier back accidents, and ageing. Occ Environ Annals of Internal Medicine 2007;147(7):492-504. Med 1997;54(11):807-11. 10. Dvorak J. Gauchat MH. Valach l. The outcome of surgery for 28. Osterman H, Seitsalo S, Karppinen J, Malmivaara A. Effectiveness lumbar disc herniation. A 4-17 years' follow-up with emphasis on of microdiscectomy for lumbar disc herniation: a randomized con- somatic aspects. Spine 1988;13(12):1418-1422. trolled trial with 2 years of follow-up. Spine 2006;31(21):2409-14. 11. Fukui S. Ohseto K. Shiotani M. et. al. Distribution of referred pain 29. Peul WC. van Houwelingen HC. van den Hout WB. Brand R. from the lumbar zygapophyseal joints and dorsa. Rami. Clin J Pain Eekhof JA. Tans JT. Thomeer RT. Koes BW. Leiden-The Hague 1997;13:303-7. Spine Intervention Prognostic Study Group. Surgery versus pro- 12. Garfin SR. Rydevik BL. Brown RA. Saratoris DJ. Compressive neu- longed conservative treatment for sciatica. New England Journal of ropathy of spinal nerve roots. A mechanical or biological problem? Medicine 2007;356(22):2245-56. Spine 1991;16:162-166. 30. Price C. Arden N. Coglan L. Rogers P. Cost-effectiveness and 13. Garfin SR. Rydevik B. Lind B. Massie J. Spinal root compression. safety of epidural steroids in the management of sciatica. Health Spine 1995;20(9):1810-1820. Technology Assessment (Winchester, England) 2005;9(33):1-58. 14. Heliovaara M. Occupation and risk of herniatied lumbar inter- 31. Sayegh F. Potoupnis M. Kapetanos G. Greater trochanteric bursitis veterbral dis or sciatica leading to hospitalization. J Chronic Dis pain syndrome in females with chronic low back pain and sciatica. 1987;40(3):259-64. Acta Orthop Belg 2004;70:423-428. 15. Herring SA. Weinstein SM. Assessment and nonsurgical management 32. Schwartzer AC. Aprill CN. Bogduk N. The sacroiliac joint in of athletic low back injury. Nicholas JA. Hershman EB. The Lower chronic low back pain. Spine 1995;20:30-7. Extremity & Spine in Sports Medicine. St. Louis: Mosby-Year Book, 33. Sharpiro S. Medial realities of cauda equina syndrome secondary to 1995, 1171-1197. lumbar disc herniation. Spine 2000;25(3):348-51. 16. Herzog RJ. The radiologic assessment for a lumbar disc herniation. 34. Stith W. J. Exercise and the intervertebral disc. Spine: State Art Rev Spine 1996;21(24S):19S-38S. 1990;4(2):259-267. 17. Hilde G. Hagen KB. Jamtvedt G. Winnem M. WITHDRAWN: 35. Von Korff M. Saunders K. The course of back pain in primary care. Advice to stay active as a single treatment for low-back pain and sciat- Spine 1996;21(24):2833-2837. ica. Cochrane Database of Systematic Reviews 2006;(2):CD003632. 36. Webster BS. Verma SK. Gatchel RJ. Relationship between early 18. Hoogland T, Schubert M, Miklitz B, Ramirez A Transforaminal pos- opioid prescribing for acute occupational low back pain and disabil- terolateral endoscopic discectomy with or without the combination ity duration, medical costs, subsequent surgery and late opioid use. of a low-dose chymopapain: a prospective randomized study in 280 Spine 2007;32(19):2127-32, 2007. consecutive cases. Spine 2006;31(24):E890-7. 37. Weinstein JN. Lurie JD. Tosteson TD. Skinner JS. Hanscom B. 19. Kawakami M. Weinstein JN. Associated neurogenic and nonneu- Tosteson AN. Herkowitz H. Fischgrund J. Cammisa FP. Albert T. rogenic pain mediators that probably are activated for nociceptive Deyo RA. Surgical vs, non-operative treatment for lumbar disk input. Weinstein JN. Gordon SL. Low Back Pain: A Scientific herniation: the Spine Patient Outcomes Research Trial (SPORT) and Clinical Overview. Rosemont, IL: American Academy of observational cohort. JAMA 2006;296(20):2451-9. Orthopedic Surgeons, 1996, 265-274. 38. Yin W. Willard F. Carreiro J. Dreyfuss P. Sensory stimulation-guided 20. Kawakami M. Weinstein JN. Spratt KF. et al. Experimental lumbar ra- sacroiliac joint radiofrequency neurotomy: technique based on neu- diculopathy: Immunohistochemical and quantitative demonstrations roanatomy of the dorsal sacral plexus. Spine 2003;28(20):2419-25. of pain induced by lumbar nerve root irritation of the rat. Spine 39. Young JL. Press JM. Herring SA. The disc at risk in athletes: 1994;19:1780-1794. perspectives on operative and nonoperative care. Med&Sci Sports Exercise 1997;29(7 Suppl):S222-232. 5

Stingers and Burners

Lawrence W. Frank, MD Assistant Professor Spine and Sports Physiatrist Elmhurst, Illinois

INTRODUCTION opathy or cervical radiculopathy had negative EMGs and had a particularly high incidence of shoulder injury. The “stinger” or “burner” is common phraseology for a phenomenon among athletes describing transient paresthesias and weakness of one upper extremity after trauma. Symptoms typically last seconds MECHANISM OF INJURY to minutes, and on rare occasions last for days to weeks. Normally, patients experience complete recovery of neurological deficits after The burner syndrome typically appears after a trauma resulting burners. Burners may have one of two etiologies: brachial plexus in forced lateral flexion or extension of the cervical spine (Figure injury4,10,15,21 or cervical nerve root injury.13,17,18,19 Cantu has 1), possibly also in combination with shoulder depression. This opined that high school athletes are more likely to suffer a brachial commonly occurs in American football during tackling, or when plexus lesion, while college and professional athletes are more likely the player becomes upended, landing on his neck and shoulder. to suffer from cervical radiculopathy.3 Clinicians should note that In wrestling, forcible contact of the head with the mat may lead to trauma-associated bilateral upper-extremity tingling (burning hands similar biomechanics. Nerve injury may occur with either traction syndrome)11 or the presence of upper and lower extremity paresthe- or compression of the nerve. Based on neuroanatomic features, it sias are ominous signs of cervical spinal cord injury.3 appears that the nerve root is more susceptible to injury than the plexus because of a relative lack of perineural tissue in the neurofo- ramen and tension is concentrated in a single funiculus versus the INCIDENCE multiple funiculi of the brachial plexus.19

The incidence of the burner syndrome is estimated at 2.2 per 100 players.6 Another study indicated that 49% of all reported injuries at two universities were of this type.4 As this syndrome often lasts seconds to minutes and is often ignored by athletes and coaches, under-reporting is likely.

The epidemiology of chronic burner syndrome has been noted in a seminal study performed at an electrodiagnostic (EDX) laboratory.8 In this study, data over 23 years was analyzed retrospectively. The review found 346 athletes reporting peripheral nerve symptoms during this time period that underwent electromyography (EMG) and nerve conduction studies (NCS). Forty athletes reporting symptoms of the burner syndrome had positive EMGs. Of the 40 athletes, 30 were American football players and 10 were wrestlers. Of note, seven athletes with electrodiagnostically proven axillary Figure 1 Forcible lateral flexion of the cervical spine may lead to the nerve injury had similar symptoms and mechanism of injury as burner syndrome burner patients. Ninety-seven patients evaluated for brachial plex- 6 Stingers and Burners AANEM Course

CLINICAL ASSESSMENT Most athletes that experience the burner syndrome have par- Athletes suffering from the burner syndrome may be easily esthesias lasting 3 to 10 seconds.15 Weakness may persist beyond identified by the watchful clinician, as they will often stand the resolution of sensory symptoms, often lasting up to several with one arm dangling at the side, perhaps holding the affected minutes. Serial motor testing beyond the resolution of sensory arm at the wrist or forearm. Again, bilateral arm radiation or symptoms is necessary to determine if the athlete is safe to return involvement of the upper and lower extremities is an ominous to competition. sign of potential spinal cord injury, and the athlete should be immobilized and imaged without delay. Athletes should be im- Chronic Burner Syndrome mediately examined. Gentle palpation of the cervical spine may reveal tenderness. Cervical range of motion (ROM) is initially When symptoms of a burner persist, return to play is not possible. assessed by asking the athlete to perform flexion, extension, rota- Persistent symptoms are unusual and a search for an etiology and tion, and side bending. Rigidity indicates cervical injury, and prognostic information is valuable. Radiographic and EDX testing any arm radiation leads to a high suspicion for radiculopathy. may be indicated in these situations. It is unwise in the face of a potentially traumatic cervical injury for the examiner to passively range the athlete’s neck. If ROM is Radiographic Evaluation otherwise normal and pain-free, the athlete should be asked to assume Spurling’s position. Again, arm radiation strongly suggests Athletes with persistent neck pain should receive plain x-rays of the a cervical radiculopathy. The examiner should also palpate the cervical spine with anteroposterior, lateral, and flexion-extension shoulders bilaterally, looking for asymmetry, fracture, swelling, views looking for fracture and potential instability. Cadaveric or tenderness. studies indicate that up to 3.5mm of intervertebral subluxation and 11 degrees of intervertebral angulation is seen with flexion and Neurological examination of the upper extremities includes extension of normal adult cervical spines with intact ligaments.20 strength, light touch sensation, and reflexes with Hoffman’s Children exhibit a greater degree of physiologic ligamentous laxity sign. In athletes with often prodigious strength, it is useful for and athletes with Down’s syndrome may have nonphysiologic in- the clinician to use leverage and bilateral simultaneous manual stability of the C1 - C2 joints leading to an increased risk of cata- muscle testing in order to detect subtle strength differences. As strophic spinal cord injury.14 Athletes with any suspicion of cervical the burner syndrome often involves C5 or C6 innervated muscle, instability should undergo spine surgery consultation. the author has found that bilateral simultaneous manual muscle testing of the shoulder external rotators is an extremely useful Athletes with a clinical suspicion of persistent cervical radiculopa- initial screening test, as the examiner can easily overpower these thy should undergo magnetic resonance imaging (MRI) scanning. muscles even in the strongest athletes. The presence of Hoffman’s In one study, 87% of athletes with recurring burner syndrome sign, particularly when particularly brisk or asymmetric, indicates had cervical disc abnormalities on MRI, the vast majority of these the possibility of spinal cord injury. abnormalities were at the C4 - C5, C5 - C6, and C6 - C7 levels.9 This is compared to disc abnormalities in 20% of asymptomatic athletes1 and 20% in those with acute burner syndrome.12 Return RETURN TO PLAY DECISIONS to play criteria for athletes with cervical abnormalities includes Acute Burner Syndrome: On-Field Management not only full, pain-free ROM with normal neurological function, but also the absence of central spinal stenosis and the presence of cerebrospinal fluid around the spinal cord at levels with disc Athletes that experience any neck pain, limitation of cervical degeneration.2 ROM, or neurological deficits should be removed from competition for further evaluation. In these athletes, return to play is EDX Evaluation predicated on the return of normal cervical ROM and a sym- metrically normal neurological examination. It is likely that athletes experiencing quick resolution of their symptoms have a neurapraxic injury.5 EDX evaluation is unnecessary for Athletes with neck pain, rigidity, restricted cervical ROM these athletes. Based on the physiology of Wallerian degeneration lasting more than a few minutes, a positive Spurling’s sign. as a response to nerve injury, most experts recommend EMG/NCS and of college age or older are more likely to have cervical ra- for athletes with persistent burner symptoms and signs at 2 to 3 diculopathy. Athletes with severe acute neck pain and rigidity weeks. Athletes experiencing symptoms and signs of the burner should be taken off-site by emergency personnel and undergo syndrome for greater than 72 hours are likely to have abnormal emergent plain film radiograph (x-ray) and possibly computed EDX testing at 4 weeks,17 indicating axonotmesis. The largest study tomography to search for fracture. Athletes with no neck pain of EDX findings in chronic burner patients revealed that localiza- or motion restrictions and of high school age are more likely tion is electrodiagnostically difficult, with fibrillations on limb to have a brachial plexopathy. This distinction is of impor- needle EMG, normal paraspinal needle EMG, and normal and tance in the longer term treatment and workup, but on the bilaterally symmetric sensory NCSs.8 Some have advocated proxi- field this distinction does not lead to any changes in return to mal NCSs for investigation of the burner syndrome,7 although this play criteria. AANEM Course Sports Related Neuromuscular Disorders 7

2. Cantu, RC. Functional cervical spinal stenosis: a contraindication to par- technique is often difficult with proximal distance measurement ticipation in contact sports. Med Sci Sports Exerc 25:316-317, 1993. problems and poor patient tolerance. 3. Cantu, RC. Stingers, transient quadriplegia, and cervical stenosis: return to play criteria. Med Sci Sports Exercise 29 (7) Suppl:233-235, The presence of fibrillation potentials in a nerve root or discrete 1997 Jul. plexus distribution of has been suggested to be a contraindication 4. Clancy WG, Brand RL, Bergfield JA. Upper trunk brachial plexus injuries in contact sports. Am J Sports Med 1977; 5: 209-16. to return to play, especially when seen in combination with persis- 5. Clancy WG. Brachial plexus and upper extremity nerve injuries. In: tent weakness. Athletes with persistent weakness and fibrillation Torg JS, ed. Athletic injuries to the head, neck and face. Philadelphia: potentials should be followed with repeat EDX studies. Symmetric Lea and Febiger, 1982:215-220. muscle strength recovery in the presence of polyphasic motor unit 6. Clarke KS. Prevention: an epidemiologic view. In: Torg JS, editor. action potentials indicates re-innervation and such athletes may Athletic injuries to the head, neck and face. Philadelphia (PA): Lea return to play. The absence of a completely normal EMG/NCS and Febiger, 1982: 15-26. examination should not used as the sole criteria for precluding 7. DiBenedetto M, Markey K. Electrodiagnostic localization of trau- athletes from returning to competition.19 matic upper trunk brachial plexopathy. Arch Phys Med Rehabil 1984; 65:15-17. 8. Krivickas LS. Wilbourn AJ. Peripheral nerve injuries in athletes: a case RECURRENT BURNER SYNDROME series of over 200 injuries. Seminars in Neurology. 20(2):225-32, 2000. 9. Levitz CL. Reilly PJ. Torg JS. The pathomechanics of chronic, recurrent cervical nerve root neurapraxia. The chronic burner syndrome. Recurrent burners bring a greater susceptibility to weakness or per- American Journal of Sports Medicine. 25(1):73-6, 1997 Jan-Feb. manent neurological injury. Football players with multiple burners 10. Markey KL, DiBennedetto M, Curl WW: Upper trunk brachial plex- in one game or those who have frequent recurrences may benefit opathy: The stinger syndrome. Am J Sports Med 21:650-655, 1993. from high shoulder pads with a soft cervical roll to help limit neck 11. Maroon JC. “Burning hands” in football spinal cord injuries. JAMA ROM.3 Such collars have been shown to decrease the mechanical 238:2049-2051, 1977 load on the cervical spine.16 In addition, proper coaching and tack- 12. Meyer SA, Schulte KR, Callaghan JJ, et al: Cervical spinal stenosis and ling techniques may decrease recurrent episodes as well. stingers in collegiate football players. Am J Sports Med 22: 158-166, 1994. 13. Poindexter DP, Johnson EW: Football shoulder and neck injury: A CONCLUSION study of the "stinger." Arch Phys Med Rehabil 65:601-602, 1984. 14. Proctor MR. Cantu RC. Head and neck injuries in young athletes. Clinics in Sports Medicine. 19(4):693-715, 2000 Oct. As burners are neurological injuries resulting from trauma to the 15. Robertson WC, Eichman PL, Clancy WG: Upper trunk brachial neck and shoulder, physicians must recognize the characteristic plexopathy in football players. JAMA 241:1480-1482, 1979. natural history of this condition to avoid further injury and for 16. Rowson S. McNeely DE. Brolinson PG. Duma SM. Biomechanical return to play decisions. Physicians must also consider an extensive analysis of football neck collars. Clinical Journal of Sport Medicine. differential diagnosis for players with unusual or persistent symp- 18(4):316-21, 2008 Jul. toms, as the consequences of releasing athletes back to competition 17. Speer KP, Bassett FJ III: The prolonged burner syndrome. Am J with cervical spine disease may be potentially catastrophic. In such Sports Med 18:591-594, 1990. cases, a number of diagnostic measures including physical exami- 18. Watkins RG: Nerve injuries in football players. Clin Sports Med nation, imaging and electrodiagnostic tests are utilized in order to 5:215-246, 1986. determine readiness to return to sports activity. 19. Weinstein SM. Assessment and rehabilitation of the athlete with a "stinger". A model for the management of noncatastrophic athletic cervical spine injury. Clinics in Sports Medicine. 17(1):127-35, 1998 Jan. 20. White AA, Johnson RM, Panjabi MM, et al. Biomechanical analysis of REFERENCES clinical instability in the cervical spine. Clin Orthop 109:85-89, 1975. 21. Wroble RR, Albright JP: Neck and low back injuries in wrestling. 1. Boden SD, McCowin PR, Davis DO, et al: Abnormal magnetic- Clinics in Sports Med 5:295-325, 1986. resonance scans of the cervical spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg 72A: 1178-1184, 1990. 8 AANEM Course 9

Upper Extremity Mononeuropathies

Andrew H. Dubin, MD, MS Associate Professor Albany Medical Center Hospital Department of Physical Medicine and Rehabilitation Albany, New York

INTRODUCTION essence, adds a whip-like movement to the body and throwing limb, further multiplying the force that was generated during Throwing injuries have been in existence as long as human the wind-up and cocking phases. Phase four, the release and beings, rocks, and projectiles have had the opportunity to in- deceleration phase, is actually the most dangerous or potentially teract with one another. Classically, if one gives a child a rock, hazardous phase in the entire throwing cycle. It is the sequence he or she will invariably find a window to throw it through or where massive eccentric forces are transmitted through the rotator another child to throw it at. With continued growth of athletic cuff in an attempt to maintain the humeral head within the participation, there has been a progressive increase in sports-related glenoid fossa. Failure of the rotator cuff in eccentric loading can neurological disorders. Throwing injuries, both neurological lead to catastrophic events and consequences. Phase five, or the and non-neurological, continue to rise. In the throwing athlete, follow-through, is the terminal part of the deceleration phase. By extreme forces that are generated across joints during a throwing this point, the damage has already been done. The follow-through motion typically cause nerve injuries to the throwing arm. The component of the throwing cycle merely serves as a way to finally most significant forces seen across joints occur across the elbow dissipate whatever residual forces were left in the system. and shoulder joints, respectively. The straightforward analysis of the different phases of the MECHANICS OF THROWING throwing cycle begins to lay the framework for an appreciation of how complex the body’s response is in terms of modulating The analysis of a basic throwing motion reveals that the mechan- and controlling forces across multiple joints. The ability of the ics of throwing can be divided into five stages or phases. The first throwing arm and shoulder to tolerate rapid eccentric loading is phase is classically referred to as the wind-up. The second phase is critical in maintaining the integrity of the throwing arm. Failure the cocking phase. The third phase is referred to as the acceleration in phase four, or the release and deceleration phase, differentiates phase. Phase four combines both the release of the object that is between the careers of a pitcher who had a successful 25-year major being thrown, and the deceleration phase of the throwing limb. league baseball career, versus a 1-year wonder, who disappears after The fifth and final phase is the follow-through. a single season, secondary to shoulder pathology.

Looking at each component phase in isolation, it becomes evident In the discussion of the sub-phases of the throwing motion, that the phases are intimately interrelated and are best viewed as a eccentric loading is the single most significant factor to consider. kinetic chain. Phases one and two, the wind-up and cocking phase, By definition, eccentric loading is a phenomenon where muscle actually serve as a functional group to initiate force generation, and generates tension while being lengthened by the application of an orient the force vector. In essence, in these phases, the human body external force. The energetics of eccentric loading occurs when is being wound up like a progressively coiled spring. Phase three, myosin and actin cross links are forcibly torn as the muscle is being the acceleration phase, is the phase in which the spring is now lengthened. It is a very energy efficient form of muscle action uncoiled. In addition to the release of energy as the spring is in that it does not require the continual supply of adenosine uncoiled, phase three adds an acceleration component that in triphosphate (ATP). Given the fact that rapid eccentric loading 10 Upper Extremity Mononeuropathies AANEM Course has been classically shown in biomechanical studies to produce and how it articulates with the shoulder, multiplied by the length the greatest forces at muscle tendon junctions and across joints, of the body and the forces that are applied through the body and it should come as no surprise that rapid eccentric loading is, in limb that relate to the concept of torque. Understanding these fact, the major etiology of injury in the throwing athlete both for four concepts and the phases of throwing clearly helps explain why neurological and non-neurological injuries. softball pitches not only generate more force than baseball pitches, but also interestingly enough, have a dramatically lower incidence A basic review of physics further guides the understanding of of injuries. Understanding these principles allows an analysis of the the principles of force, acceleration, and torque, and how these various nerve injuries seen in the throwing athlete. principles apply to the throwing athlete. Newton's first law of physics is the law of inertia. It states: a body continues in its state of rest or uniform motion unless an unbalanced force acts on it. UPPER EXTREMITY NERVE INJURIES The property of an object that causes it to remain in its state of either rest or motion is called its inertia. Because of inertia, force is A review of the literature describes injuries to various nerves in the needed to change the velocity of the object. The measure of inertia upper extremities. Some injuries prove to be more common than or the body's resistance to change in motion is its mass. Phases others. Nerves that have been noted to be injured in the throwing one and two of the throwing cycle are the phases that introduce athlete include the axillary nerve, suprascapular nerve, musculocu- an unbalanced force on a ball. The introduction of an unbalanced taneous nerve, and the ulnar and median nerves. There have been force, namely the wind-up and cocking phase, are what initiate the reports of injury to the long thoracic nerve, as well as the spinal movement of the ball and orient it in its ultimate direction. accessory nerve. However, these injuries are much less common in the throwing athlete than in athletes that engage in weightlifting or Newton's second law is the law of acceleration. It proclaims that wrestling activities. the acceleration of an object is directly proportional to the force causing it, that the acceleration moves in the same direction as Axillary nerve injuries the force, and that it is inversely proportional to the mass of the object. The velocity of a pitched ball reflects the force with which Axillary nerve injuries are commonly seen in athletes following an the ball is thrown. It moves in the direction of the line of force anterior shoulder dislocation. The literature reports an incidence at the moment of release. Newton’s second law links phase ranging between 9% and 20% in individuals who sustained an three and phase four. The mathematical construct allows for an anterior shoulder dislocation. Interestingly enough, with an inferior understanding of the interrelationship between force, mass, and shoulder dislocation, the rate of axillary nerve injury climbs as high acceleration, which can easily be written as the formula F=ma. as 60%. In throwing athletes, chronic axillary nerve compression is Converting this to biomechanical principles, the concept of the more classic cause of axillary nerve injury. Axillary nerve com- impulse or the force which is utilized to move an object, can pression typically occurs in the throwing athlete at the level of the be looked at as the application of the force multiplied by a time quadrilateral space. The onset of symptoms tends to be insidious function. In this new formula, Force(t) is equal to the mass of the as it is a progressive and compressive neuropathy. It is not typi- object and the change in the velocity of the object over time where cally associated with trauma. On surgical evaluation in refractory V final -V1 or V initial, the change in velocity over a given time cases, it has been noticed that fibrous bands of the inferior edge of interact as acceleration (F(t)= m x V(f)- V(i)/ t). the teres minor appear to form a compressive-type structure. This has been implicated in the etiology of axillary nerve compression. Newton's third law is the law of reaction. It clearly states that an Typically the compression occurs when the involved arm is in the object at rest exerts a downward force on the substrate that it is abducted, externally rotated position, or in the throwing position. resting upon. A classic example of this would be a book that is lying Complaints may include a sensation of tenderness in the posterior on a table exerts a downward force on the table because the book is shoulder at the level of the quadrilateral space. Athletes will also stationary and an equal and opposite force is acting on the book. As complain of a sensation of positional weakness of the shoulder, a result, there is no motion because the forces are equal, opposite, deltoid atrophy, and rarely, an altered sensation in axillary nerve and are balanced. Newton's third law is clearly related to the first distribution. By far, the most common finding on physical exami- law that says in order to get an object moving or to change its veloc- nation is focal tenderness in the region of the posterior shoulder at ity, one must apply an unbalanced force. This clearly reverts back to the level of the quadrilateral space. the first two phases of the throwing cycle where the introduction of an unbalanced force generates the initial movement of the ball. Electrodiagnostic (EDX) evaluation is critical in helping to differentiate an axillary nerve neuropathy from the C5 - C6 Considering these three classic laws, one can now look at the concept radiculopathy or upper trunk versus posterior cord plexus lesion. of rotational equivalents and how they relate to Newtonian physics. Above all else, a good physical examination is the most critical The concept of rotational equivalents introduces the idea of torque. aspect of the evaluation. EDX testing should never supersede a Torque is related to the application of the force over the length of physical examination and in fact, a meticulous examination will the perpendicular momentum. In this instance, the perpendicular invariably differentiate between an axillary nerve neuropathy from momentum is the length of the limb segment that is being used to a C5 - C6 radiculopathy versus a plexus level injury. Treatment for throw the ball, namely the arm. It is the length of the limb segment chronic axillary nerve compression is usually conservative. A review AANEM Course Sports Related Neuromuscular Disorders 11 of recent publication indicates that the adjustment in pitching the forearm in a fully supinated posture. This will isolate, from a mechanics seen in college and major league pitchers has been biomechanical standpoint, the biceps and brachialis as the primary shown to be effective in 75% to 90% of cases. Surgery with release flexors of the elbow and relegate the brachioradialis to its much of fibrous bands is relegated to cases that have failed to respond more tertiary role as an elbow flexor. Should elbow flexion be to conservative management. With conservative treatment to the performed with the forearm in a pronated state or with the forearm affected limb or even in cases where surgery is required, the overall in a neutral state, elbow flexion weakness may easily be overlooked. prognosis tends to be good. In these positions, the brachioradialis functionally becomes the primary elbow flexor. The major differential diagnosis to distinguish Suprascapular Nerve Injuries from an injury to the musculocutaneous nerve is that of a rupture of the distal biceps tendon at the level of the elbow. In both cases, Suprascapular nerve injuries can also be seen in the throwing the athlete will present with weakness of elbow flexion; however, athlete. The typical mechanism of injury in the throwing athlete is in the case of a rupture of the distal biceps tendon at the level of a combination of cross body abduction and/or scapular protraction the elbow, there will be associated loss of contour of the muscle with forward flexion. This is a fairly classic body posture of the belly. In general, musculocutaneous nerve neuropathies in athletes throwing athlete and manifests during the deceleration and release resolve spontaneously and do not require surgical intervention. The phase as well as the follow-through phases of the throwing cycle. literature implies that surgical intervention is typically associated with poor outcome and with an increased incidence of sensory Similar to axillary nerve injuries, suprascapular nerve injuries dysesthesias in a lateral antibrachial cutaneous distribution. tend to present in an insidious fashion. Complaints include vague posterior shoulder pain, weakness of abduction, and external Ulnar Nerve Injuries rotation. Atrophy of both the infraspinatus and supraspinatus can be seen along with isolated infraspinatus atrophy. Whether both Of particular interest and concern in the throwing athletes are spinatii are involved, or atrophy to the infraspinatus is seen in injuries to the ulnar nerve. These classically occur at the level of isolation depends upon the level of entrapment and compression the elbow and are commonly associated with concomitant injury of the suprascapular nerve. The needle electromyography (EMG) to the ulnar collateral ligament. Refractory pain at the level of the examination is critical in localization of this neuropathy. Of elbow in the distribution of the ulnar collateral ligament should particular importance is that the major differential diagnosis in engender detailed analysis and evaluation of the ulnar nerve. the suprascapular nerve injury is a significantly more common When a throwing athlete sustains significant injury to an ulnar injury, namely a rotator cuff tear. Rotator cuff tears are significantly collateral ligament, there is a high likelihood that there has also more common than suprascapular nerve neuropathies and must been at least a partial injury to the ulnar nerve at the level of the be aggressively evaluated and treated. Management of the elbow. A common mechanism of injury in throwing athletes in suprascapular nerve injury includes rest, utilization of nonsteroidal regards to ulnar nerve injury is repetitive, low-grade trauma with anti-inflammatory drugs, and in more refractory cases, steroid stretching and compression of the ulnar nerve at the level of the injection at the level of the suprascapular notch. Suprascapular elbow. EMG studies in this scenario are invaluable for localizing the nerve compression secondary to a cyst can be seen in a degen- lesion, assessing acuity versus chronicity, and are also helpful in erative shoulder. Surgical decompression may be required. In determining the potential for recovery. It is critical in an ulnar the given scenario, there is a structural, mechanical etiology to nerve injury that EDX testing be utilized to help differentiate ulnar the nerve entrapment. Historically, conservative management has nerve neuropathy at the level of the elbow from true neurogenic a poor outcome in this patient population subset. Even after thoracic outlet syndrome as described by Wilburn.10 successful surgical decompression, atrophy of the spinatii may persist. Persistence of atrophy does not preclude the return of Median and Radial Nerve Injuries throwing activities provided the throwing athlete is asymptomatic when he or she is throwing. A review of the literature reveals a rather interesting phenomenon that has been described by several sports medicine physicians. Musculocutaneous Nerve Injuries The term “the pitchers arm” was coined after Long and colleagues observed abnormalities of sensory nerve action potential Musculocutaneous nerve injuries, while not common in the amplitudes (SNAPs) among many pitchers. As part of the study, throwing athlete, have been reported and typically occur during the group obtained data on numerous pitchers who have been the throwing cycle when the musculocutaneous nerves stretch evaluated for complaints of neuromuscular symptoms. Repeatedly, across the humeral head or coracoid. Musculocutaneous nerve it has been observed that abnormal SNAPs in pitchers' throwing neuropathies typically present with biceps and brachialis atrophy arms are seen independent of presenting symptoms. Of particular and involve associated weakness of elbow flexion. It may be difficult concern is that these abnormalities have been observed even when to discern elbow flexion weakness in the well-conditioned athlete, symptoms have been in the nonthrowing arm. This has typically been particularly if the athlete has a well-developed brachioradialis and described in high-level throwing athletes and is believed to potentially only has a partial injury to the musculocutaneous nerve. In this represent an element of chronic recurrent low-level stretch at scenario, in an attempt to isolate biceps and brachialis function, the level of the brachioplexus, given the diffuse involvement of the athlete should be asked to perform elbow flexion activity with multiple SNAPs. The major implication for this scenario, however, 12 Upper Extremity Mononeuropathies AANEM Course is one of data over-interpretation and misdiagnosis. As such, Long shoulder complex, hyperabduction or overhead traction. Chronic and colleagues recommended that an isolated study not be used recurrent stretch and compression may occur, particularly if the as the sole determinant for nerve injury in the throwing athlete. throwing athlete happens to have underlying anatomic anomalies In fact, several authors recommend the use of serial studies to such as a cervical rib. Generally, brachial plexus level injuries are determine, over time, if there is a trend towards worsening nerve uncommon unless there is an occurrence of an associated sudden parameters in EDX testing before establishing the diagnosis of stretch. Sudden stretch injuries to the brachial plexus in throw- nerve injury. It is the contention that the use of serial studies in ing athletes have been described in weight-throwing athletes (e.g., determining trends are more appropriate and may help avoid shot putters, and discus throwers). This injury is classically seen in unnecessary treatment and potentially invasive interventions. novice weight throwers who have yet to develop sufficient shoulder and trunk musculature bulk to protect the shoulder and underlying Median nerve and anterior interosseous nerve neuropathies plexus structures. are quite uncommon in the throwing athlete. In a general population, the most common median nerve neuropathy is carpal In cases of brachial plexus injuries from sudden stretch, one of the tunnel syndrome (CTS) or median nerve compression at the more common complaints is classically described as the stinger or level of the wrist. However, this is an uncommon finding in the burner. This typically refers to the sudden onset of circumferential throwing athlete. When examining the anatomic course of the paresthesias and dysesthetic pain throughout the upper limb and median nerve, a median nerve injury at the level of the shoulder hand and may be associated with flaccid paresis. This tends to or upper arm is a very rare. Pitchers, however, can develop median occur in association with a downward force on the shoulder and is nerve compression at the level of the pronator teres secondary sometimes accompanied by lateral flexion of the head or neck to to eccentric muscle trauma to the pronator teres. As a result of the opposite side. This has been well described in football tackling, eccentric trauma to the pronator teres, subsequent swelling but it can also occur in the weight-throwing athlete. A shot putter and transient median nerve compression can result. The classic learning a spin technique, novice discus throwers, or novice shot- mechanism of rapid eccentric loading and trauma to the pronator put gliders are at a high risk. teres is seen in a pitcher that is working on a curve ball and has less than optimal mechanics. EMG examination in this scenario can be Multiple nerves can be involved in the throwing athlete. For helpful in distinguishing median nerve neuropathy at the level of illustrative purposes, two cases are presented for review. the pronator teres and more classically described CTS. On clinical examination, there may be significant symptom overlap between CTS and pronator teres syndrome. CASE DISCUSSIONS

Radial nerve neuropathy, secondary to true entrapment, is The first case involves a 17-year-old female shot putter. She is a rare. Also rare is recurrent radial nerve trauma, secondary to nervous thrower with noted weakness and currently lacks sufficient repetitive limb use. Isolated posterior interosseous nerve neuropa- shoulder strength. She is a glider as opposed to a spinner. Both thies; however, do occur and have been described at the level of gliders and spinners require significant amounts of strength, but the arcade of Froshe. This is a fibrous band between the two heads gliders need even more strength than spinners. Spinners typically of supinator. Classic posterior interosseous nerve neuropathies in generate their linear throwing forces through torque develop- the throwing athlete at the level of the arcade of Froshe have been ment. This effectively converts shot putting to a speed as opposed believed to occur secondary to edema, synovitis, ganglion, or to a strength activity. The patient developed right arm pain after lipoma formation. All of these are believed to serve as compres- throwing in a tournament. She experienced immediate paresthesias sive forces on the posterior interosseous nerve. Eccentric injury in the entire arm with a sensation of weakness. By description, she to the supinator, classically seen in screwball pitchers, can cause a had a burner or a stinger. Her primary physician initially diagnosed posterior interosseous nerve neuropathy. EDX evaluation includ- her as having sustained a shoulder sprain. The patient noted that ing needle EMG and nerve conduction studies help distinguish activities such as bench pressing worsened her pain. Her physical between a true posterior interosseous nerve neuropathy versus a examination showed no evidence of muscle asymmetry. This is radial nerve neuropathy proximal to the level of the arcade. important because a weight thrower should be asymmetric, with the dominant throwing arm hypertrophied, relative to the Brachial Plexus Injuries nondominant arm. A sensory examination revealed decreased pin sensation in the right thumb and index finger involving both the Multiple nerves can be involved in throwing athletes. Some nerves, dorsal and palmer surfaces and altered sensation in the lateral such as the ulnar nerve, are more commonly involved than others. forearm. She was noted to have weakness in the deltoid, biceps, There are significant ramifications with ulnar nerve involvement and pronator teres as well as in the wrist extensors. Triceps were given the fact that it supplies the hand intrinsics of the throwing noted to be strong. Differential diagnosis included transient stinger arm. As such, a detailed analysis of the function of the ulnar nerve or burner, C6 radiculopathy, plexus level injury, musculocutaneous is necessary in all pitchers. nerve neuropathy, and possibly even CTS. Rank ordering of the differential diagnosis placed plexopathy versus C6 radiculopathy Brachial plexus injuries are typically more commonly associated as the highest likelihood. EDX testing revealed on the right, a with traumatic events such as rapid downward compression of the small lateral antebrachial cutaneous SNAP, and a small radial AANEM Course Sports Related Neuromuscular Disorders 13

SNAP. Motor nerve conduction studies revealed a small right assists in concluding that the patient is experiencing a combination musculocutaneous to biceps compound motor action potential of an acute chronic plexopathy and an acute C7 radiculopathy. (CMAP). Needle EMG examination showed evidence of active denervation in the deltoid, biceps, extensor carpi radialis longus, and pronator teres with an unremarkable triceps and unremarkable CONCLUSION paraspinals. Clearly in this scenario, the patient has an upper trunk level brachial plexopathy. The throwing athlete is a rather remarkable individual. He or she is not only able to generate tremendous forces over short periods Case 2 involves a 23-year-old professional baseball player. He is of time, but can accurately locate these forces and translate them an AA outfielder for a local baseball team. He had a history of into horizontal vectors that allow for the accurate throwing of rotator cuff repair that was performed 18 months prior with anchor projectiles. It is, however, the unique capacity of the high-level fixation and good outcome. History reveals that he developed throwing athlete to sum a myriad of forces to a final common right shoulder pain after playing long toss in the outfield with a pathway that ultimately exposes the overhead-throwing athlete to teammate. He did not have acute pain during the throwing potentially catastrophic injury. It is imperative for physicians that activity, which would suggest it was not acute rotator cuff care for these individuals to be fully versed in the neurological pathology. He noted the development of pain the day after and non-neurological sequelae of the force applications that are throwing. Shortly thereafter, he noticed altered sensation in the generated by the throwing athlete. thumb, index finger, and long fingers of the right hand. The patient noted weakness of the right triceps and a dramatic loss of strength during bench press activities. His physical examination was BIBLIOGRAPHY significant for rather profound triceps atrophy, and loss of the triceps reflex. On manual muscle testing, he was noted to have significant weakness in the triceps, extensor carpi radialis longus, 1. Bosconi, B. Injuries in the Overhand Throwing Athlete. AAPMR deltoid, as well as external rotators. The sensory examination 2007. revealed decreased sensation in the axillary nerve distribution as 2. Duralde, XA: Neurologic Injuries in the Athlete’s Shoulder: Journal well as a radial nerve distribution. Differential diagnoses included of Athletic Training 35(3) 2000. p.316-328. cervical polyradiculopathy at the C5, C6, and C7 levels, isolated 3. McKowen HC, Voorhies RM. Axillary nerve entrapment in the brachial plexopathy, combined axillary nerve and radial nerve quadrilateral space: a case report. J Neurosurg 1987; 66:932-934. neuropathy, and a combination of brachial plexopathy and 4. Muscolino, JE: Kinesiology: The Skeletal System and Muscle radiculopathy. EMG data revealed small CMAP amplitude for the Function; Elseiver Health Sciences 2006. extensor indicis proprius on the right and a small right radial SNAP. 5. Ringel SP, Treihart M, Cary M, et al Suprascapular neuropathy in Needle EMG results showed acute on chronic denervation of the pitchers. Am J Sports Med. 1990;18(1):80-86. right deltoid and acute on chronic denervation of the teres minor. 6. Sears, and Zemansky’s University Physics and Modern Physics, 11th The patient was noted to have acute denervation of the right triceps edition, Pearson. 2003. and extensor indices proprius as well as acute denervation at the C7 7. Wells ,K. Luttgens K. Kinesiology- scientific basis of human motion paraspinal level. This patient has two processes in occurrence. He WB Saunders, Phila. 1976. has acute on chronic findings of deltoids and teres minor, which 8. Wilbourn AJ Electrodiagnostic testing neurologic injuries in athletes. are axillary nerve and posterior cord innervated. He also has acute Clin Sports Med. 1990;9:229-245. denervation in the triceps and extensor indicis proprius, both 9. Wilbourn AJ, Hershman EB, Bergfeld J : Brachial plexopathies in of which share radial nerve and posterior cord innervation. athletes: the EMG findings. Muscle & Nerve. 1986;9(suppl):254. Additionally, acute dennervation is noted in right C7 level 10. Wilbourn, AJ, Porter JM: Thoracic outlet syndrome. Spine 2 1988. p paraspinals. This in concert with a small radial SNAP amplitude 597. 14 Upper Extremity Mononeuropathies AANEM Course 15

Mononeuropathies of the Lower Extremities in Sports

Francis P. Lagattuta, MD

Medical Director LAGS Spine & Sportscare Santa Maria, California

INTRODUCTION multiple branches within the femoral triangle. It divides into sensory branches in the proximal thigh to innervate the upper Kobe Bryant gets carried off the court with an ankle sprain. Most and anterior thigh and muscular branches to quadriceps sports fans feel that the ligaments in the ankle will heal and the muscles. One sensory nerve branches lateral to form the femoral player will return to play as soon as possible. In some cases in grade cutaneous nerve. The femoral nerve also divides into the medial II and grade III ankle sprains, the peroneal nerve is injured as well femoral cutaneous nerve which originates just distal to the as the ligaments, delaying the return of the player to his team. The inguinal ligament to descend on the sartorius muscle and penetrates lower limbs are the most frequently injured body parts in sports. the deep fascia. This splits into two terminal nerve branches; one This is because all sports require locomotion, which is generated by branch innervates the skin covering the medial aspect of the distal the legs. Therefore, there is going to be a higher incidence of knee, thigh and knee joint region, and the second branch supplies the skin ankle, and hip injuries in almost all sports. The most serious inju- superior to the patella through several community branches with the ries are in the knees, with fewer in the ankles, and even less in the saphenous nerve. The posterior branch of the medial cutaneous hips. The significant injuries to the lower limbs and the knee are nerve also communicates with the saphenous nerve and provides primarily of ligaments and cartilage but in 11% of the cases, there cutaneous sensation to the patellar region. The saphenous nerve is can be nerve injuries as well.18 The nerve injuries may or may not also derived from the femoral nerve (Figure 1). be obvious. For the neuromuscular physician, the patient may have been referred following a workup for the muscles, ligaments, and The femoral nerve is not commonly entrapped in sports. However, cartilage injuries with the primary care provider or orthopedic phy- when the nerve becomes entrapped, it is in close proximity to the sician. Therefore, most of the structural elements have already been femoral head, the tendinous insertion of the vastus interomedia- evaluated, and it is the neuromuscular physician’s role to identify lis, the psoas tendon, the hip, and the joint capsule. The nerve is the nerve injury, confirm the diagnosis, and treat the injury. vulnerable in this area. In sports it may be seen with hip dislocations, pelvic fractures, and acute hyperextension of the thigh. The patients may be more vulnerable if they are diabetic, especially if FEMORAL NERVE INJURIES their disease is not well controlled. 18,24,29

Anatomy Etiology

The femoral nerve arises from the posterior divisions of the Femoral neuropathy has also been seen in gymnastics and in female ventral primary rami of L2, L3, and L4. These nerves form the modern dancers with the hinge maneuver. This is a hyperexten- largest branch of the lumbosacral plexus. The femoral nerve sion of the hips while in the kneeling position which causes a merges from the lateral border of the psoas muscle. It divides into stretch injury. 16 Mononeuropathies of the Lower Extremities in Sports AANEM Course

tion studies (NCSs) may show prolonged conduction velocity and a decreased amplitude from side to side picking up with the electrodes on the vastus medialis. A saphenous study may also be performed which would have a decreased amplitude and can be prolonged from the contralateral side. When performing the needle EMG study, it is important to look at the adductor muscles to rule out a lumbar radiculopathy as the obturator nerve is also supplied by the L2, L3, and L4 nerves. If the adductor muscles are involved, it is most likely a lumbar radiculopathy and not a pure femoral neuropathy.

Treatment

Surgical treatment for the hip and pelvis trauma may be necessary. The goal of nonsurgical treatment is to decrease the inflammation on the nerve as well as provide symptomatic treatment for pain and dysethesias. Acute neural inflammation can be treated with a dosing regiment of oral corticosteroids, (prednisone or medrol). Intramuscular (IM) corticosteroids, as well as an injection with intravenous (IV) soluble corticosteroids, preferably ultrasound guided, can be given directly at the site of the injury. After the initial corticosteroids, nonsteroidal anti-inflammatory drugs can be given at appropriate doses for continued inflammatory control.

Symptomatic treatment for nerve pain includes such antiepileptic medicines as pregabalin and off-label use of gabapentin, carbamazepine, or lamotrigine and others that work to decrease the neural signal through calcium channel blockers. Other pharmaceutical treatment includes duloxetine and off-label use of tricyclic antidepressants through the norepinephrine and serotonin mechanisms. Topical treatments using capsaicin and topical lidocaine can also be used as an adjunctive treatment. Analgesic medicines such as tramadol and other opioids can be used in moderately severe cases. Methadone, due to its special Figure 1 Anatomy of the femoral nerve and its distal sensory continuation properties with N-methyl-D-aspartic receptors, may be especially of the saphenous nerve. (Source: Johnson EW and colleagues, Practical useful in severe cases. TeNS units and other physical modalities Electromyography 1997;179.) may also be used. This is called the neuropathic treatment model. In femoral neuropathy, the quadriceps weakness may be treated Clinical with a locking knee brace and an assistive device to prevent instability. In refractory cases, 70% of patients experience Clinical findings of a femoral neuropathy involve pain in the in- significant relief with this approach or surgery.16 A strengthen- guinal region that may be relieved from flexion and external rota- ing program of the lower limbs, including proprioception, is tion of the hip. There can be dysesthesias over the anterior thigh necessary after surgical or nonsurgical treatment. and anterior medial leg. Patients complain of knee buckling when walking, numbness in the distribution of the saphenous nerve, and also anterior knee pain. SAPHENOUS NERVE INJURY Anatomy On physical examination, the patient may present with weak hip flexion and knee extension, decreased quadriceps tendon reflex, and decreased sensation in the anteromedial aspect of the thigh. The The saphenous nerve is the terminal branch from the femoral pain can be increased with hip extension and relieved with external nerve. The longest branch of the femoral nerves is a pure sensory rotation. If the nerve is compressed in the inguinal ligament, there nerve and is made up of fibers from the L3 and L4 spinal seg- would be no hip flexor weakness since the motor branch to the hip ments. It may become entrapped in multiple locations from the flexors muscles is before the ligament. thigh to the leg. The saphenous nerve can be entrapped where it pierces connective tissue at the roof of Hunter’s canal. The sharp Electromyography (EMG) testing may show needle changes in the angulations of the nerve through the Hunter’s canal is under muscles innervated by the femoral nerve, which is the quadriceps and dynamic forces from the muscles in this area. Contraction and the hip flexor muscles including the psoas muscle. Nerve conduc- relaxation impinges the nerve. AANEM Course Sports Related Neuromuscular Disorders 17

Etiology Etiology

The saphenous nerve can be injured by a surfer who is holding Meralgia paresthetica may be caused by direct trauma such as a a surfboard between his legs or as a complication of a runner “hip pointer” which is a contusion to the anterior superior iliac who has swelling from pes anserinus bursitis. It can also be spine (ASIS). This can occur in any contact sport such as football, injured in traumatic injuries such as patellar dislocations in rugby hockey, soccer, or basketball. It is also seen in overuse syndromes and football. Knee surgery complications can also lead to saphen- such as jumping rope, using uneven parallel bars in gymnastics, and ous nerve damage.6,9,11,17,18,21 at times, when a weight-lifting belt is being worn too tightly.

Clinical Clinical

The symptoms of an entrapment include a deep aching sensa- Symptoms of meralgia paresthetica consist of anterior and lateral tion in the thigh, knee pain, and paresthesias in the distribution thigh burning, tingling, or numbness. The pain is worsened with of the saphenous nerve in the leg and foot. The infrapatellar branch standing and walking, but relieved by sitting. may also be entrapped as it passes through a separate foramen in the sartorius muscle tendon and courses horizontally through Diagnosis is primarily made in clinical terms, although NCSs can the prominence of the medial femoral epicondyle. Patients have be performed side-to-side, comparing amplitudes and latencies reported paresthesias and numbness in the infrapatellar region, (Figure 2). A needle EMG examination should be performed and which worsens with knee flexion, or from the compression of found negative to rule out a femoral neuropathy or lumbar radicu- garments or knee braces. lopathy. 19,22,27

On physical examination, the patient should have no weakness. If there is weakness, the examining physician should consider a femoral nerve injury or a L3 or L4 radiculopathy. There should be numbness along the course of the nerve, and deep palpation proximal to the medial epicondyle may reproduce the pain.

Diagnosis can be made by an NCS with side-to-side changes as well as a local injection along the course of the nerves and proximal site of the entrapment under ultrasound guidance. Needle EMG examination should be normal. This includes all L3 and L4 innervated muscles as well as muscles that are innervated by both the femoral and obturator nerves. Additionally, the lumbar paraspinal muscles should be tested to rule out a radiculopathy.

Treatment

Entrapment in Hunter's canal is treated with an IV soluble corticosteroid and a local anesthetic, preferably ultrasound guided. If this fails after multiple attempts, surgical decompression may be necessary. Persistent symptoms may also be treated with the neuropathic treatment model.

LATERAL FEMORAL CUTANEOUS NERVE INJURY Anatomy

The lateral femoral cutaneous nerve consists of the L2, L3, and L4 nerves and it can be entrapped or compressed as it goes through a fibromuscular ring through the inguinal ligament, the iliopsoas muscle, and distal femoral fascia. Meralgia paresthetica is another term used to describe this. Figure 2 Anatomy and stimulation technique for the lateral cutaneous nerve of the thigh. (Source: Johnson EW and colleagues, Practical Electromyography 1997;179.) 18 Mononeuropathies of the Lower Extremities in Sports AANEM Course

Treatment important branch allows for the identification of a sciatic nerve lesion’s location (Figure 3).29 Treatment for a lateral cutaneous nerve injury is an injection that uses local anesthetics and corticosteroids and can be ultrasound guided. If the injection provides complete but only short-term relief, surgical decompression or a neurolysis can be performed on the nerve. Persistent symptoms may be treated with the neuropathic treatment model.

OBTURATOR NERVE INJURY Anatomy

The obturator nerve is made up of the L2, L3, and L4 branches. It enters the obturator canal and leaves through the obturator foramen, supplies the adductor muscles as well as gracilis and obturator externus, and may be entrapped between the muscles.27

Clinical Figure 3 Anatomy of the sciatic nerve in the gluteal region. (Source: Johnson EW and colleagues, Practical Electromyography 1997;181.) The symptoms include weakness between the thigh and a sensory M = muscle; N = nerve deficit in the inner thigh. This is seen in rugby players with chronic groin pain. The players present with post-exercise thigh pain and the injury occurs at the level of the obturator foramen. The patient may Etiology also complain that his or her ability to jump is lessened. The symptoms worsen with exercise. In severe injuries, loss of adduction and The main etiology for sciatic nerve injuries in sports is from internal rotation occur, leaving the patient with an externally rotated major trauma. This includes falls on the buttocks, posterior hip foot. Wasting of the adductor muscles of the thigh may occur.3,4,18 dislocations, proximal tibia fractures and lower leg fractures, and as seen in football, direct trauma to the thigh. In addition, posterior Diagnosis can be made by needle EMG examination that would femoral cutaneous nerve lesions can be seen with patients who are indicate membrane irritability in the adductor muscles which are sitting on a bike, or after a hamstring tear with a complication of innervated by the obturator nerve. The femoral nerve and the myositis ossificans. This can cause direct entrapment of the nerve. lumbar paraspinals would be normal. This test must be performed The peroneal division is injured more frequently than the tibial to rule out other causes. division and tends to involve more severe injuries, yet the tibial nerve heals better than the peroneal branch. 7,18,19 Treatment Clinical Treatments for entrapment include electrical stimulation of the adductor and hip flexor muscles, stretching, and massage. Surgery On physical examination, symptoms may include weakness in the may be necessary in refactory cases. The surgery involves dividing hamstrings or other symptoms relating to the peroneal or tibial the fascia over the pectineus and the adductor longus muscles and nerves. Numbness in the foot and the back of the leg, as well as dissecting the space between the two muscles to relieve the anterior weakness in the dorsi and plantar flexion could also be experi- branch of the nerve. For chronic pain, the neuropathic treatment enced, depending on which branch is more severely injured. model is recommended. Diagnosis is made by neurodiagnostic studies with classic findings involving the peroneal, tibial, and sciatic innervated muscles SCIATIC NERVE INJURY with a prolonged H reflex and abnormal F waves to both the Anatomy tibial and peroneal nerves, as compared to the contralateral side. The paraspinals would be spared, ruling out an L5 and or S1 radiculopathy. The sciatic nerve is made up of the anterior rami of the tibial nerve and the posterior ramus of the peroneal nerve. The sciatic Treatment nerve exits through the pelvis of the greater sciatic foramen lateral to the ischial tuberosity beneath the piriformis muscle and The main focus for this type of injury is treating the trauma. The branches the four hamstrings before the bifurcation. The peroneal injured nerve treatment would focus on the peroneal or tibial fibers provide innervation to the short head of the biceps.23 This component. If there is weakness of the peroneal division, the AANEM Course Sports Related Neuromuscular Disorders 19 treatment is discussed below under treating common peroneal The examination reveals a variable pattern of weakness nerve injuries. Persistent symptoms and numbness can be treated with the extensor digitorum brevis (EDB) being affected with the neuropathic treatment model. as well as the ankle and toe dorsiflexions. Radiographs are important in the diagnosis of underlying trauma such as fibular head fracture. An ultrasound, computed tomography scan, or COMMON PERONEAL NERVE NEUROPATHY magnetic resonance imaging (MRI) of the knee may also be Anatomy of benefit. The EDX examination is the best method for evaluating the peroneal nerve. Sensory NCSs of the superficial peroneal are performed bilaterally. If the nerve is abnormal, it implies The common peroneal nerve arises from the sciatic nerve to that the lesion is distal to the dorsal ganglion and most likely approximately the distal third of the thigh region. At this point, not an L5 radiculopathy. Comparisons of side-to-side superfi- it descends to the popliteal fossa innervating the short head of the cial peroneal sensory nerve action potential (SNAP) evaluates biceps femoris muscle. In the fibular head, the common peroneal the degree of axonal loss and prognosis. Motor NCSs are gives off two branches, the sural communicating branch, and the performed with the active electrode on the EDB muscle. lateral cutaneous nerve of the calf. The common peroneal nerve Calculation of the peroneal nerve across the fibular head is then courses around the fibular neck and passes through the important. If the nerve conduction velocity is less than 40 ms, fibrous osseous opening in the superficial head of the peroneal it is considered abnormal and side-to-side testing may be longus muscle. Distal to the fibular tunnel, the common peroneal of benefit. If the compound muscle action potential is smaller divides into the superficial and deep peroneal branches. The from side-to-side, this may also be of benefit although the EDB superficial peroneal provides innervation to the peroneus longus may not be as reliable as other more proximal muscles. EMG and brevis muscles, and travels to pierce and open the deep fascia is important in confirming the exact location of the nerve injury. in the distal third of the anterior leg. The superficial peroneal In this situation, if the common peroneal nerve is the site of the nerve splits into the medial and lateral terminal sensory branches lesion, there should be abnormalities in both the deep peroneal that pass anterior to the ankle and innervate the dorsum of the as well as the superficial peroneal muscles. If the short head of foot, except for the region between the first and second toes. The the biceps muscle is involved it indicates that the lesion is proxi- deep peroneal nerve descends along the leg between the tibialis mal to the fibular head. In addition, the tibial nerve needs to be anterior and extensor hallucis longus, innervating those muscles examined, especially the flexor digitorum longus, to rule out an as well as supplying the extensor digitorum longus and the L5 or sciatic nerve injury.15,33 peroneus tertius muscle. Treatment Etiology In all acute nerve compromise or nerve compressions, reducing The etiology of the common peroneal nerve would be a direct inflammation is of primary importance. Oral or IM corticoster- compression from a stretch injury at the region of the fibular oids can be used as well as an ultrasound guided injection that head. This is seen in almost all sports and includes anterior bathes the nerve at the site of the compression. cruciate ligament (ACL) tears, lateral collateral ligament (LCC) tears, and posterior cruciate ligament (PCL) tears. It can be An ankle foot orthotic may be needed to be worn if severe foot seen in 20% of knee dislocations. Direct trauma from hockey drop occurs. Shoe orthotics may also be beneficial in patients pucks, direct blows from hockey sticks to the leg, kicking in with severe flatfoot or cavus foot. In a patient with a mild soccer, and helmet hits to the nerve itself are also causes. It is also lesion, taping the ankle or wearing high-top shoes may allow seen in cricket with tight bands on the uniform. Additionally, it the patient to participate in sports earlier. Electrical stimula- can be seen in hematomas or compartment syndrome, grade II tion may be used to decrease atrophy. Surgery should not be and grade III inversion ankle sprains, and in chronic repetitive performed unless there has been no improvement in over 4 months. activity such as runners with tight fascial bands or hypermobilities of Persistent sensory symptoms can be treated with the neuropathic the fibular head.18,19,20 It is seen in fabella syndrome, which is treatment model. entrapment by the accessory ossicle in the lateral gastrocnemius muscle. It is also seen as a surgical complication with lateral meniscus surgery and as a side effect of cryotherapy after an ice DEEP AND SUPERFICIAL PERONEAL NERVE NEUROPATHY bag has been taped on too tightly. Anatomy Clinical The superficial peroneal nerve travels in the lateral compartment, The patient presents with an altered gait, secondary to weak ankle innervates the peroneal longus and EBD muscles, and provides dorsiflexors. This could be referred to as a steppage gait. In certain sensation of the dorsum of the foot. The deep peroneal nerve cases, pain may not be present. The patient will have difficulty innervates the tibialis anterior, peroneus tertius, extensor hallucis, walking on his heels, have a noticeable foot slap on foot strike, or and provides sensation at the web of the first and second toes trip while walking. (Figures 4, 5, 6). 20 Mononeuropathies of the Lower Extremities in Sports AANEM Course

Figure 4 Deep branch of the peroneal nerve. Following major injury, surface conduction studies may not be sensitive enough to detect limited residual function. (Source: Johnson EW and colleagues, Practical Electromyography 1997;184.) M = muscle; N= nerve

Figure 6 Peroneal nerve sensory distribution. (Source: Johnson EW and colleagues, Practical Electromyography 1997;184.) N= nerve

Etiology

Compartment syndromes, due to fascial defects or a neuroma, are the most common injuries to these areas.5 The superficial peroneal can be directly injured with tight lacing of shoes. Injury can occur in the deep peroneal nerve in a variety of ways that include the use of tight- fitting ski boots, the act of kicking a soccer ball, or by tight en pointe movements performed by ballet dancers (Figures 7a and 7b).18,27

Clinical

The symptoms of the deep peroneal nerve injury include a vague burning sensation over the dorsum of the foot. In severe cases, Figure 5 Superficial branch of the peroneal nerve. (Source: there is decreased sensation in the first two toes, a first toe drop, or Johnson EW and colleagues, Practical Electromyography 1997;183.) a patient that trips when walking. The superficial peroneal nerve n = nerve injury has findings of decreased sensation and pain at the dorsum of the foot. The symptoms worsen with exercise. AANEM Course Sports Related Neuromuscular Disorders 21

Treatment

Treatment options for the deep and superficial peroneal nerves are similar to those for the common peroneal nerve injury with the added recommendation that no pressure is placed on the dorsum of the foot. Aggressive treatment with corticosteroids can be used.

Proper physical therapy, ankle-foot orthoses, and shoe orthotics may be used if necessary. Persistent symptoms should be treated with the neuropathic treatment model.

TIBIAL NEUROPATHY

Figure 7a Deep peroneal neuropathy. a Schematic drawing of the dorsal Anatomy midfoot with the ankle in plantar flexion illustrates the mechanism of deep peroneal neuropathy related to compression of the nerve (black arrowheads) against the underlying bones by external forces (arrow). A spindle The tibial nerve comes from the L3 to the S3 nerve roots. When neuroma (white arrowheads) may develop from the injured nerve fascicles the posterior tibial nerve is entrapped, it is called tarsal tunnel syn- at the site of trauma. b Long-axis 12-5 MHz US image of a 32-year-old drome (TTS). It is the most common type of entrapment of the soccer player who had received repetitive blows to the dorsum of the foot foot and ankle area (Figure 8). The nerve is a branch of the sciatic shows focal hypo echoic thickening (arrow) of the deep peroneal nerve nerve and enters the leg between the two heads of the gastrocne- (arrowheads) at the point where the nerve is closely apposed to the flat mius. Most individuals have a single calcaneal nerve which arises dorsal surface of the middle cuneiform (Cun/). M, metatarsal. c-e Serial from the posterior tibial nerve but sometimes may arise from the 12-5 MHz US images obtained from c proximal to e distal over the short lateral plantar nerve. Twenty-one percent of people have multiple axis of the injured nerve reveal progressive swelling of the fascicles (ar- calcaneal branches originating from the posterior nerve, lateral rowheads) evolving into a neuroma (arrow). a, dorsalis pedis artery. In plantar or medial plantar nerve, or a combination of the nerves. the diagram, the insert at the upper left indicates the area of interest. Source: Bianchi S & Martinoli C, Ultrasound of the Musculoskeletal The tarsal tunnel is formed by the medial surface of the talus, System, 2007;860. the inferomedial navicular, the sustentaculum tali, and the curved medial surface of the calcaneus. The fibrous portion of the canal is the flexor retinaculum which is also called the lacinate ligament. The retinaculum is formed by the deep superficial aponeurosis of the leg, as closely attached to the sheath of the posterior tibial at the flexor digitorum longus and flexor hallucis longus. The three branches are the lateral plantar, medial plantar and medial calcaneal divisions and provide sensation to the soles of the feet (Figure 9).

Etiology

TTS is seen in runners and has been described by Rask as joggers foot.28 He theorized that the excessive valgus or external rotation of the foot during running and excessive stretch on the medial Figure 7b Superficial peroneal neuropathy in an athlete complain- plantar nerve resulted in TTS.28 TTS is seen in runners with flat ing of numbness and paresthesias over the dorsolateral aspect of the feet who use corrective orthotics that actually compress the nerve in foot following a severe inversion trauma at the ankle. a Longitudinal the medial arch.13 TTS can be seen with tibial fractures or in frank 12-5 MHz US image of the lateral leg demonstrates fusiform swelling and hypoechoic appearance (arrows) of the superficial peroneal nerve dislocations of the ankle or deep lacerations that may be caused by (arrowheads) at the point where it crosses the fascia. b-e Transverse the blade of a skate. It can also occur in runners from compression Tl-weighted MR images of the lateral leg obtained from cranial (b) to by a Baker's cyst. The proximal tibial nerve can be entrapped by caudal (e) show the nerve (white arrowhead) as a small hypointense the tendinous arch of the origin of the psoas muscle. It can also be structure deep to the fascia and, more distally, coursing in the subcuta- a complication of surgery of the anterior cruciate ligament repair neous tissue close to the anterolateral aspect of the fibular shaft (open or Achilles tendon repair. TTS is also commonly seen in mountain arrowhead). At the level of the fascial opening (c,d), the nerve (arrow) climbers and skiers.19,20 appears markedly thickened as a result of traction injury. Note the relationship of the nerve with the extensor digitorum longus (edl), the per- Patients will present with diffuse vague discomfort or pain with oneus brevis muscle (pbm) and the peroneus longus tendon (asterisk). burning, tingling, or frank numbness in the plantar area of the foot. Source: Bianchi S & Martinoli C, Ultrasound of the Musculoskeletal Occasionally, there might be a report of proximal radiation of pain System, 2007;760. in the medial leg. Prolonged standing and walking exacerbate the symptoms while rest can improve the symptoms. 22 Mononeuropathies of the Lower Extremities in Sports AANEM Course

Figure 8 Tarsal tunnel syndrome in patient who had a prominent bony spur at the posteromedial talus following a fracture. a,b Transverse 12-5 MHz US images of the tarsal tunnel obtained a in plantar flexion and b during forced eversion and dorsiflexion of the foot. a In plantar flexion, the bony spur (arrow) is seen as a hyperechoic image which bulges in the tunnel between the flexor digitorum longus (fdl) and the flexor hallucis longus (fhl) tendons. The tibial nerve (arrowheads) is located behind the posterior tibial artery (a) and veins (v) and appears swollen and hypoechoic in comparison with its normal appearance depicted in Fig. 16.30. tp, tibialis posterior tendon b During eversion and dorsiflexion of the foot, the nerve appears flattened and compressed against the anomalous bone. c,d The location and appearance of the bony spur (arrows) is well depicted on a c CT scan and d T2*-weighted MR image. e,f Photographs of the medial aspect of the ankle with the patient's foot e plantar flexed and f dorsiflexed and everted. In f note the abnormal surface prominence of the spur (curved arrow). MM, medial malleolus. Figure 9 The tarsal tunnel and course of the tibial nerve. Source: Source: Bianchi S & Martinoli C, Ultrasound of the Musculoskeletal Johnson EW and colleagues, Practical Electromyography 1997;189. System, 2007;816. N = nerve

Patients also present with night pain that improves with massage Differential diagnosis includes plantar fasciitis, heel spurs, plantar or walking. It is worse with extreme dorsiflexion secondary to the cellulitis, tibial sciatic neuropathy, lumbar radiculopathy, and a nerve tension. Patients with entrapment of the lateral nerve have Morton's neuroma. experience of chronic heel pain that may be present for nearly 9 to 12 months. The symptoms are similar to those of plantar fas- The diagnosis is made by history and physical examination. EMG ciitis. These patients can have pain when they are weight bearing, and NCSs of the medial and lateral plantar nerves can be used to when they are seated, and during the evening hours. Patients are confirm the diagnosis. Motor, sensory, and mixed NCSs can be usually asymptomatic in the mornings prior to weight bearing, performed. Needle EMG of the muscles innervated by both the but find that symptoms worsen with increased activity (e.g., long medial and lateral plantar nerves is necessary. It has been reported periods of standing, walking, or running) and toward the end of that the accuracy of the SNAP and mixed nerve potentials are the day. almost identical, but the SNAPs were found to be more sensitive and less specific while the mixed nerves were less sensitive and Clinical more specific. The mixed NCS is technically easier to perform and is better tolerated in patients. Approximately 90% of patients with On physical examination, the patients experience the most severe TTS will have abnormal findings on EMG and NCSs.8 tenderness over the first branch of the lateral plantar nerve, and over the plantar medial heel under the abductor hallucis muscle. Treatment Many patients have tenderness along the entire posterior tibial nerve starting from the distal medial malleolus. Tenderness may Treatment for TTS is directed towards the underlying etiology of also be present over the plantar fascial insertion in the medial cal- neural compression.32 Nonoperatively, patients can have a trial of caneal tuberosity. immobilization with the use of a cast, walking boots, and orthotic management that will relieve the postural abnormalities caused by Patients with entrapment of the medial plantar nerve may chronic traction or compression traction to the nerve. Treatment notice tenderness over the medial arch inferior to the navicu- such as corticosteroids and local anesthetic injections guided by lar tuberosity and not directly over the plantar fascia, and may ultrasound can also be of benefit. Chronic pain symptoms may be have Tinel's sign at that area with prolonged weight bearing. treated with the neuropathic treatment model. 23

SURAL NERVE INJURY the lower fibers of the transverse abdominal muscle and internal oblique and divides into lateral and anterior cutaneous branches. Anatomy Etiology The sural nerve comes from the tibial and common peroneal nerves. It is from the S1 nerve root and it is a pure sensory nerve to The nerve is rarely injured in isolation. Surgical procedures are the lateral part of the leg and foot. recognized as the most common cause, but nerve injury may also occur in sports as a direct trauma. The sports injuries are seen Etiology with groin injuries and tears of the lower abdominal muscle in hockey, rugby, soccer, and any other type of sport that involves The etiology of injury is from direct compression from a Baker's spinal rotation. 2 cyst that may include tight boots worn while skiing or skating, ankle reconstruction surgery, or a fifth metatarsal fracture. 18 Clinical

Clinical The symptoms include burning or lancinating pain in the groin area. The pain occasionally may extend into the genitalia due to the Symptomatically, the patient will have pain or numbness in the significant overlap of the other cutaneous nerves. There is usually posterior leg with no weakness. Differential diagnosis includes an no loss of sensation. S1 radiculopathy or lumbosacral plexopathy. On examination, there is pain and tenderness in the area of the Treatment scarring or entrapment. There may be hyperesthesia or hypoesthesia in the area supplied by the nerve. Nonoperative treatment is similar to treatment in the neuropathic treatment model. Three major criteria are used to diagnose the nerve. The first is a history of the injury. Pain can be elicited by palpating laterally near the scar injury area. Second, a definite area of hypoesthesia Pudendal Neuropathy or hyperesthesia should be identified in the region of supply of the Anatomy iliohypogastric nerve. Third, infiltration of a local anesthetic into the region where the iliohypogastric and ilioinguinal nerves depart the internal oblique muscle where symptoms can be reproduced The pudendal nerve arises from the S2 to S4 nerves. on physical examination by palpation should provide relief. This could be enhanced by ultrasound guidance. If there is no relief Etiology with the injection, a different etiology should be sought to explore the problem. Differential diagnosis includes upper lumbar or lower In cyclists, 11% to 27% experience penile numbness and up to thoracic nerve root pathology from a discogenic injury. No reliable 13% are impotent. In addition, female cyclists or those who par- EDX techniques are available to define the integrity of the nerve, ticipate in spinning classes have reported desensitization in the although needle EMG of the lower abdominal musculature may genital area. suggest injury.

Treatment Treatment

Special seat coverings, such as the Spenco seat cushion, distribute Nonoperative treatments include ultrasound guided local injections the pressure over a greater area. Conservative treatment is the neu- of anesthetic and corticosteroid, oral medications, and physical ropathic treatment model. therapy. Nonoperative treatment would include the neuropathic treatment model. If this is unsuccessful, surgical excision may be necessary.32 SPORTS HERNIAS

Anatomy IlIOINGUINAL NEUROPATHY Anatomy The iliohypogastric nerve arises primarily from the ventral primary ramus of L1 with a contribution from T12. The iliohypogastric nerve traverses the psoas major and pierces the lateral border an- The illoinguinal nerve arises from T12 and L1 nerve roots. The nerve terior to the quadratus lumborum muscle. It is posterior to the supplies the sensory branches that supply the pubic symphysis, the su- kidney and transverse to the lateral abdominal wall. The nerve perior and medial aspect of the femoral triangle, the root of the penis penetrates the transverse abdominal muscle near the iliac crest and anterior scrotum in males, or the mons pubis and labia majora that comes between the internal oblique musculature. It supplies in females. 24 Mononeuropathies of the Lower Extremities in Sports AANEM Course

11. Haig, AJ. Pedal pusher’s palsy. N Engl J Med. Jan 1989; Ilioinguinal nerve injuries have been reported in hockey players. 14 320(1):63. Harms BA, DeHaas Dr. Jr, Starling JR. Diagnosis and management of genitofemoral neuralgia. Arch Surg. MAR 1984; Clinical 119(3):339-41. [Medline]. 12. Hemler, DE, Ward, WK, Karstetter, KW, Bryant, P.M. Saphenous The patients present with hyperesthesia or hypoesthesia. This nerve entrapment caused by pes anserine bursitis mimicking stress fracture of the tibia. Arch Phys Med.Rehab. Apr 1991;72(5):336-7. injury is along the inguinal ligament and may radiate into the 13. Henricson AS, Westlin NE. Chronic calcaneal pain in athletes: lower abdomen. Pain or tenderness may be present with applica- entrapment of the calcaneal nerve? Am J Sports Med. MAR-Apr tion of pressure where the nerve exits the inguinal canal in up to 1984;12(2):152-4. 75% of the patients. Sensory impairment is common in this same [Medline]. distribution. Diagnosis is made by local infiltration of anesthetic 14. Irshad K, Feldman LS, Lavole C, et al. Operative management and should provide relief within 10 minutes. of “hockey groin syndrome”; 12 years of experience in National Hockey League players. Surgery. Oct 2001;130(4):759-64; discussion Treatment 764-6. [Medline]. 15. Katirji MB, Wilbourn AJ. Common peroneal mononeuropathy: a Treatment is similar to that of the iliohypogastric nerve. clinical and electrophysiologic study of 116 lesions. Neurology. Nov 1988;38(11)1723-8. [Medline]. 16. Kim DH, Kline DG. Surgical outcome for intra- and extrapel- CONCLUSION vic femoral nerve lesions. J Neurosurg. Nov 1995;83(5):730-90. [Medline]. 17. Kopell HP, Thompson WA. Knee pain due to saphenous nerve en- In conclusion, for an athlete to return to competitive sports, he or trapment. N Engl J Med. 1962;266:16-9. she must have the injured leg equal to 90% of the noninjured limb. 18. Kriuickas LS, Wilbourn AJ. Semin Neurol 2000(2):225-32 . The sooner the diagnosis has been made and treatment begins, the [Medline]. sooner the athlete can return to play. The athlete is very grateful 19. Kriuickas, LS, Wilbourn, AJ. Sports and physical nerve injuries, when a difficult diagnosis is made and when appropriate treatment report of 190 injuries evaluated in a single electromyography lab. is provided. Removing the swelling from the nerve, allowing the Muscle and Nerve. Aug 1998;21(8)1092-4. nerve to heal, and finally exercising to allow the athlete to return 20. Leach, RE, Pernell, MB, Saito A. Peroneal nerve entrapment in to the sport of their choice. Through the use of a neurological runners. Am. J Sports Med. Mar-Apr 1989;17(2):287-91. 21. Logue, EJ III, Drez D, Jr. Dermatitis complicating saphenous nerve examination and EDX testing, the neuromuscular physician is able injury after arthroscopic debridement of a medial meniscal cyst ar- to assist the athlete in the rehabilitation process. throscopy. Apr 1996;12(2):228-31. 22. Macgregor, J, Moneur, JA. Meralgia paresthetica—a sports lesion in a girl gymnast. Br J Sports Med. Apr 1977;11(1):16-9. REFERENCES 23. McCrory P, Bell S, Bradshaw C. Nerve entrapments of the lower leg, ankle and foot in sport. Sports Med.2002;32(6):371-91. [Medline]. 1. Austin KS. Complications of arthroscopic meniscal repair. Clin 24. Miller EH, Benedict FE. Case report: Stretch of the femoral nerve in Sports Med. Jul 1966;15(3):613-9. [Medline]. a dancer. J Bone Joint Surg. Am. Feb 1985;67(2):315-7. 2. Bower S, Moore BB, Weiss, SM. Neuralgia after inguinal hernia 25. Mitra A, Stern JD, Perrotta VJ, Moyer RA. Peroneal nerve entrap- repair. Am. Surg. Aug 1996;62(8):664-7. [Medline]. ment in Athletes. Ann Plast Surg. Oct 1995;35(4):366-8. [Medline]. N 3. Bradshaw, C, McCrory P. Obturator nerve entrapment. J Sports Med. Engl J Med. 1962;266:16-9. Jul 1997;7(3)217-9. 26. Nitz, AJ, Polsner, JJ, Kersey D. Nerve injury and grade II and III 4. Brukner P, Bradshaw C, McCrory P. Obturator neuropathy: a cause ankle sprain. Am. J Sports Med. May-Jun 1985;13(3):177-82. of exercise related groin pain. Physician Sports Med. 1999;27:62-73. 27. Peri, G. The critical zones of entrapment of the nerves of the lower 5. Detmer, DE, Sharp K, Sufit, RL, Girdley, FM. Chronic compartment limb. Surg Radiol. Anat. Jul-Aug 1991;13(21);139-43. syndronme, diagnosis, management, and outcomes. Am. J Sports 28. Rask, Mr. Medial plantar neuropraxia (jogger’s foot) report of 3 Med. May-Jun 1985;13(3):162-70. cases. Clinical Orthop. Relat. Res. 1978 Jul-Aug;(134):173. 6. Fabian, RH, Norcross, KA, Hancock, MD. Surfer’s neuropathy. New 29. Sammarco GJ, Stephens, MM. Neuropraxia of the femoral nerve in Eng J Med. Feb 1987;316(9):555. a dancer. Am. J Sports Med. Jul-Aug 1991;19(4):413-4. 7. Fassler, PR, Swiontkowski, MF, Kilroy, AN, Routh, MI Jr. Injury of 30. Sridhara CR, Izzo KL. Terminal sensory branches of the superficial sciatic nerve associated with acetabula fracture. J Bone Joint Surg peroneal nerve: an entrapment syndrome. Arch Phys Medication Am. Aug 1993;75(8):1157-66. Rehabil. Nov 1985;66(11):789-91. [Medline]. 8. Galardi G, Armadio S, Maderna L, et al. Electrophysiological studies 31. Starling JR, Harms BA. Diagnosis and treatment of genitofemoral in tarsal tunnel syndrome. Diagnostic reliability of motor distal and ilioinguinal neuralgia. World J Surg. Sep-Oct 1989;13(5):586-91. latency, mixed nerve and sensory nerve conduction studies. Am J [Medline]. Phys Med Rehabil. Jun 1994;73(3):193-8. [Medline]. 32. Weiman TJ, Patel VG. Treatment of hyperesthetic neuropathic pain 9. Gleeson, AP, Kern, JG. Patella dislocation neuropraxia injury. in diabetics. Decompression of the tarsal tunnel. Ann Surg. June Sep 1995;27(7):519-20. 1995:221(6):660 4; discussion 664-5. Medicine. 10. Grosz CR. Iliohypogastric nerve injury. Am J Surg. Injury to iliohy- 33. Wilbourn AJ. AAEE case report #12: Common peroneal mononeu- pogastric nerve after hernia surgery. 1981;142(5):628. [Medline]. ropathy at the fibular head. Muscle Nerve. Nov-Dec 1986;9(9):825- 36. [Medline]. Exercise in Neuromuscular Diseases

Mark A. Tarnopolsky, MD, PhD Tanja Taivassalo, PhD Timothy J. Doherty, MD, PhD, FRCP(C) Gregory T. Carter, MD, MS David D. Kilmer, MD

2008 COURSE H AANEM 55th Annual Meeting Providence, Rhode Island

Faculty

Mark A. Tarnopolsky, MD, PhD Tanja Taivassalo, PhD Professor Assistant Professor Department of Pediatricsand Medicine Department of Kinesiology and Physical Education McMaster University McGill University Hamilton, Ontario, Canada Montreal, Quebec, Canada Dr. Tarnopolsky received his bachelor’s degree in physical education, Dr. Taivassalo completed her PhD at McGill and the Montreal Neurological his medical degree, and his PhD in cell biology and metabolism from Institute assessing the potential benefits of exercise training in patients with McMaster University in Hamilton, Ontario, Canada. He is a clinician mitochondrial disease. Postdoctoral studies at the Institute for Exercise scientist who holds the Hamilton Hospitals Assessment Centre Endowed and Environmental Medicine in Dallas, Texas advanced her knowledge Chair in Neromuscular Disorders and is also the director of the Corkins/ in cardiovascular physiology and integrative exercise testing. Now back Lammert Neuromuscular and Neurometabolic Clinic at McMaster at McGill in the Department of Kinesiology and Physical Education, Dr. University Medical Centre. Taivassalo’s laboratory focuses on the study of genetic mutations affecting skeletal muscle mitochondrial function, their impact on physiological Dr. Tarnopolsky is also a member of the school's graduate faculty in the and exercise capacity, and interventions designed to reverse their effects in departments of medical sciences, cell biology, and metabolism. He is the conditions of human disease and aging. Her research combines cell and author of over 200 publications, has contributed to several books, and also molecular analyses of muscle tissue with physiological studies of heart, serves on the editorial board of Muscle and Nerve, Mitochonrdial, Clinical lung, and blood flow responses during exercise, along with magnetic reso- Journal of Neuromuscular Disorders, and is an assosicate editor for Medicine nance imaging and spectroscopy. Current grant-funded research studies and Science in Sports and Exercise. His areas of interest include expertise focus on exercise training strategies for mitochondrial disease, particularly in the areas of nutrition and metabolism in neuromuscular and neuro- assessing whether endurance exercise provides a safe and effective means of metabolic diseases and the effects of aging on mitochondrial function. improving muscle oxidative capacity and exercise tolerance by increasing numbers of functional mitochondria. A second strategy, resistance exercise, is aimed at activating muscle satellite cells thereby also increasing numbers of functional mitochondria. Another research focus is to elucidate the role of muscle mitochondrial dysfunction on regulating oxygen delivery during exercise.

Authors had nothing to disclose.

Course Chair: Mark A. Tarnopolsky, MD, PhD

The ideas and opinions expressed in this publication are solely those of the specific authors and do not necessarily represent those of the AANEM. iii

Timothy J. Doherty, MD, PhD, FRCPC David D. Kilmer, MD Associate Professor Professor and Chair of the Physical Medicine & Rehabitation Departments of Clinical Neurological Sciences and Rehabilitation Department Medicine University of California Davis Medical Center University of Western Ontario Sacramento, California London, Ontario, Canada Dr. Kilmer received his medical degree and training in physical medicine Dr. Doherty is an assistant professor in the Departments of Clinical and rehabilitation (PMR) at the University of California, (UC) Davis. He Neurological Sciences and Rehabilitation Medicine at the University of currently serves as Professor and Chair of the Department of PMR at UC Western Ontario in London, Ontario. In March, 2005, he was named Davis Medical Center in Sacramento, CA, and is Director of the PMR the Canada Research Chair in Neuromuscular Function in Health, Aging, Electrodiagnostic Laboratory. He is subspecialty certified in neuromuscu- and Disease. He is a consultant physiatrist and clinical neurophysiologist lar medicine, and a member of the Neuromuscular Medicine Examination at London Health Sciences Centre. Dr. Doherty is the author of over Committee of the American Board of Psychiatry and Neurology. Dr. 50 peer-reviewed papers. His research focuses on the examination of the Kilmer’s research interests focus on exercise and functional performance in motor system and motor units in health, aging, and disease. He and his persons with neuromuscular diseases. collaborators have developed a number of electrophysiological methods for examining the numbers and properties of human motor units, including electromyography decomposition analysis. These methods are being applied to the study of aging, motor neuron disease, and hereditary neuropathy.

Gregory T. Carter, MD Clinical Professor Department of Rehabilitation Medicine University of Washington Centralia, Washington Dr. Carter is Clinical Professor of Rehabilitation Medicine at the University of Washington, where he co-directs the Muscular Dystrophy Association (MDA)/Amyotrophic Lateral Sclerosis Center. He also directs MDA Clinics in the Providence Health System, Southwest Washington. His clinical research assesses pain and quality of life in neuromuscular disease (NMD). His pre-clinical research characterizes electromyography in mutant and transgenic murine models of NMD. He has over 100 peer-reviewed publications and has previously received the Best Research Paper Award from the American Academy of Physical Medicine and Rehabilitation, the Excellence in Research Writing Award from the Association of Academic Physiatrists, and the Excellence in Clinical Care Award from the MDA. iv

Contents

Faculty ii

Objectives v

Course Committee vi Exercise in the Treatment of Aging Associated Sarcopenia and Metabolic Myopathy 1 Mark A. Tarnopolsky, MD, PhD

Exercise Training in Metabolic Myopathies 9 Tanja Taivassalo, PhD

Exercise in Diseases of the Motor Neuron and Motor Axon 15 Timothy J. Doherty, MD, PhD, FRCP(C)

Exercise Training in Muscular Dystrophy 19 Gregory T. Carter, MD, MS

Measuring and Promoting Exercise in a Free-living Environment in Persons With Neuromuscular Disease 29 David D. Kilmer, MD

CME Activity and Faculty Evaluation 33

O b j e c t i v e s —After attending this session, participants will be able to (1) review the effect of aging on muscle mitochondrial capacity and explore the link with sarcopenia, (2) assess the effects of physical activity and inactivity on skeletal muscle and cardiopulmonary exercise response in patients with metabolic myopathies, (3) understand the role of physical activity monitoring in a community environment to both measure and promote physical activity in persons with NMD, (4) review the effects chronic injury to the motor neuron and motor axon have on skeletal muscle function, (5) examine the role of electrodiagnostic studies in predicting response to exercise therapy, (6) evaluate the role of resistance exercise in acute and chronic diseases of the motor neuron and motor axon, as a countermeasure to sarcopenia at the molecular level, and as a rehabilitation modality in humans with muscle disease, (7) review the pertinent animal studies examining the effect of exercise on dystrophic muscle disease and the effect of exercise on humans with muscle disease, and (8) compare and contrast results seen in animal models versus human trials. P rerequisite —This course is designed as an educational opportunity for physicians. A c c r e d i t a t i o n St a t e m e n t —The AANEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. CME Cr e d i t —The AANEM is accredited by the ACCME to provide continuing medical education (CME) for physicians. The AANEM designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s) TM. Each physician should only claim credit commensurate with the extent of their participation in the activity. This event is an Accredited Group Learning Activity as defined by the Maintenance of Certification Program of The Royal College of Physicians and Surgeons of Canada. CME for this activity is available 9/08 - 9/11. vi Exercise in Neuromuscular Diseases

2007-2008 AANEM COURSE COMMITTEE Anthony E. Chiodo, MD, Chair Ann Arbor, Michigan

Shawn J. Bird, MD Erick A. Grana, MD Simon Zimnowodzki, MD Philadelphia, Pennsylvania Tampa, Florida Chicago, Illinois

Kevin B. Boylan, MD Thomas Y.C. Pang, MD Sasa Zivkovic, MD Jacksonville, Florida Chicago, Illinois Pittsburgh, Pennsylvania

Gary L. Branch, DO David Bryan Shuster, MD Owosso, Michigan Dayton, Ohio

2007-2008 AANEM PRESIDENT Peter D. Donofrio, MD Nashville, Tennessee 1

Exercise in the Treatment of Aging Associated Sarcopenia and Metabolic Myopathy

Mark A. Tarnopolsky, MD, PhD Professor Departments of Pediatrics and Medicine McMaster University Medical Center Hamilton, Ontario, Canada

and the prevalence of falls and fractures.40,76 Clearly INTRODUCTION countermeasures designed to increase strength and decrease the prevalence of sarcopenia should have a significant impact Sarcopenia is a term describing the age-related loss of muscle on society. Mitochondria and oxidative stress play an im- mass to less than 2 standard deviations below age-matched portant role as modulators of age-associated sarcopenia. normal subjects. It is usually measured as fat free mass (FFM) by whole body imaging methods such as dual energy x-ray Table 1 Molecular causes of sarcopenia absorptiometry.67 Sarcopenia has been reported in nearly 10% of people over age 70, and in 20% of those over age 80.10,34,58,67 The accompanying muscle weakness in sarcopenia leads to functional • Physical inactivity impairments in tasks that are important to personal independence, • Oxidative stress and can lead to a greater risk of falls. It has been estimated that • Mitochondrial dysfunction the annual costs attributable to sarcopenia related impairments • Apoptosis is approximately $18 billion (US dollars).50 Sarcopenia is clearly a • Alpha motor neuron loss multi-factorial process that involves apoptosis, motor unit (MU) • Reduced protein synthetic rate loss, oxidative stress, alterations in protein turnover, inflamma- • Accumulation of aging pigments including advanced glycosylation tion, hormonal dysregulation, disuse, and mitochondrial dysfunc- end products and lipofuscin tion (Table 1). 1,4,35,38,62,63,105 In addition to strength loss with • Alterations in protein degradation (increased myofibrillar; decrease aging, there is also a reduction in aerobic capacity.79 Although in other proteins) central factors such as cardiac output contribute significantly to the loss of aerobic capacity,30 there are a number of muscle- Additionally, exercise has the ability to provide a countermeasure related factors that also contribute, especially a reduction in for sarcopenia. mitochondrial capacity.

Sarcopenia ultimately leads to a decrease in physical func- EFFECT OF AGING ON SKELETAL MUSCLE tion and capacity. Falls occur in about 30% of people over Changes in Muscle Mass and Strength the age of 65 who live independently. Nursing home residents who had a history of falls showed significantly lower dynamic strength measurements of the knees and ankles when compared A common characteristic of the aging process is a reduction in to nonfallers.98 Leg muscle weakness results in a slowing of skeletal muscle mass and an infiltration of muscle with intramyo- walking speed as well as a reduction in the ability to stair cellular lipid and connective tissue.18,27 Cross-sectional studies climb and rise from a chair.5,25 Finally, studies have have shown that FFM is maintained until about the sixth decade shown an inverse relationship between leg strength of life and then begins to decline.67,69 Several other studies have 2 Exercise in the Treatment of Aging Associated Sarcopenia and Metabolic Myopathy AANEM Course found an age-associated loss of FFM.32,63 A progressive decline the myofibrillar protein fractional synthetic rate was 30% lower in strength is seen in association with lower muscle mass:29 for in 60-to 70-year-old men, as compared to men less than 35 years example, the isometric torque of the knee extensors (- 44%) and of age,95 and the age-related reduction in muscle synthetic rate elbow flexors (-32%) are both lower in a 69 year old than in a is associated with a reduction in myofibrillar protein messenger 28-year-old man.53 Muscle power decreases even more rapidly with ribonucleic acid (mRNA) content (i.e., fast myosin isoforms).97 age than strength, and this reduction is also associated with impair- Importantly, knee extension strength and muscle mass were also ments in physical function.64 positively correlated with myosin protein synthesis rates in older adults.4 The mitochondrial protein synthesis rates and electron Several studies show that the age-associated decline in muscle transport chain activity show parallel declines with age,80 with strength is predominantly a function of the loss of skeletal muscle no aging associated changes in the sarcoplasmic protein synthe- mass per se.20,29,42,52 For example, a 12-year longitudinal study of sis rates.4 Together, the data suggests that the synthetic rates of men from age 65 to 77 years found that the vast majority (90%) contractile and mitochondrial proteins are negatively affected by of the 20% to 30% strength loss (approximately 1.4 %/years) human aging and that these are linked to the functional deficits was explained by the reduction in cross-sectional muscle area over associated with aging.75 the time period.29 Single-fiber experiments have shown that the amount of contractile proteins and the peak force normalized to Studies that have measured protein breakdown in older muscle fiber size was not affected by aging.92 This finding implies and younger adults did not indicate a difference in whole body that individual fiber “quality” is maintained with aging and that proteolysis or urinary 3-methylhistidine excretion (an indirect sarcopenia is a quantitative and not a qualitative process. In measure of myofibrillar proteolysis).96,103 It has been reported that contrast, others have reported that there is an age-related decline basal induced, but not acute exercise induced levels of 3-methyl- in strength, independent of the muscle mass loss and have histidine were higher in skeletal muscle microdialysate from older suggested that muscle quality also declines with age.68 At the whole men as compared to younger men.93 In contrast, others have muscle level, an increase in glycation-related collagen cross-linking suggested that aging is associated with an accumulation of damaged in skeletal muscle from older adults,44 could also attenuate proteins, as evidenced by an increase in the half-life of proteins and contractile force independent of muscle mass. An increase in a lower ubiquitin-proteosome activity.36 Proteomic studies in rat other age-associated pigments, such as lipofuscin, is a characteristic skeletal muscle have shown lower overall abundance of proteins feature of the aging process, but may not be linked directly with such as creatine kinase, myosin light chain-3, and tropomyosin; mitochondrial dysfunction.47 and higher levels of myosin light chain-1, aconitase, and adenylate kinase.70 The apparent conflicting myosin light chain results from In addition to a reduction in muscle fiber size, there appear to the latter study,70 show that the crude measurements of synthesis be some changes in fiber type proportion that can also influ- and breakdown do not give the complete picture of the specific ence strength. The age-associated loss of muscle appears to affect proteins that are altered by sarcopenia. type II fibers more than type I, with studies finding both smaller type II muscle fibers,2,15,39,53,57 and a lower proportion of type II Mitochondrial Dysfunction and the Link With muscle fibers.49,57 Others have shown that the size of type IIa Sarcopenia and Apoptosis fibers and myosin heavy chain IIa composition were smaller only in older women, but not men, as compared to younger adults.92 Several studies have demonstrated a reduction in mitochon- These observations suggest a general trend towards a decrease drial enzyme activity with aging.15,80 The cause of the age- in whole muscle strength, through losses in type II fiber size and related decrease in mitochondrial capacity is unclear; however, proportion. The cause of the loss of type II fibers is unclear; studies have shown that there is a coordinate down-regu- however, there are only about half the number of (MUs) remain- lation of genes involved in mitochondrial function in ing in the biceps brachii muscle of 60-to 80-year-old adults as skeletal muscle from older adults.66,106 Using a targeted quan- compared to 20-to 40-year-old adults.20 A reduction in the titative real time polymerase chain reaction approach, robust number of MUs could explain the observation that the total evidence for mitochondrial dysfunction in skeletal muscle from number of type II muscle fibers in an entire muscle are reduced older versus younger adults was found (Figure 1). In addition, in older adults.62,63 Overall, the data implies that sarcopenia is there has been a discovery of an age-associated accumulation of mi- associated with a reduction in the total number of muscle fibers, tochondrial deoxyribonucleic acid (mtDNA) deletions in human with a propensity for the type II fibers to be more affected. skeletal muscle55,72 (Figure 2). Animal studies suggest that the accumulation of mtDNA deletions with aging is highest in the type I fibers (with higher mitochondrial volume).74 Given the few introns Changes in Protein Turnover and lack of protective histones in mtDNA versus nuclear deoxyribonucleic acid (DNA), there is a higher propensity for the stochas- At the protein level, sarcopenia is a consequence of an imbalance tic accumulation of oxidative damage mediated DNA mutations in between the rates of muscle protein synthesis and muscle protein mtDNA as compared to nuclear DNA.102 Although somewhat con- breakdown, with a negative net muscle protein balance. The rate of troversial, it has been suggested that the progressive accumulation mixed muscle protein synthesis is lower in 60-to 70-year-old men of mtDNA mutations is thought to occur as a result of a “vicious and women as compared to 20-to 32-year-old adults.103 Similarly, cycle,” whereby ETC generated free radicals further induce mtDNA AANEM Course Exercise in Neuromuscular Diseases 3

Antioxidant/Oxidative Stress have shown that aging is associated with an increase in cytochrome c and endonuclease G from mitochondria in association with a SOD1 SOD2 11 0.3 0.15 30% reduction in mitochondrial content in type II muscle fibers. Skeletal muscle from older rats and mice also show evidence of 0.2 0.10 22,88 * a p53 associated activation of apoptotic pathways. Finally, 0.1

0.05 Fold change * Fold change the mitochondrial mutator mouse has a large increase in mtDNA

0.00 0.0 deletions and point mutations. This is caused by a defective Young Old Young Old polymerase gamma mutation and displays an aging phenotype94 which is associated with an increase in cleaved caspase-3 in skel- Apoptosis etal muscle.56 Although definite evidence for apoptosis in human

bcl-2 bax sarcopenia is still somewhat circumstantial, it is well supported in 0.06 0.03 the animal-based literature. It is important to note that a loss of * 0.04 0.02 only 0.5% of the myonuclei from age 30 to 70 years could account for a 20% decline in muscle mass, and yet such a low level of 0.02 0.01 Fold change * Fold change myonuclei undergoing apoptosis at any given point in time would

0.00 0.00 Young Old Young Old

Mitochondrial Structure and Function

COX IV Mfn 2 0.6 0.04

0.03 0.4 * * 0.02 0.2 Fold change Fold change 0.01

0.0 0.00 Mitochondrial DNA deletions in skeletal muscle. Shaded arrow Young Old Young Old Figure 2 = full length mitochondrial DNA product through long-range PCR; bracket Figure 1 mRNA abundance for selected genes involved in antioxidant = short length mitochondrial DNA fragments in older adults characteristic defenses, apoptosis, and mitochondrial structure/function in vastus lateralis of mitochondrial DNA deletions. Also note the reduction in full length from young (20 to 26 years) n=12) and older (65 to 79 years) n=12) adults. mitochondrial DNA product in older adults which is primarily a technical issue due to oxidative damage to the mitochondrial DNA with aging inter- COXIV = cytochrome c oxidase sub-unit IV; mfn2 = mitofusin 2; fering with polymerase action. MRNA=messenger ribonucleic acid; SOD1 = Copper zinc-super-oxide dismutase; SOD2 = magnesium-super-oxide dismutase; DNA = deoxyribonucleic acid; PCR = polymerase chain reaction mutations that, in turn, alter ETC proteins and increase reactive oxygen species generation. Associated with the mtDNA mutations is an increased occurrence of cytochrome c oxidase (COX), complex be difficult to detect with current in situ methods such as termi- IV negative muscle fibers, and COX enzyme deficiency.55,59,72 nal deoxynucleotidyl transferase-mediated dUTP-biotin nick end A link between muscle atrophy and mitochondrial dysfunction has labeling staining. been shown by demonstrating that focal atrophy of skeletal muscle has been found in regions with a reduction in COX activity and an increase in mtDNA deletions.1,59 AGING AND RESISTANCE EXERCISE (EFFECTS ON MUSCLE MASS AND FUNCTION Some have suggested that part of the sarcopenia process is related to apoptosis of myonuclei and a subsequent loss of the myonuclear Several groups have reported that resistance (RES) exercise domain under control of the lost nuclei. The mitochondria also training induces muscle hypertrophy and increases the rate play an important role in the activation of apoptosis through the of muscle protein synthesis in middle aged, elderly, and physically release of cytochrome-c, which interacts with Apaf-1 and caspase-9 frail adults.8,12,24-26,28,65,90,104 For example, 12 weeks of whole to form the apoptosome, which activates downstream effector body RES exercise resulted in an increase in type II muscle caspases, such as caspase-3. Activation of apoptosis by the fiber area in 64-to 86-year-old women12 and 65-to 72-year-old mitochondrial pathway appears to involve an opening of the mi- men.8,28 Increases have been found in both type I and IIx muscle tochondrial permeability transition, which in turn is opened by fiber areas following 4 months of RES training in older men and free radicals (predominantly peroxynitrate).85 The abundance of a women.7 A 2-year longitudinal trial of RES exercise training number of transcripts for apoptosis factors including caspases-3, -8, reported increased leg press (32%) and military press (90%) one- and -9 and apoptosis inducing factor were higher in skeletal muscle repitition concentric maximum (1 RM), and knee extensor muscle from older rats.3 There is an increase in DNA fragmentation cross-sectional area (9%) in 60 to 80 year old men and women. 71 (a marker of apoptosis) in gastrocnemius muscle of a 24-month- Long-term exercise also appears to be protective against age-associ- old rat, as compared to that seen in 6-month-old rats.19 Others ated strength loss for Master’s athletes (69 ± 1 year), who performed 4 Exercise in the Treatment of Aging Associated Sarcopenia and Metabolic Myopathy AANEM Course

A B * RES exercise training and had muscle strength that was similar, and 250 350 53 * 300 200 * in some movements, higher than young, sedentary men. An in- 250 150 crease in strength after RES exercise as well as robust improvements * 200 100 150 in strength following 4 and 7 months of RES exercise training are 100 50 7,89 1RM leg press (lb) consistent findings. 50 0 0 Isometric Knee Extension (Nm) Men Women Men Women C 10.0 Studies have suggested that the increase in strength following RES D 9.5 training in older adults was largely due to neural adaptations, given 20 9.0 * * * * that muscle hypertrophy was less than expected for the magni- 8.5 15 25,26,48,65 tude of the strength improvement. A 2-year longitudinal 8.0 10 7.5

RES training study in older men and women found that the Timed stairs (s) 7.0 5 Sit and Stand (#) increase in leg press (32%) and military press (90%) strength was 5 0 0 much greater that the corresponding increase in the cross-sectional Men Women Men Women thigh area which increased by only 9%.25,26,48,65 Part of the neural E F 25 adaptation could be due to the fact that the neuromuscular junction 300 20 undergoes degeneration with hypodynamia and aging, and neural 200 15 adaptations always precede muscle hypertrophy in response to RES 10 82 100

training. Another factor that may explain an RES training in- 1RM leg press (lb) 5 crease in strength with only a minimal to modest increase in muscle 0 0 0 100 200 300 400 500 Isometric Knee Extension (Nm) 5 6 7 8 9 10 11 12 mass would be an increase in muscle quality, as measured with Stair climb (s) Sit and Stand (#) 90 functional testing in 65-to 75-year-old men. At the single-fiber Figure 3 Strength and functional improvements seen after RES train- level, there appears to be an increase in muscle fiber area, strength, ing (adapted and calculated from Tarnopolsky M, Zimmer A, Paikin J, and contractile strength and power for men, with no effect of RES Safdar A, Aboud A, Pearce E, Roy B, Doherty T. Creatine monohydrate training in women.91 One study found that the minimal increase and conjugated linoleic Acid improve strength and body composition fol- in strength and size of single fibers following RES training in older lowing resistance exercise in older adults. PLoS ONE 2007;2:e991). men (80 to 86 years) was minimal in comparison to the increase in whole muscle strength. The authors concluded that an increase in RES = resistance exercise training neural activation was the likely explanation.84 PRE Resistance training POST Resistance training The functional benefits of RES exercise training have been L S1 S1 S2 S3 S4 S5 S6 S7 S8 -ve L L S1 S2 S3 S3 S4S4 S5 S6 S6 S7 S8 --veve A evaluated in a large-scale trial of 72-to 98-year-old physically frail nursing home residents. The RES exercise training increased muscle strength (113%), gait velocity (12%), stair climbing 16.5 kb power (28%), spontaneous physical activity, and thigh muscle Deletion cross-sectional area (2.7%).26 There have also been findings of con- products sistent improvements in functional capacity in older adults following both a 4 and 6 month supervised RES exercise program.7 An increase in muscle function can have significant beneficial effects on activities of daily living (ADL) and may have a significant long-term B beneficial impact upon heath care costs by reducing the burden of illness associated with weakness and immobility.26 Following 6 months of RES training, improvements in strength and functional capacity in older adults has been seen, (Figure 3).89

The data suggests that some of the possible aerobic benefits of RES training in older adults may be due to a direct effect on mitochondrial function at the level of the skeletal muscle. Recently it has been found that 4 months of RES training is associated with an increase in COX enzyme activity as well as citrate synthase 72,73 total protein content in older adults. Furthermore, 6 months Figure 4 Reduction in mitochondrial deoxyribonucleic acid (mtDNA) of RES exercise training reduced mtDNA deletions in skeletal deletions following 6 months of RES training. A. Vastus lateralis derived muscle from older men and women (Figure 4A), and “reversed” the mtDNA deletion analysis (very long range PCR) from older adults (> 65 years) transcriptome signature of aging at the skeletal muscle level.66 RES training 2 times per week for 6 months. B. Oxidative stress marker RES exercise training has been shown to be associated with a for DNA damage (8-hydroxy-2-deoxy guanosine) from skeletal muscle of reduction in whole body and muscle markers of oxidative stress, young adults and before and after RES exercise training as in Figure 3 A. and an increase in antioxidant defense enzymes such as manganese superoxide dismutase.72,73 More recently, it has been discovered that PRC = polymerase chain reaction; RES = resistance exercise training AANEM Course Exercise in Neuromuscular Diseases 5

CONCLUSION 6 months of RES training also reduces a marker of DNA damage in skeletal muscle (8-hydroxy-2–deoxy-guanosine)(Figure 4B). Aging is associated with a reduction in skeletal muscle mass and function that can lead to limitations in ADLs. A reduction in One potential source of the improvements in mitochondrial func- functional capacity can lead to an increase in healthcare costs due tion and anti-oxidant defenses following RES training could be the to an increased reliance upon institutionalized living and the costs recruitment of the satellite cells which can fuse with the mature associated with falls (i.e., hospitalization for fractures and other muscle and “dilute” the older dysfunctional mitochondria. Some51 injuries). The aging process is multifactorial and eventually leads but not all studies have shown that the total number of satellite cells to an increase in markers of oxidative stress and mitochondrial are lower in older adult muscle, yet they retain the full ability to dysfunction. Whether or not mitochondrial dysfunction and activate and regenerate damaged muscle;16 however, other studies oxidative stress are directly linked, as suggested by the original have shown several properties of aged satellite cells are altered, mitochondrial theory of aging, is still controversial; however, they including antioxidant defenses.31 Following an acute bout of both improve following RES and END exercise. There is no eccentrically biased RES exercise, there is an increase in the number question that RES exercise can lead to improvements in muscle of activated satellite cells in older adults, however, it was only one function in older adults. This is likely due to both intrinsic third of that found in younger adults.21 Recent data shows that improvements in muscle structure and function as well as an mtDNA deletions and reduced mitochondrial enzyme activity were enhancement of neural activation. END exercise is associated not present in myoblast cultures derived from older versus younger with improvements in aerobic capacity and mitochondrial func- adults (myoblasts are derived from the satellite cells) (Safdar, A., tion, with benefits also seen in cardiovascular risk factors. Unlike and colleagues, manuscript in preparation, 2008). In combination, RES exercise training, where there is a “spill over” effect of benefits these data suggest that RES training in older adults is associated in the classical adaptations due to END exercise (i.e., increased with an activation and recruitment of the satellite cells into the mitochondrial capacity), there has been little work examining mature muscle in older adults, which represents a form of mtDNA whether END exercise training leads to an increase in strength. It gene shifting.13,87 This phenomenon may occur because satellite is quite likely that a combination of both END and RES exercise cells remain quiescent and relatively undamaged from lifelong training will lead to the optimal benefit for older adults, but experi- exposure to free radicals derived from mitochondrial respiration. mental evidence is currently lacking. They become activated and fuse only after responding to signals for muscle growth or repair of muscle damage. The benefits of exercise training in older adults may extend far beyond the observations of higher muscle mass and strength and mitochondrial capacity. For example, a Cochrane review listed AGING AND ENDURANCE EXERCISE (EFFECTS ON “muscle strengthening” as the first intervention associated with a MITOCHONDRIA AND FUNCTION) reduction in falls in older adults (3 trials, n = 566, relative risk = 0.80),33 due in part to an improvement in balance.46 In addition At the whole body level, several longitudinal studies to the benefits of RES exercise training as a countermeasure to sar- have found that the maximum rate of oxygen consumption copenia, several studies in animals45 and humans60, 61 ,71 have found

(VO2max) increases following endurance (END) exercise that habitual physical activity can also increase longevity. A recent training in older adults.9,17,23,37,41,43,54,99,100 At the skeletal muscle study has discovered that higher levels of physical activity are more level, this is associated with an increase in capillarization,43 mito- important than body fat as a predictor of all cause related mortal- chondrial function,78, 80, 81and an increase in myosin heavy chain ity.86 In most developed countries, the proportion of the popula- I mRNA and protein content.83 Studies have also found that tion over the age of 65 years is expected to grow over the next few END exercise training increased intramyocellular lipid content, decades. It will therefore be important to evaluate and implement whole body aerobic capacity, and mitochondrial enzyme capac- optimal exercise programs. ity in older adults.77 Cross-sectional studies have found that Masters END athletes did not show the expected age-related decline in mitochondrial function,6 and Master’s athletes show REFERENCES about 50% of the decline in aerobic capacity as compared to sedentary individuals.79 There is also a significant decline in insulin 1. Aiken J, Bua E, Cao Z, Lopez M, Wanagat J, McKenzie D, McKiernan sensitivity with aging,14 which can be significantly improved S. Mitochondrial DNA deletion mutations and sarcopenia. Ann N Y following END exercise training.78 In addition, END exercise Acad Sci 2002;959:412-423. training has been associated with a reduction in both abdominal 2. Aniansson A, Hedberg M, Henning GB, Grimby G. Muscle mor- fat and dyslipidemia.37,99,101 Furthermore, in older adults, reduc- phology, enzymatic activity, and muscle strength in elderly men: a tions in blood pressure are more consistently observed following follow-up study. Muscle Nerve 1986;9:585-591. END exercise training as compared with RES exercise training.17 3. Baker DJ, Hepple RT. Elevated caspase and AIF gene expression correlate with progression of sarcopenia during aging in male END exercise does not usually lead to an increase in muscle mass; F344BN rats. Exp Gerontol 2006;41:1149-1156. however, given the robust benefits of END training on enhancing 4. Balagopal P, Rooyackers OE, Adey DB, Ades PA, Nair KS. Effects of the mitochondrial capacity, it is tempting to speculate that END aging on in vivo synthesis of skeletal muscle myosin heavy-chain and training may attenuate the progression towards sarcopenia. sarcoplasmic protein in humans. Am J Physiol 1997;273:E790-800. 6 Exercise in the Treatment of Aging Associated Sarcopenia and Metabolic Myopathy AANEM Course

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78. Rimbert V, Boirie Y, Bedu M, Hocquette JF, Ritz P, Morio B. Muscle 94. Trifunovic A, Hansson A, Wredenberg A, Rovio AT, Dufour E, fat oxidative capacity is not impaired by age but by physical inactivity: Khvorostov I, Spelbrink JN, Wibom R, Jacobs HT, Larsson NG. association with insulin sensitivity. Faseb J 2004;18:737-739. Somatic mtDNA mutations cause aging phenotypes without affect- 79. Rogers MA, Hagberg JM, Martin WH, 3rd, Ehsani AA, Holloszy JO. ing reactive oxygen species production. Proc Natl Acad Sci U S A Decline in VO2max with aging in master athletes and sedentary men. 2005;102:17993-17998. J Appl Physiol 1990;68:2195-2199. 95. Welle S, Thornton C, Jozefowicz R, Statt M. Myofibrillar protein 80. Rooyackers OE, Adey DB, Ades PA, Nair KS. Effect of age on synthesis in young and old men. Am J Physiol 1993;264:E693-698. in vivo rates of mitochondrial protein synthesis in human skeletal 96. Welle S, Thornton C, Statt M. Myofibrillar protein synthesis in young muscle. Proc Natl Acad Sci U S A 1996;93:15364-15369. and old human subjects after three months of resistance training. Am 81. Rossiter HB, Howlett RA, Holcombe HH, Entin PL, Wagner HE, J Physiol 1995;268:E422-427. Wagner PD. Age is no barrier to muscle structural, biochemical and 97. Welle S, Bhatt K, Thornton CA. High-abundance mRNAs in angiogenic adaptations to training up to 24 months in female rats. J human muscle: comparison between young and old. J Appl Physiol Physiol 2005;565:993-1005. 2000;89:297-304. 82. Sale DG. Neural adaptation to resistance training. Med Sci Sports 98. Whipple RH, Wolfson LI, Amerman PM. The relationship of knee Exerc 1988;20:S135-145. and ankle weakness to falls in nursing home residents: an isokinetic 83. Short KR, Vittone JL, Bigelow ML, Proctor DN, Coenen-Schimke study. J Am Geriatr Soc 1987;35:13-20. JM, Rys P, Nair KS. Changes in myosin heavy chain mRNA and 99. Wilmore JH, Despres JP, Stanforth PR, Mandel S, Rice T, Gagnon J, protein expression in human skeletal muscle with age and endurance Leon AS, Rao D, Skinner JS, Bouchard C. Alterations in body weight exercise training. J Appl Physiol 2005;99:95-102. and composition consequent to 20 wk of endurance training: the 84. Slivka D, Raue U, Hollon C, Minchev K, Trappe SW. Single Muscle HERITAGE Family Study. Am J Clin Nutr 1999;70:346-352. Fiber Adaptations to Resistance Training in Old (>80 y) Men: 100. Wilmore JH, Green JS, Stanforth PR, Gagnon J, Rankinen T, Leon Evidence for Limited Skeletal Muscle Plasticity. Am J Physiol Regul AS, Rao DC, Skinner JS, Bouchard C. Relationship of changes in Integr Comp Physiol 2008. maximal and submaximal aerobic fitness to changes in cardiovascu- 85. Stachowiak O, Dolder M, Wallimann T, Richter C. Mitochondrial cre- lar disease and non-insulin-dependent diabetes mellitus risk factors atine kinase is a prime target of peroxynitrite-induced modification with endurance training: the HERITAGE Family Study. Metabolism and inactivation. J Biol Chem 1998;273:16694-16699. 2001;50:1255-1263. 86. Sui X, LaMonte MJ, Laditka JN, Hardin JW, Chase N, Hooker SP, 101. Wilund KR, Ferrell RE, Phares DA, Goldberg AP, Hagberg JM. Blair SN. Cardiorespiratory fitness and adiposity as mortality predic- Changes in high-density lipoprotein-cholesterol subfractions with ex- tors in older adults. JAMA 2007;298:2507-2516. ercise training may be dependent on cholesteryl ester transfer protein 87. Taivassalo T, Fu K, Johns T, Arnold D, Karpati G, Shoubridge EA. (CETP) genotype. Metabolism 2002;51:774-778. Gene shifting: a novel therapy for mitochondrial myopathy. Hum 102. Yakes FM, Van Houten B. Mitochondrial DNA damage is more ex- Mol Genet 1999;8:1047-1052. tensive and persists longer than nuclear DNA damage in human cells 88. Tamilselvan J, Jayaraman G, Sivarajan K, Panneerselvam C. Age- following oxidative stress. Proc Natl Acad Sci U S A 1997;94:514- dependent upregulation of p53 and cytochrome c release and sus- 519. ceptibility to apoptosis in skeletal muscle fiber of aged rats: role of 103. Yarasheski KE, Zachwieja JJ, Bier DM. Acute effects of resistance carnitine and lipoic acid. Free Radic Biol Med 2007;43:1656-1669. exercise on muscle protein synthesis rate in young and elderly men 89. Tarnopolsky M, Zimmer A, Paikin J, Safdar A, Aboud A, Pearce E, and women. Am J Physiol 1993;265:E210-214. Roy B, Doherty T. Creatine monohydrate and conjugated linoleic 104. Yarasheski KE, Pak-Loduca J, Hasten DL, Obert KA, Brown MB, Acid improve strength and body composition following resistance Sinacore DR. Resistance exercise training increases mixed muscle exercise in older adults. PLoS ONE 2007;2:e991. protein synthesis rate in frail women and men >/=76 yr old. Am J 90. Tracy BL, Ivey FM, Hurlbut D, Martel GF, Lemmer JT, Siegel EL, Physiol 1999;277:E118-125. Metter EJ, Fozard JL, Fleg JL, Hurley BF. Muscle quality. II. Effects 105. Yasuda N, Glover EI, Phillips SM, Isfort RJ, Tarnopolsky MA. Sex- Of strength training in 65- to 75-yr-old men and women. J Appl based differences in skeletal muscle function and morphology with Physiol 1999;86:195-201. short-term limb immobilization. J Appl Physiol 2005;99:1085-1092. 91. Trappe S, Godard M, Gallagher P, Carroll C, Rowden G, Porter D. 106. Zahn JM, Sonu R, Vogel H, Crane E, Mazan-Mamczarz K, Rabkin Resistance training improves single muscle fiber contractile function R, Davis RW, Becker KG, Owen AB, Kim SK. Transcriptional pro- in older women. Am J Physiol Cell Physiol 2001;281:C398-406. filing of aging in human muscle reveals a common aging signature. 92. Trappe S, Gallagher P, Harber M, Carrithers J, Fluckey J, Trappe T. PLoS Genet 2006;2:e115. Single muscle fibre contractile properties in young and old men and women. J Physiol 2003;552:47-58. 93. Trappe T, Williams R, Carrithers J, Raue U, Esmarck B, Kjaer M, Hickner R. Influence of age and resistance exercise on human skeletal muscle proteolysis: a microdialysis approach. J Physiol 2004;554:803-813. 9

Exercise Training in Metabolic Myopathies

Tanja Taivassalo, PhD Assistant Professor Department of Kinesiology McGill University Montreal, Quebec, Canada

INTRODUCTION contractions of muscle fibers of approximately 50% to 75% of one maximal repetition.3 Physiological and phenotypic adaptations to Exercise intolerance is an important clinical manifestation of the regular performance of the two modes are generally different. impaired skeletal muscle metabolism, where in addition to the underlying disease process, secondary effects of deconditioning and Endurance Training physical inactivity contribute to its progressive worsening. Exercise intolerance may be clinically defined by dyspnea, tachycardia, Endurance training (ET) or aerobic training induces adaptations in weakness, or a perception of fatigue in active muscle, all of which the heart, peripheral circulation, and skeletal muscle systems that present during minimal to moderate levels of physical exertion. It increase both maximal and submaximal exercise capacity by en- is well known that exercise training reverses the effects of decondi- hancing the delivery of O2 to the exercising muscle and increasing tioning in healthy individuals and is being used to improve exercise muscle capacity for O2 utilization through oxidative metabolism. tolerance in a variety of chronic conditions (e.g., cardiopulmonary Greater O2 delivery is achieved through increases in cardiac output disease). However, until recently, the effects of exercise training in (due to increases in stroke volume rather than maximal heart rate), metabolic myopathies have not been well-studied, due in part to whereas greater utilization of available O2 by trained skeletal muscle the heterogeneous nature of these disorders and the unfamiliarity (resulting in a greater arteriovenous O2 difference) is attributable of the field of exercise physiology within the context of neuromus- to increases in capillary density, vascular conductance, and mito- cular medicine. Although the application, safety, and efficacy of chondrial oxidative capacity.18 These peripheral adaptive responses exercise training remain to be firmly established in adult patients are localized and evident only in trained muscles. A key feature with metabolic myopathies, the current understanding in the field of enhanced muscle oxidative capacity is increased mitochondrial as it relates to two disorders representing glycolytic and mitochon- biogenesis, which is associated with increases in respiratory chain drial metabolic pathways will be reviewed. These disorders are enzyme levels that lead to an increased capacity to generate energy myophosphorylase deficiency (MD also known also as McArdle’s via oxidative phosphorylation.11 In healthy individuals, this adapta- disease) and mitochondrial myopathies, attributable to defects of tion in metabolic efficiency is thought to play a major role in the the electron transport chain(ETC). ability to perform submaximal work with less effort and for longer duration. This can be evidenced by lower blood lactate levels and heart rates than those of untrained individuals at the same absolute ADAPTATIONS TO EXERCISE TRAINING AND DETRAINING level of submaximal exercise. Furthermore, increases in maximal ex-

ercise capacity VO2max are limited by improvements in O2 delivery Exercise training can involve either endurance activity, resistance (cardiac output).18 activity, or a combination of the two. Endurance is generally defined as aerobic activity that involves the use of large muscle Mitochondrial biogenesis is a notably complex process owing to the groups for sufficient intensity and duration (30 minutes, 50% fact that the formation of mitochondria are under dual genomic to 85% of peak rate of oxygen [O2] utilization or the maximum control with the majority of genes encoded in the cellular nucleus 14 amount of O2 consumed while exercising [VO2max]). Resistance and a subset of genes (22 transfer ribonucleic acid [tRNA], 2 ribo- activity typically involves a demand of low volume, highly intense somal RNA, and 13 polypeptides) encoded by copies of mitochon- 10 Exercise Training in Metabolic Myopathies AANEM Course drial deoxyribonucleic acid (mtDNA) within the mitochondrial muscles are particularly susceptible to mitochondrial dysfunction matrix.31 Endurance exercise-specific muscle contractions signal due to their high requirements for oxidative energy metabolism. a cascade leading to the coordinated increase in the rate of tran- Skeletal muscle is almost invariably affected in adult patients, and scription of nuclear-encoded genes, as well as mtDNA replication, while myalgias often involve fixed weakness and recurrent myo- and copy number that support the increased rate of synthesis of globinuria, exercise intolerance is a more common manifestation of mitochondrial-encoded genes.6,11 The gene products from both the underlying defect in oxidative phosphorylation with severity genomes must then be combined form a functional electron trans- that can range from mild to disabling.4,27 The underlying molecular port chain with the help of an increasing number of identified defect involves either a mutation in nuclear or mtDNA, both of assembly factors. which ultimately impair electron transport and oxidative phosphorylation. While the combined prevalence of these defects is esti- Resistance Training mated to be 1 in 5000, the diagnosis is complicated by molecular and phenotypic heterogeneity, as well as by other unique features Resistance training (RT) normally induces physiological adapta- of mitochondrial genetics.19 tions that differ from those of ET. The lifting of heavy weights to overload skeletal muscle during concentric (muscle shortening) The majority of known mutations are in mtDNA, with over 200 or eccentric (muscle lengthening) contractions leads primarily to mutations identified in the 16.5 Kb circular molecule to date.31 increases in strength, power, and local muscle endurance.3 Both Depending on the location of the mutation within the genome neural and muscular factors modify the expression of human as well as the type (deletion or point mutation), a single complex strength, however, as evidenced from surface electrode electro- or multiple complexes (those containing mtDNA encoded sub- myography, enhanced neural facilitation (increased motor unit units; complex I, III, IV, and V) of the ETC may be affected.31 recruitment and efficiency) predominates in the earlier phases of Furthermore, mutations in mtDNA coexist with wild-type mtDNA training.3 Beyond the first few weeks, muscle hypertrophy occurs molecules within the cell in a condition known as heteroplasmy. as a result of the synthesis and accretion of contractile proteins The level of mutation can vary, but once it exceeds a certain criti- myosin and actin. This occurs both within the whole muscle and cal threshold, phenotypic expression of the mutation occurs and in the individual myofibrils through the addition of intracellular is evidenced by cellular oxidative impairment. These oxidatively myofibrils.3 Essential to the process of hypertrophy is the activa- deficient myofibers are distributed variably throughout the muscle, tion of satellite cells, mononuclear, and myogenic progenitor cells intermixed with myofibers that contain a normal capacity for oxi- that typically exist in a state of relative mitotic quiescence under dative phosphorylation and predominantly wild-type mtDNA (or the basal lamina of mature myofibers.13 In response to stimuli subthreshold levels of mutant mtDNA). such as overload or trauma, satellite cells become activated, and proliferate daughter cells to either fuse to the existing fiber or par- In addition to mtDNA defects, mutations in nuclear genes are ticipate in fiber regeneration.10 The fusion of satellite cell contents an important and growing cause of mitochondrial myopathy. provides additional nuclei to the existing fiber, leading to synthesis Nuclear genes encode for the majority of mitochondrial proteins of additional contractile proteins and maintaining the nuclear (approximately 1500), however, only about half of these have cytoplasmic ratio. been identified, which contributes to difficulties in diagnosis.5 Mutations in nuclear DNA are involved in impairing electron Deconditioning transport chain function as they either encode for a complex subunit directly, encode ancillary proteins needed for complex These previously mentioned physiological and metabolic changes assembly, or encode genes that affect intergenomic signaling that are responsible for improved exercise capacity are not perma- which affects the abundance and quality of mtDNA.5 While nent but are reversible upon cessation or marked reduction of an the classification and molecular effects of nuclear mutations in exercise training stimulus. This leads to partial or complete reversal mitochondrial disease is complex and can be reviewed in other of training-induced adaptations throughout the cardiopulmonary sources31, in adult muscle, these mutations are generally associ- and skeletal muscle systems that decrease maximal and submaximal ated with residual activity of affected enzymes and the condition exercise performance. Notably, detraining leads to decreases in of mitochondrial heteroplasmy does not exist. maximal cardiac output, muscle capillary density, mitochondrial volume, and oxidative enzymes, as well as a loss of neural adaptations and muscle contractile proteins.15,17 Rationale for ET

Based on the normal adaptive processes within skeletal muscle, MITOCHONDRIAL MYOPATHIES the rationale for ET in patients with mitochondrial myopathies is evident: to induce mitochondrial biogenesis, thereby stimulating Mitochondrial myopathies constitute a heterogenous group of increases in numbers of functional mitochondria and capacity for metabolic disorders in terms of clinical presentation that range oxidative phosphorylation. This rationale is important as it ad- from single organ (affecting visual and auditory pathways, gastric dresses both the disease process as well as the maladaptive effects and endocrine systems, central nervous system, myopathy, or of deconditioning. Habitual inactivity and sedentary lifestyles have cardiomyopathy) to multi-system involvement.5 Brain and skeletal been postulated to lead to a down-regulation of muscle mitochon- AANEM Course Exercise in Neuromuscular Diseases 11 drial volume which further restricts the capacity of muscle for have assessed ET effects on mutation load in a group of patients oxidative phosphorylation.25 ET would be expected to ameliorate with a homogenous mutation in mtDNA (single large-scale dele- the disease process and reverse deconditioning, ultimately improv- tion)24 and a group with more varied mtDNA mutations 12. In ing exercise tolerance. both studies, significant increases in physiological and biochemical markers of mitochondrial function were detected without any However, given the often disabling level of exercise intolerance changes in level of mutant mtDNA12,24, which is in contrast to reported in patients with mitochondrial myopathies, exercise was the previous report 26. Moreover, they demonstrated the loss of discouraged by neuromuscular physicians for many years due to ET-induced gains in exercise and mitochondrial capacity follow- fears of worsening the clinical condition. Furthermore, patients ing the cessation of training, confirming the maladaptive effects of themselves tended to avoid physical activity in response to their detraining. Studies are currently ongoing to determine the effects symptoms. The first case study performed in 1996 was designed of mitochondrial biogenesis within single myofibers and on ab- to assess the feasibility of ET in this condition. Not only did the solute levels of wild-type mtDNA, which may ultimately dictate patient tolerate the 8-week training protocol, but a significant im- improvements in cellular oxidative capacity in response to the provement in exercise capacity had been recognized.28 Two subse- ET stimulus. Evidence supporting increases in wild-type mtDNA quent studies in groups of patients carrying variable mitochondrial despite changes in mutant mtDNA are needed to safely prescribe mutations supported findings of improved peak and submaximal ET as a therapeutic approach for patients with mitochondrial exercise capacity, and suggested ET could, at least in part, reverse myopathy. To summarize, the effects of ET on the mutant mtDNA the effects of detraining.21,22 Interestingly, increases in cardiac proportions within muscle have not been firmly established and out output during maximal exercise, a normal adaptation to ET, have of the seven published reports (Table 1) no adverse effects (other not been detected in patients with mitochondrial myopathies.26 than the cellular increase in mutant mtDNA) have been reported.

The effects on the actual disease process were not determined Rationale for RT in these early studies, and the impact of exercise training on mitochondrial biogenesis could be governed by the type of mi- While fixed weakness attributable to the underlying genetic defect tochondrial mutation. In patients with suspected nuclear defects may present in patients with mitochondrial myopathy, general that affected mitochondria, a coordinated increase in nuclear and physical inactivity contributes more prominently to a reduction in mitochondrial encoded proteins would be expected in response to overall muscle strength. Although RT may be expected to reverse the exercise stimuli, leading to improvement in the residual activity this loss, studies that address this directly in patients with nuclear of the affected mitochondrial enzyme to a level compatible with or mtDNA mutations are scant. Cejudo and colleagues1 incor- normal mitochondrial function. Although ET studies that assess porated moderate-intensity upper body strength training into an this mutation type are scant, patients with suspected nuclear defects overall exercise training program which included ET and reported who were included in three studies21,22,28 were reported to show a marked improvements in muscle strength and endurance with no greater improvement than patients with mtDNA mutations. adverse effects.

In the case of mtDNA mutations, the situation becomes more More intriguingly however, is that although RT does not normally complex given the condition of heteroplasmy and in questioning induce mitochondrial biogenesis in healthy, younger individuals, a whether the training stimulus would induce expansion of wild- unique and alternate rationale has focused on using RT to improve type and mutant mtDNA equally or selectively. The first study the actual disease process in a subgroup of patients with spo- designed to address this critical question assessed training effects radic mutations of mtDNA (nonmaternally inherited mutations). upon the overall proportion of mutant versus wild-type mtDNA, Dramatic tissue variation in mitochondrial heteroplasmy has been and confirmed increases in work and oxidative capacity26 that were found to exist in these patients, where despite high abundance in likely associated with increases in enzymatic activity of respira- mature skeletal muscle, levels of the causative mutation are low or tory chain complexes affected by the mutation. However, along undetectable in satellite cells.7,30 The idea of gene-shifting (fusion with these positive findings, the proportion of mutant mtDNA of satellite cells devoid of mutant mtDNA) was proposed through increased in six of nine subjects and decreased in none. These data two case studies where experimentally induced muscle necrosis were interpreted to suggest that the overall volume of wild-type (biopsy trauma and toxin injection) was followed by myofiber mtDNA increased, but that levels of mutant mtDNA increased regeneration containing lower mutation levels.2,20 Because RT is disproportionately. This raised the concern that despite substan- known to serve as a stimulus for satellite cell induction within tial functional and biochemical improvement, ET may promote active skeletal muscle10,16 and offers a more feasible, physiological progressive expansion of mutant mtDNA with ultimately delete- approach, it was hypothesized that RT would lead to shifting of rious effects, particularly because clinical worsening is associated normal mitochondrial genes from satellite cells to mature muscle, with increasing mutation loads.30 However, other factors need to lowering the level of mutation below threshold and improving be considered as described in greater detail in a 2004 paper by muscle oxidative capacity. The first case study showed a significant Taivassalo and colleagues25, namely a mutation-specific response to decrease in mutant mtDNA levels following short-term, high- ET, the effects of ET on absolute levels of wild-type mtDNA (and intensity strength training in the arm, however, markers of muscle functional mitochondria), as well as the distribution of mutant strength and oxidative capacity were not assessed.23 A recent study mtDNA throughout muscle fibers. More recently, two studies (in submission) involving 12 weeks of progressive overload leg RT 12 Exercise Training in Metabolic Myopathies AANEM Course

Myophosphorylase Deficiency Table 1 Endurance training studies in mitochondrial myopathies Myophosphory Deficiency, also known as McArdle’s disease or Study Patient mutation Training Main Findings glycogen storage disease type V, is the most common inborn error characterization Protocol of muscle carbohydrate metabolism and one of the most common 29 Taivassalo and N=1; nuclear 8 weeks; ↑ aerobic capacity causes of recurrent myoglobinuria. Mutations in the myophos- colleagues mutation 20-30 min at (20%); SF36 QOL phorylase gene typically lead to complete loss of enzymatic activity. As such, there is a block in muscle glycogen breakdown resulting 1996 70% HR max (64%); ↓submax lactate (50%); HR in severe limitation in both anaerobic metabolism as well as aerobic (28%), PCr (1.7 metabolism due to the fact that MD limits substrate availability as fold) muscle glycogen is required for peak rates of oxidative phosphoryla- Taivassalo and N=10; 2 suspected 8 weeks; 30 ↑Estimated aerobic tion.8 Without glycogen, the capacity for aerobic exercise is reduced colleagues nuclear, 2 mtDNA min at 70% capacity (30%, and is greatly dependent on an availability of bloodborne fuels 1998 point, 5 LSD; 1 HR max ADP recovery (glucose and free fatty acids). In addition to exercise intolerance, unknown (60%) ↓submax more strenuous muscle activities (which normally engage anaerobic lactate (30%), HR glycogenolysis rather than oxidative phosphorylation) often trigger (15%) muscle contractures, rhabdomyolysis, and myoglobinuria 9, leading Siciliano and N=12; 6 CPEO, 10 weeks; ↓peak lactate to potentially severe consequences. In general, the avoidance of colleagues 1 tRNA, 3 30-45 min; (39%) exercise has been recommended to patients with MD. As previously 2000 multiple deletions, lactate mentioned, the adoption of a sedentary lifestyle can be expected to unknown threshold further limit exercise tolerance by decreasing circulatory and muscle Taivassalo and M=10 all mtDNA; 14 weeks; ↑Peak VO2 (20%); metabolic capacity. In this case, the delivery of bloodborne fuels that colleagues 2 LSD; 2 30-40 min at work (30%); O 2 are essential for oxidative metabolism when glycogen breakdown is 2001 microdeletions; 5 70%-80% HR extraction (20%); blocked would be limited, as well as utilization or metabolism of fuels point mutations max CS (50%);↑ in within mitochondria. mutation load (6 pts); no ∆ in 3 ET’s potential benefit to patients with MD has only recently been Cejudo and N=20; EI, CPEO, 12 weeks; 30 ↑Peak VO (29%); 2 assessed. As part of a study, eight patients underwent 14 weeks of colleagues histology & min at 70% work (15%); cycle training at 60% to 70% of maximal heart rate.9 The patients 2005 biochemistry peak + upper submaximal identified body strength endurance (62%), all completed the training program without symptoms of muscle peripheral muscle pain or cramping. As indicated by blood creatine kinase levels strength (35%) before and after individual training rides, exercise within the prescribed guidelines did not provoke muscle injury. Significant im- Taivassalo and N=8 all mtDNA; 14 weeks; ↑Peak VO2 (11%), provements were detected in peak work, oxidative capacity, cardiac colleagues single, large scale 30-40 min at work (26%), O2 output during initial exercise, as well as after the spontaneous 2006 mtDNA deletions 70%-80% HR extraction (11%), (LSD) max submax lactate second wind, which is the characteristic increase in oxidative capac- (13%) HR (14%), ity that occurs after the first 8 to 10 minutes of sustained aerobic no ∆ mutation load activity attributable to arrival and increased oxidation of blood- Jeppesen and N=20 all 12 weeks; 30 12 weeks; 30 min borne fuels in muscle. Furthermore, increased muscle mitochon-

colleagues mtDNA; 14 point min at 70% at 70% VO2max drial volume was detected in response to the training. Therefore, mutations, 5 LSD, VO max no mutation load 2006 2 ∆ although exercise training can not augment activity of the missing 1 microdeletion myophosphorylase, the authors concluded that ET-induced adaptations increase the capacity to deliver bloodborne fuels to working ADP = adenosine diphosphate; CPEO = chronic progressive external opthalmoplegia; CS = muscle as well as the range of oxidative capacity within muscle.9 citrate synthase; EI = exercise intolerance; HRmax = maximal heart rate; LSD = single large- scale deletions in mitochrondrial deoxyribonuliec acid; PCr = phosphocreatine; QOL = quality This raises the threshold at which dynamic exercise could pose a risk for muscle injury while also supporting the safety and efficacy of life; VO2 = maximal oxygen consumption; ∆ = change; SF36 = short form health survey of regular submaximal (an intensity which is fuelled by oxidative in a group of eight patients with single large-scale deletions dem- metabolism) exercise as a component of therapy for MD, provided onstrated significant increases in muscle strength, despite myofibre that the patients exercise within specified heart rate guidelines. damage and regeneration, and improvement in muscle oxidative capacity along with increases in the proportion of neural cell Due to the susceptibility of skeletal muscle to contractures, adhesion molecule positive satellite cells. Together, these findings rhabdomyolysis, and myoglobinuria, MD patients must be support the notion of RT-induced mitochondrial gene-shifting in advised not to engage in ischemic, isometric, and maximal effort muscle containing satellite cells which have low or absent levels of dynamic exercises. These types of activities normally engage deleted mtDNA. Further studies are aimed at refining parameters anaerobic glycogenolysis which are known to trigger injury.9 of the exercise training protocol in order to maximize the training Therefore, although the precise conditions of injury-provoking effect on wild-type mtDNA levels and promote RT as a potential exercise need to be more clearly defined, RT is not recommended for treatment approach. MD patients. AANEM Course Exercise in Neuromuscular Diseases 13

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Sport Sci. Rev. 1996;24: 289– 319. Disorders 2000;10:40±45. 7. Fu K, Hartien R, Johns T, Genge A, Karpati G, Shoubridge EA. A 22. Taivassalo T, De Stefano N, Argov Z, Matthews PM, Chen J, Genge novel heteroplasmic tRNAleu(CUN) mtDNA point mutation in a A, Karpati G, Arnold DL: Effects of aerobic training in patients sporadic patient with mitochondrial encephalomyopathy segregates with mitochondrial myopathies. Neurology 1998;50:1055-1060. rapidly in skeletal muscle and suggests an approach to therapy. Hum 23. Taivassalo T, Fu K, Johns T, Arnold DL, Karpati G, Shoubridge E. Mol Genet 1996;5:1835-1840. Gene shifting: a novel therapy for mitochondrial myopathy. Human 8. Haller RG, Vissing J. Functional evaluation of metabolic myopathy. Molecular Genetics 1999;8(6):1047-1052. In: Engel AG, Franzini-Armstrong C, eds. Myology, 3rd ed. Vol 1. 24. Taivassalo T, Gardner JL, Taylor RW, Schaeer AM, Newman J, Barron New York: McGraw-Hill, 2004:665-679. MJ, Haller RH, Turnbull DM. 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Jeppesen TD, Schwartz M, Olsen DB, Wibrand F, Krag T, Dunø Annals of Neurology 2001;50:133-141. M, Hauerslev S, Vissing J. Aerobic training is safe and improves 27. Tarnopolsky M. Exercise testing as a diagnostic entity in mitochondrial exercise capacity in patients with mitochondrial myopathy. Brain myopathies. Mitochondrion 2004;4:529–542. 2006;129:3402-3412. 28. Taivassalo T, Matthews PM, De Stefano N, et al. Combined aerobic 13. Mauro A. Satellite cell of skeletal muscle fibers. J Biophys Biochem training and dichloroacetate improve exercise capacity and indices Cytol 1961;9:493–494 of aerobic metabolism in muscle cytochrome oxidase deficiency. 14. Michael L. Pollock, Glenn A. Gaesser, Janus D. Butcher, Jean-Pierre Neurology 1996;47:529-534. Despre´s, Rod K. Dishman, Barry A. Franklin, Carol Ewing Garber, 29. Tonin P, Lewis P, Servidei S, DiMauro S. Metabolic causes of myo- Position stand: the recommended quantity and quality of exercise for globinuria. Ann Neurol 1990;27:181-185. developing and maintaining cardiorespiratory and muscular fitness, 30. Weber K, Wilson JN, Taylor L, Brierley E, Johnson MA, Turnbull and flexibility in healthy adults, Med. Sci. Sports Exerc.1998;30:975– DM, Bindoff LA. A new mtDNA mutation showing accumula- 991. tion with time and restriction to skeletal muscle. Am J Hum Genet. 15. Neufer PD The effect of detraining and reduced training on the 1997;60:373-80. physiological adaptations to aerobic exercise training. Sports Med. 31. Zeviani M, DiDonato S. Mitochondrial disorders. Brain. 2004;127(Pt 1989;8:302– 320. 10):2153-2172. 14 Exercise Training in Metabolic Myopathies AANEM Course 15

Exercise in Diseases of the Motor Neuron and Motor Axon

Timothy J. Doherty, MD, PhD Associate Professor Departments of Clinical Neurological Sciences and Rehabilitation Medicine Schulich School of Medicine and Dentistry The University of Western Ontario London, Canada

INTRODUCTION Although the cause of atrophy and weakness varies, based on the specific disorder, some general observations regarding the under- The role of exercise in disorders affecting the motor neuron (MN) lying pathophysiology can be made. The primary mechanism in and motor axon will be examined. The hallmark of many of these most cases is degeneration, or loss of MNs or motor axons with disorders is progressive muscle atrophy and weakness, which leads associated denervation of muscle.18 Even in the most rapidly to substantial impairment and disability. Many diseases affect- progressive disorders, collateral reinnervation may result in some ing the MNs or axons are slowly progressive, with weakness that compensation, but this is eventually unable to keep up with the advances over the course of many years (e.g., Charcot-Marie-Tooth extent of MN or motor axon loss and as a result, atrophy and weak- disease [CMT]). Others are much more rapidly progressive (e.g., ness occur. 4 However, factors other than progressive denervation amyotrophic lateral sclerosis [ALS]), while still others may present that contribute to weakness may include: reduced or inadequate with long periods of relative stability followed by more rapid or central drive to the lower MN, upper MN involvement in ALS, stepwise progression (e.g., post-polio syndrome [PPS]). atrophy of the still existing muscle fibers, possible neuromuscular transmission failure or distal conduction block in immature rein- Great strides have been made in recent years with regard to under- nervated motor units (MUs), fatigue that is secondary to decondi- standing the biological processes of these various diseases. However, tioning (both cardiovascular and peripheral), and non-neurologic to date, no curative treatments exist, and the few available pharma- factors such as joint contracture, altered joint biomechanics, and cological therapies (e.g., riluzole for ALS) only minimally alter the instability. 15,24,25 Obviously, resistance exercise can ameliorate only course of disease progression. Therefore, rehabilitation interven- some of the factors that lead to weakness, and in some cases there tions are at the center of caring for individuals with these disorders. may be deleterious effects. Exercise, particularly resistance training, may be useful to increase or maintain muscle mass and strength and help maintain the Charcot-Marie-Tooth Disease highest levels of ability and function in these patients. Resistance exercise plays an important rehabilitative role in disorders of the CMT or the hereditary motor sensory neuropathies encom- MN and motor axon. The following will focus primarily on the pass a family of inherited peripheral neuropathies that present role of resistance exercise in CMT, ALS, and PPS. with slowly progressive, distal to proximal muscle atrophy, and weakness.17,27 The genetic defect in CMT1A, which is General Considerations involved in the most common form of CMT (70% of cases), is caused by either a duplication, or less commonly, a point mutation The majority of the progressive diseases of the peripheral motor in the PMP22 gene, resulting in functionally abnormal compact system result in weakness stemming from skeletal muscle atrophy. myelin in the peripheral nervous system. CMT1A is character- In turn, muscle weakness is the primary cause of disability in ized by markedly slowed conduction velocities in motor and patients suffering from these disorders. Lower extremity (LE) sensory nerves (often 15–20 m/s), areflexia, and the occurrence of weakness and limited functional mobility are often the most progressive motor and sensory deficits by the mid-teens in most concerning problem for these patients.15 cases. CMT-X presents with similar clinical features but with inter- 16 Exercise in Diseases of the Motor Neuron and Motor Axon AANEM Course mediate nerve conduction slowing.28 Alternatively, CMTII encom- muscles. The question remains as to whether or not resistance passes a number of disorders where the primary pathology is within exercise could improve strength and function in the more severely the axon, as opposed to the myelin (e.g., mutation in Mitofusin2 affected distal muscles given the underlying pathophysiology. for CMT 2A2). However, regardless of whether the primary pathology is within the myelin or axon, the eventual disability is Post-Polio Syndrome secondary to progressive axonal loss that results in motor and sensory deficits.18,28 Other causes of weakness, such as disuse atrophy and Paralytic poliomyelitis, an infectious disease of the anterior horn deconditioning, may compound the situation. To date, there are cell, has been eliminated in the Western world as a result of effective no effective pharmacologic therapies for the inherited neuropa- vaccination programs, and its worldwide incidence has dramatically thies. Therefore, rehabilitation interventions, including resistance decreased. However, over the past 20 years, there has been increas- exercise, are the mainstay of treatment. ing acceptance and recognition of the development of new motor deterioration in those previously affected by paralytic polio, follow- 33 A number of studies have examined the role of resistance exercise ing long periods (often decades) of relative neurological stability. in patients with slowly progressive neuromuscular disorders. In In addition to new motor deficits, many patients with the so-called some of these studies, patients with CMT have been included. PPS experience neuromuscular fatigue, central fatigue, and pain. It These studies, in general, have suffered from a number of short- has been reported that as many as 60% of those affected by prior 33 comings. For example, in most studies patients with a number polio may develop new weakness. A survey conducted in 1987 of different disorders were combined (e.g., patients with muscular showed that because there were more than 600,000 people in the dystrophy [MD] and CMT were in the treatment group). All United States with prior polio, PPS may become the most common too often, inadequate sample sizes were used and the studies were MN disorder. likely underpowered. Additionally, most studies suffer from the absence of non-exercising controls and in most cases, no functional A full review of the pathophysiology of PPS is beyond the scope of outcome measures were used. Lindeman and colleagues carried this manuscript. There are two leading hypotheses to explain the out the most methodologically sound and comprehensive study of new motor deficits in PPS. The first suggests that there is progres- resistance exercise in patients with CMT. 19 The study also in- sive deterioration of the distal motor axons in the greatly enlarged cluded a group with myotonic dystrophy, but the groups were ana- MUs.33 This is supported by single-fiber EMG (SFEMG) observa- lyzed separately. Subject assignment to either a training or control tions as well as data from muscle biopsies.36,37 The other leading group was performed randomly and the subjects were matched hypothesis suggests that loss of entire MUs leads to the new onset based on baseline strength. The training group performed knee weakness.23 Aging, in and of itself, is associated with significant extension and flexion exercises, as well as hip abduction exercises MU losses, the impact of which is substantially greater, as those with with weights strapped to the limb 3 times per week for 24 weeks. prior polio have less and larger MUs.7,8 This “accelerated aging” The primary outcomes were isokinetic knee extension and flexion hypothesis is based largely on electrophysiological data wherein torque, as well as functional outcomes (e.g., timed motor tasks, MU estimation techniques have shown reductions in MU numbers timed ascending and descending stairs). The myotonic dystrophy in longitudinal studies.23,29,30,32, Other contributing factors to group showed no improvement in torque or function, whereas the weakness include disuse, pain inhibition, overuse of severely CMT group demonstrated improved torque, but not improved affected muscle groups, and immunological mechanisms. 33 function. There was no evidence of muscle damage, as measured by serum myoglobin levels. Lindeman and colleagues later It is not surprising that resistance exercise is of considerable interest reported that the maximum surface electromyography (EMG) signal to patients with PPS and to those involved in their care. As a result increased substantially during the first 8 weeks of training, of new motor deterioration, patients often experience new or greater suggesting that the increased strength observed in this time period disability that impacts ADLs, as well as occupational and recre- was related to neural factors (improved central drive) and that ational activities.33 Therefore, any intervention that might lead to the subsequent smaller gains were likely related to muscle hyper- functional improvement is of great interest, and resistance exercise trophy.20 More recently, Chetlin and colleagues examined the has been the topic of a number of investigations. Early reports potential benefit of combining strength training with creatine were often single case studies or uncontrolled studies with small supplementation in patients with CMT. 6 Twenty patients were sample sizes.12,34 Most of these studies reported improved strength, randomized into two groups that would either perform resistance however, some noted the development of overuse weakness and training alone, or would perform the training and take 5 gm/day of cautioned against exercising weak muscles.11 A number of more creatine supplementation. While there were no differences between recent studies examined strength training in PPS in a more con- the creatine and training groups, the combined analysis revealed an trolled fashion. Though they were generally positive, none of increased Type I fiber diameter, increased strength, and improved them included an evaluation of the potential negative effects on activities of daily living (ADLs) on timed functional tasks. Thus, the MU itself.10,26,31 One rather comprehensive study by Agre and there was evidence of strength gains and muscle hypertrophy, but colleagues examined the potential benefits of a 12-week, home- no further added benefit from creatine supplementation was found. based program of quadriceps training in 12 men and women with Overall, there is reasonable evidence that progressive resistance clinical feature of PPS, all of whom had at least grade 3+ strength exercise can improve strength and possibly function in patients on manual muscle testing and features consistent with prior with mild to moderately severe CMT, at least for larger proximal polio on electrodiagnostic (EDX) assessment.1 An overall mean AANEM Course Exercise in Neuromuscular Diseases 17 increase of 61% was reported in the weight lifted, but there was to the exercise. Alternatively, high intensity treadmill running at no significant improvement in isokinetic or isometric peak torque 22 m/min did not delay disease onset in G93A-SOD1 male and of the knee extensors. Creatine kinase values did not change over female mice, and was found to shorten lifespan in the males.22 the course of the program and perhaps most importantly, there was Therefore, there is evidence from these animal studies that low no evidence of increased jitter, blocking on SFEMG, or change to moderate intensity exercise may be of benefit, whereas, high in the macro EMG amplitudes to indicate any further injury or intensity endurance exercise may be detrimental. deterioration to the enlarged MUs. Chan and colleagues extended these findings and examined the impact of 12 weeks of isometric There have been very few controlled studies that have examined training of the thenar muscles in five subjects with clinical and the potential benefit of resistance exercise in patients with ALS. EDX features of PPS as compared to a non-exercising PPS control Traditional thinking cautioned against therapeutic exercise due group.5 These subjects were comprehensively examined at baseline to concerns of overuse of denervated or severely weak muscles. with MU number estimates, maximal voluntary and evoked force However, early case reports provided generally positive results that measures, and twitch interpolation to assess adequacy of central have led to at least two controlled studies. drive. They reported significant improvements in strength in the PPS training group that were largely explained by increased central Drory and colleagues examined the potential benefit of a twice drive. There was no indication of further MU loss as a result of daily, home based exercise program consisting of an individual- the training. Therefore, strength training appears to be safe and ized program of modest intensity exercise designed to improve potentially beneficial for muscle groups with at least moderate endurance in comparison to a usual activities control group. 9 weakness in patients with PPS. To date, no studies have demon- They reported less deterioration on the ALS Functional Rating strated functional improvement. This would likely require much Scale (FRS) and Ashworth spasticity scale at 3 months, but no larger sample sizes and longer durations of training. difference at 6 months. There were too few subjects remaining at 9 and 12 months for analysis. The most rigorous examination Amyotrophic Lateral Sclerosis of resistance exercise in ALS patients to date involved 27 patients with clinically definite or probable ALS that were randomized to a ALS is a progressive, ultimately fatal, disorder of the upper and daily stretching and resistance exercise group, or control group that lower MNs. ALS often presents with focal weakness limited to performed daily stretching.2 Of the 27 patients, only 8 patients in one limb but eventually spreads to other segments of that limb and the resistance exercise group and 10 patients in the control group becomes generalized. The hallmarks of ALS are muscle atrophy completed the study. Despite the drop-out rates, at 6 months, the and weakness from lower MN loss and weakness, as well as fatigue resistance exercise group had significantly higher ALS-FRS scores, and spasticity from upper MN involvement. The overall incidence SF-36 physical function subscale scores, and less decline in leg ranges between 0.4 to 2.4 cases per 100,000, which will likely strength. No deleterious effects were reported. Therefore, there increase as the population ages.21 Currently, the only pharmaco- is some support for resistance exercise to be used as a potential logic treatment that has been shown to prolong life is riluzole.21 intervention to slow disease progression and maintain higher levels Therefore, there is considerable interest in exploring other potential of function in patients with ALS. However, larger studies are therapeutic interventions that may improve strength and ultimately required to provide more definitive evidence and to further examine improve function, or at least ameliorate the rate of decline. the optimal exercise modes, intensities, and overall volumes.

Traditionally, due to the progressive nature of ALS, exercise was believed to be deleterious. It has been postulated that severely CONCLUSION weak muscles are more susceptible to overuse injury as they are already functioning at levels close to maximal voluntary contraction In summary, there is considerable support for the prescription of when simply performing ADLs. 3,13 Therefore, some experts have resistance exercise in disorders of the MU and axon. There is little recommended that patients with ALS do no exercise beyond that evidence that light to moderate exercise is detrimental in muscle required for day-to-day activities. groups with at least grade 3 or better strength. However, much remains to be learned in terms of optimizing resistance training Recent studies using animal models of MN disease have provided programs for these patient populations. Ideally, future studies some evidence that endurance exercise slows disease progression. will require homogeneous patient populations, adequate sample It has been reported that treadmill running 5 days per week at sizes, training durations of 6 months or greater, and functional 13 m/min led to a significant increase in the life span of G93A- outcome measures. SOD1 male, but not in female mice.16 Alternatively, another study found that treadmill running at 16 m/min delayed disease onset and prolonged survival in transgenic low-copy hSOD1 REFERENCES female mice, whereas there was no effect in males.35 The most pronounced effects of exercise using the SOD1 mouse model were 1. Agre JC, Rodriquez AA, Franke TM, Swiggum ER, Harmon RL, reported in an adjunct study by Kaspar and colleagues.14 Mice that Curt JT. Low-intensity, alternate-day exercise improves muscle per- were exposed to an exercise wheel 6 hours per day, beginning in the formance without apparent adverse effect in postpolio patients. Am pre-symptomatic state, survived 33% longer than those not exposed J Phys Med Rehabil 1996;75(1):50-58. 18 Exercise in Diseases of the Motor Neuron and Motor Axon AANEM Course

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Physiological Adaptations and Responses to Exercise Training in Neuromuscular Disease

Gregory T. Carter, MD, MS Clinical Professor of Rehabilitation Medicine University of Washington School of Medicine Seattle, Washington Support obtained through Research and Training Center Grant #HB133B980008 from the National Institute on Disability and Rehabilitation Research

BACKGROUND (BMD) phenotype. There are at least four sarcoglycan subunits (α, It is well established in both humans and animals that β, γ, and δ) in muscle and mutations that can result in four types of exercise causes muscle injury and that eccentric exercise has a more autosomal recessive MD. Alpha laminin-2 (LAMA2) is a basement damaging effect than concentric exercise.4,21,22,23,47,49,59 In humans membrane protein and binds to β -dystroglycan. Mutations in the with neuromuscular disease (NMD), there has been considerable LAMA2 gene result in the MDC1A type of congenital MD.33,66 It controversy regarding the use of exercise, particularly high intensity is thought that mutations in components of the DGC complex lead strengthening programs. 4,21,22,23,47,49,59 Animal studies have been to a loss of sarcolemmal integrity and render muscle fibers more used to investigate the adaptive mechanisms that diseased muscles susceptible to exercise-induced damage. use in accommodating to exercise training to gain further insight into the fundamental biology of the response.4,49,59 Long before a genetic understanding of the basis of MDs was known, researchers used heredity animal models of MD to examine One of the problems in studying the effect of exercise in NMDs is the effect of exercise on dystrophic muscle. Animal models that that muscular dystrophies are a heterogeneous group of disorders have been used in investigations of increased muscle activity that have traditionally been classified by clinical phenotype, includ- include the dystrophic chicken, cardiomyopathic hamster, dy/dy ing mode of inheritance, age of onset, and overall progression of mouse, mdx mouse, and the xmd dog. These and other animal the disease. However, in the last 10 years, an increasing number of models have been the subject of several recent reviews.1,3,5 Type of defects in specific genes have been identified as the underlying cause inheritance, gene location, affected gene product, and the human of different forms of muscular dystrophy (MD). Most of the genes correlates are reviewed in Table 1. Species with the same gene encode for components of the dystrophin-glycoprotein complex pool abnormality often have a different phenotypic expression and (DGC), an assembly of transmembrane and membrane-associ- even a different gene-chromosome location than humans. The ated proteins that form a structural linkage between the F-actin same genetic defect can produce diverse pathologic findings when cytoskeleton and the extracellular matrix in muscle. The proteins expressed in different species. Awareness of the gene product func- that comprise the DGC are organized into three subcomponents: tion, contractile characteristics, fiber type and pathologic character- the cytoskeletal proteins, the sarcoglycans, and the sarcospan.8,9 istics of each species at various ages are important in evaluating the Many of the different types of MDs arise from primary mutations effect of interventions, since these characteristics are used as criteria in gene encoding components of this complex. Mutations in the when evaluating responses to a given intervention. dystrophin gene that result in a complete loss of dystrophin, lead to a Duchenne MD (DMD) phenotype. Mutations that cause the The gene location(s) and affected product(s) of the autosomal production of reduced amount dystrophin or production of a trun- dominant dystrophic chicken are unknown. White, fast-twitch cated, dysfunctional form of dystrophin, produce a Becker MD muscle is the most severely involved. Muscle degeneration does 20 Physiological Adaptations and Responses to Exercise Training in Neuromuscular Disease AANEM Course

muscles by avoiding activity, yet the diaphragm must continu- TABLE 1 Animal models used in exercise investigations ally contract to do the work of breathing. Compared to larger mammals, mice have more muscle power per body weight. During normal activity, mouse limb muscles are not significantly Inheritance Human Gene Affected Gene Human strained. The xmd dog, which also lacks dystrophin, shows Location Product Correlate overt clinical signs of the dystrophy at 6 to 9 weeks of age. mdx mouse XR Xp21.2 Dystrophin & DMD/BMD These include weakness, stiff gait, bunny-hopping and increased and xmd associated serum creatine kinase levels.70 Morphologically, necrosis and dog dlycoproteins regeneration are observed with marked endomysial fibrosis dy/dy AR 6q2 Laminin-N Congenital and fiber size variation.69 The xmd dog has a clinical progres- mouse (merosin) muscular sion closer to that of DMD than does the mdx mouse. The dystrophy dog, being a larger mammal like the human, has a relative Hamster AR 5q33-q34 Delta SCARMD- biomechanical disadvantage compared to the mouse. Thus, sarcoglycan LGD for larger mammals with a dystrophin deficient condition, Chicken AD Unknown Unknown None locomotion and other less intense forms of activity may place a great enough burden on skeletal muscle to induce injury and subsequent necrosis. AD = autosomal dominant; AR = autosomal recessive; DMD/BMD = Duchenne and Becker muscular dystrophy; LGD = limbagridle distrphy; SCARMD = Severe childhood autosomal recessive muscular dystrophy; XR = x-linked recessive. The autosomal recessive dy/dy mutant mouse (129 ReJ) and the 129B6F1/J hybrid have a deficiency in the laminin alpha 2 chain (merosin) and are considered models for the MDC1A not become severe until after age 1. The muscles also appear to type of congenital MD.66 There are several other murine models be myotonic.5,60 The dystrophic chicken is now rarely used as an for laminin alpha 2 deficient congenital MD. Skeletal muscle animal model, since there is no known human correlate. fiber degeneration occurs early and progresses very rapidly in the 129 Re J mutant, and only slightly less so in the hybrid. The In rodents and in other animals with dystrophy such as the dog, life spans vary but are much shorter than normal. Hind-limb fast-twitch muscles and type 2B fibers are the earliest and most paralysis, progressive ataxia and twitching, and scoliosis are ap- severely affected.1 However, there is a marked difference between parent as early as 2 weeks of age. There is normal development species in pathology, gene location, and gene product. The major during the first week postnatal, followed by a severe progres- organ system involved in the hamster is the heart, while the sion of the disease during the second week of life. During the diaphragm is more severely affected than skeletal muscle in third week, there is rapid degeneration followed by a relatively the mdx mouse.1,27,65 The peripheral nerves are also involved stable period between the fourth and eighth weeks of age. in the dy/dy mouse, which is the most severely impaired Thereafter, there is general fiber atrophy and dedifferentiation and has the most rapid disease progression of any of the of the fiber histochemical profile of the fiber. The phenotype rodent models of MD, although this may be due in part to of DMD is more like that of the dy/dy mouse than of the the neuropathy.29 mdx mouse.1,3,57

The X-linked recessive mdx mouse lacks dystrophin, similar to The autosomal recessive BIO cardiomyopathic hamster has a mu- young males with DMD. A lack of dystrophin affects the entire tation in the delta-sarcoglycan gene and is considered a model for DGC. The life span of the mdx mouse is normal and it has minimal one type of autosomal recessive limb-girdle MD. The life span of clinical muscular weakness. After the initial bout of extensive the cardiomyopathic hamster is about 12 months and it has no degeneration at 2 to 4 weeks of age, the muscles almost completely obvious locomotor physical disability at the time of death from regenerate and exhibit subsequent hypertrophy.58 However, follow- cardiomyopathy. In the early phase (1 month) and mid-phase (4 to ing this occurrence, the muscles undergo a continuous low level of 6 months), the fundamental pathologic events are repeated cycles degeneration and regeneration. Although their functional perfor- of segmental necrosis of groups of fibers, followed by vigorous mance, as determined by contractile studies, progressively declines regeneration.1,3,57 with age, the changes are relatively mild, even at 2 years of age.61 While the skeletal muscle has mild progression, the diaphragm Many of the exercise experiments on animal models of MD were exhibits more severe degeneration and fibrotic infiltration similar performed before there was an understanding of the underlying to that seen in DMD.65 The mechanism that causes the mdx genetic defects. These experiments were typically conducted to mouse diaphragm to have so much evidence of dystrophy simulate exercise training or to study contraction-induced injury. while mouse limb muscles do not, has not yet received satis- The objective of the exercise training studies was primarily to factory explanation. Gillis proposed that forced lengthening, compare the adaptations of normal and dystrophic muscle to exercise. induced by the elastic recoil of the thorax as the diaphragm The studies of contraction-induced injury utilized vigorous short- contracts during the first half of expiration, induces an eccentric term exercise testing or simulated exercise to determine whether contraction injury.32 There are likely other mechanisms at play dystrophin-deficient muscles were more susceptible to injury than as well. During exercise, the mouse can spare the hindlimb normal muscles. AANEM Course Exercise in Neuromuscular Diseases 21

EXERCISE TRAINING: WHAT DOES EXERCISE DO TO cinic dehydrogenase activity in fast and slow twitch muscles. No DISEASED MUSCLE? 21-week-old hamsters exhibited these changes, but 45-week-old hamsters exhibited a decrease in fiber size, fiber area, and succinic Regardless of differences in methodology, the objective of most of dehydrogenase activity. the following investigations was to evaluate the effect of exercise training on functional performance, muscle contractile characteris- After 4 weeks of vigorous treadmill running, the cardiomyopathic tics, and muscle pathology. Animal models included the dystrophic hamsters failed to increase their myoglobin concentration in the chicken, cardiomyopathic hamster, dy/dy mouse, and mdx mouse. same manner as normal hamsters.7 Tate and colleagues found that With the exception of only one study, exercise training consisted one bout of swimming to exhaustion had no effect on cardiac or of high-repetitive, aerobic type activity (e.g., swimming, treadmill skeletal muscle, calcium uptake, or adenosine triphosphatase ad- running, and voluntary-wheel running). Daily exercise intensity enosine triphoshatase Pase activity.67 ranged from submaximal exercise to maximal exhaustive exercise. The exercise protocols ranged from 1 week to several months. There Laminin-deficient dy/dy Mouse was also marked variability in the age of the animals at the initia- tion of the studies and, hence, variability in the degree of muscle There have been three swimming, one voluntary-wheel running, degeneration and regeneration at baseline. In most investigations, and two treadmill exercise investigations in the dy/dy mouse. Ages the number of animals was adequate, and nonexercised dystrophic at the start of the exercise programs ranged from 3 to 14 weeks, and animals, normal animals, and exercised normal animals served as the exercise programs lasted from 6 days to 5 weeks. control subjects. In functional performance studies, dy/dy mice produced less work Dystrophic Chickens and power and had lower levels of fatigue resistance than normal mice.34 The dy/dy mice also swam or ran more slowly and devel- In the investigations using dystrophic chickens, rotating cage exer- oped a higher percentage of muscle fibers with large diameter.35,64 cise or righting practice were reported to improve functional ability, but did not retard the muscle atrophy.5,44,60 In a voluntary wheel running study, Hayes and colleagues compared 4-week-old exercised dy/dy, mdx, and C57 mice with their sedentary control subjects.35 The mdx and C57 mice ran for 16 Dystrophic Hamster weeks, while the dy/dy mice ran for 5 weeks. The difference in performance between species was marked. The C57 mice ran 6.5 There have been three swimming studies, one weight-lifting km/day, mdx mice ran 1.6 km/day, and dy/dy mice ran only 0.5 exercise study, and three treadmill studies of the cardiomyopathic km/day. The exercised mdx and dy/dy mice produced increased hamster. Homburger and colleagues reported that swimming to tension and exhibited less fatigue resistance in fast-twitch muscle exhaustion for 8 days accelerated cardiac and skeletal necrosis.40 as compared to their sedentary controls. There were no significant and colleagues examined the effect of swimming with tail weights changes in slow-twitch muscle. Several dy/dy mice with extremely for 30 to 60 minutes per day for 8 weeks on the histopathology reduced hind limb function died before the end of the experiment. of the heart.39 Greater calcium necrosis was found in the heart The results from these animals were not included in the study. of the exercised hamsters than in the heart of the nonexercised control subjects. Sembrowich and colleagues examined the effect In a study by Taylor and colleagues, 2 weeks of maximal tread- of 18 weeks of vigorous treadmill exercise.63 The results indicated a mill running resulted in a marked decrease in slow-twitch muscle beneficial contractile response in the heart, while there was no dif- tension as compared to sedentary controls.68 There was high ference in the skeletal muscle weight or severity of skeletal muscle mortality in the more severely involved mice. In a related study necrosis after exercise. Fowler and colleagues reported that 3 weeks of submaximal treadmill running resulted in increased slow muscle fiber twitch tension, In young developing hamsters, vigorous treadmill running for 2 increased rate of twitch tension development, and increased rate of hours per day for 1 month had no effect; while running for 4 hours twitch tension relaxation.30 There was no change in the contractile per day for 1 month resulted in significant increases in muscle properties of the fast-twitch muscle. However, exercise significantly tension and less muscle necrosis in both fast and slow-twitch retarded the histopathologic progression of the disease in both fast- muscles. There was an increase in the oxidative capacity of the skel- twitch and slow-twitch muscles. There was a reduction in the vari- etal muscles, with hypertrophy of type l fibers, an increase in the ability of the fiber sizes in the type 1 fibers of the slow-twitch soleus percentage of type 1 fibers in slow-twitch muscles, and an increase muscle and the type 2B fibers of the fast-twitch extensor digitorum in the number and area of type 1 fibers of the plantaris muscles.28 longus (EDL) muscle.

In the only animal investigation using resistive exercise training, In a simulated exercise study, Luthert and colleagues subjected Howells and Goldspink subjected hamsters at 9 weeks to a pro- dy/dy mice to low frequency (10 hz) electrical stimulation for 1 gressive weight lifting program for 5 weeks.41,42,43 Nonexercised week.52 This stimulation resulted in increased tensions of slow hamsters had decreased fiber size and area, while the exercised ham- and fast-twitch muscle when compared to the control contralateral sters had an increase in fiber size and area, and an increase in suc- muscles. The succinic dehydrogenase activity of the stimulated 22 Physiological Adaptations and Responses to Exercise Training in Neuromuscular Disease AANEM Course muscles also was increased. A similar electrical stimulation study resistance of fast-twitch EDL muscles, but had no effect on their by Dangain and Vrbova resulted in a speeding of the time course tension development.74 of the muscle contraction and an increase in the fatigue resistance of skeletal muscles.25 There was an increase in the force output of Biondi and colleagues recently showed a slower rate of disease pro- weak dystrophic muscles with smaller fibers, but a slight decrease in gression and postnatal motor unit (MU) death in a type 2 spinal force output of the relatively strong dystrophic muscles. It was sug- muscular atrophy-like mice.6 Physical exercise (running) delayed gested that stimulation promotes growth and development of small motor neuron (MN) death and lead to an increase in the postnatal regenerating fibers and induces an increase in the mitochondrial maturation rate of the MUs. Exercise training also enhanced the content of the muscle fibers. expression of the gene encoding the major activating subunit of the NMDA receptor in MNs, namely the NR2A subunit (which is Dystrophin-deficient mdx Mice dramatically down-regulated in the spinal cord of type 2 SMA-like mice). There have been four voluntary wheel-running studies and three swimming investigations in the mdx mouse. Ages at the start of the A recent study showed that exercise improves graft success and exercise program ranged from 3 weeks to 2 years, and the exercise hybrid fiber distribution within mdx muscle.8 eGFP(+) Muscle periods lasted from 4 to 52 weeks. Several drug-exercise studies precursor cells were transplanted into tibialis anterior (TA) muscles were also performed in this study.26,37,45,76 of mdx mice using a single injection trajectory. During the following weeks, muscle fiber breaks were induced by making mdx mice Hayes and colleagues in a 15 week endurance swimming program swim. Twenty minutes of swimming was used to induce damage that started with the mice at 5 weeks of age, observed increased in about 30% of TA muscle fibers. Graft success, evaluated as the tension, increased fatigue resistance, and a greater percent of type percentage of hybrid fibers which are eGFP(+), was improved by 1 fibers in the soleus of the exercised mdx mice.38 The EDL 1.9-fold after swimming 3 times per week during 4 weeks and by muscles exhibited a longer half-relaxation time and an increase in 1.8-fold after daily swimming. Hybrid muscle fiber transversal and the number of type 2A fibers. Lynch, using the same swimming longitudinal distribution were also increased after repeated physi- exercise protocol, measured the contractile properties of skinned cal efforts. Exercise-induced fiber breaks, which improved muscle fibers.53 Type 2B fibers from the EDL and type 2A fibers from the precursor cells recruitment and fusion, and increased long-term soleus of exercised animals were found to be less sensitive to Ca++ graft success as well as transverse and longitudinal distribution of and Sr++ when compared to sedentary mice. In a 1998 study, hybrid fibers. Hayes and colleagues examined the effects of a 10 week, once a day endurance swimming protocol using adult (8 to 10 months) Dystrophin, which is absent in muscles of the mdx mouse, is and older (24 months) mdx and C57 mice.36 The exercised mice thought to stabilize the sarcolemma during contractions of normal had increased tension per cross sectional area in both the soleus and muscle.3 This is supported by studies which have shown transient the EDL, but there was no effect on body mass, fatigue properties, localized plasma membrane instability in dystrophin-deficient muscle mass, or fiber type profiles in either muscle. fibers. Carter and colleagues investigated the use of intravenously injected fluorescent dextran molecules (FDx) as a histological Ten to 12 months of voluntary wheel running increased the marker of sarcolemmal injury in dystrophin-deficient mdx and maximal tetanic tension and the contraction time of the mdx control mice.14 Using fluorescent microscopy, uptake of FDx was diaphragm, but had no effect on the slow twitch soleus muscle.27 assessed in sections of quadriceps muscles from three models: non- Carter and colleagues examined the effect of 4 weeks of voluntary exercised normal mice, normal mice run downhill (0, 3, and 7 days wheel running in mdx and C57 mice using two different age post exercise), and non-exercised mdx mice. In non-exercised groups, young (4 weeks of age) and adult (6 months of age).17 The normal muscles, strong intercellular fluorescence was seen between young mdx mice ran 78% of the distance run by the C57 mice, fibers. In normal mice run downhill, only small amounts of in- while the adult mdx mice ran only 31% of the distance run by the tracellular FDx were observed within cells of the quadriceps from C57 mice. After exercise, the slow-twitch soleus muscle of both at days 0 and 3 post exercise, but not at day 7. With hematoxylin the young and the old mdx mice exhibited hypertrophy with no and eosin (H&E) staining, no muscle pathology was observed at change in tension per cross sectional area and no change in fatigue day 0, slight pathology was observed at day 3, and regeneration resistance. The mdx EDL exhibited slight hypertrophy and loss was observed at day 7. In contrast, extensive intracellular FDx was of tension in the adult, while the young exhibited no changes. observed within the muscles of non-exercised mdx mice, particu- There was a significant increase in serum levels of creatine kinase larly in fibers that appeared pre-necrotic on H&E stained sections. in the adult exercised mdx mice when compared to their sedentary In studies using exhaustive exercise and electromyography (EMG), controls. Hayes and Williams reported that 16 weeks of voluntary significant evidence of sarcolemal damage and instability in both wheel running beginning at 4 weeks of age resulted in hypertrophy mdx and myotonic (mto) mice was shown. In the mto mice, of the soleus and an increase in soleus tension, fatigue resistance, membrane instability was not helped by blocking the fast sodium and proportion of type 1 fibers.35 In the EDL, there was no effect channels with amitriptyline, procainamide, and phenytoin, indicat- on tension but there was an increase in fatigue resistance and a ing that the leaks may not be coming through a known or exist- conversion to oxidative fiber types. Wineinger reported that 12 ing membrane ion channel and could be novel, exercise-induced months of voluntary wheel running slightly increased the fatigue damage.13,15,16,34 Newer agents like mexilitine have not been tried AANEM Course Exercise in Neuromuscular Diseases 23 in this model however. A similar phenomenon is particularly fibers and may reduce the risk for further mechanical damage to evident in mdx diaphragm.12 Interestingly, some of this phenom- these fibers. However, this type of training had little impact on enon is also seen in neuropathic mice.55 fast-twitch fibers. The major factors determining the beneficial or deleterious effect of exercise training in animals with MD include: Several investigators have examined the effect of different types of (1) the age of the animal at the start of the study, (2) the severity running exercise on the susceptibility to injury on various animal of the dystrophy at the start of the study, (3) the intensity of the models of MD. In the canine model (CXMD), Valentine and col- training (sub-maximal or maximal), (4) the length of the train- leagues showed that even mild exercise can cause significant eleva- ing, and (5) the type of training (repetitive aerobic or resistive tion of serum creatine kinase that reached a peak at 4 hours post strength). These factors are similar to those reported in humans exercise and returned to baseline values at 24 hours post exercise.69 with dystrophy. Sandri and coworkers demonstrated that the apoptotic index in mdx mice dramatically increased after short-term wheel running, Studies have demonstrated that mechanical weakness and con- whereas in the skeletal muscle of control mice only a minor increase traction-induced muscle injury are not always required for muscle in apoptotic cells was detectable.62 This was the first evidence that degeneration and the dystrophic process. Evans blue dye, which exercise may trigger the apoptosis in dystrophin deficient mice. does not cross into skeletal muscle fibers in normal mice, shows Using fluorescent dye, Clarke and colleagues examined triceps marked accumulation in the muscles of mdx mice and in muscles of muscles of mdx mice after a single bout of downhill running.20 transgenic mice bearing different dystrophin mutations. However, Seventy-five percent of the fibers of the mdx triceps exhibited tran- the muscles of the dy/dy mouse, which have defects in the laminin sient membrane disruptions which was 7-fold greater than control alpha 2-chain, an extracellular ligand of DGC, showed little dye mice. Furthermore, no difference was observed between muscles accumulation.66 There was no evidence for contraction-induced of control mice following running and those of non-exercised injury in mice lacking γ-sarcoglycan that were subjected to an control mice. Brusee examined the effect of downhill running for extended, rigorous exercise regimen.33 Isolated muscles lacking 3 days on the histology of mdx mice.61 A 31% increase in positive γ-sarcoglycan have shown normal resistance to mechanical strain staining for Evans blue muscle in young mdx mice was reported induced by eccentric muscle contraction with normal peak isomet- while there was only up to a 3% increase in staining in normal ric force generation. muscle. Stained fibers were also present in 2% to 15 % of non- exercised mdx mice. Further evidence of injury and repair was Regardless of species and differences in methodology, the shown by Vilquin, who investigated skeletal muscle fibers in trans- majority of these investigations reported that dystrophic animals genic dystrophinless mice expressing beta galactosidase.73 Adult had a normal and beneficial adaptation to mild, submaximal mdx/beta galactosidase (dystrophin negative) and normal/beta aerobic exercise, while maximal exhaustive exercise had a deleteri- galactosidase (dystrophin positive) mice were submitted to one ous effect, especially to fast-twitch muscle. The beneficial adap- short session of eccentric, downhill running exercise. The leakage tations to mild aerobic exercise training included an increase in of creatine kinase and beta galactosidase was investigated prior to, muscle strength and a reduction in muscle degeneration. There 1 hour after, and 3 days after the running session. A significant and was a hypertrophic response in the muscles that were not severely transient rise in the level of these enzymes was noted in the serum affected by the dystrophy. High repetitive, low impact exercise of mdx mice following the exercise session. The peak leakage was increased the oxidative capacity and the proportion of oxidative transient, suggesting that muscle fiber lesions were rapidly repaired fibers, especially in slow-twitch muscles. Younger animals tend to following this short, noninvasive eccentric running session. All benefit more from exercise studies than older animals. However, of these running experiments revealed increased susceptibility to high-repetitive exercise typically had no effect or a deleterious injury in dystrophic animals as compared to control subjects. It is effect in fast-twitch muscles that were more severely affected by the important to note that transient damage is the stimulus for adap- disease and are more likely to incur damage by eccentric exercise. tion. Many acute exercise induced damaged studies have been There are not enough reports examining the effect of high-resistive erroneously misinterpreted as suggesting that exercise training is not strength training exercises in dystrophic animals to allow any con- good for dystrophic muscles, as the exercise does lead to evidence of clusions to be drawn.11 muscle damage. This same philosophy has led some investigators to suggest that the acute increase in oxidative stress seen after a single It is now well accepted that dystrophinopathies confer increased bout of exercise may be deleterious. Yet it would appear that exercise susceptibility to oxidative stress, both in human and animal training actually lowers oxidative stress in mdx mice.2,11,46 models. Tarnopolsky’s group recently examined the effect of low intensity exercise training (LIT) on markers of oxidative stress in All of the investigations used repetitive exercise training protocols, skeletal muscle of mdx and wild-type mice.46 LIT was associated usually submaximal wheel running or swimming, with the excep- with lower levels of malondialdehyde and protein carbonyls in tion of one investigation, which used a resistive strengthening train- white muscle of mdx mice (decreased 38% and 44%, p<0.001 ing protocol. Regardless of species and differences in methodology, and p<0.01, respectively). Antioxidant and mitochondrial enzyme all of these investigations reported a relatively normal and beneficial activities were higher in white muscle of mdx than in wild type adaptation to aerobic exercise. The benefits of the high-repetitive, mice (p<0.05). LIT in mdx mice induced physiological adaptation, low-impact training, whether by running, swimming, or electrical resulting in lower levels of markers of oxidative stress to levels that stimulation, typically has a greater effect on the more oxidative did not differ from those of wild type mice. 24 Physiological Adaptations and Responses to Exercise Training in Neuromuscular Disease AANEM Course

Most of the exercise studies using animal models of MD were an exercise program should be cautioned of the warning signs of performed with the assumption that they were models of DMD. overwork weakness, which include feeling weaker rather than stron- However, it is known that some of these animal models were more ger within 30 minutes post exercise, or excessive muscle soreness 24 similar to other MDs. The dy/dy mouse is a model of one of the to 48 hours following exercise. Other warning signs include severe congenital MDs, the BIO hamster is a model of one of the limb- muscle cramping, heaviness in the extremities, and prolonged girdle MDs, while the mdx mouse and xmd dog are models of shortness of breath. DMD. With the advent of genetic techniques, models that have the same genetic defect as their human counterpart can now be Early intervention with gentle, low-impact aerobic exercise such as studied. Identification of the defect and understanding the role of walking, swimming, and stationary bicycling improves cardiovas- the gene product will help us elucidate the role of exercise in NMD. cular performance, increases muscle efficiency, and lessens fatigue. In the future, current knowledge of the response of diseased muscle Based on the available investigations, there is adequate evidence to to exercise will provide a benchmark to compare the possible ben- generally advocate a submaximal strengthening program for persons efits of corrective gene therapy. with slowly progressive NMDs. There seems to be no additional benefit to high-resistance, low-repetition training sets, and the risk of actually increasing weakness becomes greater. Improvement in HUMAN STUDIES strength hopefully translates to more functional issues such as improved endurance and mobility. Human studies examining the effects of exercise in subjects with NMD are difficult at best for many reasons. One of the problems Tarnopolsky’s group has shown this type of effect in healthy young in studying the effect of exercise in NMDs is that MDs are a het- men recovering from exercise-induced muscle damage.54 Subjects erogeneous group of disorders that have traditionally been classified (n = 4) performed 300 maximal eccentric contractions, and skel- by clinical phenotype, including mode of inheritance, age of onset, etal muscle biopsy samples were analyzed at 3 hours and 48 hours and overall progression of the disease. These are also relatively after exercise. Changes in gene expression were studied 3 hours uncommon, if not rare, disorders. Thus, unfortunately, much of and 48 hours post exercise. By 48 hours post exercise, 59 genes the existing literature mixes myopathic and neuropathic subjects had increased activity while 29 had decreased. Based on that initial together, likely to simply increase sample sizes. In slowly progres- data, 19 gene changes were selected and a subsequent analyses was sive NMDs a 12-week, moderate-resistance (30% of maximum conducted using real-time polymerase chain reaction on muscle isometric force) exercise program resulted in strength gains ranging biopsy samples taken from a larger number of subjects (n = 11) from 4% to 20% without any notable deleterious effects.2 who performed an identical bout of exercise to induce muscle damage. This led to a rapid (3 hour) increase in sterol response In a mixed population of subjects with myopathies and neuropa- element binding protein 2 (SREBP-2), followed by a delayed thies, a 12 week home aerobic program also improved endurance.75 (48 hour) increase in the SREBP-2 gene targets Acyl CoA:cholesterol However, in the same population, a 12-week, high-resistance exer- acyltransferase (ACAT)-2 and insulin induced gene 1 (insig-1). The cise program (training at the maximum weight a subject could lift expression of the IL-1 receptor, a known regulator of SREBP-2, was 12 times) showed no further added beneficial effect compared to also elevated after exercise. This data clearly shows that human skel- the moderate resistance program and there was evidence of over- etal muscle growth and remodeling due to severe exercise is under work weakness in some of the subjects.48,54 In a comparative study, direct regulatory control and that exercise does induce significant patients having Charcot-Marie-Tooth (CMT) disease appeared to alterations in steady state mRNA content gene. The novel genes benefit significantly from a strengthening program; whereas myo- identified here are likely involved the ones in recovery from exercise tonic MD (MMD) (DM1) patients showed neither beneficial or –induced damage. This lends credence to the concept that even a detrimental effects.18,51 Tarnopolsky’s group also duplicated some single bout of exercise can lead to profound cellular adaptations, of Kilmer’s earlier findings on resistance training, although in this even at the gene expression level. Ultimately these rapid adapta- study, they isolated the study group from patients with CMT only, tions may help the muscle become increasingly resistant to future as opposed to mixing all diagnoses.18,19 It is clear that there are dif- damage from future bouts of exercise. How this would play out in ferences between myopathic and neuropathic subjects, as was dem- diseased muscle is still unclear and more rigorous studies in larger onstrated nicely by Lindeman and coworkers.50,51 The myotonic groups of subjects are needed before conclusions can be drawn group (DM1) group showed neither positive nor negative effects with any degree of confidence. of the moderate resistance training protocol, whereas in the CMT groups, the training produced a moderate increase in strength and Krivickas’s group recently conducted a Cochrane review of exercise leg-related functional performance.51 in randomized or quasi-randomized controlled trials of people with a diagnosis of definite, probable, probable with laboratory support, Due to the active muscle degeneration in the rapidly progressive or possible ALS, as defined by the El Escorial criteria.24 This in- NMDs like DMD or amyotrophic lateral sclerosis (ALS), the risk cluded progressive resistance or strengthening exercise and endur- for overwork weakness is great and exercise should be prescribed ance or aerobic exercise. The control condition was no exercise or cautiously using a common sense approach. All patients with standard rehabilitation management, and the primary outcome NMD should be advised not to exercise to exhaustion due to the measure was improvement in functional ability, decrease in dis- risk of muscle damage and dysfunction. Patients participating in ability or reduction in rate of decline, as measured by a validated AANEM Course Exercise in Neuromuscular Diseases 25 outcome tool at 3 months. Secondary outcome measures included High-resistance eccentric exercise should be avoided as it may the improvement in psychological status or quality of life, decrease produce muscle damage. However, it should be noted that no in fatigue, increase in, or reduction in rate of decline of muscle studies of strength training in neuromuscular patients have dem- strength (strengthening or resistance studies), increase in, or reduc- onstrated translation of the modest strength gains achieved into tion in rate of decline of aerobic endurance (aerobic or endurance improved function in activities of daily living or the overall course studies) at 3 months and frequency of adverse effects. They identi- of the disease. Nonetheless, it would be prudent to recommend fied two randomized controlled trials that met inclusion criteria. beginning a strengthening program as soon as possible after an The first examined the effects of a twice-daily exercise program of NMD diagnosis. The objective of such a program is to maxi- moderate load, endurance exercise versus "usual activities" in 25 mize the strength of unaffected or mildly affected muscles in an people with ALS. The second examined the effects of thrice weekly attempt to delay the time at which function becomes impaired. moderate load and moderate intensity resistance exercises compared Weight training or strengthening exercise should be performed to usual care (stretching exercises) in 27 people with ALS. After with a weight that the individual can lift 20 times; this is a 3 months, when the results of the two trials were combined, there simple way for the patient to select a weight that is in the 20% was a significant weighted mean improvement in the Amyotrophic to 40 % of maximum voluntary contraction range (alternatively Lateral Sclerosis Functional Rating Scale measure of function in the selecting a weight the NMD patient can lift 20 times and then exercise compared with the control groups (3.21, 95% confidence do sets of 10 repetitions. This assures that one remains within interval 0.46 to 5.96) in favor of the exercise group. No statistically this range). The patient should then perform 2 or 3 sets of 10 significant differences in quality of life, fatigue, or muscle strength repetitions. This guideline will prevent overworking the muscles were found. with excessively heavy weights. Another general guideline is that if an exercise regimen consistently produces muscle soreness A similar Cochrane review was done for strength training or aerobic or fatigue lasting longer than one half hour after exercise, it is exercise programs in patients with muscle disease.72 The goal was too strenuous. to examine the efficacy and safety of strength training and aerobic exercise training in patients with muscle diseases. To be included in the review, the studies had to be randomized or quasi-random- REFERENCES ized controlled trials comparing strength training and/or aerobic exercise programs, lasting at least 10 weeks. They only identified 1. Abresch RT, Walsh SA, Wineinger MA. Animal models of neuro- two randomized trials fulfilling all inclusion criteria. The first muscular diseases: pathophysiology and implications for rehabilitation. trial compared the effect of strength training versus no training Rehabilitation of Neuromuscular Disorders in Physical Medicine and in 36 patients with myotonic dystrophy. The other trial compared Rehabilitation Clinics of North America 1998; 9: 285-299. strength training versus no training combined with albuterol or 2. Aitkens S, McCrory M, Kilmer DD, Bernauer EM. Moderate resis- placebo in 65 patients with facioscapulohumeral MD (FSHD). tance exercise program: Its effect in slowly progressive neuromuscu- The authors concluded that in myotonic dystrophy and FSHD lar disease. Arch Phys Med Rehabil 1993; 74: 711-715. 3. Allamand V, Campbell KP. Animal models for muscular dystrophy: moderate-intensity strength training does not appear to do harm valuable tools for the development of therapies. Hum Mol Genet but there is insufficient evidence to establish that it offers benefit. 2000; 9: 2459-2467. Limitations in the design of studies in other muscle diseases 4. Armstrong RB, Ogilvie RW, Schwane JA. Eccentric exercise-induced prevent general conclusions in these disorders. injury to rat skeletal muscle. J Appl Physiol 1983; 54: 80-93. 5. Asmundson VS, Kratzer FH, Julian LM. Inherited myopathy in the Another recent study which noted that pain and fatigue are im- chicken. Ann N Y Acad Sci 1966; 138: 49-60. portant features in FSHD, tried to assess strength training and 6. Biondi O, Grondard C, Lécolle S, Deforges S, Pariset C, Lopes P, albuterol in this disease, but ultimately concluded that these Cifuentes-Diaz C, Li H, della Gaspera B, Chanoine C, Charbonnier modalities do not have a positive or negative effect on pain, the F. Exercise-induced activation of NMDA receptor promotes motor extent of fatigue experienced, functional status, and/or psycho- unit development and survival in a type 2 spinal muscular atrophy logical distress.71 model mouse.. J Neurosci. 2008 28(4):953-6. 7. Booth FW. Inability of myoglobin to increase in dystrophic skeletal muscle during daily exercise. Pflugers Arch 1978; 373: 175-178. CONCLUSION 8. Bouchentouf M, Benabdallah BF, Mills P, Tremblay JP. Exercise improves the success of myoblast transplantation in mdx mice. Neuromuscul Disord. 2006;16(8):518-29. One may conclude from strengthening studies in these diverse 9. Brussee V, Tardif F, Tremblay JP. Muscle fibers of mdx mice are populations of neuromuscular patients that with moderate re- more vulnerable to exercise than those of normal mice. Neuromuscul sistance training, overuse weakness and muscle damage likely Disord 1997; 7: 487-492. does not occur in muscles with ≥ 3/5 strength (Medical Research 10. Campbell KP, Kahl SD. Association of dystrophin and an integral Council scale). Thus, strength gains may be achieved, although membrane glycoprotein. Nature 1989; 338: 259-262. they are not as great as they would be in subjects without a NMD. 11. Carter GT, Abresch RT, Fowler WM: Adaptations to exercise train- Strength gain would appear to be roughly proportional to the ing and contraction-induced muscle injury in animal models of neuromuscular disease. Am J Phys Med Rehabil 2002; (81):151-161. initial muscle strength, suggesting that a strengthening program should be initiated as early as possible in the course of the disease. 26 Physiological Adaptations and Responses to Exercise Training in Neuromuscular Disease AANEM Course

12. Carter GT, Abresch RT, Walsh SA, Wineinger MA. The mdx mouse 33. Hack AA, Cordier L, Shoturma DI, Lam MY, Sweeney HL, McNally diaphragm: exercise-induced injury. Muscle Nerve 1997; 20:393-394. EM. Muscle degeneration without mechanical injury in sarcoglycan 13. Carter GT, Kikuchi N, Abresch RT, Walsh SA, Horasek S, Fowler deficiency. Proc Natl Acad Sci U S A 1999; 96: 10723-10728. WM. Effects of exhaustive concentric and eccentric exercise on 34. Han JJ, Carter GT, Ra JJ, Abresch RT, Chamberlain JS, Robinson LR. murine skeletal muscle. Arch Phys Rehabil 1994; 75(5):555-559. Electromyographic studies in mdx and wild-type C57 mice. Muscle 14. Carter GT, Kikuchi N, Horasek SJ, Walsh SA. The use of fluorescent Nerve 2006; 33:208-214. dextrans as a marker of sarcolemmal injury. Histol Histopathol 1994; 35. Hayes A, Williams DA. Beneficial effects of voluntary wheel running 9: 443-447. on the properties of dystrophic mouse muscle. J Appl Physiol 1996; 15. Carter GT, Longley KJ, Entrikin RK. Electromyographic and nerve 80: 670-679. conduction studies in the mdx mouse. Am J Phys Med Rehabil 1992; 36. Hayes A, Williams DA. Contractile function and low-intensity ex- 71(1):2-5. ercise effects of old dystrophic (mdx) mice. Cell Physiol 1998; 274: 16. Carter GT, Longley KJ, Walsh SA, Entrikin RK. Lack of effect of C1138-C1144. amitriptyline in murine myotonia. Am J Phys Med Rehabil 1992; 37. Hayes A, Williams DA. Contractile properties of clenbuterol-treated 71(5):279-282. mdx muscle are enhanced by low-intensity swimming. J Appl Physiol 17. Carter GT, Wineinger MA, Walsh SA, Horasek SJ, Abresch RT, 1997; 82: 435-439. Fowler WM, Jr. Effect of voluntary wheel-running exercise on 38. Hayes A, Lynch G, Williams DA. The effects of endurance exercise muscles of the mdx mouse. Neuromusc Disord 1995; 5: 323-332. on dystrophic mdx mice: I. Contractile and histochemical properties 18. Chetlin R. D., Gutmann L., Tarnopolsky M. A., Ullrich I. H., of intact muscles. Proc R Soc Lond 1993; 253: 19-25. and Yeater R.A. Resistance training effectiveness in patients with 39. Ho KW, Carrow R, Taylor J, Roy R, Lindstrom J, Heusner W, Van Charcot-Marie-Tooth disease, recommendations for exercise pre- Huss W. Effects of swimming on dystrophic Syrian hamster heart. scription. Arch. Phys. Med. Rehabil 2004a. 85(8), 1217-1223. Exp Pathol (Jena 1975; 11: 247-254. 19. Chetlin R. D., Gutmann L., Tarnopolsky M. A., Ullrich I. H., and 40. Homburger F, Nixon CW, Eppenberger ME, Baker JR. Hereditary Yeater R. A. Resistance training exercise and creatine in patients with myopathy in the Syrian hamster: studies on pathogenesis. Ann N Y Charcot-Marie-Tooth disease.Muscle Nerve 2004b; 30(1), 69-76. Acad Sci 1966; 138: 14-27. 20. Clarke MS, Khakee R, McNeil PL. Loss of cytoplasmic basic fi- 41. Howells KF, Goldspink G. The effects of age and exercise on the broblast growth factor from physiologically wounded myofibers of succinic dehydrogenase content of dystrophic hamster muscle fibres. normal and dystrophic muscle. J Cell Sci 1993; 106: 121-133. Histochem J 1974; 6: 523-530. 21. Clarkson PM. Eccentric exercise and muscle damage. Int J Sports 42. Howells KF, Goldspink G. The effects of age and exercise on the Med 1997; 18 Suppl 4: S314-S317. succinic dehydrogenase content of individual muscle fibres from fast, 22. Clarkson PM. Exercise-induced muscle damage--animal and human slow and mixed hamster muscles. Histochemie 1974; 38: 195-201. models. Med Sci Sports Exerc 1992; 24: 510-511. 43. Howells KF, Goldspink G. The effect of exercise on the progress of 23. Clarkson PM, Sayers SP. Etiology of exercise-induced muscle the myopathy in dystrophic hamster muscle fibres. J Anat 1974; 117: damage. Can J Appl Physiol 1999; 24: 234-248. 385-396. 24. Dalbello-Haas V, Florence J, Krivickas L. Therapeutic exercise for 44. Hudecki MS, Pollina CM, Bhargava AK, Fitzpatrick JE, Privitera CA, people with amyotrophic lateral sclerosis or motor neuron disease. Schmidt D. Effect of exercise on chickens with hereditary muscular Cochrane Database Syst Rev 2008; 16;:CD005229. dystrophy. Exp Neurol 1978; 61: 65-73. 25. Dangain J, Vrbova GA. Long term effect of low frequency chronic 45. Hudecki MS, Pollina CM, Granchelli JA, Daly MK, Byrnes T, Wang electrical stimulation on the fast hind limb muscles of dystrophic JC, Hsiao JC. Strength and endurance in the therapeutic evaluation mice. J Neurol Neurosurg Psychiatry 1989; 52: 1382-1389. of prednisolone-treated mdx mice. Res Commun Chem Pathol 26. Dupont-Versteegden EE. Exercise and clenbuterol as strategies to Pharmacol 1993; 79: 45-60. decrease the progression of muscular dystrophy in mdx mice. J Appl 46. Kaczor JJ, Hall JE, Payne E, Tarnopolsky MA.Low intensity training Physiol 1996; 80: 734-741. decreases markers of oxidative stress in skeletal muscle of mdx mice. 27. Dupont-Versteegden EE, McCarter RJ, Katz MS. Voluntary exercise Free Radic Biol Med. 2007 1;43(1):145-54. decreases progression of muscular dystrophy in diaphragm of mdx 47. Kilmer DD. The role of exercise in neuromuscular disease. Physical mice. J Appl Physiol 1994; 77: 1736-1741. Medicine and Rehabilitation Clinics of North America 1998; 9: 28. Elder GC. Beneficial effects of training of developing dystrophic 115-125. muscle. Muscle Nerve 1992; 15: 672-677. 48. Kilmer DD, McCrory MA, Wright NC, Aitkens SG, Bernauer EM. 29. Fowler WMJ. Management of musculoskeletal complications in The effect of a high resistance exercise program in slowly progressive neuromuscular diseases: weakness and the role of exercise. In: neuromuscular disease. Arch Phys Med Rehabil 1994; 75: 560-563. Fowler WMJ, ed. Physical medicine and rehabilitation state of the 49. Lieber RL, Friden JO. Selective damage of fast glycolytic muscle art reviews: advances in the rehabilitation of neuromuscular diseases. fibres with eccentric contraction of the rabbit tibialis anterior. Acta Philadelphia: Hanley & Belfus, Inc.; 1988. pp 489-507. Physiol Scand 1988; 133: 587-588. 30. Fowler WM, Jr., Abresch RT, Larson DB, Sharman RB, Entrikin 50. Lindeman E, Leffers P, Reulen J, Spaans F, Drukker J.Quadriceps RK. High-repetitive submaximal treadmill exercise training: effect on strength and timed motor performances in myotonic dystrophy, normal and dystrophic mice. Arch Phys Med Rehabil 1990; 71: 552- Charcot-Marie-Tooth disease, and healthy subjects. Clin Rehabil 557. 1998;12(2):127-35. 31. Gey GO, Kennard DW. Work and power capacity of normal mice 51. Lindeman E, Leffers P, Spaans F, Drukker J, Reulen J, Kerckhoffs M, and those suffering from muscular dystrophy, measured during sta- Koke A. Strength training in patients with myotonic dystrophy and tionary swimming. Nature 1964; 202: 264-266. hereditary motor and sensory neuropathy: a randomized clinical trial. 32. Gillis JM. The mdx mouse: why diaphragm? Muscle Nerve 1996; 19: Arch Phys Med Rehabil 1995; 76(7):612-20. 1230. 52. Luthert P, Vrbova GA, Ward KM. Effects of slow frequency electrical stimulation on muscles of dystrophic mice. J Neurol Neurosurg Psychiatry 1980; 43: 803-809. AANEM Course Exercise in Neuromuscular Diseases 27

53. Lynch GS, Hayes A, Lam MH, Williams DA. The effects of endur- mdx mouse diaphragm reproduces the degenerative changes of ance exercise on dystrophic mdx mice. II. Contractile properties Duchenne muscular dystrophy. Nature 1991; 352: 536-539. of skinned muscle fibres. Proc R Soc Lond B Biol Sci 1993; 253: 65. Straub V, Rafael JA, Chamberlain JS, Campbell KP. Animal models 27-33. for muscular dystrophy show different patterns of sarcolemmal dis- 54. Mahoney DJ, Safdar A, Parise G, Melov S, Fu M, Macneil L, Kaczor ruption. J Cell Biol 1997; 139: 375-385. JJ, Payne ET, Tarnopolsky MA. Gene expression profiling in human 66. Tate CA, McMurray RG, Riggs CE, Setaro F, Horvath SM. Exercise skeletal muscle during recovery from eccentric exercise. Am J Physiol and mitochondrial calcium transport in the BIO 14.6 hamster. Eur J Regul Integr Comp Physiol. 2008; in press. Appl Physiol 1980; 43: 167-172. 55. Meekins GD, Carter GT, Emery MJ, Weiss MD. Axonal degeneration 67. Taylor RG, Fowler WM, Jr., Doerr L. Exercise effect on contractile in the Trembler-J mouse evident by stimulated single fiber electro- properties of skeletal muscle in mouse muscular dystrophy. Arch myography. Muscle Nerve 2007 ; 36(1):81-86. Phys Med Rehabil 1976; 57: 174-180. 56. Nonaka I. Animal models of muscular dystrophies. Lab Anim Sci 68. Valentine BA, Cooper BJ, Cummings JF, DeLahunta A. Canine 1998; 48: 8-17. X-linked muscular dystrophy: morphologic lesions. J Neurol Sci 57. Pastoret C, Sebille A. Age-related differences in regeneration of dys- 1990; 97: 1-23. trophic (mdx) and normal muscle in the mouse. Muscle Nerve 1995; 69. Valentine BA, Cooper BJ, DeLahunta A, O'Quinn R, Blue JT. Canine 18: 1147-1154. X-linked muscular dystrophy. An animal model of Duchenne mus- 58. Peeze BF, Slaaf DW, Kuipers H, Tangelder GJ, Reneman RS. cular dystrophy: clinical studies. J Neurol Sci 1988; 88: 69-81. Exercise-induced swelling of rat soleus muscle: its relationship with 70. van der Kooi EL, Kalkman JS, Lindeman E, Hendriks JC, van intramuscular pressure. J Appl Physiol 1990; 69: 67-73. Engelen BG, Bleijenberg G, Padberg GW. Effects of training and 59. Peterson DW, Hamilton WH, Lilyblade AL. Retardation of fatty albuterol on pain and fatigue in facioscapulohumeral muscular dys- infiltration in atrophic muscle of genetically dystrophic chickens by trophy. J Neurol. 2007; 254(7):931-40. diet or exercise. J Nutr 1971; 101: 453-464. 71. van der Kooi EL, Lindeman E, Riphagen I. Strength training and 60. Rafael JA, Nitta Y, Peters J, Davies KE. Testing of SHIRPA, aerobic exercise training for muscle disease. Cochrane Database Syst a mouse phenotypic assessment protocol, on Dmd(mdx) and Rev. 2005 Jan 25;(1):CD003907. Dmd(mdx3cv) dystrophin-deficient mice. Mamm Genome 2000; 72. Vilquin JT, Brussee V, Asselin I, Kinoshita I, Gingras M, Tremblay JP. 11: 725-728. Evidence of mdx mouse skeletal muscle fragility in vivo by eccentric 61. Sandri M, Podhorska-Okolow M, Geromel V, Rizzi C, Arslan P, running exercise. Muscle Nerve 1998; 21: 567-576. Franceschi C, Carraro U. Exercise induces myonuclear ubiquitination 73. Wineinger MA, Abresch RT, Walsh SA, Carter GT. Effects of aging and apoptosis in dystrophin-deficient muscle of mice. J Neuropathol and voluntary exercise on the function of dystrophic muscle from Exp Neurol 1997; 56: 45-57. mdx mice. Am J Phys Med Rehabil 1998; 77: 20-27. 62. Sembrowich WL, Knudson MB, Gollnick PD. Muscle metabolism 74. Wright NC, Kilmer DD, McCrory MA, Aitkens SG, Holcombe J, and cardiac function of the myopathic hamster following training. J Bernauer EM. Aerobic walking in slowly progressive neuromuscular Appl Physiol 1977; 43: 936-941. disease: effect of a 12-week program. Arch Phys Med Rehabil 1996; 63. Soltan HC. Swimming stress and adaptation by dystrophic and 77: 64-69. normal mice. Am J Physiol 1962; 203: 91-94. 75. Zeman RJ, Peng H, Danon MJ, Etlinger JD. Clenbuterol reduces 64. Stedman HH, Sweeney HL, Shrager JB, Maguire HC, Panettieri RA, degeneration of exercised or aged dystrophic (mdx) muscle. Muscle Petrof B, Narusawa M, Leferovich JM, Sladky JT, Kelly AM. The Nerve 2000 Apr ;23 (4 ):521 -8 2000; 23: 521-528. 28 Physiological Adaptations and Responses to Exercise Training in Neuromuscular Disease AANEM Course AANEM Course Exercise in Neuromuscular Diseases 29

Measuring and Promoting Physical Activity in a Free-living Environment in Persons With Neuromuscular Diseases

David Kilmer, MD Professor and Chair Department of Physical Medicine & Rehabilitation University of California, Davis School of Medicine Sacramento, California

INTRODUCTION Ideally, clinicians and researchers are interested in daily activities in the patient’s own home “free-living” environment. The gold Most clinicians treating ambulatory patients with diseases standard for measurement of free-living total energy expendi- affecting the peripheral nervous system support the promotion of ture associated with physical activity is the doubly labeled water physical activity in order to maintain and hopefully increase energy technique8. The technique, however, is cumbersome, expensive, expenditure as well as retard the effects of a sedentary lifestyle and and provides no information about patterns of physical activity. deconditioning. With increases in lifespan, secondary conditions Other investigators have used laboratory measures such as timed such as diabetes mellitus and cardiovascular disease are of greater up-and-go or 6-minute walk tests. The difficulty with extrapo- relevance. Unfortunately, there is a paucity of literature that lation in regards to a person’s home and community still exists explores methods of appropriately recommending and monitoring with these measures, since they are performed in an artificial physical activity in patients with mobility limitations. environment and deal with potential, rather than actual activity. Self-reported physical activity diaries have shown poor correlation The differences between physical activity and energy expenditure with objective measures of activity.21,22 A few studies have uti- must be fully understood. One parameter cannot be directly lized indirect markers, such as the SF-36, a life satisfaction survey. inferred from the other. Physical activity represents muscular Although this provides useful information of a person’s perceived movement, while the energy expenditure that is associated with health status, it too, is of poor correlation with day-to-day physi- the movement may be a reflection of age, gender, body mass, and cal activities.21 Newer quantitative methods to measure physical movement efficiency. In physical disabilities, this last factor may be activity in a free-living, community and home environment will the greatest cause of discrepancies from those who are able-bodied, be addressed. These tools can potentially be used to measure the as well as provide an opportunity for intervention. For example, practical effects of a rehabilitation intervention, or be used as a energy expenditure will be increased in a patient with bilateral method to stimulate physical activity while providing feedback to ankle dorsiflexor weakness from peripheral neuropathy during gait, both the patient with NMD as well as the clinician. The selec- but may be markedly reduced with the use of ankle-foot orthoses. tion of a measurement device is dependent on what information a clinician is attempting to collect. Some devices simply count steps, Traditionally, investigators devised exercise intervention studies measure the intensity of activity, or estimate total daily energy involving persons with neuromuscular diseases (NMDs) to expenditure. The latter is typically favored in a research setting. demonstrate improvement in strength and/or endurance. Gains in these areas could be extrapolated to presumed benefits in mobility, Pedometry energy expenditure, functional activities, and quality of life in the home and community. There is minimal experimental evidence Pedometers are typically worn on the waist and measure the to support these assumptions. Motivating sedentary able-bodied number of steps taken over a given time period, typically a day. adults to become more active is challenging. Therefore, with Three consecutive days of data are generally sufficient to reflect the additional issues relating to muscular weakness, fatigue, and typical daily variation in ambulation.25 The devices are inexpen- possible cardiorespiratory disease involvement, persons with NMD sive ($10-$50), easy to use, and well suited for larger population have major additional hurdles to overcome. studies. Accuracy and reliability have been demonstrated in able- 30 Measuring and Promoting Physical Activity in a Free-living Envi. in Persons With NM Diseases AANEM Course bodied populations; however, concerns exist about their reliability pedometers. The most frequently used device in the literature in the presence of abnormal gait and very slow gait speeds.9,10 is the StepWatchTM step activity monitor (SAM).7 It can be calibrated according to height, cadence, and walking style of the In nondisabled populations, investigators have shown inverse cor- individual. In addition to total number of steps, the intensity of relation between steps/day and body-mass index (BMI) measure- activity can be measured by recording the number of steps in a ment, as well as components of the metabolic syndrome.6 Typically, predetermined time interval as low as 6 seconds (Table 1). The these populations average around 7000 steps/day (with a large measure of reliability and validity as compared to HR monitoring standard deviation), while those with chronic diseases average has been demonstrated in able-bodied adults as well as in children less than 5500 steps/day.26 Although a goal of 10,000 steps/day and adolescents.17,20 has been proposed as a method to decrease obesity and diabetic/ cardiovascular risk factors in the general population, there is no Table 1 Typical step rate definitions for the step activity strong research support for this claim. For research purposes in monitor disabled populations, the greatest limitations for pedometry involve accuracy issues, an inability to measure the intensity of ambulatory Activity Level Steps/Minute Description activity, and the resultant inability to accurately measure free-living Inactive 0 Watching television, playing computer energy expenditure. games Heartrate Monitoring Low 1-15 Intermittent steps taken during activities of daily living such as moving about the house One experimental method used to indirectly measure energy expenditure is continuous heartrate (HR) monitoring, particu- Medium 16-30 Slow walking or moderate activity larly when coupled with calibration to VO2 at a given HR in the High >30 Continuous walking or running for part laboratory. The obvious limitation is a lack of tight correlation of of the time interval HR to physical activity in community settings, which is dependent on the catecholamine state of the subject. Typically, HR moni- The device appears to provide accuracy in the presence of an toring underestimates energy expenditure as compared to other abnormal gait. The SAM has an electronic filter to reject extrane- methods. Although cumbersome, combining HR monitoring ous signals, adjust parameters of threshold, cadence, and motion to with a motion sensor may yield a strong relationship to free-living enhance sensitivity in a wide variety of gait styles. Several studies energy expenditure.23 have examined the accuracy of the device in hemiparetic gait. The SAM was highly accurate for quantifying ambulatory activity in Accelerometry and Energy Expenditure stroke patients as compared to the pedometer16 and conventional accelerometer.11 However, there may be some error when the device In order to measure different types of physical activity that are not is attached to the paretic limb while walking over a variety of limited to ambulation, accelerometers attached to the beltline or outdoor terrains.19 An overall accuracy of 97% to 99% was shown waistline may be used to measure motion in three planes. Physical when the SAM was used in persons with lower-limb amputation7 activity is measured in terms of “activity counts” which can be and incomplete spinal cord injury.2 In a study of 10 adult subjects stratified by intensity (e.g., activity count/specific time interval). with a variety of NMD, the step activity monitor demonstrated Accelerometers are more costly ($75-$800) than pedometers, but good reliability.4 Neurologic patients had reduced daily step are believed to provide a better estimation of energy expenditure counts, with moderate correlation between gait speed and 7 day with continuous 7 day measurement. Limitations include the mean step counts. A larger follow-up study (n=74), with neuro- inability to exclude passive movement counts due to activities such logic patients grouped by type of neuromuscular (NM) pathol- as riding in an automobile or on a bicycle, and the inability to define ogy, also revealed that decreased step counts and self-selected gait the specific activity that is associated with the count. Accelerometry speeds were significant predictors of daily mean step count.5 All has been used in numerous studies to estimate energy expenditure subjects had significantly weaker knee extensors and/or flexors than associated with physical activity. Unfortunately, most investiga- control subjects. tions have not shown agreement with the criterion standard doubly labeled water method, emphasizing the difficulty in converting McDonald and colleagues demonstrated that boys with Duchenne body movement to energy expenditure on an individual basis.15 muscular dystrophy (DMD) walked fewer steps/day and spent There have been no studies to date that use beltline or waistline fewer minutes/day at moderate and high step rates than age- accelerometry to measure patterns of activity in persons with NMD, matched controls (Figure 1).18 In the DMD group, the number of and it is unknown how abnormal gait impacts activity counts. steps correlated with knee extensor strength normalized for body mass. The DMD group also had a significantly higher baseline Step Activity Monitoring HR, and showed less increase in HR with increased step rate. Similar findings of a decreased number of steps and less time spent Step activity monitoring devices represent a type of accelerometry at higher step rates were found in adults with various types of that is specifically designed for ambulation. This method of mobil- slowly progressive NMD as compared to control subjects (unpub- ity assessment overcomes many limitations of the waist attached lished data) (Figure 2).

AANEM Course Exercise in Neuromuscular Diseases 31

Steps at High Activity Level per Day

8000 2 5 0 0 7000 Control DMD 2 0 0 0 6000 5000 1 5 0 0

4000 1 0 0 0 3000 5 0 0 Steps per Day Steps 2000 1000 0

Steps at Activity High Level per Day C o n t ro l B MD C MT F S H MM D LG 0 1-15 16-30 >30 Total Steps Step Rate, steps per minute Figure 2 Average steps per day at a high activity level (>30 steps/minute) in subjects with various slowly progressive neuromuscular diseases (NMD) Figure 1 Average steps per day at each of the step rates during 3 days using the step activity monitor. All NMD groups are significantly different of community ambulation for control and Duchenne Muscular Dystrophy from the control group (p<0.05). Values are mean ± standard error (SE). (DMD) groups using the step activity monitor. *Control and DMD groups BMD = becker muscular dystropy; CMT = Charcot-Marie-Tooth Disease; differed significantly from each other (p<0.05). Values are mean ± stan- FSH = facioscapulohumeral muscular dystrophy; MMD = myotonic muscu- dard error (SE). (McDonald CM, Widman LM, Walsh DD, Walsh SA, lar dystrophy; LG = limb-girdle syndrome. Abresch RT. Use of step activity monitoring for continuous physical activity assessment in boys with Duchenne Muscular Dystrophy. Arch Phys Med Rehabil 2005;86:802-808).18 crease in daily step activity was noted (Figure 3). Six months following the protocol, the number of steps/day was still increased from the baseline count, but no longer reached sta- Klein and colleagues examined SAM-determined and perceived tistical significance. In overweight/obese subjects with Type activity levels in polio survivors in a post-polio (PPS) group and II diabetes mellitus, provision of a pedometer with step goals nonPPS group as compared to controls.14 Subjects in the PPS resulted in an average increase of 3000 steps/day.24 Thus, group averaged the fewest number of steps/day, followed by it appears that an activity prescription using a pedometer nonPPS subjects and the control groups. Although perceived may help to provide a clear goal and effective feedback in the activity of the PPS group decreased over the 3 year study period, ambulatory disabled. there was no change in average daily walking activity. Preferred walking speed in this group was close to maximal speed. Thus, the polio survivors ambulate with minimal physiologic Steps/day at Baseline, 6 Months, and 6 Months functional reserve. Post-Intervention

Step Measurement as a Method to Increase 7000 * Physical Activity 6000 5000

Diet and moderate exercise in the form of walking 30 minutes/ 4000 day, most days of the week has been linked to healthful outcomes (reduction in BMI, blood pressure [BP], total cholesterol) in Steps/d 3000 able-bodied overweight populations.1 A recent review of studies 2000 using pedometry as a motivational tool to increase physical 1000 activity found that pedometer use is associated with significant 0 3 increases in physical activity of about 2000 steps/day. Individuals Baseline 6 Months Post found benefit in setting a personal step goal and using a step diary Measurement Point to record progress. After pooling the studies, pedometer users significantly decreased BMI and systolic BP. Therefore, increased physical activity appears to directly translate into beneficial Figure 3 Number of pedometry measured steps per day in persons with health outcomes. slowly progressive neuromuscular diseases at baseline, at 6 months of an intervention in which subjects were instructed to increase steps by 25% Pedometry was used as a community-based intervention compared to baseline, and 6 months following completion of the interven- to increase physical activity in ambulatory adults with slowly tion. * p<0.05 Values are mean ± standard error (SE). (Kilmer DD, Wright progressive hereditary NMD.13 After baseline measurements NC, Aitkens S. Impact of a home-based activity and dietary intervention in were recorded, subjects were instructed to increase physical people with slowly progressive neuromuscular diseases. Arch Phys Med activity (via daily step counts) by 25%. The use of quanti- Rehabil 2005;86:2150-2156).13 tative feedback appeared to be effective, as a significant in- 32 Measuring and Promoting Physical Activity in a Free-living Envi. in Persons W ith NM Diseases AANEM Course

8. Conway JM, Seale JL, Jacobs DR Jr, Irwin ML, Ainsworth BE. Unresolved issues in the consideration of pedometry for the Comparison of energy expenditure from doubly labeled water, a disabled include the impact of gait inefficiencies and mobil- physical activity questionnaire, and physical activity records. Am J ity limitation on creating a realistic recommendation for a Clin Nutr 2002;75:519-525. specific patient. For example, a patient with myopathy in which 9. Crouter SE, Schneiger PL, Karabulut M, Bassett DR Jr. Validity of 10 electronic pedometers for measuring steps, distance, and energy even household ambulation severely taxes the muscular and cost. Med Sci Sports Exerc 2003;35:1455-1460. cardiovascular systems is not going to be able to meaning- 10. Cyarto EV, Myers AM, Tudor-Locke C. Pedometer accuracy in fully achieve significant increases in physical activity with nursing home and community-dwelling older adults. Med Sci Sports activity prescription. Additionally, it may be assumed that Exerc 2004;36:205-209. increased physical activity improves glycemic control and reduces 11. Haeuber E, Shaughnessy M, Forrester LW, Coleman KL, Macko RF. cardiovascular risk factors in patients with NMD. However, Accelerometer monitoring of home- and community-based ambula- the increased number or percentage of steps/day required to tory activity after stroke. Arch Phys Med Rehabil 2004;85:1997-2001. impact risk factors is unknown. The aforementioned study in 12. Johnson ST, Tudor-Locke C, McCargar LJ, Bell RC. Measuring which subjects with NMD increased steps by 24% did not result habitual walking speed of people with type 2 diabetes: Are they in significant reduction of metabolic syndrome risk factors. 13 meeting recommendations? Diabetes Care 2005;28:1503-1504. Finally, the relationship between self-selected gait speed and 13. Kilmer DD, Wright NC, Aitkens S. Impact of a home-based activity and dietary intervention in people with slowly progressive neuromus- community walking activity in persons with NMD requires 5 cular diseases. Arch Phys Med Rehabil 2005;86:2150-2156. further investigation. 14. Klein MG, Braitman LE, Costello R, Keenan MA, Esquenazi A. Actual and perceived activity levels in polio survivors and older CONCLUSION controls: A longitudinal study. Arch Phys Med Rehabil 2008;89:297- 303. 15. Leenders NY, Sherman WM, Nagaraja HN. Energy expenditure In summary, quantitative activity devices are a useful real- estimated by accelerometry and doubly labeled water: do they agree? world tool in determining the extent of sedentary versus active Med Sci Sports Exerc 2006;38:2165-2172. behaviors of patients in their homes and communities. Simple 16. Macko RF, Haeuber E, Shaughnessy M, Coleman KL, Boone DA, pedometry may be highly effective as a motivational tool. Smith GV, Silver KH. 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