New Insights in Lumbosacral Plexopathy

Kerry H. Levin, MD Gérard Said, MD, FRCP P. James B. Dyck, MD Suraj A. Muley, MD Kurt A. Jaeckle, MD

2006 COURSE C AANEM 53rd Annual Meeting Washington, DC

Printed by Johnson Printing Company, Inc. C-ii

New Insights in Lumbosacral Plexopathy

Faculty

Kerry H. Levin, MD P. James. B. Dyck, MD Vice-Chairman Associate Professor Department of Neurology Department of Neurology Head Mayo Clinic Section of Neuromuscular Disease/Electromyography Rochester, Minnesota Cleveland Clinic Dr. Dyck received his medical degree from the University of Minnesota Cleveland, Ohio School of Medicine, performed an internship at Virginia Mason Hospital Dr. Levin received his bachelor of arts degree and his medical degree from in Seattle, Washington, and a residency at Barnes Hospital and Washington Johns Hopkins University in Baltimore, Maryland. He then performed University in Saint Louis, Missouri. He then performed fellowships at a residency in internal medicine at the University of Chicago Hospitals, the Mayo Clinic in peripheral nerve and electromyography. He is cur- where he later became the chief resident in neurology. He is currently Vice- rently Associate Professor of Neurology at the Mayo Clinic. Dr. Dyck is chairman of the Department of Neurology and Head of the Section of a member of several professional societies, including the AANEM, the Neuromuscular Disease/Electromyography at Cleveland Clinic. Dr. Levin American Academy of Neurology, the Peripheral Nerve Society, and the is also a professor of medicine at the Cleveland Clinic College of Medicine American Neurological Association. His current research interests include of Case Western Reserve University. His current research interests include pathological studies of peripheral nerve disorders and clinical trials in myasthenia gravis, polyneuropathy, and radiculopathy. peripheral neuropathies.

Gérard Said, MD, FRCP Suraj A. Muley, MD Professor and Chief Assistant Professor Service of Neurology Department of Neurology University Hospital of Bicêtre University of Minnesota Medical Center Paris, France Minneapolis, Minnesota Dr. Said is Secretary-general of the European Neurological Society (ENS) Dr. Muley received his medical degree from the University of Bombay, and which he co-founded in 1986. He has also organized the yearly ENS later performed a residency in neurology and a fellowship in clinical neu- congress since 1988. He has been Professor and Chief of the Service of rophysiology and neuromuscular diseases at the University of Minnesota. Neurology of the University Hospital of Bicêtre since 1987. Starting in He is currently Assistant Professor at the University of Minnesota and 2006, Professor Said became the Director of the Research Group on Neuromuscular Director at the Minneapolis Veteran’s Administration Neuromuscular Disorders of the World Federation of Neurology, and from Medical Center. He is involved in clinical studies of diabetic amyotrophy 1998 through 2000 he was President of the Peripheral Nerve Society. His and is leading the nerve biopsy program and the University of Minnesota. main fields of investigation are disorders of the peripheral nervous system, Dr. Muley is also the Director of the Myasthenia Gravis Program at the diabetic neuropathy, vasculitic neuropathy, and infectious neuropathies. University. His current research includes a clinical study of the use of intravenous immunoglobulin in myasthenia gravis, as well as a multicenter study about thymectomy in myasthenia gravis. C-iii

Kurt A. Jaeckle, MD Professor Departments of Neurology and Oncology Mayo Clinic Jacksonville, Florida Dr. Jaeckle is currently Professor of Neurology and Professor of Oncology at the Mayo Clinic Jacksonville and has had an interest in clinical research involving primary and metastatic central nervous system cancer for over 20 years. After completing his residency at Vanderbilt University, he received his training in neuro-oncology at Memorial Sloan-Kettering Cancer Center, which was followed by faculty appointments at the University of Utah and, subsequently, the University of Texas M.D. Anderson Cancer Center in Houston. Dr. Jaeckle has served as a past chair for the American Academy of Neurology’s section on neuro-oncology and was instrumental in the development of a subspecialty certification and acccreditation program neuro-oncology. That program recently received United Council of Neurologic Subspecialties approval. His initial research interests involved the study of paraneoplastic disorders, and in particular, anti-yo antibody-positive cerebellar degeneration and limbic encephalitis. His current research focus involves clinical trial development as chair of the Neuro-oncology Committee of the North Central Cancer Treatment Group, and the study of the neurologic complications of cancer.

Authors had nothing to disclose.

Course Chair: Kerry H. Levin, 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.

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. C-iv C-

New Insights in Lumbosacral Plexopathy

Contents

Faculty i

Objectives ii

Course Committee iv

Update on Lumbosacral Plexopathy: Anatomy and Electrodiagnostic Considerations 1 Kerry H. Levin, MD

Diabetes and the Lumbosacral Plexus 9 Gérard Said, MD, FRCP

Nondiabetic Lumbosacral Radiculoplexus Neuropathy 13 P. James B. Dyck, MD

Treatment Strategies in Lumbosacral Plexopathy 23 Suraj A. Muley, MD

Lesions of the Lumbosacral Plexus 27 Kurt A. Jaeckle, MD

CME Self-Assessment Test 35

Evaluation 39

O b j e c t i v e s —After attending this course, participants will understand the anatomy of the lumbosacral plexus and electrodiagnostic testing available to uncover lesions of the lumbosacral plexus. Participants will learn how to differentiate diabetic from nondiabetic idiopathic lumbosacral plexus disease and will learn about treatment strategies for these conditions. Participants will learn about other lesions of the lumbosacral plexus and their diagnosis. P rerequisite —This course is designed as an educational opportunity for residents, fellows, and practicing clinical EDX physicians at an early point in their career, or for more senior EDX practitioners who are seeking a pragmatic review of basic clinical and EDX principles. It is open only to persons with an MD, DO, DVM, DDS, or foreign equivalent degree. A c c r e d i tat i o n S tat 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 C r e d i t —The AANEM designates this activity for a maximum of 3.25 hours in AMA PRA Category 1 Credit(s)TM. This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he or she actually spent in the educational activity. CME for this course is available 10/06 - 10/09. C-vi

2005-2006 AANEM COURSE COMMITTEE Kathleen D. Kennelly, MD, PhD Jacksonville, Florida

Thomas Hyatt Brannagan, III, MD Dale J. Lange, MD Jeremy M. Shefner, MD, PhD New York, New York New York, New York Syracuse, New York

Hope S. Hacker, MD Subhadra Nori, MD T. Darrell Thomas, MD San Antonio, Texas Bronx, New York Knoxville, Tennessee

Kimberly S. Kenton, MD Bryan Tsao, MD Maywood, Illinois Shaker Heights, Ohio

2005-2006 AANEM PRESIDENT Janice M. Massey, MD Durham, North Carolina

Update on Lumbosacral Plexopathy: Anatomy and Electrodiagnostic Considerations

Kerry H. Levin MD Vice-Chairman, Department of Neurology Head, Section of Neuromuscular Disease/EMG Cleveland Clinic Cleveland, Ohio

ANATOMY OF THE LUMBOSACRAL PLEXUS Ilioinguinal Nerve

The lumbosacral plexus is constituted from the L1-S4 spinal nerve The ilioinguinal nerve is constituted from L1 nerve fibers and roots, with a minor contribution from the T12 spinal nerve root. travels with the iliohypogastric nerve, giving off motor branches The structure can be divided into the lumbar and sacral plexus to lower abdominal wall muscles. Its sensory branches supply the (Figure 1). The lumbosacral plexus is further divided anatomically skin over the symphysis, root of the penis, upper scrotum (men), into an anterior division that contains motor fibers innervating skin over the mons pubis and labia majora (women), and proximal muscles responsible for flexion and adduction, and a posterior divi- medial thigh (Figure 3). Aside from the lesions previously noted, sion innervating muscles responsible for extension and abduction. the ilioinguinal nerve may also be damaged during herniorrhaphy.

The Lumbar Plexus Genitofemoral Nerve

The lumbar plexus is constituted from the L1-L3 roots, most of The genitofemoral nerve is constituted from L1 and L2 nerve the L4 root, and a small component of the T12 root. It courses fibers. The genital branch supplies a motor branch to the cremas- posterior to, or mingles with, fascicles of the psoas muscle before ter muscle and a sensory branch to the skin of the scrotum, labia convergence of the lumbar anterior primary rami to form the majora, and mons pubis (Figure 3). The femoral branch passes lumbar plexus, branches distribute to the psoas muscle and the under the inguinal ligament to supply the skin of the groin. It quadratus lumborum. Major branches of the lumbar plexus are can be damaged by retroperitoneal masses and procedures such as described below (Figure 2). herniorrhaphy.

Iliohypogastric Nerve Lateral Femoral Cutaneous Nerve of the Thigh

The iliohypogastric nerve is constituted from the L1 nerve root, The lateral femoral cutaneous nerve is a pure sensory nerve derived with occasional contribution from T12. It supplies motor branches from the anterior divisions of the L2 and L3 roots (Figure 3). to lower abdominal wall muscles. It supplies cutaneous innervation It tends to pass under the inguinal ligament over the sartorius to a narrow band of skin overlying the iliac spine and inguinal muscle, and subcutaneously onto the lateral thigh, but variations ligament, upper lateral buttock, skin of the groin, and skin overly- can occur.2 ing the symphysis pubis (Figure 3). The nerve can be damaged by paravertebral and flank lesions and by incisions in the flank. C-C- C- Update on Lumbosacral Plexopathy AANEM Course

Figure 1 Lumbosacral Plexus n = nerve

Figure 3 Cutaneous Distributions of the Lumbosacral Plexus in the Perineal Region. Modified from Stewart.14 n = nerve

Femoral Nerve

The femoral nerve trunk is derived from the posterior divisions of the L2-L4 nerve roots. It exits the psoas muscle at its lateral border and travels between the psoas and iliacus muscles beneath the inguinal ligament. Within the pelvis, branches are distributed to the psoas and iliopsoas muscles. The femoral nerve passes below the inguinal ligament and divides into motor branches (innervating the vastus, sartorius, iliacus, and pectineus muscles) and sensory branches to the anterior and medial thigh, ending as the saphenous nerve.

Figure 2 Nerve Trunks Derived from the Lumbar Plexus. Modified Obturator Nerve from Stewart.14 m = muscle; n = nerve The obturator nerve trunk is derived from the anterior divisions of the L2-L4 nerve roots. It travels through the psoas muscle to its medial border, then through the pelvic cavity, and through the ob- AANEM Course New Insights in Lumbosacral Plexopathy C-

turator foramen into the thigh. Motor branches reach the adductor certainty in the diagnosis, given the potential for other diagnoses to longus and brevis. Sensory fibers supply a small area of skin on the have a similar EDX pattern. medial thigh (Figure 3). Sacral plexopathy and sciatic neuropathy, affecting both the pero- The Sacral Plexus neal and tibial divisions, have identical patterns of NCS abnormalities. The distinction lies in the NEE, where muscles innervated by The sacral plexus is constituted from the L5-S3 roots, with a small the superior and inferior gluteal nerves are not involved in sciatic contribution from the L4 root. Anatomically, the sacral plexus is neuropathy. However, the experienced EDX physician will know formed at the point where sacral anterior primary rami are joined that patchy or mild cases of sacral plexopathy may also spare those by the lumbosacral trunk (also known as the nerve of Furcul), muscles. Thus, in cases where the degree of axon loss in involved which is comprised of the entire L5 anterior primary ramus and muscles is mild, the final impression in sciatic neuropathy may a few fascicles of the L4 anterior primary ramus. The plexus lies require the disclaimer that sacral plexopathy cannot be completely on the posterior and posterolateral walls of the pelvis close to the excluded. sacroiliac joint and just lateral to the prostate and cervix. Confusion in using EDX studies can also occur in distinguishing The L4-S2 fibers segregate into anterior and posterior divisions. an L5 radiculopathy, a lumbosacral trunk lesion, and a peroneal From the posterior division, superior and inferior gluteal nerves neuropathy. Radiculopathy is classically distinguishable from branch off to innervate the gluteus medius and maximus, respec- plexus and peripheral nerve lesions because the sensory responses tively. A small posterior division branch innervates the piriformis are preserved. An occasional exception arises due to a variation in muscle. Other posterior division fibers converge with S3 fibers the anatomy of the L5 spinal nerve root, whose dorsal root ganglion to form the posterior femoral and perforating cutaneous nerves. resides in an intraspinal canal location in up to 30% of individu- Branches from the anterior division form nerve branches to the als.7,8 In this situation an intraspinal L5 root compression can cause obturator internus, superior genellus, quadratus femoris, and in- axon loss along both the sensory and motor nerve trunks, giving rise ferior gemellus muscles. Remaining nerve fibers combine to form to a pattern of NCS abnormality identical to a lumbosacral trunk the sciatic nerve, maintaining separation between anterior division lesion or peroneal neuropathy (either above or below the popliteal fibers that will constitute the tibial nerve, and posterior fibers that fossa).9 A lesion of the common peroneal nerve demonstrates a will become the common peroneal nerve. NCS pattern identical to that of a lumbosacral trunk lesion, but the NEE easily distinguishes these two conditions. Separate branches from the S2-S5 anterior primary rami form pelvic nerves, including the pudendal nerve, pelvic splanchnic A lumbosacral trunk lesion and L5 radiculopathy have an essen- nerves, and nerve branches to the levator ani, coccygeus, and tially identical pattern of abnormalities on the NEE of the leg. external anal sphincter muscles. Autonomic nerve fibers from While the lumbosacral plexus is organized topographically into pe- lumbar and sacral segments combine with somatic fibers from the ripheral nerve distributions, the lumbosacral trunk is almost purely pudendal nerve to serve bladder, rectal, anal, sexual, and circulatory a continuation of the L5 anterior primary ramus, making its motor functions. Preganglionic parasympathetic nerve fibers are carried content indistinguishable from the intraspinal spinal nerve root. in the S2-S4 anterior rami, and then branch off to form the pelvic Furthermore, while acute motor radiculopathy is classically associ- splanchnic nerves, which supply motor fibers to the bladder detru- ated with paraspinal fibrillation, this finding is not reliably present, sor and rectum, inhibitory fibers to the internal urethral sphincter, especially at the low lumbar spinal segments.6,16 and vasomotor fibers to the penis and clitoris.14 The distinction between lumbar plexopathy and L2-L3-L4 radiculopathy is one of the most difficult tasks for the EDX physician. ELECTRODIAGNOSTIC FEATURES Nerve conduction studies available to assess these conditions are limited to the femoral motor response and the saphenous sensory The electrodiagnosic (EDX) examination of lumbosacral plexopa- response. The femoral motor response will not distinguish either thy is complex and requires a specific pattern of nerve conduction lumbar plexopathy or L2-L3-L4 radiculopathy, and the saphenous study (NCS) abnormalities in combination with a specific distribu- sensory response is likely to be absent beyond middle age and in tion of changes on the needle electrode examination (NEE). Both those with increased thigh girth. In regard to the NEE, there is an the NCS pattern and the NEE pattern observed in lumbosacral essentially complete overlap of muscle involvement in the two con- plexopathy can be seen in other lower extremity disorders, but ditions. The presence of lumbar or high sacral paraspinal fibrillation when combined, the NCS and NEE patterns form a relatively in the setting of acute L2-L3-L4 radiculopathy is the only potential specific signature of lumbosacral plexopathy. Tables 1 and 2 list the distinguishing feature. As a result of these limitations, it is difficult typical NCS and NEE patterns in various lower extremity disor- to separate L2-L3-L4 radiculopathy and lumbar plexopathy elec- ders. The challenge for the EDX physician is to define the level of trodiagnostically, unless there is paraspinal fibrillation or saphenous C-C-C- Update on Lumbosacral Plexopathy AANEM Course

Table 1 Nerve Conduction Findings in Various Lower Extremity Disorders

SP SN LT P P L5 T T S1 L3/4 LP APF BPF APF BPF

Peroneal M ++ ++ ++ ++ ++ + Sup Per S ++ ++ ++ ++ +/- +/- Tibial M ++ ++ ++ ++ + H Reflex ++ ++ ++ ++ Sural S ++ ++ ++ Plantar S ++ ++ ++ ++ Femoral M + + Saph S +/- +/-

+ = degree of abnormality; L3/4 = L3/4 radiculopathy; L5 = L5 radiculopathy; LP = lumbar plexopathy; LT = lumbosacral trunk; M = motor; P/APF = peroneal neuropathy above popliteal fossa; P/BPF = peroneal neuropathy below popliteal fossa; T/APF = tibial neuropathy above popliteal fossa; T/BPF = tibial neuropathy below popliteal fossa; SN = sciatic neuropathy; S = sensory; S1 = S1 radiculopathy; SP = sacral plexopathy; Sup Per = superficial peroneal; Saph = saphenous

Table 2 Distribution of Needle Electrode Examination Changes in Various Lower Extremity Disorders

SP LT L5 S1 S P P T T L2/3/4 LP APF BPF APF BPF

PSP +/- +- +/- GMed ++ ++ ++ TFL ++ ++ ++ GMax ++ ++ BFSH ++ ++ ++ +/- BFLH ++ ++ ++ +/- ST ++ ++ ++ ++ +/- TA ++ ++ ++ ++ ++ ++ Gast ++ ++ ++ ++ PT/FDL ++ ++ ++ ++ ++ +/- EDB ++ + + +/- ++ ++ ++ AH ++ ++ ++ ++ ++ Quads ++ ++

+ = degree of abnormality; AH = abductor hallucis; BFSH = biceps femoris (short head); BFLH = biceps femoris (long head); EDB = extensor digitorum brevis; Gast = gastrocnemius; GMax = gluteus maximus; GMed = gluteus medius; PSP = paraspinal muscles; PT/FDL = posterior tibialis/flexor digitorum longus; Quads = quadriceps muscles; ST = semitendinosus; TA = tibialis anterior; TFL = tensor fascia lata. AANEM Course New Insights in Lumbosacral Plexopathy C-C-C-

sensory nerve action potential (SNAP) change. The clinical setting may help inform the EDX findings, but a disclaimer in the EDX report describing the differential diagnosis of the electrical pattern is usually unavoidable.

Unusual Sensory Nerve Conduction Studies

Several infrequently studied sensory nerve trunks may be of value in the assessment of lumbosacral plexopathy. These nerve trunks are difficult to study due to their variable anatomic courses, small caliber, small SNAP responses, and deep subcutaneous location in overweight individuals. Even in patients of normal size, the stimulation and recording sites may be relatively deep, hampering the technique and resulting in a diminished SNAP amplitude. Nerve conduction studies of the saphenous nerve, the lateral femoral cutaneous nerve of the thigh, and the posterior cutaneous nerve of the thigh will be reviewed.

Saphenous Nerve Conduction Study

Several NCS techniques have been described in literature for study- ing the saphenous nerve.5,12,15,17 The technique of Wainapel and colleagues places the R2 (reference) electrode just anterior to the prominence of the medial malleolus, in the space between the malleolus and the medial border of the tibialis anterior tendon17 (Figure Figure 4 Saphenous Sensory Nerve Conduction Study. Wainapel 4). The R1 electrode is placed 3 cm proximal to the R2, parallel technique.17 to the medial border of the tibialis anterior tendon. Stimulation is m = muscle; n = nerve applied 14 cm proximal to the R1 electrode, deep to the medial border of the tibia. Pressure is required between the tibia and the medial gastrocnemius muscle to allow penetration of the stimulus inguinal ligament 1 cm medial to the anterior superior iliac spine, to the nerve.3 The recorded negative peak latency is 3.6 ± 0.4 ms (± over the origin of the sartorius muscle10 (Figure 6). The R1 record- 1 SD), and the amplitude is 9.0 ± 3.4 µV. ing electrode is placed 17-20 cm distally, along a line connecting the anterior superior iliac spine and the lateral border of the patella. The method described by Ma, Kim, and Liveson employs stimula- The R2 electrode is placed 3 cm distal to the R1 electrode. With tion at the medial knee, between the tendons of the sartorius and stimulation above the inguinal ligament, the recorded onset latency gracilis muscles, 1 cm above the inferior border of the patella of is 2.8 ± 0.4 ms (range 2.3-3.2) at a distance from 17-20 cm; the the slightly flexed knee11 (Figure 5). The R1 electrode is placed 15 recorded amplitude is 6.0 ± 1.5 µV (range 3.0-10.0). With stimu- cm distal to the stimulation site along a line from the stimulation lation below the inguinal ligament, the recorded latency is 2.5 ± point to the medial border of the tibia. The R2 electrode is placed 0.2 ms (range 2.2-2.8) at a distance from 14-18 cm; the recorded 3 cm distal to the R1 electrode. The recorded onset latency is 2.5 ± amplitude is 7.0 ± 1.8 µV (range 4.0-11.0). Other techniques have 0.19 ms (range 2.2-2.8) at a distance from 13-16 cm. The recorded been described.1,13 amplitude is 10.23 ± 2.05 µV (range 7.0-15.0). A number of technical challenges are encountered with the study Lateral Femoral Cutaneous Nerve Conduction Study of the lateral femoral cutaneous nerve of the thigh. Shock artifact and the compound muscle action potential response can obscure The technique of lateral femoral cutaneous NCS as described by the SNAP. The orientation of the stimulating electrodes (anode Ma and Liveson employs stimulation either above or below the and cathode) should be changed to minimize artifact and search C- Update on Lumbosacral Plexopathy AANEM Course

Figure 6 Lateral Femoral Cutaneous Sensory Nerve Conduction Study. Ma technique10 n = nerve

Figure 5 Saphenous Sensory Nerve Conduction Study. Ma technique.11 m = muscle; n = nerve AANEM Course New Insights in Lumbosacral Plexopathy C-

for maximal amplitude of the SNAP response. Stimulation should be delivered at various locations until the patient feels the stimulus radiating down the nerve trunk. The response cannot be obtained in overweight individuals.

Posterior Cutaneous Nerve of the Thigh Conduction Study

The posterior cutaneous nerve of the thigh conduction study described by Dumitru and Nelson requires that the patient be placed in the prone position with their legs completely relaxed.4 The R1 electrode is placed in the midline of the posterior thigh 6 cm proximal to the mid popliteal region, with the R2 electrode 3 cm distal (Figure 7). Stimulation is performed 12 cm proximal to the R1 electrode along a line connecting the R1 electrode and the ischial tuberosity in the groove between the medial and lateral hamstring muscles. The recorded negative peak latency is 2.8 ± 0.2 ms (normal limit 3.2 ms) and the peak-to-peak amplitude is 6.5 ± 1.5 µV (normal limit 4.4 µV).

SUMMARY

Electrodiagnostic studies are important in the diagnosis of lumbosacral plexopathy. They help localize and confirm the presence of nerve damage at that level and rule out other neuromuscular disorders in the differential diagnosis. A knowledge of the peripheral neuroanatomy of this complex region improves EDX decision making and clinical skills.

REFERENCES

1. Butler ET, Johnson EW, Kaye ZA. Normal conduction velocity in lateral femoral cutaneous nerve. Arch Phys Med Rehabil 1974;55:31- 32. 2. de Ridder VA, de Lange S, Popta JV. Anatomical variations of the lateral femoral cutaneous nerve and the consequences for surgery. J Orthop Trauma 1999;13:207-211. 3. Delisa JA, Mackenzie K, Baran EM. Manual of nerve conduction velocity and somatosensory evoked potentials, 2nd edition. New York: Raven Press; 1987. p 134. 4. Dumitru D, Nelson MR. Posterior femoral cutaneous nerve conduction. Arch Phys Med Rehabil 1990;71:979-982. 5. Ertekin C. Saphenous nerve conduction in man. J Neurol Neurosurg Psychiatry 1969;32:530-540. 6. Gough J, Koepke G. Electromyographic determination of motor root levels in erector spinae muscles. Arch Phys Med Rehabil 1966;47:9-11. 7. Hamanishi C, Tanaka S. Dorsal root ganglia in the lumbosacral region observed from the axial views of MRI. Spine 1993;18:1753- Figure 7 Posterior Femoral Cutaneous Sensory Nerve Conduction 1756. Study. Dumitru technique.4 8. Kikuchi S, Sato K, Konno S, Hasue M. Anatomic and radiographic n = nerve study of dorsal root ganglia. Spine 1994;19:6-11. C- Update on Lumbosacral Plexopathy AANEM Course

9. Levin KH. L5 radiculopathy with reduced superficial peroneal 14. Stewart JD. Focal peripheral neuropathies, 3rd edition. Philadelphia: sensory responses: intraspinal and extraspinal causes. Muscle Nerve Lippincott Williams and Wilkins; 2000. p 490-491. 1998;21:3-7. 15. Stohr M, Schumm F, Ballier R. Normal sensory conduction in the 10. Ma DM, Liveson JA. Nerve conduction handbook. Philadelphia: FA saphenous nerve in man. Electroencephalogr Clin Neurophysiol Davis Company; 1983. p 183-185. 1978;44:172-178. 11. Ma DM, Liveson JA. Nerve conduction handbook. Philadelphia: FA 16. Tsao B, Levin KH, Bodnar RA. Comparison of surgical and electro- Davis Company; 1983. p 192-194. diagnostic findings in single root lumbosacral radiculopathies. Muscle 12. Senden R, Van Mulders J, Ghys R, Rosselle N. Conduction velocity and Nerve 2003;27:60-64. of the distal segment of the saphenous nerve on normal adult sub- 17. Wainapel SF, Kim DJ, Ebel A. Conduction studies of the saphenous jects. Electromyogr Clin Neurophysiol 1981;21:3-10. nerve in healthy subjects. Arch Phys Med Rehabil 1978;59:316-319. 13. Stevens A, Rosselle N. Sensory nerve conduction velocity of n. cutaneous femoris lateralis. Electromyogr 1970;10:397-398. C-

Diabetes and the Lumbosacral Plexus

Gérard Said, MD, FRCP Professor and Chief Service de Neurologie Centre Hospitalier Universitaire de Bicêtre Université Paris-Sud Paris, France

INTRODUCTION muscle weakness and atrophy. This syndrome, which was originally described by Bruns in 1890,5 has been subsequently reported The development of sensorimotor deficits in the territory of one or under the terms of diabetic myelopathy,15 diabetic amyotrophy,14 several nerve trunks, radicular, or plexus territories, occurs without femoral neuropathy,6,16 proximal diabetic neuropathy (PDN),2,6,28 evidence of a superimposed cause for neuropathy in diabetic femoral-sciatic neuropathy,27 the Bruns-Garland syndrome,3,8 and patients. Such cases are extremely rare considering the frequency diabetic lumbosacral radiculoplexus neuropathy.11 The neurological of distal symmetrical diabetic neuropathy and should always be picture is limited to the lower limbs and is usually asymmetrical.1 investigated as in nondiabetic patients. In particular, it is necessary Clinically, the different patterns and the course of PDN strikingly to perform electrophysiological testing to more accurately local- differ from those of distal symmetrical sensory polyneuropathy ize the lesions. When clinical and electrophysiological data point (DSSP) suggesting different pathophysiologic features. In a study to spinal root lesions, magnetic resonance imaging of the spine, of 27 patients,9 24 had noninsulin dependent diabetes mellitus or other testing should be performed to exclude another cause of (NIDDM), 3 had insulin-dependent diabetes (IDDM), and the neuropathy. When nerve trunks are clearly affected clinically and mean age at diagnosis was 62 years (range 46-71); the male to electrophysiologically, a nerve and muscle biopsy in an affected ter- female ratio was 16:11. ritory should be considered to exclude primary necrotizing arteritis, sarcoidosis, or leprosy. In some cases however, no other cause than The onset of the neuropathy is acute or subacute. The patient diabetes is found and the diagnosis of diabetic neuritis is likely. In complains of numbness or pain of the anterior aspect of the thigh, the lower limbs, the most common pattern of focal neuropathy is often of the burning type and worse at night. Difficulty in walking characterized by proximal sensory and motor manifestations. It is and climbing stairs occurs, due to weakness of the quadriceps and worth noting that markers of systemic inflammation are normal iliopsoas muscles. Muscle wasting is also an early and common phe- in diabetic multifocal neuropathy, but dramatic weight loss is nomenon, which is often easier to palpate than to see in overweight common. patients. The patellar reflex is decreased or more often abolished. The syndrome progresses over weeks or months in most cases, then stabilizes and spontaneous pains decreases, sometimes rapidly. In PROXIMAL DIABETIC NEUROPATHY OF THE LOWER many instances, as in those originally reported, there is little or LIMBS no sensory loss, as emphasized by Garland.14 He found inconsis- tent extensor plantar responses and increased cerebrospinal fluid Diabetic patients over the age of 50 may present with proximal protein content, and believed that they resulted from a metabolic neuropathy of the lower limbs characterized by a variable degree myelopathy in patients who were treated for diabetes but not under of pain and sensory loss associated with uni- or bilateral proximal full diabetic control.14 In approximately one-third of the patients, C-10 Diabetes and the Lumbosacral Plexus AANEM Course there is a definite sensory loss over the anterior aspect of the thigh, myopathy.19,28 Nerve conduction studies indicate axonal loss rather and in the others a painful contact dysesthesia in the distribution than demyelination19 and the compound muscle action potential in of the cutaneous branches of the femoral nerve, without definite the quadriceps muscles on femoral nerve stimulation is reduced in sensory loss. amplitude. The F-wave latencies to distal muscles8,37 are difficult to interpret in view of the frequent co-existence of a distal polyneu- Bruns, who had described the condition, found that the disorder ropathy.4,17,28 was reversible by dietetic restriction only.5 Garland also noticed a striking recovery of power with less obvious improvement of muscle wasting in four of his five patients.14 Most of the features Pathological Aspects of Proximal Distal identified by Garland were subsequently confirmed, including the Neuropathy usually good long-term prognosis, independent of the quality of diabetic control. In a recent pathological study of biopsy specimens of the intermediate cutaneous nerve of the thigh, a sensory branch of the femoral In most cases, the patient’s condition improves after months, but nerve which conveys sensation from the anterior aspect of the thigh sequelae including disabling weakness and amyotrophy, sensory (a territory commonly involved in PDN) this author and colleagues loss, and patellar areflexia are common.9,25 In a long-term follow-up found that the pathology of proximal nerves varied with the clinical survey covering a 14-year span, recovery began after a median inter- aspects of the neuropathy.25 Examination of the biopsy specimen val of 3 months (range 1-12 months).25 Pain was the first symptom in patients with the most severe sensory and motor deficit revealed to improve, with resolution being comparatively rapid, beginning lesions characteristic of severe nerve ischemia, including total axon within a few weeks and becoming nearly complete at 12 months. loss in two patients with the most severe deficit, and centrofascicu- Residual discomfort took up to 3 years to subside in the patients of lar degeneration of fibers associated with a large number of regen- Coppack and Watkins.9 Motor recovery was satisfactory and none erating fibers in one, following a pattern of axonal loss observed in of their 27 cases showed disabling residual deficits, but 7 com- clinical and experimental nerve ischemia.13,22 Lesions of nerve fibers plained of some persisting weakness, and significant wasting of the coexisted with occlusion of a perineurial blood vessel in one patient thigh was evident in half of the cases.9 Denervation atrophy found in the study. This finding was consistent with the only detailed in the muscle samples fit well with the long-term, or permanent, postmortem study of PDN available.23 The authors in this study weakness and amyotrophy that often affect distal muscles. Relapses found a small infiltration with mononuclear cells associated with on the other side were common, often in spite of good diabetic the occlusion of an interfascicular artery of the obturator nerve, in control. In one-fifth of the patients investigated for this syndrome, a patient with a proximal and distal deficit of the left lower limb. In relapses occurred on the other side within a few months, the same a patient who developed a rapid, asymmetrical, distal, sensorimotor proportion as reported in a study by Coppack and Watkins.9 Thus deficit shortly after the onset of the proximal deficit, recent occlu- the clinical features of PDN (frequent motor involvement, asym- sion of a perineurial blood vessel and perivascular, perineurial, and metry of the deficit, gradual yet often incomplete spontaneous subperineurial inflammatory infiltration with mononuclear cells recovery) markedly differ from those of DSSP in which the length- was demonstrated, along with axonal degeneration of the major- dependent symmetrical sensory deficit is associated with motor ity of nerve fibers of the superficial peroneal nerve. In the other signs only in extreme cases, and which virtually never improves. patients, lesions of nerve fibers and of endoneurial capillaries were In the syndrome described by Garland as “diabetic amyotrophy,” similar to those observed in the sural nerve in diabetic patients with motor manifestations were more prominent and both sides were symptomatic DSSP. In four patients, mixed, axonal, and demy- affected. However, the syndrome is a variant of PDN, because elinative nerve lesions were associated with increased endoneurial lesions of the sensory branch of the femoral nerve were also present cellularity made of mononuclear cells that suggested the presence in patients who had no sensory signs or symptoms.25 of a low-grade endoneurial inflammatory process. In a recent study of patients with extremely painful PDN, this author’s group found similar inflammatory lesions with B and T lymphocytes mixed with Electrophysiological Studies macrophages.24 Similar observations were made by others in biopsy specimens of the intermediate cutaneous nerve of the thigh20 and Needle electromyography reveals signs of denervation in affected in the sural nerve.11 In the author’s series, the patients, who were muscles with spontaneous fibrillation, usually bilaterally even in already treated with insulin for weeks or months, became pain-free cases with weakness restricted to one side. In more severe cases, shortly after performance of the biopsy, without additional treat- there may be evidence of widespread denervation affecting distal ment. These observations show that the presence of inflammatory leg muscles as well, and also those innervated by the lower thoracic infiltrates does not preclude spontaneous recovery.24 spinal roots. In cases of long duration, motor unit action potentials (MUAPs) are of increased amplitude, reflecting reinnervation by The relationship among the occurrence of inflammatory infiltrates, collateral sprouting from surviving motor axons. The MUAPs may vasculitis, and diabetes is not clear. Small inflammatory infiltrates be polyphasic and of low amplitude leading to the misperception of have been occasionally encountered in sural nerve biopsy specimens AANEM Course New Insights in Lumbosacral Plexopathy C-11

of diabetic patients with neurological deficit18 and in autonomic remyelination. Necrotizing vasculitis of perineurial and endoneu- nerve bundles and ganglia.10 Lesions of nerve fibers and of blood rial blood vessels were found in six patients. Evidence of present or vessels due to diabetes may trigger an inflammatory reaction and past endoneurial bleeding that included seepage of red cells, haem- reactive vasculitis in some patients. Alternatively, diabetes may orrhage, or ferric iron deposits, were found in the majority of the make the nerves more susceptible to intercurrent inflammatory specimens. Perivascular mononuclear cell infiltrates were present or immune processes. In both cases, lesions of epi- or perineurial in the nerve specimens of 21 of 22 patients, prominently in 4 pa- blood vessels can induce ischemic nerve lesions responsible for tients. In comparison, nerve biopsy specimens of 30 patients with severe proximal sensory and motor deficits. Conversely, in milder severe DSSP showed mild epineurial mononuclear cell infiltrate in forms the lesions are more reminiscent of those observed in distal 1 patient and endoneurial seepage of red cells in another. Thus, this symmetrical polyneuropathy. author believes that MDN is related to precapillary blood vessel involvement in elderly diabetic patients with a secondary inflammatory response. Multifocal Diabetic Neuropathy Besides the high frequency both of endoneurial bleeding and of In a small proportion of diabetic patients, a multifocal diabetic inflammatory infiltrates, occlusion of small- and middle-sized neuropathy (MDN) is observed with successive or simultaneous epineurial and perineurial arteries differentiates MDN from DSSP. involvement, of roots and nerves of the lower limbs, trunk, and The intensity and distribution of the lesions seemed more severe in upper extremities. The author’s group prospectively studied 22 MDN than in PDN, but both patterns can be included in MDNs. consecutive diabetic patients with MDN, for which other causes of The outcome is better in MDN than in DSP. Improvement occurs neuropathy were excluded by appropriate investigations, including in all patients after a few months, but sequelae are common. biopsy of a recently affected sensory nerve.26 Three patients had a relapsing course, the others an unremitting subacute-progressive course. Painful multifocal sensory-motor deficit progressed over TREATMENT OF FOCAL DIABETIC NEUROPATHIES 2 to 12 months. Distal lower limbs were involved in all patients, unilaterally in seven, bilaterally in the others, with an asynchro- Proximal diabetic neuropathy is often very painful and should nous onset in most cases. In addition, proximal deficits of the be treated with paracetamol (acetaminophen) and codeine. As lower limbs were present on one side in seven patients, on both some of our patients with disabling painful proximal neuropathy sides in six. Thoracic radiculoneuropathy was present bilaterally responded only to corticosteroids, this treatment should be con- in two patients, unilaterally in one. The ulnar nerve was involved sidered in severe forms.25 This will require adjustment of diabetic in one patient, the radial nerve in two. The cerebrospinal fluid control with insulin in most cases. Others have suggested the use protein ranged from 0.40 to 3.55 g/l. The mean was 0.87 g/l. of immunosuppression or immunomodulation, such as intravenous Electrophysiological testing showed severe, multifocal, axonal nerve immunoglobulins, but one should keep in mind that the overall lesions in all cases. Multifocal diabetic neuropathy is comparable spontaneous prognosis of focal diabetic neuropathies is good. to the lumbosacral radiculoplexus neuropathy;12 however, since this subacute neuropathy can also affect territories beyond the lumbosacral area MDN seems more appropriate. It is also obvious SUMMARY that MDN or lumbosacral radiculoplexopathy is not specific to diabetic patients, as further shown,12 which underlines the need to Proximal diabetic neuropathy represents a form of ischemic neu- exclude other causes of neuropathy in this setting, including a su- ropathy from a pathological point of view. Inflammatory compo- perimposed cause in diabetic patients, such as necrotizing arteritis nents are now also recognized. These factors should help with the or chronic inflammatory demyelinating polyneuropathy, both of development of improved treatment strategies in the future. which require specific treatment.21

REFERENCES Pathological Aspects of Multifocal Diabetic Neuropathy 1. Asbury AK. Focal and multifocal neuropathies of diabetes. In: Dyck PJ, Thomas PK, Asbury AK, Winegrad AI, Porte D Jr, editors. Asymmetrical axonal lesions were present in all nerve specimens of Diabetic neuropathy. Philadelphia: WB Saunders; 1987. p 43-55. patients with MDN. The mean density of myelinated and of un- 2. Asbury AK. Proximal diabetic neuropathy. Ann Neurol 1977;2:179- myelinated axons was reduced to 1340 per mm2 of endoneurial area 180. and to 5095 per mm2 (extremes: 0-26,600), respectively. On teased 3. Barohn RJ, Sahenk Z, Warmolts JR, Mendell JR. The Bruns-Garland fiber preparations one-third of the fibers were at different stages of syndrome (diabetic amyotrophy). Revisited 100 years later. Arch Neurol 1991;48:1130-1135. axonal degeneration while 7% showed segmental demyelination or C-12 Diabetes and the Lumbosacral Plexus AANEM Course

4. Bastron JA, Thomas JE. Diabetic polyradiculopathy: clinical and elec- 18. Krendel DA, Costigan DA, Hopkins LC. Successful treatment tromyographic findings in 105 patients. Mayo Clin Proc 1981;56:725- of neuropathies in patients with diabetes mellitus. Arch Neurol 732. 1995;52:1053-1061. 5. Bruns L. Ueber neuritische Lähmungen beim diabetes mellitus. Berl 19. Lamontagne A, Buchthal F. Electrophysiological studies in diabetic Klin Wochenscher 1890;27:509-515. neuropathy. J Neurol Neurosurg Psychiatry 1970;33:442-452. 6. Calverley JR, Mulder DW. Femoral neuropathy. Neurology 20. Llewelyn JG, Thomas PK, King RH. Epineurial microvasculitis in 1960;10:963-967. proximal diabetic neuropathy. J Neurol 1998;245:159-165. 7. Chokroverty S. Proximal nerve dysfunction in diabetic proximal amy- 21. Lozeron P, Nahum L, Lacroix C, Ropert A, Guglielmi JM, Said G. otrophy. Electrophysiology and electron microscopy. Arch Neurol Symptomatic diabetic and non-diabetic neuropathies in a series of 1982;39:403-407. 100 diabetic patients. J Neurol 2002;249:569-575. 8. Chokroverty S, Reyes MG, Rubino FA. Bruns-Garland syndrome of 22. Nukada H, Dyck PJ. Microsphere embolization of nerve capillaries diabetic amyotrophy. Trans Am Neurol Assoc 1977;102:173-177. and fiber degeneration. Am J Pathol 1984;115:275-287. 9. Coppack SW, Watkins PJ. The natural history of diabetic femoral 23. Raff MC, Sangalang V, Asbury AK. Ischemic mononeuropathy neuropathy. Q J Med 1991;79:307-313. and mononeuropathy multiplex in diabetes mellitus. Arch Neurol 10. Duchen LW, Anjorin A, Watkins PJ, Mackay JD. Pathology of auto- 1968;18:487-499. nomic neuropathy in diabetes mellitus. Ann Intern Med 1980;92:301- 24. Said G, Elgrably F, Lacroix C, Planté V, Talamon C, Adams D, et al. 303. Painful proximal diabetic neuropathy: inflammatory nerve lesions 11. Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic and spontaneous favourable outcome. Ann Neurol 1997;41:762- lumbosacral radiculoplexus neuropathy. Neurology 1999;10:2113- 770. 2121. 25. Said G, Goulon-Goeau C, Lacroix C, Moulonguet A. Nerve biopsy 12. Dyck PJ, Norell JE, Dyck PJ. Non-diabetic lumbosacral radiculo- findings in different patterns of proximal diabetic neuropathy. Ann plexus neuropathy: natural history, outcome and comparison with Neurol 1994;35:559-569. the diabetic variety. Brain 2001;124:1197-1207. 26. Said G, Lacroix C, Lozeron P, Ropert A, Planté V, Adams D. 13. Fujimura H, Lacroix C, Said G. Vulnerability of nerve fibers to isch- Inflammatory vasculopathy in multifocal diabetic neuropathy. Brain emia. Brain 1991;114:1929-1942. 2003;126:376-385. 14. Garland HT. Diabetic amyotrophy. Br Med J 1955;2:1287-1290. 27. Skanse B, Gydell K. A rare type of femoral-sciatic neuropathy in 15. Garland HT, Taverner D. Diabetic myelopathy. Br Med J 1953;1:1405- diabetes mellitus. Acta Med Scand 1956;155:463-468. 1408. 28. Subramony SH, Wilbourn AJ. Diabetic proximal neuropathy. Clinical 16. Goodman JI. Femoral neuropathy in relation to diabetes mellitus: and electromyographic studies. J Neurol Sci 1982;53:293-304. report of 17 cases. Diabetes 1954;3:266-273. 29. Williams IR, Mayer RF. Subacute proximal diabetic neuropathy. 17. Isaacs H, Gilchrist G. Diabetic amyotrophy. S Afr Med J 1960;134:501- Neurology 1976;26:108-116. 505. C-13

Nondiabetic Lumbosacral Radiculoplexus Neuropathy

P. James B. Dyck, MD Peripheral Neuropathy Research Laboratory Mayo Clinic College of Medicine Rochester, Minnesota

INTRODUCTION diculoplexus neuropathy (DCRPN, CRPN).11 The syndromes are similar in diabetic and nondiabetic patients. Diabetic lumbosacral radiculoplexus neuropathy (DLRPN) (also known as diabetic amyotrophy, proximal diabetic neuropathy, Much remains to be learned about the diabetic and the nondiabetic diabetic polyradiculopathy, and other names) is an asymmetrical RPNs. It seems best to group these conditions together under the lower limb syndrome of pain, weakness, paresthesia, and weight heading of RPN due to the patchy involvement of roots, plexuses, loss that usually occurs in patients with mild type II diabetes mel- and peripheral nerves in these disorders based on abnormalities litus.16 Although the condition is severe and debilitating, it usually observed in clinical, electromyographic (EMG), laboratory, and is monophasic with the symptoms and deficits resolving in months histopathological studies of nerves. These syndromes are best or years, but improvement is often incomplete.16 grouped together given their strong clinical similarities; they begin with pain followed by weakness, are asymmetrical, usually are A similar syndrome of unilateral or asymmetrical lower limb pain, monophasic illnesses, often the same patient has several anatomical weakness, and paresthesia that affects patients without diabetes is sites involved (for example both thoracic and lumbosacral levels), nondiabetic lumbosacral radiculoplexus neuropathy (LRPN). This and are associated with weight loss. The clinical, laboratory, elec- condition has been recognized more recently than DLRPN; the first trophysiologic, and pathologic features of the lower limb form descriptions were not published until 1981 when two groups de- of RPN that occurs in diabetic patients will be outlined and the scribed a subacute painful, paralytic lower-limb neuropathy attrib- natural history and treatment will be discussed. Because all of these utable to pathological involvement of the lumbosacral plexus.17,27 syndromes appear to be caused by a microvasculitis and ischemic Like its diabetic counterpart, it appears to be a monophasic illness injury, immunotherapy may be the best treatment, but this has not that usually has incomplete recovery and prolonged morbidity yet been demonstrated. with pain and weakness.15,17 Both DLRPN and LRPN are part of a bigger category of neuropathies that begin suddenly with pain and weakness and involve the roots, plexus and peripheral nerves, and CLINICAL FEATURES OF LUMBOSACRAL are called the radiculoplexus neuropathies (RPN). Radiculoplexus RADICULOPLEXUS NEUROPATHY neuropathies can be divided into three subtypes: (1) a lower limb syndrome, diabetic and nondiabetic lumbosacral radiculoplexus Most commonly, the first symptom of LRPN is pain, which usually neuropathy (DLRPN, LRPN); (2) a truncal syndrome, diabetic comes in several forms. In almost all cases, there is hurting or deep- and nondiabetic thoracic radiculoneuropathy (DTRN, TRN); and aching pain. Other frequently described pains include sharp, lanci- (3) an upper limb syndrome, diabetic and nondiabetic cervical ra- nating or electrical-shock-like pain, burning or fire-like pain, and C-14 Nondiabetic Lumbosacral Radiculoplexus Neuropathy AANEM Course contact allodynia. Patients with allodynia often do not like to wear orthostatic intolerance, change in sexual function, urinary dysfunc- clothes or to have bedsheets touch them because these stimuli cause tion, diarrhea, constipation, or change in sweating. Quantitative excessive pain. The pain in this disorder may be severe. In a series autonomic testing showed abnormalities in almost all patients by this author and colleagues, essentially all patients received an- tested, and the median composite autonomic severity score (CASS) algesic pain medication and most required narcotics.15 Most com- showed moderate autonomic dysfunction.15 Consequently, LRPN monly, the pain begins asymmetrically (usually unilaterally) and is not just a motor neuropathy—sensory and autonomic systems focally, involving proximal segments (the hip and thigh) somewhat are involved. more commonly than distal segments (the foot and leg) (Table 1). However, the disorder quickly spreads to involve the initially Weight loss is also common in LRPN15 and 42 of the 57 patients unaffected segments and the contralateral side so that by time of in this series had weight loss exceeding 10 pounds. In DLRPN, the evaluation the disorder is much more widespread and symmetrical weight loss is often attributed to poorly controlled diabetes mel- than when it first began. Occasionally, it can begin bilaterally and litus, but this explanation is not applicable in LRPN because these symmetrically. In this author’s series, the syndrome began unilater- patients are not diabetic. ally in 50 of 57 patients, but eventually became bilateral in 51 of 57.15 The median time to bilateral disease was 3 months (Table One reassuring fact about LRPN is that it is a monophasic illness 2). Consequently, early in the disease course, one segment (back, and some improvement occurs in almost all patients.15,17 This is a buttock, hip, thigh, leg, or toe) is often primarily involved. These moderately severe neuropathy; the median value of the Neuropathy initially involved segments can be proximal or distal. For example, Impairment Score (NIS)10 (a global score of neurologic impairment it is not uncommon to find isolated weak thigh muscles and absent taking into account weakness, reflex change and sensory loss) was knee reflexes in one patient and a foot drop and no proximal find- 36.5 points (Table 2). This NIS is indicative of moderate to severe ings in another. The process is multifocal, so a patient may have impairment. Recovery is usually delayed and is commonly incom- proximal involvement of one lower limb and distal involvement of plete as nerves regrow slowly, often incompletely and incorrectly. It the other limb. is difficult to know in a specific patient whether there still is active disease or whether there is residual damage to nerves and partial Although pain is the most problematic early symptom, weakness regeneration. There usually is long-term morbidity in LRPN from soon becomes the biggest problem (Table 1). As with the pain, the pain, sensory loss, and weakness. Of 42 LRPN patients followed weakness usually begins focally either proximally or distally but over time, only 3 believed that they had completely recovered after progresses to become multifocal and bilateral. Consequently, both a median time of 3 years.15 Most patients have substantial improve- proximal weakness (difficulty rising from low chairs or climbing ment of both pain and weakness, and few require the long term and decending stairs) and distal weakness (foot drop and difficulty use of wheelchairs (in this author’s series, only 5 of the 25 patients walking on toes) are frequent complaints from LRPN patients. who initially needed wheelchairs still used them 3 years later). The thigh muscles are often affected, causing the knee to buckle However, some degree of ongoing pain, sensory loss, and weakness and the patient to fall. Consequently, bone fractures—especially are common. In general, younger patients fare better than older hips—can occur in patients with LRPN. The weakness is usually patients and proximal injury usually recovers earlier and more ef- severe and half of the patients in this author’s series (28 of 57) were fectively than does distal injury. Consequently, foot drop tends to wheelchair-bound at the time of evaluation and almost all of them be a common long-term problem for LRPN patients. It is believed required some form of aid to ambulate (brace, cane, or walker) that the explanation for this is that reinnervation occurs sooner and (Table 1). When the disease remains unilateral, patients usually can more completely in proximal nerve segments. Many patients also continue ambulating, although they often will need help. However, have some long-term pain and sensory loss, which is usually much when the disease becomes bilateral with predominant involvement less severe than it was early in the disease course. In this author’s of thigh muscles, patients usually become wheelchair-dependent. LRPN cohort, approximately 17% of patients (7 of 42) had recurrent episodes of lumbosacral plexopathy (pain and weakness of the In many cases of LRPN, autonomic and sensory systems are lower extremities). prominent. Essentially, all patients with LRPN suffer from pain, which implies involvement of sensory fibers. Furthermore, 49 of 57 patients from this author’s series had paresthesias and most COMPARISON OF LUMBOSACRAL RADICULOPLEXUS had distal or proximal sensory loss on examination. Quantitative NEUROPATHY TO DIABETIC LUMBOSACRAL sensory testing showed that there is unequivocal sensory abnormal- RADICULOPLEXUS NEUROPATHY ity at different anatomical sites (foot, leg, and thigh) to all sensory modalities (large and small fibers resulting in abnormalities of vi- Diabetic lumbosacral radiculoplexus neuropathy is a clinical bration, cooling, and heat-pain).15 Similarly, autonomic symptoms syndrome that has received much more attention than LRPN.1,3, are common in LRPN and one-half of patients in this study had 6,8,14,18,19,23 Based on large cohorts of LRPN (n = 57) and of new autonomic symptoms at the time of their illness, including DLRPN (n = 33) evaluated by this author, it is believed that the AANEM Course New Insights in Lumbosacral Plexopathy C-15

Table 1 Severity of symptoms, anatomic location and use of ambulating aids in DLRPN and LRPN

DLRPN LRPN DLRPN vs. LRPN Mayo Telephone Mayo Telephone Mayo Telephone Onset Evaluation Follow Up Onset Evaluation Follow Up Onset Evaluation Follow Up (n=33) (n=33) (n=31) † (n=57) (n=57) (n=42) † Most severe symptom Pain 27 13 6 49 10 12 Prickling 0 0 2 1 0 1 Weakness 6 20 21 7 47 26 None 0 0 2 0 0 3 significance * < 0.001 0.05 < 0.0001 0.03 NS 0.03 NS

Most involved site Foot or Leg 12 14 24 21 27 32 Hip or Thigh 18 19 5 33 30 7 Buttock or Back 3 0 0 3 0 0 None 0 0 2 0 0 3 significance NS < 0.001 NS 0.0001 NS NS NS

Aids in ambulation Wheelchair 16 3 28 5 Walker, Cane or Brace 14 16 28 21 None 3 12 1 16 significance < 0.001 < 0.0001 NS NS

DLRPN = diabetic lumbosacral radiculoplexus neuropathy; LRPN = lumbosacral radiculoplexus neuropathy; NS = not significant (p>0.05). * Fisher’s exact test. † Three LRPN and two DLRPN patients reported they were recovered. (Dyck PJB, Norell J, Dyck PJ, Non-diabetic lumbosacral radiculoplexus neuropathy. Natural history, outcome and comparison with the diabetic variety. Brain 2001;124:1197-1207. Modified and reprinted with permission.)

two conditions are essentially the same except for the occurrence of ments. However, with time, most patients develop proximal and diabetes mellitus in DLRPN.12,14-16 The clinical features are almost distal symptoms and have bilateral involvement (in this author’s indistinguishable. As in LRPN, DLRPN begins focally with pain series, 32 of 33). The NIS is similar to that of patients with LRPN involving the back, buttock, thigh, or leg. It starts in an acute or (Table 2). subacute fashion and patients frequently will remember the day their symptoms began. Over time, the symptoms will spread so As is the case for LRPN, DLRPN is not solely a motor neu- that within months the disorder usually involves both proximal and ropathy and sensory and autonomic systems are unequivocally distal segments and becomes bilateral. Early in the course, pain is involved. Essentially, all patients with DLRPN have pain (a sensory the predominant symptom, whereas later weakness is more impor- symptom) and there is involvement of all classes of sensory fibers tant (Table 1). As in LRPN, the proximal segments in DLRPN are (vibration, cooling, and heat-pain) at different anatomical sites initially involved somewhat more frequently than the distal seg- (foot, leg, and thigh). About one-half of patients have new auto- C-16 Nondiabetic Lumbosacral Radiculoplexus Neuropathy AANEM Course

Table 2 Clinical and laboratory characteristics of DLRPN and LRPN patients and a population-based diabetic cohort (RDNS)

DLRPN LRPN RDNS p* DLRPN DLRPN vs. vs. Continuous n Median Range SD n Median Range SD n Median Range SD LRPN RDNS Age, years 33 65.4 35.8 - 75.9 10.4 57 69.4 27.8 - 86.5 12.3 195 65.0 19.0 - 88.0 15.1 0.03 NS Duration of 33 4.1 0.0 - 35.8 7.9 NA 195 15.0 5.9 - 74.8 8.5 <0.001 diabetes, years Duration of 33 6.7 1.4 - 42.0 8.9 57 7.0 0.5 - 60.0 12.4 NA NS neuropathy at evaluation, months Onset to 32 3.0 0.0 - 60.0 10.6 45 3.0 0.0 - 72.0 11.6 NA NS bilateral, months Fasting plasma 30 144.5 75.0 - 225.0 44.3 57 96.0 69.0 - 124.0 11.5 195 169.9 94.2 - 389.0 41.9 0.0001 0.001 glucose, mg/dL Glycated 30 7.5 5.1 - 12.9 2.0 34 5.5 4.3 - 7.1 0.7 195 9.8 5.5 - 16.5 2.0 0.0001 <0.001 hemoglobin, % Body mass 29 25.7 17.8 - 36.7 4.9 50 25.1 17.8 - 35.4 4.6 195 28.6 17.8 - 50.8 5.7 NS 0.002 index, kg/m2 Weight change, lb † 33 -30.0 -120.0 - 0.0 32.6 57 -15.0 -90.0 - 0.0 19.6 195 0.4 -8.7 - 10.1 2.6 0.002 <0.001 Creatinine, mg/dL 30 0.9 0.7 - 3.4 0.5 53 1.0 0.6 - 1.9 0.2 195 1.0 0.5 - 2.5 0.2 NS 0.023 Cerebrospinal fluid 26 85.0 56.0 - 130.0 19.4 49 63.0 48.0 - 88.0 9.3 0.0001 glucose, mg/dL Cerebrospinal fluid 26 89.5 44.0 - 214.0 35.3 50 66.5 18.0 - 283.0 56.9 0.009 protein, mg/dL Cerebrospinal fluid 26 1.0 1.0 - 11.5 2.1 49 1.0 0.0 - 12.0 2.2 NS cells, cells/µL Erythrocyte 31 6.0 0.0 - 60.5 14.6 56 13.5 0.0 - 62.0 14.4 0.02 sedimentation rate, mm/h NIS Total 33 43.0 7.0 - 87.0 18.6 57 36.5 6.0 - 106.3 21.2 195 0.0 0.0 - 18.0 2.5 NS 0.0001 NIS Lower limb 33 37.0 7.0 - 62.0 14.4 57 33.5 6.0 - 77.0 17.0 195 0.0 0.0 - 14.0 2.3 NS 0.0001 Dichotomous Yes No Yes No Yes No Sex, male 33 20 13 57 29 28 195 96 99 NS NS Diabetes, type II 33 32 1 NA 194 148 46 0.005 Insulin use 31 13 18 NA 195 134 61 0.007 Retinopathy 17 4 ‡ 13 195 128 67 0.001 Nephropathy 33 2 31 195 20 175 NS Cardiovascular disease 33 3 30 195 73 122 0.001 Rheumatoid factor, 27 2 25 40 6 34 NS reactive ANA, positive 32 7 25 50 8 42 NS

DLRPN = diabetic lumbosacral radiculoplexus neuropathy; LRPN = lumbosacral radiculoplexus neuropathy; RDNS = Rochester Diabetic Neuropathy Study; SD=standard deviation; NS = not significant (p>0.05); NA = not applicable; NIS = Neuropathy Impairment Score. * Wilcoxon rank sum test for continuous data and Fisher’s exact test for dichotomous data. † For DLRPN and LRPN, weight change is from onset to valuation; for RDNS, weight change is over one year.‡ Nonproliferative retinopathy. (Dyck PJB, Norell J, Dyck PJ, Non-diabetic lumbosacral radiculoplexus neuropathy. Natural history, outcome and comparison with the diabetic variety. Brain 2001;124:1197-1207. Modified and reprinted with permission.) AANEM Course New Insights in Lumbosacral Plexopathy C-17

nomic symptoms which include orthostatic hypotension, urinary coexisting neurological disorders are unlikely for most patients; dysfuntion, diarrhea, constipation, change in sexual function, or rather, it is more likely that there is unequal pathological involve- change in sweating.14 ment of different nerve segments producing a widespread but asymmetric radiculoplexus neuropathy. Long-term morbidity is severe in both LRPN and DLRPN. From this author’s series, only 2 of 31 DLRPN patients reported that The NCS and needle EMG findings in LRPN and DLRPN are they had complete recovery after a median follow-up time of 2 more suggestive of axonal degeneration than of segmental demy- years. The others still had residual weakness, pain or sensory loss elination. In this author’s cohorts of LRPN and DLRPN, there are (Table 1). However, as in DLRPN, real improvement had occurred marked reductions in amplitudes of the compound muscle action in most patients. At the time of initial evaluation, 16 DLRPN potentials and of the sensory nerve action potentials with only mild patients used a wheelchair, whereas only 3 used a wheelchair at the slowing of nerve conduction velocities.14,15 Needle EMG shows time of follow-up. The most problematic long-term impairments fibrillation potentials, decreased recruitment, long duration, high were confined to the distal segments (legs and feet)—this often was amplitude motor unit action potentials in muscles innervated by foot drop (as in LRPN). As in LRPN, DLRPN can be a recurrent multiple nerve roots and different peripheral nerves. Upper lumbar condition. and lower lumbar levels both tend to be involved. Paraspinal muscles are also usually involved. Fibrillation potentials in lumbosacral paraspinal muscles were seen in 33 of 48 LRPN patients and TESTING IN LUMBOSACRAL RADICULOPLEXUS 29 of 30 DLRPN patients who had paraspinal muscles examined. NEUROPATHY The electrophysiological abnormalities tend to be more widespread than the clinical deficits. The findings are essentially the same in Previous authors have argued that markers of altered immunity, the two conditions with the diabetic group having slightly more especially elevated erythrocyte sedimentation rates, distinguish pa- severe abnormalities.14,15 Although axonal degeneration is the main tients with immune mediated lumbosacral plexopathies from ones abnormality, an occasional patient will show slowed conduction with different etiologies.5 It is agreed that an elevated sedimentation velocities somewhat suggestive of demyelination. In general, the rate may imply an immune etiology. However, it has not been this electrophysiological abnormalities are in keeping with a pathologi- author’s experience that patients with elevated erythrocyte sedimen- cal process that involved the roots, plexus, and peripheral nerves (a tation rates differ markedly from other RPN patients.15 Some of the radiculoplexus neuropathy) which usually predominantly involves patients from the DLRPN and LRPN cohorts had elevated sedi- the lumbosacral segments, but which often also involves the tho- mentation rates, reactive rheumatoid factors, positive antinuclear racic and cervical segments. antibodies, or other markers of altered immunity, but most did not (Table 2). It is believed that an immune cause underlies all of the RPNs. In both DLRPN and LRPN, the cerebrospinal fluid (CSF) PATHOLOGY OF LUMBOSACRAL RADICULOPLEXUS protein concentration is significantly elevated (Table 2)—evidence NEUROPATHY that the disease process extends to the nerve root level. Previously, only a few studies exist about the underlying patho- The nerve conduction study (NCS) and electromyogram (EMG) logical mechanisms of LRPN. Bradley and coworkers showed in abnormalities in LRPN and DLRPN have been extensively six patients with painful lumbosacral plexopathies and elevated studied.4,15,28 Bastron and Thomas emphasized the multifocal and sedimentation rates (three with and three without diabetes mel- patchy involvement of lumbosacral and thoracic myotomes in litus) that there were perivascular inflammatory cell cuffing and DLRPN.4 Subramony and Wilbourn proposed that there were multifocal fiber loss.5 In contrast, much more has been written two distinct electrophysiological subtypes of DLRPN: one group about the pathology of DLRPN. In the only autopsy case by Raff in which there are focal abnormalities confined to the affected and colleagues, ischemic injury was reported.23,24 Some authors lower limb(s) (multiple lumbosacral radiculopathies) and a second have argued that ischemic injury is the most important finding,3 group in which there is evidence of a diffuse peripheral neuropathy whereas others have argued that metabolic factors were more im- with more severe abnormalities superimposed in the affected lower portant.7,8 Others have found evidence that some cases are due to limb(s) (multiple lumbosacral radiculopathies).28 While this author ischemic injury and vasculitis, whereas other cases are due to meta- believes that the observation of these authors is correct, it is not bolic derangement.25 Some have stressed that DLRPN is due to believed to be helpful to divide patients into two groups. It is likely microvasculitis causing ischemic injury.14,21,22,26 Because of the simi- that the subgroup reported to have a separate polyneuropathy are larity in the clinical, laboratory, and electrophysiological features of the more severely affected patients and have more diffuse electro- DLRPN and LRPN, it seemed likely that the two conditions are physiological abnormalities. It is also believed that two separate, due to the same pathophysiological mechanisms. Consequently, a C-18 Nondiabetic Lumbosacral Radiculoplexus Neuropathy AANEM Course

pathological study was performed identifying LRPN patients who tion (Figure 1). All of these changes are attributable to ischemic had nerve biopsies in order to determine whether the pathological damage. As in DLRPN, the ischemic changes seemed to be caused findings were the same in the two conditions. by altered immunity and microvasculitis. Epineurial perivascular inflammatory collections were seen in all nerves. There were fea- It was found that the pathological findings in LRPN are strikingly tures suggestive of microvasculitis with inflammatory cells separat- similar to those of DLRPN (Table 3).12 There was multifocal fiber ing microvessel wall elements in half of nerves. Serial skip sections loss, regions of abortive regeneration within or beyond the original demonstrated that the microvasculitis regions were focal with some fascicle forming microfasciculi (injury neuroma), focal degenera- areas affected and adjacent areas unaffected (Figure 2). Fibrinoid tion or scarring of the perineurium, and epineurial neovasculariza- degeneration (typical of large vessel vasculitis) was rarely seen.

Table 3 Pathologic results of distal cutaneous nerve biopsies from DLRPN compared with LRPN, diabetic polyneuropathy (DPN) and healthy control nerves

DLRPN LRPN DPN Healthy Controls Variable n n p* n p* n p* Characteristics of Patients Biopsied n 33 47 21 14 Sex, male 20 24 NS 15 NS 9 NS Median Age, years 65.4 67.2 NS 57.0 0.002 61.5 NS

Paraffin and Epoxy Sections Endoneurial and Perineurial Abnormality Fiber degeneration or loss 25 37 NS 15 NS 0 < 0.001 Multifocal fiber degeneration or loss 19 31 NS 2 < 0.001 0 < 0.001 Focal perineurial degeneration 6 7 NS 0 NS 0 NS Focal perineurial thickening 24 27 NS 2 < 0.001 2 < 0.001 Injury neuroma † 12 16 NS 0 0.002 0 0.009 Interstitial Abnormality Perivascular inflammation 33 47 NS 6 < 0.001 2 < 0.001 Individual cells (< 10 cells) 0 5 5 2 Small collections (11-50 cells) 21 29 1 0 Moderate collections (51-100 cells) 7 6 0 0 Large collections (> 100 cells) 5 7 0 0 Inflammation of vessel wall 15 24 NS 0 < 0.001 0 0.002 Diagnostic of microvasculitis 2 7 NS 0 NS 0 NS Hemosiderin in macrophages 19 25 NS 0 < 0.001 0 < 0.001 Neovascularization 21 21 NS 1 < 0.001 1 < 0.001

DLRPN = diabetic lumbosacral radiculoplexus neuropathy; LRPN = lumbosacral radiculoplexus neuropathy; NS = not significant (p >0.05). * Wilcoxon rank sum test for continuous data and Fisher’s exact test for dichotomous data. † Injury neuroma = abortive regenerative activity outside of the original perineurium. (Dyck PJB, Engelstad J, Norell J, Dyck PJ, Microvasculitis in Non-Diabetic Lumbosacral Radiculoplexus Neuropathy (LSRPN): Similarity to the Diabetic Variety (DLSRPN), J Neuropathol Exp Neurol 2000;59:525-538. Dyck PJB, Norell JE, Dyck PJ, Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy, Neurology 1999;53:2113-2121. Modified and reprinted with permissions.) AANEM Course New Insights in Lumbosacral Plexopathy C-19

Overall, the pathological findings of DLRPN and LRPN are very much alike. Findings provide evidence that the primary event in both DLRPN and in LRPN is nerve ischemia due to a microvasculitis.

It is believed these conditions are forms of nonsystemic vasculitis of nerve. A vasculitic process could explain the clinical pattern of sudden onset, painful, asymmetric neuropathy. Weight loss is common in vasculitis disorders (as it is in DLRPN and LRPN). The small size of blood vessels involved may help explain the patchy, widespread asymmetric process rather than discrete multiple mononeuropathies more typical of large-nerve vessel necrotizing vasculitis. It is unclear why the lumbosacral roots, plexus, and nerves are particularly susceptible in LRPN and DLRPN, but as noted above, it is common to get co-existing truncal radiculopathies (DTRN, TRN) and upper limb neuropathies (DCRPN, CRPN) in these patients. Furthermore, EMG changes tend to be more diffuse than clinical involvement would suggest.

One of the most compelling arguments that DLRPN is not due to metabolic derangement from hyperglycemia is the similarity between the clinical course and pathology of DLRPN and LRPN. As LRPN patients are not diabetic, it is difficult to implicate hyperglycemia and metabolic derangement as the cause of their neuropathy. Consequently, chronic hyperglycemia also probably does not play the major role in the pathogenetics of DLRPN. One could ask whether patients with LRPN really have undetected mild diabetes mellitus. This seems unlikely as only 2 of 42 LRPN patients eventually developed diabetes mellitus.15 It is possible that they have mild glucose impairment, but this has not been definitely demonstrated, although others have found abnormal glucose tolerance tests in some LRPN patients.20 It is believed that hyperglycemia probably is a risk factor for developing DLRPN, if not the direct cause. The frequency of DLRPN is about 1% among diabetic patients,9 whereas the frequency of LRPN among the general population is not known. Nonetheless, most investigators Figure 1 Transverse paraffin sections of sural nerves showing typical believe that lumbosacral radiculoplexus neuropathies occur more changes seen in diabetic and nondiabetic lumbosacral radiculoplexus commonly among diabetic patients. Consequently, the diabetic neuropathies. The upper frame (Masson’s trichrome stain) shows state (hyperglycemia) probably plays a role in the disease process, inflammation in the wall of an epineurial microvessel (right upper), even if it is not the direct cause of the condition. probably fibrinoid degeneration of the perineurium (long arrow), and a region of neovascularization (arrowhead). The middle frame (Luxol fast blue-periodic acid Schiff stain) shows several fascicles surrounded by IMMUNOTHERAPY normal thickness perineurium (right middle, between two arrowheads) and one fascicle with extremely thick perineurium (left middle, between two arrowheads). The latter is attributed to scarring and repair after Little is known about the treatment of LRPN. Bradley and col- ischemic injury (note all fascicles are devoid of myelinated fibers). The leagues5 reported that four of their six patients had improvement lower frame (Turnbull blue stain) shows accumulation of hemosiderin with prednisone. Awerbuch’s group2 reported that their patients (iron stains bright blue, arrow) deposited along the inner aspects of treated with prednisone did not have improvement. Verma and the perineurium. All of these pathologic features are frequently seen Bradley30 reported two patients who responded to high-dose in- together and are best explained by ischemic injury. (Dyck PJB and travenous immunoglobulin (IVIg), and Triggs and colleagues29 colleagues. Microvasculitis in nondiabetic lumbosacral radiculoplexus reported that five patients had improvement with IVIg. [LSRPN]: Similarity to the diabetic variety. J Neuropathol Exp Neurol 2000;59:525-538. Reprinted with permission.) C-20 Nondiabetic Lumbosacral Radiculoplexus Neuropathy AANEM Course

Figure 2 Paraffin sections of sural nerve from patients with nondiabetic lumbosacral radiculoplexus neuropathy(LRPN) (upper three panels) and diabetic lumbosacral radiculoplexus neuropathy (DLRPN) (lower panel) reacted for anti-human smooth muscle actin (Dako) and counter-stained with hematoxylin and eosin showing microvasculitis of four nerve vessels (right column) and an unaffected level of the same vessel proximal or distal to the lesion (left column). Compared with the relatively unaffected regions of the same microvessels (left), in the regions of microvasculitis (right) the smooth muscle is separated by mononuclear cells, fragmented, displaced outward, and decreased in amount. These changes were interpreted as typical of microvasculitis. They were encountered most commonly in the epineurium but were also found in the endoneurium and perineurium. Note the similarity of the microvasculitis in the LRPN nerves (top three) and the DLRPN nerve (bottom). Note also the adjacent unaffected vessels are often larger in size. (Dyck PJB and colleagues. Microvasculitis in nondiabetic lumbosacral radiculoplexus [LSRPN]: Similarity to the diabetic variety. J Neuropathol Exp Neurol 2000;59:525-538. Reprinted with permission.) AANEM Course New Insights in Lumbosacral Plexopathy C-21

probably was helpful because in all cases the improvement of symptoms began with the initiation of treatment. Placebo-controlled double-blind prospective studies are needed to answer whether im- munomodulating therapies are effective in treating LRPN.

SYMPTOMATIC TREATMENT

All of the RPNs (including LRPN and DLRPN) are severe illnesses with great morbidity. Because they are usually monophasic and improve with time, physicians may underappreciate the suffering and disability experienced. Patients frequently are so weak and have such severe pain that they are unable to work; they often require hospitalization to achieve adequate pain control. Most patients with an RPN will need narcotic medication at some point in their illness as well as treatment with other chronic neuropathic pain medications (such as tricyclic antidepressants and anti-seizure agents). Patients should be warned that it is often impossible to relieve the pain completely, and the goal is to make the pain toler- able. Because the RPNs begin abruptly and severely, these conditions are often misdiagnosed, and many patients get unnecessary operations for suspected disk disease. Patients often worry that the disease will be progressive and fatal, and because of the associated weight loss they (or their physicians) believe they may have a cancer or amyloidosis. Commonly, patients with RPNs become depressed due to protracted pain, weakness, sensory loss, and loss of sleep.

Patients should be advised that although the disease may be self- limited and monophasic, its course tends to be long and recovery Figure 3 Neuropathy impairment score (NIS) of 11 patients with is often incomplete. Axonal degeneration is the main pathological nondiabetic lumbosacral radiculoplexus neuropathy plotted with time process, and although nerves do regenerate, they do so at a very after a course of intravenous methylprednisolone therapy. Each line slow rate. Patients who are younger and have predominantly proxi- represents a different patient, the dots represent patient evaluations, mal disease have a better prognosis. Depression should be treated and the solid lines represent the treatment period. Without exception, with appropriate antidepressant medication and patients should the NIS improved (score decreased) during the treatment period, some- be encouraged to stay involved with hobbies and other interests. times dramatically (see text for discussion). (Dyck PJB and colleagues. Methylprednisolone may improve lumbosacral radiculoplexus neuropa- Physical therapy should be used and homes should be made as safe thy. Can J Neurol Sci, 2001;28:224-227. Reprinted with permission.) as possible. Bracing such as ankle-foot orthoses should be fitted and used if needed. Physicians need to be aggressive in helping patients with pain control and in obtaining health and disability insurance when needed. Patients need to keep the perspective that although An open trial of weekly intravenous infusions of methylpredniso- the illness may get worse in the short term, nearly all patients with lone in 11 LRPN patients was conducted over 9 to 16 weeks.13 All RPN (including LRPN) will improve to some degree, even if in- had marked improvement of pain and many had complete resolu- completely, over time. tion of the pain. All patients had some improvement of weakness, and 9 of the 11 graded this improvement as marked. The median neuropathy impairment score was statistically improved after treat- Summary ment (Figure 3). Before treatment one-half of the patients were in wheelchairs and all but one used an aid in ambulating. After Nondiabetic lumbosacral radiculoplexus neuropathy has re- treatment, only one patient was still in a wheelchair and six walked ceived much less attention than its diabetic counterpart DLRPN. independently. These treatment data are considered preliminary Comparison of large cohorts with DLRPN and LRPN demon- and not definitive. There were no control patients, and LRPN can strated that age of onset, course, type and distribution of symptoms improve spontaneously. However, it is believed that the treatment and impairments, laboratory findings, and outcomes are similar. C-22 Nondiabetic Lumbosacral Radiculoplexus Neuropathy AANEM Course

12. Dyck PJB, Engelstad J, Norell J, Dyck PJ. Microvasculitis in non- Both conditions are lumbosacral radiculoplexus neuropathies that diabetic lumbosacral radiculoplexus neuropathy (LSRPN): similar- are associated with weight loss and begin focally with pain, but that ity to the diabetic variety (DLSRPN). J Neuropath Exp Neurol evolve into widespread, bilateral paralytic disorders. Although both 2000;59:525-538. are monophasic illnesses, patients have prolonged morbidity from 13. Dyck PJB, Norell JE, Dyck PJ. Methylprednisolone may improve lum- pain and weakness, and many patients become wheelchair-depen- bosacral radiculoplexus neuropathy. Can J Neurol Sci 2001;28:224- dent. Although motor predominant, there is unequivocal evidence 227. that autonomic and sensory nerves are also involved. Cutaneous 14. Dyck PJB, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic nerves from patients with LRPN and DLRPN show pathologi- lumbosacral radiculoplexus neuropathy. Neurology 1999;53:2113- cal evidence of ischemic injury and microvasculitis. Controlled 2121. trials with immune-modulating therapies in DLRPN have been 15. Dyck PJB, Norell JE, Dyck PJ. Non-diabetic lumbosacral radiculo- completed, and there is preliminary data that such therapy may plexus neuropathy: natural history, outcome, and comparison with the diabetic variety. Brain 2001;124:1197-1207. be beneficial in LRPN. It is likely that DLRPN or LRPN are 16. Dyck PJB, Windebank AJ. Diabetic and non-diabetic lumbosacral immune-mediated neuropathies that should be separated from radiculoplexus neuropathies: new insights into pathophysiology and chronic inflammatory demyelinating polyneuropathy and from treatment. Muscle Nerve 2002;25:477-491. systemic necrotizing vasculitis. 17. Evans BA, Stevens JC, Dyck PJ. Lumbosacral plexus neuropathy. Neurology 1981;31:1327-1330. 18. Garland H. Diabetic amyotrophy. Br Med J 1955;2:1287-1296. REFERENCES 19. Garland H. Diabetic amyotrophy. Br J Clin Pract 1961;15:9-13. 20. Kelkar P, Hammer-White S. Impaired glucose tolerance in non- 1. Auche MB. Des alterations des nerfs peripheriques. Arch Med Exp diabetic lumbosacral radiculoplexus neuropathy. Muscle Nerve Anat Pathol 1890;2:635-676. 2005;31:273-274. 2. Awerbuch GI, Nigro MA, Sandyk R, Levin JR. Relapsing lumbosa- 21. Kelkar PM, Masood M, Parry GJ. Distinctive pathologic findings cral plexus neuropathy. Eur Neurol 1991;31:348-351. in proximal diabetic neuropathy (diabetic amyotrophy). Neurology 3. Barohn RJ, Sahenk Z, Warmolts JR, Mendell JR. The Bruns-Garland 2000;55:83-88. syndrome (diabetic amyotrophy). Revisited 100 years later. Arch 22. Llewelyn JG, Thomas PK, King RH. Epineurial microvasculitis in Neurol 1991;48:1130-1135. proximal diabetic neuropathy. J Neurol 1998;245:159-165. 4. Bastron JA, Thomas JE. Diabetic polyradiculopathy: clinical and elec- 23. Raff MC, Asbury AK. Ischemic mononeuropathy and mononeurop- tromyographic findings in 105 patients. Mayo Clin Proc 1981;56:725- athy multiplex in diabetes mellitus. N Engl J Med 1968;279:17-22. 732. 24. Raff MC, Sangalang V, Asbury AK. Ischemic mononeuropathy mul- 5. Bradley WG, Chad D, Verghese JP, Liu HC, Good P, Gabbai AA, tiplex associated with diabetes mellitus. Arch Neurol 1968;18:487- Adelman LS. Painful lumbosacral plexopathy with elevated eryth- 499. rocyte sedimentation rate: a treatable inflammatory syndrome. Ann 25. Said G, Goulon-Goeau C, Lacroix C, Moulonguet A. Nerve biopsy Neurol 1984;15:457-464. findings in different patterns of proximal diabetic neuropathy. Ann 6. Bruns L. Ueber neuritsche Lahmungen beim diabetes mellitus. Berlin Neurol 1994;35:559-569. Klin Wochenschr 1890;27:509. 26. Said G, Lacroix C, Lozeron P, Ropert A, Plante V, Adams D. 7. Chokroverty S. Proximal nerve dysfunction in diabetic proximal Inflammatory vasculopathy in multifocal diabetic neuropathy. Brain amyotrophy. Electrophysiology and electromicroscopy. Arch Neurol 2003;126:376-385. 1982;39:403-407. 27. Sander JE, Sharp FR. Lumbosacral plexus neuritis. Neurology 8. Chokroverty S, Reyes MG, Rubino FA, Tonaki H. The syndrome of 1981;31:470-473. diabetic amyotrophy. Ann Neurol 1977;2:181-199. 28. Subramony SH, Wilbourn AJ. Diabetic proximal neuropathy: clinical 9. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. and electromyographic studies. J Neurol Sci 1982;53:293-304. The prevalence by staged severity of various types of diabetic neu- 29. Triggs WJ, Young MS, Eskin T, Valenstein E. Treatment of idio- ropathy, retinopathy, and nephropathy in a population-based cohort: pathic lumbosacral plexopathy with intravenous immunoglobulin. the Rochester Diabetic Neuropathy Study. Neurology 1993;43:817- Muscle Nerve 1997;20:244-246. 824. 30. Verma A, Bradley WG. High-dose intravenous immunoglobulin 10. Dyck PJ, Sherman WR, Hallcher LM, Service FJ, O’Brien PC, Grina therapy in chronic progressive lumbosacral plexopathy. Neurology LA, et al. Human diabetic endoneurial sorbitol, fructose, and myo- 1994;44:248-250. inositol related to sural nerve morphometry. Ann Neurol 1980;8:590- 596. 11. Dyck PJB. Radiculoplexus neuropathies: diabetic and nondiabetic varieties. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy, 4th edition. Philadelphia: Elsevier; 2005. p 1993-2015. C-23

Treatment Strategies in Lumbosacral Plexopathy

Suraj A. Muley, MD Assistant Professor Department of Neurology University of Minnesota Medical Center Minneapolis, Minnesota

Introduction resultant microangiopathy of diabetes. Three patients were treated with prednisone and two patients with prednisone and cyclophos- The clinical course and the natural history of diabetic lumbosacral phamide; four patients had improvement in pain, two patients had radiculoplexus neuropathy (DLSRPN) suggest that pain, weakness, improvement in weakness, and in two patients weakness stabilized and the resultant difficulty with ambulation are the major sources without worsening. Interestingly, in the three diabetic patients, of morbidity. The disease evolves over months or years and recovery there was significant improvement despite marked worsening of is slow and incomplete.2,3,18 diabetic control.

Various treatment strategies for DLSRPN have been explored and In another study by Krendel and colleagues, 13 patients with the approach to treatment has varied with time based on the prevail- DLSRPN were treated with prednisone or intravenous immuno- ing concepts regarding the pathogenetic mechanisms. Originally, globulin (IVIg) either alone or in conjunction with azathioprine or DLSRPN was thought to be related to metabolic derangement cyclophosphamide.16 All symptoms stopped worsening and there in diabetic patients.6 Treatment consisted of improving glycemic was improvement in strength, which lead to improvement in the control by more aggressive treatment of the diabetes. Response performance of daily living activities in the majority of the patients. to treatment was variable with reports of marked improvement in The interval between the onset of the disease and the institution of some patients and significant residual disability in others.5 treatment was not mentioned. Pascoe and colleagues18 reported improvement in 9 of 12 patients with diabetes and proximal leg weak- The overwhelming pathological evidence from various studies over ness. It is unclear whether these patients had DLSRPN because the last decade indicates that an immune-mediated vasculopathy patients with significant demyelination were also included in the is the most likely mechanism underlying DLSRPN.7,14,17,19 It was study. Two patients had conduction block and four had temporal therefore intuitive that immunosuppressive treatments would be dispersion on needle electromyography (EMG), and patients with effective in treatment. This was first suggested in a study by Bradley unilateral weakness were excluded. It is possible that some of these and colleagues of six patients with painful lumbosacral plexopathy.4 patients may have had DLSRPN, but the clinical syndrome was not Three of the six patients had diabetes, but all had elevated eryth- characteristic of DLSRPN in all patients. These studies would seem rocyte sedimentation rate (ESR) and mononuclear infiltration of to suggest that immunosuppression is efficacious in the treatment epineurial arterioles. The three diabetic patients worsened despite of DLRPN. However, when another study by Said and colleagues control of their diabetes, which supports the current notion that reported four patients with DLSRPN who underwent a biopsy of DLSRPN is likely not related to impaired metabolism and the the intermediate cutaneous nerve of the thigh and reported resolu- C-24 Treatment Strategies in Lumbosacral Plexopathy AANEM Course tion of pain within 1 week of the nerve biopsy procedure without symptom onset. Further controlled studies with early treatment are any other form of treatment, doubt was cast.20 It is unclear whether needed to establish this with certainty. the weakness also improved. Moreover, inflammatory nerve lesions were found suggesting that spontaneous improvement was possible despite an immune-mediated pathophysiology in this condition. Nondiabetic Lumbosacral RadiculoPlexus Neuropathy The overall conclusion that can be drawn from these studies is that an immune-mediated vasculopathy with secondary nerve infarction Lumbosacral radiculoplexus neuropathy (LRPN) can also occur in is the pathological basis of DLSRPN and that it is possible that im- patients without diabetes and is similar to DLSRPN in its presenta- munosuppressive treatments in the form of prednisone or IVIg may tion, clinical course, prognosis and pathogenetic mechanisms.8 alter the natural course of the disease. Lumbosacral radiculoplexus neuropathy was described relatively In order to further study the issue of immunosuppressive treat- recently by Evans and Said13,21 as a painful asymmetric weakness ments, Dyck and colleagues conducted a randomized double-blind and atrophy affecting proximal leg muscles, essentially identical to multi-center study investigating the role of intravenous methyl- DLSRPN. As in the DLSRPN, long-term morbidity can be severe. prednisolone in the treatment of DLSRPN.9 A significant differ- A study by Dyck and colleagues reported that 3 of 42 patients had ence in the primary outcome measure (neuropathy impairment complete recovery at 3 years.12 The histopathology is also similar to score of the lower limb) was not found, suggesting a lack of efficacy. DLSRPN with epineurial perivascular inflammation in all nerves Even so, there was improvement in pain and positive neuropathy biopsied and features suggestive of microvasculitis in half the symptoms in the treatment group, indicating some beneficial nerves, as reported by Dyck and colleagues.10 effects of treatment. Lack of efficacy may have been from delay in institution of treatment. It is therefore likely that treatment responses to immunosuppression would be similar in both DLSRPN and LRPN. There are In a retrospective study conducted by this author’s group,5 10 epi- no controlled studies investigating efficacy of immunosuppressive sodes in 9 patients with DLSRPN were treated with oral or intra- treatments in LRPN, but observational studies suggest a benefit venous pulsed methylprednisolone 500 mg for 2 days every 2 weeks from immunosuppression. for up to 3 months depending on response to treatment. Treatment was instituted from 1 week to 5 months from symptom onset. In a study by Bradley and colleagues, treatment with prednisone There was dramatic improvement in pain in 6 of 8 episodes treated lead to improvement in four of six patients with lumbosacral within 3 months of symptom onset. In patients treated at 4 and 5 plexopathy three of whom were diabetic.4 In a study by Awebuch months, there was delayed improvement which was probably con- and colleagues, one patient treated with prednisone had no re- sistent with the natural history of the disease. When treatment was sponse to treatment.1 Time interval between onset of symptoms instituted within 3 months of onset, moderate to severe weakness and treatment was not mentioned in either of these studies. High either resolved or improved markedly after 3 months of treatment dose IVIg (0.8 g/kg/day for 5 days) lead to marked improvement in 7 of 9 episodes (78%). In conclusion, treatment started within in a patient with progressive lumbosacral plexopathy who did not 3 months of disease onset improves pain and weakness sooner and respond to the regular dose of IVIg (0.4 g/kg/day for 5 days) or perhaps more than the natural history of the disease. In an addi- to prednisone or plasmapheresis.23 In another study by Triggs and tional three patients treated at this author’s center, treatment with colleagues, 4 patients treated with regular dose IVIg (0.4 g/kg/day oral methylprednisolone within 3 months of symptom onset lead for 5 days) and 1 patient with high-dose IVIg (0.8 g/kg/day for 3 to dramatic improvement in pain and significant improvement in days) at a mean of 3.8 months from onset had significant improve- weakness that was clearly greater than the natural history described ment in pain and weakness, suggesting treatment efficacy.22 Lastly, in the literature. The delay in the institution of treatment in the 10 patients treated with intravenous methylprednisolone and 1 multicenter study was probably the reason why treatment was inef- patient treated with prednisone at a comparable dose had improve- fective and does not rule out the possibility of efficacy with early ment in pain, weakness, and ability to ambulate, again suggesting treatment. efficacy. Treatment was instituted at a median of 5 months from onset (range 1-48 months).11 In conclusion, although no controlled data exist that demonstrate treatment efficacy, this author’s experience and that of other investigators (along with the fact that microvasculitis is commonly seen Summary in nerve biopsies of DLSRPN patients), suggest that immunosuppressive treatments may be a reasonable approach in the manage- The overall conclusion that can be drawn from these observational ment of these conditions especially if instituted within 3 months of studies, supported by the fact that an immune-mediated vasculopa- AANEM Course New Insights in Lumbosacral Plexopathy C-25

11. Dyck PJB, Norell JE, Dyck PJ. Methylprednisolone may improve lum- thy is the underlying pathogenetic mechanism, is that immunosup- bosacral radiculoplexus neuropathy. Can J Neurol Sci 2001;28:224- pressive treatments such as IVIg or steroids may be efficacious in 227. the treatment of LRPN. Controlled studies are necessary to estab- 12. Dyck PJB, Norell JE, Dyck PJ. Non-diabetic lumbosacral radiculoplexus neuropathy. Natural history, outcome and comparison with lish this with certainty. the diabetic variety. Brain 2001;124:1197-1207. 13. Evans BA, Stevens JC, Dyck PJ. Lumbosacral plexus neuropathy. Neurology 1981;31:1327-1330. REFERENCES 14. Kelkar P, Masood M, Parry GJ. Distinctive pathological findings in proximal diabetic neuropathy (diabetic amyotrophy). Neurology 1. Awerbuch GI, Nigro MA, Sandyk R, Levin JR. Relapsing lumbosa- 2000;55:83-88. cral plexus neuropathy. Report of two cases. Eur Neuol 1991;31:348- 15. Kilfoyle D, Kelkar P, Parry GJ. Pulsed methylprednisolone is a safe 351. and effective treatment for diabetic amyotrophy. J Clin Neuromus 2. Barohn RJ, Sahenk Z, Warmolts JR and Mendell JR. The Bruns- Dis 2003;4:168-170. Garland syndrome (diabetic amyotrophy). Revisited 100 years later. 16. Krendel DA, Costigan DA, Hopkins LC. Successful treatment Arch Neurol 1991;48:1130-1135. of neuropathies in patients with diabetes mellitus. Arch Neurol 3. Bastron JA, Thomas JE. Diabetic polyradiculopathy. Clinical and elec- 1995;52:1053-1061. tromyographic findings in 105 patients. Mayo Clin Proc 1981;56:725- 17. Llewelyn JG, Thomas PK, King RH. Epineurial microvasculitis in 732. proximal diabetic neuropathy. J Neurol 1998;245:159-165. 4. Bradley WG, Chad D, Verghese JP, Liu H, Good P, Gabbai AA, 18. Pascoe MK, Low PA, Windebank AJ, Litchy WJ. Subacute diabetic Adelman LS. Painful lumbosacral plexopathy with elevated eryth- proximal neuropathy. Mayo Clin Proc 1997;72:1123-1132. rocyte sedimentation rate: a treatable inflammatory syndrome. Ann 19. Said G, Goulon-Goeau C, Lacroix C, Moulonguet A. Nerve biopsy Neurol 1984;15:457-464. findings in different patterns of proximal diabetic neuropathy. Ann 5. Casey EB, Harrison MJ. Diabetic amyotrophy: a follow-up study. Br Neurol 1994;35:559-569. Med J 1972;1:656-659. 20. Said G, Elgrably F, Lacroix C, Plante V, Talamon C, Adams D, Tager 6. Chokroverty S, Reyes MG, Rubino FA, Tonaki H. The syndrome of M, Slama G. Painful proximal diabetic neuropathy: inflammatory diabetic amyotrophy. Ann Neurol 1977;2:181-194. nerve lesions and spontaneous favorable outcome. Ann Neurol 7. Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic 1997;41:762-770. lumbosacral radiculoplexus neuropathy. Neurology 1999;53:2113- 21. Sander JE, Sharp FR. Lumbosacral plexus neuritis. Neurology 2121. 1981;31:470-473. 8. Dyck PJ, Windebank AJ. Diabetic and nondiabetic lumbosacral 22. Triggs WJ, Young MS, Eskin T, Valenstein E. Treatment of idio- radiculoplexus neuropathies: new insights into pathophysiology and pathic lumbosacral plexopathy with intravenous immunoglobulin. treatment. Muscle Nerve 2002;71:477-491. Muscle Nerve 1997;20:244-246. 9. Dyck PJ, O’Brien P, Bosch PE, Grant I, Burns T, Windebank A, 23. Verma A, Bradley WG. High-dose intravenous immunoglobulin Klein C, Haubenschild J, Peterson D, Norell J, Capelle S, Lodermeier therapy in chronic progressive lumbosacral plexopathy. Neurology K, Dyck P. S27.005. AAN Abstract 2006. 1994;44:248-250. 10. Dyck PJB, Engelstad J, Norell J, Dyck PJ. Microvasculitis in nondiabetic lumbosacral radiculoplexus neuropathy (LSRPN): similarity to the diabetic variety (DLSRPN). J Neuropathol Exp Neurol 2000;59:525-538. C-26 AANEM Course C-27

Lesions of the Lumbosacral Plexus

Kurt A. Jaeckle, MD Professor Departments of Neurology and Oncology Mayo Clinic Jacksonville, Florida

INTRODUCTION Typically, patients develop deep, aching pain located in the lateral or anterior neck, shoulder, or throat. The pain can be exacerbated Metastasis to the brachial or lumbosacral plexus is generally a late by cough, neck movement, and swallowing. Occasionally the stage complication of cancer. Patients often have concomitant, neck musculature may be tender. Neck pain from other causes is active systemic disease. The most commonly involved plexuses are common, therefore the diagnosis may be delayed until the pain the cervical, brachial, and lumbosacral plexus; the latter two are becomes severe and unrelenting and provokes further investiga- most frequently encountered in clinical practice. tion. The diagnosis is supported by the finding of palpable tumors within the region, or in situations where there is a known history of Table 1 lists common tumors associated with neoplastic plexopathy. tumor involving the head and neck or cervical chain lymph nodes. The frequency of neoplastic brachial plexopathy is 0.43% in cancer Sensory loss is often patchy and a vague tingling or numbness may patients; lumbosacral plexopathy occurs in approximately 0.71% of be present in the anterior neck region or over the upper clavicle and patients.16,21 The frequency is probably higher in breast carcinoma shoulder. Prior surgery, such as radical neck dissections, can make patients with 1.8%-4.9% of patients developing symptomatic interpretation of sensory symptoms difficult. Head and neck dis- plexopathy by 5 years following treatment.27,28,32 section usually affects superficial branches of the greater auricular nerve or the transverse cervical branches, producing numbness of the upper anterior neck and submandibular area, and there is a NEOPLASTIC PLEXOPATHY: CLINICAL SYNDROMES temporal relationship to the surgery. Cervical Plexopathy Involvement of the spinal accessory XI cranial nerve may affect the upper trapezius, producing shoulder weakness. There may be The cervical plexus is usually invaded by tumor from the neigh- phrenic nerve involvement, producing a paralyzed hemidiaphragm boring tissues. The cervical plexus is generally involved via direct with associated shortness of breath, particularly when the patient extension from soft or bony tissues in the case of head and neck lies recumbent. Chest radiograph or fluoroscopy with a “sniff” test tumors, or from regional lymph nodes involved by lymphoma or can confirm phrenic nerve involvement. metastases from distant organs. The most common tumors include squamous cell carcinoma of the head and neck, follicular and One important point to stress is that involvement of the cervical diffuse non-Hodgkin’s lymphomas, and metastases from adenocar- plexus implies proximity of the neoplasm to the cervical spine. It is cinomas of the lung and breast. important to suspect and rule out impending epidural spinal cord C-28 Lesions of the Lumbosacral Plexus AANEM Course

tions or as a late stage complication of radiotherapy to the region Table 1 Neoplastic Plexopathy Associated Cancers* of the plexus. BRACHIAL LUMBOSACRAL Tumor % Tumor % Lumbosacral Plexopathy Lung 37 Colorectal 20 Pelvic primary neoplasms, particularly colorectal malignancies, gy- Breast 32 Sarcoma 16 necologic malignancies, lymphoma, and retroperitoneal sarcomas Lymphoma 8 Breast 11 are most frequently associated with neoplastic lumbosacral plexopa- 16,30 Sarcoma 5 Lymphoma 9 thy (Figure 2). In patients who ultimately develop neoplastic plexopathy, 15% have plexus involvement at the time of presenta- Cervix 7 tion of the malignancy. Tumor can directly invade the plexus, or in- Others 18 Others 37 directly invade by tracking along the epineurium.11 This tendency to extend in a linear fashion along nerve trunks without necessarily 20 16 * Kor and colleagues; Jaeckle and colleagues. producing bulky disease, may explain the frequent initial discor- dance between the physical examination and the neuroimaging procedures (Ladha and colleagues, in press). involvement in this situation. If sharp pain occurs with neck move- ments, then spine percussion tenderness or Horner’s syndrome is Relatively distinct clinical syndromes of upper plexus (L1-L4), present and appropriate neuroimaging procedures (including the lumbosacral trunk (L4-L5), and lower plexus (S1-S4) have been cervical spine) are warranted. described.16 Plexopathy is usually clinically unilateral, but needle EMG suggests a bilateral component in up to 25% of patients. Brachial Plexopathy Many of these patients have received radiotherapy to the region, which probably accounts for the bilateral involvement detected only Lung and breast carcinomas most commonly are associated with on neurophysiologic evaluation in a portion of these patients. neoplastic brachial plexopathy21 (Figure 1). Earlier reports called attention to the frequent involvement of the lower plexus in this Lumbosacral plexopathy generally begins with leg pain, but within disorder, particularly the inferior trunk and medial cord, which is a month most patients will develop local numbness and weakness. presumably due to extension from the upper lung field or nodes Pain is so typical that its absence suggests an alternative cause of within the supraclavicular space or surrounding the plexus. This the focal neurologic dysfunction, and too often this turns out to be syndrome was first clearly described as the superior sulcus or due to neoplastic meningitis. As with brachial plexopathy, the pain “Pancoast” syndrome,26 which includes a palpable mass in the is constant, dull, and aching with superimposed sharp components supraclavicular or axillary area and involvement of the inferior or cramping in the lower extremity. Pain is often worse when the trunk or medial cord producing C8-T1 weakness in the hand and patient is supine or recumbent, but later in the course patients associated electromyographic (EMG) findings. However, more complain of the pain despite all alterations of their position. On recent publications have called attention to the involvement of the occasion, there is a crescendo pattern whereby the patient develops mid- or upper plexus, particularly when head and neck neoplasms increasing and severe pain in episodes lasting minutes to several or lymphomas grow inferiorly, invading the superior plexus from hours, only to remit for unclear reasons for intervening periods of above. Sometimes the pattern of plexus involvement includes skip relative comfort. This latter pain syndrome is particularly distress- or patchy areas, presumably due to irregular and random involve- ing to the patient and when episodes are frequent, patients may ment of different areas of the plexus proximally and distally. This express suicidal thoughts. Often this type of pain requires continu- is perhaps due to random distribution of metastases to local lymph ous administration of systemic opiate analgesics, and it is important nodes or soft tissues within the plexus and the axilla. that this complication not be undertreated. Irritation of the soft tissues of the paravertebral gutter and proximal iliopsoas muscle Pain is the most common presenting symptom (75%) in brachial may make patients rest with their legs and hips flexed, similar to plexopathy,21 and is usually located in the axilla and shoulder. that seen with meningeal inflammation. Pain is often exascerbated Radicular pain is typically located along the medial aspect of the by valsalva, weight bearing, or sitting for prolonged periods. arm and forearm, and the fourth and fifth digits. Motor weakness and reflex loss is commonly located (approximately 75%) in the Weakness and sensory complaints eventually occur develop in lower plexus distribution, especially C8-T1. Horner’s syndrome most patients (60%). The most common findings on neurologic occurs in 23% of patients with neoplastic brachial plexopathy, but examination include leg weakness (86%), sensory loss (73%), implies proximity of the tumor to the vertebral column and the asymmetrical reflex loss (64%), and edema of the extremity (47%). T1 level, and the potential of impending epidural involvement Patients may have positive straight leg and reverse-straight leg tests, by neoplasm. Lymphedema in the involved extremity is relatively and tenderness or pain induced by pressure in the sciatic notch and infrequent (15%), and is more typical of postsurgical node dissec- buttock or on rectal examination. AANEM Course New Insights in Lumbosacral Plexopathy C-29

Figure 1 Brachial plexopathy from lung adenocarcinoma. Magnetic resonance imaging, T1 nonenhanced image. Mass (arrows) in shoulder of patient with diffuse weakness in upper arm. C-30 Lesions of the Lumbosacral Plexus AANEM Course

Figure 2 Metastases to left upper lumbar paraspinal region and iliacus muscle (arrows) a patient with carcinoma of the cervix and left side lumbosacral plexopathy.

Rectal and cervical carcinomas typically are associated with lower between the true and false pelvis. This complication can be dis- plexus involvement. In this situation, pain typically radiates down tinguished from common peroneal neuropathy (also common in the posterior leg, calf or posterior thigh, and is associated with cachetic patients) by associated involvement of the posterior tibial cramping in the calf and often foot dorsiflexor weakness. Dalmau nerve with weakness of medial plantar flexors, which are typically and colleagues have described lateralized sympathetic denervation spared in peroneal neuropathy. Incontinence and impotence gener- producing a “hot dry foot.”10 ally implies bilateral plexus involvement, or associated meningeal or epidural metastases.16 Higher involvement of the lumbar plexus typically produces pain in the anterior thigh and foreleg with weakness of hip flexion. Typically patients will complain that they have to lift the involved DIAGNOSIS extremity onto the bed or out of the car. Numbness is usually in Neuroimaging Procedures the groin in the distribution of the ilioinguinal and iliohypogastric nerves, or the anterior or lateral femoral cutaneous nerve distributions. A positive reverse-straight leg raising test on the involved side Neuroimaging of the abdomen and pelvis with either magnetic raises suspicion of this level of involvement by stretching the ilio- resonance imaging (MRI) or computed tomography (CT) is ap- psoas and its insertion into the lateral processes of the upper lumbar propriate in patients with clinical symptoms or signs suggestive vertebrae, and can be useful (although not specific) for distinguish- of lumbosacral plexopathy. Magnetic resonance imaging has been ing this complication from neoplastic meningitis, which less com- shown to be more sensitive than CT in the identification of tumor monly is associated with a positive reverse-straight leg raising test. plexopathy.30,34,36 However, CT is necessary in patients where MRI The lumbosacral trunk syndrome includes foot drop and numbness is contraindicated. Computed tomography is a shorter procedure of the dorsum of the foot, and implies involvement of the plexus and can facilitate completion of the study in confused or agi- anterior to the sacral ala, over which the lumbosacral trunk courses, tated patients. Magnetic resonance imaging should be performed AANEM Course New Insights in Lumbosacral Plexopathy C-31 with and without contrast and include T2-weighted images. Occasionally, linear enhancement along one or more nerve trunks Table 2 Other Causes of Plexopathy in Cancer Patients resulting from tumor invasion is present in the absence of a mass. Increased T2 intensity within nerve trunks with or without en- Radiation plexopathy hancement has been identified in patients with neoplastic plexopathy.37 Even if the scan does not disclose clear plexus invasion, the Paraneoplastic plexopathy presence of a regional tumor recurrence, by clinical examination or Retroperitoneal hemorrhage imaging, supports the diagnosis of tumor plexopathy. For example, Post-infectious plexopathy most (95%) of patients with CT evidence of brachial plexus tumor Toxicity of chemotherapy have a palpable axillary mass.24 Epidural cord compression Positron emission tomography (PET) scans can also detect active Neoplastic meningitis neoplasm in the area of the plexus. This procedure is very helpful in screening for plexopathy in a patient with known metastatic disease, although not specific for neoplasm. In one study, 14 of 19 breast carcinoma patients with symptoms of brachial plexopathy Palliation of pain is an important part of management of patients had abnormal fluorodeoxyglucose uptake by PET in the area of with neoplastic plexopathy. Studies have shown that pain is often the plexus.1 poorly controlled in these patients. A multimodality approach is necessary, including appropriate use of opiate analgesics, local and Needle Electromyography regional blocks, infusion pumps or epidural opiate analgesia, and on occasion sympathetic ganglion blocks, rhizotomy, or other spe- Needle EMG can also supplement the neuroimaging studies. The cialized procedures. If the quality of the pain includes a causalgic distribution of active denervation often is more extensive than or dysesthetic component, gabapentin, tricyclic antidepressants, would have been predicted clinically. In addition, bilateral plexus carbamazepine, topirimate, valproic acid, or phenytoin may be involvement that is not suspected clinically can be identified. It helpful. Transcutaneous nerve stimulators may also provide relief should be remembered, however, that bilateral involvement is when the pain is localized. Occasional relief of chronic pain has more typical of neoplastic meningitis, which should also be con- been achieved with plexus dissection and neurolysis.33 sidered in these patients. Needle EMG can be helpful in following the clinical course after treatment, and is somewhat helpful The relative immobility produced by plexopathy can result in in distinguishing tumor plexopathy from radiation plexopathy. delayed complications, including painful contractures, compres- Finally, when planning radiation treatment ports, the distribution sive neuropathies, pressure ulcerations, respiratory or urinary of electrophysiologic involvement should be considered in addition tract infections, joint subluxations, and deep venous thromboses. to the neuroimaging findings, as occasionally these studies reveal Lymphedema may be treated with compressive devices and eleva- discordant results. tion. Preventative measures, including adequate pain management, initiation of physical rehabilitation measures, and excellent nursing care may have a significant impact on quality of life. TREATMENT Other Causes of Plexopathy in the Cancer Patient There is only limited published information regarding neurologic outcome following treatment of metastatic plexopathy. Other causes of plexopathy in cancer patients are listed in Table 2. Radiotherapy produced subjective improvement of symptoms The most frequent differential diagnostic consideration is radia- in 85% of patients with lumbosacral plexopathy and objective tion-induced plexopathy. Many patients receive radiotherapy to the improvement in 48%, which was defined as neurologic improve- area of the plexus in treatment of their primary neoplasm, and later ment or reduction in measurable tumor. The average duration of develop plexopathy that can be difficult to distinguish from tumor response, however, was only 4 months.35 In another study, treat- plexopathy. Both conditions may also be present in the patient. ment with radiotherapy (>3000 cGy) and systemic chemotherapy Radiation causes direct toxic effects on axons and delayed effects on (if indicated) produced subjective responses in 35% of patients, and the vascular supply to the nerve, with secondary microinfarction.14 objective responses as well (neurologic improvement - 17%; radio- This injury appears dose-related, and is generally not observed at graphic response - 28%).16 In a study involving patients with bra- doses below 1000 cGy. Histopathologic abnormalities occur in chial plexopathy due to tumor, radiotherapy relieved pain in 46% Schwann cells, endoneurial cells, and fibrocytes.8 Experimentally, of cases.21 Regional intra-arterial chemotherapy received limited use 3500 cGy produced anterior and posterior nerve root damage in a in earlier studies but was largely ineffective. rodent model.7 C-32 Lesions of the Lumbosacral Plexus AANEM Course

Figure 3 Radiation plexopathy. Edema (arrows) noted in region of right brachial plexus and upper arm in this patient with history of metastatic breast carcinoma.

There are several excellent prior studies describing the clinical risk was less than 1% when dose fractions of 2.2-2.5 Gy were features of radiation plexopathy.2,3,5,15,19,21,23,25,27,28,32,35 It should utilized, and total doses received were in the range of 34-40 Gy.13 be remembered that many of these studies were based on older It is not clear whether radiation damage to the plexus is enhanced radiation techniques, including orthovoltage therapy, and it is pre- by concomitant administration of chemotherapy; however, in one sumed that plexopathy was more common with this technique. In descriptive retrospective analysis, radiation plexopathy was present the older literature, the overall frequency of radiation plexopathy in 5% of breast cancer patients treated with radiotherapy versus 9% was approximately 1.8%-4.9%.27,28,32 Radiation plexopathy was in those receiving radiotherapy and chemotherapy.9 diagnosed in 2% of patients with stage III breast cancer at 5 years following treatment with 4500-5000 cGy.32 A 34-year follow-up of There are clinical features which help distinguish radiation plexop- 71 breast cancer patients receiving loco-regional radiotherapy at 57 athy from neoplastic plexopathy, although none are completely Gy identified clinically relevant brachial plexopathy in 12 (17%).17 specific. Radiation plexopathy often presents with dysesthesias and Typically, radiation plexopathy has its onset at 3 months to 14 numbness and often lymphedema, whereas pain is less common years, with a median of approximately 1.5 years.19,21 One recent (10%) at initial diagnosis.16 In tumor plexopathy, pain is usually review of breast cancer patients treated with supraclavicular lymph present at diagnosis and lymphedema is less common. The most node telecobalt irradiation found the median onset of plexopathy common symptoms in radiation plexopathy are weakness (60%), at 88 months, and determined that the risk of development of this numbness, and paresthesias (50%).35 Radiation brachial plexopathy complication remained linear throughout the remainder of the has been reported to affect the upper plexus more often (77%); in patient’s life.4 Radiation plexopathy has been reported to begin as tumor plexopathy, the lower plexus (75%) is more frequently af- long as 20 years following treatment.12 Radiation-induced lumbo- fected.21,23 Other reports describe diffuse involvement of the plexus sacral plexopathy most frequently develops between 12 months with radiation plexopathy.6 Radiation plexopathy generally is ac- and 5 years following treatment, with a range from 1 month to companied by additional evidence of radiation effects within neigh- 31 years; it is more commonly bilateral in this case than in tumor boring tissues.27 Often, skin telangectasias, atrophy, and induration plexopathy.2,35 This disorder has been reported at doses as low as of soft tissues may be noted on physical examination. Imaging 1700 cGy. In one review, the use of 2.2-4.58 Gy per fraction, studies may show fibrotic or other changes in organ parenchyma with total doses between 43.5-60 Gy, may be associated with an within the prior treatment port, such as the lung, marrow, and increased frequency of brachial plexus injury (1.7%-73%). The even osteonecrosis of bone in the local field. Edema of the associ- AANEM Course New Insights in Lumbosacral Plexopathy C-33

ated extremity can be seen from lymphatic obstruction (Figure 3). commonly associated with head and neck tumors and lymphoma; The course of progression is generally slower than with neoplastic brachial plexopathy is most common with breast and lung ad- plexopathy. In general, evidence of active systemic neoplasm, and enocarcinomas, and lumbosacral plexopathy generally is associ- in particular, tumor within the region of the involved plexus in- ated with colorectal adenocarcinomas, gynecologic malignancies, creases the risk of the plexopathy being due to neoplasm.36 lymphomas and retroperitoneal sarcomas. Typically, neoplastic plexopathy often presents with unrelenting pain followed by weak- Diagnostic studies can also help aid in the distinction. Myokymia ness and numbness in the distribution of plexus involvement. The can be identified on needle EMG in approximately 60% of patients distribution and associated findings often allow clinical distinc- with a clinical diagnosis of radiation-induced plexopathy, but is less tion from peripheral nerve, epidural or meningeal involvement by common with tumor plexopathy.31 Neuroimaging can be helpful, tumor; however, these conditions do show symptom overlap and with MRI being the preferred technique.24,34 Neoplasm generally may co-exist in the same patient. The main differential diagnostic produces enhancement of nerve trunks, and there may be hyperin- consideration in previously treated patients is radiation-induced tensity within involved nerve on T2-weighted images. In radiation plexopathy. Treatment of metastatic plexopathy is palliative, and plexopathy, enhancement is less common, although patchy increase often includes a combination of radiotherapy to the tumor mass, in T2 signal may be present.30 There has been increasing use of appropriate chemotherapy for the tumor type, aggressive pain whole body 2-fluorodeoxyglucose PET as a detection method for management, and rehabilitative therapy to prevent complications systemic metastases, and this may be helpful as a companion study of immobility resulting from neuromuscular dysfunction. to anatomical imaging with MRI or CT, and may be more sensitive. In one study of 14 plexopathy patients, 6 had positive PET scans but normal CT imaging.1 REFERENCES

Most patients with radiation plexopathy require supportive care, 1. Ahmad A, Barrington S, Maisey M, Rubens RD. Use of positron and there is no specific treatment to date which has unequivocally emission tomography in evaluation of brachial plexopathy in breast been associated with benefit. There are only a few studies in the cancer patients. Br J Cancer 1999;79:478-482. literature which describe outcome following treatment. Limited 2. Ashenhurst EM, Quartey GR, Starreveld A. Lumbo-sacral radicu- recovery of motor function has been anecdotally observed follow- lopathy induced by radiation. Can J Neurol Sci 1977;4:259-263. ing anticoagulants. Hyperbaric oxygen has been used, but no large 3. Bagley FH, Walsh JW, Cady B, Salzman FA, Oberfield RA, Pazianos randomized prospective trials have been reported. A study of 34 AG. Carcinomatous versus radiation-induced brachial plexus neuropathy in breast cancer. Cancer 1978;41:2154-2157. patients treated with hyperbaric oxygen for clinically diagnosed 4. Bajrovic A, Rades D, Fehlauer F, Tribius S, Hoeller U, Rudat V, et radiation plexopathy showed no benefit in motor function, and no 29 al. Is there a life-long risk of brachial plexopathy after radiotherapy evidence of delay in the progression of the plexopathy. of supraclavicular lymph nodes in breast cancer patients? Radiother Oncol 2004;71:297-301. There are also other causes of plexopathy in cancer patients. 5. Basso-Ricci S, della Costa C, Viganotti G, Ventafridda V, Zanolla R. Paraneoplastic plexopathy has been described and may partially Report on 42 cases of postirradiation lesions of the brachial plexus respond to steroid therapy in some cases.22 Intra-arterial chemo- and their treatment. Tumori 1980,66:117-122. therapy has also produced plexopathy.18 Of course, patients with 6. Boyaciyan A, Oge AE, Yazici J, Aslay I, Baslo A. Electrophysiological cancer may development plexopathy that might otherwise appear findings in patients who received radiation therapy over the brain noncancer patients, such as those with a postinfectious or chial plexus: a magnetic stimulation study. Electroencephalogr Clin posttraumatic etiology. Hemorrhage into the retroperitoneum or Neurophysiol 1996;101:483-490. 7. Bradley WG, Fewings JD, Cumming WJ, Harrison RM. Delayed my- iliopsoas muscle may affect the lumbosacral plexus, and can be eloradiculopathy produced by spinal X-irradiation in the rat. J Neurol observed in association with anticoagulation or thrombocytopenia Sci 1977;31:63-82. resulting from chemotherapy, or in association with hematologic 8. Cavanaugh JB. Prior x-irradiation and the cellular response to nerve malignancies. Since patients with metastatic systemic cancer often crush: duration of effect. Exp Neurol 1968;22:253-258. have more than one site of nervous system involvement, one must 9. Dale E, Olsen DR. Regarding, Ting, IJROBP 38:1105-1111. Int J always consider the possibility of concomitant leptomeningeal or Radiat Oncol Biol Phys 1998;40:1010-1011. epidural metastases, which can have a similar clinical appearance. 10. Dalmau J, Graus F, Marco M. “Hot and dry foot” as initial manifesta- tion of neoplastic lumbosacral plexopathy. Neurology 1989;39:871- 872. Summary 11. Ebner I, Anderl H, Mikuz G, Frommhold H. Plexus neuropathy: tumor infiltration or radiation damage. Rofo 1990,152:662-666. 12. Fathers E, Thrush D, Huson SM, Norman A. Radiation-induced Metastatic (neoplastic) plexopathy is usually a late stage, disabling brachial plexopathy in women treated for carcinoma of the breast. accompaniment of systemic cancer. Cervical plexopathy is most Clin Rehabil 2002;16:160-165. C-34 Lesions of the Lumbosacral Plexus AANEM Course

13. Galecki J, Hicer-Grzenkowicz J, Grudzien-Kowalska M, Michalska T, 27. Pierce SM, Recht A, Lingos TI, Abner A, Vicini F, Silver B, Herzog Zalucki W. Radiation-induced brachial plexopathy and hypofraction- A, Harris JR. Long-term radiation complications following conser- ated regimens in adjuvant irradiation of patients with breast cancer--a vative surgery (CS) and radiation therapy (RT) in patients with early review. Acta Oncol 2006;45:280-284. stage breast cancer. Int J Radiat Oncol Biol Phys 1992;23:915-923. 14. Greenfield MM, Stark GM. Post-irradiation neuropathy. AJR Am J 28. Powell S, Cooke J, Parsons C. Radiation-induced brachial plexus Roentgenol 1948;60:617-622. injury: follow-up of two different fractionation schedules. Radiother 15. Harper CM, Thomas JE, Cascino TL, Litchy WJ. Distinction Oncol 1990;18:213-220. between neoplastic and radiation-induced brachial plexopathy, with 29. Pritchard J, Anand P, Broome J, Davis C, Gothard L, Hall E, emphasis on the role of EMG. Neurology 1989;39:502-506. Maher J, McKinna F, Millington J, Misra VP, Pitkin A, Yarnold JR. 16. Jaeckle KA, Young DF, Foley KM. The natural history of lumbosa- Double-blind randomized phase II study of hyperbaric oxygen in cral plexopathy in cancer. Neurology 1985;35:8-15. patients with radiation-induced brachial plexopathy. Radiother Oncol 17. Johansson S, Svensson H, Larsson LG, Denekamp J. Brachial 2001;58:279-286. plexopathy after postoperative radiotherapy of breast cancer pa- 30. Qayyum A, MacVicar AD, Padhani AR, Revell P, Husband JE. tients--a long-term follow-up. Acta Oncol 2000;39:373-382. Symptomatic brachial plexopathy following treatment for breast 18. Kahn CE Jr, Messersmith RN, Samuels BL. Brachial plexopathy as cancer: utility of MR imaging with surface-coil techniques. Radiology a complication of intraarterial cisplatin chemotherapy. Cardiovasc 2000;214:837-842. Intervent Radiol 1989;12:47-49. 31. Roth G, Magistris MR, Le Fort D, Desjacques P, Della Santa D. 19. Killer HE, Hess K. Natural history of radiation-induced brachial [Post-radiation branchial plexopathy. Persistent conduction block. plexopathy compared with surgically treated patients. J Neurol Myokymic discharges and cramps.] Rev Neurol (Paris) 1988;144:173- 1990;237:247-250. 180. 20. Kori SH. Diagnosis and management of brachial plexus lesions in 32. Sheldon T, Hayes DF, Cady B, Parker L, Osteen R, Silver B, Recht cancer patients. Oncology (Williston Park) 1995;9:756-760. A, Come S, Henderson IC, Harris JR. Primary radiation therapy for 21. Kori SH, Foley KM, Posner JB. Brachial plexus lesions in patients locally advanced breast cancer. Cancer 1987;60:1219-1225. with cancer: 100 cases. Neurology 1981;31:45-50. 33. Sundaresan N, DiGiacinto GV. Antitumor and antinociceptive ap- 22. LaChance VH, O’Neill BP, Harper CM Jr, Banks PM, Cascino proaches to control cancer pain. Med Clin North Am 1987;71:329- TL. Paraneoplastic brachial plexopathy in a patient with Hodgkin’s 348. disease. Mayo Clin Proc 1991;66:97-101. 34. Taylor BV, Kimmel DW, Krecke KN, Cascino TL. Magnetic reso- 23. Mondrup K, Olsen NK, Pfeiffer P, et al. Clinical and electrodiagnos- nance imaging in cancer-related lumbosacral plexopathy. Mayo Clin tic findings in breast cancer patients with radiation-induced brachial Proc 1997;72:823-829. plexus neuropathy. Acta Neurol Scand. 1990, 81:153-8. 35. Thomas JE, Cascino TL, Earle JD. Differential diagnosis between 24. Moskovic E, Curtis S, A’Hern RP, Harmer CL, Parsons C. The role radiation and tumor plexopathy of the pelvis. Neurology 1985;35:1- of diagnostic CT scanning of the brachial plexus and axilla in the 7. follow-up of patients with breast cancer. Clin Oncol (R Coll Radiol) 36. Thyagarajan D, Cascino T, Harms G. Magnetic resonance imaging in 1992;4:74-77. brachial plexopathy of cancer. Neurology 1995;45:421-427. 25. Olsen NK, Pfeiffer P, Mondrup PK, Rose C. Radiation-induced 37. Wouter van Es H, Engelen AM, Witkamp TD, Ramos LM, Feldberg brachial plexus neuropathy in breast cancer patients. Acta Oncol MA. Radiation-induced brachial plexopathy: MR imaging. Skeletal 1990;29:885-90. Radiol 1997;26:284-288. 26. Pancoast HK. Superior pulmonary sulcus tumor. J Am Med Assoc 1932;99:1391-1396. AANEM Course C-35

New Insights in Lumbosacral Plexopathy CME SELF-ASSESSMENT TEST

Select the ONE best answer for each question.

Instructions for filling out your parSCORE sheet

On the right-hand side of the parSCORE sheet, you will need to fill in the following:

Under ID number, please write out and fill 1 2 3 4 in the last 4 digits of your phone number. Last 4 digits of Be sure to start in the first box on the left your phone number (as shown).

Under Test Form, please fill in “A”.

Leave the completed form at the table outside your session. Fill in answers here

1. The lumbosacral trunk contains nerve fibers that can best be 3. The electrodiagnostic examination cannot easily distinguish described as primarily: which of the following pairs of diagnoses? A. Peroneal. A. Sacral plexopathy and tibial neuropathy. B. Tibial. B. Sacral plexopathy and sciatic neuropathy. C. Femoral. C. Sacral plexopathy and S1 radiculopathy. D. L5. D. Lumbar plexopathy and L3 radiculopathy. E. S1. E. Lumbar plexopathy and lumbosacral trunk lesion.

2. The typical findings on nerve conduction study (NCS) in a 4. Sacral plexopathy can be distinguished from sciatic neuropathy patient with a common peroneal neuropathy are identical to when which of the following muscles demonstrates fibrillation those in which of the following conditions? potentials? A. Lumbosacral trunk lesion. A. Biceps femoris short head. B. L5 radiculopathy. B. Biceps femoris long head. C. S1 radiculopathy. C. Tensor fascia lata. D. Sacral plexopathy. D. Semitendinosus. E. Lumbar plexopathy. E. Semimembranosus. C-36 CME Self-Assessment Test AANEM Course

5. One reliable method for obtaining the saphenous sensory 12. It is important to treat diabetic and nondiabetic lumbosacral response uses recording electrodes in which of the following plexopathies because: locations: A. Pain can be disabling. A. Over the medial mid-thigh. B. Weakness can be severe and lead to difficulty with ambu- B. Anterior to the medial malleolus. lation. C. Anterior to the lateral malleolus. C. Progressive phase of the disease may be prolonged. D. Over the mid-anterior thigh. D. Treatment may be effective. E. Over the lateral thigh. E. All of the above.

6. The underlying pathology in lumbosacral radiculoplexus 13. Treatment of diabetic lumbosacral plexopathy with which (LRPN) is: agents has been shown to be useful in anecdotal reports: A. The result of chronic hyperglycemia. A. Steroids (prednisone or methyl-prednisolone) and intra- B. The result of ischemic injury from microvasculitis. venous immunoglobulin (IVIg). C. The result of ischemic injury caused by damaged endo- B. Plasma exchange and IVIg. neurial vessels from chronic hyperglycemia. C. Steroids and plasma exchange. D. The result of compressive injury. D. Steroids and interferons. E. None of the above. E. IVIg and interferons.

7. LRPN and diabetic lumbosacral radiculoplexus neuropathy 14. A recent randomized, double-blind, multicenter study investi- (DLRPN) are alike in the following ways: gating the effect of intravenous methylprednisolone in treating A. Both usually begin with pain. diabetic lumbosacral plexopathy demonstrated: B. Weakness usually follows pain but becomes the primary A. Improvement in neuropathy impairment scores in the problem in both. lower limbs. C. Sensory symptoms and findings are common in both. B. Improvement in pain and positive neuropathy symp- D. Both syndromes begin focally but become more wide toms. spread. C. Improvement in weakness and disability. E. All of the above. D. Lack of efficacy in regards to pain, positive neuropathy symptoms and neuropathy impairment scores. 8. In LRPN, the anatomical site exclusively involved by the E. Worsening of neuropathy related to treatment. pathological process is: A. The lumbosacral roots. 15. Lack of improvement in neuropathy impairement scores with B. The lumbosacral plexus. methylprednisolone in treating diabetic lumbosacral plexopa- C. The proximal lower extremity nerves. thy, seen in the controlled trial may be related to: D. The distal lower extremity nerves. A. Inadequate dose of methylprednisolone. E. All of the above. B. Shorter duration of treatment. C. Worsening of diabetes with steroid use. 9. In LRPN, there are occasionally associated upper limb neu- D. Delay in the institution of treatment. ropathies and thoracic radiculopathies: E. Lack of aggressive treatment of diabetes. A. True. B. False. 16. Generally, brachial plexopathy due to tumor invasion occurs in the setting of: 10. Immunosuppressant medications and steroids have been A. Widespread metastases. shown in controlled trials to be effective treatment in LRPN: B. Localized disease. A. True. C. Disease in remission. B. False. D. Known brain metastases. E. None of the above. 11. Immunosuppressive treatments should be considered in the treatment of diabetic and nondiabetic lumbosacral radiculo- 17. If a patient with brachial plexopathy due to cancer also has an plexus neuropathy because pathogenesis is related to: ipsilateral Horner’s syndrome, the most important and likely A. Diabetic microangiopathy. associated condition that one must exclude is/are: B. Microvasculitis. A. Brain metastasis. C. Nerve infarction. B. Leptomeningeal metastases. D. Metabolic abnormalities. C. Paravertebral tumor with epidural extension. E. Inflammation. D. Use of opiate analgesics. E. None of the above. AANEM Course CME Self-Assessment Test C-37

18. Lumbosacral plexopathy due to tumor most typically presents 20. In a cancer patient who has undergone prior radiotherapy with: and has no obvious mass lesion on imaging in the area of the A. Weakness in the leg. plexus, one of the features on magnetic resonance imaging B. Numbness in the leg. which is of relative help in the distinction of plexus invasion C. Pain. by tumor from radiation plexopathy is the presence of: D. Incontinence. A. Epidural metastases. E. All of the above. B. Vertebral invasion. C. T2 hyperintensities in the trunks of the plexus. 19. Radiation plexopathy, as compared with tumor plexopathy, D. Enhancement in the trunks of the plexus. can be implicated by the needle electromyographic finding E. None of the above. of: A. Sharp waves. B. Brief short amplitude multiphasic potentials. D. Myokymia. D. Myotonic discharges. E. None of the above. C-38 AANEM Course

C-39

New Insights in Lumbosacral Plexopathy

EVALUATION

Select ANY of the answers that indicate your opinions.

Your input is needed to critique our courses and to ensure that we use the best faculty instructors and provide the best course options in future years. Make additional comments or list suggested topics or faculty for future courses on the comment form provided at the end of this handout.

21. How would you rate the quality of instruction received during 26. Did you perceive any commercial bias in Dr. Said’s presenta- Dr. Levin’s presentation? tion? A. Best possible. A. Yes. B. Good. B. No. C. Average. D. Poor. 27. How would you rate the quality of instruction received during E. Worst possible. Dr. Dyck’s presentation? A. Best possible. 22. Select any item(s), that, if changed, would have appreciably B. Good. improved Dr. Levin’s presentation: C. Average. A. Quality of slides. D. Poor. B. Quality of handout. E. Worst possible. C. Amount of clinically relevant information in the presentation. 28. Select any item(s), that, if changed, would have appreciably D. Amount of scientific content in the presentation. improved Dr. Dyck’s presentation: E. Other: please explain on the comment form at the back of A. Quality of slides. this handout. B. Quality of handout. C. Amount of clinically relevant information in the presenta- 23. Did you perceive any commercial bias in Dr. Levin’s presentation. tion? D. Amount of scientific content in the presentation. A. Yes. E. Other: please explain on the comment page at the back of B. No. this handout.

24. How would you rate the quality of instruction received during 29. Did you perceive any commercial bias in Dr. Dyck’s presenta- Dr. Said’s presentation? tion? A. Best possible. A. Yes. B. Good. B. No. C. Average. D. Poor. 30. How would you rate the quality of instruction received during E. Worst possible. Dr. Muley’s presentation? A. Best possible. 25. Select any item(s), that, if changed, would have appreciably B. Good. improved Dr. Said’s presentation: C. Average. A. Quality of slides. D. Poor. B. Quality of handout. E. Worst possible. C. Amount of clinically relevant information in the presentation. D. Amount of scientific content in the presentation. E. Other: please explain on the comment page at the back of this handout. C-40 Evaluation AANEM Course

31. Select any item(s), that, if changed, would have appreciably 38. Select ALL items where improvement was needed. improved Dr. Muley’s presentation: A. The accuracy of advance descriptions of this course. A. Quality of slides. B. The specific topics selected for presentation. B. Quality of handout. C. The number of speakers in this course. C. Amount of clinically relevant information in the presenta- D. The amount of time allotted for discussion in this tion. course. D. Amount of scientific content in the presentation. E. Other: please add other areas and outline specific rec- E. Other: please explain on the comment page at the back of ommendations for areas needing improvement on the this handout. comment page at the back of this handout.

32. Did you perceive any commercial bias in Dr. Muley’s presenta- 39. I plan to attend the 2007 AANEM Annual Meeting in tion? Phoenix, AZ October 17-20. A. Yes. A. Yes, definitely. B. No. B. No, definitely. C. Will wait to see the program content. 33. How would you rate the quality of instruction received during D. Will wait to see if budget allows my attendance. Dr. Jaeckle’s presentation? A. Best possible. 40. We would like the AANEM Annual Meeting to be one of B. Good. your “must attend” meetings each year. In order to do this, we C. Average. would have to do what to make it happen? Please explain on D. Poor. the comment page at the back of this handout. E. Worst possible. 41. If you are a member of the AANEM, what would you rate as 34. Select any item(s), that, if changed, would have appreciably the most valuable benefit of your membership? improved Dr. Jaeckle’s presentation: A. My subscription to the journal Muscle & Nerve. A. Quality of slides. B. Receiving free educational materials such as the Muscle & B. Quality of handout. Nerve Invited Reviews and the AANEM Resource CD. C. Amount of clinically relevant information in the presenta- C. The availability of CME opportunities. tion. D Member discounts on AANEM CME products and ser- D. Amount of scientific content in the presentation. vices. E. Other: please explain on the comment page at the back of E. AANEM’s advocacy work on issues that impact my pro- this handout. fession.

35. Did you perceive any commercial bias in Dr. Jaeckle’s presenta- 42. In 2006, the AANEM distributed 6 bound copies of the tion? Muscle & Nerve Invited Reviews. How would you rate this new A. Yes. member benefit? B. No. A. Very valuable. B. Somewhat valuable. 36. As a result of your attendance at this educational session, did C. Not very valuable. you learn anything that will improve the care of your pa- D. I do not receive this since I am not an AANEM tients? member. A. Yes, substantially. E. Other: please explain on the comment page at the back of B. Yes, somewhat. this handout. C. Not sure. D. Probably not. E. This session was not applicable to my patients.

37. Do you feel that the information presented in this session was based on the best evidence available? A. Yes. B. No: please explain on the comment page at the back of this handout. AANEM Course Evaluation C-41

43. When you receive the bound copies of the Muscle & Nerve 45. The AANEM has recently launched new Marketing Slides on Invited Reviews, you can visit the AANEM website and the website that can assist EDX physicians in marketing to complete CME questions to receive a certificate at no charge. referral sources. How would you rate this member benefit? Have you utilized this new service? A. Very valuable. A. Yes, I have completed CME for the Invited Reviews B. Somewhat valuable. online and found the system easy to utilize. C. Not very valuable. B. Yes, I have completed CME for the Invited Reviews D. I have not reviewed the marketing slides yet. online, but found the system difficult to utilize. E. Other: please explain on the comment page at the back of C. No, I have not utilized this service because I was unaware this handout. it was available. D. No, I have not utilized it although I was aware of its availability: please explain on the comment page at the back of this handout. E. Other: please explain on the comment page at the back of this handout.

44. In 2006, the AANEM added Online Case Studies to the website which are also available for CME credit. How would you rate this new member benefit? A. Very valuable. B. Somewhat valuable. C. Not very valuable. D. I was not aware that this was available on the AANEM website. E. Other: please explain on the comment page at the back of this handout.

Muscle and Nerve Pathology

Arthur P. Hays, MD Anthony A. Amato, MD Kurenai Tanji, MD, PhD Annabel K. Wang, MD

2006 COURSE D AANEM 53rd Annual Meeting Washington, DC

Printed by Johnson Printing Company, Inc. D-ii

Muscle and Nerve Pathology

Faculty

Arthur P. Hays, MD Kurenai Tanji, MD, PhD Director Assistant Professor Laboratory of Neuromuscular Pathology Department of Clinical Pathology Columbia University Medical Center Columbia University Medical Center New York, New York New York, New York Dr. Hays earned his medical degree at the University of Colorado in Dr. Tanji stepped into the clinical research of mitochondrial diseases in Denver, and went on to specialize in pathology. He is certified in neu- 1991 as a postdoctoral research fellow from Japan at Columbia University’s ropathology by the American Board of Pathology. He is currently the Department of Neurology, led by Drs. L.P. Rowland and S. DiMauro. Her director of the Laboratory of Neuromuscular Pathology at New York primary project was related to muscle biology in Duchenne and Becker Presbyterian Hospital, and an associate professor of clinical neuropathol- muscular dystrophies, but she simultaneously developed a great interest ogy in the College of Physicians and Surgeons at Columbia University. in mitochondrial diseases. After the fellowship, Dr. Tanji remained in He has trained many fellows in clinical research, and belongs to several the mitochondrial research group to concentrate her efforts on clinical societies, including the American Association of Neuropathologists, the research, particularly the correlation between mitochondrial genetics and New York Pathological Society, and the Peripheral Nerve Society. Dr. Hays tissue morphology in various mitochondrial encephalomyopathies. She is also an ad hoc reviewer for Neurology and the Journal of Neurological subsequently took the pathology residency and neuropathology fellow- Sciences. ship at Columbia’s Department of Pathology and became an attending neuropathologist in 2004. Her current interests include the dysfunctional blood-brain barrier in mitochondrial encephalomyopathies, especially Anthony A. Amato, MD Leigh syndrome and mitochondrial myopathy, encephalopathy, lactic Vice Chairman acidosis, and stroke-like episodes. Department of Neurology Brigham and Women’s Hospital Annabel K. Wang, MD Boston, Massachusetts Assistant Professor Dr. Amato is the vice-chairman of the Department of Neurology, the chief Department of Neurology of the Neuromuscular Division, and the director of the neuromuscular medicine fellowship at Brigham and Women’s Hospital in Boston. He Mount Sinai Medical Center is also an associate professor of neurology at Harvard Medical School. New York, New York Dr. Amato is an author or co-author of over 125 articles, chapters, and Dr. Wang is an assistant professor in the Department of Neurology at the books. He has been involved in clinical research trials involving patients Mount Sinai Medical Center in New York City. She received her bachelor with amyotrophic lateral sclerosis, peripheral neuropathies, neuromuscular of science degree in neurobiology and her medical degree from McGill junction disorders, and myopathies. University in Montréal, Canada. In addition to the pathology of motor neuropathies, she is interested in the somatic and autonomic neuropathies of disorders such as diabetes and amyloidosis. She is currently a Hartford Center of Excellence Scholar in Geriatrics and a Reynolds’ Master Clinician Educator in Geriatrics.

Dr. Hays is a consultant for Therapath, a company that performes epidermal nerve fiber analysis (skin) biopsies. Other authors had nothing to disclose.

Course Chair: Arthur P. Hays, 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. D-iii

Muscle and Nerve Pathology

Contents

Faculty i

Objectives ii

Course Committee iv

Muscle and Nerve Biopsy: An Introduction 1 Arthur P. Hays, MD

Histopathology of Muscular Dystrophies 7 Anthony A. Amato, MD

Pathology of Muscle in Mitochondrial Disorders 27 Kurenai Tanji, MD, PhD

Pathology of Motor Nerve Biopsy 37 Annabel K. Wang, MD

CME Self-Assessment Test 41

Evaluation 45

O b j e c t i v e s —After attending this course, participants will understand muscle and nerve biopsy and the histopathology of muscular dystrophies. The pathology of muscle in mitochondrial disorders as well as the pathology of motor nerve biopsy will also be discussed. P rerequisite —This course is designed as an educational opportunity for residents, fellows, and practicing clinical EDX physicians at an early point in their career, or for more senior EDX practitioners who are seeking a pragmatic review of basic clinical and EDX principles. It is open only to persons with an MD, DO, DVM, DDS, or foreign equivalent degree. A c c r e d i tat i o n S tat 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 C r e d i t —The AANEM designates this activity for a maximum of 3.25 hours in AMA PRA Category 1 Credit(s)TM. This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he or she actually spent in the educational activity. CME for this course is available 10/06 - 10/09.

2005-2006 AANEM COURSE COMMITTEE Kathleen D. Kennelly, MD, PhD Jacksonville, Florida

Thomas Hyatt Brannagan, III, MD Dale J. Lange, MD Jeremy M. Shefner, MD, PhD New York, New York New York, New York Syracuse, New York

Hope S. Hacker, MD Subhadra Nori, MD T. Darrell Thomas, MD San Antonio, Texas Bronx, New York Knoxville, Tennessee

Kimberly S. Kenton, MD Bryan Tsao, MD Maywood, Illinois Shaker Heights, Ohio

2005-2006 AANEM PRESIDENT Janice M. Massey, MD Durham, North Carolina Muscle and Nerve Biopsy: An Introduction

Arthur P. Hays, MD Director Laboratory of Neuromuscular Pathology Columbia University Medical Center New York, New York

INTRODUCTION cells and other artifacts and can render it useless for enzyme histochemical analysis. It is recommended that the tissue be wrapped in Muscle and nerve biopsies are performed in patients with neuro- a piece of gauze or surgical tefla that is barely moistened to prevent muscular disorders.33 The pathological findings may be diagnostic drying. Once the sample is removed surgically it must be kept cold (e.g., a necrotizing arteritis) and provide a basis for proper clini- during transportation using regular ice or cold packs. Fourth, in cal management. Unfortunately, biopsies are often nonspecific or the case of muscle as well as nerve, the procedure requires an open supply limited information. The yield of a biopsy is significantly biopsy rather than a needle biopsy, to provide an adequate sample influenced by the quality of the tissue, sample size, and site of surgi- size. Sample size is a major issue in focal disorders such as derma- cal removal, and it is worthwhile to restate a few general principles tomyositis or necrotizing arteritis, and requires generous sampling. to guide physicians at each step of the procedure.31,33 In addition, specimens should be submitted for routine histology, electron microscopy (EM), and biochemical analysis. Biochemical First, expert physicians recommend a muscle or nerve biopsy only assay and deoxyribonucleic acid (DNA) analysis have become es- after thorough clinical and laboratory evaluation of the patient, sential for the diagnosis of inherited disorders and require a cube including electrodiagnostic (EDX) studies. Second, the site of the of tissue about 1 cm in each dimension that is frozen immediately, biopsy should be selected using the clinical and electrophysiologi- preferably in liquid nitrogen. Finally, the physician formulates cal findings to maximize diagnostic yield. The general rule for both a preliminary diagnosis and informs the pathologist to perform muscle and nerve is to choose a biopsy specimen that is affected analysis of the sample using special histochemistry and immuno- clinically, but that is not severe, in order to avoid end-stage tissue. histochemistry, as well as other methods. If these special methods Third, the surgeon or physician who performs the biopsy must be are not available locally, the service may be provided at a regional experienced and provide tissue of good quality. In particular, the research center. tissue should never be submerged in saline.31 Surgeons are often trained to place tumor specimens into a jar of saline prior to providing a frozen section diagnosis. In some instances, surgeons are MUSCLE BIOPSY familiar with the proper handling of the muscle and nerve, but then the specimen is transferred to a general pathologist who may then The three major goals of a muscle biopsy are to (1) distinguish place it into a jar of saline before sending it to a neuromuscular between a myopathy from a neurogenic disorder; (2) screen my- laboratory. Exposure of tissue to an excess of saline causes lysis of opathies for inherited disorders to direct biochemical analysis and D- Muscle and Nerve Biopsy: An Introduction AANEM Course achieve a molecular diagnosis, and (3) identify acquired disorders of muscle with the exception of debrancher enzyme deficiency in of muscle with particular emphasis on treatable disorders such as adults who have slowly progressive weakness and marked accu- polymyositis and dermatomyositis. mulation of glycogen in the subsarcolemmal region. Fortunately, the most common disorder in this group is myophosphorylase Inherited Disorders deficiency (McArdle disease), which can be tested by a simple histochemical stain of muscle. Most patients have clinical manifestations Genetic defects affecting muscle fall into three major groups based of exercise intolerance, such as cramps and myalgia, but a minority on the muscle biopsy. The first group includes the muscular dys- have persistent weakness or elevated serum creatine kinase (hyper- trophies. These disorders often show increased variation of muscle CKemia) activity with no muscle symptoms. The histochemical fiber size, necrotic fibers, regenerating fibers, and fibrosis of the reaction for phosphorylase should be performed in this clinical endomysium.10,22 setting. It also should be considered by pathologists as a screening procedure in all muscle biopsies that are not definitive, particularly The second group consists of the congenital myopathies and is with little or no abnormalities.19,26 The diagnosis requires confir- defined by morphological distinctive alterations within muscle mation by biochemical assay of the enzyme or by documentation fibers such as nemaline rods, central cores, numerous fibers with of a PGYM gene mutation. If phosphorylase activity is normal, central nuclei (myotubular myopathy), and others.10,22 These dis- the frozen muscle should be subjected to additional biochemical orders usually appear in infants with hypotonia, but rarely present analysis of other enzymes involved in glycogen or lipid metabolism in children or adults. Central core disease is normally inherited in depending on the patient’s clinical symptoms. an autosomal dominant pattern, myotubular myopathy is x-linked, and nemaline myopathy is either autosomal recessive or autosomal The physician can strongly suspect adult-onset acid maltase defi- dominant. As a rule, muscle biopsy in congenital myopathies is ciency by the clinical features, needle electromyography examina- often associated with predominance and atrophy of type 1 fibers tion (complex repetitive discharges and other features), and the and does not exhibit necrotic fibers, regenerating fibers, or fibrosis presence of glycogen storage within lysosomes of muscle biopsy of the endomysium. Deoxyribonucleic acid analysis of such patients specimens.23 However, adult-onset acid maltase may not be typical is gradually becoming available in commercial laboratories and re- and may mimic polymyositis or a muscular dystrophy. In patients search centers for molecular diagnosis. The name and addresses of with adult-onset acid maltase deficiency, the muscle biopsy shows these laboratories are provided at www.genetests.org. At this time, variable accumulation of glycogen within lysosomes. These appear gene sequencing is available for nemaline myopathy, central core as a few vacuoles that are distributed throughout the cytoplasm. In disease, x-linked myotubular myopathy, and certain others. some cases the biopsy may not display overt glycogen accumulation by routine histology in paraffin sections or frozen sections. A third group of inherited disorders of muscle result in defects of However, the muscle provides a clue to this disorder if there is intermediary metabolism and include disorders of glycogen and an increase in the size and number of lysosomes based on the lipid metabolism.9,19,32 Clinical presentations are quite variable, but histochemical stain of the lysosomal enzyme, acid phosphatase. most patients with muscle symptoms exhibit either exercise intol- Electron microscopic examination can offer additional evidence erance or progressive weakness. The muscle biopsy often provides of adult-onset acid maltase deficiency by displaying accumulation a clue to these inborn errors by demonstrating accumulation of of membrane-bound glycogen particles. The diagnosis requires glycogen, triglyceride, or mitochondria in muscle fibers. In general, confirmation by biochemical assay of the muscle enzyme or by the muscle biopsy does not exhibit necrotic fibers, regenerating documentation of a mutation of the GAA gene. fibers, or fibrosis of the endomysium. One exception to this rule exists in muscle biopsies of patients with exercise intolerance when Muscle biopsy plays an especially important role in mitochondrial vigorous activity triggers acute breakdown of muscle fibers (so- disorders.32 Ragged red fibers are the hallmark of mitochondrial called rhadomyolysis). If the physician suspects that the patient has DNA mutations, but the recognition of this alteration is only the an inherited disorder during an episode of exercise-induced symp- first step in the full pathological workup of muscle. Analysis of the toms, the muscle biopsy should be delayed for at least 1 month to oxidative enzymes, succinate dehydrogenase (complex II), and cy- allow myofiber regeneration to restore a normal or nearly normal tochrome c oxidase (complex IV) are essential to assess mitochon- structure. The delay facilitates biochemical analysis of the tissue as dria in more detail. The results may help to narrow the possibilities the results are easier to interpret in muscle without superimposed and direct molecular analysis of enzymes and DNA. acute muscle fiber necrosis and reactive changes. Acquired Disorders In disorders of glycogenolysis (deficiency of phosphorylase or debrancher enzyme) or glycolysis (deficiency of phosphofructokinase The most important group of acquired disorders are the inflamma- and other enzymes of the pathway that lead to lactic acid), glyco- tory myopathies. These can subclassified into three major groups; gen typically accumulates in the subsarcolemmal zone.19 Glycogen dermatomyositis, polymyositis, and inclusion body myositis storage is often too subtle to detect in paraffin or frozen sections (IBM).2,3,4,11,14,15,16,24 The first two disorders are thought to be AANEM Course Muscle and Nerve Pathology D- autoimmune disorders and respond to glucocorticoids and other noglobulins and complement components and can interfere with immunomodulatory treatments, although the target antigens are reliable interpretation. The findings in the other two procedures, not known. Inclusion body myositis may also be an autoimmune immunohistochemical analysis of MHC class I molecules and disorder, but it does not usually respond to therapy. In many cases, EM of blood vessels, are not completely specific but are strongly all three disorders are likely based on the clinical features, labora- supportive of the diagnosis of dermatomyositis. Limited literature tory tests, and EDX studies, but muscle biopsy is important to help suggests that both tests are specific and sensitive for diagnostic confirm the diagnosis before starting treatment, as therapy entails evaluation of muscle biopsies.7,43 The characteristic pathological potential adverse side effects. Rarely, the biopsy indicates some other findings of dermatomyositis may be seen also in weak patients with type of muscle disease, such as an inherited disorder. It is impor- systemic lupus erythematosus, mixed connective tissue disease, sys- tant to realize that roughly 20%-30% or more of muscle biopsies temic sclerosis, and rarely, other collagen vascular diseases. classified as inflammatory myopathies by clinical and laboratory testing do not show significant lymphocytic infiltration.14,18,24,41 In Polymyositis is uncommon in comparison to IBM and dermatomy- this instance, the biopsy findings expand the differential diagnosis ositis.3,41 T cells and histiocytes infiltrate chiefly the endomysium5,24 to include a side effect of a lipid-lowering medication (statin), and occasionally appear to invade nonnecrotic muscle fibers in the muscular dystrophy, and many others. Muscular dystrophy is context of MHC class I antigen expression in polymyositis.21 The tricky as occasionally the biopsy may be accompanied by significant invading T cells are CD8 positive and are activated as indicated by lymphocytic infiltration, most notably dysferlin deficiency, fa- expression of MHC class II antigens (HLA-DR)25 and other pro- cioscapulohumeral dystrophy, or merosin deficiency. The finding teins. In addition, nearly half of the cells that make contact with the of dysferlin deficiency (limb-girdle muscular dystrophy [LGMD], muscle fibers contain perforin, a molecule that plays a major role in LGMD type 2B, or Miyoshi myopathy) can lead to a misdiagnosis cytotoxicity.28 The findings suggest that the disorder is mediated by of polymyositis or IBM.3,27 T cells. Morphologically, the muscle biopsy demonstrates necrotic fibers and regenerating fibers that seem to be randomly distributed Dermatomyositis is believed to be an antibody-mediated disorder throughout the muscle.14,24 T cells and histiocytes predominate in and targets blood vessels.7,8,11,12,16,17,24,29 The vessels show pathologi- the endomysium with few, if any, B cells. The pattern of muscle cal signs of endothelial necrosis and regeneration with the eventual fiber injury, the type of lymphocytes, and inflammatory infiltration disappearance of capillaries, presumably resulting in ischemic of the endomysium help to distinguish this disorder from derma- injury of muscle fibers.7,12,17 Pathological evidence of vasculitis is tomyositis. Because polymyositis is usually a subacute disorder, well-described in autopsies in muscle, skin, and gastrointestinal there is often little evidence of chronic changes such as atrophic organs,8 but is rare in muscle biopsies. The findings in the biopsy fibers, hypertrophic fibers, or prominent endomysial fibrosis. In are extremely variable and range from normal to a clear multifocal addition, immunohistochemical stains of MHC class I antigens are disorder pathologically. Perifascicular atrophy of muscle fibers is helpful for diagnosis as most or all of the muscle fibers express these typical. The tissue sample rarely shows focal tissue infarcts, often molecules at the surface of muscle fibers, even in the absence of predominating along the edge of muscle fascicles in a perifascicular lymphocytes.21,34 This widespread immunostaining of MHC class fashion. The muscle may demonstrate little or no inflammatory I proteins in muscle fibers contrasts with the patchy, perifascicular cells as in other antibody-mediated disorders such as myasthenia pattern observed in dermatomyositis or the limited expression in gravis, acute motor axonal neuropathy, and anti-myelin associated noninflammatory myopathies. The interpretation of the biopsy in glycoprotein neuropathy. The inflammatory cells are significant polymyositis is a diagnosis by exclusion as the pathological findings perhaps in 60% of specimens, and they predominate in the peri- are characteristic, but not entirely specific.14 Similar muscle biopsy mysium. The inflammatory cells consist of chiefly B cells, CD4 T findings may be found in patients with collagen vascular disease cells, and histiocytes.6 and human immunodeficiency virus infection.

An uninformative biopsy in a patient with suspected dermato- Inclusion body myositis resembles polymyositis pathologically but myositis requires further pathological evaluation of the sample to is chronic and typically demonstrates small groups of atrophic provide supportive evidence of the diagnosis by demonstrating: (1) fibers, hypertrophic fibers, and endomysial fibrosis.4,6,13,14,15,30,38 deposits of membrane attack complex (C5b-9) in the walls of blood The abnormalities are not as evenly distributed as in polymyositis. vessels;20,35 (2) focal expression of major histocompatibility complex In addition, IBM displays characteristic rimmed vacuoles that are (MHC) class I antigen (HLA-ABC) at the surface membrane and occasionally associated with small eosinophilic inclusions. The within cytoplasm of muscle fibers, most pronounced at the edge of inclusions are weakly congophilic indicating that they represent an muscle fascicles;21,37 or (3) EM detection of tubuloreticular aggre- intracellular form of amyloid.6,39 The most distinctive congophilic gates in endothelial cells of blood vessels.7,17 Immunohistochemical inclusions have a fibrillar substructure and help to establish the stains of immune complexes are performed on frozen, unfixed diagnosis. The Congo red stain has largely replaced EM to identify tissue and are nearly specific for the disorder, but exhibit variable the characteristic abnormal 12-18 nm tubular filaments of the sensitivity in different studies. Unfortunately, a delay in freezing the inclusions for diagnostic purposes. The congophilic inclusions are tissue or other adverse handling can result in alterations of immu- composed, in part, of the microtubular-associated protein, tau.6 D- Muscle and Nerve Biopsy: An Introduction AANEM Course

This protein expresses a cross-reacting phosphorylated epitope that SUMMARY binds the anti-neurofilament protein monoclonal antibody, SMI- 31, and is reported to be useful in the diagnosis.42 The pathological The pathological findings of nerve biopsy may be diagnostic and features of IBM are nearly diagnostic, but they rarely resemble the provide a basis for proper clinical management. Expert physicians muscle biopsies of muscular dystrophies and other disorders. In ad- recommend a muscle or nerve biopsy only after thorough clinical dition, the biopsy in IBM may not demonstrate rimmed vacuoles and laboratory evaluation of the patient. The site of the biopsy or congophilic inclusions. If the muscle biopsy is not informative should be selected by clinical and electrophysiological findings to in IBM or other suspected inflammatory myopathies, the physician maximize diagnostic yield. The surgeon or physician that performs can justify a second biopsy. the biopsy must be experienced and provide tissue of good quality. The muscle biopsy can help distinguish between a myopathy from a neurogenic disorder, screen myopathies for inherited disorders to NERVE BIOPSY direct biochemical analysis and achieve a molecular diagnosis, and identify acquired disorders of muscle with particular emphasis on Biopsy of a cutaneous nerve (sural or superficial peroneal nerve) treatable disorders such as polymyositis and dermatomyositis. allows identification of a specific disorder in a minority of patients with peripheral neuropathy such as necrotizing arteritis, amyloidosis, sarcoidosis, and others.40 Diagnostic yield is greatest in patients REFERENCES with mononeuritis multiplex or an enlarged nerve identified by palpation or radiographic imaging. Symmetrical neuropathies 1. Abouzahr MK, Lange DJ, Latov N, Olarte M, Rowland LP, Hays are often not informative. The biopsy in patients with chronic AP, Corbo M. Diagnostic biopsy of the motor nerve to the gracilis inflammatory demyelinating neuropathy was initially proposed as muscle. Technical note. J Neurosurg 1997;87:122-124. a mandatory part of the diagnostic criteria. This was subsequently 2. Amato AA, Barohn RJ. Idiopathic inflammatory myopathies. Neurol modified for making this diagnosis because the biopsy was often Clin 1997;15:615-648. uninformative. This is related, in part, because cutaneous biopsy is 3. Amato AA, Griggs RC. Unicorns, dragons, polymyositis, and other typically limited to the distal part of the nerve and may not reflect mythological beasts. Neurology 2003;61:288-289. 4. Amato AA, Gronseth GS, Jackson CE, Wolfe GI, Katz JS, Bryan abnormalities located in motor nerve fibers or in sensory fibers in WW, Barohn RJ. Inclusion body myositis: clinical and pathological places other than the biopsy site. In addition, distinction between boundaries. Ann Neurol 1996;40:581-586. primary demyelination and secondary demyelination as a result of 5. Arahata K, Engel AG. Monoclonal antibody analysis of mono- axonal degeneration is particularly problematic in chronic disorders. nuclear cells in myopathies. I: Quantitation of subsets according to Occasionally, biopsy may be necessary in chronic inflammatory diagnosis and sites of accumulation and demonstration and counts demyelinating polyneuropathy patients because of an equivocal or of muscle fibers invaded by T cells. Ann Neurol 1984;16:193-208. atypical presentation or because another diagnosis, such as vasculi- 6. Askanas V, Engel WK. Inclusion-body myositis: newest concepts tis, is suspected based on the clinical or laboratory profile. of patholgenesis and relation to aging and Alzheimer disease. J Neuropathol Exp Neurol 2001;60:1-14. Skin biopsy for epidermal nerve fiber analysis has become estab- 7. Banker BQ. Dermatomyostis of childhood, ultrastructural altera- lished as an important part of the assessment of patients with tious of muscle and intramuscular blood vessels. J Neuropathol Exp Neurol 1975;34:46-75. painful or other small fiber neuropathy.36 The procedure is most 8. Banker BQ, Victor M. Dermatomyositis (systemic angiopathy) of useful in patients with no signs of a neuropathy by neurological childhood. Medicine (Baltimore) 1966;45:261-289. examination and no detectable EDX abnormalities. The biopsy 9. Bruno C, Hays A, DiMauro S. Glycogen storage diseases of muscle. provides objective evidence of a neuropathy by counting the In: Jones HR, De Vivo DC, Darras BT, editors. Neuromuscular number of epidermal nerve fibers for a given length of epidermis disorders of infancy, childhood, and adolescence. A clinicians’s ap- (epidermal nerve fiber density) and demonstrating a significant proach. New York: Butterworth-Heinemann; 2003. p 813-832. reduction of normal values (below the fifth percentile). The sample 10. Carpenter S, Karpati G. Pathology of skeletal muscle. New York: of skin biopsy could also potentially establish a specific diagnosis of Oxford University Press; 2001. amyloidosis or other disorders, but is rare. 11. Carpenter S, Karpati G. The pathological diagnosis of specific inflammatory myopathies. Brain Pathol 1992;2:13-19. Motor nerve biopsy has been limited in the past because of con- 12. Carpenter S, Karpati G, Rothman S, Watters G. The childhood type of dermatomyositis. Neurology 1976;26:952-962. cerns that it will make the patient even weaker. This has been 13. Dalakas MC. Inflammatory, immune, and viral aspects of inclusion- overcome by selecting a motor nerve that supplies a “dispensable” 1 body myositis. Neurology 2006;66:S33-38. muscle, such as the gracilis muscle. In this case, other large adduc- 14. Dalakas MC. Muscle biopsy findings in inflammatory myopathies. tor muscles take over the function of the muscle after motor nerve Rheum Dis Clin North Am 2002;28:779-798. biopsy. AANEM Course Muscle and Nerve Pathology D-

15. Dalakas MC. Polymyositis, dermatomyositis and inclusion-body 31. Hays A. Muscle biopsy. In: Aminoff MJ, Daroff RB, editors. myositis. N Engl J Med 1991;325:1487-1498. Encyclopedia of the neurological sciences, volume 3. Boston: 16. Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet Academic Press; 2003. p 270-274. 2003;362:971-982. 32. Hays A, Oskoui M, Tanji K, Kaufmann P, Bonilla E. Mitochondrial 17. De Visser M, Emslie-Smith AM, Engel AG. Early ultrastructural myopathy. II: myopathies and peripheral neuropathies. In: DiMauro alterations in adult dermatomyositis. Capillary abnormalities precede S, Hirano M, Schon E, editors. Mitochondrial medicine. London: other structural changes in muscle. J Neurol Sci 1989;94:181-192. Taylor & Francis; 2006. p 47-74. 18. DeVere R, Bradley WG. Polymyositis: its presentation, morbidity and 33. Hays AP, Daras MD. Muscle and nerve biopsy. In: Rowland LP, mortality. Brain 1975;98:637-666. editor. Merritt’s neurology, 11th edition. Philadelphia: Lippincott 19. DiMauro S, Hays A, Tsujino S. Non-lysosomal glycgenoses. In: Williams & Wilkins; 2005. p 127-129. Engel A, Franzini-Armstrong C, editors. Myology, 3rd edition. New 34. Karpati G, Pouliot Y, Carpenter S. Expression of immunoreac- York: McGraw-Hill; 2004. tive major histocompatibility complex products in human skeletal 20. Emslie-Smith A, Engel AG. Microvascular changes in early and muscles. Ann Neurol 1988;23:64-72. advanced dermatomyositis: a quantitative study. Ann Neurol 35. Kissel JT, Mendell JR, Rammohan KW. Microvascular deposition of 1990;27:343-356. complement membrane attack complex in dermatomyositis. N Engl 21. Emslie-Smith AM, Arahata K, Engel AG. Major histocompatibility J Med 1986;314:329-334. complex class I antigen expression, immunolocalization of inter- 36. Lauria G, Cornblath DR, Johansson O, McArthur JC, Mellgren SI, feron subtypes, and T cell-mediated cytotoxicity in myopathies. Hum Nolano M, et al. EFNS guidelines on the use of skin biopsy in the Pathol 1989;20:224-231. diagnosis of peripheral neuropathy. Eur J Neurol 2005;12:747-758. 22. Engel A. The muscle biopsy. In: Engel A, Franzini-Armstrong C, 37. Li CK, Varsani H, Holton JL, Gao B, Woo P, Wedderburn LR. MHC editors. Myology, 3rd edition. New York: McGraw-Hill; 2004. Class I overexpression on muscles in early juvenile dermatomyositis. 23. Engel A, Hirschhorn R, Huie M. Acid maltase deficiency. In: Engel J Rheumatol 2004;31:605-609. A, Franzini-Armstrong C, editors. Myology, 3rd edition. New York: 38. Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ. Inclusion McGraw-Hill; 2004. p 1559-1586. body myositis. Observations in 40 patients. Brain 1989;112:727-747. 24. Engel A, Reinhard H. The polymyositis and dermatomyositis syn- 39. Mendell J, Sahenk Z, Gales T, Paul L. Amyloid filaments in inclusion dromes. In: Engel A, Franzini-Armstrong C, editors. Myology, 3rd body myositis. Novel findings provide insight into nature of fila- edition. New York: McGraw-Hill; 2004. p 1321-1366. ments. Arch Neurol 1991;48:1229-1234. 25. Engel AG, Arahata K. Monoclonal antibody analysis of mono- 40. Mendell JR, Cornblath DR, Kissel JT. Diagnosis and management nuclear cells in myopathies. II: Phenotypes of autoinvasive cells in of peripheral nerve disorders. New York: Oxford University Press; polymyositis and inclusion body myositis. Ann Neurol 1984;16:209- 2001. 215. 41. van der Meulen MF, Bronner IM, Hoogendijk JE, Burger H, van 26. Fernandez C, de Paula AM, Figarella-Branger D, Krahn M, Giorgi R, Venrooij WJ, Voskuyl AE, et al. Polymyositis: an overdiagnosed Chabrol B, et al. Diagnostic evaluation of clinically normal subjects entity. Neurology 2003;61:316-321. with chronic hyperCKemia. Neurology 2006;66:1585-1587. 42. van der Meulen MF, Hoogendijk JE, Moons KG, Veldman H, 27. Gallardo E, Rojas-Garcia R, de Luna N, Pou A, Brown RH Jr, Illa I. Badrising UA, Wokke JH. Rimmed vacuoles and the added value Inflammation in dysferlin myopathy: immunohistochemical charac- of SMI-31 staining in diagnosing sporadic inclusion body myositis. terization of 13 patients. Neurology 2001;57:2136-2138. Neuromuscul Disord 2001;11:447-451. 28. Goebels N, Michaelis D, Engelhardt M, Huber S, Bender A, 43. van der Pas J, Hengstman GJ, ter Laak HJ, Borm GF, van Engelen Pongratz D, et al. Differential expression of perforin in muscle-in- BG. Diagnostic value of MHC class I staining in idiopathic inflam- filtrating T cells in polymyositis and dermatomyositis. J Clin Invest matory myopathies. J Neurol Neurosurg Psychiatry 2004;75:136- 1996;97:2905-2910. 139. 29. Greenberg SA, Amato AA. Uncertainties in the pathogenesis of adult dermatomyositis. Curr Opin Neurol 2004;17:359-364. 30. Griggs RC, Askanas V, DiMauro S, Engel A, Karpati G, Mendell JR, Rowland LP. Inclusion body myositis and myopathies. Ann Neurol 1995;38:705-713. D- AANEM Course D-

Histopathology of Muscular Dystrophies

Anthony A. Amato, MD Vice Chairman Department of Neurology Brigham and Women’s Hospital Boston, Massachusetts

INTRODUCTION Dystrophin is also present in the brain where it localizes subcel- lularly to the postsynaptic density (PSD), a disc-shaped structure In order to understand the histopathology of the muscular beneath the postsynaptic membrane in chemical synapses. The dystrophies, it is important to have an understanding of the rel- PSD may play an important role in synaptic function by stabiliz- evant muscle proteins that are affected in the various dystrophies. ing the synaptic structure, anchoring postsynaptic receptors, and Interestingly, muscular dystrophies can result from mutations af- transducing extracellular matrix-cell signals. fecting structural proteins localizable to the sarcolemma proteins, nuclear membrane, basement membrane, and sarcomere as well as Dystrophin-associated Proteins/Glycoproteins nonstructural enzymatic proteins. Dystrophin is tightly associated with a large oligomeric complex of sarcolemmal proteins forming the dystrophin-glycoprotein DYSTROPHIN-GLYCOPROTEIN COMPLEX AND RELATED complex (DGC) (Figure 1).32,33,41 Mutations in the various genes PROTEINS that encode for the different proteins of the DGC are now known to be responsible for many forms of muscular dystrophy (Table Dystrophin 1). In addition to dystrophin, the DGC is composed of an entirely cytoplasmic group of proteins referred to as the syntrophin The identification and characterization of dystrophin as an abnor- complex, the dystroglycan complex, and the sarcoglycan complex mal gene product in Duchenne and Becker muscular dystrophies (Figure 1). The syntrophin complex binds to the carboxy terminus was the seminal event in medicine’s understanding of the muscular of dystrophin and is composed of three distinct 59 kD dystrophin- dystrophies.67,68,77 Dystrophin localizes to the cytoplasmic face of associated proteins (DAPs) that are encoded by separate genes. skeletal and cardiac muscle membrane and is 5% of sarcolemmal β-syntrophin is expressed only in muscle and the gene has been cytoskeletal protein. Dystrophin is a rod-shaped molecule com- localized to chromosome 20q11.2. Beta-1-syntrophin and β2- posed of four domains.77 The amino-terminal domain binds to the syntrophin are more widely expressed and their genes have been cytoskeletal filamentous actin. The second domain bears similarity localized to chromosomes 8q23-24 and 16q22-23, respectively. to spectrin, and provides structural integrity to red blood cells. The Dystrobrevin is encoded on chromosome 2p22-23 and is a cyto- third domain is a cysteine-rich region and the fourth domain is the plasmic protein that binds to the syntrophin complex and to the carboxy-terminal. The cysteine-rich domain and the first half of the C-terminus of dystrophin. The dystroglycan complex is composed carboxy-terminal domain of dystrophin are important in linking of alpha (α)-dystroglycan and β-dystroglycan. Beta-dystroglycan dystrophin to beta(β)-dystroglycan and the glycoproteins that span spans the sarcolemmal membrane and has a cytoplasmic tail that the sarcolemma. binds to dystrophin while the extracellular tail binds α-dystroglycan. D- Histopathology of Muscular Dystrophies AANEM Course

Figure 1 Sarcolemmal, sarcoplasmic, and basement membrane proteins responsible for forms of muscular dystrophy. From: Dalkilic I, Kunkel LM. Muscular dystrophies: genes to pathogenesis. Curr Opin Genet Dev 2003;13:231-238.43

Alpha-dystroglycan, which is entirely extracellular, also binds to sarcoglycan complex and the dystrophin-dystroglycan complex α-laminin, a basal lamina protein. Of note, a gene located on is still unclear. Mutations in the various sarcoglycan genes are chromosome 3p21 encodes for both the α- and β-dystroglycans. responsive for limb girdle muscular dystrophy (LGMD) 2C, 2D, Importantly, α-dystroglycan undergoes N-linked and extensive 2E, and 2F. O-linked glycosylation which appears to be important for normal binding to merosin and perhaps other extracellular matrix pro- Merosin/Laminin teins.94 The basal lamina surrounding each muscle fiber is closely adher- The sarcoglycan complex includes four membrane spanning pro- ent to the sarcolemma and is composed of type I and IV collagen, teins: (1) α-sarcoglycan (previously known as adhalin); (2) β-sar- heparan sulfate, proteoglycan, entactin, fibronectin, and laminin. coglycan; (3) gamma (γ)-sarcoglycan; and (4) delta (δ)-sarcoglycan. Laminin is a large flexible heterotrimer composed of three differ- In addition, there is a 25 kD transmembrane protein, sarcospan, ent but homologous α, β, and γ chains held together by disulfide which co-localizes with the sarcoglycan complex. The sarcoglycan bonds. There are five different α chains, three β chains, and two γ complex associates with the cysteine-rich domain and/or the first chains that have been characterized. The major isoform of laminin half of the carboxy terminal of dystrophin directly or indirectly heavy chains in muscle is laminin-2, which is composed of α2, via the dystroglycan complex. The exact relationship between the β1, γ1 chains. Muscle also contains laminin-4, composed of α2, AANEM Course Muscle and Nerve Pathology D-

β2, γ1 subunits. Merosin is the collective name for laminins that surface on the muscle membrane, but it has a small transmembrane share a common α2 chain. Alpha-dystroglycan binds specifically to spanning tail (Figure 1). The protein does not appear to be directly laminin-2 but not to the other extracellular components (Figure connected to the dystrophin-glycoprotein complex. The function 1). Ligands for the sarcoglycan complex are unknown, but it has of dysferlin is not entirely known. Dysferlin may have a role in been postulated that the complex is directly or indirectly linked to membrane fusion and repair by regulating vesicle fusion with the laminin-4.137 membrane.9,38 Additionally, dysferlin may assist in stabilizing the sarcolemmal membrane, or in signal transduction.12,87 Merosin is also expressed in the endoneurial basement membrane surrounding the myelin sheath of peripheral nerves.89 Likewise, Caveolin α-and β-dystroglycan are found in peripheral nerves. Expression α-and β-dystroglycan is restricted to where the Schwann cell’s Caveolae are 10-100 nm invaginations in the sarcolemma derived outer membrane; they are not present in the inner membrane or by the oligomerization of approximately 14-16 caveolin-3mono- on compact myelin. Transmembrane β-dystroglycan anchors ex- mers that form a scaffolding complex of proteins and lipids (Figure tracellular α-dystroglycan to the outer membrane of Schwann cells 1).37,96 It co-fractionates with the dystrophin-glycoprotein complex, and myelin sheath. As in muscle, merosin serves as a ligand in the but is thought to be part of a discrete complex. It does not directly Schwann cell dystroglycan complex by binding to α-dystroglycan. bind to dystrophin or the sarcoglycans, but does apparently interact This complex appears to have a role in peripheral myelinogenesis. with dysferlin. Caveolin-3 is necessary for the proper formation of Mutations involving the merosin gene not only result in a form of T-tubules and may assist in the organization of signally complexes, congenital muscular dystrophy (MDC), but they also are associated calcium channels (i.e., dihydropyridine and ryanodine receptors, with mild dysmyelination in the central and peripheral nervous and sodium channels). Mutations in the gene encoding for ca- systems. veolin-3 are responsible for causing LGMD 1C, rippling muscle disease, a form of distal myopathy, and some cases of idiopathic Integrins increased serum creatine kinase (hyper-CK-emia).123,139

Integrins are transmembrane, heterodimeric (α/β) receptors that play key roles in establishing linkages between the extracellular SARCOMERIC PROTEINS matrix and the cytoskeleton as well as in transducing extracellular matrix-cell signals.132 Integrins are important in cell adhesion, In addition to the previously mentioned sarcolemmal and related migration, differentiation, proliferation, and cytoskeletal organiza- proteins, there are a number of important proteins that compose tion. The major integrin expressed throughout the sarcolemma in and support the sarcomere. The major contractile myofibrillar mature muscle fibers is α7β1D. Studies have demonstrated that proteins are the thick and thin filaments. The thin filament is com- α7β1D integrin binds to merosin in skeletal muscle and this inter- posed of three subcomponents: actin, tropomyosin, and troponin. action appears to be as important as the linkage of α-dystroglycan Polymerized globular or G-actin molecules form two helical strands to merosin in providing structural stability (Figure 1). Mutations of filamentous or F-actin. Two chains of tropomyosin molecules of the α7 subunit lead to abnormal binding of merosin to integrin wind loosely within the helical structure of the F-actin. The tropo- and are causative of some forms of MDC. myosin molecules overlie “active sites” on the actin molecules that link with the myosin heads forming the crossbridges. The third Utrophin (Dystrophin-related Protein) major subcomponent of the thin filament, troponin, consists of three globular proteins: troponin I, T, and C. Troponin I binds Utrophin is an autosomal homologue of dystrophin. It is ubiqui- strongly to actin, troponin T is attached to tropomyosin, while tously expressed but is localized exclusively at the neuromuscular troponin C has an affinity for calcium. The troponin complex at- junction in normal skeletal muscle. Utrophin associates with taches the tropomyosin molecules to the actin molecules thereby DAPs, suggesting that the utrophin-glycoprotein complex plays a forming the complete thin filament. The interaction between the role in the formation and integrity of the neuromuscular junction. myosin crossbridges and actin filaments causes the muscle fiber to Up-regulation of utrophin is evident in the dystrophinopathies, shorten or contract because the above-noted filaments slide past perhaps as a compensatory mechanism. each other.

One end of the actin filaments are firmly anchored to the Z disk OTHER SARCOLEMMAL PROTEINS and the other end projects out between myosin filaments. These Dysferlin Z disks extend from myofibril to myofibril across the diameter of a muscle fiber. The region of muscle or myofibril between two Z disks is called a sarcomere. The major protein of the Z disk is α- Dysferlin is another cytoskeletal protein present in skeletal and actinin. Nebulin is a giant protein that is attached to α-actinin at cardiac muscle. It is located predominantly on the subsarcolemmal the Z disk and spans the entire length of the thin filament. There D-10 Histopathology of Muscular Dystrophies AANEM Course

Table 1 Genetic Classification of the Muscular Dystrophies

Disease Inheritance Chromosome Affected Protein X-linked dystrophies Duchenne/Becker XR Xp21 Dystrophin Emery-Dreifuss XR Xq28 Emerin Limb-girdle muscular dystrophies LGMD 1A AD 5q22.3-31.3 Myotilin LGMD 1B AD 1q11-21 Lamin A & C LGMD 1C AD 3p25 Caveolin-3 LGMD 1D AD 6q23 ? LGMD 1E AD 7q ? LGMD 2A AR 15q15.1-21.1 Calpain 3 LGMD 2B* AR 2p13 Dysferlin LGMD 2C AR 13q12 γ-sarcoglycan LGMD 2D AR 17q12-21.3 α-sarcoglycan LGMD 2E AR 4q12 β-sarcoglycan LGMD 2F AR 5q33-34 δ-sarcoglycan LGMD 2G AR 17q11-12 Telethonin LGMD 2H AR 9q31-33 E3-ubiquitin-ligase (TRIM 33) LGMD 2I AR 19q13 Fukutin-related protein (FKRP) LGMD 2J AR 2q31 Titin

Congenital muscular dystrophies Laminin- α-2 CMD AR 6q22-23 Laminin- α-2 chain α-7 Integrin CMD AR 12q13 α-7 Integrin AR 19q13 Fukutin-related protein (FKRP) Fukuyama CMD A 9q31-33 Fukutin Walker-Warburg CMD AR 9q31 POMT1 Muscle-eye-brain CMD AR 1p32 POMGnT1 Rigid spine syndrome AR 1p35-36 Selenoprotein N1

Distal dystrophies/myopathies Late adult onset 1A (Welander) AD 2p13 ? Late adult onset 1B (Udd) AD 2q31 Titin Early adult onset 1A (Nonaka) AR 9p1-q1 GNE Early adult onset 1B* (Miyoshi) AR 2p13 Dysferlin Early adult onset 1C (Laing) AD 14q11 myosin heavy chain 7 AANEM Course Muscle and Nerve Pathology D-11

Table 1 Continued Other dystrophies Facioscapulohumeral AD 4q35 ? Scapuloperoneal dystrophy AD 5q22.3-31.3 Myotilin AD 12 ? Oculopharyngeal AD 14q11.2-13 PABP2 Myotonic dystrophy-1 AD 19q13.3 DMPK Myotonic dystrophy–2 AD 3q21 ZNF9

*LGMD 2B and Miyoshi distal dystrophy are the same condition

AD = autosomal dominant; AR = autosomal recessive; CMD = congenital muscular dystrophies; GNE = UDP-N-acetylglucosamine 2-epimerase/n-acetylmannosamine kinase; LGMD = limb-girdle muscular dystrophy; POMT1 = O-mannosyltransferase gene; POMGnT1 = O-mannose β-1,2-N-acetylglucosaminyl transferase

are two nebulin molecules for every thin filament. Desmin is an in- minal tail, while the remainder of the protein projects into the nu- termediate-sized filament that encircles the Z disk and helps to link cleoplasm. The lamins bind to emerin, specific lamin receptors, and the Z disk to the sarcolemma, myonuclei, and adjacent myofibers. perhaps other LAPs located on the inner nuclear membrane. This The cytoplasmic heat-shock protein, αB-crystallin, interacts with complex of proteins is important in the organization and structural desmin in the assembly and stabilization of the Z disk. Syncoilin, integrity of the nuclear membrane. In addition, LAPs, lamin recep- together with plectin, also may link desmin filaments to the Z tors, and the lamins bind chromatin and promote its attachment disk.118 to the nuclear membrane. Abnormalities in these nuclear envelope proteins apparently disrupt the structure of the nuclear membrane, Other filamentous proteins are also important in providing stability the organization of interphase chromatin, and perhaps also signal to the sarcomere. The giant protein titin (also known as connectin) transduction between the nucleus and sarcoplasm.20,57 Mutations is attached to the Z disk and spans from the M-line to the Z-line in the genes that code for emerin and lamin A/C are responsible of the sarcomere. Titin serves to connect the myosin filaments to for X-linked Emery-Dreifuss muscular dystrophy (EDMD) and the Z disk. Telethonin is another sarcomeric protein present in autosomal dominant EDMD/LGMD 1B, respectively. skeletal and cardiac muscle. It co-localizes with titin to the Z disk and along the thick filaments. Telothonin is also linked to myotilin which in turn interacts with α-actinin and actin. The interaction ENZYMATIC (SARCOPLASMA) PROTEINS of myotilin, telethonin, and titin may be important in myofibrillogenesis. As will be discussed, mutations affecting the genes Calpain-3 is a muscle-specific, calcium-dependent, nonlysosomal, encoding for these various sarcomeric proteins are responsible for proteolytic enzyme present in muscle. The pathophysiologic causing different dystrophies, congenital myopathies, and inherited mechanism of how mutations involving this enzyme result in a cardiomyopathies. dystrophic process is unknown. Calpain-3 exists in both the cytosol and nuclei of skeletal muscle fibers (Figure 1) where it may be directly involved in or participate in the activation of another enzyme NUCLEAR MEMBRANE PROTEINS involved in muscle metabolism. Mutation in the calpain-3 gene are responsible for LGMD 2A. Emerin is a member of the nuclear lamina-associated protein (LAP) family and is located on the inner nuclear membranes of skeletal, Tripartite motif-containing protein 32 (TRIM 32), also known as cardiac and smooth muscle fibers (Figure 2).105,106,109,116 The nuclear E3-ubiquitine ligase, may function by tagging proteins (e.g., ubi- lamina is a multimeric matrix composed of a complex of intermedi- quination) for degradation by proteosomes. Mutations in TRIM 32 ate-sized filaments (lamins -A, -B, and -C) that associates with the cause LGMD 2H.59 nucleoplasmic surface of the inner nuclear membrane. Of note, alternative splicing of a single gene produces lamins A and C. Emerin Fukutin is a glycosyltransferase and its deficiency is associated with is attached to the inner nuclear membrane through its carboxy-ter- abnormal glycosylation of α-dystroglycan and results in Fukuyama’s D-12 Histopathology of Muscular Dystrophies AANEM Course

Figure 2 Nuclear membrane and sarcomeric proteins responsible for Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy 1B. From: Dalkilic I, Kunkel LM. Muscular dystrophies: genes to pathogenesis. Curr Opin Genet Dev 2003;13:231-238.43

congenital muscular dystrophy (FCMD). Mutations in a protein SPECIFIC MUSCULAR DYSTROPHIES of similar function, fukutin-related protein (FKRP), are found in some patients with MDC with normal merosin (MDC 1C) The muscular dystrophies are a group of hereditary, progressive and in LGMD 2I.27,29,30 Interestingly, impaired glycoslylation of muscle diseases in which there is necrosis of muscle tissue and α-dystroglycan are believed to be responsible for other forms of replacement by connective and fatty tissue. Muscular dystrophies MDC (muscle-eye-brain [MEB] disease and Walker-Warburg traditionally have been classified according to their pattern of weak- syndrome[WWS]).16 Muscle-eye-brain disease is caused by mu- ness (e.g., limb-girdle, facioscapulohumeral, scapuloperoneal) and tations in O-mannose-β-1,2-N-acetylglucosaminyl transferase mode of inheritance (Table 1). Advances in genetics have led to (POMGnT1) and WWS is the result of mutations in O-manno- the classification of muscular dystrophies based on the responsible syltransferase (POMT1). Mutations in the human LARGE gene gene defect. (also is required for glycoslylation of α-dystroglycan) is responsible for another rare form of MDC with mental retardation.28,83 Thus, it appears that normal glycoslylation of α-dystroglycan is impor- THE DYSTROPHINOPATHIES tant for muscle function, but also normal development of the Duchenne Muscular Dystrophy central nervous system which is affected in these forms of MDC. In addition, UDP-N-acetylglucosamine 2-epimerase/n-acetylman- Histopathology nosamine kinase (GNE), which is involved in the post-translational glycosylation of proteins, is mutated in some forms of autosomal Muscle biopsy in Duchenne muscular dystrophy (DMD) reveals recessive inclusion body myopathy (IBM) also known as the necrotic and regenerating muscle fibers, variability in muscle fiber Nonaka type of distal myopathy. size, and increased endomysial and perimysial connective tissue. AANEM Course Muscle and Nerve Pathology D-13

Female Carriers There are also scattered hypertrophic and hypercontracted fibers in addition to small, rounded, regenerating fibers. Fiber splitting and The daughters of men with BMD (males with DMD are usually in- central nuclei can also be seen but occur less often than in other fertile) and the mothers of affected children who also have a family muscular dystrophies. The process of degeneration and regenera- history of DMD or BMD are obligate carriers of the mutated tion continues until the limited regenerative capacity of the satellite dystrophin gene. Mothers and sisters of isolated DMD or BMD cells is exceeded at which time the necrotic muscle tissue is replaced patients are at risk for being carriers. Women carriers are usually with fat and connective tissue. asymptomatic, but a few develop muscle weakness.66 These cases are usually explained by the Lyon hypothesis: skewed inactivation Endomysial inflammatory cells consisting of cytotoxic T-lym- of the normal X-chromosome and dystrophin gene results in in- phocytes (two-thirds) and macrophages (one-third) are present creased transcription of the mutated dystrophin gene. Females with to a variable degree as well as phagocytize necrotic fibers.3 Rarely translocations at the chromosomal Xp21 site or Turner’s syndrome nonnecrotic fibers expressing major histocompatibility antigen (XO genotype) may also develop dystrophinopathies. are invaded by CD8+ cytotoxic T-cells. Immunohistochemistry demonstrates reduced or absent dystrophin on the sarcolemma. Manifesting carriers typically have a mild limb-girdle phenotype Approximately 60% of DMD patients will have some faint stain- similar to BMD. Prior to the recent advances in molecular genetics, ing of the muscle membrane utilizing antibodies directed against these women were often diagnosed with LGMD, particularly when the amino-terminal or rod domain of dystrophin. However, less there was no family history of DMD or BMD. Rarely, females than 1% of muscle fibers have sarcolemmal staining with antibod- manifest severe weakness as seen in DMD. ies directed against the carboxy-terminal of dystrophin. The few dystrophin-positive muscle fibers are known as revertants. They Histological features of manifesting carriers are similar to those arise secondary to spontaneous subsequent mutations that restore discussed for DMD and BMD. Immunostaining for dystrophin the “reading frame” and allow transcription of dystrophin, albeit of demonstrates an absent, decreased, or mosaic pattern of staining in abnormal size and shape. On the other hand, utrophin, which is many female carriers, however staining can be normal.4,40,66,95 Thus, normally restricted to the neuromuscular junction, is overexpressed immunostaining and Western blot analysis is not very sensitive in in DMD and is present throughout the sarcolemma. identifying the carrier status of asymptomatic females.

Immunoblot or Western blot of muscle tissue assesses both the quantity and size of the dystrophin present. Using carboxy-terminal MOLECULAR GENETICS AND PATHOGENESIS OF THE antibodies, Western blot reveals 0% to 3% of the normal amount DYSTROPHINOPATHIES of dystrophin present in muscle tissue, and the size of remaining dystrophin is usually diminished.68 With amino-terminal or Dystrophin is a structural protein that is intimately bound to the rod-domain antibodies, approximately 50% of DMD patients sarcolemma and provides structural integrity to the muscle mem- have some detectable truncated dystrophin. Immunohistochemical brane (Figure 1).41 Abnormal quantity or quality of dystrophin analysis in dystrophinopathies may also demonstrate a reduction of results in the muscle losing its ability to maintain its integrity dystroglycan, dystrobrevin, and all the sarcoglycan proteins, includ- during contraction leading to membrane tears and subsequent ing sarcospan. muscle fiber necrosis.

Becker Muscular Dystrophy The dystrophin gene, located on chromosome Xp21, is composed of approximately 2.4 megabases of genomic deoxyribonucleic Histopathology acid (DNA), and includes 79 exons, which code for a 14 kb transcript.67,77 The large size of the gene probably accounts for the The histological features of Becker muscular dystrophy (BMD) are high spontaneous mutation rate responsible for one-third of new similar to those observed for DMD, but are less severe.73 Becker cases. Large deletions—several kilobases to over one million base muscular dystrophy may be distinguished histologically from pairs—can be demonstrated in approximately two-thirds of dystro- DMD with immune staining. In most BMD patients, the pres- phinopathy patients. Approximately 5%-10% of DMD cases are ence of dystrophin utilizing carboxy-terminal antibodies on muscle caused by point mutations resulting in premature stop codons.112 membranes is present. In contrast, immunostaining with antibod- Duplications are evident in another 5% of cases. Mutations occur ies directed against the carboxy-terminal of dystrophin is usually primarily in the center (80%) and near the amino-terminal (20%) negative in DMD. However, the degree and intensity of the dystro- of the gene.112 Mutations that disrupts the translational reading phin staining is usually not normal in BMD. The staining pattern frame of the gene lead to near total loss of dystrophin and DMD, may be uniformly reduced or can vary between and within fibers. while in-frame mutations result in the translation of semifunc- Western blot analysis of muscle tissue typically reveals an abnormal tional dystrophin of abnormal size and/or amount and in outlier or quantity and/or size of the dystrophin protein.68,69 BMD clinical phenotypes.68 Although there are exceptions to the D-14 Histopathology of Muscular Dystrophies AANEM Course

Limb-Girdle Muscular Dystrophy 1B “reading-frame rule,” 92% of phenotypic differences are explained by in-frame and out-of-frame mutations.112 The clinical severity Histopathology does not appear to correlate with the location of mutations in DMD. It appears that the quality or remaining functional capabil- In LGMD 1B, muscle biopsies demonstrate variation in fiber ity of the mutated dystrophin protein is more important than the size, increased endomysial connective tissue, normal dystrophin, actual quantity. The reduction in the various sarcoglycans, which is sarcoglycan, and emerin staining. Occasionally, rimmed vacuoles also evident on immunohistochemical studies of DMD and BMD, are evident on muscle biopsy similar to those seen in one of the suggests that normal dystrophin is important for the integrity of the IBMs.53,133 Lamin A/C expression on the nuclear membrane may be sarcoglycan complex. normal or reduced. On EM, myonuclei exhibit the loss of peripheral heterochromatin or its detachment from the nuclear envelope, altered interchromatic texture, and fewer nuclear pores compared LIMB-GIRDLE MUSCULAR DYSTROPHY to normal.116

The LBMDs are a heterogeneous group of disorders that clinically Molecular Genetics and Pathogenesis resemble the dystrophinopathies except for the equal occurrence in males and females (Table 1).13,31,32,34,41 The incidence and prevalence Limb-girdle muscular dystrophy 1B is caused by mutations in of LGMD is approximately 6.5 per 100,000 live births. These dis- lamin A/C on chromosome 1q11-21.19,20,57 The pathogenic role of orders are inherited in an autosomal recessive or dominant fashion. lamin A/C is discussed in more detail in the EDMD section. In the past, patients with a phenotype similar to DMD have been called “severe childhood autosomal recessive muscular dystrophies” Limb-Girdle Muscular Dystrophy 1C (SCARMD), while patients with milder phenotypes similar to BMD have been labeled with the term “limb girdle muscular Histopathology dystrophy.” Autosomal dominant LGMDs are classified as type 1 (e.g., LGMD 1), while recessive forms are termed type 2 (e.g., Muscle biopsies in patients with LGMD 1C show nonspecific myo- LGMD 2). Further alphabetical subclassification has been applied pathic features with normal dystrophin, sarcoglycan, and merosin to these disorders as they have become genotypically distinct (e.g., staining. In contrast, there is reduced caveolin-3 staining along the LGMD 2A, LGMD 2B, etc., Table 1). For the most part, the clini- sarcolemma. Electron microscopy reveals a decreased density of cal, laboratory, and histopathological features of the LGMDs are caveoli on the muscle membrane. nonspecific. There are a few that will be discussed later. Molecular Genetics and Pathogenesis

AUTOSOMAL DOMINANT LIMB-GIRDLE MUSCULAR Limb-girdle muscular dystrophy 1C is caused by mutations in DYSTROPHIES the caveolin-3 gene located on chromosome 3p25.37,96 Caveolin-3 is localized by immunostaining to the sarcolemma (Figure 1). It Limb-Girdle Muscular Dystrophy 1A co-fractionates with the dystrophin-glycoprotein complex, but is Histopathology thought to be part of a discrete complex. Caveolins play a role in the formation of caveolae membranes, where they act as scaffolding In LGMD 1A, muscle biopsies are notable for the frequent occur- proteins to organize and concentrate caveolin-interacting lipids and rence of rimmed vacuoles and occasional nemaline rod-like inclu- proteins.96 Caveolin-3 might also function to facilitate organization sions.39,85 Muscle biopsies can demonstrate features of myofibrillar of signaling complexes and the sodium channels that might con- myopathy on routine light microscopy, immunohistochemistry, tribute to the pathogenesis of rippling muscle disease. and electron microscopy (EM).118

Molecular Genetics and Pathogenesis AUTOSOMAL RECESSIVE LIMB-GIRDLE MUSCULAR DYSTROPHIES Limb-girdle muscular dystrophy 1A is caused by mutations in the Limb-Girdle Muscular Dystrophy 2A gene that encodes for myotilin located on chromosome 5q22.3- 31.3.62,118 Myotilin is a sarcomeric protein that co-localizes with Histopathology α-actinin at the Z-disc. Some of the clinical, laboratory, and histological features are similar to those described in autosomal Muscle biopsies in patients with LGMD 2A show variation in fiber dominant hereditary IBM (h-IBM) and myofibrillar myopathy. In size and increased endomysial connective tissue. One of the striking fact, recently some patients with myofibrillar myopathy have been features is the frequent lobulated appearance of fibers on nicotin- found to have mutations in the myotilin gene.118 amide adenine dinucleotide hydrogen (NADH) staining. However, AANEM Course Muscle and Nerve Pathology D-15

Molecular Genetics and Pathogenesis this finding is not specific for calpainopathies. Interestingly, severe cases of eosinophic myositis in children were subsequently shown Mutations within the dysferlin gene are the cause of Miyoshi to be LGMD 2A.78 As this is a cytosolic enzyme, immunostaining myopathy, LGMD 2B, and some distal myopathies with anterior cannot be performed for diagnosis. However, Western blot analysis tibial weakness.12,70,81 A study of 407 muscle biopsies from patients demonstrates reduced calpain-3. Definite diagnosis requires dem- with unclassified myopathies (normal dystrophin and sarcoglycan) onstration of a mutation in calpain-3 gene because secondary defi- demonstrated that 6.5% had abnormal dysferlin by Western blot ciency in calpain-3 can be seen in other dystrophies, most notably and immunostaining.56 Dysferlinopathy accounted for 1% of pa- the dysferlinopathies and titinopathies. tients with an unknown LGMD and 60% of patients with a distal myopathy. The clinical phenotype of patients with dysferlinopathy Molecular Genetics and Pathogenesis broke down as follows: 80% manifest with distal weakness, 8% have LGMD phenotype, and 6% present with asymptomatic Limb-girdle muscular dystrophy 2A is caused by mutations in the hyper-CK-emia. calpain-3 gene.14,55,114,115,124 Large series of LGMD patients have shown that calpainopathies account for approximately 20%-26% Dysferlin shares amino acid sequence homology with C. elegans sper- of dystrophies with normal dystrophin and sarcoglycans.55,56 Over matogenesis factor FER-1, thus, the origin of its name. Dysferlin two-thirds of patients with calpainopathy manifest with a BMD- is located predominantly on the subsarcolemmal surface on the like phenotype, approximately 10% present with severe childhood muscle membrane, but it has a small transmembrane spanning tail onset weakness early similar to DMD, 3% have a distal myopathy, (Figure 1). It does not appear to have a significant interaction with and 6% have asymptomatic hyper-CK-emia.56 the dystrophin-glycoprotein complex and immunostaining for dystrophin, dystroglycans, merosin, and the sarcoglycans are normal. Calpain-3 is a muscle-specific, calcium-dependent, nonlysosomal, The major role of dysferlin is patching defects in skeletal membrane proteolytic enzyme. The mutations lead to an absence or reduction and mutations in the gene result in defective membrane repair.9,38 in this enzyme, but how this results in the dystrophic process is Dysferlin is present on white blood cells and therefore Western blot unknown. Calpain-3 activates other enzymes involved in muscle of these cells can confirm the deficiency.65 metabolism.114 Lack of calpain-3 might lead to the accumulation of toxic substances in muscle cells. Perhaps calpain-3 plays a role in Sarcoglycanopathies gene expression by regulating turnover or activity of transcription factors or their inhibitors.114 Histopathology

Limb-Girdle Muscular Dystrophy 2B In sarcoglycanopathies (LGMD 2C, LGMD 2D, LGMD 2E, LGMD 2F), muscle biopsies demonstrate normal dystrophin, Histopathology however, each of the sarcoglycans are absent or diminished on the sarcolemma, regardless of the primary sarcoglycan mutation. In patients with LGMD 2B, muscle biopsies show variation in fiber size and increased endomysial connective tissue. Immunostaining Molecular Genetics and Pathogenesis reveals absent or diminished sarcolemmal staining with dysferlin antibodies. In contrast, there may be increased cytoplasmic stain- Limb-girdle muscular dystrophy 2C, 2D, 2E, and 2F are caused by ing. The reduced sarcolemmal immunostaining can be secondary mutations in the γ-sarcoglycan, α-sarcoglycan, β-sarcoglycan, and and seen in other types of LGMD,111 therefore Western blot needs δ-sarcoglycan genes, respectively.1,2,21,36,41,45,46,47,54,82,91 The clinical to be performed on the muscle or white blood cells to confirm a phenotypes appear to correlate with the expression of the sarcogly- primary deficiency. Not uncommonly, a prominent mononuclear cans. The proteins of the sarcoglycan complex appear to function inflammatory cell infiltrate is evident in the endomysium and as a unit. Mutations involving any of the sarcoglycans results in surrounding blood vessels. Many cases of dysferlinopathy are thus destabilization of the entire complex and reduced expression of initially misdiagnosed as polymyositis.60 In contrast to polymyo- the other proteins. As apparent with the dystrophinopathies, the sitis, the inflammatory cells do not appear to invade nonnecrotic clinical severity of the sarcoglycanopathies may correlate with the fibers. Another helpful immunohistological feature is demonstrat- type of mutation (i.e., whether the reading frame is preserved) and ing deposition of membrane attack complex on the sarcolemma of subsequent level of functional protein expression. nonnecrotic muscle fibers. This is seen as an early finding in dysferlinopathies and other dystrophies with inflammation not seen in Limb-Girdle Muscular Dystrophy 2G primary inflammatory myopathies such as polymyositis, diabetes mellitus, and IBM. On EM, reduplication of the basal lamina, Histopathology disruption in the sarcolemma, invaginations or papillary exophytic defects of the muscle membrane, and subsarcolemma vesicles may In patients with LGMD 2G, besides the usual dystrophic fea- be appreciated.119 tures, many muscle fibers had one or more rimmed vacuoles. D-16 Histopathology of Muscular Dystrophies AANEM Course

Molecular Genetics and Pathogenesis Immunohistochemistry and Western blot analysis demonstrate a deficiency of telethonin.100 Limb-girdle muscular dystrophy 2I is caused by mutations in the gene that encodes for FRRP located on chromosome 19q13.29 Molecular Genetics and Pathogenesis Mutations in this gene are also responsible for MDC type 1C. Fukutin-related protein is a glycosyltransferase and its defi- Limb-girdle MD 2G is caused by mutations in the telethonin ciency is associated with abnormal glycosylation of α-dystroglycan, gene located on chromosome 17q11-12.100 Telethonin is a 19 kD which apparently disrupts the dystrophin-glycoprotein complex. sarcomeric protein that is expressed in skeletal and cardiac muscles, Abnormalities in glycosylation of α-dystroglycan is a recurring where it localizes to the central parts of the Z-disk.101 It is a ligand theme in the MDCs as this is also a causative mechanism in FCMD, for the giant sarcomeric protein, titin, which itself phosphorylates MEB, WWS, and LARGE-related MDC (MDC 1D). There is a the C-terminal domain of telethonin in early differentiating myo- correlation between a reduction in α-dystroglycan, the mutation, cytes. Telethonin may also overlap with myosin. It is one of the and the clinical phenotype in MDC 1C and LGMD 2I.30 most abundant proteins in muscle. The interaction of telethonin with titin appears to be important in myofibrillogenesis.90,101 Fukutin-related protein localizes in rough endoplasmic reticulum, while fukutin localizes in the cis-Golgi compartment.88 Fukutin Limb-Girdle Muscular Dystrophy 2H/Sarcotubular and FKRP appear to be involved at different steps in O-mannosylg- Myopathy lycan synthesis of α-dystroglycan, and FKRP is most likely involved in the initial step in this synthesis. Endoplasmic reticulum-reten- Histopathology tion of mutant FKRP may play a role in the pathogenesis of these dystrophies and potentially explain why the allelic disorder LGMD Typical dystrophic features are seen on muscle biopsy of patients 2I is milder, because the mutated protein is able to reach the Golgi with LGMD 2H. Increases in internal nuclei, muscle-fiber splitting, apparatus.52 and many fibers (mostly type 2) with small vacuoles are seen.72,117 These vacuoles abut T-tubules and appear to be membrane bound, Limb-Girdle Muscular Dystrophy 2J and also appear empty or contain a small amount of amorphous debri on EM. The vacuoles immunostain for sarcoplasmic reticu- Histopathology lum-associated adenosine triphosphase (ATPase). Muscle biopsies in patients with LGMD 2J demonstrate vari- Molecular Genetics and Pathogenesis ability in fiber size, increased central nuclei, split fibers, increased endomysial connective tissue and often rimmed vacuoles (as in Limb-girdle muscular dystrophy and sarcotubular myopathy are Markesbery-Griggs/Udd distal myopathy, to be discussed later). allelic disorders caused by mutations in the gene that encodes for E3-ubiquitine ligase (also known as TRIM 32)117 located on chro- Molecular Genetics and Pathogenesis mosome 9q31-q33, as was recently reported.59 E3-ubiquitine ligase may function by ubiquinating proteins that need degradation by Limb-girdle muscular dystrophy 2J is caused by mutations in the proteosomes. The mechanism by which this leads to muscle de- titin gene. struction is unclear, but it is speculated that it is related to the possible toxic accumulation of “aged” or otherwise abnormal proteins not cleared by proteasomes. CONGENITAL MUSCULAR DYSTROPHIES

Limb-Girdle Muscular Dystrophy 2I The MDCs are a heterogeneous group of autosomal recessive inherited disorders characterized by perinatal onset of hypotonia and Histopathology weakness, dystrophic-appearing muscle biopsies, and the exclusion of other recognizable causes of myopathy of the newborn (Table 1). Nonspecific dystrophic features are evident on muscle biopsy in The abbreviation assigned by the Human Genome Organization patients with LGMD 2I. A clue to the diagnosis is that there is is “MDC” for muscular dystrophy, congenital. The MDCs have reduced α-dystroglycan and occasional merosin with immunostain- been classified in the past according to clinical, ophthalmological, ing. radiological, and pathological features. A more recent classification AANEM Course Muscle and Nerve Pathology D-17

was proposed based on the location of the defective proteins and recessive condition, and homozygous or compound heterozygous purported pathogeneses of the individual dystrophies: (1) those mutations have been defined in COL6A2 and COL6A3. In con- associated with mutations in genes encoding structural proteins trast, the milder disorder Bethlem myopathy, shows clear dominant of the basal lamina, extracellular matrix, or sarcolemmal proteins inheritance and is caused by heterozygous mutations in COL6A1, that bind to the basal lamina, (2) those associated with impaired COL6A2, and COL6A3.7 Recent studies have demonstrated that glycolylation of α-dystroglycan, and (3) those associated with sele- UCMD can be inherited in a dominant fashion as well.7 noprotein 1 mutations. Congenital Muscular Dystrophies Associated With Congenital Muscular Dystrophy Associated With Impaired Glycoslylation of Alpha-Dystroglycan Genetic Defects of Structural Proteins of the Basal Lamina or Extracellular Matrix The primary sequence of α-dystroglycan predicts a molecular mass of 72 kD; however, the mass of α-dystroglycan in skeletal muscle Histopathology is 156 kDa.104 The increase in actual size is due to the post-translational modification of α-dystroglycan. In this regard, O-linked Muscle biopsies of MDC 1A (also known as MDC with laminin α2 glycosylation of the protein makes the major contribution to the or merosin deficiency or the classic/occidental type) reveal a varia- observed molecular weight. The glycosyltransferase O-mannosyl- tion in muscle fiber size, scattered regenerating and degenerating transferase 1 (POMT1) forms a complex with a second putative fibers, and increased endomysial connective tissue. Immunostaining O-mannosyltransferase (POMT2) to catalyzes the first step in reveals reduced or absent merosin. O-mannosylglycosylation.103,104 Subsequently, the transfer of N- acetylglucosamine to O-mannose of glycoproteins is catalyzed by Congenital muscular dystrophy 1A is associated with mutations in O-mannose β-1,2-N-acetylglucosaminyltransferase (POMGnT1). a-2 subchain of merosin on chromosome 6q21-22. The gene codes Fukutin, FKRP, and LARGE are other secretory enzymes involved for a 390 kD protein that is synthesized as one chain but processed in posttranslational glycoslylation of α-dystroglycan although the into two fragments. On immunoblot, these two fragments have exact reactions they catalyze are not known.103,104 Glycosylation molecular masses of approximately 80 kD (C-terminal) and 300 of α-dystroglycan is required for normal binding to merosin.74 kD (N-terminal).120 Merosin binds to α-dystroglycan and α7b1D Impaired glycosylation of α-dystroglycan is not only important for integrin (Figure 1). As with primary dystrophinopathies and ad- proper muscle function, it also leads to defects in neuronal migra- halinopathies, the merosinopathies may result in a disruption and tion and the abnormalities in the central nervous system (CNS) loss of integrity of the dystrophin-glycoprotein complex. In addi- seen with FCMD, WWS, MEB disease, MDC 1C, and MDC tion, mutations involving the α7 subunit of integrin that binds to 1D. merosin also results in a form of MDC.63 Muscle biopsy findings are indistinguishable from other forms of Ullrich Disease/Bethlem Myopathy MDC using routine stains. A striking inflammatory infiltrate is occasionally present which has led to the erroneous diagnosis of a Histopathology congenital inflammatory myopathy or polymyositis. Importantly, abnormal glycosylation of a-dystroglycan caused by mutations In patients with Ullrich disease, muscle biopsies reveal variation in responsible for FCMD, MEB, WWS, MDC 1C, and MDC 1D muscle fiber size, scattered regenerating and degenerating fibers, can be appreciated by reduced immunostaining of the sarcolem- and increased endomysial connective tissue. Immunohistochemistry mal membrane with antibodies directed against α-dystroglycan and reveals that collagen VI is present in the interstitium but absent merosin.15,42,44,136 from the sarcolemma.71 Ultrastructural studies demonstrate that collagen VI in the interstitium fails to anchor normally to the basal Fukuyama Congenital Muscular Dystrophy lamina surrounding muscle fibers. Molecular Genetics and Pathogenesis Molecular Genetics and Pathogenesis Fukuyama congenital muscular dystrophy is caused by muta- Collagen VI is composed of three chains, α1, α2, and α3 and is tions in the fukutin gene which is located on chromosome a ubiquitously expressed extracellular matrix protein. The three 9q31.76,127,128,140 Fukutin is a secretory enzyme that localizes to the chains are encoded by the genes COL6A1 and COL6A2 on chro- cis-Golgi compartment and is thought to have a role in posttransla- mosome 21q223 and COL6A3 on chromosome 2q37. Ullrich tional glycoslylation of α-dystroglycan.88 In addition to the skeletal congenital muscular dystrophy (UCMD) had been considered a muscle involvement, the disruption of normal glycosylation of D-18 Histopathology of Muscular Dystrophies AANEM Course

α-dystroglycan or other proteins leads to defects in neuronal migra- and potentially explain why the allelic disorder LGMD 2I is milder, tion and differentiation that accounts for the many abnormalities because the mutated protein is able to reach the Golgi apparatus.52 seen within the CNS. There is a correlation between a reduction in α-dystroglycan, the mutation, and the clinical phenotype in MDC 1C and LGMD Walker-Warburg Syndrome 2I.30 Patients with MDC 1C have a profound depletion of α-dystroglycan, those with a Duchenne-like phenotype have a moderate Molecular Genetics and Pathogenesis reduction in α-dystroglycan, and individuals with the milder form of LGMD 2I demonstrate a variable but subtle alteration in α-dys- So far, four genes (the POMT1, POMT2, fukutin, and FKRP troglycan immunolabeling. genes) have been implicated in WWS, but they account for only a minority of cases.15,42,44,104,135 Mutations in the POMT1 gene on Congenital Muscular Dystrophy 1D chromosome 9q31-33 account for the majority of cases (20%) of WWS, but in most cases the genetic defects remain unknown.42,104 Molecular Genetics and Pathogenesis The clinical phenotype of patients with mutations in the POMT1 gene is also variable with rare cases reported with LGMD and mild Mutations in the human LARGE gene (also required for glyco- mental retardation.8 Glycosylation of α-dystroglycan is required for slylation of α-dystroglycan) is responsible MDC 1D, a rare form normal binding to merosin.74 of CMD.28,83 This gene encodes for another putative glycosyltransferase. Muscle-Eye-Brain Disease or Santavouri Type Congenital Muscular Dystrophy Associated With Molecular Genetics and Pathogenesis Selenoprotein n1 Mutations

Muscle-eye-brain disease is caused by mutations in the gene that Rigid Spine Syndrome encodes for O-mannose-β-1,2-N-acetylglucosaminyl transferase (POMGnT1) on chromosome 1p32-p34.42,44,140 POMGnT1 cata- Rigid spine syndrome or rigid spine muscular dystrophy (RSMD) lyzes the transfer of N-acetylglucosamine to O-mannose of glyco- is a heterogeneic disorder. One subtype, RSMD 1, manifests in proteins. infancy with hypotonia, proximal weakness, and delayed motor milestones.84,92,93,98,99,113,126 Affected patients develop progressive Congenital Muscular Dystrophy 1C limitation of spine mobility often associated with scoliosis and contractures at the knees and elbows. Clinical Features Histopathology Congenital muscular dystrophy 1C is allelic to LGMD 2I and caused by mutations in the FKRP gene. The FKRP-related myopa- Muscle biopsies in RSMD patients reveal nonspecific myopathic thies are common—especially among Caucasians—and give rise features including variability in fiber size, increased internal nuclei, to the largest phenotypic spectrum of muscular dystrophies so far type-1 fiber predominance, and moth-eaten fibers and lobulated connected to mutations of a single gene.103,104 The age of onset can fibers on NADH dehydrogenase stains. Some cases are associated range from infancy (e.g., congenital) to the fourth decade of life with multiple minicores. Cytoplasmic bodies, Mallory bodies, with a pattern of weakness similar to MDC 1A, MDC with CNS increased desmin expression, and sarcoplasmic and intranuclear abnormalities typical of WWS, or a mild proximal weakness with tubulofilamentous inclusions may also be present.113 Endomysial onset in adulthood similar to BMD or a LGMD. fibrosis is apparent, particularly in axial muscles (i.e., rectus ab- dominus and paraspinal muscles). Immunostains for dystrophin, Molecular Genetics and Pathogenesis sarcoglycans, and the dystroglycans are normal.

Congenital muscular dystrophy 1C is caused by mutations in the Molecular Genetics and Pathogenesis gene that encodes for FRKP located on chromosome 19q13.3. Fukutin related protein localizes in rough endoplasmic reticulum Some cases of autosomal recessive RSMD have been linked to and appears to be involved in one of the initial steps in O-man- mutations in the gene that encodes for selenoprotein N1 located nosylglycan synthesis of α-dystroglycan.88 Endoplasmic reticulum- on chromosome 1p35-36.58,98,99 Mutations in this gene have also retention of mutated FKRP may play a role in the pathogenesis been shown in some patients with multi/minicore myopathy. AANEM Course Muscle and Nerve Pathology D-19

Molecular Genetics and Pathogenesis Selenoprotein N1 is an endoplasmic reticulum glycoprotein. The function of this protein is not known. Emery-Dreifuss muscular dystrophy is caused by mutations in a gene (STA) located on chromosome Xq28 which encodes for emerin (Table 1).17 Emerin is located on the inner nuclear mem- OTHER REGIONAL FORMS OF MUSCULAR DYSTROPHY branes of skeletal, cardiac, and smooth muscle fibers as well as 105,106 Facioscapulohumeral Muscular Dystrophy skin cells. The carboxy-terminal tail anchors the protein to the inner nuclear membrane while the remainder of the protein Histopathology projects into the nucleoplasm. Emerin is a member of the nuclear lamina-associated protein (LAP) family.105,106,109 The nuclear lamina Muscle biopsy in facioscapulohumeral muscular dystrophy (FSHD) is composed of intermediate sized filaments (i.e., lamins A, B, and demonstrates variation in muscle fiber size with atrophic and hy- C) associated with the nucleoplasmic surface of the inner nuclear pertrophic fibers, scattered necrotic and regenerating fibers, in- membrane. These lamins bind to various LAPs, including LAP1, creased internalized nuclei, and increased endomysial connective LAP2, and lamin B receptor, which are located on the inner nuclear tissue.75 Prominent mononuclear inflammatory infiltrate may be membrane. Lamina-associated protein 2, lamin B receptor, and the appreciated in the endomysium, which can lead to confusion with lamins also bind to chromatin and thereby promote its attachment polymyositis.102 Immunostaining with antibodies directed against to the nuclear membrane. Mutations in emerin conceivably lead to membrane attack complex may demonstrate deposition on the disorganization of the nuclear lamina and heterochromatin that is sarcolemma of nonnecrotic muscle fibers. apparent on EM and immunohistochemistry.109

Molecular Genetics and Pathogenesis Autosomal Dominant Emery-Dreifuss Muscular Dystrophy The pathogenesis of FSHD is unknown. Facioscapulohumeral muscular dystrophy is an autosomal dominant disorder linked to The histopathological features of autosomal dominant Emery- the telomeric region of chromosome 4q35.138 An EcoRI polymor- Dreifuss muscular dystrophy (LGMD 1B) are identical to those phism in this region is present in the majority of FSHD patients described above for typical X-linked EDMD.19,20,57 Thus, as noted on chromosome 4q35. This EcoRI polymorphism is variable in size, previously, AD-EDMD and LGMD 1B are allelic disorders caused but is reduced compared to normal subjects (FSHD 10 to 30 kB; by mutations in the lamin A/C gene (LMNA) located on chromo- normal subjects 50 to 300 kB). Within this EcoRI polymorphism some 1q11-23.13,19,20,134 lies a tandem array of 3.3 kB repeats. Normally there are 12-96 copies of this repeat, but in FSHD there are less than 8 copies. Lamins A and C are produced by alternative splicing of the lamin A/C ribonucleic acid (RNA) transcript. As previously discussed X-Linked Emery-Dreifuss Muscular Dystrophy with X-linked EDMD, these lamins are important in the organization and integrity of the nuclear membrane. Muscle biopsies dem- Histopathology onstrate variation in fiber size, increased endomysial connective tissue, normal emerin expression, but lamin A/C expression may The muscle biopsy findings for X-linked Emery-Dreifuss muscular be reduced on nuclear membranes. However, immunostaining with dystrophy can be quite variable depending upon the degree of lamin A/C antibodies is sometimes normal. Electron microscopy weakness of the biopsied muscle.51 There is usually muscle-fiber size reveals nuclear alterations similar to X-linked EDMD in 10% of variation with type-1 fiber atrophy. There can be a predominance muscle fibers.105,116 There is loss of peripheral heterochromatin or of either type-1 or type-2 muscle fibers. Muscle fiber splitting, detachment from the nuclear envelope, alterations in interchroma- increased central nuclei, and endomysial fibrosis may be seen. tin texture, and fewer nuclear pores compared to normal. Immunohistochemistry reveals the absence of emerin as well as abnormal lamin A/C and lamin B2 on the nuclear membrane.106,109 Oculopharyngeal Muscular Dystrophy Ultrastructural studies demonstrates the focal absence of peripheral heterochromatin in areas between the nuclear pores, irregular and Histopathology uniform thickening of the nuclear lamina, compaction of heterochromatin in areas of irregular thickening of the nuclear lamina, The muscles most severely involved in oculopharyngeal muscular and areas where the peripheral heterochromatin does not adhere dystrophy (OPMD) are the extraocular and pharyngeal muscles, to the nuclear lamina.109 Diagnosis can be confirmed by immunos- although minor abnormalities may be detectable in the limb taining muscle or skin tissue for emerin or by immunoblot analysis muscles in advanced cases. Muscle biopsies reveal variation in fiber of leukocytes. size, degenerating and regenerating fibers, increased internal nuclei, D-20 Histopathology of Muscular Dystrophies AANEM Course

and an increase in adipose and endomysial connective tissue.26,64 may lead to disruption of various nuclear or cytoplasmic processes Rimmed vacuoles similar to those found in IBM/myopathy and leading to cell death. some of the distal myopathies are often, though not universally, observed. Intranuclear inclusions are evident in up to 9% of muscle nuclei on EM.18 These tubulofilamentous inclusions have an outer DISTAL MUSCULAR DYSTROPHIES diameter of approximately 8.5 nm, an inner diameter of 3 nm, are up to 0.25 µm in length, and are often arranged in tangles or This author considers the distal myopathies to be forms of muscular palisades.18 In addition, 15-18 nm tubulofilaments may be evident dystrophy.10,11 The distal myopathies are characterized clinically by in the cytoplasm as seen in inclusion body myositis, hereditary progressive atrophy and weakness of distal arm or leg muscles and inclusion body myopathy, and some of the distal myopathies. histologically by nonspecific myopathic features on muscle biopsy. Oculopharyngeal muscular dystrophy can be distinguished from Advances in the molecular genetics of these disorders support this various mitochondrial myopathies by the lack of ragged red fibers. notion as some types of distal myopathy have been found to be However, there have been a few cases of abnormal mitochondrial allelic with specific types of LGMD (Markesbery-Griggs/Udd distal structure and quantity on EM, although these findings are mostly myopathy and LGMD caused by titin mutations; Miyoshi my- suspected to be age-related. Further, muscle biopsies of pharyngeal opathy and LGMD 2B caused by dysferlin mutations). The distal muscles (taken at time of cricopharyngeal myotomy-anectdotal myopathies can be subdivided based upon the clinical features, age observations) reveal more severe abnormalities along with frequent of onset, CK levels, muscle histology, and mode of inheritance. rimmed vacuoles, ragged red fibers, and nemaline rods. Sural nerve biopsy in a few patients revealed a mild reduction in myelinated Welander Distal Myopathy and unmyelinated nerve fibers; however, this could have been normal given the patients’ advanced ages. Histopathology

Molecular Genetics and Pathogenesis In Welander distal myopathy, muscle biopsies demonstrate variability in fiber size, increased central nuclei, split fibers, increased Oculopharyngeal muscular dystrophy is caused by expansions of a endomysial connective tissue, and adipose cells in long-standing short glucagons (GCG) repeat within the poly(A) binding protein disease.22,23,24,48,80,86 Furthermore, rimmed vacuoles typical of IBM, nuclear (PABN1) gene on chromosome 14q11.1.18,25,26,64 Normally, h-IBM, and OPMD are seen in scattered muscle fibers. Electron there are six GCG repeats encoding for a polyalanine tract at the N- microscopy also reveals 15-18 nm cytoplasmic and nuclear fila- terminus of the protein, but approximately 2% of the population ments similar to those observed in IBM, h-IBM, and OPMD. In have polymorphism with seven GCG repeats (GCG)7. In OPMD, addition, disruption of myofibrils and accumulation of Z-disk there is an expansion to 8-13 repeats (GCG)8-13. Patients who are derived material similar to that found in myofibrillar myopathy heterozygous for (GCG)8-13 and the (GCG)7 polymorphism are also also can be demonstrated. Nerve biopsies may reveal a moderate more severely affected. Interestingly, a late-onset, autosomal reces- reduction of mainly small diameter, myelinated fibers.23 sive form of OPMD can develop in patients who are homozygous for the (GCG)7 polymorphism. The PABN1 (GCG)7 allele was the Molecular Genetics and Pathogenesis first example of a polymorphism that could act as a modifier of a dominant phenotype or as a recessive mutation. The pathogenesis of Welander distal myopathy is unknown. It has been linked to chromosome 2p13; the gene has not been identi- Poly(A) binding protein nuclear is found mostly in dimeric and fied. oligomeric form in the nuclei.35,121 Poly(A) binding protein nuclear is involved in polyadenylation of mitochondrial RNA (mRNA) and Udd Distal Myopathy is adjoined to the polyadenylated mRNA complex for transport through the nuclei pores into the cytoplasm. In the cytoplasm, Histopathology the PABPN1 detaches from the mRNA. The mRNA is translated into protein and the PABPN1 is actively transported back into In Udd distal myopathy, muscle biopsies reveal nonspecific the nuclei. The expansion of the GCG repeats probably results in myopathic features similar to that seen in Welander myopa- abnormal folding of the polyalanine domains of PABPN1. The thy.86,110,129,130 misfolded proteins are ubiquinated but are resistant to nuclear proteosomal degradation. The mutated PABPN1 oligomers then Molecular Genetics and Pathogenesis accumulate as the 8.5 nm intranuclear tubulofilamentous inclusions become apparent on EM.25,35,121 The more severe clinical phe- Mutations in the gene that encode for titin on chromosome 2q31- notypes are associated with a large number of myonuclei containing 33 have been identified.61,131 The giant protein titin (also known intranuclear inclusions.18 The aggregation of mutated PABPN1 as connectin) is attached to the Z disk and spans from the M-line AANEM Course Muscle and Nerve Pathology D-21

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Neurology 1991;41:1288-1292. ological and morphological comparison. J Neurol Sci 1991;103:76- 96. Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, 81. Masetti E, Mazzocco M, Egeo A, Donati MA, Volonte D, Galbiati F, 81. Liu J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C, Serrano C, Cordone G, Bricarelli FD, Lisanti MP, Zara F. Mutations in the caveo- Urtizberea JA, Hentati F, Hamida MB, Bohlega S, Culper EJ, Amato lin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. AA, Bossie K, Oeltjen J, Bejaoui K, McKenna-Yasek D, Hosler BA, Nat Genet 1998;18:365-368. Schurr E, Arahata K, de Jong PJ, Brown RH Jr. Dysferlin, a novel 97. Mizusawa H, Kurisaki H, Takatsu M, Inoue K, Mannen T, Toyokura skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle Y, Nakanishi T. Rimmed vacuolar distal myopathy: a clinical, electro- muscular dystrophy. Nat Genet 1998;20:31-36. physiological, histopathological and computed tomographic study of seven cases. 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98. Moghadaszadeh B, Petit N, Jaillard C, Brockington M, Roy SQ, 115. Richard I, Roudaut C, Saenz A, Pogue R, Grimbergen JE, Anderson Merlini L, Romero N, Estournet B, Desguerre I, Chaigne D, Muntoni LV, Beley C, Cobo AM, de Diego C, Eymard B, Gallano P, Ginjaar F, Topaloglu H, Guicheney P. Mutations in SEPN1 cause congenital HB, Lasa A, Pollitt C, Topaloglu H, Urtizberea JA, de Visser M, van muscular dystrophy with spinal rigidity and restrictive respiratory der Kooi A, Bushby K, Bakker E, Lopez de Munain A, Fardeau M, syndrome. Nat Genet 2001;29:17-18. Beckmann JS. Calpainopathy-a survey of mutations and polymor- 99. Moghadaszadeh B, Topaloglu H, Merlini L, Muntoni F, Estournet phisms. Am J Hum Genet 1999;64:1524-1540. B, Sewry C, Naom I, Barois A, Fardeau M, Tome FM, Guicheney P. 116. Sabatelli P, Lattanzi G, Ognibene A, Columbaro M, Capanni C, Genetic heterogeneity of congenital muscular dystrophy with rigid Merlini L, Maraldi NM, Squarzoni S. Nuclear alterations in autoso- spine syndrome. Neuromuscul Disord 1999;9:376-382. mal-dominant Emery-Dreifuss muscular dystrophy. Muscle Nerve 100. Moreira ES, Wiltshire TJ, Faulkner G, Nilforoushan A, Vainzof M, 2001;24:826-829. Suzuki OT, Valle G, Reeves R, Zatz M, Passos-Bueno MR, Jenne 117. Schoser BG, Frosk P, Engel AG, Klutzny U, Lochmuller H, DE. Limb-girdle muscular dystrophy type 2G is caused by mutations Wrogemann K. Commonality of TRIM32 mutation in causing sar- in the gene encoding the sarcomeric protein telethonin. Nat Genet cotubular myopathy and LGMD2H. Ann Neurol 2005;57:591-595. 2000;24:163-166. 118. Selcen D, Engel AG. Mutations in myotilin cause myofibrillar myopa- 101. Mues A, van der Ven PF, Young P, Furst DO, Gautel M. Two im- thy. Neurology 2004;62:1363-1371. munoglobulin-like domains of the Z-disc portion of titin interact 119. Selcen D, Stilling G, Engel AG. The earliest pathologic alterations in in a conformation-dependent way with telethonin. FEBS Lett dysferlinopathy. Neurology 2001;56:1472-1481. 1998;428:111-114. 120. Sewry CA, Naom I, D’Alessandro M, Sorokin L, Bruno S, Wilson 102. Munsat TL, Piper D, Cancilla P, Mednick J. Inflammatory myopathy LA, Dubowitz V, Muntoni F. Variable clinical phenotype in merosin- with facioscapulohumeral distribution. Neurology 1972;22:335-347. deficient congenital muscular dystrophy associated with differential 103. Muntoni F, Voit T. 133rd ENMC International Workshop on immunolabelling of two fragments of the laminin alpha 2 chain. Congenital Muscular Dystrophy (IXth International CMD Workshop) Neuromuscul Disord 1997;7:169-175. 21-23 January 2005, Naarden, The Netherlands. Neuromuscul 121. Shanmugam V, Dion P, Rochefort D, Laganiere J, Brais B, Rouleau Disord 2005;15:794-801. GA. PABP2 polyalanine tract expansion causes intranuclear inclusions 104. Muntoni F, Voit T. The congenital muscular dystrophies in 2004: a in oculopharyngeal muscular dystrophy. Ann Neurol 2000;48:798- century of exciting progress. Neuromuscul Disord 2004;14:635-649. 802. 105. Nagano A, Arahata K. Nuclear envelope proteins and associated 122. Sivakumar K, Dalakas MC. The spectrum of familial inclusion body diseases. Curr Opin Neurol 2000;13:533-539. myopathies in 13 families and a description of a quadriceps-sparing 106. Nagano A, Koga R, Ogawa M, Kurano Y, Kawada J, Okada R, phenotype in non-Iranian Jews. Neurology 1996;47:977-984. Hayashi YK, Tsukahara T, Arahata K. Emerin deficiency at the 123. Sotgia F, Woodman SE, Bonuccelli G, Capozza F, Minetti C, Scherer nuclear membrane in patients with Emery-Dreifuss muscular dystro- PE, Lisanti MP. Phenotypic behavior of caveolin-3 R26Q, a mutant phy. Nat Genet 1996;12:254-259. associated with hyperCKemia, distal myopathy, and rippling muscle 107. Nonaka I, Sunohara N, Ishiura S, Satoyoshi E. Familial distal myopa- disease. Am J Physiol Cell Physiol 2003;285:C1150-C1160. thy with rimmed vacuole and lamellar (myeloid) body formation. J 124. Spencer MJ, Tidball JG, Anderson LV, Bushby KM, Harris JB, Neurol Sci 1981;51:141-155. Passos-Bueno MR, Somer H, Vainzof M, Zatz M. Absence of 108. Nonaka I, Sunohara N, Satoyoshi E, Terasawa K, Yonemoto K. calpain 3 in a form of limb-girdle muscular dystrophy (LGMD2A). J Autosomal recessive distal muscular dystrophy: a comparative study Neurol Sci 1997;146:173-178. with distal myopathy with rimmed vacuole formation. Ann Neurol 125. Sunohara N, Nonaka I, Kamei N, Satoyoshi E. Distal myopathy with 1985;17:51-59. rimmed vacuole formation. A follow-up study. Brain 1989;112:65- 109. Ognibene A, Sabatelli P, Petrini S, Squarzoni S, Riccio M, Santi S, 83. Villanova M, Palmeri S, Merlini L, Maraldi NM. Nuclear changes in a 126. Taylor J, Muntoni F, Robb S, Dubowitz V, Sewry C. Early onset case of X-linked Emery-Dreifuss muscular dystrophy. Muscle Nerve autosomal dominant myopathy with rigidity of the spine: a possible 1999;22:864-869. role for laminin beta 1? Neuromuscul Disord 1997;7:211-216. 110. Partanen J, Laulumaa V, Paljarvi L, Partanen K, Naukkarinen A. Late 127. Toda T, Kobayashi K, Kondo-Iida E, Sasaki J, Nakamura Y. onset foot-drop muscular dystrophy with rimmed vacuoles. J Neurol The Fukuyama congenital muscular dystrophy story. Neuromuscul Sci 1994;125:158-167. Disord 2000;10:153-159. 111. Piccolo F, Moore SA, Ford GC, Campbell KP. Intracellular accu- 128. Toda T, Yoshioka M, Nakahori Y, Kanazawa I, Nakamura Y, mulation and reduced sarcolemmal expression of dysferlin in limb-- Nakagome Y. Genetic identity of Fukuyama-type congenital muscular girdle muscular dystrophies. Ann Neurol 2000;48:902-912. dystrophy and Walker-Warburg syndrome. Ann Neurol 1995;37:99- 112. Prior TW, Bartolo C, Pearl DK, Papp AC, Snyder PJ, Sedra MS, 101. Burghes AH, Mendell JR. Spectrum of small mutations in the dys- 129. Udd B, Haravuori H, Kalimo H, Partanen J, Pulkkinen L, Paetau trophin coding region. Am J Hum Genet 1995;57:22-33. A, Peltonen L, Somer H. Tibial muscular dystrophy--from clinical 113. Reichmann H, Goebel HH, Schneider C, Toyka KV. Familial mixed description to linkage on chromosome 2q31. Neuromuscul Disord congenital myopathy with rigid spine phenotype. Muscle Nerve 1998;8:327-332. 1997;20:411-417. 130. Udd B, Partanen J, Halonen P, Falck B, Hakamies L, Heikkila H, Ingo 114. Richard I, Broux O, Allamand V, Fougerousse F, Chiannilkulchai N, S, Kalimo H, Kaariainen H, Laulumaa V. Tibial muscular dystrophy. Bourg N, Brenguier L, Devaud C, Pasturaud P, Roudaut C. Mutations Late adult-onset distal myopathy in 66 Finnish patients. Arch Neurol in the proteolytic enzyme calpain 3 cause limb-girdle muscular dys- 1993;50:604-608. trophy type 2A. Cell 1995;81:27-40. D-26 Histopathology of Muscular Dystrophies AANEM Course

131. Udd B, Vihola A, Sarparanta J, Richard I, Hackman P. Titinopathies 136. Wewer UM, Durkin ME, Zhang X, Laursen H, Nielsen NH, and extension of the M-line mutation phenotype beyond distal my- Towfighi J, Engvall E, Albrechtsen R. Laminin beta 2 chain and opathy and LGMD2J. Neurology 2005;64:636-642. adhalin deficiency in the skeletal muscle of Walker-Warburg syn- 132. Vachon PH, Xu H, Liu L, Loechel F, Hayashi Y, Arahata K, Reed JC, drome (cerebro-ocular dysplasia-muscular dystrophy). Neurology Wewer UM, Engvall E. Integrins (alpha7beta1) in muscle function 1995;45:2099-2101. and survival. Disrupted expression in merosin-deficient congenital 137. Wewer UM, Engvall E. Merosin/laminin-2 and muscular dystrophy. muscular dystrophy. J Clin Invest 1997;100:1870-1881. Neuromuscul Disord 1996;6:409-418. 133. van der Kooi AJ, Ledderhof TM, de Voogt WG, Res CJ, Bouwsma 138. Wijmenga C, Hewitt JE, Sandkuijl LA, Clark LN, Wright TJ, G, Troost D, Busch HF, Becker AE, de Visser M. A newly recognized Dauwerse HG, Gruter AM, Hofker MH, Moerer P, Williamson R. autosomal dominant limb girdle muscular dystrophy with cardiac Chromosome 4q DNA rearrangements associated with facioscapu- involvement. Ann Neurol 1996;39:636-642. lohumeral muscular dystrophy. Nat Genet 1992;2:26-30. 134. van der Kooi AJ, van Meegen M, Ledderhof TM, McNally EM, de 139. Woodman SE, Sotgia F, Galbiati F, Minetti C, Lisanti MP. Visser M, Bolhuis PA. Genetic localization of a newly recognized Caveolinopathies: mutations in caveolin-3 cause four distinct autoso- autosomal dominant limb-girdle muscular dystrophy with cardiac in- mal dominant muscle diseases. Neurology 2004;62:538-543. volvement (LGMD1B) to chromosome 1q11-21. Am J Hum Genet 140. Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H, Mizuno 1997;60:891-895. M, Inazu T, Mitsuhashi H, Takahashi S, Takeuchi M, Herrmann R, 135. van Reeuwijk J, Janssen M, van den Elzen C, Beltran-Valero de Straub V, Talim B, Voit T, Topaloglu H, Toda T, Endo T. Muscular Bernabe D, Sabatelli P, Merlini L, Boon M, Scheffer H, Brockington dystrophy and neuronal migration disorder caused by mutations in a M, Muntoni F, Huynen M, Verrips A, Walsh C, Barth P, Brunner glycosyltransferase, POMGnT1. Dev Cell 2001;1:717-724. H, van Bokhoven H. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker Warburg syndrome. J Med Genet 2005;42:907-912. D-27

Pathology of Muscle in Mitochondrial Disorders

Kurenai Tanji, MD, PhD Assistant Professor Department of Clinical Pathology Columbia University Medical Center New York, New York

INTRODUCTION The mitochondrial genome is a double-stranded circular molecule of 16,569 bp that encodes for 13 structural proteins of the RC, Mitochondrial diseases are a heterogeneous group of disorders and the 22 transfer ribonucleic acid (tRNAs) and 2 ribosomal which are a result of dysfunctional oxidative phosphorylation ribonucleic acids (rRNAs) that are necessary for their translation. (OXPHOS). The OXPHOS system is composed of four enzyme There are basic rules to understund the mitochondrial genetics:18 complexes (Complex I – IV) that make up the mitochondrial (1) maternal inheritance; (2) polyplasmy; (3) heteroplasmy; (4) respiratory chain (RC), and the adenosine triphosphate (ATP) threshold effect; and (5) tissue and temporal variation. These rules synthase complex (Complex V) which use energy generated by explain at least in part clinical and pathological heterogeneity of electron transport along the RC to produce ATP. Impairment mtDNA-related disorders. of this system can produce pathological alterations in any organ system. This makes the recognition, diagnosis, and classification The signature muscle pathology in many, but not all, patients of mitochondrial diseases challenging, because patients can present are ragged red fibers (RRFs). Ragged red fibers are detected by with a wide variety of signs and symptoms that often do not fit into the modified Gomori trichrome stain, but the most sensitive and preconceived clinical phenotypes. precise method to demonstrate the segmental accumulations of mitochondria is succinate dehydrogenase (SDH) (Figure 1). The The OXPHOS enzyme assembly is governed by two genomic ragged appearance of RRFs is due to the proliferation of subsar- systems, mitochondrial deoxyribonucleic acid (mtDNA) and colemmal and interfibrillar mitochondria, which are abnormal ge- nuclear DNA (nDNA). Of more than 80 structural subunits in 5 netically, morphologically, and histochemically. The percentage of complexes, mtDNA encodes 13. In addition to the essential struc- RRFs can vary from 2%-70%. Ragged red fibers are usually absent tural components, a set of proteins is necessary for assembly and of cytochrome c oxidase (COX) activity or have greatly reduced maintenance of the complexes, which are nDNA encoded. Thus, COX activity relative to the increased mitochondrial volume as mitochondrial diseases can demonstrate any mode of inheritance: seen by the SDH stain (Figure 2), and they are known as COX- maternal, autosomal dominant or recessive, or sporadic. negative or COX-deficient fibers. The mitochondrial proliferation D-28 Pathology of Muscle in Mitochondrial Disorders AANEM Course

Figure1 Serial sections stained by Gomori trichrome (A) and succinate dehydrogenase (SDH) (B). Ragged red fibers are detected by the modified Gomori trichrome stain, but the most sensitive and precise method to demonstrate the segmental accumulations of mitochondria is SDH.

Figure 2 Cytochrome c oxidase (COX)-negative ragged red fibers. Ragged red fibers are often negative or show greatly reduced cytochrome c oxidase (COX) reactivity (A: succinate dehydrogenase, B: COX). AANEM Course Muscle and Nerve Pathology D-29 in RRFs is presumably a compensation mechanism, however, the compromised translation of the genome due to removal of mtDNA signals triggering segmental proliferation of mitochondria remain encoded tRNA genes by each deletion.38 to be elucidated. Point Mutations in Transfer Ribonucleic Acid Genes MITOCHONDRIAL DEOXYRIBONUCLEIC ACID MUTATIONS Genetics Mitochondrial DNA mutations have been classified into three main categories: large-scale deletions, point mutations in tRNAs or Point mutations are the most common form of mtDNA muta- rRNAs, and point mutations in protein coding genes. tions associated with mitochondrial myopathies. Over 60 different mutations in the tRNA genes have been reported, including Large-scale Deletions the two most common clinical phenotypes of mitochondrial diseases, namely mitochondrial encephalopathy, lactic acidosis, Genetics and stroke-like episodes (MELAS), and myoclonic epilepsy and RRFs (MERRF). These mutations interfere with the translation Large-scale deletions (delta [Δ]-mtDNAs) remove multiple tRNAs of the mitochondrial genome, and they are always heteroplasmic. and protein coding genes,37 and impair the translation of mito- Mitochondrial encephalopathy, lactic acidosis, and stroke-like chondrial genomes, producing multiple deficiencies in the RC episodes have been associated with at least 10 different point muta- enzyme activities. Most cases are sporadic except for rare reports of tions, 4 of which are located in the same gene, tRNALeu(UUR). The germline transmission.56 The mechanism by which Δ-mtDNAs are most common point mutation (80% of cases) is an A3243G transi- generated is unknown, although slip replication and recombination tion in the tRNALeu(UUR).18 This mutation is also an important cause have been suggested.36 All patients with Δ-mtDNAs are hetero- of PEO.39 The pathogenicity of A3243G mutation is well estab- plasmic,59 and the clinical phenotypes depend on the distribution lished. The altered tRNA fails to undergo proper posttranslational of mutation load at birth and subsequent random segregation in modification (misaminoacylation), leading to impaired mitochon- daughter cells during growth. The sizes of deletions vary by patient, drial protein synthesis.72 In MERRF, 80% of the cases are associ- but each given patient has deleted molecules of the same size. It is ated with A8344G mutations in the tRNALys gene and a smaller suggested that the Δ-mtDNA arises early in oogenesis. percentage of the patients have T8356C mutation in the same gene.57,61 These mutations also cause a defective aminoacylation of Clinical Aspects the tRNALys, resulting in premature translation termination.20 The threshold effect in the A8344G mutation has been demonstrated The phenotypes vary from the most common and mildest form, in muscle culture cells: Myotubes harboring the A8344G muta- a myopathy with progressive ophthalmoplegia (PEO), ptosis, and tion show no biochemical defect until the proportion of mutant proximal limb weakness, to a more severe form, Kearns-Sayre mtDNAs exceeds 85%,8 and there is a good correlation between the syndrome (KSS), to the most severe form, Pearson syndrome (PS). extent of the translation defect and the lysine content of different Pearson syndrome is almost invariably fatal in infancy with sidero- mtDNA-encoded polypeptides.20 blast anemia and exocrine pancreatic dysfunction. Children that outlive PS develop KSS later in life. Kearns-Sayre syndrome is clini- Clinical Aspects cally characterized by PEO, pigmentary degeneration of the retina, and heart block, plus a variety of less consistent additional symp- The majority of tRNA mutations are most commonly associ- toms, such as ataxia, dementia, nephropathy, or endocrinopathy. ated with disorders of the central nervous system, peripheral nerve, skeletal muscle, and myocardium. In MELAS, the clinical Pathology hallmarks are the stroke-like episodes with hemiparesis or hemi- anopsia, almost invariably occurring before age 40, and often in Muscle biopsies show characteristic RRFs. The RRF segments childhood. Common additional findings include lactic acidosis, contain large accumulation of Δ-mtDNAs and their transcripts, focal and generalized seizures, recurrent migraine-like headaches indicating that the mutation does not affect transcription.35 The and vomiting, and dementia. The course is one of gradual dete- relative proportion of wild-type mtDNAs in the RRF segments rioration, and MELAS families often have oligosymptomataic and is always decreased and they have reduced or absent staining of asymptomatic maternal relatives. Myoclonic epilepsy and RRFs are COX. Polypeptides encoded by mtDNA are not detectable by im- characterized by myoclonus, seizures, ataxia, and myopathy with munohistochemistry in RRFs, even those encoded outside the dele- RRFs. Less consistent features include cardiomyopathy, dementia, tion, indicating that the pathogenicity of Δ-mtDNA is related to neuropathy, multiple symmetrical lipomatosis, and short stature. D-30 Pathology of Muscle in Mitochondrial Disorders AANEM Course

The myoclonic jerks occur at rest and worsen during movement (3) cytochrome b (Cyt b) mutations; and (4) COX subunit muta- (action myoclonus). Onset is usually in childhood, but adult onset tions. has been described. As seen in MELAS, maternal family members in MERRF may be oligosymptomatic or asymptomatic. Complex I Genes Mutations

Pathology Genetics and Clinical Aspects

These mutations are almost always associated with RRFs, and all Leber hereditary optic neuropathy (LHON) has been associated show threshold behavior in muscle. Characteristically, in MELAS, with G11778A (ND4 gene), G3460A (ND1), and T14484C RRFs are COX-positive in contrast to many other tRNA point (ND6) mutations.71 Isolated myopathy characterized by exercise mutations and large-scale Δ-mtDNA, although careful analysis intolerance, myalgia, lactic acidosis, and complex I deficiency has finds that the activity is usually reduced relative to the mito- been linked to mutations in the ND1,40 ND2,53 and ND42 genes. chondrial proliferation observed by the SDH stain (Figure 3). In In one case report, the 2-bp deletion in the ND2 gene of a patient addition, blood vessels in MELAS show an interesting pathology was remarkable because it was discovered that the muscle mtDNA called “strongly SDH reactive blood vessels (SSVs)”24 (Figure 4), was mostly of paternal origin. Although this situation does not indicating mitochondrial proliferation in smooth muscle, pericytes, negate the general rule that mtDNA is transmitted maternally, it and endothelial cells of arterial walls. Unlike MELAS patients raises the possibility that tissue-specific paternal mtDNA inheri- muscle biopsies of MERRF patients reveal COX-negative RRFs tance might somehow favor mutagenesis, since the patient’s father and SSVs. was healthy and did not carry the mutation in blood. Mutations in the ND5 gene have been associated with multisystemic disorders such as MELAS51 and various overlap syndromes including MELAS Point Mutations in Ribosomal Ribonucleic Acids Gene and Leigh syndrome (LS),13 MELAS and MERRF,41 MELAS and 47 30 Genetics and Clinical Aspects LHON, and MELAS, LS, and LHON. Pathology A1555G substitution in the 12S rRNA gene has been associated with deafness,14 deafness and Parkinson’s disease,58 and cardiomy- Leber hereditary optic neuropathy mutations cause pathology only opathy.52 in the optic nerve. Patients with other mutations in complex I invariably show isolated complex I deficiency in the muscle biop- Pathology sies. The myopathies associated with ND1 and ND4 genes show COX-positive RRF in muscle biopsies. The case report53 of paternal Rare RRFs are found in muscle biopsies from the patients with inheritance (ND2 mutation) also described the presence of RRFs deafness. The RRFs are either COX-positive or COX-negative.14 (COX staining was not reported). In ND5 mutations associated No SSV has been demonstrated. In a cardiomyopathy case, the with multisystemic disorders, RRFs (either COX-positive or COX- muscle biopsy showed central or paracentral minicores and reduc- negative fibers) and SSV are usually evident. tions in COX and nicotinamide adenin dinucleoacid hydrogen (NADH)-dehydrogenase activities.52 ATP 6 Gene Mutations Genetics and Clinical Aspects POINT MUTATIONS IN PROTEIN CODING GENES A mutation in the ATP6 gene (T8993G) was first reported in a Point mutations in protein coding genes defects lead to specific syndrome that includes neuropathy, ataxia, and retinitis pigmen- deficiencies in RC complexes. These mutations are less common tosa (NARP).25 The onset occurs in infancy or early childhood. than deletions and tRNA mutations. Most common phenotypes Myopathy is rare. Interestingly, patients with heteroplasmy that include: (1) complex I mutations; (2) ATPase 6 gene mutations; have a mutant load between 70%-90% of mtDNA manifest AANEM Course Muscle and Nerve Pathology D-31

Figure 3 Cytochrome c oxidase (COX)-positive ragged red fibers (RRFs) in a case of mitochondrial encephalomyopathy with lactic acidosis and stroke- like episodes (MELAS) (A: succinate dehydrogenase [SDH], B:COX). Characteristically, in MELAS, RRFs are COX-positive in contrast to many other transfer ribonucleic acid gene point mutations and large-scale Δ-mitochondrial deoxyribonucleic acid, although the activity is usually reduced relative to the mitochondrial proliferation observed by the SDH stain.

Figure 4 Strongly succinate dehydrogenase reactive blood vessels (SSVs) indicate mitochondrial proliferation in smooth muscle, pericytes, and endothelial cells of arterial walls. In mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes cases, SSVs are also Cytochrome c oxidase (COX)-positive (A: succinate dehydrogenase, B: COX). D-32 Pathology of Muscle in Mitochondrial Disorders AANEM Course

Pathology variable clinical symptoms, while patients with more than 90% of mutant mtDNAs usually present with LS. Leigh syndrome, Muscle morphology usually reveals RRFs. Strikingly, these muta- historically called subacute necrotizing encephalomyelopathy, is tions also show a number of COX-negative fibers that are not characterized by hypotonia, failure to thrive, seizures, respiratory RRFs. Note, however, that there are no “dogmas” in muscle pathol- dysfunction, and ataxia. T2-weighted magnetic resonance imaging ogy, as two patients have been reported without RRFs.10,23 (MRI) shows bilateral, often symmetrical, hyperintensity in the basal ganglia, cerebellum, and brainstem. A T8993G mutation One case with COX III mutation and a typical clinical phenotype causes a leucine to arginine substitution within the proton channel of MELAS showed a few RRFs, but surprisingly, no histochemical 67 34 of the F0 segment of complex V that impairs ATP synthesis. evidence of COX deficiency was present.

Pathology NUCLEAR DIOXYRIBONUCLEIC ACID MUTATIONS Patients with NARP mutation do not show RRFs in muscle biopsies, although some cases reveal neurogenic (denervation) atrophy. Nuclear DNA mutations are a particularly interesting group of disorders because the primary genetic defect is in the nDNA, but Cytochrome b Gene Mutations the consequence of the nDNA mutation is either a quantitative (mtDNA depletion syndromes) or a qualitative defect of mtDNA Genetics and Clinical Aspects (multiple Δ-mtDNAs). This is due to the fact that, in the course of evolution, the symbiotic protobacteria have lost much of their Most patients with Cyt b mutations present with exercise intol- autonomy and have become increasingly dependent on the host erance, myalgia, and lactic acidosis, sometimes accompanied by cell’s genome, which encodes the factors controlling mtDNA repli- myoglobinuria.3 There is a single report of a patient with Cyt b cation, transcription, and translation. mutation that clinically had juvenile Parkinson/MELAS overlap syndrome.15 Two other patients have been reported with severe hypertrophic cardiomyopathy.4 Most of them had mutations within NUCLEAR-MITOCHONDRIAL COMMUNICATION or close to the ubiquinone-binding sites of Cyt b, suggesting that DISORDERS most Cyt b mutations are likely to have a severe effect on mito- Mitochondrial Dioxyribonucleic Acid Depletion chondrial energy production. Syndrome Pathology Genetics

Muscle morphology reveals COX-positive RRFs. In patients with Mitochondrial DNA depletion syndrome is caused by a quan- the isolated myopathy, the mutant mtDNA was absent in blood titative defect of mtDNA. Muscular dystrophies are usually and/or fibroblasts in all cases examined. This is consistent with the inherited as autosomal recessive (AR) traits, but they can be drug- restriction of the clinical phenotype to skeletal muscle, the sponta- induced.6,14,65 Mutations in two nuclear genes have been identified: neous occurrence of these mutations, and the likelihood that they the deoxyguanosine kinase (dGK) gene with the hepatic form,33,50 would not be transmitted to the patient’s offspring. It may also in- the thymidine kinase 2 (TK2) gene with the myopathic form.48 dicate that the mutation in these patients may have arisen in muscle However, not all patients of muscular dystrophies have these two progenitor cells, after differentiation of the primary germ layers.3 mutations, which indicates the involvement of other genes.

Cytochrome C Oxidase Genes Mutations Clinical Aspects

Genetics and Clinical Aspect The AR forms fall into two major groups; one dominated by myopathy, and the other by hepatopathy, though both presentations Mutations in each of the three COX subunits that are encoded by involve other tissues including brain, kidney, and heart.70 The mtDNA can cause either tissue specific disorders such as myopathy myopathic form can be apparent at birth and cause fatal respira- (COX I and II)23,27 and sideroblastic anemia (COX I),21 or multi- tory failure within a month, or develop at about 1 year of age and systemic disorders such as MELAS (COX III),34 an amyotrophic progress more slowly, often simulating muscular dystrophies. The lateral sclerosis-like phenotype (COX I),12 and encephalopathies differential diagnosis is sometimes difficult because of the fact (COX I and II).10,11 that muscular dystrophies can show, unlike other mitochondrial AANEM Course Muscle and Nerve Pathology D-33

myopathies, marked elevation of serum creatine kinase (CK). In a to cachexia and early death. Additional signs include ptosis, PEO, case report, one of two siblings with a homozygous mutation in the peripheral neuropathy, and leukoencephalopathy. Some AR-PEO TK2 gene was reported to present a phenotype of spinal muscular had mutaions in the POLG gene,29,69 and MNGIE is caused by loss atrophy (SMA) type I.32 Another case report described a child with of function mutation in the thymidine phosphorylase (TP).42 This the SMA phenotype and mtDNA depletion.45 These cases with TP mutation may cause disruption of the mitochondrial nucleotide SMA phenotypes raise an important point—that mitochondrial pool, resulting in mtDNA abnormalities, both MDs and mtDNA dysfunction should be considered when patients do not show mu- depletion. tations in the survival motor neuron (SMN) gene. Pathology Pathology Muscle biopsy usually shows RRF and COX-negative fibers, and In the congenital myopathic form of mtDNA depletion syndrome, biochemical analysis reveals combined respiratory chain defects. muscle biopsy shows RRF and diffuse COX deficiency. In addition, muscle biopsy of some muscular dystrophy patients may exhibit significant myopathic alterations, similar to what are observed in NUCLEAR GENE MUTATIONS CAUSING ISOLATED muscular dystrophies. In the later onset form, initial biopsies may RESPIRATORY CHAIN COMPLEX DEFICIENCIES show only nonspecific changes, while samples taken later show RRF and COX-negative fibers. The biopsies of cases with SMA Respiratory chain complex deficiencies diseases are caused by muta- phenotype reveal characteristic neurogenic abnormalities as seen in tions in nuclear genes encoding proteins that are essential for the SMA with SMN gene mutations. Biochemical analysis of muscular biosynthesis of specific cofactors for assembly of the complexes. dystrophy cases reveals combined defects of respiratory chain com- Disorders associated with complex IV deficiency will be reviewed. plexes that contain mtDNA-encoded subunits. Complex IV-deficient Leigh Syndrome Multiple Deletions Genetics and Clinical Aspects Genetic and Clinical Aspects One of the most common causes of LS is COX deficiency and it is inherited as an AR trait.60 Surprisingly, no mutation was found in Multiple deletions (MDs) are qualitative defects of mtDNA. the nDNA-encoded subunits of COX, despite extensive sequence Syndromes associated with MDs affect predominantly muscle, and studies.1,26 Recently, mutations were detected in several COX-as- usually present as PEO or as isolated proximal muscle weakness. sembly genes: the SURF1 gene in patients with LS,68,74 and the Both AR and autosomal dominant (AD) traits have been reported. SCO2 gene with fatal cardioencephalomyopathy,44 and SCO1, Autosomal dominnant-PEO, not unlike the sporadic form of PEO COX10, and COX15 genes with multisystem disorders associated due to single Δ-mtDNA, is also a relatively benign condition with with COX deficiency.60 onset in adolescence or young adult life and slow progression. However, multisystemic symptoms can also occur in these patients Pathology such as dysphagia, dysphonia, neuropathy, hearing loss, cataracts, and depression.55,64 Mutations in three genes have been reported In these patients COX activity is reduced in most tissues, with ap- with AD-PEO: adenine nucleotide translocator 1 (ANT1),28 parently little or no tissue specificity as reflected by the degree of Twinkle,62 and polymerase γ (POLG).69 However, these three genes enzyme deficiency.31 Muscle histochemistry in patients with SURF1 do not explain all cases of AD-PEO and other genes remain to be or SCO2 genes show only minor cytoarchitectural changes and no identified. Autosomal recessive-PEO is most often multisystemic, as RRFs. Complex IV histochemical staining is diffusely reduced, illustrated by two syndromes, (1) AR cardiomyopathy and ophthal- but not totally absent, affecting equally type I and II myofibers, moplegia (ARCO),7 and (2) mitochondrial neurogastrointestinal intrafusal muscle fibers, and the vascular walls.66 This pattern of encephalopathy (MNGIE).43 Autosomal recessive cardiomyopathy COX deficiency is more severe in patients with SCO2 mutations and ophthalmoplegia presents with childhood-onset PEO, facial than SURF1 mutations, and is consistent with results of biochemi- and proximal limb weakness, and severe cardiomyopathy requir- cal studies.63 The profuse COX-deficiency associated with SCO2 ing cardiac transplantation. Mitochondrial neurogastrointestinal mutations may relate to the observation that all known SCO-like encephalopathy is dominated by gastrointestinal tract symptoms proteins bind copper, and that COX I and II contain copper.22 such as intestinal pseudo-obstruction and chronic diarrhea leading Pathogenesis of the SURF1 mutation is not yet well understood. D-34 Pathology of Muscle in Mitochondrial Disorders AANEM Course

Complex IV-deficient Infantile Myopathy 3. Andreu AL, Hanna MG, Reichmann H, Bruno C, Penn AS, Tanji K, et al. Exercise intolerance and mutations in the cytochrome b gene Genetic and Clinical Aspects of mitochondrial DNA. N Eng J Med 1999;341:1037-1044. 4. Andreu AL, Checcarelli N, Iwata S, Shanske S, DiMauro S. A missense mutation in the mitochondrial cytochrome b gene in a revisited Two myopathic variants, fatal and benign infantile myopathies, are case with histiocytoid cardiomyopathy. Pediatr Res 2000;48:311-314 presumably due to mutations in muscle-specific and developmen- 5. Arbustini E, Diegoli M, Fasani R, Grasso M, Morbini P, Banchieri N, tally regulated COX subunits or COX-assembly proteins, although et al. Mitochondrial DNA mutations and mitochondrial abnormali- 9,19 gene defects have not been identified in either condition. The ties in dilated cardiomyopathy. Am J Pathol 1998;153:1501-1510. fatal infantile myopathy causes respiratory insufficiency and death 6. Arnaudo E, Dalakas M, Shanske S, Moraes CT, DiMauro S, Schon before 1 year of age. Renal dysfunction is often associated, and EA. Depletion of muscle mitochondrial DNA in AIDS patients with patients suffer from Toni-Fanconi syndrome.16 The benign infantile zidovudine-induced myopathy. Lancet 1991;337:508-510. myopathy also causes severe weakness early in life, often requiring 7. Bohlega S, Tanji K, Santorelli FM, Hirano M, al-Jishi A, DiMauro S. assisted ventilation, but symptoms improve spontaneously and Multiple mitochondrial DNA deletions associated with autosomal these children are usually normal by 2 or 3 years of age.17,49,54,73 recessive ophthalmoplegia and severe cardiomyopathy. Neurology 1996;46:1329-1334. 8. Boulet L, Karpati G, Shoubridge EA. Distribution and threshold Pathology expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERFF). Am J Hum Muscle biopsy of fatal infantile myopathy shows RRFs and diffuse Genet 1992;51:1187-1200. lack of COX reactivity in myofibers, but normal reaction in intra- 9. Bresolin N, Zeviani M, Bonilla E, Miller RH, Leech RW, Shanske S, muscular blood vessels and in the muscle spindles.49 Muscle biopsies et al. Fatal infantile cytochrome c oxidase deficiency: decrease of im- from the benign form are peculiar. Biopsies taken from the neonatal munologically detectable enzyme in muscle. Neurology 1985;35:802- period show no RRF but diffuse absence of COX stain, except for 812. blood vessels and spindles. However, biopsies taken at later times 10. Bruno C, Martinuzzi A, Tang Y, Andreu AL, Pallotti F, Bonilla E, show increasing numbers of COX-positive fibers and RRFs, which et al. A stop-codon mutation in the human mtDNA cytochrome eventually return to a normal or near-normal morphology. c oxidase I gene disrupts the structure and function of respiratory chain complex IV. Am J Hum Genet 1999;65:611-620. 11. Clark KM, Taylor RW, Johnson MA, Chinnery PF, Chrzanowska- SUMMARY Lightowlers ZM, Andrews RM, et al. An mtDNA mutation in the initiation codon of the cytochrome c oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalopathy. Over the past 20 years, many mitochondrial diseases have been Am J Hum Genet 1999;64:1330-1339. genetically, clinically, and pathologically defined. Many are associ- 12. Comi GP, Bordoni A, Salani S, Franceschina L, Sciacco M, Prelle A, ated with mtDNA mutations, while others are caused by nDNA et al. Cytochrome c oxidase subunit I microdeletion in a patient with mutations that affect mtDNA and the respiratory chain in vari- motor neuron disease. Ann Neurol 1998;43:110-116. able fashions. Certainly, many more new genetic and/or clinical 13. Crimi M, Galbiati S, Moroni I, Bordoni A, Perini MP, Lamantea E, et phenotypes will be discovered, and the mechanisms by which such al. A missense mutation in the mitochondrial ND5 associated with a genetic alterations are ultimately demonstrated as human diseases Leigh-MELAS overlap syndrome. Neurology 2003;60:1857-1861. remain to be elucidated. Mitochondrial disorders characteristically 14. Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL. Mitochondrial myopathy caused by long-term zidovudine therapy. involve multiple organ systems, with a predilection for tissues that N Engl J Med 1990;322:1098-1105. are highly dependent upon oxidative metabolism, such as muscle 15. De Coo IF, Renier WO, Ruitenbeek W, Ter Laak HJ, Bakker M, and brain. It is important to recognize neuromuscular involvement Schagger H, et al. A 4-base pair deletion in the mitochondrial cy- in the patients through muscle biopsy, and it is hoped that this tochrome b gene associated with parkinsonism/MELAS overlap manuscript provides a practical and theoretical guidance to biopsy syndrome. Ann Neurol 1999;45:130-133. interpretation. 16. DiMauro S, Mendell JR, Sahenk Z, Bachman D, Scarpa A, Scofield RM, Reiner C. Fatal infantile mitochondrial myopathy and renal dysfunction due to cytochrome c oxidase deficiency. Neurology REFERENCES 1980;30:795-804. 17. DiMauro S, Nicholson JF, Hays AP, Eastwood AB, Papadimitriou A, Koenigsberger R, DeVivo DC. Benign infantile mitochondrial 1. Adams PL, Lightowlers RN, Turnbull DM. Molecular analysis of myopathy due to reversible cytochrome c oxidase deficiency. Ann cytochrome c oxidase deficiency in Leigh’s syndrome. Ann Neurol Neurol 1983;14:226-234. 1997:41:268-270. 18. DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N 2. Andreu AL, Tanji K, Bruno C, Hadjigeorgiou GM, Sue CM, Jay C, et Engl J Med 2003;348:2656-2668. al. Exercise intolerance due to a nonsense mutation in the mtDNA 19. DiMauro S, Bonilla E, Mancuso M, Filosto M, Sacconi S, Salviati L, ND4 gene. Ann Neurol 1999;45:820-823. et al. Mitochondrial myopathies. 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Pathology of Motor Nerve Biopsy

Annabel K. Wang, MD Assistant Professor Department of Neurology Mount Sinai Medical Center New York, New York

INTRODUCTION interstitial changes and not to differentiate, for example, between demyelinating and axonal neuropathies. In a multifocal pattern, Traditionally, nerve biopsies have been utilized in sensory nerves nerve biopsy can be used to make a diagnosis of vasculitis or ma- such as the sural and superficial peroneal nerves, to avoid com- lignancy. When noninvasive tests are inconclusive, and diagnoses plications such as weakness. Pathological study of sensory nerves, such as inflammation, vasculitis, granuloma, demyelination, infec- however, is generally not useful in the evaluation of lower motor tion, neoplasia, or amyloidosis are suspected, nerve biopsy could be neuron syndromes. Recently, judicious use of fascicular biopsies in helpful. In focal nerve enlargements, nerve biopsy can differentiate focal mononeuropathies of mixed motor and sensory nerves has between disorders such as focal infection (leprosy), tumor (lym- been demonstrated to aid in the evaluation of neuropathies (Dyck phoma, neurofibroma, Schwannoma), and inflammation. PJB, personal communication). Biopsies of motor nerves—motor branches of mixed sensory and motor nerves—have been also Biopsies can be performed to obtain specimens from of the entire helpful in the evaluation of polyneuropathies with either purely nerve (whole) or the individual fascicle(s). The advantage of a motor or predominantly motor features. whole nerve biopsy (epineurium, perineurium, and endoneurium), is that additional information about the surrounding interstitial In patients with neuropathy, motor nerve biopsies may be used tissues, including blood vessels, is available for review. Small motor to improve treatment or, in some cases, avoid unnecessary treat- branches are usually obtained as whole nerve biopsies. Fascicular bi- ment.5,13 The utility of motor nerve biopsies, of course, depends on opsies are obtained from mixed motor and sensory nerves to avoid patient selection, the expertise of the surgeon, and the expertise of leaving a significant motor deficit. the pathologists and their laboratories. Although motor nerve biopsies have previously been described for focally enlarged nerves, more recently, motor nerves have been INDICATIONS FOR MOTOR NERVE BIOPSIES used in generalized polyneuropathies or predominantly motor neuropathies. Single cases have been reported using biopsies of the Similar to sensory nerve biopsies, motor nerve biopsies should only musculocutaneous7 and peroneal3,9 nerves. Taylor and colleagues be utilized if a thorough evaluation of the patient does not reveal examined fascicular biopsies of motor nerves in patients with the underlying diagnosis or if the results of the nerve biopsy will multifocal motor neuropathy (MMN).14 In addition, biopsies of alter therapeutic decisions. Biopsies should be used to look for the obturator nerve to gracilis1 have been used in the evaluation of D-38 Pathology of Motor Nerve Biopsy AANEM Course

Guillain-Barré Syndrome (GBS),10 amyloidosis,12 motor neuropa- nerve to the muscle. More commonly, it is necessary to follow the thies, and motor neuron disease (MND).4 median nerve more proximally in the antecubital fossa to find a small branch leaving its anterior surface to run on the underside of the pronator muscle. A biopsy of the pronator teres can also be COMPLICATIONS OF MOTOR NERVE BIOPSIES obtained at the same level. (Ting J, personal communication.)

There are concerns about the complications of motor nerve biopsies; however, only transient motor deficits have been reported with REVIEW OF MOTOR NERVE BIOPSIES 2,3,8,14 whole motor branch and fascicular biopsies. Complications Guillain-Barré Syndrome of nerve biopsies are based on the data from sural nerve biopsies.6 Temporary discomfort can be present for approximately 3 months after the biopsy in approximately 40% of cases. Lasting discomfort Motor nerve biopsies have been used to understand the patho- has been reported in approximately 10% of cases, while severe genesis of GBS and to differentiate severe forms of GBS from the complications, such as infection or neuroma, have been reported in axonal forms of GBS. In 1992, Hall and colleagues reported that less than 1% of cases. a terminal branch biopsy of the musculocutaneous nerve from a patient with a severe case of GBS7 revealed pronounced subperineurial edema, macrophage infiltration, and complete demyelin- TECHNIQUES FOR MOTOR NERVE BIOPSIES ation of many axons. This case was helpful in demonstrating that primary demyelination is the underlying pathological process of It is important to understand the techniques used to obtain speci- GBS. Another study by Massaro and colleagues11 tried to determine mens for biopsy. In order to obtain fascicular biopsies at the site of whether or not inexcitable motor nerves in early GBS represented conduction block,14 the lower edge of conduction block in the af- a primary axonal attack. Two children with severe GBS and inex- fected nerve is marked prior to biopsy. Intraoperatively, individual citable motor nerves at days 6 and 7, underwent sural nerve and or small groups of fascicles are exposed surgically and stimulated superficial peroneal motor nerve branch biopsies to extensor digi- with microelectrodes to determine the distal site of conduction torum brevis. Both children had delayed recovery and residual dis- block. Usually two to three fascicles are biopsied in order to include ability despite early treatment with intravenous immunoglobulin epineurial tissue for evaluation. (IVIg). Both sural and superficial peroneal nerves revealed severe macrophage-associated demyelination, abundant myelin debris in Although gracilis muscles and obturator nerves have been used for macrophages, and Schwann cells with completely demyelinated many years by plastic surgeons for grafting, the biopsy techniques axons. The biopsy findings were consistent with the demyelinating were only first described in 1997.1 The obturator nerve to gracilis form of GBS, although clinically and based on electrodiagnostic is exposed using a 7 cm longitudinal incision, which is made along evaluation, both patients appeared to have the acute motor-sensory an imaginary line between the pubic tubercle and medial tibial axonal neuropathy (AMSAN) variant of GBS. Only rare axonal condyle, posterior to the adductor longus muscle. The intermus- degeneration was seen in their biopsies. cular plane between the adductor longus anteriorly and the gracilis posteriorly is then dissected. The vascular pedicle is identified In another study of GBS patients,10 four obturator nerve and graci- piercing the inner surface of the muscle at a 90 degree angle. The lis muscle biopsies were reviewed to determine if immunological motor nerve to the gracilis muscle can usually be found just deep abnormalities were more evident in motor than sensory nerves. to the vascular pedicle and coursing at a 45 degree angle to the long Three motor nerve biopsies revealed CD3 T cells and macrophages axis of the limb. A biopsy of the gracilis is often taken simultane- using immunostaining. Occasional Schwann cells devoid of axons ously with the motor nerve. were seen. Inflammation, a focus of perivascular lymphocytes, was only seen in one muscle biopsy. Two of the patients had medial Recently, median nerve and pronator muscle biopsies were used in cutaneous sensory nerve to thigh biopsies which were normal, sug- the evaluation of patients with atypical motor neuropathy.15 In this gesting that immunological abnormalities were more evident in technique, the median nerve is exposed with a longitudinal incision motor compared to sensory nerves. starting at the flexion crease of the antecubital fossa and extending 7-8 cm distally. The antecubital fascia and distal fibers of the lacer- tus fibrosis are divided. The brachial artery and its bifurcation into Amyloidosis radial and ulnar arteries are dissected out at or just proximal to this level. The brachial artery is retracted out of harm’s way. The prona- Biopsy of the motor nerve to gracilis has been helpful in the diag- tor teres muscle is then retracted to expose the median nerve which nosis of amyloidosis. In 1998, Quattrini and colleagues reported can usually be found deep in the muscle. The nerve is followed into the a case involving a 57-year-old man with progressive symmet- the pronator tunnel, coursing between the two heads of the pro- ric weakness and fasciculations affecting the legs. His evaluation nator muscle. The underside of the pronator muscle is examined was negative until amyloidosis was found on his obturator nerve and occasionally a small branch is seen coursing from the median biopsy.12 Autonomic and sensory symptoms, along with serum AANEM Course Muscle and Nerve Pathology D-39 lambda light chains, did not manifest until 6 months after the Motor Neuropathies motor nerve biopsy had been performed. In an unreported case, a 58-year-old man first developed bilateral proximal leg weakness In 1990, Kolimas and colleagues performed a biopsy of deep pe- after initation of a cholesterol-lowering agent, but subsequently roneal nerve to the extensor digitorum brevis to look for evidence developed a progressive sensorimotor polyneuropathy, with only of immunological and demyelinating changes in a patient with mild autonomic symptoms. Initial evaluation, including sural MMN.9 The biopsy revealed mild perivascular and endoneurial nerve biopsy, was uninformative and there was no response to im- mononuclear cell infiltrates and demyelination. Subsequent studies munotherapy (steroids, plasmapheresis, and IVIg). Biopsies of the have confirmed the demyelinating nature of MMN, but inflam- obturator nerve and gracilis muscle were both positive for amyloid, matory changes have rarely been seen. In one study, a 38-year-old and the patient was subsequently diagnosed with familial amyloi- man with 6 years of upper extremity wasting and weakness without dosis polyneuropathy through genetic testing. (Lange DJ, personal sensory symptoms was found to have conduction block in proxi- communication.) mal median and ulnar motor nerves only. Biopsy of the proximal right ulnar nerve in axilla revealed a chronic demyelinating process: thinly myelinated fibers with onion bulbs without evidence of Amyotrophic Lateral Sclerosis inflammation.2 In another case report,8 a 49-year-old man, with a 3-year history of right distal and proximal upper extremity weak- Bradley and colleagues evaluated a combination of motor nerve ness, atrophy, and fasciculations, was found to have a mass adjacent biopsy and postmortem tissue in order to determine whether the to the subclavian artery on magnetic resonance imaging. Surgical underlying pathophysiology of amyotrophic lateral sclerosis (ALS) exploration revealed multifocal enlargements of the distal end of was due to neuronopathy.3 They reviewed postmortem studies the lower trunk and proximal medial and posterior cords of the on 11 patients with ALS and 9 control subjects, and collected brachial plexus. Nerve biopsy of the medial pectoral nerve at the phrenic nerves from the apex of the pleural cavity to the inser- level of conduction block revealed subperineurial edema and slight tion in diaphragm. Sections of phrenic nerves were evaluated both thickening of perineurium. The perivascular area contained scat- proximally and distally. The common peroneal (mixed sensory and tered axons without myelin, thinly myelinated axons, and small motor) nerves were also obtained 5 cm above the fibular head in onion bulbs without inflammation. Eight fascicular biopsies,14 also the popliteal fossa. Fascicular biopsies from the common peroneal at the site of conduction block, revealed multifocal fiber loss with nerves were also taken from six live patients with ALS. Anterior loss of large fibers, and the presence of regenerating clusters. Unlike tibial strength, which was assessed before and after the biopsy the two previous case reports, no onion bulbs or other evidence for using dynamometric measurements, revealed transient impairment demyelination were seen. Small inflammatory infiltrates were seen in one patient (20% compared to baseline), which improved after in two biopsies, suggestive of an inflammatory or immune process. 24 hours. Severe loss of myelinated fibers with acute axonal de- The authors postulated that their pathological findings suggest the generation and rare clusters of regenerating axons were seen in the presence of a functional alteration due to the physiological block phrenic nerves. The total number of myelinated fibers was reduced of motor axons, which can lead to fiber degeneration and faulty to 70% and large myelinated fibers were reduced by 33% in control regeneration, as a possible explanation for decreasing responses to subjects. Less than 18% of fibers were lost distally compared to therapy over time. Eleven motor nerve biopsies from either the proximally, consistent with neuronopathy rather than a dying back obturator nerve to gracilis or the median nerve to pronator were phenomena. The study reported that in the common peroneal reviewed in patients with atypical motor neuropathies15 (Wang nerve biopsies, a small number of myelinated fibers undergoing AK, submitted for publication). Biopsies revealed loss of large acute axonal degeneration, occasional clusters of regenerating fibers myelinated fibers, with some evidence for multifocal fiber loss, and a moderate number of denervated Remak processes were seen. but no evidence for inflammation. Unlike previous studies, axonal There were no differences in myelinated and unmyelinated fibers clusters suggestive of regeneration and onion bulbs, suggestive for compared to control subjects. myelin remodeling, were abundant in several nerves. These findings suggest that there may be a spectrum of both clinical and pathologi- Obturator nerve biopsies from patients with MMN and MND cal findings in motor neuropathies. have also been compared. In a study4 of nine patients with MND and six patients with MMN (two without anti-GM1 antibodies; three with conduction block; three with demyelination), evidence CONCLUSION for demyelination with thinly myelinated axons and small onion bulb formation were seen only in three patients with MMN and Biopsy of motor nerves can be useful in selected cases: focal mono- not in patients with MND. A lower density of regenerative clusters neuropathies, predominantly motor neuropathies, and purely was seen in the biopsies from patients with MND biopsies, con- motor neuropathies. Pathological findings from motor nerve biop- firming the presence of neuronopathy. sies have provided information about the underlying pathogenesis D-40 Pathology of Motor Nerve Biopsy AANEM Course

7. Hall SM, Hughes RA, Atkinson PF, McColl I, Gale A. Motor nerve of GBS and ALS, and have provided clues into the pathogenesis of biopsy in severe Guillain-Barré syndrome. Ann Neurol 1992;31:441- MMN. More research into the utility of motor nerve biopsy and 444. normative data are required. 8. Kaji R, Oka N, Tsuji T, Mezaki T, Nishio T, Akiguchi I, Kimura J. Pathological findings at the site of conduction block in multifocal motor neuropathy. Ann Neurol 1993;33:152-158. 9. Kolimas RJ, Harati Y. Multifocal motor neuropathy: value of REFERENCES electrophysiologic studies and motor nerve biopsy. Muscle Nerve 1990;13:868. 1. Abouzahr MK, Lange DJ, Latov N, Olarte M, Rowland LP, Hays 10. Lange DJ, Abouzahr MK, Hays AP, Latov N. Motor nerve biopsy in AP, Corbo M. Diagnostic biopsy of the motor nerve to the gracilis Guillain-Barré syndrome. Ann Neurol 1997;42:450-451. muscle. Technical note. J Neurosurg 1997;87:122-124. 11. Massaro ME, Rodriguez EC, Pociecha J, Arroyo HA, Sacolitti M, 2. Auer RN, Bell RB, Lee MA. Neuropathy with onion bulb formations Taratuto AL, Fejerman N, Reisin RC. Nerve biopsy in children and pure motor manifestations. Can J Neurol Sci 1989;16:194-197. with severe Guillain-Barré syndrome and inexcitable motor nerves. 3. Bradley WG, Good P, Rasool CG, Adelman LS. Morphometric and Neurology 1998;51:394-398. biochemical studies of peripheral nerves in amyotrophic lateral scle- 12. Quattrini A, Nemni R, Sferrazza B, Ricevuti G, Dell’Antonio G, rosis. Ann Neurol 1983;14:267-277. Lazzerini A, Iannaccone S. Amyloid neuropathy simulating lower 4. Corbo M, Abouzahr MK, Latov N, Iannaccone S, Quattrini A, motor neuron disease. Neurology 1998;51:600-602. Nemni R, Canal N, Hays AP. Motor nerve biopsy studies in motor 13. Said G. Indications and usefulness of nerve biopsy. Arch Neurol neuropathy and motor neuron disease. Muscle Nerve 1997;20:15- 2002;59:1532-1535. 21. 14. Taylor BV, Dyck PJ, Engelstad J, Gruener G, Grant I, Dyck PJ. 5. Dyck PJ, Dyck PJ, Grant IA, Fealey RD. Ten steps in characterizing Multifocal motor neuropathy: pathologic alterations at the site of and diagnosing patients with peripheral neuropathy. Neurology conduction block. J Neuropathol Exp Neurol 2004;63:129-137. 1996;47:10-17. 15. Wang AK, Kleinman GM, Lange DJ. Motor nerve and muscle 6. Dyck PJ, Dyck PJ, Engelstad J. Pathologic alterations of nerves. In: biopsy findings in multifocal motor neuropathy: implications for Dyck PJ, Thomas PK, editors. Peripheral neuropathy. Philadelphia: pathogenesis. Ann Neurol 2005;58:S30. WB Saunders; 2005. p 733-830. AANEM Course D-41

Muscle and Nerve Pathology CME SELF-ASSESSMENT TEST

Select the ONE best answer for each question.

Instructions for filling out your parSCORE sheet

On the right-hand side of the parSCORE sheet, you will need to fill in the following:

Under ID number, please write out and fill 1 2 3 4 in the last 4 digits of your phone number. Last 4 digits of Be sure to start in the first box on the left your phone number (as shown).

Under Test Form, please fill in “A”.

Leave the completed form at the table outside your session. Fill in answers here

1. All of the following rules are true about the muscle biopsy 2. All of the following statements about myophosphorylase defi- procedure EXCEPT: ciency are true EXCEPT: A. The selected muscle should be weak but not flaccid. A. The patients may have either McArdle syndrome, slowly B. The specimen should be accompanied by clinical infor- progressive weakness, or asymptomatic elevated serum mation. creatine kinase (CK) activity. C. An open biopsy is preferred rather than a needle biopsy. B. The biopsy should be performed shortly after an episode D. The sample for enzyme histochemistry should be sub- of myoglobinuria to document necrosis of muscle fibers. merged in saline during transportation. C. Some patients may have a normal muscle biopsy with no E. The sample for enzyme histochemistry should be kept detectable glycogen accumulation in muscle fibers based cool during transportation. on histology and histochemistry. D. Myophosphorylase deficiency can be detected by a histochemical stain for the enzyme. E. Glycogen tends to accumulate in the subsarcolemmal region of myofibers. D-42 CME Self-Assessment Test AANEM Course

3. Which one of the following disorders of glycogen metabolism 7. Which is the most sensitive test in evaluation of a male for typically shows large deposits of glycogen in the subsarcolem- possible Becker muscular dystrophy? mal region of muscle fibers? A. Serum creatine kinase (CK) level. A. Myophosphorylase deficiency. B. Electromyography. B. Debrancher enzyme deficiency. C. Muscle biopsy with routine histochemistry. C. Phosphofructokinase deficiency. D. Muscle biopsy with immunostain for dystrophin expres- D. Deficiency of enzymes in the terminal pathway of glycoly- sion on the sarcolemma of muscle fibers. sis. E. Western blot analysis of dystrophin in a muscle biopsy E. Adult-onset acid maltase deficiency. sample.

4. All of the following statements are true about the muscle 8. Rimmed vacuoles are not a histological feature commonly biopsy of dermatomyositis EXCEPT: seen in which type of muscular dystrophy? A. Necrotic myofibers and regenerating fibers are distributed A. Nonaka type distal myopathy. randomly throughout the muscle. B. Oculopharyngeal muscular dystrophy. B. Muscle fiber atrophy predominates at the edge of muscle C. Limb-girdle muscular dystrophy (LGMD) 2B or Miyoshi fascicles (perifascicular atrophy). myopathy. C. B cells, CD4-positive T cells, and histiocytes predominate D. Welander type distal myopathy. in the perimysium. E. Myotilinopathies. D. Blood vessels show ultrastructural features of endothelial injury and reactive changes including tubuloreticular ag- 9. Prominent endomysial and perivascular inflammatory cell gregates. infiltration can be seen in the following dystrophies: E. Express of major histocompatibility complex (MHC) A. Facioscapulohumeral muscular dystrophy. class I antigens in muscle fibers are typically focal and are B. LGMD 2A. most pronounced along the edge of muscle fascicles. C. LGMD 2B or /Miyoshi myopathy. D. All of the above. 5. All of the following pathological features of inclusion body E. None of the above. Inflammatory cell infiltrate is diagnos- myositis are true EXCEPT: tic of polymyositis. A. Necrotic fibers and regenerating fibers seem to be randomly distributed throughout the muscle as in polymyo- 10. The following dystrophy cannot be diagnosed on muscle sitis. biopsy with routine immunohistochemistry: B. CD8-positive T cells predominate in inflammatory in- a. X-linked Emery-Dreifuss muscular dystrophy. filtrates and occasionally appear to invade non-necrotic b. LGMD 2A. muscle fibers. c. LGMD 2C-F (one of the sarcoglycanopathies). C. Typically, the muscle shows widespread expression of d. MDC 1A. MHC class I antigens at the surface of myofibers. e. Duchenne muscular dystrophy. D. Rimmed vacuoles and congophilic inclusions are found in 11. The abnormality that is demonstrated by Gomori trichrome the cytoplasm of muscle fibers in most muscle biopsies. stain of muscle shown here is characteristic of: E. Electron microscopic examination of the muscle is necessary to confirm the diagnosis by demonstrating the abnormal 12-18 nm filaments.

6. Which of the following muscular dystrophies would be considered forms of secondary alpha-dystroglycanopathies? A. Fukuyama. B. Muscle-eye-brain disease. C. Walker-Warburg. D. Congenital muscular dystrophy (MDC) 1C caused by fukutin-related protein mutation. E. All of the above.

A. LGMD 2D. B. Nemaline myopathy. C. Spinal muscular atrophy (SMA) type I. D. Kearns-Sayre syndrome (KSS). E. Centronuclear myopathy. AANEM Course CME Self-Assessment Test D-43

12. The following statements about mitochondrial encephalomy- 16. The utility of motor nerve biopsies depends on: opathy with lactic acidosis and stroke-like episodes (MELAS) A. Patient selection. are true EXCEPT: B. Expertise of the surgeon. A. The point mutation in the transfer ribonucleic acidleu(UUR) C. Expertise of the neuropathologist. gene, A3243G transition, is the most common genetic D. Quality of the pathology laboratory. alteration found in MELAS. E. All of the above. B. Activity of complex II (succinate dehydrogenase [SDH]) is often reduced. 17. Complications from motor nerve biopsy include: C. Ragged red fibers (RRFs) often stain positively with cyto- 1. Weakness. chrome c oxidase (COX). 2. Discomfort. D. Muscle biopsy often reveals strongly SDH reactive blood 3. Hematoma. vessels (SSV). 4. Neuroma. E. A mutation in the ND5 (complex I) can be associated 5. Infection. with the clinical phenotype of MELAS. A. Only 1, 2, and 3 are correct. B. Only 1 and 3 are correct. 13. Which is the correct statement about KSS? C. Only 2 and 4 are correct. A. KSS is associated with a nuclear gene mutation that D. Only 4 is correct. qualitatively affects mitochondrial deoxyribonucleic acid E. All are correct. (mtDNA). B. RRFs often stain positively with COX. 18. The main advantage of a fascicular nerve biopsy is: C. The vast majority of cases are maternally inherited. A. Evaluation of interstitial tissue. D. Cerebrospinal fluid protein is usually found to be low. B. Evaluation of perineurium. E. Patients who outlive Pearson’s syndrome develop KSS C. Decreased likelihood of infection. later in life. D. Decreased likelihood of permanent deficit. E. Decreased likelihood of neuroma formation. 14. The following statements about mitochondrial depletion syndrome (MDS) are correct EXCEPT: 19. Fascicular motor nerve biopsies have been useful in the evalu- A. MDS is associated with a large deletion of mtDNA. ation of all of the following EXCEPT: B. MDS may present with similar clinical phenotypes to A. Focal mononeuropathies. those seen in SMA. B. Sensory neuronopathies. C. Muscle biopsy shows RRFs that stain negatively with C. Predominantly motor neuropathies. COX. D. Motor neuropathies. D. Drug-induced MDS is a serious complication of acquired E. Motor neuron disease (MND). immunodeficiency syndrome treatment. 20. Motor neuropathy can be differentiated from MND by the E. Biochemical analysis of MDS reveals combined defects of following changes on nerve biopsy EXCEPT: respiratory chain complexes containing mtDNA-encoded A. Onion bulbs. subunits. B. Thinly myelinated fibers 15. Which statement is correct about mitochondrial disease and C. Inflammation. its pathology? D. Axonal degeneration. A. MELAS and myoclonic epilepsy with RRFs are two E. Axonal clusters. separate clinical entities caused by point mutations in the same mtDNA transfer ribonucleic acid gene. B. In addition to RRFs, most of mitochondrial myopathies show necrotic and/or regenerative fibers in muscle biopsy. C. Gomori trichrome stain has been widely used to demonstrate RRFs in muscle biopsy, but histochemical staining of SDH is the most sensitive method to visualize the segmental proliferation of mitochondria. D. Recently discovered SCO2 and SURF1 mutations are associated with ophtalmoplegia and late-onset myopathy. E. RRFs are the specific, morphological alteration found only in mitochondrial myopathy. D-44 AANEM Course AANEM Course D-45

Muscle and Nerve Pathology

EVALUATION

Select ANY of the answers that indicate your opinions.

21. How would you rate the quality of instruction received during 26. Did you perceive any commercial bias in Dr. Amato’s presenta- Dr. Hays’s presentation? tion? A. Best possible. A. Yes. B. Good. B. No. C. Average. D. Poor. 27. How would you rate the quality of instruction received during E. Worst possible. Dr. Tanji’s presentation? A. Best possible. 22. Select any item(s), that, if changed, would have appreciably B. Good. improved Dr. Hays’s presentation: C. Average. A. Quality of slides. D. Poor. B. Quality of handout. E. Worst possible. C. Amount of clinically relevant information in the presentation. 28. Select any item(s), that, if changed, would have appreciably D. Amount of scientific content in the presentation. improved Dr. Tanji’s presentation: E. Other: please explain on the comment form at the back of A. Quality of slides. this handout. B. Quality of handout. C. Amount of clinically relevant information in the presenta- 23. Did you perceive any commercial bias in Dr. Hays’s presentation. tion? D. Amount of scientific content in the presentation. A. Yes. E. Other: please explain on the comment page at the back of B. No. this handout.

24. How would you rate the quality of instruction received during 29. Did you perceive any commercial bias in Dr. Tanji’s presenta- Dr. Amato’s presentation? tion? A. Best possible. A. Yes. B. Good. B. No. C. Average. D. Poor. 30. How would you rate the quality of instruction received during E. Worst possible. Dr. Wang’s presentation? A. Best possible. 25. Select any item(s), that, if changed, would have appreciably B. Good. improved Dr. Amato’s presentation: C. Average. A. Quality of slides. D. Poor. B. Quality of handout. E. Worst possible. C. Amount of clinically relevant information in the presentation. D. Amount of scientific content in the presentation. E. Other: please explain on the comment page at the back of this handout. D-46 Evaluation AANEM Course

31. Select any item(s), that, if changed, would have appreciably B. Receiving free educational materials such as the Muscle & improved Dr. Wang’s presentation: Nerve Invited Reviews and the AANEM Resource CD. A. Quality of slides. C. The availability of CME opportunities. B. Quality of handout. D Member discounts on AANEM CME products and ser- C. Amount of clinically relevant information in the presenta- vices. tion. E. AANEM’s advocacy work on issues that impact my pro- D. Amount of scientific content in the presentation. fession. E. Other: please explain on the comment page at the back of this handout. 39. In 2006, the AANEM distributed 6 bound copies of the Muscle & Nerve Invited Reviews. How would you rate this new 32. Did you perceive any commercial bias in Dr. Wang’s presenta- member benefit? tion? A. Very valuable. A. Yes. B. Somewhat valuable. B. No. C. Not very valuable. D. I do not receive this since I am not an AANEM 33. As a result of your attendance at this educational session, did member. you learn anything that will improve the care of your pa- E. Other: please explain on the comment page at the back of tients? this handout. A. Yes, substantially. B. Yes, somewhat. 40. When you receive the bound copies of the Muscle & Nerve C. Not sure. Invited Reviews, you can visit the AANEM website and D. Probably not. complete CME questions to receive a certificate at no charge. E. This session was not applicable to my patients. Have you utilized this new service? A. Yes, I have completed CME for the Invited Reviews 34. Do you feel that the information presented in this session was online and found the system easy to utilize. based on the best evidence available? B. Yes, I have completed CME for the Invited Reviews A. Yes online, but found the system difficult to utilize. B. No: please explain on the comment page at the back of C. No, I have not utilized this service because I was unaware this handout. it was available. D. No, I have not utilized it although I was aware of its avail- 35. Select ALL items where improvement was needed. ability: please explain on the comment page at the back of A. The accuracy of advance descriptions of this course. this handout. B. The specific topics selected for presentation. E. Other: please explain on the comment page at the back of C. The number of speakers in this course. this handout. D. The amount of time allotted for discussion in this course. 41. In 2006, the AANEM added Online Case Studies to the E. Other: please add other areas and outline specific rec- website which are also available for CME credit. How would ommendations for areas needing improvement on the you rate this new member benefit? comment page at the back of this handout. A. Very valuable. B. Somewhat valuable. 36. I plan to attend the 2007 AANEM Annual Meeting in C. Not very valuable. Phoenix, AZ October 17-20. D. I was not aware that this was available on the AANEM A. Yes, definitely. website. B. No, definitely. E. Other: please explain on the comment page at the back of C. Will wait to see the program content. this handout. D. Will wait to see if budget allows my attendance. 42. The AANEM has recently launched new Marketing Slides on 37. We would like the AANEM Annual Meeting to be one of the website that can assist EDX physicians in marketing to your “must attend” meetings each year. In order to do this, we referral sources. How would you rate this member benefit? would have to do what to make it happen? Please explain on A. Very valuable. the comment page at the back of this handout. B. Somewhat valuable. 38. If you are a member of the AANEM, what would you rate as C. Not very valuable. the most valuable benefit of your membership? D. I have not reviewed the marketing slides yet. A. My subscription to the journal Muscle & Nerve. E. Other: please explain on the comment page at the back of this handout. Neuromuscular Quality of Life

Richard T. Abresch, MS Craig M. McDonald, MD Mark B. Bromberg, MD, PhD

2006 Course E AANEM 53rd Annual Meeting Washington, DC

Printed by Johnson Printing Company, Inc. E-ii

Neuromuscular Quality of Life

Faculty

Richard T. Abresch, MS Mark B. Bromberg, MD, PhD Director of Research Professor and Vice-chairman Research and Training Center on Neuromuscular Disease Department of Neurology Department of Physical Medicine and Rehabilitation University of Utah University of California Davis Salt Lake City, Utah Davis, California Dr. Bromberg began his academic career in basic science research. Richard T. Abresch, MS is the Director of Research for the Rehabilitation He received a doctorate in neurophysiology from the Department of Research and Training Center in Neuromuscular Diseases. His research Physiology at the University of Vermont and conducted research in the interests include quality of life issues of the disabled, development of clini- somatosensory and motor systems. Dr. Bromberg attended medical school cal trials and outcome measures in neuromuscular disease, and the effect of at the University of Michigan and also completed his neurology training neuromuscular diseases on the body composition, strength, and function. and neuromuscular/EMG fellowship there. He was on the faculty at the University of Michigan until 1994, when he joined the University of Utah. He is currently a professor and vice-chairman in the Department of Craig M. McDonald, MD Neurology. Dr. Bromberg is Director of the Neuromuscular Program and EMG laboratory, and the Muscular Dystrophy Association clinics. His Professor research interests are in quantitative EMG, including motor unit number Departments of Physical Medicine and Rehabilitation and Pediatrics estimation (MUNE) and algorithms for automated motor unit analysis, University of California Davis School of Medicine and in clinical aspects of amyotrophic lateral sclerosis. Davis, California Dr. McDonald is Professor of Physical Medicine and Rehabilitation and Pediatrics and Director of the Neuromuscular Disease Clinics at the University of California Davis Medical Center. He is Director of the National Institute on Disability and Rehabilitation Research’s Rehabilitation Research and Training Center in Neuromuscular Diseases at UC Davis. His research interests include clinical endpoints in muscular dystrophy, exercise in neuromuscular disease, energy expenditure, quantitative assessment of physical activity, and quality-of-life assessment.

Authors had nothing to disclose.

Course Chair: Gregory T. Carter, MD, MS

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

Neuromuscular Quality of Life

Contents

Faculty i

Objectives ii

Course Committee iv

Tools for Measuring Quality of Life 1 Richard T. Abresch, MS

Outcome Measures for Clinical Trials of Muscle Diseases 7 Craig M. McDonald, MD

Quality of Life in Amyotrophic Lateral Sclerosis 15 Mark B. Bromberg, MD, PhD

CME Self-Assessment Test 21

Evaluation 23

O b j e c t i v e s —After attending this course, participants will understand (1) the tools for measuring quality of life, (2) the issues that impact quality of life in Duchenne muscular dystrophy, and (3) the quality of life in amyotrophic lateral sclerosis. P rerequisite —This course is designed as an educational opportunity for residents, fellows, and practicing clinical EDX physicians at an early point in their career, or for more senior EDX practitioners who are seeking a pragmatic review of basic clinical and EDX principles. It is open only to persons with an MD, DO, DVM, DDS, or foreign equivalent degree. A c c r e d i tat i o n S tat 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 C r e d i t —The AANEM designates this activity for a maximum of 3.25 hours in AMA PRA Category 1 Credit(s)TM. This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he or she actually spent in the educational activity. CME for this course is available 10/06 - 10/09. E-iv

2005-2006 AANEM COURSE COMMITTEE Kathleen D. Kennelly, MD, PhD Jacksonville, Florida

Thomas Hyatt Brannagan, III, MD Dale J. Lange, MD Jeremy M. Shefner, MD, PhD New York, New York New York, New York Syracuse, New York

Hope S. Hacker, MD Subhadra Nori, MD T. Darrell Thomas, MD San Antonio, Texas Bronx, New York Knoxville, Tennessee

Kimberly S. Kenton, MD Bryan Tsao, MD Maywood, Illinois Shaker Heights, Ohio

2005-2006 AANEM PRESIDENT Janice M. Massey, MD Durham, North Carolina

Tools for Measuring Quality of Life

Richard T. Abresch, MS Director of Research Research and Training Center on Neuromuscular Disease Department of Physical Medicine and Rehabilitation University of California Davis Davis, California

INTRODUCTION working, while another might quit their job and have significant depression. The World Health Organization defines quality of life (QOL) as “individuals’ perception of their position in life in the context of In addition, the way an individual views their own QOL is fre- the culture and value systems in which they live and in relation to quently different than that reported by close relatives or caregivers. their goals, expectations, standards, and concerns.27 It is a broad To determine if the opinions of close relatives can be used as proxies concept affected in a complex way by the person’s physical health, to assess QOL, McKusker and Stoddard examined the responses psychological state, personal beliefs, social relationships and their from patients who were terminally ill and proxy responses of close relationship to salient features of their environment.” Although relatives.18 They found that the correlation between the two sets of many people discuss factors of QOL, few studies have systemati- responses on the Sickness Impact Profile, a general comprehensive cally assessed the QOL of individuals with peripheral neuropathies. measure of QOL, was only 0.55. Whereas the proxy reports of The goals of this manuscript are to: (1) show the value of perform- observable domains such as physical functioning were highly cor- ing health-related QOL (HRQOL) measurements, (2) briefly de- related, reports of role functioning and physical limitations were scribe methods used to assess QOL, and (3) to examine the results poorly correlated. In general, the proxy respondents considered from studies that have assessed the HRQOL of individuals with the patients more impaired than the patients themselves. This is peripheral neuropathies. important because clinicians frequently make judgments based upon reported behavior and perceptions of a patient’s relatives and caregivers. VALUE OF HEALTH-RELATED QUALITY OF LIFE MEASUREMENTS Misconceptions regarding the QOL of individuals with disabilities are not limited to close relatives. Several studies have shown that Why should a clinician measure HRQOL? Whereas biochemical healthcare professionals frequently underestimate the QOL of their and physiological information is often of interest to clinicians, they patients. This misconception often affects their own expectations are of limited interest to patients. Patients are more interested in and their treatment choices.2,11,20 In the most glaring cases, a physi- functional status and emotional well-being. Two patients with the cian’s subjective, but incorrect, assessment of a disabled individual’s same clinical symptoms may function quite differently. Although QOL may prevent life-sustaining interventions. Since judging a two patients may have similar ratings of pain and mobility, they patient’s QOL is often used to determine appropriate medical pro- may have significantly different role functions. One might be cedures, an accurate assessment of a patient’s QOL is critical.2,11 E- Tools for Measuring Quality of Life AANEMAANEM PlenaryCourse

METHODS TO ASSESS QUALITY OF LIFE In their landmark study entitled, “The Quality of American Life,” Campbell and colleagues measured satisfaction with respect to mar- Research methods used to measure QOL began in 1960 with riage, family life, health, neighborhood, friendships, housework, a report of the President’s Commission on National Goals.21 job, usefulness of education, amount of education, and standard of Economists and social scientists performed the first measurements living.5 Individuals were asked to rate their satisfaction in a particu- of QOL and equated it with the goods and services required lar domain on a seven-point Likert scale by reporting whether their for better living. Indicators in these studies included per capita QOL was excellent, good, poor, etc. These individuals were also energy consumption, life expectancy, percentage of children in the asked to rate the importance of each domain. In this conceptualiza- labor force, physicians per 1000 population, and gross domestic tion, an individual could be dissatisfied with a domain considered product. to be of relatively little importance and still maintain a satisfactory overall QOL. Dissatisfaction with a domain of great importance, To study the effect of disablement on QOL, investigators have however, would clearly contribute to a lower overall life quality. traditionally focused on objective indicators, such as an individual’s functional ability in terms of their capacity to carry out activities One of the criticisms of using subjective measures of QOL is that of daily living, their ability to work, their employment status, their perceptions of well-being could mean different things to different income, and the number of times an individual engages in social people. Proponents of subjective tests argue that the individual is the activities per week. Quality of life is inferred from these findings. best judge of whether or not their own needs are being met. They The effectiveness of rehabilitation treatments is evaluated by the acknowledge that people can and do interpret tests differently, but improvement in these domains. This method uses the sum total of as long as the methods are easy to use and psychometrically sound, a person’s scores on components that can objectively be measured they are valid, reliable, and replicable measures of QOL. to define QOL. These objective components are valued by most people as having easily established “best” and “worst” extremes. For These types of studies are frequently referred to as “overall QOL” example, being more educated is valued higher than being less edu- or “global QOL.” It is the broadest of all concepts and is influenced cated. The Craig Handicap Assessment and Reporting Technique by all of the dimensions of life that contribute to its richness and (CHART) is an example of a QOL instrument that uses objective reward, and its pleasure and pain. Quality of life is a broad concept measurements to assess five dimensions of handicap in people with that takes into consideration physical, psychological, social and spinal cord injury.25 It measures physical independence, mobility, financial attributes that describe an individual’s ability to function activity (occupation), social integration, and economic self-suf- and derive satisfaction in his or her life (Table 1). Hundreds of in- ficiency by asking questions that a person without a disability will struments have been developed to measure QOL. Excellent reviews typically obtain with maximum scores. However, a person with a of the conception and use of QOL assessment tools in rehabilita- spinal cord injury, who has a number of impairments and disabili- tion have been presented by Ware,22 Dijkers,6 and Flanagan.8 ties, usually will score lower. A typical question to measure social integration would be, “How many relatives (not in your household) To better define the major domains that affect the QOL of do you visit, telephone, or write to at least once a month?” Studies Americans, Flanagan used a critical incident technique to identify have shown that CHART scores discriminate between people who experiences that were especially satisfying or dissatisfying to the have high and low levels of handicap and between people who participant.8 Approximately 6500 critical incidents were collected have high and low levels of impairment. This instrument has high and classified into a set of 15 dimensions, which are shown in Table test-retest reliability and validity. However, use of these objective 2. The five dimensions that were most frequently described as im- instruments has not been able to explain the significant amount of portant were health, children, understanding yourself, work, and variance in the QOL.9 spouse. The five dimensions that were the least well met were participating in government, active recreation, learning and education, Since these objective approaches do not take into account other creative expression, and helping others. The five dimensions that dimensions affecting QOL (such as expectations), assessment in- most highly correlated with overall QOL were material comforts, struments have also been developed to ascertain patients’ subjective work, health, active recreation, and learning/education. feelings about various aspects of their life. The purpose of these instruments is to determine the congruence of aspirations and accom- It should be noted that in Flanagan’s definition, health is not merely plishments in a variety of different areas.1,5,19 The benefit of using the absence of disease, but a concept that incorporates notions subjective scales is that they permit individuals to ascribe meaning of well-being or wellness in all areas of life (physical, mental, to their situation. It also permits comparison between the objective emotional, social, and spiritual).8 The health domain ranges from and subjective measurements. Many researchers and clinicians now negatively valued aspects of life, including death, to positive aspects agree that assessment of QOL requires a multifaceted approach in such as happiness. Although health is affected by other factors such order to obtain a comprehensive assessment of the impact of an as income and freedom, these factors are not usually the focus illness, a treatment, or rehabilitative services on QOL.1 of healthcare professionals. Health-related QOL concerns itself AANEM Course Neuromuscular Quality of Life E-

Table 1 Dimensions of Quality of Life

Physical Psychological Social Health Control of one’s life Ability to communicate Physical functioning Level of stress Role functioning Ambulation and motility Life satisfaction Social support resources Exercise tolerance Meaningfulness of life Usefulness to others Energy/stamina Body image Recreation Adequate sleep/rest Self-acceptance Social interaction Nutrition Absence of negative moods Marital and family relations Absence of pain Self esteem/self-worth Standard of living Control of symptoms Psychological well-being Financial independence Somatic comfort Achievement of life goals Neighborhood Physical independence Intellectual functioning Sexual relations Freedom from illness Illness concerns & prognosis Employment Sexuality Adjustment to illness & disability Spiritual support Learning fulfillment Standard of living

Table 2 Flanagan’s 15 QOL Dimensions primarily with those factors concentrated on by healthcare providers and systems.26 These include health status, functional status (physical, psychological, social, and spiritual), emotional status, Physical and material Material well-being and financial security and impairment. well-being Health and personal safety Relations with Relations with spouse Health status is an individual’s relative level of wellness and illness, other people Having and rearing children taking into account the presence of biological or physiological Relations with parents, siblings, or other dysfunction, symptoms, and functional impairment. Health per- relatives ceptions (or perceived health status) are subjective ratings by the Relations with friends affected individual of his or her health status. Some people perceive Social, community, Helping and encouraging others themselves as healthy despite suffering from one or more chronic civic activities Participating in local and governmental affairs diseases, while others perceive themselves as ill when no objective Personal development, Intellectual development evidence of disease can be found. fulfillment Understanding and planning Occupational role career Functional status is an individual’s ability to perform normal daily Creativity and personal expression activities required to meet basic needs, fulfill usual roles, and main- Recreation Socializing with others tain health and well-being. Functional status subsumes related con- Passive and observational recreational cepts of interest: functional capacity and functional performance. activities While functional capacity represents an individual’s maximum Participating in active recreation capacity to perform daily activities in the physical, psychological, E- Tools for Measuring Quality of Life AANEMAANEM PlenaryCourse social, and spiritual domains of life, functional performance refers tinguish whether changes in their role or function is trivial, small, to the activities people actually perform during the course of their moderate, or large. daily lives. A maximal exercise test measures physical functional capacity, while a self-report of activities of daily living measures There are two basic approaches to HRQOL measurement instru- functional performance. Functional status can be influenced by ments. There are (1) generic instruments that relate to particular biological or physiological impairment, symptoms, mood, and dimensions of life that have been determined to be important to other factors. It is also likely to be influenced by health perceptions. people in general, and (2) instruments that focus on problems For example, a person judged to be well by most, may view himself associated with single-disease states, patient groups, or area of as ill and may have a low level of functional performance in relation function. Hundreds of validated generic instruments have been to his capacity.12,16 developed that apply to a variety of populations and are good for broad comparisons between patients with different diseases. The Most QOL instruments assess the emotional responses to short- or more commonly used instruments that have been used to describe long-term stressors such as changes in health state. These transient the HRQOL are shown in Table 3. emotional reactions to life experiences are usually reflected in an individual’s affect: the face one presents to the world. Depression, On the other hand, specific instruments may better determine the anxiety, and anger are emotions that sometimes coexist with physi- effect on the QOL for certain diseases. This is because detailed cal illness, and may affect the individual’s functional performance, measures can be developed that are more specific, and hence, re- symptom and health perceptions, and QOL. Conversely, decreased sponsive to the changes due to the disease (such as diabetes), the functional status may contribute to a depressed emotional state. population studied (such as the elderly), a symptom (such as pain), or a certain function (such as sleep). The problem with specific instruments is that they: (1) do not allow cross-condition compari- WHAT MAKES A GOOD HEALTH-RELATED QUALITY OF sons, (2) may be limited in terms of populations or interventions, LIFE INSTRUMENT? and (3) they must be independently validated. Generic instruments and specific instruments are often used in combination to provide Some goals of HRQOL measures are to differentiate between information about the range and magnitude of treatment effects individuals who have a better HRQOL and those with a worse on HRQOL. This information is helpful in measuring the health HRQOL, as well as to evaluate the degree of change to HRQOL. of populations, assessing the effectiveness of clinical trials and reha- The measure must be suitable for its intended use in order to be an bilitation services and providing information for health care policy appropriate clinical tool. The results from the test must be valid, decisions. Table 4 describes the different types of measures that are reliable, and accurate. Reliability in an HRQOL test means that used in HRQOL studies. stable patients would give the same response after repeated administration. Accuracy in an HRQOL test means that the instrument There are many reasons to perform HRQOL measurement. is responsive and able to detect small longitudinal changes. These Assessing the patient’s QOL gives the clinician valuable informa- instruments must also be interpretable and sensitive enough to dis- tion that can help in making the best choices patient care. By

Table 3 Most commonly used instruments for measuring health-related quality of life in 3921 reports (from Garratt10)

Instrument # of records Instrument # of records SF-36 408 Health utilities index 41 Sickness impact profile 111 COOP charts 33 Nottingham health profile 93 Functional assessment of cancer 32 EORTC QLQ-C30 82 WHOQOL 24 QALY 79 EuroQol 77 Healthy years equivalent 24 Health assessment questionnaire 62 Beck depression inventory 23 Arthritis impact measurement scales 59 Asthma quality of life questionnaire 21 Quality of well-being scale 53 McGill pain questionnaire 19 General health questionnaire 43 Hospital anxiety and depression scale 18

COOP = Care Cooperative Information Project; SF = short form; EORTC = European Organization for Research and Treatment of Cancer; EuroQOL = European Quality of Life scale; WHOQOL = World Health Organization Quality of Life; QALY = quality-adjusted life-year AANEM Plenary Course Neuromuscular Quality of Life E-

Table 4 Types of Measures Used in HRQOL studies.

Dimension-specific measures focus on particular aspects of health such as psychological well-being and usually produce a single score—for example, Beck depression inventory.3 Disease or population specific measures include aspects of health that are relevant to particular health problems and may measure several health domains—for example, asthma quality of life questionnaire.17 Generic measures can be used across different patient populations; they usually measure several health domains—for example, the Medical Outcomes Study short form 3623, the Nottingham Health Profile,15 the Sickness Impact Profile4 and the World Health Organization Quality of Life instrument.28 Individualized measures allow respondents to include and weight the importance of aspects of their own life; they usually sum to produce a single score— for example, patient generated index.22 Utility measures have been developed for economic evaluation, incorporate preferences for health states, and produce a single index—for example, EuroQol EQ-5D.7

EuroQol = European Quality of Life scale; HRQOL = health-related quality of life

understanding how a disease affects the QOL of a patient, the in- Table 5 Questions to Ask When Choosing an HRQOL Measure teraction between the doctor and patient will improve. Information (from Higginson and Carr14) on how a disease affects the functional and emotional status of the patient gives the doctor better insight into the patient’s needs. It can provide longitudinal data regarding changes in the patent’s QOL. 1. Are the domains covered relevant? It may also indicate the functional and emotional trade-offs of a 2. In what population and setting was it developed and tested, and particular treatment such as chemotherapy, which may prolong are these similar to those situations in which it is planned to be a person’s life, but at considerable cost to their QOL. Reliable used? measurements of QOL can be an important tool in the appraisal 3. Is the measure valid, reliable, responsive, and appropriate? of healthcare services and healthcare policy. Research that utilizes 4. What were the assumptions of the assessors when determining QOL as an outcome measurement will ensure that factors that validity? affect the whole person over a range of areas will be taken into consideration. To determine whether a particular QOL measurement is 5. Are there floor and ceiling effect—that is, does the measure fail to identify deterioration in patients who already have a poor appropriate for a given application, Higginson and Carr14 provided quality of life or improvement in patients who already have a step-by-step methods of choosing a QOL measure (Table 5). good quality of life? 6. Will it measure differences between patients or over time and to SUMMARY what extent? 7. Who completes the measure: patients, their family, or a It is now possible for the clinician to use multidimensional measures professional? What effect will this have – will they complete it? to assess the QOL of their patients. Some of the more widely used 8. How long does the measure take to complete? 6,23 instruments include the Medical Outcomes Study short form 9. Do staff and patients find it easy to use? the Nottingham Health Profile,15 the Sickness Impact Profile,4 10. Who will need to be trained and informed about the measure? and the World Health Organization Quality of Life instrument.28 Potential uses of QOL assessment tools for the clinician include: HRQOL = health-related quality of life (1) monitoring the health and social status of a given population, E- Tools for Measuring Quality of Life AANEM Course

(2) evaluating healthcare policy, (3) conducting clinical trials, (4) 13. Grant M, Padilla GV, Ferrell BR, Rhiner M. Assessment of quality of assessing the effectiveness of rehabilitation services, (5) justifying life with a single instrument. Semin Oncol Nurs 1990;6:260-270. 14. Higginson IJ, Carr AJ. Measuring the quality of life: Using quality of the allocation of limited social and healthcare resources, and (6) life measures in the clinical setting. BMJ 2001;322:1297-1300. tailoring management to the needs of the patient. 15. Hunt SM, McEwen J. The development of a subjective health indicator. Sociolgy of Health and Illness 1980;2:231-246. 16. Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE. Measuring quality of REFERENCES life in asthma. Am Rev Respir Dis 1993;147:832-838. 17. McKusker J, Stoddard AM. Use of surrogate for Sickness Impact 1. Andrews F, Withey S. Social indicators of well-being: American’s Profile. Med Care 1984;22:789-795. perception of life quality. New York:Plenum;1976. 18. Oleson M. Subjectively perceived quality of life. Image 1990;22:187- 2. Bach JR, Campagnolo DI. Psychosocial adjustment of post-po- 190. liomyelitis ventilator assisted individuals. Arch Phys Med Rehabil 19. Paris MJ. Attitudes of medical students and health-care professionals 1992;73:934-939. toward people with disabilities. Arch Phys Med Rehabil 1993;74:818- 3. Beck A, Ward C, Mendelson M, Mock J, Erbaugh J. An inventory for 825. measuring depression. Arch Gen Psychiatry 1961;4:561-571. 20. President’s Commission on National Goals: Goals for Americans. 4. Bergner M, Bobbitt R, Carter W, Gilson B. The Sickness Impact New York: Columbia University; 1960. Profile: development and final revision of a health status measure. 21. Ruta DA, Garratt AM, Russell IT. Patient centred assessment of Med Care 1981;19:955-962. quality of life for patients with four common conditions. Qual 5. Campbell A, Converse PE, Rodgers WL. In: Andrews FM, Robinson Health Care 1999;8:22-29. JP, editors. The quality of American life: perceptions, evaluation and 22. Ware J, Sherbourne CD. The MOS 36-item short form health survey satisfaction. New York: Russell Sage; 1976. (SF-36). I. Conceptual framework and item selection. Med Care 6. Djikers M. Measuring quality of life. In: Fuhrer MJ. Assessing 1992;30:473-483. medical rehabilitation practices: the promise of outcomes research. 23. Ware JE. The status of health assessment 1994. Annu Rev Public Baltimore: Paul H Brookes Publishing; 1997. p 153-180. Health 1995;16:327-354. 7. EuroQol Group. EuroQol: a new facility for the measurement of 24. Whitneck G, Charlifue S, Gerhart K, Overholser J, Richardson G. health-related quality of life. Health Policy 1990;16:199-208. Quantifying handicap: a new measure of long-term rehabilitation 8. Flanagan J. Measurement of quality of life: current state of the art. outcomes. Arch Phys Med Rehabil 1992;73:519-526. Arch Phys Med Rehabil 1982;63:56-59. 25. Wilson IB, Cleary PD. Linking clinical variables with health-related 9. Foreman MD, Kleinpell R. Assessing the quality of life of elderly quality of life. JAMA 1995;1995:59-65. persons. Semin Oncol Nurs 1990;6:292-297. 26. World Health Organization. International classification of impair- 10. Garratt A, Schmidt L, Mackintosh, Fitzpatrick R. Quality of life mea- ments, disabilities, and handicaps. A manual of classification relating surement: bibliographic study of patient assessed health outcome to the consequences of diseases. Geneva: WHO Press; 1980. measures. BMJ 2002;324:1417. 27. World Health Organization. Measuring quality of life: the WHO 11. Gerhart KA, Koziol-McLain J, Lowenstein SR, Whiteneck GG. Quality of Life instruments (WHOQOL-100 and WHOQOL- Quality of life following spinal cord injury: knowledge and attitudes Brief). WHO Mental Health Bull 1999;5:8-10. of emergency care providers. Ann Emerg Med 1994;23:807-812. 12. Gill TM, Feinstein AR. A critical appraisal of quality of quality-of-life measurements. JAMA 1994;272:619-626. E-

Outcome Measures for Clinical Trials of Muscle Diseases

Craig M. McDonald, MD Professor Departments of Physical Medicine and Rehabilitation and Pediatrics University of California Davis School of Medicine Davis, California

INTRODUCTION lack of appropriate, valid, and reliable clinical outcome measures that conform to regulatory policy. Health-related quality of life (HRQOL) assessments have several potential uses. They can be used by physicians to measure the Clinically meaningful outcomes must make a difference in the way effects of chronic illness in patients and to better understand how a patient feels, functions, or survives. Death or major morbidities, an illness affects day-to-day life. Public health professionals use such as the need for assisted positive-pressure ventilation or the HRQOL to measure the effects of numerous disorders, short- development of congestive heart failure, have consensus as clinically and long-term disabilities, and diseases in different populations. meaningful events. Clinically meaningful endpoints may include Tracking HRQOL in different populations can identify subgroups measures at a specific time point or events such as occurrence of a with poor physical or mental health and can help guide policies or complication or progression to a specific landmark. Specific mea- interventions to improve their health. Recently, HRQOL assess- surements may provide relatively high sensitivity to detect a treatments and other personal reported outcomes have been used in ment effect, but they may represent unimportant changes to the conjunction with more traditional clinical measures to assess the patient or family. Events, on the other hand, may provide relatively efficacy and safety of new clinical treatments and new drugs. This low sensitivity to detect a treatment effect, but may be more clini- manuscript will review some of the clinical outcome measures that cally meaningful and interpretable than measurements. The use of are being used to assess the effect of potential drug therapies for specific measures which correlate with clinically meaningful events individuals with muscle disease. is often desirable.

There are three critical steps to be taken from the identification In order to expedite the drug development process, the FDA has of new disease/patient targets, to putting a new drug onto the recently ruled that, in certain circumstances, drug approval may be market. The first concerns the integration of new bio-technolo- based on demonstrated clinical effects (i.e., the surrogate measure) gies in a wider context; the second is the translation from basic that can reasonably predict a clinically meaningful outcome. A sur- research to early clinical research; and the third is the evaluation rogate endpoint is defined as “a laboratory or physical sign that is of the clinical incremental value of new health interventions and used in therapeutic trials as a substitute for a clinically meaningful its prompt delivery to clinical practice. In bringing any agent to endpoint that is a direct measure of how a patient feels, functions, market that could benefit the lives of patients, the Food and Drug or survives and that is expected to predict the effect of the therapy.” Administration (FDA) must assure both safety and efficacy, as well The surrogate measure itself need not confer direct clinical benefit, as advance the public health by bringing promising innovations to but ideally has a pathophysiological connection. This is well-illus- market in a timely fashion. One of the largest hurdles limiting the trated in cardiovascular disease where surrogates (such as lowering development of pharmaceutical therapies in muscle diseases is the blood pressure or cholesterol), prolong life. For muscle disorders, E- Outcome Measures for Clinical Trials of Muscle Diseases AANEM Course identifying surrogates is more challenging. For example, a reason- tool for clinical trials is enhanced in muscle groups either too weak able goal would be to demonstrate that an average muscle score or too strong for MMT, a problem frequently encountered as an for 34 muscle groups, assessed by manual muscle testing (MMT), age-dependent correlate of muscle disorders. For example, MVIC could predict months or years of prolonged ambulation, or that a demonstrates a decline in strength in older DMD boys while forced vital capacity less than a defined percentage predicts recur- side-by-side MMT studies fail to reveal changes.6 A disadvantage rent episodes of pneumonia with certainty. The FDA requirements of QMT is the equipment expense and the need for computer- for clinical trials emphasize placing a high priority on the need to dependent software. The critical challenge for clinical myologists develope natural history databases that are disease-specific, incor- employing either MMT or QMT is to demonstrate how changes in porate genotype-phenotype correlations, and establish the time of score correlate with clinically meaningful outcomes. This represents onset of specific, clinically meaningful outcomes. Such carefully the major objective for future clinical studies. constructed databases would help provide the surrogate clinical endpoints that predict critical, and life-altering events, setting the stage for implementation of short-term clinical trials that can be FUNCTIONAL ASSESSMENTS carried out over 6 to 12 months in contrast to decades. Functional testing, which provides objective measures derived by clinicians in the laboratory or clinic regarding functional status, CLINICAL ENDPOINTS IN MUSCLE DISEASES has been traditionally used to measure functional status in patients with muscle disease. The lower extremity18 and upper extremity2 Clinical endpoints in muscle disease have generally included functional grading scales have historically been applied to patients strength measurement, functional assessments (including functional with chronic muscle diseases in both natural history studies and testing and self-report scales of function), pulmonary and cardiac clinical trials. Intra- and interrater reliability scores are exceptional assessments, and patient-reported outcomes. These measures vary (0.96 to 0.99 for DMD).3 However, these scales are nonlinear and in terms of clinical meaning to the patient and family, but many show poor correlation when compared to loss of muscle strength. A clinical assessments measured over the short term may be used as weakness in functional grading scales is that important functional clinical surrogate markers for clinically meaningful outcomes and transitions occur in a nonlinear fashion when functional grades are events. Additional surrogate markers may include enzyme levels, compared to strength loss and age. muscle histology, gene expression, and muscle imaging. There are some clinical endpoints related to muscle diseases that have been Timed testing protocols have included: the time needed to walk well developed for specific diseases and specific disease stages. Other or run 30 feet, the time needed to climb four steps, and the time measures need further development, refinement, and validation. needed to stand from a supine position. Advantages to this approach are that it; measures changes in disease progression over short-time intervals, is highly reliable, and is easily obtained. Interclass correla- STRENGTH ASSESSMENT tions for these timed testing measures have exceeded 0.95 in DMD. Similar timed testing protocols involving fine motor skills (e.g., Strength measures rely predominantly on two methodologies: drinking water, cutting out a 3-inch square, pegboard activities), MMT and quantitative muscle testing (QMT). Both methodolo- or speech rate have been applied to amyotrophic lateral sclerosis, gies measure muscle strength (not endurance), and both have pros spinal muscular atrophy, and myotonic dystrophy. The weaknesses and cons when designing a clinical trial. A typical MMT protocol to the use of timed testing as an outcome measure in isolation consists of an average of 34 muscle groups, scored on a modified centers around the clinical meaningfulness of these measures to a Medical Research Council (MRC) 0 to 10 scale.3 Manual muscle patient or family. For example, a 1-second improvement in the time testing is cost-effective and reliable when used by well-trained needed to climb 4 steps may have limited significance to a patient clinical evaluators.5 Its value has been demonstrated in defining or family member. the natural history in Duchenne muscular dystrophy (DMD), facioscapulohumeral muscular dystrophy (FSHD), and myotonic An alternative approach has been to use strength or timed testing as dystrophy, and has been used to delineate a therapeutic benefit clinical surrogates in the short-term to predict a clinically meaning- for corticosteroids.7,11,14,17 Manual muscle testing lacks sensitivity ful event or functional milestone, such as time or age of full-time for testing individual muscle groups, making this method a poor wheelchair transition. In one natural history study of DMD the age choice for assessing efficacy following local muscle injections of at wheelchair transition ranged from ages 7 to 13 with a mean age anti-sense oligonucleotides, or recombinant gene transfer vectors. of 10 years. Data concerning the time needed to walk or run 30 feet In contrast, QMT, expressed as maximal voluntary isometric showed that this measure was highly predictive of time to full-time contraction (MVIC), is ideally suited to test the efficacy of agents wheelchair transition. All boys who could walk/run 30 feet in less transferred to individual muscle groups. Quantitative muscle than 6 seconds were greater than 2 years to wheelchair transition. testing can document natural history progression as demonstrated Those who took 6 to 12 seconds to travel this distance were 1 to for DMD, FSHD, and myotonic dystrophy.6,11,17 Its precision as a 2 years from wheelchair transition. All boys who took greater than AANEM Course Neuromuscular Quality of Life E-

12 seconds to walk 30 feet transitioned to a wheelchair in less than of the disease. Challenges and questions remain. Which functional 1 year.12 testing approaches yield data clinically meaningful to patients and families? Which functional tests are sensitive to changes in the There are alternative approaches which involve longer walking specific disease? Which functional testing approaches are reliable, protocols or community-based measures. For example a 6-minute objective/accurate, and practical? In addition, developmental and run or walk is used as a national fitness measure in the United maturational considerations present a challenge because the norma- States and a great deal of normative data is available for boys and tive data is a moving target. There is a need for further refinement girls. Measurement of distance traveled in 6 minutes may provide of burden of disease and QOL measures to yield disease specific information about strength, fatigue, and cardiopulmonary reserve. measures. These function status measures need to be correlated Recently this author and colleagues applied a step-activity monitor with patient report measures of their functional ability. to the measure of real-world community ambulatory activity or physical activity.13 The monitor is accurate at various gait cadences and can be a valid measure of physical activity versus heart rate PULMONARY TESTING while being unobtrusive and storing minute-to-minute step data for periods of weeks or months. The monitor has been shown to Pulmonary measures have obvious importance as clinically mean- demonstrate a profound decrease in real-world ambulatory activity ingful endpoints because restrictive pulmonary disease accounts for both in terms of total real-world activity and high-intensity activ- 80% of the morbidity in some muscle diseases such as DMD. Any ity. A similar ability of the monitor to detect functional declines in therapy that improves respiratory muscle strength or compensates the real world activities of adults with Becker muscular dystrophy, for respiratory muscle weakness will potentially improve ventila- FSHD, and myotonic muscular dystrophy has been demonstrated. tion and airway clearance and extend life expectancy. Measurable Thus, the monitor is a quantitative measure of real-world commu- parameters include spirometry, peak cough flow, oxygen saturation nity mobility and physical activity and a potential clinically mean- both awake and asleep, peak inspiratory pressure, peak expiratory ingful endpoint measure for a variety of muscle diseases. Examples pressure, and occurrence of pneumonia, hospitalization, and respi- of therapist-derived clinical functional assessments include the ratory failure. Pediatric Evaluation of Disability Inventory (PEDI), Gross Motor Function Measure (GMFM), Functional Independence Measure Forced vital capacity (FVC) is reproducible and has been widely (WeeFIM), and Jebsen-Taylor Hand Function Test.3,4,8,10,16 The applied to natural history studies of DMD and other neuromus- PEDI has been recently applied to Pompe’s disease and provides cular diseases. It is effort dependent, and requires a cooperative information about functional skills such as self-care and mobility. patient and specialized equipment. To obtain consistent reliable It is a fairly labor-intensive instrument that appears more useful in measurement requires training on the part of the clinical evaluator, children with severe motor involvement. The GMFM consists of similar equipment, and the use of predicted values standardized to 88 questions in the full format, and includes information about age, gender, and body size. An FVC less than 20% predicts carbon such gross motor abilities as lying and rolling, sitting, crawling dioxide (CO2) retention and respiratory failure. The predictive and kneeling, standing, and walking, running, and jumping. The value of FVC for survival is good for DMD.9 In addition, the peak FIM / WeeFIM includes 18 items including self care (e.g., eating, obtained FVC (which usually occurs in the early second decade) is grooming, bathing, upper-body dressing, lower-body dressing, and predictive of disease progression with regard to respiratory and limb toileting); sphincter control (i.e., bowel and bladder management); weakness, level of function, and development of subsequent scolio- mobility (e.g., transfers for toilet, tub, or shower, as well as bed, sis.12 Thus, FVC appears to be a useful clinical endpoint because it chair, and wheelchair); locomotion (e.g., walking, wheelchair, and correlates with clinically meaningful progression, events, and clini- stairs); communication, including comprehension and expression; cal landmarks. Forced expiratory volume at one second (FEV1) is and social cognition (e.g., social interaction, problem solving, and a useful measure in chronic obstructive pulmonary disease, cystic memory). It was developed primarily for individuals receiving fibrosis, and asthma, but adds little to FVC in muscle diseases with acute in-patient rehabilitation as a burden of disease measure. The respiratory weakness. An FEV1 less than 40% predicts nighttime disadvantages of WeeFIM involve its lack of applicability to muscle hypoventilation and sleep hypoxemia.9 It is a part of routine spi- diseases, and differences between the independence scales and rometry parameter that is highly correlated with FVC so it is a rea- actual patient function. For example, provision of an ankle foot sonable clinical surrogate endpoint measure along with FVC. Peak orthotic to improve gait would result in a patient declining in score inspiratory and expiratory pressures are easily obtained measures in from a 7 (completely independent) to a 6 (modified independence the clinic that are fairly reproducible. Predictive values of FEV1for with a device). children are available are often the first pulmonary measures to show decline in boys with DMD ages 6 to 10.12 Functional tests are useful to monitor disease natural history and to assess the efficacy of therapeutic agents in clinical trials. A peak expiratory pressure of less than 60 cm H2O predicts inef- However, a single test is often not applicable throughout all stages fective cough. Thus, peak inspiratory and expiratory pressures E-10 Outcome Measures for Clinical Trials of Muscle Diseases AANEM Course

are useful clinical endpoints. Peak expiratory flow rate (PEFR) is affect individuals. Many aspects of patients’ subjective experience, reported in spirometry. Peak cough flow involves coughing into a such as symptom severity and frequency, emotional and social Wright flow meter. This is an inexpensive bedside test that has a well-being, and perceived level of health and functional ability are correlation with airway clearance (< 160 cm H2O predicts inad- important targets for disease intervention that are not measured by equate airway clearance).1 A disadvantage of this measure is that radiographs or laboratory results. Measurement of patient-reported it is effort-dependent and somewhat variable, but the ease of as- outcomes is particularly important in clinical trials, in which certainment and correlation with airway clearance make it a useful changes in clinical measurements or imaging results may not trans- clinical endpoint. late into important benefit to the patients, or in trials where two treatments may be comparable in limiting or curing disease, but

Arterial oxygen saturation (SaO2) by pulse oximetry is easily ob- have different adverse-effect profiles differentially affecting symp- tained, reliable, and inexpensive. Forced vital capacity and FEV1 toms, functioning, or other aspects of patients’ QOL. have been shown to correlate with sleep desaturation by pulse oximetry.9 However, oxygen saturation is influenced by airway disease, The last several decades have seen a proliferation of tools to is poorly predictive of respiratory insufficiency, and daytime SaO2 measure symptoms, QOL, functional status, emotional status, may not predict nighttime SaO2. Daytime oxygen saturation is and general perception of health. Although many of these instru- therefore not useful as a primary clinical endpoint or clinical surro- ments have demonstrated good reliability and validity, there are gate measure. However, nighttime oximetry appears to be a useful many limitations to current measurement approaches. One critical predictor of nighttime hypoventilation and sleep hypoxemia. disadvantage is the inability to compare results of different studies when different measurement tools are used, as these instruments

End-tidal CO2 corresponds to arterial CO2 tension (PaCO2), will have noncomparable or noncombinable scores because each a noninvasive measure, but not readily available in the clinical scale may use a different number of items, different response setting. Wakeful end-tidal CO2 greater than 45 predicts nighttime options, different reference periods, or different item content. For respiratory failure. Unfortunately, wakeful end-tidal CO2 does not example, progress in clinical pain research is slowed by the use of predict survival in DMD as normal values have been seen in those various pain measurement scales that are not directly comparable. with poor survival.15 A reduced FEV1 less than 20% predicted has The length and complexity of questionnaires and batteries can also 9 been shown to correlate with elevated PaCO2 in DMD. Thus, it be problematic, creating a level of respondent burden that hampers appears that spirometry is much more readily obtainable and will recruitment, results in too much missing data, or is detrimental to suffice as a clinical endpoint measure. response validity and reliability.

While formal sleep studies may be sensitive and useful in DMD Recently, the FDA suggested the use of patient-reported outcomes and other muscle diseases, very few pediatric sleep laboratories (PROs) to capture the patient’s perspective and subjective per- exist and these studies are fairly expensive. In addition, there is ception of treatment benefits in conjunction with clinical trials. great variability in interpretation from laboratory to laboratory There are a number of reasons for including PROs such as the and normal standards have not been well developed in children. HRQOL and the assessment of symptoms and more recently, A formal sleep evaluation may certainly be useful clinically to sort treatment satisfaction, in clinical trials evaluating pharmaceuticals. out central versus obstructive sleep apnea in adults with neuromus- The PROs assist in providing a better understanding of treatment cular diseases. However, as an endpoint for large scale clinical trials outcomes from the patient’s perspective by translating clinical formal sleep studies will likely play a limited role. improvement into patient-centered outcomes. The PROs complement and extend information provided by clinical endpoints, and There is a need to include clinically meaningful pulmonary events add relevant outcome data not captured by these instruments. An and complications in both natural history data-gathering efforts increasing need to evaluate health care technologies with respect to and future clinical trials. These events should include pneumonia, individual and societal values and an increasing focus on recogniz- hospitalizations, development of respiratory failure, use of various ing and valuing patient perceptions of changes with treatment are modes of ventilation and airway clearance strategies, and documen- other reasons for including PROs such as the HRQOL assessment tation of the occurrence of and cause of death. in clinical trials.

The PROs represent a unique indicator of the impact of disease PERSONAL REPORTED OUTCOMES AND HEALTH- and its treatment. In many situations, the physician relies almost RELATED QUALITY OF LIFE entirely on patient reports in evaluating disease activity and symptoms. The management and monitoring of conditions such as pain Clinical and functional measures of disease status do not fully is based almost entirely on the patient’s report of symptoms and capture the ways in which chronic diseases and their treatment how those symptoms impact daily functioning and well-being. In AANEM Course Neuromuscular Quality of Life E-11

conditions in which there are no physical or physiological markers component in relation to the research question needs to be explicit, of disease activity, the PROs become the outcome of choice. and the PROs need to be clearly defined in the study. The PRO Therapy-related improvement in such conditions is best measured measurement strategy should be operationalized according to what by questioning patients about the severity of their symptomatic study questions are being asked. In this context, it is necessary to complaint and how troubled they are by it (i.e., how it affects their understand and demonstrate the relevance of the selected PROs to well-being and daily life). the target disease, patient population, treatments, and study setting. Identification of PRO measures for use in clinical trials requires an In chronic diseases, which are the major causes of mortality and understanding of both the epidemiology and burden of the disease morbidity, more attention has been paid to the HRQOL issues in from the patient’s perspective and the theoretical and empirical response to a change in the goals of treatment from a traditional relationships between treatment, clinical outcomes, and the PROs. curative aim to the prevention and control of disease. For those There are many approaches to measure the PROs, including single individuals diagnosed with a chronic condition where no cure is domain, multiple domains, disease-specific, or generic measures. attainable and therapy may be prolonged, maintenance or improve- No one measurement approach is ideal for all clinical trial applica- ment in the HRQOL is likely to be the most essential outcome. In tions and ultimately investigators need to determine how well the other diseases, patient assessments are important elements in the different approaches and instruments match their research ques- evaluation of treatment impact, alongside other clinical indicators. tion, study design, and targeted disease population. This is because the therapy is frequently associated with significant toxicity, and in this situation it is important to evaluate the effect of Well-documented measurement properties are essential to the use adverse events versus potentially small gains in survival. of PROs in clinical trials. The psychometric evidence (i.e., reliability and validity) of potentially useful PRO instruments should Treatment satisfaction could be a useful outcome in clinical trials be reviewed and evaluated to determine which of the instruments to provide insight into the patient’s attitude towards treatment. is best suited for the clinical trial. These measurement characteris- Evaluating satisfaction with treatment may assist healthcare provid- tics are widely accepted and considered essential for assuring that ers in understanding the issues that influence adherence and may a PRO instrument is meaningful to patients and clinicians and help identify aspects of the treatment that require improvement to provides accurate and valid documentation of treatment effects to enhance long-term treatment outcomes. For many patients, infor- industry and regulators. mation about the impact therapy will have on their daily life and well-being is often much more relevant than information about The PROs must meet the same standards as traditional clinical small changes in exercise capacity, FEV1, or joint stiffness clinical measures used in randomized controlled trials. In order to be able endpoints that have been shown to be rather poorly correlated to to support a claim based on the PROs, the study must be powered the HRQOL. adequately. The sample size for the endpoint of the PRO should therefore always be calculated before the final decision about in- Since PROs are based on the patient’s subjective perception, the cluding the PROs in a trial. The power calculation should be based best and easiest way to obtain this information is to directly ask on what is considered to be the minimal important difference the patient. Whereas clinicians often express concern over burden- between a PRO questionnaire based on developers’ recommenda- ing their patients with PRO assessments, experience shows that tions or be based on previous experience of using the questionnaire the majority of patients welcome the opportunity to report how in clinical trials of similar patient populations. their disease and treatment are affecting their daily life. Clinical trials assessing PROs often involve large patient populations. Analysis of the PROs raises a number of issues to be considered in Self-administered questionnaires represent an attractive solution the analysis plan. Questions related to interpretability or “identifi- because they enable uniform administration and unbiased scoring cation of the minimal important change” as well as how to handle and quantification of data in a cost-effective fashion. Moreover, missing data and the adjustment for multiplicity are all of critical standard questionnaires provide valid and reproducible data, and concern. The statistical analysis procedures must be outlined and are comparatively cheap. developed to relate to the prespecified hypotheses and the targeted claim, even when the PRO is a secondary endpoint. A full analysis The rationale for measuring PROs needs to be made explicit as plan must be developed a priori with specification of the data analy- part of the planning and documentation of clinical trials compar- sis strategy and statistical models. By definition, the HRQOL is a ing medications in order to put forward labeling or promotional subjective and multi-dimensional construct. Hence most HRQOL claims. The PROs relevance in assessing the outcome in relation to instruments result in a number of repeated measurements for dif- the disease, as well as the clinical characteristics of the patient popu- ferent domains, which are more or less correlated—a situation that lation under study, needs to be described and linked to previous re- creates a multiplicity problem. It is important to identify these search and to the planned treatment. The reason for using the PRO problems and describe how they should be dealt with in the study E-12 Outcome Measures for Clinical Trials of Muscle Diseases AANEM Course

protocol and the statistical analysis plan. In order to counteract a variety of advantages (e.g., feasibility, sensitivity, resistance to bias, problems related to multiplicity, the most relevant domains in rela- and clinical meaningfulness at varied stages of the disease). Other tion to the patient population and the drug under study should be factors which determine the appropriateness of endpoint selection prespecified as the “primary” PRO measures. Due to the complex- include age and developmental status of the patient, and the extent ity and multiplicity inherent in PRO measures missing data can of disease burden in terms of selection of both patient-centered and occur. In clinical trials, missing data may lead to potential bias. family-centered measures. These factors should be used to develop Hence, every effort should be made when designing the study to the primary and secondary endpoints for clinical trials. ensure that patients and investigators are motivated to comply with the collection of PRO data. REFERENCES Lack of clarity with regard to the definition of PRO, especially the HRQOL, will have an adverse impact on any scientific endeavor 1. Bach JR, Saporito LR. Criteria for extubation and tracheostomy tube in the research area. Therefore, it is essential that there be a con- removal for patients with ventilatory failure. A different approach to sensus on a clear definition and classification of outcomes, and, in weaning. Chest 1996;110:1566-1571. particular, PROs (i.e., a term that captures the patient’s perspective 2. Brooke MH, Griggs RC, Mendell JR, Fenichel GM, Shumate and subjective perception). Current methods for selecting, develop- JB.Clinical trial in Duchenne dystrophy. 1. The design of the proto- ing, validating, measuring, and reporting the PROs are similar to col. Muscle Nerve 1981;4:186-197. other measures of clinical effectiveness. However, the PROs focus 3. Brooke MH, Fenichel GM, Griggs RC, Mendell JR, Moxley R, Miller JP, Province MA. Clinical investigation in Duchenne dystrophy: 2. attention on the patient’s perspective by highlighting the patient’s Determination of the “power” of therapeutic trials based on the contribution to the drug evaluation process. natural history. Muscle Nerve 1983;6:91-103. 4. Deutsch A, Braun S, Granger C. The Functional Independence SUMMARY Measure (FIM sm Instrument) and the Functional Independence Measure for Children (WeeFIM): ten years of development. Crit Rev Phys Med Rehabil 1996;8:267-281. The ideal clinical endpoint is reliable, clinically meaningful, fea- 5. Escolar DM, Henricson EK, Mayhew J, Florence J, Leshner R, Patel sible, objective, sensitive, and clinically interpretable. Clinical ef- KM, Clemens PR. Clinical evaluator reliability for quantitative and ficacy ultimately is defined as an effect of direct clinical meaning manual muscle testing measures of strength in children. Muscle (importance) to a patient in how they feel or function. It generally Nerve 2001;24:787-793. must be an effect of value to the patient directly. A clinical or bio- 6. Escolar DM, Buyse G, Henricson E, Leshner R, Florence J, Mayhew J, et al. CINRG randomized controlled trial of creatine and glutamine chemical surrogate measure validated to correlate with or predict in Duchenne muscular dystrophy. Ann Neurol 2005;58:151-155. a clinically meaningful endpoint (such as an event or landmark) 7. Griggs RC, Moxley RT 3rd, Mendell JR, Fenichel GM, Brooke MH, may be a useful approach. However, the nature of the relationship Pestronk A, Miller JP. Prednisone in Duchenne dystrophy. A ran- between the surrogate measure and the clinically meaningful end- domized, controlled trial defining the time course and dose response. point must be defined through reliability and validation studies, Clinical Investigation of Duchenne Dystrophy Group. Arch Neurol natural history studies, and related clinical trials. Although some 1991;48:383-388. events appear to be life-altering, such as loss of ambulation, loss of 8. Haley SM, Fragala MA, Skrinar AM. Pompe disease and physical disability to climb stairs, or loss of ability to get up from a toilet seat, ability. Dev Med Child Neurol 2003;45:618-623. they require correlation with a QOL scale. Natural history studies 9. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventila- provide data that helps enormously in the selection of appropriate tion in Duchenne muscular dystrophy. Am J Respir Crit Care Med clinical endpoints. The design of natural history studies should 2000;161:166-170. 10. Jebsen RH, Taylor N, Trieschmann RB, Trotter MJ, Howard LA. An ideally involve the selection of a combination of traditional clinical objective and standardized test of hand function. Arch Phys Med endpoints with patient-reported outcomes to capture all aspects of Rehabil 1969;50:311-319. the specific disease. The use of combinations of measures may offer AANEM Course Neuromuscular Quality of Life E-13

11. Mathieu J, Boivin H, Richards CL. Quantitative motor assessment in 15. Phillips MF, Quinlivan RC, Edwards RH, Calverley PM. Changes myotonic dystrophy. Can J Neurol Sci 2003;30:129-136. in spirometry over time as a prognostic marker to patients with 12. McDonald CM, Abresch RT, Carter GT, Fowler WM Jr, Johnson Duchenne muscular dystrophy. Am J Respir Crit Care Med ER, Kilmer DD, Sigford BJ. Profiles of neuromuscular diseases. 2000;164:2191-2194. Duchenne muscular dystrophy. Am J Phys Med Rehabil 1995;74: 16. Russell DJ, Rosenbaum PL, Cadman DT, Gowland C, Hardy S, Jarvis S70-S92. S. The gross motor function measure: a means to evaluate the effects 13. McDonald CM, Widman L, Abresch RT, Walsh SA, Walsh DD. of physical therapy. Dev Med Child Neurol 1989;31:341-352. Utility of a step activity monitor for the measurement of daily ambu- 17. The FSH-DY Group. A prospective, quantitative study of the natural latory activity in children. Arch Phys Med Rehabil 2005;86:793-801. history of facioscapulohumeral muscular dystrophy (FSHD): impli- 14. Mendell JR, Moxley RT, Griggs RC, Brooke MH, Fenichel GM, Miller cations for therapeutic trials. Neurology 1997;48:38-46. JP, et al. Randomized, double-blind six-month trial of prednisone in 18. Vignos PJ, Spencer GE, Archibald KC. Management of progressive Duchenne’s muscular dystrophy. N Engl J Med 1989;320:1592- muscular dystrophy of childhood. JAMA 1963;184:89-96. 1597. E-14 AANEM Course E-15

Quality of Life in Amyotrophic Lateral Sclerosis

Mark B. Bromberg, MD, PhD Professor and Vice-Chairman Department of Neurology University of Utah Salt Lake City, Utah

INTRODUCTION periences), expectations (past and future), current support (family, friends), and spiritual beliefs (organized religion or beliefs). The When a patient with amyotrophic lateral sclerosis (ALS) says, “…I World Health Organization states that quality of life “…is a broad- do not want to be totally dependent and have no quality of life…” ranging concept affected in a complex way by the person’s physical how does a physician respond? Quality of life (QOL) is one of health, psychological state, level of independence, social relation- the most important concerns for an ALS patient and their family ships, personal beliefs, and their relationship to salient features of and a very challenging one to address for the physician both from their environment.” The environment in this case includes ALS, pragmatic and emotional perspectives. From the pragmatic per- fears about dying, and concerns for others (caregiver and family). spective are the underlying questions, what is quality of life, how do we measure it, and what are the results? From the emotional When asked the question, “How is it going?” a person usually perspective is the ability to convey to a patient at an early stage answers positively from a superficial perspective and rarely digs of the disease what it will be like at a later stage. Further, personal deep into their personal lives. Most people probably have a pretty attitudes of the physician are incorporated in the answers to these good QOL. However, in a medical setting, the perspective may questions. Given the uniform progression of ALS and the repeated change and a new level may surface and the patient’s illness may clinical experiences of ALS physicians, it is appropriate for them drive the answer, especially with a serious illness such as ALS. Thus to periodically review personal views of QOL. This manuscript the question may not be answered from a global perspective, and reviews concepts of QOL, how it is measured, and data that indi- negative aspects of the illness (and most illnesses are negative) cate QOL for ALS patients. It concludes with suggestions on how govern the response. This unbalanced perspective likely leads to to guide the patient. despair. In most medical settings the answer to the question of “How is it going?” is likely to be “Not so well!” However, it is important to help the patient find a more distant viewpoint to provide WHAT IS QUALITY OF LIFE? an overall perspective.

It is perhaps easy to dismiss the question, “what is quality of life?” by invoking the oft-used response: “it is difficult to define, but you HOW IS QUALITY OF LIFE MEASURED? will know it and know how well it is going when you experience it.” There are many factors that contribute to a person’s QOL, and at a When one wants a more substantive answer to the question, “how minimum include a person’s background (ethnic, cultural, past ex- is quality of life measured?” formal instruments or questionnaires E-16 Quality of Life in Amyotrophic Lateral Sclerosis AANEM Course are used. Questionnaires may be simple or complex. The simplest subscores for each dimension and a total score. For unclear reasons, is to ask the subject to rate their life using a visual analogue scale the ALSAQ-40 (and a shorter version, ALSAQ-5) has not gained from 0 to 10 cm with marks being measured in metric units. This wide usage. approach is similar to the answer “I know it when I see it” to the question, “what is quality of life?” Despite the simplicity, there is Another approach is to modify an existing validated QOL scale merit to letting the subject reach their own conclusion in a single for another disorder. The McGill Quality of Life Questionnaire score. (MQOL) was originally designed for cancer and human immunodeficiency virus patients.6 It is attractive for ALS because it is This approach is in contrast to the use of a complex questionnaire not heavily weighted toward physical function and includes an with a number of sections resulting in section subscores and a sum- existential element (perception of purpose, meaning in life, and mation score to yield an overall measure of QOL. Complex QOL capacity for personal growth). The existential element is likely questionnaires are developed and validated by a multi-step and important to ALS patients as it is to cancer patients. Recent efforts rigorous process. The areas or elements of interest are frequently have been made to modify the MQOL questionnaire for ALS pa- identified from interviews with the groups of interest (such as patients, and the modified version is the ALS-specific Quality Of Life tients and caregivers). Questions are then designed to address issues (ALSSQOL) questionnaire (Simmons and colleagues, in press). and concerns brought out in the interviews. The initial version of Changes include reformatting for ease of administration and incor- the questionnaire is then tested in the designated group. During porating nondominant physical function, psychological, support the initial testing the various elements are assessed for validity by and existential elements, and a broad spiritual element. There is comparisons with other focused questionnaires that have been es- also an open question asking the patient to list things that had tablished as good measures of the element. To reduce the number the greatest effect on their QOL over the past 7 days. In addition of questions to a minimal number while retaining full informa- to a questionnaire focusing on QOL, many studies in ALS focus tion, the answers to each question are compared to each other to on a specific area and include additional questionnaires that more determine which questions are always answered in the same way. directly assess specifics in the area of interest. Thus, a section was The final shortened version is then retested. The QOL question- added asking the patient to identify troublesome symptoms from a naires developed for other patient populations can be used for ALS list of 10 symptoms. patients, but should be formally assessed in the new patient population. Frequently, when using an existing questionnaire, questions A different approach is to let the subject decide what elements are changed, added or dropped, and therefore modified question- make up their QOL at the time.21 This concept has been formal- naires must be reassessed. ized in the Schedule of the Evaluation of Individual Quality of Life (SEIQoL) and a shorter direct weigh version (SEQoL-DW).9 In Early efforts to measure QOL in ALS made use of health status this questionnaire, the subject is asked to list five areas that make questionnaires, such as the Sickness Impact Profile (SIP),1 a shorter up their QOL at the time. In each area they should rank how well version (SIP/ALS-19),17 and the short form (SF)-36.28 A major they are doing on a visual analogue scale. They are then asked to concern with such questionnaires is that they include a functional rank the importance of each area to each other. The available data element that assesses activities of daily living, in addition to ele- include the five areas, how they are doing in each area, the relative ments assessing physical, emotional, and mental well-being. Since importance of each area, and a combined index score. An advantage strength will inexorably decline in ALS as will the ability to perform of this open questionnaire is that the same questionnaire can be activities of daily living, the functional element subscores will fall used to assess QOL for both the patient and the caregiver. over time even though the patient may judge their QOL as good and stable. Despite these issues, the SF-36 is being used as an It must be kept in mind that conclusions may differ because of overall measure, frequently supplemented by other more focused the large number of psychometric instruments available and the questionnaires in a battery of questionnaires. vast number of combinations that can be assembled for a particular study. What follows is a selection that appears stable across There have been efforts to develop QOL questionnaires specific studies. for ALS patients. The most basic approach is to design a questionnaire from the ground up (interviews with patients and caregivers) with formal verification and statistical analysis. One such scale was HOW IS QUALITY OF LIFE MEASURED IN AMYOTROPHIC developed in the United Kingdom and called the Amyotrophic LATERAL SCLEROSIS? Lateral Sclerosis Assessment Questionnaire (ALSAQ)-40.10 This questionnaire included five dimensions: (1) physical mobility, (2) It is not unexpected that when one is asked to imagine QOL activities of daily living/independence, (3) eating and drinking, with impaired function one projects a poor rating. This is clearly (4) communication, and (5) emotional functioning. There were the feeling when an ALS patient imagines being dependent upon AANEM Course Neuromuscular Quality of Life E-17

others for care. However, by reviewing life in overall general terms, impaired respiratory function, and inadequate nutrition (from dys- as people age they are less able to perform certain tasks and often phagia).2,12,15 The latter two factors are amenable to treatment that require more help. However, they still enjoy a good QOL. It is can improve QOL. perhaps the innate ability to adapt that allows for satisfying changes to be made over time. The majority of ALS patients die from respiratory failure. There are efforts to assist respiration with noninvasive ventilation for patient The issue of an ALS patient wishing to end their life through comfort and possibly to increase longevity. A common issue in dis- suicide or assisted death is perhaps the most significant example of cussing noninvasive ventilation with patients is their QOL. Quality predicting a QOL so poor that it is not felt to be worth living. A of life as measured by a number of questionnaires has been shown survey of ALS patients posed the question, “Under some circum- to be improved with noninvasive ventilation.18 While few patients stances I would consider taking a prescription medicine for the sole chose full-time tracheal (invasive) ventilation, studies indicate that purpose of ending my life,” and 56% answered in the affirmative.7 QOL is perceived as good by the patient.3 Inadequate nutrition Differences between “considering” suicide and taking any further and the mechanics of eating in the setting of marked dysphagia actions represents a broad spectrum. Further, there are differences can affect QOL, and a feeding tube can lead to improvements in between taking one’s life and aiding the dying process. In a study quality for the patient and the caregiver who must officiate during from the Netherlands, physicians were queried about their care of long meals.16 ALS patients and 17% said they participated in euthanasia while only 3% participated in suicide.26 One factor from both studies is In addition to the term “quality of life” it is appropriate to consider that religion has a positive role in ALS patients’ attitude toward the term “quality of death.” The question “how am I going to die?” living. The final interpretation of these data must remain open is a major concern of ALS patients and their caregivers, although and cannot be generalized because attitudes about life and death it is rarely asked. Overall, death from ALS occurs peacefully, which likely differ among cultures and what actually occurs with respect can be defined as the manner of death one would chose if there to possible assistance in the death process by patients, families, and were a choice.19 There are issues that can prevent such a death, healthcare providers as gathered by questionnaires will be inexact. including a poor ability to communicate, shortness of breath, dif- Wishing for a hastened death and actively hastening death may be ficulty sleeping, and pain.8 These issues are manageable with the two different issues.22 help of hospice services.13

When QOL has been measured in ALS patients either serially or As the ALS patient becomes weaker, they will need greater care. at one specific time, it has remained relatively high. Quality of life This burden usually falls to the caregiver, and as the patients loses does not fall even though strength and ability to carry out activi- independence, so does the caregiver. This results in greater numbers ties of daily life falls. This adaptation is called the response shift, of hours spent in giving care leading to feelings of physical and and is likely similar to the natural changes with aging.29 A striking psychological health.11 Quality-of-life questionnaires given to care- example comes from a study using the SEQoL-DW in a German givers show this burden. The SEQoL-DW allows the same ques- ALS patient who listed football (soccer) as one of the five important tionnaire to be given to both the patient and caregiver, and in one elements in his QOL.20 As he became weaker over time, he shifted study the caregiver scored lower than the patient.4 However, there from actively playing football to watching football. Despite a shift are positive factors for the caregiver, including finding a positive in his type of involvement in football, it remained high in satisfac- meaning in providing care to the patient. Negative issues are stress tion, and its relative contribution to QOL remained unchanged. (loss of independence, increased financial strain, and loss of prior Clearly this same shift in involvement would have occurred in this coping mechanisms) that are correlated with the stresses perceived patient as he grew older even if he did not have ALS; the disease by the patient.22 speeds up the response shift. Hospice services can contribute to the QOL and quality of death Cross-sectional studies show good QOL and a lack of depression for the patient and the caregiver. Hospice services include home in ALS patients.4,24,25 Longitudinal studies uniformly show a stable aids, nursing evaluation to assist in patient management, drugs assessment of QOL in the setting of declining physical function.20,23 for management of discomfort, and social and spiritual support. This is one of the most important findings to keep in mind when Despite hospice services being open to ALS patients, less than talking to patients. The likely explanation is the natural response two-thirds use them.13 Most ALS patients meet hospice criteria for shift, as discussed above. Important positive factors associated with progression of a disability over 12 months, but have no wish for a perceived good QOL are contributed to the strength and role of aggressive treatment or management. Other factors for admission religion and spirituality in a patient’s life.27 Physical factors that can into a hospice program are the need to show increased respiratory have a negative impact are general and increased physical fatigue, distress and impaired nutrition. The reasons behind patients not E-18 Quality of Life in Amyotrophic Lateral Sclerosis AANEM Course

2. Bourke SC, Shaw PJ, Gibson GJ. Respiratory function vs sleep- embracing hospice services are many and include the feeling that disordered breathing as predictors of QOL in ALS. Neurology the end is near.5 However, in practice it is hard to accurately predict 2001;57:2040-2044. a time course and ALS patients not infrequently remain on hospice 3. Bromberg M, Forshew D, Iaderosa S, McDonald E. Ventilator de- care longer than 6 months if they continue to show a decline. pendency in ALS; management, disease progression, and issues of coping. J Neuro Rehab 1996;10:195-216. 4. Bromberg MB, Forshew D. Comparison of instruments addressing Quality of life for the caregiver and family should also be consid- quality of life in patients with ALS and their caregivers. Neurology ered after the death of the patient. There are often feelings of being 2002;58:320-322. burned-out from providing constant care, from changes in living 5. Carter GT, Bednar-Butler LM, Abresch RT, Ugalde VO. Expanding arrangements to accommodate progressive weakness of the patient, the role of hospice care in amyotrophic lateral sclerosis. Am J Hosp and from financial hardships.14 One can also take the data on Palliat Care 1999;16:707-710. caregiver stress gathered after death and periodically ask caregivers 6. Cohen S, Mount B, Strobel M, Bui F. The McGill Quality of Life about their QOL while the patient is living. While it may be chal- Questionnaire: a measure of quality of life appropriate for people lenging to modify some of the issues, acknowledging that giving with advanced disease. A preliminary study of validity and accept- care is stressful can be an important message for the caregiver to ability. Pall Med 1995;9:207-219. hear. 7. Ganzini L, Johnston WS, McFarland BH, Tolle SW, Lee MA. Attitudes of patients with amyotrophic lateral sclerosis and their care givers toward assisted suicide. N Engl J Med 1998;339:967-973. CONCLUSION 8. Ganzini L, Johnston WS, Silveira MJ. The final month of life in patients with ALS. Neurology 2002;59:428-431. 9. Hickey A, Bury G, O’Boyle C, Bradley F, O’Kelly F, Shannon W. What should a physician tell an ALS patient? First, acknowledge A new short form individual quality of life measure (SEIQoL- that ALS is a challenging disease. Emphasize that the physician will DW): application in a cohort of individuals with HIV/AIDS. BMJ be there to guide them. Second, discuss the course of changes in 1996;313:29-33. ALS in a metered fashion. Explain that there will be time to look 10. Jenkinson C, Fitzpatrick R, Brennan C, Bromberg M, Swash M. ahead, review, and make recommendations on care as issues arise. Development and validation of a short measure of health status for Third, review objective QOL data with the patient and note that individuals with amyotrophic lateral sclerosis/motor neurone disease: QOL is perceived to be relatively high by ALS patients and that the ALSAQ-40. J Neurol 1999;246:III16-III21. over time this remains stable. For some patients, ALS has allowed 11. Krivickas LS, Shockley L, Mitsumoto H. Home care of patients with amyotrophic lateral sclerosis (ALS). J Neurol Sci 1997;152:S82-S89. them to refocus their priorities and has had a positive impact on 12. Lou JS, Reeves A, Benice T, Sexton G. Fatigue and depression are their life. Fourth, explain how people naturally adapt to the disease associated with poor quality of life in ALS. Neurology 2003;60:122- as it progresses. Emphasize that this adaptation will, in part, mirror 123. the general challenges that everyone faces as they age. Fifth, assure 13. Mandler R, Anderson F, Miller R, Clawson L, Cudkowicz M, Del patients that changes in ALS do not happen suddenly and there will Bene M, The ALS C.A.R.E. The ALS Patient Care Database: insights be time to actively make adaptations. Explain that the physician is into end-of-life care in ALS. Amyotroph Lateral Scler Other Motor there to look ahead and make suggestions to enhance factors that Neuron Disord 2001;2:203-208. affect QOL, such as durable equipment, feeding tubes, and nonin- 14. Martin J, Turnbull J. Lasting impact in families after death from ALS. vasive ventilation. Sixth, emphasize that the end of life is manage- Amyotroph Lateral Scler Other Motor Neuron Disord 2001;2:181- able and patients die a peaceful death. Further, hospice services can 187. aid in the quality of death. Seventh, acknowledge that there will be 15. Max M, Lynch S, Muir J, Shoaf S, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neu- challenges for the caregiver and that they are important to discuss. ropathy. New Engl J Med 1992;326:1250-1256. Emphasize that hospice services can help both the patient and the 16. Mazzini L, Corrà T, Zaccala M, Mora G, Del Piano M, Galante caregiver. Eighth, remind patients that spirituality and religious M. Percutaneous endoscopic gastrostomy and enteral nutrition in connectedness are important factors that can have a positive influ- amyolateral sclerosis. J Neurol 1995;242:695-698. ence on a patient’s outlook and QOL and quality of death. Ninth, 17. McGuire D, Garrison L, Armon C, Barohn R, Bryan W, Miller R, it is important to suggest counseling as an important part of adapt- et al. A brief quality-of-life measure for ALS clinical trials based on ing, both for the patient and caregiver. Tenth, always call and write a subset of items from the Sickness Impact Profile. The Syntex- a letter of condolence to the patient’s family because it gives closure Synergen ALS/CNTF Study Group. J Neurol Sci 1997;152:S18- both to the family and to the physician. S22. 18. Mustfa N, Walsh E, Bryant V, Lyall RA, Addington-Hall J, Goldstein LH, et al. The effect of noninvasive ventilation on ALS patients and their caregivers. Neurology 2006;66:1211-1217. REFERENCES 19. Neudert C, Oliver D, Wasner M, Borasio G. The course of the terminal phase in patients with amyotrophic lateral sclerosis. J Neurol 1. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The Sickness Impact 2001;248:612-616. Profile: development and final revision of a health status measure. Med Care 1981;19:787-805. AANEM Course Neuromuscular Quality of Life E-19

20. Neudert C, Wasner M, Borasio GD. Patients’ assessment of quality 25. Trail M, Nelson ND, Van JN, Appel SH, Lai EC. A study comparing of life instruments: a randomised study of SIP, SF-36, and SEIQoL- patients with amyotrophic lateral sclerosis and their caregivers on DW in patients with amyotrophic lateral sclerosis. J Neurol Sci measures of quality of life, depression, and their attitudes toward 2001;191:103-109. treatment options. J Neurol Sci 2003;209:79-85. 21. O’Boyle C, McGee H, Joyce C. Quality of life: assessing the in- 26. Veldink JH, Wokke JH, van der Wal G, Vianney de Jong JM, van den dividual. In: Albrecht G, Fitzpatrick R, editors. Quality of life in Berg LH. Euthanasia and physician-assisted suicide among patients health care advances in medical sociology, volume 5. Greenwich, with amyotrophic lateral sclerosis in the Netherlands. N Engl J Med Connecticut: JAI Press Inc; 1994. p 159-180. 2002;346:1638-1644. 22. Rabkin J, Wagner G, Del Bene M. Resilience and distress among 27. Walsh SM, Bremer BA, Felgoise SH, Simmons Z. Religiousness amyotrophic lateral sclerosis patients and caregivers. Psychosom Med is related to quality of life in patients with ALS. Neurology 2000;62:271-279. 2003;60:1527-1529. 23. Robbins R, Simmons Z, Bremer B, Walsh S, Fischer S. Quality of 28. Ware JE Jr, Sherbourne C. The MOS 36-item short-form survey life in ALS is maintained as physical function declines. Neurology (SF-36). I. Conceptual framework and item selection. Med Care 2001;56:442-444. 1992;30:473-483. 24. Simmons Z, Bremer B, Robbins R, Walsh S, Fischer S. Quality of life 29. Wilson IB. Clinical understanding and clinical implications of re- in ALS depends on factors other than strength and physical function. sponse shift. Soc Sci Med 1999;45:1577-1588. Neurology 2000;55:388-392. E-20 AANEM Course E-21

Neuromuscular Quality of Life CME SELF-ASSESSMENT TEST

Select the ONE best answer for each question.

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Leave the completed form at the table outside your session. Fill in answers here

1. Which of the following is most correct? 2. Ideally instruments that measure QOL should be valid, re- A. Quality of life (QOL) is a subjective assessment that sponsive, appropriate, sensitive, and interpretable. Which of cannot be statistically measure quantitatively. the following questions needs to be answered to determine if B. Proxy reports of physical function do not correlate well the instrument devised to measure QOL is responsive? with assessments made by patients. A. Does the instrument measure what it is intended to C. Proxy reports of role functioning correlate well with as- measure? sessments made by patients. B. Does the measure produce the same results when repeated D. Objective indicators of disablement, such as the Craig in the same population? Handicap Assessment and Reporting Technique C. Is the measure suitable for its intended use? (CHART), are able to explain a significant amount of D. Does the measure detect clinically meaningful changes? variance that is reported in subjective measures of QOL. E. Are results from the measure relevant? E. In general, proxy respondents consider patients more impaired than the patients consider themselves. E-22 CME Self-Assessment Test AANEM Course

3. All of the following questions should be addressed before 6. Quality of life represents: choosing a health-related QOL measure for a given application A. A static concept affecting an individual uniformly EXCEPT: throughout life. A. Are the domains covered relevant? B. A dynamic concept that can change during life. B. Is the population and setting in which the assessment C, A concept that cannot be defined in a useful manner. device was developed similar to those situations in which D. A concept that is fixed at an early age. it is planned to be used? E. An interesting but not clinically useful concept. C. Do the questions allow the respondents to include and weight the importance of aspects of their own life? 7. Quality of life can be measured by: D. Is the measure sensitive enough to distinguish changes A. Simple visual analogue scales. over time? B. General health questionnaires. E. Has the measure been pretested on the patient popula- C. Disease-specific questionnaires. tion? D. Battery of questionnaires. E. All of the above. 4. QOL assessments are used for the following reasons EXCEPT: 8. Quality of life questionnaires are most robust when: A. Assessing the patient’s QOL gives the clinician valuable A. Based on simple questions. information that can help in making the best choices B. Modifications are made to established questionnaires. patient care. C. Based on single visual analogue scale. B. By understanding how a disease affects the QOL of a D. Statistically analyzed for validity. patient, the interaction between the doctor and patient E. None of the above. will improve. 9. Quality of life in amyotrophic lateral sclerosis (ALS) is usually C. Information about how a disease affects the functional rated poor by all EXCEPT: and emotional status of the patient gives the doctor a A. Providers (physicians, nurses, etc.). better insight into the patient’s needs. B. Health caregivers. D. Self-reported personal reported QOL measures are often C. Patients. used by the Food and Drug Administration as the primary D. Family (parents, children, etc.). outcome to determine the effectiveness of drug trials. E. Friends. E. All of the above are true. 10. Quality of life in ALS: 5. Potential uses for disease-specific QOL measures include all of A. Can remain high in the setting of progressive weakness. the following EXCEPT: B. May be lower for the caregiver than the patient. A. Comparing the health and social status of a diabetic and C. Is not commonly influenced by patient depression. asthmatic population. D. Can be influenced by the concept of “response shift”. B. Tailoring management to the needs of the patient. E. All of the above. C. Being the primary outcome measure for a clinical trial. D. Assessing the effectiveness of rehabilitation services. E. Justifying the allocation of limited social and healthcare resources. 2006 AANEM Course C: 2006 AANEM Course D: 2006 AANEM Course E: New Insights in Lumbosacral Muscle & Nerve Pathology Quality of Life in Neuromuscular Plexopathy Disease SELF-ASSESSMENT EXAMINATION SELF-ASSESSMENT EXAMINATION ANSWER SHEET SELF-ASSESSMENT EXAMINATION ANSWER SHEET ANSWER SHEET 1. D 1. D 1. E 2. B 2. A 2. D 3. B 3. D 3. C 4. A 4. C 4. E 5. E 5. B 5. A 6. E 6. B 6. B 7. E 7. E 7. E 8. C 8. E 8. D 9. D 9. A 9. C 10. B 10. B 10. E 11. D 11. B 12. B 12. E 13. E 13. A 14. A 14. B 15. C 15. D 16. E 16. A 17. E 17. C 18. D 18. C 19. B 19. C 20. C 20. D

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