Myopathies Madison Pilato

Myopathy Case Congenital Myopathies Critical Illness Myopathy Inflammatory Myopathies References

Case 68 yo M w/o significant medical history p/w slowly progressive muscle weakness for 5 years. First symptom R knee giving out on stairs Today has difficulty rising from a chair and grasping with right hand Exam: Intact CN, sensation and DTRs RUE: 5/5 shoulder abduction, 5/5 elbow flexion and extension, 4/5 wrist flexion 5/5 wrist extension, 3-/5 finger flexion LUE: 4+/5 finger flexion, rest is 5/5 RLE: 4+/5 knee extension, rest 5/5 LLE: 4+/5 hip flexion, 3+/5 knee extension, 4+/5 dorsiflexion Case from Continuum, “Pattern Recognition Approach to Myopathy” Volume 12, Issue 3, p13-32

Congenital Myopathies

Core Myopathy Central core disease https://adc.bmj.com/content/88/12/1051 Core Myopathy Central core disease Clinical spectrum: apparent normalcy to severe weakness Typically: hypotonia in infancy, developmental delay in childhood Proximal limbs, axial muscles w/musculoskeletal abnormalities (hip dislocation, kyphoscoliosis, joint contractures) Autosomal dominant RYR1 mutation – majority of cases, rare resp weakness, rare cardiomyopathy. Malignant hyperthermia SEPN1 severe respiratory weakness, severe scoliosis Pathology: Fibers w/regions devoid of oxidative enzyme activity Predominance of type 1 muscle fibers RYR1 Malignant hyperthermia

Nemaline (rod) myopathy “Nema”=thread https://www.sciencedirect.com/science/article/pii/S0960896613009942#f0005 Nemaline (rod) myopathy “Nema”=thread Variable presentation; genetically heterogeneous (AD, AR) Infantile hypotonia: prominent facial and respiratory weakness (classic presentation), severe form with 20% mortality Adult-onset: head-drop, dysphagia, respiratory insufficiency Pattern of weakness: facial muscles, neck/trunk flexors, dorsiflexors, toe extensors Earlier onset usually more severe. Less severe forms can stabilize or even improve Pathology: Rod shaped structures within muscle fibers atrophic fibers without grouping Trichrome stain: reddish purple thread-like inclusions within sarcoplasm Type 1 fiber predominance Ultrastuctural – intracytoplasmic rod-shaped structures

Centronuclear Myopathy Myotubular Myopathy Clinically and genetically heterogeneous Muscle fibers with large central nuclei that resemble myotubes (early fetal muscle fibers) Severe, more common form is X linked. Occurs in male infants, marked hypotonia and weakness, respiratory muscle weakness and failure. Facial weakness and impaired bulbar function. Female carriers can have limb girdle or facial weakness. 1/3 die from respiratory complications in infancy Less common form is AD or AR. Mild weakness and hypotonia may be unrecognized. Pathology: One or more centrally placed nuclei with surrounding clear area Persistent fetal characteristics of muscle

Critical Illness Myopathy AKA acute quadriplegic myopathy Steroids Neuromuscular Blockade Severe systemic illness Critical Illness Myopathy AKA acute quadriplegic myopathy Critically ill patient cannot be weaned off of ventilator, diffuse flaccid paralysis 2/3 conditions usually required: corticosteroid therapy, neuromuscular blockade, severe systemic illness (e.g., sepsis) ~25% of critically ill patients on MV longer than 1 week Rapid onset, proximal weakness; may be asymmetric, may be muscle wasting More common females Resolves 3 weeks to one year; stop any offending agents Pathology: atrophy of muscle fibers (non-specific) Electronic microscopic features are diagnostic/pathognomonic, selective loss of thick (myosin) filaments

Inflammatory Myopathies

Inclusion body myositis http://n.neurology.org/content/66/1_suppl_1/S20.figures-only Inclusion body myositis Most common primary muscle disease over age 50; 3:1 male predominance Slow symptom progression; asymmetric Early involvement of quadriceps and ankle dorsiflexors; frequent falls Early involvement wrist and finger flexor muscles ~50% swallowing difficulties; ~1/3 facial weakness Muscle atrophy can be prominent Can include peripheral polyneuropathy and sensory complaints Poorly responsive to immunosuppressive tx, 50% WC bound after 10 years Tx: supportive, exercise, supplement with creatine monohydrate Pathology: Intracytoplasmic vacuoles rimmed with granular material; inclusions react w/Abs associated with neurodegenerative diseases including beta-amyloid, tau, ubiquitin Ultrastructual: diagnostic feature, inclusions w/in muscle cytoplasm, nuclei or both

Dermatomyositis = small vessel vasculitis Proximal muscle weakness, weeks to months Characteristic rash: red rash over eyelids and extremities (heliotrope, shawl, Gottrons) Humorally mediated microangiopathy/vasculitis with ischemic necrosis of muscle fibers Most common inflammatory myopathy of childhood, seen in all ages 3:2 female predominance Frequency of cancer increased for 3 years after onset in adults Tx: immunosuppressive Pathology: Inflammation of perimysial blood vessels Lymphocytes plus plasma cells and eosinophils (mixed infiltrate) Necrosis and phagocytosis in groups (microinfarcts) Perifascicular atrophy = sublethal myofiber stress @ distal end of blood supply

Polymyositis Controversial; diagnosis of exclusion Proximal muscle weakness over weeks to months with elevated CPK without skin changes of dermatomyositis. 2:1 female predominance Oculobulbar rarely affected May be associated with other autoimmune/collagen vascular diseases Tx with immunosuppressive therapies (corticosteroids); 1/3 pts left with disability Pathology: Lymphocytic inflammation surrounding and invading otherwise healthy-appearing muscle fibers. Rimmed vacuoles (IBM) and other types of inflammatory cells should be absent CD-8 positive T cells, muscle fibers demonstrate upregulation MHC-I

References Continuum, “Pattern Recognition Approach to Myopathy” Volume 12, Issue 3, p13-32 Prayson Neuropathology, 2nd Edition, Skeletal Muscle and Peripheral Nerve Disorders Up to date: Congenital Myopathies Up to date: Clinical manifestations of dermatomyositis and polymyositis in adults