Case 1: History of J.H. Outside Evaluation. Outside Labs. Question #1

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1 Case 1: History of J.H. 64 yo man seen at UCSF months ago onset progressive weakness of arms and legs, with muscle atrophy in arms. 4 months ago red scaly rash on face, back of hands and elbows, with edema and violaceous tint of eyelids. Outside Evaluation April 2007: Red, scaly rash on face, knuckles, elbows, knees and anterior trunk. Erythema and hypertrophy of cuticles. Diffuse weakness of limbs and trunk, worst in upper extremities. Question #1 At that time, the most likely diagnosis was dermatomyositis. 1. True 2. False 83% 17% Outside Labs Dec 2006: Serum CK normal. April 2007: Serum CK 6,750. EMG myopathic with profuse muscle fiber irritability. ANA, anti-dsdna strongly positive. Proteinuria in nephrotic range. Creatinine 1.3. True False 1

2 Question #2 At this point, the most likely diagnosis is: 1. Dermatomyositis 2. Polymyositis 3. Myositis in mixed connective tissue disease. Dermatomyositis 15% Polymyositis 5% Myositis in mixed co... 80% Further Course April 13, 2007: Deltoid muscle bioopsy. Late May, 2007: I.V. methylprednisolone 300 mg/d x 3 days, then prednisone 60 mg/d p.o. My exam on June 25: In wheelchair. Diffuse limb weakness, proximal>distal. Skin as previously described. H&E 40X What did the muscle biopsy show? 2

3 H&E 100X H&E 100X H&E 200X H&E 200X 3

4 H&E 200X Trichrome 200X Trichrome 400X MHC1 immunohistochemistry 40x 4

5 MHC1 immunohistochemistry 100x MHC1 immunohistochemistry 200x Question #3 This pathology is typical of: 1. Dermatomyositis 2. Polymyositis 3. Myositis in connective tissue disease 4. Inclusion body myositis Dermatomyositis 4% Polymyositis 1% Myositis in connectiv... 37% 58% Inclusion body myositis Pathology of PM Endomysial lymphocytic infiltration, mainly T cells, with invasion of healthy muscle fibers. Scattered muscle fiber degeneration and regeneration. Endomysial fibrosis. Staining for major histocompatibility complex (MHC1) on surface of muscle fibers is widespread throughout biopsy. 5

6 Pathology of DM Perifascicular atrophy in DM Perimysial and perivascular lymphocytic infiltration, mainly B cells. Perifascicular atrophy and degeneration of muscle fibers. MHC1 staining predominantly in perifascicular muscle fibers. Pathology of IBM Many very large muscle fibers, with fiber splitting (like a dystrophy). Endomysial lymphocytic infiltration (mainly T cells) and fibrosis (as in PM). Scattered muscle fiber degeneration and regeneration (as in PM). Widespread MHC1 staining of muscle fibers (as in PM) Rimmed vacuoles in many muscle fibers. Question #4 What treatment do you recommend? 1. Since the clinical picture resembles DM or a mixed connective tissue disease, continue steroids and add immunosuppressive drug. 2. Since the biopsy is typical of IBM, which does not respond to immunotherapy, no treatment is indicated. Since the clinical pictu.. 63% 37% Since the biopsy is ty... 6

7 Outcome The patient began to improve as soon as steroids were started. The nephrotic syndrome resolved quickly. Skin rash and muscle weakness improved steadily. Methotrexate 20 mg per week was added in June, and prednisone dose gradually tapered. Serum CK became normal and by October he was walking unassisted. Inclusion body myositis: : Clinical and pathological boundaries AA Amato et al, Ann Neurol 1996;40: In a study of 46 patients with DM, PM or IBM, patients with IBM had a characteristic clinical picture: age>50, slow course, mild CK elevations, weakness predominant in forearm flexors, quads and anterior tibs, and lack of response to immunotherapy. In some cases, this clinical picture was seen with path Dx of PM, but patients still didn t respond to treatment. Conclusion In a similar way, this patient s clinical course was typical of DM with added features of general CTD. Although the biopsy showed IBM, he responded well to treatment. Thus, the clinical picture trumps the pathology! There is 1 reported case of clinical DM with pathology of IBM, in a man with bladder cancer (Brit J Dermatol 1999;141:926). This patient s cancer workup was negative. Case 2: History of G.D. In July 2005, a 63 y.o.. man developed progressive proximal arm weakness along with progressive neck extensor weakness causing head drop. 3 months later he developed progressive proximal lower extremity weakness. Feb 2006: started on prednisone 50 mg/d. Legs felt stronger but neck weaker. 7

8 Question #1 Which of these diseases is not a major cause of dropped head? 1. ALS 2. MG 3. Steroid myopathy 4. Polymyositis/dermatomyosi tis 9% 50% 20% 21% Outside Labs Serum CK 629. EMG: Abundant fibrillatrions, myopathic motor unit potentials. Quadriceps muscle biopsy Feb 2006: No inflammation. Rare degenerating muscle fibers. Mild variation in muscle fiber diameter. ALS MG Steroid myopathy Polymyositis/derm... Left quadriceps biopsy Feb 2006(before prednisone) H&E Left quadriceps biopsy, Feb 2006 NADH dehydrogenase 8

9 Exam Lower face sl.. weak. FVC 4.1L (87%). Neck mod. weak, esp. extension. Severe weakness shoulder girdles (including pectoral and scapular muscles) and upper arms; unable to raise arms to horizontal. Mild proximal weakness in LE s. Tone normal, no fasciculations. Question #2 At this point, what diagnosis do you favor? 1. MG 2. Polymyositis 3. ALS 4. Steroid myopathy 5. None of the above 16% 17% 19% MG Polymyositis ALS Steroid myopathy 0% 49% None of the above 2nd Visit Right deltoid biopsy H&E Continued prednisone 50 mg/d, added CellCept 2000 mg/d in April. Muscle exam a bit worse. Recent polyuria and polydipsia: : blood glucose 1,231 Outside deltoid biopsy May 8 looked neurogenic. EMG at UCSF: myopathy with muscle fiber irritability. 9

10 Right deltoid biopsy NADH 3rd Visit On insulin for diabetes. Prednisone tapering; CellCept 2000 mg/d. Muscle strength stable. Scheduled biopsy #3, biceps muscle. A third biopsy one month after the second: left biceps H&E A third biopsy one month after the second: left biceps NADH 10

11 A third biopsy one month after the second: left biceps NADH Question #3 This pathological appearance is typical of: 1. Myotonic muscular dystrophy 2. Trabecular myopathy 3. Nemaline myopathy 4. Limb-girdle muscular dystrophy 5. None of the above 1% Myotonic muscular d... Trabecular myopathy 41% 36% 12% 11% Nemaline myopathy Limb-girdle muscular... None of the above Trabecular myopathy Originally described by Weller et al (Neuromuscular Disord 1999) Clinical picture resembles adult-onset limb- girdle muscular dystrophy Proximal weakness predominates, but the clinical picture is heterogeneous (dropped head, camptocormia, association with respiratory failure) Trabecular Myopathy Family history is negative There is no response to immunosuppressive therapy Presence of abundant trabecular (or lobulated) fibers is the predominant pathological finding 11

12 Trabecular Myopathy Trabecular fibers are found in other neuromuscular diseases such as IBM, dermatomyositis, scapuloperoneal muscular dystrophy, FSH, and late- onset acid maltase deficiency. In those diseases, <30% fibers are trabecular. The trabecular pattern is caused by a maldistribution of the intermyofibrillar mitochondria Not the End of the Story Steroids and CellCept discontinued. Weakness continued to worsen slowly. Seen at Mayo Clinic Oct Review of biopsy slides: diagnosis changed to nemaline myopathy. Biclonal gammopathy IgG-kappa> kappa>igg- lambda. Third biopsy on Mr. G.D. H&E Trichrome Stain 12

13 Adult Nemaline Myopathy Muscle Nerve 1999;22: Literature review: 12 cases, age Painful, progressive weakness of proximal and axial muscles over months or a few years, severe and sometimes fatal Dropped head in most cases CPK normal. EMG myopathic with fibrillations. Muscle Bx: : atrophic fibers, central nuclei, cytoplasmic rods A few cases with monoclonal gammopathy Mayo Clinic Series Neurology 2005;65: cases adult nemaline myopathy Age Subacute course. CK normal. EMG myopathic w/ fibs. 7/14 had monoclonal gammopathy. 13

14 Mayo Series: Response to Treatment 8 patients received received prednisone, alone or in combination with other immunosuppresants. 4 became stable or may have improved 5/7 with gammopathy died within 5 years. 0/5 without gammopathy died within years. G.D.:Response to Treatment Bone marrow and skeletal survey negative. Prednisone 40 mg/d, CellCept 2000 mg/d, monthly IVIG. Slow, modest improvement in strength. 14