Approach to myopathy

Approach to myopathy

1. Approach to myopathy DR VINOD SINGH JATAV SR NEUROLOGY GMC KOTA

2. Type of muscle fiber

3. Introduction MYOPATHY means primary skeletal muscle dysfunction.

4. History Which negative and/or positive symptoms and signs does the patient demonstrate? What is the distribution of weakness? Family history What is the temporal evolution? Are there precipitating factors that trigger episodic weakness or myotonia? Are associated systemic symptoms or signs present?

5. Et i o l og y Acquired Endocrine Drug induced Toxic Inflammatory/immune Associated with systemic illness Critical illness myopathy Hereditary Channelopathies Congenital Mitochondrial Metabolic Muscular dystrophy Myotonia

6. Symptoms associated with myopathies Negative symptoms Fatigue Exercise intolerance Weakness Atrophy Positive symptoms Cramp Contracture Hypertrophy Myalgia Stiffness

7. Myalgia Toxin and drug induced myopathy Eosinophilia myalgia syndrome Hypothyroid myopathy Inflammatory myopathies Myotonic disorder Mitochondrial myopathy Muscular dystrophy (X linked myalgia and cramps/ becker dystrophy variant) Fatigue NMJ Glycolysis Lipid abnormality Mitochondrial myopathy Chronic myopathy

8. Stiffness: decrease ability to relax Improve with exercise Myotonia: Na or Ca channelopathy Worsen with exercise/ cold Paramyotonia Brody disease With fixed weakness Myotonic dystrophy Becker disease (AR Cl channelopathy Other Malignant hyperthermia Neuromyotonia Stiffperson syndrome

9. Other symptoms pseudohypertrophy Duchenne ’ s muscular dystrophy, Becker ’ s muscular dystrophy, LGMD (2C-F, 2G, 2I) Scapular wining FSHD. LGMD1B (laminopathy), LGMD2A ( calpainopathy ), LGMD2C–2F ( sarcoglycanopathies ). Metabolic myopathies - Pompe ’ s disease and debrancher deficiency (Cori-Forbes disease) Myotonia congenita, Hypothyroidism, Amyloid and sarcoid myopathies, Parasitic myositis, SMA Muscle hypertrophy

10. Temporal evolution: onset age Myopathies Presenting at Birth Congenital myotonic dystrophy Centronuclear (myotubular) myopathy Congenital fiber-type disproportion Central core disease Nemaline (rod) myopathy Congenital muscular dystrophy Lipid storage diseases (carnitine deficiency) Glycogen storage diseases (acid maltase and phosphorylase deficiencies)

11. Myopathies Presenting in Childhood Muscular dystrophies Duchenne Becker Emery- Dreifuss Facioscapulohumeral Limb-girdle Congenital Inflammatory myopathies Dermatomyositis Polymyositis (rarely) Congenital myopathies Nemaline Centronuclear Central core Lipid storage disease (carnitine deficiency) Glycogen storage disease (acid maltase deficiency) Mitochondrial myopathies Endocrine-metabolic disorders Hypokalemia Hypocalcemia Hypercalcemia

12. Myopathies Presenting in Adulthood Muscular dystrophies Limb-girdle Facioscapulohumeral Becker Emery-Dreifuss Inflammatory myopathies Polymyositis Dermatomyositis Inclusion body myositis Viral [HIV] Metabolic myopathies Acid maltase deficiency Lipid storage diseases Debrancher deficiency Phosphorylase b kinase deficiency Mitochondrial myopathies Endocrine myopathies Thyroid Parathyroid Adrenal Pituitary disorders Toxic myopathies Alcohol Corticosteroids Local injections of narcotics Colchicine Chloroquine Statins Myotonic dystrophy Distal myopathies Nemaline myopathy, Centronuclear myopathy

13. Temporal evolution: episodic or constant weakness? Causes of episodic weakness :- Hypo and hyper kalemic periodic paralysis Anderson- tawil syndrome Secondary PP Metabolic myopathy (glycolytic enzyme defect)

14. Constant weakness acute or subacute progression inflammatory myopathies (dermatomyositis and polymyositis); chronic slow progression over years most muscular dystrophies IBM nonprogressive weakness with little change over decades congenital myopathies

15. Precipitating factors illegal drug or prescription medication use that might produce a myopathy. weakness, pain, and/or myoglobinuria provoked by exercise a glycolytic pathway defect. Episodes of weakness with a fever carnitine palmityl transferase deficiency. Periodic paralysis -provoked by exercise or ingestion of a carbohydrate meal followed by a period of rest. paramyotonia congenita - cold exposure

16. Pattern of weakness:- proximal Most dystrophies(dystrophinopathies, limb girdle, myotonic dystrophy 2, rare FSHD) Congenital myopathies( nemaline, central core) Metabolic myopathies(glycogen and lipid storage) Mitochondroal myopathy PM, DM Toxic myopathy Endocrine myopathy

17. Myopathies Characterized by Predominantly Distal Weakness Distal Myopathies Late adult-onset distalmyopathy type 1 ( Welander ) Late adult-onset distal myopathy type 2 ( Markesbery/Udd ) Early adult-onset distal myopathy type 1 ( Nonaka ) Early adult-onset distal myopathy type 2 (Miyoshi) Early adult-onset distal myopathy type 3 (Laing) Desmin myopathy Childhood-onset distal myopathy" Myotonic Dystrophy FSHD*" Scapuloperoneal Myopathy*" OPMD Emery-Dreifuss Humeroperoneal Dystrophy*" Inflammatory Myopathies (IBM) Metabolic Myopathies Debrancher deficiency Acid-maltase deficiency*" Congenital Myopathies Nemaline myopathy* Central core myopathy* Centronuclear myopathy *" Scapuloperoneal pattern can occur

18. Proximal arm and distal leg :- Facioscapulohumeral dystrophy Scapuloperoneal dystrophy Emery dreifuss humeroperoneal dystrophy LGMD 2A( calp a in), 2C-F(sarcoglycan) 2I(F K RP) Nemaline and central core myopathy Acid maltase deficiency Distal arm and proximal leg: - IBM Myotonic dystrophy

19. Pattern of weakness:- axial Cervico brachial myositis hIBM FSHD MD 2 Hyperparathyroidism/vit d deficiency Metabolic ( late onset pompe and mc ' ardle )

20. Pattern of weakness:- Ptosis Ptosis without opthalmoparesis Myotonic dystrophy Nemaline myopathy Central core myopathy Myofibrillar myopathy Ptosis with opthalmoparesis OPMD Mitochondrial myopathy Centronuclear myopathy NMJ disorder

21. Myopathies With Prominent Neck Extensor Weakness Isolated neck extensor myopathy" Polymyositis " Dermatomyositis " Inclusion body myositis " Carnitine deficiency " Facioscapulohumeral dystrophy " Myotonic dystrophy " Congenital myopathy " Hyperparathyroidism

22. Family History X-Linked Duchenne Becker Emery- Dreifuss Autosomal Dominant Facioscapulohumeral Limb-girdle Oculopharyngeal muscular dystrophy Myotonic dystrophy Periodic paralysis Paramyotonia congenita Thomsen disease Central core myopathy" Autosomal Recessive Limb-girdle Metabolic myopathies Becker myotonia Maternal Transmission Mitochondrial myopathies

23. Are associated systemic symptoms or signs present? Cardiac disease Arrhythmias Kearns-Sayre syndrome Andersen’s syndrome Polymyositis Muscular dystrophies Myotonic Limb-girdle 1B, 2C-2F, 2G Emery- Dreifuss Congestive Heart Failure Muscular dystrophies Duchenne Becker Emery- Dreifuss Myotonic Limb-girdle 1B, 2C-2F, 2G Nemaline myopathy Acid maltase deficiency Carnitine deficiency Polymyositis

24. Respiratory Insufficiency Muscular Dystrophies Duchenne Becker Emery- Dreifuss Limb-girdle Myotonic Congenital Metabolic Myopathies Acid maltase deficiency Carnitine deficiency Mitochondrial Myopathies Congenital Myopathies Nemaline Centronuclear Inflammatory Myopathies Polymyositis

25. Hepatomegaly may be seen in acid maltase, debranching enzyme deficiency mitochondrial disorder.

26. DMD sarconoglycanopathy inheritance X- linked recessive Autosomal recessive Female sex Less likely May be affected Calf hypertrophy present May be present Muscle knee extensors and hip abductors more commonly involved than knee flexors and hip adductors Deltoid and infraspinatus preserved Hamstring>quadriceps Biceps and deltoid involved Triceps preserved intelligence May be subnormal normal cardiac involved Less likely Scapular winging Not usually May be present

27. GNE myopathy- quadriceps sparing myopathy Distal anoctaminopathy - Asymmetrical calf atrophy, distal upper limbs may remain spared

28. Approach to metabolic myopathy Darras BT, Friedman NR. Metabolic myopathies: A clinical approach; Part I. Pediatr Neurol 2015;22:87-97 . When to suspect • Cramps, myalgias and exercise intolerance • Rhabdomyolysis How to investigate • Ischemic exercise test • Muscle biopsy • Genetic tests

29. Examination Muscle appearance – wasting ,atrophy (neurogenic) ABSENT fasciculations (+Denervation) Tenderness on palpation Tone –normal ,decreased in advanced cases. Distribution of weakness –proximal,distal (distal myopathies) Tendon reflexes – normal /hypoactive in adv.cases Babinski sign negative SENSORY system is normal. GAIT – lordosis on stance,increased on toe walking Waddling gait – b/l pelvic girdle weakness Genu recurvatum –quadriceps weakness

30. Creatinine kinase CK is elevated in the majority of myopathies but may be normal in slowly progressive myopathies. CK level may not be elevated in corticosteroid administration, collagen diseases, Alcoholism hyperthyroid profound muscle wasting Metabolic myopathies

31. Differential Diagnosis of Creatine Kinase Elevation Myopathies Muscular dystrophies Congenital myopathies Metabolic myopathies( macrdle disease) Inflammatory myopathies Drug/toxin-induced Carrier state ( dystrophinopathies ) Channelopathies Motor Neuron Diseases ALS SMA Postpolio syndrome Neuropathies GBS CIDP Viral Illness Medications Hypothyroidism/ Hypoparathyroidism Surgery/Trauma (electromyography studies, intramuscular or subcutaneous injections) Strenuous Exercise Increased Muscle Mass Race Sex ‘‘Idiopathic HyperCKemia ’’

32. Other laboratory test Electrolytes including calcium and magnesium S.myoglobin level Urinanalysis:- myoglobinuria ESR TFT ANA

33. EM G Indication:- To confirm muscle localization and rule out AHC, neuropathy Guide for muscle biopsy Common pattern:- Brief duration small amplitude MUAP with early recruitment

34. Muscle biopsy Should not be taken from muscle with grade 3 or less power Avoid biopsy from EMG needle site insertion Punch biopsy is preferred over open biopsy Common site:- biceps, deltoid, vastus lateralis Emergence of genetics has reduce need of biopsy

35. Muscle biopsy Common pattern :- Central nuclei, both small and large hypertrophic round fibers, split fibers, and degenerating and regenerating fibers Inflammatory myopathy :- Presence of mononuclear inflammatory cells in the endomysial and perimysial connective tissue between fibers and occasionally around blood vessels Dermatomyositis, atrophy of fibers located on the periphery of a muscle fascicle, perifascicular atrophy, is a common finding Chronic myopathies frequently show evidence of increased connective tissue and fat.

36. Stain used in myopathy

37. G e n e t i c T e st i n g

38. F S H D Pradhan S. Poly-hill sign in facioscapulohumeral dystrophy. Muscle Nerve 2002;25:754-5

39. Valley sign :-DMD Pradhan S. Valley sign in duchenne muscular dystrophy : importance in patients with inconspicuous calves. Neurol India [serial online] 2002 [cited 2021 Jul 16];50:184 valley sign- simultaneous hypertrophy of deltoid superolaterally , infraspinatus inferomedially and wasting of posterior axillary fold

40. Diamond sign :- dysferlinopathy Pradhan S. Diamonds on quadriceps sign in dysferlinopathy . Neurology 2008;70:322 Biceps lump in a patient with dysferlinopathy

41. Calf head sign:- Miyoshi myopathy Calf heads on a trophy sign: Miyoshi myopathy M. Mundayadan Shyma , P. Sreedharan Roopchand , K. Mohan Ram, C. Velayudhan Shaji J Neurosci Rural Pract . 2015 Jul-Sep; 6(3): 428–430.  doi : 10.4103/0976-3147.158798

42. Fish mouth:- C ong . Myotonic dystrophy

43. Which myopathy? Myotonic d y s t r op h y

44. Dermatomyositis Gottron papules Shawl sign V sign Heliotrope rash Mechanics hand

45. Clinical features frequently observed in patients with LGMD: Gower’s manoeuvre in LGMD2A (a), atrophy of gastrocnemius muscle in distal Miyoshi myopathy (b), Achilles tendon retraction in LGMD2A (c), scapular winging and atrophy of scapular girdle muscles in LGMD2A (d), scoliosis in LGMD1F (e), severe hip and knee contractures in LGMD2C (f), tongue muscle hypertrophy or macroglossia in LGMD2E (g).

46. Calpainopathy . (a) Scapular winging. (b) Abdominal hernia due to weakness of external oblique muscle GNE myopathy . (a) Wasting of tibialis anterior muscle resulting in prominence of shin of tibia. (b) Wasting of first dorsal interosseous muscle (distal myopathy) quadriceps sparing myopathy.

47. Swan neck in myotonic dystrophy. The hip abduction sign- LGMD ( sarcoglycanopathy ) Khadilkar SV, Singh RK. Hip abduction sign: A new clinical sign in sarcoglycanopathies . J Clin Neuromusc Dis 2001;3:13-5 Mild ptosis, hatchet face and thin neck in a patient with DM1

48. Rigid spine syndrome Emery– Dreifuss muscular dystrophy Nemaline myopathy, multiminicore disease, Bethlem myopathy, and rigid spine muscular dystrophy Contractures of the spine: As this patient tries to bend forward, the lower and mid spine remain in the extended position. Herculean appearance in two brothers with MC a ) Asymmetrical left > right foot drop and ( b ) asymmetrical calf atrophy ( left > right ) in brothers with anoctaminopathy

49. Pradhan S. Shank sign in myotonic dystrophy type-I (DM-I): Utility in differentiation from DM-II and some other common muscular dystrophies. J Clin Neurosci 2007;14:27-32

50. References Jackson et al A Pattern Recognition Approach to Myopathy Continuum ( Minneap Minn ) 2013;19(6):1674–1697 Khadilkar SV, Singh RK. Limb girdle muscular dystrophies in India. Neurol India [serial online] 2008 [cited 2021 Jul 16];56:281-8 Bradely’s Neurology In Clinical Practise, 8th Edition Pradhan S. Clinical and magnetic resonance imaging features of 'diamond on quadriceps' sign in dysferlinopathy . Neurol India 2009;57:172-5 Pradhan S. Shank sign in myotonic dystrophy type-I (DM-I): Utility in differentiation from DM-II and some other common muscular dystrophies. J Clin Neurosci 2007;14:27-32 Up to date.com

51. Case A 55-year-old man noticed gradually progressive weakness of both lower limbs since age of 25 years. Initially, he noticed weakness of the left calf and soon within months the right calf weakened. In the ensuing 3 years, he developed bilateral progressive foot drop. Over the next few years, he developed wasting of calves and then anterior leg muscles, which was much more prominent on the left calf. Since 10–11 years, he noticed gradually progressive weakness of both lower limbs and had developed difficulty in getting up from chair. Since 5–6 years, he has noticed mild weakness of arms associated with wasting, more noticeable on the left side. On examination, there was evidence of asymmetric (left > right), bilateral distal > proximal lower limb weakness affecting plantar flexors > dorsiflexors, quadriceps, hamstrings and hip adductors. Deep tendon reflexes were present. Sensory examination was normal. His brother was also affected with similar phenotype. Investigations revealed CK value of 3430 U/L. NEE showed myopathic potentials Summary: Familial, slowly progressive, asymmetric distal (calves > anterior leg muscles) > proximal lower limb weakness followed by wasting, mild affection of upper limb proximal muscles and much elevation of serum CK. Discussion: Since calves were affected at the onset of illness, possibilities of dysferlinopathy and anoctaminopathy were considered. The asymmetry of weakness, very gradual course of the illness and involvement of upper limbs starting after almost 30 years of illness favoured anoctaminopathy . On genetic testing, no mutation was detected in dysferlin gene. There was homozygous mutation in ANO5 gene which suggested diagnosis of anoctaminopathy .

52. Thank you