Neuropathies & myopathies - an overview

This ppt is an overview of Neuropathies and myopathies..and from the physiologist view..hope will be useful template!

1. Neuropathies & Myopathies Dr. Dinesh T, Junior resident 1 Jipmer physiologist 20-11-2011

2. Neuropathies 2 Jipmer physiologist 20-11-2011

3. Definition Damage to nerves which may be caused either by diseases or trauma to the nerve or as a component of systemic illness 3 Jipmer physiologist 20-11-2011

4. The neuropathy is a symptom of another disorder In most common forms of polyneuropathy , the nerve fibers most distant from the brain and the spinal cord malfunction first. Pain and other symptoms often appear symmetrically 4 Jipmer physiologist 20-11-2011

5. The peripheral nerves include: Cranial nerves (with the exception of the second) Spinal nerve roots Dorsal root ganglia Peripheral nerve trunks and their terminal branches Peripheral autonomic nervous system 5 Jipmer physiologist 20-11-2011

6. Symptoms in neuropathy A wide array of symptoms can occur when nerves are damaged Paresthesia Sensitivity to touch, Positive Pins and needles Tingling Burning Negative Numbness Deadness As if wearing shocks and walk 6 Jipmer physiologist 20-11-2011

7. In chronic course symptoms worse, muscle wasting, paralysis, or gland dysfunction 7 Jipmer physiologist 20-11-2011

8. Neuropathy - Signs Distal sensory loss Distal weakness and atrophy Decreased or absent reflexes Ankle jerks lost first 8 Jipmer physiologist 20-11-2011

9. Various classifications 9 Jipmer physiologist 20-11-2011

10. Etiological Classification of neuropathies Hereditary Neuropathies Hereditary motor and sensory neuropathy – type I HMSN – Type II Dejerine – Sottas Neuropathy HMSN- type III HSMN – type IV HSMN – type V Inflammatory neuropathies Immune mediated Guillain-Barré syndrome Chronic inflammatory demyelinating polyradiculoneuropathy Infectious Leprosy Diphtheria Varicella – zoster Acquired metabolic and toxic neuropathies Peripheral neuropathy in adult onset Diabetes Metabolic and nutritional peripheral neuropathies Neuropathies associated with malignancy Toxic neuropathies Traumatic neuropathies 10 Jipmer physiologist 20-11-2011

11. Medications Causing Neuropathies Axonal Vincristine Paclitaxel Nitrous oxide Colchicine Isoniazid Hydralazine Metronidazole Pyridoxine Didanosine Lithium Alfa interferon Dapsone Phenytoin Cimetidine Disulfiram Chloroquine Ethambutol Amitriptyline Demyelinating Amiodarone Chloroquine Suramin Gold Neuronopathy Thalidomide Cisplatin Pyridoxine 11 Jipmer physiologist 20-11-2011

12. Pathophysiological classification Motor , sensory, or autonomic Mononeuropathy , polyneuropathy or mononueritis multiplex Focal, multifocal or symmetric Proximal or distal Axonal, demyelinating or both Acute, sub acute or chronic 12 Jipmer physiologist 20-11-2011

13. Some neuropathies may affect all three types of nerves, others primarily affect one or two types. Predominately motor neuropathy Predominately sensory neuropathy Sensory-motor neuropathy Autonomic neuropathy Impaired function and symptoms depend on the type of nerves that are damaged. 13 Jipmer physiologist 20-11-2011

14. Mononeuropathy involve damage to only one nerve When multiple nerves supplying one limb are affected-called polyneuropathy . Two or more isolated nerves in separate areas of the body are affected-called mononeuritis multiplex 14 Jipmer physiologist 20-11-2011

15. Focal neuropathies include common compressive neuropathies such as carpal tunnel syndrome, ulnar neuropathy , peroneal neuropathy Multifocal neuropathy suggests a mononeuritis multiplex that may be caused, for example, by vasculitis or diabetes 15 Jipmer physiologist 20-11-2011

16. Axonal degeneration Primary destruction of the axon with secondary degeneration of its myelin sheath Generalized abnormality in the neuron cell body- neuronopathy Abnormality in the axon - axonapathy 16 Jipmer physiologist 20-11-2011

17. Segmental demyelination 17 Jipmer physiologist 20-11-2011

18. Neurophysiological classification Uniform demyelinating sensorimotor poly neuropathy Segmental demyelinating , motor more than sensory neuropathy Axonal , motor more than sensory polyneuropathy Axonal sensory polyneuropathy Axonal mixed sensorimotor polyneuropathy Mixed axonal and demyelinating sensorimotor polyneuropathy 18 Jipmer physiologist 20-11-2011

19. Uniform demyelinating sensorimotor poly neuropathy Hereditary motor sensory neuropathy- type I, III,IV Leucodystrophies Tangier disease Cockayne syndrome Congenital cerebrotendinous xanthomatosis Congenital hypomyelinating neuropathies 19 Jipmer physiologist 20-11-2011

20. HMSN I (Charcot- Marie- Tooth I) HSMN I – AD is the most common hereditary neuropathy. CMT-I A chromosome 17p11 , CMT-IB chromosome 1q22 , CMT-IC 16p13, chromosome , CMT-IX chromosome Xq13.1 Slowly progressive distal weakness Foot deformity, areflexia , distal sensory loss Upper limb ataxia, tremor, peripheral n hypertrophy 20 Jipmer physiologist 20-11-2011

21. Neurophysiological features Conduction velocity less than 25% of lower limit Median motor forearm conduction< 38 m/s Uniform NCV changes in adjacent nerves Absence of conduction block and temporal dispersion F response Needle EMG shows minimal fibrillations in distal muscles. 21 Jipmer physiologist 20-11-2011

22. Electrophysiological studies ( NCS ) show Uniform slowing of NCV Similar NCV slowing in adjacent nerves Absence of conduction block and temporal dispersion Prolongation of F response commensurate with NCV slowing Uniform demyelinating sensorimotor poly neuropathy- 22 Jipmer physiologist 20-11-2011

23. Segmental demyelinating motor more than sensory neuropathy Acute inflammatory demyelinating poly radiculo neuropathy AIDP Chronic inflammatory demyelinating poly radiculo neuropathy CIDP Multifocal motor neuropathy Paraproteinemia HIV neuropathy Lyme disease Diphtheria Penicillamine 23 Jipmer physiologist 20-11-2011

24. AIDP The prototype Distal paresthesia with symmetric weakness Distal areflexia Variants are pure motor, pure sensory, autonomic, relapsing, and Miller fisher types Cranial nerves esp facial n and bulbar may be involved Respiratory muscles are severely involved in about 25 24 Jipmer physiologist 20-11-2011

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26. Pathophysiology of GBS Pathological findings include inflammatory and demyelinating changes. Monocytes and macrophages appear to attack myelin sheaths. Myelinated fibers show segmental demyelination during the first few days. Segmental remyelination occurs subsequently. The lesions have a perivenular distribution 26 Jipmer physiologist 20-11-2011

27. Chronic inflammatory demyelinating polyneuropathy Chronic progressive or relapsing neuropathy, motor > sensory. Electrophysiology: slow conduction velocity & conduction block Pathology: segmental demyelination and remyelination , onion bulbs, fibrosis and little or no lymphocytic infiltration of tissue . 27 Jipmer physiologist 20-11-2011

28. Segmental demyelinating motor more than sensory neuropathy Nerve conduction studies Slowing of motor and sensory conduction velocity Prolongation of terminal latency Conduction block Dispersion and prolonged or absent F waves 28 Jipmer physiologist 20-11-2011

29. Axonal, motor more than sensory neuropathy Axonal type of GBS Acute intermittent porphyria HSMN type II , V Toxic neuropathies such as lead, dapsone Paraneoplastic syndrome Metabolic – hypoglycemia Critical care neuropathy 29 Jipmer physiologist 20-11-2011

30. Distal symmetric weakness and wasting with minimal sensory loss 30 Jipmer physiologist 20-11-2011

31. Axonal,motor more than sensory neuropathy Nerve conduction studies Reduced CMAP amplitude NCV is normal SNAP amplitudes are also decreased Fibrillations appear in distal muscles 31 Jipmer physiologist 20-11-2011

32. Sensory axonal polyneuropathy Diabetic neuropathy Carcinomatous sensory neuropathy HSMN type I- IV Friedrich ataxia Abetalipoproteinemia Toxins - cisplatin Pyridoxine overdosage Vt –E neuropathy Malabsorption Acromegaly , 32 Jipmer physiologist 20-11-2011

33. Diabetic neuropathy Onset of neuropathy depends upon the duration of illness 50% diabetics have peripheral neuropathy of which 80% have had the illness for >15 years Distal symmetric sensory or sensorimotor , autonomic, focal or multifocal asymmetric Symmetric neuropathy involves distal sensory , motor nerves . Decreased sensation, loss of pain sensation – ulcer 33 Jipmer physiologist 20-11-2011

34. Diabetic neuropathy Predominant pathology is axonal neuropathy. In chronic cases segmental demyelination also seen Pathophysiology – Loss of small myelinated fibers and unmyelinated fibers. But large fibers can also be affected. Endoneurial arterioles show thickening, hyalination , intense PAS positivity in the walls and extrensive reduplication basement membrane 34 Jipmer physiologist 20-11-2011

35. Sensory axonal polyneuropathy Nerve conduction studies Diminished or absent SNAP amplitude in the setting of normal motor nerve conduction velocity 35 Jipmer physiologist 20-11-2011

36. Axonal type of mixed sensorimotor neuropathy Nutritional deficiencies (vitamin deficincy , alcoholism) Metabolic ( diabetic, uraemia , liver disease, amyloidosis ) Connective tissue disorders (rheumatoid arthritis, SLE, PAN) Multiple myeloma Carcinoma Cryoglobunemia Heavy metals – lead, arsenic, gold, mercury Drugs- metronidazole , phenytoin etc 36 Jipmer physiologist 20-11-2011

37. Paresthesia and dyesthesia of feet and distal legs Wasting is marked Loss of ankle reflex Pathophysiology – evidence of degeneration of distal portion of axons 37 Jipmer physiologist 20-11-2011

38. Axonal type of mixed sensorimotor neuropathy Nerve conduction studies Reduced or absent SNAP CMAP amplitude decreases and motor conduction velocity also decrease in later stage EMG Fibrillations and positive sharp waves are prominent in distal muscles. Temporal dispersion on proximal stimulation is not found as in demyelinating neuropathies 38 Jipmer physiologist 20-11-2011

39. Mixed axonal loss and demyelinating neuropathy Diabetes Uremia Paraproteinemia 39 Jipmer physiologist 20-11-2011

40. Paresthesia , dyesthesia or numbness Reduced vibration and two point discrimination Pathophysiology – segmental demyelination and remyelination along with axonal degeneration 40 Jipmer physiologist 20-11-2011

41. Mixed axonal loss and demyelinating neuropathy Nerve conduction studies Reduced or unrecordable CMAP, SNAP or both Moderate to severe slowing of NCV with temporal dispersion of CMAP 41 Jipmer physiologist 20-11-2011

42. Clinical examination Thorough history and physical examination is needed. Cranial nerve examination Motor , sensory, autonomic nervous system examination Fundus examination Lymphadenopathy , hepatomegaly or splenomegaly , and skin lesions 42 Jipmer physiologist 20-11-2011

43. Lab tests: CBC, electrolytes, ESR Fasting serum glucose, glycosylated hemoglobin, blood urea nitrogen, creatinine , Liver , kidney,, thyroid function studies Inflammatory markers, Total protein level Vit D, B12, Cytology CSF Urinalysis Nerve biopsy 43 Jipmer physiologist 20-11-2011

44. Electrophysiologic studies EMG and nerve conduction studies (NCS) are often the most useful initial laboratory studies in the evaluation of a patient with peripheral neuropathy Confirm the presence of a neuropathy Provide information as to the type of fibers involved (motor, sensory, or both), the pathophysiology (axonal loss versus demyelination ) and a symmetric versus asymmetric or multifocal pattern of involvement. 44 Jipmer physiologist 20-11-2011

45. The limitations of EMG/NCS. There is no reliable means of studying proximal sensory nerves. NCS results can be normal in patients with small-fiber neuropathies Lower extremity sensory responses can be absent in normal elderly patients. EMG/NCS are not substitutes for a good clinical examination. Electrophysiologic studies 45 Jipmer physiologist 20-11-2011

46. Treatment The goal of treatment is to manage the underlying condition causing the neuropathy and repair damage, as well as provide symptom relief. 46 Jipmer physiologist 20-11-2011

47. Treatment Medical management Analgesics . antiepileptic drugs, including gabapentin , phenytoin , and carbamazepine some classes of antidepressants, including tricyclics such as amitriptyline . Mexiletine local anesthetics such as lidocaine or topical patches containing lidocaine Codeine/ oxycodone 47 Jipmer physiologist 20-11-2011

48. Mechanical aids can help reduce pain and lessen the impact of physical disability. Hand or foot braces can compensate for muscle weakness or alleviate nerve compression. Orthopedic shoes can improve gait disturbances and help prevent foot injuries in people with a loss of pain sensation. If breathing becomes severely impaired, mechanical ventilation can provide essential life support. Treatment 48 Jipmer physiologist 20-11-2011

49. Surgical intervention often can provide immediate relief from mononeuropathies caused by compression or entrapment injuries. Repair of a slipped disk can reduce pressure on nerves where they emerge from the spinal cord; the removal of benign or malignant tumors can also alleviate damaging pressure on nerves. Nerve entrapment often can be corrected by the surgical release of ligaments or tendons. Treatment 49 Jipmer physiologist 20-11-2011

50. Myopathies 50 Jipmer physiologist 20-11-2011

51. Definition Neuromuscular disorders in which the primary symptom is muscle weakness due to dysfunction of muscle fiber 51 Jipmer physiologist 20-11-2011

52. Introduction Worldwide incidence of all inheritable myopathies is about 14% Overall incidence of muscular dystrophy is about 63 per 1 million. Worldwide incidence of inflammatory myopathies is about 5–10 per 100,000 people. More common in women Corticosteroid myopathy is the most common endocrine myopathy and endocrine disorders are more common in women Incidence of metabolic myopathies – increasing 52 Jipmer physiologist 20-11-2011

53. Myopathy : symptoms Muscle pain and fatigue; exercise intolerance Proximal and symmetric weakness Waddling gait; difficulty of rising from sitting, climbing stairs; Gower’s sign Hyperextension of the knee Increased lordosis of the lumbar spine, scoliosis Contractures, tight Achilles tendons Myopathic face Muscle atrophy; pseudohypertrophy Myotonia Tendon reflexes are normal or depressed 53 Jipmer physiologist 20-11-2011

54. Clinical examination Thorough clinical examination! Observation – look for muscle atrophy, deformities Strength testing Functional testing Stand up from a chair Walk Step up on a low stool REFLEXES and SENSATION 54 Jipmer physiologist 20-11-2011

55. Types of muscle diseases Hereditary muscle diseases Denervation atrophy Muscle dystrophies Muscle channelopathies Mitochondrial myopathies Metabolic myopathies Acquired muscle diseases Inflammatory myopathies Endocrine and toxic myopathies Infectious muscle diseases 55 Jipmer physiologist 20-11-2011

56. Myopathic Disorders Inflammatory Myopathies Polymyositis Dermatomyositis Inclusion body myositis Viral Muscular dystrophies Duchenne muscular Limb-girdle Congenital Fasioscapulohumeral Oculopharyngeal Emery – Dreifuss Distal ( Welander ) Myotonic Syndromes Myotonic dystrophy Inherited Schwarz- Jampel Drug-induced Congenital myopathies Central core disease Nemaline myopathy Myotubular Fiber-type disproportion Metabolic myopathies Glycogenoses Mitochondrial Periodic paralysis Endocrine myopathies Thyroid Parathyroid Adrenal/steroid Pituitary Drug-induced/toxic 56 Jipmer physiologist 20-11-2011

57. Diagnostic histological features of myopathies Absence of neurogenic abnormalities Necrotic muscle fibers Basophilic (regenerating) myofibers Fibrosis of the endomysium Special pathological features (inflammatory cells, ragged red fibers etc.) 57 Jipmer physiologist 20-11-2011

58. Muscle dystrophies Hereditary myopathies , characterized by progressive weakness and muscle atrophy Genetic defect of proteins constituting the sarcolemma -associated cytoskeleton system 58 Jipmer physiologist 20-11-2011

59. Duchenne muscular dystrophy First described in 1881- dystrophin gene discovered in the early 1980's 59 Jipmer physiologist 20-11-2011

60. Duchenne muscular dystrophy X-chromosome linked , recessive inheritance 1 in 3500 live births, 60 Jipmer physiologist 20-11-2011

61. Clinical features Onset of weakness before age 5 Progressive weakness, proximal>distal, and muscle wasting Gower’s sign Hypertrophy of calves, psuedohypertrophy of deltoid, gluteal Skeletal deformities Cardiomyopathy wheel chair dependence by the age of 12, respiratory infection at 16-18 years. Fatal in the third decade 61 Jipmer physiologist 20-11-2011

62. Electrophysiology EMG changes – rate of muscle fiber destruction and extent of regeneration. Fiber loss-Low amplitude short duration MUPs, Fiber degeneration- polyphasic MUPs Necrosis - fibrillations with low amplitude and short duration Nerve conduction studies – generally normal 62 Jipmer physiologist 20-11-2011

63. Elevated CPK levels to 20 to 100 folds Variation in size and shape of muscle fibers and small groups of necrotic and regenerating fibers- muscle biopsy. Absence of dystrophin gene in biopsied muscles or genetic defect analysis in WBCs 63 Jipmer physiologist 20-11-2011

64. Management No specific treatment Physiotherapy Aerobic exercise Low intensity anabolic steroids Prednisone supplements Orthoses (orthopaedic appliances used for support) Orthopaedic surgery Critical care 64 Jipmer physiologist 20-11-2011

65. Beckers muscular dystrophy Allelic defect in DMD gene. 10 times less frequent than DMD Better prognosis. Patient lives upto 40-50 years. Mental retardation and heart failure can occur Muscle biopsy – variable muscle fiber size with aberrant large fibers. Endomysial fibrosis and fatty infiltration Patchy staining of DMD gene 65 Jipmer physiologist 20-11-2011

66. ge Gene Clinical feature Pathophysiology Fascioscapulohumeral MD - AD FSHMD1B Progressive muscular weakness and atrophy involving the face, scapular, proximal arm and peroneal muscles  myopathic face, Dystrophic myopathy with inflammatory infiltrates Oculopharyngeal MD - AD PABP2 Ptosis and extra ocular muscle weakness Dystrophic myopathy incl rimmed vacuoles Emery – Dreifuss MD – X - linked EMD , LMNA Triad of early contracture, humero - peroneal weakness and cardiac conduction defects Mild myopathic changes. Absent emerin by immunohistochemistry Congenital –MD AR Laminin alpha 2 Neonatal hypotonia , muscle weakness Variable fiber size and extensive endomysial fibrosis Congenital –MD – Fukuyama type AR Fukutin Neonatal hypotonia and MR Variable fiber size and extensive endomysial fibrosis. CNS malformation Congenital –MD Walker – warnburg type Protein o mannosyl transferase Neonatal hypotonia and MR, ocular malformation Variable fiber size and extensive endomysial fibrosis. CNS, ocular malformation 66 Jipmer physiologist 20-11-2011

67. ge Gene Clinical feature Pathophysiology Limb-girdle dystrophies Sarcoglycanopathies AR Α, β, γ, δ sarcoglycans α, β, γ, δ sarcoglycans Starts between 2 and 20 years Clinically indistinguishable from duchenne-dystrophy No cardiac involvement , Normal dystrophin immunostaining, abnormal immunostaining with sarcoglycans Genetic defect analysis Myotonic dystrophy AD CTG repeat expansion in a gene on chr. 19 Myotonia: hyperexcitability of muscle membrane  inability of quick muscle relaxation Progressive muscular weakness and wasting, most prominent in cranial and distal muscles Cataracts, frontal balding, testicular atrophy Cardiac abnormalities, mental retardation Muscle biopsy showing mild myopathic changes and grouping of atrophic fast fibres Myotonia congenita AD, AR Mucle cl gene Autosomal dominant form: Thomsen, autosomal recessive form: Becker Myotonia (hyperexcitability of the muscle membrane): muscle stiffness and abnormal muscle relaxation, warm-up phenomenon Hypertrophied muscles 67 Jipmer physiologist 20-11-2011

68. Inflammatory myopathies PATHOPHYSIOLOGY Polymyositis and inclusion body myositis (IBM) have autoaggressive CD8 lymphocytes that appear to attack myofibers and suggest an autoimmune role. However,a major question exists about the etiology of IBM. Dermatomyositis is thought to be caused by auto antibodies, possibly targeting an antigen of the endothelium. Fiber injury may be caused by ischemia. 68 Jipmer physiologist 20-11-2011

69. Dermatomyositis Polymyositis Incusion body myositis Sub acute progressive weakness Sub acute progressive weakness Slowly progressive weakness, proximal>distal proximal>distal proximal and distal. Children and adults, women adults, women adults, mostly men Characteristic rash and periorbital heliotrope. Electromyogram myopathic potentials, spontaneous myopathic potentials, spontaneous myopathic potentials, spontaneous activity Elevated serum creatine kinase activity. Elevated serum creatine kinase activity Mildly elevated serum creatine kinase or normal. inflammatory myopathy affecting chiefly the perimysium with perifascicular atrophy. inflammatory myopathy chiefly the endomysium : inflammatory myopathy affecting chiefly the endomysium , but chronic and has rimmed vacuoles and amyloid inclusions Usually respond to glucocorticoids or IVGG. respond to glucocorticoids does not respond to glucocorticoids . 69 Jipmer physiologist 20-11-2011

70. Polymyositis Inclusion body myositis Dermatomyositis 70 Jipmer physiologist 20-11-2011

71. Congenital myopathies Group of muscle disorders Early onset Slowly progressive Hereditary Generalised or proximal weakness and wasting Hypotonia Contractures Normally or mildly elevated CPK Normal or myopathic EMG 71 Jipmer physiologist 20-11-2011

72. Congenital myopathies Central core disease Nemaline myopathy Myotubular myopathy Inheritence AD AD , AR XL, AD, AR Gene RYR- 1 gene AD –NEM1 -TMP3 AR- NEM2 - NEB AR- NEM3 - ACTA AR- NEM4 – TMP2 AR- NEM5 - TNNT1 AR- NEM7 - CFL2 XL – MTM1 AD – DNM2 AR – BIN1 Clinical features Early onset hypotonia and weakness . Floppy infant . Associated skeletal deformities Chilhood weakness .variable presentation. Floppy infant Severe congenital hypotonia . Floppy infant .poor prognosis Pathophysiology Cytoplasmic cores are distinct from surrounding Sarcoplasm . Aggregates of subsarcolemmal spindle shaped rods Abundance of centrally located nuclei involving the majority of muscles 72 Jipmer physiologist 20-11-2011

73. Distal myopathies Welander distal myopathy Miyoshi distal myopathy 73 Jipmer physiologist 20-11-2011

74. Metabolic myopathies Disorders of muscle energy metabolism Disorders of lipid metabolism Mitochontrial myopathies 74 Jipmer physiologist 20-11-2011

75. Mitochontrial myopathies Kearn – sayre syndrome Myoclonic – epilepsy with ragged red fibers Mitochontrial myopathy , lactic acidosis, stroke Mitochontrial myopathies with recurrent myoglobunuria Mitochontrial DNA depletion syndrome Progressive external opthalmoplegia and ragged red fibers 75 Jipmer physiologist 20-11-2011

76. Endocrine myopathies Thyrotoxic myopathies Cushing syndrome and steroid myopathy Myopathy associated with oarathyroid disorders. 76 Jipmer physiologist 20-11-2011

77. Toxic myopathies Myotonic disorders Necrotizing myopathies Acute muscle necrosis Mitochontrial myopathy Hypokalemic myopathy Inflammatory myopathy Autophagic myopathy Focal myopathy Envenomation myopathy 77 Jipmer physiologist 20-11-2011

78. Muscle channelopathies 78 Jipmer physiologist 20-11-2011

79. Treatment There is no single treatment for myopathy . Treatment of the symptoms to specific cause-targeting treatments. Drug therapy Physical therapy Bracing for support, Surgery Massage 79 Jipmer physiologist 20-11-2011

80. Care !….the best rehabilitation method 80 Jipmer physiologist 20-11-2011

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