Neuromuscular Disease of Infants and Children. A Guide to Diagnosis of Genetic and Acquired Conditions

Transcription

1 Neuromuscular Disease of Infants and Children A Guide to Diagnosis of Genetic and Acquired Conditions

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3 Genetic Effects and Infant/Neonatal Neuromuscular Conditions Who did I get this from?

4 Onset, progression, Distribution of symptoms HISTORY Associated symptoms - myalgia, cramps, tenderness, difficulty relaxing a grip Development - regression, progressive difficulty ambulating Concomitant medication Family history - type of inheritance

5 PHYSICAL EXAMINATION Inspection - obvious distribution of weakness or atrophy; proximal/distal unilateral/symmetric, bilateral Peripheral nerves enlarge? Gastrocnemius hypertrophic? Myotonia or myoedema with percussion Pattern of unusual tone to palpation of muscle Distribution of weakness: cranial nerve involvement - facial weakness, ptosis, EOM, scapular winging, lumbar lordosis, waddling gait, Gowers sign, ataxia, Romberg sign, sensory awareness, Babinski sign, fasciculations, polyminimyoclonus

6 LABORATORY EVALUATION CK, LDH, SGOT, SGPT, Aldolase Pigmenturia with myoglobin ESR, ANA, immune complexes Lactic acid, pyruvic acid elevation Electrophysiologic studies EMG/NCV Muscle imaging Muscle-nerve biopsy DNA analysis

7 Neurogenic EMG

8 The Floppy Newborn In the presence of hypoxic ischemic injury or neonatal infection no further workup is warranted Many causes are hereditary, uncommon and potentially reversible with time Lethal conditions are usually genetic

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11 MYOTONIC DYSTROPHY Autosomal dominant Chr 19q Most prevalent inherited NM disease in adults CTG repeats > 50, Anticipation with increase CTG repeat # Distal weakness; arm, hand, foot drop, scm atrophy, Narrow triangular facies, temporalis weakness, ptosis, myotonic grasp CK usually normal, EKG may show AV block or sinus bradycardia EMG - characteristic myotonic bursts (dive bomber) and distal myopathic changes Muscle biopsy - ring fibers and some dystrophic changes Treatment: phenytoin, tricyclic antidepressants, calcium channel blockers, quinidine for myotonia typically not effective Prognosis: variable, sudden death due to cardiac involvement

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13 PWS

14 Prader-Willi Syndrome(PWS) Floppy newborn Poor feeder requiring gavage feedings 1:25,000 frequency M=F Defect on chromosome 15 easily found on appropriate genetic testing With time improved feeding Obesity, mental def, voracious appetite, small digits, obstructive sleep apnea, diabetes & CV risks

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18 Case Report 1 A 22 month old girl was developing well until 10 months of age when she exhibited gradual loss of motor milestones. On exam there was diffuse hypotonia, normal sensation and fine tongue and finger tremors at rest(pmm). DTRs were absent. A brother died at age 8 years from respiratory failure. CK=468, EMG was neurogenic(fibrillations,psws and large motor unit potentials) ALT=36, lactate=1.8, organic acid screen WNL.

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21 Likely diagnosis is? Congenital myopathy Prader-Willi Spinal muscular atrophy type2 Infantile botulism West Nile associated polio

22 Motor Neuron Disease 1:10,000 births Autosomal recessive M=F Type I (Werdnig-Hoffman) is lethal Type II onset in several months but non ambulator in later childhood Type III can ambulate and live well into adulthood

23 SPINAL MUSCULAR ATROPHY (SMA) AR, Chr 5 SMN gene deletion 1:10,000 births All forms characterized by reduced to absent DTRs, hypotonia, generalized weakness, fasciculations, and a normal sensory examination Lab: CK normal or mildly elevated; EMG neuronopathicfibrillation, fasciculation, large complex potentials wider motor unit territory Muscle biopsy group atrophy, and secondary hypertrophy Anterior horn cell population of the spinal cord is markedly reduced and is best preserved at the level of phrenic nerve (C2-4), cranial motor nuclei are also reduced in number

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25 Case Report 2 A 14 year old girl presents with intermittent palpebral ptosis, diurnal fatigue and 2 bouts of pneumonia. She has difficulty swallowing and lost 9 pounds in the past month. Speech is slurred on occasion Sensory exam is normal and DTRs are +2 Initial lab; ck=80, esr=36, alt=48

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27 Polymyositis Guillain-Barre Myasthenia Gravis Hysteria West Nile Polio Your Diagnosis is?

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29 MYASTHENIA GRAVIS (Autoimmune) NMJ disorder, sporadic with few exceptions Variable muscle weakness over the course of the day Ptosis and bulbar weakness may predominate Lab: Acetylcholine Receptor Antibodies present 80% of patients & anti MuSK 1-10% ANA, anti-thyroid antibodies may be positive Thymoma rare in children, but thymic hyperplasia common Positive Tensilon test(blinded), neuromuscular transmission - decremental response at 3 Hz stimulation with minimum of % reduction of amplitude Tx: cholinesterase inhibitors, steroids, pheresis, IVIG, thymectomy, azathioprine and other immune modulators

30 Myasthenia Gravis

31 A New Issue She is now 24 years old and she and her husband wish to have a child Weakness is minimal following thymectomy at age 16 and she remains on a stable dose of mestinon What precautions are necessary to discuss?

32 NEONATAL MG % of infants born to mothers with autoimmune MG Local or generalized weakness Respiratory depression Symptoms subside over 1-4 weeks Dx Confirm MG in mother; Anti-AChR Ab usually positive; anticholinesterase inhibitors Tx Pyridostigmine or Neostigmine, ventilate if necessary, IVIG or exchange transfusion

33 Case report # 3 A 5 year old boy was noted by his teacher to be slower than his peers in most physical activities Initial exam reveals large firm strong calves, inability to run and normal sensory exam. Initial lab alt=440, ck=35,000, esr=10 Family hx significant in that a maternal uncle died at age 22 after being wheel chair active 11 years

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35 Case Report 3 A 3 year old boy had an ALT=760, AST=460 and underwent an uninformative liver biopsy. A CK was 30,000, serum myoglobin 10 fold elevated and GGT was 66 Minimal proximal weakness was noted Family history was uninformative

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37 What does he have? How do you prove it? A. More biochemistry? B.Muscle biopsy? C. DNA test for dystrophin deletion? D. EMG?

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40 DUCHENNE MUSCULAR DYSTROPHY X-linked recessive Xp21, one third without identifiable X-linked pattern Incidence 1/3679 live male births Absent dystrophin Progressive proximal muscle weakness - present with difficulty running by age of 2-3 y Gower s sign by age 6 y, DTRs depressed proximally, progressive contractures Wheel-chair bound by age 9-11, death y due to respiratory &/or cardiac failure

41 DUCHENNE MUSCULAR DYSTROPHY Lab: CK higher during infancy up to 30,000-40,000 units, LDH, SGPT, SGOT elevated EMG myopathic small, easily recruited motor units Biopsy degeneration and regeneration of muscle fibers, fiber splitting, internal nuclei, endomysial fibrosis Prenatal diagnosis for future pregnancies if the affected child is informative(dna deletion) can be done within days of conception

42 DMD C0-Morbidities Learning disability, mental retardation Cardiomyopathy, LV dysfunction leading to heart failure GI motility disturbances with delayed gastric emptying, dilated colon with obstipation Chronic hypoxemia and hypercarbia

43 DMD Treatment Treatment: Supportive; maintain joint mobility, have the child stand as long as possible using bracing, physical therapy. Surgery for scoliosis may enhance pulmonary function. Treatment of cardiac failure and CPAP/BIPAP. Nutritional needs. Steroids may prolong ambulation but numerous side effects Gene therapy Eteplirsen restored dystrophin in the 30 and 50 mg/kg/wk cohorts(exon skip pts), and in subsequently treated, placebo-controlled subjects. Duration, more than dose, accounted for dystrophin production, also resulting in ambulation stability. No severe adverse events were encountered. Ann Neurol 2013;74: Mendell et al

44 Case Report 4 A 13 year old girl presents with a 3 week history of progressive weakness. 2 weeks prior she had a viral upper respiratory illness She has dyspnea with minimal exertion and has back and leg pain with the straight leg raise test When coming to standing she faints Exam is significant for trace to absent reflexes and distal sensory loss

45 Your Diagnosis is? Conversion reaction Polymyositis Myasthenia gravis Guillain-Barre Syndrome(GBS) Transverse myelitis

46 GBS Incidence 1:100,000 per year Associated systemic disorders include URIs (cytomegalovirus), Epstein-Barr( ), influenza, Gastrointestinal disorders (Campylobacter jejuni), Mycoplasma pneumonei Vaccinations

47 POLYNEURITIS GUILLAIN-BARRE SYNDROME Progressive ascending weakness usually accompanied by stocking-glove sensory loss often preceded by paresthesias Typically follows respiratory viral infection or gastroenteritis Areflexia with variable autonomic function Lab: abnormal nerve conduction study - demyelinating or axonal (less common), CSF - albuminocytologic dissociation Tx: IVIG(2, plasmapheresis which may need to be repeated Steroids to be avoided

48 Cross Section of Adjacent Nerve Fascicles (Toluidine Blue Stain, 250). Sander HW, Hedley-Whyte ET. N Engl J Med 2003;348:

49 kot/dysauto kot/dysauto

50 Case Report 5 A 12 year old boy has progressive fatigue and on exam has moderate proximal weakness. Sensation is normal. The CK=1288, ESR=44 ANA=1:360 Cardiac exam is WNL What more do you want??

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54 What is the likely diagnosis? Guillain-Barre Dermatomyositis Chronic fatigue syndrome Malingering Myasthenia gravis Paraneoplastic syndrome

55 DERMATOMYOSITIS Gradual onset of muscle weakness infrequently accompanied by myalgia Heliotrope rash, interphalangeal swelling and striation with pretibial and elbow erythema and scaling Proximal weakness and atrophy No sensory impairment Lab: Moderately elevated CK, ESR, inconsistent + ANA Complications: diffuse calcinosis, carditis (rare) Muscle biopsy: perimysial inflammation, atrophy, myofiber necrosis Caveat: may be part of more complex immune disease(paraneoplastic in adults)

56 Treatment of Dermatomyositis Oral steroids(prednisone) is the mainstay and may be required for a prolonged time Azathioprine Methotrexate Cellcept I VIG Physical and occupational therapy

57 End Neuromuscular diseases in infants and children are uncommon Diagnosis is essential to initiate treatment and provide genetic counseling for future pregnancies Effective therapies are available for immune related disorders and increasingly for metabolic based conditions.

58 MDAUSA.org The WEB Washington University Neuromuscular Page Online Mendellian Inheritance in Man (OMIM) E-medicine-dystrophies