Faculty Disclosure. Sanjay P. Singh, MD, FAAN. Dr. Singh has listed an affiliation with: Consultant Sun Pharma Speaker s Bureau Lundbeck, Sunovion

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1 Faculty Disclosure Sanjay P. Singh, MD, FAAN Dr. Singh has listed an affiliation with: Consultant Sun Pharma Speaker s Bureau Lundbeck, Sunovion however, no conflict of interest exists for this conference. Neuromuscular Disorders Sanjay Pratap Singh, MD, FAAN Chairman & Professor,Department of Neurology, Creighton University School of Medicine, Director Neurological Institute, CHI Health 1

2 Upper Motor Neuron Lower Motor Neuron Hyperreflexic Hyporeflexic Babinski + - tone tone No Atrophy Atrophy + 2

3 L.M.N. Anterior Horn Cell Peripheral Nerve N.M.J. Muscle Motor Motor + Sensory Motor Motor Fasciculations i.e. ALS, Polio EMG/NCS i.e. GBS Neuropathy Temporal Relationship i.e. M.G. Proximal CPK i.e. Myopathy Brachial Plexus 3

4 Weak Hand!! Nerve Supply Root A.P.B. [Abduction of thumb] F.D.I. [Abduction of index finger] E.I. [Extension of index finger] Weak Hand Nerve Supply Root A.P.B. [Abduction of thumb] F.D.I. [Abduction of index finger] E.I. [Extension of index finger] Median Ulnar Radial 4

5 Peripheral Nerve vs Root -Hand Nerve Supply Root A.P.B. [Abduction of thumb] F.D.I. [Abduction of index finger] E.I. [Extension of index finger] Median Ulnar Radial C8T1 C8T1 C8T1 1/3 weak nerve APB, FDI & EI 2/3 weak plexus 3/3 weak root 5

6 FOOT DROP Tibialis Anterior [Dorsiflexion of foot] NERVE Deep Peroneal Nerve ROOT SUPPY L-5 Tibialis Posterior [Inversion of foot] [Plantar flexion] Tibial Nerve L-5 Peripheral Neuropathy Lower motor neuron Sensory + motor ROOT, PLEXUS, NERVE Pattern Recognition 6

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8 Symmetric proximal & distal weakness with sensory loss Symmetric distal weakness with sensory loss Asymmetric distal weakness with sensory loss Asymmetric distal weakness without sensory loss Asymmetric proximal & distal weakness with sensory loss Symmetric sensory loss without weakness Autonomic Neuropathies Asymmetric propioceptive sensory loss GBS, CIDP CMT, DM, Vasculitis, CN HNPP, HIV, Motor Neuron Disease Plexopathy,Pol yradiculopathy DM, CSPN, Cryptogenic Amyloid, DM S.N. Treatment of Peripheral Neuropathy 1. Treat the Cause Diabetes, Sarcoidosis 2. Treat the Pain Elavil, CBZ., Gabapentin, Topical Capsaicin 3. Treat the disability AFO, P.T., O.T. 8

9 Guillain Barre Syndrome Acute Inflammatory Demyelinating Polyneuropathy Rapidly evolving ascending weakness, areflexia, sensory loss. Associated with Campylobacter jejuni, Mycoplasma pneumoniae. Guillain Barre Syndrome Initial symptoms are numbness & tingling of extremities. Weakness starts in legs[56%], arms[12%]. Hyporeflexia to areflexia. Does not worsen after 4 weeks. 50%-2 weeks, 80%-3 weeks. B/l facial weakness. CSF Albumino-cytological dissociation after 1 week. EMG/NCS Demyelination. conduction velocity, conduction block 9

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11 Treatment of GBS Plasmapheresis IVIg Steroids no benefit Supportive care Pain & autonomic dysfunction Monitor FVC. Intubate if needed. Prognosis 70%-minor deficits, 15%-no deficits, 5%-die, 10%-residual weakness Myasthenia Gravis 70,000 patients in the U.S.A. Under age 40 years M:F = 3:1 Pathology - Auto antibodies against nicotinic acetylcholine receptors. Clinical Fluctuating weakness, Ocular 60%, Neck Flexors, Progress in 90%. Labs Tensilon test, Repetitive stimulation [EMG], Single fiber EMG jitter, Achr A/B [80% in Gen. - 50% ocular], MuSK Antibody [40-70% in seronegative] 11

12 Autoimmune 12

13 Treatment of Myasthenia Gravis Acetylcholinesterase inhibitors Pyridostigmine [Mestinon]. S/E N/V, Diarrhea, salivation, bradycardia, weakness. Steroids Plasmapheresis IVIg Thymectomy thymoma, <60 years of age. Immunosuppresants Cyclophosphamide. Suppotive care. 13

14 Myasthenic Crisis Requiring mechanical ventilation Plasmapheresis d/c Mestinon Steroids Close monitoring. 14

15 Lambert-Eaton Myasthenic Syndrome Antibodies to voltage gated Calcium channels in the presynaptic cholinergic neuron. Associated [60% small cell lung cancer]. May get stronger with sustained contraction. Rep. Stim. Incremental response to >10 Hz. Tx. Treat tumor, 3,4 DAP[Diaminopyridine] 15

16 Botulism Caused by exotoxin of Clostridium botulinum. Toxin interferes with presynaptic release of Ach hrs. after ingestion. Evolve over 2-4 days Begin with eye symptoms. Pupillary reflex lost. Constipation & Ileus. Rep. Stim. Incremental response to > 10 Hz. Serum for toxin assay. Stool for culture. Tx. Trivalent antiserum ( Antitoxin). CDC. 16

17 MUSCULAR DYSTROPHY Duchenne s M.D. Absence of dystrophin X-linked recessive Onset in childhood Wheelchair by 12 years Cardiac conduction abnl. Death by years Tx. Steroid, Rehab Becker s M.D. Decrease in Dystrophin X-Linked recessive Later Onset Not wheel chair bound by 12 years. Death in 5 th decade POLYMYOSITIS DERMATOMYOSITIS Females > Males After age 20 years No rash Most common acquired myopathy Proximal weakness Dysphagia 1/3 rd Labs - CK, Antimyosin Ab in 90% EMG Myopathic Myocarditis, ILD Tx. Steroids, IS, IVIg Females > Males Childhood and adult Rash heliotrope rash, scaly knuckles Proximal weakness CK Bx. Perimysial inflammation EMG Myopathic CD-4 Myocarditis, ILD Malignancy 6-45% Tx. Steroids, IS, IVIg 17

18 Neuromuscular Therapy New Era Spinal Muscular Atrophy (SMA) Spinal Muscular Atrophy (SMA) Most common genetic cause of infant death. SMA caused by decrease in survival of motor neuron protein-smn protein leads to motor neuron death its innervated muscles become weak and atrophic. 18

19 Spinal Muscular Atrophy (SMA) In most eukaryotic genes, coding regions (exons) are interrupted by noncoding regions (introns). During transcription, the entire gene is copied into a premrna, which includes exons and introns. During the process of RNA splicing, introns are removed and exons joined to form a contiguous coding sequence. This "mature" mrna is ready for translation. Introns & Exons 19

20 Spinal Muscular Atrophy (SMA) Spinal Muscular Atrophy (SMA) 20

21 Spinal Muscular Atrophy (SMA) SMA - Nusinersen 21

22 SMA - Nusinersen SPINRAZA (nusinersen) 22

23 SPINRAZA (nusinersen) How SPINRAZA works: SPINRAZA is an antisense oligonucleotide (ASO) designed to treat spinal muscular atrophy (SMA) caused by mutations in chromosome 5q that lead to survival motor neuron (SMN) protein deficiency SPINRAZA was shown to increase production of fulllength SMN protein by increasing exon 7 inclusion in survival motor neuron 2 (SMN2) messenger ribonucleic acid (mrna), using in vitro assays and studies in transgenic animal models of SMA SPINRAZA (nusinersen) -MOA SPINRAZA was shown to increase exon 7 inclusion in SMN2 mrna transcripts and production of full-length SMN protein. SPINRAZA, administered intrathecally, delivers concentrations in the cerebrospinal fluid (CSF) 23

24 SPINRAZA (nusinersen) - Cost The drug will cost $125,000 per injection = >Rs. 81 LAKHS per injection. Amounting to $750,000 for the first year and $375,000 after that. Yes you heard right!! 24