1. Neuromuscular Diseases Radim Mazanec, MD, Ph.D Department of Neurology

2. Disorders of the Motor Unit Peripheral nerve disorders Motor neuron disease Neuromuscular junction disease Muscle disease

3. Peripheral Nerve Disorders Mononeuropathy –Pattern of weakness and sensory loss conforms to the distribution of a single nerve Carpal tunnel syndrome Peroneal palsy at the fibular head Mononeuritis multiplex –Multiple nerves affected in a random pattern Acute onset, frequently painful Diabetes mellitus, vasculitis Polyneuropathy (peripheral neuropathy) –Distal, symmetric

4. Polyneuropathies Can affect different types of fibers –Autonomic –Motor –Sensory Large well myelinated Small poorly myelinated or unmyelinated

5. Symptoms of a Polyneuropathy Sensory symptoms –Start in feet, move proximally –Hand sxs appear when LE sxs up to knees –Positive Pins and needles Tingling Burning –Negative Numbness Deadness “Like I’m walking with thick socks on”

6. Exams of peripheral neuropathy Sensory impairment akroparesthesias or tactile hypestesias glove or sock distribution Vibration disturbances pallhypestesia distally (tuning fork C 128 Hz)

7. Bed side tests tactile vibration thermal myotatic reflexes

8. Clinical features of polyneuropaties Weaknes of LL Atrophies of distal muscles Deformities pes cavus Walk on heels Normal muscles strenght at proximal muscles

9. Diabetic feet and ulcerations Amputation CR 8 000/y Germany 30 000/y

10. Foot deformity in hereditary neuropathy (CMT disease) pes cavus

12. Classification of Polyneuropathies By types of fibers involved –Pure sensory –Sensory motor –Pure motor –Autonomic By pathology –Demyelinating –Axonal –Mixed By tempo –Acute –Subacute –Chronic

13. Acute Polyneuropathies Guillain Barre Syndrome Porphyria –Neuropathy, psychiatric disorder, unexplained GI complaints Toxins –Glue sniffing (n-hexane) –Arsenic

14. Guillain-Barré Syndrom G Guillain JA Barré A.Strohl Bulletin de Societe des Medicines Hopitals de Paris,1916;40:1462. Guillain Barré syndrom from 1927

15. Guillain Barre Syndrome Most common cause of rapidly progressive weakness Demyelinating neuropathy Ascending weakness which may include cranial neuropathies Exam reveals symmetric weakness with areflexia and large fiber sensory loss Bowel and bladder usually preserved

16. Guillain Barre Syndrome, cont Respiratory failure can be precipitous Other causes of morbidity and mortality –Autonomic instability –DVT –Infection Immune mediated, may be post infectious Treatment –Plasma exchange –Intravenous immunoglobulin

17. Subacute Polyneuropathies Vasculitis –Can be isolated to peripheral nerves or part of a more systemic process Paraneoplastic –May be presenting symptom of the cancer Chronic inflammatory demyelinating polyneuropathy –With or without a gammopathy Toxins Drug

18. Chronic Polyneuropathies Metabolic –Diabetes mellitus –Chronic renal failure –Chronic liver failure –Thyroid disease Nutritional –B12 deficiency Infections –HIV –Leprosy Inherited – Charcot Marie Tooth disease since 1886

19. Evaluation of a Polyneuropathy Lab work Nerve conduction study/electromyography –Distinguishes between axonal and demyelinating –Helps ascertain severity Nerve biopsy –Frequently non-diagnostic –Can establish the dx in certain disorders, such as vasculitis and amyloidosis

20. Electromyography functional diagnostic method Conduction studies Needle EMG Test of NM transmision

21. Conduction study of peroneal n. Conduction study of sural n.

22. Needle electromyography Concentric electrode

23. Myogenic lesion 1 mV

24. Chronic neurogenic lesion 8 mV

25. Disorders of the Motor Unit Peripheral nerve disorders Motor neuron disease Neuromuscular junction disease Muscle disease

26. Motor Neuron Disease Diseases that can involve Betz cells of the motor cortex, the lower CN motor nuclei, the CST, and/or the anterior horn cells –Amyotrophic Lateral Sclerosis (ALS) – 80% –Progressive bulbar palsy – 10% –Progressive muscular atrophy, spinal muscular atrophy – 8% –Primary lateral sclerosis – 2%

27. Dion PA et al.Genetics of motor neuron disorders:new insight into patogenic mechanism.Nature Genetics 2009,10:769-782.

28. Epidemiology of ALS ALS (Lou Gehrig´s disease) Prevalence - 4-6 : 100 000 Incidence - 0.5-3 : 100 000 90-95% sporadic forms of ALS (SALS) No family history 5-10% familial forms of ALS (FALS)

29. Classical ALS First symptoms : limbs 75% bulbar sy 25% Upper limbs - 41% Lower limbs - 34%

30. ALS – clinical features Loss of motor neurons in the cortex, brainstem and spinal cord Mix of upper motor neuron and lower motor neuron findings –Weakness, atrophy, fasciculations –Slurred speech, difficulty swallowing, shortness of breath Can start in any extremity or the bulbar musculature Relentlessly progressive

31. ALS - prognosis 50 % dead in 3 years, 80% dead in 5 years, 5 - 10% live more than 10 years Death usually from respiratory failure

32. Diagnostic algorhitm in ALS Clinical symptoms UMN + LMN Electromyography MRI brain + C spinal cord Liquor evaluation (infection) Sometimes paraneoplastic exams

37. Treatment of ALS Causative treatment is not available Neuroprotective treatment riluzol - inhibitor of glutamate acid antioxidans – koenzym Q10 + vitamin E Experimental and clinical studies on more than 200 moleculs – IGF-1, minocycline, creatine ethyl ester, tamoxifen…

38. Treatment of ALS Symptomatic-paliative treatment – most important today 1.Mobility – -sticks, wheelchair, multifunctional bed 2.Nutrition – PEG + Nutrizone 3.Communication – tables, books,vocal communicators, PC 4.Anxiety and depresion – antideperesive drugs, psychotherapy 5.Respiration – non-invasive BiPAP or invasive 6.Whole family care

39. Treatment of ALS Stem cell therapy – clinical studies are ongoing, including University Hospital Motol (2012-2014 – 30 ALS pts) 10 mio per kg Systemic aplication i.v. Intrathecal aplication Combination i.v. + i.th. Intraspinal aplication – L spinal cord, later C spinal cord Up to date – no EBM data, but in next year – several studies will be finished