Muscle Channelopathies

Transcription

1 Queen Square Centre for Neuromuscular Diseases Muscle Channelopathies Professor Michael G Hanna

2 What is a skeletal muscle channelopathy? Muscle and nerves communicate by electrical signals Electrical signals are made by the movement of positively and negatively charged ions in and out of cells The ions can only move through dedicated ion channels Dysfunction disturbs muscle membrane excitability Genetic disorders Episodic

3 Myotonia and paralysis Two main symptoms Paralysis = an inexcitable muscle Muscles are very weak or paralysed Myotonia = an overexcited muscle Muscle keeps contracting and become stuck

4 CHLORIDE CHANNELS Myotonia congenita CLCN1 Paramyotonia congenita SCN4A MYOTONIA SODIUM CHANNELS Hyperkalaemic periodic paralysis SCN4A Hypokalaemic periodic paralysis 80% CACNA1S CALCIUM CHANNELS 10% SCN4A PARALYSIS Andersen-Tawil Syndrome KCNJ2 (+KCNJ5) POTASSIUM CHANNELS Thyrotoxic periodic paralysis KCNJ18

5 Sodium and chloride channels + Depolarisation due to Na + entry Na + channels open - Na + channels close K + channels open Repolarisation due to K + exit Cl - K + channels close

6 What is myotonia? Clinically: delayed muscle relaxation after forced contraction Muscle are stuck, stiff, cramp Electrophysiologically: spontaneous depolarisations of the muscle membrane

7 In what conditions do you see myotonia? Myotonic dystrophy type 1 (DM1) Cardiac, cataracts, frontal balding, endocrine Myotonic dystrophy type 2 (DM2) Cardiac, cataracts, endocrine Non-dystrophic myotonia (hyperpp) No systemic features Myopathies - Pompes Schwartz-Jampel syndrome (neuromyotonia) Brody s disease (pseudomyotonia)

8 Myotonia Congenita CLCN1 Gene CLC-1 Channel Loss of function Dominant or recessive Most common + Depolarisation due to Na + entry Na + channels open - Na + channels close K + channels open Repolarisation due to K + exit Cl - K + channels close

9 Myotonia Congenita Age of onset variable up to 40s Myotonia = stiff or stuck muscles Difficulty starting to move or with sudden movement may fall warm up once I m moving I m ok Legs>arms or face +/- transient muscle weakness usually improves with repetition (recessive > dominant) Myopathy

10 Paramyotonia Congenita SCN4A gene alpha sub-unit Nav1.4 channel Dominant + Depolarisation due to Na + entry Na + channels open - Na + channels close K + channels open Repolarisation due to K + exit Cl - K + channels close

11 Paramyotonia Congenita Onset first decade Myotonia worse with repetition COLD!!! Exercise Eyes + face/jaw+hands > legs Dysphagia, respiratory rare Episodic weakness/paralysis (hyperpp) may last hours Hypertrophy Myopathy

12 Investigations History and Clinical exam Blood tests: Potassium, CK, TFTs, WCC enzymes, vacuolated lymphocytes ECG Neurophysiology short exercise test MRI scan Genetic tests SCN4A/CLCN1 (DM1/2)

13 EMG - Myotonia

14 Clinical Neurophysiology tests 2. Long & short exercise tests Record from ADM Stimulate ulnar nerve Record a series of CMAPs before and after exercising the muscle:

15 CMAP amplidtue and area (% Baseline) EMG - Myotonia Congenita Time

16 CMAP amplidtue and area (% Baseline) EMG Paramyotonia Congenita Time

17 MRI in non-dystrophic myotonia Morrow et al, Neuromuscular Disorders, 2013

18 Management

19 Exacerbating Factors Temperature Food Exercise

20 Pharmacological Therapy Myotonia Extracellular Intracellular Depolarisation Activation Inactivation Sodium channel blockers X Closed Open Antiepileptics phenytoin carbamazepine lamotrigine Antiarrythmics procainamide mexiletine flecainide propafenone

21 7 centres, 4 countries Mexiletine 200mg TDS vs placebo Four weeks crossover with one week washout Primary endpoint = self reported stiffness Period 1 means Period 2 means Mexiletine Placebo Difference P value < Statland.Matthews Hanna. JAMA 2012 October 3; 308(13):

22 Mexiletine Audit Patient Demographics Female Male TOTAL Male/female Hyper PP PMC & MC PMC SCM SCN4A MC Dom MC Rec MC CLCN Mean length of follow up 4.8 years, median 3.3, range 0.7 to 17.8 years.

23 % of Patients Reporting Symptom Mexiletine adverse effects % reported one or more adverse effect Dyspepsia most common, 16 required medical therapy, 4 had to stop Mexiletine because of symptoms 6 of 9 who had stopped because of SE previously found it effective & tolerable on retrial with slow dose titration

24 Mexiletine Safety No Serious adverse patient events No change in ECG parameters off mexiletine or at highest dose at which ECG recorded. 16 patients referred to cardiology with concerns over initiating or continuing Mexiletine therapy All advised to start or continue Mexiletine

25 Implications for Practice Mexiletine is a safe long term treatment for patients with non-dystrophic myotonia Patients with chloride channel myotonia likely to require higher dose of mexiletine for efficacy. Slow dose titration of 50 to 100mg per week up to either 200mg TDS or resolution of symptoms recommended. Dyspeptic therapy often needed to enable adequate dose titration of Mexiletine.

26 Implications for Practice Baseline ECG and cardiac history Repeat ECG after initial dose titration complete (approximately 2 weeks after stabilised at effective dose) Repeat ECG if significant dose change Repeat ECG if any concern over cardiac symptom and consider referral to Cardiology If mexiletine dose unchanged, no new cardiac symptoms, interacting medications or other related patient concerns than routine annual monitoring ECG not indicated. Mexiletine guidelines available le/muscle_channelopathy_tabs/options/edit/tab_preview

27 16 Most prominent symptom Pain No. of patients 19 NDM patients 3/19 pain most prominent symptom 16/19 some pain 100% SCN4A reported pain 0 Pain Weakness Stiffness Fatigue Severity of pain 50% CLCN1 reported pain Pain without stiffness was common 2 studies: pain more common in SCN4A than CLCN % of those with SCN4A muts (Trip et al,jnnp 2009, Trivedi et al, Brain, 2013)

28 Myotonia and anaesthetics May be worsened by anaesthetic agents Precipitating agents include suxamethonium, anticholinesterase agents and opioids Myotonia may make intubation and ventilation impossible myotonic crisis Treatment is with Na+ channel blockers (e.g. lidocaine)

29 Pregnancy and birth Fertility normal Symptoms may worsen in pregnancy? No more assisted deliveries than average? Some babies can be floppy and need extra help to feed Anaesthetic considerations

30 Neonatal hypotonia sodium channel Sex APGAR Onset of hypotonia Impairment of sucking Family 1 F NA Birth Day 1, bottle fed unable to breastfeed Family2 F NA Birth No hypotonia limited to limbs Family 3 F 10 Day 1 -hrs after birth M 10 Day 1 when bathed NG tube Day 1 cyanosis Day 1 no Rx reported Family 4 M NA Day 1 Day 1 no Rx reported M 10 Day 1 hrs after birth NG tube Day 2-6, nasal oxygen Desaturation Kalaemia Motor devpt No Na Delayed walking 19/12 No NA Delayed walking 22/ then normal No Normal NA Normal No NA Normal Normal NA

31 Severe Neonatal Episodic Laryngospasm Intermittent stridor from birth or within a few hrs of birth Difficult/prolonged feeding common GORD and laryngomalacia not uncommonly diagnosed Episodic stridor with laryngospasm, general stiffness with hypoxia and cyanosis requiring ICU support from 0-3 months Bradycardia and LOC may accompany Muscle hypertrophy and myotonia from c.6 months Mild delay in motor development 2 fatalities 1 posthumous diagnosis 1 MEX (no response to CBZ), died LRTI and resp arrest Good response to sodium channel blockers generally reported Gay et al. Am J Med Genet A 2008 Feb 1;146: Other features: dysmorphic features, congenital hip dislocation and psychomotor delay

32 Periodic Paralysis POTASSIUM Hyperkalaemic Any time Mins to hours High potassium foods SCN4A POTASSIUM Hypokalaemic Night/early morning Hours to days Carbohydrates CACNA1S/SCN4A

33 Modelling of sodium channel myotonia and paralysis Gain of function; persistent inward sodium current MRC Centre for Neuromuscular Disease

34 Sodium and calcium channels + Depolarisation due to Na + entry Na + channels open - Na + channels close K + channels open Repolarisation due to K + exit Cl - K + channels close

35 Hypokalaemic periodic paralysis P loop E E E E S5 and S6 pore forming segments Voltage sensor Pore closed P loop D E K A S5 and S6 pore forming segments I F M Pore open

36 K Day 3 Day 4 Day 5 9am 10am 2pm 5pm Day 6 Day 7 examination tone NORMAL power NORMAL reflexes NORMAL sensation NORMAL

37 K Day 3 Day 4 Day 5 9am 10am 2pm 5pm Day 6 Day 7 examination tone FLACCID power 1-2/5, exc. EE 4/5 reflexes ABSENT, exc. tri sensation NORMAL

38 ECG during weakness U-wave

39 ECG following recovery

40 Andersen Tawil Syndrome Periodic paralysis Cardiac conduction Characteristic features Andersen et al. (Acta Paediat Scan 1971)

41 Investigations History and Clinical exam Blood tests: Potassium, CK, TFTs, Renal tests ECG Neurophysiology MRI scan Genetic tests

42 CMAP Amplitude and Area (% of baseline) EMG Periodic Paralysis McManis long exercise test CMAP amp CMAP area

43 HypoPP and Myopathy Morrow et al, in preparation

44 Treatment

45 Exacerbating Factors Temperature Food Exercise

46 Pharmacological Therapies Periodic Paralysis Hypokalaemic Periodic Paralysis K supplements Acetazolamide Diuretics: Spirinolactone, Amiloride Hyperkalaemic periodic paralysis Acetazolamide Thiazide diuretics

47 Emergency Treatment Don t forget TFTs! IV potassium replacement MUST be monitored with electrolytes and ECG

48 Pregnancy Anaesthetic considerations

49 The Team Professor Michael Hanna Emma Matthews - neurologist Doreen Fialho - neurophysiology Natalie James CNS Sarah Holmes - neurophysiotherapist Karen Suetterlin & Matthew Evans research fellows Richa Sud & Samuel McCall - genetics Roope Mannikko electrophysiology Sally-Ann de Souza - senior secretary Jackie Kasozi-Batende service manager Trish Turner- neuromuscular manager Mary Sweeney & Professor Henry Houlden - genetics