David Orlikowski M.D., Ph.D. Clinical investigation center INSERM 1429 Intensive care and home ventilation unit, reference centre for neuromuscular

Transcription

1 David Orlikowski M.D., Ph.D. Clinical investigation center INSERM 1429 Intensive care and home ventilation unit, reference centre for neuromuscular disease hôpital Raymond Poincaré, Garches

2 stimulating hormone concentrations are frequently increased, even in subclinical hypogonadism.1 Electrophysiological studies Before diagnostic genetic testing was available, electromyography showing the combination of myotonia and myopathic changes was pathognomonic for diagnosis.1 However, in mildly affected, young adult patients the myopathic component might be missing, leading to considerations of myotonia congenita. Findings of nerve conduction studies are normal. In myotonic dystrophy type 2, the less prominent and frequently missing, or conspicuously absent, myotonic component can easily mislead diagnostic efforts towards polymyositis.13 Muscle histopathology Muscle biopsy findings in myotonic dystrophy type 1 are well established and are more pronounced in distal than proximal muscle, including a highly increased number of internal nuclei, sarcoplasmic masses, ring fibres, and moderate atrophy of type 1 fibres in clinically weak muscles (figure 2).1 Histopathological features in type 2 disease are very different, despite early reports describing Vol 11 October 2012 Muscle Biopsy C D Figure 2: Differential histopathological features on muscle biopsy In myotonic dystrophy type 1, the characteristic feature detected on conventional haemat (A) is fibre size variation and an increased number of internal nuclei in the fibres (arrow) in immunohistochemical fibre typing (B), slow type 1 fibres (brown) are on average smaller th (blue). In myotonic dystrophy type 2, the early finding at diagnosis on haematoxylin and e increased number of small atrophic fibres containing, almost exclusively, nuclei (so-called n even in asymptomatic proximal muscles (arrow). On immunohistochemical fibre typing (D fast type 2 fibres (brown) is highly atrophic (arrow). Both nuclear clump fibres and other ty Original magnification 400.

3 myotonic dystrophy type 1, theoretically they could also operate in type 2 disease. TF=transcription factor. account for the multisystemic phenotype in myotonic dystrophy. 67,75,76 For most mis spliced genes identified so far, patients with types 1 and 2 disease show comparable splicing abnormalities, sug gesting that qualitative differences in splicing do not account for phenotypic differences. However, whereas missplicing of CLCN1 (by giving rise to a non-functional transcript) can account for myotonia, a clear pathogenic role for most other misspliced genes has not been shown and evidence remains circumstantial. Missplicing of exon 11 of the amphiphysin gene (BIN1), mediated by MBNL1 loss, was linked to tubular defects in both myotonic dystrophy types 1 and Missplicing was more common in type 1 disease than type 2 and was seen only in affected muscles, with secondary changes of muscle tubulation and defective phosphoinositide signalling. These results were replicated in mouse models, and the noted changes might be associated with central nucleation and developmental weakness and hypotonia in congenital myotonic internal nuclei in muscl with myotonic dystrophy related to this missplicing of the CaV1.1 calcium c CELF1, was linked functi altered Ca² + gating. 82 Mis muscle proteins, such as L by LDB3), myomesin ( chain 14 non-muscle (M patients with myotonic dy Data from several anim foci, and muscle patho events (table 2) Mb mice, 85,97 and the Cugbp1 tr CELF1, 87,102 show aberrant mutant RNA. Transgen repeats (known as HSA L both show the same patt Udd and Krahe, Lancet Neurol 2012

4 The diagnosis of this form of DM1 is often missed in affected adolescents or children because of uncharacteristic symptoms for a muscular dystrophy and apparently negative family history (16). Cases of DM1 that come to medical attention during childhood typically manifest developmental abnormalities that are less severe than seen in congenital onset cases (17). Unlike the CDM patients, in which maternal transmission is the rule, the sex of the parents does not influence the development of childhood onset DM1. These patients have cognitive deficits and learning abnormalities (18). As in the congenital cases, degenerative features often develop as these children reach adulthood. There is increasing evidence of early conduction abnormalities, and from the age of 10, annual electrocardiograms and consideration of electrophysiological studies should be a part of routine management. 156 talking, chewing, and swallowing. El rum creatine kinase is present. Cardi common in DM1 and includes condu ties with arrhythmias and conduction ing significantly to the morbidity and disease (19-22). In some patients and cardiomyopathy may be observed. Po lar cataracts develop in most patients, at an early age without any other m which will develop later in their dis intellectual deficits are present in man trast with CDM and childhood onset obsessive-compulsive and passive-agg ity features have also been reported (2 apnoeic episodes and daytime sleepin manifestation. Gastrointestinal tract in irritable bowel syndrome, symptomat gamma-glutamyltransferase elevation Meola, Acta Myologica 2013

5 Multisystemic disorder: cataract, calvitia, heart (conduction, rythm) Diabete, CNS and peripheral impairment Respiratory insufficiency : Sleep apnea, sleepiness++

6 Muscle strength variations Visible muscle atrophy Calf hypertrophy Laboratory findings Concentration of creatine kinase in serum Muscle biopsy findings Fibre atrophy Nuclear clump fibres Sarcoplasmic masses Ring fibres Internal nuclei Cardiac symptoms Conduction defects Other neurological symptoms Tremors Behavioural changes Hypersomnia Other features Manifest diabetes Frontal balding in men Incapacity (work and activities of daily living) Life expectancy Occasional Face, temporal, distal hands, Absent Normal-to-moderate increas Smallness of type 1 fibres In late stage only Very frequent in distal muscl Frequent Massive in distal muscle Common Absent Common Prominent Occasional Generally present Typically after age yea Reduced Modified from Vihola and colleagues, 17 with permission of Springer-Verlag. Table 1: Clinical manifestations in the myotonic dystrophies Vol 11 October 2012 Udd and Krahe, Lancet Neurol 2012

7 MORTALITY/SEVERITY in DM1 RR death x 10.9 if proximal weakness RR death increases with RR Respiratory origin x 56,6 Importance of motor weakness RR Cardiovascular origin x 4,9 Mean age of death = years 54 Duration of disease J. Mathieu et al., Neurology 1999

8 Walk

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10 Groh WJ et al., NEJM 2008

11 Wahbi et al., JAMA 2012

12 Respiratory muscles weakness VC, Pi max, Pe max Myotonia Sleep DISORDERS Apneas, hypopneas Alveolar Hypoventilation Altered respiratory mechanics Respiratory drive disorders Volontary? Central? Peripheral?

13 VC ml MDRS Bégin et al., AJRCCM 1997

14 r= 0.439; p=0.041 r=0.53; p=0.011 Monteiro et al., Sleep Breath 2013

15 r= 0.67 ; p=0.001 p=0.02 Monteiro et al., Sleep Breath 2013

16 Intercostal muscles Diaphragm SCM Control DM1 Jammes et al., Muscle and Nerve 1985 Fitting, Am Rev Respir Dis 1989 Rimmer et al., Am Rev Respir Dis 1993

17 Multiple abnormalities Myogen /Myotonia 76% Central Conduction 20% Phrenical conduction 20 % Zifko et al., Brain 1996

18 Bégin et al.,am Rev Respir Dis 1981

19 Calabrese et al., Respiration Physiology 2000

20 Wakefulness Sleep Cirignotta et al., J Neurol 1987 Stade 3-4 Stade 1-2

21 Significant apnea/ hyponea predominantly obstructive: 86% of subjects Sleepiness not explained by Apnea/Hypopnea Epworth not related to objective sleepiness (MSLT) Objective daytime sleepiness= greater muscular impairment, weaker respiratory muscles, lower lung volumes and higher PCO2 Mathieu et al., JNNP 2009

22 PCO2=50 mmhg, VCsit 62 % and Vcsup 35%, Pimax and Pe max 37 and 31 mmhg. EXCESSIVE DAYTIME SLEEPINESS

23 PCO2= 47 mmhg, VC=88%, Pimax= 87 cm H2O, Pemax= 17 cm H2O, No sleepiness

24 PCO2=41mmHg, VC 70 % and EXCESSIVE DAYTIME SLEEPINESS

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26 207 th ENMC Workshop: Chronic respiratory insufficiency in Myotonic Dystrophies: management and implications for research

27 207 th ENMC Workshop: Chronic respiratory insufficiency in Myotonic Dystrophies: management and implications for research

28 207 th ENMC Workshop: Chronic respiratory insufficiency in Myotonic Dystrophies: management and implications for research

29 Clinical signs? PCO2? Muscular Weakness? Respiratory muscles weakness? Apnea Hypopnea syndrome? Multiple criteria?

30 Indications of ventilation of restrictive syndromes 1) Symptoms (fatigue, dyspnoea, morning headaches, etc.) 2) One of the following functional criteria. paco2 > 45 mmhg sao2 < 88 % during 5 minutes CV < 50 % or Pimax < 60 cmh2o Respiratory insuffisiency in the sleep Diaphragmatic dysfunction Consensus conference (Chest on 1999; 116: )

31 At least one symptom Daytime hypercapnia, PaCO 2 45mmHg (6.0kPa) or FVC < 50% of predicted based on the best of 3 measures and MIP < 60 cmh20 or Evidence of nocturnal hypoventilation, such as: A rise in PaCO 2 of 8mmHg (1kPa)between evening and morning ABGs or other accurate CO 2 surrogate A rise in TcCO 2 or ETCO 2 > 50mmHg (6.7kPa)for more than 50% of total sleep time Whilst not ideal - when a measure of CO 2 is not available - nocturnal oximetry demonstrates sustained oxygen desaturation (SpO 2 ) 88% for 5 consecutive minutes or SpO 2 <90% for >10% of total sleep time 207 th ENMC Workshop: Chronic respiratory insufficiency in Myotonic Dystrophies: management and implications for research

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33 Motive of lauching ventilation (%) DM1 N= Sleepiness Diurnal Hypercapnia Sleeping disorders Dyspnea Cough weakness Headache Nocturnal Hypercapnia PaO2 kpa PaCO2 kpa BE mmol/l VC % 8,3 6, Laub et al., J Rehabil Med 2006

34 Table 1. Characteristics of the Study Cohort. Characteristic Patients (N=255) Age yr * 41.0 ± 16.0 Male sex no. (%) 182 (71) Diagnosis Groups no. (%) DM1 78 (31) Dystrophinopaty 61 (24) Nerve and spinal 36 (14) Limb girdle 25 (10) Other myopathy 22 (14) SMA 11 (4) Poliomyelitis 9 (4) FSHD 7 (3) Congenital 6 (2) * The plus minus value is a mean ±SD.

35 Table 2. Indication criteria of HMV per diagnosis. Indications criteria * Existence of at least one clinical sign CV<30% of theory PaC02>45 mmhg free breathing Existence of a nocturnal desaturation Diagnosis Groups no. (%) DM1 73(94) 9(12) 57(73) 58(74) Dystrophinopaty 35(57) 59(97) 44(72) 15(25) Nerve and spinal 31(86) 14(39) 29(81) 12(33) Limb girdle 24(96) 16(64) 23(92) 11(44) Other myopathy 21(95) 12(55) 17(77) 11(50) SMA 8(73) 8(73) 7(64) 5(45) Poliomyelitis 8(89) 4(44) 9(100) 3(33) FSHD 5(71) 3(43) 6(86) 4(57) Congenital 6(100) 3(50) 3(50) 2(33) * number of patients per diagnosis with criteria.

36 Table 3. Initial respiratory status. Diagnosis groups no. (%) Clinical sign no. (%) Dyspnea at rest Dyspnea effort morning headaches or a distance of MVH Orthopnea sleep disturbances Diurnal sleepiness DM1 8(10) 54(69) 27(35) 23(29) 43(55) 57(73) Dystrophinopaty 10(16) 22(36) 10(16) 20(33) 14(23) 10(16) Nerve and spinal 12(33) 24(67) 16(44) 9(25) 11(31) 15(42) Limb girdle 4(16) 20(80) 13(52) 15(60) 15(60) 14(56) Other myopathy 4(18) 16(73) 8(36) 5(23) 10(45) 6(27) SMA 3(27) 6(55) 1(9) 2(18) 5(45) 4(36) Poliomyelitis 1(11) 6(67) 3(33) 3(33) 3(33) 5(56) FSHD 3(43) 4(57) 3(43) 2(29) 1(14) 2(29) Congenital 2(33) 5(83) 2(33) 1(17) 2(33) 0(0)

37 Table 3. Initial respiratory status. Diagnosis groups no. (%) Blood gases in free respiratory Vital capacity PaO2 (mmhg) PaCO2 (mmhg) ph CO2 total (mmol/l) Steated VC (ml) Supine VC (ml) DM1 75.8± ± ± ± ± ±876.0 Dystrophinopaty 83.0± ± ± ± ± ±322.4 Nerve and spinal 70.9± ± ± ± ± ±841.1 Limb girdle 76.4± ± ± ± ± ±396.3 Other myopathy 80.4± ± ± ± ± ±917.3 SMA 74.1± ± ± ± ± ±677.5 Poliomyelitis 71.1± ± ± ± ± ±280.8 FSHD 66.0± ± ± ± ± ±287.9 Congenital 81.3± ± ± ± ± ±885.8

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39 Ventilation duration 50 % < 4h / 24 h and 10 (15%) no use of ventilation

40 13 patients 10 wheelchair Severe respiratory impairment Improvement of symptoms of arterial blood gazes of quality of life? Low Compliance 3 died Nugent et al., CHEST 2002

41 Ogna et al., JIVD 2015

42 Table 5. Dead in the Study Cohort.* Follow-up Rate. (%) Diagnosis Groups no. 3 yr 5 yr DM1 78 9/63 (14) 18/55 (33) Dystrophinopaty 61 5/56 (9) 10/52 (19) Nerve and spinal 36 8/29 (28) 10/28 (36) Limb girdle 25 3/25 (12) 4/25 (16) Other myopathy 22 4/21 (19) 6/21 (29) SMA 11 3/9 (33) 3/9 (33) Poliomyelitis 9 0/9 (0) 0/8 (0) FSHD 7 1/7 (14) 2/7 (29) Congenital 6 0/5 (0) 0/5 (0) * Total diagnosis groups in Table. ratio represents the number of patients who died on the number of patients follow-up this percentage is not taken into account for the lost patients

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44 p=0,01

45 Mexiletine Procainamide Logigian et al., Neurology 2010, Fitting, Am Rev Respir Dis 1989

46 Dysney; Drug Discov Today 2013

47 Home ventilation in DM1 A real challenge to achieve Optimal criteria for ventilation in DM1? Optimal criteria for efficacy? For what benefit in term of quality of life and survival? Controlled studies? Impact of new therapeutics?