Adult-Onset Nemaline Myopathy Presenting As Respiratory Failure

Case Reports

Adult-Onset Nemaline Myopathy Presenting as Respiratory Failure

Emer Kelly MD, Michael A Farrell MB FRCPI FRCPC FRCPath, and Noel G McElvaney MB BCh BAO FRCPI

Nemaline myopathy is a rare congenital myopathy that generally presents in childhood. We report a case of a 44-year-old man who presented with severe hypoxic hypercapnic respiratory failure as the initial manifestation of nemaline myopathy. After starting noninvasive ventilation, his pulmonary function test results improved substantially, and over the 4 years since diagnosis his respiratory function remained stable. There are few reported cases of respiratory failure in patients with adult-onset nemaline myopathy, and the insidious onset in this case is even more unusual. This case highlights the varied presenting features of adult-onset nemaline myopathy and that noninvasive ventilation improves respiratory function. Key words: nemaline myopathy, respiratory failure. [Respir Care 2008;53(11):1490–1494. © 2008 Daedalus Enterprises]

Introduction had noted some mild lower-extremity weakness, which occasionally caused him to fall. He noted difficulty in Nemaline myopathy is a rare congenital myopathy that moving his toes appropriately. He still walked approxi- can have a varied presentation. Despite the congenital na- mately 1 km each morning but noted difficulty climbing ture of nemaline myopathy, it may not present until adult- hills or stairs, due to the weakness. This progressed to hood. Its rarity and diverse symptoms can make it difficult involve the upper limbs, and he had some difficulty ab- to diagnosis. We saw a former athlete who presented with ducting both arms and found it difficult to lift objects off subacute respiratory insufficiency in middle age. Nonin- a table. By the time of presentation to the respiratory clinic vasive ventilation (NIV) improved his symptoms and sta- this had progressed to involve more proximal muscles, in bilized his respiratory function. particular the hip flexors. He had only noticed involvement of his shoulder girdle very recently. Case Report

A 44-year-old man was referred by his family doctor to SEE THE RELATED EDITORIAL ON PAGE 1434 the respiratory clinic for cough, dyspnea on climbing stairs, and reduced energy, for 8–12 weeks. The cough and shortness of breath were present prior to On detailed history, the patient stated that he had noted 4 months preceding respiratory review, and he had noted no weakness until 6 years ago, at age 38 years. Initially he some problems with his breathing over the last 6 years. This had been characterized by a very insidious onset of dyspnea, about which he was slow to comment. He had Emer Kelly MD is affiliated with the Department of Respiratory Re- not suffered respiratory infections. He did note morning search, Michael A Farrell MB FRCPI FRCPC FRCPath is affiliated with headaches, daytime somnolence, and decreased concentra- the Department of Neuropathology, and Noel G McElvaney MB BCh tion in the last year. BAO FRCPI is affiliated with the Department of Respiratory Medicine, He was the son of healthy, non-consanguineous white Beaumont Hospital, Dublin, Ireland. parents. He had 6 siblings, 5 of whom were alive and well. The authors report no conflicts of interest related to the content of this One of his brothers was a smoker and had respiratory paper. difficulties thought to be related to chronic obstructive Correspondence: Emer Kelly MD, Department of Respiratory Research, pulmonary disease. There was no family history of neu- Royal College of Surgeons in Ireland (RCSI), Smurfit Building, Beau- romuscular disease. Our patient’s birth had been a full- mont Hospital, Dublin 9, Ireland. E-mail: [email protected]. term normal vaginal delivery and his mother did not note

1490 RESPIRATORY CARE • NOVEMBER 2008 VOL 53 NO 11 ADULT-ONSET NEMALINE MYOPATHY PRESENTING AS RESPIRATORY FAILURE any respiratory or feeding difficulties in his neonatal period. His motor and speech development were normal and he had met the developmental milestones within expected norms. He described a normal childhood, in which he was able to run and play games without any limitations. He had played competitive football until his early thirties. On initial examination he was noted to have cyanosis and chemosis. On respiratory examination he had poor chest expansion (only 3 cm), reduced air entry, crackles in the base of the left lung, reduced tidal percussion, and marked orthopnea. Cardiovascular examination was unre- markable. Neurologic examination, including cranial nerve examination and fundoscopy, was normal. No facial weakness or fatigability was noted. There was bilateral muscle wasting at the superior head of the pectoralis major, the dorsal rotator cuff, and, to a lesser degree, the biceps and triceps. There was moderate and symmetrical weakness in: shoulder abduction and adduction; elbow flexion and extension; Fig. 1. The flow-volume waveform shows a classic restrictive pat- wrist flexion and extension; finger flexion, extension, and tern, with mainly extrathoracic involvement, consistent with neu- abduction/adduction; hip flexion, extension, and abduc- romuscular problems. tion/adduction; knee flexion and extension; ankle dorsi- flexion; and plantar flexion and inversion/eversion. Coor- Table 1. Pulmonary Function Test Results dination was normal throughout. Reflexes were present but reduced throughout. Proprioception, vibration, temper- Reference Measured % ature, pain, and light touch were normal in the upper and Value Value Predicted lower limbs. Gait examination revealed a high-stepping FVC (L) 4.65 1.53 33 gait with bilateral foot drop. FEV1 (L) 3.80 1.28 34

Blood tests showed polycythemia (hemoglobin 17.8 g/ FEV1/FVC 0.79 0.84 106 dL) but normal creatine kinase, aldolase, erythrocyte sed- FEF25-75 (L/s) 4.22 1.57 37 imentation rate, C-reactive protein, serum protein electro- MEF (L/s) 9.06 4.72 52 phoresis, antinuclear antibody, rheumatoid factor, anti- TLC (L) 6.98 3.20 46 neutrophilic cytoplasmic antibody, thyroid function, RV (L) 2.04 1.65 81 vitamin B12, and folate. Arterial blood gas analysis re- RV/TLC 0.31 0.52 167 vealed hypoxic hypercapnic respiratory failure: pH 7.31, FRC (L) 3.42 2.01 59 MIP (cm H O) ND 33 NA P 80 mm Hg, P 40 mm Hg, and HCO 39 mmol/L. 2 aCO2 O2 3 Sniff nasal inspiratory ND 38 NA Those values indicate severe hypoxia and hypercapnia. pressure (cm H2O) The elevated HCO3 indicates a compensatory metabolic Sniff nasal expiratory ND 94 NA alkalosis. However, that pH is low, which indicates only pressure (cm H2O) partial compensation and an element of acute-on-chronic ϭ respiratory failure. FVC forced vital capacity FEV1 ϭ forced expiratory volume in the first second Pulmonary function tests showed a classic restrictive FVC ϭ forced vital capacity FEF25-75 ϭ forced expiratory flow during the middle half of the forced vital capacity pattern, with mainly extrathoracic involvement, consistent maneuver with neuromuscular problems (Fig. 1 and Table ). MEF ϭ maximum expiratory flow TLC ϭ total lung capacity Electromyogram showed spontaneous activity in most RV ϭ residual volume of the muscles tested, along with the predominantly short FRC ϭ functional residual capacity MIP ϭ maximum inspiratory pressure and low-amplitude motor action potentials, which suggest ND ϭ no data available myopathy. He also had high-amplitude long action poten- NA ϭ not applicable tials, which is a mixed result that can sometimes be consistent with inflammatory myopathies. There was no neu- rophysiologic evidence of a multifocal motor neuropathy or demyelinating process. sistent with nemaline myopathy. Electron microscopy Left quadriceps and left triceps muscle biopsies (Fig. 2) (Fig. 3) showed dense sarcoplasmic bodies originating from showed multiple subsarcolemmal dark nemaline rods con- Z-bands.

RESPIRATORY CARE • NOVEMBER 2008 VOL 53 NO 11 1491 ADULT-ONSET NEMALINE MYOPATHY PRESENTING AS RESPIRATORY FAILURE

and FEV1/FVC increased to 0.92. His pulmonary function test results continued to be consistent with a restrictive defect. His maximum inspiratory pressure at the time of

diagnosis was 33 cm H2O, and it was 31 cm H2O at recent follow-up, 5 years after diagnosis. His maximum expira-

tory pressure has been in the range 86–100 cm H2O (normal value for his age approximately 130 cm H2O) over all the years of follow-up. In the first few months after diagnosis he required supplemental oxygen. Following initial treatment with NIV plus oxygen for 3 months, oximetry indicated that supplemental oxygen was no longer required, and he has not used supplemental oxygen since then. His arterial blood gas values at 3 months were pH 7.41, P 40 mm Hg, P CO2 aO2 107 mm Hg, and HCO3 24.5 mmol/L while breathing Fig. 2. Biopsy of the left quadriceps muscle (transverse section room air. There was no longer evidence of carbon dioxide with Gomori’s trichrome stain) shows multiple subsarcolemmal retention, and the acidosis had corrected. He no longer had dark nemaline rods (arrows) consistent with nemaline myopathy. orthopnea but always used NIV during sleep or any other extended period of lying down. The daytime somnolence, morning headache, and decreased concentration had re- solved. He performed the 10-m shuttle-walk test (an objective test of functional exercise capacity and index of disability for patients with chronic airflow limitation) within the first month of diagnosis, again after starting NIV, and again after 6 months of NIV. His 10-m shuttle-walk distance improved from level 7 (360 m) with a Borg breathlessness score of 7 (very severe) to level 8 (440 m) with a Borg breathlessness score of 3 (moderate). Originally he had desaturated to 85%, but on his follow-up tests he no longer desaturated, and the only limitation to his exercise was that his limb weakness made him unable to increase propulsion speed. Recent physiotherapy evaluation found no change in muscle strength over the last 5 years, which indicates no further progression of the condition.

Discussion

Fig. 3. Electron microscopy of quadriceps muscle shows dense Nemaline myopathy is a rare congenital myopathy that sarcoplasmic bodies originating from Z-bands. generally presents in childhood. In a series of 143 cases, presentation was typical congenital, severe congenital, in- We commenced NIV via oronasal mask, with a pres- termediate congenital, childhood-onset, and adult-onset in sure-targeted mode, and titrated the settings based on over- 46%, 16%, 20%, 13%, and 4%, respectively.1 Weakness night oximetry. He tolerated the NIV very well, and he mostly affects the facial muscles, flexors of the neck and stabilized at NIV inspiratory pressure of 10 cm H2O and trunk, dorsiflexors of the feet, and extensors of the toes. expiratory pressure of 4 cm H2O. He was discharged and The distal limb muscles and limb-girdle muscles are weaker seen on an out-patient basis. During a later admission to than the proximal limb muscles. Sporadic late-onset nema- review NIV settings, inspiratory pressure was titrated up to line myopathy is uncommon.

16 cm H2O and expiratory pressure to 6 cm H2O. His In making the diagnosis of nemaline myopathy, clinical pulmonary function test results improved after 3 months of suspicion is the first step. Creatine kinase may be normal NIV. Over the 5 years since diagnosis his respiratory func- or slightly elevated. Electromyography may show myo- tion has remained stable. FVC improved to 2.25 L (51% of pathic changes such as action potentials of small ampli- 2 predicted), FEV1 increased to 2.07 L (58% of predicted), tude and short duration, but those changes are not spe-

1492 RESPIRATORY CARE • NOVEMBER 2008 VOL 53 NO 11 ADULT-ONSET NEMALINE MYOPATHY PRESENTING AS RESPIRATORY FAILURE cific. Diagnosis is confirmed with muscle biopsy, which line myopathy.14 Another case report was of a patient with shows characteristic rod bodies, best seen with modified mild nemaline myopathy and sleep hypoventilation due to Gomori trichrome staining. a mutation in the skeletal muscle ␣-actin gene.15 That The initial differential diagnosis in our patient included 39-year-old woman had a previous diagnosis of nemaline many causes of neuromuscular respiratory failure, includ- myopathy when she developed life-threatening respiratory ing demyelinating neuropathy, an unusual myopathy, or failure following a pneumonia. Kudou et al described 2 mitochondrial disease. Motor neuron disease was consid- cases of congenital nemaline myopathy that presented with ered, but the absence of wasting and symmetry was against respiratory failure: one had muscle weakness since birth, that diagnosis. Myasthenia gravis was also considered, but and the other presented with slowly progressing respira- there were no bulbar symptoms. Muscle biopsy provided tory failure.16 the definitive diagnosis of nemaline myopathy. Our 44-year-old male patient presented with minimal Nemaline myopathy derives its name from the charac- clinical symptoms but severe hypoxic hypercapnic respi- teristic rod bodies in muscle, which appear threadlike in ratory failure as the initial manifestation of adult-onset longitudinal section. Engel first described sporadic late- nemaline myopathy. Presentation with respiratory failure onset nemaline myopathy in 1966, in 2 patients.3 Since is exceptionally rare in nemaline myopathy. Previous pub- then much has been discovered about nemaline myopathy lished cases often had either preexisting nemaline myop- and its complex genetics. athy or known muscle weakness from birth.15,16 Two case Nemaline myopathy is clinically and genetically heter- reports have described adult-onset nemaline myopathy that ogeneous.4 Mutations in 5 different genes that code for presented with respiratory failure.14,16 Our patient’s respi- sarcomeric proteins have been reported to cause nemaline ratory function initially improved and then stabilized with myopathy: the nebulin gene,5 ␣-tropomyosin gene,6,7 ␤-tro- nocturnal NIV and has remained stable for the 5 years pomyosin gene,8 ␣-actin gene,9,10 and the gene that en- since diagnosis. codes slow skeletal muscle troponin T.11 The 70th Inter- The reason(s) for our patient’s improvement and stabi- national Workshop on Nemaline Myopathy in 1999 reached lization is unclear. Long-term mechanical ventilation has consensus on 5 categories of nemaline myopathy:12 severe an established role in the management of ventilatory fail- congenital (which is the typical form); intermediate con- ure due to neuromuscular disease, having gained credence genital; mild childhood-onset or juvenile-onset; adult-on- during the polio myelitis epidemics in the middle of the set forms; and other forms. Although the adult-onset forms last century.17 It was not until the early 1980s that NIV via have the inclusion criterion that onset is as an adult, age of mask was pioneered by Rideau et al18 in France, and sub- onset is clearly not always the same as age at presentation, sequently by Bach et al19 in the United States. Large- thus careful history-taking and scrutinizing of clinical notes cohort studies found that NIV can extend survival in pa- are necessary to determine age of onset in individual cases. tients with nonprogressive conditions, such that these After a normal childhood and appropriately reaching de- individuals are likely to have a nearly normal life expect- velopmental milestones, our patient developed muscle ancy.20-22 The benefits of nighttime NIV are sustained dur- weakness in adult life, so his was adult-onset nemaline ing the day. Several possible mechanisms have been con- myopathy. sidered. Hill suggested that NIV may work by improving Nemaline myopathy with respiratory symptoms is very ventilatory mechanics, resting fatigued respiratory mus- uncommon. In 2005, Chahin et al described observations cles and thereby improving strength and endurance, or 23 and long-term follow-up in 14 patients with sporadic late- enhancing ventilatory sensitivity to CO2. Some of the onset nemaline myopathy, examined at the Mayo Clinic initial improvement in our patient may have been due to between 1975 and 2003.13 A conclusion of that study was reversal of atelectasis, which is likely to be present be- that sporadic late-onset nemaline myopathy presents with cause of chronic hypoventilation. Reversing the micro- subacutely evolving weakness after age 40. The weakness atelectasis probably accounts for the improved FVC. was predominantly proximal in 11 patients, equally prox- After intermittent ventilation, Annane et al found: in- imal and distal in 3 patients, and asymmetric in 4 patients. creased daytime P ; decreased P and total bicarbon- aO2 aCO2 The weakness began in the arms in 6 patients, and in ate; unchanged vital capacity, total lung capacity, maxi- 8 patients the arms were more severely affected than the mum inspiratory or expiratory pressure, or alveolar-arterial legs. One patient had head-drop and 2 patients also had oxygen difference; decreased apnea-hypopnea index and substantial abdominal-muscle weakness. Six patients had time spent with arterial oxygen saturation Ͻ 90%; in- dysphagia. Sensory examination was normal in all the pa- creased sleep efficiency and mean arterial oxygen satura- tients. No patient in that study presented with respiratory tion; and significantly increased ventilatory response to complaints. CO .24 The reduction in P after NIV correlated solely 2 aCO2 Falga`-Tirado et al reported on a 49-year-old woman with the increase in the slope of ventilatory response to the ϭϪ ϭ who presented with respiratory insufficiency from nema- CO2 curve (r 0.68, P .008). They concluded that

RESPIRATORY CARE • NOVEMBER 2008 VOL 53 NO 11 1493 ADULT-ONSET NEMALINE MYOPATHY PRESENTING AS RESPIRATORY FAILURE improvement of daytime hypoventilation with nocturnal patients with actin myopathy and nemaline myopathy. Nat Genet NIV may be from an adaptation of the central chemore- 1999;23(2):208-212. ceptors to the reduction of profound hypercapnia during 10. Ilkovski B, Cooper ST, Nowak K, Ryan MM, Yang N, Schnell C, et al. Nemaline myopathy caused by mutations in the muscle ␣-skele- sleep, or from better sleep quality. Further work found that tal-actin gene. Am J Hum Genet 2001;68(6):1333-1343. patients who used NIV for Ͼ 4 h per night had signifi- 11. Johnston JJ, Kelley RI, Crawford TO, Morton DH, Agarwala R, cantly improved hypercapnic ventilatory response and Koch T, et al. A novel nemaline myopathy in the Amish caused by P after 3 months, whereas in patients who averaged a mutation in troponin T1. Am J Hum Genet 2000;67(4):814-821. aCO2 Ͻ 4 h of NIV per night, chemosensitivity and arterial 12. Wallgren-Pettersson C, Laing NG. Report of the 70th ENMC Inter- national Workshop: nemaline myopathy. June 11th-13th, 1999, Naar- blood gas values returned to baseline at 3 months, after den, The Netherlands. Neuromuscul Disord 2000;10(4-5):299-306. initial improvement at 5 days.25 A Cochrane review from 13. Chahin N, Selcen D, Engel A. Sporadic late onset nemaline myop- Annane et al, however, concluded that, although the evi- athy. Neurology 2005;65(8):1158-1164. dence is directionally consistent, more randomized con- 14. Falga`-Tirado C, Pe´rez-Pema´n P, Ordi-Ros J, Bofill JM, Balcells E. trolled trials of long-term nocturnal NIV in neuromuscular Adult onset nemaline myopathy presenting as respiratory insufficiency. Respiration 1995;62(6):353-354. 26 disease are required. 15. Jungbluth H, Sewry CA, Brown SC, Nowak KJ, Laing NG, Wall- Our patient made a rare presentation of a very uncom- gren-Pettersson C, et al. Mild phenotype of nemaline myopathy with mon condition. The case highlights the broad differential sleep hypoventilation due to a mutation in the skeletal muscle ␣-ac- diagnosis of dyspnea, the varied presentation of adult- tin (ACTA1) gene. Neuromusc Disord 2001;11(2):35-40. onset nemaline myopathy, and the potential respiratory- 16. Kudou M, Kobayashi Y, Yamashita K, Kita H, Yasuba H, Hamada K. [Two cases of nemaline myopathy diagnosed after episodes of function benefit of NIV. respiratory failure.] Nihon Kokyuki Gakkai Zasshi 2006;44(6):474- 478. Article in Japanese. REFERENCES 17. Simonds AK. Recent advances in respiratory care for neuromuscular disease. Chest 2006;130(6):1879-1886. 1. Ryan MM, Schnell C, Strickland CD, Shield LK, Morgan G, Ian- 18. Rideau Y, Janoski LW, Grellet G. Respiratory function in the mus- naccone ST, et al. 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