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Progressive external ophthalmoplegia

Progressive external ophthalmoplegia is a disorder of the mitochondria. It is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles (ophthalmoplegia) and exercise intolerance. more...

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Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. Both autosomal dominant and autosomal recessive inheritance can occur; autosomal recessive inheritance is usually more severe.

It is usually diagnosed by neurologists. There is no proven treatment; experimental agents such as coenyzme Q10 may provide benefit.


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Respiratory failure revealing mitochondrial myopathy in adults
From CHEST, 3/1/92 by Didier Cros

A number of neuromuscular disorders may be complicated by respiratory insufficiency, but ventilatory failure is rarely the presenting manifestation.[1,2] There are reports of respiratory failure revealing acid maltase deficiency in adults[3] but not adult-onset mitochondrial myopathy. Our cases represent a new clinical presentation of mitochondrial disease to add to the already complex clinical patterns characteristic of these disorders. Mitochondrial myopathy should therefore be ruled out in respiratory failure thought to be due to dysfunction of the neuromuscular system.

The spectrum of clinical manisfestations in mitochondrial disease is extremely broad, from pure muscle disease to complex multisystem disorders. The manifestations confined to striated muscle vary greatly and may include myalgia, exercise intolerance, proximal muscle weakness, external ophthalmoplegia, or facioscapulohumeral syndrome.[4] The clinical course is also extremely variable, from rapidly progressive to static deficits, with even remitting forms, as in the benign infantile mitochondrial myopathy due to reversible cytochrome oxidase deficiency.[5] Mitochondrial multisystem disorder predominantly involve brain and muscle. Amomg them, several syndromes have been recognized: the Kearns-Sayre syndrome.[6] myoclonic epilepsy with ragged red fibers (MERRF),[7] and a syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).[8] A mitochondrial disease affecting muscle and kidney has also been reported in association with cytochrome c oxidase deficiency.[8]

Many biochemical defects have been identified in mitochondrial disease.[9] However, there is considerable variability in the clinical syndromes associated with any one of these defects. As research in the biochemistry and the molecular genetics of these disorders progresses,[10,11] new classifications will undoubtedly be developed; however, at this time, clinicians must be well aware of the protean manifestations of mitochondrial disease. We report herein a hitherto underscribed presentation of mitochondrial disease in adults, isolated respiratory failure.



A 56-yr-old black man had a 15-yr history of recurrent respiratory difficulties attributed to emphysema. During those years, he had made several visits to emergency rooms but had never been admitted. The patient had been receiving prednisone (10 mg daily) for a year at the of admission. There was no personal or family history suggesting neuromuscular disease.

The patient developed increasing shortness of breath over a 3-wk period, which eventually culminated in acute respiratory failure. On admission, arterial blood gas analysis show the following: pH of 7.36, [PaCO.sub.2] of 59 mm Hg, and [PaO.sub.2] of 48 mm Hg on [FIo.sub.2] of 0.21; and P(A-a) [O.sub.2] of 32 ,, Hg, suggesting chronic respiratory failure and hypoxemia due probably to a combination of V/Q mismatching and alveolar hypoventilation, The patient was treated with intravenous aminophylline, epinephrine, and steroids. Despite aggressive therapy, his blood gas levels continued to deteriorate; he was intubated, and ventilatory assistance was begun.

After 3 wk, the patient could not been weaned from the ventilator despite multiple attempts. He was on maximum doses of brochodilators. There were no signs of infection or abundant respiratory secretions. There were no electrolyte, metabolic, hemodynamic, or nutritional abnormalities to explain the failure to wean. On the ventilator and CPAP of 5 cm [H.sub.2.O] with [FLo.sub.2] of 0.25, arterial blood gas analysis showed a pH of 7.19, [PaCO.sub.2] of 78 mm Hg, and [PaO.sub.2] of 168 mm Hg, suggesting alveolar hypoventilation with adequate oxygenation. At this point a neurology consultation was obtained to evaluate a neuromuscular cause of this failure to wean. No ptosis or limitation of extraocular movements was noted. There were mild proximal muscle weakness and wasting, both of recent onset, which were thought to be iatrogenic (steroid therapy). The tendon reflexes were normal. No cerebellar signs of long tract involvement were noted. Findings from the funduscopic examination were unremarkable.

Relevant laboratory results included negative ANA and rheumatoid factor, mildly elevated serum creatine kinase (CK) (three times normal), normal serum lactic acid (less than 0.5 mEq/L), normal results on thyroid function tests, and mildly elevated CSF protein (0.59 g/L) with 1 cell per milliliter. A CT scan of the head was normal. Conduction studies of the peroneal, tibial, median, and sural nerves were normal. F responses in the peroneal, tibial, and median nerves were normal as well. Needle electromyography of the deltoid, biceps, vastus lateralis, and anterior tibia muscles was unremarkable. Repetitive stimulation of the median nerve showed no decremental response in the abductor policis brevis muscle. A muscle biopsy was obtained from sternocleidomastoid muscle at the time of tracheostomy.

The patient remained dependent on the ventilator for 5 mo. He was eventually extubated but died a week late. Permission for autopsy was not granted.


A 70-yr-old black woman initially admitted to the orthopedic service for an elective total knee replacement. As part of the preoperative evaluation, she was noted to have markedly abnormal arterial blood gas levels (pH of 7.33, [PaCO.sub.2] of 76 mm Hg, and [PaO.sub.2] of 34 mm Hg on [Flo.sub.2] of 0.21 with normal P(A-a)[O.sub.2] of 25 mm Hg). This suggested alveolar hypoventilation as the cause of her hypoxemia and respiratory acidosis. The patient was in no respiratory distress and was able to walk two city blocks without shortness of breath. She never smoked and had never suffered from any lung or neuromuscular disease. She had a history of hypertension for many years, with evidence of a hypertensive cardiomyopathy, and had had a bout of congestive heart failure the previous year. The patient was receiving digoxin (Lanoxin), furosemide, prazosin, and tocainide hydrochloride. On examination, her blood pressure was normal, her lungs were clear, and she showed no signs of congestive heart failure. The chest x-ray film was normal. Pulmonary function studies performed then revealed an FVC of 1.53 L (77 percent of predicted value), [FEV.sub.1] of 1.10 L/s (70 percent of predicted value), and [FEV.sub.1]/FVC of 72 percent. This suggested a mild restrictive ventilatory impairment. The surgery was cancelled; and the patient was discharged, and further outpatient work-up was arranged.

The patient was lost to follow-up until May 1987, when she presented to the emergency room with a 2-day history of altered mental status, shortness of breath, and fever. She was lethargic and had signs of a pneumonia. Her arterial blood gas analysis this time showed a ph of 7.32, [PaCO.sub.2] of 88 mmHg, and [PaO.sub.2] of 28 mm Hg on [Flo.sub.2] of 0.21, and P(A-a)[O.sub.2] of 17 mm Hg, again suggesting that alveolar hypoventilation was the cause of her hypoxia and respiratory acidosis. A CT scan of the head showed cerebral atrophy. A chest x-ray film showed an infiltrate in the left lower lobe. A lung V/Q scan was interpreted al slow probability for pulmonary emboli.

The acute episode required intubation and ventilatory assistance. The patient could not be weaned from the ventilator for 6 wk despite multiple attempts. The pneumonia had cleared. There were no electrolyte, metabolic, or nutritional abnormalities to explain the failure to wean. A neurologic consultation was obtained to assess the possibility of neurogenic ventilatory failure. Neurologic examination revealed absence of ptosis, full extraocular movements, and an absence of cerebellar signs, long tract dysfunction, or muscle weakness. Tendon reflexes were normal throughout. An endrophonium test was normal. Mental status and the results of neurologic examinations performed at some distance from the acute episode were entirely normal. Findings from a complete ophthalmologic evaluation were normal.

Laboratory investigations revealed normal levels of serum CK, glucose, BUN, lactate and pyruvate. The results of thyroid function tests were normal. Stimulation of the phrenic nerve at the neck elicited normal responses bilaterally. Motor conduction of the peroneal and median nerves (with F response studies) and sensory conduction of the median and sural nerves were normal. Repetitive stimulation of the spinal accessory nerve showed no decrement of the compound response evoked in the upper trapezius muscle. Needle electromyography revealed brief, low-amplitude, and polyphasis motor unit potentials in the cervical and lumbar paraspinal muscles and in the vastus lateralis muscles bilaterally, with normal recruitment pattern, suggesting primary muscle disease. A biopsy of the deltoid muscle was obtained.

The patient's respiratory function improved gradually, and artificial ventilation was discontinued 6 wk after admission. The patient was followed up to a year after this episode. She had returned to her usual of health and had developed no additional respiratory problem.


In both cases, the muscle specimen was processed with a battery of routine histochemical reactions and embedded in epoxy resin (Epon) for electron microscopy.


In the sternomastoid muscle, light microscopy revealed normal fascicular architecture, connective tissue, and blood vessels; there was no inflammation , fiber necrosis, or regeneration. There was increased variability in muscle fiber size. The myonuclei were normal in number and location. Many fibers exhibited purplish subsarcolemmal deposits with the modified Gomori trichrome stain, the typical appearance of ragged red fibers. The NADH-tetrazolium reductase reaction revealed alterations of the normal intermyofibrillary network with dense, mostly subsarcolemmal deposits of the reaction product (Fig 1). The reactions for myofibrillar ATPase at different pH levels showed the normal pattern of fiber type distribution. The ragged red fibers were mostly type 1. Electron microscopy revealed large subsarcolemmic and intermyofibrillar mitochondrial aggregates. Some mitochondria exhibited paracrystalline inclusions. Concentric laminated bodies were seen in several fibers.


Light microscopic examination of a deltoid muscle biopsy showed normal fascicular architecture, connective tissue, and intramuscular vessels without inflammation. Increased variability in muscle fiber size was noted, but no necrosis or regeneration was seen. The myonuclei were normal. Many fibers exhibited subsarcolemmal deposits (Fig 2) which stained purplish with the modified Gomori trichrome stain. Many fibers contained nemaline bodies (Fig 3). The NADH-tetrazolium reductase reaction demonstrated marked subsarcolemmal and intermyofibrillar accumulation of the reaction product. The ATPase reactions showed the normal distribution of the two fiber types. Electron microscopy revealed multiple subsarcolemmal and intermyofibrillar mitochondrial aggregates without intramitochondrial inclusions. Z-band streaming, nemaline body formation, and areas of focal disorganization of the myofibrillar pattern were seen in many fibers.


The activity of the following enzymes was measured in crude extracts prepared from frozen muscle as previously described:[12] cytochrome oxidase; succinate-cytochrome c reductase; rotenone-sensitive NADH-cytochrome c reductase; citrate synthase; NADH dehydrogenase; and succinate dehydrogenase.

Patient 1 had cytochrome oxidase (complex 4) deficiency with residual enzyme activity of 29 percent of mean control value. Immunotitration of the enzyme protein of the enzyme-linked immunosorbent assay (ELISA) using polyclonal antibodies against cytochrome oxidase purified from human heart[13] showed a normal amount of immunologically reactive protein (data not shown). Patient 2 had an isolated defect of succinate-cytochrome c reductase activity, suggesting complex 2 deficiency (Table 1).



In both cases, neuromuscular disease was considered a possible cause of respiratory insufficiency, as the patients could not be weaned from the respirator after weeks of ventilatory assistance. In patient 1, mild emphysema without any superimposed pulmonary infection was not sufficient to explain protracted ventilatory failure. In patient 2, there was no preexisting lung disease or ongoing parenchymal alteration to explain respiratory failure. Although this patient had been treated for congestive heart failure a year earlier, there was no sign of cardiac decompensation during this episode. In both cases the most common neuromuscular causes of acute respiratory difficulties, the Guillain-Barre syndrome and myasthenia gravis, had been ruled out by multiple nerve conduction studies and late responses and by edrophonium test or repetitive stimulation of peripheral nerves, respectively. A muscle biopsy was performed in patient 1 because of mild proximal weakness and in patient 2 because the EMG showed myopathic features.

Muscle biopsy was the diagnostic procedure of choice to provide an answer without undue delay. It is important to stress that sections should be stained with the modified Gomori trichrome stain to easily identify the ragged red fibers.[14] In patient 2, the biopsy findings included ragged red fibers and a large number of nemaline bodies in many muscle fibers. Nemaline bodies may be seen in addition to other abnormalities in a number of neuromuscular diseases, including mitochondrial myopathy.[15,16] Although nemaline bodies were very abundant in patient 2's muscle biopsy, the enzyme abnormalities noted on biochemical analysis suggest that the nemaline bodies were an epiphenomenon to the mitochondrial myopathy.

The other laboratory tests were of limited diagnostic value. The serum CK concentration was elevated in one case only, which drew attention to the possibility of muscle disease; serum pyruvate and lactate levels were normal in both patients; needle EMG revealed no spontaneous activity in either case and some brief, polyphasic motor unit potentials suggesting myophathy in case 2, which is in agreement with the relative paucity of EMG findings in mitochondrial disease.[14,16,17] Our cases suggest that mitochondrial myopathy should be considered and a muscle biopsy performed once the common causes of neurogenic respiratory failure have been excluded, even if serum CK assay, serum lactate levels, and EMG are unrevealing.

The alterations of enzymatic activities indicated partial complex 4 deficiency in patient 1 and complex 2 deficiency in patient 2. Studies of series of patients with complex 4 deficiency indicate that the corresponding phenotypes are variable, from pure myopathy to central nervouse system disease.[9] Complex 2 deficiency has been suggested but not clearly documented in a few patients, and the clinical phenotypes associated with this biochemical defect remain to be defined.[9] The reasons for the clinical heterogeneity of mitochondrial diseases are unclear, and further progress in molecular genetics will undoubtedly lead to a better understanding of these biochemical defects and of their consequences.[10]

Two pathophysiologic mechanisms could lead to respiratory failure in these patients: abnormality of the respiratory drive due to dysfunction of the respiratory centers in the brain stem, on the one hand; or weakness or fatigue of the inspiratory muscles, on the other hand. Caroll and associates[18] found decreased ventilatory responses to hypoxia and hypercapnia in four patients with opthalmoplegia and mitochondrial disease. Similar data were recently reported in several patients with mitochondrial myopathy and recurrent bouts of respiratory insufficiency.[19] Caroll and colleagues[18] pointed out that although dysfunction of the medullary respiratory centers was unlikely in the absence of clinical signs of damage to medullary structures, the reduced ventilatory response to hypoxia and hypercapnia seemed out of proportion to the mild degree of weakness demonstrated on pulmonary function tests (PFTs); however, it is essential to distinguish muscle weakness from muscle fatigue. Weakness is the failure to develop the required or expected force, whereas fatigue is the failure to sustain it.[20] Mitochondrial disease is often accompanied by myopathy causing marked fatigability with only mild weakness.[15,21,22] Pathologic fatigue with moderate weakness of the respiratory muscles could conceivably have resulted in moderately altered PFTs, since spirometry requires only a phasic effort, whereas hypoxia and hypercapnia, which generate a sustained increase in work load, may have unmasked fatigability. Fatigue is a reversible phenomenon, yet its electrophysiologic manifestations may persist for several days following the triggering episode.[23,24] Fatigue of the respiratory muscles can be assessed by physiologic methods.[24,25] Although we did not perform this type of evaluation in our patients , we suggest that in future studies the respiratory muscles should be carefully tested for low-frequency fatigue[23-25] to distinguish between failure of the central drive and fatigue of the effector.

Both patients were eventually weaned from the ventilator. Assuming that muscle fatigue was a factor in their respiratory failure, ventilatory assistance provided the necessary conditions for their muscles to recover from that state. An important question concerning the long-term management of these patients arises: should the weakened and fatigable respiratory muscles be treated with rest (for example, ventilatory assistance at night with a cuirass ventilator), or should they be gradually trained (ie, breathing against resistance) to augment their endurance?[24] Of note is the fact that some reports indicate that myopathic muscle is indeed trainable.[26,27]


[1] Aldrich TK, Aldrich MS. Primary muscle disorders. In: Kamholz SL, ed. Pulmonary aspects of neurologic diseases. New York: PMA Publishing Corp, 1987:85-110 [2] Bennett DA, Bleck TB. Diagnosis and treatment of neuromuscular causes of acute respiratory failure. Clin Neuropharmacol 1988; 11:303-47 [3] Rosenow EC, Engel AG. Acid maltase deficiency in adults presenting as respiratory failure. Am J Med 1978; 64:485-91 [4] DiMauro S, Bonilla E, Zeviani M, Nakagawa M, DeVivo DC. Mitochondrial myopathies. Ann Neurol 1985; 17:521-38 [5] Schon EA, Bonilla E, Lombes A, Moraes CT, Nakase H, Rizutto R, et al. Clinical and biochemical studies on cytochrome oxidase deficiencies. Ann NY Acad Sci 1988; 550:348-59 [6] Berenberg RA, Pellock JM, DiMauro S, Schotland DL, Bonilla E, Eastwood A, et al. Lumping or splitting? "ophthalmoplegia plus" of Kearns-Sayre syndrome? Ann Neurol 1977; 1:37-54 [7] Fukuhara N. Myoclonus epilepsy and mitochondrial myopathy. In: Scarlato G, Cerri C, ed. Mitochondrial pathology in muscle diseases. Padova, Italy: Piccin Medical Books, 1983:88-110 [8] Pavlakis SG, Phillips PC, DiMauro S, DeVivo D, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes: a distinctive clinical syndrome. Ann Neurol 1984; 16:481-88 [9] Zeviani M, Bonilla E, DeVivo DC, DiMauro S. Mitochondrial diseases. Neurol Clinics 1989; 7:123-56 [10] DiMauro S, Bonilla E, Schon EA, Zeviani M, Servidei S, Miranda AF, et al. Mitochondrial disease. In: Rowland LP, Wood DS, Schon EA, DiMauro S, ed. Molecular genetics in diseases of brain, nerve, and muscle. Oxford, England: Oxford University Press, 1989:285-98 [11] Harding AE. The mitochondrial genome: breaking the magic circle. N Engl J Med 1989; 320:1341-43 [12] DiMauro S, Servidei S, Zeviani M, DiRoco M, DeVivo DC, DiDonato S, et al. Cytochrome c oxidase deficiency in Leigh syndrome. Ann Neurol 1987; 22:498-506 [13] Bresolin N, Zeviani M, Bonilla E, Miller RH, Leech RW, Shanske S, et al. Fatal infantile cytochrome c oxidase deficiency: decrease of immunologically detectable enzyme in muscle. Neurology 1985; 35:802-12 [14] Olson W, Engel WK, Walsh GO, Einaugher R. Oculocraniosomatic neuromuscular disease with "ragged-red" fibers. Arch Neurol 1972; 26:193-211 [15] D'Agostino AN, Ziter FA, Rallison ML, Bray PF. Familial myopathy with abnormal muscle mitochondria. Arch Neurol 1968; 18:388-401 [16] Kamienicka S. Myopathies with abnormal mitochondria. Acta Neurol Scand 1976; 55:57-75 [17] Fawcett PRW, Mastaglia FL, Mechler F. Electrophysiological findings including single fiber EMG in a family with mitochondrial myopathy. J Neurol Sci 1982: 53:397-410 [18] Carroll JE, Zwillich C, Weil JV, Brooke MH. Depressed ventilatory response in oculocraniosomatic neuromuscular disease. Neurology 1976; 26:140-46 [19] Barohn RJ, Clanton TL, Sahenk Z, Mendell JR. Recurrent respiratory insufficiency and depressed ventillatory drive complicating mitochondrial myopathy. Neurology 1990; 40:103-06 [20] Wiles CM, Jones DA, Edwards RHT. Fatigue in humans metabolic myopathy. In: Human muscle fatigue (Ciba Foundation symposium 82). London: Pitman Medical, 1981:264-82 [21] Munsat TM, Coleman RF, Pearson CM, Price HM. Mitochondrial myopathy. Neurology 1967; 17:309-19 [22] Rawles JM, Weller RO. Familial association of metabolic myopathy, lactic acidosis and sideroblastic anemia. Am J Med 1974; 56:891-97 [23] Edwards RHT, Hill DK, Jones DA, Merton PA. Fatigue of long duration in human skeletal muscle after exercise. J Physiol (Lond) 1977; 272:769-78 [24] Moxham J, Wiles CM, Newham D, Edwards RHT. Sternomastoid muscle function and fatigue in man. Clin Sci Mol Med 1980; 59:436-68 [25] Grassino A, Macklem PT. Respiratory muscle fatigue and ventilatory failure. Ann Reve Med 1984; 35:625-47 [26] Hagberg JM, Carroll JE, Brooke MH. Endurance exercise training in a patient with central core disease. Neurology 1980; 30:1242-44 [27] Martin RJ, Sufit RL, Ringel SP, Hudgel DW, Hill PL. Respiratory improvement by muscle training in adult-onset acid maltase deficiency. Muscle Nerve 1983; 6:201-03

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