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Ondine's curse in a woman with Leber's hereditary optic neuropathy
  1. M Sadler1,
  2. C M Wiles1,
  3. N Stoodley2,
  4. S J Linnane3,
  5. A P Smith3
  1. 1Department of Neurology, University Hospital of Wales, Cardiff, UK
  2. 2Department of Radiology, University Hospital of Wales
  3. 3Department of Respiratory Medicine, Llandough Hospital, Llandough, UK
  1. Correspondence to:
 Dr M Sadler, Department of Neurology, University Hospital of Wales, Heath Park, Cardiff CF4 4XN, UK;

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Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease of mitochondrial DNA. Several mutation sites have been described. All have been associated with visual loss, but mutations at nucleotide position 11778, 3460, and recently 14484, have also been associated with a multiple sclerosis (MS)-like disease.1–3

We report a woman with undiagnosed LHON who presented with life threatening ventilatory failure.

A 39 year old woman who had had bilateral synchronous severe visual loss to perception of light some two years earlier (see below), was admitted after a two week illness with a purulent cough. She was confined to bed and had received oral antibiotics from her general practitioner. She had a history of chronic headaches but reported no change in their frequency before presentation. On admission she was obtunded with a Glasgow Coma Scale (GCS) score of 3/15. She was hypoventilating, with a severe respiratory acidosis. Arterial blood gas (ABG) showed pH 7.04, Po2 40.9 kPa, Pco2 16.2 kPa, and bicarbonate 22 mmol/l. She was admitted to an intensive care unit and ventilated with later tracheostomy. She was weaned from the ventilator after 31 days and transferred to a ward. Five days later she had a second respiratory arrest requiring further ventilation. She was transferred to another unit 73 days after admission for consideration of long term non-invasive ventilation.

This patient had consumed alcohol to excess and had been admitted previously for benzodiazepine overdose and complications of alcoholic liver disease. Two years earlier she had presented to an ophthalmologist complaining of two months of painless visual loss. Visual acuity was counting fingers bilaterally with central scotomata and absent pupil reactions. Fundoscopy showed bilateral disc oedema, dilated capillaries around the disc margins, and venous pulsations. A CT brain scan was normal, but the patient declined further investigation and a diagnosis of possible toxic amblyopia was made. There was no family history of visual loss. She had three siblings in their 30s, and three children aged 9–12 years who were well.

On examination after transfer (two months after her first respiratory arrest), she was alert, oriented, and breathing room air spontaneously. She was unable to stand and had globally wasted limbs consistent with prolonged illness. She could just perceive light bilaterally and both optic discs looked pale and the pupils were mid-dilated and unreactive. She had a divergent gaze in the primary position with coarse gaze evoked nystagmus in all directions. A jaw jerk was present and she had a mild facial diplegia with intact sensation. She could speak and swallow adequately and was able to cough and hold her breath to command. She had a spastic quadriparesis with grade 4/5 power in the arms but weaker legs and a flicker of movement only at the toes. Anterior abdominal motion during breathing while lying supine was normal. Reflexes were brisk throughout and plantar responses were extensor. There was a subjective sensory abnormality to light touch to the mid-thighs and joint position sense was severely impaired in the feet but intact in the fingers. Breath sounds were quiet and chest excursion limited. She had a distended abdomen with a four finger breadth liver edge palpable and shifting dullness consistent with ascites. ABG on air showed pH 7.31, Po2 6.8 kPa, Pco2 10.5 kPa, and bicarbonate 34.8 mmol/l. Four hours later she became drowsy with a GCS of 8/15. Further ABG revealed pH 7.19, Pao2 5.5 kPa, Pco2 12.8 kPa, and bicarbonate 28.3 mmol/l. After four hours of non-invasive intermittent positive pressure ventilation (NIPPV); ABG on two litres of entrained oxygen showed pH 7.44, Po2 16.4 kPa, Pco2 5.2 kPa, HCO3 27.4 mmol/l. She was subsequently transferred to a ward and treated with NIPPV, on room air, at a pressure of 14 cm H2O overnight and during daytime naps.

An MRI scan of her brain showed symmetrical high signal lesions in the brainstem in the floor of the fourth ventricle at the level of the obex and in the medulla and upper cervical cord (fig 1). The remainder of the brain was spared and in particular there were no lesions suggestive of central pontine myelinolysis or alcoholic damage. CSF examination was unremarkable except for a marginally increased protein at 0.48 g/l. CSF and plasma lactate were both 2.1 mmol/l and oligoclonal bands were not found. DNA was extracted from a blood sample and analysed for mtDNA mutations using standard procedures and was negative at positions 3243, 8344, 8993, 3460, and 14484, but with a homoplasmic mutation at position 11778.

Our patient had the mutation most often associated with MS-like CNS lesions and visual loss in women.1 Brain stem lesions have been previously described in a patient with visual loss, complete ophthalmoplegia, and bilateral tinnitus.3 However, to our knowledge, this is the first description of LHON in association with brain stem lesions presenting with respiratory arrest and loss of involuntary ventilation (Ondine's curse). The high signal lesions in the pons and medulla involved the nucleus ambiguus and nucleus of the solitary tract, which are part of the ventral and dorsal respiratory groups respectively, and would seem well placed to account for loss of respiratory control during sleep with well preserved capacity for volitional respiratory manoeuvres while awake. Ondine's curse produced by lesions of these structures and their tracts through a variety of causes has been well described.4,5 However, the exact nature of CNS lesions in patients with mitochondrial cytopathy remains obscure.

Our patient tolerated NIPPV. She improved on this regimen such that 123 days after admission she was able to take a 45 minute daytime nap and maintain an oxygen saturation of >97% throughout, while breathing room air unassisted. Eight months after her respiratory arrest, she was able to take a few steps with a Zimmer frame and had successfully weaned off NIPPV support. This patient provides a further example of the broad manifestations of mitochondrial disease.

Figure 1

Left: T2 weighted axial MRI through the medulla. Right: diagram showing relevant medullary components.


We thank Dr M Hebden for permission to report a patient under his care.


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