Dilated fixed pupils and respiratory failure: a rare clinical course of Lambert-Eaton myasthenic syndrome

Introduction

The clinical triad of Lambert-Eaton myasthenic syndrome (LEMS) consists of proximal muscle weakness, autonomic symptoms and reduced tendon reflexes. Presentation with severe respiratory failure has been described, although it is uncommon.1 2 Sluggish pupillary reflexes are common but dilated fixed pupils are rare.3 Additionally, articles regarding the differential diagnosis of bilateral mydriasis do usually not list LEMS.4–6

We present a case of a conscious patient with both respiratory failure and dilated fixed pupils after cardiac resuscitation, ultimately diagnosed with LEMS.

Case presentation

A 62-year-old woman with a history of over 50 pack-years of smoking was admitted with dyspnoea. Two weeks prior to hospitalisation, she was evaluated for overall discomfort and progressive symptoms of a dry mouth and eyes and increasing difficulty with ambulation since 8 weeks. On examination, she had a notably dry oral mucosa, without any other abnormalities, especially no dyspnoea. Her pupils were equal and reactive to light. Standard laboratory workup, including a venous blood gas, was normal. Sjögren’s syndrome was suspected.

Two weeks later, she returned with progressive dyspnoea. She now was clearly dyspneic with an oxygen saturation of 90%. Results of routine laboratory testing are listed in table 1. Chest X-ray showed signs of pneumonia and she was admitted at the pulmonology ward.

The next day she suffered an in-hospital cardiac arrest based on hypoxia, which was attributed to sputum stasis. Beforehand, it was reported that the patient was too weak to cough up sputum herself. A significant amount of sputum was removed during bronchoscopic suctioning. Return of spontaneous circulation was achieved after 8 min of resuscitation. Subsequently, she was sedated and intubated. Sedation was terminated the next day, however, she did not trigger on the ventilator afterwards and was severely hypercapnic. Therefore, the neurology was consulted.

Further course

Treatment with 3,4-diaminopyridine, four times 20 mg daily and IVIg, was initiated. Initially, this led to an increase of muscle strength (proximally an MRC 3 and distally MRC 5), but she still required ventilation. Eventually, her pupils became smaller and responsive to light again. Six days after the first investigation, electrophysiological testing of the ulnar nerve was repeated. With low frequent stimulation (3 Hz, 5 s) a decremental response of >30% (31.2%) was recorded. During 10 s of high frequent stimulation (20 Hz), a decremental response was seen initially followed by an incremental response of >100% (66% increment compared with the first CMAP amplitude, 150% increment compared with the lowest CMAP amplitude, figure 1). These results, together with the low CMAP amplitude found at the first NCS, supported the diagnosis LEMS.8 Shortly after, the patient tested positive for VGCC antibodies (0.045 nmol/L (reference <0.040 nmol/L)).

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Figure 1

(1) Low frequent (3 Hz) 5 s stimulation; (2) high frequent (20 Hz) 10 s stimulation.

A paraneoplastic form of LEMS was suspected due to a Delta-P score of 4, correlating with a high chance of (occult) small-cell lung carcinoma (SCLC).7 However, a conventional chest CT with intravenous contrast was negative for lung carcinoma. Additional positron emission tomography CT (PET-CT) showed a small but clear intrapulmonary FDG-avide lesion with a pathologically active node, highly suspicious for SCLC. Meanwhile, after 4 weeks of continuous improvement, muscle strength deteriorated to MRC 1 proximally. High-dose prednisone and plasmapheresis were started without result. Biopsy and treatment options were discussed with the patient, but she refused further diagnostic and therapeutic procedures and passed away after extubation.

Discussion

We presented a patient, who was diagnosed at the intensive care unit with LEMS.

Developing severe respiratory failure is rare in LEMS.1 2 9 10 It has been observed that respiratory failure induced by anaesthesia can occur in LEMS patients and that the risk for development of prolonged muscle weakness or postoperative respiratory failure after being exposed to neuromuscular blocking agents is increasing in patients with undiagnosed or untreated LEMS.2 11 Rocuronium, used for intubation, may have contributed to clinical deterioration in our patient, as LEMS patients have an increased sensitivity to neuromuscular blocking drugs.11 However, we feel that the prolonged generalised weakness could not be attributed to a single dose of rocuronium only.

Autonomic dysfunction is part of the classical triad of LEMS, however, when encountering fixed dilated pupils in an otherwise awake patient, LEMS is usually not considered.5 6

The diameter of the pupil is a result of the balance between constriction and dilatation function. Sympathetic nerve stimulation causes pupillary dilatation.12 The pupil constricts as a reflex in response to light and accommodation and as result of parasympathetic activation. The neurons of the Edinger-Westphal nucleus form the parasympathetic fibres of the third cranial nerve, which synapses in the ciliary ganglion. The ciliary ganglion sends postganglionic axons which innervate the sphincter pupillae muscle as well as the ciliary muscles.13 14 Pupil abnormalities in LEMS are thought to be a result of (pupillary) autonomic dysfunction. The return of pupillary light reflexes following administration of 3,4-diaminopyridine supports the hypothesis that the pathophysiological mechanism of autonomic dysfunction in LEMS is similar to that of the muscle weakness and relates to antibody-mediated inhibition of neurotransmitter release in cholinergic autonomic synapses.3

(Non-reactive) mydriasis after rocuronium infusion has been reported in literature.15–18 However, this encompasses cases with continuous infusion for a prolonged time. In these studies, mydriasis was observed within a range of 8–156 hours after start of continuous infusion. Pupillary response normalised within 12–36 hours after discontinuation. Short-term administration of neuromuscular blocking agents has been shown to have no effect on pupil size.18 19

In cases of rapid sequence intubation (which also applied to our patient), a case series did not find altered pupillary response after administration of rocuronium.19

The patient had a normal renal function. Altogether, we deem it highly unlikely that the wide, fixated pupils could be attributed to the rocuronium (alone) and rather were a result autonomic dysfunction in the setting of LEMS. There was no relevant topical application of pharmacological agents that could have caused the mydriasis.

During the first electrophysiological study, our patient contracted during 30 s before repeating the measurements and we did not find an incremental response. In practice, voluntary contraction ranges from 10 to 30 s, however, a significantly higher diagnostic sensitivity after 10 s contraction compared with 30 s exercise has been described.20 Regarding high frequent RNS, it has been reported that the most severe form of LEMS results in an electrophysiological pattern with an initial decremental response at high frequent RNS followed by an incremental response (type 3 response according to Oh).8 Therefore, it is important to stimulate long enough (in our patient 10 s) to see this incremental response.

Our patient had relatively low anti-VGCC antibodies (0.045 nmol/L). Elevated antibodies against VGCC without corresponding clinical symptoms are not specific for LEMS and should be interpreted with caution.21 22 Furthermore, studies did not show a correlation between extent of disease, survival and levels of serum anti-VGCC.23

The presence of VGCC-antibodies combined with the classic clinical triad including wide fixed pupils, respiratory failure and the electrophysiological results confirmed the diagnosis of LEMS in our patient.