Significance of phrenic nerve electrophysiological abnormalities in Guillain–Barré syndrome

Respiratory failure is the most serious short-term complication of Guillain–Barré syndrome (GBS),¹ and endotracheal mechanical ventilation (EMV) is still required in 20% to 30% of patients.^2,3 Diaphragm weakness is the main mechanism of respiratory failure in GBS.⁴ A retrospective study showed that reduced amplitude of the diaphragm compound muscle action potential (CMAP) was correlated with vital capacity (VC) reduction and subsequent EMV.⁵ Therefore, phrenic nerve electrophysiologic testing may be helpful for anticipating respiratory deterioration. Several studies assessed risk factors for respiratory failure,^2,3,6,7 but none involved phrenic nerve electrophysiologic testing. We prospectively investigated potential associations linking phrenic nerve electrophysiology to respiratory function test findings and subsequent need for EMV.

Methods.

Electrophysiologic testing was performed in all unventilated adults referred to our intensive care unit (ICU) for GBS.⁸ Exclusion criteria were nonidiopathic GBS and Miller–Fisher syndrome. Our institutional review board waived informed consent. The inclusion day was the electrophysiologic testing day. Standard clinical and laboratory tests were performed. Maximal inspiratory (MIP) and expiratory mouth pressure (MEP) and VC were assessed on alternate days during the first 8 days.⁷

A neurophysiologist (M.-C.D.) conducted the electrophysiologic tests using a NEUROPACK SIGMA EMG device (M.E.S.A. Nihon Kohden), measuring nerve conduction in the median, ulnar, common peroneal, and tibial nerves⁷ and classifying results as primary demyelinating, primary axonal, unexcitable, equivocal, or normal.⁹ Physicians were told whether the findings supported GBS but were given no details.

Right and left diaphragm CMAPs were elicited by transcutaneous electrical stimulation of the phrenic nerve at the posterior edge of the sternocleidomastoid muscle, at the level of the thyroid cartilage; they were recorded with two surface electrodes positioned in the eighth intercostal space.¹⁰ The intensity of electrical stimulation was increased until no additional increment in diaphragm CMAP amplitude was observed. Then, three supramaximal stimulations were delivered to each phrenic nerve, at the end of expiration. CMAP amplitudes of 300 μV or greater and latencies of 9.0 milliseconds or less were considered normal because these values were the lower (mean − 2 SD) and upper (mean + 2 SD) limits of the normal range in 15 healthy controls.

Endotracheal mechanical ventilation was used routinely in patients who met criteria for respiratory failure,⁴ as evaluated by the physician, who was unaware of electrophysiologic findings.

Results.

Between October 2000 and November 2003, 70 patients with GBS underwent electrophysiologic testing, on average 2 days (range 1 to 8 days) after admission. Results of investigations are reported in table 1, and VC changes over time are shown in the figure. Phrenic nerve electrophysiology was normal in 12 patients (17%). Diaphragm CMAP latency was prolonged in 38 patients (54%), and amplitude was reduced in 54 patients (77%).

• Download figure
• Open in new tab
• Download powerpoint

Figure. Change in vital capacity (VC; mean ± SD) from inclusion to day 8 in the overall population (diamonds), in patients who subsequently required endotracheal mechanical ventilation (triangles), and in those who did not require endotracheal mechanical ventilation (squares).

From inclusion to day 8, diaphragm CMAP latency did not correlate with VC (p = 0.50), MIP (p = 0.20), or MEP (p = 0.24). Neither was CAMP amplitude correlated with MIP (p = 0.19) or MEP (p = 0.30). Diaphragm CMAP amplitude was weakly correlated with VC at inclusion, on day 2, and on day 4 (p = 0.05 and r² = 0.06; p = 0.04 and r² = 0.07; and p = 0.04 and r² = 0.08, respectively). VC was not correlated with median or ulnar nerve electrophysiologic features.

Diaphragm CMAP amplitude did not differ across electrophysiologic categories (p = 0.20), whereas latency was longer (p = 0.05) in the demyelinating group (table 2) and correlated with median nerve F-wave latency (r² = 0.24, p = 0.0001). Diaphragm CMAP amplitude was not correlated with median or ulnar nerve electrophysiologic features.

Ten patients (14%) required EMV, on average 3 days (range 1 to 10 days) after inclusion. At inclusion, patients who subsequently required EMV had greater limb weakness (manifesting as worse disability and arm grades), greater respiratory–muscle weakness (with lower values for VC, MIP, and MEP), and higher rates of bulbar and liver dysfunctions (see table 1). The EMV and non-EMV groups were not significantly different for diaphragm CMAP latency and amplitude or for the proportions of patients with abnormal diaphragm CMAP latency or amplitude (see table 1).

Discussion.

Although electrophysiologic abnormalities of the phrenic nerve were common in our GBS patients, their intensity was weakly correlated with VC reduction and did not predict a need for EMV. These results contradict a previous study in which diaphragm CMAP amplitude was proportional to VC and significantly reduced in patients requiring EMV.⁵ This discrepancy may be ascribable to differences in electrophysiologic technique, study design, collected data, patient population, and EMV criteria.

The stimulation site was the posterior edge of the sternocleidomastoid muscle. In the study mentioned above,⁵ stimulation was in the supraclavicular area. However, stimulation site influences latency but not amplitude. The previous study⁵ was retrospective, and the report does not specify whether electrophysiologic testing preceded EMV initiation.⁵ The percentage of patients requiring EMV was three times smaller in our study (15% vs 40%), suggesting less severe GBS in our patients. However, the populations are difficult to compare because limited data are available on clinical severity at inclusion, type of treatment, and, more important, EMV criteria.⁵ We have no satisfactory explanation for the difference in relationships between respiratory function test results and concomitant diaphragm electrophysiologic test results between our study and the previous work.⁵ We interpret our findings as indicating that phrenic nerve electrophysiologic abnormalities did not reflect diaphragm weakness. Latency was not correlated with respiratory function tests, and diaphragm CMAP amplitude showed a weak correlation with VC (r² < 0.06) and no correlation with MIP, which is considered a better indicator of diaphragm strength. These findings are not surprising, given the well-known lack of proportionality between severity of electrophysiologic abnormalities (except conduction block) and muscle strength. Moreover, VC depends not only on diaphragm strength, but also on contraction of accessory respiratory muscles, which were not subjected to electrophysiologic testing.

As previously reported,^2,3,7 inclusion features in patients who experienced respiratory failure included worse limb and neck weakness, worse diaphragm weakness, and higher rates of bulbar and liver dysfunction. Conversely, ventilated and nonventilated patients did not differ regarding diaphragm CMAP amplitude and latency. Therefore, clinical manifestations and VC, but not phrenic nerve electrophysiology, are essential for anticipating respiratory deterioration. Nevertheless, our findings do not mean that phrenic nerve dysfunction plays no part in the pathophysiology of GBS-related respiratory failure; instead, they probably reflect the limitations of electrophysiologic phrenic nerve testing. The EMV and non-EMV groups may have differed in terms of phrenic nerve conduction velocity, F-wave latency, or presence of conduction block. Because these variables cannot be assessed, it is difficult to determine whether phrenic nerve electrophysiologic impairment is ascribable to axonal injury or to demyelination. Reduced diaphragm CMAP amplitude seems to denote axonal injury because it was often associated with diaphragm fibrillation and correlated with median-nerve distal CMAP amplitude.⁵ Increased phrenic nerve latency reflects demyelination: it was longer in our GBS patients with demyelinating electrophysiology and was correlated with median nerve F-wave latency.

In our study, times separating electrophysiologic testing from symptom onset or ICU admission tended to be shorter in the EMV group, suggesting that a further reduction in diaphragm CMAP amplitude occurred in patients who experienced respiratory failure. This study provides no information on whether repeated phrenic nerve electrophysiologic testing is helpful for predicting EMV, because each patient was tested only once. However, we believe that electrophysiology is not feasible on a routine basis and is unlikely to be more powerful than VC.

Acknowledgment

The authors thank the Laboratoire Français des Biotechnologies for helping them develop a serum bank from patients with Guillain–Barré syndrome.