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Table of Contents    
ORIGINAL ARTICLE
Year : 2020  |  Volume : 68  |  Issue : 6  |  Page : 1394-1399

Respiratory Assessment of Myasthenia Gravis Patients Using Repetitive Nerve Stimulation of Phrenic and Intercostal Nerves


Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, India

Date of Web Publication19-Dec-2020

Correspondence Address:
Dr. Sunil Pradhan
Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, 226014
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.304128

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 » Abstract 


Background: We evaluated decremental response from phrenic and intercostal nerves using slow repetitive nerve stimulation test (RNST) to look for its diagnostic significance in sero-negative predominantly bulbar myasthenia gravis (MG) with normal peripheral or cranial nerve RNST.
Methods: RNST from phrenic and intercostal nerves was performed along with standard RNST from abductor digiti minimi (ADM), trapezius, nasalis and orbicularis oculi muscles in 10 normal individuals (group I), 10 patients with neurological disorders other than MG (group II) and 10 patients with MG (group III). We evaluated the presence of positive response in first two groups (group I and II) and absence of negative response in group III. Spirometry was also performed in MG patients.
Results: Mean baseline decrement in I/C RNST in three groups was -2.06±1.33 %, -2.5±2.18% and -27.1±17.9 % respectively. One minute post exercise decrement in I/C RNST in three groups was -2.9±1.36%,-2.9±1.36% and -32.9±17.9% respectively. RNST of phrenic nerve showed mean baseline decrement of -2.1±2.3%, -3.2±2.6 % and -18.3±30.3% in three groups respectively. One minute post exercise decrement percentage were -2.2±1.18% in group I, -4.8±2.18% in group II and -29.2±19.2% in group III. RNST of peripheral nerves were negative in two patients who were bulbar sero-negative MG, however, significant decrement was seen in intercostal and phrenic nerve RNST.
Conclusion: Intercostal and phrenic nerve RNST are a better test for assessing respiratory involvement specially in patients presenting with bulbar symptoms and having negative RNST of peripheral nerves.


Keywords: Respiratory assessment in myasthenia gravis, RNST intercostal, RNST phrenic
Key Messages: Repetitive nerve stimulation test of the phrenic and the lower intercostal nerves are best way to assess respiratory function. This is especially true in patients of myesthenia gravis, presenting with bulbar symptoms.


How to cite this article:
Pradhan S, Anand S. Respiratory Assessment of Myasthenia Gravis Patients Using Repetitive Nerve Stimulation of Phrenic and Intercostal Nerves. Neurol India 2020;68:1394-9

How to cite this URL:
Pradhan S, Anand S. Respiratory Assessment of Myasthenia Gravis Patients Using Repetitive Nerve Stimulation of Phrenic and Intercostal Nerves. Neurol India [serial online] 2020 [cited 2021 Jan 21];68:1394-9. Available from: https://www.neurologyindia.com/text.asp?2020/68/6/1394/304128




Myasthenia gravis is a post-synaptic neuromuscular disorder primarily involving extra-ocular, bulbar, respiratory and proximal limb muscles. Repetitive nerve stimulation test (RNST) is a sensitive test for myasthenia gravis which is used to assess the function of neuromuscular junction. It may be negative in mild form of myasthenia gravis like ocular form as well as in some of the severe forms involving bulbar and respiratory muscles probably because of relative sparing of peripheral neuromuscular junctions.[1],[2],[3],[4] Assessment of respiratory function is important in MG as respiratory involvement could be life threatening. Breathing difficulty in MG is primarily because of weakness of diaphragm and intercostal muscles. Phrenic and intercostal nerves (ICN) are the main nerves supplying diaphragm and intercostal muscles respectively. Predominant bulbar and respiratory involvement without proximal limb muscle involvement is more common in patients who have absence of acetylcholine receptor antibody with or without the presence of anti-MUSK antibody. Keeping this in mind, we performed phrenic RNST which is already a known method for respiratory assessment in myasthenia patients. We also used intercostal nerve RNST for respiratory assessment as intercostal muscles also plays a significant role in respiration.[5] Since ICN RNST (7th -11) have not been performed before, we planned to first standardize this method in normal healthy controls, patients other than neuromuscular disorder and in patients of myasthenia gravis. The method for recording ICN potential was used in accordance to technique described before.[6] However, in this study we did seventh ICN recording because only lower ICN have a role in inspiration, gives a consistent potential and is easier to perform. We, therefore, conducted RNST from this nerve and tried to correlate its utility in assessing respiratory dysfunction in myasthenia patients.


 » Methods Top


This study was conducted in a tertiary care Institute of Northern India. The study involved patients of myasthenia gravis presenting to Neurology out patient department/ward/emergency. The patients were explained about the study in detail and written informed consent was taken. This study was approved by ethical committee of the Institute.

Three groups were made, each consisting of ten subjects. Group I consisted of normal healthy subjects, group II of patients other than neuromuscular disorder (motor neuron disease, peripheral neuropathy, and muscular dystrophy) and group III of myasthenia gravis patients.

In myasthenia patients demographic profile, type of myasthenia, type of antibody positivity, duration of treatment, response to treatment and type of immunosuppression used were noted. RNST of peripheral nerves denoted by muscles i.e., trapezius, abductor digiti minimi, nasalis, orbicularis oculi, diaphragm, and intercostal muscles was performed. Spirometry was also performed in every myasthenia gravis patient.

Baseline compound muscle action potential (CMAP) amplitude of these muscles were noted. RNST was done at a rate of three hertz (Hz) and number of stimulations were five. Percentage of decrement in amplitude between first and fourth CMAP was noted and value of decrement above 10% was considered as a positive test. Ten second post exercise decrement at 1 and 2 minutes was noted. RNST of the above-mentioned muscles was done in accordance with standard protocol. However, for phrenic RNST, we used our method in which active electrode was placed in the tenth intercostal space 2.5 cm away from para-spinal muscles, reference electrode was placed in the eighth intercostal space just medial to the subcostal margin and ground electrode was placed between stimulation site and reference electrode. Stimulation was done lateral to the posterior head of sternocleidomastoid muscle at the level of crico-thyroid space [Figure 1]. Seventh ICN-RNST was done using active electrode 1 cm above and 2.5 cm lateral to tip of xiphoid process [Figure 2] and [Figure 3]. The site of stimulation was in seventh intercostal space 5 cm lateral to the subcostal margin.
Figure 1: The stimulation and recording points for phrenic RNST. Active electrode is placed over tenth intercostal space 2.5 cm lateral to lateral border of para-spinal muscles (mid scapular line), reference electrode placed just medial to the subcostal margin at a point close to the 8th intercostal space (marked) and ground electrode placed between active electrode and stimulation site. Stimulation is done near or just under the lateral border of sternocleidomastoid muscle at the level of crico-thyroid space

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Figure 2: The stimulation and recording points for ICN RNST. Active electrode is placed 1 cm above the tip of xiphoid process (marked) and reference electrode 2.5–3 cm away from it. Ground electrode is placed between active electrode and stimulation site. Stimulation is done in the seventh intercostal space (marked) 5 cm lateral to the subcostal margin

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Figure 3: Reproduced from “Intercostal nerve conduction study in man. Pradhan S, Taly A; Journal of Neurology, Neurosurgery & Psychiatry 1989; 52: 763-766” with permission from BMJ Publishing group Ltd (2018). The illustration shows best recording at the middle of the width of the rectus abdominis muscle during recording of CMAPs at different sites in the transverse plane of the muscle at the level of best vertical recording sites for 7th to 11th intercostal nerves

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Post exercise RNST was done according to protocol. In phrenic and ICN exercise was done using deep inspiration and expiration for 10 sec. Decrement response was noted at baseline, 1 min, and 2 min post exercise.

The entire procedure was performed on Synergy electro-myography machine product version 22.0.2.146 copyright 2013 Natus. Gain at 100 μV/division, sweep at 10 ms/divison.

Analysis

The data was analyzed using SPSS version 23. Mean, median and standard deviation were calculated.


 » Results Top


Total thirty subjects were studied. Demographic features of each group is mentioned in the [Table 1]. In group I, out of ten patients three were females, mean age was 24.7 ± 8.87 years with minimum age of 16 years and maximum age was 38 years. RNST of seventh intercostal nerve showed average amplitude of 4.5 ± 2.1 millivolt. RNST showed non-significant baseline and post exercise decrement [Table 1].
Table 1: Results of decrement percentage in ICN and phrenic nerve RNST in three groups

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In group II, i.e., other than neuromuscular disorders, total ten patients were included. Out of these five were females. Mean age was 30.1 ± 19.96 years with minimum age of 14 years and maximum age was 63 years. The disease pattern was as follows: two patients of GBS, two had peripheral neuropathy, three were of muscular dystrophy and three were motor neuron disease. RNST showed non-significant baseline as well as post exercise decrement [Table 1].

In group III, total ten patients of myasthenia gravis were included. Out of these four were females. Mean age was 37.6 ± 16.9 years. Modified Osserman's classification was used for further categorizing myasthenia patients. Four patients were of class IIIa, two belonged to class IIIb and the rest two were categorized into class IVb; two patients were of class V. Two patients with bulbar myasthenia gravis were negative for antibodies, one was MUSK positive, and rest of the patients had high acetylcholine receptor antibody titers. Seven patients were on immuno-suppressive therapy and three patient had acute onset bulbar symptoms which responded only to plasma-pharesis [Table 2]. One of the patient had thymoma and was planned for thymectomy. This patient presented with acute onset bulbar symptoms and respiratory distress and required mechanical ventilation.
Table 2: Clinical characteristics of myasthenia gravis patients

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RNST of peripheral nerves was negative in two patients of bulbar myasthenia and one patient of generalized myasthenia gravis. However, every patient showed baseline decrement in ICN and phrenic RNST [Table 1]. Decremental response in ICN and phrenic nerve is shown in [Figure 3] and [Figure 4], respectively. Two patients, who were bulbar myasthenia as well as antibody negative, RNST showed decrement only in ICN and phrenic nerves even when other peripheral RNST were negative [Table 3].
Figure 4: Decremental response in intercostal RNST

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Table 3: Decremental percentage i.e. baseline and post exercise (PE) in ICN and phrenic nerve response in two bulbar myasthenia gravis patients with negative conventional RNST

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Mean and median decremental values in ICN and phrenic nerve at the baseline, post exercise (PE) 1 min and 2 min are shown in [Table 4].
Table 4: Intercostal (ICN) and phrenic nerve decremental percentage values at baseline and post exercise (PE) 1 min and 2 min

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 » Discussion Top


Phrenic and ICN play an important role in respiration.[5] Phrenic nerve supplies diaphragm muscle which is the main muscle for two-thirds of the respiration.[7] The technique of RNST using ICN is reliable and gives consistent results. In our study, decrement using ICN RNST in normal subjects was not significant. Similarly, in patients with other neurological disorders like muscular dystrophy, motor neuron disease and peripheral neuropathy the decrement was insignificant. Among patients of myasthenia gravis, decrement was seen in every patient despite normal RNST in other peripheral nerves.

The points which highlights the importance of this technique are as following:

  1. Positive decrement from ICN and phrenic nerves despite non-significant decrement of other peripheral nerves in MG patients. In some other studies the sensitivity of conventional RNST was 89% for generalized myasthenia gravis and 68% for ocular myasthenia.[1],[2] Costa et al. showed that RNST of anconeus and nasalis muscles to be more sensitive test in patients with predominant bulbar symptoms.[8] However, RNST of the anconeus is difficult and is not done routinely. Similarly, RNST of nasalis is more painful and patient may not co-operate fully. In this context ICN and phrenic nerve RNST may prove useful in all such patients of MG where conventional RNST is normal or equivocal.
  2. Sero-negative patients or patients with bulbar symptoms showed positive decrement in ICN and phrenic RNST [Figure 4] and [Figure 5]. Thus, both these tests are reliable and useful in diagnosing these difficult to diagnose MG patients. In our study, two patients were sero-negative for both antibodies (acetyl choline receptor antibody and MUSK antibody). Both of these patients had predominant bulbar symptoms and had normal RNST from the conventional nerves of upper limbs and face. Therefore, intercostal RNST may be of value in patients having bulbar symptoms and absence of antibodies. In around 15% of patients with generalized MG and in up to 50% of patients with ocular forms of the disease, no anti-body against AChR and MuSK are detected. These cases are identified as double-sero-negative MG (dSNMG).[9],[10] These patients will always be in a diagnostic dilemma because of negative RNST and absence of antibodies. Although all our group III patients had generalized myasthenia, two of them were double sero-negative and predominantly bulbar. The presence of negative RNST in the peripheral nerves and positive RNST in the ICN and phrenic nerves suggests high value of examining these nerves in predominantly bulbar sero-negative form of MG.
  3. Dyspnoea in a patient of myasthenia may be due to many other causes like cardiomyopathy, cholinergic crisis, denervation of diaphragm, or weakness of diaphragm secondary to impaired neuromuscular transmission.[11] Intercostal and phrenic RNST can corroborate clinical assessment in patients of respiratory dysfunction in neuro-muscular weakness and predict impending respiratory crisis.
  4. Phrenic RNST is a known method for assessing respiratory function in myasthenia.[12],[13] However, it's more painful and difficult to perform and may not be positive in every patient. Whereas, ICN RNST is a reliable method and it is easier to perform. Furthermore, it was positive in a patient who had negative phrenic RNST.
  5. Spirometry was performed in every patient of myasthenia group. No patient could perform spirometry during acute bulbar or respiratory crisis phase of the disease. When performed after the crisis was over, they had essentially normal spirometry. This may be explained by the fact that in myasthenia most sensitive indices are mean inspiratory pressure and mean expiratory pressure,[11] however, both of these require full patient co-operation as well as facial muscle strength. Thus, it is difficult to rely on spirometry as a test for respiratory assessment and impending respiratory crisis.
  6. Usually anti-choline-esterase drugs are stopped at least 24 hours before performing RNST because it alters the decremental response.[14] ICN- RNST shows positivity even while patients have taken anticholinergic drugs prior to the test. It is possible that these drugs may be having lesser effect on respiratory muscles compared to other peripheral muscles. The advantage may be taken of this fact as respiratory evaluation in any clinical situation is generally required acutely while the patient is already on anti-choline-esterase agents.
  7. The patients who presented in respiratory crisis, follow-up RNST done after extubation showed improvement in decremental response. This small observation may suggest role of serial RNST from ICN and phrenic nerves in deciding about extubation in corroboration with clinical assessment. However, only two patients belonged to this group and further studies are required for confirming this finding.
Figure 5: Decremental response in phrenic RNST

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This study involves only a small number of MG patients. However, the encouraging results from this study entails further larger study to confirm these findings particularly in patients with sero-negative predominantly bulbar MG.


 » Conclusion Top


We conclude that patients of bulbar weakness with absence of antibodies are always in a diagnostic dilemma and RNST of ICN and phrenic may be important in the diagnosis and prognostication of these patients.

This paper was presented at The Annual Conference of the Indian Academy of Neurology, at Raipur in September 2018.

Acknowledgements

We acknowledge Ms. Pranjul Asthana, who works in Clinical Neurophysiology lab, for technical help.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Claussen GC, Fesenmeier JT, Hah JS, Brooks J, Oh SJ. The accessory nerve repetitive nerve stimulation: A valuable second-line test in myasthenia gravis. Eur J Neurol 1995;2:492-7.  Back to cited text no. 1
    
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Stalberg E. Clinical electrophysiology in myasthenia gravis. J Neurol Neurosurg Psychiatry 1980;43:622-33.  Back to cited text no. 2
    
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Stalberg E, Sanders DB. Electrophysiological tests of neuromuscular transmission. In: Stalberg E, Young RR, editors. Clinical Neurophysiology. London: Butterworths; 1981. p. 88-116.  Back to cited text no. 3
    
4.
Oey PL, Wienecke GH, Hougenraad TU, van Huffelen AC. Ocular myasthenia gravis: The diagnosis yield of repetitive nerve stimulation and stimulated single fiber EMG of the orbicularis oculi muscle and infrared reflection oculography. Muscle Nerve 1993;16:142-9.  Back to cited text no. 4
    
5.
Taylor A. The contribution of the intercostal muscles to the effort of respiration in man. J Physiol 1960;151:390-402.  Back to cited text no. 5
    
6.
Pradhan S, Taly A. Intercostal nerve conduction study in man. J Neurol Neurosurg Psychiat 1989;52:763-6.  Back to cited text no. 6
    
7.
Simpson JA. Myasthenia gravis and myasthenic syndromes. In: Walton JN, editor. Disorders of Voluntary Muscle. 4th ed. Edinburgh: Churchill Livingstone; 1981. p. 585-624.  Back to cited text no. 7
    
8.
Costa J, Evangelista T, Conceição I, de Carvalho M. Repetitive nerve stimulation in myasthenia gravis--relative sensitivity of different muscles. Clin Neurophysiol 2004;115:2776-82.  Back to cited text no. 8
    
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Romi F, Aarli JA, Gilhus NE. Seronegative myasthenia gravis: Disease severity and prognosis. Eur J Neurol 2005;12:413-8.  Back to cited text no. 9
    
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Mossman S, Vincent A, Newsom-Davis J. Myasthenia gravis without acetylcholine-receptor antibody: A distinct disease entity. Lancet 1986;1:116-9.  Back to cited text no. 10
    
11.
Mier-Jedrzejowicz AK, Brophy C, Green M. Respiratory muscle function in myasthenia gravis. Am Rev Respir Dis 1988;138:867-73.  Back to cited text no. 11
    
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Mier A, Brophy C, Moxham J, Green M. Repetitive stimulation of phrenic nerves in myasthenia gravis. Thorax 1992;47:640-4.  Back to cited text no. 12
    
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Zifko UA, Nicolle MW, Grisold W, Bolton CF. Repetitive phrenic nerve stimulation in myasthenia gravis. Neurology 1999;53:1083-97.  Back to cited text no. 13
    
14.
ChiouTan FY, Tim RW, Gilchrist JM. Practice parameter for repetitive nerve stimulation and single fiber EMG evaluation of adults with suspected Myasthenia gravis or Lambert -Eaton myasthenic syndrome: Summary statement. AAEM Quality Assurance Committee (1997-2000).  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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