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OBSTETRIC ANESTHESIOLOGY

Obstetric and Anesthetic Management of Severe Congenital Myasthenia Syndrome

Nico Terblanche, MD, FCA(SA)^*, Cynthia Maxwell, MD, FRCPSC, Johannes Keunen, MD, and Jose C. A. Carvalho, MD, PhD, FANZCA, FRCPC^*

From the Departments of *Anesthesia and Pain Management, and Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada.

Address correspondence to Nico Terblanche, MD, Department of Anesthesia and Pain Management, Mount Sinai Hospital, 600 University Ave., Room 781, Toronto, M5G 1X5. Address e-mail to nicoterblan{at}mweb.co.za.

Abstract

The congenital myasthenia syndromes form a heterogeneous group of genetic diseases characterized by defective neuromuscular transmission. Although they have muscle fatigability in common with the acquired immune myasthenia syndrome, there are important pathophysiological, diagnostic, management and progression pattern differences between them. We report the management of a 28-yr-old patient with longstanding congenital myasthenia syndromes, who underwent an elective cesarean delivery under spinal anesthesia. Muscle imbalance plus weakness-related scoliosis and chronic respiratory failure complicated her management. Ultrasonography was used to facilitate the spinal anesthetic. Intraoperative noninvasive positive pressure ventilation maintained lung volumes effectively and prevented deterioration in respiratory function.

The congenital myasthenia syndromes (CMS) form a heterogeneous group of genetic diseases, mostly of autosomal recessive inheritance, characterized by defective neuromuscular transmission resulting in "myasthenic" fatigable muscle weakness.1,2 There are similarities and differences when compared to myasthenia gravis, an acquired autoimmune disorder characterized by a decreased number of nicotinic acetylcholine receptors in the neuromuscular junctions, due to auto antibodies directed against the receptor.3,4 CMS is uncommon in comparison to myasthenia gravis.5 We report the management of a pregnant patient with CMS unresponsive to anticholinesterase therapy who presented with chronic respiratory failure and severe scoliosis. A review of the literature revealed only one other case report of a CMS patient undergoing an elective cesarean delivery.6 Written consent for publication of the present report was obtained from the patient.

CASE DESCRIPTION

This 28-yr-old gravida 2 para 1 woman, 51 kg, 151 cm, with a longstanding history of CMS, was referred to our hospital at 24 wk gestation. The patient had respiratory difficulties from birth, which initially presented with a weak cry and required a tracheostomy from 3 mo to 2-yr-of-age. Blepharoptosis was noted at age 4 yr. At age 7 yr she had multiple hospital admissions, resulting in a second tracheostomy and implementation of nocturnal noninvasive positive pressure ventilation (NiPPV). The diagnosis of CMS was confirmed based on muscle fatigability, a positive edrophonium test, and single-fiber electromyography showing a neuromuscular transmission defect. She was seronegative for acetylcholine receptor antibodies and had no thymoma. Neostigmine aggravated her muscle weakness. Drug therapy consisting of ephedrine, potassium chloride, and calcium supplementation was initiated. Her condition improved over the course of the next 2 mo and the tracheostomy was closed at age 9 yr. She subsequently developed two complications related to muscle weakness: scoliosis and chronic respiratory failure. She underwent spinal fusion at age 14 yr, with rods extending from T2–L2. At age 15 yr she developed papilledema from CO₂ retention. Noninvasive bilevel positive airway pressure (BiPAP) was initiated for nighttime respiratory support.

Her first pregnancy at age 25 yr ended at 6 wk gestation with a spontaneous abortion. She required a dilation and curettage under general anesthetic due to a failed spinal anesthesia. During the second pregnancy, her condition remained stable until 13 wk gestation, when she began to experience worsening shortness of breath and tachycardia. Her continued deterioration required local hospital admission at 20 wk. BiPAP settings were gradually adjusted over weeks. The inspiratory positive airway pressure (IPAP) was increased from 18 to 20 cm H₂O, and the expiratory positive airway pressure remained at 4 cm H₂O. An ambulatory ventilator was provided for when she mobilized.

At the time of admission, she appeared in slight discomfort while breathing at rest. She had slight bilateral ptosis and decreased lateral gaze, but no dysarthria or dysphagia. There was a scar on her neck from the previous tracheostomies. Her airway examination was normal (Mallampati 1). The assessment of her spine revealed a scar that extended from high thoracic to low lumbar levels. We assessed her lumbar spine sonoanatomy using a curved array low frequency (2–5 MHz) probe. The L4–5 interspace showed preserved anatomy, with the ligamentum flavum at 4.7 cm from the skin. All interspaces above the level of L4–5 showed abnormal anatomy.

A computed tomography of her neck excluded subglottic stenosis. Pulmonary function tests revealed a forced expiratory volume in 1 s (FEV₁) of 0.7 L/min (32% of predicted), forced vital capacity (FVC) of 0.8 L (<30% of predicted) and the maximum expiratory flow (MEF) 50% of vital capacity was 1.66 L (56% of predicted). An electrocardiogram showed sinus tachycardia and an echocardiogram revealed pulmonary hypertension with mild right ventricular dysfunction (ventricular systolic pressure of 49 mm Hg), but normal left ventricular function.

Between 31 and 33 wk gestation she experienced worsening shortness of breath at rest and become very dependent on ambulatory BiPAP. Her IPAP was increased by 2 cm H₂O weekly to a maximum of 23.5 cm H₂O. After a multidisciplinary discussion, it was decided to perform a cesarean delivery at 33 wk gestation, due to severe deterioration in her respiratory condition. Despite an increasing IPAP, the patient remained dyspneic at rest and could not complete her sentences while talking. Estimated fetal weight was 2218 g (40th percentile).

The cesarean delivery was performed under spinal anesthesia. In addition to standard monitoring, an arterial line was inserted before the procedure. Ultrasonography was used to identify the L4–5 interspace and the subarachnoid space was located after a single pass with a 27-gauge Whitacre spinal needle. Spinal anesthesia was induced with hyperbaric bupivacaine 12 mg, fentanyl 10 µg, and morphine 100 µg. The patient was positioned supine with left tilt, and noninvasive BiPAP was initiated to prevent deterioration in respiratory function. The maximum T4 sensory level was reached after 20 min. A Pfannenstiel skin incision with low transverse uterine incision was used. A male infant weighing 2270 g was delivered with Apgar scores of 8 and 9 at 1 and 5 min, respectively. Physical examination of the infant revealed mild subcostal retraction, which required continuous positive airway pressure at a fraction of inspired oxygen (Fio₂) concentration of 0.37 for 12 h.

An arterial blood gas analysis performed 15 min after delivery revealed a decrease in Pco₂ (37 mm Hg) from the preoperative/preanesthetic value (42 mm Hg), and improvement in the Po₂ from 89 to 92 mm Hg. The surgery was uncomplicated with satisfactory anesthesia, hemodynamic stability and no respiratory compromise. Estimated blood loss was 700 mL.

Both the mother and baby had an uncomplicated postoperative course. The patient was monitored for 4 h in a high acuity bed on the labor floor and then transferred to the postpartum unit, where the BiPAP was titrated back to her prepregnancy baseline settings over a 4-day period. Intrathecal morphine analgesia was supplemented with acetaminophen (1 g PO q6h) and diclofenac (50 mg PO q8h) with good effect. As a precautionary measure, to observe for signs of respiratory deterioration, she remained hospitalized for 12 days postpartum. The baby was transferred to a local hospital at 34 wk postgestational age where he remained for a further 2 wk before being discharged home. Early neonatal follow-up suggested the infant was not affected by CMS.

DISCUSSION

The classification of CMS is based on the location of the neuromuscular transmission dysfunction. The defect can be presynaptic (defects in acetylcholine resynthesis or decreased release), synaptic (an anomaly of the cholinesterase collagen tail), or postsynaptic. Postsynaptic defects include the decreased expression of acetylcholine receptors and rapsyn (the endplate maintenance protein) and fast-channel CMS (acetylcholine receptors do not stay open long enough) or slow channel CMS (acetycholine receptors that stay open too long).1,7

Most individuals with CMS present at birth or shortly thereafter with opthalmoplegia, weak cry, swallowing disturbances, and muscle fatigability.7 However, some individuals become symptomatic only later in life.8 The severity of CMS is variable, with differing degrees of gate deficits, bulbar dysfunction and respiratory difficulties. Respiratory failure may occur, usually triggered by infectious episodes. The associated muscle weakness and instability can lead to facial malformation, tendon retraction, and scoliosis.

Hantai et al.7 suggest the following diagnostic criteria for CMS: (a) family history of CMS; (b) absence of antibodies against acetylcholine receptor; (c) electromyography evidence of a neuromuscular transmission block; (d) muscle biopsy excluding the diagnosis of myopathy and demonstrating the predominance of type 1 fibers. Genetic testing can confirm a specific disease entity. The fact that our patient failed to respond to anticholinesterase treatment but had a positive edrophonium test, suggests the diagnosis of either a slow-channel syndrome or an atypical form of partial acetylcholinesterase deficiency, or Dok-7 ("limb- girdle" myasthenia).7

The treatment of CMS includes both nonspecific and specific measures.7 The nonspecific measures include the treatment of respiratory distress with NiPPV. Specific measures target the site of the neuromuscular defect with drugs. Anticholinesterases are effective in all CMS, with the exception of acetylcholinesterase deficiency (synaptic) and slow channel CMS (postsynaptic). Quinine is effective in treating slow channel syndrome, through its propensity to correct the prolonged opening of the acetylcholine receptor to a normal duration. At present, there is no effective therapy for acetylcholinesterase deficiency. Ephedrine's mode of action is unknown.

The natural history of CMS is highly variable.7 Similar to myasthenia gravis, myasthenic bouts of CMS can be triggered by pregnancy; however, its general course during pregnancy has not been established. A favorable outcome is possible in cases of CMS initially thought to be severe. In contrast, motor and respiratory degradation occurring late in adulthood have been reported in patients initially only slightly affected.

The ideal anesthetic for patients with CMS is not known. The advantages of neuraxial anesthesia include avoidance of IV opioids, neuromuscular blocking drugs, and anticholinesterases. In cases where general anesthesia is indicated, the principles guiding anesthetic management of patients with CMS are similar to those used for myasthenic gravis patients. Due to acetylcholine receptor down regulation, patients are very sensitive to nondepolarizing muscle relaxants and potentially resistant to depolarizing muscle relaxants. It is advisable to use short-acting opioids, muscle relaxants, and inhaled anesthetics.

We opted to initiate neuraxial anesthesia with supportive noninvasive ventilation in the perioperative period, although we were fully prepared for tracheal intubation and full ventilatory support should her respiratory status deteriorate.

Although we ultimately decided to use a single-shot spinal technique, we initially considered continuous techniques, both spinal and combined spinal-epidural anesthesia, as they allow titration of the local anesthetic dose. Continuous spinal anesthesia would have required dural puncture with an epidural needle, and the consequent increased risk of postdural puncture headache. We decided not to initiate continuous spinal anesthesia because we assumed that the disruption of the epidural space secondary to the patient's laminectomy would compromise the reliability of the technique.9 In one study, the rate of satisfactory epidural labor analgesia in patients with Harrington rods was <60%.10

The combination of her extensive back surgery with the presence of instrumentation and scoliosis required assessment of a possible site for safe and reliable spinal puncture. Yeo and French,9 described a case of an obstetric patient with Harrington rods, in which ultrasonography allowed successful spinal analgesia at first attempt after two failed attempts without ultrasonography. The ultrasound examination11 demonstrated clearly that the only interspinous space with preserved anatomy was L4–5 and the imaging not only assisted in determining the puncture site, but also the angle of the needle advancement.

Some authors suggest that it is prudent to secure the airway before surgery in patients with respiratory compromise. There are a number of arguments in favor of this approach. Spinal and epidural anesthesia can significantly decrease FVC and forced expiratory volume in 1 min,12–14 and the supine position will result in a further decrease in functional residual capacity, which could induce hypoxemia. Despite these arguments, impending hypoxemic respiratory failure has been successfully managed with NiPPV during spinal anesthesia.13 We did not observe any additional impairment of the patient's respiratory effort or oxygen saturation. A slight improvement in ventilation and oxygenation was seen intraoperatively after delivery of the infant.

Our patient had an uneventful recovery, and we believe that this might have been related to the benefits of NiPPV in preserving pulmonary function and of neuraxial analgesia in providing excellent analgesia. Although the typical postpartum course of CMS has not been well described, that of myasthenia gravis can be troublesome. The main risk is the need for postoperative ventilation. There are currently no criteria for predicting the need for postoperative ventilation in CMS. The following factors are predictors of the need for postoperative ventilation in patients with myasthenia gravis: (a) female gender; (b) forced expiratory flow 25%–75% <3.3 L/s and <78% of predicted; (c) FVC <2.6 L; (d) maximum expiratory flow 50% <3.9 L/s and <80% of predicted.15 According to these predictors, our patient would most likely have required ventilation had she received a general anesthetic.

In summary, this case report illustrates the complex decision-making process involved in the management of CMS in pregnancy, particularly as regards to the time of delivery relative to the progression of respiratory insufficiency, the usefulness of ultrasonography to facilitate neuraxial anesthesia, and the role of intraoperative NiPPV in the management of patients with chronic respiratory failure.

Footnotes

Accepted for publication May 30, 2008.

REFERENCES

1. Beeson D. Congenital myasthenic syndromes. Adv Clin Neurosci Rehabil 2005;4:12–14
2. Englel AG, Kinji O, Sine SM. Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Nat Rev Neurosci 2003;4:339–53[Web of Science][Medline]
3. Bader AM. Neurologic and neuromuscular disease. In: Chestnut DH, ed. Obstetric Anesthesia Principles and Practice. 3rd ed. Philadelphia: Elsevier Mosby, 2004:877–78
4. Drachman D. Myasthenia gravis. N Engl J Med 1994;330: 1797–810[Free Full Text]
5. Kurtzke JF, Kurland LT. The epidemiology of neurologic disease. In: Joynt RJ, ed. Clinical Neurology. Rev ed. Vol 4. Philadelphia: JB Lippincott, 1992;80–8
6. Koh LK, Ip-Yam PC, Tan ASA. Perioperative management of a patient with congenital myasthenia syndrome for elective cesarean section. Singapore Med J 2001;42:61–3[Medline]
7. Hantai D, Richard P, Koenig J, Eymard B. Congenital myasthenic syndromes. Cur Opin Neurol 2004;17:539–51[Web of Science][Medline]
8. Englel AG, Ohno K, Sine SM. Congenital myasthenic syndromes: progress over the past decade. Muscle Nerve 2003;27: 4–25[Web of Science][Medline]
9. Yeo S, French R. Combined spinal-epidural in obstetric patients with Harrington rods assisted by ultrasonography. Br J Anaesth 1999;83:670–2[Abstract/Free Full Text]
10. Ho A, Ngan Kee W, Chung D. Should laboring parturients with Harrington rods receive lumbar epidural analgesia. Int J Gynaecol Obstet 1999;67:41–3[Medline]
11. Arzola C, Davies S, Rofaeel A, Carvalho JCA. Ultrasound using the transverse approach to the lumbar spine provides reliable landmarks for labor epidurals. Anesth Analg 2007;104:189–92
12. Esther Y, Topulos G, Body S, Datta S, Bader AM. Pulmonary function changes during epidural anesthesia for cesarean delivery. Anesth Analg 1996;82:750–3[Abstract]
13. Ferrandiere M, Hazouard E, Ayoub J, Laffon M, Gage J, Mercier C, Fusciardi J. Non-invasive ventilation corrects alveolar hypoventilation during spinal anesthesia. Can J Anaesth 2006;53: 404–8[Web of Science][Medline]
14. Ungern-Sternberg BS, Regli A, Bucher E, Reber A, Schneider MC. Impact of spinal anesthesia and obesity on maternal respiratory function during elective cesarean section. Anaesthesia 2004;59:743–9[Web of Science][Medline]
15. Naguib M, el Dawlatly A, Ashour M, Bamgboye EA. Multivariate determinants of the need for postoperative ventilation in myasthenia gravis. Can J Anaesth 1996;43:1006–13[Web of Science][Medline]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Terblanche, N. Articles by Carvalho, J. C. A. Search for Related Content PubMed PubMed Citation Articles by Terblanche, N. Articles by Carvalho, J. C. A. Related Collections Obstetrics Preoperative Evaluation Patient Safety