Perioperative management of patients with genetic multisystem diseases associated with pre excitation

The cardiac electrical stimuli are generated in the sino-atrial node, reach the atrio-ventricular (AV) node and the His bundle/Purkinje fibers, and finally spread to the left and right ventricular myocardium. In the AV node, the action potential relies on a slow calcium current, which delays the conduction of incoming electrical impulses, thus preventing the development of ventricular tachycardias. However, abnormal fibro-muscular anatomic tracts – with action potentials depending upon rapid sodium currents – may connect the atria with the ventricles. Through these alternative pathways, the cardiac impulses can bypass the AV node and travel very fast towards the ventricular myocardium, causing its activation (depolarization) earlier than if the impulses travelled through the normal conduction system. The extra electrical conduction tracts are called “accessory pathways” and the electrophysiological phenomenon of the earlier than normal ventricular excitation is named “pre-excitation” [1]. This mechanism may precipitate serious, even lethal arrhythmias, such as ventricular tachycardia and ventricular fibrillation [2-4].
An accessory pathway (AP) may be located anywhere along the AV ring, while up to 10% of patients may have more than one accessory bundle [1]. An AP may be capable of conducting impulses anterogradely (towards the ventricle) or retrogradely (from ventricles to atria) or in both directions [1]. Based on electrocardiographic (ECG) findings, anterograde conduction may be overt or latent; in patients with overt conduction, the ventricular pre-excitation is manifested on surface ECG as an upstroke at the beginning of QRS, known as a “delta wave”. The delta wave indicates that the part of the ventricle which is directly connected to the AP is depolarized first. In patients with latent AP conduction, the delta wave may be absent on the resting surface ECG or may present intermittently. However, pre-excitation may become apparent in specific conditions (i.e. an episode of atrial fibrillation or flutter or atrio-ventricular node block). The prevalence of arrhythmia and the risk of malignancy in overt and latent pre-excitation are similar. In APs with retrograde conduction, pre-excitation is concealed during sinus rhythm (absence of ECG signs) but may be revealed during atrio-ventricular re-entrant tachycardia (AVRT) [1, 3, 5].
The AVRTs, orthodromic or antidromic, are the commonest arrhythmias that may develop in patients with APs [3, 5, 6]. Atrial or ventricular premature beats may trigger an AVRT, which usually presents on the ECG as a regular, narrow- or wide-complex tachycardia, with very high ventricular rates (i.e. 150-250 bpm). The orthodromic AVRTs are characterized by narrow QRS complexes, because the impulses travel to the ventricle through the AV node and return via the AP, while the antidromic AVRTs have wide QRS complexes, because the impulses travel down through the AP and return via the AV node [5, 6]. If atrial fibrillation or flutter develops, the conduction of stimuli towards the ventricle may occur via the AP, which usually has a shorter refractory period than the AV node; in this case, very fast anterograde conduction of atrial impulses may cause extremely high ventricular rates, even ventricular fibrillation [3, 5, 6].
The most well known AP is named the “bundle of Kent”, and is found in the Wolff-Parkinson-White (WPW) syndrome [5, 6]. Other, less common APs have also been identified, and rarer pre-excitation conditions have been described, such as the Mahaim fibers and the Lown-Ganong-Levine syndrome. The Mahaim fibers are APs that may arise from the AV node or the His bundle or most likely from the right atrium and terminate in the right ventricular myocardium or close/into the right bundle branch (nodo-ventricular or fasciculo-ventricular or atrio-ventricular or atrio-fascicular fibers) [3]. They are characterized by anterograde transmission only, and longer conduction times than the bundle of Kent [3]. In the Lown-Ganong-Levine syndrome, possible mechanisms of pre-excitation include the fast conduction of atrial stimuli through a defective AV node or their transmission via an AP (i.e. James fibers or Brechenmacher fibers) which bypass – completely or partly – a normal AV node [3].
Diagnosis of pre-excitation is based on the combination of ECG findings and development of symptoms, usually palpitations, or more rarely syncope or even cardiac arrest [6]. The pre-excitation pattern on surface ECG is characterized by a shortened PQ (PR) interval (< 120 ms in adults), a prolonged QRS complex (> 120 ms) and a delta wave, with secondary ST-T changes directed opposite to the major delta wave and QRS vector [5-6]. This characteristic pattern, usually called the “WPW pattern”, may not be present in all pre-excitation conditions, depending on the type of the AP and its specific characteristics. For example, the ECG pattern in the Lown-Ganong-Levine syndrome, which may represent a perinodal AP, is characterized by a short PQ (PR) interval and a normal QRS complex, without a delta wave [3].
Electrophysiology testing is the gold standard for certain diagnosis of pre-excitation and identification of the AP. The procedure can be combined with ablation of the pathway, which represents the definite treatment in cases with recurrent episodes or life-threatening arrhythmias [6]. Finally, congenital heart defects associated with pre-excitation abnormalities may co-exist in these patients and should be sought (i.e. Ebstein’s anomaly in WPW syndrome) [6].
The most widely known pre-excitation condition, almost synonymous with the term “pre-excitation”, is the WPW syndrome. Nevertheless, there are a few familial forms of pre-excitation found in rare multisystem diseases [7], namely γ-2 regulatory subunit of AMP-activated protein kinase gene (PRKAG2) mutation, Danon, Fabry and Pompe disease, tuberous sclerosis, Leber hereditary optic neuropathy (LHON) and mitochondrial encephalopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) [7]. Patients with the above syndromes and diseases may present at some time in their lives for elective or emergency surgery. The perioperative management of such cases may be quite complex and difficult due to the several co-existing abnormalities. Especially in case of emergency, the challenge is greater due to the lack of time for extensive investigation and adequate preparation of the patients. Moreover, anaesthesia may unmask an undiagnosed pre-excitation abnormality and facilitate the development of life-threatening arrhythmias. The present review aims to focus on the anaesthetic management and perioperative care of patients with rare genetic diseases associated with pre-excitation, due to the existence of a bundle of Kent or other APs.
We conducted a PubMed literature search for all types of publications – up to January 2018 – combining the terms: “preexcitation”, “pre-excitation”, “PRKAG2”, “Danon disease”, “Fabry disease”, “Pompe disease”, “tuberous sclerosis”, “Leber hereditary optic neuropathy”, “LHON”, “mitochondrial encephalopathy”, “mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome”, “MELAS syndrome” and “anaesthesia” or “perioperative management ” or “perioperative care”. Articles in languages other than English were used only if they had an informative English abstract. We found 56 articles suitable for inclusion in this review. Additionally, two published papers were found by manual searching of the references in the electronically retrieved articles. The articles we identified were mostly case series and reports, and a few retrospective studies. We also used articles that provided information on genetics, clinical presentation, diagnosis and treatment of the diseases. In total 82 articles were included in the present review.

Metabolic disorders associated with pre-excitation

There are a number of genetic metabolic diseases associated with pre-excitation, combined with structural cardiac and other organ abnormalities [7, 8]. The most well known are the Danon, Fabry and Pompe disease, which are lysosomal storage disorders due to enzymatic deficiency. They are characterized by accumulation and deposition of substrates in various organs, including the cardiovascular system. PRKAG2 deficiency is a more heart-specific, non-lysosomal metabolic disease, involving glycogen accumulation [7, 8].
The above disorders share similar cardiac manifestations, namely hypertrophic cardiomyopathy, short PQ (PR) interval and AV blocks [7, 8]. An electrophysiological study is required to confirm the presence of an AP, since pseudo-pre-excitation has been described in patients with Fabry disease and PRKAG2 mutation [7, 9, 10]. In these cases, fast AV node transmission, combined with His-Purkinje conduction abnormalities, may result in short PQ (PR) intervals, giving the false impression of existence of an accessory pathway [7, 9, 10]. Compared to the classic WPW syndrome, the prognosis is much poorer, since these diseases include major structural and functional cardiac abnormalities [7]. Not rarely, the gradual deterioration of myocardial function finally necessitates heart transplantation [11]. Also, the perioperative management of these rare syndromes is probably more challenging, since it should be tailored to the various systems involved. Publications on the perioperative management of patients with rare metabolic disorders associated with pre-excitation are presented in Table 1.

Danon disease

Danon disease is typically characterized by cardiomyopathy, proximal skeletal myopathy and cognitive dysfunction [12, 13]. Pre-excitation, other cardiac conduction abnormalities, hepatic, pulmonary and ophthalmic pathology may also co-exist [12, 13].
An X-linked dominant pattern of inheritance and mutations in the gene encoding the lysosome-associated membrane protein 2 (LAMP2) have been identified [14]. Deficiency of the LAMP-2B isoform causes lysosomal dysfunction with accumulation of autophagic material in the cardiac and skeletal muscles [13, 14]. Hypertrophic cardiomyopathy – obstructive or not – is a prominent feature of Danon disease; it usually progresses to dilated cardiomyopathy and congestive heart failure [7, 13, 15]. Men are mostly affected and usually live only until early adulthood [12, 13, 16].
The co-existing electrophysiological abnormalities, especially ventricular pre-excitation, differentiate the disease from other forms of hypertrophic cardiomyopathy [17]. The mechanism of pre-excitation may be inherent, due to the abnormal autophagy per se, or mechanical, due to myocardial hypertrophy [13]. While conduction abnormalities are encountered in both genders (> 80%), an electrocardiographic WPW pattern is mostly found in men (70% of males versus 27% of females) [13]. Thus, the combination of hypertrophic cardiomyopathy, WPW pattern and male gender raises strong suspicion for Danon disease and should be investigated by genetic testing.
Atrial and ventricular arrhythmias develop in about 50% of patients and implantable cardioverter defibrillators are used for their treatment [13]. Nevertheless, DC shocks are not always effective [16], and lethal dysrhythmias occur in about 30% of high risk patients [13]. Also, over 1/3 of patients undergo ablation for pre-excitation; notably, multiple attempts may be required due to the development of diffuse fibrosis [13].
The literature on anaesthesia for patients with Danon disease is poor. In a child who received general anaesthesia for dental procedures, the management mainly focused on the existing hypertrophic cardiomyopathy with outflow obstruction [15]. Inhalational anaesthesia with N2O and sevoflurane was safe and no arrhythmias or other cardiovascular complications occurred [15].

Fabry disease

Fabry or Anderson-Fabry disease is another lysosomal storage abnormality with an X-linked recessive inheritance. It is characterized by deficiency of α-galactosidase Α and accumulation of the glyco­lipid globotriaosylceramide (Gb3) in various organs [8]. The heart is always affected, while cutaneous, renal, respiratory and nervous system involvement is also quite common [8]. Enzyme replacement therapy seems to reduce the Gb3 deposits [8].
Cardiac involvement includes lesions in the myocardium, in the valves and conduction pathways; left ventricular hypertrophy and valvular regurgitation are common echocardiography findings, while supraventricular tachycardias, atrial fibrillation or flutter, bundle branch blocks, AV conduction delay and nodal dysfunction may also be encountered [7, 8, 10]. Ventricular tachycardias – occasionally resistant or even fatal – occur in more than 8% of patients [10].
The ECG findings include a short PQ (PR) interval which is not followed by the classic delta wave of the WPW syndrome, features of left ventricular hypertrophy, pathological Q waves and ST interval changes [8, 10, 18, 19]. Accessory pathways connecting the atria and His bundle or ventricular tissue have been suggested as possible causes of pre-excitation and AVRTs [20], while Gb3 deposits on AV junction can also cause accelerated AV nodal and subsequently AV conduction [9, 10].
Commonly used general anaesthetics, such as propofol, thiopental, isoflurane, sevoflurane and desflurane, combined with fentanyl or remifentanil, have been described as safe [18, 21, 22]. Intraoperative lidocaine IV infusion has also been used without problems [21]. Enzyme replacement therapy should be continued perioperatively, as no interaction with anaesthetics has been reported [21]. There are no data about regional anaesthesia in patients with Fabry disease.

Pompe disease

Pompe disease is a glycogen storage disorder characterized by musculature damage due to acid α-glucosidase deficiency [8]. Ιt follows an autosomal recessive pattern of inheritance, and may present at any time of life, mainly as skeletal muscle weakness and hypotonia [8]. Glycogen deposition on cardiac muscle, nodes and conduction pathways causes left ventricular hypertrophy – with or without outflow obstruction – and serious arrhythmias [8, 23–25]. Specifically, the infantile Pompe disease has been strongly associated with pre-excitation [23]. Enzyme replacement therapy has a positive effect on cardiac hypertrophy, but seems less beneficial for arrhythmias [8].
Characteristic ECG findings include a short PQ (PR) interval and high QRS voltages due to the hypertrophic cardiomyopathy [8, 24]. Also, ST-segment depression and T-wave inversion may be seen [24, 26]. Echocardiography can reveal possible dynamic obstruction and assess the ventricular cavity volume; left ventricular mass index values higher than 350 g m-2 seem to correlate with the development of lethal arrhythmias [25-27].
There is no evidenced relation between a specific anaesthetic drug and cardiovascular complications [25]. Nevertheless, haemodynamic instability, especially after anaesthesia induction, has been reported in patients with Pompe disease, who seem to be extremely sensitive to the negative inotropic and vasodilating actions of general anaesthetics [24–27]. The use of dexmedetomidine (1 μg kg-1 in 10 min, followed by 0.5 μg kg-1 h-1 infusion) has been recently described as useful and haemodynamically stable [28]; it should be noted, though, that this particular patient had no signs suggesting serious cardiac involvement, according to preoperative ECG and echocardiography. Among neuromuscular blockers, succinylcholine should probably be avoided due to the risk of hyperkalaemia from the damaged muscular tissue [29, 30].
Most patients with Pompe disease requiring anaesthesia are infants undergoing muscle biopsy or placement of central venous catheters [24–26, 30–33]. Wang et al. described the anaesthetic management and complications in 9 patients with infantile Pompe disease: seven patients developed ventricular tachycardia, ventricular fibrillation or torsades de pointes, and three of them died [25]. Notably, all arrhythmias occurred under propofol or sevoflurane anaesthesia [25]. Based on complications they encountered, other authors also suggest that propofol should be used with caution or avoided [31, 34], while ketamine exhibits a more favorable profile [25, 30, 31, 34].
Regional anaesthetic techniques have been advocated [27, 32], especially in parturients undergoing caesarean delivery [35, 36]. Successful labour epidural analgesia [37], peripheral nerve blocks for muscle biopsies [34, 38], and patient-controlled epidural analgesia [27] have also been reported. Caution is needed, especially with spinal local anaesthetics and subsequent intense sympathetic block; a phenylephrine infusion for maintenance of systemic vascular resistance, and consequently blood pressure, seems useful [36].

Other rare syndromes associated with pre-excitation

Tuberous sclerosis

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder characterized by benign growths, mainly in the skin, heart, brain, kidneys and lungs [39-41]. It has an autosomal dominant inheritance, with mutations in TSC1 and TSC2 genes, which are responsible for the proteins hamartin and tuberin [41]. The characteristic triad of facial angiofibromas, mental retardation and seizures is found in 30% of patients [39, 40]. Cardiac rhabdomyomas are found in about 80% of patients, causing blood flow obstruction, cardiac failure or life-threatening arrhythmias, such as blocks, supraventricular tachycardias, ventricular tachycardia or ventricular fibrillation [40]. Pre-excitation is encountered in about 10% of patients, especially in those with cardiac tumors [40].
Surgical procedures may be performed for tumor excision due to the disease per se or for unrelated reasons. Rhabdomyomas, causing severe arrhythmias or heart failure, may require cardiac surgery [39, 40]. Sedation [42, 43], general anaesthesia [39, 40, 44–50] and regional anaesthesia [40, 44, 51, 52] have all been used in patients with TSC. Shenkman et al. studied retrospectively 24 paediatric patients who received 52 general anaesthetics, while epidural anaesthesia was performed in two cases [40]. Both inhalational and intravenous agents were used for induction of general anaesthesia. The authors suggest that an anticholinergic agent, such as glycopyrrolate, should be readily available, since pre-existing conduction defects (i.e. sinus node dysfunction) render these patients prone to bradyarrhythmias [40]. This should be taken into account when drugs reducing the sympathetic outflow, such as central alpha-2 agonists (i.e. clonidine, dexmedetomidine), are used [42]. Publications on the perioperative management, complications and outcome of patients with TSC are presented in Table 2.

MELAS and LHON syndrome

The MELAS and LHON syndromes are rare genetic diseases with mutations in the mitochondrial DNA [7, 53]. The LHON syndrome is characterized by bilateral loss of central vision, while the MELAS syndrome involves mainly the musculoskeletal system and brain, manifested as muscle weakness, seizures and progressive dementia [7, 53]. Cardiovascular abnormalities may exist in both diseases, namely cardiomyopathy, conduction abnormalities (i.e. AV blocks) and pre-excitation [7, 53–56]. Specifically, about 13% of MELAS patients have pre-excitation ECG abnormalities of the WPW type; in some cases, ablation of the accessory pathway is required, because pre-excitation is symptomatic, causing recurrent episodes of supraventricular tachycardia [53–55, 57].
While information about the anaesthetic management of patients with LHON syndrome is lacking, there are several case reports describing the anaesthetic implications for MELAS syndrome. Unfortunately, most of them focus on the musculoskeletal abnormalities. Regarding their cardiovascular responses, patients with MELAS syndrome generally exhibit good tolerance to common anaesthetics, neuromuscular blockers and their standard reversals (i.e. anticholinergic/neostigmine) [54, 58–60]. Due to possible susceptibility to malignant hyperthermia, caution is needed with potentially triggering agents, such as succinylcholine and volatiles [54, 61–63], although no complications have been reported in published cases where these agents were used [54, 64, 65]. Drug interactions, especially between anticonvulsants and general anaesthetics/adjuvants, should also be taken into account [66]. Monitoring of the anaesthetic depth and neuromuscular transmission should be considered, since the patients may exhibit excessive sensitivity to sedatives and hypnotics [58, 67], and also an unpredictable response to NMBs [67]. The latter ones should better be omitted, if possible [55, 62].
Gurrieri et al. described 20 anaesthetics for 9 patients with MELAS syndrome; three of the patients had significant cardiac pathology, such as AV blocks, cardiomyopathy, WPW, and valvulopathy [54]. Propofol, etomidate and thiopental were given for induction, while desflurane, isoflurane or halothane were used in the majority of cases for maintenance of anaesthesia, without complications [54]. Total intravenous anaesthesia with propofol – with or without remifentanil – seems advantageous in terms of minimizing the risk of MH [61], and is preferred by many authors [58–61, 67–70]. Notably, although propofol infusion has been used uneventfully for a few hours [54, 58–60, 71], caution is needed in case of prolonged administration – i.e. for sedation in intensive care units – because it may further decrease the mitochondrial ATP production and cause severe acidosis [72]. Actually, mitochondrial dysfunction is considered to be involved in the pathophysiology of propofol infusion syndrome, and the death of a patient with LHON, who developed the syndrome after five days of propofol infusion, has been reported [73].
Regional anaesthesia may be preferred in order to avoid the risk of malignant hyperthermia or drug interactions [64, 66, 74]. Spinal anaesthesia has been used without complications [64, 66, 74, 75], but caution is needed to definitely exclude any pre-existing neurological problems [75]. Light sedation may be added to reduce patients’ anxiety [66]. Surgical, postoperative and labour epidural anaesthesia/analgesia have also been used uneventfully [57, 58, 60, 66, 70, 72], and may effectively reduce the metabolic demands associated with pain and perioperative stress [72].
Hyponatraemia and hyperkalaemia are often encountered in these patients, and may increase the risk of arrhythmias [54, 65]. In this regard, succinylcholine should be avoided due to possible induction of hyperkalaemia [60]. Echocardiography should be performed, especially in patients with severe muscle weakness possibly masking their limited cardiovascular reserves [65].
Regarding the relation between other mitochondrial diseases and pre-excitation, little is known. Driessen et al. analyzed retrospectively the records of 122 children diagnosed with mitochondrial defects; cardiomyopathy or conduction defects were found in 10 patients (8.2%) [76]. Relative anaesthetic data are lacking [77–80]. Publications on the perioperative management of patients with rare mitochondrial diseases associated with pre-excitation are presented in Table 3.

General principles of the perioperative care in patients with rare multisystem syndromes associated with pre-excitation

Multidisciplinary perioperative care should be provided to patients with the abovementioned multisystem syndromes, according to the affected organs [37]. Pre anaesthetic assessment should focus on end-organ damage, starting with a detailed history about the age of presentation, sympto­matology, course and treatment of the disease [21]. The patients should undergo careful and extensive cardiological evaluation, regarding history of arrhythmias or syncopal episodes, symptoms of heart failure, detailed physical examination with vital signs and auscultation, and an X-ray for revealing possible cardiomegaly [40]. An ECG is mandatory, since it may show features of cardiac hypertrophy, arrhythmias, conduction abnormalities and patterns of pre-excitation [40, 60, 65, 68, 70]. A 24h-Holter may also be considered, according to cardiologic consultation [13]. Echocardiography is indicated in the majority of cases to exclude cardiomyopathy, to assess the cardiac function accurately [22, 60, 65, 68], and guide cardiovascular monitoring, anaesthesia and perioperative management. Non-invasive cardiac stress testing may also be required in selected cases [22]. In the case of cardiomyopathy, it should be kept in mind that the cardiac function may significantly deteriorate over a short period of time (i.e. over 3-6 months in Danon disease) [13, 15]. Regarding the preparation and optimization of patients who are scheduled for elective surgery, specialized consultation – including cardiological – and improvement of the function of all affected systems are mandatory, by the use of drugs or invasive methods, if required. Arrhythmias should be adequately suppressed and cardiac function should be optimized. Antiarrhythmics should be continued perioperatively, while implantable cardioverter defibrillators should be temporarily inactivated for the operation in order to avoid the risks of electromagnetic and electrocautery interference. Nevertheless, a back-up source for external defibrillation should be available. In the presence of conduction abnormalities, an external pacemaker should also be prepared before anaesthesia induction. Intravenous antiarrhythmic agents should be available for treatment of arrhythmias in haemodynamically stable patients [70], while a defibrillator should also be ready for use in case of hemodynamic compromise.
Intraoperative cardiovascular monitoring should include a five-lead ECG and invasive arterial pressure measurement, while cardiac output monitoring is also indicated in cases with significant cardiac function impairment. Arrhythmias associated with pre-excitation should be managed according to their type and hemodynamic consequences. In the algorithm of arrhythmia management, emphasis should be given to the first step, which is the prompt assessment of patient’s hemodynamic status [81, 82]. In case of hemodynamic instability, the patient should undergo urgent electrical synchronized cardioversion [82]. Synchronized cardioversion is also indicated for supraventricular tachycardia and atrial fibrillation resistant to drugs [82]. Immediate defibrillation, combined with cardiopulmonary resuscitation and drugs (adrenaline, amiodarone), is indicated in ventricular fibrillation or pulseless ventricular tachycardia, according to the Advanced Life Support algorithm [82].
Patients who are haemodynamically stable can be evaluated and treated according to the type of arrhythmia with appropriate maneuvers and/or drugs. Regular supraventricular (narrow-complex) tachycardia should be terminated by the use of vagal maneuvers, and IV adenosine [81]. Beta blockers (esmolol and propranolol) can also be helpful. Irregular wide complex tachycardia may indicate pre-excited atrial fibrillation; amiodarone can be given, while digoxin, verapamil, adenosine and diltiazem should be avoided, because they facilitate the conduction via the AP and may increase the risk of ventricular fibrillation [82].
Preload, afterload, inotropy and anaesthetics should be titrated according to the cardiac disease [15]. Adequate hydration to ensure optimal ventricular filling and maintenance of peripheral vascular resistance are mandatory for avoiding hypotension and coronary hypoperfusion in patients with hypertrophic cardiomyopathy [25, 28, 34]. Arrhythmogenic or triggering factors such as stress, fever, pain, intravascular volume depletion/haemor­rhage, light anaesthesia and hypercarbia should be avoided [24, 27, 31]. Electrolyte and acid-base monitoring, with prompt correction of any abnormality, is also required to reduce the risk of arrhythmias [54, 65]. Careful selection of agents – regarding their chronotropic, dromotropic and inotropic action – and titration of doses is required, especially during anaesthesia induction [24–26]. Also, smooth recovery from anaesthesia, adequate postoperative analgesia, prevention of nausea/vomiting that may cause stress and tachycardia, should be taken care of. Finally, close postoperative follow-up and cardiovascular monitoring in a high dependency unit are usually required for early diagnosis and prompt treatment of arrhythmias and other cardiovascular complications [26, 27, 35, 36, 40, 65, 68].

Limitations

In the present review, we used information from a few retrospective studies, and mainly from case series and reports. For some conditions the data were limited, since only a small number of case reports were identified. Nevertheless, we believe that the present review may help to achieve a better understanding of rare genetic multisystem diseases associated with pre-excitation and provide some useful information on their perioperative management.

Conclusions

The anaesthetic management of patients with rare genetic multisystem diseases associated with pre-excitation may be quite challenging, especially in case of emergencies, when there is not adequate time for thorough investigation and clinical optimization. In these patients pre-excitation usually co-exists with structural cardiac abnormalities, thus increasing the risk of serious perioperative arrhythmias and other life-threatening cardiovascular complications. A multidisciplinary approach and perioperative care are required, according to the affected organs. Also, close observation, invasive cardiovascular monitoring and a high level of alertness are mandatory for prevention and prompt treatment of arrhythmias.

Acknowledgements

1. Financial support and sponsorship: none.
2. Conflict of interest: none.

References

1. Öhnell RF. Pre-excitation, cardiac abnormality, patho-physiological, patho-anatomical and clinical studies of excitatory spread phenomenon bearing upon the problem of the WPW (Wolff, Parkinson, and White) electrocardiogram and paroxysmal tachycardia. Acta Med Scand 1944; 152: 74-167.
2. Mark DG, Brady WJ, Pines JM. Preexcitation syndromes: diagnostic consideration in the ED. Am J Emerg Med 2009; 27: 878-888. doi: 10.1016/j.ajem.2008.06.013.
3. Staikou C, Stamelos M, Stavroulakis E. Perioperative management of patients with pre-excitation syndromes. Rom J Anaesth Intensive Care 2018; 25: 131-147. doi: 10.21454/rjaic.7518.252.stk.
4. Wellens HJ, Brugada P, Penn OC. The management of preexcitation syndromes. JAMA 1987; 257: 2325-2333. doi: 10.1001/jama.1987. 03390170081032.
5. Keating L, Morris F, Brady W. Electrocardiographic features of Wolff-Parkinson-White syndrome. Emerg Med J 2003; 20: 491-493. doi: 10.1136/emj.20.5.491.
6. Al-Khatib SM, Pritchett ELC. Clinical features of Wolff-Parkinson-White syndrome. Am Heart J 1999; 138: 403-413.
7. Koneru JN, Wood MA, Ellenbogen KA. Rare forms of preexcitation: a case study and brief overview of familial forms of preexcitation. Circ Arrhythm Electrophysiol 2012; 5: e82-87. doi: 10.1161/CIRCEP. 111.968917.
8. Nagueh SF. Anderson-Fabry disease and other lysosomal storage disorders. Circulation 2014; 130: 1081-1090. doi: 10.1161/CIRCULATIONAHA.114.009789.
9. Jastrzebski M, Bacior B, Dimitrow PP, Kawecka-Jaszcz K. Electrophysiological study in a patient with Fabry disease and a short PQ interval. Europace 2006; 8: 1045-1047. doi: 10.1093/europace/eul121.
10. Linhart A, Elliott PM. The heart in Anderson-Fabry disease and other lysosomal storage disorders. Heart 2007; 93: 528-535. doi: 10.1136/hrt.2005.063818.
11. Schofield RS, McGarry K, Murphy CL, O’Hare K. Cardiac transplant in a family pedigree of hypertrophic cardiomyopathy secondary to a mutation in the AMP gene. BMJ Case Rep 2013; doi: 10.1136/bcr-2013-009929.
12. Danon MJ, Oh SJ, DiMauro S, Manaligod JR, Eastwood A, Naidu S, Schliselfeld LH. Lysosomal glycogen storage disease with normal acid maltase. Neurology 1981; 31: 51-57. doi: 10.1212/wnl.31.1.51.
13. D’souza RS, Levandowski C, Slavov D, et al. Danon disease: clinical features, evaluation, and management. Circ Heart Fail 2014; 7: 843-849. doi: 10.1161/CIRCHEARTFAILURE.114.001105.
14. Nishino I, Fu J, Tanji K, et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 2000; 406: 906-910. doi: 10.1038/35022604.
15. August DA. Anesthetic implications of Danon disease. Paediatr Anaesth 2009; 19: 1026-1028. doi: 10.1111/j.1460-9592.2009.03125.x.
16. Maron BJ, Roberts WC, Arad M, et al. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA 2009; 301: 1253-1259. doi: 10.1001/jama.2009.371.
17. Arad M, Maron BJ, Gorham JM, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2005; 352: 362-372. doi: 10.1056/NEJMoa033349.
18. Watanabe H, Aoki T, Ono A. The anesthetic management of a patient with Fabry’s disease. Masui 1995; 44: 1258-1260.
19. Gambarin FI, Disabella E, Narula J, et al. When should cardiologists suspect Anderson-Fabry disease? Am J Cardiol 2010; 106: 1492-1499. doi: 10.1016/j.amjcard.2010.07.016.
20. Omar AR, Harris L, Cameron DA, Chauhan VS. WPW and Fabry’s disease: evidence for atrioventricular and atriohisian accessory pathway conduction. Heart Rhythm 2006; 3: S214.
21. Krüger S, Nowak A, Müller TC. General anesthesia and Fabry disease: a case report. A A Case Rep 2017; 8: 247-249. doi: 10.1213/XAA. 0000000000000479.
22. Woolley J, Pichel AC. Peri-operative considerations for Anderson-Fabry disease. Anaesthesia 2008; 63: 101-102. doi: 10.1111/j.1365-2044.2007.05387.x.
23. Bulkly BH, Hutchins GM. Pompe’s disease presenting as hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome. Am Heart J 1978; 96: 246-252.
24. Desena HC, Brumund MR, Superneau D, Snyder CS. Ventricular fibrillation in a patient with Pompe disease: a cautionary tale. Congenit Heart Dis 2011; 6: 397-401. doi: 10.1111/j.1747-0803.2010. 00471.x.
25. Wang LY, Ross AK, Li JS, et al. Cardiac arrhythmias following anesthesia induction in infantile-onset Pompe disease: a case series. Paediatr Anaesth 2007; 17: 738-748. doi: 10.1111/j.1460-9592.2007.02215.x.
26. Al Atassi A, Al Zughaibi N, Naeim A, Al Basha A, Dimitriou V. Anesthesia management in an infant with glycogen storage disease type II (Pompe disease). Middle East J Anaesthesiol 2015; 23: 34334-34336.
27. Kim WS, Cho AR, Hong JM, Kim ES, Park SC, Yoon JY, Kim TK. Combined general and epidural anesthesia for major abdominal surgery in a patient with Pompe disease. J Anesth 2010; 24: 768-773. doi: 10.1007/s00540-010-0984-4.
28. Kumbar V, Simha J, Gundappa P. Anaesthetic management of a patient with Pompe disease for kyphoscoliosis correction. Indian J Anaesth 2016; 60: 3493-3451. doi: 10.4103/0019-5049.181597.
29. Cilliers HJ, Yeo ST, Salmon NP. Anaesthetic management of an obstetric patient with Pompe disease. Int J Obstet Anesth 2008; 17: 170-173. doi: 10.1016/j.ijoa.2007.11.001.
30. McFarlane HJ, Soni N. Pompe’s disease and anaesthesia. Anaesthesia 1986; 41: 1219-1224.
31. Ing RJ, Cook DR, Bengur RA, et al. Anaesthetic management of infants with glycogen storage disease type II: a physiological approach. Paediatr Anaesth 2004; 14: 514-519. doi: 10.1111/j.1460-9592.2004.01242.x.
32. Sato Y, Yamaguchi K, Miwa T, Hiroki K. Anesthetic management for a child with Pompe disease. Masui 2007; 56: 324-325.
33. Sakakibara M, Teramoto Y, Aoyama T, et al. A case report of anesthesia for a child with Pompe’s disease (glycogen storage disease type II). Masui 2009; 58: 219-222.
34. Walker RW, Briggs G, Bruce J, Fletcher J, Wraith ED. Regional anes­thetic techniques are an alternative to general anesthesia for infants with Pompe’s disease. Paediatr Anaesth 2007; 17: 697-702. doi: 10.1111/ j.1460-9592.2007.02196.x.
35. Weida J, Hainline BE, Bodkin C, Williams MK. Management of a pregnancy complicated by pompe disease. Case Rep Obstet Gynecol 2012; 2012: 137861. doi: 10.1155/2012/137861.
36. Dons-Sinke IJ, Dirckx M, Scoones GP. Anaesthetic management of two patients with pompe disease for caesarean section. Case Rep Anesthesiol 2014; 2014: 650310. doi: 10.1155/2014/650310.
37. Perniconi B, Vauthier-Brouzes D, Morélot-Panzini C, et al. Multidisciplinary care allowing uneventful vaginal delivery in a woman with Pompe disease. Neuromuscul Disord 2016; 26: 610-613. doi: 10.1016/j.nmd.2016.02.016.
38. Rosen KR, Broadman LM. Anaesthesia for diagnostic muscle biopsy in an infant with Pompe’s disease. Can Anaesth Soc J 1986; 33: 790-794.
39. Lee JJ, Imrie M, Taylor V. Anaesthesia and tuberous sclerosis. Br J Anaesth 1994; 73: 421-425.
40. Shenkman Z, Rockoff MA, Eldredge EA, Korf BR, Black PM, Soriano SG. Anaesthetic management of children with tuberous sclerosis. Paediatr Anaesth 2002; 12: 700-704. doi: https://doi.org/10.1046/j.1460-9592.2002.00917.x
41. Islam MP, Roach ES. Tuberous sclerosis complex. Handb Clin Neurol 2015; 132: 97-109. doi: 10.1016/B978-0-444-62702-5.00006-8.
42. Mason KP, Zgleszewski S, Forman RE, Stark C, DiNardo JA. An exaggerated hypertensive response to glycopyrrolate therapy for bradycardia associated with high-dose dexmedetomidine. Anesth Analg 2009; 108: 906-908. doi: 10.1213/ane.0b013e3181948a6f.
43. Sugi Y, Yasumoto M, Higa K, Dan K. Anesthetic management of a patient with tuberous sclerosis. Masui 1996; 45: 227-229.
44. Causse-Mariscal A, Palot M, Visseaux H, Daigremont-Botmans C, Malinovsky JM. Labor analgesia and cesarean section in women affected by tuberous sclerosis: report of two cases. Int J Obstet Anesth 2007; 16: 277-280. doi: 10.1016/j.ijoa.2006.10.012.
45. Cho SY, Kim KH, Jeon WJ. Caesarean delivery under general anaesthesia for a woman with undiagnosed tuberous sclerosis complex and lymphangioleiomyomatosis. Anaesth Intensive Care 2009; 37: 142-143.
46. Papaioannou EG, Staikou CV, Lambadariou A, Karavokyros IG, Tsinari K. Anesthetic management of a patient with tuberous sclerosis presenting for renal transplantation. J Anesth 2003; 17: 193-195. doi: https://doi.org/10.1007/s00540-003-0167-7.
47. Nott MR, Halfacre J. Anaesthesia for dental conservation in a patient with tuberous sclerosis. Eur J Anaesthesiol 1996; 13: 413-415. doi: https://doi.org/10.1046/j.1365-2346.1996.00956.x.
48. Tsukui A, Noguchi R, Honda T, Tobita T, Fukuda S, Shimoji K. Aortic aneurysm in a four-year-old child with tuberous sclerosis. Paediatr Anaesth 1995; 5: 67-70.
49. Ong EL, Koay CK. Tuberous sclerosis presenting for laparotomy. Anaesth Intensive Care 2000; 28: 94-96.
50. Bowditch J, Russell R, McCready S. General anaesthesia for caesarean section in a woman with tuberous sclerosis. Int J Obstet Anesth 2017; 31: 110-111. doi: 10.1016/j.ijoa.2017.04.011.
51. Takahashi K, Yano Y, Miyata Y, Terai T. Anesthetic management of a patient with pulmonary tuberous sclerosis complicated with renal angiomyolipoma. Masui 2009; 58: 641-644.
52. McLoughlin L, Thomas G, Hasan K. Pregnancy and lymphangioleiomyomatosis: anaesthetic management. Int J Obstet Anesth 2003; 12: 40-44. doi: https://doi.org/10.1016/S0959-289X(02)00138-3.
53. Sproule DM, Kaufmann P, Engelstad K, Starc TJ, Hordof AJ, De Vivo DC. Wolff-Parkinson-White syndrome in patients with MELAS. Arch Neurol 2007; 64: 1625-1627. doi: 10.1001/archneur.64.11.1625.
54. Gurrieri C, Kivela JE, Bojanić K, et al. Anesthetic considerations in mitochondrialencephalomyopathy, lactic acidosis, and stroke-like episodes syndrome: a case series. Can J Anaesth 2011; 58: 751-763. doi: 10.1007/s12630-011-9528-0.
55. Uchida S, Nakajima K, Saito S. Woman with mitochondrial encephalomyopathy who died of cardiogenic shock after surgery. Masui 2010; 59: 784-787.
56. Lee MH, Sung YJ, Yoon JH, et al. Wolff-Parkinson-white syndrome in a patient with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome. Korean Circ J 2011; 41: 674-676. doi: 10.4070/kcj.2011.41.11.674.
57. Okajima Y, Tanabe Y, Takayanagi M, Aotuska H. A follow up study of myocardial involvement in patients with mitochondrialencephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Heart 1998; 80: 292-295. doi: 10.1136/hrt.80.3.292.
58. Gentili ME, Raud C, Enel D, Hénot M, Bothereau H. Combination of general anaesthesia and postoperative epidural analgesia in mitochondrial myopathy. Ann Fr Anesth Reanim 2013; 32: e149. doi: 10.1016/j.annfar.2013.07.798.
59. Pedroviejo V, García Mostaza A, Pérez J, Ayuso M. Anesthesia during laparoscopic cholecystectomy in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS-syndrome). Rev Esp Anestesiol Reanim 2010; 57: 120-122.
60. Sasano N, Fujita Y, So M, Sobue K, Sasano H, Katsuya H. Anesthetic management of a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) during laparotomy. J Anesth 2007; 21: 72-75. doi: 10.1007/s00540-006-0449-y.
61. Imai Y, Kitamura T, Kawamura G, Nakamura M, Yamada Y. Anesthetic management of emergency total gastrectomy in a patient with mitochondrial encephalomyopathy: a case of gastric perforation accompanied by systemic inflammatory response syndrome. Masui 2010; 59: 765-769.
62. Singh B, Low PS, Yeo JF. MELAS : a case report. Ann Acad Med Singapore 2004; 33: 69-71.
63. Itaya K, Takahata O, Mamiya K, Saito T, Tamakawa S, Akama Y, Kubota M, Ogawa H. Anesthetic management of two patients with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Masui 1995; 44: 710-712.
64. Maslow A, Lisbon A. Anesthetic considerations in patients with mitochondrial dysfunction. Anesth Analg 1993; 76: 884-886.
65. Humeidan ML, Dalia J, Traetow WD. Anesthetic considerations for renal transplant surgery in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome: a case report. J Clin Anesth 2016; 34: 344-347. doi: 10.1016/j.jclinane. 2016.05.025.
66. Blair MT, Heard G. Neuraxial anaesthesia in MELAS syndrome. Anaesth Intensive Care 2011; 39: 1152-1153.
67. Aouad MT, Gerges FJ, Baraka AS. Resistance to cisatracurium in a patient with MELAS syndrome. Paediatr Anaesth 2005; 15: 1124-1127. doi: 10.1111/j.1460-9592.2005.01583.x.
68. Park JS, Baek CW, Kang H, et al. Total intravenous anesthesia with propofol and remifentanil in a patient with MELAS syndrome – a case report. Korean J Anesthesiol 2010; 58: 409-412. doi: 10.4097/kjae.2010.58.4.409.
69. Thiel A, Ritzka M, Saur G. Anesthesia in mitochondrial encephalomyopathies. Anasthesiol Intensivmed Notfallmed Schmerzther 2001, 36: 437-439. doi: 10.1055/s-2001-15476.
70. Bolton P, Peutrell J, Zuberi S, Robinson P. Anaesthesia for an adolescent with mitochondrial encephalomyopathy-lactic acidosis-stroke-like episodes syndrome. Paediatr Anaesth 2003; 13: 453-456. doi: https://doi.org/10.1046/j.1460-9592.2003.01001.x.
71. Thompson VA, Wahr JA. Anesthetic considerations in patients presenting with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Anesth Analg 1997; 85: 1404-1406.
72. Maurtua M, Torres A, Ibarra V, DeBoer G, Dolak J. Anesthetic management of an obstetric patient with MELAS syndrome: case report and literature review. Int J Obstet Anesth 2008; 17: 370-373. doi: 10.1016/j.ijoa.2007.11.011.
73. Vanlander AV, Jorens PG, Smet J, et al. Inborn oxidative phosphorylation defect as risk factor for propofol infusion syndrome. Acta Anaes­thesiol Scand 2012; 56: 520-525. doi: 10.1111/j.1399-6576.2011. 02628.x.
74. Bell JD, Higgie K, Joshi M, Rucker J, Farzi S, Siddiqui N. Anesthetic management of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS syndrome) in a high-risk pregnancy: a case report. A A Case Rep 2017; 9: 38-41. doi: 10.1213/XAA.0000000000000520.
75. Hsiao PN, Cheng YJ, Tseng HC, Chuang YH, Kao PF, Tsai SK. Spinal anesthesia in MELAS syndrome: a case with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Acta Anaesthesiol Sin 2000; 38: 107-110.
76. Driessen J, Willems S, Dercksen S, Giele J, van der Staak F, Smeitink J. Anesthesia-related morbidity and mortality after surgery for muscle biopsy in children with mitochondrial defects. Paediatr Anaesth 2007; 17: 16-21. doi: 10.1111/j.1460-9592.2006.02043.x.
77. Rosaeg OP, Morrison S, MacLeod JP. Anaesthetic management of labour and delivery in the parturient with mitochondrial myopathy. Can J Anaesth 1996; 43: 403-407. doi: 10.1007/BF03011722.
78. Kelly A, O’Connor M. Mitochondrial myopathy and anaesthesia. Anaesthesia 1990; 45: 596.
79. Fritz T, Wessel K, Weidle E, Lenz G, Peiffer J. Anesthesia for eye operations in mitochondrial encephalomyelopathy. Klin Monbl Augenheilkd 1988; 193: 174-178. doi: 10.1055/s-2008-1050241.
80. Klockgether-Radke A, Henze T, Braun U, Kettler D. General anesthesia in two patients with mitochondrial myopathy. Anaesthesist 1993; 42: 111-114.
81. Olgin JE, Zipes DP. Specific arrythmias: diagnosis and treatment. In: Libby P, Bonow RO, Mann DL, Zipes DP (eds.). Braunwald’s Heart Disease – A text book of cardiovascular medicine. 8th ed. Saunders, Philadelphia 2008; 884-893.
82. Lockey A, Balance J, Domanovits A, et al. Advanced Life Support, ERC Guidelines, Course Manual. 6th ed. European Resuscitation Council Secretariat vzw, Edegem 2010; 83-84, 112-115.