Anaesthesia and orphan disease

Editor, Neuronal ceroid lipofuscinosis (NCL) diseases are a group of autosomal recessive neurodegenerative storage diseases characterised by lysosomal accumulation of autofluorescent material in neurones and other cell types. They manifest during childhood and adolescence, and are classified as CLN1 to CLN8, which share similar symptoms such as loss of vision, epilepsy, dementia and accumulation of unusual ceroid lipofuscin in brain and other tissues. All NCL disorders are incurable, slowly progressive and lead to early death.1,2 In juvenile NCL (JNCL or CLN3), membrane proteins with unknown function are deficient.2 These patients receive numerous medications associated with serious side effects, such as antiepileptic drugs (AEDs).2 The use of a vagus nerve stimulator (VNS) is an adjunctive treatment for certain types of intractable epilepsy.3 Children with NCL often require anaesthetic care for diagnostic procedures, gastrostomy, insertion of VNS or other types of surgery. We report the successful management of anaesthesia for a patient with JNCL. Written parental consent for publication of this case has been obtained. A 14-year-old boy (42 kg) with JNCL was scheduled for insertion of a VNS under general anaesthesia. By the age of 6 years, signs of growth retardation and decrease of visual acuity had appeared. At 9 years of age, he became blind and unable to swallow, thus needing a gastrostomy tube. By the age of 10 years, myoclonic seizures and abnormal activity on the electroencephalogram (EEG) developed and he became bedridden. The diagnosis was made by microscopic examination of a blood smear, electron microscopy of isolated lymphocytes and skin biopsy. A search for a mutation in the CLN3 gene showed a 1.02-kb deletion. The child responded to painful stimulation but not to verbal command. He was taking zonisamide, phenytoin, clobazam, clonazepam and valproic acid, but grand mal and myoclonic seizures persisted with a frequency of about 10 to 12 times per day. Preoperative vital signs, blood tests including haemostasis tests, ECG and chest radiograph were all normal. The child was premedicated with ranitidine 150 mg and the AEDs were continued. Regular intraoperative monitoring, a rectal temperature probe and bispectral index (BIS) were used. Glycopyrrolate 0.2 mg was given intravenously 10 min before induction of anaesthesia to reduce secretions. General anaesthesia was induced using a remifentanil infusion at a rate of 1 μg kg−1 min−1 for 1 min (during which time the lungs were preoxygenated) followed by thiopental 7 mg kg−1. No neuromuscular blocking agent (NMBA) was administered. Tracheal intubation was performed successfully. Mechanical ventilation was started using 40% oxygen in air, maintaining normocapnia. Anaesthesia was maintained with a continuous infusion of remifentanil 0.1 to 0.4 μg kg−1 min−1 (to keep haemodynamic variables within normal limits) and isoflurane to maintain a BIS value of 40 to 50. Temperature was maintained between 36.5°C and 37°C using forced air-warming blankets. Insertion of the VNS (Cyberonics, Houston, Texas, USA) lasted 90 min. At the end of surgery, paracetamol 650 mg was given intravenously to provide postoperative analgesia. The trachea was extubated 110 min after induction of anaesthesia when surgery had been completed and after safe extubation criteria had been achieved: stable vital signs, a spontaneous respiratory rate of about 18 breaths per minute, a tidal volume of about 5 ml kg−1, normocapnia on capnography and spontaneously sustained eye opening. The postoperative course was uneventful and neurological symptoms were not exacerbated. Only a few cases of anaesthesia management of patients with NCL have been described in the literature. Defalque4 reported slow recovery from anaesthesia in an adult with NCL undergoing laparotomy under general anaesthesia using isoflurane with an NMBA. Yamada et al.5 described postoperative hypothermia in an infantile NCL using thiamylal and sevoflurane without NMBA. Gopalakrishnan et al.6 reported a case of juvenile NCL undergoing ocular evaluation under general anaesthesia involving propofol and sevoflurane, without any complications. Pereira et al.7 described a case of infantile NCL and another of JNCL undergoing anaesthesia involving sevoflurane without an NMBA, with no complication. In order not to exacerbate neurological symptoms, our patient was given his regular AEDs. The risk of exacerbating neurological symptoms was a consideration that influenced the choice of anaesthetic agents. First, because there was increased muscle tone and myoclonus, we chose not to use an NMBA for tracheal intubation to avoid a possible prolonged effect of these drugs and the need to reverse residual neuromuscular block. In addition, AEDs may affect NMBAs by causing acetylcholine receptors to be upregulated at the neuromuscular junction.8 Isoflurane can provide sufficient muscle relaxation to facilitate tracheal intubation and this surgical procedure did not require muscle relaxation. A previous study4 has confirmed that a short-acting NMBA can be used safely in patients with NCL if neuromuscular block is monitored carefully. Second, cytochrome p450 enzyme induction by AEDs may alter the metabolism of anaesthetic drugs.9 Third, all inhaled anaesthetics, with the exception of halothane, can produce EEG burst suppression at haemodynamically acceptable doses. Epileptiform EEG activity has been reported during sevoflurane induction with spontaneous ventilation in paediatric and nonepileptic populations.10 Isoflurane can be used as a therapy in status epilepticus, but produces epileptiform EEG activity when given to epileptic patients in high doses.10 Thus, avoiding sevoflurane and using isoflurane at low doses was expected to have anticonvulsant effects. Fourth, anaesthetics can have effects on seizure threshold. Intravenous induction drugs such as propofol and thiopental produce depressant EEG effects. Using titrated doses of thiopental for induction deployed its anticonvulsants mechanism of action.9 Previous studies11–15 have indicated that all synthetic opioids activate epileptic discharges and have a dose-related effect on spike activity. Among these drugs, alfentanil has the most pronounced epileptogenic effects.13 Fentanyl and sufentanil in moderate to large doses have been shown to cause epileptiform EEG activity in nonepileptic patients.14 High-dose remifentanil activates the limbic system without inducing clinical seizures.15 As remifentanil is an ultrashort-acting μ-opioid agonist with a rapid onset and offset, it is attractive for use in neurologically impaired patients. Insertion of the VNS was not a very painful procedure, and low doses of other opioids might have been used. Total intravenous anaesthesia with propofol and remifentanil could be an alternative anaesthetic technique in these patients. Fifth, patients with NCL have a swallowing disorder. To minimise the consequences of acid aspiration, premedication with a histamine H2-receptor antagonist and an anticholinergic is recommended. These patients also have a reduced baseline body temperature. During anaesthesia, they are at an increased risk of hypothermia because they have autonomic nerve dysfunction and abnormalities in metabolic processes. To avoid the complications associated with profound hypothermia, careful planning for anaesthesia including temperature monitoring and use of active warming techniques was imperative.11 Sixth, alterations in cardiac morphology and function, such as left ventricular hypertrophy and repolarisation disturbances, have been reported;16 at autopsy, myocardial and valvular storage of lipopigments have been observed histologically and associated with hypertrophy and dilation of ventricles, degenerative myocardial changes, interstitial fibrosis and fatty replacement. Abundant accumulation of lipopigments and degeneration were seen in all components of the conduction system. Bradycardia, sinus arrest and severe supraventricular tachycardia during anaesthesia in patients with JNCL have also been reported. Some episodes of bradycardia were associated with hypothermia and were successfully treated with anticholinergics. Therefore, preoperative ECG and echocardiography in patients with NCL are considered essential.11,16 Finally, BIS monitoring in epileptic patients may give useful information not only on the sedative-hypnotic state but also on the development of and recovery from abnormal epileptiform EEG activity. During epileptic activity, the EEG on the BIS monitor screen changes abruptly from low frequency waves to high voltage, high frequency waves, followed by sudden increases in the BIS value. However, in a recent study17 comparing propofol-remifentanil with sevoflurane-remifentanil, the authors concluded that the lower the BIS value, the higher the spike frequency and amplitude. In summary, anaesthetic planning in patients with NCL should include careful assessment of neurological and cardiac function. AEDs should not be interrupted in the perioperative period. During anaesthesia, EEG monitoring could be considered in patients with severe epilepsy. Short-acting anaesthetic agents should ensure rapid recovery after surgery. The combination of isoflurane and low doses of remifentanil without NMBA was successful in this case. Acknowledgements relating to this article Assistance with the letter: none. Financial support and sponsorship: none. Conflicts of interest: none.