Seizures and paroxysmal events
Frequent multifocal and erratic or generalized myoclonic jerks have been the most prominent seizures in our patients and are the most frequently mentioned seizure type in neonates and infants with PDE and PNPO.1–3,8–20 In our neonatal video archive most myoclonic jerks occurred in isolation and during sleep. Frequent multifocal and erratic myoclonic jerks were exceptional and were recorded in neonates with abstinence syndrome (four neonates), intracranial haemorrhage (one neonate), developmental defects (one neonate), unknown aetiology (two neonates), and metabolic diseases (one with propionic acidemia, one with methylmalonic aciduria).
As with those patients reported by Nabbout et al.,15 our infants exhibited a great variety of intermixed seizures consisting of myoclonic jerks, tonic seizures, spasms, abnormal eye movements, grimacing, crying, and irritability. In our archive only three other neonates (one with developmental defect, one with methylmalonic aciduria, one unknown) showed comparable intermixed seizures. As in our patients, seizures in PDE have been reported to be prolonged or to proceed to status epilepticus.8,9,12,14–16,19–21 Irritability, agitation, excessive crying, and sleeplessness are common symptoms in infants with PDE.10,15 In our experience, these symptoms are often intermixed with other paroxysmal symptoms or they are associated with frightened facial expressions.
Focal or generalized clonic, tonic, or tonic–clonic seizures, which have been mentioned in various series,1–3,8,12,14,16,19,20 were seen in only one of our neonates (patient 2), but were reported when they were older (patients 1, 2, 3, 5). Generalized tonic–clonic seizures are very exceptional in neonates. It might be supposed that the intermixed tonic–myoclonic seizures in patients with PDE were classified as generalized tonic–clonic.
Abnormal eye movements and grimacing have been described in PDE12,13,17 and PNPO2,18 and were prominent symptoms in our patients. In our video archive we observed abnormal eye movements in 10 neonates (four with hypoxic–ischaemic encephalopathy, two with intracranial haemorrhage, two with intracranial infection, one with developmental defects, one with unknown aetiology). Only one preterm infant with intraventricular haemorrhage showed such grotesque eye deviations as were observed in patients 2 and 5, but these eye deviations were associated with ictal EEG changes.
Other symptoms reported are apnoea, cycling movements, atonic seizures, staring or atypical absence, hiccups, myoclonic seizures provoked by intermittent photic stimulation, startle reactions to touch and sound, and spasms.2,3,9–12,14–16,19,20 Startle reactions were reported in patient 1 before the introduction and after the withdrawal of pyridoxine, and in patient 3 during febrile infection. Serial spasms were recorded in patient 5. Although these spasms are similar to infantile spasms, inter-spasm intervals of 1 to 2 minutes, the absence of ictal pattern, and almost normal interictal EEGs are not readily compatible with such a diagnosis.
Visual symptoms as suspected in patient 2 and reported by patient 5 are described in the recent literature.16,19,20 They comprise intermittent loss of vision, flashing lights, and visual hallucinations, and they are sometimes followed by generalized tonic–clonic seizures. Probably they are more frequent in PDE or PNPO than so far reported.
The EEG during the seizures and/or paroxysmal events was surprisingly inconclusive. We observed continuous or intermittent focal or generalized discharges of sharp waves or rhythmic sharp theta waves during the seizures, but more frequently, we observed no discernable ictal changes. The lack of ictal EEG discharge during distinct paroxysmal events is perhaps more suggestive of PDE or PNPO than the inconstantly obvious ictal discharges. In neonates, myoclonic seizures and other symptoms may occur with and without associated EEG seizure activity.22 Not all paroxysmal events in PDE and PNPO are necessarily of epileptic origin. Vitamin B6 is a required enzyme in the biosynthesis of dopamine and serotonin. Abnormal eye movements, myoclonic jerks, flexor spasms, orofacial dystonia, irritability, startle responses, or behavioural abnormalities might be non-epileptic and could be due to impaired dopaminergic transmission. Some of the clinical features in patients with aromatic l-amino acid decarboxylase deficiency, a disorder of monoamine neurotransmitter metabolism, are similar to those seen in our patients.23,24 Even here, EEG often revealed no apparent ictal change.
In the light of our results, the inconsistent reports on ictal recordings in infants with PDE are not surprising. Nabbout et al.15 presented three ictal EEG records during intermixed spasms, myoclonic, and partial seizures which did not differ greatly. Other ictal EEGs in patients with PDE were described as bilaterally synchronous, lateralized or focal sharp waves, or as focal rhythmic sharp theta waves.11 Spike and poly-spike waves were observed during focal, multifocal, or generalized myoclonic, tonic–clonic, or tonic seizures8,9,12,20 and burst suppression pattern during status epilepticus, infantile spasms, generalized myoclonic jerks, or hiccups.9,12,20 Electrographic seizures without symptoms have also been found.8,13 Hellstrom-Westas et al.17 described a ‘saw-tooth’ pattern in the aEEG of patients with PDE. We performed aEEG in patient 4 and detected a continuous increase in the lower and upper margins over a period of 80 minutes, which is typical of neonatal status epilepticus.
In addition, interictal EEG was inconclusive with normal and abnormal registrations. Often we recorded normal and abnormal EEGs in the same patient before pyridoxine or pyridoxal 5′-phosphate. Normal EEGs have been reported repeatedly,9,11,12,15–17 but burst suppression pattern, bilaterally synchronous sharp and slow waves, intermittent or continuous slow waves, focal dysrhythmia, focal or multifocal spike and poly-spike waves, hypsarrhythmia, and photoparoxysmal response have also been reported.1–3,8,11–15,17–21 Burst suppression characterized as periods of inactive background (lower than 10–15μV) interrupted by bursts of activity which persist in both sleep states and even in wakefulness25 was seen in only one neonate, shortly after a single dose of pyridoxine and several hours after hemicolectomy. It is conceivable that preterm birth, acute respiratory distress syndrome, and antiepileptic or sedative drugs might have contributed to the burst suppression pattern in some of the reported patients with PDE or PNPO. The most frequent abnormal EEG patterns in our patients were multifocal sharp waves and discontinuous activity. We observed no impressive EEG changes after the first administration of pyridoxine or pyridoxal 5′-phosphate.