Panayiotopoulos syndrome (named after C. P. Panayiotopoulos) is a common idiopathic childhood-related seizure disorder that occurs exclusively in otherwise normal children (idiopathic epilepsy) and manifests mainly with autonomic epileptic seizures and autonomic status epilepticus.Panayiotopoulos CP. Panayiotopoulos syndrome: a common and benign childhood epileptic syndrome. London: John Libbey & Company; 2002. An expert consensus has defined Panayiotopoulos syndrome as "a benign age-related focal seizure disorder occurring in early and mid-childhood. It is characterized by seizures, often prolonged, with predominantly autonomic symptoms, and by an EEG [electroencephalogram] that shows shifting and/or multiple foci, often with occipital predominance."Ferrie C, Caraballo R, Covanis A, Demirbilek V, Dervent A, Kivity S et al. Panayiotopoulos syndrome: a consensus view. Dev Med Child Neurol 2006; 48(3):236-240.
Signs and symptoms Panayiotopoulos syndrome occurs exclusively in otherwise normal children and manifests mainly with infrequent autonomic epileptic seizures and autonomic status epilepticus.Panayiotopoulos CP. Panayiotopoulos syndrome: a common and benign childhood epileptic syndrome. London: John Libbey & Company; 2002.Koutroumanidis M. Panayiotopoulos Syndrome: An Important Electroclinical Example of Benign Childhood System Epilepsy. Epilepsia 2007; 48(6):1044-1053Caraballo R, Cersosimo R, Fejerman N. Panayiotopoulos syndrome: a prospective study of 192 patients. Epilepsia 2007; 48(6):1054-1061.Panayiotopoulos CP, Michael M, Sanders S, Valeta T, Koutroumanidis M. Benign childhood focal epilepsies: assessment of established and newly recognized syndromes. Brain 2008; 131(Pt 9):2264-2286. Onset of seizures is from age 1 to 14 years with 76% starting between 3–6 years. Autonomic seizures consist of episodes of disturbed autonomic function with nausea, retching and vomiting as predominant symptoms. Other autonomic manifestations include pallor (or, less often, flushing or cyanosis), mydriasis (or, less often, miosis), cardiorespiratory and thermoregulatory alterations, incontinence of urine and/or feces, hypersalivation, and modifications of intestinal motility. In approximately one fifth of the seizures the child becomes unresponsive and flaccid (syncope-like epileptic seizures or ictal syncope) before or often without convulsions. Syncope-like epileptic seizures (ictal syncope) with the child becoming "completely unresponsive and flaccid like a rag doll" occur in one fifth of the seizures.Koutroumanidis M, Ferrie CD, Valeta T, Sanders S, Michael M, Panayiotopoulos CP. Syncope-like epileptic seizures in Panayiotopoulos syndrome. Neurology 2012 July 31;79(5):463-7. More-conventional seizure symptoms often appear after the onset of autonomic manifestations. The child, who was initially fully conscious, becomes confused and unresponsive. Eyes turn to one side or gaze widely open. Only half of the seizures end with brief hemiconvulsions or generalized convulsions. Autonomic symptoms may be the only features of the seizures. None of the above symptoms alone is a prerequisite for diagnosis. Recurrent seizures may not be stereotyped. The same child may have brief or prolonged seizures and autonomic manifestations may be severe or inconspicuous. The full emetic triad (nausea, retching, vomiting) culminates in vomiting in 74% of the seizures; in others only nausea or retching occur, and in a few, none of the emetic symptoms are apparent.
Most of the seizures are prolonged and half of them last more than 30 minutes thus constituting autonomic status epilepticus, which is the more common nonconvulsive status epilepticus in normal children.Ferrie CD, Caraballo R, Covanis A, Demirbilek V, Dervent A, Fejerman N et al. Autonomic status epilepticus in Panayiotopoulos syndrome and other childhood and adult epilepsies: a consensus view. Epilepsia 2007; 48(6):1165-1172. Characteristically, even after the most severe seizures and autonomic status epilepticus, the child is normal after a few hours of sleep, which is both diagnostic and reassuring. However, it has been recently reported that sometime after status epilepticus in children with Panayiotopoulos syndrome the growth of the frontal and prefrontal lobes is slightly decreased and the scores on neuropsychological tests is decreased.Kanemura H, Sano F, Ohyama T, Aoyagi K, Sugita K, Aihara M. Sequential prefrontal lobe volume changes and cognitive dysfunctions in children with Panayiotopoulos syndrome presenting with status epilepticus. Epilepsy Res 2015; 112: 122-129.
Focal onset hemiconvulsions or generalised convulsions occur in nearly half of the seizures. These are usually shorter than the preceding autonomic manifestations but in a few cases they may be prolonged constituting convulsive status epilepticus or the preceding autonomic manifestations are brief and not apparent Verrotti A, Sebastiani M, Giordano L et al. Panayiotopoulos syndrome with convulsive status epilepticus at the onset: a long-term study. Seizure 2014; 23: 728-731.
Seizures can occur at any time but they are more common during sleep.
Cause Panayiotopoulos syndrome is probably genetically determined, though conventional genetic influences may be less important than other mechanisms. Usually, there is no family history of similar seizures, although siblings with Panayiotopoulos syndrome or Panayiotopoulos syndrome and rolandic epilepsy or, less common, Panayiotopoulos syndrome and idiopathic childhood occipital epilepsy of Gastaut have been reported. There is a high prevalence of febrile seizures (about 17%).Cordelli DM, Aldrovandi A, Gentile V, Garone C, Conti S, Aceti A et al. Fever as a seizure precipitant factor in Panayiotopoulos syndrome: a clinical and genetic study. Seizure 2012 March;21(2):141-3.
SCN1A mutations have been reported in a child and in 2 siblings with relatively early onset of seizures, prolonged time over which many seizures have occurred, and strong association of seizures with febrile precipitants even after the age of 5 years. However, no such mutations were found in another couple of siblings and many other cases with typical Panayiotopoulos syndrome.Cordelli DM, Aldrovandi A, Gentile V, Garone C, Conti S, Aceti A et al. Fever as a seizure precipitant factor in Panayiotopoulos syndrome: a clinical and genetic study. Seizure 2012 March;21(2):141-3. These data indicate that SCN1A mutations when found contribute to a more severe clinical phenotype of Panayiotopoulos syndrome.
Pathophysiology In Panayiotopoulos syndrome there is a diffuse multifocal cortical hyperexcitability, which is age (maturation)-related. This diffuse epileptogenicity may be unequally distributed, predominating in one area, which is often posterior. Epileptic discharges in Panayiotopoulos syndrome, irrespective of their location at onset, activate emetic and autonomic centers prior to any other conventional neocortical seizure manifestations. An explanation for this is that children are susceptible to autonomic disorders as illustrated by the cyclic vomiting syndrome, which is a nonepileptic condition specific to childhood.
Panayiotopoulos syndrome and all other benign childhood focal seizures, with rolandic epilepsy as their main representative, are probably linked due to a common, genetically determined, mild, and reversible functional derangement of the brain cortical maturational process that Panayiotopoulos proposed as "benign childhood seizure susceptibility syndrome". The various EEG and seizure manifestations often follow an age- (maturation-) related localization. Panayiotopoulos syndrome is probably the early onset phenotype of the benign childhood seizure susceptibility syndrome. During a recorded autonomic seizure, there was a small increase in blood pressure (+5/4 mm Hg, systolic/diastolic), pronounced increases in heart rate (+59 bpm) and plasma concentrations of norepinephrine (+242 pg/mL), epinephrine (+175 pg/mL), and vasopressin (+22.1 pg/mL); serum glucose was also elevated (206 mg/dL).Gonzalez-Duarte A, et al, Cardiovascular and neuroendocrine features of Panayiotopoulos syndrome in three siblings, Epilepsy Behav (2011), The significant increase in plasma vasopressin may explain the emetic autonomic symptoms.
Diagnosis
Diagnostic tests
The most important determinant of the neurodiagnostic procedures is the state of the child at the time of first medical attendance:
(1) The child has a brief or lengthy seizure of Panayiotopoulos syndrome but fully recovers prior to arriving in the accident and emergency department or being seen by a physician. A child with the distinctive clinical features of Panayiotopoulos syndrome, particularly ictus emeticus and lengthy seizures, may not need any investigations other than EEG. However, because approximately 10% to 20% of children with similar seizures may have brain pathology, an MRI may be needed.
(2) The child with a typical lengthy seizure of Panayiotopoulos syndrome partially recovers while still in a postictal stage, tired, mildly confused, and drowsy on arrival to the accident and emergency department or when seen by a physician. The child should be kept under medical supervision until fully recovered, which usually occurs after a few hours of sleep. Then guidelines are the same as in (1) above.
(3) The child is brought to the accident and emergency department or is seen by a physician while ictal symptoms continue. This is the most difficult and challenging situation. There may be dramatic symptoms accumulating in succession, which demand rigorous and experienced evaluation. The seizure may be very dramatic, with symptoms accumulating in succession, convulsions may occur and a child who becomes unresponsive and flaccid demands rigorous and experienced evaluation. The most prominent acute disorders in the differential diagnosis include encephalitis or an encephalopathic state from causes such as infections, metabolic derangement (either inborn error or others such as hypoglycaemia), raised intracranial pressure and so forth. A history of a previous similar seizure is reassuring and may prevent further procedures.
Electroencephalography (EEG). EEG is the only investigation with abnormal results, usually showing multiple spikes in various brain locations (Figure).Panayiotopoulos CP. Panayiotopoulos syndrome: a common and benign childhood epileptic syndrome. London: John Libbey & Company; 2002.Caraballo R, Cersosimo R, Fejerman N. Panayiotopoulos syndrome: a prospective study of 192 patients. Epilepsia 2007; 48(6):1054-1061.Panayiotopoulos CP, Michael M, Sanders S, Valeta T, Koutroumanidis M. Benign childhood focal epilepsies: assessment of established and newly recognized syndromes. Brain 2008; 131(Pt 9):2264-2286.Ohtsu M, Oguni H, Imai K, Funatsuka M, Osawa M. Early-onset form of benign childhood epilepsy with centro-temporal EEG foci - a different nosological perspective from panayiotopoulos syndrome. Neuropediatrics 2008; 39(1):14-19. There is marked variability of interictal EEG findings from normal to multifocal spikes that also change significantly in serial EEGs. Occipital spikes are common but not necessary for diagnosis. Frontal or centrotemporal spikes may be the only abnormality. Generalised discharges may happen alone or together with focal spikes. A few children have consistently normal EEG, including sleep EEG. EEG abnormalities may persist for many years after clinical remission. Conversely, spikes may appear only once in successive EEGs. Series of EEGs of the same child may present with all of the above variations from normal to very abnormal. EEG abnormalities do not appear to determine clinical manifestations, duration, severity, and frequency of seizures or prognosis.