Ohtahara syndrome

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Ohtahara syndrome [1]
Other namesEarly infantile epileptic encephalopathy with burst-suppression
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg

Ohtahara syndrome (OS), also known as early infantile epileptic encephalopathy (EIEE) [2] is a progressive epileptic encephalopathy. The syndrome is outwardly characterized by tonic spasms and partial seizures within the first few months of life, [3] and receives its more elaborate name from the pattern of burst activity on an electroencephalogram (EEG). It is an extremely debilitating progressive neurological disorder, involving intractable seizures and severe intellectual disabilities. No single cause has been identified, although in many cases structural brain damage is present. [4]

Contents

Presentation

Ohtahara syndrome is rare and the earliest-appearing age-related epileptic encephalopathy, with seizure onset occurring within the first three months of life, and often in the first ten days. [5] Many, but not all, cases of OS evolve into other seizure disorders, namely West syndrome and Lennox-Gastaut syndrome. [4]

The primary outward manifestation of OS is seizures, usually presenting as tonic seizures (a generalized seizure involving a sudden stiffening of the limbs). [6] Other seizure types that may occur include partial seizures, clusters of infantile spasms, and, rarely, myoclonic seizures. In addition to seizures, children with OS exhibit profound mental and physical disabilities.[ citation needed ]

Clinically, OS is characterized by a "burst suppression" pattern on an EEG. This pattern involves high voltage spike wave discharge followed by little brain wave activity. [4]

It is named for the Japanese neurologist Shunsuke Ohtahara (1930–2013), who identified it in 1976. [5]

Signs and symptoms

MRIs of a normal individual (left) and a patient with microcephaly caused by genetic mutation (right) Microcephaly.png
MRIs of a normal individual (left) and a patient with microcephaly caused by genetic mutation (right)

Both female and male infants born with OS may experience symptoms while asleep or awake. Many children die from OS within their first 2 years of life, while those who survive maintain physical and cognitive disabilities such as excessive fatigue, difficulty feeding, chest infections and slow developmental progress. [2] [7] Although birth history and head size of infants is typically normal, microcephaly may occur. [3] Certain genetic variants manifest with additional signs such as dyskinetic movements and an atypical Rett-syndrome appearance. [8]

Causes

No single cause of OS has been identified. In most cases, there is severe atrophy of both hemispheres of the brain. Cerebral malformations such as hemimegalencephaly, porencephaly, Aicardi syndrome, olivary-dentate dysplasia, agenesis of mamillary bodies, linear sebaceous nevus syndrome, cerebral dysgenesis, and focal cortical dysplasia have been noted as suspect causes. [9]

Pathophysiology

Although it was initially published that no genetic connection had been established, [10] several genes have since become associated with Ohtahara syndrome. It can be associated with mutations in ARX , [11] [12] CDKL5 , [13] SLC25A22 , [14] STXBP1 , [15] SPTAN1 , [16] KCNQ2 , [17] ARHGEF9 , [18] PCDH19 , [19] PNKP , [20] SCN2A , [21] PLCB1 , [22] SCN8A , [23] ST3GAL3, [2] TBC1D24, [2] BRAT1 [2] and likely others.

Less often, the root of the disorder is an underlying metabolic syndrome, though mitochondrial disorders, non-ketotic hyperglycinemia, and enzyme deficiency remain elusive as causes. Their mechanisms are not entirely known. [3]

Diagnosis

Electroencephalogram (EEG) displaying burst suppression patterns. Onset of bursts are indicated by solid arrows; offset, by open arrows. In both A and B, the interval between each vertical dotted line is one second Bonthius2b.gif
Electroencephalogram (EEG) displaying burst suppression patterns. Onset of bursts are indicated by solid arrows; offset, by open arrows. In both A and B, the interval between each vertical dotted line is one second

The diagnosis is based on the clinical presentation and on typical electroencephalographic patterns based on time of onset. [24] [2] Typically, onset of seizures and spasms have been indicative of OS diagnosis, while MRI and abnormal EEG "burst suppression" pattern can confirm. Genetic testing with chromosomal microarray analysis followed by an epilepsy gene panel or whole exome sequencing may be considered after MRI imaging has been exhausted. [25] [26]

Differential diagnoses between other epileptic encephalopathies such as West syndrome or Lennox-Gastaut syndrome are distinguished by myoclonic seizures and differences in spike-and-wave patterns on EEG. [27]

Treatment

Treatment outlook is poor. Anticonvulsant drugs and glucocorticoid steroids may be used to try to control the seizures, but their effectiveness is limited. Most therapies are related to symptoms and day-to-day living. [4] For cases related to focal brain lesions, epilepsy surgery or functional hemispherectomy may be considered. [7] [3] [28] Risk factors include infection, blood loss, loss of vision, speech, memory, or movement.[ citation needed ]

Therapy for those with OS are based on severity of seizure activity and are supportive in nature. This may include treatment for abnormal muscle tone, stomach or lung problems. [7] A ketogenic diet may be suggested for reduction of symptoms. [2] Should the child survive past the age of three, vagus nerve stimulation could be considered. [2] No recent findings allude to preventive methods for pregnant mothers.[ citation needed ]

Prognosis

Prognosis is poor for infants with OS, and can be characterized by management of seizures, effects of secondary symptoms and shortened life span (up to 3 years of age). Survivors have severe psychomotor impairments and are dependent on their caretaker for support. Family members of infants with OS may consult with a palliative care team as symptoms may worsen or develop. Death is often due to strain from seizure activity, pneumonia or other complications from motor disabilities. [8]

Prospects of recovering from OS after hemispherectomy surgery has been shown to be favorable, with patients experiencing "catch up" in development. [29]

Epidemiology

Incidence has been estimated at 1/100 000 births in Japan and 1/50,000 births in the U.K. [30] Approximately 100 cases total have been reported but this may be an underestimate. since OS neonates with early death may escape clinico-EEG diagnosis. [9] Male cases slightly predominate those of females.

Current research

Currently, only one clinical trial has been performed to examine the efficacy of high-definition (HD) transcranial direct-current stimulation (HD-tDCS) in reducing epileptiform activity. [31]

Notable cases

Ivan Cameron, son of David Cameron, former leader of the British Conservative Party and Prime Minister of the UK, was born with the condition and cerebral palsy. He died aged six on 25 February 2009, while his father was still opposition leader. [32]

Dr William H. Thomas, a United States doctor, has two daughters with this condition. He spoke about them during a PBS interview. [33]

Related Research Articles

Absence seizures are one of several kinds of generalized seizures. These seizures are sometimes referred to as petit mal seizures. Absence seizures are characterized by a brief loss and return of consciousness, generally not followed by a period of lethargy. Absence seizures are most common in children. They affect both sides of the brain.

<span class="mw-page-title-main">Myoclonus</span> Involuntary, irregular muscle twitch

Myoclonus is a brief, involuntary, irregular twitching of a muscle or a group of muscles, different from clonus, which is rhythmic or regular. Myoclonus describes a medical sign and, generally, is not a diagnosis of a disease. These myoclonic twitches, jerks, or seizures are usually caused by sudden muscle contractions or brief lapses of contraction. The most common circumstance under which they occur is while falling asleep. Myoclonic jerks occur in healthy people and are experienced occasionally by everyone. However, when they appear with more persistence and become more widespread they can be a sign of various neurological disorders. Hiccups are a kind of myoclonic jerk specifically affecting the diaphragm. When a spasm is caused by another person it is known as a provoked spasm. Shuddering attacks in babies fall in this category.

<span class="mw-page-title-main">Lennox–Gastaut syndrome</span> Medical condition

Lennox–Gastaut syndrome (LGS) is a complex, rare, and severe childhood-onset epilepsy. It is characterized by multiple and concurrent seizure types, cognitive dysfunction, and slow spike waves on electroencephalogram (EEG). Typically, it presents in children aged 3–5 years and can persist into adulthood. It has been associated with several gene mutations, perinatal injuries, congenital infections, brain tumors/malformations, and genetic disorders such as tuberous sclerosis and West syndrome. The prognosis for LGS is poor with a 5% mortality in childhood and persistent seizures into adulthood (80–90%).

Myoclonic epilepsy refers to a family of epilepsies that present with myoclonus. It starts in both sides of the body at once, and last for more than a second or two. When myoclonic jerks are occasionally associated with abnormal brain wave activity, it can be categorized as myoclonic seizure. If the abnormal brain wave activity is persistent and results from ongoing seizures, then a diagnosis of myoclonic epilepsy may be considered. Myoclonic seizures frequently occur in day-to-day life. During sleep, abrupt jerks and hiccups occurred.

Epileptic spasms is an uncommon-to-rare epileptic disorder in infants, children and adults. One of the other names of the disorder, West syndrome, is in memory of the English physician, William James West (1793–1848), who first described it in an article published in The Lancet in 1841. The original case actually described his own son, James Edwin West (1840–1860). Other names for it are "generalized flexion epilepsy", "infantile epileptic encephalopathy", "infantile myoclonic encephalopathy", "jackknife convulsions", "massive myoclonia" and "Salaam spasms". The term "infantile spasms" can be used to describe the specific seizure manifestation in the syndrome, but is also used as a synonym for the syndrome itself. West syndrome in modern usage is the triad of infantile spasms, a pathognomonic EEG pattern, and developmental regression – although the international definition requires only two out of these three elements.

<span class="mw-page-title-main">Hypsarrhythmia</span> Medical condition

Hypsarrhythmia is very chaotic and disorganized brain electrical activity with no recognizable pattern, whereas a normal brain electrical activity shows clear separation between each signal and visible pattern. It is an abnormal interictal pattern, consisting of high amplitude and irregular waves and spikes in a background of chaotic and disorganized activity seen on electroencephalogram (EEG), and frequently encountered in infants diagnosed with infantile spasms, although it can be found in other conditions such as tuberous sclerosis.

Seizure types most commonly follow the classification proposed by the International League Against Epilepsy (ILAE) in 1981. These classifications have been updated in 2017. Distinguishing between seizure types is important since different types of seizure may have different causes, outcomes and treatments.

Idiopathic generalized epilepsy (IGE) is a group of epileptic disorders that are believed to have a strong underlying genetic basis. Patients with an IGE subtype are typically otherwise normal and have no structural brain abnormalities. People also often have a family history of epilepsy and seem to have a genetically predisposed risk of seizures. IGE tends to manifest itself between early childhood and adolescence although it can be eventually diagnosed later. The genetic cause of some IGE types is known, though inheritance does not always follow a simple monogenic mechanism.

<span class="mw-page-title-main">Generalized epilepsy</span> Epilepsy syndrome that is characterised by generalised seizures with no apparent cause

Generalized epilepsy is a form of epilepsy characterised by generalised seizures with no apparent cause. Generalized seizures, as opposed to focal seizures, are a type of seizure that impairs consciousness and distorts the electrical activity of the whole or a larger portion of the brain. Generalized seizure occurs due to abnormalities in both hemispheres.

Progressive Myoclonic Epilepsies (PME) are a rare group of inherited neurodegenerative diseases characterized by myoclonus, resistance to treatment, and neurological deterioration. The cause of PME depends largely on the type of PME. Most PMEs are caused by autosomal dominant or recessive and mitochondrial mutations. The location of the mutation also affects the inheritance and treatment of PME. Diagnosing PME is difficult due to their genetic heterogeneity and the lack of a genetic mutation identified in some patients. The prognosis depends largely on the worsening symptoms and failure to respond to treatment. There is no current cure for PME and treatment focuses on managing myoclonus and seizures through antiepileptic medication (AED).

<span class="mw-page-title-main">Spike-and-wave</span>

Spike-and-wave is a pattern of the electroencephalogram (EEG) typically observed during epileptic seizures. A spike-and-wave discharge is a regular, symmetrical, generalized EEG pattern seen particularly during absence epilepsy, also known as ‘petit mal’ epilepsy. The basic mechanisms underlying these patterns are complex and involve part of the cerebral cortex, the thalamocortical network, and intrinsic neuronal mechanisms.

Myoclonic astatic epilepsy (MAE), also known as myoclonic atonic epilepsy or Doose syndrome, is a generalized idiopathic epilepsy. MAE was first coined in 1970 by Dr. Hermann Doose. It is characterized by the development of myoclonic seizures and/or myoclonic astatic seizures. Some of the common monogenic causes include mutations in the genes SLC6A1 (3p25.3),CHD2 (15q26.1), AP2M1 (10q23.2). Myoclonic atonic epilepsy (MAE) is an intermittent childhood epilepsy syndrome. MAE is characterized by jerking muscle contractions followed by sudden muscle limpness. The onset of MAE is in early childhood. Almost all patients with MAE experienced their first seizures before the age of five years. Majority of children with MAE have normal development until the time of diagnosis, though few faces minor delay in development with speech delay. Boys tend to be affected more than girls. Genetics plays a significant role in the cause of this disorder. It is a rare childhood epilepsy, to be found in 1 to 2 out of 100 of all childhood-onset epilepsies. For the majority of MAE patients, the first seizure is a generalized tonic-clonic seizure. Even though generalized tonic-clonic seizures are the first seizure that occurred in MAE, few of the patients experienced absence seizures in their onset. For those children, whose onset is after four years they are more likely to experience absence seizures. There is an important role of Genetic in Doose Syndrome. These seizures occur more often in the early hours of the morning during sleep. The seizure response to the medication is very poor. Almost one-third have continuing seizures. The development of children progresses once seizures are controlled. Some children return to their regular functions. But few still remain with fluctuating grades of intellectual disability. Atypical absence often related with reduced muscle tone. Pure atonic seizures may also happen. Generalized tonic seizures are less frequently seen. Though Ancestor and natal history are typical. There is frequently a family history of seizures. The patients are having normal neurological examination and head size. This seizure is considered an 'epileptic encephalopathy. Current indication has suggested possible genetic links to the GEFS+ family. Though the frequency of seizures is more, and also poor cognition outcomes can be surprisingly good.

Jeavons syndrome is a type of epilepsy. It is one of the most distinctive reflex syndromes of idiopathic generalized epilepsy characterized by the triad of eyelid myoclonia with and without absences, eye-closure-induced seizures, EEG paroxysms, or both, and photosensitivity. Eyelid myoclonia with or without absences is a form of epileptic seizure manifesting with myoclonic jerks of the eyelids with or without a brief absence. These are mainly precipitated by closing of the eyes and lights. Eyelid myoclonia is the defining seizure type of Jeavons syndrome.

Epilepsy-intellectual disability in females also known as PCDH19 gene-related epilepsy or epileptic encephalopathy, early infantile, 9 (EIEE9), is a rare type of epilepsy that affects predominately females and is characterized by clusters of brief seizures, which start in infancy or early childhood, and is occasionally accompanied by varying degrees of cognitive impairment. The striking pattern of onset seizures at a young age, genetic testing and laboratory results, potential developmental delays or developmental regression and associated disorders, eases diagnosis.

Early myoclonic encephalopathy (EME) is a rare neonatal-onset epilepsy developmental and epileptic encephalopathy (DEE) with an onset at neonatal period or during the first 3 months of life. It is marked by the presence of myoclonic seizures but multiple seizure types may occur. The electroencephalographic recording is abnormal with eitherusually a suppression-burst pattern or other significantly abnormal patterns. On most occasions the seizures are drug-resistant. After several months, the seizure pattern may develop into infantile spasms syndrome. The neurological exam is abnormal with a significant risk of early death. Various genetic and metabolic disorders are responsible. At present, EME and Ohtahara syndrome are recorded as distinct patterns in the categorization of epilepsies but both neonatal-onset epilepsy syndromes are considered to be merged in one unique entity. It is a severe type of epilepsy syndrome associated with high level of resistance to treatment and a high risk for cognitive impairment. The myoclonic seizures could be seen in other epilepsy syndromes. Multiple types of childhood epilepsies are usually mentioned as myoclonic epilepsies when the myoclonic seizures are a predominant feature.

People with epilepsy may be classified into different syndromes based on specific clinical features. These features include the age at which seizures begin, the seizure types, and EEG findings, among others. Identifying an epilepsy syndrome is useful as it helps determine the underlying causes as well as deciding what anti-seizure medication should be tried. Epilepsy syndromes are more commonly diagnosed in infants and children. Some examples of epilepsy syndromes include benign rolandic epilepsy, childhood absence epilepsy and juvenile myoclonic epilepsy. Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for instance Lennox-Gastaut syndrome and West syndrome.

<span class="mw-page-title-main">SLC25A22</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 25 member 22 is a protein that in humans is encoded by the SLC25A22 gene. This gene encodes a mitochondrial glutamate carrier. Mutations in this gene are associated with early infantile epileptic encephalopathy. Expression of this gene is increased in colorectal tumor cells.

Barakat-Perenthaler syndrome is a rare neurodevelopmental genetic disorder, presenting with a severe epileptic encephalopathy, developmental delay, Intellectual disability, progressive microcephaly and visual disturbance. It is listed by the standard reference, Online Mendelian Inheritance in Man (OMIM) as #618744. and classified as EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 83; EIEE83. It was first described in 2019 by Dr. Stefan Barakat and his team at the Erasmus University Medical Center in Rotterdam in the journal Acta Neuropathologica; the most recent reviews were published in Epilepsy Currents. and Trends in Endocrinology and Metabolism

Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic syndrome that onsets before 6 months of age, commonly in the first few weeks of life. Once seizures start, the site of seizure activity repeatedly migrates from one area of the brain to another, with few periods of remission in between. These seizures are 'focal' (updated term for 'partial'), meaning they do not affect both sides of the brain at the same time. These continuous seizures cause damage to the brain, hence the descriptor 'malignant.'

PRICKLE1-related progressive myoclonus epilepsy with ataxia is a very rare genetic disorder which is characterized by myoclonic epilepsy and ataxia.

References

  1. ↑ Berg AT, Berkovic SF, Brodie MJ, et al. (April 2010). "Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009". Epilepsia. 51 (4): 676–85. doi: 10.1111/j.1528-1167.2010.02522.x . PMID   20196795.
  2. 1 2 3 4 5 6 7 8 "Ohtahara Syndrome". Epilepsy Foundation. Retrieved 2019-12-13.
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  4. 1 2 3 4 National Institute of Neurological Disorders and Stroke (5 December 2008). "NINDS Ohtahara Syndrome Information Page". Archived from the original on 28 February 2009. Retrieved 2009-03-10.
  5. 1 2 Ohtahara S, Ishida T, Oka E, et al. (1976). "特異な年齢依存性てんかん性脳症the early-infantile epileptic encephalopathy with suppression-burstに関する研究" [On the specific age dependent epileptic syndrome: the early-infantile epileptic encephalopathy with suppression-burst]. No to Hattatsu (in Japanese). 8 (4): 270–80. doi:10.11251/ojjscn1969.8.270.
  6. ↑ Holmes, Gregory L. (January 2004). "Tonic". Epilepsy.com/Professionals. Retrieved 2007-11-26.
  7. 1 2 3 "Ohtahara Syndrome Information Page | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 2019-12-13.
  8. 1 2 RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Early infantile epileptic encephalopathy Ohtahara syndrome". www.orpha.net. Retrieved 2019-12-13.
  9. 1 2 "Ohtahara Syndrome". Epilepsy Foundation. Retrieved 2019-12-13.
  10. ↑ Nabbout, Rima (July 2004). "Early infantile epileptic encephalopathy" (PDF).
  11. ↑ Online Mendelian Inheritance in Man (OMIM): 308350
  12. ↑ Kato M, Saitoh S, Kamei A, et al. (August 2007). "A Longer Polyalanine Expansion Mutation in the ARX Gene Causes Early Infantile Epileptic Encephalopathy with Suppression-Burst Pattern (Ohtahara Syndrome)". Am. J. Hum. Genet. 81 (2): 361–6. doi:10.1086/518903. PMC   1950814 . PMID   17668384.
  13. ↑ Online Mendelian Inheritance in Man (OMIM): 300203
  14. ↑ Online Mendelian Inheritance in Man (OMIM): 609302
  15. ↑ Online Mendelian Inheritance in Man (OMIM): 602926
  16. ↑ Online Mendelian Inheritance in Man (OMIM): 182810
  17. ↑ Online Mendelian Inheritance in Man (OMIM): 602235
  18. ↑ Online Mendelian Inheritance in Man (OMIM): 300429
  19. ↑ Online Mendelian Inheritance in Man (OMIM): 300460
  20. ↑ Online Mendelian Inheritance in Man (OMIM): 605610
  21. ↑ Online Mendelian Inheritance in Man (OMIM): 182390
  22. ↑ Online Mendelian Inheritance in Man (OMIM): 607120
  23. ↑ Online Mendelian Inheritance in Man (OMIM): 600702
  24. ↑ Beal C, Cherian K, Moshe SL, et al. (2012). "Early-Onset Epileptic Encephalopathies: Ohtahara Syndrome and Early Myoclonic Encephalopathy". Pediatric Neurology. 47 (5): 317–23. doi: 10.1016/j.pediatrneurol.2012.06.002 . PMID   23044011.
  25. ↑ "Early Infantile Epileptic Encephalopathy". Centogene. 2017-07-20. Retrieved 2019-12-13.
  26. ↑ "CentoPortal ®". www.centoportal.com. Retrieved 2019-12-13.
  27. ↑ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Early infantile epileptic encephalopathy". www.orpha.net. Retrieved 2019-12-13.
  28. ↑ "Aaron's Ohtahara Foundation". sites.google.com. Retrieved 2019-12-13.
  29. ↑ Malik, Saleem I.; Galliani, Carlos A.; Hernandez, Angel W.; Donahue, David J. (December 2013). "Epilepsy surgery for early infantile epileptic encephalopathy (ohtahara syndrome)". Journal of Child Neurology. 28 (12): 1607–1617. doi:10.1177/0883073812464395. ISSN   1708-8283. PMID   23143728. S2CID   21646215.
  30. ↑ "Maternal mortality ratio in selected countries, 2015". 2016-10-24. doi:10.1787/eco_surveys-idn-2016-graph65-en.{{cite journal}}: Cite journal requires |journal= (help)
  31. ↑ "Examining the Efficacy of tDCS in the Attenuation of Epileptic Paroxysmal Discharges and Clinical Seizures - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. 7 November 2016. Retrieved 2019-12-13.
  32. ↑ "Cameron's 'beautiful boy' dies". BBC News Online. 25 February 2009. Retrieved 2009-03-10.
  33. ↑ "Nursing Home Alternative". PBS . 2002-02-27.
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