Ohtahara Syndrome

What Causes Ohtahara Syndrome?

Ohtahara syndrome can stem from numerous underlying causes. Most often, it is caused by structural malformations of the brain. Other causes include metabolic disorders and abnormal changes (mutations) in specific genes. Scientists believe that in many cases, the metabolic and genetic triggers produce seizure-causing brain malformations.

Brain malformations associated with OS include:

• Hemimegalencephaly (one half of the brain is larger than the other)
• Agenesis of the corpus callosum (absence of the structure that connects one side of the brain to the other)
• Porencephaly (a fluid-filled cavity forms in the brain)
• Agenesis of the mammillary bodies (absence of structures that control some memory functions)

Metabolic disorders associated with OS include:

• Nonketotic hyperglycinemia (a condition that causes abnormal accumulation of a specific amino acid in the brain)
• Cytochrome C oxidase deficiency (deficiency of a chemical crucial for energy production in cells)
• Pyridoxine dependency (deficiency of a chemical that aids in the communication between brain cells)
• Carnitine palmitoyltransferase deficiency (a disorder that interferes with cells’ ability to use fats to produce energy)

Research has identified mutations in more than a dozen genes that appear to be associated with Ohtahara syndrome.

Is Ohtahara Syndrome Hereditary?

The research linking gene mutations to Ohtahara syndrome is relatively recent, and the likelihood of the mutations being inherited by children from their parents is still largely undetermined. Some mutations have been associated with epileptic disorders that can run in families. More research is necessary to determine how or if these mutations increase the risk of OS inheritance.

How Is Ohtahara Syndrome Detected?

One challenge in diagnosing Ohtahara syndrome is differentiating it from another similar type of epilepsy called early myoclonic encephalopathy (EME). Both disorders produce seizures early in infancy, and similar conditions can cause them. Differences between the two include:

• Focal motor seizures are common in OS. In EME, myoclonic seizures (a seizure affecting a single muscle or muscle group) are common.
• EME is more likely to have a metabolic cause. Brain malformations are a more common cause of OS.
• OS often progresses to other epileptic disorders as the child gets older. EME often remains unchanged over a long period.

How Is Ohtahara Syndrome Diagnosed?

When a baby’s symptoms match those of Ohtahara syndrome, doctors will typically administer an electroencephalogram (EEG). This non-invasive, painless test measures the electrical activity in the baby’s brain. The doctor will look for a brain-wave pattern characteristic of OS, including:

• A pattern called burst suppression, in which spikes in electrical activity are followed by periods of abnormally low activity
• Burst suppression occurs when the baby is both awake and asleep

Doctors may also conduct a variety of tests to look for the cause of OS, including:

• Magnetic resonance imaging (MRI) to identify structural abnormalities in the brain
• Blood and/or urine tests to look for possible metabolic disorders
• Genetic testing to look for gene mutations associated with OS

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Ohtahara Syndrome Treated?

Ohtahara syndrome has no cure, but some treatments may lessen the impact of seizures. Other treatment options focus on improving the child’s quality of life.

Common treatments include:

• Anti-seizure medications including vigabatrin, prednisone, clonazepam, topiramate, zonisamide, phenobarbital, valproate, or felbamate. However, OS seizures often don’t respond well to medication.
• Surgery to remove damaged areas of the brain. This treatment may be considered if the structural abnormalities affect certain specific parts of the brain. If surgery is an option, it is most effective when performed early, before seizures have caused severe developmental complications.
• Ketogenic diet
• Vagus nerve stimulation
• Physical therapy
• Speech therapy
• Occupational therapy

How Does Ohtahara Syndrome Progress?

Ohtahara syndrome is typically progressive, meaning its symptoms and effects get worse over time. Seizures can be life-threatening, and some babies with the disorder do not survive infancy. In almost all cases, the seizures cause severe developmental impairments, both physical and cognitive.

In many cases, the symptoms of OS will be replaced by those of other epileptic disorders, such as West syndrome and Lennox-Gastaut syndrome, as the child gets older. Some scientists believe that the three syndromes make up a spectrum of age-dependent disorders that evolve in a predictable sequence as the child ages.

How Is Ohtahara Syndrome Prevented?

There is no known way to prevent Ohtahara syndrome. Parents with a family history of OS or other epileptic disorders may consult a genetic counselor to assess their risks if they plan to have another child.

Ohtahara Syndrome Caregiver Tips

• Learn all you can about the disorder. With its multitude of causes, symptoms, and possible treatments, Ohtahara syndrome can be confusing for parents. When you learn about the complexities of the disorder, you’ll be a better part of your child’s medical team.
• Keep a diary of your child’s symptoms and be alert for seizure activity. In some cases, early diagnosis and intervention can lessen the long-term impact of OS. Consult your doctor right away when you see any of the disorder’s warning signs.
• Find support from people who know what you’re going through. The Epilepsy Foundation operates a 24/7 helpline through which you can find information and links to support resources.

Ohtahara Syndrome Brain Science

Research into the similarities between Ohtahara syndrome and early myoclonic encephalopathy has led to discoveries that might shed light on the neurological origins of both disorders.

• The conditions that often underlie OS and EME cause abnormal neuronal migration. During normal development, nerve cells (neurons) move from where they’re born to their proper location elsewhere in the brain. Certain disorders interfere with this process, leading to brain malformations that can cause OS and EME.
• Both disorders often occur when there are malformations of the brain stem. These malformations may interfere with communication between different parts of the brain. Some scientists think this communication problem, called “cortical deafferentation,” may explain why OS seizures are difficult to control.

Ohtahara Syndrome Research

Title:  Genetics of Severe Early Onset Epilepsies

Stage: Recruiting

Principal Investigator: Annapurna Poduri, MD, MPH

Boston Children’s Hospital

Boston, MA

Many children with epilepsy experience seizures that respond well to treatment. However, a few types of epilepsy are characterized by seizures that begin very early in childhood and are associated with severe intellectual and/or developmental disabilities. These conditions, known as progressive epileptic encephalopathies, are particularly severe and are often difficult to treat. These syndromes include infantile spasms, early infantile epileptic encephalopathy with suppression bursts (Ohtahara syndrome), malignant migrating partial epilepsy of infancy, early myoclonic epileptic encephalopathy, and severe myoclonic epilepsy of infancy (Dravet syndrome).

The investigators’ current research effort is focused on children with epileptic encephalopathies, in particular Ohtahara syndrome. The investigators’ goal is to identify genetic alterations (known as “mutations”) that cause Ohtahara syndrome. By doing so, the investigators hope to improve the diagnosis and treatment for this condition. It is also possible that understanding the genetic basis of Ohtahara syndrome may, in some instances, make it possible to prevent it from occurring in the future.

Title: Long-term Cardiac Monitoring in Epilepsy (LOOP)

Stage: Recruiting

Principal investigator:  Ruben I. Kuzniecky, MD

Northwell Health

New York, NY

Most cardiac studies have investigated patients with intractable focal epilepsy who have a high risk for co-morbidities, accidents, injury, and SUDEP. This is compounded by the significant antiepileptic drug burden in this population. Very little, however, is known about the risk of cardiac arrhythmias in patients with a lower seizure burden, i.e., patients with infrequent focal seizures and/or those without secondarily generalized convulsions. Furthermore, no chronic cardiac data is available in patients with epileptic encephalopathies, especially given that some of these patients are known to carry mutations that increase the risk for cardiac arrhythmias. In addition, periods of reduced cerebral blood flow during tachy or brady arrhythmias may exacerbate seizure severity and duration. Diagnosing and treating these arrhythmias may not only prevent adverse cardiac events but also reduce seizure burden. This study primarily aims to compare the frequency of cardiac rhythm abnormalities in patients with epilepsy of different severity, assess the long-term cardiac risk, and evaluate the possible preventive role of anti-arrhythmic agents and/or cardiac pacemaker/defibrillator needs.

Title: Pharmacokinetic Study With an Oral Suspension of Perampanel as Adjunctive Therapy in Pediatric Subjects With Epilepsy

Stage: Recruiting

Principal investigator: Esai Inc.

Children’s of Alabama

Birmingham, AL

The purpose of this study is to evaluate the pharmacokinetics (PK) of perampanel during the Maintenance Period of the Core Study following oral suspension administration given as an adjunctive therapy in pediatric participants from 1 month to less than 4 years of age with epilepsy.

This is a multicenter, open-label study comprised of pretreatment, treatment (core study), and extension phases that is designed to evaluate the PK of an oral suspension of perampanel (maximum dose must not exceed 12 milligrams per day [mg /day] for participants taking the non-enzyme-inducing antiepileptic drug [non-EIAED] or 16 mg/day for participants taking EIAED) when given as an adjunctive therapy in participants ranging from 1 month to less than 4 years of age with epilepsy. The Pretreatment Phase will last up to 2 weeks, during which participants will be assessed for their eligibility to participate in the study.