Nearly 70-90 percent of Rett syndrome patients experience seizures. They occur because of the abnormal and repeated firing of nerve cells in either localized parts of the brain (focal seizures) or most of the brain (generalized seizures). In most cases, seizures appear during stages 2 or 3 of the disease, which occur when the patient is around age 4. The maximal seizure frequency is seen between ages 7 and 12. In a few patients with mutations in the CDKL5 gene, seizures may even occur in the neonatal stage or within the first 28 days of a full-term birth.
Diagnosis
The diagnosis of epileptic seizures is difficult in Rett syndrome patients because non-epileptic paroxysmal events are also common. A non-epileptic paroxysmal event is a non-epileptic seizure that does not involve abnormal, rhythmic electrical discharges of cells in the brain. Therefore, clinical diagnosis by an experienced pediatric neurologist is the gold standard.
An electroencephalogram (EEG) is an important diagnostic tool that helps distinguish between an epileptic seizure and a non-epileptic seizure. EEG findings generally follow the four stages of Rett syndrome. Before 18 months of age, the EEG is usually normal. Between ages 2 and 10, partial motor seizures that affect one side of the face and the upper limb appear. After age 10, the EEG may show multi-focal, generalized abnormalities with rhythmic activity primarily in the frontal-central regions of the brain.
Types of seizures
The type of seizure a person is having is determined based on neurological examination, EEG findings, and neuroimaging.
Early seizures or convulsions are more frequent in children with Rett syndrome than in children with other types of epilepsy.
The most common types of seizures are tonic (sudden stiffening and contraction of the muscles of the body, arms, or legs), myoclonic (brief shock-like jerks of a muscle or group of muscles), and tonic-clonic (a combination of tonic and clonic seizures in a specific pattern).
Absence seizures (blanking out or staring into space for few seconds) and clonic seizures (rhythmic twitching or jerking of one or several muscles) are less frequent.
Treatment
Anti-epileptic drugs
There are several anti-epilepsy drugs that can be used to treat seizures in people with Rett syndrome. A specific diagnosis of the seizure type that the patient is experiencing is the most important factor in selecting the anti-epileptic drug to be used.
- Tegretol (carbamazepine) is often considered for partial seizures.
- Depakene (valproate) is the first-line treatment for generalized seizures.
- Lamictal (lamotrigine) is used in adults for partial and generalized seizures and as adjunctive treatment.
- Trileptal (oxcarbazepine), a compound structurally related to carbamazepine, is useful as monotherapy or adjunctive treatment in partial seizures or generalized tonic-clonic seizures. It may be an alternative in patients intolerant to carbamazepine.
- Lyrica (pregabalin), Topamax (topiramate), Neurontin (gabapentin), Keppra (levetiracetam), and Gabitril (tiagabine) are newer anti-epileptic drugs, mainly used as adjunctive treatment.
- Sabril (vigabatrin) is used only when all other treatment combinations have failed.
Anti-epileptic drugs work through various mechanisms to prevent the rapid, repetitive stimulation of the brain that causes seizure activity. For example, Tegretol and Lamictal work by blocking voltage-gated sodium channels, preventing repeated stimulation. Neurontin and Gabitril increase levels of a chemical messenger called GABA, which stops repeated stimulation.
Anti-epileptic drugs have several side effects, including rashes, vomiting, weight loss or gain, walking problems, tremors, sleepiness, irritability, and decreased alertness. Some anti-epileptic drugs also have specific side effects such as behavioral issues (levetiracetam), anorexia and kidney stones (topiramate), marked sedation (benzodiazepines), or risk of fracture (valproate).
Vagal nerve stimulation (VNS) therapy
VNS therapy has been approved by the U.S. Food and Drug Administration (FDA) as an add-on therapy for patients age 4 and older who have focal or partial seizures and who do not respond to seizure medications. This is called drug-resistant epilepsy or refractory epilepsy.
VNS may prevent or reduce seizures by sending regular, mild pulses of electrical energy to the brain via the vagus nerve through a device that is implanted under the skin in the left chest area. An electrode or wire is attached to the generator and placed under the skin. The wire is attached or wound around the vagus nerve in the neck, and the device is programmed to deliver pulses or stimulation at regular intervals. VNS is usually safe and well-tolerated, with no surgical complications.
Ketogenic diet
Several studies have reported positive effects of the classical ketogenic diet on seizure frequency and behavior in Rett syndrome. Many children with Rett syndrome are fed with gastrostomy tubes, making them good potential candidates for dietary therapy because they can be easily started on the ketogenic diet without compliance issues.
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