NORD gratefully acknowledges Diana Walleigh, MD, Assistant Professor, Pediatrics-Neurology, University of Colorado School of Medicine, Department of Neurology, Children's Hospital Colorado, for assistance in the preparation of this report.
West syndrome is a constellation of symptoms characterized by epileptic/infantile spasms, abnormal brain wave patterns called hypsarrhythmia and intellectual disability. The spasms that occur may range from violent jackknife or "salaam" movements where the whole body bends in half, or they may be no more than a mild twitching of the shoulder or eye changes. These spasms usually begin in the early months after birth and can sometimes be helped with medication. They can also occur in older patients; if this happens, they are called "epileptic spasms" rather than infantile spasms. Currently, the International League Against Epilepsy (ILAE) has revised the terminology and epileptic spasms is now preferentially used to encompass the different age groups of onset. There are many different causes of epileptic spasms and if a specific cause can be identified, a diagnosis of symptomatic epileptic spasms can be made. If a cause cannot be determined, a diagnosis of cryptogenic epileptic spasms is made.
Symptoms associated with West syndrome usually begin during the first year of life. The average age of onset for epileptic spasms is at 6 months. Epileptic spasms are characterized by involuntary muscle spasms that occur due to episodes of uncontrolled electrical disturbances in the brain (seizures). Each involuntary spasm typically begins suddenly and lasts for only a few seconds and occurs usually in clusters that can last over 10-20 minutes. Such episodes, which may occur upon awakening or after feeding, are characterized by sudden, involuntary contractions of the head, neck, and trunk and/or uncontrolled extension of the legs and/or arms. The duration, intensity, and muscle groups affected by seizures vary from infant to infant.
Infants with West syndrome also have very abnormal electroencephalogram (EEG) with high amplitude, chaotic spike wave patterns (hypsarrhythmia). Most children will have regression of skills or delays in acquiring skills that require coordination of muscles and voluntary movements (psychomotor retardation).
Approximately a third of children with West syndrome may develop recurrent epileptic seizures as they age. The syndrome often develops into Lennox-Gastaut syndrome with mixed types of seizures that are difficult to control and is associated with intellectual disability. (For more information on Lennox-Gastaut syndrome, see the Related Disorders section below.). Approximately another third of children with West syndrome will continue to have epileptic spasms at an older age . The last third to quarter of patients will have spasms that resolve with time, usually in patients who have no clear etiology.
A specific cause for West syndrome can be identified in approximately 70-75% of those affected. Any disorder that can lead to brain damage can be an underlying cause of West syndrome including trauma, brain malformations such as hemimegalencephaly or cortical dysplasia, infections, chromosomal abnormalities such as Down syndrome, neurocutaneous disorders such as tuberous sclerosis complex (TSC), Sturge Weber syndrome, incontinentia pigmenti, different metabolic/genetic diseases such as pyridoxine deficiency, non-ketotic hyperglycemia, maple syrup urine disorder, phenylketonuria, mitochondrial encephalopathies and biotinidase deficiency, Otahara’s syndrome, and an abnormality (mutation) in the ARX gene or CDKL5 gene located on the X chromosome.
The most common disorder responsible for West syndrome is tuberous sclerosis complex. (TSC). TSC is an autosomal dominant genetic condition associated with seizures, eye, heart and kidney tumors and skin findings. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
X-linked West syndrome can be caused by a mutation in the CDKL5 gene or the ARX gene in the X chromosome. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
West syndrome is a rare neurological syndrome that can affect males and females. The X-linked form of West syndrome affects males more often than females.
West syndrome has been estimated to affect .31 per 1000 live births in the United States. West syndrome accounts for approximately 30 percent of all cases of epilepsy affecting infants.
The first step is to characterize the patterns of brain activity through measurement with various devices. Among these are:
This is a painless and non-invasive means of recording the patterns of electrical activity of the brain. Electrodes are placed on the scalp and pick up and record the electrical waves during periods of activity and, with luck, during periods of sleep. If a pattern called hypsarrhythmia is noted, especially during sleep, this can help to suggest that a patient has epileptic spasms. However, there are times when a patient may have epileptic spasms and does not have the hypsarrhythmia pattern due to a lag time between clinical symptoms and EEG pattern. In addition, there are several illnesses that can mimic epileptic spasms and a long-term videoEEG may confirm the diagnosis of epileptic spasms. Therefore, an overnight, long term video EEG monitoring is preferable compared to a routine 20-minute EEG study in cases of epileptic spasms.
Brain Scans, such as:
Computed Tomography (CT). Harnessing X-rays to a computer generates pictures of cross-sections of the brain from which the detail of development may be determined. CT is also very good at showing areas of calcification that in some cases, may be essential for the diagnosis. However, this does not provide as detailed a picture as a MRI.
Magnetic Resonance Imaging (MRI). This radiological technique produces detailed images of cross-sections or slices of the brain by using the magnetic properties of particular atoms found in the brain. The images are more detailed than a CT and can provide information concerning any malformations of the brain structures or other types of lesions commonly seen in epileptic spasms.
Infection as a cause of epileptic spasms may be determined by blood tests, urine tests and lumbar puncture.
A Wood’s lamp is used to examine skin for lesions with lack of pigment in order to determine if tuberous sclerosis is a possible diagnosis.
Molecular genetic testing is available for mutations in the ARX and CDKL5 genes associated with X-linked West syndrome. It is also available for the genes associated with tuberous sclerosis complex. Some genetic disorders will require cerebrospinal fluid (CSF) for genetic testing. Testing for nonketotic hyperglycemia may require a CSF sample to test for glycine and testing for mitochondrial diseases may require CSF to test for lactate. A mutation in the STXBP1 gene has recently been noted in patients with Otahara’s syndrome as well. There are several genetic panels available that can test children of a certain age for a variety of genetic conditions that are seen in epilepsies such as epileptic spasms.
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, surgeons, and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
In some children, it is possible that treatment with anticonvulsant drugs may help reduce or control various types of seizure activity associated with West syndrome. The most common medications used to treat epileptic spasms include adrenocorticotropic hormone (ACTH), prednisone, vigabatrin and pyridoxine. The benefits of the medication need to be weighed with the risks of side effects of each treatment. For example, ACTH, prednisone and other steroids are known to cause issues with immunosuppression, hypertension, glucose, gastric issues, agitation and irritability. Vigabatrin may cause an irreversible visual field defect, irritability, and transient hyperintensity of deep structures in the MRI. There is no standard protocol for using ACTH or other steroid treatment. It is unknown whether high dose ACTH or low dose ACTH is effective or whether the use of prednisone is more effective than ACTH. In a recent multicenter study looking at steroid treatment compared to vigabatrin, it was felt that steroids may have better seizure control compared to vigabatrin at 2 weeks of treatment, but that the effectiveness was the same after a year. In addition, vigabatrin was more effective in patients with tuberous sclerosis or cortical dysplasia compared to steroids. More recently a multicenter European/Australian/New Zealand consortium (ISCC) found that hormonal therapy with vigabatrin is significantly more effective at stopping infantile spasms than hormonal therapy alone. The investigations in the US are ongoing for combination hormonal and vigabatrin therapy.
It is felt that a shorter time between diagnosis and treatment will have a less deleterious effect on development compared to a longer lead-time to treatment. If these treatments are not successful, other medications such as benzodiazepines (for example, clobazam), valproic acid, topiramate, rufinamide and zonisamide may be used. Ketogenic diet has also been successful at times in the treatment of epileptic spasms. Finally, in cases where there is a malformation or tuberous sclerosis complex, epilepsy surgery may be helpful to control spasms.
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