West syndrome: symptoms, diagnosis and treatment of this rare disease

By Cristiano Antonino On Jun 14, 2022

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.

Signs & Symptoms of West Syndrome

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.

The last third to quarter of patients will have spasms that resolve with time, usually in patients who have no clear etiology.

Causes of West Syndrome

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.

Related Disorders

Symptoms of the following disorders can be similar to those of West syndrome.

Comparisons may be useful for a differential diagnosis:

Epilepsy is a group of neurological disorders characterized by abnormal electrical discharges in the brain.

It is characterized by loss of consciousness, convulsions, spasms, sensory confusion, and disturbances in the autonomic nervous system.

Attacks are frequently preceded by an “aura”, a feeling of unease or sensory discomfort; the aura marks the beginning of the seizure in the brain.

There are many different types of epilepsy and the exact cause is generally unknown.

Epileptic spasm is a type of epilepsy.

Lennox-Gastaut syndrome (LGS) is a rare type of epilepsy disorder that typically becomes apparent during infancy or early childhood.

The disorder is characterized by seizures and, in many cases, abnormal delays in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor delayes). Individuals with the disorder may experience several different types of seizures.

Lennox-Gastaut syndrome may be due to, or occur in association with, a number of different underlying disorders or conditions.

Myoclonic seizures can be seen in numerous types of epilepsies ranging from myoclonic epilepsy of infancy to Dravet syndrome or myoclonic astatic epilepsy and are often times confused with infantile spasms.

These types of seizures are quick jerks of the arms and legs, faster than in infantile spasms and sometimes occur singly rather than in epileptic spasms that tend to occur in clusters.

As epileptic spasms are very subtle seizures with small brief movements of the trunk or arms, it can be easily misdiagnosed as gastroesophageal reflux, constipation, behavior and other types of non-neurological illness.

Myoclonus is a neurological movement disorder in which there are sudden involuntary muscle contractions.

There are many different types of myoclonus including some that are hereditary.

Other causes include lack of oxygen, viral, malignancies, and lesions of the central nervous system along with drugs and metabolic disorders.

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Diagnosis of West Syndrome

The first step is to characterize the patterns of brain activity through measurement with various devices.

Among these are:

Electroencephalography (EEG):

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.

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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.

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Standard Therapies

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.

References:

REVIEW ARTICLES
O’Callaghan FJ, Edwards SW, Alber FK, et al. Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomized, multicenter, open-label trial. Lancet Neurol. 2016 Nov 9; doi: 10.1016/S1474-4422(16)30294-0.

Hancock EC, et al. Treatment of infantile spasms. Cochrane Database Syst Rev. 2013 Jun 5; 6 CD001770.

Hrachovy RA, et al. Infantile spasms. Handb Clin Neurol. 2013; 111: 611-8.

Lux AL. Latest American and European updates on infantile spasms. Curr Neurol Neurosci Rep. 2013 Mar; 13(3): 334.

Go CY, et al. Evidence-based guideline update: medical treatment of infantile spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2012 Jun 12; 78(24): 1974-80.

Pellock JM, et al. Infantile spasms: a US consensus report. Epilepsia. 2010;51(10):2175-89 Riikonen RS. Favourable prognostic factors with infantile spasms. Eur J Paediatri neurol. 2010:14(1): 13-8.

Maguire MJ, et al. Prevalence of visual field loss following exposure to vigabatrin therapy: a systematic review. Epilepsia 2010:51(12):2423-31.

JOURNAL ARTICLES
Djuric M, et al. Long-term outcome in children with infantile spasms treated with vigabatrin: a cohort of 180 patients. Epilepsia 2014 Dec; 55 (12): 1918-25.

Hussain SA, et al. Treatment of infantile spasms with very high dose prednisolone before high dose adrenocorticotropic hormone. Epilepsia 2014 Jan; 55(1): 103-7.

Poulat AL, et al. A proposed diagnostic approach for infantile spasms based on a spectrum of variable aetiology. Eur J Paediatr Neurol. 2014 Mar; 18 92): 176-82.

Auvin S, et al. Diagnosis delay in West syndrome: misdiagnosis and consequences. Eur J Pedatric 2012 Nov; 171(11): 1695-701.

Mytinger JR, et al. The current evaluation and treatment of infantile spasms among members of the Child Neurology Society. J Child Neuro 2012 Oct; 28(10): 1289-94.

Caraballo RH, et al. Infantile spasms without hypsarrythmia: a study of 16 cases. Seizure. Apr 2011. 20(3): 197-202.

O’Callaghan FJ. et al. The effect of lead time to treatment and of age of onset as evidence from the United Kingdom Infantile Spasms trial. Epilepsia. Jul 2011. 52(7): 1359-64.

Mohamed BP, et al. Seizure outcome in infantile spasms- a retrospective study. Epilepsia. 2011: 52(4):746-52.

Yum MS. Surgical treatment for localization related infantile spasms. Clinical Neurology and Neurosurgery. Apr 2011. 113 (3):213-7.

Olson HE, et al. Rufinamide for the treatment of epileptic spasms. Epilepsy and Behavior. Feb 2011. 20(2):344-8.

Hong AM, et al. Infantile spasms treated with the ketogenic diet: prospective single-center experience in 104 consecutive infants. Epilepsia 2010:51(8):1403-7.

Darke K, et al. Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomised trial. Arch Dis Child. 2010:95(5): 382-6.

Osborne, JP, et al. The underlying etiology of infantile spasms (West syndrome) from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification. Epilepsia. Oct 2010. 51(10):2168-74.

Peltzer B, et al. Topiramate and adrenocorticotropic hormone (ACTH) as initial treatment for infantile spasms. J Child Neurol. 2009:24(4): 400-5.

Yum MS, et al. Zonisamide in West syndrome: an open label study. Epileptic Disord. 2009:11(4):339-44.

Lux, AL, et al. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicenter randomized trial. Lancet Neurol 2005; 4:714-7.

Sherr EH. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Curr Opin Pediatr. 2003;15(6):567-71.

Riikonen R. Long-term outcome of patients with West syndrome. Brain Dev.2001;23:683-87.

INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Epileptic Encephalopathy, Early Infantile, 1; EIEE1. Entry No: 308350. Last Edited: 02/18/2019. http://omim.org/entry/308350 Accessed March 11, 2019.

Glauser, TA. Infantile Spasm (West Syndrome) Medscape. http://www.emedicine.com/neuro/topic171.htm Updated: Updated: Jan 11, 2019.Accessed March 11, 2019.

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