Title of article: West Syndrome
Authors: Ayman Khaled, Saeed Bakeer
Editors: Ainaa A.Alzamari, Hamid Ghanem
Reviewer: Ethar Hazaimeh

Keywords: Genetic disorder, Infantile spasms, Hypsarrhythmia, Epilepsy

 

Abstract 

Background: West syndrome, also known as infantile spasms (IS), is a rare genetic disorder characterized by hypsarrhythmia, psychomotor delay, and clinical spasms. Causes include genetic variants, injuries, infectious processes, and brain structural abnormalities. Over 200 possible causes are grouped into prenatal, perinatal, and postnatal disorders, including structural, infectious, genetic, immune, or metabolic disorders.

Methodology: A systematic review search was done which studied West syndrome primarily through the PubMed databases

 

Introduction

West syndrome, also referred to as infantile spasms (IS), is a rare and heterogeneous genetic disorder characterized by the triad of hypsarrhythmia, psychomotor delay, and clinical spasms. Causes include genetic variants, acquired injuries, infectious processes, and brain structural abnormalities (1).

West syndrome cases are mostly sporadic. Currently, there are more than 200 causes identified as possible causes for infantile spasm (IS) (Marcdante et al., 2023), which can be grouped into prenatal disorders, perinatal disorders, and postnatal disorders. These causes could be structural, infectious, genetic, immune, or metabolic disorders.

Pathophysiology

The pathogenesis is not well understood, genetic variants or hypoxic events that affect the brain during fetal development are thought to be the underlying cause. It has been suggested that the disorder may be caused by certain events that affect the brain during fetal development; any factor that impedes sufficient blood flow to specific brain regions could precipitate these episodes. (2).

Patients who receive injections of ACTH analogs have relief from spasms; this suggests that the neuroendocrine function of the hypothalamus-pituitary axis, which secretes CRH, is inhibited. This is due to the convulsant nature of CRH neuropeptide, and scientists think that disruptions in the hypothalamic axis, which release more CRH, may be one of the pathogenic causes (3).

Lesions in the occipital, centro-temporo-parietal, and frontal brain regions have been linked to the pathophysiology of West syndrome, as evidenced by an analysis of approximately ninety-five cases (2). A potential cause that has been proposed is a disruption of the immune system. This is characterized by a reduction in the quantity of IL-1 receptor antagonists, without a corresponding alteration in the levels of the primary proinflammatory cytokines (Haginoya et al., 2009). Support for this theory comes from another study that identified a correlation between increased serum IL-1 receptor antagonist levels and a decrease in the clinical symptoms of the syndrome  (4).

Spasms may originate from both the brainstem and the cortical hemispheres, although some studies suggest the cortical areas as the source. This is corroborated by autopsy findings and neuroimaging scans, as seen in cases of West’s syndrome (5,6), Conversely, autopsy reports and neuroendocrine irregularities suggest the brainstem and subcortical areas as potential sources. Autopsies have shown reduced diameters of the brainstem tegmentum and lesions in the spongy tissue of the brainstem compared to a healthy control group, highlighting the intricate nature of spasms and their potential causes (7).

Finding animal models with naturally occurring clinical manifestations is challenging, hence, those used in West syndrome studies are genetically modified. These models must develop and exhibit the associated symptoms to serve as reliable subjects for research. In a particular study, genetic techniques disrupted inhibitory GABAergic activity and enhanced excitatory neuronal stimulation. This was accomplished by altering or deactivating the ARX and APC genes, indicating the significant involvement of inhibitory interneurons in the disease’s development, thereby implying a genetic component in West syndrome (8).

Etiology

Multiple factors have been implicated in the development of this disease. These include genetic abnormalities and acquired factors such as infectious causes and structural abnormalities. Many theories try to provide explanations of the pathophysiology of the disease, such as brainstem dysfunction, primary cortical dysfunction, and hypothalamic-pituitary-adrenal axis dysfunction (9).

The most common causes of IS are prenatal disorders as they account for approximately 10-45% of cases (10). The most common examples include tuberous sclerosis, CNS malformations (e.g. cortical dysplasia, cortical dysgenesis, lissencephaly), hydrocephalus, hydranencephaly, chromosomal abnormalities (e.g., Down syndrome), inborn errors of metabolism, congenital infections, and various genetic causes (10). On the other hand, perinatal disorders and postnatal disorders are more likely attributed to trauma, meningitis, hypoxic-ischemic encephalopathy, and neonatal hypoglycemia (10).

Tuberous sclerosis is the most common neurocutaneous disorder to cause IS, and it accounts for 10-30% of prenatal causes (10). This disease is characterized by hypobigmented macule known as ash leaf spots; angiofibromas, shagreen patches, intellectual disability, and IS (11).

CNS malformations are the most common prenatal conditions to cause IS, with cortical dysplasia being the most common CNS malformation, accounting for over 30% of cases. (10). It is characterized by abnormalities in the cortical layer organization of the brain. Lissencephaly is a disease characterized by a smooth brain and the absence of sulci. Its causes include nongenetic factors such as viral infections during pregnancy or genetic factors such as Miller-Dieker syndrome (12,13). Aicardi syndrome, an X-linked dominant disorder, is lethal among males and presents with symptoms in female patients, resulting in the partial or complete absence of the corpus callosum, onset of IS, and severe intellectual disability (14,15).

Over 30 genes have been linked to IS development, including ARX, CDKL5, TUBA1A, FOXG1, GRIN1, GRIN2A, and MAGI2 (16). The inheritance form could be autosomal dominant, autosomal recessive, or X-linked, depending on the affected gene (16). ARX is the first gene linked to IS development, expressed mainly in the telencephalon and ventral thalamus (17). Mutations in ARX exhibit variable expressivity and pleiotropy, with truncations leading to more severe phenotypes than do missense mutations or in-frame expansions (18–20). CDKL5 is also frequently associated with IS, with mutations identified in West syndrome and ISSX (21). It is important to point out that not all patients with mutations in these genes develop IS but the phenotype is consistent that these genes are considered as IS-associated genes.

Numerous attempts have been made to provide a genetic classification of IS, with one notable effort being the classification of disorders into known and unknown genetic causes. This classification categorized disorders into two main groups, disorders with known genetic causes and others with unknown causes (20). This classification aims to enhance our understanding of the condition and facilitate advancements in diagnosing and treating it.

Classification

Previously, epilepsy syndromes were classified, by the International League Against Epilepsy (ILAE) in 1989, into symptomatic, cryptogenic, and idiopathic subtypes (22).

IS patients who have a specific etiology were classified as having ‘symptomatic’ IS. This category accounts for 70-75% of IS cases, and patients usually present with developmental delay before the onset of spasms. On the other hand, IS patients with unknown etiology were classified as having ‘cryptogenic’ IS. They are presumed symptomatic but the cause is yet to be known, and they typically present with developmental delay as do symptomatic patients (Marcdante et al., 2023; Pellock et al., 2010). As medicine and genetic testing develop, the number of patients diagnosed with cryptogenic IS decreases. Idiopathic IS patients do not have a known, clear etiology for their condition; do not present with developmental delay prior to onset of spasms; and have no other neurological or neuroradiologic abnormalities.

While idiopathic IS is not included in the U.S. consensus, symptomatic and cryptogenic IS patients are distinguished using a dichotomous classification system (23). This classification assumes that cryptogenic IS patients have normal development at the onset of spasms, highlighting the importance of distinguishing between these two groups.

The classification of epilepsy syndrome (IS) has been a contentious topic in medical literature. The West Delphi Proposal suggests that developmental delay should not be considered a defining feature of West syndrome, allowing diagnosis solely based on spasms and hypsarrhymthmic EEG (24). The term ‘cryptogenic’ has been a subject of debate, with some referring to it as ‘probably symptomatic’ and others as ‘nonsymptomatic’.

In 2010, the International League of Epileptics (ILAE) recommended replacing terms like symptomatic, cryptogenic, and idiopathic with terms describing the specific causes of the disorder (25). This was due to new diagnostic methods and genetic testing indicating that all forms of IS may be symptomatic. Despite these recommendations, the old terminology is still frequently used in the literature, which necessitates familiarity with the terms.

Clinical Manifestations

Infants with West syndrome typically exhibit a characteristic triad of developmental regression, an EEG pattern of hypsarrhythmia, and epileptic spasms, the latter being the most prevalent seizure type in this demographic. These spasms often last around five seconds and tend to occur in clusters. (23). They are generally characterized by symmetric and synchronous contractions, primarily affecting the muscles of the neck, trunk, and limbs, although other clinical patterns may also be observed (23).

Electromyography is utilized to monitor muscle activity during spasms, which can be categorized into two phases: a phasic contraction and a tonic phase. The initial phase is characterized by sudden, brief contractions that usually last under two seconds, while the subsequent phase is less intense but significantly longer, ranging from two to ten seconds. However, some studies indicate that the tonic phase may sometimes be absent, with spasms comprising solely a phasic contraction of less than 0.5 seconds (26).

Kellaway et al. (26) monitored, studied, and characterized 5042 spasms in 24 infants, using time-synchronized video and polygraphic recording techniques. They described five clinical types of spasms (seizure types): flexor spasms, extensor spasms, mixed flexor-extensor spasms, asymmetrical spasms, and arrests. distinguished largely by the muscle groups involved and the nature of the movements executed by these muscles. The incidence of each seizure type in the study p{Citation}atient population was 33.9%, 22.5%, 42.0%, 0.6%, and 1.0%, respectively. The majority of the study subjects (21 out of 24 infants) had more than one seizure type, with the most common pattern reported being a combination of flexor and mixed flexor-extensor spasms.

Kellaway et al. (26) provided a thorough description of each seizure type. Flexor spasms involve the neck, trunk, arms, and leg flexion, accompanied by abdominal muscle extension, which can cause the torso to jackknife at the waist. These spasms often resemble a “self-hugging” motion due to upper limb muscle contraction and arm adduction. The intensity and muscle group involvement can vary between infants, with some cases affecting only the neck muscles or primarily the shoulder girdle muscles, resulting in a shrug-like movement.

Extensor spasms are marked by the extension of the neck and trunk, along with either extensor abduction or adduction of the arms and/or legs. The most frequently reported seizure type in the study is mixed flexor-extensor spasms, typically involving the flexion of the neck, trunk, and arms with leg extension. However, there are rarer cases with leg flexion and arm extension.

Asymmetrical spasms, the least common seizure type noted in the study, were observed in only one infant. This patient was often seen in an unusual “fencing position,” experiencing brief increases in muscle contractions. The term “arrest” refers to a state of motionlessness and diminished responsiveness, which can follow other spasms lasting around 90 seconds or occur independently as a seizure without preceding spasms.

The spasms, regardless of the type, were often accompanied by changes in respiratory pattern (59.2%) and eye deviation or rhythmic nystagmoid eye movements (55%) (26). Bouts of screaming or crying were frequently observed following the spasms, but they were not considered as a part of the spasm (26). While it has been reported that loud sounds, handling, feeding, and photic stimulation could precipitate seizures, no precipitating factors of seizures were observed in the study (26).

The study also revealed that 78.3% of infantile spasms occurred in clusters lasting several minutes, with up to 125 spasms reported in a single cluster (26). These spasms typically increased in intensity and frequency, peaking before slowly declining, displaying a “crescendo-decrescendo” pattern. Clusters were most commonly observed following arousal from sleep, without an increased incidence during sleep. Only 2.5% of spasms occurred while infants were asleep (26). In younger children, spasms most frequently occurred between 9 am to 12 pm and 3 pm to 6 pm, while in older children, they occurred between 6 am and 9 am. The variability and subtle nature of spasms often lead to underestimation by parents (27).a

Lacy and Penry (28) proposed a three-stage clinical course for Infantile Spasms (IS). The first stage is marked by the onset of spasms, which are typically isolated, mild, and infrequent. At this stage, developmental regression begins to manifest in previously healthy infants with normal development. The second stage is characterized by an increase in the frequency and intensity of spasms, which may escalate to hundreds of spasms within 24 hours. Developmental regression becomes more severe and pronounced during this stage.

In the final stage, the frequency and intensity of the spasms start to decline, either rapidly or gradually, leading to spontaneous remission in most patients, usually by the age of five, as noted by M. Wong and Trevathan (29). A retrospective cohort study of 44 patients with IS observed the cumulative rate of spontaneous remission over time, with rates of 2% at one month, 5% at three months, 14% at eight months, and 25% at 12 months (30).

Although spasms may eventually cease in some patients, other types of seizures—such as partial, myoclonic, tonic, and tonic-clonic seizures—often emerge and persist in a significant portion of the patient population (29). Studies by Glaze et al. (31), Koo et al. (32), and Riikonen (33) reported the occurrence of other seizure types in 53%, 51%, and 60% of their study populations, respectively, following the cessation of spasms.

 Diagnosis

The diagnosis of Infantile Spasms (IS) requires a comprehensive history and physical examination, looking for indicators such as adenoma sebaceum, skin hamartomas, and ash-leaf hypopigmented spots. Tuberous sclerosis is a major genetic contributor, accounting for 10-30% of IS cases. The presence of three or more ash-leaf spots, particularly when examined under a Wood’s lamp, is a diagnostic criterion (10). Most patients with severe growth delay have normal physical examinations and no specific etiology. Neurologic examinations may reveal developmental delay, abnormalities in consciousness, and cranial nerve function, but these findings are usually unspecific (23).

Ophthalmic examinations can help identify potential congenital infections like Chorioretinal Lacunar Defects (IS) in patients. Electroencephalography (EEG) is necessary to confirm IS diagnosis in patients with suspicion or clinical features (23). A 24-hour video EEG, including a full sleep-wake cycle, is preferred (34). Hypsarrhythmia is a defining feature of IS, but only found in 60% of patients (35,36). It usually develops in early infancy and resolves by early childhood, at which time it may evolve into other abnormal EEG patterns (29). It can be resolved with hormonal therapy, but the infantile spasms persist either way (27).

Hypsarrhythmia is an interictal EEG pattern marked by random, chaotic, disorganized, high-voltage slow waves and spikes (37) (Figure 1). Hrachovy and colleagues (38) identified several variants, including modified or atypical hypsarrhythmias. The first variant involves hypsarrhythmia with increased interhemispheric synchronization, noted for its enhanced organization and symmetry. The second variant is asymmetrical hypsarrhythmia, which varies from regional asymmetry to unilateral hypsarrhythmia restricted to one hemisphere. Additionally, localized hypsarrhythmia may occur in some patients due to bilateral structural lesions.

The research conducted by Donat & Lo (39) was designed to assess whether asymmetric EEG patterns have diagnostic or prognostic significance. Out of 77 patients, 38% exhibited focal or lateralized characteristics on video-EEG. The predicted location of lesions corresponded with the findings from CT scans and MRIs. However, for patients with clinically asymmetric infantile spasms—an uncommon condition marked by asymmetrical ictal EEG—no additional localizing value was observed. Moreover, patients with symmetric ictal EEG infrequently present with focal or asymmetrical structural lesions, instead typically showing diffuse structural brain abnormalities.

Hypsarrhythmia is a phenomenon primarily observed during NREM sleep, with an increase in background activity amplitude (38,40). However, it is typically reduced or nonexistent during REM sleep, making EEG monitoring challenging. Long-term monitoring studies are needed to capture hypsarrhythmias. After arousal, the hypsarrhythmic pattern decreases or disappears, causing “relative normalization.” Some patients may experience identical EEG changes to those seen in ictal events during clinical spasms, which are not associated with clinical spasms but may continue following the patient’s awakening (38,40).

Etiologic Evaluation

Once the presence of spasms and hypsarrhythmias is confirmed, an etiological evaluation involving a comprehensive metabolic panel, genetic testing, and neuroimaging becomes crucial to ascertain the cause of IS. These diagnostics can modify treatment approaches and facilitate targeted therapies (23). Vigabatrin is particularly beneficial for IS infants with tuberous sclerosis, whereas ACTH is the primary treatment for other etiologies. A specific cause can be identified in 55-80% of instances (42,43).

Neuroimaging with MRI or CT scan is crucial for identifying structural causes or cerebral lesions in patients with IS disorder (44,45). MRI is preferred due to its higher sensitivity and prognostic value, especially in motor development (23). It also has a prognostic value, specifically regarding motor development (46). It should be performed before therapy to avoid misleading changes, such as brain atrophy or T2 changes (47). However, treatment should not be delayed if imaging is delayed for later (23).

The use of specific imaging protocols and MRI sequences for diagnosing myelinopathy in children is not universally agreed upon. However, most cases require three-dimensional (3D) T1-weighted gradient-recalled-echo sequence, axial and coronal T2, and fluid-attenuated inversion recovery (FLAIR) sequences. Children under 2 years of age should use high-resolution coronal and axial T2-weighted sequences due to immature myelination patterns (48). Magnetization transfer imaging and magnetic resonance spectroscopy may be useful in the detection of malformations of cortical development and inborn errors of metabolism, respectively (23).

The study by Chugani & Conti (49) found that Positron emission tomography (PET) can significantly increase the number of symptomatic IS cases in infants. After using PET, the number of symptomatic cases increased from 30.0% to 95.7%, with 92 out of 97 cryptogenic patients diagnosed as symptomatic IS. The authors strongly advocate for using PET in cryptogenic IS patients with intractable infantile spasms.

About 70% of patients with a history of seizures will have a diagnosis and etiology identified without metabolic and genetic testing. The remaining 30% will have an identified etiology after metabolic studies, while the rest will likely be labeled as cryptogenic IS. The U.S. consensus report recommends early testing for pyridoxine deficiency, a reversible and potentially treatable cause of IS. Other tests include organic acids in urine, serum lactate and amino acids, serum biotinidase, CSF neurotransmitters, and chromosomal studies (23).

Treatment

Studies for describing and noticing the treatment approaches rely on either the complete resolution of symptoms or on a decrease in the frequency of the spasms. The choice of treatment by physicians depends on whether the goal is full or partial resolution.

Hormonal treatments such as ACTH, corticosteroids, and Vigabatrin are supported by the strongest evidence for effectiveness (50), However, data from related studies still lack probability measures and require further evaluation in well-conducted randomized clinical trials. This has led researchers to investigate new topics and treatment methods, including the ketogenic diet and resection surgeries (51).

ACTH is considered the most effective treatment and is therefore the first-line therapy, with therapeutic responses typically appearing within 14 days or less (52). Despite its effectiveness, ACTH has side effects and limitations, such as rising costs and high relapse rates (50). The dosing varies across different cases, which hinders the adoption of a standardized formulation (53).

Studies on ACTH usage indicate that high-dose and low-dose ACTH have equivalent effects, suggesting that starting treatment with either dosage should not pose a problem If low-dose ACTH fails initially, it is usually recommended to switch to a higher dose (50).

Corticosteroids, specifically Prednisolone, are considered cost-effective alternatives to ACTH due to their greater availability, although low-dose Prednisolone is less effective than ACTH.

Prednisolone has been trialed as a first-line therapy for infantile spasms (54), with side effects considered tolerable (55), and responses typically observed within 14 days, similar to ACTH. If unsuccessful, an ACTH dose is often recommended. The ketogenic diet is advised for younger patients and is used alongside specific antiepileptic drugs, but not as a sole treatment, despite ongoing research into this approach.

For infantile spasms associated with tuberous sclerosis, Vigabatrin is the preferred first-line therapy (56). A common side effect is visual field constriction (57), leading to the recommendation of discontinuing the therapy after six months to prevent this adverse outcome (58).

Conclusion

West syndrome is a rare childhood epileptic disorder characterized by the triad of hypsarrhythmia, psychomotor delay, and clinical spasms. It has a wide range of different causes, and a significant percentage of cases are idiopathic. The pathophysiology is unclear, but various theories implicating genetic variants, hypoxic events, hypothalamic axis disruption, CNS lesions, and immune system disruption have been proposed. Diagnosis is suspected by the presence of the characteristic clinical spasms and is confirmed by establishing the presence of hypsarrhythmias on EEG. Treatment options include ACTH therapy, corticosteroids, and vigabatrin, but treatment responses are relatively poor and depend on the underlying etiology.

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