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Case Report and Discussion
Jin Li, MD and Martin L. Kutscher, MD. Departments of Neurology and Pediatrics, New York Medical College, Valhalla, NY.
This is a fairly typical case of infantile spasms, which began at one year of age. Initially it was misinterpreted as abdominal discomfort. After infantile spasms were diagnosed, the childs spasms responded well to the antiepileptic medication. What are infantile spasms? How can we recognize the syndrome in order to achieve early diagnosis and treatment?
Historical background and epidemiology
Infantile spasm (IS) is an age-related triad of epileptic spasms, hypsarrhythmia, and frequently cognitive problems. The syndrome was first described by Dr. West as jerks and mental deterioration in 1841. Hypsarrhythmia was well defined by Gibbs and Gibbs in 1952. The incidence of infantile spasm is 1 per 2000 to 4000 live births. Boys are more prone to have infantile spasms and account for about 60% of the cases.
The initial onset of IS is at 3 to 7 months, in which more than 50% of the cases occur. More than 90% of cases begin before 2 years of the age. Spasms are often the first presentation, but it is not uncommon that cognitive deterioration may precede the spasms by weeks. Infantile spasms are the major cause of cognitive deterioration in the first year of life.
Spasms consist of clusters of sudden, briefly sustained movements of the axial musculature. Flexion spasms, like the presentation of our patient, are the most frequent and give the disorder its many names including jackknife convulsions and salaam seizures. The child seems to be embracing himself with sudden flexion the neck and all four extremities with adduction of the arms. Extensor spasms involve abrupt extension of the neck and lower extremities with extension and abduction of the arms, simulating a Moro reflex. At onset, spasms usually are mild, which may delay the recognition of abnormal movements by parents. Then, the symptoms progress over several days to involve a large proportion of the musculature.
Cognitive deterioration is an important component of infantile spasms and developmental assessment at the onset of IS has great prognostic value. Previously normal infants may have behavioral regression with the onset of IS. Patients may show decreased interest in their surroundings along with decreased social interaction. Absence of psychomotor regression is the best prognostic factor of favorable outcome. Neurologic abnormalities, including focal motor deficits, microcephaly, blindness, or deafness, have been described in more than half of patients. Clinically, if infantile spasm is suspected as a possibility, expedient child neurological consultation and EEG is warranted.
The diagnostic and characteristic interictal EEG finding of IS is hypsarrhythmia, which involves (1) multifocal spikes; (2) disorganized background; and (3) burst-suppression (where a burst of brain activity is followed by diminished brain activity). At onset of IS, some patients have hypsarrhythmia only during drowsiness and light sleep, or the EEG may actually be normal initially. It is not clear whether a cluster of spasms consists of a series of individual seizures or whether the whole cluster is itself a single seizure.
Conditions mimicking IS
Unfortunately, some patients with IS remain misdiagnosed for months with colic, gastrointestinal reflux, or intussusception; because the paroxysmal movements were followed by crying and apparent abdominal pain. There are other conditions that can mimic IS:
Table 1. Distinguishing moro response vs. myoclonic seizure.
Symptomatic Etiologies of Infantile Spasms
Table 2. Disorders or syndromes associated with "symptomatic" infantile spasms.
The etiology of IS is highly variable. "Symptomatic cases" are those where the history or work up reveal an identifiable cause. See Table 2. These children tend to be quite neurologically impaired; and tend to fair poorly despite aggressive treatment. "Cryptogenic cases" are those where developmental history, exam, and evaluation are negative. These children tend to do much better with aggressive care.
CT or MRI reveals malformations, atrophy, calcifications, or space-occupying lesions in many patients. (The calcifications of TORCH infections and tuberous sclerosis are detected better with CT scan; other lesions are better detected with MRI.) Cerebral malformations are reported in 30% of neuropathologic cases. Microdysgenesis has been found in about 25% of patients with malformations. In symptomatic infantile spasms, tuberous sclerosis is the major cause of IS. 50% of all patients with TS have IS. Other neurological disorders, including Von Recklinghausens neurofibromatosis, Aicardi syndrome, agyria, pachygyria and laminar heterotopia, hemimegalencephaly, hydranencephaly, schizencephaly, polymicrogyria, Sturge-Weber, incontinentia pigmenti, and Downs syndrome, have been reported to be associated with symptomatic IS. A variety of cortical or basal ganglion tumors may cause IS. They include ependymomas, gliomas, gangliogliomas, and choroid plexus papillomas.
CNS insults include trauma, hemorrhage, hypoxia-ischemia, and infection. Neonatal bacterial meningitis, brain abscess, and herpetic encephalitis may be causative. In these conditions, infantile spasms represent "end stage" brain disease, similar in concept to "end stage renal disease," i.e., any severe insult ends up with the same problematic outcome. Various metabolic diseases including amino acidopathies, organic acidemias, and vitamin deficiency have been reported to cause IS (see Table 2).
A family history of epilepsy or febrile convulsions is found in about 10% of patients. The familial incidence of IS ranges only from 3% to 6%. Many diseases associated with IS are genetically determined and involve inheritance of single genes, including inborn errors of metabolism.
"Cryptogenic" West syndrome is used when the patient has normal development prior to the disease, no other type of seizure, no known etiology of the disease, and normal laboratory investigation, including MRI. Because the quality of available tests has improved, the proportion of cryptogenic cases has decrease progressively.
The patient presented in this patient appears to fall into the symptomatic category based on the developmental delay and the focal abnormalities in the EEG and SPECT.
Course and prognosis
Infantile spasm is self-limited. Hypsarrhythmia resolves. However, 75% of patients will show abnormalities on the follow-up EEG at age of 5 or older. Especially, symptomatic IS patients may evolve into Lennox Gastaut syndrome with slow spike-wave pattern on EEG. The overall long-term outcome is poor for infantile spasm patients in the symptomatic group. No amount of treatment can reverse the pre-existing damage. Prognostic features for an unfavorable outcome include: other kinds of seizures, neurologic and developmental deficits that precede IS, asymmetric spasms, unilateral abnormalities or gross asymmetry on EEG tracings, and abnormal neuroradiologic findings prior to therapy. Mental retardation occurs in more than 50% of the cases. Psychiatric disorders including autism and ADHD accompany more than 25% of patients
In our patient, there are asymmetric spasms, asymmetric EEG tracing, and developmental delay. All these indicate an unfavorable outcome.
The pathophysiology of infantile spasm involves both cortical and subcortical structures.
Age dependence is due to the transient imbalance between excitatory and inhibitory pathways, which disappears with brain maturation. Young infants have difficulty keeping a seizure focus from spreading. During the acute stage, hypsarrhythmia would disorganize cognitive function. A cluster of seizures is frequently associated with change in the state of alertness.
The goal of treatment of IS is to obtain seizure control and maximize possible mental development. The effectiveness of ACTH was reported in 1958. A wide range of daily doses has been reported. A dose around 40 IU is often advised, with initial seizure control observed in about 75% of patients. Following an initial course of steroids, the relapse rate ranges about 40%. Complete recovery in terms of cognitive outcome ranges from 14-58%. Improvements in cognitive outcome or neurologic condition occur much more often in cryptogenic cases than in symptomatic cases. The mechanisms of action of corticotropin are felt to be multiple. The side effects include cardiovascular (including hypertension and cardiac hypertrophy), infectious, electrolyte, behavioral, weight gain, osseous, and gastric disorders. Mortality of ACTH treatment can be around 1%.
Benzodiazepines, including nitrazepam and clonazepam, are effective medications for seizure control, although their effectiveness in maximizing cognitive function remains less clear. Nitrazepam is the most popular benzodiazepine prescribed worldwide for IS, but it is generally not available in the United States. Other antiepileptic medications used for IS include valproate, pyridoxine, vigabatrin and lamotrigine. Vigabatrin is the newest effective antiepileptic drug in IS.
Response was better in patients who began therapy shortly after spasms began (particularly those treated within 1 month after symptom onset). The rate of improvement was even higher when only symptomatic patients are considered. In Japan, large doses of vitamin B6 (40-50 mg/kg/day) combined with low doses of synthetic ACTH (0.01 mg/kg/day) appear to be the first choice to treat IS. Vitamin B6 is a coenzyme of glutamic acid decarboxylase and enhances GABA synthesis. Surgery is sometimes of consideration in IS treatment. Spasms have ceased in response to tumor removal and hemispherectomy for hemimegalencephaly. The type of procedure varies according to the extent and location of the pathology.
Overall, the treatment of IS is not standardized. In the United States, corticotropin is the most commonly used initial treatment. It is more effective in cryptogenic than in symptomatic IS. Early treatment--in particular starting within the first month of symptoms--is essential to maximize outcome. Apparently, our patient responded well to clonazepam in junction with ACTH and vitamin B6. We hope the seizure control will persist.
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