Jin Li, MD and Martin L. Kutscher, MD. Departments of Neurology and Pediatrics, New York Medical College, Valhalla, NY.

Case presentation

AP is a 13 month old black boy, who presented with a history of the following spells. Over 5 minutes, there were clusters of sudden forward flexion of the head and neck; along with flaring of arms outward, and then inward. The eyes would roll up briefly with each spell. The intensity of the spasms increased as the time progressed, and then decreased. The child remained quiet with glassy eyes during and between the spasms. There was no frothing at the mouth, tonic-clonic movement, tongue biting, cyanosis, or relation to feeding. These clusters occurred about three times per day, usually shortly after awakening. The mother thought he was having abdominal cramps. Changing formula had no effect.

The patient had a normal birth. He had never been hospitalized before. Vaccinations were up to date. There was no family history of epilepsy.

General physical examination including growth parameters was normal. On neurological examination, the child was developmentally delayed. He babbled without words, and could not stand without wobbling.  Routine admission labs were normal.

Infantile spasms were suspected.  EEG showed modified hypsarrhythmia with low amplitude and less fast activity on the left hemisphere, which suggested a left hemisphere onset event.  ACTH  steroid injections were started. The patient was discharged after a 10-day hospital stay.

Discussion

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 child’s 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.

Clinical features

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.

Interictal EEG

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.

Differential diagnosis

Conditions mimicking IS

Unfortunately, some patients with IS remain misdiagnosed for months with colic, gastrointestinal reflux, or other stomach problem  because the paroxysmal movements were followed by crying and apparent abdominal pain. There are other conditions that can mimic IS, including:

Table 1. Distinguishing moro response vs. myoclonic seizure.

Etiology

Symptomatic Etiologies of Infantile Spasms

Genetic Syndromes: Tuberous sclerosis, Down’s syndrome, Aicardi’s syndrome, Incontinentia pigmenti, neurofibromatosis, Sturge Weber.

Malformation syndromes: schizencephaly, pachygyria, microgyria, etc.

Infectious: Congenital infections, meningtitis, encephalitis, brain abscess.

Hypoxic-Ischemic or hemorrhagic insult

Trauma

Tumor

Metabolic: including nonketotic hyperglycinemia, PKU, Maple Syrup Urine Disease and other amino and organic acidopathies, pyridoxine deficiency and dependancy, mitochondrial encephalopathies, and degenerative diseases.

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.

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.

Treatment

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. 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 combined with low doses of synthetic ACTH  appear to be the first choice to treat IS.

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 is important to maximize outcome. Apparently, our patient responded well to ACTH and vitamin B6.

References

Epilepsy: A comprehensive Textbook. Edited by J Engel, Jr. and TA Pedley. Lippincott-Raven Publishers, Philadephia, 1997.

The Treatment of Epilepsy: Principles and Practice. Edited by E Wyllie. Williams & Wilkins, 1997.

Pediatric Neurology. Edited by KF Swaiman and S Ashwal. Mosby. 1999.

ACTH therapy for infantile spasms: A combination therapy with high-dose pyridoxal phosphate and low-dose ACTH. Y Takuma. 1998. Epilepsia, 39(suppl.5): 42-45, 1998.

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