A 6-month-old boy is brought to the physician by his mother for abnormal movements. Several times a day, he experiences paroxysmal episodes of crying, bending at the waist, and jerking of the arms and legs. These episodes last 1-2 seconds, but occur in clusters every 20-30 seconds for several minutes. His mother's pregnancy, labor, delivery, and his neonatal course have been unremarkable. He is rolling over less frequently than before, has worse head control, and no longer smiles socially. His temperature is 98.6°F (37°C), blood pressure is 92/46 mmHg, pulse is 115/min, and respirations are 34/min. On examination, no dysmorphic features are noted. A 24-hour electroencephalography (EEG) is performed, during which the patient has one of these spells. A chaotic pattern of slowing and multifocal epileptiform charges is seen. Which of the following is the pathophysiology of this patient's condition?
Decreased gamma aminobutyric acid (GABA) levels
Vitamin B6 deficiency
Excess of corticotropin releasing hormone
Anti-N-methyl-D-aspartate (NMDA) receptor antibodies
Excess of corticotropin releasing hormone
This patient with infantile spasms (bending at the waist and jerking out the arms and legs), developmental regression (rolling over less frequently, worsening head control, loss of social smile), and hypsarrhythmia on video-EEG (slowing and multifocal epileptiform discharges) are characteristic of West syndrome. West syndrome is caused in part by an excess of corticotropin-releasing hormone which leads to increased neuronal excitability.

The pathogenesis of West syndrome is incompletely understood. Infantile spasms are often idiopathic, but may also be secondary to tuberous sclerosis, hypoxic-ischemic encephalopathy, congenital brain malformations, aminoacidopathies, and organic acidopathies. Brain insults may activate a neuroendocrine stress response, which in turn leads to abnormalities of the hypothalamic-pituitary-adrenal axis. Disturbed immune activation may also play a role. Patients will present with infantile spasms, developmental regression, and slowing and multifocal epileptiform discharges known as hypsarrhythmia. Many affected infants are responsive to ACTH therapy, with cessation of spasms and resolution of hypsarrhythmia in many cases.

D’Alonzo et al. review the epidemiology, clinical presentation, pathophysiology, and treatment of West syndrome. They discuss how patients will present with the classic symptoms of spasms and regression. They recommend early diagnosis of this syndrome so that patients can be treated appropriately.

Incorrect Answers:
Answer B: Abnormalities in T-type calcium channels may contribute to absence seizures. Absence seizures are generalized seizures that involve brief, sudden lapses of consciousness and are more common in children. This child’s developmental regression, infantile spasms, and EEG findings are more consistent with West syndrome.

Answer C: Anti-N-methyl-D-aspartate (NMDA) receptor antibodies may cause anti-NMDA encephalitis. Anti-NMDA encephalitis presents with seizures, psychiatric manifestations, and decreased level of consciousness. Hypsarrhythmia is characteristic of West syndrome and is not consistent with anti-NMDA encephalitis.

Answer D: Decreased gamma-aminobutyric acid (GABA) levels were once theorized to be the basis of epilepsy syndromes. This theory is less accepted today. Moreover, West syndrome is likely not mediated by disturbances in GABA. Nonetheless, vigabatrin, which in part works by inhibiting GABA metabolism, is an effective medication for patients with West syndrome.

Answer E: Vitamin B6 deficiency has not been documented in West syndrome. Some studies have suggested vitamin B6 may be of some benefit in the treatment of infantile spasms; however, there is no evidence that response rates to B6 are different from the spontaneous remission rates predicted from natural history data. Therefore, the pathophysiology of West syndrome is more likely CRH-excess mediated rather than due to a deficiency of vitamin B6.

Bullet Summary:
West syndrome, which may be caused by CRH excess, presents with hypsarrhythmia, developmental regression, and infantile spasms.