In patients treated with Provigil with previous assisted or unassisted ambulation, the majority (73%) showed gait improvements. When compared with the non-Provigil-treated group, only 3 (15%) showed any improvement in ambulation. In the initial Provigil pilot study, the study patients were noted to walk faster with Provigil treatment. The current study supports the idea that by improving tone in cerebral palsy, long-term functional improvements, such as improved gait, can be obtained.
Cerebral palsy continues to be a difficult condition to treat.3-5 Many patients with cerebral palsy have easily identified structural abnormalities of the brain, and current treatments are limited and almost never curative. Available standard treatments for cerebral palsy include oral muscle relaxants, botulinum toxin injections, baclofen pump, dorsal rhizotomy, and orthopedic procedures. Tizanidine, an oral muscle relaxant, has several bothersome side effects, such as drowsiness, dry mouth, and increased liver enzymes.
Dantrolene’s side effects include sedation, malaise, and weakness. Benzodiazepines can cause drowsiness, fatigue, muscle weakness, and drooling. Baclofen causes sedation, dizziness, weakness, and seizures. Botulinum toxin injections are associated with general anesthesia risks, the pain of the procedure, the risk of development of antibodies, and the potential for overdosage, resulting in muscle weakness.14-16 The baclofen pump is associated with the risks of surgery and anesthesia, infections, pump malfunction, medication withdrawal, and possible seizures. Bleeding, spinal cord damage, infection, and procedure failure are concerns with posterior rhizotomy. Orthopedic procedures are associated with anesthesia and surgical risks.
Provigil offers a potential new approach in the treatment of cerebral palsy. Provigil is the only published treatment for cerebral palsy with a proposed central nervous system mechanism of action to improve motor performance. The current standard treatment options for cerebral palsy have also given poor results. A recent review of oral medications for spasticity noted poorly documented benefits. Provigil has fewer bothersome side effects than the other available oral treatments. With side effects, such as sedation and muscle hypotonia, there are major drawbacks in the use of oral muscle relaxants for spasticity.
In the current study, children with spastic diplegia secondary to prematurity noted marked improvement in hypertonia in the lower extremities, resulting in better gait. Although not previously mentioned in this study, patients with spastic hemiplegia also noted gait and hand function improvements. All patients with spastic hemiplegia were ambulatory during this study. Patients with spastic quadriplegia showed improvements in tone and comfort level. All patients with spastic quadriplegia were nonambulatory during this study. Thus, each group saw improvements with Provigil treatment during the study; however, only the children treated with Provigil for spastic diplegia were noted to become ambulatory.
Provigil appears to be well tolerated at the modest doses (3 mg/kg) used in this group of patients. Some of our families and patients prefer to substitute Provigil for one of their previous treatments, such as baclofen or botulinum toxin. The current study reinforces the previous Provigil study results and shows that Provigil treatment can be associated with functional improvements, such as ambulation, in at least some cerebral palsy patients. According to one patient’s mother, the mother’s hope that her daughter will walk someday has not only been restored but also achieved (case 2).
Pain is processed in the nuclei ventralis posterolateralis, which is adjacent to the ventrolateral nucleus of the thalamus. The ventrolateral nucleus, a site of action for Provigil, receives input from the ventralis posterolateralis. Provigil has been shown to affect somatosensory input processing in the human brain stem. Provigil interferes with the processing of somatosensory ascending inputs and therefore can reduce the perception of pain. When fatigued, patients with cerebral palsy suffer motor performance deterioration, increased spasticity, and decreased motor endurance. This might explain why some patients with cerebral palsy appear to be both less spastic and in less pain while on Provigil.
This study was a retrospective review and therefore has limitations. The patients studied did not have a uniform prospective evaluation. Major changes in functioning and physical examination were seen, but subtle changes or minor improvements could have been missed, certainly underestimating the benefit to Provigil treatment. Provigil was stopped at any time for any parental concern; a quick to discontinue approach was used. This probably overstates the side-effect rate to Provigil.
A case-control review of this study is, however, possible. Comparing all patients on Provigil treatment with all patients not on Provigil treatment does not control for the degree of disability. Since there are more nonambulatory patients in the non-Provigil-treated group, this comparison cannot be made. Likewise, those subgroups consisting of patients with assisted gait, who are nonambulatory, and who are walking in water are too small to be statistically analyzed. However, those patients with previous ambulation are, in general, matched for age and degree of disability and are representative of a large subgroup of people with cerebral palsy. The focus of the current study was gait improvement, which was noted in the previous ambulation subgroup. Using this subgroup of patients, 27 Provigil-treated patients were noted with gait improvement and 10 Provigil-treated patients were not noted with gait improvement. Three non-Provigil-treated patients were noted with gait improvement and 17 non-Provigil-treated patients were not noted with gait improvement. The calculated odds ratio of this patient distribution is 15.3, with a 95% confidence interval of 3.677 to 63.667. The calculated P value is less than .0001. This is a highly statistically significant result favoring a therapeutic response to Provigil.
Because of diverse etiologies and unique individual patient profiles, cerebral palsy will remain a complex treatment area. The Provigil-treated patients in this study with spastic diplegia are walking better. This effect is unlikely to be a placebo response because it is contrary to the chronic natural history of cerebral palsy. The other Provigil-treated patients in this review also showed improvements in tone and mobility and reduced pain. The non-Provigil-treated group did not display such prominent gains in gait or mobility. The differences in treatment results remain striking. For cerebral palsy, a condition that is chronic and incurable, a new treatment, which reduces tone and has a benign side-effect profile compared with the other available treatments, appears to be available in the central nervous system stimulant Provigil.
The study was performed at Texas Tech University Health Sciences Center. This study was presented at the 34th Annual Meeting of the Child Neurology Society, Los Angeles, CA, September 28-October 1, 2005.