L-dopa Plus Occlusion for Childhood Amblyopia
NATIONWIDE CHILDREN’S HOSPITAL
DEPARTMENT OF OPHTHALMOLOGY
L-dopa Plus Occlusion for Childhood Amblyopia
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PUBLISHED LITERATURE (funded by the OLERF)
Leguire, L. E., Komaromy, K. L., Nairus, T. M., and Rogers, G. L. Long-term Follow-up of L-dopa Treatment in Children with AMblyopia. J. of Pediatric Ophthalmology ans Strabismus. Nov/Dec p326-330, 2002.
Nahada, M. C., Morosco, R. S., and Leguire, L. E. Development of Two Stable Oral Suspensions of Levodopa-Carbidopa for Children with Amblyopia. J. Pediatric Ophthalmology & Strabismus, 37: 333-337, 2000.
Leguire, L.E., Rogers, G.L., Walson, P.D., Bremer, D.L., McGregor, M.L.: Occlusion and Levodopa – Carbidopa Treatment for Childhood Amblyopia. Journal of the AAPOS, 2(5): 1-7, 1998.
Leguire, L.E., Jende D.L., Nairus, T.M., Walson, P.D., Rogers, G.L., Bremer,D.L. and McGregor, M.L.: Levodopa – Carbidopa and Childhood Retinal Disease. Journal of the AAPOS, 2(2): 79-85, 1998.
Leguire L.E.: Treating Older Children with Intractable Lazy Eye. A compilation of papers presented at the 13th Biennial Eye Research Seminar. Research to Prevent Blindness, p 37-39, 1995.
Leguire, L.E., Walson, P., Rogers, G.L, Bremer, D.L. and McGregor, M.L.: Levodopa/Carbidopa Treatment for Amblyopia in Older Children. Journal of Pediatric Ophthalmology and Strabismus, 32: 143-151, 1995b.
Leguire, L.E., Nairus, T and Walson, P.: Influence of Levodopa/ Carbidopa on Body Temperature in Children. Current Therapeutic Research, 56: 333-340, 1995.
Leguire, L.E., Walson, P., Rogers, G.L., Bremer, D.L. and McGregor, M.L.: Longitudinal Study of Levodopa/ Carbidopa for Childhood Amblyopia J Ped Ophthalmol & Strab, 30: 354-360, 1993.
Leguire, L.E., Rogers, G.L., Bremer, D.L., Walson, P.D., and McGregor, M.L.: Levodopa/Carbidopa for Childhood Amblyopia. Investigative Ophthalmology and Visual Science, 34: 3090-3095, 1993.
Leguire, L.E., Rogers, G.L., Bremer, D.L., Walson, P., Neff, M: Levodopa and Childhood Amblyopia. Journal of Pediatric Ophthalmology and Strabismus, 29: 290-298, 1992.
Note: There is some new scientific evidence that L-dopa plus occlusion therapy may also work in amblyopic adults. See Wizov, S. S., Reinecke, R. D., and Gottlob, I. Visual Acuities After Three Weeks Levodopa Administration in Human Amblyopia with Occlusion Therapy. Investigative Ophthalmology and Visual Science Supplement, March 15, Vol. 40, No. 4, pS57 Paper presented to the annual meeting of the Association for Research in Vision and Ophthalmology, 1999.
Tolerance and Side-effects Information
From Leguire et al, 1998
There were no significant, statistical or clinical, changes in systolic or diastolic blood pressure or pulse rate over the 11 week study period. There was a systematic decrease over the seven week treatment trial in respiration (Repeated Measures ANOVA: F=20.93, p<.0001) and in body temperature (F=5.06, p=.002). Respiration deceased from an average of 24.92 respirations/minute at baseline to 20.31 respirations/ minute at the end of the seven week treatment trial (paired t=5.79,df=12, p<.001). At follow-up, respiration was significantly lower (19.08) than at baseline (paired t=9.45,df=12, p<.001). Body temperature systematically decreased from 98.97° at baseline to 97.78° at the end of the seven week treatment regimen (paired t=2.99, df=12, p<.02). Body temperature returned to baseline levels at the follow-up test trial (98.65°; paired t=1.94, df=11, p>.05). (See Change in oral body temperature discussed below). It is believed that the change (decrease) in resperation was due to increased relaxation and comfort of the patient as the study progressed.
Table 1 lists the number of subjects with specific symptoms and complaints across trials. One subject (#12) accounted for 42% of the listed symptoms and complaints. The number of symptoms and complaints and the number of subjects with these symptoms and complaints were similar when the subjects were on the study drug (i.e. trials 1,3,5,7) and when they were off the study drug (Baseline, Follow-up).
Recently, longterm follow-up (1 – 2 1/2 years) has shown that L-dopa plus part-time occlusion of the dominant eye may provide longterm benefits for the preservation of visual acuity in the amblyopic eye following termination of treatment (Leguire et al, 2003).
Laboratory Tests:
Standard laboratory tests included a panel of 20 tests referred to as a “CHEM 20” including those of liver function, a Complete Blood Count (CBC) and a differential was also performed at baseline and at the end of the 7-week treatment trial. In comparing the baseline and 7-week trial results, no consistent increase or decrease in the various laboratory tests or CBC results could be identified. In particular, no specific changes were noted on tests of liver function. One subject (#9) exhibited low uric acid at baseline (1.1mg/DL; normal range: 2.2-8.7mg/DL) and at the 7-week trial (1.1 mg/DL). Seven subjects exhibited isolated cell counts above or below normal ranges at the 7-week trial; however, 11 of the subjects exhibited similar abnormalities at baseline. There were no systematic trends noted.
Change in Body Temperature:
Leguire, L.E., Nairus, T and Walson, P.: Influence of Levodopa/ Carbidopa on Body Temperature in Children. Current Therapeutic Research, 56: 333-340, 1995.
Leguire et al (1995) have documented that 1.02/0.25 mg/kg of levodopa/carbidopa tid for seven weeks reduced oral body temperature in amblyopic children an average of 1.2 degrees F. However, no behavioral effects, such as coldness, were noted. In contrast, 0.55/0.14 mg/kg of levodopa/carbidopa tid for seven weeks did not change oral body temperature. Both doses were shown to improve visual acuity with part time occlusion of the dominant eye. It is recommended that clinical trials of L-dopa in children be utilized that do not influence body temperature and that body temperature be monitored throughout and after the clinical trial.
Off-label Use of Levodopa/Carbidopa (“L-dopa”)
Children’s Hospital, Columbus, Ohio Outpatient pharmacy has a formula for Levodopa 5mg/ml Suspension (also containing Carbidopa 1.25mg/ml) which we are currently using in Dr. Leguire’s double masked , placebo controlled study with dosing of 0.75mg/kg/dose (based on the levodopa component) tid. This preparation can be ordered for a patient outside of the study and dispensed here or we can share the formula with a community/retail pharmacy. The suspension has a 2 month stability, with a patient cost of about $40.00/200 ml , and generally will take 1-2 days to prepare. Scripts can be called in directly to the pharmacy at 614-722-2160.
Exclusion Criteria for Patients in levodopa/carbidopa (“L-dopa”) Studies:
Amblyopic children with any significant health problems, except for the amblyopia, should not be entered into the study. Specifically, patients cannot have: narrow angle glaucoma, cardiovascular disease, pulmonary disease, asthma, renal disease, hepatic disease, endocrine disease, gastrointestinal disease, or known psychological problems. Similarly, patients must not have a known hypersensitivity to levodopa and must not have taken or plan to take monoamine oxidase (MAO) inhibitors within a month, before or after, levodopa treatment.
Patients should be instructed to avoid taking vitamins, especially vitamin B6 (pyridoxine) or iron, to minimize the consumption of beef and sodium (salt), and to avoid antacids because they decrease the effectiveness of levodopa.
Parents should call their Ophthalmologist and/or Pharmacist before the patient takes a prescription medicine while on the L-dopa. If the child is currently taking a prescription medicine, be sure to tell the doctor before enrollment into the study.
Problem: Infantile Nystagmus Syndrome (INS) also called Congenital Nystagmus
Infantile nystagmus syndrome (INS) which was formerly known as congenital nystagmus (CN) is defined as conjugated, spontaneous and involuntary ocular oscillations that appear at birth or during the first three months of life (Orssaud, 2003). These involuntary movements in effect cause a decrease in visual acuity and may lead to legal blindness in children. In fact, INS is one of the leading causes of significant vision loss in children and affects about 1 in 1000 to 6000 births (e.g., Abadi and Bjerre, 2002; Oetting et al, 2000). INS accounts for about 2 – 8% of children with visual impairment or legal blindness that utilize services for the visually impaired.
What causes infantile nystagmus syndrome (INS)? The nystagmus itself is the direct result of an ocular motor control instability that may develop with or without an accompanying sensory deficit (Dell’Osso, 2005). This ocular motor instability may affect the oculomotor nerve (cranial nerve III) which is responsible for controlling eye movements. This nerve originates in the midbrain, and supplies most of the muscles attached to the eye. Any deficiency in one of these muscles, whether from the cranial nerves or another cause, can lead to an abnormal function (movements) in one or both eyes such as nystagmus. As to what causes INS, it is still not clear which makes it difficult to treat. However, after much research has been done, INS can now be characterized more precisely which can help rule out some unnecessary treatment.
Visual acuity in INS patients is related primarily to the duration of foveation periods, during which the image of the target is relatively stationary in the foveal area (Sheth, 1995). With INS visual acuity and contrast sensitivity are reduced, but usually patients have a null zone in which they can gaze or turn their heads to reduce the nystagmus. Some patients actually have two null zones, one in each gaze direction (Orssaud, 2003). The phenomenon of null zone is what most of the current treatment is based on. In general, treatment of INS includes correcting the refractive errors, drugs and eye muscle surgery with the main goal of improving vision. Optic lens and prismatic spectacles can be used for correction of refractive errors. Also, base out prisms may be used to damp INS during distance fixation in patients with null zone in convergence (Orssaud, 2003).
Currently there does not exist a complete drug treatment specifically for INS, however there are drug treatments for several other forms of nystagmus. Some of these drug treatments have been discussed and analyzed (Leigh, 2003). Unfortunately, taking these specific drugs and applying to INS is not sufficient, mainly because there are inherent differences across these types of nystagmus, although Baclofen can improve visual acuity in a small series of patients (Orssaud, 2003).
As for the surgical approach, there are two main surgical procedures, the Kestenbaum and Spielmann. Kestenbaum proposed to perform recessions and/or resections of the four horizontal muscles in order to shift horizontally the null position into primary position. The Spielmann procedure consists of a slanting or the insertion of the rectus muscles (Orssaud, 2003). The problem with these procedures is that they are invasive and that multiple surgeries may need to be done. A more recent surgical treatment, horizontal rectus tenotomy, has been performed on patients with INS and the results proved successful in 9 out of 10 patients in which the tenotomy was of all four horizontal recti with reattachment at the original insertion.
Fortunately, advancements in technology, such as magnetic resonance imaging (MRI), is allowing researchers to have a better understanding of these eye movement disorders. With better understanding more effective and less invasive treatments can be prescribed. At present studies have been taken a step further and functional MRI (fMRI) have been in use. Although, no specific fMRI studies have been published on INS, there have been several on optokinetic nystagmus (OKN) and saccades. More details about these studies will be described now.
By taking the same approach that several groups (Dieterich, 2000; Dieterich, 1998; Kimmig, 2001; Dieterich, 2002; Cornelissen, 2002; Mort, 2003; Schmitz, 2004; Stephan, 2004) have pursued, a thorough analysis of INS can also be performed using fMRI. The objective in these studies is to compare normal brain activity to abnormal (nystagmus). Thus normal oculomotor function can be analyzed as the control in an fMRI scan and then an abnormal oculomotor function can be compared at the cortex levels. Overall, the purpose of performing these fMRI studies is to isolate the brain regions responsible for nystagmus by characterizing the locations where activation may show up to the smallest regions.
The exact anatomical location of the source of the instability present INS is still unknown (Dell’Osso, 2005). Thus it is encouraging to continue to try and characterize INS. The future work for INS is inevitably with fMRI. This approach has been proven to have potential as was done previously with amblyopia (Algaze, 2002).
Methods: Functional magnetic resonance imaging (fMRI)
We approach the topic of INS from an applied, clinical perspective; to identify the brain site(s) responsible for the involuntary, abnormal eye movements that characterize INS in our patient population by means of functional magnetic resonance imaging (fMRI). Our long term (clinical) goal is to develop a therapeutic intervention for INS, be it surgical, pharmacologic or by other means. For the first time, the proposed novel affords a method to identify the anatomical correlate(s) of INS. Identification of the brain site(s) responsible for INS will result if the proposed fMRI method is successful. The success of the novel method is the first step in directing our future efforts for therapeutic intervention of INS. No other psychophysical, electrophysiological, or other approach or type of animal study has been able to successfully address this issue.
Expected Results:
All experiments include predictions about INS patients (within subjects) and a comparison with normal age-matched controls (between subjects). The experimental approach is a form of converging operations. While the experiments tap different oculomotor function (fixation, saccade, pursuit, stare and look OKN), it is predicted that all experiments will show fMRI activation of the site(s) responsible for INS.
Regardless of the type of site(s) associated with INS, there should be higher fMRI activation of the site in the INS patients than in the normal controls because fMRI activation is dependent on the oculomotor frequency response (Kimmig et al, 2001). In INS patients, the excessive degree of oculomotor function (INS is in the 3 Hz range) exceeds normal oculomotor function. We hypothesize that the brain site(s) responsible for INS are in “overdrive” and should yield a very high degree of fMRI activation. Thus, in response to one reviewer comment; yes, we expect brain sites responsible for INS to produce significantly higher fMRI activation than found in normal controls. A comparison of fMRI activation sites among the various experiments between normal controls and INS patients should reveal common sites across experiments – those responsible for INS. Preliminary results presented to ARVO 2009 by Leguire, Kashou et al.
Implications:
If we are able to find regions in the brain that are common to INS patients then we can further develop treatments specifically to target these sites. For instance, we can then introduce drug, surgical or more advance therapies to help prevent this disorder from developing and mainly preventing blindness and improving eye sight.