Preliminary Report
High Doses of 4-Aminopyridine Improve Functionality in Chronic Complete Spinal Cord Injury Patients with MRI Evidence of Cord Continuity

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Background and Aims

Many patients with complete spinal cord injury (SCI) exhibit demyelinated and poorly myelinated nerve fibers traversing the lesion site. Conventional doses of 4-aminopyridine (4-AP, 30 mg/day) have shown to provide no or minor functional improvement in these patients. We undertook this study to test the functional effect of high doses of 4-AP on patients with chronic complete SCI with cord continuity at the site of injury demonstrated by magnetic resonance imaging.

Methods

Fourteen patients were included in a double-blind, randomized, placebo-controlled trial followed by an open label long-term follow-up. Initially, patients received 4-AP or placebo orally, with 4-AP being increased gradually (5 mg/week) to reach 30 mg/day. For long-term treatment, 4-AP was increased 10 mg periodically according to negative electroencephalogram and blood test abnormalities and minor adverse reactions. Pre-treatment, 12 and 24 weeks of the controlled trial, and 6 and 12 months of open trial evaluations, or with the highest doses reached were obtained.

Results

Three of 12 patients were able to walk with the assistance of orthopedic devices, 1/12 became incomplete (AIS B), 7/12 improved their somatosensory evoked potentials, 5/12 had sensation and control of bladder and anal sphincters, and 4/9 male patients had psychogenic erection.

Conclusions

Positive changes were seen mainly in patients with cyst (4/5) or atrophy (3/5) of the injury site. Two patients withdrew from the study: one had seizures and one had intolerant adverse reactions. We conclude that high doses of 4-AP in the studied population produced several functional benefits not observed using lower doses.

Introduction

Spinal cord injury (SCI) in humans leads to motor, sensory and autonomic dysfunction. Despite neurological scores improving progressively during the first months post-injury, 90% patients initially classified as complete remained complete 1 year post-injury 1, 2, 3, 4, 5, 6, 7 and <6% became incomplete during the first 5 years after the injury including motor gain (8). There is no documented information about patients with an ASIA Impaired Scale (AIS) grade A SCI who were able to walk again at least 5 years post-injury 8, 9, 10.

About half of the patients judged to have a functionally complete injury exhibited nerve fibers traversing the lesion site and a persistent rim of spinal cord parenchyma between rostral and caudal segments of the injured spinal cord (11). The sprouting of some neural systems has been also demonstrated (12). Additionally, some detailed anatomic postmortem studies of chronic SCI showed that residual connections across the lesion can preserve some functions 13, 14. On the other hand, after both experimental and human SCI, many of the axons that survive in the epicenter of the injured zone are demyelinated and poorly myelinated 11, 15, 16, 17. Because demyelination has been suggested to be an important contributing factor to long-term sensory and motor impairment, restoration of conduction in demyelinated fibers has been identified as an important strategy for promoting functional recovery 18, 19, 20, 21, 22.

4-Aminopyridine (4-AP) is a voltage-gated fast potassium channel blocker capable of improving neurological function in several ways, including restoring conduction in demyelinated axons 18, 19, 20, 21, 22. 4-AP has demonstrated efficacy in several SCI clinical trials, but with no or little benefit for complete injured patients 23, 24, 25, 26.

Magnetic resonance imaging (MRI) is a method to assess and classify patterns of spinal cord abnormalities in patients with chronic SCI and can usually differentiate between cord continuity or interruption at the injured site 27, 28.

The present study was carried out to assess the functional effect of unusually high doses of 4-aminopyridine on clinically complete (AIS grade A) but with MRI of spared spinal cord in chronic injured patients.

Section snippets

Patients and Methods

The present study was carried out from March 2003 to February 2008 at the Spinal Cord Clinic of the Medical Research Unit for Neurological Diseases at the Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS) in Mexico City. The study was initiated after acceptance by both the local Research Committee of the hospital and the National Research Council of the IMSS. All patients were appropriately informed about the trial, received a written

General Characteristics

Fourteen patients were included (ten males and four females) who completed the first part of the clinical trial. Twelve patients completed the second part of the trial and two withdrew from the study because of AR. Age, post-injury time, mechanism of lesion and injury level characteristics are reported in Table 1. High doses of 4-AP oscillated from 1.0–1.45 mg/kg/day.

Efficacy

Although in the first phase of the trial few patients showed some improvement in motor, sensation or independence evaluations (

Discussion

Several of the reports on functional recovery after traumatic SCI based on the first clinical evaluation at discharge from the hospital, after rehabilitation or 1 year post-injury, established that if there is a complete motor and sensory lesion no recovery of functional value is to be expected 1, 3. However, there are reports in other papers stating that a small number of initially complete neurological lesions became incomplete 2, 5, 8. Ditunno et al. (9) demonstrated, in tetraplegic patients

Acknowledgments

This study was carried out partially with IMSS funds (2005/1/I/179).

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