Preliminary ReportHigh Doses of 4-Aminopyridine Improve Functionality in Chronic Complete Spinal Cord Injury Patients with MRI Evidence of Cord Continuity
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.
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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).
References (38)
- et al.
Late neurological recovery after traumatic spinal cord injury
Arch Phys Med Rehabil
(2004) Cellular morphology of chronic spinal cord injury in the cat: analysis of myelinated axons by line-sampling
Neuroscience
(1983)- et al.
Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury
Exp Neurol
(2005) Effect of 4-aminopyridine on axonal conduction-block in chronic spinal cord injury
Brain Res Bull
(1989)- et al.
Conduction block in acute and chronic spinal cord injury: different dose-response characteristics for reversal by 4-aminopyridine
Exp Neurol
(1997) - et al.
4-Aminopyridine enhances motor evoked potentials following graded spinal cord compression injury in rats
Brain Res
(1999) Imaging in chronic spinal cord injury indications and benefits
Eur J Radiol
(2002)International inquiry on neurological terminology and prognosis in paraplegia and tetraplegia
Paraplegia
(1969)- et al.
Recovery from spinal cord injury
Clin Neurosurg
(1983) Some thoughts about neurological recovery in spinal cord injuries: a philosophical review
Paraplegia
(1985)
Late neurological changes following traumatic spinal cord injury
J Neurosurg
Motor and sensory recovery following complete tetraplegia
Arch Phys Med Rehabil
Functional outcome of patients with spinal cord injury: rehabilitation outcome study
Clin Rehabil
Corticospinal function studied over time following incomplete spinal cord injury
Spinal Cord
Motor recovery of upper extremities in traumatic quadriplegia: a multicenter study
Arch Phys Med Rehabil
Late recovery following spinal cord injury. Case report and review of the literature
J Neurosurg (Spine 2)
Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination
Adv Neurol
Calcitonin gene-related peptide (CGRP)-like immunoreactivity in motoneurons of the human spinal cord following injury
J Neurotrauma
A review of the neuropathology of human spinal cord injury with emphasis of special features
J Spinal Cord Med
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Restoration of Visual Function by Enhancing Conduction in Regenerated Axons
2016, CellCitation Excerpt :Likewise, 4-AP, an FDA-approved potassium channel blocker, could represent a possibly translatable therapeutic paradigm to overcome the conduction blockade following damage or diseases. In this aspect, Grijalva et al. (2010) showed that a high dose of 4-AP treatment resulted in significant functional recovery in patients of chronic spinal cord injury with cord continuity at injury site. Although high doses of 4-AP lead to troubling side-effects (Hayes, 2004), we show that its derivative 4-AP-3-Me mimics the effects of 4-AP at lower doses, suggesting an alternative treatment to 4-AP.
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