John C. Oakley

Prospective, multicenter study of spinal cord stimulation for relief of chronic back and extremity pain.

Study Design This prospective, multicenter study was designed to investigate the efficacy and outcome of spinal cord stimulation using a variety of clinical and psychosocial outcome measures. Data were collected before implantation and at regular intervals after implantation. This report focuses on 70 patients who had undergone 1 year of follow‐up treatment at the time of data analysis. Objectives To provide a more generalizable assessment of long‐term spinal cord stimulation outcome by comparing a variety of pain and functional/quality‐of‐life measures before and after management. This report details results after 1 year of stimulation. Summary of Background Data The historically diverse methods, patient selection criteria, and outcome measures reported in the spinal cord stimulation literature have made interpretation and comparison of results difficult. Although short‐term outcomes are generally consistent, long‐term outcomes of spinal cord stimulation, as determined by prospective studies that assess multidimensional aspects of the pain complaint among a relatively homogeneous population, are not well established. Methods Two hundred nineteen patients were entered at six centers throughout the United States. All patients underwent a trial of stimulation before implant of the permanent system. Most were psychologically screened. One hundred eighty‐two patients were implanted with a permanent stimulating system. At the time of this report, complete 1‐year follow‐up data were available on 70 patients, 86% of whom reported pain in the back or lower extremities. Patient evaluation of pain and functional levels was completed before implantation and 3, 6, 12, and 24 months after implantation. Complications, medication usage, and work status also were monitored. Results All pain and quality‐of‐life measures showed statistically significant improvement during the treatment year. These included the average pain visual analogue scale, the McGill Pain Questionnaire, the Oswestry Disability Questionnaire, the Sickness Impact Profile, and the Beck Depression Inventory. Overall success of the therapy was defined as at least 50% pain relief and patient assessment of the procedure as fully or partially beneficial and worthwhile. Using this definition, spinal cord stimulation successfully managed pain in 55% of patients on whom 1‐year follow‐up is available. Complications requiring surgical intervention were reported by 17% (12 of 70) of patients. Medication usage and work status were not changed significantly. Conclusions This prospective, multicenter study confirms that spinal cord stimulation can be an effective therapy for management of chronic low back and extremity pain. Significant improvements in many aspects of the pain condition were measured, and complications were minimal.

NaV1.1 channels and epilepsy

Voltage‐gated sodium channels initiate action potentials in brain neurons, and sodium channel blockers are used in therapy of epilepsy. Mutations in sodium channels are responsible for genetic epilepsy syndromes with a wide range of severity, and the NaV1.1 channel encoded by the SCN1A gene is the most frequent target of mutations. Complete loss‐of‐function mutations in NaV1.1 cause severe myoclonic epilepsy of infancy (SMEI or Dravets Syndrome), which includes severe, intractable epilepsy and comorbidities of ataxia and cognitive impairment. Mice with loss‐of‐function mutations in NaV1.1 channels have severely impaired sodium currents and action potential firing in hippocampal GABAergic inhibitory neurons without detectable effect on the excitatory pyramidal neurons, which would cause hyperexcitability and contribute to seizures in SMEI. Similarly, the sodium currents and action potential firing are also impaired in the GABAergic Purkinje neurons of the cerebellum, which is likely to contribute to ataxia. The imbalance between excitatory and inhibitory transmission in these mice can be partially corrected by compensatory loss‐of‐function mutations of NaV1.6 channels, and thermally induced seizures in these mice can be prevented by drug combinations that enhance GABAergic neurotransmission. Generalized epilepsy with febrile seizures plus (GEFS+) is caused by missense mutations in NaV1.1 channels, which have variable biophysical effects on sodium channels expressed in non‐neuronal cells, but may primarily cause loss of function when expressed in mice. Familial febrile seizures is caused by mild loss‐of‐function mutations in NaV1.1 channels; mutations in these channels are implicated in febrile seizures associated with vaccination; and impaired alternative splicing of the mRNA encoding these channels may also predispose some children to febrile seizures. We propose a unified loss‐of‐function hypothesis for the spectrum of epilepsy syndromes caused by genetic changes in NaV1.1 channels, in which mild impairment predisposes to febrile seizures, intermediate impairment leads to GEFS+ epilepsy, and severe or complete loss of function leads to the intractable seizures and comorbidities of SMEI.

Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy

Heterozygous loss-of-function mutations in the α subunit of the type I voltage-gated sodium channel NaV1.1 cause severe myoclonic epilepsy in infancy (SMEI), an infantile-onset epileptic encephalopathy characterized by normal development followed by treatment-refractory febrile and afebrile seizures and psychomotor decline. Mice with SMEI (mSMEI), created by heterozygous deletion of NaV1.1 channels, develop seizures and ataxia. Here we investigated the temperature and age dependence of seizures and interictal epileptiform spike-and-wave activity in mSMEI. Combined video-EEG monitoring demonstrated that mSMEI had seizures induced by elevated body core temperature but wild-type mice were unaffected. In the 3 age groups tested, no postnatal day (P)17–18 mSMEI had temperature-induced seizures, but nearly all P20–22 and P30–46 mSMEI had myoclonic seizures followed by generalized seizures caused by elevated core body temperature. Spontaneous seizures were only observed in mice older than P32, suggesting that mSMEI become susceptible to temperature-induced seizures before spontaneous seizures. Interictal spike activity was seen at normal body temperature in most P30–46 mSMEI but not in P20–22 or P17–18 mSMEI, indicating that interictal epileptic activity correlates with seizure susceptibility. Most P20–22 mSMEI had interictal spike activity with elevated body temperature. Our results define a critical developmental transition for susceptibility to seizures in SMEI, demonstrate that body temperature elevation alone is sufficient to induce seizures, and reveal a close correspondence between human and mouse SMEI in the striking temperature and age dependence of seizure frequency and severity and in the temperature dependence and frequency of interictal epileptiform spike activity.

Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome

Heterozygous loss-of-function mutations in the brain sodium channel NaV1.1 cause Dravet syndrome (DS), a pharmacoresistant infantile-onset epilepsy syndrome with comorbidities of cognitive impairment and premature death. Previous studies using a mouse model of DS revealed reduced sodium currents and impaired excitability in GABAergic interneurons in the hippocampus, leading to the hypothesis that impaired excitability of GABAergic inhibitory neurons is the cause of epilepsy and premature death in DS. However, other classes of GABAergic interneurons are less impaired, so the direct cause of hyperexcitability, epilepsy, and premature death has remained unresolved. We generated a floxed Scn1a mouse line and used the Cre-Lox method driven by an enhancer from the Dlx1,2 locus for conditional deletion of Scn1a in forebrain GABAergic neurons. Immunocytochemical studies demonstrated selective loss of NaV1.1 channels in GABAergic interneurons in cerebral cortex and hippocampus. Mice with this deletion died prematurely following generalized tonic-clonic seizures, and they were equally susceptible to thermal induction of seizures as mice with global deletion of Scn1a. Evidently, loss of NaV1.1 channels in forebrain GABAergic neurons is both necessary and sufficient to cause epilepsy and premature death in DS.

Sudden unexpected death in a mouse model of Dravet syndrome

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in intractable epilepsies, but physiological mechanisms that lead to SUDEP are unknown. Dravet syndrome (DS) is an infantile-onset intractable epilepsy caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes brain type-I voltage-gated sodium channel NaV1.1. We studied the mechanism of premature death in Scn1a heterozygous KO mice and conditional brain- and cardiac-specific KOs. Video monitoring demonstrated that SUDEP occurred immediately following generalized tonic-clonic seizures. A history of multiple seizures was a strong risk factor for SUDEP. Combined video-electroencephalography-electrocardiography revealed suppressed interictal resting heart-rate variability and episodes of ictal bradycardia associated with the tonic phases of generalized tonic-clonic seizures. Prolonged atropine-sensitive ictal bradycardia preceded SUDEP. Similar studies in conditional KO mice demonstrated that brain, but not cardiac, KO of Scn1a produced cardiac and SUDEP phenotypes similar to those found in DS mice. Atropine or N-methyl scopolamine treatment reduced the incidence of ictal bradycardia and SUDEP in DS mice. These findings suggest that SUDEP is caused by apparent parasympathetic hyperactivity immediately following tonic-clonic seizures in DS mice, which leads to lethal bradycardia and electrical dysfunction of the ventricle. These results have important implications for prevention of SUDEP in DS patients.

Spinal cord stimulation for complex regional pain syndrome: a prospective study of 19 patients at two centers.

Objectives. Prospective studies using specific outcome measures for the treatment of complex regional pain syndromes (CRPS) using spinal cord stimulation are lacking in the literature. The current prospective study followed 19 patients with the objective of analyzing such patients using specific outcome measures including the McGill Pain Rating Index, the Sickness Impact Profile, Oswestry Disability, Beck Depression Inventory, and Visual Analog Scale Scores.

Spinal Cord Stimulation for Complex Regional Pain Syndrome I [RSD]: a Retrospective Multicenter Experience from 1995 to 1998 of 101 Patients.

Objective. To evaluate effectiveness of spinal cord stimulation (SCS) applied to complex regional pain syndrome I (CRPS I). To analyze trends to focus the design of a multicenter prospective study.

Prevention of Mechanical Failures in Implanted Spinal Cord Stimulation Systems

Introduction.  Spinal cord stimulation (SCS) is an effective procedure for the treatment of neuropathic extremity pain, with success rates approaching 70%. However, mechanical failures, including breakage and migration, can significantly limit the long‐term effectiveness of SCS. A systematic analysis of surgical techniques was undertaken by a consensus group, coupled with extensive in vivo and in vitro biomechanical testing of system components.

Transverse Tripolar Spinal Cord Stimulation: Results of an International Multicenter Study

Experienced neurosurgeons at eight spinal cord stimulation centers in the United States, Canada, and Europe participated in a study from 1997 to 2000 investigating the safety, performance, and efficacy of a Transverse Tripolar Stimulation (TTS) system invented at the University of Twente, the Netherlands. This device was proposed to improve the ability of spinal cord stimulation to adequately overlap paresthesia to perceived areas of pain. Fifty‐six patients with chronic, intractable neuropathic pain of the trunk and/or limbs more than three months’ duration (average 105 months) were enrolled with follow‐up periods at 4, 12, 26, and 52 weeks. All patients had a new paddle‐type lead implanted with four electrodes, three of them aligned in a row perpendicular to the cord. Fifteen of these patients did not undergo permanent implantation. Of the 41 patients internalized, 20 patients chose conventional programming using an implanted pulse generator to drive four electrodes, while 21 patients chose a tripole stimulation system, which used radiofrequency power and signal transmission and an implanted dual‐channel receiver to drive three electrodes using simultaneous pulses of independently variable amplitude. On average, the visual analog scale scores dropped more for patients with TTS systems (32%) than for conventional polarity systems (16%). Conventional polarity systems were using higher frequencies on average, while usage range was similar. Most impressive was the well‐controlled “steering” of the paresthesias according to the dermatomal topography of the dorsal columns when using the TTS‐balanced pulse driver. The most common complication was lead migration. While the transverse stimulation system produced acceptable outcomes for overall pain relief, an analysis of individual pain patterns suggests that it behaves like spinal cord stimulation in general with the best control of extremity neuropathic pain. This transverse tripole lead and driving system introduced the concept of electrical field steering by selective recruitment of axonal nerve fiber tracts in the dorsal columns.

ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice.

The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1(-/-) or Cnr2(-/-) mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntingtons disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy.