Richard D. Penn

Neuronal ensemble control of prosthetic devices by a human with tetraplegia.

Neuromotor prostheses (NMPs) aim to replace or restore lost motor functions in paralysed humans by routeing movement-related signals from the brain, around damaged parts of the nervous system, to external effectors. To translate preclinical results from intact animals to a clinically useful NMP, movement signals must persist in cortex after spinal cord injury and be engaged by movement intent when sensory inputs and limb movement are long absent. Furthermore, NMPs would require that intention-driven neuronal activity be converted into a control signal that enables useful tasks. Here we show initial results for a tetraplegic human (MN) using a pilot NMP. Neuronal ensemble activity recorded through a 96-microelectrode array implanted in primary motor cortex demonstrated that intended hand motion modulates cortical spiking patterns three years after spinal cord injury. Decoders were created, providing a ‘neural cursor’ with which MN opened simulated e-mail and operated devices such as a television, even while conversing. Furthermore, MN used neural control to open and close a prosthetic hand, and perform rudimentary actions with a multi-jointed robotic arm. These early results suggest that NMPs based upon intracortical neuronal ensemble spiking activity could provide a valuable new neurotechnology to restore independence for humans with paralysis.

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.

Glial cell line–derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open‐label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin).

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD

Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson’s Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. “On” and “off” total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues—putamen and substantia nigra.

Intrathecal baclofen for severe spinal spasticity

We studied the effect of the intrathecal infusion of baclofen, an agonist of gamma-aminobutyric acid, on abnormal muscle tone and spasms associated with spinal spasticity, in a randomized double-blind crossover study. Twenty patients with spinal spasticity caused by multiple sclerosis or spinal-cord injury who had had no response to treatment with oral baclofen received an intrathecal infusion of baclofen or saline for three days. The infusions were administered by means of a programmable pump implanted in the lumbar subarachnoid space. Muscle tone decreased in all 20 patients (mean [+/- SD] Ashworth score for rigidity, from 4.0 +/- 1.0 to 1.2 +/- 0.4; P less than 0.0001), and spasms were decreased in 18 of the 19 patients who had spasms (mean [+/- SD] score for spasm frequency, from 3.3 +/- 1.2 to 0.4 +/- 0.8; P less than 0.0005). Tests for motor function, neurologic examination, and assessments by the patients correctly indicated when baclofen was being infused in all cases. All patients were then entered in an open long-term trial of continuous infusion of intrathecal baclofen. During a mean follow-up period of 19.2 months (range, 10 to 33), muscle tone has been maintained within the normal range (mean Ashworth score, 1.0 +/- 0.1) and spasms have been reduced to a level that does not interfere with activities of daily living (mean spasm score, 0.3 +/- 0.6). No drowsiness or confusion occurred, one pump failed, and two catheters became dislodged and had to be replaced. No infections were observed. Our observations suggest that intrathecal baclofen is an effective long-term treatment for spinal spasticity that has not responded to oral baclofen.

Intraspinal morphine for chronic pain : A retrospective, multicenter study

Intraspinal opioids are frequently used in the treatment of cancer and noncancer pain, but few studies have evaluated the efficacy of this technique. This multicenter, retrospective study surveyed physicians in the United States regarding their standard practices when using intraspinal opioids delivered via an implanted drug administration device. Thirty-five physicians (50.0%) responded, providing 429 usable patient forms (52.4%), which sought information about screening, outcomes, dosing, and adverse effects. Patients with malignant (32.7%) and noncancer (67.3%) pain had been treated for an average of 14.6 +/- 0.57 months (range, 8-94 months) at the time of form completion. For all patients, the mean percent relief was 61.0% +/- 1.35%. Patients with somatic pain tended to have greater relief, as measured by a global rating of pain relief, than did patients with other types of pain (Mann-Whitney test, P = 0.0003). After titration during the first 3 months, intrathecal morphine doses increased only twofold from 6.84 +/- 0.65 mg/day at 3 months to 13.19 +/- 1.76 mg/day at 24 months. Compared to those with noncancer pain, malignant pain patients had a higher average initial dose. The average dose used by cancer patients escalated quickly and then stabilized, whereas the average doses used by noncancer pain patients exhibited a more gradual, linear increase in dose. Long-term adverse drug effects were uncommon, but system malfunction, usually catheter related, occurred in 21.6% of patients. Prospective, randomized, controlled clinical studies of long-term efficacy and adverse effects are warranted.

A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis.

BACKGROUND: Brain derived neurotrophic factor (BDNF) is a potent survival factor for motoneurons. This study investigated the safety and tolerability of recombinant methionyl ( r -metHuBDNF) infused intrathecally by means of an implanted pump in patients with ALS. METHODS: Twenty-five probable or definite ALS were treated with either r -metHuBDNF (25, 60, 150, 400 or 1000 mug/day) or placebo in a 12- week, randomized, double-blinded, sequential, dose-escalation study. Test treatment was interrupted by a washout period from days 11 to 25 to allow the evaluation of laboratory safety measures. In each dose cohort four patients received r -metHuBDNF and one received placebo. On completion of the double-blind period of the study all patients continued to receive r -metHuBDNF in an open-label extension for up to 60 weeks. Lumbar cerebrospinal fluid (CSF) samples were taken periodically from all patients for the measurement of r -metHuBDNF levels and in a minority of patients these were supplemented by cisternal samples. RESULTS: Within days after the initiation of infusion the majority of patients receiving r -metHuBDNF reported mild sensory symptoms, including paraesthesias or a human BDNF sense of warmth, which were usually confined to the lower limbs and were frequently exacerbated by neck flexion. In most instances these symptoms patients with decreased or even disappeared over several weeks. Sleep disturbance, dry mouth, agitation and other behavioural effects were encountered at higher doses (>150 mug/day) and necessitated dose reductions. The spinal CSF levels of r -metHuBDNF were directly related to dose, with a lumbar to cervical ratio of approximately 4:1. CONCLUSIONS: The intrathecal delivery of r -metHuBDNF in doses of up to 150 mug/day was well tolerated and appears feasible. The reversible CNS effects with higher dose indicate that BDNF can be delivered cranially against CSF flow. The small number of patients and the design of the study did not permit conclusions to be drawn about the efficacy of the treatment. (ALS 2000; 1:201-206)

United Parkinson Foundation Neurotransplantation Registry on adrenal medullary transplants Presurgical, and 1‐ and 2‐year follow‐up

Thirteen centers participated in a multicenter database with systematic evaluation of US and Canadian patients who had adrenal medullary transplantation for Parkinsons disease. This voluntary registry collected demographic, safety, and efficacy data using the same scoring measures over a 2-year follow-up period. Baseline data on 61 patients and 2-year follow-up data on 56 patients were compared. Eighteen percent died during the study period, and one-half of these deaths were related or questionably related to the surgery. Of the remaining 45 patients with data, global improvement, defined as an improved summed score of the “n” and “off” motor and activities of daily living functions from the Unified Parkinsons Disease Rating Scale, occurred in 32% of the patients at 2 years after surgery. At follow-up, significant group improvement persisted in the amount of daily “on” time and the quality of “off” function, but other measures were no better than baseline. When the global improvement calculation was based on the total sample and included deaths and patients lost to follow-up as “not improved,” only 19% were improved 2 years after surgery. Twenty-two percent of survivors had persistent psychiatric morbidity not present prior to surgery. These data document a modest group improvement in “off” function after neurotransplantation, but a serious level of mortality and morbidity.

Evidence-Based Review of the Literature on Intrathecal Delivery of Pain Medication

Evidence-based medicine depends on the existence of controlled clinical trials that establish the safety and efficacy of specific therapeutic techniques. Many interventions in clinical practice have achieved widespread acceptance despite little evidence to support them in the scientific literature; the critical appraisal of these interventions based on accumulating experience is a goal of medicine. To clarify the current state of knowledge concerning the use of various drugs for intraspinal infusion in pain management, an expert panel conducted a thorough review of the published literature. The exhaustive review included 5 different groups of compounds, with morphine and bupivacaine yielding the most citations in the literature. The need for additional large published controlled studies was highlighted by this review, especially for promising agents that have been shown to be safe and efficacious in recent clinical studies.

Stiff‐man syndrome treated with intrathecal baclofen

Stiff-man syndrome is a rare, progressive motor disorder causing disabling muscle rigidity and spasms, which is often associated with insulin-dependent diabetes mellitus. In patients with this syndrome, Solimena et documented the presence of autoantibodies against glutamic acid decarboxylase (GAD), an enzyme selectively concentrated in pancreatic beta cells and CNS neurons secreting the major inhibitory neurotransmitter yaminobutyric acid (GARA). Although plasmapheresis has been tried,3 diazepam remains the most effective treatment; it acts on the GABA receptors, making them more sensitive to GABA.4 Unfortunately, as the disease progresses, diazepam becomes less effective and severe spasms occur. Baclofen is a direct GABA-B agonist that does not require GAHA secretion to activate its receptor. Thus, baclofen would logically be a useful medication for treating stiff-man syndrome if it could be provided in sufficiently high concentration to the spinal cord receptors. We have treated severe spasticity of spinal origin with intrathecal baclofen and found that i t significantly reduces spasms and rigidity when oral medications failed.J We now report similar success with two patients with stiff-man syndrome. Patient I . A 42-year old man reported 7 years of progressive rigidity and spasms that began in his trunk musculature and gradually involved both legs and made walking difficult. Diazepam had afforded initial relief, but as the disease progressed, he became disabled and unable t,o work at his job as a machinist. Pain became worse as the intensity and frequency of spasms increased. He gradually elevated his diazepam dose to 140 mgid, without significant improvement. At age 34, he developed diabetes mellitus and was placed on insulin. His only neurologic abnormalities were demonstrated on motor examination. He had increased muscle tone in his axial muscles, with a pronounced lumbar lordosis. Xild sensory stimulation or volitional movements would set off sevore spasms in his back and legs. His reflexes were normal and a Babinski sign was not present. A lumbar puncture was performed and 75 pg baclofen (CibaGeigy, Basel, Switzerland) was injected. One hour later, his rigidity and spasms completely disappeared and hc was able to walk normally. By 8 hours, the effect was decreasing, and by 24 hours he returned to baseline. A programmable drug pump and catheter (SynchroMed, Medtronic, Inc., Minneapolis, MN) going t o the lumbar subarachnoid space was implanted, and his spasms were completely controlled with baclofen 120 pgid. Over the next 2X years, the dose of intrathecal baclofen was gradually increased to 1,200 pg/d to suppress his spasms; diazepam has been reduced to 20 mg/d, but is still necessary in low dose. He has had a n episode of meningitis requiring antibiotics and replacement of the pump and catheter system, and twice the catheter has dislocated from the subarachnoid space and needed replacement. Each time he stopped receiving intrathecal badofen his spasms recurred. Patient 2. A 63-year-old woman was diagnosed with stiffman syndrome in 1988. At that time, she had a one-year history of progressive spasms in her back and legs and difficulty with gait, and she required a walker. Pain occurred during attacks of spasms. On motor examination, she had hyperextension of the lumbar spine and severe spasms at the hips and knees, without weakness, atrophy, or fasciculations. The reflexes were normal and a Babinski sign was not present. An extensive work-up was normal except for antibodies t o GAD in her CSF (by Dr. DeCaricelli a t Yale University). Diazepam was given and helped initially, but a year la ter she was bedridden and having markedly increased pain. Intrathecal preservative-free methylprednisolone and systemic immunotherapy with azathioprine and plasmapheresis were tried without significant effect. By 1992, she had developed ankylosis at her hip, knees, and feet, secondary atrophy of her leg muscles, and severe pain due to her

Clinical guidelines for intraspinal infusion: Report of an expert panel

Consensus guidelines developed by an expert panel are helpful to clinicians when there is variation in practice and lack of a firm evidence base for an intervention, such as intraspinal therapy for pain. An internet-based survey of practitioners revealed remarkable variation in practice patterns surrounding intraspinal therapy. This prompted an interdisciplinary panel with extensive clinical experience in intraspinal infusion therapy to evaluate the results of the survey, the systematic reviews of the literature pertaining to this approach, and their own clinical experience with long-term spinal infusions. The panel proposed a scheme for the selection of drugs and doses for intraspinal therapy, and suggested guidelines for administration that would increase the likelihood of a successful outcome. These expert panel guidelines were designed to provide an initial structure for clinical decision making that is based on the best available evidence and the perspectives of experienced clinicians.