Abstract
Background
Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF. Perispinal administration may enhance etanercept delivery across the blood–CSF barrier.
Objective
The objective of this study was to systematically examine the clinical response following perispinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and TBI.
Methods
After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with perispinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed.
Results
The treated cohort included 629 consecutive patients. Charts of 617 patients following stroke and 12 patients following TBI were reviewed. The mean age of the stroke patients was 65.8 years ± 13.15 (range 13–97). The mean interval between treatment with PSE and stroke was 42.0 ± 57.84 months (range 0.5–419); for TBI the mean interval was 115.2 ± 160.22 months (range 4–537). Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioural function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence. Improvements in multiple domains were typical. Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI. In the TBI cohort, motor impairment and spasticity were statistically significantly reduced.
Discussion
Irrespective of the methodological limitations, the present results provide clinical evidence that stroke and TBI may lead to a persistent and ongoing neuroinflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury.
Conclusion
Excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI. Perispinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI. The therapeutic window extends beyond a decade after stroke and TBI. Randomized clinical trials will be necessary to further quantify and characterize the clinical response.
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References
Creutzfeldt CJ, Holloway RG, Walker M. Symptomatic and palliative care for stroke survivors. J Gen Intern Med. 2012;27(7):853–60.
Langhorne P, Coupar F, Pollock A. Motor recovery after stroke: a systematic review. Lancet Neurol. 2009;8(8):741–54.
Patel M, Coshall C, Rudd AG, et al. Natural history of cognitive impairment after stroke and factors associated with its recovery. Clin Rehabil. 2003;17(2):158–66.
Patel MD, Coshall C, Rudd AG, et al. Cognitive impairment after stroke: clinical determinants and its associations with long-term stroke outcomes. J Am Geriatr Soc. 2002;50(4):700–6.
Toole JF, Bhadelia R, Williamson JD, et al. Progressive cognitive impairment after stroke. J Stroke Cerebrovasc Dis. 2004;13(3):99–103.
Vakhnina NV, Nikitina LY, Parfenov VA, et al. Post-stroke cognitive impairments. Neurosci Behav Physiol. 2009;39(8):719–24.
Christensen MC, Morris S, Vallejo-Torres L, et al. Neurological impairment among survivors of intracerebral hemorrhage: The FAST Trial. Neurocrit Care. (Epub 2011 Oct 6)
Klit H, Finnerup NB, Jensen TS. Central post-stroke pain: clinical characteristics, pathophysiology, and management. Lancet Neurol. 2009;8(9):857–68.
Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lancet. 2011;377(9778):1693–702.
Smith M. Management of hemiplegic shoulder pain following stroke. Nurs Stand. 2012;26(44):35–44.
Miller A, Pratt H, Schiffer RB. Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments. Expert Rev Neurother. 2011;11(7):1077–88.
Beattie EC, Stellwagen D, Morishita W, et al. Control of synaptic strength by glial TNFalpha. Science. 2002;295(5563):2282–5.
Clark IA. How TNF was recognized as a key mechanism of disease. Cytokine Growth Factor Rev. 2007;18(3–4):335–43.
Cheng X, Yang L, He P, et al. Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer’s disease and non-demented patients. J Alzheimers Dis. 2010;19(2):621–30.
Jiang H, Hampel H, Prvulovic D, et al. Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer’s disease. Mol Neurodegener. 2011;6:69.
Nadeau S, Rivest S. Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood–brain barrier. Neuroscience. 1999;93(4):1449–64.
Clark IA, Rockett RA, Cowden WB. TNF in cerebral malaria. Q J Med. 1993;86(3):217–8.
Clark IA, Rockett KA. The cytokine theory of human cerebral malaria. Parasitol Today. 1994;10(10):410–2.
Tarkowski E, Blennow K, Wallin A, et al. Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol. 1999;19(4):223–30.
Paty DW. TNF neutralization induces an increase in relapses in patients with multiple sclerosis. Can J Neurol Sci. 1998;25(Suppl. 2):G-09.
The Lenercept Multiple Sclerosis Study Group, The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology. 1999;53(3):457–65.
Pardridge WM. The blood–brain barrier: bottleneck in brain drug development. NeuroRx. 2005;2(1):3–14.
Banks WA, Plotkin SR, Kastin AJ. Permeability of the blood–brain barrier to soluble cytokine receptors. Neuroimmunomodulation. 1995;2(3):161–5.
van Oosten BW, Barkhof F, Truyen L, et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology. 1996;47(6):1531–4.
Clark IA, Alleva LM, Vissel B. The roles of TNF in brain dysfunction and disease. Pharmacol Ther. 2010;128(3):519–48.
Tobinick E. Deciphering the physiology underlying the rapid clinical effects of perispinal etanercept in Alzheimer’s disease. Curr Alzheimer Res. 2012;9(1):99–109.
Rossi D, Martorana F, Brambilla L. Implications of gliotransmission for the pharmacotherapy of CNS disorders. CNS Drugs. 2011;25(8):641–58.
Tweedie D, Ferguson RA, Fishman K, et al. Tumor necrosis factor-alpha synthesis inhibitor 3,6′-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease. J Neuroinflammation. 2012;9:106.
Cavanagh C, Colby-Milley J, Farso M, et al. Early molecular and synaptic dysfunctions in the prodromal stages of Alzheimer’s disease; focus on TNF-alpha and IL-1beta. Futur Neurol. 2011;6(6):757–69.
Clark I, Atwood C, Bowen R, et al. Tumor necrosis factor-induced cerebral insulin resistance in Alzheimer’s disease links numerous treatment rationales. Pharmacol Rev. 2012;64(4):1004–26.
Wang G, Gilbert J, Man HY. AMPA receptor trafficking in homeostatic synaptic plasticity: functional molecules and signaling cascades. Neural Plast. 2012;2012:825364. doi:10.1155/2012/825364.
Chou SH, Feske SK, Atherton J, et al. Early elevation of serum tumor necrosis factor-alpha is associated with poor outcome in subarachnoid hemorrhage. J Investig Med. 2012;60(7):1054–8.
Butchart J, Holmes C. Systemic and central immunity in Alzheimer’s disease: therapeutic implications. CNS Neurosci Ther. 2012;18(1):64–76.
Belarbi K, Jopson T, Tweedie D, et al. TNF-alpha protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J Neuroinflammation. 2012;9:23.
Shi JQ, Shen W, Chen J, et al. Anti-TNF-alpha reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res. 2011;1368:239–47.
Felger JC, Miller AH. Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol. (Epub 2012 Sep 21).
Chio CC, Lin JW, Chang MW, et al. Therapeutic evaluation of etanercept in a model of traumatic brain injury. J Neurochem. 2010;115(4):921–9.
Frankola KA, Greig NH, Luo W, et al. Targeting TNF-alpha to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS Neurol Disord Drug Targets. 2011;10(3):391–403.
Giuliani F, Vernay A, Leuba G, et al. Decreased behavioral impairments in an Alzheimer mice model by interfering with TNF-alpha metabolism. Brain Res Bull. 2009;80(4–5):302–8.
Griffin WS. Perispinal etanercept: potential as an Alzheimer therapeutic. J Neuroinflammation. 2008;5:3.
Kaushal V, Schlichter LC. Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci. 2008;28(9):2221–30.
McNaull BB, Todd S, McGuinness B, et al. Inflammation and anti-inflammatory strategies for Alzheimer’s disease: a mini-review. Gerontology. 2010;56(1):3–14.
Shichita T, Sakaguchi R, Suzuki M, et al. Post-ischemic inflammation in the brain. Front Immunol. 2012;3:132.
Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440(7087):1054–9.
Tarkowski E, Andreasen N, Tarkowski A, et al. Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2003;74(9):1200–5.
Tobinick E. Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs. 2009;23(9):713–25.
Tobinick E. Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases. CNS Drugs. 2011;25(2):145–55.
Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation. 2008;5:2.
Tweedie D, Sambamurti K, Greig NH. TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets. Curr Alzheimer Res. 2007;4(4):378–85.
Tancredi V, D’Arcangelo G, Grassi F, et al. Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci Lett. 1992;146(2):176–8.
Tobinick E. Perispinal etanercept for treatment of Alzheimer’s disease. Curr Alzheimer Res. 2007;4(5):550–2.
Bains JS, Oliet SH. Glia: they make your memories stick! Trends Neurosci. 2007;30(8):417–24.
Halassa MM, Fellin T, Haydon PG. The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med. 2007;13(2):54–63.
Tobinick E. Perispinal etanercept for neuroinflammatory disorders. Drug Discov Today. 2009;14(3–4):168–77.
Tobinick EL, Britschgi-Davoodifar S. Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly. 2003;133(11–12):170–7.
Tobinick EL. Targeted etanercept for discogenic neck pain: uncontrolled, open-label results in two adults. Clin Ther. 2003;25(4):1211–8.
Tobinick EL. Targeted etanercept for treatment-refractory pain due to bone metastasis: two case reports. Clin Ther. 2003;25(8):2279–88.
Tobinick E, Davoodifar S. Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. Curr Med Res Opin. 2004;20(7):1075–85.
Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother. 2010;10(6):985–1002.
Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC Neurol. 2008;8:27.
Batson OV. The vertebral vein system: Caldwell lecture, 1956. Am J Roentgenol Radium Ther Nucl Med. 1957;78(2):195–212.
Esposito E, Cuzzocrea S. Anti-TNF therapy in the injured spinal cord. Trends Pharmacol Sci. 2011;32(2):107–15.
Nathoo N, Caris EC, Wiener JA, et al. History of the vertebral venous plexus and the significant contributions of Breschet and Batson. Neurosurgery. 2011;69(5):1007–14. (discussion 14).
Pearce JM. The craniospinal venous system. Eur Neurol. 2006;56(2):136–8.
Tobinick E, Vega CP. The cerebrospinal venous system: anatomy, physiology, and clinical implications. MedGenMed. 2006;8(1):53.
Tobinick E, Gross H, Weinberger A, et al. TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. MedGenMed. 2006;8(2):25.
Tobinick E. Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Medscape J Med. 2008;10(6):135.
Tobinick EL, Chen K, Chen X. Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging. BMC Res Notes. 2009;2:28.
Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4:147ra11.
Johanson CE, Duncan JA, Stopa EG, et al. Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route. Pharm Res. 2005;22(7):1011–37.
Cohen SP, Bogduk N, Dragovich A, et al. Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology. 2009;110(5):1116–26.
Kato K, Kikuchi S, Shubayev VI, et al. Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve. Neuroscience. 2009;160(2):492–500.
Kato K, Liu H, Kikuchi S, et al. Immediate anti-tumor necrosis factor-alpha (etanercept) therapy enhances axonal regeneration after sciatic nerve crush. J Neurosci Res. 2010;88(2):360–8.
Ohtori S, Miyagi M, Eguchi Y, et al. Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: a prospective randomized study. Spine. 2012;37(6):439–44.
Shen CH, Tsai RY, Shih MS, et al. Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats. Anesth Analg. 2011;112(2):454–9.
Shen CH, Tsai RY, Tai YH, et al. Intrathecal etanercept partially restores morphine’s antinociception in morphine-tolerant rats via attenuation of the glutamatergic transmission. Anesth Analg. 2011;113(1):184–90.
Watanabe K, Yabuki S, Sekiguchi M, et al. Etanercept attenuates pain-related behavior following compression of the dorsal root ganglion in the rat. Eur Spine J. 2011;20(11):1877–84.
Zanella JM, Burright EN, Hildebrand K, et al. Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine (Phila Pa 1976). 2008;33(3):227–34.
Buchhave P, Zetterberg H, Blennow K, et al. Soluble TNF receptors are associated with Abeta metabolism and conversion to dementia in subjects with mild cognitive impairment. Neurobiol Aging. 2010;31(11):1877–84.
Furrer E, Hulmann V, Urech DM. Intranasal delivery of ESBA105, a TNF-alpha-inhibitory scFv antibody fragment to the brain. J Neuroimmunol. 2009;215(1–2):65–72.
Zhou QH, Sumbria R, Hui EK, et al. Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor. J Pharmacol Exp Ther. 2011;339(2):618–23.
Genovese T, Mazzon E, Crisafulli C, et al. Immunomodulatory effects of etanercept in an experimental model of spinal cord injury. J Pharmacol Exp Ther. 2006;316(3):1006–16.
Marchand F, Tsantoulas C, Singh D, et al. Effects of etanercept and minocycline in a rat model of spinal cord injury. Eur J Pain. 2009;13(7):673–81.
Price CJ, Wang D, Menon DK, et al. Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke. 2006;37(7):1749–53.
Macrez R, Ali C, Toutirais O, et al. Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol. 2011;10(5):471–80.
Atkinson HH, Rosano C, Simonsick EM, et al. Cognitive function, gait speed decline, and comorbidities: the health, aging and body composition study. J Gerontol A Biol Sci Med Sci. 2007;62(8):844–50.
Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–9.
Smith T, Gildeh N, Holmes C. The Montreal Cognitive Assessment: validity and utility in a memory clinic setting. Can J Psychiatry. 2007;52(5):329–32.
Harrison JE, Buxton P, Husain M, et al. Short test of semantic and phonological fluency: normal performance, validity and test–retest reliability. Br J Clin Psychol. 2000;39(Pt 2):181–91.
Wong GK, Lam S, Ngai K, et al. Evaluation of cognitive impairment by the Montreal Cognitive Assessment in patients with aneurysmal subarachnoid haemorrhage: prevalence, risk factors and correlations with 3 month outcomes. J Neurol Neurosurg Psychiatry (Epub 2012 Jul 31).
Schweizer TA, Al-Khindi T, Macdonald RL. Mini-Mental State Examination versus Montreal Cognitive Assessment: rapid assessment tools for cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. J Neurol Sci. 2012;316(1–2):137–40.
Dong Y, Sharma VK, Chan BP, et al. The Montreal Cognitive Assessment (MoCA) is superior to the Mini-Mental State Examination (MMSE) for the detection of vascular cognitive impairment after acute stroke. J Neurol Sci. 2010;299(1–2):15–8.
Balakrishnan P, Rosen H. The causes and treatment of pseudobulbar affect in ischemic stroke. Curr Treat Options Cardiovasc Med. 2008;10(3):216–22.
Hrobjartsson A, Kaptchuk TJ, Miller FG. Placebo effect studies are susceptible to response bias and to other types of biases. J Clin Epidemiol. 2011;64(11):1223–9.
Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001;344(21):1594–602.
Hrobjartsson A, Gotzsche PC. Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment. J Intern Med. 2004;256(2):91–100.
Hrobjartsson A, Gotzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Syst Rev. 2010;(1):CD003974.
Linde K, Fassler M, Meissner K. Placebo interventions, placebo effects and clinical practice. Philos Trans R Soc Lond B Biol Sci. 2011;366(1572):1905–12.
Glasziou P, Chalmers I, Rawlins M, et al. When are randomised trials unnecessary? Picking signal from noise. BMJ. 2007;334(7589):349–51.
Benucci M, Saviola G, Manfredi M, et al. Tumor necrosis factors blocking agents: analogies and differences. Acta Biomed. 2012;83(1):72–80.
Antoniou C, Vergou T, Dessinioti C, et al. Etanercept: effectiveness and safety data of a retrospective study. J Eur Acad Dermatol Venereol. 2011;25(9):1113–5.
Gladman DD, Bombardier C, Thorne C, et al. Effectiveness and safety of etanercept in patients with psoriatic arthritis in a Canadian clinical practice setting: the REPArE trial. J Rheumatol. 2011;38(7):1355–62.
Gottlieb AB, Gordon K, Giannini EH, et al. Clinical trial safety and mortality analyses in patients receiving etanercept across approved indications. J Drugs Dermatol. 2011;10(3):289–300.
Kerensky TA, Gottlieb AB, Yaniv S, et al. Etanercept: efficacy and safety for approved indications. Expert Opin Drug Saf. 2012;11(1):121–39.
Klareskog L, Gaubitz M, Rodriguez-Valverde V, et al. Assessment of long-term safety and efficacy of etanercept in a 5-year extension study in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2011;29(2):238–47.
Pariser DM, Leonardi CL, Gordon K, et al. Integrated safety analysis: short- and long-term safety profiles of etanercept in patients with psoriasis. J Am Acad Dermatol. 2012;67(2):245–56.
Vender R. An open-label, prospective cohort pilot study to evaluate the efficacy and safety of etanercept in the treatment of moderate to severe plaque psoriasis in patients who have not had an adequate response to adalimumab. J Drugs Dermatol. 2011;10(4):396–402.
Clausen BH, Lambertsen KL, Babcock AA, et al. Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice. J Neuroinflammation. 2008;5:46.
Demonaco HJ, Ali A, Hippel E. The major role of clinicians in the discovery of off-label drug therapies. Pharmacotherapy. 2006;26(3):323–32.
Vandenbroucke JP. In defense of case reports and case series. Ann Intern Med. 2001;134(4):330–4.
Tobinick EL. The value of drug repositioning in the current pharmaceutical market. Drug News Perspect. 2009;22(2):119–25.
Elliott MJ, Maini RN, Feldmann M, et al. Repeated therapy with monoclonal antibody to tumour necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet. 1994;344(8930):1125–7.
Sumbria RK, Boado RJ, Pardridge WM. Brain protection from stroke with intravenous TNFalpha decoy receptor-Trojan horse fusion protein. J Cereb Blood Flow Metab. 2012;32(10):1933–8.
Flansbjer UB, Holmback AM, Downham D, et al. Reliability of gait performance tests in men and women with hemiparesis after stroke. J Rehabil Med. 2005;37(2):75–82.
Cumming TB, Bernhardt J, Linden T. The montreal cognitive assessment: short cognitive evaluation in a large stroke trial. Stroke. 2011;42(9):2642–4.
Pendlebury ST, Cuthbertson FC, Welch SJ, et al. Underestimation of cognitive impairment by Mini-Mental State Examination versus the Montreal Cognitive Assessment in patients with transient ischemic attack and stroke: a population-based study. Stroke. 2010;41(6):1290–3.
Toglia J, Fitzgerald KA, O’Dell MW, et al. The Mini-Mental State Examination and Montreal Cognitive Assessment in persons with mild subacute stroke: relationship to functional outcome. Arch Phys Med Rehabil. 2011;92(5):792–8.
Pilcher M, MacArthur J. Patient experiences of bladder problems following stroke. Nurs Stand. 2012;26(36):39–46.
Rotar M, Blagus R, Jeromel M, et al. Stroke patients who regain urinary continence in the first week after acute first-ever stroke have better prognosis than patients with persistent lower urinary tract dysfunction. Neurourol Urodyn. 2011;30(7):1315–8.
Patel M, Coshall C, Rudd AG, et al. Natural history and effects on 2-year outcomes of urinary incontinence after stroke. Stroke. 2001;32(1):122–7.
Langdon PC, Lee AH, Binns CW. Dysphagia in acute ischaemic stroke: severity, recovery and relationship to stroke subtype. J Clin Neurosci. 2007;14(7):630–4.
Skilbeck CE, Wade DT, Hewer RL, et al. Recovery after stroke. J Neurol Neurosurg Psychiatry. 1983;46(1):5–8.
Wade DT, Langton-Hewer R, Wood VA, et al. The hemiplegic arm after stroke: measurement and recovery. J Neurol Neurosurgery Psychiatry. 1983;46(6):521–4.
Wade DT, Wood VA, Hewer RL. Recovery after stroke: the first 3 months. J Neurol Neurosurg Psychiatry. 1985;48(1):7–13.
Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med. 2000;342(25):1887–92.
Wolinsky H. Paths to acceptance: the advancement of scientific knowledge is an uphill struggle against ‘accepted wisdom’. EMBO Rep. 2008;9(5):416–8.
Lang L. Barry Marshall 2005 Nobel laureate in medicine and physiology. Gastroenterology. 2005;129(6):1813–4.
Sobel RK. Barry Marshall: a gutsy gulp changes medical science. US News World Rep. 2001;131(7):59.
Kuhn T. The structure of scientific revolutions. Chicago (IL): The University of Chicago Press; 1962.
Zivin JA, Simmons JG. tPA for stroke: the story of a controversial drug. New York (NY): Oxford University Press; 2010.
Neurex. Meeting on the roles of TNF in brain dysfunction and disease, Basel. 2012. http://www.neurex.org/en/events/2012/workshop-on-the-roles-of-tnf-in-brain-dysfunction-and-disease-en,25445.html. Accessed 17 Oct 2012.
Acknowledgments
Funding for the study was provided by the Institute of Neurological Recovery® (INR®). Edward Tobinick, Nancy M. Kim, Gary Reyzin, Helen Rodriguez-Romanacce and Venita DePuy played an important role in the acquisition, analysis and interpretation of the data, wrote the manuscript, made substantive suggestions for revision and approved the final submitted version. Venita DePuy performed the statistical analyses. Edward Tobinick was responsible for the conception and planning of the work that led to the manuscript. The authors acknowledge the general assistance of Lynna Sim, Daniel Gendler, Shea Sullivan and Young Hee Jennifer Kim. Edward Tobinick is the named inventor and receives royalties from multiple issued and pending US and international patents assigned to TACT IP LLC that describe perispinal administration of etanercept for the treatment of stroke and other methods of use of etanercept and other biologics for the treatment of neurological disorders. These patents include, but are not limited to, US patents 6419944, 6537549, 6982089, 7214658, 7629311, 8119127, 8236306 and Australian patent 758,523. The INR® is a private medical practice that has licensed the TACT IP LLC patents. Nancy Kim, Helen Rodriguez-Romanacce and Gary Reyzin are INR® employees. Venita DePuy received payment for her authorship contributions.
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Tobinick, E., Kim, N.M., Reyzin, G. et al. Selective TNF Inhibition for Chronic Stroke and Traumatic Brain Injury. CNS Drugs 26, 1051–1070 (2012). https://doi.org/10.1007/s40263-012-0013-2
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DOI: https://doi.org/10.1007/s40263-012-0013-2