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ISSN: Print -2349-0977, Online - 2349-4387

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Year : 2018  |  Volume : 5  |  Issue : 1  |  Page : 5-9

Unravelling the exciting new therapeutic pathways in clinical neurology

Director, Comprehensive Stroke Center and Sleep Center, Day Kimball Hospital, Putnam, Connecticut, USA

Date of Web Publication28-Jan-2019

Correspondence Address:
Majaz Moonis
Director, Comprehensive Stroke Center and Sleep Center, Day Kimball Hospital, Putnam, Connecticut, USA
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2349-0977.250926

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How to cite this article:
Moonis M. Unravelling the exciting new therapeutic pathways in clinical neurology. Astrocyte 2018;5:5-9

How to cite this URL:
Moonis M. Unravelling the exciting new therapeutic pathways in clinical neurology. Astrocyte [serial online] 2018 [cited 2023 Oct 4];5:5-9. Available from: http://www.astrocyte.in/text.asp?2018/5/1/5/250926

Piecing together priceless nuggets of the most recent advances in clinical neurology, this special edition of “Astrocyte” holds a mine of information from some of the tallest figures in the realm. Welding triumphant scientific breakthroughs that have heralded new panoramas of hope in millions of lives, the content would distinctly benefit physicians practicing general medicine and neurology, either as a refresher or to provide new information to those not familiar with the current advances.

Called the decade of the brain, the closing years of the twentieth century {1990-1999} brought several therapeutic advances to the fore. As a result, neurological disorders hitherto considered untreatable, came to be tamed. The impact has been very considerable. It has brought a new morning, filled with glowing hopes, in areas as wide as stroke, multiple sclerosis (MS), neurodegenerative disorders, epilepsy, neuromuscular diseases and a host of other conditions. Still, some challenges linger. Of them, primary tumors of the CNS and a significant majority of neurodegenerative disorders are the most difficult.

Primarily, two quantum changes have led to these advances. Firstly, a paradigm shift that has fueled a greater understanding of genomics and molecular genetics which drive disease processes. Secondly, the beginning of the 21st century has witnessed the end of the purist and the beginning of a new multidisciplinary approach to neurological diseases.[1] While these disease specific approaches have impacted several different neurological disorders, the greatest impact has occurred in the areas of stroke, MS, sleep and a few selective neuromuscular disorders.

The changed landscape

Acute ischemic stroke treatment is completely transformed as is the concept of stroke prevention. The National Institute of Neurological Disorders and Stroke (NINDS) study was a pivotal trial that confirmed the safety and efficacy of recombinant tissue plasminogen activator (rtPA). Given as an intravenous infusion within 3 hours of stroke onset, there was a 13.3% absolute risk reduction in the risk of a poor outcome and a relative risk reduction of 33% (1/3 patients treated within the window of 3-hours would be free of any disability at 3 months after stroke onset) The European Cooperative Acute Stroke Trial further extended the window of intravenous thrombolysis to 4.5 hours and the most recent EXTEND trial has taken it to 9 hours based on identification of the tissue at risk (penumbra) vs. infarcted tissue (core) as well as the site of vascular obstruction.

Vascular imaging was key to improving outcomes. This was important because intravenous thrombolysis does not work where there is large vessel occlusion or a large clot burden and either a combined approach or embolectomy is required.[2] Patients with a large vessel occlusion did not do well with this treatment alone. Based on the data, the present author created a stroke service where the first bridge was not only a non-contrast CT (NCCT) but an additional CT angiogram (CTA) and possibly CT perfusion (CTP) to determine the ischemic penumbra. Patients with large vessel occlusion (LVO) were sent for embolectomy with intravenous rtPA running. We also moved from a strictly time-based window to a tissue-based approach. At any given time after stroke onset, if there is tissue to be saved, meaning a large penumbra, intra-arterial intervention was the choice given that there was an LVO. The results in most carefully selected cases have been dramatic. Subsequently 6 randomized trials of LVO treated with mechanical thrombectomy validated this approach. With careful patient selection, the time window was extended up to 24 hours (DAWN).[3],[4]

With the advent of HMG CoA reductase inhibitors (statins), the risk of recurrent ischemic stroke and improved outcome after stroke onset became apparent.[5],[6] The chapter is not over yet with CREST-2 examining whether current best medical therapy is better than carotid endarterectomy (CEA) in patients with large artery internal carotid stenosis.

More recently, PCSK-9 inhibitors exhibiting the same properties as statins and complementary to these drugs as well as an alternative in patients with statin intolerance appear to hold much promise.[7]

The healing molecules

The management of MS has undergone a revolutionary change in the recent. No longer considered a demyelinating disease alone, the discovery that interferons and other medications are capable of downgrading the immune response associated with MS has come as a major milestone. Therapies based on the better understanding of pathophysiology of MS have evolved at a rapid rate. The discovery of interferons, more effective oral medications (dimethyl fumarate, fingolimod etc.) followed by even more powerful treatment modalities requiring monthly intravenous infusion (the MAB era) has made the disease almost treatable. Addition of immunosuppressive medications (Rituximab) was another milestone. With adequate compliance and monitoring of risks of treatment, patients are expected to live a normal functional life.[8] An exciting new medication is Ocrelizumab, that for the first time offers hope to patients with primary progressive MS.[9]

The expanding canvas

While many new medications continue to surface for the management of epilepsy, there were no head-to-head trials that compared the efficacy of these newer more expensive medications. Having said that, they did offer a better risk profile compared to the older therapies. The management paradigm of status epilepticus changed from intravenous fosphenytoin to include several additional options. These include levetiracetam and valproate as alternate and safer choices. Medications like lacosamide as well as levetiracetam and valproate now can be seamlessly moved from oral to IM/IV therapy offering a choice beyond pheytoin to patients who are unable to swallow.[10]

Vagal nerve stimulation and evolution of epilepsy surgery in carefully selected patients has had dramatic effects in seizure reduction and improved quality of life.[11] Recently cannabis related therapies for childhood refractory epilepsies seem to reduce the frequency of seizures.

Coming of age

Sleep medicine has evolved from an art fantasy to a well-defined science. With the recognition that sleep apnea is not the only sleep problem, other sleep disorders gained attention. These included excessive daytime sleepiness, circadian rhythm disorders and insomnia amongst others. It was then realized that management of these varied sleep disorders requires a multidisciplinary team approach including but not limited to neurologists, pulmonologists and psychologists. The field moved from observational science to understanding the basic pathophysiology, receptors and molecular genetics. As an example, this approach resulted in targeted highly effective therapies for narcolepsy.[12] With the understanding of the hypocretin deficiency in narcolepsy with cataplexy, came the distinction that this disease differs from pure narcolepsy and requires a different approach to management.[13]

Mending neuromuscular disorders

Neuromuscular disorders including immune neuropathies including acute idiopathic demyelinating neuropathy (AIDP), chronic immune demyelinating neuropathy (CIDP), other immune neuromyopathies, myasthenia gravis and several others are considered treatable disorders.[14],[15]

The path ahead

The future holds major promise with a better understanding of the molecular basis of disease which can produce potential novel treatments. As an example, in case of childhood neuromuscular disorder spinomuscular atrophy (SMA), understanding the defects in gene and then successfully being able to implant it in the genome is a giant leap transforming a once fatal disabling disease to a treatable one.[16],[17],[18] As these collaborative networks grow, hope rises that newer treatment options will evolve for many of the untreatable diseases such as amyotrophic lateral sclerosis (ALS) and primary brain tumors.

Guest editor for this special edition of Astrocyte, Prof. Majaz Moonis {MD, DM, MRCPI, FRCPE, FAAN, FAHA, FAASM} is a key thought leader in the realm of Clinical Neurology. A Professor of Neurology and Psychiatry, he is associated with Department of Neurology, University of Massachusetts Medical School and affiliated UMass Memorial Hospital, and is the Director of in-patient Stroke Services, Worcester, Massachusetts, and Director of the Comprehensive Stroke Center and Sleep Center, Day Kimball Hospital, Putnam, Connecticut, USA.

His major contributions in research has focused on statins, and, in particular, their role in improving outcomes in stroke and familial Alzheimerfs disease. He has been a principal investigator for several stroke trials.

Dr. Moonis has a large body of published work, including more than 140 research publications and presentations in peer reviewed journals, and a full-length work, Controversies in Stroke Care. He has served on the editorial boards of several international journals, including the journal gStrokeh and has been a key figure in the inception of the Indian and Tabasco (Mexico) Stroke associations as well as the NeuroIMC courses in Madrid Spain. Presently, he is also the president of the Tabasco Mexico Stroke Society.

Dr. Moonis has held several key positions in central Massachusetts, American Heart Association, American Academy of Neurology and the educational committee of the Royal College of Physicians of Edinburgh. His work stands recognized with several honors and awards internationally.

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Albright KC, Zhao H, Blackburn J, Limdi NA, Beasley TM, Howard G, et al. Racial differences in statin adherence following hospital discharge for ischemic stroke. Neurology. 2017;88 (19):1839-48.  Back to cited text no. 3
Jovin TG, Saver JL, Ribo M, Pereira V, Furlan A, Bonafe A, et al. Diffusion-weighted imaging or computerized tomography perfusion assessment with clinical mismatch in the triage of wake up and late presenting strokes undergoing neurointervention with Trevo (DAWN) trial methods. Int J Stroke. 2017;12 (6):641-52.  Back to cited text no. 4
Moonis M, Kane K, Schwiderski U, Sandage BW, Fisher M. HMG-CoA reductase inhibitors improve acute ischemic stroke outcome. Stroke. 2005;36 (6):1298-300.  Back to cited text no. 5
Potey C, Ouk T, Petrault O, Petrault M, Berezowski V, Salleron J, et al. Early treatment with atorvastatin exerts parenchymal and vascular protective effects in experimental cerebral ischaemia. Br J Pharmacol. 2015;172 (21):5188-98.  Back to cited text no. 6
Monami M, Sesti G, Mannucci E. PCSK9 Inhibitor Therapy: A Systematic Review And Meta-Analysis of Metabolic And Cardiovascular Outcomes in Patients With Diabetes. Diabetes Obes Metab. 2018.  Back to cited text no. 7
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Kremer D, Kury P, Hartung HP. ECTRIMS/ACTRIMS 2017: Closing in on neurorepair in progressive multiple sclerosis. Mult Scler. 2018;24 (6):696-700.  Back to cited text no. 9
Alexovic M, Dotsikas Y, Bober P, Sabo J. Achievements in robotic automation of solvent extraction and related approaches for bioanalysis of pharmaceuticals. J Chromatogr B Analyt Technol Biomed Life Sci. 2018;1092:402-21.  Back to cited text no. 10
Bialer M, Johannessen SI, Koepp MJ, Levy RH, Perucca E, Tomson T, et al. Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development. Epilepsia. 2018;59 (10):1842-66.  Back to cited text no. 11
Wang C, Wang Q, Ji B, Pan Y, Xu C, Cheng B, et al. The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases. Front Mol Neurosci. 2018;11:220.  Back to cited text no. 12
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