Neurological Disorders Overview
Epilepsy is a common, chronic, heterogenous condition with onset commonly in childhood and adolescence and characterised by recurrent and seemingly unprovoked seizures13,14.
Epilepsy can have a devastating impact on quality of life, health and daily living activities15 and classifying, diagnosing and treating epilepsy in adults and children can be difficult.
Treatment options include non-pharmacological, pharmacological and surgical options, and patient-specific factors such as seizure type and genetic factors are key to selecting the best treatment from the wide variety of antiepileptic drugs available 16,17.
AD is a chronic progressive neurodegenerative disorder characterised by cognitive dysfunction, non-cognitive symptoms and difficulties with performing daily living tasks2.
Treatment early in the course of AD helps maintain cognitive and functional performance and delays the emergence of distressing behavioural and psychological symptoms, such as depression, anxiety and apathy3.
Rapid diagnosis is therefore important as is individualised care for this heterogeneous condition. The mainstay of therapy for AD are cholinesterase inhibitors such as rivastigmine4, the partial N-methyl-D-aspartate (NMDA) memantine5 and treatments for secondary symptoms including antidepressants, antianxiety agents and antipsychotics. Drug combinations and different formulations may be useful to maintain treatment adherence and persistence6.
Affecting 8 – 12% of children worldwide, ADHD is the most commonly diagnosed neurodevelopmental disorder7. This heterogeneous condition is characterised by the core symptoms of impulsivity, hyperactivity and inattention8,9 and is more frequently observed in males and individuals with other neurological conditions including epilepsy and autism spectrum disorder (ASD)10.
Although onset of ADHD usually occurs in childhood, it can affect patients throughout their life, and can cause academic underachievement, unemployment, relationship and legal problems, substance abuse, psychiatric illness and higher mortality in adults9–11.
While no curative treatment has been identified, ADHD can be well managed through psychological and pharmacological interventions with stimulants such as methylphenidate being an established treatment12. Early diagnosis and treatment adherence are particularly important7.
Migraine affects quality of life and a patient’s functional ability during, immediately after, and between migraine episodes. Consequently the condition has a large socioeconomic impact18,19.
Migraine pain starts with ‘abnormal’ activation of the trigeminovascular system (TGVS) which causes release of various neuropeptides at the meninges that can induce neurogenic inflammation including calcitonin gene-related peptide (CGRP)20,21.
Until recently, treatment for migraine prevention utilised drugs developed for other conditions such as antihypertensives, antidepressants, antiepileptics and botulinum toxin type A22,23. However, agents targeting the CGRP pathway have been the recent focus of migraine research, and erenumab was the first human monoclonal antibody injection blocking the activity of CGRP to be approved for migraine prevention24.
MS attacks myelinated axons in the central nervous system, destroying the myelin and the axon to produce eventual physical disability. Cognitive impairment progresses continuously and is associated with brain atrophy and lesion accumulation25.
There are four types of MS based on the frequency of symptoms, time to disease progression and lesion development26 and correct diagnosis aids treatment decisions:
- Relapsing-remitting MS (RRMS)
- Secondary progressive MS (SPMS)
- Primary progressive MS (PPMS)
- Progressive-relapsing MS (PRMS)
Disease-modifying treatments for MS fall into several categories, interferons (e.g. interferon beta-1b27), sphingosine 1-phosphate (S1P) receptor modulators (e.g. Siponimod28, fingolimod29), monoclonal antibodies (e.g. ocrelizumab30) and various immunomodulators. There are currently more treatments available for relapsing forms of MS but there are several treatments in clinical development for all types of MS.
There are no disease-modifying treatments for the progressive neurodegenerative condition PD and current medical management focuses on controlling the classic motor symptoms of bradykinesia, tremor, rigidity and postural instability31,32.
Dopaminergic pharmacotherapies, such as levodopa, designed to restore depleted dopamine in the substantia nigra pars compacta are the mainstay of PD treatment and need to be administered with agents to prevent endogenous dopamine breakdown.
Around 90% of levodopa is inactivated by catechol-O-methyl transferase (COMT)33 but adjunctive COMT inhibitors such as tolcapone, entacapone and opicapone, prolong the half-life of levodopa and significantly improve its delivery to the brain which helps control motor symptoms32.
SMA is a heterogeneous genetic neuromuscular disease caused by loss of function mutations or deletions in the SMN1 gene, which results in insufficient levels of the survival of motor neuron (SMN) protein causing muscular atrophy and multi-organ disease34.
An additional gene, SMN2 can produce low levels of functional SMN protein but cannot compensate for the loss of SMN1 present in these patients and the number of copies of SMN2 genes in SMA correlates inversely with age of onset and disease severity35.
A multidisciplinary approach is important for treating patients which include extremely compromised neonates through to infants to adults with minimal symptoms36. Until recently treatment focussed mainly on orthopaedic, pulmonary and nutritional management but excitingly two SMN-targeted treatments, nusinersen (Spinraza) and gene therapy onasemnogene abeparvovec (Zolgensma), have been approved that address the underlying cause of the illness37,38. In addition, a number of small molecules drugs are in development for SMA. These include branaplam39 and risidiplam40 which target SMN2 splicing to increase full length SMN protein.
- National Academies of Sciences, Engineering and MH and MDB on HSPF on N and NSD. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood-Brain Barrier. 2018. National Academies Press doi:10.17226/25044.
- Perl DP. Neuropathology of Alzheimer’s disease. Mount Sinai Journal of Medicine. 2010;77(1):32–42.
- Steinberg M, Shao H, Zandi P, Lyketsos CG, Welsh-Bohmer KA, Norton MC, et al. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: The Cache county study. Int J Geriatr Psychiatry. 2008;23(2):170–177.
- Exelon Summary of Product Characeristics. 2009. Available at: https://www.ema.europa.eu/en/documents/product-information/exelon-epar-product-information_en.pdf. Accessed 17 July 2020.
- Axura Summary of Product Characteristics. 2009. Available at: https://www.ema.europa.eu/en/documents/product-information/axura-epar-product-information_en.pdf. Accessed 17 July 2020.
- Matsunaga S, Kishi T, Iwata N. Combination therapy with cholinesterase inhibitors and memantine for Alzheimer’s disease: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2014;18(5). doi:10.1093/ijnp/pyu115.
- Luo Y, Weibman D, Halperin JM, Li X. A review of heterogeneity in Attention Deficit/Hyperactivity Disorder (ADHD). Front Hum Neurosci. 2019;13:42.
- Faraone S V., Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: A meta-analysis of follow-up studies. Psychological Medicine. 2006;36(2):159–165.
- Lambez B, Harwood-Gross A, Golumbic EZ, Rassovsky Y. Non-pharmacological interventions for cognitive difficulties in ADHD: A systematic review and meta-analysis. Journal of Psychiatric Research. 2020;120:40–55.
- Ougrin D, Chatterton S, Banarsee R. Attention deficit hyperactivity disorder (ADHD): Review for primary care clinicians. London J Prim Care (Abingdon). 2010;(1):45–51.
- Dalsgaard S, Ostergaard SD, Leckman JF, Mortensen PB, Pedersen MG. Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: A nationwide cohort study. Lancet. 2015;385(9983):2190–2196.
- Ritalin Summary of Product Characteristics. 1997. Available at: https://www.medicines.org.uk/emc/product/1035/smpc. Accessed 17 July 2020.
- Beghi E, Giussani G, Sander JW. The natural history and prognosis of epilepsy. Epileptic Disord. 2015;17(3):243–253.
- Helbig I, Abou Tayoun AN. Understanding genotypes and phenotypes in epileptic encephalopathies. Molecular Syndromology. 2016;7(4):172–181.
- Baranowski CJ. The quality of life of older adults with epilepsy: A systematic review. Seizure. 2018;60:190–197.
- Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, Guerreiro C, et al. ILAE treatment guidelines: Evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2006;47(7):1094–1120.
- Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kälviäinen R, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551–563.
- Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltrán E, et al. Blocking CGRP in migraine patients – a review of pros and cons. Journal of Headache and Pain. 2017;18(1). doi:10.1186/s10194-017-0807-1.
- The Work Foundation. The socioeconomic impact of migraine. April 2018. Available at: www.theworkfoundation.com. Accessed 17 July 2020.
- Burgos-Vega C, Moy J, Dussor G. Meningeal afferent signaling and the pathophysiology of migraine. In: Progress in Molecular Biology and Translational Science. 2015. Elsevier B.V.: 537–564.
- Burstein R, Noseda R, Borsook D. Migraine: Multiple processes, complex pathophysiology. J Neurosci. 2015;35(17):6619–6629.
- BASH. Guidelines for all healthcare professionals in the diagnosis and management of migraine tension-type headache cluster headache medication-overuse headache. Available at: https://www.bash.org.uk/wp-content/uploads/2012/07/10102-BASH-Guidelines-update-2_v5-1-indd.pdf. Accessed 17 July 2020.
- National Institute for Health and Care Excellence (NICE). Botulinum toxin type A for the prevention of headaches in adults with chronic migraine. Technology appraisal guidance [TA260]. Available at: https://www.nice.org.uk/guidance/ta260. Accessed 17 July 2020.
- Aimovig Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/aimovig-epar-product-information_en.pdf. Accessed 17 July 2020.
- Ouellette R, Bergendal Å, Shams S, Martola J, Mainero C, Kristoffersen Wiberg M, et al. Lesion accumulation is predictive of long-term cognitive decline in multiple sclerosis. Mult Scler Relat Disord. 2018;21:110–116.
- Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014;83(3):278–286.
- Betaferon Summary of Product Characteristics. 2009. Available at: https://www.ema.europa.eu/en/documents/product-information/betaferon-epar-product-information_en.pdf. Accessed 17 July 2020.
- Mayzent Summary of Product Characteristics. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/mayzent-epar-product-information_en.pdf. Accessed 17 July 2020.
- Gilenya Summary of Product Characteristics. 2011. Available at: https://www.ema.europa.eu/en/documents/product-information/gilenya-epar-product-information_en.pdf. Accessed 17 July 2020.
- Ocrevus Summary of Product Characteristics. 2018. Available at: https://www.ema.europa.eu/en/documents/product-information/ocrevus-epar-product-information_en.pdf. Accessed 17 July 2020.
- Kalia L, Lang A. Parkinson’s disease. The Lancet. 2015;386(9996):896–912.
- Zahoor I, Shafi A, Haq E. Pharmacological Treatment of Parkinson’s Disease. 2018 http://www.ncbi.nlm.nih.gov/pubmed/30702845. Accessed 16 January 2020.
- Dingemanse J, Waters, Schapira, Nutt, Obeso, Reichmann, et al. Issues important for rational COMT inhibition. Neurology. 2000;55(11 SUPPL. 4).
- Shababi M, Lorson CL, Rudnik-Schöneborn SS. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat. 2014;224(1):15–28.
- Butchbach MER. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases. Front Mol Biosci. 2016;3:7.
- Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197–207.
- Spinraza Summary of Product Characteristics. 2017. Available at: https://www.ema.europa.eu/en/documents/product-information/spinraza-epar-product-information_en.pdf. Accessed 17 July 2020.
- Zolgensma Summary of Product Characteristics. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/zolgensma-epar-product-information_en.pdf. Accessed 17 July 2020.
- Charnas L, Voltz E, Pfister C, Peters T, Hartmann A, Berghs-Clairmont C, et al. Safety and efficacy findings in the first-in-human trial (FIH) of the oral splice modulator branaplam in type 1 spinal muscular atrophy (SMA): interim results. Neuromuscul Disord. 2017;27:S207–S208.
- Ratni H, Ebeling M, Baird J, Bendels S, Bylund J, Chen KS, et al. Discovery of risdiplam, a selective Survival of Motor Neuron-2 ( SMN2 ) gene splicing modifier for the treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018;61(15):6501–6517.
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