Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Current Neurology and Neuroscience Reports
Published in: Current Neurology and Neuroscience Reports 9/2017

01-09-2017 | Dementia (K Marder, Section Editor)

New Therapeutic Strategies for Lewy Body Dementias

Authors: Latha Velayudhan, Dominic Ffytche, Clive Ballard, Dag Aarsland

Published in: Current Neurology and Neuroscience Reports | Issue 9/2017

Login to get access

Abstract

This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson’s disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson’s disease but have not yet been tested in dementias. Disease-modifying approaches are aimed at preventing, slowing or ameliorating the production, aggregation and deposition of pathological proteins, including immunotherapy targeting α-synuclein and an ongoing trial using ambroxol which increases glucocerebrosidase activity to lower the levels of the protein alpha-synuclein. Other disease-modifying clinical trials are using agents to augment insulin signalling, stem cell therapy, reducing amyloid pathology and gene therapy.
Literature
1.
2.
Mueller C, Ballard C, Corbett A, Aarsland D. The prognosis of dementia with Lewy bodies. Lancet Neurol. 2017;16(5):390–8.CrossRefPubMed
3.
• Matsunaga S, Kishi T, Yasue I, Iwata N (2015) Cholinesterase inhibitors for Lewy body disorders: a meta-analysis. Int J Neuropsychopharmacol 19(2).The meta-analysis included only randomized controlled trials and seventeen studies (n = 1798) were assessed. Cholinesterase inhibitors significantly improved cognitive function, behavioral disturbances, activities of daily living and global function compared with control treatments. Changes in motor function were not significantly different from control treatments. However treatment compliance and side effects needs to be monitored.
4.
Wang HF, Yu JT, Tang SW, Jiang T, Tan CC, Meng XF, et al. Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis. J Neurol Neurosurg Psychiatry. 2015;86(2):135–43.CrossRefPubMed
5.
• Stinton C, McKeith I, Taylor JP, Lafortune L, Mioshi E, Mak E, et al. Pharmacological management of Lewy body dementia: a systematic review and meta-analysis. Am J Psychiatry. 2015;172(8):731–42. Forty-four studies examining 22 strategies were included in the review. Meta-analysis indicated beneficial effects of donepezil and rivastigmine for cognitive and psychiatric symptoms. Rivastigmine, but not donepezil, was associated with greater risk of adverse events. Meta-analysis of memantine suggested that it is well tolerated but with few benefits. Piracetam, amantadine, selegiline, olanzapine, quetiapine, risperidone, and citalopram do not appear to be effective. CrossRefPubMed
6.
• Mori E, Ikeda M, Kosaka K, Donepezil DLBSI. Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Ann Neurol. 2012;72(1):41–52. A randomized, double-blind, placebo-controlled exploratory phase 2 trial which recruited 140 patients with DLB, from 48 specialty centers in Japan, and given placebo or 3, 5, or 10 mg of donepezil hydrochloride daily for 12 weeks ( n = 35, 35, 33, and 37, respectively). Donepezil at 5 and 10mg/day showed good tolerability and significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose. CrossRefPubMed
7.
• Ikeda M, Mori E, Kosaka K, Iseki E, Hashimoto M, Matsukawa N, et al. Long-term safety and efficacy of donepezil in patients with dementia with Lewy bodies: results from a 52-week, open-label, multicenter extension study. Dement Geriatr Cogn Disord. 2013;36(3–4):229–41. A 52-week, multicenter, open-label extension study which administered donepezil at 5 mg/day in patients with DLB and showed that it was well tolerated and had lasting effects on cognitive function and psychiatric symptoms up to 52 weeks. CrossRefPubMed
8.
Aarsland D, Ballard C, Walker Z, Bostrom F, Alves G, Kossakowski K, et al. Memantine in patients with Parkinson’s disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2009;8(7):613–8.CrossRefPubMed
9.
Stubendorff K, Larsson V, Ballard C, Minthon L, Aarsland D, Londos E. Treatment effect of memantine on survival in dementia with Lewy bodies and Parkinson’s disease with dementia: a prospective study. BMJ Open. 2014;4(7):e005158.CrossRefPubMedPubMedCentral
10.
Aarsland D, Perry R, Larsen JP, McKeith IG, O'Brien JT, Perry EK, et al. Neuroleptic sensitivity in Parkinson's disease and parkinsonian dementias. J Clin Psychiatry. 2005;66(5):633–7.CrossRefPubMed
11.
Ffytche DH, Creese B, Politis M, Chaudhuri KR, Weintraub D, Ballard C, et al. The psychosis spectrum in Parkinson disease. Nat Rev Neurol. 2017;13(2):81–95.CrossRefPubMed
12.
13.
•• Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533–40. In this 6 week, randomised, double-blind, placebo-controlled study, 40 mg of Pimavanserin, a selective serotonin 5-HT2A inverse agonist was given to 95 patients with PDD and 90 patients received placebo. Pimavanserin improved psychosis and was well tolerated. CrossRefPubMed
14.
Meltzer HY, Mills R, Revell S, Williams H, Johnson A, Bahr D, et al. Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of parkinson's disease psychosis. Neuropsychopharmacology. 2010;35(4):881–92.CrossRefPubMed
15.
Ballard C, Isaacson S, Mills R, Williams H, Corbett A, Coate B, et al. Impact of current antipsychotic medications on comparative mortality and adverse events in people with Parkinson disease psychosis. J Am Med Dir Assoc. 2015;16(10):898 e1–7.CrossRef
16.
Saito Y, Ishikawa J, Harada K. Postprandial and orthostatic hypotension treated by Sitagliptin in a patient with dementia with Lewy bodies. Am J Case Rep. 2016;17:887–93.CrossRefPubMedPubMedCentral
17.
• Lapid MI, Kuntz KM, Mason SS, Aakre JA, Lundt ES, Kremers W, et al. Efficacy, safety, and tolerability of armodafinil therapy for hypersomnia associated with dementia with Lewy bodies: a pilot study. Dement Geriatr Cogn Disord. 2017;43(5–6):269–80. In this 12-week pilot trial of armodafinil therapy (125-250 mg orally daily) in DLB outpatients with hypersomnia, 17 patients out of 20 completed the protocol. Armodafanil therapy was found to be reasonably safe and tolerable and improved hypersomnia, wakefulness and also NPI scores and caregiver quality of life. CrossRefPubMedPubMedCentral
18.
Banerjee S, Hellier J, Romeo R, Dewey M, Knapp M, Ballard C, et al. Study of the use of antidepressants for depression in dementia: the HTA-SADD trial—a multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effectiveness of sertraline and mirtazapine. Health Technol Assess. 2013;17(7):1–166.CrossRefPubMedPubMedCentral
19.
Aarsland D. Cognitive impairment in Parkinson’s disease and dementia with Lewy bodies. Parkinsonism Relat Disord. 2016;22(Suppl 1):S144–8.CrossRefPubMed
20.
Pena J, Ibarretxe-Bilbao N, Garcia-Gorostiaga I, Gomez-Beldarrain MA, Diez-Cirarda M, Ojeda N. Improving functional disability and cognition in Parkinson disease: randomized controlled trial. Neurology. 2014;83(23):2167–74.CrossRefPubMedPubMedCentral
21.
Strouwen C, Molenaar EA, Keus SH, Munks L, Munneke M, Vandenberghe W, et al. Protocol for a randomized comparison of integrated versus consecutive dual task practice in Parkinson’s disease: the DUALITY trial. BMC Neurol. 2014;14:61.CrossRefPubMedPubMedCentral
22.
• Strouwen C, Molenaar E, Munks L, Keus SHJ, Zijlmans JCM, Vandenberghe W, et al. Training dual tasks together or apart in Parkinson’s disease: results from the DUALITY trial. Mov Disord 2017. In this randomized study patients ( N = 121) with a diagnosis of PD were randomized to 6 weeks of at-home physiotherapist-led Training: (1) a consecutive group in which gait and cognitive tasks were trained separately or (2) an integrated group in which gait and cognitive tasks were trained simultaneously. Consecutive and integrated dual-task training showed similar and sustained improvements in dual-task gait velocity without increasing fall risk.
23.
• Diez-Cirarda M, Ojeda N, Pena J, Cabrera-Zubizarreta A, Lucas-Jimenez O, Gomez-Esteban JC, et al. Increased brain connectivity and activation after cognitive rehabilitation in Parkinson’s disease: a randomized controlled trial. Brain Imaging Behav 2016. A randomized controlled trial three-month which used integrative cognitive rehabilitation program (REHACOP). Forty-four PD patients were randomly divided into REHACOP group (cognitive rehabilitation) and a control group (occupational therapy) and found that an integrative cognitive rehabilitation program can produce significant functional cerebral changes in PD patients and cognitive performance.
24.
Aarsland D, Creese B, Politis M, Chaudhuri KR, Ffytche DH, Weintraub D, et al. Cognitive decline in Parkinson disease. Nat Rev Neurol. 2017;13(4):217–31.CrossRefPubMed
25.
van de Weijer SC, Duits AA, Bloem BR, Kessels RP, Jansen JF, Kohler S, et al. The Parkin'Play study: protocol of a phase II randomized controlled trial to assess the effects of a health game on cognition in Parkinson's disease. BMC Neurol. 2016;16(1):209.CrossRefPubMedPubMedCentral
26.
• David FJ, Robichaud JA, Leurgans SE, Poon C, Kohrt WM, Goldman JG, et al. Exercise improves cognition in Parkinson’s disease: the PRET-PD randomized, clinical trial. Mov Disord. 2015;30(12):1657–63. In this prospective, parallel-group, single-center randomized controlled trial, 51 nondemented patients with mild-to-moderate PD were randomly assigned either to modified Fitness Counts (mFC) or to Progressive Resistance Exercise Training (PRET) and were followed for 24 months. This study provides class IV level of evidence that 24 months of PRET or mFC may improve attention and working memory in nondemented patients with mild-to-moderate PD. CrossRefPubMedPubMedCentral
27.
Lefaucheur JP. A comprehensive database of published tDCS clinical trials (2005-2016). Neurophysiol Clin. 2016;46(6):319–98.CrossRefPubMed
28.
• Elder GJ, Firbank MJ, Kumar H, Chatterjee P, Chakraborty T, Dutt A, et al. Effects of transcranial direct current stimulation upon attention and visuoperceptual function in Lewy body dementia: a preliminary study. Int Psychogeriatr. 2016;28(2):341–7. Attentional, but not visuoperceptual, improved following tDCS in 13 patients with LBD. Larger-scale, placebo-controlled trials are suggested to confirm whether tDCS is a useful treatment option for attentional deficits in LBD. CrossRefPubMed
29.
Heinrichs-Graham E, McDermott TJ, Mills MS, Coolidge NM, Wilson TW. Transcranial direct-current stimulation modulates offline visual oscillatory activity: a magnetoencephalography study. Cortex. 2017;88:19–31.CrossRefPubMed
30.
Takahashi S, Mizukami K, Yasuno F, Asada T. Depression associated with dementia with Lewy bodies (DLB) and the effect of somatotherapy. Psychogeriatrics. 2009;9(2):56–61.CrossRefPubMed
31.
Tofaris GK, Spillantini MG. Alpha-synuclein dysfunction in Lewy body diseases. Mov Disord. 2005;20(Suppl 12):S37–44.CrossRefPubMed
32.
McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology. 2005;65(12):1863–72.CrossRefPubMed
33.
Maroteaux L, Campanelli JT, Scheller RH. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci. 1988;8(8):2804–15.PubMed
34.
Scott DA, Tabarean I, Tang Y, Cartier A, Masliah E, Roy S. A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. J Neurosci. 2010;30(24):8083–95.CrossRefPubMedPubMedCentral
35.
Olanow CW, Brundin P. Parkinson’s disease and alpha synuclein: is Parkinson’s disease a prion-like disorder? Mov Disord. 2013;28(1):31–40.CrossRefPubMed
36.
37.
Ffytche DH, Pereira JB, Ballard C, Chaudhuri KR, Weintraub D, Aarsland D. Risk factors for early psychosis in PD: insights from the Parkinson’s progression markers initiative. J Neurol Neurosurg Psychiatry. 2017;88(4):325–31.CrossRefPubMed
38.
Schneeberger A, Mandler M, Mattner F, Schmidt W. Vaccination for Parkinson’s disease. Parkinsonism Relat Disord. 2012;18(Suppl 1):S11–3.CrossRefPubMed
39.
•• Mandler M, Valera E, Rockenstein E, Weninger H, Patrick C, Adame A, et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol. 2014;127(6):861–79. This study investigated the potential therapeutical value of active vaccination with novel α-syn AFFITOPEs® (AFF) in two different tg models of PD and DLB-like pathology and based on these results, a Phase I clinical trial for PD has been initiated. CrossRefPubMedPubMedCentral
40.
Lindstrom V, Ihse E, Fagerqvist T, Bergstrom J, Nordstrom E, Moller C, et al. Immunotherapy targeting alpha-synuclein, with relevance for future treatment of Parkinson’s disease and other Lewy body disorders. Immunotherapy. 2014;6(2):141–53.CrossRefPubMed
41.
Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N, et al. Apomorphine treatment in Alzheimer mice promoting amyloid-beta degradation. Ann Neurol. 2011;69(2):248–56.CrossRefPubMed
42.
Yarnall AJ, Lashley T, Ling H, Lees AJ, Coleman SY, O'Sullivan SS, et al. Apomorphine: a potential modifier of amyloid deposition in Parkinson’s disease? Mov Disord. 2016;31(5):668–75.CrossRefPubMed
43.
• Martinez-Martin P, Reddy P, Katzenschlager R, Antonini A, Todorova A, Odin P, et al. EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson’s disease. Mov Disord. 2015;30(4):510–6. This open-label, prospective, observational, 6-month, multicenter study compared 43 PD patients on subcutaneous apomorphine infusion and 44 on intrajejunal levodopa infusion and found improvement in motor symptoms, nonmotor symptoms, quality-of-life and some NMS. CrossRefPubMed
44.
Rockenstein E, Desplats P, Ubhi K, Mante M, Florio J, Adame A, et al. Neuropeptide treatment with cerebrolysin enhances the survival of grafted neural stem cell in an alpha-synuclein transgenic model of Parkinson’s disease. J Exp Neurosci. 2015;9(Suppl 2):131–40.PubMed
45.
Bogaerts V, Engelborghs S, Kumar-Singh S, Goossens D, Pickut B, van der Zee J, et al. A novel locus for dementia with Lewy bodies: a clinically and genetically heterogeneous disorder. Brain. 2007;130(Pt 9):2277–91.CrossRefPubMed
46.
Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, et al. GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology. Neurology. 2012;79(19):1944–50.CrossRefPubMedPubMedCentral
47.
Joshi SN, Butler DC, Messer A. Fusion to a highly charged proteasomal retargeting sequence increases soluble cytoplasmic expression and efficacy of diverse anti-synuclein intrabodies. MAbs. 2012;4(6):686–93.CrossRefPubMedPubMedCentral
48.
• Valera E, Spencer B, Masliah E. Immunotherapeutic approaches targeting amyloid-beta, alpha-synuclein, and tau for the treatment of neurodegenerative disorders. Neurotherapeutics. 2016;13(1):179–89. This paper provides an overview of the most novel and relevant immunotherapeutic advances as promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. CrossRefPubMed
49.
• Athauda D, Foltynie T. Insulin resistance and Parkinson’s disease: a new target for disease modification. Prog Neurobiol. 2016;145-146:98–120. A review of the underlying cellular links between insulin resistance and the pathogenesis of PD and which discusses current and future pharmacological strategies being developed to restore neuronal insulin signalling as a potential strategy for slowing neurodegeneration in Parkinson's disease. CrossRef
50.
Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122(4):1316–38.CrossRefPubMedPubMedCentral
51.
Stoeckel LE, Arvanitakis Z, Gandy S, Small D, Kahn CR, Pascual-Leone A, et al. Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction. F1000Res. 2016;5:353.PubMedPubMedCentral
52.
Tong JF, Yan X, Zhu MJ, Du M. AMP-activated protein kinase enhances the expression of muscle-specific ubiquitin ligases despite its activation of IGF-1/Akt signaling in C2C12 myotubes. J Cell Biochem. 2009;108(2):458–68.CrossRefPubMed
53.
Valera E, Masliah E. Combination therapies: the next logical step for the treatment of synucleinopathies? Mov Disord. 2016;31(2):225–34.CrossRefPubMed
54.
Whitfield DR, Vallortigara J, Alghamdi A, Howlett D, Hortobagyi T, Johnson M, et al. Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment. Neurobiol Aging. 2014;35(12):2836–44.CrossRefPubMed
55.
Sardi SP, Clarke J, Viel C, Chan M, Tamsett TJ, Treleaven CM, et al. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc Natl Acad Sci U S A. 2013;110(9):3537–42.CrossRefPubMedPubMedCentral
56.
Xing H, Lim YA, Chong JR, Lee JH, Aarsland D, Ballard CG, et al. Increased phosphorylation of collapsin response mediator protein-2 at Thr514 correlates with beta-amyloid burden and synaptic deficits in Lewy body dementias. Mol Brain. 2016;9(1):84.CrossRefPubMedPubMedCentral
57.
Chong JR, Chai YL, Lee JH, Howlett D, Attems J, Ballard CG, et al. Increased transforming growth factor beta2 in the neocortex of Alzheimer’s disease and dementia with Lewy bodies is correlated with disease severity and soluble Abeta42 load. J Alzheimer's Dis. 2017;56(1):157–66.CrossRef
58.
Baek JH, Whitfield D, Howlett D, Francis P, Bereczki E, Ballard C, et al. Unfolded protein response is activated in Lewy body dementias. Neuropathol Appl Neurobiol. 2016;42(4):352–65.CrossRefPubMed
59.
Al-Mansoori KM, Hasan MY, Al-Hayani A, El-Agnaf OM. The role of alpha-synuclein in neurodegenerative diseases: from molecular pathways in disease to therapeutic approaches. Curr Alzheimer Res. 2013;10(6):559–68.CrossRefPubMed
60.
61.
Fan X, Jin WY, Lu J, Wang J, Wang YT. Rapid and reversible knockdown of endogenous proteins by peptide-directed lysosomal degradation. Nat Neurosci. 2014;17(3):471–80.CrossRefPubMedPubMedCentral
62.
Lee HJ, Bae EJ, Lee SJ. Extracellular alpha—synuclein-a novel and crucial factor in Lewy body diseases. Nat Rev Neurol. 2014;10(2):92–8.CrossRefPubMed
63.
Tse W, Frisina PG, Halbig TD, Gracies JM, Liang L, Tarshish C, et al. The effects of withdrawal of dopaminergic medication in nursing home patients with advanced parkinsonism. J Am Med Dir Assoc. 2008;9(9):670–5.CrossRefPubMed
64.
Lee HB, Hanner JA, Yokley JL, Appleby B, Hurowitz L, Lyketsos CG. Clozapine for treatment-resistant agitation in dementia. J Geriatr Psychiatry Neurol. 2007;20(3):178–82.CrossRefPubMed
65.
Pollak P, Tison F, Rascol O, Destee A, Pere JJ, Senard JM, et al. Clozapine in drug induced psychosis in Parkinson’s disease: a randomised, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry. 2004;75(5):689–95.CrossRefPubMedPubMedCentral
66.
McCarter SJ, Boswell CL, St Louis EK, Dueffert LG, Slocumb N, Boeve BF, et al. Treatment outcomes in REM sleep behavior disorder. Sleep Med. 2013;14(3):237–42.CrossRefPubMedPubMedCentral
67.
Fujishiro H. Effects of gabapentin enacarbil on restless legs syndrome and leg pain in dementia with Lewy bodies. Psychogeriatrics. 2014;14(2):132–4.CrossRefPubMed
68.
Goldberg NR, Caesar J, Park A, Sedgh S, Finogenov G, Masliah E, et al. Neural stem cells rescue cognitive and motor dysfunction in a transgenic model of dementia with Lewy bodies through a BDNF-dependent mechanism. Stem Cell Rep. 2015;5(5):791–804.CrossRef
Metadata
Title
New Therapeutic Strategies for Lewy Body Dementias
Authors
Latha Velayudhan
Dominic Ffytche
Clive Ballard
Dag Aarsland
Publication date
01-09-2017
Publisher
Springer US
Published in
Current Neurology and Neuroscience Reports / Issue 9/2017
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI
https://doi.org/10.1007/s11910-017-0778-2

Other articles of this Issue 9/2017

Current Neurology and Neuroscience Reports 9/2017 Go to the issue

Dementia (K Marder, Section Editor)

Emerging Diagnostic and Therapeutic Strategies for Tauopathies

Epilepsy (CW Bazil, Section Editor)

Laser Interstitial Thermal Therapy for Epilepsy

Stroke (H Diener, Section Editor)

Unresolved Issues in Thrombectomy

Demyelinating Disorders (J Bernard and M Cameron, Section Editors)

CLIPPERS

Stroke (H Diener, Section Editor)

Non-Vitamin K Oral Anticoagulants (NOACs) and Their Reversal

Stroke (H Diener, Section Editor)

Secondary Stroke Prevention in Cryptogenic Stroke and Embolic Stroke of Undetermined Source (ESUS)