fb948faf2b4a0c40d0ee133d44211fc3 pmc_34202784.pdf 9f88d451d77a9ed5386b69ad561f13260dba3108 pmc_34202784.pdf 428c5b186ba6a62a1304c005806c97c42fa00f5716ba852ebae317efeca617d6 pmc_34202784.pdf Title: Epilepsy in Down Syndrome: A Highly Prevalent Comorbidity Subject: Individuals with Down syndrome (DS) have an increased risk for epilepsy during the whole lifespan, but especially after age 40 years. The increase in the number of individuals with DS living into late middle age due to improved health care is resulting in an increase in epilepsy prevalence in this population. However, these epileptic seizures are probably underdiagnosed and inadequately treated. This late onset epilepsy is linked to the development of symptomatic Alzheimer’s disease (AD), which is the main comorbidity in adults with DS with a cumulative incidence of more than 90% of adults by the seventh decade. More than 50% of patients with DS and AD dementia will most likely develop epilepsy, which in this context has a specific clinical presentation in the form of generalized myoclonic epilepsy. This epilepsy, named late onset myoclonic epilepsy (LOMEDS) affects the quality of life, might be associated with worse cognitive and functional outcomes in patients with AD dementia and has an impact on mortality. This review aims to summarize the current knowledge about the clinical and electrophysiological characteristics, diagnosis and treatment of epileptic seizures in the DS population, with a special emphasis on LOMEDS. Raised awareness and a better understanding of epilepsy in DS from families, caregivers and clinicians could enable earlier diagnoses and better treatments for individuals with DS. Keywords: down syndrome; aging; seizures; epilepsy; Alzheimer’s disease Author: Miren Altuna, Sandra Giménez and Juan Fortea Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Jun 24 14:49:18 2021 CEST ModDate: Thu Jun 24 14:57:25 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4349392 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- HOYUHQ+VnURWPalladioL Type 1 Custom yes yes no 10 0 QCUNIN+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 QHTLZO+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 MIYJKT+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 XPUSBJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 36 0 BSDWLC+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 39 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 56 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 60 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 64 0 PXTEMV+CMSY10 Type 1 Builtin yes yes no 76 0 LWLIVD+EURM10 Type 1 Builtin yes yes no 98 0 RAMSXI+wasy9 Type 1 Builtin yes yes no 128 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 136 0 ABCDEE+Courier New TrueType WinAnsi yes yes no 140 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 144 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 148 0 Arial TrueType WinAnsi no no no 152 0 ABCDEE+Wingdings CID TrueType Identity-H yes yes yes 155 0 GEJNTL+VnURWPalladioL-Italic Type 1 Custom yes yes no 169 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2021-09-11 03:06:34 CEST RepresentationInformation: pmc_34202784.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2021-07-12 03:37:27 CEST Size: 4349392 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 559 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Methodology Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Epilepsy in Early Childhood (0 5 Years) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: Pathogenesis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Febrile Seizures Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Other Epileptic Seizures Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Electrophysiological Characterization Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Response to Antiepileptic Drugs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Epilepsy in Children over 5 Years and Young Adulthood Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Children: Item: Title: Pathogenesis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Clinical Characterization Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Electrophysiological Characteristics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Response to Antiepileptic Drugs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Epileptic Seizures in Late Adulthood (40 Years) and Their Relationship with AD Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Children: Item: Title: Pathogenesis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Clinical Characterization Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Electrophysiological Characteristics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Response to Antiepileptic Drugs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Recommendations in Clinical Practice and Future Directions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Info: Title: Epilepsy in Down Syndrome: A Highly Prevalent Comorbidity Author: Miren Altuna, Sandra Giménez and Juan Fortea Subject: Individuals with Down syndrome (DS) have an increased risk for epilepsy during the whole lifespan, but especially after age 40 years. The increase in the number of individuals with DS living into late middle age due to improved health care is resulting in an increase in epilepsy prevalence in this population. However, these epileptic seizures are probably underdiagnosed and inadequately treated. This late onset epilepsy is linked to the development of symptomatic Alzheimer’s disease (AD), which is the main comorbidity in adults with DS with a cumulative incidence of more than 90% of adults by the seventh decade. More than 50% of patients with DS and AD dementia will most likely develop epilepsy, which in this context has a specific clinical presentation in the form of generalized myoclonic epilepsy. This epilepsy, named late onset myoclonic epilepsy (LOMEDS) affects the quality of life, might be associated with worse cognitive and functional outcomes in patients with AD dementia and has an impact on mortality. This review aims to summarize the current knowledge about the clinical and electrophysiological characteristics, diagnosis and treatment of epileptic seizures in the DS population, with a special emphasis on LOMEDS. Raised awareness and a better understanding of epilepsy in DS from families, caregivers and clinicians could enable earlier diagnoses and better treatments for individuals with DS. Keywords: down syndrome; aging; seizures; epilepsy; Alzheimer’s disease Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Jun 24 14:49:18 CEST 2021 ModDate: Thu Jun 24 14:57:25 CEST 2021 ID: 0x393cd3d1ceddc395a1217375090d0fd3, 0x393cd3d1ceddc395a1217375090d0fd3 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: RAMSXI+wasy9 FontSubset: true FirstChar: 35 LastChar: 35 FontDescriptor: FontName: RAMSXI+wasy9 Flags: Symbolic FontBBox: -21, -1667, 1768, 753 FontFile: true Font: BaseFont: LWLIVD+EURM10 FontSubset: true FirstChar: 12 LastChar: 12 FontDescriptor: FontName: LWLIVD+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: QHTLZO+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 150 FontDescriptor: FontName: QHTLZO+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: MIYJKT+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 246 FontDescriptor: FontName: MIYJKT+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: GEJNTL+VnURWPalladioL-Italic FontSubset: true FirstChar: 178 LastChar: 189 FontDescriptor: FontName: GEJNTL+VnURWPalladioL-Italic Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: HOYUHQ+VnURWPalladioL FontSubset: true FirstChar: 129 LastChar: 230 FontDescriptor: FontName: HOYUHQ+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: BTFGED+VnURWPalladioL-Bold FontSubset: true FirstChar: 178 LastChar: 178 FontDescriptor: FontName: BTFGED+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: PXTEMV+CMSY10 FontSubset: true FirstChar: 15 LastChar: 21 FontDescriptor: FontName: PXTEMV+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: QCUNIN+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 122 FontDescriptor: FontName: QCUNIN+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 35, 759, 176, 795 Annotation: Subtype: Link Rect: 515, 759, 560, 795 Annotation: Subtype: Link Rect: 55, 358, 154, 367 Annotation: Subtype: Link Rect: 35, 346, 75, 355 Annotation: Subtype: Link Rect: 35, 162, 97, 184 Annotation: Subtype: Link Rect: 153, 89, 154, 98 Annotation: Subtype: Link Rect: 35, 77, 147, 86 Annotation: Subtype: Link Rect: 383, 255, 390, 264 ActionDest: 166 Annotation: Subtype: Link Rect: 393, 255, 400, 264 ActionDest: 166 Annotation: Subtype: Link Rect: 243, 242, 250, 251 ActionDest: 166 Annotation: Subtype: Link Rect: 253, 242, 260, 251 ActionDest: 166 Annotation: Subtype: Link Rect: 248, 217, 260, 226 ActionDest: 166 Annotation: Subtype: Link Rect: 492, 217, 499, 226 ActionDest: 166 Annotation: Subtype: Link Rect: 441, 192, 448, 201 ActionDest: 166 Annotation: Subtype: Link Rect: 448, 192, 455, 201 ActionDest: 166 Annotation: Subtype: Link Rect: 456, 192, 468, 201 ActionDest: 166 Annotation: Subtype: Link Rect: 468, 192, 480, 201 ActionDest: 166 Annotation: Subtype: Link Rect: 431, 167, 438, 176 ActionDest: 166 Annotation: Subtype: Link Rect: 439, 167, 451, 176 ActionDest: 166 Annotation: Subtype: Link Rect: 454, 167, 466, 176 ActionDest: 166 Annotation: Subtype: Link Rect: 263, 142, 275, 151 ActionDest: 166 Annotation: Subtype: Link Rect: 275, 142, 287, 151 ActionDest: 166 Annotation: Subtype: Link Rect: 467, 142, 474, 151 ActionDest: 166 Annotation: Subtype: Link Rect: 474, 142, 481, 151 ActionDest: 166 Annotation: Subtype: Link Rect: 482, 142, 494, 151 ActionDest: 166 Annotation: Subtype: Link Rect: 497, 142, 509, 151 ActionDest: 173 Annotation: Subtype: Link Rect: 247, 117, 254, 126 ActionDest: 166 Annotation: Subtype: Link Rect: 254, 117, 266, 126 ActionDest: 166 Annotation: Subtype: Link Rect: 267, 117, 279, 126 ActionDest: 173 Annotation: Subtype: Link Rect: 279, 117, 291, 126 ActionDest: 173 Annotation: Subtype: Link Rect: 187, 104, 194, 113 ActionDest: 166 Annotation: Subtype: Link Rect: 194, 104, 206, 113 ActionDest: 166 Annotation: Subtype: Link Rect: 207, 104, 219, 113 ActionDest: 173 Annotation: Subtype: Link Rect: 222, 104, 233, 113 ActionDest: 173 Annotation: Subtype: Link Rect: 131, 17, 268, 28 Annotation: Subtype: Link Rect: 422, 17, 558, 28 Annotation: Subtype: Link Rect: 35, 423, 87, 442 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 341, 596, 348, 608 ActionDest: 73 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 191, 695, 198, 706 ActionDest: 83 Annotation: Subtype: Link Rect: 202, 697, 214, 706 ActionDest: 173 Annotation: Subtype: Link Rect: 215, 697, 227, 706 ActionDest: 173 Annotation: Subtype: Link Rect: 436, 443, 443, 452 ActionDest: 166 Annotation: Subtype: Link Rect: 443, 442, 455, 452 ActionDest: 173 Annotation: Subtype: Link Rect: 456, 442, 468, 452 ActionDest: 173 Annotation: Subtype: Link Rect: 420, 266, 432, 275 ActionDest: 173 Annotation: Subtype: Link Rect: 433, 266, 445, 275 ActionDest: 173 Annotation: Subtype: Link Rect: 448, 266, 460, 275 ActionDest: 173 Annotation: Subtype: Link Rect: 531, 191, 543, 200 ActionDest: 173 Annotation: Subtype: Link Rect: 544, 191, 556, 200 ActionDest: 173 Annotation: Subtype: Link Rect: 354, 153, 366, 162 ActionDest: 173 Annotation: Subtype: Link Rect: 220, 115, 232, 125 ActionDest: 173 Annotation: Subtype: Link Rect: 232, 115, 244, 125 ActionDest: 173 Annotation: Subtype: Link Rect: 245, 115, 257, 125 ActionDest: 173 Annotation: Subtype: Link Rect: 393, 78, 405, 87 ActionDest: 173 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 318, 644, 330, 653 ActionDest: 173 Annotation: Subtype: Link Rect: 278, 577, 289, 586 ActionDest: 173 Annotation: Subtype: Link Rect: 290, 577, 302, 586 ActionDest: 173 Annotation: Subtype: Link Rect: 302, 577, 314, 586 ActionDest: 173 Annotation: Subtype: Link Rect: 317, 577, 329, 586 ActionDest: 173 Annotation: Subtype: Link Rect: 363, 574, 370, 586 ActionDest: 86 Annotation: Subtype: Link Rect: 450, 514, 462, 523 ActionDest: 173 Annotation: Subtype: Link Rect: 463, 514, 475, 523 ActionDest: 173 Annotation: Subtype: Link Rect: 475, 514, 487, 523 ActionDest: 173 Annotation: Subtype: Link Rect: 488, 514, 500, 523 ActionDest: 173 Annotation: Subtype: Link Rect: 503, 514, 514, 523 ActionDest: 173 Annotation: Subtype: Link Rect: 233, 200, 245, 209 ActionDest: 173 Annotation: Subtype: Link Rect: 245, 200, 257, 209 ActionDest: 173 Annotation: Subtype: Link Rect: 260, 200, 272, 209 ActionDest: 176 Annotation: Subtype: Link Rect: 345, 171, 357, 180 ActionDest: 173 Annotation: Subtype: Link Rect: 358, 171, 369, 180 ActionDest: 176 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 282, 710, 294, 719 ActionDest: 173 Annotation: Subtype: Link Rect: 374, 685, 386, 694 ActionDest: 173 Annotation: Subtype: Link Rect: 387, 685, 399, 694 ActionDest: 176 Annotation: Subtype: Link Rect: 292, 642, 304, 651 ActionDest: 173 Annotation: Subtype: Link Rect: 304, 642, 316, 651 ActionDest: 176 Annotation: Subtype: Link Rect: 229, 592, 241, 601 ActionDest: 176 Annotation: Subtype: Link Rect: 518, 541, 530, 550 ActionDest: 176 Annotation: Subtype: Link Rect: 503, 516, 515, 525 ActionDest: 176 Annotation: Subtype: Link Rect: 517, 441, 529, 450 ActionDest: 176 Annotation: Subtype: Link Rect: 376, 391, 388, 400 ActionDest: 173 Annotation: Subtype: Link Rect: 388, 391, 400, 400 ActionDest: 173 Annotation: Subtype: Link Rect: 401, 391, 413, 400 ActionDest: 173 Annotation: Subtype: Link Rect: 413, 391, 425, 400 ActionDest: 176 Annotation: Subtype: Link Rect: 350, 252, 362, 261 ActionDest: 176 Annotation: Subtype: Link Rect: 300, 164, 312, 173 ActionDest: 173 Annotation: Subtype: Link Rect: 313, 164, 325, 173 ActionDest: 176 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 201, 735, 213, 744 ActionDest: 176 Annotation: Subtype: Link Rect: 240, 546, 247, 555 ActionDest: 166 Annotation: Subtype: Link Rect: 247, 546, 259, 555 ActionDest: 166 Annotation: Subtype: Link Rect: 260, 546, 272, 555 ActionDest: 166 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 302, 685, 309, 694 ActionDest: 166 Annotation: Subtype: Link Rect: 309, 685, 316, 694 ActionDest: 166 Annotation: Subtype: Link Rect: 316, 685, 328, 694 ActionDest: 173 Annotation: Subtype: Link Rect: 544, 647, 556, 656 ActionDest: 166 Annotation: Subtype: Link Rect: 488, 559, 500, 568 ActionDest: 176 Annotation: Subtype: Link Rect: 271, 521, 283, 530 ActionDest: 176 Annotation: Subtype: Link Rect: 493, 509, 505, 518 ActionDest: 176 Annotation: Subtype: Link Rect: 455, 496, 466, 505 ActionDest: 176 Annotation: Subtype: Link Rect: 500, 459, 512, 468 ActionDest: 176 Annotation: Subtype: Link Rect: 514, 459, 526, 468 ActionDest: 176 Annotation: Subtype: Link Rect: 524, 421, 536, 430 ActionDest: 176 Annotation: Subtype: Link Rect: 450, 396, 462, 405 ActionDest: 176 Annotation: Subtype: Link Rect: 458, 308, 470, 317 ActionDest: 166 Annotation: Subtype: Link Rect: 471, 308, 483, 317 ActionDest: 166 Annotation: Subtype: Link Rect: 483, 308, 495, 317 ActionDest: 166 Annotation: Subtype: Link Rect: 496, 308, 508, 317 ActionDest: 173 Annotation: Subtype: Link Rect: 508, 308, 520, 317 ActionDest: 176 Annotation: Subtype: Link Rect: 521, 308, 533, 317 ActionDest: 176 Annotation: Subtype: Link Rect: 536, 308, 548, 317 ActionDest: 176 Annotation: Subtype: Link Rect: 457, 283, 469, 292 ActionDest: 176 Annotation: Subtype: Link Rect: 470, 283, 482, 292 ActionDest: 176 Annotation: Subtype: Link Rect: 499, 270, 511, 279 ActionDest: 176 Annotation: Subtype: Link Rect: 511, 270, 523, 279 ActionDest: 176 Annotation: Subtype: Link Rect: 202, 245, 214, 254 ActionDest: 166 Annotation: Subtype: Link Rect: 215, 245, 227, 254 ActionDest: 176 Annotation: Subtype: Link Rect: 248, 220, 260, 229 ActionDest: 166 Annotation: Subtype: Link Rect: 261, 220, 273, 229 ActionDest: 166 Annotation: Subtype: Link Rect: 273, 220, 285, 229 ActionDest: 166 Annotation: Subtype: Link Rect: 286, 220, 298, 229 ActionDest: 173 Annotation: Subtype: Link Rect: 298, 220, 310, 229 ActionDest: 173 Annotation: Subtype: Link Rect: 311, 220, 323, 229 ActionDest: 176 Annotation: Subtype: Link Rect: 323, 220, 335, 229 ActionDest: 176 Annotation: Subtype: Link Rect: 336, 220, 347, 229 ActionDest: 176 Annotation: Subtype: Link Rect: 380, 217, 387, 229 ActionDest: 95 Annotation: Subtype: Link Rect: 247, 146, 258, 155 ActionDest: 176 Annotation: Subtype: Link Rect: 369, 146, 380, 155 ActionDest: 176 Annotation: Subtype: Link Rect: 380, 146, 391, 155 ActionDest: 176 Annotation: Subtype: Link Rect: 502, 146, 513, 155 ActionDest: 173 Annotation: Subtype: Link Rect: 513, 147, 524, 155 ActionDest: 176 Annotation: Subtype: Link Rect: 384, 87, 394, 95 ActionDest: 176 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 247, 699, 258, 707 ActionDest: 176 Annotation: Subtype: Link Rect: 369, 699, 380, 707 ActionDest: 176 Annotation: Subtype: Link Rect: 380, 699, 391, 707 ActionDest: 176 Annotation: Subtype: Link Rect: 502, 699, 513, 707 ActionDest: 173 Annotation: Subtype: Link Rect: 513, 699, 524, 707 ActionDest: 176 Annotation: Subtype: Link Rect: 381, 661, 392, 670 ActionDest: 176 Annotation: Subtype: Link Rect: 396, 613, 407, 621 ActionDest: 176 Annotation: Subtype: Link Rect: 408, 613, 419, 621 ActionDest: 176 Annotation: Subtype: Link Rect: 370, 498, 382, 507 ActionDest: 176 Annotation: Subtype: Link Rect: 350, 482, 357, 494 ActionDest: 83 Annotation: Subtype: Link Rect: 232, 457, 239, 469 ActionDest: 95 Annotation: Subtype: Link Rect: 504, 422, 516, 431 ActionDest: 173 Annotation: Subtype: Link Rect: 338, 397, 350, 406 ActionDest: 179 Annotation: Subtype: Link Rect: 455, 385, 467, 394 ActionDest: 166 Annotation: Subtype: Link Rect: 468, 385, 479, 394 ActionDest: 166 Annotation: Subtype: Link Rect: 480, 385, 492, 394 ActionDest: 173 Annotation: Subtype: Link Rect: 492, 385, 504, 394 ActionDest: 173 Annotation: Subtype: Link Rect: 505, 385, 517, 394 ActionDest: 176 Annotation: Subtype: Link Rect: 517, 385, 529, 394 ActionDest: 179 Annotation: Subtype: Link Rect: 532, 385, 544, 394 ActionDest: 179 Annotation: Subtype: Link Rect: 242, 347, 254, 356 ActionDest: 166 Annotation: Subtype: Link Rect: 255, 347, 267, 356 ActionDest: 166 Annotation: Subtype: Link Rect: 267, 347, 279, 356 ActionDest: 166 Annotation: Subtype: Link Rect: 280, 347, 292, 356 ActionDest: 173 Annotation: Subtype: Link Rect: 292, 347, 304, 356 ActionDest: 173 Annotation: Subtype: Link Rect: 305, 347, 317, 356 ActionDest: 179 Annotation: Subtype: Link Rect: 317, 347, 329, 356 ActionDest: 179 Annotation: Subtype: Link Rect: 330, 347, 342, 356 ActionDest: 179 Annotation: Subtype: Link Rect: 381, 344, 388, 356 ActionDest: 105 Annotation: Subtype: Link Rect: 293, 309, 305, 318 ActionDest: 166 Annotation: Subtype: Link Rect: 305, 309, 317, 318 ActionDest: 173 Annotation: Subtype: Link Rect: 237, 246, 248, 256 ActionDest: 173 Annotation: Subtype: Link Rect: 260, 209, 272, 218 ActionDest: 166 Annotation: Subtype: Link Rect: 273, 209, 285, 218 ActionDest: 166 Annotation: Subtype: Link Rect: 285, 209, 297, 218 ActionDest: 166 Annotation: Subtype: Link Rect: 298, 209, 310, 218 ActionDest: 173 Annotation: Subtype: Link Rect: 310, 209, 322, 218 ActionDest: 176 Annotation: Subtype: Link Rect: 323, 209, 335, 218 ActionDest: 179 Annotation: Subtype: Link Rect: 335, 209, 347, 218 ActionDest: 179 Annotation: Subtype: Link Rect: 383, 146, 390, 155 ActionDest: 166 Annotation: Subtype: Link Rect: 391, 146, 403, 155 ActionDest: 173 Annotation: Subtype: Link Rect: 403, 146, 415, 155 ActionDest: 176 Annotation: Subtype: Link Rect: 416, 146, 428, 155 ActionDest: 179 Annotation: Subtype: Link Rect: 339, 121, 351, 130 ActionDest: 166 Annotation: Subtype: Link Rect: 292, 96, 299, 105 ActionDest: 166 Annotation: Subtype: Link Rect: 299, 96, 311, 105 ActionDest: 166 Annotation: Subtype: Link Rect: 312, 96, 324, 105 ActionDest: 176 Annotation: Subtype: Link Rect: 324, 96, 336, 105 ActionDest: 179 Annotation: Subtype: Link Rect: 339, 96, 351, 105 ActionDest: 179 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 434, 210, 441, 219 ActionDest: 166 Annotation: Subtype: Link Rect: 441, 210, 453, 219 ActionDest: 166 Annotation: Subtype: Link Rect: 454, 210, 466, 219 ActionDest: 166 Annotation: Subtype: Link Rect: 466, 210, 478, 219 ActionDest: 179 Annotation: Subtype: Link Rect: 481, 210, 493, 219 ActionDest: 179 Annotation: Subtype: Link Rect: 194, 185, 206, 194 ActionDest: 166 Annotation: Subtype: Link Rect: 207, 185, 219, 194 ActionDest: 173 Annotation: Subtype: Link Rect: 252, 160, 264, 169 ActionDest: 166 Annotation: Subtype: Link Rect: 256, 97, 268, 106 ActionDest: 166 Annotation: Subtype: Link Rect: 268, 97, 280, 106 ActionDest: 173 Annotation: Subtype: Link Rect: 281, 97, 293, 106 ActionDest: 173 Annotation: Subtype: Link Rect: 394, 69, 401, 81 ActionDest: 111 Annotation: Subtype: Link Rect: 234, 60, 241, 69 ActionDest: 166 Annotation: Subtype: Link Rect: 241, 59, 253, 69 ActionDest: 166 Annotation: Subtype: Link Rect: 254, 60, 266, 69 ActionDest: 166 Annotation: Subtype: Link Rect: 266, 60, 278, 69 ActionDest: 173 Annotation: Subtype: Link Rect: 279, 59, 291, 69 ActionDest: 179 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 488, 735, 500, 744 ActionDest: 166 Annotation: Subtype: Link Rect: 500, 735, 512, 744 ActionDest: 179 Annotation: Subtype: Link Rect: 299, 697, 311, 706 ActionDest: 176 Annotation: Subtype: Link Rect: 312, 697, 324, 706 ActionDest: 179 Annotation: Subtype: Link Rect: 344, 336, 356, 345 ActionDest: 179 Annotation: Subtype: Link Rect: 312, 258, 319, 270 ActionDest: 117 Annotation: Subtype: Link Rect: 388, 122, 395, 131 ActionDest: 166 Annotation: Subtype: Link Rect: 396, 122, 408, 131 ActionDest: 166 Annotation: Subtype: Link Rect: 408, 122, 420, 131 ActionDest: 166 Annotation: Subtype: Link Rect: 421, 122, 433, 131 ActionDest: 166 Annotation: Subtype: Link Rect: 261, 97, 268, 106 ActionDest: 166 Annotation: Subtype: Link Rect: 269, 97, 281, 106 ActionDest: 173 Annotation: Subtype: Link Rect: 281, 97, 293, 106 ActionDest: 173 Annotation: Subtype: Link Rect: 294, 97, 306, 106 ActionDest: 179 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 353, 722, 365, 731 ActionDest: 173 Annotation: Subtype: Link Rect: 366, 722, 378, 731 ActionDest: 173 Annotation: Subtype: Link Rect: 289, 694, 296, 706 ActionDest: 124 Annotation: Subtype: Link Rect: 301, 572, 313, 581 ActionDest: 166 Annotation: Subtype: Link Rect: 314, 572, 326, 581 ActionDest: 179 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 430, 447, 437, 459 ActionDest: 124 Annotation: Subtype: Link Rect: 301, 299, 318, 308 ActionDest: 179 Annotation: Subtype: Link Rect: 357, 247, 364, 258 ActionDest: 124 Annotation: Subtype: Link Rect: 278, 71, 285, 82 ActionDest: 124 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 417, 381, 495, 393 Annotation: Subtype: Link Rect: 280, 346, 292, 355 ActionDest: 179 Annotation: Subtype: Link Rect: 485, 346, 502, 355 ActionDest: 179 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 95, 609, 133, 619 Annotation: Subtype: Link Rect: 278, 585, 316, 596 Annotation: Subtype: Link Rect: 274, 562, 311, 573 Annotation: Subtype: Link Rect: 317, 562, 353, 573 Annotation: Subtype: Link Rect: 134, 528, 171, 538 Annotation: Subtype: Link Rect: 232, 505, 270, 515 Annotation: Subtype: Link Rect: 200, 482, 237, 492 Annotation: Subtype: Link Rect: 243, 482, 279, 492 Annotation: Subtype: Link Rect: 157, 459, 194, 469 Annotation: Subtype: Link Rect: 215, 436, 252, 446 Annotation: Subtype: Link Rect: 259, 436, 295, 446 Annotation: Subtype: Link Rect: 198, 412, 235, 423 Annotation: Subtype: Link Rect: 241, 412, 277, 423 Annotation: Subtype: Link Rect: 91, 390, 128, 400 Annotation: Subtype: Link Rect: 104, 367, 141, 377 Annotation: Subtype: Link Rect: 59, 332, 97, 343 Annotation: Subtype: Link Rect: 103, 332, 139, 343 Annotation: Subtype: Link Rect: 59, 298, 97, 308 Annotation: Subtype: Link Rect: 103, 298, 139, 308 Annotation: Subtype: Link Rect: 95, 275, 133, 285 Annotation: Subtype: Link Rect: 59, 252, 97, 262 Annotation: Subtype: Link Rect: 352, 228, 390, 239 Annotation: Subtype: Link Rect: 396, 228, 432, 239 Annotation: Subtype: Link Rect: 206, 205, 243, 216 Annotation: Subtype: Link Rect: 249, 205, 285, 216 Annotation: Subtype: Link Rect: 493, 193, 530, 204 Annotation: Subtype: Link Rect: 59, 171, 97, 181 Annotation: Subtype: Link Rect: 189, 147, 226, 158 Annotation: Subtype: Link Rect: 519, 124, 557, 135 Annotation: Subtype: Link Rect: 59, 114, 95, 124 Annotation: Subtype: Link Rect: 337, 90, 375, 101 Annotation: Subtype: Link Rect: 288, 68, 326, 78 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 317, 721, 354, 732 Annotation: Subtype: Link Rect: 360, 721, 396, 732 Annotation: Subtype: Link Rect: 519, 709, 557, 720 Annotation: Subtype: Link Rect: 59, 699, 95, 709 Annotation: Subtype: Link Rect: 95, 664, 132, 674 Annotation: Subtype: Link Rect: 59, 641, 97, 651 Annotation: Subtype: Link Rect: 103, 641, 139, 651 Annotation: Subtype: Link Rect: 131, 618, 169, 628 Annotation: Subtype: Link Rect: 175, 618, 211, 628 Annotation: Subtype: Link Rect: 327, 594, 365, 605 Annotation: Subtype: Link Rect: 371, 594, 407, 605 Annotation: Subtype: Link Rect: 187, 572, 225, 582 Annotation: Subtype: Link Rect: 417, 548, 454, 559 Annotation: Subtype: Link Rect: 191, 525, 227, 536 Annotation: Subtype: Link Rect: 439, 502, 476, 513 Annotation: Subtype: Link Rect: 482, 502, 518, 513 Annotation: Subtype: Link Rect: 439, 491, 476, 502 Annotation: Subtype: Link Rect: 468, 479, 506, 490 Annotation: Subtype: Link Rect: 86, 456, 376, 467 Annotation: Subtype: Link Rect: 489, 456, 526, 467 Annotation: Subtype: Link Rect: 95, 434, 133, 444 Annotation: Subtype: Link Rect: 458, 410, 495, 421 Annotation: Subtype: Link Rect: 501, 410, 537, 421 Annotation: Subtype: Link Rect: 374, 387, 412, 398 Annotation: Subtype: Link Rect: 418, 387, 454, 398 Annotation: Subtype: Link Rect: 283, 364, 320, 375 Annotation: Subtype: Link Rect: 477, 341, 514, 352 Annotation: Subtype: Link Rect: 284, 319, 321, 329 Annotation: Subtype: Link Rect: 327, 319, 363, 329 Annotation: Subtype: Link Rect: 275, 307, 313, 318 Annotation: Subtype: Link Rect: 319, 307, 355, 318 Annotation: Subtype: Link Rect: 205, 284, 242, 295 Annotation: Subtype: Link Rect: 183, 262, 221, 272 Annotation: Subtype: Link Rect: 59, 238, 97, 249 Annotation: Subtype: Link Rect: 308, 203, 346, 214 Annotation: Subtype: Link Rect: 160, 181, 198, 191 Annotation: Subtype: Link Rect: 184, 157, 221, 168 Annotation: Subtype: Link Rect: 430, 146, 467, 157 Annotation: Subtype: Link Rect: 59, 123, 97, 134 Annotation: Subtype: Link Rect: 204, 100, 241, 111 Annotation: Subtype: Link Rect: 145, 77, 183, 88 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 59, 710, 97, 720 Annotation: Subtype: Link Rect: 167, 687, 204, 697 Annotation: Subtype: Link Rect: 210, 687, 246, 697 Annotation: Subtype: Link Rect: 336, 640, 374, 651 Annotation: Subtype: Link Rect: 274, 617, 311, 628 Annotation: Subtype: Link Rect: 145, 584, 182, 594 Annotation: Subtype: Link Rect: 265, 549, 302, 559 Annotation: Subtype: Link Rect: 197, 515, 234, 525 Annotation: Subtype: Link Rect: 246, 492, 283, 502 Annotation: Subtype: Link Rect: 289, 492, 325, 502 Annotation: Subtype: Link Rect: 304, 457, 342, 467 Annotation: Subtype: Link Rect: 419, 433, 456, 444 Annotation: Subtype: Link Rect: 462, 433, 499, 444 Annotation: Subtype: Link Rect: 86, 400, 124, 410 Annotation: Subtype: Link Rect: 213, 376, 250, 387 Annotation: Subtype: Link Rect: 499, 353, 537, 364 Annotation: Subtype: Link Rect: 59, 319, 97, 329 Annotation: Subtype: Link Rect: 379, 295, 416, 306 Annotation: Subtype: Link Rect: 423, 295, 459, 306 Annotation: Subtype: Link Rect: 441, 284, 478, 295 Annotation: Subtype: Link Rect: 319, 261, 357, 272 Annotation: Subtype: Link Rect: 517, 249, 554, 260 Annotation: Subtype: Link Rect: 261, 227, 298, 237 Annotation: Subtype: Link Rect: 519, 203, 557, 214 Annotation: Subtype: Link Rect: 59, 192, 95, 203 Annotation: Subtype: Link Rect: 59, 169, 97, 180 Annotation: Subtype: Link Rect: 519, 157, 556, 168 Annotation: Subtype: Link Rect: 392, 134, 429, 145 Annotation: Subtype: Link Rect: 465, 123, 502, 134 Annotation: Subtype: Link Rect: 254, 100, 291, 111 Annotation: Subtype: Link Rect: 371, 88, 408, 99 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 520, 721, 557, 732 Annotation: Subtype: Link Rect: 59, 710, 95, 720 Annotation: Subtype: Link Rect: 225, 686, 263, 697 Annotation: Subtype: Link Rect: 108, 664, 146, 674 Annotation: Subtype: Link Rect: 152, 664, 188, 674 Annotation: Subtype: Link Rect: 59, 641, 97, 651 Annotation: Subtype: Link Rect: 103, 641, 139, 651 Annotation: Subtype: Link Rect: 435, 617, 473, 628 Annotation: Subtype: Link Rect: 95, 584, 132, 594 Annotation: Subtype: Link Rect: 397, 560, 435, 571 Annotation: Subtype: Link Rect: 59, 538, 97, 548 Annotation: Subtype: Link Rect: 103, 538, 139, 548 Annotation: Subtype: Link Rect: 520, 525, 557, 536 Annotation: Subtype: Link Rect: 215, 503, 252, 513 Annotation: Subtype: Link Rect: 254, 468, 292, 479 Annotation: Subtype: Link Rect: 298, 468, 334, 479 Annotation: Subtype: Link Rect: 59, 446, 97, 456 Annotation: Subtype: Link Rect: 476, 433, 513, 444 Annotation: Subtype: Link Rect: 59, 411, 97, 421 Annotation: Subtype: Link Rect: 410, 387, 448, 398 Annotation: Subtype: Link Rect: 217, 364, 254, 375 Annotation: Subtype: Link Rect: 260, 364, 296, 375 Annotation: Subtype: Link Rect: 397, 307, 434, 318 Annotation: Subtype: Link Rect: 341, 272, 378, 283 Checksum: 5b319879 Type: CRC32 Checksum: fb948faf2b4a0c40d0ee133d44211fc3 Type: MD5 Checksum: 9f88d451d77a9ed5386b69ad561f13260dba3108 Type: SHA-1