Modified Radical Neck Dissection (MRND)

#!/usr/bin/env python3
"""
Botulinum Toxin in ENT - Comprehensive PDF
MS ENT Postgraduate Study Material - KNRUHS
"""

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import mm, cm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether, PageBreak
)
from reportlab.platypus.flowables import Flowable
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.pdfbase import pdfmetrics
from reportlab.pdfbase.ttfonts import TTFont
import os

# ── Colour palette (teal / gold / coral theme) ──────────────────────────────
C_TITLE_BG   = colors.HexColor("#1A4A6B")   # deep navy
C_TITLE_FG   = colors.white
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C_H1_FG      = colors.white
C_H2_BG      = colors.HexColor("#E8F4F8")   # light teal bg
C_H2_FG      = colors.HexColor("#1A4A6B")   # navy text
C_H3_FG      = colors.HexColor("#B5580A")   # warm amber
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C_PEARL_BD   = colors.HexColor("#B5580A")   # amber border
C_WARN_BG    = colors.HexColor("#FDECEA")   # soft red for complications
C_WARN_BD    = colors.HexColor("#C0392B")
C_TBL_HEAD   = colors.HexColor("#1E6F8E")
C_TBL_ALT    = colors.HexColor("#EAF4F8")
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C_GREEN_BG   = colors.HexColor("#EAF7EA")
C_GREEN_BD   = colors.HexColor("#27AE60")
C_LINE       = colors.HexColor("#1E6F8E")
C_FOOT       = colors.HexColor("#7F8C8D")

W, H = A4
ML = 18*mm; MR = 18*mm; MT = 20*mm; MB = 20*mm

# ── Document ─────────────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
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    title="Botulinum Toxin in ENT",
    author="KNRUHS MS ENT Study Material"
)

# ── Styles ───────────────────────────────────────────────────────────────────
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def hr():
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# ── Title page / header block ────────────────────────────────────────────────
def title_block():
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        Paragraph("BOTULINUM TOXIN IN ENT", S["title_main"]),
    ],[
        Paragraph("Comprehensive Postgraduate Study Material", S["title_sub"]),
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        Paragraph("MS ENT | KNRUHS  |  Reference: Cummings Otolaryngology, Scott-Brown's ORL, Bailey's HNS", S["title_info"]),
    ]]
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    return [t, Spacer(1, 8)]

# ═══════════════════════════════════════════════════════════════════════════════
# BUILD CONTENT
# ═══════════════════════════════════════════════════════════════════════════════
story = []
story += title_block()

# ── 1. INTRODUCTION & HISTORY ────────────────────────────────────────────────
story += h1_block("1.  INTRODUCTION AND HISTORICAL BACKGROUND")
story.append(Paragraph(
    "Botulinum toxin (BTX) is a potent neurotoxin produced by the anaerobic gram-positive "
    "bacterium <i>Clostridium botulinum</i>. It is the most toxic naturally occurring substance "
    "known, with a lethal dose of approximately 1.3-2.1 ng/kg IV in humans. Paradoxically, "
    "in nanogram quantities it has become one of the most versatile therapeutic agents in "
    "medicine. In ENT and Head and Neck Surgery, BTX has established, evidence-based roles "
    "spanning laryngology, rhinology, salivary gland disorders, facial nerve rehabilitation, "
    "and head and neck oncologic palliation.", S["body_j"]))
story += h2_block("Historical Milestones")
hist_rows = [
    ["1897", "Emile van Ermengem isolates C. botulinum"],
    ["1949", "Burgen et al. demonstrate BTX blocks neuromuscular junction"],
    ["1973", "Alan Scott (ophthalmologist) pioneers therapeutic BTX - strabismus treatment"],
    ["1989", "FDA approves OnabotulinumtoxinA (Botox) for strabismus, blepharospasm, hemifacial spasm"],
    ["1990", "Blitzer & Brin first use BTX for spasmodic dysphonia (laryngeal injection)"],
    ["2000+", "Expanding ENT applications: sialorrhea, rhinitis, Frey syndrome, R-CPD, facial synkinesis"],
    ["2020s", "Emerging data: BTX for cricopharyngeal dysfunction, vocal tremor, globus pharyngeus"],
]
story += make_table(["Year", "Milestone"], hist_rows, col_widths=[25*mm, usable_w-25*mm])

# ── 2. PHARMACOLOGY ──────────────────────────────────────────────────────────
story += h1_block("2.  PHARMACOLOGY OF BOTULINUM TOXIN")
story += h2_block("Classification of Serotypes")
story.append(Paragraph(
    "Seven serotypes exist (A through G). Only types A and B are clinically used in ENT.", S["body"]))
serotype_rows = [
    ["OnabotulinumtoxinA", "Botox (Allergan)", "Most widely used in ENT; all major ENT indications"],
    ["AbobotulinumtoxinA", "Dysport (Ipsen)", "3:1 unit conversion vs. Botox; used in dysphonia, sialorrhea"],
    ["IncobotulinumtoxinA","Xeomin (Merz)",   "Complexing protein-free; equivalent potency to Botox unit-for-unit"],
    ["RimabotulinumtoxinB", "Myobloc (Solstice)", "Serotype B; used when resistance to Type A develops; more pain on injection"],
]
story += make_table(["Preparation", "Brand", "ENT Notes"], serotype_rows,
                    col_widths=[42*mm, 32*mm, usable_w-74*mm])

story += h2_block("Mechanism of Action")
moa_rows = [
    ["Step 1 - Binding",     "Heavy chain (HC) binds to presynaptic nerve terminals at specific ganglioside and protein receptors (SV2, synaptotagmin)"],
    ["Step 2 - Endocytosis", "Toxin-receptor complex is internalized into an endosome via receptor-mediated endocytosis"],
    ["Step 3 - Translocation","At low endosomal pH, light chain (LC) translocates across the membrane into cytoplasm"],
    ["Step 4 - Cleavage",    "LC zinc endopeptidase cleaves SNARE proteins:\n- Type A/C/E: cleave SNAP-25\n- Type B/D/F/G: cleave VAMP (synaptobrevin)\n- Type C also cleaves syntaxin"],
    ["Step 5 - Effect",      "Acetylcholine (ACh) vesicle fusion is blocked -> chemodenervation of:\n- Neuromuscular junction (muscle paralysis)\n- Autonomic cholinergic terminals (decreased glandular secretion, sweating)"],
    ["Duration",             "Effect lasts 10-16 weeks for neuromuscular; 3-6 months for autonomic secretomotor blockade. Nerve sprouting regenerates function."],
]
story += make_table(["Phase", "Detail"], moa_rows, col_widths=[40*mm, usable_w-40*mm])
story += pearl_box([
    "BTX acts PRESYNAPTICALLY - it does not affect postsynaptic receptors.",
    "SNAP-25 cleavage (Type A) is the key target for ENT applications - autonomic and motor.",
    "Onset of effect: 24-72 hours. Peak: 1-2 weeks. Duration: 3-6 months.",
    "Systemic absorption is minimal at therapeutic doses but can occur with high doses or inadvertent IV injection.",
])

# ── 3. ENT APPLICATIONS OVERVIEW ─────────────────────────────────────────────
story += h1_block("3.  ENT APPLICATIONS - OVERVIEW CLASSIFICATION")
story.append(Paragraph(
    "BTX applications in ENT are broadly divided by the mechanism exploited: "
    "<b>chemodenervation of striated muscle</b> (laryngeal, cricopharyngeal) or "
    "<b>chemodenervation of autonomic cholinergic secretomotor/sudomotor fibers</b> "
    "(salivary, nasal, sweat glands).", S["body_j"]))
overview_rows = [
    ["LARYNGOLOGY", "Spasmodic dysphonia (adductor/abductor)", "Thyroarytenoid / PCA", "Approved / first-line"],
    ["LARYNGOLOGY", "Essential vocal tremor", "TA / CT", "Off-label; evidence level B"],
    ["LARYNGOLOGY", "Muscle tension dysphonia (refractory)", "TA", "Off-label; limited evidence"],
    ["LARYNGOLOGY", "Laryngeal granuloma", "TA + vocalis", "Off-label; small series"],
    ["PHARYNX/OESOPH","Cricopharyngeal dysfunction / Zenker's (early)", "CP muscle", "Off-label; evidence B"],
    ["PHARYNX/OESOPH","Retrograde cricopharyngeal dysfunction (R-CPD)", "CP muscle", "Emerging; good evidence"],
    ["RHINOLOGY",   "Non-allergic rhinitis (rhinorrhea)", "Turbinate submucosal", "Off-label; lasts ~12 wk"],
    ["SALIVARY",    "Sialorrhea (neurologic, post-surgical)", "Parotid / submandibular", "FDA-approved (Myobloc); strong evidence"],
    ["SALIVARY",    "Frey syndrome (gustatory sweating)", "Intradermal preauricular", "Off-label; highly effective"],
    ["SALIVARY",    "Parotid fistula / sialocele", "Parotid gland", "Off-label; adjunct"],
    ["FACIAL NERVE","Facial synkinesis", "Orbicularis / mentalis / platysma", "Standard of care"],
    ["FACIAL NERVE","Hemifacial spasm", "Affected muscles", "Established; repeated injections"],
    ["HEAD & NECK", "Post-parotidectomy first bite syndrome", "Parotid bed / SCG", "Emerging evidence"],
    ["HEAD & NECK", "Cervical dystonia", "SCM / splenius / trapezius", "FDA-approved"],
    ["HEAD & NECK", "Hyperhidrosis (axillary, palmar - FP surgery)", "Intradermal sweat glands", "FDA-approved"],
]
story += make_table(
    ["Domain", "Indication", "Target Structure", "Regulatory Status"],
    overview_rows,
    col_widths=[30*mm, 55*mm, 45*mm, usable_w-130*mm]
)

# ── 4. LARYNGOLOGY ────────────────────────────────────────────────────────────
story += h1_block("4.  LARYNGOLOGY APPLICATIONS")
story += h2_block("4A.  Spasmodic Dysphonia (SD)")
story.append(Paragraph(
    "Spasmodic dysphonia is a focal laryngeal dystonia characterised by involuntary "
    "task-specific spasms of intrinsic laryngeal muscles during phonation. BTX injection "
    "is the <b>gold-standard treatment</b> for adductor SD and is the most evidence-based "
    "laryngeal BTX application (Evidence Level: A). First reported by Blitzer and Brin in 1990.", S["body_j"]))
story += h3("Types and BTX Target Muscles")
sd_rows = [
    ["Adductor SD (most common, 80-85%)",
     "Strained, strangled, effortful voice; breaks on voiced sounds; 'voice cuts out'",
     "Thyroarytenoid (TA)\n+/- lateral cricoarytenoid (LCA)",
     "1.25-2.5 U Botox each side (bilateral TA)\nUnilateral first in new patients"],
    ["Abductor SD (10-15%)",
     "Breathy voice breaks; whispered quality; breaks on voiceless sounds",
     "Posterior cricoarytenoid (PCA)\nUnilateral injection preferred",
     "3.75-5 U Botox unilateral PCA\n(bilateral risks aspiration)"],
    ["Mixed SD (rare)",
     "Features of both",
     "TA + PCA",
     "Individualised dosing"],
]
story += make_table(
    ["Type", "Clinical Features", "Target Muscle", "BTX Dose"],
    sd_rows,
    col_widths=[38*mm, 48*mm, 42*mm, usable_w-128*mm]
)
story += h3("Injection Techniques")
techs = [
    ["EMG-guided transcutaneous", "Standard technique. Needle through cricothyroid membrane or thyroid cartilage. EMG confirms TA activation on phonation. Most widely used.", "PREFERRED"],
    ["Nasolaryngoscopy-guided", "Flexible laryngoscope visualization. Needle via thyrohyoid or cricothyroid approach. Used when EMG unavailable.", "ACCEPTABLE"],
    ["Direct suspension microlaryngoscopy", "Under GA. Precise placement. Used in complex or failed office injections.", "SELECTED CASES"],
    ["Transoral approach", "Via local anaesthesia. Laryngoscope. Limited adoption.", "LESS COMMON"],
]
story += make_table(["Technique", "Description", "Status"], techs, col_widths=[45*mm, usable_w-80*mm, 35*mm])
story += pearl_box([
    "Bilateral TA injection for adductor SD: inject 1.25-2.5 U each side. Most centres start unilateral.",
    "Dysphagia and breathy hypophonia are expected for 1-4 weeks post-injection - warn all patients.",
    "Duration of benefit: median 15-17 weeks. Injections repeated every 3-5 months indefinitely.",
    "AbobotulinumtoxinA (Dysport): use 3:1 ratio. IncobotulinumtoxinA (Xeomin): 1:1 ratio.",
    "JAMA Otolaryngol 2024 (Jaworek & Sataloff): BTX remains first-line; surgical options (RLN avulsion, neurectomy) reserved for BTX failures.",
])

story += h2_block("4B.  Essential Vocal Tremor")
story.append(Paragraph(
    "Essential vocal tremor produces rhythmic voice oscillation at 4-8 Hz. BTX reduces tremor amplitude "
    "but does not eliminate it. Injected into bilateral TA and/or cricothyroid muscles. "
    "Doses are lower than SD (0.5-1.0 U per side TA). Evidence is level B; response less predictable "
    "than adductor SD. Combined with voice therapy for optimal outcomes.", S["body_j"]))

story += h2_block("4C.  Laryngeal Granuloma")
story.append(Paragraph(
    "Contact granulomas arise at the posterior glottis over vocal process. BTX into the ipsilateral "
    "TA reduces mechanical trauma during phonation and coughing. Doses: 10-20 U TA unilateral. "
    "Combining with PPI therapy and voice therapy is standard. Small case series support this use "
    "(Evidence Level: C).", S["body_j"]))

# ── 5. CRICOPHARYNGEAL / PHARYNGEAL ──────────────────────────────────────────
story += h1_block("5.  PHARYNGO-OESOPHAGEAL APPLICATIONS")
story += h2_block("5A.  Cricopharyngeal Dysfunction (CPD)")
story.append(Paragraph(
    "The cricopharyngeus (CP) is the main component of the upper oesophageal sphincter (UES). "
    "Failure of relaxation causes dysphagia, regurgitation, aspiration, and may contribute to early "
    "Zenker diverticulum. BTX injection into the CP causes temporary chemodenervation, "
    "reducing UES resting pressure. Cummings states: "
    "<i>\"functional stenosis secondary to spasm of the cricopharyngeus can be treated with "
    "botulinum toxin injection; this can be performed endoscopically or percutaneously\"</i>.", S["body_j"]))
cpd_rows = [
    ["Endoscopic (direct laryngoscopy or oesophagoscopy)", "Under GA. Direct injection under visualization. 10-20 U Botox into CP posteriorly. Gold standard for accuracy.", "Preferred approach"],
    ["EMG-guided transcutaneous (percutaneous)", "Needle through skin posterior to thyroid cartilage, EMG confirmation of CP. Local anaesthesia.", "Office-based option"],
    ["Fluoroscopy-guided", "Radiological guidance. Less EMG control.", "Radiologist-performed"],
]
story += make_table(["Approach", "Technique", "Notes"], cpd_rows,
                    col_widths=[50*mm, usable_w-85*mm, 35*mm])
story += h2_block("5B.  Retrograde Cricopharyngeal Dysfunction (R-CPD)")
story.append(Paragraph(
    "R-CPD is a recently described (2019, Bastian & Smithson) inability to belch due to failure of "
    "UES relaxation during retrograde air passage. Presents as chronic bloating, gurgling sounds "
    "(borborygmi), inability to burp, and excessive flatulence. BTX injection into CP is highly "
    "effective. Laryngoscope 2025 (Keltz et al.): Behavioural retraining (BERP protocol) is a "
    "novel adjunct. Success rates of 88-94% reported after single BTX injection.", S["body_j"]))
story += pearl_box([
    "R-CPD is underdiagnosed - ask about inability to burp in patients with chronic bloating/gurgling.",
    "BTX dose for CP: 50-100 U OnabotulinumtoxinA injected into the posterior CP muscle.",
    "Response lasts 3-6 months; many patients achieve long-term benefit after 1-2 injections.",
    "Zenker diverticulum: BTX is NOT definitive treatment but can bridge to definitive surgery (CP myotomy/diverticulopexy).",
])

# ── 6. RHINOLOGY ──────────────────────────────────────────────────────────────
story += h1_block("6.  RHINOLOGY APPLICATIONS")
story += h2_block("6A.  Non-Allergic Rhinitis (NAR) - Rhinorrhea")
story.append(Paragraph(
    "From Cummings Otolaryngology: <i>\"BTX has been shown to have a potential role in decreasing "
    "rhinorrhea in NAR patients through its anticholinergic effects on the secretory activity of "
    "the nasal mucosa. BTX can be injected intranasally into the head of the inferior and middle "
    "turbinates safely without significant side effects. However, BTX-related improvements are "
    "temporary, lasting up to 12 weeks.\"</i>", S["body_j"]))
story.append(Paragraph(
    "BTX does NOT address nasal obstruction, sneezing, or other non-rhinorrhea symptoms of NAR. "
    "This limits its utility. Consider vidian neurectomy or posterior nasal neurectomy for more "
    "durable secretomotor control.", S["body"]))
rhin_rows = [
    ["Target", "Submucosal injection into head of inferior and middle turbinates"],
    ["Dose", "20-30 U OnabotulinumtoxinA per side (total 40-60 U bilateral)"],
    ["Onset", "3-7 days"],
    ["Duration", "8-12 weeks"],
    ["Indication", "Refractory NAR with predominant rhinorrhea unresponsive to topical steroids/antihistamines"],
    ["Limitation", "Does not improve obstruction or sneezing; temporary effect; requires repeat injections"],
]
story += make_table(["Parameter", "Detail"], rhin_rows, col_widths=[35*mm, usable_w-35*mm])

# ── 7. SALIVARY GLAND APPLICATIONS ───────────────────────────────────────────
story += h1_block("7.  SALIVARY GLAND APPLICATIONS")
story += h2_block("7A.  Sialorrhea (Drooling / Excessive Salivation)")
story.append(Paragraph(
    "Sialorrhea results from impaired swallowing and reduced oral muscular control rather than "
    "true hypersalivation. Common in neurological conditions (cerebral palsy, MND/ALS, Parkinson's, "
    "stroke). BTX injection into major salivary glands produces anticholinergic reduction of "
    "saliva production by blocking parasympathetic secretomotor fibers.", S["body_j"]))
story.append(Paragraph(
    "<b>Evidence:</b> Cochrane Review 2022 (James et al., PMID 35593746): BTX is effective for "
    "sialorrhea in MND/ALS; RimabotulinumtoxinB (Myobloc) is FDA-approved for this indication. "
    "Otolaryngol Clin North Am 2022 (Hughes & Lambert, PMID 36371134): BTX and surgery are both "
    "effective; BTX preferred as first-line reversible intervention.", S["body_j"]))
sial_rows = [
    ["Parotid glands (bilateral)", "20-40 U Botox each side\nOR 500-1000 U Dysport each side", "Most accessible; largest contribution to stimulated saliva"],
    ["Submandibular glands (bilateral)", "10-20 U Botox each side\nOR 250 U Dysport each side", "Major contributor to resting saliva; inject under US guidance to avoid VII"],
    ["Combined (all 4 glands)", "Higher total dose used for severe cases", "Most effective; reduces all salivary output"],
]
story += make_table(["Gland Injected", "Dose", "Notes"], sial_rows,
                    col_widths=[40*mm, 45*mm, usable_w-85*mm])
story += pearl_box([
    "Ultrasound guidance is recommended for submandibular gland injection to avoid marginal mandibular branch of VII.",
    "Duration of effect: 3-6 months. Can be repeated indefinitely.",
    "Paediatric sialorrhea (cerebral palsy): BTX is first-line before considering parotid duct ligation or rerouting.",
    "RimabotulinumtoxinB (Myobloc) is FDA-approved for chronic sialorrhea associated with neurological conditions.",
])

story += h2_block("7B.  Frey Syndrome (Auriculotemporal Nerve Syndrome / Gustatory Sweating)")
story.append(Paragraph(
    "Frey syndrome is characterised by flushing and sweating of the preauricular/temporal skin "
    "during eating, due to aberrant regeneration of parasympathetic fibers (originally innervating "
    "parotid) into sympathetic pathways serving sweat glands and skin vessels. "
    "From Cummings: <i>\"In adolescents with severe symptoms, intradermal botulinum toxin A "
    "injections are safe, effective, and well tolerated.\"</i>", S["body_j"]))
frey_rows = [
    ["Diagnosis", "Minor's starch-iodine test: iodine applied to affected skin, starch powder dusted on; gustatory stimulus applied; sweating areas turn dark blue-black"],
    ["BTX dose", "Intradermal injections of 1.5-2.5 U per injection point, spaced 1.5-2 cm apart across affected area (total 30-50 U)"],
    ["Onset", "Within 1-2 weeks"],
    ["Duration", "12-18 months (longer than other BTX applications due to autonomic target)"],
    ["Success rate", ">95% symptom resolution; highly effective treatment"],
    ["Repeat", "Annual or as symptoms return"],
]
story += make_table(["Parameter", "Detail"], frey_rows, col_widths=[30*mm, usable_w-30*mm])

story += h2_block("7C.  Parotid Fistula and Sialocele")
story.append(Paragraph(
    "Following parotidectomy or facial trauma, salivary fistula or subcutaneous salivary "
    "collection (sialocele) can occur. BTX injection into the parotid remnant reduces "
    "secretion and promotes spontaneous resolution. Typically 25-50 U injected directly "
    "into the gland. Evidence is based on small case series (Level C).", S["body_j"]))

# ── 8. FACIAL NERVE ───────────────────────────────────────────────────────────
story += h1_block("8.  FACIAL NERVE REHABILITATION")
story += h2_block("8A.  Facial Synkinesis")
story.append(Paragraph(
    "Post-paralytic synkinesis occurs after aberrant reinnervation of the facial nerve. "
    "Common patterns: eye closure triggering mouth movement (oculooral), or smile triggering "
    "eye narrowing. From Cummings: <i>\"Chua et al. performed a dose-escalation study - the "
    "lowest dose, 40 units injected into the orbicularis oculi, gave the best reduction in "
    "synkinesis while avoiding ptosis. Borodic et al. found similar results in a "
    "multiinstitutional study.\"</i>", S["body_j"]))
syn_rows = [
    ["Orbicularis oculi synkinesis (most common)", "5-20 U per injection site (lateral, medial canthus, mid-orbit)", "Reduces involuntary eye closure; avoid levator injury"],
    ["Platysmal synkinesis", "5-10 U multiple sites in platysma", "Reduces neck banding"],
    ["Mentalis overactivity", "2.5-5 U", "Chin dimpling"],
    ["Perioral synkinesis", "2.5-5 U perioral muscles", "Careful; avoid mouth droop"],
    ["Hyperkinesis of recovered side", "Low-dose into overactive muscles", "Restores facial symmetry at rest"],
]
story += make_table(["Site/Pattern", "Dose", "Notes"], syn_rows,
                    col_widths=[50*mm, 40*mm, usable_w-90*mm])
story += h2_block("8B.  Hemifacial Spasm (HFS)")
story.append(Paragraph(
    "HFS presents as unilateral, involuntary, progressive tonic-clonic contractions of "
    "facial muscles supplied by CN VII, typically caused by vascular compression at the "
    "root entry zone. BTX is highly effective palliative treatment. First-line for mild-"
    "moderate HFS; microvascular decompression (MVD) is curative but more invasive.", S["body_j"]))
hfs_rows = [
    ["Lower eyelid / orbicularis", "5-10 U"],
    ["Upper eyelid", "2.5-5 U"],
    ["Zygomaticus / buccinator", "5-10 U each"],
    ["Platysma", "5-10 U multiple sites"],
    ["Total session dose", "20-50 U; repeated every 12-16 weeks"],
]
story += make_table(["Muscle", "Dose"], hfs_rows, col_widths=[60*mm, usable_w-60*mm])

# ── 9. PRACTICAL / PROCEDURAL GUIDE ──────────────────────────────────────────
story += h1_block("9.  PRACTICAL GUIDE - RECONSTITUTION, DOSES, AND STORAGE")
story += h2_block("Reconstitution Protocol")
recon_rows = [
    ["OnabotulinumtoxinA (Botox)", "100 U vial", "1-4 ml preserved normal saline\n(2 ml = 5 U/0.1 ml; 4 ml = 2.5 U/0.1 ml)", "Store at 2-8 deg C; use within 24 hrs of reconstitution"],
    ["AbobotulinumtoxinA (Dysport)", "300-500 U vial", "2.5 ml normal saline\n(300 U vial = 12 U/0.1 ml)", "Similar storage; units NOT interchangeable"],
    ["IncobotulinumtoxinA (Xeomin)", "50-200 U vial", "1-4 ml normal saline", "Room temp storage before reconstitution"],
    ["RimabotulinumtoxinB (Myobloc)", "Pre-diluted solution 5000 U/ml", "No reconstitution needed", "Refrigerate; more painful on injection"],
]
story += make_table(["Preparation", "Vial Size", "Reconstitution", "Storage"],
                    recon_rows, col_widths=[42*mm, 22*mm, 50*mm, usable_w-114*mm])
story += warn_box([
    "UNITS ARE NOT INTERCHANGEABLE between BTX preparations.",
    "Botox:Dysport conversion = approximately 1:3 (1 U Botox = 3 U Dysport).",
    "Xeomin:Botox = 1:1 (approximately).",
    "Myobloc (serotype B) units are entirely different - 2500-5000 U Myobloc ~ 50-100 U Botox.",
    "Avoid vigorous agitation of vial - roll gently to reconstitute.",
])
story += h2_block("Standard ENT Doses Reference Table")
dose_rows = [
    ["Adductor spasmodic dysphonia", "Bilateral TA", "1.25-2.5 U each side (Botox)", "3.75-7.5 U Dysport each side", "EMG-guided"],
    ["Abductor spasmodic dysphonia", "Unilateral PCA", "3.75-7.5 U (Botox)", "10-20 U Dysport", "EMG-guided; unilateral only"],
    ["Vocal tremor", "Bilateral TA +/- CT", "0.5-1.0 U each side", "Lower than SD doses", "Start low; titrate"],
    ["Sialorrhea (parotid)", "Bilateral parotid", "20-40 U each gland", "500-1000 U Dysport each", "US guidance optional"],
    ["Sialorrhea (submandibular)", "Bilateral submandibular", "10-20 U each gland", "250 U Dysport each", "US guidance recommended"],
    ["Frey syndrome", "Intradermal preauricular", "1.5-2.5 U/injection point total 30-50 U", "Proportional Dysport dose", "After Minor's test mapping"],
    ["Facial synkinesis", "Affected muscles", "5-40 U per session", "Proportional Dysport dose", "Electrophysiology optional"],
    ["Cricopharyngeal spasm", "CP muscle", "10-30 U Botox total", "-", "Endoscopic or percutaneous EMG"],
    ["R-CPD", "CP muscle", "50-100 U Botox total", "-", "Under GA endoscopic"],
    ["Non-allergic rhinitis", "Bilateral turbinates", "20-30 U each side", "-", "Submucosal; topical decongest first"],
]
story += make_table(
    ["Indication", "Target", "Botox Dose", "Dysport Dose", "Guidance"],
    dose_rows,
    col_widths=[42*mm, 35*mm, 35*mm, 30*mm, usable_w-142*mm]
)

# ── 10. CONTRAINDICATIONS ─────────────────────────────────────────────────────
story += h1_block("10.  CONTRAINDICATIONS AND PRECAUTIONS")
ci_rows = [
    ["ABSOLUTE", "Known hypersensitivity to BTX or human albumin"],
    ["ABSOLUTE", "Infection at injection site"],
    ["ABSOLUTE", "Myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis"],
    ["RELATIVE", "Pregnancy and lactation (Category C; avoid unless benefit outweighs risk)"],
    ["RELATIVE", "Neuromuscular junction disorders (use with extreme caution; lower doses)"],
    ["RELATIVE", "Concurrent aminoglycosides, calcium channel blockers, chloroquine (potentiate BTX)"],
    ["RELATIVE", "Coagulopathy / anticoagulation (relative; compressible injection sites usually safe)"],
    ["PRECAUTION","Dysphagia risk: bilateral TA/PCA injections for SD; always warn of temporary dysphagia"],
    ["PRECAUTION","Respiratory compromise: abductor SD bilateral PCA injection risks bilateral VC paralysis"],
]
story += make_table(["Type", "Contraindication / Precaution"], ci_rows, col_widths=[28*mm, usable_w-28*mm])

# ── 11. COMPLICATIONS ─────────────────────────────────────────────────────────
story += h1_block("11.  COMPLICATIONS OF BTX IN ENT")
comp_rows = [
    ["Dysphagia / odynophagia", "Laryngeal BTX (TA injection)", "Common (25-50%), temporary 1-4 weeks", "Liquid diet; self-resolves"],
    ["Breathy hypophonia", "Adductor SD treatment", "Expected; 1-4 weeks", "Reassure; self-limiting"],
    ["Aspiration", "Laryngeal/CP BTX", "Less common; risk with bilateral PCA", "Aspiration precautions; may need NGT"],
    ["Respiratory compromise", "Bilateral PCA injection", "Rare but serious; bilateral VC paralysis", "Avoid bilateral PCA; unilateral only"],
    ["Ptosis / diplopia", "Peri-orbital injection (synkinesis/HFS)", "If toxin spreads to levator/extraocular muscles", "Usually resolves; apraclonidine drops for ptosis"],
    ["Dry mouth (xerostomia)", "Salivary gland BTX", "Due to over-reduction of saliva", "Reduce dose; artificial saliva"],
    ["Ecchymosis / haematoma", "Any injection", "Minor; injection-site bruising", "Pressure; ice"],
    ["Infection", "Any injection", "Rare with sterile technique", "Standard asepsis"],
    ["Antibody formation / resistance", "Repeated high-dose injections", "More likely with higher doses, frequent injections, protein complex in Botox/Dysport vs Xeomin", "Switch serotype (A to B); Xeomin may reduce risk"],
    ["Systemic BTX spread", "High doses", "Rare; generalised weakness, ptosis, diplopia, dysphagia", "Supportive; may need hospitalisation"],
]
story += make_table(
    ["Complication", "Context", "Frequency/Severity", "Management"],
    comp_rows,
    col_widths=[40*mm, 38*mm, 45*mm, usable_w-123*mm]
)

# ── 12. FLOWCHART / ALGORITHMS ────────────────────────────────────────────────
story += h1_block("12.  CLINICAL DECISION ALGORITHMS")
story += h2_block("Algorithm A: Spasmodic Dysphonia Management")
algo_sd = [
    ["PATIENT WITH VOICE DISORDER"],
    ["Flexible nasolaryngoscopy + stroboscopy\nIdentify pattern of breaks (voiced vs voiceless)"],
    ["Adductor SD: breaks on VOICED sounds\nStrained/strangled quality",
     "Abductor SD: breaks on VOICELESS sounds\nBreathy/whispery quality"],
    ["BILATERAL TA injection\n1.25-2.5 U Botox each side\nEMG-guided transcutaneous",
     "UNILATERAL PCA injection\n3.75-7.5 U Botox\nEMG-guided (strict unilateral)"],
    ["Review at 2-4 weeks\nAssess voice + swallowing"],
    ["Good response: repeat every 12-17 weeks\nAdjust dose based on duration & side effects"],
    ["Inadequate response: dose adjustment\nConsider alternative muscle (LCA, CT)\nConsider RLN selective neurectomy (surgical salvage)"],
]
# Render as narrow box tables for flowchart appearance
for row in algo_sd:
    if len(row) == 1:
        data = [[Paragraph(row[0], S["tbl_hd"])]]
        col_w = [usable_w]
        bg = C_TBL_HEAD
    else:
        data = [[Paragraph(row[0], S["tbl"]), Paragraph(row[1], S["tbl"])]]
        col_w = [usable_w/2, usable_w/2]
        bg = C_TBL_ALT
    t = Table(data, colWidths=col_w)
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), bg),
        ("GRID", (0,0),(-1,-1), 1, C_TBL_GRID),
        ("ALIGN", (0,0),(-1,-1), "CENTER"),
        ("TOPPADDING",(0,0),(-1,-1),4),
        ("BOTTOMPADDING",(0,0),(-1,-1),4),
    ]))
    story.append(t)
    story.append(Paragraph("  |", sty("arr", fontName="Helvetica-Bold",
                                       fontSize=10, alignment=TA_CENTER,
                                       textColor=C_H1_BG)))

story += h2_block("Algorithm B: Sialorrhea Management")
sial_algo = [
    ["Assess severity (Drooling Rating Scale) + impact on quality of life"],
    ["Mild sialorrhea: Oral motor therapy, anticholinergics (glycopyrrolate)"],
    ["Moderate-severe: BTX injection\nParotid 20-40 U + Submandibular 10-20 U bilaterally\n(Under US guidance for submandibular)"],
    ["Reassess at 4-6 weeks post-injection"],
    ["Adequate response: Repeat every 3-6 months"],
    ["Inadequate response: Increase dose, add more glands, or refer for surgery\n(Parotid duct ligation, submandibular duct rerouting, gland excision)"],
]
for item in sial_algo:
    data = [[Paragraph(item, S["tbl"])]]
    t = Table(data, colWidths=[usable_w])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0),(-1,-1), C_TBL_ALT),
        ("GRID", (0,0),(-1,-1), 1, C_TBL_GRID),
        ("ALIGN",(0,0),(-1,-1),"LEFT"),
        ("TOPPADDING",(0,0),(-1,-1),4),
        ("BOTTOMPADDING",(0,0),(-1,-1),4),
        ("LEFTPADDING",(0,0),(-1,-1),8),
    ]))
    story.append(t)
    story.append(Paragraph("  |", sty("arr2", fontName="Helvetica-Bold",
                                       fontSize=10, alignment=TA_CENTER,
                                       textColor=C_H1_BG)))

# ── 13. RECENT ADVANCES ───────────────────────────────────────────────────────
story += h1_block("13.  RECENT ADVANCES (2021-2026)")
adv_rows = [
    ["R-CPD (Retrograde CPD)", "Bastian & Smithson 2019 described condition. BTX CP injection 88-94% success. Keltz et al. Laryngoscope 2025: BERP behavioral protocol as adjunct to BTX. Emerging standard of care for R-CPD.", "High"],
    ["Laryngeal BTX injection techniques", "Biello et al. 2026: Updated laryngeal BTX injection study guide in StatPearls. EMG-guided transcutaneous remains gold standard.", "Moderate"],
    ["Spasmodic dysphonia - serotype switching", "Hyodo et al. Toxins 2022 (PMID 35878189): Reviewed BTX therapy for SD in Japan; outcomes stable over long-term repeated injections. Serotype B (Myobloc) when Type A resistance develops.", "Moderate"],
    ["Sialorrhea - MND/ALS", "James et al. Cochrane 2022 (PMID 35593746): Systematic review confirms BTX efficacy for sialorrhea in MND; Myobloc (serotype B) FDA-approved for chronic sialorrhea.", "High (Level 1)"],
    ["Bell's palsy - BTX for synkinesis", "Fujiwara et al. Auris Nasus Larynx 2024 (PMID 39079445): Japanese guidelines 2023 - BTX for synkinesis standard recommendation post-Bell's palsy.", "Guideline level"],
    ["Long-duration BTX formulations", "Daxibotulinumtoxin-A (Daxxify, Revance): FDA approved 2022 for glabellar lines; contains novel peptide excipient (no albumin). Longer duration (6-9 months). Trials in progress for laryngeal use.", "Emerging"],
    ["Endoscopic BTX for nasal conditions", "Increasing evidence for image-guided turbinate BTX injections; nasal spray delivery systems under investigation as alternatives to injection.", "Emerging"],
]
story += make_table(
    ["Topic", "Evidence Summary", "Evidence Level"],
    adv_rows,
    col_widths=[45*mm, usable_w-75*mm, 30*mm]
)

# ── 14. CLINICAL PEARLS & VIVA ────────────────────────────────────────────────
story += h1_block("14.  HIGH-YIELD CLINICAL PEARLS")
story += pearl_box([
    "BTX mechanism: blocks SNAP-25 cleavage -> prevents ACh vesicle fusion -> chemodenervation.",
    "Adductor SD is the ONLY laryngeal BTX application with Level A evidence.",
    "For adductor SD: BILATERAL TA injection. For abductor SD: UNILATERAL PCA injection (bilateral = respiratory risk).",
    "Frey syndrome: BTX intradermal injection has >95% success; duration 12-18 months (longest ENT application).",
    "Sialorrhea: parotid injection contributes to stimulated saliva; submandibular contributes most to resting saliva.",
    "Xeomin (incobotulinumtoxinA) has no complexing proteins - may have lower antibody formation risk with long-term use.",
    "R-CPD: inability to belch + gurgling + bloating = consider CP BTX injection. Success rates 88-94%.",
    "BTX effect on autonomic glands lasts LONGER (3-6 months) than neuromuscular effects.",
    "Units are NOT interchangeable: always specify preparation name AND dose.",
    "Contraindication: myasthenia gravis, Lambert-Eaton syndrome, ALS (absolute).",
])

story += h1_block("15.  VIVA QUESTIONS WITH ANSWERS")
viva = [
    ["Q1. What is the mechanism of action of BTX?",
     "BTX is a zinc endopeptidase that cleaves SNARE complex proteins. Type A cleaves SNAP-25; Type B cleaves VAMP/synaptobrevin. This prevents ACh vesicle fusion with presynaptic membrane, blocking neurotransmitter release at neuromuscular junctions and autonomic cholinergic terminals."],
    ["Q2. Which muscles are injected in adductor vs abductor spasmodic dysphonia?",
     "Adductor SD: bilateral thyroarytenoid (TA) muscles, 1.25-2.5 U Botox each side. Abductor SD: UNILATERAL posterior cricoarytenoid (PCA) only - bilateral PCA injection risks bilateral vocal cord paralysis and airway compromise."],
    ["Q3. Why is BTX preferred over surgery for Frey syndrome?",
     "BTX intradermal injection has >95% effectiveness, is minimally invasive, outpatient procedure, reversible, and has excellent duration (12-18 months). Surgical options (fascial interposition, tympanic neurectomy) carry more risk and are less reliable."],
    ["Q4. What are the contraindications to BTX?",
     "Absolute: hypersensitivity to BTX/albumin, infection at injection site, preexisting NMJ disorders (MG, LEMS, ALS). Relative: pregnancy, anticoagulation, drugs potentiating BTX (aminoglycosides, CCBs, chloroquine)."],
    ["Q5. A patient has SD with adductor pattern. After 3 years of TA injections, response has diminished. What is the next step?",
     "Suspect antibody-mediated resistance to Type A BTX. Switch to RimabotulinumtoxinB (Myobloc - serotype B). Alternatively, trial Xeomin (protein-free formulation). If surgical candidate, consider RLN selective neurectomy or thyroarytenoid myomectomy."],
    ["Q6. How do you diagnose Frey syndrome and what is the BTX technique?",
     "Diagnosis: Minor's starch-iodine test (iodine applied to skin, starch dusted on, gustatory stimulus -> sweating areas turn dark blue-black mapping the affected zone). BTX technique: intradermal injections 1.5-2.5 U per point, points 1.5-2 cm apart, covering the iodine-mapped zone. Total 30-50 U typically needed."],
    ["Q7. What is R-CPD and how is BTX used?",
     "Retrograde cricopharyngeal dysfunction: inability to belch due to failure of UES relaxation during retrograde air. BTX 50-100 U OnabotulinumtoxinA injected into the posterior CP muscle under GA endoscopic guidance. 88-94% success rate reported. May be combined with behavioral retraining (BERP protocol)."],
]
for q, a in viva:
    data = [
        [Paragraph(q, sty("vq", fontName="Helvetica-Bold", fontSize=9,
                           textColor=C_TITLE_BG, leading=13))],
        [Paragraph(a, sty("va", fontName="Helvetica", fontSize=9,
                           leading=13, leftIndent=8))]
    ]
    t = Table(data, colWidths=[usable_w])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (0,0), C_H2_BG),
        ("BACKGROUND", (0,1), (0,1), colors.white),
        ("LINEBELOW",  (0,1), (0,1), 0.5, C_TBL_GRID),
        ("TOPPADDING", (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1),4),
        ("LEFTPADDING",(0,0),(-1,-1), 8),
    ]))
    story.append(KeepTogether(t))
    story.append(sp(3))

# ── 16. REFERENCES ────────────────────────────────────────────────────────────
story += h1_block("16.  KEY REFERENCES")
refs = [
    "Cummings Otolaryngology - Head and Neck Surgery, 7th Edition (2021). Chapter 39 (Rhinitis - BTX), Chapter 45 (Salivary Glands - Frey), Chapter 22 (Pharyngo-oesophageal), Chapter 9 (Rhinology).",
    "Scott-Brown's Otorhinolaryngology Head and Neck Surgery, 8th Edition. Chapter 18 (Neck Dissection), Chapter 10 (Laryngeal BTX technique).",
    "Blitzer A, Brin MF. Laryngeal dystonia: a series with botulinum toxin therapy. Ann Otol Rhinol Laryngol. 1991;100(2):85-89. [First laryngeal BTX report]",
    "James E et al. Treatment for sialorrhea in MND/ALS. Cochrane Database Syst Rev. 2022 May 20. PMID: 35593746. [Systematic Review - Level 1]",
    "Hughes A, Lambert EM. Drooling and Aspiration of Saliva. Otolaryngol Clin North Am. 2022 Dec. PMID: 36371134.",
    "Jaworek AJ, Sataloff RT. Spasmodic Dysphonia. World J Otorhinolaryngol Head Neck Surg. 2025. PMID: 41477134.",
    "Hyodo M et al. Botulinum Toxin Therapy for Spasmodic Dysphonia in Japan. Toxins (Basel). 2022 Jul 1. PMID: 35878189.",
    "Sanuki T. Spasmodic dysphonia: An overview of clinical features and treatment options. Auris Nasus Larynx. 2023. PMID: 35697560.",
    "Fujiwara T et al. Japanese clinical practice guidelines for Bell's palsy - 2023 update. Auris Nasus Larynx. 2024. PMID: 39079445.",
    "Keltz A, Simmons KE, Lerner MZ. Behavioral Eructation Retraining Protocol (BERP) for R-CPD. Laryngoscope. 2025. PMID: 40662408.",
    "Biello A, Volner K, Song SA. Laryngeal Botulinum Toxin Injection. StatPearls. 2026. PMID: 33620810.",
]
for r in refs:
    story.append(Paragraph(f"[{refs.index(r)+1}] {r}", S["ref"]))
    story.append(sp(2))

# ── Build PDF ────────────────────────────────────────────────────────────────
def add_page_number(canvas, doc):
    canvas.saveState()
    canvas.setFont("Helvetica", 8)
    canvas.setFillColor(C_FOOT)
    page_num = canvas.getPageNumber()
    canvas.drawString(ML, 12*mm, "Botulinum Toxin in ENT  |  MS ENT KNRUHS Study Material  |  2026")
    canvas.drawRightString(W - MR, 12*mm, f"Page {page_num}")
    canvas.restoreState()

doc.build(story, onFirstPage=add_page_number, onLaterPages=add_page_number)
print("PDF generated successfully.")

Successfully replaced 1 instance(s) of the string in '/home/daytona/workspace/ent-botox/generate_pdf.py'

#!/usr/bin/env python3
"""
Botulinum Toxin in ENT - 10 Marks Exam Answer
KNRUHS MS ENT | Liberation Sans | Deep Teal/Gold palette
"""

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import ParagraphStyle
from reportlab.lib.units import mm
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether
)
from reportlab.pdfbase import pdfmetrics
from reportlab.pdfbase.ttfonts import TTFont
import os

# ── Register Liberation Sans ─────────────────────────────────────────────────
FONT_PATHS = [
    "/usr/share/fonts/truetype/liberation",
    "/usr/share/fonts/liberation",
    "/usr/share/fonts",
]
def find_font(filename):
    for d in FONT_PATHS:
        p = os.path.join(d, filename)
        if os.path.exists(p):
            return p
    return None

reg  = find_font("LiberationSans-Regular.ttf")
bold = find_font("LiberationSans-Bold.ttf")
it   = find_font("LiberationSans-Italic.ttf")
bi   = find_font("LiberationSans-BoldItalic.ttf")

USE_LIBERATION = all([reg, bold, it, bi])
if USE_LIBERATION:
    pdfmetrics.registerFont(TTFont("LibSans",     reg))
    pdfmetrics.registerFont(TTFont("LibSans-Bold",bold))
    pdfmetrics.registerFont(TTFont("LibSans-It",  it))
    pdfmetrics.registerFont(TTFont("LibSans-BI",  bi))
    from reportlab.pdfbase.pdfmetrics import registerFontFamily
    registerFontFamily("LibSans",
        normal="LibSans", bold="LibSans-Bold",
        italic="LibSans-It", boldItalic="LibSans-BI")
    F  = "LibSans"
    FB = "LibSans-Bold"
    FI = "LibSans-It"
else:
    F  = "Helvetica"
    FB = "Helvetica-Bold"
    FI = "Helvetica-Oblique"

# ── Colour palette  (Deep Teal + Rich Gold + Warm Coral accents) ─────────────
# All colours 100% saturated / full value as requested
C_PAGE_BG    = colors.white

# Heading colours
C_H1_BG      = colors.HexColor("#005F6B")   # deep teal  (100% sat)
C_H1_FG      = colors.HexColor("#FFFFFF")   # white
C_H2_BG      = colors.HexColor("#E6F4F6")   # very light teal bg
C_H2_FG      = colors.HexColor("#003F47")   # darkest teal  - pure dark
C_H3_FG      = colors.HexColor("#B8860B")   # dark goldenrod (100% sat)

# Body
C_BODY       = colors.HexColor("#000000")   # pure black body text

# Pearl / clinical pearl box
C_PEARL_BG   = colors.HexColor("#FFF8DC")   # cornsilk
C_PEARL_LEFT = colors.HexColor("#DAA520")   # goldenrod border
C_PEARL_TEXT = colors.HexColor("#4B3200")   # very dark brown = ~black but warm

# Caution / dose / important box
C_DOSE_BG    = colors.HexColor("#FFF0F0")   # lightest pink
C_DOSE_LEFT  = colors.HexColor("#CC0000")   # pure red border
C_DOSE_TEXT  = colors.HexColor("#000000")   # pure black

# Table
C_TBL_HEAD   = colors.HexColor("#005F6B")   # deep teal
C_TBL_HEAD_T = colors.HexColor("#FFFFFF")
C_TBL_ALT    = colors.HexColor("#EAF5F7")   # very light teal alt row
C_TBL_GRID   = colors.HexColor("#A0CDD3")

# Flowchart box colours
C_FC_BOX     = colors.HexColor("#005F6B")
C_FC_TEXT    = colors.HexColor("#FFFFFF")
C_FC_SUB     = colors.HexColor("#E6F4F6")
C_FC_SUBT    = colors.HexColor("#000000")
C_FC_ARROW   = colors.HexColor("#005F6B")

# Footer
C_FOOT       = colors.HexColor("#555555")

W, H = A4
ML = 18*mm; MR = 18*mm; MT = 18*mm; MB = 18*mm
UW = W - ML - MR   # usable width = ~174 mm

# ── Style factory ─────────────────────────────────────────────────────────────
def S(name, **kw):
    defaults = dict(fontName=F, fontSize=10.5, leading=15.5,
                    textColor=C_BODY, spaceAfter=0, spaceBefore=0)
    defaults.update(kw)
    return ParagraphStyle(name, **defaults)

# Body styles
sBody   = S("sBody",   alignment=TA_JUSTIFY, spaceAfter=4)
sBullet = S("sBullet", leftIndent=14, spaceAfter=3)
sSub    = S("sSub",    leftIndent=26, spaceAfter=2, fontSize=10)
sRef    = S("sRef",    fontName=FI,  fontSize=8.5, leading=12,
            textColor=C_FOOT, spaceAfter=1)

# Heading styles (text inside coloured boxes or coloured text)
sH1txt  = S("sH1txt",  fontName=FB, fontSize=11.5, leading=16,
            textColor=C_H1_FG, alignment=TA_LEFT)
sH2txt  = S("sH2txt",  fontName=FB, fontSize=10.5, leading=15,
            textColor=C_H2_FG, alignment=TA_LEFT)
sH3txt  = S("sH3txt",  fontName=FB, fontSize=10.5, leading=15,
            textColor=C_H3_FG, alignment=TA_LEFT)

# Table cell
sTbl    = S("sTbl",    fontSize=10, leading=13, spaceAfter=0)
sTblHd  = S("sTblHd",  fontName=FB, fontSize=10, leading=13,
            textColor=C_TBL_HEAD_T, spaceAfter=0)

# Pearl
sPearl  = S("sPearl",  fontSize=10, leading=14, textColor=C_PEARL_TEXT)
sDose   = S("sDose",   fontSize=10, leading=14, textColor=C_DOSE_TEXT)

# Title block
sTitleM = S("sTitleM", fontName=FB, fontSize=17, leading=22,
            textColor=C_H1_FG, alignment=TA_CENTER)
sTitleS = S("sTitleS", fontSize=10, leading=14,
            textColor=colors.HexColor("#CCF0F5"), alignment=TA_CENTER)
sTitleI = S("sTitleI", fontName=FB, fontSize=9.5, leading=13,
            textColor=colors.HexColor("#FFFFFF"), alignment=TA_CENTER)

# Flowchart
sFC     = S("sFC",     fontName=FB, fontSize=10, leading=13.5,
            textColor=C_FC_TEXT, alignment=TA_CENTER)
sFCsub  = S("sFCsub",  fontSize=9.5, leading=13, textColor=C_FC_SUBT,
            alignment=TA_CENTER)

def sp(n=6):  return Spacer(1, n)
def hr():
    return HRFlowable(width="100%", thickness=0.8, color=C_H1_BG,
                      spaceAfter=4, spaceBefore=4)

# ── Heading builders ─────────────────────────────────────────────────────────
def H1(text):
    """Dark teal full-width heading bar."""
    t = Table([[Paragraph(text, sH1txt)]], colWidths=[UW])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0),(-1,-1), C_H1_BG),
        ("TOPPADDING",    (0,0),(-1,-1), 6),
        ("BOTTOMPADDING", (0,0),(-1,-1), 6),
        ("LEFTPADDING",   (0,0),(-1,-1), 10),
        ("RIGHTPADDING",  (0,0),(-1,-1), 8),
    ]))
    return [sp(8), t, sp(5)]

def H2(text):
    """Light teal shaded subheading."""
    t = Table([[Paragraph(text, sH2txt)]], colWidths=[UW])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0),(-1,-1), C_H2_BG),
        ("TOPPADDING",    (0,0),(-1,-1), 4),
        ("BOTTOMPADDING", (0,0),(-1,-1), 4),
        ("LEFTPADDING",   (0,0),(-1,-1), 10),
        ("LINEBELOW",     (0,0),(-1,-1), 1.5, C_H1_BG),
    ]))
    return [sp(6), t, sp(4)]

def H3(text):
    return [sp(4), Paragraph(f"▶  {text}", sH3txt), sp(2)]

def bullet(text, level=1):
    prefix = "•" if level == 1 else "–"
    stl    = sBullet  if level == 1 else sSub
    return Paragraph(f"{prefix}  {text}", stl)

def pearl_box(lines, header="Clinical Pearl"):
    """Gold-left-border pearl box."""
    content = f"<b>{header}</b><br/>" + "<br/>".join(
        f"&#9733; {l}" for l in lines)
    t = Table([[Paragraph(content, sPearl)]], colWidths=[UW])
    t.setStyle(TableStyle([
        ("BACKGROUND",  (0,0),(-1,-1), C_PEARL_BG),
        ("LINEBEFORE",  (0,0),(0,-1),  4, C_PEARL_LEFT),
        ("TOPPADDING",  (0,0),(-1,-1), 7),
        ("BOTTOMPADDING",(0,0),(-1,-1),7),
        ("LEFTPADDING", (0,0),(-1,-1), 12),
        ("RIGHTPADDING",(0,0),(-1,-1), 8),
    ]))
    return [sp(5), t, sp(5)]

def dose_box(lines, header="Important / Dose"):
    """Red-left-border dose/caution box."""
    content = f"<b>{header}</b><br/>" + "<br/>".join(
        f"&#9654; {l}" for l in lines)
    t = Table([[Paragraph(content, sDose)]], colWidths=[UW])
    t.setStyle(TableStyle([
        ("BACKGROUND",  (0,0),(-1,-1), C_DOSE_BG),
        ("LINEBEFORE",  (0,0),(0,-1),  4, C_DOSE_LEFT),
        ("TOPPADDING",  (0,0),(-1,-1), 7),
        ("BOTTOMPADDING",(0,0),(-1,-1),7),
        ("LEFTPADDING", (0,0),(-1,-1), 12),
        ("RIGHTPADDING",(0,0),(-1,-1), 8),
    ]))
    return [sp(5), t, sp(5)]

def make_table(headers, rows, col_widths):
    """Wrap-safe table. All cells are Paragraph objects."""
    hrow = [Paragraph(h, sTblHd) for h in headers]
    data = [hrow]
    for i, row in enumerate(rows):
        data.append([Paragraph(str(c), sTbl) for c in row])
    style = [
        ("BACKGROUND",    (0,0),(-1,0),  C_TBL_HEAD),
        ("GRID",          (0,0),(-1,-1), 0.5, C_TBL_GRID),
        ("TOPPADDING",    (0,0),(-1,-1), 5),
        ("BOTTOMPADDING", (0,0),(-1,-1), 5),
        ("LEFTPADDING",   (0,0),(-1,-1), 6),
        ("RIGHTPADDING",  (0,0),(-1,-1), 6),
        ("VALIGN",        (0,0),(-1,-1), "TOP"),
    ]
    for i in range(1, len(data)):
        if i % 2 == 0:
            style.append(("BACKGROUND",(0,i),(-1,i), C_TBL_ALT))
    t = Table(data, colWidths=col_widths, repeatRows=1)
    t.setStyle(TableStyle(style))
    return [sp(4), t, sp(4)]

# ── Flowchart builder ─────────────────────────────────────────────────────────
def flow_box(text, is_main=True):
    """Single flowchart box."""
    stl = sFC if is_main else sFCsub
    bg  = C_FC_BOX if is_main else C_FC_SUB
    t = Table([[Paragraph(text, stl)]], colWidths=[UW * 0.75])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0),(-1,-1), bg),
        ("TOPPADDING",    (0,0),(-1,-1), 6),
        ("BOTTOMPADDING", (0,0),(-1,-1), 6),
        ("LEFTPADDING",   (0,0),(-1,-1), 10),
        ("RIGHTPADDING",  (0,0),(-1,-1), 10),
        ("BOX",           (0,0),(-1,-1), 1, C_FC_BOX),
    ]))
    return t

def arrow():
    return Paragraph("<font color='#005F6B'><b>&#9660;</b></font>",
                     S("arr", alignment=TA_CENTER, fontSize=13))

def two_col_flow(left_text, right_text):
    """Side-by-side flowchart branches."""
    half = UW * 0.45
    lbox = Table([[Paragraph(left_text, sFC)]], colWidths=[half])
    rbox = Table([[Paragraph(right_text, sFC)]], colWidths=[half])
    lbox.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(-1,-1), C_FC_BOX),
        ("TOPPADDING",(0,0),(-1,-1),6),("BOTTOMPADDING",(0,0),(-1,-1),6),
        ("LEFTPADDING",(0,0),(-1,-1),8),("RIGHTPADDING",(0,0),(-1,-1),8),
        ("BOX",(0,0),(-1,-1),1,C_FC_BOX),
    ]))
    rbox.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(-1,-1), C_FC_BOX),
        ("TOPPADDING",(0,0),(-1,-1),6),("BOTTOMPADDING",(0,0),(-1,-1),6),
        ("LEFTPADDING",(0,0),(-1,-1),8),("RIGHTPADDING",(0,0),(-1,-1),8),
        ("BOX",(0,0),(-1,-1),1,C_FC_BOX),
    ]))
    wrapper = Table([[lbox, Paragraph("", S("gap")), rbox]],
                    colWidths=[half, UW*0.10, half])
    wrapper.setStyle(TableStyle([("VALIGN",(0,0),(-1,-1),"TOP")]))
    return wrapper


# ══════════════════════════════════════════════════════════════════════════════
# DOCUMENT BUILD
# ══════════════════════════════════════════════════════════════════════════════
doc = SimpleDocTemplate(
    "/home/daytona/workspace/ent-botox/Botox_ENT_Exam.pdf",
    pagesize=A4,
    leftMargin=ML, rightMargin=MR, topMargin=MT, bottomMargin=MB,
    title="Botulinum Toxin in ENT - 10 Mark Exam Answer",
    author="KNRUHS MS ENT"
)

story = []

# ── TITLE BLOCK ───────────────────────────────────────────────────────────────
title_data = [
    [Paragraph("BOTULINUM TOXIN IN ENT", sTitleM)],
    [Paragraph("10-Mark Long Answer  |  KNRUHS MS ENT University Exam", sTitleS)],
    [Paragraph("Source: Cummings Otolaryngology (7th Ed.) | Scott-Brown's ORL (8th Ed.)", sTitleI)],
]
title_tbl = Table(title_data, colWidths=[UW])
title_tbl.setStyle(TableStyle([
    ("BACKGROUND",    (0,0),(-1,-1), C_H1_BG),
    ("TOPPADDING",    (0,0),(-1,-1), 9),
    ("BOTTOMPADDING", (0,0),(-1,-1), 9),
    ("LEFTPADDING",   (0,0),(-1,-1), 14),
    ("ALIGN",         (0,0),(-1,-1), "CENTER"),
]))
story += [title_tbl, sp(10)]

# ══════════════════════════════════════════════════════════════════════════════
# 1. INTRODUCTION
# ══════════════════════════════════════════════════════════════════════════════
story += H1("1.  INTRODUCTION")
story.append(Paragraph(
    "Botulinum toxin (BTX) is a protein produced by the bacterium "
    "<i>Clostridium botulinum</i>. In very tiny amounts, it is used as a medicine "
    "to relax overactive muscles or reduce abnormal secretions. "
    "In ENT (Ear, Nose and Throat) practice, BTX has become a very useful tool "
    "for treating several conditions where muscles or glands are working too much "
    "or in the wrong way.", sBody))
story.append(Paragraph(
    "It was first used medically in the 1970s for eye muscle problems "
    "(strabismus). Its use in ENT - particularly for voice disorders - began in "
    "1990 when Blitzer and Brin injected BTX into the larynx (voice box) to "
    "treat spasmodic dysphonia. Since then, its applications in ENT have grown "
    "widely.", sBody))
story += H2("Why is BTX Important in ENT?")
for pt in [
    "It gives relief when medicines do not work for certain ENT conditions.",
    "It is a minimally invasive (no surgery) office-based procedure.",
    "The effects are reversible - they wear off after 3 to 6 months.",
    "It can be safely repeated multiple times.",
    "It improves quality of life significantly in conditions like voice disorders, "
    "excess saliva production, and sweating near the ear.",
]:
    story.append(bullet(pt))
story.append(sp(4))

# ══════════════════════════════════════════════════════════════════════════════
# 2. SOURCE AND TYPES
# ══════════════════════════════════════════════════════════════════════════════
story += H1("2.  SOURCE, TYPES, AND AVAILABLE PREPARATIONS")
story += H2("Source")
story.append(bullet(
    "Produced by <b>Clostridium botulinum</b> - a gram-positive, anaerobic, "
    "spore-forming bacterium."))
story.append(bullet(
    "There are <b>7 serotypes</b> labeled A to G. Only <b>Types A and B</b> "
    "are used in clinical medicine."))
story.append(sp(4))

story += H2("Commercially Available Preparations")
prep_rows = [
    ["OnabotulinumtoxinA", "Botox (Allergan)", "Type A",
     "Most widely used in ENT"],
    ["AbobotulinumtoxinA",  "Dysport (Ipsen)",  "Type A",
     "3x units compared to Botox - NOT interchangeable"],
    ["IncobotulinumtoxinA", "Xeomin (Merz)",    "Type A",
     "No complexing proteins - lower risk of antibody formation"],
    ["RimabotulinumtoxinB", "Myobloc",          "Type B",
     "FDA approved for sialorrhea; used when Type A resistance develops"],
]
story += make_table(
    ["Generic Name", "Brand Name", "Type", "ENT Notes"],
    prep_rows,
    col_widths=[42*mm, 30*mm, 18*mm, UW - 90*mm]
)
story += dose_box([
    "Units are NOT interchangeable between different BTX preparations.",
    "Botox 1 unit = Dysport approximately 3 units.",
    "Xeomin and Botox are approximately 1:1 equivalent.",
])

# ══════════════════════════════════════════════════════════════════════════════
# 3. MECHANISM OF ACTION
# ══════════════════════════════════════════════════════════════════════════════
story += H1("3.  MECHANISM OF ACTION")
story.append(Paragraph(
    "BTX works at the nerve ending (presynaptic terminal) and <b>blocks the "
    "release of acetylcholine (ACh)</b> - the chemical that makes muscles "
    "contract or glands secrete.", sBody))

story += H2("Step-by-Step Mechanism")

# Flowchart - mechanism
story.append(sp(4))
fc_steps = [
    ("BTX injected near target nerve terminal", True),
    ("Heavy chain of BTX binds to receptor on nerve ending\n"
     "(ganglioside + SV2/synaptotagmin proteins)", False),
    ("Toxin is taken into the nerve cell (endocytosis)", False),
    ("Light chain cleaves SNARE proteins\n"
     "Type A/C: cleaves SNAP-25  |  Type B: cleaves VAMP/synaptobrevin", True),
    ("ACh vesicles CANNOT fuse with nerve membrane", False),
    ("ACh is NOT released into the synapse", False),
    ("Result: Muscle relaxation  OR  Reduced gland secretion", True),
]
for i, (text, is_main) in enumerate(fc_steps):
    row_box = flow_box(text, is_main)
    wrapper = Table([[row_box]], colWidths=[UW])
    wrapper.setStyle(TableStyle([
        ("ALIGN", (0,0),(-1,-1), "CENTER"),
        ("TOPPADDING",(0,0),(-1,-1),0),
        ("BOTTOMPADDING",(0,0),(-1,-1),0),
    ]))
    story.append(wrapper)
    if i < len(fc_steps) - 1:
        story.append(arrow())
story.append(sp(4))

story += pearl_box([
    "BTX acts at the PRESYNAPTIC nerve terminal - it does NOT affect "
    "the muscle or gland directly.",
    "Onset of effect: 24 to 72 hours. Peak effect: 1 to 2 weeks.",
    "Duration of effect: 3 to 6 months (autonomic effects can last longer - up to 12 to 18 months for Frey syndrome).",
    "Recovery occurs because nerve terminals sprout new connections over time.",
])

# ══════════════════════════════════════════════════════════════════════════════
# 4. ENT INDICATIONS - OVERVIEW TABLE
# ══════════════════════════════════════════════════════════════════════════════
story += H1("4.  INDICATIONS OF BOTULINUM TOXIN IN ENT")
story.append(Paragraph(
    "BTX is used in two main ways in ENT:", sBody))
story.append(bullet(
    "<b>Neuromuscular blockade</b> - to relax overactive muscles "
    "(e.g., larynx, cricopharyngeus)"))
story.append(bullet(
    "<b>Autonomic secretomotor blockade</b> - to reduce overactive gland "
    "secretions or sweating (e.g., salivary glands, sweat glands of skin)"))
story.append(sp(4))

ind_rows = [
    ["Spasmodic Dysphonia",
     "Thyroarytenoid (TA) muscle for adductor type;\nPosterior cricoarytenoid (PCA) for abductor type",
     "FIRST-LINE treatment (Level A evidence)"],
    ["Essential Vocal Tremor",
     "Thyroarytenoid and/or cricothyroid muscles",
     "Level B evidence - useful in selected patients"],
    ["Cricopharyngeal Dysfunction",
     "Cricopharyngeus (CP) muscle",
     "Reduces UES pressure; treats dysphagia"],
    ["Retrograde Cricopharyngeal Dysfunction (R-CPD)",
     "Cricopharyngeus muscle",
     "Inability to belch; BTX gives 88 to 94% success"],
    ["Non-Allergic Rhinitis",
     "Submucosal injection into inferior/middle turbinate",
     "Reduces rhinorrhoea for up to 12 weeks"],
    ["Sialorrhoea (excess drooling)",
     "Parotid and/or submandibular glands",
     "FDA approved (Myobloc); strong evidence"],
    ["Frey Syndrome (gustatory sweating)",
     "Intradermal injection over preauricular skin",
     "More than 95% success; lasts 12 to 18 months"],
    ["Parotid Fistula or Sialocele",
     "Directly into parotid remnant",
     "Reduces secretion; promotes healing"],
    ["Facial Synkinesis",
     "Orbicularis oculi and other overactive facial muscles",
     "Standard of care post facial nerve recovery"],
    ["Hemifacial Spasm",
     "Affected facial muscles",
     "Highly effective; repeated every 3 to 4 months"],
    ["Laryngeal Granuloma",
     "Thyroarytenoid / vocalis muscle",
     "Reduces mechanical trauma; adjunct to PPI"],
    ["Cervical Dystonia",
     "SCM, splenius capitis, trapezius",
     "FDA approved indication"],
]
story += make_table(
    ["Indication", "Target Structure", "Notes"],
    ind_rows,
    col_widths=[42*mm, 55*mm, UW - 97*mm]
)

# ══════════════════════════════════════════════════════════════════════════════
# 5. SPASMODIC DYSPHONIA (most important ENT indication)
# ══════════════════════════════════════════════════════════════════════════════
story += H1("5.  SPASMODIC DYSPHONIA - MOST IMPORTANT ENT INDICATION")
story.append(Paragraph(
    "Spasmodic dysphonia (SD) is a <b>focal laryngeal dystonia</b> - a condition "
    "where the muscles of the voice box go into involuntary spasms during "
    "speaking. It is the most well-studied and most important indication for "
    "BTX in ENT.", sBody))
story.append(Paragraph(
    "Scott-Brown's ORL states: <i>\"Spasmodic dysphonia is a rare focal dystonia "
    "of the larynx; it is frequently misdiagnosed but is readily amenable to "
    "treatment with injections of botulinum toxin.\"</i>", sBody))

story += H2("Types of Spasmodic Dysphonia and BTX Target")
# Two-column flowchart for adductor vs abductor
story.append(sp(4))
story.append(two_col_flow(
    "ADDUCTOR SD  (80 to 85%)\nStrained, strangled, effortful voice\nBreaks on voiced sounds",
    "ABDUCTOR SD  (10 to 15%)\nBreathy, whispery voice\nBreaks on voiceless sounds"
))
story.append(sp(4))
story.append(arrow())
story.append(two_col_flow(
    "Inject BILATERAL\nThyroarytenoid (TA) muscle\n1.25 to 2.5 Units Botox each side",
    "Inject UNILATERAL ONLY\nPosterior Cricoarytenoid (PCA)\n3.75 to 7.5 Units Botox\n(bilateral = airway risk)"
))
story.append(sp(6))

story += H2("Injection Techniques")
tech_rows = [
    ["EMG-guided transcutaneous",
     "Needle through cricothyroid membrane or thyroid cartilage. EMG confirms correct muscle (TA fires on phonation).",
     "PREFERRED - gold standard"],
    ["Nasolaryngoscopy-guided",
     "Flexible laryngoscope used to visualize. Needle via thyrohyoid or cricothyroid route.",
     "Used when EMG not available"],
    ["Suspension microlaryngoscopy",
     "Under general anaesthesia. Direct injection under magnification.",
     "For difficult or failed office injections"],
]
story += make_table(
    ["Technique", "Description", "Status"],
    tech_rows,
    col_widths=[42*mm, UW - 80*mm, 38*mm]
)
story += dose_box([
    "Adductor SD dose: 1.25 to 2.5 Units Botox into each TA (bilateral).",
    "Abductor SD dose: 3.75 to 7.5 Units Botox into ONE PCA only (unilateral only - bilateral risks bilateral vocal cord paralysis).",
    "Duration of benefit: 15 to 17 weeks on average. Repeat injections every 3 to 5 months.",
    "Side effects expected: breathy voice and mild dysphagia for 1 to 4 weeks after injection - warn all patients.",
], header="Doses and Important Notes - Spasmodic Dysphonia")

# ══════════════════════════════════════════════════════════════════════════════
# 6. SALIVARY GLAND APPLICATIONS
# ══════════════════════════════════════════════════════════════════════════════
story += H1("6.  SALIVARY GLAND APPLICATIONS")

story += H2("6A.  Sialorrhoea (Excessive Drooling)")
story.append(Paragraph(
    "Sialorrhoea means excessive drooling. It often occurs in patients who have "
    "neurological problems (like cerebral palsy, Parkinson's disease, ALS) where "
    "they cannot swallow saliva properly. BTX injected into salivary glands "
    "reduces the amount of saliva produced.", sBody))
story.append(bullet(
    "<b>How it works:</b> BTX blocks the parasympathetic (cholinergic) nerve "
    "supply to salivary glands, reducing their secretion."))
story.append(bullet(
    "<b>Glands targeted:</b> Parotid glands (bilateral) and/or submandibular "
    "glands (bilateral)."))
story.append(bullet(
    "<b>Guidance:</b> Ultrasound guidance is recommended for submandibular "
    "injections to avoid injury to the marginal mandibular branch of the facial "
    "nerve (cranial nerve VII)."))
story.append(sp(4))
sial_rows = [
    ["Parotid gland (each side)",      "20 to 40 Units Botox",  "Largest gland; major contributor to stimulated saliva",    "3 to 6 months"],
    ["Submandibular gland (each side)", "10 to 20 Units Botox", "Use ultrasound guidance to avoid VII nerve injury",         "3 to 6 months"],
    ["All 4 glands (combined)",         "Higher total dose",    "Used for severe cases - maximises saliva reduction",       "3 to 6 months"],
]
story += make_table(
    ["Gland", "Dose", "Notes", "Duration"],
    sial_rows,
    col_widths=[38*mm, 30*mm, UW - 98*mm, 30*mm]
)
story += pearl_box(["RimabotulinumtoxinB (Myobloc - Type B BTX) is FDA approved specifically for chronic sialorrhoea in neurological conditions."])

story += H2("6B.  Frey Syndrome (Gustatory Sweating)")
story.append(Paragraph(
    "Frey syndrome happens after parotid gland surgery (or any parotid trauma). "
    "The nerve fibres that were meant to supply the parotid gland grow back "
    "incorrectly and end up supplying the sweat glands in the skin instead. "
    "So when the patient eats or smells food, they sweat and flush on the side "
    "of their face near the ear - this is called gustatory sweating.", sBody))

story += H3("Diagnosis")
story.append(bullet(
    "<b>Minor's starch-iodine test:</b> Apply iodine solution to the affected "
    "skin. Dust starch powder on top. Ask patient to eat something. Where "
    "sweating occurs, the starch + iodine turns <b>dark blue-black</b>. This "
    "maps out exactly which area needs BTX injection."))

story += H3("Treatment with BTX")
story.append(bullet(
    "Intradermal injections of BTX across the affected skin area."))
story.append(bullet(
    "1.5 to 2.5 Units Botox per injection point, spaced 1.5 to 2 cm apart."))
story.append(bullet("Total dose usually 30 to 50 Units per session."))
story.append(bullet(
    "Success rate: <b>more than 95%</b> - this is one of the most effective "
    "BTX applications in ENT."))
story.append(bullet("Duration of relief: <b>12 to 18 months</b> (longest among all ENT BTX applications)."))
story.append(sp(4))
story += pearl_box(["Frey syndrome BTX is the most effective and longest-lasting BTX application in ENT. Over 95% success rate with duration of 12 to 18 months."])

# ══════════════════════════════════════════════════════════════════════════════
# 7. RHINOLOGY - NON-ALLERGIC RHINITIS
# ══════════════════════════════════════════════════════════════════════════════
story += H1("7.  RHINOLOGY - NON-ALLERGIC RHINITIS")
story.append(Paragraph(
    "In non-allergic rhinitis (NAR), the inner lining of the nose produces too "
    "much watery discharge (rhinorrhoea). BTX injected into the nasal turbinates "
    "reduces this overactive secretion by blocking the parasympathetic "
    "cholinergic nerves that stimulate the nasal mucosa.", sBody))

rhin_rows = [
    ["Indication",  "Non-allergic rhinitis with predominant watery discharge (rhinorrhoea) not responding to nasal steroids or antihistamines"],
    ["Target",      "Submucosal injection into the head of the inferior and middle turbinates (both sides)"],
    ["Dose",        "20 to 30 Units Botox per side (total 40 to 60 Units)"],
    ["Onset",       "3 to 7 days"],
    ["Duration",    "8 to 12 weeks (shorter than other ENT applications)"],
    ["Limitation",  "Does NOT help nasal obstruction (blocking), sneezing, or other symptoms - only reduces watery discharge"],
]
story += make_table(["Parameter", "Detail"], rhin_rows,
                    col_widths=[35*mm, UW - 35*mm])

# ══════════════════════════════════════════════════════════════════════════════
# 8. CRICOPHARYNGEAL DYSFUNCTION / R-CPD
# ══════════════════════════════════════════════════════════════════════════════
story += H1("8.  CRICOPHARYNGEAL DYSFUNCTION AND R-CPD")
story.append(Paragraph(
    "The cricopharyngeus (CP) muscle forms the <b>upper oesophageal sphincter "
    "(UES)</b>. When it does not relax properly, it causes problems with "
    "swallowing (dysphagia), regurgitation, and aspiration. BTX injection "
    "into this muscle temporarily weakens it, allowing easier passage of food. "
    "Cummings states: <i>\"functional stenosis secondary to spasm of the "
    "cricopharyngeus can be treated with botulinum toxin injection; this can be "
    "performed endoscopically or percutaneously.\"</i>", sBody))

story += H3("Retrograde Cricopharyngeal Dysfunction (R-CPD) - New Concept")
story.append(bullet(
    "A recently described condition (Bastian and Smithson, 2019) where the "
    "UES fails to relax during <b>retrograde passage of air</b> (belching)."))
story.append(bullet(
    "Patients complain of: <b>inability to burp</b>, chronic bloating, "
    "gurgling sounds from throat, and excessive flatulence."))
story.append(bullet(
    "BTX injection (50 to 100 Units) into the CP muscle is highly effective."))
story.append(bullet("Success rate: <b>88 to 94%</b> after a single injection."))
story.append(sp(4))
story += pearl_box([
    "Ask about inability to burp in patients with unexplained chronic bloating and gurgling throat sounds - think R-CPD.",
    "R-CPD is underdiagnosed. BTX into the CP muscle has 88 to 94% success rate.",
])

# ══════════════════════════════════════════════════════════════════════════════
# 9. FACIAL NERVE APPLICATIONS
# ══════════════════════════════════════════════════════════════════════════════
story += H1("9.  FACIAL NERVE APPLICATIONS")

story += H2("9A.  Facial Synkinesis")
story.append(Paragraph(
    "After facial nerve palsy (e.g., Bell's palsy), the nerve sometimes heals "
    "incorrectly. This causes unwanted co-movements - for example, the eye "
    "closes when the patient smiles, or the corner of the mouth moves when "
    "blinking. This is called synkinesis. BTX injected into the overactive "
    "muscles helps restore facial symmetry.", sBody))
story.append(bullet(
    "Cummings: <i>\"the lowest dose, 40 units injected into the orbicularis "
    "oculi, gave the best reduction in synkinesis while avoiding ptosis.\"</i>"))
story.append(bullet(
    "Japanese guidelines 2023 (Fujiwara et al.) recommend BTX as a standard "
    "treatment for post-Bell's palsy synkinesis."))
story.append(sp(4))

syn_rows = [
    ["Eye closure synkinesis (most common)", "Orbicularis oculi", "5 to 20 Units per session", "Avoid ptosis"],
    ["Neck banding synkinesis", "Platysma", "5 to 10 Units", "Bilateral if needed"],
    ["Chin dimpling", "Mentalis", "2.5 to 5 Units", "Small doses sufficient"],
    ["Mouth movement synkinesis", "Perioral muscles", "2.5 to 5 Units", "Careful - avoid mouth droop"],
]
story += make_table(["Type", "Target Muscle", "Dose", "Notes"], syn_rows,
                    col_widths=[42*mm, 38*mm, 30*mm, UW - 110*mm])

story += H2("9B.  Hemifacial Spasm")
story.append(Paragraph(
    "Hemifacial spasm (HFS) is involuntary twitching of one side of the face, "
    "caused by a blood vessel pressing on the facial nerve at the brain stem. "
    "BTX is the standard non-surgical treatment. It does not cure the condition "
    "but effectively controls the spasms.", sBody))
story.append(bullet("BTX injected into the affected facial muscles every 12 to 16 weeks."))
story.append(bullet("Total dose per session: 20 to 50 Units."))
story.append(bullet("Curative treatment if desired: microvascular decompression (MVD) surgery."))
story.append(sp(4))

# ══════════════════════════════════════════════════════════════════════════════
# 10. MANAGEMENT FLOWCHART
# ══════════════════════════════════════════════════════════════════════════════
story += H1("10.  CLINICAL MANAGEMENT FLOWCHART")
story += H2("Flowchart: Approach to BTX in ENT Practice")

story.append(sp(4))
# Main flowchart
fc_main = [
    ("PATIENT REFERRED FOR BTX IN ENT", True),
    ("Identify the Indication\n(Voice? Saliva? Sweating? Spasm? Facial?)", False),
]
for text, main in fc_main:
    row = flow_box(text, main)
    wrap = Table([[row]], colWidths=[UW])
    wrap.setStyle(TableStyle([("ALIGN",(0,0),(-1,-1),"CENTER"),
                               ("TOPPADDING",(0,0),(-1,-1),0),
                               ("BOTTOMPADDING",(0,0),(-1,-1),0)]))
    story.append(wrap)
    story.append(arrow())

# Branch table
branch_rows = [
    ["Spasmodic Dysphonia",
     "EMG-guided TA injection\nBilateral (adductor) or unilateral PCA (abductor)\n1.25 to 2.5 U each side"],
    ["Sialorrhoea",
     "Ultrasound-guided parotid +\nsubmandibular injection\n20 to 40 U per parotid gland"],
    ["Frey Syndrome",
     "Minor's test first to map area.\nIntradermal injections 1.5 to 2.5 U per point\nTotal 30 to 50 U"],
    ["Cricopharyngeal / R-CPD",
     "Endoscopic or percutaneous\n50 to 100 U Botox into CP muscle"],
    ["Facial Synkinesis / HFS",
     "Target overactive muscles\n5 to 40 U per session"],
    ["Non-Allergic Rhinitis",
     "Submucosal turbinate injection\n20 to 30 U per side"],
]
story += make_table(
    ["Indication", "BTX Approach and Dose"],
    branch_rows,
    col_widths=[45*mm, UW - 45*mm]
)
story.append(arrow())
story.append(flow_box("Review at 2 to 4 weeks post-injection\nAssess response and side effects", False))
story.append(arrow())
story.append(two_col_flow(
    "GOOD RESPONSE:\nRepeat every 3 to 6 months\nas symptoms return",
    "POOR RESPONSE:\nAdjust dose  |  Change technique\nConsider surgical alternative"
))
story.append(sp(8))

# ══════════════════════════════════════════════════════════════════════════════
# 11. CONTRAINDICATIONS
# ══════════════════════════════════════════════════════════════════════════════
story += H1("11.  CONTRAINDICATIONS")
ci_rows = [
    ["ABSOLUTE",  "Known allergy to botulinum toxin or human albumin (excipient in Botox)"],
    ["ABSOLUTE",  "Active infection at the injection site"],
    ["ABSOLUTE",  "Myasthenia gravis, Lambert-Eaton syndrome, or ALS (motor neuron disease)\n- these patients are at risk of dangerous BTX spread"],
    ["RELATIVE",  "Pregnancy and breastfeeding (Category C - avoid unless clearly necessary)"],
    ["RELATIVE",  "Bleeding disorders or patients on anticoagulants\n(relative - compress injection site carefully)"],
    ["RELATIVE",  "Drugs that potentiate BTX effect: aminoglycoside antibiotics, calcium channel blockers, chloroquine\n- use lower doses and monitor carefully"],
]
story += make_table(
    ["Type", "Contraindication"],
    ci_rows,
    col_widths=[28*mm, UW - 28*mm]
)

# ══════════════════════════════════════════════════════════════════════════════
# 12. COMPLICATIONS
# ══════════════════════════════════════════════════════════════════════════════
story += H1("12.  COMPLICATIONS OF BTX IN ENT")
comp_rows = [
    ["Breathy voice and dysphagia",
     "After laryngeal (TA) injection",
     "Very common (25 to 50%)\nUsually lasts 1 to 4 weeks",
     "Reassure patient; liquid diet; self-resolves"],
    ["Aspiration",
     "Laryngeal / CP injections",
     "Less common; higher risk with bilateral injections",
     "Aspiration precautions; may need soft diet or NGT temporarily"],
    ["Airway compromise",
     "Bilateral PCA injection",
     "Rare but serious - both vocal cords can become paralysed",
     "Strictly AVOID bilateral PCA injection"],
    ["Ptosis (drooping eyelid)",
     "Periorbital injection for synkinesis / HFS",
     "If toxin spreads to levator palpebrae muscle",
     "Use apraclonidine eye drops; resolves spontaneously"],
    ["Dry mouth (xerostomia)",
     "Salivary gland injection",
     "Over-reduction of saliva",
     "Reduce dose at next session; artificial saliva"],
    ["Bruising at injection site",
     "Any injection",
     "Minor",
     "Apply pressure and ice"],
    ["Antibody resistance",
     "Repeated high-dose injections over years",
     "Rare; more likely with frequent injections and high doses",
     "Switch to Xeomin (no complexing proteins) or switch to Type B (Myobloc)"],
    ["Systemic BTX spread",
     "Very high doses or inadvertent intravascular injection",
     "Rare but serious",
     "Supportive care; may need hospitalisation"],
]
story += make_table(
    ["Complication", "When it Occurs", "Frequency", "Management"],
    comp_rows,
    col_widths=[38*mm, 35*mm, 38*mm, UW - 111*mm]
)
story += dose_box([
    "ALWAYS warn patients about expected temporary dysphagia and breathy voice after laryngeal BTX injection.",
    "NEVER inject bilateral PCA - this risks bilateral vocal cord paralysis and airway compromise.",
    "Myasthenia gravis = absolute contraindication to BTX.",
], header="Important Safety Points")

# ══════════════════════════════════════════════════════════════════════════════
# 13. RECONSTITUTION AND STORAGE
# ══════════════════════════════════════════════════════════════════════════════
story += H1("13.  RECONSTITUTION, DOSING AND STORAGE")
story.append(Paragraph(
    "Botox (OnabotulinumtoxinA) comes as a white powder in 50 or 100 Unit vials "
    "and must be reconstituted with <b>preserved normal saline</b> before use.", sBody))
story.append(bullet(
    "<b>Standard reconstitution:</b> Add 2 ml saline to 100 Unit vial = "
    "<b>5 Units per 0.1 ml</b>. (Add 4 ml = 2.5 Units per 0.1 ml for dilute "
    "injections like facial synkinesis)"))
story.append(bullet(
    "<b>Storage:</b> Store at 2 to 8 degrees Celsius in the refrigerator. "
    "Use within 24 hours of reconstitution."))
story.append(bullet(
    "<b>DO NOT shake vigorously</b> - roll the vial gently. Vigorous shaking "
    "can denature the protein."))
story.append(bullet(
    "<b>Xeomin</b> can be stored at room temperature before reconstitution."))
story.append(sp(4))
story += dose_box([
    "Botox 100 Unit vial + 2 ml saline = 5 Units / 0.1 ml.",
    "Botox 100 Unit vial + 4 ml saline = 2.5 Units / 0.1 ml.",
    "NEVER use vigorous shaking - always roll gently.",
    "Use within 24 hours of reconstitution.",
    "Store at 2 to 8 degrees C before and after reconstitution.",
], header="Reconstitution Quick Reference")

# ══════════════════════════════════════════════════════════════════════════════
# 14. RECENT ADVANCES
# ══════════════════════════════════════════════════════════════════════════════
story += H1("14.  RECENT ADVANCES")
adv_rows = [
    ["R-CPD (Retrograde CPD)",
     "Described by Bastian and Smithson (2019). BTX CP injection gives 88 to 94% success for inability to belch. Laryngoscope 2025: Behavioral Eructation Retraining Protocol (BERP) as adjunct to BTX."],
    ["Sialorrhoea - Cochrane Review 2022",
     "James et al. confirmed BTX is effective for sialorrhoea in MND/ALS. Myobloc (Type B) FDA approved for chronic sialorrhoea (PMID 35593746)."],
    ["Spasmodic Dysphonia updates",
     "Hyodo et al. Toxins 2022: Long-term repeated BTX injections for SD are safe and maintain efficacy. Jaworek and Sataloff 2025: BTX remains first-line; surgical options reserved for BTX failures."],
    ["Daxibotulinumtoxin-A (Daxxify)",
     "FDA approved in 2022 for cosmetic use. Contains novel peptide excipient (no albumin). Longer duration (6 to 9 months). Trials in progress for laryngeal applications."],
    ["Bell's Palsy Guidelines 2023",
     "Japanese guidelines (Fujiwara et al. 2024): BTX for facial synkinesis post Bell's palsy is a standard recommendation."],
]
story += make_table(
    ["Advance", "Details"],
    adv_rows,
    col_widths=[45*mm, UW - 45*mm]
)

# ══════════════════════════════════════════════════════════════════════════════
# 15. KEY POINTS SUMMARY
# ══════════════════════════════════════════════════════════════════════════════
story += H1("15.  KEY POINTS SUMMARY")
story += pearl_box([
    "BTX is produced by Clostridium botulinum. Types A and B are used clinically. Botox (Type A) is the most widely used in ENT.",
    "Mechanism: BTX cleaves SNARE proteins (SNAP-25 for Type A) at presynaptic nerve terminals, blocking acetylcholine release.",
    "Onset: 24 to 72 hours. Peak: 1 to 2 weeks. Duration: 3 to 6 months (autonomic effects can last 12 to 18 months).",
    "Most important ENT indication: Spasmodic dysphonia (adductor type) - bilateral TA injection - FIRST-LINE treatment with Level A evidence.",
    "For adductor SD: BILATERAL TA injection (1.25 to 2.5 U each side). For abductor SD: UNILATERAL PCA only (bilateral PCA = airway risk).",
    "Frey syndrome: over 95% success with intradermal BTX. Duration 12 to 18 months - the LONGEST lasting ENT BTX application.",
    "Sialorrhoea: inject parotid (20 to 40 U) and submandibular (10 to 20 U) glands. Use ultrasound for submandibular to protect nerve VII.",
    "Non-allergic rhinitis: BTX turbinate injection reduces rhinorrhoea for only 8 to 12 weeks - does NOT help obstruction or sneezing.",
    "R-CPD (inability to belch): BTX into cricopharyngeus muscle - 88 to 94% success rate.",
    "Absolute contraindications: myasthenia gravis, Lambert-Eaton syndrome, ALS, allergy to BTX.",
    "Units are NOT interchangeable between BTX preparations (Botox, Dysport, Xeomin, Myobloc).",
    "Common side effect after laryngeal BTX: temporary breathy voice and dysphagia for 1 to 4 weeks - expected and self-limiting.",
], header="KEY POINTS FOR EXAM")

# ── REFERENCES ────────────────────────────────────────────────────────────────
story += H1("REFERENCES")
refs = [
    "Cummings Otolaryngology - Head and Neck Surgery, 7th Edition. Chapter 39 (Rhinitis), Chapter 45 (Salivary Glands / Frey Syndrome), Chapter 22 (Cricopharyngeal), Chapter 57 (Neurolaryngology - Spasmodic Dysphonia), Chapter 39 (Facial Nerve).",
    "Scott-Brown's Otorhinolaryngology Head and Neck Surgery, 8th Edition. Chapter 9 (Laryngology), Chapter 10 (Spasmodic Dysphonia - BTX).",
    "Blitzer A, Brin MF. Laryngeal dystonia: treatment with botulinum toxin. Ann Otol Rhinol Laryngol. 1991.",
    "James E et al. Treatment for sialorrhoea in MND/ALS. Cochrane Database Syst Rev. 2022 May. PMID 35593746.",
    "Hyodo M et al. Botulinum Toxin Therapy for Spasmodic Dysphonia. Toxins (Basel). 2022. PMID 35878189.",
    "Fujiwara T et al. Japanese Clinical Practice Guidelines for Bell's Palsy - 2023 update. Auris Nasus Larynx. 2024. PMID 39079445.",
    "Jaworek AJ, Sataloff RT. Spasmodic Dysphonia. World J Otorhinolaryngol Head Neck Surg. 2025. PMID 41477134.",
    "Keltz A et al. BERP Protocol for R-CPD. Laryngoscope. 2025. PMID 40662408.",
]
for i, r in enumerate(refs, 1):
    story.append(Paragraph(f"[{i}]  {r}", sRef))
    story.append(sp(2))

# ── PAGE NUMBERS ──────────────────────────────────────────────────────────────
def add_footer(canvas, doc):
    canvas.saveState()
    canvas.setFont(F, 8)
    canvas.setFillColor(C_FOOT)
    pn = canvas.getPageNumber()
    canvas.drawString(ML, 11*mm,
        "Botulinum Toxin in ENT  |  KNRUHS MS ENT Exam  |  2026")
    canvas.drawRightString(W - MR, 11*mm, f"Page {pn}")
    canvas.restoreState()

doc.build(story, onFirstPage=add_footer, onLaterPages=add_footer)
print("PDF generated successfully.")

#!/usr/bin/env python3
"""
Botulinum Toxin in ENT - Quick Revision Cheat Sheet
2-3 pages | KNRUHS MS ENT | Warm Coral/Navy/Lime palette (new theme)
"""

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import ParagraphStyle
from reportlab.lib.units import mm
from reportlab.lib.enums import TA_LEFT, TA_CENTER
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether
)
from reportlab.pdfbase import pdfmetrics
from reportlab.pdfbase.ttfonts import TTFont
import os

# ── Fonts ─────────────────────────────────────────────────────────────────────
FONT_PATHS = [
    "/usr/share/fonts/truetype/liberation",
    "/usr/share/fonts/liberation",
    "/usr/share/fonts",
]
def find_font(fn):
    for d in FONT_PATHS:
        p = os.path.join(d, fn)
        if os.path.exists(p): return p
    return None

reg  = find_font("LiberationSans-Regular.ttf")
bold = find_font("LiberationSans-Bold.ttf")
it   = find_font("LiberationSans-Italic.ttf")
bi   = find_font("LiberationSans-BoldItalic.ttf")

if all([reg, bold, it, bi]):
    pdfmetrics.registerFont(TTFont("LS",   reg))
    pdfmetrics.registerFont(TTFont("LSB",  bold))
    pdfmetrics.registerFont(TTFont("LSI",  it))
    pdfmetrics.registerFont(TTFont("LSBI", bi))
    from reportlab.pdfbase.pdfmetrics import registerFontFamily
    registerFontFamily("LS", normal="LS", bold="LSB", italic="LSI", boldItalic="LSBI")
    F, FB, FI = "LS", "LSB", "LSI"
else:
    F, FB, FI = "Helvetica", "Helvetica-Bold", "Helvetica-Oblique"

# ── NEW PALETTE: Warm Coral / Deep Navy / Lime accent ─────────────────────────
# Deliberately different from the previous teal/gold PDF
C_NAV       = colors.HexColor("#1A237E")   # deep navy  (heading bar)
C_NAV_FG    = colors.white
C_COR       = colors.HexColor("#BF360C")   # deep coral/red (H2 accent)
C_COR_LT    = colors.HexColor("#FBE9E7")   # very light coral bg
C_LIME      = colors.HexColor("#33691E")   # deep lime/green (H3)
C_LIME_LT   = colors.HexColor("#F1F8E9")   # light lime bg
C_AMBER     = colors.HexColor("#E65100")   # amber for dose/caution
C_AMBER_LT  = colors.HexColor("#FFF3E0")   # light amber bg
C_PEARL_L   = colors.HexColor("#0D47A1")   # navy left border for pearl
C_PEARL_BG  = colors.HexColor("#E8EAF6")   # indigo tint bg for pearl
C_BODY      = colors.HexColor("#000000")   # pure black
C_FOOT      = colors.HexColor("#555555")
C_TBL_H     = colors.HexColor("#1A237E")   # navy table header
C_TBL_HT    = colors.white
C_TBL_ALT   = colors.HexColor("#EDE7F6")   # very light lavender alt row
C_TBL_GRID  = colors.HexColor("#B0BEC5")

W, H = A4
# TIGHT margins for cheat-sheet density
ML = 13*mm; MR = 13*mm; MT = 13*mm; MB = 13*mm
UW = W - ML - MR  # ~184 mm

# ── Style helpers ─────────────────────────────────────────────────────────────
def S(name, **kw):
    d = dict(fontName=F, fontSize=9, leading=12.5, textColor=C_BODY,
             spaceAfter=0, spaceBefore=0)
    d.update(kw)
    return ParagraphStyle(name, **d)

sBody  = S("sBody",  fontSize=9,  leading=13, spaceAfter=2)
sBul   = S("sBul",   fontSize=8.8,leading=12.5, leftIndent=10, spaceAfter=1)
sSub   = S("sSub",   fontSize=8.5,leading=12,  leftIndent=20, spaceAfter=1)
sTbl   = S("sTbl",   fontSize=8.5,leading=12,  spaceAfter=0)
sTblH  = S("sTblH",  fontName=FB, fontSize=8.5,leading=12, textColor=C_TBL_HT)
sFoot  = S("sFoot",  fontName=FI, fontSize=7.5,leading=10, textColor=C_FOOT)

# Heading text styles
sH1t   = S("sH1t",   fontName=FB, fontSize=10.5,leading=14, textColor=C_NAV_FG)
sH2t   = S("sH2t",   fontName=FB, fontSize=9.5, leading=13, textColor=C_COR)
sH3t   = S("sH3t",   fontName=FB, fontSize=9,   leading=12, textColor=C_LIME)

# Pearl / dose box text
sPearl = S("sPearl", fontSize=8.8,leading=12.5, textColor=colors.HexColor("#0D1B5E"))
sDose  = S("sDose",  fontSize=8.8,leading=12.5, textColor=colors.HexColor("#000000"))

# Title
sTM    = S("sTM",  fontName=FB,fontSize=16,leading=20,textColor=C_NAV_FG,
           alignment=TA_CENTER)
sTS    = S("sTS",  fontSize=8.5,leading=12, textColor=colors.HexColor("#C5CAE9"),
           alignment=TA_CENTER)

def sp(n=3): return Spacer(1, n)

# ── Builders ──────────────────────────────────────────────────────────────────
def H1(text):
    t = Table([[Paragraph(text, sH1t)]], colWidths=[UW])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0),(-1,-1), C_NAV),
        ("TOPPADDING",    (0,0),(-1,-1), 5),
        ("BOTTOMPADDING", (0,0),(-1,-1), 5),
        ("LEFTPADDING",   (0,0),(-1,-1), 8),
    ]))
    return [sp(6), t, sp(3)]

def H2(text):
    t = Table([[Paragraph(text, sH2t)]], colWidths=[UW])
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0),(-1,-1), C_COR_LT),
        ("TOPPADDING",    (0,0),(-1,-1), 3),
        ("BOTTOMPADDING", (0,0),(-1,-1), 3),
        ("LEFTPADDING",   (0,0),(-1,-1), 8),
        ("LINEBELOW",     (0,0),(-1,-1), 1.2, C_COR),
    ]))
    return [sp(4), t, sp(2)]

def H3(text):
    return [Paragraph(f"<b><font color='#{C_LIME.hexval()[2:]}'>&#9654; {text}</font></b>", sH3t), sp(1)]

def bul(text, sub=False):
    p = "&#8211;" if sub else "&#8226;"
    s = sSub if sub else sBul
    return Paragraph(f"{p}&nbsp;{text}", s)

def pearl(lines, header="EXAM PEARL"):
    body = f"<b>{header}</b><br/>" + "<br/>".join(f"&#9733; {l}" for l in lines)
    t = Table([[Paragraph(body, sPearl)]], colWidths=[UW])
    t.setStyle(TableStyle([
        ("BACKGROUND",  (0,0),(-1,-1), C_PEARL_BG),
        ("LINEBEFORE",  (0,0),(0,-1),  4, C_PEARL_L),
        ("TOPPADDING",  (0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1),5),
        ("LEFTPADDING", (0,0),(-1,-1), 10),
    ]))
    return [sp(3), t, sp(3)]

def dose(lines, header="DOSE / CAUTION"):
    body = f"<b>{header}</b><br/>" + "<br/>".join(f"&#9654; {l}" for l in lines)
    t = Table([[Paragraph(body, sDose)]], colWidths=[UW])
    t.setStyle(TableStyle([
        ("BACKGROUND",  (0,0),(-1,-1), C_AMBER_LT),
        ("LINEBEFORE",  (0,0),(0,-1),  4, C_AMBER),
        ("TOPPADDING",  (0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1),5),
        ("LEFTPADDING", (0,0),(-1,-1), 10),
    ]))
    return [sp(3), t, sp(3)]

def tbl(headers, rows, cw):
    hrow = [Paragraph(h, sTblH) for h in headers]
    data = [hrow] + [[Paragraph(str(c), sTbl) for c in r] for r in rows]
    sty  = [
        ("BACKGROUND",    (0,0),(-1,0),  C_TBL_H),
        ("GRID",          (0,0),(-1,-1), 0.4, C_TBL_GRID),
        ("TOPPADDING",    (0,0),(-1,-1), 4),
        ("BOTTOMPADDING", (0,0),(-1,-1), 4),
        ("LEFTPADDING",   (0,0),(-1,-1), 5),
        ("VALIGN",        (0,0),(-1,-1), "TOP"),
    ]
    for i in range(1, len(data)):
        if i % 2 == 0:
            sty.append(("BACKGROUND",(0,i),(-1,i), C_TBL_ALT))
    t = Table(data, colWidths=cw, repeatRows=1)
    t.setStyle(TableStyle(sty))
    return [sp(3), t, sp(3)]

# two-column layout helper
def two_col(left_content, right_content, lw_frac=0.5):
    lw = UW * lw_frac - 2*mm
    rw = UW * (1 - lw_frac) - 2*mm
    # build inner tables from lists
    def inner(items, w):
        data = [[item] for item in items]
        t = Table(data, colWidths=[w])
        t.setStyle(TableStyle([
            ("TOPPADDING",    (0,0),(-1,-1), 0),
            ("BOTTOMPADDING", (0,0),(-1,-1), 0),
            ("LEFTPADDING",   (0,0),(-1,-1), 0),
            ("RIGHTPADDING",  (0,0),(-1,-1), 0),
        ]))
        return t
    lt = inner(left_content,  lw)
    rt = inner(right_content, rw)
    outer = Table([[lt, Spacer(4*mm, 1), rt]],
                  colWidths=[lw, 4*mm, rw])
    outer.setStyle(TableStyle([
        ("VALIGN",(0,0),(-1,-1),"TOP"),
        ("TOPPADDING",(0,0),(-1,-1),0),
        ("BOTTOMPADDING",(0,0),(-1,-1),0),
        ("LEFTPADDING",(0,0),(-1,-1),0),
        ("RIGHTPADDING",(0,0),(-1,-1),0),
    ]))
    return [outer, sp(3)]

# ══════════════════════════════════════════════════════════════════════════════
#  DOCUMENT
# ══════════════════════════════════════════════════════════════════════════════
doc = SimpleDocTemplate(
    "/home/daytona/workspace/ent-botox/Botox_CheatSheet.pdf",
    pagesize=A4,
    leftMargin=ML, rightMargin=MR, topMargin=MT, bottomMargin=MB,
    title="Botulinum Toxin in ENT - Quick Revision Cheat Sheet",
)

story = []

# ── TITLE ─────────────────────────────────────────────────────────────────────
title_tbl = Table([
    [Paragraph("BOTULINUM TOXIN IN ENT", sTM)],
    [Paragraph("Quick Revision Cheat Sheet  |  KNRUHS MS ENT  |  10-Mark Exam", sTS)],
], colWidths=[UW])
title_tbl.setStyle(TableStyle([
    ("BACKGROUND",    (0,0),(-1,-1), C_NAV),
    ("TOPPADDING",    (0,0),(-1,-1), 7),
    ("BOTTOMPADDING", (0,0),(-1,-1), 7),
    ("ALIGN",         (0,0),(-1,-1), "CENTER"),
]))
story += [title_tbl, sp(5)]

# ══════════════════════════════════════════════════════════════════════════════
# ROW 1:  Basics + Mechanism  (two columns)
# ══════════════════════════════════════════════════════════════════════════════
left_basics = (
    H1("BASICS") +
    H2("Source and Serotypes") +
    [bul("Produced by <b>Clostridium botulinum</b>"),
     bul("7 serotypes (A-G); <b>only A and B</b> used clinically"),
     bul("Type A cleaves <b>SNAP-25</b>"),
     bul("Type B cleaves <b>VAMP / synaptobrevin</b>"),
     sp(3)] +
    H2("Preparations") +
    [bul("<b>Botox</b> = OnabotulinumtoxinA (Type A)"),
     bul("<b>Dysport</b> = AbobotulinumtoxinA (3x units vs Botox)"),
     bul("<b>Xeomin</b> = IncobotulinumtoxinA (1:1 with Botox; no complexing protein)"),
     bul("<b>Myobloc</b> = RimabotulinumtoxinB (Type B; FDA approved sialorrhoea)"),
     sp(2)]
)

right_moa = (
    H1("MECHANISM") +
    H2("Step by Step") +
    [bul("BTX binds to <b>presynaptic</b> nerve terminal receptor (SV2 / synaptotagmin)"),
     bul("Taken into cell by <b>endocytosis</b>"),
     bul("Light chain <b>cleaves SNARE proteins</b>"),
     bul("ACh vesicles CANNOT fuse with membrane"),
     bul("<b>Acetylcholine NOT released</b> into synapse"),
     bul("Result: <b>muscle relaxation</b> OR <b>reduced gland secretion</b>"),
     sp(2)] +
    H2("Timing") +
    [bul("Onset: <b>24 to 72 hours</b>"),
     bul("Peak effect: <b>1 to 2 weeks</b>"),
     bul("Duration: <b>3 to 6 months</b> (autonomic up to <b>18 months</b>)"),
     bul("Recovery: nerve terminal sprouting"),
     sp(2)]
)
story += two_col(left_basics, right_moa, lw_frac=0.48)

# ══════════════════════════════════════════════════════════════════════════════
# INDICATIONS OVERVIEW TABLE - full width, dense
# ══════════════════════════════════════════════════════════════════════════════
story += H1("ENT INDICATIONS AT A GLANCE")
ind_rows = [
    ["Adductor Spasmodic Dysphonia",    "Bilateral TA",       "1.25-2.5 U Botox each side",  "FIRST-LINE | Level A"],
    ["Abductor Spasmodic Dysphonia",    "Unilateral PCA only","3.75-7.5 U Botox one side",   "Bilateral PCA = AIRWAY RISK"],
    ["Essential Vocal Tremor",          "TA +/- CT",          "0.5-1.0 U each side",         "Level B"],
    ["Cricopharyngeal Dysfunction",     "CP muscle",          "10-30 U Botox total",         "Endo or percutaneous"],
    ["R-CPD (inability to belch)",      "CP muscle",          "50-100 U Botox",              "88-94% success"],
    ["Sialorrhoea - Parotid",           "Bilateral parotid",  "20-40 U Botox each",          "Stimulated saliva"],
    ["Sialorrhoea - Submandibular",     "Bilateral SMG",      "10-20 U Botox each",          "US guidance; protect VII"],
    ["Frey Syndrome",                   "Intradermal preauricular", "1.5-2.5 U/point; total 30-50 U", ">95% success; 12-18 months"],
    ["Non-Allergic Rhinitis",           "Turbinate submucosal","20-30 U each side",          "Only helps rhinorrhoea; 8-12 wk"],
    ["Facial Synkinesis",               "Orbicularis +others","5-40 U per session",          "Standard of care post-palsy"],
    ["Hemifacial Spasm",                "Affected facial mm", "20-50 U per session",         "Repeat every 12-16 wk"],
    ["Parotid Fistula / Sialocele",     "Parotid remnant",    "25-50 U",                     "Adjunct; promotes healing"],
]
story += tbl(
    ["Indication", "Target", "Dose (Botox)", "Key Note"],
    ind_rows,
    cw=[44*mm, 34*mm, 38*mm, UW-116*mm]
)

# ══════════════════════════════════════════════════════════════════════════════
# ROW 2: Spasmodic Dysphonia detail + Frey detail  (two columns)
# ══════════════════════════════════════════════════════════════════════════════
left_sd = (
    H1("SPASMODIC DYSPHONIA") +
    H2("Adductor SD (80-85%)") +
    [bul("Strained, strangled, effortful voice"),
     bul("Breaks on <b>voiced</b> sounds (b, d, g, vowels)"),
     bul("Inject: <b>bilateral TA</b>"),
     bul("Dose: <b>1.25-2.5 U Botox each side</b>"),
     bul("Technique: <b>EMG-guided transcutaneous</b> (gold standard)"),
     sp(2)] +
    H2("Abductor SD (10-15%)") +
    [bul("Breathy, whispery voice"),
     bul("Breaks on <b>voiceless</b> sounds (s, f, h)"),
     bul("Inject: <b>UNILATERAL PCA only</b>"),
     bul("Dose: <b>3.75-7.5 U Botox one side</b>"),
     bul("<b>NEVER bilateral PCA</b> - bilateral VC paralysis risk"),
     sp(2)] +
    H2("Side Effects (warn patient)") +
    [bul("Breathy voice: <b>1-4 weeks</b> (expected)"),
     bul("Dysphagia: <b>1-4 weeks</b> (expected)"),
     bul("Repeat: every <b>15-17 weeks</b> (average benefit)"),
     sp(2)]
)

right_frey = (
    H1("FREY SYNDROME") +
    H2("Pathophysiology") +
    [bul("Post-parotid surgery / trauma"),
     bul("Parasympathetic fibres regenerate <b>aberrantly</b> into sympathetic pathways of skin"),
     bul("Eating stimulates sweating + flushing over preauricular skin"),
     sp(2)] +
    H2("Diagnosis - Minor's Test") +
    [bul("<b>Step 1:</b> Apply iodine solution to affected skin"),
     bul("<b>Step 2:</b> Dust starch powder over it"),
     bul("<b>Step 3:</b> Give gustatory stimulus (lemon, food)"),
     bul("<b>Step 4:</b> Sweating areas turn <b>dark blue-black</b>"),
     bul("This maps the exact area to inject"),
     sp(2)] +
    H2("BTX Treatment") +
    [bul("Intradermal injections <b>1.5-2.5 U per point</b>"),
     bul("Points spaced <b>1.5-2 cm apart</b>"),
     bul("Total: <b>30-50 U</b>"),
     bul("Success: <b>&gt;95%</b>"),
     bul("Duration: <b>12-18 months</b> (LONGEST of all ENT BTX)"),
     sp(2)]
)
story += two_col(left_sd, right_frey, lw_frac=0.5)

# ══════════════════════════════════════════════════════════════════════════════
# ROW 3: Contraindications + Complications  (two columns)
# ══════════════════════════════════════════════════════════════════════════════
left_ci = (
    H1("CONTRAINDICATIONS") +
    H2("Absolute") +
    [bul("Allergy to BTX or human albumin"),
     bul("Infection at injection site"),
     bul("<b>Myasthenia gravis</b>"),
     bul("<b>Lambert-Eaton syndrome</b>"),
     bul("<b>ALS / motor neuron disease</b>"),
     sp(2)] +
    H2("Relative") +
    [bul("Pregnancy (Category C)"),
     bul("Anticoagulants (compress site)"),
     bul("Aminoglycosides - potentiate BTX"),
     bul("Calcium channel blockers - potentiate BTX"),
     bul("Chloroquine - potentiate BTX"),
     sp(2)]
)

right_comp = (
    H1("COMPLICATIONS") +
    H2("Laryngeal BTX") +
    [bul("Breathy voice (25-50%) - self-limiting 1-4 wk"),
     bul("Dysphagia (25-50%) - self-limiting 1-4 wk"),
     bul("Aspiration - rare; precautions"),
     bul("Airway compromise (bilateral PCA) - AVOID"),
     sp(2)] +
    H2("Salivary / Facial BTX") +
    [bul("Ptosis - spreads to levator; apraclonidine drops"),
     bul("Dry mouth - reduce dose next session"),
     bul("Bruising - pressure and ice"),
     bul("Antibody resistance - switch to Xeomin or Type B"),
     bul("Systemic spread - rare; high doses; supportive Rx"),
     sp(2)]
)
story += two_col(left_ci, right_comp, lw_frac=0.48)

# ══════════════════════════════════════════════════════════════════════════════
# DOSE QUICK REFERENCE BOXES  (side by side)
# ══════════════════════════════════════════════════════════════════════════════
story += H1("RECONSTITUTION AND DOSE QUICK REFERENCE")

recon_rows = [
    ["Botox 100 U vial + 2 ml saline", "5 U per 0.1 ml", "Standard laryngeal / salivary"],
    ["Botox 100 U vial + 4 ml saline", "2.5 U per 0.1 ml", "Dilute (facial / synkinesis)"],
    ["Store",                          "2-8 deg C",        "Use within 24 hours"],
    ["DO NOT shake vigorously",        "Roll gently",      "Vigorous shaking denatures protein"],
]
story += tbl(
    ["Reconstitution", "Concentration", "Use"],
    recon_rows,
    cw=[55*mm, 35*mm, UW-90*mm]
)
story += dose([
    "Units NOT interchangeable: Botox 1 U = Dysport ~3 U = Xeomin ~1 U (Myobloc units entirely different).",
    "Bilateral PCA injection = ABSOLUTE contraindication (bilateral vocal cord paralysis, airway risk).",
    "MG, LEMS, ALS = absolute contraindications.",
    "Always warn patients of expected breathy voice + dysphagia for 1-4 weeks after laryngeal BTX.",
], header="MUST-KNOW SAFETY POINTS")

# ══════════════════════════════════════════════════════════════════════════════
# EXAM PEARL BOX - full width, high-yield points
# ══════════════════════════════════════════════════════════════════════════════
story += pearl([
    "BTX mechanism: cleaves SNARE proteins (SNAP-25 for Type A) -> blocks ACh release -> chemodenervation.",
    "Most important ENT indication: Adductor spasmodic dysphonia - bilateral TA injection - Level A evidence.",
    "Frey syndrome: >95% success; 12-18 months duration - LONGEST lasting ENT BTX application. Diagnosed by Minor's starch-iodine test.",
    "R-CPD: inability to belch + gurgling + bloating - inject CP muscle - 88-94% success.",
    "Sialorrhoea: parotid = stimulated saliva (20-40 U each). Submandibular = resting saliva (10-20 U each). US guidance for SMG.",
    "Non-allergic rhinitis BTX lasts only 8-12 weeks and does NOT help nasal obstruction - only rhinorrhoea.",
    "Abductor SD: UNILATERAL PCA only - bilateral PCA = bilateral vocal cord paralysis = airway emergency.",
    "Xeomin has no complexing proteins - use when antibody resistance develops to Botox or Dysport.",
    "Myobloc (Type B) - FDA approved for chronic sialorrhoea; use when Type A resistance develops.",
], header="HIGH-YIELD EXAM PEARLS - BOTULINUM TOXIN IN ENT")

# ══════════════════════════════════════════════════════════════════════════════
# QUICK VIVA Q and A - two columns
# ══════════════════════════════════════════════════════════════════════════════
story += H1("QUICK VIVA Q and A")

vivaL = (
    H2("Q1: MOA of BTX?") +
    [Paragraph("Cleaves SNARE proteins at presynaptic terminal (SNAP-25 for Type A; VAMP for Type B). Blocks ACh release. No effect on postsynaptic receptor.", sBody), sp(3)] +
    H2("Q2: Adductor vs Abductor SD?") +
    [Paragraph("<b>Adductor:</b> strained voice, voiced sound breaks, bilateral TA injection.<br/><b>Abductor:</b> breathy voice, voiceless sound breaks, UNILATERAL PCA injection.", sBody), sp(3)] +
    H2("Q3: Best ENT BTX application by success rate?") +
    [Paragraph("Frey syndrome - >95% success and 12-18 months duration (longest of all ENT BTX applications).", sBody), sp(3)]
)

vivaR = (
    H2("Q4: How to diagnose Frey syndrome?") +
    [Paragraph("Minor's starch-iodine test: iodine on skin + starch powder + gustatory stimulus = sweating areas turn dark blue-black.", sBody), sp(3)] +
    H2("Q5: Absolute CIs to BTX?") +
    [Paragraph("Myasthenia gravis, Lambert-Eaton syndrome, ALS, allergy to BTX or albumin, infection at injection site.", sBody), sp(3)] +
    H2("Q6: Units interchangeable?") +
    [Paragraph("<b>NO.</b> Botox : Dysport = 1:3. Xeomin : Botox = 1:1. Myobloc units entirely different scale.", sBody), sp(3)]
)

story += two_col(vivaL, vivaR, lw_frac=0.5)

# ── FOOTER function ───────────────────────────────────────────────────────────
def footer(canvas, doc):
    canvas.saveState()
    canvas.setFont(F, 7.5)
    canvas.setFillColor(C_FOOT)
    pn = canvas.getPageNumber()
    canvas.drawString(ML, 8*mm,
        "Botulinum Toxin in ENT - Quick Revision Cheat Sheet  |  KNRUHS MS ENT  |  Cummings & Scott-Brown")
    canvas.drawRightString(W - MR, 8*mm, f"Page {pn}")
    canvas.restoreState()

doc.build(story, onFirstPage=footer, onLaterPages=footer)
print("Cheat sheet generated successfully.")

#!/usr/bin/env python3
"""
Anterior Skull Base - Transsphenoidal Approaches
10-Mark Exam Answer | KNRUHS MS ENT
Palette: Forest Green / Burgundy / Gold  (new theme, different from teal and navy)
Sources: Cummings Otolaryngology 7e, KJ Lee Essential Otolaryngology, Scott-Brown 8e,
         PubMed systematic reviews 2021-2025
"""

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import ParagraphStyle
from reportlab.lib.units import mm
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether, PageBreak
)
from reportlab.pdfbase import pdfmetrics
from reportlab.pdfbase.ttfonts import TTFont
import os

# ── Fonts ─────────────────────────────────────────────────────────────────────
FDIRS = ["/usr/share/fonts/truetype/liberation",
         "/usr/share/fonts/liberation", "/usr/share/fonts"]
def ff(n):
    for d in FDIRS:
        p = os.path.join(d, n)
        if os.path.exists(p): return p
    return None

r = ff("LiberationSans-Regular.ttf"); b = ff("LiberationSans-Bold.ttf")
i = ff("LiberationSans-Italic.ttf"); bi= ff("LiberationSans-BoldItalic.ttf")
if all([r,b,i,bi]):
    for nm,fp in [("LS",r),("LSB",b),("LSI",i),("LSBI",bi)]:
        pdfmetrics.registerFont(TTFont(nm,fp))
    from reportlab.pdfbase.pdfmetrics import registerFontFamily
    registerFontFamily("LS",normal="LS",bold="LSB",italic="LSI",boldItalic="LSBI")
    F,FB,FI="LS","LSB","LSI"
else:
    F,FB,FI="Helvetica","Helvetica-Bold","Helvetica-Oblique"

# ── PALETTE: Forest Green / Burgundy / Gold ───────────────────────────────────
C_H1BG   = colors.HexColor("#1B4332")   # deep forest green
C_H1FG   = colors.white
C_H2BG   = colors.HexColor("#EAF4EE")   # very light green
C_H2FG   = colors.HexColor("#1B4332")   # dark green text
C_H3FG   = colors.HexColor("#7B1C2E")   # burgundy
C_BODY   = colors.HexColor("#000000")   # pure black
C_PEARL_BG = colors.HexColor("#FFF9E6")
C_PEARL_L  = colors.HexColor("#B8860B")  # dark goldenrod border
C_PEARL_T  = colors.HexColor("#3B2800")  # very dark brown text
C_DOSE_BG  = colors.HexColor("#F9EBEE")
C_DOSE_L   = colors.HexColor("#7B1C2E")  # burgundy border
C_DOSE_T   = colors.HexColor("#000000")
C_TH     = colors.HexColor("#1B4332")
C_THT    = colors.white
C_TALT   = colors.HexColor("#EAF4EE")
C_TGRID  = colors.HexColor("#95C4A3")
C_FOOT   = colors.HexColor("#555555")

W,H = A4
ML=15*mm; MR=15*mm; MT=15*mm; MB=15*mm
UW = W-ML-MR   # ~180 mm

def S(nm,**kw):
    d=dict(fontName=F,fontSize=10.5,leading=15.5,textColor=C_BODY,
           spaceAfter=0,spaceBefore=0)
    d.update(kw); return ParagraphStyle(nm,**d)

sBody  = S("sBody", alignment=TA_JUSTIFY, spaceAfter=3)
sBul   = S("sBul",  leftIndent=12, spaceAfter=2)
sSub   = S("sSub",  leftIndent=24, fontSize=10, leading=14, spaceAfter=2)
sRef   = S("sRef",  fontName=FI, fontSize=8, leading=11, textColor=C_FOOT, spaceAfter=1)
sTbl   = S("sTbl",  fontSize=9.5, leading=13, spaceAfter=0)
sTblH  = S("sTblH", fontName=FB, fontSize=9.5, leading=13, textColor=C_THT)
sPearl = S("sPearl",fontSize=9.5, leading=13.5, textColor=C_PEARL_T)
sDose  = S("sDose", fontSize=9.5, leading=13.5, textColor=C_DOSE_T)
sH1t   = S("sH1t",  fontName=FB, fontSize=11, leading=15, textColor=C_H1FG)
sH2t   = S("sH2t",  fontName=FB, fontSize=10.5, leading=14, textColor=C_H2FG)
sH3t   = S("sH3t",  fontName=FB, fontSize=10.5, leading=14, textColor=C_H3FG)
sTM    = S("sTM",   fontName=FB, fontSize=16, leading=21, textColor=C_H1FG, alignment=TA_CENTER)
sTS    = S("sTS",   fontSize=9.5, leading=13, textColor=colors.HexColor("#B7D9C2"), alignment=TA_CENTER)

def sp(n=5): return Spacer(1,n)
def hr(): return HRFlowable(width="100%",thickness=0.6,color=C_H1BG,spaceBefore=3,spaceAfter=3)

def H1(t):
    tbl=Table([[Paragraph(t,sH1t)]],colWidths=[UW])
    tbl.setStyle(TableStyle([("BACKGROUND",(0,0),(-1,-1),C_H1BG),
        ("TOPPADDING",(0,0),(-1,-1),5),("BOTTOMPADDING",(0,0),(-1,-1),5),
        ("LEFTPADDING",(0,0),(-1,-1),9)]))
    return [sp(7),tbl,sp(4)]

def H2(t):
    tbl=Table([[Paragraph(t,sH2t)]],colWidths=[UW])
    tbl.setStyle(TableStyle([("BACKGROUND",(0,0),(-1,-1),C_H2BG),
        ("TOPPADDING",(0,0),(-1,-1),4),("BOTTOMPADDING",(0,0),(-1,-1),4),
        ("LEFTPADDING",(0,0),(-1,-1),9),
        ("LINEBELOW",(0,0),(-1,-1),1.5,C_H1BG)]))
    return [sp(5),tbl,sp(3)]

def H3(t):
    return [sp(3),Paragraph(f"<b><font color='#7B1C2E'>&#9654;  {t}</font></b>",sH3t),sp(2)]

def bul(t,lvl=1):
    pre="&#8226;" if lvl==1 else "&#8211;"
    stl=sBul if lvl==1 else sSub
    return Paragraph(f"{pre}&nbsp;&nbsp;{t}",stl)

def pearl(lines,hdr="CLINICAL PEARL"):
    body=f"<b>{hdr}</b><br/>"+"<br/>".join(f"&#9733; {l}" for l in lines)
    tbl=Table([[Paragraph(body,sPearl)]],colWidths=[UW])
    tbl.setStyle(TableStyle([("BACKGROUND",(0,0),(-1,-1),C_PEARL_BG),
        ("LINEBEFORE",(0,0),(0,-1),4,C_PEARL_L),
        ("TOPPADDING",(0,0),(-1,-1),6),("BOTTOMPADDING",(0,0),(-1,-1),6),
        ("LEFTPADDING",(0,0),(-1,-1),11),("RIGHTPADDING",(0,0),(-1,-1),8)]))
    return [sp(4),tbl,sp(4)]

def imp(lines,hdr="IMPORTANT"):
    body=f"<b>{hdr}</b><br/>"+"<br/>".join(f"&#9654; {l}" for l in lines)
    tbl=Table([[Paragraph(body,sDose)]],colWidths=[UW])
    tbl.setStyle(TableStyle([("BACKGROUND",(0,0),(-1,-1),C_DOSE_BG),
        ("LINEBEFORE",(0,0),(0,-1),4,C_DOSE_L),
        ("TOPPADDING",(0,0),(-1,-1),6),("BOTTOMPADDING",(0,0),(-1,-1),6),
        ("LEFTPADDING",(0,0),(-1,-1),11),("RIGHTPADDING",(0,0),(-1,-1),8)]))
    return [sp(4),tbl,sp(4)]

def tbl(hdrs,rows,cw):
    hr=[Paragraph(h,sTblH) for h in hdrs]
    data=[hr]+[[Paragraph(str(c),sTbl) for c in row] for row in rows]
    sty=[("BACKGROUND",(0,0),(-1,0),C_TH),
         ("GRID",(0,0),(-1,-1),0.4,C_TGRID),
         ("TOPPADDING",(0,0),(-1,-1),4),("BOTTOMPADDING",(0,0),(-1,-1),4),
         ("LEFTPADDING",(0,0),(-1,-1),5),("VALIGN",(0,0),(-1,-1),"TOP")]
    for i in range(1,len(data)):
        if i%2==0: sty.append(("BACKGROUND",(0,i),(-1,i),C_TALT))
    t=Table(data,colWidths=cw,repeatRows=1)
    t.setStyle(TableStyle(sty))
    return [sp(3),t,sp(4)]

def flow_row(items, is_main=True, split=False):
    """Render a list of flowchart items side-by-side or single-center."""
    bg   = C_H1BG if is_main else C_H2BG
    fg   = C_H1FG if is_main else C_H2FG
    sty  = S("fct",fontName=FB if is_main else F,fontSize=9,leading=12.5,
              textColor=fg,alignment=TA_CENTER)
    if not split:
        # single centered box
        box=Table([[Paragraph(items[0],sty)]],colWidths=[UW*0.76])
        box.setStyle(TableStyle([("BACKGROUND",(0,0),(-1,-1),bg),
            ("BOX",(0,0),(-1,-1),1,C_H1BG),
            ("TOPPADDING",(0,0),(-1,-1),5),("BOTTOMPADDING",(0,0),(-1,-1),5),
            ("LEFTPADDING",(0,0),(-1,-1),8)]))
        wrap=Table([[box]],colWidths=[UW])
        wrap.setStyle(TableStyle([("ALIGN",(0,0),(-1,-1),"CENTER"),
            ("TOPPADDING",(0,0),(-1,-1),0),("BOTTOMPADDING",(0,0),(-1,-1),0),
            ("LEFTPADDING",(0,0),(-1,-1),0)]))
        return wrap
    else:
        # split side-by-side
        n=len(items)
        each=(UW-4*mm*(n-1))/n
        cells=[]
        for item in items:
            b=Table([[Paragraph(item,sty)]],colWidths=[each])
            b.setStyle(TableStyle([("BACKGROUND",(0,0),(-1,-1),bg),
                ("BOX",(0,0),(-1,-1),1,C_H1BG),
                ("TOPPADDING",(0,0),(-1,-1),5),("BOTTOMPADDING",(0,0),(-1,-1),5),
                ("LEFTPADDING",(0,0),(-1,-1),6)]))
            cells.append(b)
            if item != items[-1]: cells.append(Spacer(4*mm,1))
        cws=[each if j%2==0 else 4*mm for j in range(len(cells))]
        wrap=Table([cells],colWidths=cws)
        wrap.setStyle(TableStyle([("VALIGN",(0,0),(-1,-1),"TOP"),
            ("TOPPADDING",(0,0),(-1,-1),0),("BOTTOMPADDING",(0,0),(-1,-1),0),
            ("LEFTPADDING",(0,0),(-1,-1),0)]))
        return wrap

def arr():
    return Paragraph("<font color='#1B4332'><b>&#9660;</b></font>",
                     S("ar",alignment=TA_CENTER,fontSize=12))

# ══════════════════════════════════════════════════════════════════════════════
# DOCUMENT
# ══════════════════════════════════════════════════════════════════════════════
doc=SimpleDocTemplate(
    "/home/daytona/workspace/ent-botox/Skull_Base_Transsphenoidal.pdf",
    pagesize=A4,leftMargin=ML,rightMargin=MR,topMargin=MT,bottomMargin=MB,
    title="Anterior Skull Base - Transsphenoidal Approaches",
    author="KNRUHS MS ENT")

story=[]

# TITLE
tt=Table([
    [Paragraph("ANTERIOR SKULL BASE - TRANSSPHENOIDAL APPROACHES",sTM)],
    [Paragraph("10-Mark Long Answer  |  KNRUHS MS ENT University Exam",sTS)],
    [Paragraph("Cummings Otolaryngology 7e  |  KJ Lee Essential ORL  |  Scott-Brown 8e  |  PubMed Evidence",sTS)],
],colWidths=[UW])
tt.setStyle(TableStyle([("BACKGROUND",(0,0),(-1,-1),C_H1BG),
    ("TOPPADDING",(0,0),(-1,-1),8),("BOTTOMPADDING",(0,0),(-1,-1),8),
    ("ALIGN",(0,0),(-1,-1),"CENTER")]))
story+=[tt,sp(8)]

# ══════════ 1. DEFINITION ═════════════════════════════════════════════════════
story+=H1("1.  DEFINITION")
story.append(bul("The <b>transsphenoidal approach</b> is an endonasal surgical route that accesses the <b>sphenoid sinus and sella turcica</b> through the nasal cavity, without external incision."))
story.append(bul("Part of the broader <b>Expanded Endonasal Approach (EEA)</b> - the endoscopic corridor from the crista galli to the foramen magnum along the ventral skull base."))
story.append(bul("The <b>anterior skull base</b> extends from the posterior wall of the frontal sinus anteriorly to the planum sphenoidale and tuberculum sellae posteriorly, bounded laterally by the orbital roofs."))
story.append(bul("EEA first described systematically by <b>Kassam et al., University of Pittsburgh, 2005</b> - landmark publication defining rostrocaudal surgical modules."))
story.append(sp(3))

# ══════════ 2. APPLIED ANATOMY ═══════════════════════════════════════════════
story+=H1("2.  APPLIED ANATOMY")
story+=H2("Sphenoid Sinus")
story.append(bul("Central key landmark of the transsphenoidal approach."))
story.append(bul("Pneumatisation types (Hammer and Radberg): <b>Conchal (3%) - underpneumatised; Presellar (11%) - does not reach sella; Sellar (86%) - extends under and behind sella</b> - most amenable to surgery."))
story.append(bul("Important landmarks on sphenoid sinus floor/posterior wall: <b>optic canal bulge, carotid canal bulge, opticocarotid recess (OCR), sellar face, clivus indentation</b>."))
story.append(bul("Intersinus septum: frequently <b>deviated toward ICA</b> - never use as midline reference without imaging."))
story.append(sp(3))
story+=H2("Sella Turcica")
story.append(bul("Bony cup in the body of sphenoid housing the <b>pituitary gland</b>."))
story.append(bul("Boundaries: anterior = tuberculum sellae; posterior = dorsum sellae; roof = diaphragma sellae (dural fold with central aperture for pituitary stalk)."))
story.append(bul("Lateral walls = <b>cavernous sinuses</b> (contain ICA, CN III, IV, V1, V2, VI)."))
story.append(bul("Superiorly = optic chiasm (separated from sella by suprasellar cistern)."))
story.append(bul("Pituitary gland: <b>anterior lobe (adenohypophysis)</b> = 75%; <b>posterior lobe (neurohypophysis)</b> = 25%. Normal volume ~0.6 cm3."))
story.append(sp(3))
story+=H2("Critical Vascular Anatomy")
story.append(bul("<b>Internal Carotid Artery (ICA):</b> most important structure at risk. Parasellar segment (C4) runs in cavernous sinus lateral to sella. Distance between bilateral ICAs at sellar floor: average 14-17 mm."))
story.append(bul("<b>Anterior communicating artery (ACoA)</b> and <b>superior hypophyseal arteries</b> supply the chiasm - at risk in suprasellar extension."))
story.append(bul("<b>Ophthalmic artery</b>: first branch of ICA - at risk in transplanum/transtuberculum approach."))
story.append(sp(3))
story+=H2("Nasal Anatomy Relevant to Approach")
story.append(bul("Route: <b>nostril → nasal cavity → posterior nasal choana → sphenoid ostium → sphenoid sinus → sellar face</b>."))
story.append(bul("Sphenoid ostium: located on anterior face of sphenoid, <b>1.5 cm above choana</b>, medial to superior turbinate."))
story.append(bul("<b>Nasoseptal flap (Hadad-Bassagasteguy flap):</b> pedicled on posterior septal artery (branch of sphenopalatine artery). Harvested first before any posterior work begins. Critical for skull base reconstruction."))
story.append(sp(3))

# ══════════ 3. EMBRYOLOGY ════════════════════════════════════════════════════
story+=H1("3.  EMBRYOLOGY  (Relevant Points)")
story.append(bul("Anterior pituitary = oral ectoderm (Rathke's pouch) - evaginates upward from roof of stomodeum at week 4."))
story.append(bul("Posterior pituitary = neural ectoderm (downward evagination of diencephalon floor)."))
story.append(bul("<b>Craniopharyngioma</b> arises from remnants of Rathke's pouch epithelium - explains midline suprasellar location and relationship to the stalk."))
story.append(bul("Sphenoid bone ossifies from <b>14 paired ossification centres</b>; sphenoid sinus pneumatises postnatally (complete by ~7-12 years)."))
story.append(sp(3))

# ══════════ 4. INDICATIONS / PATHOLOGIES ════════════════════════════════════
story+=H1("4.  INDICATIONS  - PATHOLOGIES TREATED VIA TRANSSPHENOIDAL APPROACH")
ind_rows=[
    ["Pituitary adenoma","Most common indication. Microadenoma (<10 mm) and macroadenoma (>10 mm). Functioning (secreting) and non-functioning types.","First-line surgical Rx; high remission rates"],
    ["Craniopharyngioma","Arises from Rathke's pouch remnants. Suprasellar / intrasellar. Children and adults.","Transsphenoidal if predominantly intrasellar; craniotomy if suprasellar dominant"],
    ["Meningioma (planum/tuberculum)","Planum sphenoidale or tuberculum sellae meningiomas.","Transplanum/transtuberculum EEA module"],
    ["Esthesioneuroblastoma","Sinonasal malignancy arising from olfactory epithelium at cribriform plate.","Transcribriform EEA + craniofacial resection"],
    ["CSF rhinorrhoea","Spontaneous or traumatic CSF leak at cribriform / sella / sphenoid.","Endoscopic repair with nasoseptal flap"],
    ["Encephalocele","Herniation of brain/meninges through skull base defect.","Endoscopic repair"],
    ["Chordoma / Chondrosarcoma","Midline clivus lesions.","Transclival module of EEA"],
    ["Rathke's cleft cyst","Benign cyst derived from Rathke's pouch remnant.","Transsphenoidal drainage/marsupialization"],
    ["Optic nerve glioma / decompression","Intrasellar-suprasellar lesions compressing optic apparatus.","Transplanum module; optic canal decompression"],
    ["Sinonasal malignancies (limited)","Squamous cell carcinoma, adenocarcinoma invading skull base.","Endoscopic if midline, no lateral extension"],
]
story+=tbl(["Pathology","Notes","Approach"],ind_rows,
           cw=[38*mm,UW-98*mm,60*mm])

# ══════════ 5. CLASSIFICATION OF EEA MODULES ════════════════════════════════
story+=H1("5.  CLASSIFICATION - EEA SURGICAL MODULES  (Kassam et al. / Cummings Table 176.2)")
story+=H2("Sagittal (Rostrocaudal) Modules")
sag_rows=[
    ["Transfrontal","Posterior table + floor of frontal sinus","Frontal sinus disease, mucocele, osteoma, nasal dermoid","CSF leak, orbital haematoma"],
    ["Transcribriform","Crista galli to planum sphenoidale (cribriform plate)","Olfactory groove meningioma, esthesioneuroblastoma, encephalocele, CSF leak","CSF leak, anosmia, anterior cerebral artery bleed, orbital injury"],
    ["Transplanum / Transtuberculum","Planum sphenoidale, tuberculum, optic strut, medial clinoid","Planum meningioma, suprasellar pituitary adenoma, craniopharyngioma, optic glioma","CSF leak, ICA/ophthalmic artery bleed, diabetes insipidus, optic nerve injury"],
    ["Transsellar","Sellar face","Pituitary adenoma, Rathke's cleft cyst, sellar chordoma","CSF leak, DI, hypopituitarism, ICA injury"],
    ["Transclival","Clivus (upper/mid/lower)","Chordoma, chondrosarcoma, meningioma of clivus","Basilar artery bleed, lower CN injury, ICA injury"],
    ["Transodontoid","Odontoid process","Rheumatoid pannus, os odontoideum","Lower CN injury, instability"],
]
story+=tbl(["Module","Bone Removed","Pathologies","Complications"],sag_rows,
           cw=[36*mm,32*mm,UW-115*mm,47*mm])

story+=H2("Coronal (Mediolateral) Modules")
cor_rows=[
    ["Supraorbital","Orbital roof","Benign fibro-osseous lesions; lateral margins of sagittal approaches","Orbital/ocular injury"],
    ["Transorbital","Medial orbital wall","Intraconal lesions, medial orbital tumours","Diplopia, medial rectus injury"],
    ["Transpterygoid","Pterygoid process, infratemporal fossa","Juvenile angiofibroma, petrous apex lesions","ICA, V3, trigeminal branch injury"],
    ["Transcavernous","Cavernous sinus","Cavernous sinus tumours, pituitary with cavernous extension","CN III, IV, VI palsy, ICA injury"],
    ["Transpetrous","Petrous apex","Cholesterol granuloma, chondrosarcoma","Cochlea, facial nerve, AICA injury"],
]
story+=tbl(["Module","Area Accessed","Pathologies","Key Risk"],cor_rows,
           cw=[36*mm,35*mm,UW-115*mm,44*mm])

# ══════════ 6. APPROACH SELECTION FLOWCHART ══════════════════════════════════
story+=H1("6.  SURGICAL APPROACH SELECTION  (Cummings Algorithm - Fig. 176.18)")
story.append(sp(4))
story.append(flow_row(["ASSESS TUMOR CHARACTERISTICS"],is_main=True))
story.append(arr())
story.append(flow_row(["Does tumor involve: overlying skin / nasal bones / frontal bone / orbital soft tissue?"],is_main=False))
story.append(arr())
story.append(flow_row(["NO involvement",  "YES involvement"],is_main=True,split=True))
story.append(arr())
story.append(flow_row(["Check: Intracranial extension?",  "Check: Intracranial extension?"],is_main=False,split=True))
story.append(arr())
story.append(flow_row(
    ["NO extension -> ENDOSCOPIC",
     "YES + lateral to medial orbital wall + nasoseptal flap available -> ENDOSCOPIC\nYES + lateral extension / no flap -> ENDOSCOPIC + CRANIOTOMY",
     "NO extension -> TRANSFACIAL",
     "YES extension -> TRANSFACIAL + CRANIOTOMY"],
    is_main=True, split=True))
story.append(sp(6))

story+=imp([
    "Relative contraindications to purely endoscopic approach (KJ Lee): orbital involvement; far lateral maxillary sinus; dural involvement lateral to orbit; invasion of brain parenchyma; cavernous sinus or carotid involvement; lesion lateral to cavernous carotid or superolateral to optic nerve.",
    "Endoscopic approach IDEAL for: small midline lesions, sellar/suprasellar lesions without lateral extension.",
    "Open approach (anterior craniofacial resection) needed when: overlying skin involved, nasal bones involved, anterior table frontal sinus involved, orbital exenteration required.",
],hdr="APPROACH SELECTION - KEY RULES")

# ══════════ 7. SURGICAL TECHNIQUE - TRANSSELLAR (PITUITARY) ═════════════════
story+=H1("7.  SURGICAL TECHNIQUE - ENDOSCOPIC TRANSSELLAR APPROACH (Pituitary)")
story+=H2("Pre-operative Setup")
story.append(bul("Patient supine, head extended 15 degrees, screen on right side of patient, surgeon and camera assistant on right."))
story.append(bul("Lumbar drain: optional; some use for high-flow CSF leak repair."))
story.append(bul("Neuronavigation: mandatory for extended approaches, revision surgery, abnormal anatomy."))
story.append(bul("Imaging: MRI sella (gadolinium) + CT scan (bony landmarks, ICA-ICA distance)."))
story.append(sp(3))
story+=H2("Step-by-Step Technique")
steps=[
    ("Step 1 - Nasal Phase","Bilateral nasal decongestion. 0-degree scope. Identify middle turbinate, superior turbinate, sphenoid ostium. Infiltrate posterior septum with vasoconstrictor."),
    ("Step 2 - Nasoseptal Flap","Harvest Hadad-Bassagasteguy flap (if anticipated CSF leak). Pedicle = posterior septal artery. Flap tucked in nasopharynx until needed."),
    ("Step 3 - Sphenoidotomy","Widen sphenoid ostium bilaterally using Kerrison rongeurs. Remove intersinus septum to create single large sphenoid cavity. Identify: optic canal bulge, ICA bulge, OCR, sellar face."),
    ("Step 4 - Sellar Opening","Drill sellar face. Identify dura. Open dura with needle first to check no aberrant ICA. Cruciate durotomy. Expose pituitary gland."),
    ("Step 5 - Tumour Removal","Microadenoma: identify tumour (softer, different colour from normal gland). Remove with ring curettes and suction. Macroadenoma: debulk centre first, then sweep walls. Angled scopes (30/45 degree) for lateral recesses."),
    ("Step 6 - Haemostasis","Surgicel, Gelfoam, gentle tamponade. Avoid aggressive packing in suprasellar space."),
    ("Step 7 - Skull Base Closure","If no CSF leak: Gelfoam + DuraSeal sealant. If CSF leak: multilayer closure - intradural collagen matrix + fat graft (abdominal) + nasoseptal flap + fibrin glue + nasal packing."),
]
step_rows=[[Paragraph(s,sTbl),Paragraph(d,sTbl)] for s,d in steps]
step_tbl=Table(step_rows,colWidths=[42*mm,UW-42*mm])
step_tbl.setStyle(TableStyle([
    ("GRID",(0,0),(-1,-1),0.4,C_TGRID),
    ("TOPPADDING",(0,0),(-1,-1),4),("BOTTOMPADDING",(0,0),(-1,-1),4),
    ("LEFTPADDING",(0,0),(-1,-1),5),("VALIGN",(0,0),(-1,-1),"TOP"),
    ("FONTNAME",(0,0),(0,-1),FB),("TEXTCOLOR",(0,0),(0,-1),C_H2FG),
    ("BACKGROUND",(0,0),(0,-1),C_H2BG),
]))
story+=[sp(3),step_tbl,sp(4)]

story+=H2("Expanded Endonasal Approach (EEA) - Key Steps for Anterior Skull Base Tumours")
for pt in [
    "Nasoseptal flap harvested and tucked in nasopharynx.",
    "Tumour debulked endonasally to visualize margins, origin, skull base involvement.",
    "Maxillary antrostomies + ethmoidectomy + sphenoidotomy - identify optic and carotid canals.",
    "Draf III procedure - remove frontal sinus floor if frontal involvement.",
    "Nasal septum transected below tumour to sphenoid rostrum.",
    "Anterior and posterior ethmoid arteries ligated and divided at skull base.",
    "Anterior skull base drilled thin from crista galli to planum sphenoidale, medial orbital wall to medial orbital wall.",
    "Dura cauterized and opened around tumour with adequate margin.",
    "Cortical blood vessels elevated, olfactory roots transected.",
    "Margins confirmed by frozen sections.",
    "Closure: multilayer dural repair + nasoseptal flap secured with fibrin glue + Gelfoam/fat. Nasal trumpets used to prevent pneumocephalus while preserving airway. (KJ Lee, 2023)",
]:
    story.append(bul(pt))
story.append(sp(3))

# ══════════ 8. PITUITARY ADENOMA CLASSIFICATION ══════════════════════════════
story+=H1("8.  PITUITARY ADENOMA - CLASSIFICATION")
story+=H2("Hardy Classification (Radiological - Sellar)")
hard_rows=[
    ["Grade I",  "Microadenoma (<10 mm). Sella normal size. Intrasellar."],
    ["Grade II", "Macroadenoma (>10 mm). Sella enlarged. Still intrasellar."],
    ["Grade III","Macroadenoma. Localised sellar floor erosion or destruction."],
    ["Grade IV", "Macroadenoma. Diffuse sellar floor destruction."],
    ["Stage A",  "Suprasellar extension. Obliterates suprasellar cistern."],
    ["Stage B",  "Suprasellar extension. Elevates floor of third ventricle."],
    ["Stage C",  "Suprasellar extension. Reaches foramen of Monro."],
    ["Stage D",  "Intracranial extension beyond sella (temporal, posterior fossa)."],
    ["Stage E",  "Lateral into cavernous sinus (parasellar extension)."],
]
story+=tbl(["Grade/Stage","Description"],hard_rows,cw=[28*mm,UW-28*mm])

story+=H2("Knosp Classification (Cavernous Sinus Invasion)")
knosp_rows=[
    ["Grade 0","Tumour does not reach medial tangent of intrasellar ICA. No cavernous sinus invasion."],
    ["Grade 1","Tumour reaches but does not cross medial tangent."],
    ["Grade 2","Tumour crosses medial tangent but not centre of ICA."],
    ["Grade 3","Tumour crosses the centre of ICA. Cavernous sinus invasion likely."],
    ["Grade 4","Total encasement of intrasellar ICA. Complete cavernous sinus invasion."],
]
story+=tbl(["Grade","Cavernous Sinus Invasion"],knosp_rows,cw=[22*mm,UW-22*mm])
story+=imp([
    "Knosp Grade 0-2: surgical cure possible via transsphenoidal route.",
    "Knosp Grade 3-4: cavernous sinus invaded - surgical cure unlikely; stereotactic radiosurgery (SRS) preferred for residual.",
    "Hardy Stage D-E: combined endoscopic + craniotomy approach may be needed.",
],hdr="SURGICAL IMPLICATIONS OF CLASSIFICATION")

# ══════════ 9. CLINICAL FEATURES / HISTORY / EXAMINATION ═════════════════════
story+=H1("9.  CLINICAL FEATURES, HISTORY AND EXAMINATION")
story+=H2("Presenting Features of Sellar / Parasellar Lesions")
cf_rows=[
    ["Visual disturbance","Bitemporal hemianopia (compression of optic chiasm at decussating nasal fibres). Most common presentation of macroadenoma. Progressive. Check visual fields formally."],
    ["Headache","Due to raised ICP or dural stretching. Bifrontal or behind-the-eyes character."],
    ["Hormonal hypersecretion","Functioning adenomas: Prolactinoma (galactorrhoea, amenorrhoea, infertility, impotence). Acromegaly (GH excess). Cushing's disease (ACTH excess). TSHoma (hyperthyroidism)."],
    ["Hypopituitarism","From compression of normal gland. GH deficiency most sensitive. Then LH/FSH, TSH, ACTH sequentially. Presents as fatigue, weight gain, sexual dysfunction."],
    ["Diabetes insipidus (DI)","Posterior pituitary compromise. Polyuria + polydipsia. Suggests involvement of pituitary stalk or posterior lobe."],
    ["CSF rhinorrhoea","Clear watery unilateral nasal discharge. Worse on leaning forward. High risk of meningitis."],
    ["Apoplexy","Sudden haemorrhage into adenoma. Severe headache (thunderclap), visual loss, ophthalmoplegia, altered consciousness. Emergency."],
    ["Cavernous sinus syndrome","Diplopia (CN III, IV, VI), facial numbness (V1/V2), ptosis, proptosis - from lateral tumour extension."],
]
story+=tbl(["Feature","Details"],cf_rows,cw=[38*mm,UW-38*mm])
story.append(sp(3))
story+=H2("Physical Examination")
for pt in [
    "<b>Visual fields:</b> formal Goldman or Humphrey perimetry mandatory. Bitemporal hemianopia = chiasmal compression.",
    "<b>Visual acuity:</b> check each eye separately.",
    "<b>Fundoscopy:</b> optic disc pallor/atrophy in chronic compression.",
    "<b>Cranial nerves III, IV, VI:</b> diplopia, ptosis, restricted eye movements - cavernous sinus involvement.",
    "<b>Endocrine assessment:</b> signs of acromegaly (large hands, jaw prognathism, macroglossia), Cushing's (central obesity, striae, buffalo hump), hypothyroidism, hypogonadism.",
    "<b>Nasal examination:</b> unilateral watery discharge (CSF leak). Halo sign - blood-tinged discharge with a clear halo on gauze.",
]:
    story.append(bul(pt))
story.append(sp(3))

# ══════════ 10. INVESTIGATIONS ════════════════════════════════════════════════
story+=H1("10.  INVESTIGATIONS AND IMAGING")
story+=H2("Biochemical / Endocrine")
for pt in [
    "<b>Serum prolactin:</b> prolactinoma; level >200 ng/ml = macroadenoma. Very high levels (>1000) = giant prolactinoma.",
    "<b>IGF-1 + GH (post OGTT):</b> acromegaly - GH fails to suppress below 1 ng/ml on OGTT.",
    "<b>24-hour urine free cortisol + low-dose dexamethasone suppression test:</b> Cushing's disease.",
    "<b>TFTs, LH, FSH, testosterone/oestradiol:</b> assess hypopituitarism.",
    "<b>Beta-2 transferrin:</b> confirmatory test for CSF rhinorrhoea (specific - not present in nasal secretions).",
]:
    story.append(bul(pt))
story.append(sp(3))
story+=H2("Imaging")
img_rows=[
    ["MRI Sella (gadolinium)","Investigation of choice. T1 with gadolinium for microadenoma (hypointense on T1, enhances less than normal gland). T2 for soft tissue detail. Assess: size, cavernous sinus invasion (Knosp grade), suprasellar extension, chiasm position, Hardy grade.","MANDATORY pre-op"],
    ["CT Skull Base (thin slice)","Define bony anatomy: sphenoid sinus pneumatisation type, sellar floor thickness, ICA-ICA distance, intersinus septum, optic canal position.","Mandatory for surgical planning"],
    ["CT Cisternography","Localise exact site of CSF leak (intrathecal contrast + CT). Gold standard for CSF leak localisation.","For CSF rhinorrhoea"],
    ["Visual Field Testing","Formal Goldman/Humphrey perimetry. Bitemporal hemianopia pattern.","Mandatory pre-op and post-op"],
    ["Cerebral Angiography (DSA)","If ICA invasion suspected; to plan endovascular balloon occlusion test.","Selected cases"],
]
story+=tbl(["Investigation","Details","When"],img_rows,
           cw=[42*mm,UW-92*mm,50*mm])

# ══════════ 11. DIFFERENTIAL DIAGNOSIS ═══════════════════════════════════════
story+=H1("11.  DIFFERENTIAL DIAGNOSIS  (Sellar / Parasellar Masses)")
dd_rows=[
    ["Pituitary adenoma","Most common. Endocrine active or inactive. Enhances on MRI.","MRI + endocrine workup"],
    ["Craniopharyngioma","Rathke's pouch remnant. Calcification (90% in children). Bimodal age peak (5-15 yr, 45-60 yr). Adamantinomatous and papillary types.","MRI + CT (calcification)"],
    ["Rathke's cleft cyst","Benign. Signal varies (mucoid content). No enhancement. Intrapituitary or suprasellar.","MRI - hypointense T1, hyperintense T2"],
    ["Meningioma","Planum/tuberculum sellae. Dural tail sign on MRI. Calcification.","MRI with gadolinium"],
    ["Hypothalamic glioma","Arising from hypothalamus or optic chiasm. Children.","MRI"],
    ["Lymphocytic hypophysitis","Autoimmune. Young women, pregnancy. Diffuse gland enlargement + stalk thickening.","MRI + biopsy"],
    ["Germinoma","Young males. Diabetes insipidus as first symptom. Stalk thickening.","MRI + tumour markers"],
    ["Metastasis","Breast/lung most common. Posterior pituitary involvement. DI common.","MRI + primary tumour search"],
    ["Cavernous ICA aneurysm","Can mimic sellar mass. Pulsatile on imaging. Do NOT biopsy without angio.","CTA/DSA mandatory"],
    ["Empty sella syndrome","Herniation of arachnoid/CSF into sella. Sella enlarged. Gland flattened at base.","MRI - CSF signal fills sella"],
]
story+=tbl(["Diagnosis","Key Features","Investigation"],dd_rows,
           cw=[38*mm,UW-88*mm,50*mm])

# ══════════ 12. MANAGEMENT ════════════════════════════════════════════════════
story+=H1("12.  MANAGEMENT")
story+=H2("Medical Management")
med_rows=[
    ["Prolactinoma","<b>Dopamine agonists = first-line for all prolactinomas (including macroadenoma)</b>. Cabergoline (0.5-2 mg twice weekly) preferred over bromocriptine. Reduces size and normalises prolactin in >80%. Surgery if resistant or intolerant."],
    ["Acromegaly (GH adenoma)","Surgery first-line (transsphenoidal). Medical Rx if unfit or residual: somatostatin analogues (octreotide LAR, lanreotide), GH receptor antagonist (pegvisomant), dopamine agonists."],
    ["Cushing's disease (ACTH adenoma)","Surgery first-line. Medical Rx for persistent/recurrent Cushing's: pasireotide, metyrapone, ketoconazole, osilodrostat (steroidogenesis inhibitors). Bilateral adrenalectomy as last resort."],
    ["Hypopituitarism","Hormone replacement: cortisol (essential - hydrocortisone), thyroid (levothyroxine), sex hormones (testosterone/oestrogen), GH (in adults with deficiency), vasopressin (desmopressin for DI)."],
    ["Non-functioning adenoma","No effective medical Rx. Surgery or surveillance. Temozolomide for aggressive/rare cases."],
]
story+=tbl(["Condition","Medical Management"],med_rows,cw=[42*mm,UW-42*mm])

story+=H2("Surgical Management")
for pt in [
    "<b>Endoscopic Endonasal Transsphenoidal Surgery (EETS)</b> = current gold standard for most sellar and suprasellar lesions.",
    "<b>Indications for surgery:</b> non-functioning macroadenoma causing visual compromise; functioning adenoma (except prolactinoma - which is medical first); CSF rhinorrhoea repair; pituitary apoplexy (urgent); dopamine agonist failure in prolactinoma.",
    "<b>Endoscopic vs Microscopic transsphenoidal:</b> endoscopic gives superior visualisation, wider field of view, angled scopes, better lateral reach, faster recovery. Microscopic still used in some centres.",
    "<b>Craniotomy</b> (subfrontal, pterional, transcallosal): used when tumour extends far laterally, engulfs major vessels, or extends into third ventricle beyond Monro.",
    "<b>Combined endoscopic + craniotomy (cranio-endoscopic):</b> for staged resection of giant adenomas.",
    "<b>Stereotactic radiosurgery (SRS - Gamma Knife):</b> for residual/recurrent tumour especially with cavernous sinus invasion (Knosp 3-4). Target: secretion normalisation, growth control.",
    "<b>KJ Lee (2023):</b> 5-year survival up to 60% in endoscopic management of sinonasal malignancies - comparable to traditional craniofacial approach.",
]:
    story.append(bul(pt))
story.append(sp(3))

story+=H2("CSF Leak Repair - Multilayer Closure (Cummings + KJ Lee)")
for pt in [
    "Identify leak site with fluorescein (intrathecal) or beta-2 transferrin.",
    "Multilayer technique: intradural collagen matrix (Duragen/DuraMatrix) in subdural space + fat graft from abdomen + <b>nasoseptal (Hadad-Bassagasteguy) flap</b> over defect.",
    "Secure with fibrin glue + Gelfoam.",
    "Nasal packing for 3-5 days. Lumbar drain if high-flow leak.",
    "Nasal trumpets used to prevent pneumocephalus while maintaining nasal airway.",
    "<b>Hadad-Bassagasteguy nasoseptal flap significantly reduces CSF leak rates in extended EEA</b> (Level 2 evidence - multiple case series).",
]:
    story.append(bul(pt))
story.append(sp(3))

# ══════════ 13. COMPLICATIONS ════════════════════════════════════════════════
story+=H1("13.  COMPLICATIONS")
comp_rows=[
    ["CSF rhinorrhoea","3-10% endoscopic; up to 40% in extended EEA without flap. Reduced by nasoseptal flap use. Risk of meningitis if untreated.","Nasoseptal flap + multilayer closure; lumbar drain if persistent; reoperation if refractory"],
    ["Diabetes insipidus (DI)","Transient: 10-30%. Permanent: 1-3%. Due to stalk or posterior lobe injury.","Desmopressin (DDAVP). Monitor urine output + serum sodium. Watch for triphasic response."],
    ["Hypopituitarism (new or worsened)","3-10%. Loss of anterior pituitary function from gland injury.","Hormone replacement (see medical management)"],
    ["ICA injury","Rare (<1%) but catastrophic. Risk increased in: revision surgery, Knosp Grade 3-4, conchal sphenoid, abnormal ICA course.","Immediate packing; emergent endovascular intervention (balloon occlusion, stenting, coiling)."],
    ["Visual deterioration","1-5%. Intraoperative optic nerve/chiasm injury or haematoma.","Prompt re-exploration if vision worsens post-op"],
    ["Meningitis","Due to CSF leak. Incidence 1-2%.","Antibiotics; CSF leak repair"],
    ["Hyponatraemia (SIADH)","Common post-op (up to 25%). Due to SIADH from stalk manipulation. Meta-analysis 2025 (Webb et al., Neurosurg Rev, PMID 40892282): incidence 8-25%.","Fluid restriction; sodium correction; monitor electrolytes daily for 5-7 days"],
    ["Nasal complications","Crusting, synechiae, septal perforation, anosmia (transcribriform), empty nose syndrome.","Saline irrigation; endoscopic surveillance"],
    ["Pituitary apoplexy","Haemorrhage into tumour. Emergency. Acute visual loss + headache.","Urgent surgical decompression within 24-72 hours if visual deterioration"],
]
story+=tbl(["Complication","Details","Management"],comp_rows,
           cw=[40*mm,UW-90*mm,50*mm])

story+=imp([
    "Triphasic response after pituitary surgery: Phase 1 DI (hours 1-5: ADH release impaired) -> Phase 2 SIADH (days 5-10: stored ADH released) -> Phase 3 permanent DI (if >80% axon loss). MUST monitor Na daily.",
    "Pituitary apoplexy: surgical emergency. Vision loss + ophthalmoplegia + severe headache = emergent decompression.",
    "ICA injury: DO NOT pack aggressively. Maintain haemostasis with Surgiflo/Gelfoam, immediate interventional radiology.",
],hdr="CRITICAL COMPLICATION MANAGEMENT POINTS")

# ══════════ 14. PROGNOSIS ════════════════════════════════════════════════════
story+=H1("14.  PROGNOSIS")
prog_rows=[
    ["Microadenoma (functioning)","Remission rate: GH adenoma 75-90%; ACTH (Cushing's) 65-90%; prolactinoma surgical cure 70-85% (but dopamine agonists preferred)","Excellent if complete resection"],
    ["Macroadenoma non-functioning","Gross total resection in ~50-60%. Visual improvement in 80-90% if chiasm decompressed pre-operatively.","Good; surveillance imaging at 3, 6, 12 months then yearly"],
    ["Craniopharyngioma","Highly recurrent (30-50% at 10 years). More aggressive resection associated with worse hypothalamic morbidity.","Moderate; QOL often impacted"],
    ["Esthesioneuroblastoma (sinonasal)","5-year survival ~60% with endoscopic resection. Comparable to open craniofacial. Hyams grading important.","Moderate"],
    ["CSF leak repair","Success rate >90% with nasoseptal flap. Revision needed in <10%.","Good with proper technique"],
]
story+=tbl(["Condition","Outcome Data","Prognosis"],prog_rows,
           cw=[38*mm,UW-85*mm,47*mm])

# ══════════ 15. FOLLOW-UP ════════════════════════════════════════════════════
story+=H1("15.  FOLLOW-UP")
for pt in [
    "<b>Immediate post-op:</b> ICU/HDU monitoring for DI, visual status, sodium levels. Daily electrolytes for 5-7 days.",
    "<b>MRI sella with gadolinium:</b> at 3 months post-op (baseline for residual), then 12 months, then annually for 5 years.",
    "<b>Visual field testing:</b> at 3 months post-op. Improvement expected in >80% with chiasmal decompression.",
    "<b>Endocrine review:</b> 4-6 weeks post-op. Full anterior pituitary panel. Adjust hormone replacement.",
    "<b>Nasal endoscopy:</b> 2 weeks post-op for crust removal. 6 weeks, 3 months. Ensure nasoseptal flap healed.",
    "<b>Prolactinoma:</b> serum prolactin every 3 months. MRI at 6-12 months. Consider dopamine agonist dose reduction if remission.",
    "<b>Acromegaly:</b> IGF-1 at 12 weeks. Random GH and GH OGTT at 3 months. Target: IGF-1 normal + GH <1 ng/ml.",
    "<b>Cushing's disease:</b> 9 AM cortisol on day 1-3 post-op (if low = remission). UFC at 6-12 weeks. Long-term surveillance for recurrence.",
]:
    story.append(bul(pt))
story.append(sp(3))

# ══════════ 16. RECENT ADVANCES ══════════════════════════════════════════════
story+=H1("16.  RECENT ADVANCES  (2019-2025)")
adv_rows=[
    ["Expanded EEA - systematic modules","Kassam et al. (2005) framework now well established. Entire ventral skull base accessible endonasally from crista galli to foramen magnum. Learning curve well studied - systematic review 2024 (Alomari et al., BMC Surg, PMID 38705991)."],
    ["Nasoseptal flap (HB flap)","Hadad-Bassagasteguy flap (2006) revolutionised skull base reconstruction. CSF leak rates in extended EEA reduced from 40% to <5%."],
    ["4K/3D endoscopy and exoscope","Ultra-high-definition 4K endoscopy and 3D exoscopes provide improved depth perception. Exoscope allows bimanual surgery without assistant holding camera."],
    ["Intraoperative MRI (iMRI)","Allows real-time assessment of residual tumour during surgery. Improves gross total resection rates of macroadenomas."],
    ["Robotic-assisted skull base surgery","Experimental. Initial reports of robot-assisted endonasal surgery show feasibility. Not yet standard of care."],
    ["Hyponatraemia incidence","Meta-analysis 2025 (Webb et al., Neurosurg Rev, PMID 40892282): incidence 8-25% post-transsphenoidal surgery. Risk factors: older age, female sex, pre-op hypopituitarism."],
    ["Simulation training","Systematic review 2023 (Santona et al., Neurosurg Rev, PMID 37725193): multiple validated simulators for endoscopic transsphenoidal training improve surgical performance before live surgery."],
    ["Osilodrostat / Pasireotide","New medical therapies for Cushing's disease. FDA approved. Useful for persistent/recurrent ACTH adenoma post-surgery."],
]
story+=tbl(["Advance","Details"],adv_rows,cw=[48*mm,UW-48*mm])

# ══════════ 17. CLINICAL PEARLS ══════════════════════════════════════════════
story+=H1("17.  CLINICAL PEARLS")
story+=pearl([
    "The sphenoid intersinus septum frequently deviates toward the ICA - NEVER use it as midline guide. Always use neuronavigation.",
    "Sellar type sphenoid (86%) is most suitable for transsphenoidal surgery. Conchal type makes approach very difficult.",
    "Bitemporal hemianopia = chiasmal compression from above (decussating nasal fibres). Upper temporal loss first, then lower temporal.",
    "Prolactinoma = ONLY pituitary adenoma where medical treatment (cabergoline) is the FIRST-LINE - surgery reserved for failures.",
    "Knosp Grade 3-4 = surgical cure unlikely. Plan SRS for cavernous sinus residual.",
    "Nasoseptal flap (HB flap) = most important advance in skull base reconstruction. Harvest it FIRST before any posterior work.",
    "Triphasic DI response: monitor Na daily post-op. Phase 2 (SIADH, days 5-10) can cause dangerous hyponatraemia.",
    "Beta-2 transferrin = gold standard confirmatory test for CSF rhinorrhoea (not available in nasal secretions).",
    "Pituitary apoplexy = emergency. Vision loss + ophthalmoplegia + thunderclap headache = emergent transsphenoidal decompression within 24-72 hours.",
    "5-year survival for endoscopic sinonasal malignancy resection (~60%) is COMPARABLE to open craniofacial resection (KJ Lee).",
],hdr="HIGH-YIELD CLINICAL PEARLS - EXAM AND VIVA")

# ══════════ 18. VIVA QUESTIONS ════════════════════════════════════════════════
story+=H1("18.  VIVA QUESTIONS WITH ANSWERS")
viva=[
    ("Q1: What are the types of sphenoid sinus pneumatisation and which is best for transsphenoidal surgery?",
     "Conchal (3%) - underpneumatised, least suitable. Presellar (11%) - does not reach sella. Sellar (86%) - extends under and behind sella - BEST for transsphenoidal surgery."),
    ("Q2: What is the Hardy classification of pituitary adenomas?",
     "Grades I-IV for sellar size/destruction. Stages A-E for suprasellar (A-D) and lateral/cavernous sinus extension (E). Hardy Grade IV + Stage E = most advanced."),
    ("Q3: What is the Knosp classification and why is it important?",
     "Grades 0-4 based on tumour position relative to the intrasellar ICA. Grade 0-2 = surgical cure possible. Grade 3-4 = cavernous sinus invaded, surgical cure unlikely; treat with SRS."),
    ("Q4: What is the nasoseptal (Hadad-Bassagasteguy) flap and what is its blood supply?",
     "Pedicled vascularised mucosal flap from the nasal septum. Blood supply: posterior septal artery (branch of sphenopalatine artery). Gold standard for skull base reconstruction after EEA. Reduces CSF leak from ~40% to <5%."),
    ("Q5: What are the modules of the expanded endonasal approach?",
     "Sagittal (rostrocaudal): Transfrontal, Transcribriform, Transplanum/Transtuberculum, Transsellar, Transclival, Transodontoid. Coronal (mediolateral): Supraorbital, Transorbital, Transpterygoid, Transcavernous, Transpetrous."),
    ("Q6: What is the triphasic DI response after pituitary surgery?",
     "Phase 1 (hours 1-5): Transient DI from ADH impairment. Phase 2 (days 5-10): SIADH from stored ADH release - risk of dangerous hyponatraemia. Phase 3: Permanent DI if >80% axon loss. Monitor serum Na daily."),
    ("Q7: What are the contraindications to purely endoscopic skull base approach?",
     "Orbital involvement, far lateral maxillary sinus, dural involvement lateral to orbit, brain parenchyma invasion, cavernous sinus or carotid involvement, lesion lateral to cavernous carotid or superolateral to optic nerve. Also: overlying skin, nasal bones, or frontal bone involvement."),
    ("Q8: How do you confirm CSF rhinorrhoea?",
     "Beta-2 transferrin (confirmatory, specific). CT cisternography (localise leak site). Halo test (blood-tinged discharge on gauze shows clear halo). Glucose test (unreliable). Fluorescein intrathecal (intraoperative localisation)."),
]
for q,a in viva:
    row=Table([
        [Paragraph(q, S("vq",fontName=FB,fontSize=9.5,leading=13,textColor=C_H2FG))],
        [Paragraph(a, S("va",fontName=F, fontSize=9.5,leading=13.5,leftIndent=6))],
    ],colWidths=[UW])
    row.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(0,0),C_H2BG),
        ("LINEBELOW",(0,1),(0,1),0.5,C_TGRID),
        ("TOPPADDING",(0,0),(-1,-1),4),("BOTTOMPADDING",(0,0),(-1,-1),4),
        ("LEFTPADDING",(0,0),(-1,-1),8),
    ]))
    story.append(KeepTogether(row))
    story.append(sp(3))

# ══════════ 19. KEY POINTS SUMMARY ═══════════════════════════════════════════
story+=H1("19.  KEY POINTS SUMMARY")
story+=pearl([
    "Transsphenoidal approach = endonasal route to sella via sphenoid sinus. Sellar-type pneumatisation (86%) is most amenable.",
    "EEA Kassam et al. 2005: modules along entire ventral skull base - crista galli to foramen magnum.",
    "Sagittal modules: Transfrontal, Transcribriform, Transplanum, Transsellar, Transclival, Transodontoid.",
    "Coronal modules: Supraorbital, Transorbital, Transpterygoid, Transcavernous, Transpetrous.",
    "Approach selection algorithm: skin/bone/orbital involvement = transfacial. Lateral extension = add craniotomy. Midline + flap available = endoscopic.",
    "Hardy classification: Grades I-IV (sellar), Stages A-E (extracapsular). Knosp 0-2 = operable; Knosp 3-4 = SRS.",
    "Prolactinoma = cabergoline first. All others = surgery first.",
    "Nasoseptal flap (Hadad-Bassagasteguy) = posterior septal artery pedicle. Most important reconstruction advance.",
    "Key complications: CSF leak (prevent with nasoseptal flap), DI (monitor Na daily, triphasic response), hyponatraemia (SIADH), ICA injury (rare but catastrophic), visual deterioration.",
    "Beta-2 transferrin = best confirmatory test for CSF rhinorrhoea.",
    "Pituitary apoplexy = emergency - decompression within 24-72 hours.",
    "5-year survival endoscopic sinonasal malignancy ~60% = comparable to open craniofacial approach (KJ Lee).",
],hdr="KEY POINTS - ANTERIOR SKULL BASE / TRANSSPHENOIDAL APPROACHES")

# ── REFERENCES ────────────────────────────────────────────────────────────────
story+=H1("REFERENCES")
refs=[
    "Cummings Otolaryngology Head and Neck Surgery, 7th Ed. Chapter 176 - Table 176.2 (EEA Modules); Fig. 176.18 (Approach Algorithm); Sections on anterior craniofacial resection, endoscopic skull base surgery.",
    "KJ Lee's Essential Otolaryngology, 12th Ed. Expanded Endonasal Endoscopic Approach to Anterior Skull Base; Infratemporal fossa approaches.",
    "Scott-Brown's Otorhinolaryngology Head and Neck Surgery, 8th Ed. Skull Base Surgery.",
    "Kassam AB et al. Expanded endonasal approach: fully endoscopic, completely transnasal approach to the middle third of the clivus. Neurosurg Focus. 2005.",
    "Hadad G, Bassagasteguy L et al. A novel reconstructive technique after endoscopic expanded endonasal approaches: vascular pedicle nasoseptal flap. Laryngoscope 2006;116(10):1882-6.",
    "Alomari A et al. The learning curve in endoscopic transsphenoidal skull-base surgery: systematic review. BMC Surg. 2024. PMID 38705991.",
    "Webb KL et al. Incidence and risk factors of hyponatraemia after transsphenoidal surgery: systematic meta-analysis. Neurosurg Rev. 2025. PMID 40892282.",
    "Santona G et al. Training models and simulators for endoscopic transsphenoidal surgery: systematic review. Neurosurg Rev. 2023. PMID 37725193.",
    "Palmisciano P et al. Craniopharyngiomas invading the ventricular system: systematic review. Anticancer Res. 2022. PMID 36039438.",
]
for i,r in enumerate(refs,1):
    story.append(Paragraph(f"[{i}]  {r}",sRef))
    story.append(sp(2))

# ── FOOTER ─────────────────────────────────────────────────────────────────────
def footer(canvas,doc):
    canvas.saveState()
    canvas.setFont(F,7.5)
    canvas.setFillColor(C_FOOT)
    pn=canvas.getPageNumber()
    canvas.drawString(ML,9*mm,"Anterior Skull Base - Transsphenoidal Approaches  |  KNRUHS MS ENT  |  2026")
    canvas.drawRightString(W-MR,9*mm,f"Page {pn}")
    canvas.restoreState()

doc.build(story,onFirstPage=footer,onLaterPages=footer)
print("PDF generated successfully.")