Febrile Altered Sensorium - Complete Casualty Notes

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm, mm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether
)
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.platypus import BaseDocTemplate, PageTemplate, Frame
from reportlab.lib.colors import HexColor
import datetime

OUTPUT = "/tmp/workspace/febrile-altered-sensorium/Febrile_Altered_Sensorium_Casualty_Notes.pdf"

# ── Colour palette ──────────────────────────────────────────────────────────
DARK_BLUE   = HexColor("#1a3c5e")
MED_BLUE    = HexColor("#2563a8")
LIGHT_BLUE  = HexColor("#dbeafe")
ACCENT_RED  = HexColor("#dc2626")
ACCENT_AMBER= HexColor("#d97706")
ACCENT_GREEN= HexColor("#16a34a")
LIGHT_GREY  = HexColor("#f1f5f9")
MID_GREY    = HexColor("#64748b")
TABLE_HEAD  = HexColor("#1e40af")
TABLE_ALT   = HexColor("#eff6ff")
WHITE       = colors.white
BLACK       = colors.black

W, H = A4

# ── Header / Footer ─────────────────────────────────────────────────────────
def draw_header_footer(canvas, doc):
    canvas.saveState()
    # Top bar
    canvas.setFillColor(DARK_BLUE)
    canvas.rect(0, H - 1.8*cm, W, 1.8*cm, fill=1, stroke=0)
    canvas.setFillColor(WHITE)
    canvas.setFont("Helvetica-Bold", 11)
    canvas.drawString(1.2*cm, H - 1.25*cm, "FEBRILE ALTERED SENSORIUM — CASUALTY MANAGEMENT GUIDE")
    canvas.setFont("Helvetica", 8)
    canvas.drawRightString(W - 1.2*cm, H - 1.25*cm, f"Page {doc.page}")
    # Bottom bar
    canvas.setFillColor(DARK_BLUE)
    canvas.rect(0, 0, W, 0.9*cm, fill=1, stroke=0)
    canvas.setFillColor(WHITE)
    canvas.setFont("Helvetica-Oblique", 7.5)
    canvas.drawString(1.2*cm, 0.32*cm,
        "Sources: Harrison's 22E · Bradley & Daroff's Neurology · Goldman-Cecil · Rosen's Emergency Medicine · Jawetz Microbiology")
    canvas.restoreState()

# ── Document setup ───────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    rightMargin=1.8*cm, leftMargin=1.8*cm,
    topMargin=2.6*cm, bottomMargin=1.6*cm,
    title="Febrile Altered Sensorium — Casualty Notes",
    author="Medical Education"
)

# ── Styles ───────────────────────────────────────────────────────────────────
base = getSampleStyleSheet()

def S(name, parent="Normal", **kw):
    return ParagraphStyle(name, parent=base[parent], **kw)

sTitle   = S("sTitle",  "Title",  fontSize=20, textColor=WHITE,      alignment=TA_CENTER, spaceAfter=4)
sSub     = S("sSub",    "Normal", fontSize=10, textColor=LIGHT_BLUE, alignment=TA_CENTER, spaceAfter=2)
sH1      = S("sH1",     "Normal", fontSize=13, textColor=WHITE,      fontName="Helvetica-Bold",
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sH2      = S("sH2",     "Normal", fontSize=11, textColor=DARK_BLUE,  fontName="Helvetica-Bold",
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sH3      = S("sH3",     "Normal", fontSize=9.5, textColor=MED_BLUE,  fontName="Helvetica-Bold",
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sBody    = S("sBody",   "Normal", fontSize=8.5, leading=13, spaceAfter=2)
sBullet  = S("sBullet", "Normal", fontSize=8.5, leading=12,
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sBullet2 = S("sBullet2","Normal", fontSize=8,   leading=11.5,
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sWarn    = S("sWarn",   "Normal", fontSize=8.5, leading=12,
             backColor=HexColor("#fff7ed"), textColor=HexColor("#92400e"),
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sAlert   = S("sAlert",  "Normal", fontSize=8.5, leading=12,
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sGreen   = S("sGreen",  "Normal", fontSize=8.5, leading=12,
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sCaption = S("sCaption","Normal", fontSize=7.5, textColor=MID_GREY,
             alignment=TA_CENTER, spaceAfter=4)

# ── Helper builders ──────────────────────────────────────────────────────────
def h1(txt):
    return Paragraph(f" {txt}", sH1)

def h2(txt):
    return [
        HRFlowable(width="100%", thickness=2, color=MED_BLUE, spaceAfter=2),
        Paragraph(txt, sH2),
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def h3(txt): return Paragraph(txt, sH3)
def body(txt): return Paragraph(txt, sBody)
def bullet(txt, level=1): return Paragraph(f"• {txt}", sBullet if level==1 else sBullet2)
def warn(txt): return Paragraph(f"⚠ {txt}", sWarn)
def alert(txt): return Paragraph(f"🔴 {txt}", sAlert)
def green(txt): return Paragraph(f"✔ {txt}", sGreen)
def sp(h=4): return Spacer(1, h)
def hr(): return HRFlowable(width="100%", thickness=0.5, color=LIGHT_GREY, spaceBefore=4, spaceAfter=4)

def make_table(headers, rows, col_widths=None, zebra=True):
    """Generic styled table."""
    data = [[Paragraph(f"<b>{h}</b>", ParagraphStyle("th", fontSize=8,
                textColor=WHITE, fontName="Helvetica-Bold", leading=10)) for h in headers]]
    for i, row in enumerate(rows):
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                       textColor=BLACK)) for c in row])
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    t = Table(data, colWidths=w, repeatRows=1)
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        ("BACKGROUND", (0,0), (-1,0), TABLE_HEAD),
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        ("LEFTPADDING", (0,0), (-1,-1), 5),
    ]
    t.setStyle(TableStyle(style))
    return t

# ── Cover page ───────────────────────────────────────────────────────────────
def cover_page():
    elems = []
    # Big blue banner
    elems.append(Spacer(1, 1*cm))
    banner_data = [[Paragraph(
        '<font size="22" color="white"><b>FEBRILE ALTERED SENSORIUM</b></font><br/>'
        '<font size="13" color="#93c5fd">Approach in Casualty — Complete Clinical Notes</font>',
        ParagraphStyle("banner", alignment=TA_CENTER, leading=30))]]
    banner = Table(banner_data, colWidths=[W - 3.6*cm])
    banner.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), DARK_BLUE),
        ("TOPPADDING", (0,0), (-1,-1), 18),
        ("BOTTOMPADDING", (0,0), (-1,-1), 18),
        ("LEFTPADDING", (0,0), (-1,-1), 20),
        ("RIGHTPADDING", (0,0), (-1,-1), 20),
        ("ROUNDEDCORNERS", [8]),
    ]))
    elems.append(banner)
    elems.append(sp(16))

    # Info boxes row
    boxes = [
        ("SCOPE", "Emergency / Casualty", MED_BLUE),
        ("LEVEL", "PG / Senior UG", MED_BLUE),
        ("SOURCES", "Harrison's · Bradley's\nGoldman-Cecil · Rosen's", MED_BLUE),
        ("DATE", datetime.date.today().strftime("%B %Y"), MED_BLUE),
    ]
    box_data = []
    for title, val, col in boxes:
        box_data.append(
            Paragraph(f'<font color="white"><b>{title}</b></font><br/>'
                      f'<font color="#bfdbfe" size="9">{val}</font>',
                      ParagraphStyle("bx", alignment=TA_CENTER, leading=14)))
    brow = Table([box_data], colWidths=[(W-3.6*cm)/4]*4)
    brow.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), MED_BLUE),
        ("TOPPADDING", (0,0), (-1,-1), 10),
        ("BOTTOMPADDING", (0,0), (-1,-1), 10),
        ("GRID", (0,0), (-1,-1), 0.5, WHITE),
    ]))
    elems.append(brow)
    elems.append(sp(20))

    # Contents outline
    elems.append(Paragraph("<b>Contents at a Glance</b>",
        ParagraphStyle("cov", fontSize=12, textColor=DARK_BLUE, spaceAfter=8)))
    sections = [
        ("Step 0", "Initial Stabilization — ABC + Glucose"),
        ("Step 1", "Define the Syndrome — Meningitis vs Encephalitis"),
        ("Step 2", "Temporal Classification — Hyperacute / Acute / Subacute / Chronic"),
        ("Step 3", "Clinical Differentiation at Bedside"),
        ("Step 4", "Investigations — Blood, CT, MRI, CSF"),
        ("Step 5", "Specific Conditions — Bacterial, HSV, TBM, Cryptococcal, JE, Autoimmune"),
        ("Step 6", "Empirical Treatment Protocol"),
        ("Step 7", "Complications and their Management"),
        ("Step 8", "Quick Reference Tables"),
    ]
    for num, desc in sections:
        row = Table([[
            Paragraph(f"<b>{num}</b>", ParagraphStyle("cn", fontSize=9, textColor=WHITE,
                alignment=TA_CENTER)),
            Paragraph(desc, ParagraphStyle("cd", fontSize=9, textColor=DARK_BLUE))
        ]], colWidths=[2*cm, W - 3.6*cm - 2*cm])
        row.setStyle(TableStyle([
            ("BACKGROUND", (0,0), (0,0), MED_BLUE),
            ("BACKGROUND", (1,0), (1,0), LIGHT_BLUE),
            ("TOPPADDING", (0,0), (-1,-1), 5),
            ("BOTTOMPADDING", (0,0), (-1,-1), 5),
            ("LEFTPADDING", (0,0), (-1,-1), 8),
            ("GRID", (0,0), (-1,-1), 0.3, HexColor("#93c5fd")),
        ]))
        elems.append(row)
        elems.append(sp(2))

    elems.append(PageBreak())
    return elems

# ═══════════════════════════════════════════════════════════════════════════════
# CONTENT
# ═══════════════════════════════════════════════════════════════════════════════
story = []
story += cover_page()

# ── STEP 0 ───────────────────────────────────────────────────────────────────
story.append(h1("STEP 0 — INITIAL STABILIZATION AT CASUALTY"))
story.append(sp(6))
story += h2("Primary Survey (ABCDE + Glucose)")
story.append(sp(3))

abcde = [
    ("A — Airway", "Ensure patent. Jaw thrust / chin lift. Intubate if GCS ≤8 or loss of protective reflexes.", ACCENT_RED),
    ("B — Breathing", "High-flow O2. Target SpO2 >94%. Watch for Cheyne-Stokes or Kussmaul breathing.", MED_BLUE),
    ("C — Circulation", "Two large-bore IV lines. NS 500 mL bolus if hypotensive. Continuous BP + pulse oximetry.", MED_BLUE),
    ("D — Disability", "GCS (E+V+M), pupil size/reactivity, limb posturing (decorticate vs decerebrate).", DARK_BLUE),
    ("E — Exposure", "Full skin exam — petechiae? herpes vesicles? meningococcal rash? Temp, signs of trauma.", DARK_BLUE),
    ("G — Glucose", "BEDSIDE CAPILLARY BGL IMMEDIATELY. Give D50 50 mL IV bolus if BGL <60 mg/dL.", ACCENT_GREEN),
]
for letter, detail, col in abcde:
    row = Table([[
        Paragraph(f"<b>{letter}</b>", ParagraphStyle("al", fontSize=9.5, textColor=WHITE, alignment=TA_CENTER)),
        Paragraph(detail, ParagraphStyle("ad", fontSize=8.5, leading=12))
    ]], colWidths=[3*cm, W - 3.6*cm - 3*cm])
    row.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (0,0), col),
        ("BACKGROUND", (1,0), (1,0), LIGHT_GREY),
        ("TOPPADDING", (0,0), (-1,-1), 6), ("BOTTOMPADDING", (0,0), (-1,-1), 6),
        ("LEFTPADDING", (0,0), (-1,-1), 8),
        ("GRID", (0,0), (-1,-1), 0.4, HexColor("#cbd5e1")),
    ]))
    story.append(row); story.append(sp(2))

story.append(sp(6))
story.append(alert("Do NOT delay empirical antibiotics for CT scan or LP results in a sick patient. Time to antibiotics target: <60 minutes from door."))

# ── STEP 1 ───────────────────────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("STEP 1 — DEFINE THE SYNDROME"))
story.append(sp(6))
story += h2("Febrile Altered Sensorium = Fever + Altered Consciousness (GCS <15 or confusion)")
story.append(sp(4))

story.append(make_table(
    ["Feature", "Meningitis", "Meningoencephalitis / Encephalitis"],
    [
        ["Predominant sign", "Meningism (neck stiffness, Kernig's, Brudzinski's)", "Altered behaviour / consciousness / focal neurology"],
        ["Parenchymal involvement", "No", "Yes"],
        ["Seizures", "Late / uncommon", "Common, early (especially HSV)"],
        ["CSF cells", "Pleocytosis", "Pleocytosis (may be normal in autoimmune)"],
        ["MRI changes", "Meningeal enhancement only", "Parenchymal signal change"],
    ],
    col_widths=[3.5*cm, 6.5*cm, 6.5*cm]
))
story.append(sCaption and Paragraph("In practice, both frequently coexist as meningoencephalitis.", sCaption))
story.append(sp(8))

story += h2("Meningeal Signs — Sensitivity & Specificity (Rosen's Emergency Medicine)")
story.append(sp(3))
story.append(make_table(
    ["Sign", "Sensitivity", "Specificity", "Clinical Pearl"],
    [
        ["Headache", "91%", "16%", "High sensitivity; very non-specific"],
        ["Nuchal rigidity", "13%", "80%", "Absence does NOT rule out meningitis"],
        ["Kernig's sign", "2%", "97%", "High specificity when present"],
        ["Brudzinski's sign", "2%", "98%", "High specificity when present"],
        ["Jolt accentuation", "21%", "82%", "Useful bedside sign"],
        ["Focal neurological deficit", "2%", "96%", "Suggests abscess / encephalitis"],
    ],
    col_widths=[3.5*cm, 2.5*cm, 2.5*cm, 8*cm]
))
story.append(warn("Classic triad (Fever + Neck stiffness + Altered sensorium) is present together in only 44% of bacterial meningitis cases. A high index of suspicion is mandatory."))

# ── STEP 2 ───────────────────────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("STEP 2 — TEMPORAL CLASSIFICATION"))
story.append(sp(4))

timeline_blocks = [
    ("HYPERACUTE\n< 24 hours", ACCENT_RED, [
        "Bacterial meningitis — N. meningitidis (petechial/purpuric rash, rapid deterioration)",
        "Bacterial meningitis — S. pneumoniae (elderly, post-splenectomy, sinusitis/otitis)",
        "Herpes simplex encephalitis (temporal lobe seizures, behavioral change)",
        "Cerebral malaria (travel history, smear positive)",
        "Subarachnoid haemorrhage (thunderclap headache, initially afebrile — mimic)",
        "Sepsis with encephalopathy (multiorgan features, source elsewhere)",
    ]),
    ("ACUTE\n1 – 7 days", MED_BLUE, [
        "Viral meningitis — Enterovirus (most common; younger patient, summer/monsoon)",
        "HSV encephalitis (personality change, temporal seizures, psychosis)",
        "West Nile virus encephalitis (flaccid paralysis, elderly, mosquito exposure)",
        "Listeria meningitis (elderly/immunocompromised, rhombencephalitis features)",
        "Early brain abscess (focal deficits, dental/ear/lung source)",
        "Typhoid encephalopathy (rose spots, relative bradycardia, endemic setting)",
        "Japanese encephalitis (bilateral thalamic involvement, monsoon, rural)",
    ]),
    ("SUBACUTE\n1 – 4 weeks", ACCENT_AMBER, [
        "Tuberculous meningitis — TBM (most common subacute in India; constitutional prodrome, basilar CN palsies)",
        "Cryptococcal meningitis (HIV, CD4 <100; headache dominant, minimal meningism)",
        "Autoimmune encephalitis — anti-NMDA-R (young female, psychiatric prodrome, orofacial dyskinesias)",
        "Japanese encephalitis (thalamic lesions on MRI; overlap with acute)",
        "Partially treated bacterial meningitis (history of antibiotics, modified CSF)",
        "Neurosyphilis (MSM, HIV, CN palsies, positive VDRL/RPR)",
    ]),
    ("CHRONIC\n> 4 weeks", DARK_BLUE, [
        "TBM (classical; TB exposure, HIV, hydrocephalus, CN palsies)",
        "Cryptococcal meningitis (AIDS, minimal meningism, very high ICP)",
        "Carcinomatous meningitis (known malignancy, multiple CN palsies)",
        "Neurosyphilis (positive serology, HIV co-infection)",
        "Neurocysticercosis (calcifications CT, seizures, India endemic)",
        "Neurosarcoidosis (CN VII palsy, systemic sarcoid features, hypercalcaemia)",
        "Brucella meningitis (animal exposure, zoonosis)",
    ]),
]

for label, col, items in timeline_blocks:
    hdr = Table([[Paragraph(f"<b>{label}</b>",
            ParagraphStyle("th", fontSize=10, textColor=WHITE, alignment=TA_CENTER, leading=14))]],
        colWidths=[W - 3.6*cm])
    hdr.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), col),
        ("TOPPADDING", (0,0), (-1,-1), 8), ("BOTTOMPADDING", (0,0), (-1,-1), 8),
    ]))
    story.append(hdr)
    for item in items:
        story.append(bullet(item))
    story.append(sp(8))

# ── STEP 3 ───────────────────────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("STEP 3 — CLINICAL DIFFERENTIATION AT BEDSIDE"))
story.append(sp(4))

story.append(make_table(
    ["Feature", "Bacterial", "HSV Encephalitis", "TBM", "JE", "Autoimmune"],
    [
        ["Onset",         "Hyperacute",    "Acute",              "Subacute (1-3 wk)",    "Acute-subacute",   "Subacute"],
        ["Fever",         "High, sudden",  "Moderate-high",      "Low-grade, evenings",  "High",             "Low/absent"],
        ["Rash",          "Petechiae (meningococcus)", "Vesicles (rare)", "None", "None", "None"],
        ["Psychiatric Sx","Absent",        "Prominent (temporal lobe)", "Late",      "Variable",         "Very prominent"],
        ["CN palsies",    "Rare early",    "Rare",               "Early (III, VI, VII)", "Rare",             "Rare"],
        ["Seizures",      "Late",          "Early, temporal",    "Common",               "Common",           "Orofacial dyskinesias"],
        ["MRI",           "Normal / meningeal enhancement", "Temporal FLAIR hyperintensity", "Basal meningeal enhancement + hydrocephalus", "Bilateral thalamic T2 signal", "Often normal"],
        ["CSF glucose",   "Very low (<40)", "Normal",            "Low (<45)",            "Normal",           "Normal"],
        ["CSF cells",     "PMN >80%",      "Lymphocytes",        "Lymphocytes",          "Lymphocytes",      "Normal / mild lymphocytes"],
        ["Specific test", "Gram stain, culture, BioFire PCR", "HSV PCR (96% sens)", "ADA, MTB PCR, AFB culture", "JE IgM serum/CSF", "Anti-NMDA-R, LGI1, CASPR2 Ab"],
    ],
    col_widths=[2.6*cm, 2.6*cm, 3*cm, 3.1*cm, 2.5*cm, 2.6*cm]
))
story.append(sp(4))
story.append(Paragraph("<i>Harrison's 22E, p.1164: \"MRI abnormalities (other than meningeal enhancement) are not seen in uncomplicated bacterial meningitis. By contrast, in HSV encephalitis, T2/FLAIR/DWI images show high-signal lesions in temporal lobes within 48h of symptom onset.\"</i>",
    ParagraphStyle("q", fontSize=8, textColor=MID_GREY, leftIndent=10, spaceAfter=4)))

# ── STEP 4 — Investigations ──────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("STEP 4 — INVESTIGATIONS"))
story.append(sp(4))

story += h2("A. Immediate Blood Tests (Order Stat)")
for b in [
    "CBC with differential — leucocytosis (bacterial); lymphocytosis (viral/TBM)",
    "Blood culture ×2 — BEFORE antibiotics, but NEVER delay antibiotics for culture results",
    "Bedside capillary glucose; serum glucose",
    "Serum electrolytes, LFT, RFT, urea, creatinine (look for SIADH — hyponatraemia is common in TBM)",
    "Serum Procalcitonin — >0.5 ng/mL suggests bacterial aetiology",
    "CRP",
    "Peripheral smear for malaria (Giemsa) — mandatory in endemic setting",
    "HIV ELISA — always order (changes entire differential and management)",
    "Coagulation profile (PT, APTT, platelet count) — assess DIC in meningococcaemia",
    "Blood lactate — raised in sepsis; helps risk-stratify",
]:
    story.append(bullet(b))

story.append(sp(6))
story += h2("B. CT Head — When to Do BEFORE LP")
story.append(alert("Perform CT head FIRST (before LP) if ANY of these are present:\nPapilledema · Focal neurological deficit · New-onset seizures · GCS <12 · Immunocompromised · Age >60 · History of CNS disease (tumour, stroke, focal infection)"))
story.append(sp(4))
story.append(green("CT normal does NOT exclude meningitis. If CT is normal, proceed to LP without further delay."))

story.append(sp(4))
story.append(make_table(
    ["Condition", "CT Finding"],
    [
        ["Bacterial meningitis", "Often normal; sulcal effacement, hydrocephalus, meningeal enhancement late"],
        ["Brain abscess", "Hypodense ring-enhancing lesion with surrounding vasogenic oedema"],
        ["HSV encephalitis", "Hypodensity in temporal lobe — may be NORMAL in first 48h (MRI far superior)"],
        ["TBM", "Basal meningeal enhancement, communicating hydrocephalus, basal ganglia infarcts"],
        ["Cryptococcal meningitis", "'Soap bubble' lesions (cryptococcomas), dilated Virchow-Robin spaces, hydrocephalus"],
        ["Neurocysticercosis", "Calcified cysts, 'hole with a dot' (scolex), perilesional oedema"],
        ["Cerebral malaria", "Diffuse cerebral oedema"],
        ["SAH", "Hyperdense subarachnoid blood in basal cisterns, sylvian fissures"],
    ],
    col_widths=[4.5*cm, 12*cm]
))

story.append(PageBreak())
story += h2("C. MRI Brain — Key Sequences and Findings")
story.append(sp(3))
story.append(make_table(
    ["Condition", "MRI Sequence", "Key Finding"],
    [
        ["HSV Encephalitis", "T2 / FLAIR / DWI", "Hyperintensity in orbitofrontal + medial/anterior temporal lobes; DWI restriction; haemorrhage possible. Changes within 48h."],
        ["TBM", "T1+Gad / T2 / DWI", "Basal (sylvian / interpeduncular) meningeal enhancement; communicating hydrocephalus; ischaemic infarcts (perforators); tuberculoma = target lesion"],
        ["Bacterial meningitis", "T1+Gad", "Meningeal enhancement; complications: subdural empyema, cortical venous thrombosis, infarcts"],
        ["Japanese Encephalitis", "T2 / FLAIR", "Bilateral thalamic hyperintensity (hallmark); substantia nigra; basal ganglia"],
        ["Anti-NMDA-R Encephalitis", "FLAIR", "Often normal; may have hippocampal, cingulate, frontal FLAIR signal"],
        ["Cryptococcal meningitis", "T2 / FLAIR", "Dilated Virchow-Robin spaces (gelatinous pseudocysts); basal meningitis; hydrocephalus"],
        ["Brain abscess", "T1+Gad / DWI", "Ring-enhancing wall (T1); T2-hypointense capsule; DWI restricted diffusion in pus (distinguishes from tumour)"],
        ["CVST", "MRV / T1", "Absent flow on MRV; T1 iso-hyperintense clot in sinus; haemorrhagic venous infarcts"],
    ],
    col_widths=[3.5*cm, 3*cm, 10*cm]
))

# ── CSF ──────────────────────────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("STEP 4D — CSF ANALYSIS (The Cornerstone)"))
story.append(sp(4))

story += h2("Contraindications to LP")
for b in [
    "Signs of raised ICP — papilledema, Cushing's triad (HTN + bradycardia + irregular breathing)",
    "Focal deficit suggesting mass lesion — do CT first",
    "Coagulopathy — platelets <50,000 or INR >1.5",
    "Infection at the proposed puncture site",
]:
    story.append(bullet(b))
story.append(warn("Brain abscess: LP plays NO role in diagnosis and risks herniation. CT-guided aspiration + antibiotics is the standard."))

story.append(sp(4))
story += h2("CSF Profile Comparison")
story.append(make_table(
    ["Parameter", "Normal", "Bacterial", "Viral", "TBM", "Cryptococcal"],
    [
        ["Opening pressure", "70–180 mm H₂O", ">200 (may be 400–500)", "Normal to ↑", "200–400", "↑↑ often >250"],
        ["Appearance", "Clear, colourless", "Turbid / purulent", "Clear", "Xanthochromic; forms cobweb", "Clear / opalescent"],
        ["WBC (cells/μL)", "<5", "10–10,000 (PMN >80%)", "50–1000 (lymphocytes)", "100–500 (lymphocytes)", "10–500 (lymphocytes)"],
        ["Glucose (mg/dL)", "45–85", "<40 (hypoglycorrhachia)", "Normal 40–80", "Low <45", "Low <45"],
        ["CSF:Serum glucose", ">0.6", "<0.4 (highly suggestive)", "Normal >0.6", "<0.4", "<0.4"],
        ["Protein (mg/dL)", "15–45", ">100 (often >200)", "60–100 (mild ↑)", ">100 (markedly ↑)", ">100"],
        ["Gram stain", "–", "Positive >60%", "–", "– (AFB rare)", "–"],
        ["Culture", "–", "Positive >80%", "Viral culture 65–75%", "AFB (6–8 wk)", "Fungal culture"],
        ["Special tests", "–", "BioFire PCR panel (1h result)", "Viral PCR (HSV, Enterovirus)", "ADA >10 U/L; MTB PCR; AFB", "India Ink; CrAg (>95% sens)"],
    ],
    col_widths=[3.5*cm, 2.6*cm, 2.8*cm, 2.8*cm, 2.8*cm, 2.9*cm]
))

story.append(sp(4))
story += h2("CSF Pearls")
pearls = [
    "<b>CSF lactate >3.5 mmol/L</b> strongly favours bacterial over viral meningitis — useful when Gram stain is negative.",
    "<b>ADA >10 U/L</b> in CSF: sensitivity 59%, specificity 96% for TBM.",
    "<b>BioFire ME Panel (multiplex PCR):</b> detects 14 pathogens (bacterial + viral + Cryptococcus) in 1 hour.",
    "<b>HSV PCR:</b> sensitivity 96%, specificity 99% when performed 72h after symptom onset.",
    "<b>Early enteroviral meningitis:</b> PMN may predominate in first 24–48h in ~50% of cases — can mimic bacterial.",
    "<b>Cobweb clot</b> on standing CSF = classic TBM feature (high protein + fibrinogen).",
    "<b>India Ink</b> positive in 60–70% of cryptococcal meningitis; Cryptococcal Antigen (CrAg) is faster and >95% sensitive.",
    "<b>CSF/serum glucose <0.4</b> is highly suggestive of bacterial, fungal, or tuberculous meningitis.",
]
for p in pearls:
    story.append(bullet(p))

# ── STEP 5 ───────────────────────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("STEP 5 — SPECIFIC CONDITIONS"))
story.append(sp(4))

# Bacterial
story += h2("5A. Bacterial Meningitis — Organisms by Age")
story.append(make_table(
    ["Age Group", "Common Organisms", "Notes"],
    [
        ["Neonates <1 month", "GBS (S. agalactiae), E. coli (K1), Listeria", "Ampicillin + Cefotaxime empirically"],
        ["Infants 1–3 months", "GBS, E. coli, H. influenzae, S. pneumoniae", "Ampicillin + Cefotaxime or Ceftriaxone"],
        ["Children 3m – 5y", "H. influenzae, S. pneumoniae, N. meningitidis", "Hib vaccine has greatly reduced H. influenzae"],
        ["Adults <55 (immunocompetent)", "S. pneumoniae, N. meningitidis", "Ceftriaxone + Vancomycin"],
        ["Adults >55 / Alcoholic", "S. pneumoniae, N. meningitidis, Listeria", "Add Ampicillin to cover Listeria"],
        ["Post-neurosurgery / Trauma", "S. aureus, CoNS, Klebsiella, Pseudomonas", "Vancomycin + Ceftazidime / Meropenem"],
        ["HIV / Immunocompromised", "Cryptococcus, Listeria, Gram-negative rods", "Add Amphotericin if Crypto suspected"],
    ],
    col_widths=[3.5*cm, 6*cm, 7*cm]
))

story.append(sp(6))
story += h2("5B. Herpes Simplex Encephalitis (HSE)")
for b in [
    "Pathogen: HSV-1 (adults); HSV-2 (neonates, immunocompromised)",
    "Predilection: temporal and orbitofrontal lobes (trigeminal ganglion reactivation route)",
    "Clinical: Fever + Headache + Altered consciousness + Personality/behavioural changes (first sign, may mimic psychiatry) + Temporal lobe seizures + Aphasia + Psychosis/hallucinations",
    "Diagnosis: CSF HSV PCR (sens 96%, spec 99%); MRI T2/FLAIR temporal hyperintensity (within 48h); EEG = PLEDs (periodic lateralised epileptiform discharges)",
    "Treatment: Acyclovir 10 mg/kg IV q8h for 14–21 days — start EMPIRICALLY even before CSF results",
]:
    story.append(bullet(b))

story.append(sp(6))
story += h2("5C. Tuberculous Meningitis (TBM)")
story.append(make_table(
    ["Phase", "Duration", "Features"],
    [
        ["Prodrome", "1–3 weeks", "Malaise, fatigue, anorexia, low-grade fever, headache, mild behavioural change"],
        ["Meningitic", "Days–weeks", "Worsening headache, neck stiffness, vomiting, photophobia, CN palsies (III, VI, VII), hyponatraemia (SIADH)"],
        ["Advanced", "Late", "Stupor, coma, hemiplegia, decerebrate posturing, communicating hydrocephalus"],
    ],
    col_widths=[3*cm, 3*cm, 10.5*cm]
))
story.append(sp(3))
story.append(h3("MRC Grading:"))
story.append(make_table(
    ["Grade", "Consciousness", "Deficit"],
    [
        ["Grade I", "GCS 15", "No focal deficit"],
        ["Grade II", "GCS 11–14", "OR any focal deficit"],
        ["Grade III", "GCS ≤10", "Any neurological deficit"],
    ],
    col_widths=[2.5*cm, 4*cm, 10*cm]
))
story.append(sp(3))
story.append(h3("Treatment — Anti-TB Therapy (ATT):"))
for b in [
    "Intensive phase (2 months): HRZE — Isoniazid + Rifampicin + Pyrazinamide + Ethambutol",
    "Continuation phase (7–10 months): HR (± Ethambutol)",
    "STEROIDS ARE MANDATORY: Dexamethasone 0.4 mg/kg/day (Grade II/III) OR Prednisolone 60 mg/day — taper over 6–8 weeks (reduces mortality and neurological sequelae)",
    "Pyridoxine 25–50 mg/day with INH to prevent peripheral neuropathy",
    "Manage SIADH: fluid restriction; hypertonic saline if Na+ <120 or symptomatic",
    "Communicating hydrocephalus: serial LP; VP shunt if refractory",
]:
    story.append(bullet(b))

story.append(sp(6))
story += h2("5D. Cryptococcal Meningitis")
for b in [
    "Setting: HIV (CD4 <100 cells/μL), transplant, steroids, lymphoma",
    "Clinical: Subacute-chronic; headache dominant; fever low-grade or absent; meningism often minimal; RAISED ICP is the most dangerous feature",
    "Diagnosis: CrAg (>95% sens — fastest); India Ink 60–70%; Fungal culture",
    "Induction (2 wk): Liposomal Amphotericin B 3–4 mg/kg/day + Flucytosine 25 mg/kg QDS",
    "Consolidation (8 wk): Fluconazole 400 mg/day",
    "Maintenance: Fluconazole 200 mg/day until CD4 >200 on ART for 6 months",
    "ICP management: Therapeutic LP daily until opening pressure <200 mm H₂O",
]:
    story.append(bullet(b))

# ── STEP 6 ───────────────────────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("STEP 6 — EMPIRICAL TREATMENT PROTOCOL"))
story.append(sp(4))

story.append(alert("ANTIBIOTICS FIRST, INVESTIGATIONS SECOND in any critically ill patient.\nDo NOT wait for: CT scan · Blood culture results · LP results\nTime to antibiotics target: <60 minutes from patient arrival."))
story.append(sp(6))

story += h2("Empirical Regimen by Clinical Scenario (Harrison's 22E, Table 143-1)")
story.append(make_table(
    ["Clinical Scenario", "Empirical Regimen"],
    [
        ["Immunocompetent adult <55", "Ceftriaxone 2g IV q12h + Vancomycin 15–20 mg/kg IV q8–12h"],
        ["Adult >55 / Alcoholic / Immunosuppressed", "Ceftriaxone 2g IV q12h + Vancomycin + Ampicillin 2g IV q4h (cover Listeria)"],
        ["Post-neurosurgery / Hospital-acquired / Neutropenic", "Vancomycin + Ceftazidime 2g IV q8h OR Meropenem 2g IV q8h"],
        ["HSV encephalitis suspected (temporal features)", "+ Acyclovir 10 mg/kg IV q8h — add to above regimen"],
        ["TBM suspected", "Start HRZE + Dexamethasone 0.4 mg/kg/day"],
        ["Cryptococcal suspected (HIV/immunocompromised)", "Liposomal Amphotericin B + Flucytosine"],
        ["Cerebral malaria", "Artesunate IV 2.4 mg/kg at 0h, 12h, 24h, then daily"],
        ["Neonates", "Ampicillin + Cefotaxime"],
        ["Rickettsial (suspected)", "Doxycycline 100 mg IV/PO q12h"],
    ],
    col_widths=[6*cm, 10.5*cm]
))

story.append(sp(6))
story += h2("Dexamethasone as Adjunct in Bacterial Meningitis")
story.append(green("Dexamethasone 0.15 mg/kg IV q6h for 4 days.\nGive 15–20 minutes BEFORE or WITH the first antibiotic dose.\nProven benefit: reduces mortality and neurological sequelae in pneumococcal meningitis.\nDiscontinue if organism is NOT S. pneumoniae (less evidence for others)."))

story.append(sp(6))
story += h2("Antibiotic Doses (Harrison's 22E)")
story.append(make_table(
    ["Antibiotic", "Adult Dose", "Duration"],
    [
        ["Ceftriaxone", "2g IV q12h", "7 days (meningococcus); 10–14 days (pneumococcus)"],
        ["Cefotaxime", "3g IV q6h (12g/day)", "Same as above"],
        ["Vancomycin", "15–20 mg/kg IV q8–12h (AUC-guided)", "With Ceftriaxone until sensitivities known"],
        ["Ampicillin", "2g IV q4h (12g/day)", "21 days (Listeria)"],
        ["Meropenem", "2g IV q8h", "21 days (gram-negative)"],
        ["Acyclovir", "10 mg/kg IV q8h (adjust for renal function)", "14–21 days (HSV)"],
        ["Metronidazole", "500 mg IV q8h", "Added for brain abscess (anaerobes)"],
    ],
    col_widths=[3.5*cm, 5.5*cm, 7.5*cm]
))

# ── STEP 7 ───────────────────────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("STEP 7 — COMPLICATIONS AND MANAGEMENT"))
story.append(sp(4))

story.append(make_table(
    ["Complication", "How to Detect", "Management"],
    [
        ["Raised ICP / Herniation", "Cushing's triad (HTN + bradycardia + irregular breathing), pupil changes, posturing", "Mannitol 1g/kg IV; elevate HOB 30°; hyperventilate to pCO₂ 30–35; urgent neurosurgery"],
        ["Status epilepticus", "EEG monitoring; clinical observation", "Lorazepam 0.1 mg/kg IV; then Levetiracetam or Phenytoin"],
        ["Hyponatraemia (SIADH)", "Serum Na+ <135; serum hypo-osmolality + urine hyperosmolality", "Fluid restriction; hypertonic saline 3% if Na+ <120 or symptomatic seizures"],
        ["Septic shock", "MAP <65 mmHg, lactate >2, poor urine output", "Norepinephrine first-line vasopressor; hydrocortisone if refractory"],
        ["DIC (meningococcaemia)", "Coagulation profile (PT↑, APTT↑, fibrinogen↓, D-dimer↑), petechiae", "FFP, platelet transfusion; address underlying infection"],
        ["Subdural empyema", "MRI contrast — crescentic extra-axial collection with restricted diffusion", "URGENT neurosurgical drainage + prolonged antibiotics"],
        ["Communicating hydrocephalus (TBM)", "Serial CT head, increasing headache, deteriorating GCS", "Serial LP (TBM); VP shunt if refractory"],
        ["Waterhouse-Friderichsen syndrome", "Bilateral adrenal haemorrhage in meningococcaemia; hypotension unresponsive to fluids", "Stress-dose hydrocortisone 100 mg IV q8h"],
        ["Cerebral venous sinus thrombosis (CVST)", "MRV; haemorrhagic venous infarcts on MRI", "Anticoagulation (LMWH / heparin) even with haemorrhage"],
        ["Brain herniation patterns", "Uncal: ipsilateral fixed dilated pupil + contralateral hemiplegia; Transtentorial: bilateral signs, Cushing's", "Emergency mannitol + intubation + neurosurgery"],
    ],
    col_widths=[4*cm, 5*cm, 7.5*cm]
))

# ── STEP 8 — Quick Ref ───────────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("STEP 8 — QUICK REFERENCE SUMMARY"))
story.append(sp(4))

story += h2("8A. Decision Algorithm — LP vs CT First")
algo = [
    "Patient arrives: Febrile + Altered Sensorium",
    "   ↓",
    "STABILIZE: ABC + Bedside Glucose + IV access + O2",
    "   ↓",
    "Papilledema? Focal deficit? GCS <12? Immunocompromised? Age >60?",
    "   YES → CT head FIRST → if no mass, proceed to LP",
    "   NO  → LP directly (blood cultures + start empirical Abx simultaneously)",
    "   ↓",
    "CSF: PMN + Low glucose + High protein → BACTERIAL → Continue Abx + Dexamethasone",
    "CSF: Lymphocytes + Normal glucose       → VIRAL     → Acyclovir (HSV) vs Supportive",
    "CSF: Lymphocytes + Low glucose + High protein → TBM/FUNGAL → ATT vs Ampho-B + CrAg",
]
for line in algo:
    story.append(Paragraph(line, ParagraphStyle("algo", fontSize=8.5, fontName="Courier",
        leading=13, spaceAfter=1, leftIndent=10)))

story.append(sp(6))
story += h2("8B. Duration of Antibiotics")
story.append(make_table(
    ["Organism", "Duration"],
    [
        ["N. meningitidis", "7 days"],
        ["H. influenzae", "7–10 days"],
        ["S. pneumoniae", "10–14 days"],
        ["L. monocytogenes", "21 days"],
        ["Gram-negative enteric rods", "21 days"],
        ["TBM (ATT)", "9–12 months total (2 HRZE + 7-10 HR)"],
        ["Brain abscess", "6–8 weeks IV ± continued oral"],
        ["HSV encephalitis", "14–21 days Acyclovir"],
    ],
    col_widths=[6*cm, 10.5*cm]
))

story.append(sp(6))
story += h2("8C. Organisms and Gram Stain Guide")
story.append(make_table(
    ["Organism", "Gram Stain", "Age/Risk Group"],
    [
        ["S. pneumoniae", "Gram +ve diplococci (lancet-shaped)", "All adults; elderly; post-splenectomy"],
        ["N. meningitidis", "Gram –ve diplococci (kidney-shaped)", "Young adults, children; petechial rash"],
        ["L. monocytogenes", "Gram +ve rods", ">55, immunocompromised, pregnancy"],
        ["H. influenzae type b", "Gram –ve coccobacilli", "Children <5y (pre-vaccine era)"],
        ["E. coli", "Gram –ve rods", "Neonates"],
        ["Cryptococcus neoformans", "India Ink (encapsulated yeast)", "HIV, CD4 <100"],
    ],
    col_widths=[5*cm, 5*cm, 6.5*cm]
))

story.append(sp(8))
story += h2("References")
refs = [
    "Harrison's Principles of Internal Medicine 22E (2025, McGraw Hill) — Chapters 142, 143",
    "Bradley and Daroff's Neurology in Clinical Practice — Chapter 79",
    "Goldman-Cecil Medicine International Edition — Chapters 381, 367",
    "Rosen's Emergency Medicine 9E — Chapter 95",
    "Jawetz Melnick & Adelbergs Medical Microbiology 28E — Chapter 48",
    "Harriet Lane Handbook 23E — Chapter 17",
    "Murray & Nadel's Textbook of Respiratory Medicine — CNS Tuberculosis",
]
for r in refs:
    story.append(Paragraph(f"• {r}", ParagraphStyle("ref", fontSize=8, leading=11,
        textColor=MID_GREY, leftIndent=14, firstLineIndent=-10, spaceAfter=2)))

# ── BUILD ────────────────────────────────────────────────────────────────────
doc.build(story, onFirstPage=draw_header_footer, onLaterPages=draw_header_footer)
print(f"PDF generated: {OUTPUT}")

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm, mm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, Image, KeepTogether
)
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.lib.colors import HexColor
import datetime, os

OUTPUT = "/tmp/workspace/autoimmune-encephalitis/Autoimmune_Encephalitis_Notes.pdf"
IMG_PATHOMECH = "/tmp/workspace/autoimmune-encephalitis/pathomech.png"

W, H = A4

# ── Colour palette ──────────────────────────────────────────────────────────
DARK_TEAL   = HexColor("#0f4c5c")
MED_TEAL    = HexColor("#0e7490")
LIGHT_TEAL  = HexColor("#cffafe")
ACCENT_PURP = HexColor("#7c3aed")
ACCENT_RED  = HexColor("#dc2626")
ACCENT_AMB  = HexColor("#d97706")
ACCENT_GRN  = HexColor("#16a34a")
LIGHT_GREY  = HexColor("#f1f5f9")
MID_GREY    = HexColor("#64748b")
TABLE_HEAD  = HexColor("#0e7490")
TABLE_ALT   = HexColor("#ecfeff")
WHITE       = colors.white
BLACK       = colors.black
GOLD        = HexColor("#854d0e")

# ── Header/Footer ────────────────────────────────────────────────────────────
def draw_hf(canvas, doc):
    canvas.saveState()
    canvas.setFillColor(DARK_TEAL)
    canvas.rect(0, H - 1.9*cm, W, 1.9*cm, fill=1, stroke=0)
    canvas.setFillColor(WHITE)
    canvas.setFont("Helvetica-Bold", 11)
    canvas.drawString(1.2*cm, H - 1.3*cm, "AUTOIMMUNE ENCEPHALITIS — Complete Clinical Notes")
    canvas.setFont("Helvetica", 8.5)
    canvas.drawRightString(W - 1.2*cm, H - 1.3*cm, f"Page {doc.page}")
    # Bottom
    canvas.setFillColor(DARK_TEAL)
    canvas.rect(0, 0, W, 0.9*cm, fill=1, stroke=0)
    canvas.setFillColor(WHITE)
    canvas.setFont("Helvetica-Oblique", 7.5)
    canvas.drawString(1.2*cm, 0.32*cm,
        "Sources: Harrison's 22E (2025) · Adams & Victor's Neurology 12E · Rheumatology 2022 · Washington Manual · PubMed 2025 Meta-Analysis [PMID: 40472799]")
    canvas.restoreState()

# ── Document ─────────────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
    OUTPUT, pagesize=A4,
    rightMargin=1.8*cm, leftMargin=1.8*cm,
    topMargin=2.7*cm, bottomMargin=1.5*cm,
    title="Autoimmune Encephalitis Notes",
    author="Medical Education"
)

# ── Styles ────────────────────────────────────────────────────────────────────
base = getSampleStyleSheet()

def S(name, parent="Normal", **kw):
    return ParagraphStyle(name, parent=base[parent], **kw)

sH1      = S("sH1",  "Normal", fontSize=14, textColor=WHITE, fontName="Helvetica-Bold",
             backColor=DARK_TEAL, spaceBefore=12, spaceAfter=5, borderPad=7)
sH2      = S("sH2",  "Normal", fontSize=11, textColor=DARK_TEAL, fontName="Helvetica-Bold",
             spaceBefore=9, spaceAfter=3)
sH3      = S("sH3",  "Normal", fontSize=9.5, textColor=MED_TEAL, fontName="Helvetica-Bold",
             spaceBefore=6, spaceAfter=2)
sBody    = S("sBody","Normal", fontSize=8.5, leading=13, spaceAfter=3)
sBullet  = S("sBullet","Normal", fontSize=8.5, leading=13,
             leftIndent=14, firstLineIndent=-10, spaceAfter=2)
sBullet2 = S("sBullet2","Normal", fontSize=8, leading=12,
             leftIndent=26, firstLineIndent=-10, spaceAfter=1.5)
sWarn    = S("sWarn","Normal", fontSize=8.5, leading=12,
             backColor=HexColor("#fff7ed"), textColor=HexColor("#92400e"),
             borderColor=ACCENT_AMB, borderWidth=1, borderPad=5,
             spaceBefore=4, spaceAfter=4)
sAlert   = S("sAlert","Normal", fontSize=8.5, leading=12,
             backColor=HexColor("#fef2f2"), textColor=ACCENT_RED,
             borderColor=ACCENT_RED, borderWidth=1, borderPad=5,
             spaceBefore=4, spaceAfter=4)
sGreen   = S("sGreen","Normal", fontSize=8.5, leading=12,
             backColor=HexColor("#f0fdf4"), textColor=HexColor("#14532d"),
             borderColor=ACCENT_GRN, borderWidth=1, borderPad=5,
             spaceBefore=4, spaceAfter=4)
sPurple  = S("sPurple","Normal", fontSize=8.5, leading=12,
             backColor=HexColor("#f5f3ff"), textColor=ACCENT_PURP,
             borderColor=ACCENT_PURP, borderWidth=1, borderPad=5,
             spaceBefore=4, spaceAfter=4)
sCaption = S("sCaption","Normal", fontSize=7.5, textColor=MID_GREY,
             alignment=TA_CENTER, spaceAfter=5, spaceBefore=2)
sQuote   = S("sQuote","Normal", fontSize=8, leading=12, textColor=GOLD,
             leftIndent=15, rightIndent=10, spaceAfter=4,
             borderWidth=0, fontName="Helvetica-Oblique")
sTH      = S("sTH","Normal", fontSize=8, textColor=WHITE, fontName="Helvetica-Bold", leading=10)
sTD      = S("sTD","Normal", fontSize=7.8, leading=10.5, textColor=BLACK)

# ── Helpers ───────────────────────────────────────────────────────────────────
def h1(t): return Paragraph(f" {t}", sH1)
def h2(t): return [HRFlowable(width="100%", thickness=2, color=MED_TEAL, spaceBefore=6, spaceAfter=2),
                   Paragraph(t, sH2)]
def h3(t): return Paragraph(t, sH3)
def body(t): return Paragraph(t, sBody)
def b1(t): return Paragraph(f"• {t}", sBullet)
def b2(t): return Paragraph(f"  – {t}", sBullet2)
def warn(t): return Paragraph(f"⚠ {t}", sWarn)
def alert(t): return Paragraph(f"🔴 {t}", sAlert)
def green(t): return Paragraph(f"✔ {t}", sGreen)
def purple(t): return Paragraph(f"★ {t}", sPurple)
def sp(h=4): return Spacer(1, h)
def hr(): return HRFlowable(width="100%", thickness=0.5, color=LIGHT_GREY, spaceBefore=3, spaceAfter=3)

def tbl(headers, rows, cw=None, zebra=True):
    data = [[Paragraph(f"<b>{h}</b>", sTH) for h in headers]]
    for row in rows:
        data.append([Paragraph(str(c), sTD) for c in row])
    cw = cw or [(W-3.6*cm)/len(headers)]*len(headers)
    t = Table(data, colWidths=cw, repeatRows=1)
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,0), TABLE_HEAD),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[WHITE, TABLE_ALT] if zebra else [WHITE]),
        ("GRID",(0,0),(-1,-1),0.35,HexColor("#a5f3fc")),
        ("VALIGN",(0,0),(-1,-1),"MIDDLE"),
        ("TOPPADDING",(0,0),(-1,-1),4),("BOTTOMPADDING",(0,0),(-1,-1),4),
        ("LEFTPADDING",(0,0),(-1,-1),5),("RIGHTPADDING",(0,0),(-1,-1),5),
    ]))
    return t

CW = W - 3.6*cm  # content width

# ══════════════════════════════════════════════════════════════════════════════
# BUILD STORY
# ══════════════════════════════════════════════════════════════════════════════
story = []

# ── COVER ─────────────────────────────────────────────────────────────────────
story.append(sp(8))
cover = Table([[Paragraph(
    '<font size="24" color="white"><b>AUTOIMMUNE ENCEPHALITIS</b></font><br/>'
    '<font size="12" color="#a5f3fc">Complete Clinical Notes — Pathogenesis · Antibodies · Diagnosis · Treatment</font>',
    ParagraphStyle("cv", alignment=TA_CENTER, leading=32))]], colWidths=[CW])
cover.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1),DARK_TEAL),
    ("TOPPADDING",(0,0),(-1,-1),20),("BOTTOMPADDING",(0,0),(-1,-1),20),
    ("LEFTPADDING",(0,0),(-1,-1),18),
]))
story.append(cover)
story.append(sp(14))

# Info strip
info_data = [
    Paragraph('<font color="white"><b>SPECIALITY</b></font><br/><font color="#a5f3fc" size="9">Neurology / Internal Medicine</font>', ParagraphStyle("inf", alignment=TA_CENTER, leading=14)),
    Paragraph('<font color="white"><b>PRESENTATION</b></font><br/><font color="#a5f3fc" size="9">Subacute Encephalopathy</font>', ParagraphStyle("inf", alignment=TA_CENTER, leading=14)),
    Paragraph('<font color="white"><b>PRIMARY SOURCE</b></font><br/><font color="#a5f3fc" size="9">Harrison\'s 22E (Dalmau &amp; Graus)</font>', ParagraphStyle("inf", alignment=TA_CENTER, leading=14)),
    Paragraph(f'<font color="white"><b>UPDATED</b></font><br/><font color="#a5f3fc" size="9">PubMed 2025 Meta-Analysis</font>', ParagraphStyle("inf", alignment=TA_CENTER, leading=14)),
]
info_row = Table([info_data], colWidths=[CW/4]*4)
info_row.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1),MED_TEAL),
    ("TOPPADDING",(0,0),(-1,-1),10),("BOTTOMPADDING",(0,0),(-1,-1),10),
    ("GRID",(0,0),(-1,-1),0.5,WHITE),
]))
story.append(info_row)
story.append(sp(16))

# Contents
story.append(Paragraph("<b>Table of Contents</b>", S("tc", fontSize=12, textColor=DARK_TEAL, spaceAfter=8)))
toc_items = [
    ("1", "Introduction & Epidemiology"),
    ("2", "Classification — Antibody Subtypes"),
    ("3", "Pathogenesis (Harrison's Figure 99-3)"),
    ("4", "Specific Syndromes — Anti-NMDA-R · LGI1 · CASPR2 · AMPA-R · GABA-B · MOG · Others"),
    ("5", "Clinical Approach & Diagnostic Criteria (Graus Criteria 2016)"),
    ("6", "Investigations — CSF · MRI · EEG · Antibody Testing · APE2 Score"),
    ("7", "Paraneoplastic vs Non-Paraneoplastic — Tumour Screening"),
    ("8", "Treatment Algorithm — First Line · Second Line · Refractory"),
    ("9", "Prognosis & Outcomes (2025 Meta-Analysis Update)"),
    ("10", "Key Differentials & Mimics"),
]
for num, desc in toc_items:
    r = Table([[
        Paragraph(f"<b>{num}</b>", S("tn", fontSize=9, textColor=WHITE, alignment=TA_CENTER)),
        Paragraph(desc, S("td", fontSize=9, textColor=DARK_TEAL))
    ]], colWidths=[1.6*cm, CW-1.6*cm])
    r.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(0,0),MED_TEAL),
        ("BACKGROUND",(1,0),(1,0),LIGHT_TEAL),
        ("TOPPADDING",(0,0),(-1,-1),5),("BOTTOMPADDING",(0,0),(-1,-1),5),
        ("LEFTPADDING",(0,0),(-1,-1),8),
        ("GRID",(0,0),(-1,-1),0.3,HexColor("#67e8f9")),
    ]))
    story.append(r); story.append(sp(2))
story.append(PageBreak())

# ── SECTION 1: INTRODUCTION ───────────────────────────────────────────────────
story.append(h1("1. INTRODUCTION & EPIDEMIOLOGY"))
story.append(sp(6))
story += h2("Definition")
story.append(body(
    "Autoimmune encephalitis (AE) is a group of inflammatory brain disorders characterized by "
    "<b>prominent neuropsychiatric symptoms</b> and, in most cases, autoantibodies against neural "
    "(neuronal or glial) antigens. The clinical presentation occurs over a <b>subacute timeframe "
    "(generally &lt;3 months)</b> and consists of a wide spectrum of neuropsychiatric features "
    "including progressive cognitive decline, memory deficits, confusion, and behavioral changes."
))
story.append(sp(4))
story += h2("Epidemiology")
for b in [
    "Overall incidence of autoimmune (paraneoplastic + non-paraneoplastic) encephalitis is <b>now estimated to be similar to that of infectious encephalitis</b> — a landmark shift in clinical thinking (Adams & Victor's 12E).",
    "Most frequent AE subtypes: Anti-NMDA-R encephalitis, ADEM (MOG-Ab in 60%), and Limbic Encephalitis (anti-LGI1 most frequent).",
    "Anti-NMDA-R and ADEM predominate in <b>children and young adults</b>; Limbic Encephalitis (LGI1) usually affects <b>patients older than 50 years</b>.",
    "Autoimmune encephalitis triggered by <b>immune checkpoint inhibitors</b> (cancer immunotherapy) is a newly recognised and increasingly common cause — always consider in oncology patients.",
    "In ~60% of paraneoplastic cases, the neurologic symptoms <b>precede the cancer diagnosis</b>.",
]:
    story.append(b1(b))

story.append(sp(4))
story.append(sQuote and Paragraph(
    '"As the detection of autoantibodies against neuronal and glial cell surface antigens has increased '
    'in recent years, it is currently estimated that the overall incidence of autoimmune encephalitis is '
    'similar to that of infectious encephalitis." — Adams & Victor\'s Neurology 12E',
    sQuote))

# ── SECTION 2: CLASSIFICATION ─────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("2. CLASSIFICATION OF AUTOIMMUNE ENCEPHALITIS"))
story.append(sp(6))
story += h2("Based on Antibody Target Location")
story.append(body(
    "The most important classification divides AE by whether the target antigen is "
    "<b>intracellular</b> or on the <b>cell surface / synaptic</b>. This distinction has "
    "profound implications for pathogenesis, tumour association, and response to treatment."
))
story.append(sp(4))
story.append(tbl(
    ["Category", "Target", "Mechanism", "Tumour Assoc.", "Treatment Response"],
    [
        ["Cell-surface / Synaptic antibodies\n(Low/Intermediate risk for tumour)",
         "NMDAR, LGI1, CASPR2, AMPA-R, GABA-B/A, DPPX, GlyR, mGluR1",
         "Antibody-mediated: receptor crosslinking & internalization (NMDAR); functional blockade (GABA-R); protein-protein disruption (LGI1)",
         "Variable (rare for LGI1; 50% for AMPA-R; >45% for GABA-B)",
         "Good — respond to immunotherapy"],
        ["Intracellular antibodies\n(High risk for tumour — >70%)",
         "Hu (ANNA1), Yo (PCA1), Ri (ANNA2), CRMP5 (CV2), Ma2, Tr (DNER)",
         "T-cell mediated cytotoxicity (CD8+ T cells in close contact with degenerating neurons); antibodies are markers, not pathogenic",
         "Very high (>70% have underlying cancer — SCLC, ovary, breast, testis)",
         "Poor — treat underlying tumour; neurological damage often irreversible"],
    ],
    cw=[3.5*cm, 4*cm, 4*cm, 3*cm, 2.5*cm]
))
story.append(sp(4))
story += h2("Tumour Risk Classification (Harrison's 22E, Tables 99-2/3/4)")
story.append(sp(3))
story.append(tbl(
    ["Risk Category", "Antibodies", "Associated Tumours"],
    [
        ["HIGH RISK >70%\n(intracellular antigens)",
         "Anti-Hu (ANNA1), Anti-Yo (PCA1), Anti-Ri (ANNA2), Anti-CRMP5 (CV2), Anti-Tr (DNER), Anti-Ma2, Anti-PCA2 (MAP1B), Anti-GFAP (in some)",
         "SCLC, Ovary/Breast (Yo), Hodgkin lymphoma (Tr), Testicular (Ma2), Thymoma"],
        ["INTERMEDIATE RISK 30–70%\n(cell-surface antigens)",
         "Anti-NMDAR, Anti-AMPA-R, Anti-GABA-B, Anti-mGluR5, Anti-DNER",
         "Ovarian teratoma (NMDAR in females ≥12y); SCLC (GABA-B); Breast/lung (AMPA-R)"],
        ["LOW RISK <30%\n(cell-surface antigens)",
         "Anti-LGI1, Anti-CASPR2, Anti-GABA-A, Anti-DPPX, Anti-GlyR, Anti-IgLON5, Anti-mGluR1, Anti-neurexin-3α",
         "LGI1: rarely tumour-associated; CASPR2: ~20% thymoma; GABA-A: thymoma in some"],
    ],
    cw=[3.5*cm, 7.5*cm, 6*cm]
))
story.append(warn("High-risk (intracellular antigen) antibodies = markers of T-cell-mediated neuronal death. The antibodies themselves are NOT directly pathogenic. Therefore, immunotherapy has limited benefit — the priority is TUMOUR TREATMENT."))

# ── SECTION 3: PATHOGENESIS ───────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("3. PATHOGENESIS"))
story.append(sp(6))
story += h2("Two Main Triggers (Harrison's Figure 99-3)")
for b in [
    "<b>Trigger A — Herpes Simplex Encephalitis:</b> HSV-induced neuronal destruction releases neuronal antigens. These are loaded into antigen-presenting cells (APCs/dendritic cells) and transported to deep cervical lymph nodes. Naive B cells, with CD4+ T-cell cooperation, become antigen-experienced and differentiate into antibody-producing plasma cells. Memory B cells enter the brain, undergo antigen-driven clonal expansion, and produce antibodies intrathecally.",
    "<b>Trigger B — Systemic Tumours:</b> Tumor cells ectopically express neural proteins. Antigens are processed by APCs in regional lymph nodes → memory B cells → antibodies. The antibodies cross the blood-brain barrier and target similar proteins expressed on neurons.",
    "<b>Other triggers:</b> Genetic susceptibility (HLA associations — IgLON5: HLA-DRB1*10:01); immune checkpoint inhibitor therapy; unknown immunologic triggers.",
]:
    story.append(b1(b))
story.append(sp(6))

# Insert pathomech image
if os.path.exists(IMG_PATHOMECH):
    img = Image(IMG_PATHOMECH, width=CW*0.9, height=CW*0.9*0.55)
    story.append(img)
    story.append(Paragraph(
        "FIGURE 99-3 (Harrison's 22E) — Proposed mechanisms of disease and functional interactions of autoantibodies "
        "with neuronal surface proteins. (A) HSV trigger, (B) Tumour trigger, (C) Memory B-cell intrathecal differentiation, "
        "(D) GABA-R: functional blockade, (E) NMDAR: receptor crosslinking + internalization → reduced NMDAR density, "
        "(F) LGI1: protein-protein disruption → decreased AMPA-R and Kv1 potassium channels.",
        sCaption))

story.append(sp(4))
story += h2("Mechanisms of Antibody-Mediated Neuronal Dysfunction")
story.append(tbl(
    ["Antibody", "Mechanism", "Functional Effect"],
    [
        ["NMDAR (IgG1)", "Receptor crosslinking and internalization (endocytosis)", "↓ NMDAR density on postsynaptic membrane → disinhibition of dopamine pathway (explains psychosis)"],
        ["GABA-A/B-R", "Functional blocking of target antigen (prevents GABA binding)", "Reduced inhibitory tone → seizures, status epilepticus"],
        ["LGI1 (IgG4)", "Disruption of protein-protein interaction (LGI1-ADAM22/23 complex)", "↓ AMPA-R density; ↓ Kv1 potassium channels → faciobrachial dystonic seizures, memory loss"],
        ["CASPR2 (IgG4)", "Disruption of CASPR2-LGI1-ADAM23 complex", "Peripheral nerve hyperexcitability (Morvan syndrome, neuromyotonia) + CNS symptoms"],
        ["AMPA-R", "Receptor internalization (like NMDAR)", "Memory deficits; relapsing limbic encephalitis"],
        ["DPPX", "Antibodies against DPPX (Kv4.2 channel regulatory protein)", "CNS hyperexcitability: seizures, myoclonus, PERM-like picture, GI dysmotility"],
    ],
    cw=[2.5*cm, 5.5*cm, 9*cm]
))

# ── SECTION 4: SPECIFIC SYNDROMES ────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("4. SPECIFIC ANTIBODY SYNDROMES"))
story.append(sp(6))

story += h2("4A. Anti-NMDA Receptor Encephalitis (Most Common)")
story.append(sp(3))
syndrome_box = Table([[Paragraph(
    '<b><font color="white">DEMOGRAPHICS:</font></b> <font color="#cffafe">Young women and children predominantly; '
    'men and older patients also affected. Most common autoimmune encephalitis overall.</font>',
    S("sb", fontSize=9, leading=14))]],
    colWidths=[CW])
syndrome_box.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,-1),DARK_TEAL),
    ("TOPPADDING",(0,0),(-1,-1),8),("BOTTOMPADDING",(0,0),(-1,-1),8),
    ("LEFTPADDING",(0,0),(-1,-1),10),
]))
story.append(syndrome_box); story.append(sp(4))

story += h2("Clinical Progression (Characteristic Stages — Harrison's 22E)")
stages = [
    ("Prodrome\n(Days 1–5)", "Fever, headache, malaise, viral-like illness — resembles aseptic meningitis", ACCENT_GRN),
    ("Psychiatric Phase\n(Days 5–14)", "Severe psychiatric symptoms: psychosis, agitation, hallucinations, paranoid delusions, bizarre behaviour. Often FIRST presentation to PSYCHIATRIST.", ACCENT_PURP),
    ("Unresponsive Phase\n(Weeks 2–4)", "Reduced verbal output (mutism), memory loss, catatonia, decreased consciousness, sleep dysfunction (insomnia → hypersomnia)", MED_TEAL),
    ("Movement Disorder Phase\n(Weeks 3–6)", "Orofacial dyskinesias (lip smacking, chewing), limb and trunk dyskinesias, dystonic postures, stereotyped movements", DARK_TEAL),
    ("Autonomic Instability\n(Peak illness)", "Tachycardia, bradycardia, hyperhidrosis, hypersalivation, labile BP, cardiac arrhythmia, central hypoventilation (often requires ICU)", ACCENT_RED),
    ("Seizures", "New-onset seizures or status epilepticus — can occur at any stage", ACCENT_AMB),
    ("Recovery Phase\n(Months 3–18)", "Slow, months to 1–2 years. 12–24% clinical relapse rate.", ACCENT_GRN),
]
for label, desc, col in stages:
    r = Table([[
        Paragraph(f"<b>{label}</b>", S("sl", fontSize=8.5, textColor=WHITE, alignment=TA_CENTER, leading=12)),
        Paragraph(desc, sTD)
    ]], colWidths=[3.2*cm, CW-3.2*cm])
    r.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(0,0),col),
        ("BACKGROUND",(1,0),(1,0),LIGHT_GREY),
        ("TOPPADDING",(0,0),(-1,-1),6),("BOTTOMPADDING",(0,0),(-1,-1),6),
        ("LEFTPADDING",(0,0),(-1,-1),8),
        ("GRID",(0,0),(-1,-1),0.3,HexColor("#94a3b8")),
    ]))
    story.append(r); story.append(sp(2))

story.append(sp(4))
story += h2("Key Features to Remember — Anti-NMDAR (Harrison's 22E)")
for b in [
    "Monosymptomatic episodes (e.g., pure psychosis) occur in ~5% — easy to miss",
    "Relapses occur in <b>12–24% of patients</b> (12% within first 2 years)",
    "<b>MRI:</b> Normal in 65% of cases; 35% show mild, transient FLAIR abnormalities in cortical/subcortical regions; rarely shows contrast enhancement",
    "<b>CSF:</b> Most patients have intrathecal synthesis of antibodies by infiltrating plasma cells in brain and meninges; CSF may show lymphocytic pleocytosis",
    "<b>EEG:</b> 'Extreme delta brush' pattern — highly characteristic (delta-frequency oscillations with superimposed high-frequency beta bursts) — seen in ~30% of severe cases",
    "<b>Tumour association:</b> 46% of females ≥12 years have uni- or bilateral <b>ovarian teratoma</b>; <7% of girls <12 years; rare in young males",
    "Patients >45 years: more frequently male; ~20% have tumours (breast, ovary, lung, thymoma, Hodgkin lymphoma)",
    "Common misdiagnoses: viral encephalitis · neuroleptic malignant syndrome · encephalitis lethargica · acute psychosis / schizophrenia",
]:
    story.append(b1(b))

story.append(PageBreak())
story += h2("4B. Anti-LGI1 (Leucine-rich Glioma Inactivated 1) Encephalitis")
for b in [
    "<b>Demographics:</b> Most commonly affects patients >50 years; slight male predominance; tumour association RARE (<5%)",
    "<b>Pathognomonic feature: Faciobrachial Dystonic Seizures (FBDS)</b> — brief (<3 seconds), frequent (up to 100+/day), ipsilateral face and arm dystonic jerks. Often precede limbic encephalitis by weeks-months",
    "Classical limbic encephalitis: subacute amnesia, confusion, psychiatric symptoms, seizures",
    "<b>Hyponatraemia (SIADH)</b> is very common — a useful clinical clue in an older patient with confusion",
    "<b>CSF:</b> Often NORMAL — does not exclude diagnosis",
    "<b>MRI:</b> Often initially normal; later T2/FLAIR hyperintensity in mesial temporal lobes (hippocampus, amygdala); may also show basal ganglia signal change",
    "<b>EEG:</b> Temporal lobe ictal/interictal discharges corresponding to FBDS",
    "Key: FBDS does NOT respond to antiseizure medications — responds to <b>immunotherapy</b>. Early treatment prevents progression to limbic encephalitis",
]:
    story.append(b1(b))

story.append(sp(6))
story += h2("4C. Anti-CASPR2 (Contactin-Associated Protein-like 2) Encephalitis")
for b in [
    "Demographics: Predominantly older men; ~20% have thymoma",
    "<b>Morvan Syndrome</b> = peripheral nerve hyperexcitability (neuromyotonia, cramps) + autonomic dysfunction + encephalopathy + insomnia — anti-CASPR2 is the antibody to test",
    "Also causes limbic encephalitis, cerebellar ataxia",
    "Often co-occurs with LGI1 antibodies (shared LGI1-CASPR2-ADAM23 complex)",
]:
    story.append(b1(b))

story.append(sp(5))
story += h2("4D. Anti-AMPA Receptor Encephalitis")
for b in [
    "Demographics: Middle-aged women; ~70% have underlying tumour (breast, lung, thymoma)",
    "Clinical: Limbic encephalitis — subacute amnesia, confusion, psychiatric symptoms",
    "Notable: <b>High relapse rate</b> after immunotherapy reduction",
    "MRI: Mesial temporal T2/FLAIR hyperintensity",
]:
    story.append(b1(b))

story.append(sp(5))
story += h2("4E. Anti-GABA-B Receptor Encephalitis")
for b in [
    "Demographics: Older adults; ~50% have SCLC (small cell lung cancer)",
    "Clinical: Limbic encephalitis with <b>prominent, often refractory seizures</b> and status epilepticus",
    "Key association: Always screen for SCLC with CT chest",
    "MRI: Mesial temporal signal changes",
]:
    story.append(b1(b))

story.append(sp(5))
story += h2("4F. Anti-GABA-A Receptor Encephalitis")
for b in [
    "Clinical: Refractory status epilepticus and multifocal seizures (distinguish from GABA-B by seizure severity)",
    "MRI: Often extensive FLAIR signal in cortical and subcortical regions (not just temporal)",
    "~30% associated with thymoma",
]:
    story.append(b1(b))

story.append(sp(5))
story += h2("4G. Anti-DPPX (Dipeptidyl-peptidase-like protein 6) Encephalitis")
for b in [
    "Key clinical triad: <b>Diarrhoea/GI dysmotility</b> (often precedes neurological symptoms by months) + CNS hyperexcitability + encephalopathy",
    "Agitation, hallucinations, myoclonus, hyperekplexia (exaggerated startle), tremor, nystagmus",
    "Some patients develop PERM (Progressive Encephalomyelitis with Rigidity and Myoclonus)-like picture",
    "Associated B-cell neoplasms in a few cases",
]:
    story.append(b1(b))

story.append(sp(5))
story += h2("4H. Anti-IgLON5 Disease")
for b in [
    "Chronic/subacute encephalopathy with <b>characteristic sleep disorder</b> — REM + NREM parasomnia, obstructive sleep apnea",
    "Bulbar symptoms: dysphagia, stridor (vocal cord palsy)",
    "Movement disorders: chorea, craniofacial dyskinesias, oculomotor dysfunction",
    "Median age: early 60s; M=F",
    "Strong HLA association: HLA-DRB1*10:01 and HLA-DQB1*05 (present in 60%)",
    "Neuropathology: <b>Neuronal tauopathy</b> predominantly in hypothalamus and brainstem tegmentum — suggests mixed autoimmune + neurodegeneration",
    "<b>Poor response to immunotherapy</b> — important to know (unlike other AE syndromes)",
]:
    story.append(b1(b))

story.append(sp(5))
story += h2("4I. MOG (Myelin Oligodendrocyte Glycoprotein) Antibody Syndromes")
for b in [
    "Most patients: children and young adults",
    "Phenotypes: optic neuritis, myelitis, brainstem encephalitis, ADEM, cortical encephalitis",
    "~85% respond to immunotherapy; ~30% relapse",
    "NOT associated with tumours",
    "Small group with <b>unilateral or bilateral cortical encephalitis</b> — response variable",
    "Poor prognosis phenotypes in children: ADEM-like relapses → leukodystrophy-like features; extensive cortical encephalitis → cortical atrophy",
]:
    story.append(b1(b))

# ── SECTION 5: DIAGNOSTIC CRITERIA ───────────────────────────────────────────
story.append(PageBreak())
story.append(h1("5. CLINICAL APPROACH & DIAGNOSTIC CRITERIA"))
story.append(sp(6))
story += h2("Graus Criteria 2016 — Definition of Autoimmune Encephalitis")
story.append(body(
    "The <b>Graus et al. (2016)</b> criteria provide the framework for diagnosing autoimmune encephalitis. "
    "They require the following elements to be present:"
))
for b in [
    "Subacute onset (rapid progression over <3 months) of: working memory deficits, seizures, or psychiatric symptoms",
    "At least ONE of: (a) New focal CNS findings, (b) CSF pleocytosis (WBC >5 cells/μL), (c) MRI features suggesting encephalitis",
    "Reasonable exclusion of alternative causes",
]:
    story.append(b1(b))
story.append(sp(4))
story.append(warn(
    "Important (Rheumatology 2022, Guasp & Dalmau 2025): Normal CSF findings do NOT exclude autoimmune encephalitis. "
    "In anti-LGI1 encephalitis, MOST patients have normal CSF and often initially normal MRI. "
    "The clinical course of rapid decline over weeks is the KEY factor."))

story.append(sp(6))
story += h2("APE2 Score (Washington Manual) — Predicts Neural-Specific Antibody Positivity")
story.append(sp(3))
ape2_data = [
    ["Clinical Feature", "Score"],
    ["New-onset, rapidly progressive mental status changes over 1–6 weeks ± new-onset seizures", "+1"],
    ["Neuropsychiatric changes: agitation, aggressiveness, emotional lability", "+1"],
    ["Autonomic dysfunction (sustained tachycardia/bradycardia, orthostatic hypotension, hyperhidrosis, labile BP, arrhythmia, GI dysmotility)", "+1"],
    ["Viral prodrome (rhinorrhoea, sore throat, low-grade fever) — scored if no systemic malignancy within 5 years", "+1"],
    ["Faciobrachial dystonic seizures", "+3"],
    ["Facial dyskinesias (without FBDS)", "+2"],
    ["Seizures refractory to ≥2 antiseizure medications", "+2"],
    ["CSF inflammation (protein >50 mg/dL and/or lymphocytic pleocytosis >5 cells/μL)", "+2"],
    ["MRI suggesting encephalitis (T2/FLAIR in mesial temporal lobes or multifocal grey/white matter)", "+2"],
]
ape2_tbl_data = []
ape2_tbl_data.append([Paragraph("<b>Clinical Feature</b>", sTH), Paragraph("<b>Score</b>", sTH)])
for feat, score in ape2_data[1:]:
    ape2_tbl_data.append([Paragraph(feat, sTD), Paragraph(f"<b>{score}</b>",
        S("sc", fontSize=9, textColor=ACCENT_PURP, fontName="Helvetica-Bold", alignment=TA_CENTER))])
ape2_t = Table(ape2_tbl_data, colWidths=[CW-2*cm, 2*cm], repeatRows=1)
ape2_t.setStyle(TableStyle([
    ("BACKGROUND",(0,0),(-1,0),ACCENT_PURP),
    ("ROWBACKGROUNDS",(0,1),(-1,-1),[WHITE, HexColor("#f5f3ff")]),
    ("GRID",(0,0),(-1,-1),0.35,HexColor("#c4b5fd")),
    ("VALIGN",(0,0),(-1,-1),"MIDDLE"),
    ("TOPPADDING",(0,0),(-1,-1),5),("BOTTOMPADDING",(0,0),(-1,-1),5),
    ("LEFTPADDING",(0,0),(-1,-1),6),
]))
story.append(ape2_t)
story.append(sp(4))
story.append(purple("APE2 Score ≥4 is 99% sensitive and 93% specific for neural-specific antibody positivity."))

# ── SECTION 6: INVESTIGATIONS ─────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("6. INVESTIGATIONS"))
story.append(sp(6))

story += h2("A. Blood Tests")
for b in [
    "CBC, LFT, RFT, electrolytes — look for <b>hyponatraemia</b> (common in LGI1 due to SIADH)",
    "Thyroid function (exclude Hashimoto encephalopathy / anti-TPO positive)",
    "Anti-nuclear antibodies (ANA), dsDNA, ANCA — exclude systemic rheumatic disease (SLE, Sjögren, Behçet, sarcoidosis)",
    "<b>Serum autoantibody panel</b>: NMDAR, LGI1, CASPR2, AMPA-R, GABA-A/B-R, DPPX, GlyR, mGluR1, MOG, GFAP, GAD65, IgLON5",
    "HIV serology, RPR/VDRL, B12, folate (exclude infective and metabolic causes)",
    "Toxicology screen (lithium, drugs of abuse)",
    "Tumour markers if malignancy suspected",
]:
    story.append(b1(b))

story.append(sp(5))
story += h2("B. CSF Analysis")
story.append(tbl(
    ["Parameter", "Typical Finding in AE", "Notes"],
    [
        ["Opening pressure", "Normal or mildly elevated", "Markedly elevated pressure uncommon"],
        ["WBC", "Mild lymphocytic pleocytosis (10–100 cells/μL)", "Can be NORMAL — does not exclude AE (especially LGI1)"],
        ["Protein", "Mildly elevated (50–100 mg/dL)", "Can be normal"],
        ["Glucose", "Normal", "Hypoglycorrhachia suggests infection/TBM instead"],
        ["Oligoclonal bands", "Present in some (NMDAR especially)", "Intrathecal IgG synthesis"],
        ["CSF antibody testing", "Same panel as serum", "CSF has higher sensitivity for NMDAR (send BOTH serum and CSF)"],
        ["PCR (HSV, VZV, Enterovirus)", "Negative", "Must exclude infectious encephalitis first"],
    ],
    cw=[2.8*cm, 4.5*cm, 9.7*cm]
))
story.append(alert("For anti-NMDAR encephalitis: ALWAYS test BOTH serum AND CSF antibodies. CSF is more sensitive. Serum alone may be falsely negative."))

story.append(sp(5))
story += h2("C. MRI Brain")
story.append(tbl(
    ["Condition", "MRI Finding"],
    [
        ["Anti-NMDAR encephalitis", "Normal in 65%; mild transient FLAIR in cortical/subcortical regions in 35%; contrast enhancement rare"],
        ["Anti-LGI1 limbic encephalitis", "T2/FLAIR hyperintensity in mesial temporal lobes (hippocampus, amygdala); may show basal ganglia signal; often initially NORMAL"],
        ["Anti-GABA-B limbic encephalitis", "Mesial temporal T2/FLAIR hyperintensity (similar to LGI1 / paraneoplastic LE)"],
        ["Anti-GABA-A encephalitis", "Extensive, multifocal cortical and subcortical FLAIR signal — more widespread than other AE"],
        ["MOG-Ab encephalitis", "Cortical FLAIR signal; optic nerve enhancement; spinal cord involvement; ADEM pattern (large demyelinating lesions)"],
        ["Anti-GFAP encephalitis", "Radial perivascular enhancement from ventricles outwards — highly distinctive pattern"],
        ["Anti-IgLON5 disease", "Often normal or minor non-specific changes; may show hypothalamic/brainstem signal"],
    ],
    cw=[3.5*cm, CW-3.5*cm]
))

story.append(sp(5))
story += h2("D. EEG")
story.append(tbl(
    ["Pattern", "Associated Antibody / Significance"],
    [
        ["Extreme delta brush", "Anti-NMDAR encephalitis — highly characteristic (delta waves + superimposed high-frequency beta bursts); seen in ~30% of severe cases"],
        ["Temporal lobe ictal discharges", "LGI1 encephalitis — corresponds to FBDS; helps map seizure focus"],
        ["Multifocal ictal/interictal discharges", "Anti-GABA-A encephalitis; severe NMDAR encephalitis"],
        ["Generalised slowing", "Non-specific but confirms encephalopathy"],
        ["Continuous diffuse slow activity with superimposed bursts", "Severe NMDAR encephalitis in ICU phase"],
    ],
    cw=[4.5*cm, CW-4.5*cm]
))

story.append(sp(5))
story += h2("E. Tumour Screening — Mandatory in All AE Patients (Harrison's 22E)")
for b in [
    "CT chest/abdomen/pelvis — screen for SCLC, thymoma, lymphoma",
    "<b>Pelvic ultrasound / transvaginal US / MRI pelvis</b> — screen for ovarian teratoma in all females ≥12 years with NMDAR-Ab",
    "<b>Testicular ultrasound</b> — in young males with NMDAR-Ab or high-risk antibodies",
    "<b>FDG-PET/CT</b> — if CT negative; detects occult tumours in PND; recommended if high-risk antibodies present",
    "Repeat tumour screening every 6 months for 3 years if initial work-up negative with high-risk antibodies",
    "Serum/urine immunofixation — exclude monoclonal gammopathy-related neuropathy",
]:
    story.append(b1(b))

# ── SECTION 7: PARANEOPLASTIC vs NON-PARANEOPLASTIC ──────────────────────────
story.append(PageBreak())
story.append(h1("7. PARANEOPLASTIC vs NON-PARANEOPLASTIC AE"))
story.append(sp(6))
story.append(tbl(
    ["Feature", "Paraneoplastic", "Non-Paraneoplastic"],
    [
        ["Antibody target", "Intracellular antigens (Hu, Yo, Ri, CRMP5, Ma2)", "Cell-surface/synaptic antigens (NMDAR, LGI1, CASPR2, AMPA-R)"],
        ["Tumour association", ">70% have underlying cancer", "Low to moderate (<30% most; AMPA-R ~70%)"],
        ["Pathogenic mechanism", "T-cell mediated cytotoxicity (CD8+ T cells); antibodies are MARKERS not effectors", "Antibody-mediated receptor dysfunction; antibodies ARE the effectors"],
        ["Neuronal damage", "Irreversible (neuronal loss, gliosis)", "Potentially reversible (receptor internalization/modulation)"],
        ["Response to immunotherapy", "Poor (treat the tumour)", "Good (glucocorticoids, IVIg, plasma exchange, rituximab)"],
        ["CSF", "Pleocytosis, oligoclonal bands, elevated protein", "Variable; often mild or normal"],
        ["Time course", "Rapid, relentlessly progressive", "Subacute; may plateau; often improve with treatment"],
    ],
    cw=[3.5*cm, 6.5*cm, 7*cm]
))
story.append(sp(4))
story.append(body(
    "In <b>paraneoplastic encephalitis</b>, neurologic symptoms precede the cancer diagnosis in ~60% of cases. "
    "The diagnosis relies on: (1) detection of high-risk antibody, (2) demonstration of cancer, and "
    "(3) exclusion of other neurological disorders. Combined CT + PET scan often uncovers tumours undetected by CT alone."
))

# ── SECTION 8: TREATMENT ──────────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("8. TREATMENT ALGORITHM"))
story.append(sp(6))
story.append(alert("Treatment for autoimmune encephalitis should be initiated AS EARLY AS FEASIBLE — the disease carries high morbidity. Early treatment hastens recovery and reduces disability and relapse. (Adams & Victor's 12E)"))
story.append(sp(6))

story += h2("Treatment Algorithm (Harrison's 22E + Adams & Victor's 12E + Expert Consensus)")
story.append(sp(4))

tx_steps = [
    ("SIMULTANEOUS\n(Immediate)",
     "• Rule out infectious encephalitis: Start empirical Acyclovir + antibiotics until HSV PCR and cultures return\n"
     "• Blood and CSF autoantibody panel\n"
     "• Tumour screening (CT ± PET; pelvic US for females)\n"
     "• Antiseizure medication for seizures (Levetiracetam first line)\n"
     "• Manage autonomic instability (ICU if needed)\n"
     "• Remove trigger if identified: Resect ovarian teratoma (in NMDAR encephalitis — tumour resection alone can improve outcome)",
     DARK_TEAL),
    ("FIRST LINE\n(Start within 48–72h)",
     "• <b>Methylprednisolone</b> 1g IV daily × 5 days (or Dexamethasone 20 mg/day × 5 days)\n"
     "  THEN oral Prednisolone 1 mg/kg/day with slow taper over 6 months\n"
     "• <b>IVIg</b> 0.4 g/kg/day × 5 days\n"
     "• <b>Plasma Exchange (PLEX)</b> — 5–7 sessions every other day\n"
     "Note: Steroids + IVIg + PLEX are often combined or given sequentially.",
     MED_TEAL),
    ("SECOND LINE\n(If no/inadequate response to\nfirst line at 2–4 weeks)",
     "• <b>Rituximab</b> 375 mg/m² weekly × 4 doses OR 1000 mg × 2 doses 2 weeks apart\n"
     "  (Anti-CD20 B-cell depletion — most evidence for anti-NMDAR encephalitis)\n"
     "• <b>Cyclophosphamide</b> 750 mg/m² IV monthly (if Rituximab unavailable or contraindicated)",
     ACCENT_PURP),
    ("REFRACTORY / MAINTENANCE\n(Non-responders)",
     "• <b>Tocilizumab</b> (anti-IL-6 receptor monoclonal antibody) — 8 mg/kg IV q4 weeks — promising results in refractory cases\n"
     "• <b>Bortezomib</b> (proteasome inhibitor; depletes antibody-producing plasma cells) — refractory NMDAR-Ab encephalitis\n"
     "• <b>Mycophenolate mofetil</b> 1–3 g/day OR <b>Azathioprine</b> 2–3 mg/kg/day — for relapse prevention (maintenance)\n"
     "• <b>Methotrexate</b> — used in some refractory cases",
     ACCENT_RED),
    ("TUMOUR-SPECIFIC\n(If paraneoplastic)",
     "• Priority: TREAT THE UNDERLYING TUMOUR\n"
     "• For intracellular antigen antibodies (Hu, Yo, Ri, Ma2): tumour treatment is the primary approach; "
     "immunotherapy has limited benefit\n"
     "• Ovarian teratoma resection (NMDAR-Ab): early resection improves neurological outcome\n"
     "• Steroids and IVIg used as bridge to tumour treatment",
     GOLD),
]

for phase, details, col in tx_steps:
    r = Table([[
        Paragraph(f"<b>{phase}</b>", S("ph", fontSize=9, textColor=WHITE, alignment=TA_CENTER, leading=13)),
        Paragraph(details, S("dt", fontSize=8.5, leading=13))
    ]], colWidths=[3.2*cm, CW-3.2*cm])
    r.setStyle(TableStyle([
        ("BACKGROUND",(0,0),(0,0),col),
        ("BACKGROUND",(1,0),(1,0),LIGHT_GREY),
        ("TOPPADDING",(0,0),(-1,-1),8),("BOTTOMPADDING",(0,0),(-1,-1),8),
        ("LEFTPADDING",(0,0),(-1,-1),8),
        ("GRID",(0,0),(-1,-1),0.3,HexColor("#94a3b8")),
        ("VALIGN",(0,0),(-1,-1),"TOP"),
    ]))
    story.append(r); story.append(sp(3))

story.append(sp(6))
story += h2("Antiseizure Medications in AE — Important Notes")
for b in [
    "Anti-NMDAR FBDS-equivalent seizures: do NOT respond to antiseizure drugs — respond to immunotherapy",
    "LGI1 FBDS: same — antiseizure drugs have limited effect; immunotherapy is the treatment",
    "Levetiracetam preferred (minimal drug interactions, IV formulation available)",
    "Avoid sodium channel blockers (carbamazepine, phenytoin) in NMDAR encephalitis — may worsen dyskinesias",
    "Status epilepticus in AE: treat aggressively (benzodiazepines, levetiracetam, propofol/midazolam infusion) AND escalate immunotherapy simultaneously",
]:
    story.append(b1(b))

# ── SECTION 9: PROGNOSIS ──────────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("9. PROGNOSIS & OUTCOMES"))
story.append(sp(6))
story += h2("2025 Meta-Analysis Update (Hoshina et al., J Neuroimmunol 2025) [PMID: 40472799]")
story.append(sp(3))
story.append(tbl(
    ["Parameter", "Pre-2019 Data", "2025 Updated Data", "Trend"],
    [
        ["First-line immunotherapy use", "91.3%", "98.3%", "↑ Significantly (p<0.001)"],
        ["Second-line immunotherapy use", "31.8%", "42.5%", "↑ Significantly (p<0.001)"],
        ["Treatment within 30 days of onset", "50.1%", "72.5%", "↑ Markedly (p<0.001)"],
        ["Favourable outcome (mRS 0–2)", "71.5%", "76.7%", "↑ Modest (p=0.024)"],
        ["Mortality", "6.3%", "6.9%", "Unchanged (p=0.714)"],
        ["Relapse rate", "12.6%", "13.2%", "Unchanged (p=0.789)"],
    ],
    cw=[4*cm, 3*cm, 3*cm, 3*cm]
))
story.append(sp(4))
story.append(green(
    "KEY MESSAGE (2025 Meta-Analysis): Despite earlier and more aggressive immunotherapy, "
    "mortality and relapse rates have NOT significantly improved since 2019. "
    "Functional outcomes (mRS 0–2) showed only modest improvement. "
    "This highlights the urgent need for prospective clinical trials — there are currently NO FDA-approved treatments for anti-NMDAR encephalitis."))

story.append(sp(6))
story += h2("Prognosis by Antibody Type")
story.append(tbl(
    ["Antibody", "Typical Outcome", "Notes"],
    [
        ["Anti-NMDAR", "Good recovery in ~77%; slow (months–years); 12–24% relapse", "Tumour removal + early immunotherapy = best predictor of good outcome"],
        ["Anti-LGI1", "Good overall; ~15–20% have residual memory deficits", "FBDS must be treated early to prevent limbic encephalitis"],
        ["Anti-CASPR2", "Moderate; refractory cases more common", "Morvan syndrome has more guarded prognosis"],
        ["Anti-AMPA-R", "Tends to relapse frequently", "Maintenance immunosuppression usually required"],
        ["Anti-GABA-B", "Depends on tumour control; poor if SCLC progresses", "Neurological often improves with tumour treatment"],
        ["Paraneoplastic (Hu, Yo, Ri)", "Generally poor neurological outcome; neuronal loss irreversible", "Focus on tumour treatment; immunotherapy rarely helps"],
        ["Anti-IgLON5", "Poor; progressive; tauopathy component", "Does not respond to immunotherapy"],
        ["MOG-Ab", "~85% respond; 30% relapse", "Overall good prognosis; relapses treatable"],
    ],
    cw=[3*cm, 5*cm, 9*cm]
))

# ── SECTION 10: DIFFERENTIALS ─────────────────────────────────────────────────
story.append(PageBreak())
story.append(h1("10. KEY DIFFERENTIALS & MIMICS"))
story.append(sp(6))
story.append(tbl(
    ["Mimic / Differential", "Key Distinguishing Features", "Helpful Tests"],
    [
        ["HSV Encephalitis", "Temporal lobe T2/FLAIR on MRI (often absent in AE); CSF pleocytosis often more prominent", "HSV PCR (CSF) — must ALWAYS rule out first; start Acyclovir empirically"],
        ["TBM (Subacute)", "TB exposure, basilar CN palsies, low glucose CSF, high protein; communicating hydrocephalus", "CSF ADA, MTB PCR, AFB culture"],
        ["Prion disease (CJD)", "Rapid dementia, myoclonus, cerebellar features; 14-3-3 protein in CSF; DWI ribbon sign", "MRI DWI, CSF 14-3-3, RT-QuIC, EEG (PSWCs)"],
        ["Hashimoto Encephalopathy", "Elevated anti-TPO and anti-thyroglobulin; responds to steroids; euthyroid usually", "Anti-TPO Ab, TSH — note: also can overlap with AE"],
        ["Primary psychiatric disorder (schizophrenia, mania)", "No fever, no CSF changes, no MRI changes; gradual onset without autonomic features", "Exclude AE in young patient with new-onset psychosis — check NMDAR Ab"],
        ["Viral encephalitis (JE, WNV, EBV)", "Epidemiologic clues (mosquito, travel); thalamic lesions (JE)", "Viral serology, PCR panel"],
        ["Metabolic encephalopathy (hepatic, uraemic, hypo-Na+)", "Reversible with correction of metabolic abnormality; no autoantibodies", "LFT, ammonia, electrolytes, RFT"],
        ["Neuroleptic Malignant Syndrome", "History of antipsychotic exposure; hyperthermia, rigidity, elevated CK", "CK, drug history — but can mimic or complicate AE (anti-NMDAR)"],
        ["Cerebral vasculitis / CNS angiitis", "Focal neurological deficits; multifocal infarcts; abnormal MRA", "MRA, conventional angiography, meningeal biopsy"],
        ["Lymphoma / CNS malignancy", "Mass lesion; systemic B symptoms; CSF cytology", "MRI contrast, CSF cytology, PET-CT, biopsy"],
    ],
    cw=[3.8*cm, 6*cm, 7.2*cm]
))

story.append(sp(6))
story += h2("When to Suspect Autoimmune Encephalitis (Clinical Red Flags)")
for b in [
    "<b>New-onset psychosis in a young woman</b> — always check NMDAR antibodies",
    "<b>Brief facial + arm jerks</b> in an older patient (FBDS) — check LGI1",
    "<b>Refractory status epilepticus</b> with no prior epilepsy — check GABA-A/B-R, NMDAR Ab",
    "<b>Progressive amnesia + confusion</b> in an older male with hyponatraemia — check LGI1",
    "<b>Rapid-onset encephalopathy after IVIG/checkpoint inhibitor therapy</b> (oncology) — consider immune-mediated",
    "<b>GI symptoms (diarrhoea) preceding encephalopathy</b> — check DPPX antibodies",
    "<b>Parasomnia + autonomic dysfunction + bulbar symptoms</b> — check IgLON5",
    "<b>Encephalitis after HSV encephalitis treatment</b> — HSV may trigger NMDAR-Ab (post-HSV autoimmune encephalitis)",
]:
    story.append(b1(b))

story.append(sp(8))
story += h2("References")
refs_list = [
    "Harrison's Principles of Internal Medicine 22E (2025, McGraw Hill) — Chapter 99 [Dalmau J, Graus F]",
    "Adams and Victor's Principles of Neurology 12th Edition — Chapter 35",
    "Rheumatology, 2-Volume Set (2022, Elsevier) — Chapter 40",
    "Washington Manual of Medical Therapeutics — Chapter 27",
    "Guasp M, Dalmau J. Autoimmune Encephalitis. Med Clin North Am. 2025 Mar [PMID: 39893022]",
    "Hoshina Y et al. Updated meta-analysis of anti-NMDAR encephalitis treatment. J Neuroimmunol. 2025 [PMID: 40472799]",
    "Graus F et al. Clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404",
    "Dalmau J et al. Antibody-mediated encephalitis. N Engl J Med. 2018;378:840",
]
for r in refs_list:
    story.append(Paragraph(f"• {r}", S("ref", fontSize=8, leading=11,
        textColor=MID_GREY, leftIndent=14, firstLineIndent=-10, spaceAfter=2)))

# ── BUILD ──────────────────────────────────────────────────────────────────────
doc.build(story, onFirstPage=draw_hf, onLaterPages=draw_hf)
print(f"PDF generated: {OUTPUT}")