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TSH Metabolism in Newborns

1. Fetal Thyroid Development and the HPT Axis

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2. Fetal T3 and the Role of Deiodinases

• Type 3 deiodinase (D3) dominates in fetal tissues and the placenta - it inactivates T4 to rT3 (rather than to active T3). This protects the fetus from premature exposure to biologically active T3.
• Because of the high D3:D1 ratio, fetal serum T3 is negligible until ~30 weeks.
• Near term, increasing D1 activity allows rising T3 levels (up to ~50 ng/dL), paralleled by a progressive decline in rT3.
• Approximately 30-50% of T4 in cord blood is maternally derived, even at term.

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3. The Postnatal TSH Surge - The Key Event

• TSH peaks at ~30 minutes after birth (the "neonatal TSH surge")
• This is the largest TSH rise seen at any point in human life
• By 2-3 days, TSH falls back toward adult levels under T3/T4 negative-feedback inhibition

• TSH stimulates the thyroid gland to massively increase T4 and T3 secretion
• T3 and T4 peak at ~24 hours after delivery
• The disproportionately greater rise in T3 vs T4 in the first 24 hours reflects acutely increased conversion of T4 → T3 via maturation of type I deiodinase (D1)
• T4 and T3 then gradually decline to stable adult-range concentrations by 4-6 weeks
• Transient hyperthyroxinemia can also be triggered by neonatal cooling and may represent a thermogenic adaptation to extrauterine life

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4. The HPT Axis in Prematurity

• FT4 and FT3 levels are low despite "normal" TSH levels
• May take 3-8 weeks after birth to achieve levels similar to term infants
• Transient hypothalamic hypothyroidism of prematurity occurs in up to 50% of infants born before 28 weeks
• It can be difficult to distinguish from true central hypothyroidism
• Transient hypothyroxinemia in premature infants is associated with cognitive and neurological delays, but optimal treatment targets are not yet established

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5. Clinical Relevance - Newborn Screening

• Screening is ideally done at 2-4 days of age in term infants (after the physiological TSH surge has resolved)
• Within 7 days for preterm infants
• TSH-first strategy: most common - elevated TSH triggers reflex FT4
• Combined TSH + FT4: detects central hypothyroidism (low FT4 with normal or low TSH), thyroid hormone resistance, and conditions causing delayed TSH elevation
• Screening with TSH alone misses central hypothyroidism (1 in 25,000-50,000 newborns)

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Summary Table

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Migraine: A Comprehensive Review

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1. Epidemiology and Incidence

• 1-year prevalence: ~12% of the general population (18% of women, 6% of men)
• Lifetime prevalence: ~33% in women and ~13% in men

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2. Pathophysiology

2a. Cortical Spreading Depression (CSD) - The Substrate of Aura

• CSD is a slow wave of neuronal and glial depolarization that originates in the occipital cortex and propagates anteriorly at 2-4 mm/min
• It produces a transient phase of neuronal excitation followed by sustained inhibition
• The rate of spread matches the classic "marching" character of visual and sensory aura
• CSD does not follow vascular territories, ruling out simple vasospasm as the mechanism
• CSD triggers activation of the trigeminal nerve and meningeal nociceptors, initiating the headache cascade

2b. The Trigeminovascular System

• Perivascular trigeminal nerve fibers innervate the meningeal and intracranial vessels
• CSD and other triggers activate these fibers, causing release of vasoactive neuropeptides: calcitonin gene-related peptide (CGRP), substance P, and neurokinin A
• These neuropeptides produce neurogenic inflammation of dural vessels (vasodilation, plasma protein extravasation, mast cell degranulation)
• Pain signals travel via the trigeminal nerve → trigeminal nucleus caudalis → thalamus → somatosensory cortex

2c. Serotonin (5-HT)

• Plasma and platelet 5-HT levels fluctuate during migraine phases
• Urinary 5-HT metabolites are elevated during attacks
• Reserpine (which depletes 5-HT) can precipitate attacks
• The efficacy of triptans (5-HT₁B/₁D agonists) confirms 5-HT's central role
• 5-HT₁B activation causes vasoconstriction of intracranial vessels; 5-HT₁D activation inhibits presynaptic release of proinflammatory neuropeptides

2d. CGRP - The Key Neuropeptide

• CGRP is the dominant vasodilatory neuropeptide released during attacks
• Blood CGRP levels are elevated during attacks and normalize with triptan treatment
• CGRP receptor antagonists (gepants) and anti-CGRP monoclonal antibodies are highly effective treatments, directly validating CGRP's pathophysiological role

2e. Central Sensitization

• Repeated activation of the trigeminovascular system leads to central sensitization
• Clinically manifests as cutaneous allodynia (pain from normally non-painful stimuli, e.g., combing hair, wearing glasses)
• Allodynia predicts poor response to triptans when present

2f. The "Migraine Generator"

• Functional MRI studies show activation of the dorsal rostral pons and posterolateral hypothalamus during the premonitory phase, before headache onset
• The hypothalamus is particularly implicated in premonitory symptoms (food cravings, yawning, mood changes, thirst, photosensitivity)
• This supports the concept of a diffuse "altered brain state" rather than a single generator

2g. Central vs. Vascular - Modern Consensus

• Functional hyperemia precedes oligemia during aura (reverse of what vasospasm predicts)
• Headache may begin while cortical blood flow is still reduced
• MRA shows no change in cerebral artery diameter during nitroglycerin-triggered attacks
• Oligemia does not follow vascular territories

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3. Classification (ICHD-3)

Primary Migraine Types

Childhood Migraine Equivalents (Migraine Precursors)

• Cyclical vomiting syndrome
• Abdominal migraine
• Benign paroxysmal vertigo of childhood
• Benign paroxysmal torticollis

IHS Diagnostic Criteria for Migraine Without Aura

1. Duration 4-72 hours
2. At least 2 of 4 headache features:
   • Unilateral location
   • Pulsating quality
   • Moderate or severe intensity
   • Aggravated by routine physical activity
3. During the headache, at least 1 of 2:
   • Nausea and/or vomiting
   • Photophobia AND phonophobia

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4. Clinical Presentation: The Four Phases

Phase 1 - Prodrome (Premonitory Phase)

• Occurs hours to 1-2 days before headache
• Present in ~60-70% of migraineurs
• Symptoms: fatigue, mild cognitive dysfunction, irritability, neck stiffness, excessive yawning, food cravings, excessive thirst, mild photo/phonophobia, blurred vision
• Reflects hypothalamic activation; when recognized, predicts migraine in ~75% of cases

Phase 2 - Aura

• Affects ~1/3 of migraineurs; most who have aura also have attacks without it
• Develops gradually over ≥5 minutes; resolves within 60 minutes
• Usually precedes but may accompany or rarely follow headache
• Types of aura (in order of frequency):
  1. Visual (>80% of aura cases): positive (scintillating scotoma - flashing lights, zigzag "fortification spectra") followed by negative (scotoma); migrates slowly across visual field
  2. Sensory (next most common): unilateral positive (tingling/paresthesias) then negative (numbness); typically starts in the hand, marches up the arm to shoulder and face; takes 10-20 min to reach maximum extent (slower than a seizure, much slower than TIA)
  3. Language: expressive dysphasia most common; usually mild
  4. Motor: true unilateral weakness; classifies as hemiplegic migraine

Phase 3 - Headache

• Duration: 4-72 hours (untreated)
• Unilateral in 60-75% (can shift sides or become bilateral)
• Pulsating/throbbing quality
• Moderate to severe intensity
• Worse with routine activity
• Associated symptoms: nausea (90%), vomiting (30%), photophobia, phonophobia, osmophobia (highly specific for migraine when present), cutaneous allodynia
• Patients typically seek dark, quiet room

Phase 4 - Postdrome

• Follows resolution of headache
• Symptoms: fatigue, cognitive fog ("migraine hangover"), mood changes, mild photophobia, GI symptoms
• Can last hours to a day

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5. Risk Factors

• Female sex (3:1 F:M after puberty)
• Family history: first-degree relatives 2x (migraine without aura) to 4x (migraine with aura) more likely to develop migraine
• Genetic variants: 44 genetic loci identified by GWAS in 375,000 individuals; genes enriched in vascular and smooth muscle tissue
• Familial Hemiplegic Migraine genes: CACNA1A (Chr 19, FHM1), ATP1A2 (Chr 1, FHM2), SCN1A (Chr 2, FHM3)
• Age at puberty and hormonal milestones

• Obesity (risk factor for chronification)
• Sleep disorders (insomnia, obstructive sleep apnea)
• Depression and anxiety (strong bidirectional association)
• Medication overuse (opioids, triptans, NSAIDs used >10-15 days/month → medication overuse headache)
• Traumatic brain injury / head trauma
• Low socioeconomic status / low educational attainment

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6. Triggers

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7. Investigations

When to investigate - "Red Flags" (SNNOOP10):

• Thunderclap onset (peak pain <1 minute) - subarachnoid hemorrhage
• Fever with headache - meningitis, encephalitis
• New neurological signs on examination
• New onset after age 50 - giant cell arteritis, intracranial mass
• Progressive worsening headache pattern
• Headache provoked by Valsalva/postural change - raised ICP, Chiari malformation
• History of cancer or immunosuppression - CNS metastasis
• Pregnancy - cerebral venous thrombosis, PRES
• Atypical aura (duration >60 min, motor aura, or no headache following)

Investigations when indicated:

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8. Management

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8a. Non-Pharmacological Management

• Identify and avoid personal triggers (trigger diary)
• Regular sleep schedule
• Regular meals (avoid fasting)
• Stress management and biofeedback
• Aerobic exercise (regular, not excessive)
• Cognitive-behavioral therapy
• Acupuncture (evidence-based for prevention)
• Patient education and lifestyle modification

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8b. Acute (Abortive) Treatment

Step 1 - Mild-to-Moderate Attacks:

• Acetaminophen 650-1000 mg
• NSAIDs: aspirin 500-1000 mg, ibuprofen 400-800 mg, naproxen 500-825 mg, diclofenac 50 mg, ketoprofen 75 mg
• Caffeine-combination analgesics (acetaminophen + aspirin + caffeine)
• Rule: if nausea is present, consider metoclopramide first to improve gastric emptying and drug absorption

Step 2 - Moderate-to-Severe Attacks (Migraine-Specific):

• Common side effects: flushing, tingling, chest tightness, "heaviness"
• Contraindications: uncontrolled hypertension, ischemic heart disease, Prinzmetal angina, stroke, within 24h of ergots or another triptan
• If nausea limits oral use → intranasal or SC route
• Combining with an NSAID improves efficacy and reduces recurrence

• 5-HT₁F receptor agonist - NO vasoconstrictive activity
• Safe when triptans are contraindicated (cardiac disease)
• Dose: 50-200 mg oral
• Key caveat: sedating - no driving for ≥8 hours

• Rimegepant 75 mg oral, Ubrogepant 50-100 mg oral
• ~10% absolute increase in pain freedom at 2 hours vs. placebo
• No vasoconstrictive effects; safe in cardiovascular disease
• Useful when triptans fail or are contraindicated
• Rimegepant also approved for preventive use (every other day)

• Ergotamine tartrate 2 mg PO/rectal at onset
• Dihydroergotamine (DHE): 1 mg SC, or 0.5-1 mg IV (requires antiemetic pretreatment)
• DHE: equivalent 2-hour efficacy to sumatriptan but lower headache recurrence
• Contraindicated: CAD, uncontrolled HTN, peripheral vascular disease, pregnancy

• Prochlorperazine 10-25 mg IM/IV
• Metoclopramide 10 mg IV
• Promethazine 25 mg (for IV DHE)
• Can be effective standalone in emergency setting

• Ketorolac 60 mg IM or 30 mg IV
• Prochlorperazine 10 mg IV over 5 min
• IV DHE with antiemetic
• IV valproate sodium
• Celecoxib 120 mg oral solution
• Opioids: last resort only (risk of chronification and medication overuse headache)

Status Migrainosus (>72 hours):

• IV hydration + IV ketorolac 30 mg + neurologic antiemetic (prochlorperazine/metoclopramide)
• Consider extracranial nerve blocks (occipital, supraorbital, sphenopalatine ganglion)
• Consider IV DHE protocol
• Hospitalization if dehydrated or refractory

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8c. Preventive (Prophylactic) Treatment

• ≥4 headache days/month with significant disability
• Attacks not responding to or contraindicated for acute therapy
• Frequent use of acute medications (risk of MOH)
• Chronic migraine (≥15 days/month)
• Hemiplegic migraine, prolonged aura, migrainous infarction
• Patient preference

Conventional Preventive Agents:

CGRP-Targeting Biologics (newer agents):

• Reserved for patients who have failed 2-3 conventional preventive classes
• ~50% reduction in monthly migraine days in ~50% of patients
• Generally well-tolerated; no significant cardiovascular contraindications

• Rimegepant 75 mg every other day (oral)
• Atogepant 10-60 mg daily

• Approved specifically for chronic migraine (≥15 headache days/month)
• 155 units injected across 31 sites on head/neck every 12 weeks
• Level A evidence

Non-pharmacological prevention:

• Biofeedback, relaxation training, CBT (Level A)
• Acupuncture
• Neuromodulation devices: non-invasive vagus nerve stimulation (nVNS), remote electrical neuromodulation (REN), transcranial magnetic stimulation (TMS), CEFALY (external trigeminal neurostimulation)

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9. Special Populations

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10. Prognosis

• Most migraineurs have a fluctuating course throughout life, with periods of more and less frequent attacks
• Tendency toward improvement with age, particularly after menopause in women
• ~30-40% of patients eventually experience spontaneous remission
• Risk factors for chronification (episodic → chronic migraine):
  • Female sex
  • Obesity
  • High baseline headache frequency
  • Medication overuse (opioids > triptans/NSAIDs)
  • Depression, anxiety, and other psychiatric comorbidities
  • Sleep disorders
  • Stressful life events
  • Low socioeconomic status
• Medication overuse headache (MOH): A major driver of chronification. Occurs when acute medications are used >10-15 days/month; withdrawal and preventive treatment are required
• Migrainous infarction is a rare but real risk, particularly in women with migraine with aura who smoke and use estrogen-containing contraceptives
• White matter hyperintensities are more prevalent on MRI in migraineurs (especially with aura) but clinical significance is uncertain; the risk of clinically overt stroke attributable to migraine alone is small

1. Epidemiology - 12% 1-year global prevalence, peak in the 4th decade, 3:1 F:M ratio after puberty, childhood equivalents, chronification rates
2. Pathophysiology - The modern neurovascular model: cortical spreading depression (CSD) as the electrophysiological substrate of aura; trigeminovascular activation and neurogenic inflammation; the central role of CGRP and 5-HT; the migraine generator debate (hypothalamus + dorsal pons); central sensitization and allodynia; why the old "vascular theory" is obsolete
3. Classification - Full ICHD-3 spectrum: migraine without aura, with aura (visual/sensory/language/motor), chronic, hemiplegic, basilar/brainstem aura, retinal, status migrainosus, migrainous infarction, childhood equivalents; diagnostic criteria
4. Clinical presentation - All four phases in detail: prodrome, aura (the "marching" sensory/visual/language phenomena and how to distinguish them from TIA or seizure), headache phase, postdrome
5. Risk factors - Genetics (FHM genes, GWAS loci), sex, age, obesity, mood disorders, medication overuse, hormonal factors
6. Triggers - Stress, hormones, sleep, diet, sensory stimuli, weather, medications - and why susceptibility fluctuates daily
7. Investigations - Primarily clinical; red flags and when to image (MRI vs. CT) or perform LP; ESR/CRP, TSH
8. Management - Non-pharmacological; acute treatment stratified by severity (analgesics → triptans → lasmiditan/gepants → DHE/ergots → ED protocols → status migrainosus); preventive treatment (beta-blockers, antiepileptics, TCAs; CGRP monoclonal antibodies; botulinum toxin A for chronic migraine; gepants); special populations
9. Prognosis - Fluctuating lifelong course, improvement post-menopause, risk of chronification, MOH, rare migrainous infarction risk