Idiopathic Intracranial Hypertension (IIH)

Definition

Epidemiology

• Mean age: ~29 years
• 97.6% female
• Mean BMI: ~39.9 kg/m²
• Incidence rises sharply with increasing obesity

Pathophysiology

• Impaired CSF absorption at arachnoid granulations (possibly due to adipokines or hormonal influences on CSF secretion/resorption)
• Venous outflow obstruction: Bilateral transverse sinus stenosis is found in nearly all IIH patients. Whether it is the cause or consequence is debated — a self-perpetuating cycle may exist where elevated ICP compresses the sinuses → venous outflow obstruction → further ICP rise
• Hormonal/metabolic factors: Obesity, sex steroids, vitamin A metabolism disorders, and glucocorticoid dysregulation have all been implicated

Clinical Features

• Headache is the most common presenting symptom; most common phenotypes are migraine (52%) and tension-type (22%)
• Transient visual obscurations result directly from papilledema and raised ICP
• Diplopia results from CN VI (lateral rectus) palsy — a false localizing sign from raised ICP
• Pulsatile/pulse-synchronous tinnitus is characteristic

Diagnostic Criteria

Pressure must be measured in the lateral decubitus position. Sitting pressures are invalid. LP opening pressure ≥250 mm CSF is required.

Workup

1. MRI brain with contrast — mandatory before LP to exclude intracranial mass, hydrocephalus
2. MR Venography (MRV) — to exclude cerebral venous sinus thrombosis (key IIH mimic) and assess for bilateral transverse sinus stenosis
3. Lumbar puncture with manometry — CSF should be clear, colorless, with normal protein/glucose/cells; high opening pressure confirms diagnosis
4. Ophthalmologic evaluation — confirm papilledema (distinguish from pseudopapilledema/drusen), assess visual fields and acuity

• Partially empty sella
• Bilateral optic nerve sheath distension
• Flattening of posterior sclera
• Bilateral transverse sinus flow gaps/stenosis on MRV

Imaging

Secondary Causes ("Pseudotumor Cerebri") — Must Exclude

Management

1. Conservative

• Weight loss: 5–10% body weight reduction can normalize ICP and resolve papilledema

2. Medical

• Acetazolamide (carbonic anhydrase inhibitor — reduces CSF production): First-line drug
  • Start: 500 mg twice daily
  • Titrate up as tolerated; doses up to 4 g/day supported by IIHTT evidence
  • The IIHTT showed acetazolamide + weight loss improves papilledema, ICP, and quality of life
• Topiramate: Alternative/adjunct (also promotes weight loss)
• Other diuretics: Furosemide used as adjunct
• Headache management: Migraine-specific therapies (triptans, etc.) based on phenotype

3. Surgical / Procedural

4. Lumbar puncture

• Serial LPs can provide temporary relief (headache + visual obscurations)
• Used as a bridge to definitive therapy, especially in pregnancy

IIH in Pregnancy

• Typically worsens with pregnancy; most commonly develops around 14th gestational week
• Visual loss in ~10–20%
• MRV is mandatory to exclude cerebral venous thrombosis
• Management:
  • Diet modification (avoid ketosis)
  • Serial LPs preferred over medications
  • Acetazolamide is controversial in pregnancy; most guidelines suggest avoiding in the first trimester; restrict its use to after 20 weeks when clinically essential
  • Corticosteroids (dexamethasone/prednisone) for 2-week courses when vision is threatened
  • ONSF or lumboperitoneal shunting if vision fails despite serial LPs
  • Vaginal delivery with epidural analgesia is generally preferred

Prognosis

• Most patients improve with weight loss ± acetazolamide
• Permanent vision loss can occur in untreated or refractory cases — visual fields (especially nasal inferior) are at greatest risk
• Risk of recurrence if weight is regained
• In pregnancy, IIH typically resolves postpartum; recurrence in subsequent pregnancies is unusual

Key References

• Bradley and Daroff's Neurology in Clinical Practice, Chapter 102
• IIHTT (IIH Treatment Trial) — Friedman et al., 2014; Smith and Friedman, 2017
• Mollan et al., J Neurol Neurosurg Psychiatry 2018 (consensus guidelines)
• Friedman et al., Neurology 2013 (revised diagnostic criteria)
• Yiangou et al., Nat Rev Neurol 2023 — recent review on disease mechanisms (PMID: 37957260)
• Friedman DI, Neurol Clin 2024 — updated clinical review of pseudotumor cerebri syndrome (PMID: 38575259)

Pseudobulbar Palsy vs Bulbar Palsy

Core Concept

Clinical Features Comparison

Pseudobulbar Affect (Emotional Lability)

• Spontaneous, unmotivated, or disproportionate laughing and crying
• Does not reflect the patient's actual emotional state
• Results from bilateral corticobulbar tract damage releasing brainstem emotional expression circuits from cortical inhibition
• Often causes significant embarrassment to the patient

"Spontaneous or unmotivated crying and laughter uniquely characterize pseudobulbar palsy." — Bradley and Daroff's Neurology in Clinical Practice

Causes

Bulbar Palsy (LMN)

• Motor neuron disease (progressive bulbar palsy — the most common cause)
• Guillain-Barré syndrome (acute onset, no atrophy)
• Poliomyelitis
• Diphtheria
• Syringobulbia
• Brainstem tumors / infarcts (if targeting motor nuclei)
• Myasthenia gravis (NMJ — mimics bulbar palsy)
• Kennedy disease (spinobulbar muscular atrophy — X-linked LMN)
• Fazio-Londe disease (childhood progressive bulbar palsy)

Pseudobulbar Palsy (UMN)

• Bilateral lacunar infarcts (most common — "lacunar state")
• ALS (mixed UMN + LMN — unique situation where both coexist)
• Multiple sclerosis
• Diffuse hypoxic-ischemic encephalopathy
• Progressive supranuclear palsy (PSP)
• Wilson disease
• Bilateral MCA territory strokes
• Cerebral vasculitis

"The most common pathologic bases are lacunar infarctions or other cerebrovascular lesions, diffuse hypoxic-ischemic encephalopathy, ALS, and multiple sclerosis." — Adams and Victor's Principles of Neurology, 12th Ed.

Special Case: ALS (Mixed Bulbar + Pseudobulbar)

Neuroanatomical Pathway Diagram

Quick Memory Summary

Note: "JNE myopathy" appears to be a typographic variant of GNE Myopathy. The answer below covers GNE myopathy in full.

GNE Myopathy

Definition

Genetics

Epidemiology

• Onset: second to third decade (late teens to twenties)
• Affects all ethnicities, but over-represented in Persian Jewish and Japanese populations
• Ultra-rare globally (~250–350 families described worldwide in earlier reports, but prevalence rising with genetic diagnosis)

Clinical Features

Onset & Pattern

• Initial weakness: anterior tibial muscles → progressive foot drop and steppage gait
• Extensor forearm muscles also affected early
• Weakness is distal-predominant, with characteristic quadriceps sparing — the hallmark that distinguishes GNE myopathy from most other myopathies
• Upper limb involvement: wrist and finger extensors, intrinsic hand muscles

Progression

• Slow but inexorably progressive
• Ambulation typically lost within 10–15 years of onset
• Ultimately all limb muscles except quadriceps become involved
• Respiratory and cardiac muscles are usually spared (important distinction from many other dystrophies)

Quadriceps Sparing

Clinical Photograph

Laboratory Features

Key Biopsy Point

MRI Findings

Distal Myopathies Comparison Table

Pathophysiology

1. Epimerase domain: UDP-GlcNAc → ManNAc
2. Kinase domain: ManNAc → ManNAc-6-phosphate

Diagnosis

1. Clinical suspicion: Young adult onset distal weakness with foot drop + quadriceps sparing
2. CK: Mildly elevated
3. EMG: Myopathic
4. Muscle biopsy: Rimmed vacuoles + EM tubulofilaments, no inflammation
5. Genetic testing: GNE gene sequencing — confirmatory

Treatment

Prognosis

• Slowly progressive over decades
• Loss of ambulation: typically 10–15 years after onset
• Respiratory and cardiac complications are rare but should be monitored in late stages
• Lifespan is generally normal

Key Differentials