Schwannoma (Neurilemmoma)

Definition & Origin

Epidemiology & Location

• Age range: 14-81 years, average ~40 years
• Most common single site: The vestibular (8th cranial) nerve - giving rise to vestibular schwannomas (acoustic neuromas), which account for ~9% of all primary brain tumors
• Head and neck: 25-45% of all schwannomas
• Sinonasal: Only ~4% of schwannomas; most arise from ophthalmic/maxillary divisions of CN V
• Peripheral (skin/soft tissue): Usually along main nerve trunks of the extremities, especially flexor surfaces of arms, wrists, and knees; also scalp, neck, and tongue
• Spine/pelvis: Can involve sacral plexus or sciatic nerve

Associations

Pathology

Gross

• Well-demarcated, encapsulated nodule, 3-30 mm (peripheral) or larger
• Firm to rubbery, yellow-tan or pale pink
• May become cystic when >3-4 cm

Histology - the hallmark is two tissue patterns:

• Source: Andrews' Diseases of the Skin, p. 719; Campbell's Operative Orthopaedics 15e, p. 1262

Immunohistochemistry

• S-100 protein: Strongly and diffusely positive (hallmark)
• Vimentin: Positive
• Myelin basic protein: Positive in hard (Antoni A-dominant) schwannomas
• EMA: Positive in perineurial capsule
• Neurofilament stain (Bodian): Very few/no nerve fibers within the tumor bulk; compressed nerve may be visible at one edge

Special variants

• Ancient schwannoma: Marked nuclear atypia without mitoses - a benign degenerative change; must not be confused with malignant peripheral nerve sheath tumor (MPNST)
• Plexiform schwannoma: Single or multiple, in dermis/subcutaneous tissue; may be associated with NF-1 or NF-2
• Melanotic psammomatous schwannoma: Associated with Carney syndrome; contains Verocay bodies + EMA-positive capsule

Imaging

MRI (modality of choice)

• Vestibular schwannoma: Densely enhancing mass enlarging the internal auditory canal, extending into the cerebellopontine angle (CPA); differential includes meningioma
• Peripheral schwannoma: Fusiform mass along the course of a major nerve
  • Split fat sign: Rim of fat on T1 around the mass
  • Target sign: Decreased T2 signal centrally, increased T2 peripherally (~50% of cases) - suggests benign diagnosis
  • Antoni A-dominant tumors: intermediate T1 and T2 signal
  • Antoni B-dominant tumors: hyperintense on T2 (loose myxoid stroma)

Clinical Features

Peripheral schwannomas

• Soft or firm nodule, may or may not be painful
• Tinel sign may be positive on percussion (rare with other soft-tissue masses)
• Symptoms from nerve compression: paresthesias, radicular pain

Vestibular schwannoma (acoustic neuroma)

• Progressive unilateral sensorineural hearing loss
• Dizziness, tinnitus
• If large: brainstem/cerebellar compression
• May be found incidentally on neuroimaging

Sinonasal schwannoma

• Headache, facial pain, nasal obstruction, epistaxis, anosmia, diplopia/proptosis, Horner syndrome

Differential Diagnosis

• Neurofibroma (not encapsulated, nerve runs through it, associated with NF-1)
• Meningioma (for vestibular/CPA lesions)
• MPNST (malignant peripheral nerve sheath tumor) - mitoses present, arises in NF-1 neurofibromas
• Solitary fibrous tumor, leiomyoma, fibrous histiocytoma, fibrosarcoma

Treatment

• Excision is almost invariably curative for benign schwannomas
• Recurrence rate is very low (3% in sinonasal series; ~0% in recent endoscopic series)
• Malignant variety (MPNST): Wide resection + radiotherapy required

Recent Evidence (2025)

Red Nucleus (Nucleus Ruber)

Location & Naming

Structure - Two Subdivisions

• Neuroanatomy through Clinical Cases, 3e; Guyton & Hall Medical Physiology

Connections (Inputs & Outputs)

Inputs to the Red Nucleus

1. Primary motor cortex - via the corticorubral tract (direct fibers + collaterals of the corticospinal tract as it passes through the mesencephalon)
2. Interposed cerebellar nuclei (emboliform + globose) - via the superior cerebellar peduncle (brachium conjunctivum) - to the magnocellular division
3. Dentate nucleus - output fibers penetrate the red nucleus; some terminate in the parvocellular division

Outputs from the Red Nucleus

1. Rubrospinal tract - from the magnocellular division:
   • Crosses immediately (decussates in the ventral tegmental decussation of Forel)
   • Descends in the lateral column of the spinal cord, adjacent to the corticospinal tract
   • Terminates on interneurons and anterior motor neurons in the intermediate gray matter, controlling distal limb muscles (especially flexors)
2. Central tegmental tract - from the parvocellular division:
   • Projects ipsilaterally down to the inferior olivary nucleus (part of the Guillain-Mollaret triangle)

Function

1. Accessory Motor Pathway (Corticorubrospinal System)

• The magnocellular portion has a somatotopic map of all muscles (less precise than motor cortex, especially in humans)
• Stimulation of a single point produces contraction of a muscle or small muscle group
• Together with the corticospinal tract, it forms the lateral motor system of the cord, controlling distal limb movements
• When the corticospinal tract is destroyed but the rubrospinal pathway is intact: discrete voluntary movements survive, but fine finger and hand movements are impaired; wrist movements are preserved
• When both are destroyed: severe impairment of fractionated limb/hand movements (confirmed in Lawrence & Kuypers' primate lesion studies)

2. Cerebellar Relay

• Acts as a key relay in cerebellar motor circuits:
  • Parvocellular red nucleus → inferior olive → cerebellum (part of the dentatorubro-olivary loop)
  • Interposed nuclei → magnocellular red nucleus → rubrospinal tract (influencing lateral motor control)

3. Evolutionary Note

Guillain-Mollaret Triangle

Red Nucleus (midbrain)
        |
  Central tegmental tract (descending, ipsilateral)
        ↓
Inferior Olivary Nucleus (medulla)
        |
  Olivocerebellar fibers (crossing via inferior cerebellar peduncle)
        ↓
Contralateral Cerebellum (dentate/interposed nuclei)
        |
  Superior cerebellar peduncle (crossing back up)
        ↑
Red Nucleus

Clinical Syndromes Involving the Red Nucleus

Benedikt Syndrome

1. Ipsilateral CN III palsy (with dilated pupil) - fascicle involvement
2. Contralateral hemiataxia with intention tremor - red nucleus destruction
3. Contralateral hemiparesis with hyperreflexia - involvement of the corticospinal tract

Claude Syndrome

• Ipsilateral CN III palsy
• Prominent contralateral cerebellar signs (ataxia, asynergia, dysmetria, dysdiadochokinesis)

Nothnagel Syndrome

• Unilateral or bilateral CN III palsy + contralateral cerebellar ataxia

Summary Table

Malignant Hyperthermia (MH)

Definition

Epidemiology

• Miller's Anesthesia, 10e; Sabiston Textbook of Surgery

Pathophysiology

Normal Excitation-Contraction Coupling (ECC)

1. Motor nerve impulse → acetylcholine release at NMJ
2. ACh activates nicotinic receptors → action potential propagates along sarcolemma into T-tubules
3. T-tubule depolarization is sensed by Cav1.1 (DHPR - dihydropyridine receptor), the L-type voltage-gated Ca²⁺ channel
4. DHPR mechanically activates the RyR1 (ryanodine receptor type 1) on the sarcoplasmic reticulum (SR)
5. RyR1 opens → Ca²⁺ floods from SR into myoplasm → muscle contraction

In MH - What Goes Wrong

• Uncontrolled, sustained opening of RyR1 → massive Ca²⁺ release from SR
• Persistently elevated myoplasmic Ca²⁺ drives skeletal muscle into a hypermetabolic state
• Rapid ATP consumption → heat generation, CO₂ production, O₂ consumption all surge
• Progressive muscle contracture → rhabdomyolysis
• Metabolic acidosis, hyperkalemia, hyperthermia ensue

Genetics

• Inheritance: Autosomal dominant with incomplete penetrance (many susceptible individuals never develop MH even with exposure)
• RYR1 gene (chromosome 19q13.2): >230 mutations identified; accounts for 50-80% of cases
  • Encodes the type 1 ryanodine receptor (SR Ca²⁺ release channel)
  • Classic porcine model: Arg615Cys missense mutation - all susceptible swine carry this identical mutation
• CACNA1S gene: 3 mutations identified; encodes the α1 subunit (pore-containing) of Cav1.1/DHPR
• At least 5 other loci have been identified
• Genetic heterogeneity means mutations vary between families; phenotype varies even within a single genotype due to sex, age, epigenetic, and environmental modifiers

Triggering Agents

Clinical Features

Early Signs

• ↑ End-tidal CO₂ despite increased minute ventilation - one of the earliest and most reliable signs
• Tachycardia
• Tachypnea / increased O₂ consumption
• Mixed metabolic and respiratory acidosis

Late / Fulminant Signs

• Masseter muscle rigidity (especially after succinylcholine) - may be the first sign
• Generalized muscle rigidity
• Hyperthermia - temperature can rise by 1°C every 5 minutes (a very late sign; do not wait for it)
• Rhabdomyolysis → myoglobinuria → acute kidney injury
• Hyperkalemia (from muscle breakdown) → life-threatening arrhythmias
• Extreme metabolic acidosis
• Disseminated intravascular coagulation (DIC) in severe cases

Key teaching point: Hyperthermia is a late sign - MH should be diagnosed and treated before temperature rises significantly. Early rising CO₂ and rigidity are the actionable clues.

Diagnosis

Intraoperative (clinical diagnosis)

Laboratory findings

• ↑↑ Creatine kinase (CK) - markedly elevated
• Metabolic + respiratory acidosis (↓pH, ↑PaCO₂, ↑lactate)
• Hyperkalemia
• Myoglobinuria
• ↑ Temperature

Confirmatory Testing (after acute episode - for susceptibility testing)

• Caffeine-halothane contracture test (CHCT / IVCT): Gold standard
  • Thin strip of explanted (biopsied) muscle stimulated electrically, then exposed to caffeine ± halothane
  • Abnormally increased contracture = positive = MH-susceptible
  • Highly operator-dependent; only done at specialized centers
• Genetic testing: RYR1/CACNA1S mutation analysis - positive in ~50-80% of confirmed cases
  • 2025 European MH Group updated guidelines (Rüffert et al., Br J Anaesth 2026) provide the current framework for susceptibility investigation [PMID: 41478797]

Treatment - Emergency Protocol

1. Stop the trigger

• Immediately discontinue all volatile agents and succinylcholine
• Switch to total IV anesthesia (propofol)
• Hyperventilate with 100% O₂ at high fresh gas flows

2. Dantrolene - the antidote

• Mechanism: Inhibits Ca²⁺ release from the SR by binding RyR1, directly counteracting the pathological process
• Dose: 2.5 mg/kg IV bolus immediately
• Re-dose: Every 10-15 minutes as needed for ongoing fever, acidosis, and rigidity
• Total dose: Up to 10 mg/kg or more may be required
• Continue dantrolene for 24-48 hours post-crisis to prevent recurrence

3. Active cooling

• Cooling blankets, ice packs to axilla/groin, cold IV saline
• Target temperature <38.5°C
• Stop cooling at ~38°C to avoid overshoot hypothermia

4. Supportive measures

5. ICU admission

• Monitoring and observation in ICU are warranted after all MH episodes
• Sabiston Textbook of Surgery; Bradley & Daroff's Neurology; Miller's Anesthesia, 10e

Preoperative Management of MH-Susceptible Patients

• Use total IV anesthesia (TIVA) - propofol-based
• Use non-depolarizing NMBAs only
• Pre-treat with oral dantrolene (controversial - most centers now use TIVA without routine prophylactic dantrolene, but have dantrolene immediately available)
• Have dantrolene drawn up and ready before induction
• Avoid volatile anesthetic machines unless thoroughly flushed (flush with O₂ for 20 min at high flow)
• Post-op monitoring for at least 4 hours

Related Conditions

Historical Landmark

2025-2026 Guideline Updates

• JSA guideline for management of MH (2025) - Japanese Society of Anesthesiologists [PMID: 41504952]
• European MH Group 2025 guidelines for investigation of MH susceptibility - updated contracture testing and genetic testing protocols [PMID: 41478797]

Hiccup (Singultus) - Treatment at Home & Hospital

What Is a Hiccup?

Classification by Duration

Common Causes

Surgical pearl: In the early postoperative period, hiccups suggest upward diaphragmatic pressure from gastric distension or paralytic ileus - insert a nasogastric tube and aspirate. - S Das Manual on Clinical Surgery, 13e

Home Remedies (Physical Maneuvers)

Vagal Stimulation Maneuvers

• Swallow a teaspoon of dry granulated sugar - as effective as most others, simple and safe
• Sip or quickly drink ice-cold water
• Breath-holding / Valsalva maneuver - increases intrathoracic pressure
• Breathing into a paper bag - raises CO₂, suppresses reflex
• Swallowing dry bread or crushed ice
• Pulling knees to chest and leaning forward (compresses diaphragm)
• Applying pressure to the eyeballs (stimulates vagus via oculocardiac reflex)
• Digital rectal massage - stimulates rectal branch of vagus (reported effective, rarely used at home)
• Gargling with water
• Tongue traction or pharyngeal stimulation

Ear

• Remove any foreign body from the external auditory canal - a hair touching the tympanic membrane stimulates the auricular branch of the vagus and is a treatable, often-missed cause

Diagnostic clue: If hiccups resolve during sleep, a psychogenic cause is more likely (though not absolute). - Tintinalli's Emergency Medicine, p. 471

Hospital Treatment

Step 1: Identify & Treat the Cause

• Check for foreign body in ear
• Chest X-ray for persistent hiccups
• Rule out: uremia, hyperglycemia, CNS lesion, drug-induced (steroids, chemotherapy)
• Postoperative hiccup → nasogastric tube insertion + aspiration
• Steroid-induced hiccup → reduce steroid dose
• Fluoroscopy (non-ED): assesses unilateral vs bilateral diaphragm movement (unilateral = focal phrenic nerve lesion)

Step 2: Drug Treatment

• Phenothiazines (in addition to chlorpromazine)
• Pregabalin - similar to gabapentin; used in CNS-origin hiccups
• Ondansetron - occasionally used
• Pethidine (meperidine) - for postoperative hiccup (S Das Manual)
• In palliative care: midazolam infusion for refractory terminal hiccups

Step 3: Invasive Options (truly intractable cases)

• Phrenic nerve block - local anesthetic injection (temporary relief)
• Phrenic nerve crush/section - last resort; risks hemidiaphragm paralysis
• Nasogastric tube insertion + aspiration (for postoperative gastric distension)
• Acupuncture - a 2023 systematic review and meta-analysis found acupuncture effective for post-stroke hiccups (PMID: 37644765)

Quick Reference Summary

HICCUP
  │
  ├─ < 48 hours → Home maneuvers (sugar, cold water, breath-holding, paper bag)
  │
  ├─ 48 hrs - 1 month (Persistent) → Treat cause + Metoclopramide / Chlorpromazine
  │
  └─ > 1 month (Intractable) → Full workup + Baclofen / Gabapentin / Chlorpromazine IV
                                Consider phrenic nerve block if all else fails