Neuropathology Quiz

Multiple Sclerosis

• Definition: A chronic, autoimmune, inflammatory, and neurodegenerative disease of the CNS that affects the brain and spinal cord, preserving the nerves.
• Characteristics: Demyelination and axonal loss, leading to non-traumatic disability in young adults.
• Epidemiology:
  • Affects 2-3 million people worldwide.
  • Most common cause of non-traumatic disability in young adults.
  • Incidence: 3/100,000.
  • Prevalence: 100/100,000 (50-300) in clinics.
• Age: Mean age of onset is 30 years, but can occur in paediatric patients and those over 60 years.
• Sex: More common in women, with a female-to-male ratio of 2.5:1.
• Global distribution: Increases with distance from the equator, except for some exceptions.

Etiology and Pathogenesis

• Multifactorial disease involving interaction between genetic substrate and environmental factors.
• Environmental factors:
  • Pathogens: EBV, CMV, HSV, and others.
  • Low vitamin D levels.
  • Pediatric obesity.
  • Cigarette smoking.
• Genetics:
  • Association with HLA region of chromosome 6.
  • Carriers of HLA-DRB1*15:01 allele are three times more likely to develop MS.
  • Genome-wide association studies identified genes associated with immune response.

Gross Anatomy

• Multifocal areas of demyelination, called plaques or lesions, occur in the CNS.
• Locations: brain, brainstem, and spinal cord.

Migraine

• Definition: A complex, chronic, and recurrent disorder characterized by episodic attacks of severe, debilitating headache.
• Characteristics:
  • Typically unilateral, throbbing, and pulsating.
  • Associated with sensitivity to light, sound, and smell.
  • Often accompanied by nausea, vomiting, and fatigue.
  • Postdrome: a feeling of exhaustion, depression, and anxiety after the attack.

Tension Headache

• Definition: A primary headache disorder characterized by pain, usually mild to moderate, and a feeling of pressure or tightness around the head.
• Characteristics:
  • Pain is non-pulsating, pressing, or tightening.
  • Often bilateral.
  • Rarely accompanied by photophobia, phonophobia, or nausea.
  • Not worsened by physical activity.

Cluster Headache

• Definition: A type of trigeminal autonomic cephalalgia characterized by unilateral, severe, and short-lasting pain.
• Characteristics:
  • Pain is sharp, stabbing, and severe.
  • Associated with homolateral autonomic system symptoms.
  • Duration: 15-180 minutes.
  • Frequency: 1 attack every other day to 8 times/day.
• Autonomic system symptoms:
  • Lacrimation.
  • Conjunctival injection.
  • Nasal congestion.
  • Facial sweating.
  • Ptosis.
  • Miosis.
  • Enophthalmos.
  • Tearing.

Treatments

• Symptomatic treatments:
  • NSAIDs.
  • Analgesic combinations.
  • Triptans.
  • Ergot alkaloids.
  • Gepants.
  • Ditans.
• Preventive treatments:
  • Beta-blockers.
  • Calcium channel blockers.
  • Anti-epileptic drugs.
  • Anti-depressants.
  • Botulinum toxin.
  • Monoclonal antibodies anti-CGRP ligand or anti-CGRP receptor.### Hypothalamic System and Cluster Headache
• The hypothalamic system is involved in the regulation of:
  • Circadian rhythm
  • Neuroendocrine homeostasis
  • Autonomic nervous system
• The hypothalamus plays a key role in cluster headache, explaining:
  • Circadian pattern (attacks occur at the same time daily)
  • Circannual pattern (attacks occur at the same time yearly)
  • Autonomic symptoms (e.g. lacrimation, nasal congestion)
• The suprachiasmatic nucleus (SCN) is the principal circadian pacemaker and is affected by photoperiodism (changes in sunlight duration)

Cranial Neuralgia

• Cranial neuralgias can be typical or atypical
• Atypical neuralgias are often secondary to another disease
• Typical cranial neuralgias are characterized by:
  • Intense, stabbing, electric shock-like pain
  • Follows nerve distribution
  • Trigeminal neuralgia is the most frequent (90% of cranial neuralgias)
• Other possible neuralgias include:
  • Glossopharyngeal neuralgia
  • Occipital neuralgia
  • Nervus intermedius neuralgia

Trigeminal Neuralgia

• Trigeminal neuralgia is a disease that affects older people (60s and over 70s)
• Incidence: 3-5/100,000
• Male:Female ratio: 1:2
• 95% of cases involve the V2 (maxillary) or V3 (mandibular) branches
• 5% of cases involve the V1 (ophthalmic) branch
• Clinical presentation:
  • Severe and sudden facial pain
  • Unilateral, short, and unpredictable attacks
  • No associated neurological deficits
  • No autonomic symptoms
• Triggers:
  • Touching or washing the face
  • Shaving
  • Chewing
  • Speaking
  • Yawning
• Pathogenesis:
  • Damage to the myelin sheath of the nerve
  • Neurovascular conflict
  • Compression of the nerve by the superior cerebellar artery (SCA) or antero-inferior cerebellar artery (AICA)

Neuromyelitis Optica Spectrum Disorder (NMOSD)

• NMOSD is a demyelinating disease that affects the CNS
• Diagnosis:
  • Detection of AQP4-IgG in serum (best assessed using live cell-based assays)
  • CSF analysis: CSF pleocytosis, CSF-restricted oligoclonal bands
• Clinical features:
  • Optic neuritis (45% of patients)
  • Myelitis (85% of patients)
  • Area postrema syndrome (15-40% of patients)
• Prognosis:
  • 90% of patients have a relapsing disease course
  • Clinical deterioration can be irreversible
  • Importance of preventive treatments
• Treatments:
  • Treatment of relapses: similar to MS (i.v. high dose steroids, plasmapheresis)
  • Preventive treatments: azathioprine, rituximab, mycophenolate mofetil, inebilizumab, satralizumab, tocilizumab, eculizumab

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD)

• MOGAD is a recently described CNS autoimmune disease
• Epidemiology:
  • 50% of patients have a pediatric onset
  • May be monophasic (one shot and never comes back without treatment)
  • F:M ratio: 1:1
  • Incidence: 1.6/million persons/year
• Pathology:
  • Characterized by the coexistence of perivenous and confluence primary demyelination with partial axonal preservation and reactive gliosis
  • Abundance of intracortical demyelinating lesions
• Pathogenesis:
  • Outside-in model: where autoantibodies and activated immune cells in the peripheral blood cross the blood-brain barrier
  • Infections could cause bystander activation and molecular mimicry
  • MOG antibody pathogenicity: opsonization of MOG, complement activation, antibody-dependent cellular cytotoxicity (ADCC), and anti-MOG ab-induced intracellular signaling cascade
• MOGAD disease phenotypes:
  • Optic neuritis
  • Myelitis
  • Brainstem syndrome
  • Encephalitis
  • ADEM-like presentation### Optic Neuritis
• Unilateral or bilateral, severe visual loss, usually good recovery
• Bilateral simultaneous clinical involvement
• Longitudinal optic nerve involvement (>50% length of the optic nerve)
• Perineural optic sheath enhancement
• Optic disc oedema (radiologically visible optic disc swelling and optic disc oedema on fundoscopy)

Transverse Myelitis

• Paraparesis, asymmetrical, sensory level, sphincteric symptoms
• Longitudinally extensive myelitis
• Central cord lesion or H-sign
• Conus lesion

Acute Disseminated Encephalomyelitis (ADEM)

• Clinical syndrome characterized by a first polyfocal CNS episode from presumed demyelination
• Includes encephalopathy not explained by fever, systemic illness, or postictal features
• Requires MRI abnormalities with large poorly demarcated lesions in the white matter with or without gray matter lesions
• Characterized by multifocal neurologic symptoms

Disease Phenotypes

• Brain, brainstem, or cerebral syndrome: radiological characteristics
  • Multiple ill-defined T2 hyperintense lesions in supratentorial and infratentorial white matter
  • Deep grey matter involvement
  • Ill-defined T2-hyperintensity involving pons, middle cerebellar peduncle, or medulla
  • Cortical lesion with or without lesional and overlying meningeal enhancement

Diagnostic Criteria

• One of the core declinating events and the positivity of the antibodies are needed for diagnosis
• If there is a clear positivity, diagnosis is made
• If there is no clear positivity or antibodies are absent, supportive clinical and radiological criteria are needed

Comparison of MOG-Ab, ADEM, MS, and NMOSD

• Age: MOG-Ab (0-40), MS (20-40), Apororin (a little bit older)
• Inflammatory event: frequent in MOG-Ab, not observed in MS
• Relapse: MS is relapsing, MOG-Ab can be monophasic
• Radiological features: differences in brain and spinal cord lesions between MOG-Ab, NMOSD, and MS
• Optic neuritis: MOG-Ab (bilateral and longitudinally extensive), MS (monolateral)
• Spinal cord lesions: MOG-Ab (longitudinally extensive), MS (short lesions)

Prognosis

• MOG-Ab can have a better prognosis compared to MS and NMOSD
• Lesions can completely disappear in MOG-Ab
• Scar formation is less common in MOG-Ab compared to MS and NMOSD