Inflammatory Neuropathies

Slide 1 · Inflammatory Neuropathies

Mechanisms, morphology, and clinicopathologic patterns

Guillain–Barré syndrome • CIDP • Autoimmune nodopathy • Vasculitis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes: From injury to clinical pattern

Nerve structure

Immune mechanism

Morphologic lesion

Clinicopathologic pattern

Distinguish segmental demyelination from axonal degeneration.

Explain immune mechanisms and pathologic findings in GBS and CIDP.

Recognize autoimmune and vasculitic patterns of nerve injury.

Integrate distribution, time course, pathology, and supportive tests.

Slide 3 · The immune-mediated neuropathy spectrum

Acute demyelinating

Guillain–Barré syndrome

Chronic demyelinating

CIDP

Nodal/paranodal

Autoimmune nodopathy

Axonal / vascular

Systemic disease; Vasculitis

Guillain–Barré syndrome: Typically acute demyelinating radiculoneuropathy.

CIDP: Acquired chronic inflammatory demyelinating neuropathy.

Autoimmune nodopathies: Antibodies target nodal/paranodal proteins.

Systemic autoimmunity and vasculitis: Often axonal patterns.

Slide 4 · Anatomy: Axon, Schwann cell, and myelin internode

Node

Node

Node

Axon

Schwann-cell myelin internodes

Peripheral axons transmit impulses from neuronal cell bodies.

Schwann cells form discrete myelin segments around individual axons.

Nodes of Ranvier separate internodes and support saltatory conduction.

Slide 5 · Primary demyelination differs from axonal injury

Demyelination: Axon remains

Axonal loss: Conducting fiber disrupted

Demyelination removes myelin segments while initially sparing the axon.

Axonal injury directly disrupts the conducting process.

Both processes may coexist as immune-mediated disease becomes severe.

Slide 6 · Electrophysiology mirrors the site of injury

Demyelinating

Impulse conduction slows

Axonal

Signal amplitude falls

Velocity

Amplitude

Myelin loss slows impulse propagation and therefore conduction velocity.

Loss of functioning axons chiefly decreases recorded signal amplitude.

A mixed lesion can produce more than one type of abnormality.

Slide 7 · Distribution identifies the involved compartment

Symmetric

Polyneuropathy

Roots + nerves

Polyradiculoneuropathy

Patchy, named nerves

Mononeuritis multiplex

Polyneuropathy affects numerous nerves, commonly symmetrically.

Polyradiculoneuropathy includes roots and peripheral nerves.

Mononeuritis multiplex injures distinct named nerves asymmetrically.

Slide 8 · Why root involvement changes the interpretation

Spinal nerve roots

Peripheral nerve trunks

Nerve-root plus peripheral nerve injury produces proximal and distal deficits.

GBS and CIDP belong to this radiculoneuropathic pattern.

Pathologic involvement cannot be inferred from a distal-nerve symptom alone.

Slide 9 · Morphologic vocabulary used throughout the lecture

Normal internodes

Node

Node

Node

Axon

Schwann-cell myelin internodes

Focal internodal myelin loss

Segmental demyelination: Loss of an internode or its myelin lamellae.

Remyelination: A repaired segment is often shorter and thinner.

Axonal degeneration/regeneration: Direct loss and attempted restoration of axons.

Inflammatory cells and abnormal vessels identify the injury context.

Slide 10 · Guillain–Barré syndrome: Acute immune neuropathy

Spinal nerve roots

Peripheral nerve trunks

GBS commonly manifests as acute inflammatory demyelinating polyradiculoneuropathy (AIDP).

Inflammatory injury involves nerve roots and peripheral nerves.

Progressive weakness can culminate in respiratory paralysis.

Slide 11 · GBS: Epidemiology and overall phenotype

Onset

Progression

Nadir / course

Clinical change over time

The textbook estimates approximately one new case per 100,000 persons annually.

Weakness often begins distally and advances toward proximal muscle groups.

This rapid ascending paralysis is a defining clinical pattern.

Slide 12 · GBS: The ascending weakness pattern

Distal

Lower limb

Proximal

Respiratory

Distal limb weakness develops first in the classic presentation.

Weakness extends to larger proximal muscle groups as disease progresses.

This clinical pattern directs attention toward an acute diffuse peripheral process.

Slide 13 · GBS: Loss of tendon reflexes

Motor pathway

Nerve root + peripheral nerve

Response

Weakness / lost reflex

Deep tendon reflexes are lost early in the illness.

Areflexia accompanies the progressive limb weakness.

Combined weakness and reduced reflexes support peripheral nerve/root dysfunction.

Slide 14 · GBS: Sensory findings are usually less prominent

Sensory disturbance may accompany weakness, including impaired pain sensation.

The motor syndrome generally dominates the clinical presentation.

Absence of a striking sensory deficit does not exclude the classic pattern.

Slide 15 · GBS: The characteristic acute time course

Onset

Progression

Nadir / course

GBS: Nadir ≤4 weeks

CIDP: ≥8 weeks

Weakness reaches its nadir within 4 weeks of onset.

The early course may be rapidly progressive rather than steadily chronic.

Time to maximal weakness distinguishes it from the typical CIDP course.

Slide 16 · Illustrative case: Acute areflexic weakness

Clinical observation

Localize the nerve dysfunction

Pathologic interpretation

Identify the injury pattern

An adult develops distal weakness after an upper respiratory illness.

Weakness rapidly extends proximally; Tendon reflexes disappear.

Question: Which clinical features favor GBS over a chronic neuropathy?

Slide 17 · The antecedent illness is a major etiologic clue

Onset

Progression

Nadir / course

Clinical change over time

Approximately two-thirds of patients have a preceding acute upper respiratory illness.

Neuropathy often begins after apparent recovery from that illness.

The temporal interval supports an immune response rather than direct nerve infection.

Slide 18 · Microbial exposures associated with GBS

C. Jejuni

CMV

EBV

M. Pneumoniae

Zika

SARS-CoV-2

Campylobacter jejuni and cytomegalovirus have epidemiologic associations.

Epstein–Barr virus and Mycoplasma pneumoniae are also associated.

The textbook also lists Zika virus and SARS-CoV-2.

Slide 19 · Vaccination: Interpret temporal reports cautiously

Rare GBS cases have been reported following certain vaccinations.

The textbook mentions influenza, varicella-zoster, and non-mRNA SARS-CoV-2 vaccines.

A report of temporal association should not be equated with proof of causality.

Slide 20 · The major distinction: Postinfectious versus infectious nerve injury

Microbial exposure

Host immune response

Peripheral nerve injury

No infectious organism has been demonstrated in affected GBS nerves.

The favored mechanism is an immune reaction following exposure to microbial antigens.

This contrasts with neuropathies resulting from direct infectious damage.

Slide 21 · Experimental models support cell-mediated demyelination

T cells

Cell-mediated activity

Antibodies

Humoral activity

Macrophages

Myelin removal

Immunization with a peripheral-nerve myelin protein can reproduce inflammatory lesions.

T-cell responses accompany macrophage-induced segmental myelin loss.

Transfer of sensitized T cells can reproduce comparable lesions.

Slide 22 · Patient lymphocytes can damage myelinated fibers

T cells

Cell-mediated activity

Antibodies

Humoral activity

Macrophages

Myelin removal

In experimental co-culture, lymphocytes from individuals with GBS cause demyelination.

This supports a role for cellular immune mechanisms.

Cell-based evidence complements, rather than excludes, antibody effects.

Slide 23 · Humoral immunity may also contribute

T cells

Cell-mediated activity

Antibodies

Humoral activity

Macrophages

Myelin removal

Circulating antibodies may cross-react with peripheral nerve components.

Antibody-mediated injury is one proposed part of the autoimmune response.

The GBS phenotype is not attributed to a single uniform mechanism.

Slide 24 · GBS pathogenesis: From trigger to myelin injury

Antecedent microbial antigen

T-cell / antibody response

Macrophage-associated myelin loss

Slowed impulse conduction

An antecedent microbial exposure is followed by immune activation.

T lymphocytes and macrophages participate in demyelinating injury.

Cross-reacting antibodies may contribute in at least some cases.

Slide 25 · AMAN: An axonal variant within the GBS spectrum

Demyelination: Axon remains

Axonal loss: Conducting fiber disrupted

Acute motor axonal neuropathy (AMAN) is an uncommon axonal form of GBS.

Its morphology features axonal degeneration and attempted regeneration.

It shows a stronger association with antecedent Campylobacter jejuni.

Slide 26 · AIDP and AMAN have different primary targets

AIDP

Segmental myelin injury

AMAN

Predominantly motor axon injury

AIDP: Segmental myelin loss and remyelination dominate the lesion.

AMAN: Motor axonal injury and regeneration dominate.

This distinction prevents all GBS cases from being mislabeled as demyelinating.

Slide 27 · GBS pathology: Inflammation accompanies demyelination

Perivenular / endoneurial inflammatory infiltrates

H&E sections show inflammation within peripheral nerves.

Inflammatory cells accumulate around venules and in the endoneurium.

Both the inflammatory pattern and the myelin lesion matter.

Slide 28 · The cellular infiltrate is macrophage-rich

Macrophage

Lymphocyte

Plasma cell

Macrophages are prominent in the affected nerves.

Lymphocyte numbers vary; Plasma cells are comparatively few.

Macrophages also participate directly in removal of damaged myelin.

Slide 29 · Segmental demyelination is the dominant AIDP lesion

Normal internodes

Node

Node

Node

Axon

Schwann-cell myelin internodes

Focal internodal myelin loss

Inflammatory attack removes portions of myelin along affected axons.

Other internodes can remain relatively preserved.

Widespread multifocal loss disrupts efficient nerve impulse conduction.

Slide 30 · Macrophages can physically strip myelin

Macrophage

Myelin segment

Macrophage processes penetrate the Schwann-cell basement membrane.

They extend between myelin lamellae and separate the sheath from the axon.

Myelin fragments are subsequently engulfed and cleared.

Slide 31 · Nodes of Ranvier are important sites of early injury

Node

Node

Node

Axon

Schwann-cell myelin internodes

Node–paranode interface

Ultrastructural observations place macrophage attack near nodal regions.

Macrophages enter between lamellae rather than requiring initial axonal destruction.

The microanatomic finding reinforces myelin-directed injury.

Slide 32 · GBS may also produce axonal damage

Demyelination: Axon remains

Axonal loss: Conducting fiber disrupted

Although myelin loss predominates in AIDP, axons can also be damaged.

Secondary axonal injury becomes particularly relevant in severe disease.

Mixed tissue injury helps explain residual functional impairment.

Slide 33 · Myelin repair does not immediately restore normal architecture

Normal internodes

Node

Node

Node

Axon

Schwann-cell myelin internodes

Focal internodal myelin loss

Schwann cells can form new myelin after segmental loss.

The replacement internodes are typically shorter and thinner.

The repaired fiber may differ structurally from the original.

Slide 34 · Inflammation may extend across the peripheral nervous system

Spinal nerve roots

Peripheral nerve trunks

Both roots and peripheral nerves can show inflammatory demyelination.

The lesions tend to be more prominent proximally, near spinal roots.

The proximal emphasis matches the designation polyradiculoneuropathy.

Slide 35 · GBS electrophysiology: Why conduction is slowed

Demyelinating

Impulse conduction slows

Axonal

Signal amplitude falls

Velocity

Amplitude

Loss of multiple myelin segments disrupts saltatory impulse transmission.

Consequently, nerve conduction velocities decrease.

This finding supports a demyelinating pattern when integrated clinically.

Slide 36 · GBS cerebrospinal fluid: Increased protein

Inflamed roots

Protein crosses altered microvessels

CSF space

Raised protein; Few cells

Inflammation alters the permeability of root microvessels.

Root-associated proteins can enter cerebrospinal fluid (CSF).

This accounts for raised CSF protein in the classic presentation.

Slide 37 · GBS cerebrospinal fluid: Few inflammatory cells

Inflamed roots

Protein crosses altered microvessels

CSF space

Raised protein; Few cells

Inflammatory leukocytes generally remain localized within affected roots.

Consequently, CSF has little or no pleocytosis despite raised protein.

The mechanism explains the characteristic protein–cell dissociation.

Slide 38 · GBS recognition integrates three evidence streams

Clinical distribution

Nerve injury pattern

Corroborating pathology

Clinical: Rapidly progressive ascending weakness with areflexia.

Electrophysiology: Conduction slowing in the demyelinating form.

CSF: High protein with few or no inflammatory cells.

Slide 39 · Respiratory failure makes GBS time-critical

Distal

Lower limb

Proximal

Respiratory

Ascending weakness can impair the muscles required for ventilation.

Severely affected individuals may require prolonged intensive care.

Respiratory function requires close supportive monitoring.

Slide 40 · Autonomic and cardiovascular complications

Motor pathway

Nerve root + peripheral nerve

Response

Weakness / lost reflex

Autonomic instability contributes to life-threatening complications.

Cardiac arrest is a recognized cause of death in severe disease.

Cardiovascular monitoring is an essential supportive measure.

Slide 41 · Supportive measures reduce preventable complications

Ventilation

Cardiovascular monitoring

DVT prevention

Improved respiratory care has contributed to lower mortality.

Cardiovascular surveillance addresses instability.

Deep venous thrombosis prophylaxis is part of supportive inpatient care.

Slide 42 · GBS immunotherapy aims to accelerate recovery

Immune-mediated nerve injury

Immunomodulatory intervention

Improved clinical function

Plasmapheresis and intravenous immunoglobulin (IVIG) hasten recovery.

Plasma exchange removes circulating pathogenic mediators, including antibodies.

IVIG is used for its immunomodulatory effects.

Slide 43 · GBS outcomes: Substantial recovery, persisting risk

2%–5%

Reported mortality

Up to 20%

Disability among hospitalized survivors

2%–5% mortality among affected individuals.

Deaths may involve respiratory paralysis, autonomic instability, or cardiac arrest.

Up to 20% of hospitalized survivors have long-term disability.

Slide 44 · Case resolution: Localizing the lesion

Clinical observation

Localize the nerve dysfunction

Pathologic interpretation

Identify the injury pattern

The combination of rapid ascent and areflexia favors an acute neuropathic process.

Root plus nerve involvement makes radiculoneuropathy appropriate.

Electrophysiologic and CSF features can support the clinical interpretation.

Slide 45 · CIDP: The principal chronic inflammatory neuropathy

Onset

Progression

Nadir / course

GBS: Nadir ≤4 weeks

CIDP: ≥8 weeks

CIDP is a chronic, acquired, inflammatory peripheral neuropathy.

The common pattern is symmetric, mixed motor and sensory impairment.

Its required duration is at least 8 weeks (about 2 months).

Slide 46 · CIDP evolves over a longer time horizon

Onset

Progression

Nadir / course

Clinical change over time

Symptoms can evolve over years rather than days to weeks.

Relapses and remissions are a common course.

Prolonged activity allows repeated cycles of injury and repair.

Slide 47 · CIDP commonly affects motor and sensory function

Symmetric

Polyneuropathy

Roots + nerves

Polyradiculoneuropathy

Patchy, named nerves

Mononeuritis multiplex

Weakness and difficulty walking reflect motor involvement.

Numbness and pain reflect sensory involvement.

The usual phenotype is a symmetric sensorimotor polyneuropathy.

Slide 48 · CIDP phenotype can be motor- or sensory-predominant

Although mixed deficits are common, isolated motor impairment may occur.

Some patients present with predominantly sensory symptoms.

Phenotypic diversity does not negate the chronic inflammatory framework.

Slide 49 · CIDP pathogenesis involves cellular and humoral immunity

T cells

Cell-mediated activity

Antibodies

Humoral activity

Macrophages

Myelin removal

T-cell–mediated and antibody-mediated mechanisms are implicated.

Immune targets include the Schwann-cell–axon junction and compact myelin.

Inflammatory injury results in cycles of demyelination and remyelination.

Slide 50 · Complement-fixing antibodies can decorate myelin

Macrophage

Myelin segment

Immunoglobulin G and immunoglobulin M may localize to myelin sheaths.

Their deposition promotes macrophage recruitment.

Macrophages contribute to removal of myelin from underlying axons.

Slide 51 · Recurrent demyelination drives repeated repair

Segmental myelin loss

Schwann-cell proliferation

Thin / short remyelinated internodes

Repetitive repair

Myelin is lost in discrete segments rather than uniformly from every axon.

Schwann cells re-form myelin around surviving axons.

Repetitive injury and repair change the architecture over time.

Slide 52 · Onion bulbs: A structural memory of repeated myelin repair

Axon

Concentric Schwann-cell layers

Repeated Schwann-cell proliferation can encircle the same axon.

Concentric cellular layers create an onion-bulb configuration.

An axon with a relatively thin myelin sheath may occupy the center.

Slide 53 · Onion bulbs are not specific for CIDP

Axon

Concentric Schwann-cell layers

They indicate repeated demyelination and remyelination.

Other chronic demyelinating neuropathies can also produce them.

This morphological finding must be interpreted within the complete context.

Slide 54 · CIDP inflammation may resemble GBS pathology

GBS

Acute root/nerve inflammation

CIDP

Chronic repeated demyelination

Macrophage infiltration accompanies myelin injury in both disorders.

The chronicity of CIDP may add conspicuous onion-bulb formation.

The principal distinction is not a uniquely identifying inflammatory cell.

Slide 55 · Time course and steroid response help separate GBS/CIDP

Onset

Progression

Nadir / course

GBS: Nadir ≤4 weeks

CIDP: ≥8 weeks

GBS: Reaches maximal weakness within 4 weeks.

CIDP: Signs and symptoms persist for at least 8 weeks.

A positive steroid response as a CIDP discriminator.

Slide 56 · CIDP treatment can yield clinical remission

Immune-mediated nerve injury

Immunomodulatory intervention

Improved clinical function

Intravenous immunoglobulin often produces improvement or remission.

Plasmapheresis and glucocorticoids are additional immunomodulatory options.

T-cell– or B-cell–directed cytotoxic agents are also described.

Slide 57 · Autoimmune nodopathy is conceptually distinct from CIDP

Node

Node

Node

Axon

Schwann-cell myelin internodes

Node–paranode interface

Antibodies directed against nodal and paranodal proteins define this emerging group.

These proteins are associated with noncompact myelin regions.

Because of overlap, such cases were previously grouped with CIDP.

Slide 58 · Why nodopathy should not be presented as ordinary CIDP

Node

Node

Node

Axon

Schwann-cell myelin internodes

Node–paranode interface

The identified antibody target lies at specialized nodal/paranodal structures.

The textbook favors a separate autoimmune nodopathy category.

Clinical/pathologic overlap alone does not establish identical mechanisms.

Slide 59 · Illustrative chronic case: Relapsing weakness and numbness

Clinical observation

Localize the nerve dysfunction

Pathologic interpretation

Identify the injury pattern

A patient reports months of gait difficulty, limb weakness, and numbness.

The presentation is symmetric with an intermittent course.

Question: Which temporal and structural clues favor CIDP over GBS?

Slide 60 · Systemic autoimmunity can also damage peripheral nerves

Acute demyelinating

Guillain–Barré syndrome

Chronic demyelinating

CIDP

Nodal/paranodal

Autoimmune nodopathy

Axonal / vascular

Systemic disease; Vasculitis

Rheumatoid arthritis, Sjögren syndrome, and systemic lupus erythematosus are examples.

Associated peripheral neuropathy often involves distal sensory or sensorimotor deficits.

Both primary axonal and demyelinating injury may be found.

Slide 61 · Connective-tissue-associated neuropathy often is axonal

Demyelination: Axon remains

Axonal loss: Conducting fiber disrupted

Classical descriptions emphasize axonal polyneuropathy.

Demyelination can nevertheless occur in some cases.

This mixed potential prevents equating all autoimmune neuropathies with AIDP.

Slide 62 · Autoimmune neuropathy is not synonymous with vasculitis

Nonvasculitic

Immune-associated axon/myelin injury

Vasculitic

Destructive blood-vessel injury

Connective-tissue disease may produce neuropathy without demonstrable vasculitis.

The same systemic disorders can also cause secondary vasculitic neuropathy.

Tissue evidence of vascular injury supports the distinct vasculitic mechanism.

Slide 63 · Vasculitic neuropathy targets the vascular supply

Vascular wall injury

Patchy axonal loss

Vasculitis is destructive, noninfectious inflammation of blood vessels.

Vessel injury can damage the peripheral nerve and produce axonal degeneration.

Its often uneven distribution differs from symmetric demyelinating disease.

Slide 64 · Vasculitic nerve involvement is clinically important

Symmetric

Polyneuropathy

Roots + nerves

Polyradiculoneuropathy

Patchy, named nerves

Mononeuritis multiplex

The textbook estimates peripheral nerve involvement in about one-third of vasculitis cases.

Neuropathy can be the first manifestation of the vascular disorder.

Mononeuritis multiplex is especially characteristic, though not exclusive.

Slide 65 · Mononeuritis multiplex creates patchy neurologic deficits

Symmetric

Polyneuropathy

Roots + nerves

Polyradiculoneuropathy

Patchy, named nerves

Mononeuritis multiplex

Different named nerves are damaged in an asymmetric, irregular sequence.

Illustrative pattern: Right radial-nerve dysfunction and left peroneal-nerve dysfunction.

The combination localizes to multiple discrete peripheral nerves.

Slide 66 · Nonsystemic vasculitic neuropathy

Vascular wall injury

Patchy axonal loss

Localized nerve vasculitis may occur without an accompanying systemic vasculitic syndrome.

Nonsystemic vasculitic neuropathy as ANCA-negative.

The localized phenotype still has destructive vascular nerve pathology.

Slide 67 · Systemic vasculitides linked to neuropathy

Polyarteritis nodosa

MPO-ANCA group

PR3-ANCA group

Polyarteritis nodosa is a major associated systemic vasculitis.

MPO-ANCA diseases include microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis.

PR3-ANCA granulomatosis with polyangiitis is less commonly associated.

Slide 68 · Vasculitic neuropathy: Patchy fascicular axon loss

Unequal axonal involvement across fascicles

Degeneration and loss of axons are distributed irregularly across fascicles.

Some fascicles are severely involved while adjacent ones are less affected.

Asymmetry supplies a key morphologic clue to vascular injury.

Slide 69 · Vasculitis morphology: Perivascular inflammation

Vascular wall injury

Patchy axonal loss

Inflammatory cells often surround affected intraneural vessels.

Vessels may show changes indicating acute or chronic wall damage.

The presence of vascular destruction strengthens a vasculitic diagnosis.

Slide 70 · The decisive observation is vessel injury

Axonal loss

Perivascular infiltrate

Vessel-wall injury

Perivascular inflammation alone requires cautious interpretation.

Characteristic acute or chronic vessel-wall damage establishes the mechanism.

Axonal loss and asymmetric fascicular distribution are supportive clues.

Slide 71 · Compare the major inflammatory neuropathy patterns

Acute

GBS

Chronic

CIDP

Nodal antibody

Nodopathy

Asymmetric axonal

Vasculitis

GBS: Acute ascending weakness; Demyelinating roots and nerves (AIDP).

CIDP: Prolonged or relapsing, symmetric sensorimotor demyelination.

Autoimmune nodopathy: Nodal/paranodal antigen-directed disorder.

Vasculitis: Destructive vascular inflammation with patchy axonal loss.

Slide 72 · A pathology-first diagnostic framework

Time course

Anatomic distribution

Axon or myelin

Inflammation / vascular injury

First define time course: Acute progression versus chronic or relapsing disease.

Next localize: Symmetric polyneuropathy, radiculoneuropathy, or multifocal nerve loss.

Then classify lesion: Segmental myelin injury or axonal loss.

Finally integrate inflammation, onion bulbs, or vessel-wall injury.

Slide 73 · Final clinical-pathologic application

Clinical observation

Localize the nerve dysfunction

Pathologic interpretation

Identify the injury pattern

A patient has abrupt, asymmetric wrist and foot weakness involving different limbs.

Nerve tissue demonstrates uneven fascicular axonal loss and damaged inflamed vessels.

Interpretation: Vasculitic neuropathy is favored over GBS/CIDP.

Slide 74 · Inflammatory neuropathies: four durable distinctions

Acute

GBS

Chronic

CIDP

Nodal antibody

Nodopathy

Asymmetric axonal

Vasculitis

Acute ascending areflexic weakness suggests GBS; assess respiratory/autonomic risk.

Chronic, often relapsing demyelination with onion bulbs supports CIDP in context.

Antibodies against nodal/paranodal proteins indicate autoimmune nodopathy.

Patchy axonal loss with destructive vascular inflammation supports vasculitis.