Infectious Neuropathies

Slide 1 · Infectious Neuropathies

Patterns of peripheral nerve injury, morphology and clinicopathologic interpretation

Leprosy

Lyme disease

HIV

Diphtheria

Varicella-zoster

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

At the end of this lecture, interpret infectious neuropathy by linking:

Agent

Recognize the five principal infections in this unit.

Target

Identify axon, myelin/Schwann cell or sensory neuron.

Pattern

Relate distribution and symptom type to injured structures.

Morphology

Explain distinguishing tissue findings and limitations.

Slide 3 · Five infectious causes, different neural targets

Infection is an etiologic category—not a single neuropathic mechanism.

Infection

Characteristic nerve involvement

Leprosy

Schwann-cell invasion or granulomatous injury

Lyme disease

Predominantly axonal radiculoneuropathy / cranial neuropathy

HIV infection

Variable patterns; later painful distal sensory axonopathy

Diphtheria

Exotoxin-associated acute demyelination

Varicella-zoster

Sensory-ganglion neuronal injury and axon loss

Slide 4 · Where injury occurs in a peripheral nerve

Anatomic localization explains the later distribution of clinical deficits.

Epineurium

Outer fibrovascular cover

Perineurium

Fascicular sheath

Endoneurium

Surrounds individual fibers

Axon + Schwann cell

Primary functional units

Schematic cross-section

Slide 5 · Three fundamental forms of nerve injury

The initial injury target determines downstream tissue changes.

Axonopathy

Primary axonal injury; Secondary breakdown of associated myelin.

Demyelination

Schwann-cell/myelin damage with relative early axonal preservation.

Neuronopathy

Sensory neuron death followed by degeneration of its peripheral axon.

Slide 6 · Axonal versus demyelinating physiology

Morphology and electrophysiology answer related but different questions.

Axonal injury

Progressive loss of functioning axons

Reduced response amplitude

Velocity relatively preserved in surviving fibers

Demyelination

Interrupted myelin internodes

Reduced conduction velocity

Signal amplitude may initially be preserved

Slide 7 · Describe the distribution before naming the agent

A pattern narrows the relevant differential diagnosis.

Mononeuropathy

One named nerve and its restricted functional territory.

Polyneuropathy

Multiple nerves, often symmetric and distal.

Mononeuritis multiplex

Patchy involvement of separate named nerves.

Polyradiculoneuropathy

Roots plus peripheral nerves; Proximal and distal deficits.

Slide 8 · Mechanistic map of infectious neuropathies

Four distinct routes from an infectious process to nerve dysfunction.

Infection / immune context

Specific neural target

Tissue injury

Characteristic deficit

Leprosy: Cell invasion or granulomatous neuritis

Diphtheria: Toxin-associated demyelination

VZV: Sensory-ganglion destruction

Schematic

Slide 9 · Leprosy: Host response determines the nerve lesion

Hansen disease prominently involves skin and peripheral nerves.

Agent

M. Leprae: Intracellular infection

Neural lesion

Schwann-cell invasion or granulomatous neuritis

Consequence

Loss of pain sensation and nerve fibrosis

Slide 10 · Why M. Leprae favors peripheral nerves

Relatively cool peripheral tissues provide a favorable setting for infection.

M. Leprae infection

Growth in cool skin / extremities

Schwann-cell tropism

Peripheral nerve damage

Organism is an obligate intracellular pathogen

Growth favors temperatures near the skin rather than core tissues

Schematic

Slide 11 · Leprosy is an immunologic spectrum

The same organism produces different neural pathology depending on host responses.

Tuberculoid pole

Strong Th1 / cell-mediated immunity

Granulomatous inflammation

Few demonstrable bacilli

Lepromatous pole

Weak cell-mediated control

Numerous bacilli in tissue cells

Widespread Schwann-cell and macrophage infection

Slide 12 · Tuberculoid leprosy: Nerve injury by granulomatous inflammation

Immune containment of bacilli can still destroy nearby cutaneous nerves.

Strong cellular response

Dermal granulomas

Adjacent nerve destruction

Localized sensory loss

Axons, myelin and Schwann cells can be lost

Endoneurial and perineurial fibrosis may follow

Schematic

Slide 13 · Tuberculoid skin lesions signal nerve involvement

Sensory examination is integral to pathology correlation.

Lesion

Dry, scaly or flat irregular skin lesion; Margins can be raised.

Nerve injury

Small nerve twigs may be engulfed or destroyed by granulomas.

Function

Localized sensory loss creates vulnerability to unnoticed injury.

Slide 14 · Tuberculoid histology: Granulomas, paucibacillary tissue

Organism scarcity is not evidence against the entity when the immune response is strong.

What may be seen

Granulomas near or involving dermal nerves

Loss of peripheral nerve elements

Endoneurial/perineurial scarring

What may be difficult

Finding acid-fast bacilli

Proving infection from a nerve section alone

Distinguishing injury from other granulomatous settings without context

Slide 15 · Tuberculoid sensory deficit has a structural basis

The sequence links a skin lesion to persistent functional disability.

Granulomatous neuritis

Loss of nerve fibers

Reduced pain perception

Recurrent unnoticed trauma

Sensory dysfunction can outlast active inflammation

Deep ulcers are consequences of absent protective sensation

Schematic

Slide 16 · Why tuberculoid disease is usually localized

Effective cell-mediated immunity restricts the organism but not local nerve injury.

Immunity

Robust T-cell/macrophage response controls bacillary burden.

Distribution

Nerve involvement is more focal than in the lepromatous pole.

Pathology

Granulomatous inflammation and fibrosis account for deficits.

Slide 17 · Lepromatous leprosy: Direct cellular infection

Schwann cells provide an important site of peripheral nerve involvement.

M. Leprae enters Schwann cells

Bacillary proliferation

Infection of additional cells

Nerve fiber degeneration

Organisms can also occur within macrophages

Later axonal loss follows early segmental myelin injury

Schematic

Slide 18 · Lepromatous morphology evolves over time

Early demyelination is accompanied later by structural nerve loss.

Earlier neural changes

Schwann-cell infection

Segmental demyelination

Attempts at remyelination

Advanced neural changes

Axonal degeneration

Loss of myelinated and unmyelinated axons

Endoneurial fibrosis; Perineurial thickening

Slide 19 · Multibacillary pathology: What special stains reveal

Abundant organisms are a discriminator from tuberculoid disease.

Tissue cells

Foamy macrophages (lepra cells) may contain clusters of bacilli.

Staining

Mycobacterial stains can readily demonstrate organisms.

Neural context

Schwann cells and nerve-associated macrophages can be invaded.

Slide 20 · Progressive scarring amplifies loss of nerve function

Perineurial and endoneurial remodeling marks advanced injury.

Chronic infection

Demyelination + axonal loss

Fibrosis of nerve coverings

Persistent dysfunction

Multilayered perineurial thickening is described

Fibrosis is an endpoint—not the primary initiating event

Schematic

Slide 21 · Why lepromatous neuropathy is distal and facial

Thermal preference helps explain its anatomical predilection.

Organism biology

M. Leprae multiplies in relatively cool tissues.

Distribution

Distal extremities and the face are favored sites.

Clinical pattern

Symmetric polyneuropathy is typical of the lepromatous pole.

Slide 22 · Small-fiber injury produces major secondary tissue damage

The most destructive visible lesions may result from loss of protection.

Pain-fiber injury

Diminished nociception

Unrecognized repeated injury

Chronic ulceration

Loss of pain is not a benign sensory finding

Skin damage is secondary to peripheral nerve dysfunction

Schematic

Slide 23 · Large superficial nerves may be clinically conspicuous

Local nerve involvement can be correlated with limb distribution.

Ulnar nerve region

Relatively superficial near elbow

Upper-limb sensory and motor territory

Can be involved in lepromatous disease

Peroneal nerve region

Relatively superficial near knee

Lower-limb functional territory

Can be involved in lepromatous disease

Slide 24 · Lepromatous disease is not confined to skin

Widespread tissue distribution accompanies weak cellular control.

Skin

Diffuse thickening, macules, papules or nodules.

Peripheral nerves

Symmetric nerve invasion and sensory impairment.

Other sites

Upper airways, anterior eye, lymphoid tissue and testes may be involved.

Slide 25 · Tuberculoid versus lepromatous: Diagnostic contrast

The immune response predicts bacillary load and neural distribution.

Tuberculoid

Granulomatous cellular response

Paucibacillary sections

Localized or asymmetric neuropathy

Lepromatous

Numerous infected tissue cells

Multibacillary sections

More diffuse symmetric polyneuropathy

Slide 26 · Leprosy tissue findings should be read together

No isolated finding substitutes for clinicopathologic integration.

Finding

Interpretation

Dominant pole

Granulomas around dermal nerves

Immune-mediated nerve destruction

Tuberculoid

Bacilli within Schwann cells

Direct organism-associated neural injury

Lepromatous

Perineurial/endoneurial fibrosis

Chronic destructive process

Both

Small pain-fiber loss

Loss of protective sensation

Prominent in lepromatous

Slide 27 · Case: Anesthetic plaque with localized nerve involvement

A patient has an insensate dry skin plaque and nearby granulomatous neuritis.

A patient has an insensate dry skin plaque and nearby granulomatous neuritis.

Which immunologic pole is most consistent with this pattern—and why might acid-fast staining be negative?

Discuss before revealing the answer

Slide 28 · Case: Symmetric distal loss of pain sensation

A patient has diffuse nodular skin disease and recurrent painless foot ulcers.

A patient has diffuse nodular skin disease and recurrent painless foot ulcers.

Identify the proposed mechanism linking organism biology to the ulcers.

Discuss before revealing the answer

Slide 29 · Lyme disease: Radicular and cranial neuropathies

Borrelia infection produces several stage-dependent neurologic manifestations.

Agent

Tick-borne Borrelia infection

Neural lesion

Primarily axonal radicular / cranial injury

Consequence

Facial palsy or polyradiculoneuropathy

Slide 30 · From tick exposure to disseminated disease

Neurologic involvement occurs after the earliest localized skin phase.

Ixodes tick inoculation

Localized dermal infection

Systemic dissemination

Neurologic manifestations

Borrelia species cause Lyme disease

Cranial nerve involvement is described in early disseminated disease

Schematic

Slide 31 · Neurologic Lyme disease is not one nerve pattern

The source describes several forms rather than a single stereotyped neuropathy.

Radicular

Polyradiculoneuropathy affecting nerve roots and peripheral nerves.

Cranial

Unilateral or bilateral facial nerve palsy.

Axonal

Neuropathic injury is described as primarily axonal.

Slide 32 · Facial neuropathy can be unilateral or bilateral

Laterality supports pattern recognition but does not establish etiology.

Unilateral facial palsy

Cranial nerve involvement is possible

Consider stage and infectious context

Not specific to Borrelia infection

Bilateral facial palsy

Also described in Lyme disease

Systemic context remains essential

Do not assume a demyelinating mechanism

Slide 33 · Immune inflammation contributes to Lyme lesions

Inflammatory responses rather than a bacterial exotoxin.

Borrelia persistence

Host innate response

Inflammatory mediators

Tissue injury

Bacterial lipoproteins engage TLR1/TLR2

This is systemic pathogenesis context; Neural cellular details are not specified

Schematic

Slide 34 · Lyme stage and neurologic timing

Avoid equating late manifestations with an obligatory sequence in every patient.

Early localized

Erythema migrans at the inoculation site is characteristic.

Early disseminated

Meningitis with cranial nerve involvement may occur.

Late disseminated

Polyneuropathy can occur but is less frequent than arthritis.

Slide 35 · Case: Cranial neuropathy after disseminated infection

A patient with compatible tick exposure develops bilateral facial weakness.

A patient with compatible tick exposure develops bilateral facial weakness.

Which infectious neuropathy in this unit specifically includes bilateral facial nerve palsies?

Discuss before revealing the answer

Slide 36 · HIV: Immune dysregulation and multiple phenotypes

HIV-associated neuropathies change in pattern across infection stages.

Setting

HIV-associated immune dysregulation

Neural lesion

Early multifocal / demyelinating; Late axonal

Consequence

Often painful distal sensory neuropathy

Slide 37 · Why HIV neuropathy resists a single mechanism

The text associates diverse patterns with immune dysregulation.

Heterogeneous

No single anatomic neuropathy pattern covers all patients.

Mechanistic uncertainty

Pathogenesis remains incompletely understood.

Context-dependent

Earlier and later stages have different common patterns.

Slide 38 · Earlier HIV: Two neuropathic presentations

Early infection may mimic disorders with very different distributions.

Mononeuritis multiplex

Asymmetric, multifocal named-nerve deficits

Pattern of scattered axonal dysfunction

Can arise early in HIV infection

Inflammatory demyelinating

GBS-like or CIDP-like syndromes

May resemble immune neuropathies

Timing and clinical pattern matter

Slide 39 · Later HIV: A painful distal sensory axonopathy

The characteristic later pattern combines length-dependent distribution and pain.

Later-stage HIV infection

Distal sensory axonal injury

Distal sensory deficit

Frequent neuropathic pain

This is the more common described later-stage pattern

Robbins does not specify a single definitive molecular mechanism

Schematic

Slide 40 · HIV: Early and late nerve involvement

Stage is contextual, not an absolute diagnostic criterion.

Earlier

Mononeuritis multiplex can occur

Demyelinating disorders may resemble GBS/CIDP

Variable distributions

Later

Distal sensory neuropathy is more common

Axonal pattern is typical

Often painful

Slide 41 · Interpreting painful distal HIV neuropathy

Combine symptom character with nerve-injury distribution.

Positive symptoms

Pain can accompany damaged sensory axons.

Negative symptoms

Distal loss of sensation reflects loss of functional fibers.

Important restraint

Immune dysregulation is implicated; A complete mechanism is not established here.

Slide 42 · Case: Painful distal feet in later HIV

A person with later-stage HIV reports distal burning discomfort and numbness.

A person with later-stage HIV reports distal burning discomfort and numbness.

Which neuropathic class is most consistent with the described pattern?

Discuss before revealing the answer

Slide 43 · Diphtheria: Toxin-mediated demyelinating neuropathy

Neural dysfunction arises from a bacterial exotoxin rather than direct nerve colonization.

Agent

C. Diphtheriae exotoxin

Neural lesion

Acute demyelinating neuropathy

Consequence

Bulbar and respiratory muscle weakness

Slide 44 · Diphtheria toxin blocks protein synthesis

A specific host molecular target.

Phage-encoded A–B exotoxin

A fragment acts on EF-2

ADP-ribosylation of EF-2

Host translation inhibited

EF-2 is required for mRNA translation

Neural disease is associated with systemic exotoxin effects

Schematic

Slide 45 · Peripheral nerve injury in diphtheria

An acute demyelinating phenotype is the principal peripheral nerve lesion.

Agent

Toxigenic Corynebacterium diphtheriae infection.

Mediator

Circulating exotoxin is responsible for peripheral nerve dysfunction.

Morphology

Acute demyelination predominates.

Slide 46 · Bulbar and respiratory dysfunction are high-stakes findings

Neural deficits can lead to life-threatening impairment.

Exotoxin-associated neuropathy

Demyelination

Bulbar / respiratory weakness

Severe disability or death

Prominent bulbar involvement distinguishes the clinical hazard

This is a clinicopathologic chain—not a treatment algorithm

Schematic

Slide 47 · Local diphtheria infection versus systemic neuropathy

The anatomic sites of organism growth and toxin effect differ.

Local infection

Respiratory mucosa often involved

Necrotizing pseudomembranous inflammation

C. Diphtheriae replicates at mucosal sites

Peripheral neuropathy

Driven by the released toxin

Acute demyelinating nerve injury

May involve bulbar/respiratory muscles

Slide 48 · Toxoid immunization targets the actual virulence mechanism

Neutralizing antibody prevents the lethal actions of the exotoxin.

Antigen

Inactivated diphtheria toxin (toxoid).

Protection

Antibodies neutralize the active toxin.

Vulnerability

Incomplete immunization or waning adult immunity can permit disease.

Slide 49 · Case: Acute bulbar weakness after diphtheria

A patient with respiratory diphtheria develops weakness and respiratory compromise.

A patient with respiratory diphtheria develops weakness and respiratory compromise.

What neural injury pattern should be anticipated, and what causes it?

Discuss before revealing the answer

Slide 50 · Varicella-zoster: Sensory neuron injury and radiculoneuritis

Reactivation of latent infection links ganglion pathology to a dermatomal rash.

Setting

Reactivation after sensory ganglion latency

Neural lesion

Neuronal death and secondary axon loss

Consequence

Painful dermatomal eruption ± weakness

Slide 51 · VZV: Primary disease, latency, reactivation

Peripheral sensory ganglia connect the two clinical presentations.

Primary varicella

Latency in sensory ganglia

Late viral reactivation

Sensory-nerve spread to skin

Chickenpox precedes the latent state

Herpes zoster is a reactivation syndrome

Schematic

Slide 52 · Why latent infection matters to neuropathy

The virus persists in a neural compartment even after the skin disease resolves.

Reservoir

Dorsal root or other sensory ganglion neurons.

Time course

Reactivation may occur many years after primary infection.

Risk context

Reduced cell-mediated immune control is suspected to contribute.

Slide 53 · A dermatome is the anatomical footprint of spread

Viral movement along sensory nerves explains the localized eruption.

Reactivation in ganglion

Anterograde neural spread

Keratinocyte infection

Painful vesicles in dermatome

Thoracic and trigeminal distributions are common

Distribution reflects innervation—not hematogenous rash spread

Schematic

Slide 54 · Chickenpox versus herpes zoster: Different distributions

Primary and recurrent cutaneous infection have distinct pathogenesis.

Chickenpox

Primary systemic infection

Widespread vesicles

Virus ultimately becomes latent in sensory ganglia

Herpes zoster

Ganglionic reactivation

Dermatomal vesicular eruption

Localized neuropathic pain and radiculoneuritis

Slide 55 · Herpes zoster pain is a neural symptom

The eruption and pain share the same segmental anatomical origin.

Radiculoneuritis

Inflammation affects sensory roots or sensory pathways.

Symptoms

Burning, sharp pain or intense itching may accompany lesions.

Anatomy

The sensory dermatome determines the skin distribution.

Slide 56 · Ganglion destruction explains downstream axonal loss

This is a neuronopathy rather than simply cutaneous viral infection.

Ganglion inflammation

Sensory neuron death

Degeneration of its axon

Segmental sensory impairment

Pathology includes prominent mononuclear infiltrates

Neuronal cell-body loss precedes secondary axonal degeneration

Schematic

Slide 57 · VZV pathology: Ganglion versus distal nerve

The sampled compartment changes what a pathologist should expect.

Sensory ganglion

Neuron death

Mononuclear inflammation

May show focal necrosis or hemorrhage

Peripheral nerve

Axonal degeneration

Loss of axons of affected sensory neurons

Secondary consequence of cell-body death

Slide 58 · A ganglion is an inflammatory lesion, not merely a reservoir

Several histologic features reflect tissue-destructive infection.

Neurons

Degeneration and death are described.

Inflammation

Predominantly mononuclear cell infiltrates may be abundant.

Severe injury

Focal necrosis and hemorrhage can accompany the lesion.

Slide 59 · VZV may also affect motor systems

Segmental weakness can accompany a primarily sensory eruption.

VZV reactivation

Sensory ganglion / nerve injury

Motor neuron involvement (subset)

Weakness in affected distribution

Anterior horn or cranial motor nuclei may show focal injury

Motor involvement is not the dominant presentation

Schematic

Slide 60 · Clinical localization: Thoracic and trigeminal pathways

The distribution of the eruption is part of the neurologic examination.

Thoracic

A unilateral band-like sensory distribution may localize a segment.

Trigeminal

Painful facial dermatomal involvement is common.

Rare motor syndrome

Ramsay Hunt syndrome can include facial paralysis.

Slide 61 · VZV histology: Skin findings and neural pathology

Do not use a skin feature as a surrogate for demonstrating ganglion injury.

Skin involvement

Vesicular keratinocyte infection

Intraepithelial blisters and viral nuclear changes may occur

Clinically conspicuous eruption

Neural involvement

Sensory ganglion inflammation/neuronal death

Axonal degeneration in downstream nerves

CNS/peripheral morphology depends on sampled site

Slide 62 · Varicella-zoster neuropathy: Diagnostic boundaries

Interpret findings in the correct clinical and tissue context.

Distribution

Dermatomal rash strongly supports localized reactivation.

Target

Sensory ganglion is the primary neuronal reservoir.

Histology caveat

The two Robbins chapter discussions differ on how frequently neural nuclear inclusions are encountered.

Slide 63 · Case: Vesicles and pain in a thoracic band

An adult develops a painful vesicular eruption confined to a thoracic dermatome.

An adult develops a painful vesicular eruption confined to a thoracic dermatome.

What cell type maintains latency, and what tissue injury explains sensory deficits?

Discuss before revealing the answer

Slide 64 · Comparative mechanisms: Which structure is injured?

Similar neuropathic symptoms arise from fundamentally different primary targets.

Disease

Principal injury mechanism

Expected pattern

Lepromatous leprosy

Schwann-cell infection → progressive axon loss

Symmetric distal neuropathy

Tuberculoid leprosy

Granulomatous cutaneous nerve injury

Focal neuropathy

Lyme disease

Infection-associated, primarily axonal

Radicular / facial cranial

HIV

Immune dysregulation; diverse patterns

Early variable, later distal sensory

Diphtheria

Exotoxin-associated demyelination

Acute, bulbar/respiratory risk

VZV

Sensory ganglion neuronopathy

Dermatomal pain ± weakness

Slide 65 · Differentiate infection from an immune mimic

Similar clinical patterns can have distinct infectious context.

Inflammatory demyelination

GBS and CIDP are primary immune-mediated neuropathies

Early HIV may resemble either syndrome

Diphtheria also produces demyelination by toxin effect

Predominant axonal injury

Later HIV sensory neuropathy is usually axonal

Lyme cranial/radicular injury is primarily axonal

VZV axon loss follows ganglionic neuron death

Slide 66 · Core morphology-to-symptom correlations

For each infection, name the primary tissue event before the clinical effect.

Lost small pain fibers

Loss of protective nociception → painless trauma and ulcers.

Demyelination

Disrupted saltatory conduction → physiologic conduction slowing.

Sensory neuron death

Distal axon degeneration → segmentally distributed deficits.

Axonal attrition

Loss of functional nerve fibers → reduced response amplitude.

Slide 67 · Integrated case: Two opposite skin–nerve relationships

Patient A: Anesthetic plaques with granulomas; Patient B: Painful dermatomal vesicles.

Patient A: Anesthetic plaques with granulomas; Patient B: Painful dermatomal vesicles.

For each, identify the initiating neural lesion and why the symptoms differ.

Discuss before revealing the answer

Slide 68 · Rapid pattern recognition: Five testable associations

The distinguishing feature is the linkage of organism, neural target and phenotype.

Clue

Most relevant disease

Underlying explanation

Anesthetic granulomatous patch

Tuberculoid leprosy

Immune destruction of cutaneous nerves

Acid-fast organisms in Schwann cells

Lepromatous leprosy

Cellular invasion, later fiber loss

Facial palsy ± radiculopathy

Lyme disease

Primarily axonal neuropathy

Painful distal sensory axonopathy in later disease

HIV infection

Immune dysregulation association

Bulbar weakness with demyelination

Diphtheria

Exotoxin

Painful dermatomal vesicles

VZV

Ganglionic reactivation

Slide 69 · Primary references and source boundaries

Content follows the supplied 11th-edition Robbins text; no external criteria or fabricated imagery.

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Chapter 27: Peripheral Nerves and Skeletal Muscles, pp. 1107–1112.

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Chapter 8: Infectious Diseases, VZV (pp. 322–323), diphtheria (p. 329), leprosy (pp. 340–341), Lyme disease (pp. 344–345).

Pathology schematics in this presentation are original editable PowerPoint illustrations, not clinical specimens or textbook photographs.

Chapter 27/Chapter 8 discrepancy concerning VZV ganglionic inclusions is recorded in slide notes.