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INFECTIONS & NEUROMUSCULAR DISORDERS

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LYME DISEASE ¹⁵

Causative organism US: Borrelia burgdorferi Europe Borrelia garinii: Associated with common neural involvement Borrelia afzelii B. burgdorferi sensu stricto Type of organism: Spirochete Vector: Bites of hard-shelled Ixodes ticks Tick types: I. scapularis in United States; I. ricinus in Europe Infections most common in late summer & autumn Transmission requires 36 hours of tick attachment Ingested blood triggers spirochete proliferation in tick gut Spirochete is disseminated in tick Spirochete is injected into host Epidemiology Age: Bimodal; Children (5 to 14 years); Adults (30 to 49 years) Peak: Late Summer & Early Fall Geography (US): 95% in Eastern coastal states from District of Columbia to Vermont/New Hampshire Wisconsin & Minnesota Occasional cases in California Clinical features Skin rash: Early & local Onset: Within 1 month of infection Erythema migrans rash Erythematous macule or papule Not painful or pruritic Progression Centrifugally expanding Spirochetes often present in leading edge Acute disseminated disease: With systemic spread of spirochete Hematogenous dissemiantion Particularly with US strains Often results in a multifocal rash Each focus represents a separate nidus of metastatic infection Other organs infected: Joints; Heart; Meninges & Peripheral nerve General clinical featues during dissemination Flu-like syndrome: Fever, Myalgias, Fatigue, Arthralgias, Headache No associated upper respiratory or gastrointestinal symptoms Meningoradiculitis (Bannwarth syndrome) Headache, Meningismus Radicular pain: Upper trunk & back Focal weakness Few sensory signs Course: Relapsing Neurologic Cardiac: A-V block, Pericarditis, Dilated cardiomyopathy Arthritis: Oligoarticular Onset days to years after infection Often relapsing - remitting Occur in 60% of cases Latency: 3 to 30 days Neurologic manifestations (Neuroborreliosis) Frequency: In 10% to 40% of Borrelia burgdorferi infections Central Nervous System Aseptic meningitis syndrome Encephalomyelitis: Often with focal features & fatigue Spastic paraparesis Bladder dysfunction Transverse myelitis Early in disease course Progressive over weeks Focal disorders Distribution: Cranial nerves; Peripheral nerves & Roots Onset: Early (First 1 or 2 months) during infection Acute onset Often associated with lymphocytic meningitis. Course Usually self-limited May resolve more rapidly with antibiotic treatment Cranial nerve syndromes Distribution Facial (VII) most common Multiple: 15% to 20%; Bilateral facial in 75% Involvement of all cranial nerves except olfactory described Frequency: 40% of neuroborreliosis Facial palsy In 10% of untreated patients Unilateral or Bilateral May not involve taste or hyperacusis May be common cause of VII palsy in children in endemic areas Full recovery in 85% with treatment Borrelia burgdorferi antigen in CSF May occur early in disease course Some: Before antibody testing becomes positive Other: Most often III, V & VI Peripheral nerve syndromes Multifocal radiculoneuropathy in acute disseminated stage Onset: Subacute; Burning radicular pain Pain distribution Dermatomal, Thoracolumbar or Distal May involve limb with tick bite More common in Europe than US Asymmetric Radicular involvement more common in Europe than US Patterns of subacute involvement: Other Subacute diffuse neuropathy: AIDP-like Brachial plexopathy Lumbosacral plexopathy Mononeuritis multiplex Perineuritis: B-cell perineurial inflammation Carpal tunnel syndrome Laboratory CSF: Pleocytosis Nerve conduction: Axonal loss EMG: Denervation, In distal, proximal or paraspinous muscles Chronic disease Distal sensory-motor neuropathy Carpal tunnel syndrome More common in Europe & Elderly Onset: 6 months to 8 years after infection Nerve conduction: Axonal loss Nerve biopsy: Perivascular inflammation Late disease with Acrodermatitis chronica atrophicans (ACA) 4 Patient age: Average 70's; Range 55 to 84 Skin lesions Bluish-red inflammatory skin lesion: Localized to acral extremities Patients: Elderly female predominance Exaggerated pain (Allodynia) Location: Bony prominences underlying ACA lesions Elevated serum IgG antibodies to B. burgdorferi Polyneuropathy Sensory loss: Especially vibration Distribution: Symmetric, Distal Mild Motor: Normal Electrophysiology: Axonal loss Nerve pathology Loss of large & small myelinated axons Occasional perivascular inflammation Lyme myositis 21 Frequency in Lyme disease: Unusual Muscle involvement: Localized Asymmetric Swelling: Muscle & Limb Painful May be near cutaneous lesions Ocular myositis: Some patients Dermatomyositis-like disorder: Rare Other clinical Contiguous monoarthritis Cardiac disorders Laboratory Serum CK: Usually normal MRI of involved muscle: Diffuse T2 signal Muscle biopsy: Inflammation Location: Often near small blood vessels; Perimysial Cell types Monocellular, lymphoplasmacytic & histiocytic Macrophages & T helper/inducer (CD4+) cells Muscle fibers: Scattered or abundant necrosis Perimysium: Thickened Histologic staining for spirochetes Treatment: Antibiotic regimens Diagnosis Typical rash Appropriate season & geographic location Laboratory testing Laboratory CSF: Mononuclear pleocytosis; Moderately elevated protein Diagnosis Culture: From edge of skin lesion; Blood culture is low yield Serology: Variable specificity & sensitivity ELISA confirmed by Western blot Western blot: Binding to specific bands Intrathecal Borrelia burgdorferi antibodies Meningitis: 92% Late CNS: 42% Seronegativity (7%) Early in disease course Antibiotic treatment: Noncurative doses early in infection Antibody complex May not indicate ongoing infection Positive serologic result may reflect infection or exposure in past False-positive: May occur with Response to microbiologically similar organisms Relapsing fever Syphilis Nonspecific B-cell proliferation with systemic inflammation Endocarditis, Bacterial SLE Vasculitis Western blot Can verify US results European strains: Too much variability DNA assay (PCR) of Borrelia burgdorferi antigen in body fluids Often disappointing Treatment Early & Local disease: 21 days oral Amoxicillin 500 mg to 1 g tid, or Doxycycline 100 mg bid NOTE: Not for children under 8 years, or pregnant or lactating women. Other neurologic: Intravenous for 2 to 4 weeks Ceftriaxone 1g bid (2 g per day) for 2 to 4 weeks Cefotaxime 2 gms tid for 14-28 days Penicillin 20 to 24 million units per day for 14-28 days Chloramphenicol: Penicillin allergy High-dose oral Effective in European patients with meningitis or cranial neuritis Doxycycline 200-400 mg/d for 21-42 days Herxheimer reaction in 10% to 20% Prognosis: Good recovery with (or rarely without) antibiotics Animal model of neuroborreliosis Rhesus macaque monkey: Often develops mononeuritis multiplex External links CDC e-medicine Quackwatch

From: CDC; Other image Ixodes dammini From ALDF Erythema migrans

HERPES ZOSTER (Varicella) ²

Clinical features   Neuralgia, Late   Plexopathy   Radiculopathy   Ramsay Hunt   Mononeuropathy   Other Laboratory Organism Predisposing factors Treatment from CDC Varicella zoster

Putnam

Zoster Radiculopathy & Rash: T7 Head, Brain 1900

• Viral properties
  • Double-stranded DNA virus
  • Herpes simplex types
    • Herpes simplex 1
    • Herpes simplex 2
    • Varicella-zoster virus (VZV)
  • Infection
    • 1° infection: Systemic; Usually in 1st decades
    • Invade & Replicate: In host nervous system
    • Latent infection: Chronic
      • Dorsal root ganglia
      • Satellite cells
    • Recurrent disease
      • Caused by viral reactivation
      • More likely with: Immune compromise
    • DRG infection confirmed by presence of: Immediate early protein VZV IE62
• Epidemiology
  • Latent infection
    • 90% of adults in US have serologic evidence of varicella–zoster virus infection
    • Overall: 60% to 90%
  • Incidence
    • 1.5 to 3.0 cases per 1000 persons/year
    • > 75 years 10 cases per 1000 persons/years
  • Lifetime risk of herpes zoster: 10% to 30%
• Clinical: Predisposing factors
  • Age: Over 60 years = 8 to 10x increased risk
  • Malignancy: Lymphoproliferative cancers; Paraneoplastic screen not productive
  • Immunosuppression: Altered cell-mediated immunity
    • Types: HIV infection (29 cases per 1000 persons/year); Drugs
    • Episodes more common & protracted
    • Infection may become disseminated
  • Diabetes mellitus
  • Surgical trauma
  • UV light
• Clinical: Disease loci
  • Dorsal root ganglion: Especially thoracic & face
  • Mucocutaneous
  • Occasionally also produces transverse myelitis
  • Recurrent activation in same distribution as 1° infection
• Clinical features: Radiculopathy
  • Onset
    • Dermatomal
    • Pain; Itching; Paresthesias
    • Persists: 4 to 6 weeks
  • Vesicular rash
    • Dermatomes
      • One or two (20%) dermatomes
      • Same dermatomes as radiculopathy
      • Simultaneous involvement of multiple noncontiguous dermatomes
        • Very rare in immunocompetent patients
    • Radiculopathy onset: 1 to 3 weeks after rash
    • External link: Rash
  • Location
    • Unilateral
    • Common dermatomes: Thoracic; Trigeminal; Ophthalmic; Cervical
  • Pain
    • Types
      • Deep aching or burning
      • Dysesthesias
      • "Post-herpetic"
        • May occur in absence of initial pain
    • Pain onset
      • Spontaneous
      • Allodynia: Light mechanical stimulation causes severe pain
    • Distribution: Often Dermatomal
  • Sensation Δ: Varied
    • Hyperesthesia
    • Reduced over affected areas
  • Itch
    • Dermatomal
    • Locations: Often in head & Neck regions
  • Motor: 2° viral spread to spinal cord
    • Onset: 1 day to 4 months after rash
    • Same segment as rash
    • Especially in cervical & lumbar dermatomes
    • Ramsay-Hunt: Ophthalmoplegia
    • Other involvement: Face; Diaphragm; Bladder
    • Partial or complete recovery
  • Recovery
    • 80% to 90% resolve spontaneously over 6 months
    • Persistent segmental pain (Post-Herpetic neuralgia) ²⁵
      • General
        • Definition: Pain > 2 to 3 months after eruption
        • Frequency: 8% to 20% at 30 days; 4.5% at 60 days
        • Occurrence correlates with
          • Severity of rash
          • Pain
            • Prodromal: Presence & Duration
            • Severity of acute pain
          • CNS MRI lesions
        • Possible mechanisms
          • Constant pain: Nociceptive afferent axon damage
          • Paroxysmal pain: Aβ axon damage
      • Clinical
        • Pain
          • Types: Neuropathic; Allodynia
          • Constant or Intermittent
          • May be evoked by sensory stimuli: Dynamic mechanical allodynia
        • Itch
        • Sensory loss (70%): Heat pain
      • Course
        • May persist for > 3 months
        • More common > 1 year with
          • Increasing age
          • Ophthalmic distribution
          • ? Female > Male
• Ramsay-Hunt syndrome ¹⁸
  

  Nosology: Herpes zoster oticus Epidemiology 5% to 12% of unilateral VII nerve palsy 2nd most common cause of non-traumatic VII paralysis More frequent cause over 6 years of age Onset age: Children & Adults Sex: Male = Female Clinical Facial nerve Weakness Unilateral Peripheral May be more severe than Bell's palsy Less recovery than Bell's palsy Taste: May be reduced on gustatory testing Unilateral or Bilateral (20% to 70%) May be worse on paretic side Pain: Periauricular Deep in the face: Often radiates to the ear Associated with Lacrimation Nasal congestion Salivation Relief obtained by section of the nervus intermedius May occur in absence of rash Only VZV culture or increasing antibody titers Prognosis No treatment: 10% with complete paralysis recover fully Worse than idiopathic Bell's palsy Better without audiovestibular symptoms MRI: Gadolinium uptake in geniculate ganglion VIII nerve Auditory Hearing Loss: No correlation with facial paralysis severity Hyperacusis Tinnitus Vestibular disorders Vertigo Nausea Nystagmus Other locations May spread to CNS Ophthalmoplegia Brain stem syndrome More common in immunocompromised patients MRI: Increased T2 signal CSF: VZV antibodies; PCR - VZV DNA Retinopathy Cause: VZV Reactivation of varicella zoster virus (VZV) From geniculate or cervical ganglia Zoster oticus: Vesicle distribution Hard palate Tongue: Anterior two-thirds Ear Ipsilateral Locations: External & Inner ear; Ear lobe May appear before, or after, facial paresis Diagnosis: PCR of ear scrapings, May be positive without rash Treatment Acyclovir: IV, 5 mg/kg q8h for 7 days; Oral 800 mg 5x/d for 10 days Corticosteroids Effects May improve recovery of strength Probably no change in hearing loss

• Zoster Mononeuropathies ²⁸
  • Onset ages: 6th decade & older
  • Clinical
    • Rash
      • Time from rash to weakness: 0 to 19 days; Mean 3 days
      • Distribution: Same limb as neuropathy
    • Anatomy
      • Nerves involved: Ulnar, Median, Sciatic, Femoral
      • Location: Often proximal regions involved
    • Weakness
      • Degree: Moderate to Severe; None complete
      • Persists for months to years
    • Sensory
      • Pain: Herpetic & Post-herpetic neuralgia; 88% at 1 month; 71% 4 months
      • Loss: Most patients
  • MRI
    • Nerve enlargement
    • T2 signal hyperintensity
  • EMG & NCV
    • Mononeuropathy: Axon loss; Occasional conduction block
    • EMG: Fibrillations
• Zoster Plexopathies ⁶⁴
  • Common
    • Levels: C5-C6
    • Nerve: Radial
  • Modalities: Mixed Motor + Sensory
  • Comorbidities: Diabetes; Immunosuppression
  • MRI: Plexus edema with chronicity
  • Disease Course
    • Pain: Hyperalgesia; Allodynia
    • Recovery 50%
    • Persistent sequelae 25%
    • Worse prognosis: Age > 70; Immunosuppression; Axonal EMG
• Clinical: Other VZV-associated syndromes ¹¹
  • Pain without rash: Radicular or Cranial nerve
  • Cranial nerve palsies: Recurrent; VII, VIII
  • Myeloradiculopathy: Subacutely evolving weakness
  • Delayed contralateral hemiparesis
  • Encephalitis
  • Retinal necrosis: Especially in HIV patients
  • Herpes zoster ophthalmicus
  • Dissemination to other organs: Lungs; Liver
• Laboratory
  • Diagnosis
    • Clinical: Appearance of rash
    • Direct immunofluorescence assay: Good sensitivity
    • Culture: virus may be difficult to recover from cutaneous lesions
    • PCR: Useful for detecting varicella–zoster virus DNA in fluid & tissues
  • CSF: Pleocytosis 50%; High Protein 25%
  • MRI: Brainstem & Spinal cord lesions in 55%
  • Pathology
    • Dorsal root ganglion
      • Cell pathology: Inflammation; Hemorrhage; DRG neuron loss, patchy
      • Dorsal region of ganglion: More severely involved
      • Common levels: Ganglia with smaller neurons; C3-4, T3-12, L1-2
    • Posterior roots: Axon loss
    • Peripheral nerve: Axon loss, varying with disease severity
    • Spinal cord: Posterior column axon loss
      • Mild to moderate
      • More in cervical than truncal lesions
• Treatment: More aggressive > 50 years of age, or severe pain
  • Topical
    • Anesthetics: Applied to painful area
      • Lidocaine (5% gel); Lidocaine & prilocaine cream
    • Analgesics: Aspirin or indomethacin with ether
    • ? Capsaicin (0.025 to 0.075%)
      • Burning from drug intolerable in 1/3 of patients
    • No role for topical antiviral drugs
  • Pain Rx: Systemic ¹⁴
    • Opioids
    • Tricyclic antidepressants
      • Amitriptyline; Desipramine; Nortriptyline; Maprotiline
    • Gabapentin: Up to 3,600 mg qd
    • Anticonvulsants: Only for lancinating component of pain
    • Nonpharmacologic: Transcutaneous stimulation.....
    • Prednisone (60 mg/day; tapered over 21 days)
      • Reduce: Early pain; Time to cutaneous healing
      • Use in combination with antiviral medications
      • Patients > 50 years
      • Refractory post-herpetic neuralgia: Intrathecal methylprednisolone acetate q week x4
  • Antiviral
    • General
      • Begin < 3 to 7 days after onset of rash
      • Patients > 50 years
    • Valacyclovir: 1 gram t.i.d for 7 days
    • Famciclovir: 750 mg t.i.d. for 7 days
    • Acyclovir
      • Oral: 800 mg 5 times/day for 10 days
      • Intravenous: 5mg/kg 3 times/day for 7 days
  • Corticosteroids + Acyclovir
    • Reduce long term risk of segmental axonal damage & weakness
    • No clear effect on post-herpetic neuralgia
• External links
  • eMedicine

LEPROSY ⁶

Clinical features   Acute   Diffuse lepromatous   Lepromatous   Tuberculoid   Borderline   Neural Diagnosis Epidemiology Organism Nerve conductions Pathology, Nerve Treatment Muscle

Codex Aureus Epternacensis (1020-1030 AD) Christ healing the lepers

• Causative organisms
  • Types
    • Mycobacterium leprae
    • Mycobacterium lepromatosis
  • Organism features
    • Acid fast rod
    • Gram positive
    • Location: Intracellular
  • Disease reservoirs
    • Most common: Humans
    • Other
      • Armadillos: Different m. Leprae serotypw
      • Some primates
  • Route of transmission
    • Most common: Nasal droplet
    • Other: Infected soil; Dermal implantation (Tattoos)
  • Dissemination
    • Hematogenous spread: Borderline & Lepromatous types
    • Neural entry: Neural vessels; Infection of endothelial cells
  • Tissues infected
    • Skin; Cutaneous nerves; Nasal mucosa
    • Infection most prominent in cool areas (34°C - 35°C)
      • Grows optimally at 27°C - 30°C
      • Locations: Chin, Malar face, Earlobes, Buttocks, Knees & Distal extremities
  • Cells infected
    • Skin: Macrophages
    • Nerve: Schwann cells
  • Tissue binding
    • Via Phenolic glycolipid-1 (PGL-1)
      • Organism-specific cell-wall antigen
      • Binds to G domain of the α2 chain of Laminin-2
    • Schwann cell receptor: α-dystroglycan
      • Binds to α2 chain of Laminin-2
      • Non-myelin producing Schwann cells
        • Invaded by M. leprae
        • Reservoir for organism growth & spread
      • Myelin producing Schwann cells: M. leprae binding causes loss of myelination
        • Immune dependent
        • Mechanism: PGL-1 disrupts DRP2–dystroglycan complex
  • Possible mechanisms of nerve damage
    • Toxic effects of M leprae on Schwann cells
    • Immune damage
  • Staining of M leprae: Modified Fite–Faraco stain
• Epidemiology
  • Geography ⁴³
    • 70% of cases in world: India, Indonesia & Myanmar
    • Asia, other: Bangladesh; Micronesia; Kiribati, Nepal; Philippines; Sri Lanka
    • Africa: Angola, Congo, Egypt, Ethiopia, Madagascar, Mozambique, Comoros
          Ivory Coast, Nigeria, South Sudan, Sudan, Somalia, Tanzania
    • South America: Brazil
    • Europe: Italy (Mostly immigrants)
    • US
      • Endemic foci: Hawaii; Florida; Louisiana & Texas (Near Mexico)
      • Most cases are immigrants (85%)
  • Incidence
    • World: 200,000 to 500,000 new cases per year
    • US: 150 new cases per year
  • Prevalence: Declining over past 50 years due to
    • Shorter treatment regimens
    • Improved nutrition & living conditions
  • Most human infection (90%): Develop effective immunity without evidence of disease
  • Frequency of nerve damage in leprosy: 20% to 30%
  • Onset age
    • Most common: 10 to 20 years
  • Incubation time: Range = 3 months to 40 years; Mean = 7 years
  • Infectious spread
    • Airbourne; ? via skin
    • Children more susceptable than adults
    • Most in population not susceptible after routine exposure
      
  • Risk factors
    • Household contact: 3.8- to 10-fold higher risk ²²
      • Poor housing & sanitation
      • Overcrowding
      • Higher risk with contact with multibacillary leprosy: 4x
      • 75% develop disease in first year
      • 70% contract paucibacillary forms
      • Mitsuda test: Negative have lower risk
      • M. leprae anti-PGL-1 antibodies: Higher risk
      • BCG vaccination
        • Protective for multibacillary forms
        • Lower risk when BCG scar present
    • Genetic: Susceptability loci
      • LPRS1
        • Chromosome 10p13
        • Paucibacillary leprosy
      • LPRS2
        • Chromosome 6q25
        • 5' regulatory region shared by the PARK2 & PACRG genes
        • Paucibacillary & Multibacillary leprosy
      • Toll-like receptors
        • Toll-like receptor 1 (LPRS5 ): Chromosome 4p14
          • Protective: Ile602Ser; Asn248Ser heterozygous
          • Susceptibility: Asn248Ser homozygous
        • Toll-like receptor 2 (LPRS3 ): Chromosome 4q32
          • R677W Polymorphism upstream of gene
      • LPRS4 : Lymphotoxin-α (LTA)
        • Chromosome 6p21
        • Single-nucleotide polymorphism
        • Susceptibility to leprosy < 16 years or age
        • Low levels of LTA production associated with higher risk of leprosy
      • LPRS6
        • Chromosome 13q14.11
        • More association in
          • Multibacillary patients
          • Vietnamese & Chinese populations
      • Vitamin D receptor (VDR)
        • Chromosome 12q13.11
        • Vitamin D3, low levels: More type 1 or type 2 reactions
      • Tumor necrosis factor (TNF)
        • Chromosome 6p21.33
        • TNF -308A: Protection from leprosy
      • Mannose binding lectin (MBL; MBL2)
        • Chromosome 10q21.1
        • G161A: Associated with protection from lepromatous leprosy
      • Natural resistance associated macrophage protein 1 (NRAMP1; SLC11A1)
        • Chromosome 2q35
        • Divalent metal transporter
        • Low expression: Disease susceptibility
      • Ninjurin-1 (NINJ1) ²³
        • Chromosome 9q22
        • Polymorphism: Asp110Ala
        • Association
          • More severe disability: Homozygotes > Heterozygotes
• Features: General ⁵⁷
  • Clinical
    • Onset ages: Childhood to 9th decade
    • Early features
      • Due to direct invasion of dermal nerves
      • Sensory (95%)
        • Small fiber modalities
          • Distribution: Non-length dependent pattern
          • Hypoesthesia (60%)
          • Paresthesias (40%)
          • Pain (20%)
        • Pain along nerves: May occur when swollen inflamed nerve is stretched
      • Mononeuropathy: 45% in disease < 1 year
    • General patterns
      • Disease course: Temporal
        • Early (< 1 year): Small fiber syndromes
        • Later (> 1 year): DTR Δ; Weakness; Large fiber sensory loss; Large nerves; Asymmetry
      • Sensory neuropathy, Asymmetric
      • Upper extremities at onset (68%)
    • Sensory loss progression
      • Temperature affected 1st
      • Then Pain
      • Later: Pressure
      • Vibration loss: More with longer (> 1 yr) disease
    • Sweating: Loss in anesthetic areas
  • Cytokine profiles

    	Tuberculoid leprosy (TT)	Lepromatous leprosy (LL)
    Predominant cytokine expression	T helper 1 (Th1)	T helper 2 (Th2)
    Interleukins secreted	IL-2, IFN-α, IL-12, IL-18, GM-CSF	IL-4, IL-5, IL-10
    TNF-α expression	Increased	Decreased
    LIR expression	Decreased	Increased

  • Nerve conduction studies
    • 1st year: Axonal sensory mononeuropathy common
    • Early: Evidence of demyelination in some patients ⁵⁸
      • Areas to study: Short segments; Coldest areas
      • Distal latencies: Prolonged
      • Conduction velocities
        • Segmental slowing: Varied along length of nerve
        • Especially across vulnerable sections: Ulnar nerve at elbow
      • Conduction block: May be found with weakness
      • CMAP amplitudes: May be spared or reduced
      • More with disease > 1 year
    • Later
      • Axon loss greater
      • More motor nerves involved
• Clinical features: Syndrome types
  • Tuberculoid leprosy: Paucibacillary
    • Disease type: Immune & other features
      • More cellular immune response
      • Localized bacterial proliferation
      • Epithelioid-cell granulomata in nerves
      • Cytokines in tissue: IL-2; IFNγ

      Skin lesions Focal hypopigmented Anesthetic Hairless Scaly & Dry Well defined border Number of lesions: Few; 1 to 5 Pathology: Granulomas Surround neurovascular elements Extend into papillary dermis Acid-fast bacilli: Not seen

      From WHO Skin lesions

    • Nerves affected
      • Sensory
        • Cutaneous: Digital
        • Sural
        • Radial
        • Posterior auricular
      • Motor + Sensory
        • Ulnar
        • Median: Lesion proximal to carpal tunnel ⁴⁷
        • Peroneal
        • Posterior tibial
    • Nerve size: Enlargement
      • Usually proximal to skin lesion
      • Asymmetric
      • Affected nerves swollen & palpable
      • May be associated with pain
      • Calcification: May occur in long-standing disease
    • Laboratory: HLA-DR3 more likely
    • Nerve biopsy: Especially useful
      • Inflammation
        • Abundant
        • In epineurium, perineurium, or endoneurium
        • Granulomas with multinucleate (Langerhans) giant cells
        • Extensive lymphocytic infiltrate: CD4 & CD8 T-cells
      • Differential fascicular loss of axons
      • Destruction of nerve trunk structure: Damaged perineurium
      • Few organisms
  • Lepromatous leprosy: Multibacillary
    • Immune features: Disease type with reduced cell-mediated immunity to leprous bacilli
      • Anergic to M. leprae
      • Less cellular response
      • Macrophages incapable of killing bacilli
      • Diffuse bacterial proliferation
      • Widespread systemic disease develops
      • Cytokines in tissue: IL-4; IL-10

      General distribution: Worst deficits in cool regions Onset: Skin lesions & sensory loss Ears (Pinnae) Arms: Dorsal hands & forearms Legs: Feet & lateral legs Skin lesions Early Widely & symmetrically distributed macules Border: Poorly defined Hypopigmentation: Mild Erythema Multiple or diffuse Not anesthetic Number of lesions: > 5 Atrophic epidermis

      From: P Bailey Sensory loss

      Neuropathy Nerve size: Diffusely enlarged nerves Sensory Loss: Distribution Stocking-glove Face (upper & bilateral) Ulnar nerves above elbow Modality of loss: Small > Large fiber Sparing Palms & Soles May be affected during leprosy reactions Scalp: Sharp border with forehead Autonomic: Widespread anhydrosis Motor: Weakness in ulnar innervated hand muscles Tendon reflexes often preserved until late Course: Some lesions may be reversible with treatment

      From WHO Enlarged nerves

    • Skeletal: Limb mutilation
    • Muscle
      • Masses: Occasional
      • Pathology: Subclinical inflammation
    • Laboratory
      • HLA-DQ1 more likely
    • Nerve biopsy
      • Axonal loss
        • Early: Especially unmyelinated
        • Multifocal
      • ± Demyelination: Naked or thinly melinated axons
      • Many organisms
      • Preservation of overall nerve architecture
      • Schwann cells filled with organisms & debris
      • Myelin: Irregular wide spacing of laminae
      • Inflammation
        • Variable in degree; More with longer disease duration
        • Macrophage infiltration
          • Location: Perineurium; Perivascular
          • Foamy inclusions
  • Borderline leprosy: Between tuberculoid & lepromatous
    • Skin
      • Many anesthetic lesions with
      • Borders: Ill-defined to indistinct borders
      • Satellite lesions: Around larger lesions
    • Nerves
      • May produce the most nerve damage: Multiple nerves can be involved
      • Involvement is earlier & more rapid than in lepromatous leprosy
    • Histopathology
      • Range from tuberculoid to lepromatous
      • Variable presence of bacilli
  • Pure neural leprosy
    • No skin lesions
    • Clinical neuropathy syndromes
      • Most common: Mononeuritis multiplex
        • Asymmetric
        • Weakness & Sensory loss
        • Ulnar nerve most affected
        • NCV: Axonal loss
      • Occasional: Sensory
        • Distal
        • Symmetric
        • Temperature & Pain loss
        • No weakness
        • NCV: May be normal
      • May be asymptomatic ("Silent Neuritis")
  • Acute neuritis: with Erythema nodosum leprosum
    • Sudden onset of local palsies
    • Cutaneous & subcutaneous nodules: Painful; Red
    • Iridocyclitis; Orchitis; Orchitis; Arthritis
    • Associated with treatment of borderline or lepromatous leprosy
    • 2° to immune response to leprous antigens & immune complex deposition
    • Pathology: Vasculitis of medium & small sized arterioles
    • Treatment: Corticosteroids
  • Single lesion leprosy
    • Worse prognosis: Age > 40 years; M. leprae PCR positivity
  • Diffuse Lepromatous Leprosy
    • Nosology: Spotted or lazarine leprosy; Diffuse Leprosy of Lucio and Latapi
    • Organism: M. lepromatosis; New species, 7.4% difference from M. leprae
    • Endemic: Mexico & Costa Rica
    • Clinical: More severe syndromes
      • Skin lesions
        • Recurrent crops of large, sharply demarcated skin lesions (Lucio phenomenon)
        • Diffuse, nonnodular cutaneous infiltration
        • Mycobacterial invasion into endothelium
        • Endothelial proliferation
        • Vascular occlusion or vasculitis: Dermis & Subcutis
        • Fatal secondary bacterial infection & sepsis
      • Neuropathy
      • Leprosy reactions: More severe
• Diagnosis
  • Serum antibodies to phenolic glycolipid-I (PGL-I)
    • Sensitive in lepromatous disease
  • Skin biopsy
    • Fite–Faraco staining
    • PCR: Only positive when staining of organisms seen
  • Nerve biopsy
    • Especially useful: Tuberculoid disease
    • Inflammation: Granulomas in 50%
    • Nerve structure: Damaged
    • M. leprae bacterium
      • Ziehl staining of paraffin sections demonstrates M. leprae
      • Bacilli present in perneurial & endoneurial cells
      • Lepromatous: Organism proliferates within Schwann cells
      • anti-BCG or MLO4 antibodies stain M. leprae antigens
      • EM: Rod-shaped cytoplasmic structures, surrounded by clear space
      • Bacteria not present in: End-stage disease
  • Nerve imaging: Enlargement; Hypervascularity
• Treatment
  • Drugs: WHO recommended
    

    	Rifampicin	Clofazimine	Dapsone
    Adult	600 mg q month	300 mg q month 50 mg qd	100 mg/d
    Child   (10 - 14 years)	450 mg q month	150 mg q month 50 mg qd	50 mg/d
    Young Child   (< 10 years or <40 kg)	10 mg/kg q month	100 mg q month 50 mg 2x/wk	2 mg/kg/d
    Duration: Multibacillary 12 months; Paucibacillary 6 months
    2nd line treatment with drug resistance: Ofloxacin + Minocycline.

  • Prognosis after treatment
    • Complete remission: 60% in early disease; 30% in longer-term disease
    • Partial remission: 27% in early disease; 48% in longer-term disease
    • Poor recovery from individual nerve lesions
    • Worsening: 1%
  • Reactional states after treatment
    • Downgrading & Reversal
      • Occurs mainly in bordeline leprosy syndromes
      • Movement of disease syndrome toward tuberculoid syndrome
      • Time course
        • Most common during 1st year of treatment
        • May occur up to 5 years after treatment
        • Increased risk with pregnancy & delivery
      • Neuropathy
        • Pain & swelling of nerve trunks: Acute onset
        • New motor & sensory loss
        • Distribution: Especially ulnar & Common peroneal
        • Neural injury more likely with pre-existing nerve damage
      • Skin lesions: New or enlarging
      • Histology: Delayed hypersensitivity-like lesions
        • CD4+ lymphocytes & Macrophages
        • Cytokine profile: Th1-like cytokine; TNF-α Interleukin-2 expression
      • Treatment: Corticosteroids
        • Dose: 1mg/kg; Increasing doses if no response at 1 to 2 days
        • Timing: More effective with earlier treatment
        • Benefit: 60% rate of salvaging nerve function
    • Erythema nodosum reactions
      • Occurs mainly in lepromatous disease
      • Timing
        • Within 2 years of start of therapy
        • May occur at disease presentation
      • Clinical
        • Skin
          • Tender skin nodules
          • May resolve spontaneously
        • General: Fever, arthritis, myalgia
        • Neuropathy: Acute
      • Laboratory
        • Anemia
        • Leukocytosis
        • Liver function: Abnormal
        • High serum
          • Tumor Necrosis Factor-α: High
          • Interleukin-1
      • Treatment
        • Thalidomide: For systemic symptoms; May cause neuropathy
        • Corticosteroids: For neuritis
  • Disability management
    • Anesthetic limbs
    • Skin lesions
  • Contact tracing
  • Clinical center: HRSA
• Leprosy: Muscle involvement
  • Clinical: Often asymptomatic
  • Leprosy Pathology: Stages
    • Invasion of muscle fibers
      • Intracellular proliferation of Mycobacterium leprae
      • Bacilli
        • Acid-fast & GMS stain
        • Present inside macrophages, myofibers & smooth muscle cells
        • May occur in muscle with normal morphology
    • Muscle fiber necrosis
      • Associated cells
        • Macrophages/Granulomas, Eosinophils & Lymphocytes
        • Granulomas: Present in endomysium & perimysium
      • Macrophages: Vacuolar
    • Replacement of muscle by connective tissue
  • Other muscle pathology
    • Muscle fiber atrophy
    • Denervation

HUMAN IMMUNODEFICIENCY VIRUS (HIV)

General Muscle Nerve

from CDC HIV

• Epidemiology: Increasing frequency of HIV/AIDS in Sub-Saharan Africa
• Immune changes
  • Early
    • CD4 T-cells: Numbers normal; Increased turnover
    • CD8 T-cells: Increased turnover
    • CD20 B-cells: Polyclonal activation; Immunoglobulin production
  • Late: Longer HIV infection duration
    • CD4 T-cells: Numbers reduced
• Clinical syndromes: Occur in specific phases of infection
• Early: Usually immune mediated
  • ALS-variant syndrome
  • Brachial plexopathy
  • CIDP
  • Guillain-Barré
  • Mononeuritis multiplex (Vasculitis)
  • Myasthenia gravis
  • Neuromyotonia
  • Immune myopathy
  • Cytoplasmic body (Rod) myopathy
• Advanced
• Autonomic neuropathy
• Cytomegalovirus
• Mononeuropathies
• Sensory motor polyneuropathy, Distal
• Drug related myopathy
  • Zidovudine
  • Other
• Wasting
• Infectious
• Carnitine deficiency
• Myopathy with muscle fiber necrosis
• Adrenal insufficiency
  
• Inclusion body myositis, Sporadic: Younger onset than typical IBM syndromes
• Early or Recovery with treatment
  • DILS
    
  • Immune reconstitution inflammatory syndromes (IRIS): Few cases
    • MuSK myasthenia gravis
    • Inflammatory myopathy
    • Myasthenia gravis: Relapse ³⁵
• HIV associated with younger onset
  • IBM
  • SLONM
• Neuropathy frequency
  • Clinical: 10% to 35%
  • Pathology: 95% of patients dying of AIDS

• Guillain-Barré
  • Disease phases
    • Seronegative (Near time of infection)
    • Seropositive (Asymptomatic)
    • > 50 CD4 cells per μL
  • Distinctive feature
    • GBS with CSF pleocytosis
• CIDP
  • Disease phase: Seropositive & Aids-related complex (ARC)
  • Difference from idiopathic CIDP
    • CSF: Lymphocytic pleocytosis (10-50 cells/mm³)
• Brachial plexopathy
  • Disease phase: Seroconversion
• Mononeuropathies
  • Herpes Zoster
    • Disease phase: ARC & AIDS
  • VII nerve palsy ²⁴
    • Epidemiology
      • Onset age: 20 to 73 years
      • Disease phase: Often at, or before, sero-conversion
      • 4.1% to 7.2% incidence in general HIV population
      • Risk increase over non-HIV: 100x
      • Facial paresis in Africa
        • Burkina Faso & Central African Republic: HIV in 64% to 100%
        • Kenya: 25%
      • Male > Female
    • Clinical
      • Unilateral or Bilateral
      • Course: Often self remitting over 2 to 24 weeks
    • Laboratory
      • CSF: Pleocytosis; High protein
      • CD4+ cell count: Often ≥ 500 cells/mm³
  • Cranial neuropathies: Other
    • Optic
    • Rule out: Lymphoma; Tuberclosis; Zoster
  
  
• Sensory > Motor neuropathy
  • Disease phase: AIDS
  • Epidemiology
    • Frequency
      • 35% of patients with AIDS
      • Most common PNS manifestation in HIV
    • Risk factors
      • HIV-related
        • Length of HIV infection
        • Degree of HIV-induced immunosuppression ¹³: CD4 level
        • Viral load: Increased frequency with higher viral load
        • May develop in patients with undetectable viral loads after treatment
        • Use of dideoxynucleoside reverse transcriptase inhibitors & protease inhibitors
      • Patient related
        • Age: Increased
        • Diabetes mellitus, Type 2
        • Triglycerides: High
        • mtDNA SNP-associated reduced prevalence ²⁹
          • A12810G: L1c; African
          • T489C: J; European
  • Clinical features
    • Onset
      • Symptoms: Pain & Dysesthesias
      • Distribution: Especially in feet
    • Sensory
      • Loss: Panmodal, Spares joint position
      • Pain: Dysesthesias; May be severe
    • Weakness: Late in course; Occasional; Mild; Intrinsic foot muscles
    • Distribution of signs: Symmetric; Distal; Legs > Arms
    • Tendon reflexes: Reduced at ankles
    • Progression: Slow
    • Treatment: Pain management; ? NGF
  • Laboratory
    • NCV: Axon loss
      • Distal
      • Sensory > Motor
      • Symmetric
    • EMG: Distal denervation
    • Pathology
      • Axonal loss: Distal
      • ± Demyelination
  • Rule out
    • Thiamine deficiency
    • Nucleoside drug toxicity
  
  
• ALS-variant syndromes ¹²
  • Epidemiology
    • Frequency: Rare; 3/1,000
    • Sex: All male
    • Patients described: 42
  • HIV Disease associations
    • Phase
      • Seropositive
      • May be presenting syndrome of HIV infection or decade later
    • Viral load: Often high
    • CD4 counts reduced or normal
    • Activation of human endogenous retrovirus K (HERV-K; ENK24)
  • Clinical syndrome
    • Onset age: Mean 34 years; Range 22 to 61 years
    • Weakness: Variable patterns
      • Monomelic; Distal
      • Diffuse
      • Proximal or Distal
      • Bulbar: Some patients
      • Arm or Leg predominant
      • Asymmetric: Often
      • Progression: Over weeks
    • Upper motor neuron signs: Most patients
      • Tendon reflexes: Brisk
      • Plantar response: Extensor
    • Fasciculations
    • Sensory: Normal
    • Survival: 3 months to > 3 years
    • Treatment
      • Protease inhibitors (AZT +...)
      • Course: Partial or Complete remission
  • Laboratory
    • CSF: Protein very high (130 to 1340); Cells 1 to 13
    • EMG: Denervation
    • NCV
      • Conduction velocities: Normal
      • CMAP amplitudes: Normal or Reduced
    • MRI: Usually non-diagnostic; Some with other CNS disease
    • HERV-K levels in plasma: May be high
  
  
• Diffuse infiltrative lymphocytosis syndrome (DILS): Sensory-Motor neuropathy
  • Disease associations
    • Phase: Seropositive; Asymptomatic
    • Severity: Fewer opportunisitic infections & longer survival
    • CD8 lymphocytosis
  • Clinical
    • Neuropathy: May be 1st manifestation of HIV infection
      • Onset: Days to weeks; Pain & Sensory loss
      • Weakness
        • Mild to Moderate
        • Facial paresis: Unilateral or Bilateral
      • Sensory loss
      • Anatomical pattern
        • Distal > Proximal
        • Symmetric (66%; CD4 count > 200)
          
        • Asymmetric (33%; CD4 count normal or low)
      • Nerve pathology: Axonal loss (83%)
    • Myositis
    • Multisystemic
      • Lymphadenopathy
      • Splenomegaly
      • Lung: Interstitial pneumonitis
      • Sicca syndrome (Parotid enlargement): Xerostomia
  • Laboratory
    • Circulation: CD8 hyperlymphocytosis (> 1000 cells per μL)
    • Immune (Salivary or Lacrimal gland): CD8-cell infiltration around epi- & endoneurial vessels (Polyclonal)
    • Nerve
      • Loss of myelinated fibers: Diffuse, not focal
      • High proviral load in nerve; Not a lymphoma
    • CSF
      • Protein: High
      • Cells: Common
  • Treatment: Prednisone; ? AZT
  
  
• Progressive polyradiculopathies
  • Autonomic neuropathy
    • Disease phase: AIDS
      • Early stages of infection may also show dysautonomia: Milder than in AIDS
    • Clinical
      • Parasympathetic: Resting tachycardia; Impotence; Urinary dysfunction
      • Sympathetic: Orthostatic hypotension; Syncope; Diarrhea; Anhidrosis
      • Pupil change
      • Anhidrosis
      • Cardiac: Palpitations; Tachycardia
      • GU: Impotence; Urinary dysfunction
    • Exacerbating factors
      • Polyneuropathy
      • Dehydration
      • Drugs: Vincristine; Tricyclics; Pentamidine
  • Multiple mononeuropathy
    • Disease phase: ARC
    • Vasculitis ⁵⁴
      • Vasculitis types with HIV
        • PAN
        • Cryoglobulinemic
        • Giant cell arteritis
        • Henoch-Schonlein purpura (IgA)
        • Kawasaki-like
        • Large vessel: Aneurysms; Occlusive disease
      • Clinical: PAN-like
        • Polyneuropathy
        • Skin rash
        • Not multisystem
        • Some patients: Predominantly sensory + CNS in 50%
        • Course
          • Indolent or Monophasic
          • Not life-threatening
          • May improve without immunosuppressive treatment
      • Laboratory: PAN-like
        • CD4 count > 200
        • Pathology
          • Necrotizing vasculitis in: Epineurium & Muscle
          • Mononuclear infilteate
          • Often observed on: Salivary gland biopsy
          • Wallerian degeneration: Common
    • Rule out: CMV
  • Cytomegalovirus (CMV)
    • Disease phase: AIDS; CD4 count < 100
    • Clinical syndromes
      • Mononeuritis multiplex
        • Often with hoarseness (recurrent laryngeal nerve lesion)
          
        • Rapid progression
      • Cauda equina syndrome (Ascending polyradiculopathy)
        • Onset: Back & radicular leg pain
          
        • Urinary incontinence
          
        • Predominantly motor progressing to flaccid paraplegia
          
        • May ascend to arms & cranial nerves
    • CSF
      • Pleocytosis
      • Hypoglycorrachia
      • High protein
      • May be normal
      • Diagnostic test: PCR of CSF for CMV
    • Systemic infection: Retina, blood, urine
    • Pathology
      • Endoneurial neutrophil inflammation
        
      • Giant cells with CMV inclusions
        
      • CMV immunoreactivity in nerve
    • Treatment
      • Ganciclovir
      • DHPG/Foscarnet
      • Cidofovir
  • Syphilis
  • Lymphoma
  • Cryptococcus neoformans (rare)
  
  
• Iatrogenic (Drugs) neuropathies
  • Nucleosides
    • Specific drugs
      • 2',3'-dideoxycytidine (ddC): 25% to 66%
      • dideoxyinosine (ddI): 12% to 34%
      • Stavudine (d4T): 15% to 55%
      • Lamivudine (3TC)
    • Epidemiology
      • Dose dependent
      • 1 month frequency: 6%
      • Symptom peak: 3 months after starting drug
      • More common with
        • Pretreatment neuropathy
        • Later stage disease
      • Less common: After no symptoms in 1st year
    • Clinical
      • Sensory loss: Legs > Arms
      • Pain
      • Asymptomatic neuropathy: 40% after 7 years of treatment
    • Pathology: Axonal loss
  • Also see: Nucleoside-associated lactic acidosis
  • Other
    • Vincristine
    • Isoniazid
    • Dapsone
    • Thalidomide
  
  
• Other syndromes
  • Neuromyotonia
  • Vitamin B₁₂ deficiency
  • Hepatitis C
  
  
• Neuromuscular syndromes occurring after treatment of AIDS
  • Inflammatory myopathy
  • Vasculitis: May be severe
  • IRIS
  
  
• HIV-2 infection
  • Distal sensory neuropathy (50%)

• Early onset: Seropositive
  • Immune myopathy
    • Syndromes
      • General
        • Some: Similar to non-HIV patients
        • Many: Evolve to IBM (IM-VAMP) syndromes
      • Onset: Subacute
      • Weakness: Proximal
      • Myalgias
    • Serum CK: Often increased
    • Muscle pathology
      • Inflammation: CD8+ T cells
      • Muscle fibers: Focal invasion
      • MHC-I: Upregulation by muscle fibers
      • Granulomas: Some patients
    • Treatment
      • Improvement with corticosteroids
      • ? Use pulse Solumedrol to reduce immunosuppression
  • Cytoplasmic body (Nemaline rod) myopathy
    • Clinical
      • Onset: Adult
      • Weakness: Proximal
      • Painless
      • Treatment: Possible improvement with corticosteroids
    • Laboratory
      • Serum CK: High or Normal
      • Muscle pathology
        • Cytoplasmic bodies or Rods in type I muscle fibers
        • Muscle fiber necrosis
        • ± Inflammation
    • Differential diagnosis
      • SLONM
      • IM-VAMP (IBM)
• Later onset: AIDS
  • Zidovudine (AZT)
    • May also be seen in early HIV infection
    • Clinical
      • Proximal weakness
      • Pain
      • Resolves when AZT stopped: Usually within 3 to 4 months
    • Serum CK: High
    • Pathology
      • Mitochondrial: Numerous COX - muscle fibers
      • Myopathy
      • Inflammation
  • Other toxic syndromes
    • Vinca alkaloids
    • Ranitidine
  • Myopathy with muscle fiber necrosis
    • Clincal
      • Weakness: Proximal
    • Laboratory
      • CK: WNL
      • Some associated with electrolyte change
      • Pathology: Necrotic muscle fibers
      • ? Related to "foamy" virus infection
  • HIV wasting
    • Definition
      • Weight loss of at least 10%
      • Presence of diarrhea or chronic weakness & fever for > 30 days
      • Not attributable to a concurrent condition
    • Epidemiology
      • Common in Sub-Saharan Africa
      • Western countries: Declining frequency
    • Clinical
      • Fatigue
      • Muscle wasting
      • No myalgias
    • Pathology: Variable
      • Type II atrophy: Most common
    • Treatment
      • Anti-retroviral therapy
      • Nutrition
      • Oxandrolone
    • Possible pathogenic factors
      • Metabolic alterations
      • Anorexia
      • Malabsorptive disorders
      • Hypogonadism
      • Excessive cytokine production
    • Other treatable disorders in 40%
      • Vasculitis
      • Polymyositis
      • Drugs: AZT & Nucleosides
    • External link: UCSF
  • Infectious (Pyomyositis) ± Lymphoma
    • Slower onset than typical pyomyositis
    • Painful limb swelling
    • Multifocal disease: More common
    • Some patients with weakness & myalgias
    • MRI: Diferential diagnosis
      • Infection: No change in subcutaneous tissue
      • Non-Hodgkin's lymphoma: May involve subcutaneous tissue
    • Pyomyositis organisms
      • Cryptococcus
      • CMV
      • Mycobacterium Avium Intracellularae (MAI)
      • Toxoplasmosis
      • Histoplasma
  • Carnitine deficiency
    • ? Myopathy
    • Risk factors: Especially zidovudine; ? Malnutrition or Malabsorption
    • Muscle pathology: Lipid storage ± Mitochondrial change
  • Adrenal insufficiency
  • Chronic fatigue
• Immune reconstitution inflammatory syndrome (IRIS)
  • Onset: After initiation of treatment
  • Myopathy
    • Weakness: Proximal > Distal; Symmetric
    • Muscle pathology
      • Inflammation: Endomysial; Many histiocytic cells
      • Muscle fiber damage: Varied size; Necrosis
      • Mitochondrial pathology: SDH+ & COX- muscle fibers
      • Cytoplasmic bodies (or rods)
  • Treatment: ? Corticosteroids
• Nucleoside-associated lactic acidosis ¹⁹
  • Epidemiology
    • Associated with nucleoside treatment
      • Period: 1 to 36 months
      • No relation to specific nucleoside
    • Frequency: 0.85 cases per 1000 patient-years of antiretroviral therapy
    • Age: 31 to 53 years
    • Male = Female: Females more than expected for frequency of HIV infection
    • CD 4 count: Mean = 199 lymphocytes/mm³; May be normal or low
  • Clinical
    • Onset: Days to weeks
    • Gastrointestinal symptoms: Most common; Abdominal pain; Vomiting
    • Respiratory: Cough; Dyspnea
    • Weight loss
    • Myopathy: Weakness
    • Neuropathy: Numbness; Painful dysesthesias
    • Treatment
      • Reduce acidosis: Fluid & Bicarbonate
      • Stop nucleoside drugs
      • Riboflavin
      • Thiamine
    • Course
      • Improvement over 1 to 24 weeks after discontinuation of antiretroviral therapy
      • Mortality: 33% to 50%; Higher with serum lactate > 10mM
  • Laboratory
    • Serum Lactate level: Range 4 to 71 mM
    • Muscle: Necrosis; Mitochondrial abnormalities
    • Liver: Microvesicular or macrovesicular steatosis
    • Axonal neuropathy

CHAGAS' DISEASE

• Causative organism: Trypanosoma cruzi
• Epidemiology
  • Endemic in Latin America: ~18 million people infected, especially Bolivia
  • Deaths: 10,000 to 14,000 annually
• Transmission
  • Endemic areas
    • Vectors (Animals (Dogs))
    • Triatomine infestans (Reduviidae): Feces; Bites
  • Non-endemic areas: Blood transfusion; Organ transplants
  • Congenital
• Acute infection
  • Many patients then remain asymptomatic
  • Clinical
    • Fever
    • Myalgias
    • Malaise
    • Erythema & Swelling: Near bite
    • Hyperhidrosis
    • Hepatosplenomegaly
    • Cardiac (90%): Myocarditis, Pericardial effusion, Heart failure
    • Meningoencephalitis
    • Lymph nodes: Local enlargement; Inflammation; Lymphocytosis
  • Course
    • Monophasic in most patients
    • High mortality with encephalitis or myocarditis
    • May be reactivated with AIDS
  • Diagnosis: Direct detection of organism in blood or CSF
  • Treatment
    • Drugs
      • Benznidazole: 5–7 mg/kg/day oral, in 2 doses daily
      • Nifurtimox: 8–10 mg/kg/day
    • Antitrypanosomal drug treatment
      • Acute disease
      • Indicated for all T. cruzi infected individuals younger than 18 years
• Chronic disease: General
  • Length: 10 to 30 years
  • 60% to 80% asymptomatic
  • Clinical features
    • Most common: Cardiomyopathy or GI
    • Embolic stroke
      • Increased frequency
      • Related to cardiomyopathy
  • Diagnosis: Serologic; IgG vs T. cruzi
• Chronic disease: Neurological involvment
  • Autonomic neuropathy
    • Early abnormality: Parasympathetic dysfunction
      • Reduced change in heart rate and blood pressure to deep breathing, Valsalva or orthostatic stress
      • Possibly related to vagal involvement
      • Abnormal tests: Often asymptomatic
        • Valsalva maneuver
        • Cold pressor
        • Orthostatic evaluation
    • Cardiovascular: Vagal & Sympathetic dysfunction
      • Orthostatic hypotension
      • Bradycardia: Resting
    • Gastrointestinal
      • Frequency: 10% to 30% of chronic Chagasic patients
      • Reduced bowel motility: Especially esophagus & colon
        • Dysphagia
        • Sialorrhea
        • Constipation
        • Megaesophagus
        • Megacolon
  • Sensory neuropathy (10%)
  • Pathology ²⁶
    • Inflammatory lesions in muscle, nerve & autonomic ganglia
    • Neuronal damage: Parasympathetic predominant
      • GI: Denervation of intrinsic enteric neurons of submucosal (Meissner) & myenteric (Auerbach) plexuses
      • May occur during acute infection: Probably related to immune response associated with infection
    • Sympathetic dysfunction: With disease progression
    • CNS MRI: Hyperintense white matter lesions
• Myositis
  • Occurs in any phase of disease
  • Weakness: Proximal
  • Discomfort: Myalgias; Muscle tendernass
  • Common during experimental Trypanosoma cruzi infection
  • Muscle pathology
    • Pseudocysts
    • Inflammation: Perivascular
• Chronic & Acute disease: Cardiomyopathy ²⁷
  • Risk
    • Lifetime: 20% to 30%
    • Increased risk with repeated or chronic infection
  • Patterns
    • Conduction abnormalities: Right bundle branch block most common
    • Arrhythmias: Sinus bradycardia; Cardiac parasympathetic (Intramural) ganglia involvement
    • Ventricular tachycardia: May be associated with regional sympathetic denervation; Later in disease course
    • Thromboembolism & Stroke
    • Dilated cardiomyopathy
    • Segmental
    • Relationship to autonomic dysfunction: Uncertain
    • Dilatation of left ventricle & Apical aneurism
    • Sudden death

SYPHILIS: Tabes dorsalis

Joseph Grünpeck, Tractatus de pestilentiali scorra, 1496

from CDC Treponema pallidum

From Bramwell: Diseases of the Spinal Cord Tabes dorsalis: Pallor of posterior columns

• Organism: Treponema pallidum
• Clinical features
  • Onset
    • 10 to 30 years after initial, often untreated, infection
    • May occur in adults or children (Congenital infection)
  • Sensory
    • Joint position & Vibration sense: Reduced
    • Hitzig zones
      • Regions of reduced sensation
      • Locations: Central face; Nipples; Ulnar forearms; Peroneal legs
    • Lightning pains: Especially lower extremity & abdomen
    • Analgesia: Leads to painless ulcers & Joint damage (Charcot's joints)
    • Sensory ataxia
      • Gait disorder
      • Romberg sign
  • Tendon reflexes: Reduced or Absent
  • Eye
    • Pupil disorder: Argyll Robertson pupils
      • Light-Near dissociation
      • Pupil reaction
        • Constrict: With focus on near object (Accommodation)
        • No constriction: in response to bright light
      • Pupil anatomy: Small; Irregular
    • Optic atrophy
  • Autonomic
    • Impotence
    • Bladder dysfunction
  • Systemic
    • Aortitis
    • Charcot's joints (Neurogenic osteoarthropathy)
      
      • Onset: Middle aged males
      • Location: Knee ± Other leg joints
      • Fractures: Common
  • Treatment: Penicillin for active neurosyphilis for 10–14 days
    • Aqueous crystalline penicillin G
      • 3–4 million units IV every 4 hr, or
      • 18–24 million units every 24 hr (continuous infusion)
    • Penicillin G procaine
      • 2.4 million units IM daily, plus
      • Probenecid, 500 mg oral 4 times a day
    • Benzylpenicillin: 3–4 million units IV every 4 hr
• Laboratory
  • Serum
    • MHA-TP positive
    • VDRL: 50% to 75% positive
    • Also: Test for HIV
  • CSF
    • Early & Active disease
      • Cells: 10 to 200/μl
      • Protein: ~100 mg/dl
      • IgG: High
    • Late (Tabes dorsalis)
      • VDRL: 30% to 75% positive
      • FTA-ABS: 95% positive; 50% to 70% specificity
      • Cells: Normal or Mild pleocytosis
• Pathology
  • Fibrosis & Inflammation
    • Posterior roots & Meninges
    • Lumbosacral: More severe
  • Sensory ganglia: Degeneration of neurons
  • Posterior columns of spinal cord: Axonal loss

HUMAN GRANULOCYTIC ERLICHIOSIS ¹

• Causative organism: Erlichia equi
• Clinical features: Brachial plexopathy

LEPTOSPIROSIS (Weil's disease) ⁵⁵

• Causative organisms: Leptospira icterohaemorrhagiae (Rats), pomona (Swine), canicola (Cattle & Dogs)
  • Epidemiology
    • Associations with animals: Farming, Abattoirs, Sewers, Camping & Fishing, Pet dogs
    • Human infection: Contact with animal urine
    • Slum conditions
    • Temporal: More frequent in summer & early fall
    • Male predominance 3:1
    • Age: 70% in 10 and 40 years
    • Geography
      • Most common in tropical environments
      • US 50% in Hawaii
  • Diagnosis: DOT ELISA; PCR; Serologic with nucleic acid amplification
  • Treatments
    • Anti-microbial: Doxycycline, azithromycin, or amoxicillin; IV ceftriaxone for severe disease
    • Supportive care for organ failure
• Most common disease presentation: Self-limited, nonspecific febrile illness
• Systemic Disease
  • General
    • Frequency: 10% to 15%
    • Course: Biphasic
    • Nosology: Icteric leptospirosis; Weil's disease
  • Incubation period: Mean 7 days; Range 2 to 20 days
  • Initial or Septicemic
    • Leptospira in blood
    • Duration 4 to 7 days
    • Fever
    • Pain: Abdominal; Muscle (Calf & thigh)
    • Encephalopathy
    • Lymphadenopathy; Hepatosplenomegaly
  • Secondary
    • After latent period of 1 to 3 days: Occurs only in some patients
    • Onset with meningitis
    • Hemorrhagic: Conjunctival hemorrhage; Rash
    • Pulmonary infiltrates
    • Leptospira in urine but not blood
    • Immune responses: Serum antibodies to L. icterohaemorrhagiae
    • Duration: 10 to 30 days
  • Mortality: Higher in oldest age group; Lowest in children.
  • Laboratory
    • Conjugated hyperbilirubinemia
    • Renal failure
• Polyneuropathy ⁵⁰
  • Clinical
    • Course
      • Prodrome: Organ failure
      • Onset: Acute
      • Occurs in secondary phase of infection
    • Sensory loss
    • Weakness
      • Lower > Upper extremities
      • Symmetric
      • May be severe
    • Cranial nerves: Pupils; V; VI, VII
    • Tendon reflexes: Reduced
  • Laboratory
    • Nerve conductions: Axon loss; Demyelination in some at later stages
    • Nerve pathology: Inflammation or hemorrrhage
    • CSF: Pleocytosis; Protein high
• Other neurologic
  • Aseptic meningitis (25%)

BRUCELLOSIS (Undulant Fever)

• Species: Brucella abortus (cattle), melitensis (sheep & goats), suis (pigs)
• Epidemiology
  • Most cases in California, Florida, Texas, & Virginia
  • Transmitted by:
    • Contact with infected animals, carcassses (adults) or milk or dairy products (children)
    • Accidental innoculation with live attenuated vaccine
  • Risk Groups: Abattoir workers, meat inspectors, animal handlers, veterinarians, and laboratorians.
• Diagnosis: Active infection
  • Standard agglutination test (SAT): Titers > 1:160
  • 2-mercaptoethanol (2ME) test: Titers > 1:80 are suggestive of active infection
• Clinical syndromes
  • Muscle
    • Symptoms: Weakness & Fatigue
    • Myositis: Some patients
      • Onset: Acute
      • Clinical
        • Pain: Muscle
        • Weakness: Proximal Legs; Asymmetric
        • Rhabdomyolysis: Some patients
        • Fever
      • Laboratory
        • Serum CK: High, 2x to 4x
        • EMG: Myopathic; Irritative
        • Muscle Pathology
          • Inflammation: Granulomas & Perimysial mononuclear cells
  • Peripheral nerve involvement: In chronic disease
    • Cranial nerves
      • Deafness (VIII): Most common
      • VI
      • VII nerve palsy: Bilateral
    • Lumbar radiculopathies & spondylitis
    • Acute polyradiculoneuropathy
    • Sensory-Motor neuropathy
  • General
    • Chills, Sweats, Anorexia
    • Aching: Generalized & Headache
    • Fever
    • Lymphadenopathy
  • Systemic
    • Organs: Enlarged liver (Granulomatous hepatitis), spleen, lymph nodes; Endocarditis
    • Rheumatologic: Prepatellar bursitis; Peripheral arthritis (Hip & Knee)
    • Hematologic: Anemia; Thrombocytopenia; Leukopenia
    • Eye: Uveitis
  • CNS (4% of Brucellosis)
    • Optic neuritis
    • Meningitis
    • Meningo-vascular
    • Myelitis
    • Abscess
• Treatments
  • Rifampicin: 6 months
  • Doxycycline: 6 months
  • Streptomycin: 3 months
  • Combination treatments: Doxycycline 45 days + Gentamycin 7 days
  • Children < 8 years: Cotrimoxazole + Rifampin for six weeks
  • Neurological or Heart: Aminoglycoside + Doxycycline + Rifampicin
• External link: CDC

HEPATITIS C ^{3, 5}

• Virus
  • Enveloped, single-stranded, RNA, Flaviviridae
  • Genotypes
    • 6 genotypes & > 50 subtypes
    • Type 1b with most severe infection
    • Types 1a & 1b most common in US
  • Cell targets: Hepatocytes; B-Lymphocytes
  • Rapid replication
    • via Error prone RNA dependent RNA polymerase
    • Rapid development of mutants: Escape from immune surveillance; Persistent infection
• Disease
  • Epidemiology
    • Distributed world-wide (2.2%)
    • Prevalence
      • Geographic: US 0.6% to 1.8%; Northern Europe 0.1%; Parts of Africa 20%
      • Age: Highest 30 to 69 years
      • Risk factors
        • US: Young adults with high-risk behavior
        • IV drug users: 80%
        • Sexual promiscuity
        • Transfusion
        • Low socio-economic status
      • Older risk factors
        • Dialysis before 1991: 10 to 60%
        • Hemophilia treated before 1986: 80%
        • Recipients of single donor blood producets before 1986: 10%
  • Transmission
    • Most efficient: Percutaneous exposure to infected blood products
    • Other
      • Environment: Occupation; Household; Surgical
      • Sexual: Most sexual partners test negative for infection
      • Perinatal exposure: More likely with high hepatitis C virus RNA concentrations in mother
    • Rates of perinatal & sexual transmission
      • 3% to 30%
      • Depends on degree of exposure & viral subtype
  • Acute infection
    • Infrequently diagnosed
    • Occasional symptoms 6 to 12 weeks after infection
    • Rare fulminant hepatitis
    • Self limited infection: 15% to 25%
    • Progression to chronic infection: 80% with chronic viremia
    • Lab tests positive
      • Serum alanine transferase (ALT)
      • HCV RNA levels
      • HCV antibody: Unreliable
  • Chronic infection
    • Most lead to hepatitis & some fibrosis
    • Eventual cirrhosis: 20% by 20 years
    • Hepatocellular carcinoma: 1% to 4% per year in patients with cirrhosis
    • Slower progression: Female; Younger onset
    • Faster progression: Male; Alcohol use; Co-Infection with other viruses
    • Extrahepatic manifestations
      • Occur during chronic HCV infection or cirrhosis
      • Can represent first indication of hepatitis C virus infection
• Diagnosis
  • HCV antibody
    • 99% to 100% sensitivity in high prevalence, immunocompetent population
    • False negative: Immunocompromise; Dialysis; Mixed cryoglobulinemia; Acute infection
  • PCR most specific
  • Other tests in evaluation
    • Serum ALT
    • Liver biopsy
• Associated disorders
  • General
    • 20% to 30% of patients with acute hepatitis C infection develop clinical symptoms
    • Symptom onset: 3 to 12 weeks after exposure
  • Neuropathy syndromes
    • General
      • Commonest neurologic complication of HCV infection: 8% to 15%
      • Onset: Subacute; Asymmetric sensory symptoms
      • More severe with: Cryoglobulins; PAN-like vasculitis
      • Other systems involved
        • Central nervous system
        • Skin: Painful palpable purpura
          • Due to: Leukocytoclastic vasculitis
          • Distribution: Legs; Distal > Proximal
      • Pathology: Often perivascular inflammatory
    • Polyarteritis nodosa
      • Uncommon
      • Mononeuritis multiplex
      • CNS: cerebral angiitis
      • Systemic features: Hypertension; Renal insufficiency
      • Lab: High Sedimentation rate & C-reactive protein
      • Pathology
        • Vessels: Medium sized arteries; Necrotizing
        • Inflammation: PMN in infiltrate
      • Treatment: Prednisone; Plasma exchanges; Interferon-α
    • Mixed essential cryoglobulinema
      • Common
      • Predominantly sensory neuropathy
      • Pathology
        • Vessels: Small
        • Inflammation: Mononuclear cell infiltrates
      • ? Treatment
    • Peripheral nerve vasculitis
    • Cranial neuropathy
    • Small fiber neuropathy
    • Subclinical neuropathy: 5%
  • Systemic
    • Hepatitis: Autoimmune
    • Rheumatologic (19%): Arthralgias; Rarely myalgias
    • Cutaneous disorders (17%)
    • B-cell lymphoproliferative disorders
      • All B-cell lymphomas: 16% to34%
      • B-cell lymphomas with cryoglobulinemia: 95%
    • HIV infection: Anticardiolipin Ab; Thrombocytopenia; Less Arthralgia or Myalgia
  • Antibodies
    • IgM M-proteins
    • Cryoglobulinema (56%)
      • Cryogloulinemia Types 2 & 3
      • Associated with: Vasculitis; HIV; + Rheumatoid factor
    • Rheumatoid factor 40%
    • ANA (> 1:80) 29%
    • Anticardiolipin 27%
    • Other: Thyroglobulin; Smooth muscle cell
• Possible associations
  • Glomerulonephritis
  • Thyroiditis
  • Sjögren's syndrome
  • Guillan-Barré syndrome
  • IgA deficiency
  • Pulmonary fibrosis
  • Mooren's corneal ulcers
  • Behçet's syndrome
  • Polyarthritis
  • Idiopathic thrombocytopenic purpura
• Treatment of Infection
  • General
    • Typical duration is 24 to 48 weeks
    • Shrorter treatement with HepC type 2 or 3
    • May assess efficacy by measuring HepC mRNA
    • Indications
      • Age: 18 to 60 years
      • Persistently high ALT
      • HepC virus RNA in serum
      • Chronic hepatitis on liver biopsy
    • External links: BMJ, JHU
  • Interferon α
    • Dose
      • 3 million units, subcutaneous 3x/week, or
      • peg IFN-α
    • Contraindications: Psychosis or Depression; Heart disease; Cirrhosis; Seizures
  • Ribavirin
    • Dose: 1000 to 1200 mg po qd
    • Contraindications: Pregnancy; Anemia; Heart disease
• Other possible treatment of immune neuropathy
  • Corticosteroids
  • Plasma exchange
  • Cyclophosphamide

WEST NILE VIRUS ⁷ *

• Virus
  • Flavivirus: Japanese encephalitis serogroup; Single-stranded RNA
  • Transmitted between Culex mosquitos & Birds*
  • Incidental infections in humans
  • Endemic to Africa, Middle East, Southwest Asia
  • Flavivirus non-structural proteins suppress host antiviral immune responses
• Epidemiology
  • North American virus
    • Imported from Middle East
    • Single lineage
    • Seasonal disease: Especially late summer; Range July to December
    • US virus distribution: Most regions; Less in Northwest
  • Human disease occurs in epidemics
    • August 1999 epidemic in New York City area
      • Virus isolated from local mosquitos & crows
    • May be preceded by deaths in bird or horse populations
    • Frequency of meningoencephalitis
      • Associated with rate of seropositivity in birds
    • Human disease with infection most commonly reported in US & Israel
  • Risk factors for neurologic disease: Advanced age (> 50 years)
  • Human infections
    • Associated with spending more time outdoors
    • Most commonly infected by mosquito bites
    • Other routes: Blood transfusion, Organ transplantation, Breast milk, Intrauterine transmission
    • Organ recipients at high risk for neuroinvasive disease: 40%
    • Present on 6 continents
• General clinical features
  • Usual infection
    • Asymptomatic in most: 80%
    • Mild febrile illness: 20%
  • Symptomatic infection
    • More severe & common (20x) in humans > 50 years
    • Median age of hospitalized patients 71 years
  • Incubation period: 3 to 15 days
  • Systemic features: Fever (90%); Nausea & Vomiting; Headache
  • Fatality: 4% to 15 %; Highest in elderly & patients with weakness
• Meningoencephalitis (63%)
  • General
    • Fever
    • Lymphadenopathy
    • Rash
    • Headache
  • CNS
    • Severe neurologic involvement occurs in 1 of 150 infections
    • Common features: Confusion; Headache
    • Occasional signs: Ataxia; Myelitis; Extrapyramidal; Cranial nerve; Seizures
  • Neuromuscular: Myalgias; Acute weakness in severe cases
  • Prognosis: Worse with encephalitis than meningitis
• Acute weakness: Severe cases
  • Weakness present in 27% to 50% of symptomatic infections
  • May be severe with respiratory failure (10%)
  • Reported syndromes
    • West Nile poliomyelitis ¹⁶
      • Onset: During acute phase of viral infectioni
      • Clinical
        • Age: Adults; 27 to 85 years
        • Onset of weakness
          • May be acute: Over days
          • Some patients present without associated encephalopathy
        • Weakness
          • Proximal > Distal
          • Asymmetric: Often
          • Patterns
            • Single limb: Arm or Leg
            • Paraparesis
            • Hemiparesis
            • Quadriparesis
            • Brachial diplegia: Proximal > Distal
          • Face (50%)
          • Course
            • Variable
            • Often persists after encephalopthy improves
            • Prolonged disability: Some weakness may be permanent
            • Weakness may be risk factor for death
        • Sensory involvement
          • Myalgias
          • Loss or Paresthesias: Little or none
        • Tendon reflexes: Increased or Decreased (32%)
        • CNS: Associated encephalopathy common
        • Poliomyelitis may occur withouf fever or meningoencephalitis
      • Laboratory
        • MRI
          • Brain: Basal ganglia; Thalami; Temporal lobe; Cerebellum; Brainstem
          • Spinal cord: Cauda equina; Ventral horn
        • CSF
          • Pleocytosis
          • Protein: High; Usually < 200
          • Glucose: Normal
        • NS Pathology
          • Motor neuron loss
          • Gliosis
          • Perivascular lymphocytes (CD3+)
          • White matter: Focal inflammation
          • Sympathetic ganglia: May have neuronal loss
        • EMG: Denervation
          • Asymmetric
          • Present after 2 to 3 weeks
        • NCV
          • CMAPs: Small after 2 weeks
          • Conduction velocity: Normal when corrected for amplitude of CMAP
          • Prolonged F-waves or distal latencies: Some patients
          • SNAPs preserved
        • Muscle pathology
          • Scattered necrotic muscle fibers
          • Perivascular inflammation
      • Differential diagnoses
        • Flavivirus: Several may produce motor neuron syndromes
          • St Louis encephalitis
          • Japanese encephalitis
          • Murray Valley encephalitis
          • Russian Spring-Summer: Cervical cord motor neuron involvement; Head drop
        • Viral motor neuron syndromes
    • Other acute neuropathy: Unusual
      • Guillain-Barré-like syndrome: Acute demyelinating polyneuropathy
      • Axonal neuropathy
      • Some patients have mixed axonal & demyelinating features
• Prognosis
  • Death & weakness most common in patients > 75 years
  • Many patients with encephalitis have disabling residual disorders
    • Fatigue
    • CNS: Memory loss; Depression
    • Weakness
    • Gait disorder
  • ? Association with myasthenia gravis: Onset 3 to 7 months after WNV infection ³⁰
• Laboratory
  • Diagnosis
    • Collect blood
      • From 8 to 21 days after symptom onset
      • 2 samples 2 weeks apart
    • Viral titers
      • Infection: 4x Rise in IgM antibody titers in serum
      • Serum more sensitive than CSF titers for diagnosis
      • Positive IgM titers may persist for 16 months after infection
  • Hyponatremia: Especially with encephalitis
  • CSF
    • Pleocytosis
      • Usually >200 cells/mm³
      • Early: May be normal early; Neutrophils
    • Protein: Mildly high
  • CBC: May be normal
  • Sedimentation rate: May be high
  • MRI
    • Abnormal in 31%
    • Enhancemant of meninges or periventricular areas
    • Abnormal signal in anterior horns
• External link: CDC

IMPP (Myofasciitis; EVIM) + Deafness: Enterovirus & Hypogammaglobulinemia-Related ⁴⁵

• Epidemiology
  • Frequency: Rare
  • Associations
    • Hypogammaglobulinemia
    • Post-Rituximab ± Ibrutinib Rx
    • Other hypogammaglobulinemia-enterovirus syndromes: EV-D68; EV-D71
• Clinical: Dermatomyopathy+
  • Myalgia
  • Fatigue
  • Strength: Often normal
  • Tendon reflexes: Reduced
  • Skin
    • Rash
    • Edema
  • Weight loss
  • Hearing loss
  • Balance impairment
  • Systemic features: More severe disease
    • Myocarditis
    • Enteritis,
    • Myeloencephalitis
    • Hepatitis
  • Course: Progressive
  • Treatment: IVIg
• Laboratory
  • Serum CK: Normal or High
  • Serum Aldolase: High
  • EMG
    • Myopathic
    • Muscles firm on needle insertion
  • Muscle pathology
    • IMPP
    • Inflammation: Especially in vascular perimysium
    • Perimysial connective tissue: Cellular; Stains for UEA-1 lectin
  • CSF
    • Protein: High or Normal
    • WBCs increased
    • Enterovirus PCR+ (Echovirus 9)
  • Muscle MRI
    • STIR myofascial signal: High
    • Edema
  • Audiometry: Sensorineural deafness

Acute Flaccid Myelitis, EV-D68 (Motor neuronopathy; AFM) ³⁴

• Case definition
  • Timing: After 8/1/2104
  • Patient age: ≤ 21 years
  • Onset: Acute
  • Weakness: Focal limb
  • MRI: Spinal gray matter lesion
• EV-D68 Virus
  • Family: Picornaviridae
  • AFM patients: Clade B1 enterovirus D68
  • EV-D68 virus is retrogradely trensported in motor neuron axons
• Epidemiology
  • AFM cases: 104 patients in 34 states; Fall 2015 Japanese epidemic
  • AFM association: Cases coincided with national outbreak
    • Severe respiratory disease among children
    • Caused by enterovirus D68 (EV-D68)
  • EV-D68 respiratory tract association with AFM
    • 20% to 64% of AFM cases tested positive for EV-D68
  • Males > Females
• Clinical
  • Onset
    • Age: Median 8 to 11 years; Range 5 months to 20 years
    • Dates of US cases: 2014 (Aug 1 to Nov 13); Summer 2016 & 2018, but not 2020
    • Preceding illness: Common
      • Type: Respiratory (81%); Febrile (68%)
      • Time before AFM: Mean 7 days; Range 3 to 16 days
  • Weakness
    • Limbs
      • Proximal > Distal
      • Arms > Legs
      • Asymmetric
    • Cranial nerves
      • Frequency: 34%
      • Nerves involved: VI, VII, IX, X, XI & XII
    • Ventilator support: 19%
  • Pain
    • Some patients
    • Neck, Back or Extremity
  • Tendon reflexes: Often reduced
  • Sensation: Normal
  • CNS: Other
    • Mental status: Altered (7%)
    • Seizures (3%)
  • Course
    • Some improvement: 64%
    • No improvement: 36%
    • Full recovery: None
    • Deaths: None
• Laboratory
  • CSF
    • Pleocytosis
    • Protein: Mildly high
    • Glucose: Normal
  • MRI lesions (T2)
    • Lumbosacral ventral roots: Acute phase
      • Contrast enhancement (40%)
      • May be in asymptomatic area
    • Spinal gray
      • Lesions spanning multiple levels: Median 17 to 20
      • Diffuse: Early in course
      • Confined to Anterior horn: Later in course
    • Pons: Dorsal, Tegmentum
    • Facial nerve: 1 patient

ENTEROVIRUS 71 ³¹

• Epidemiology
  • Most common viral cause of acute flaccid paralysis
  • Worldwide outbreaks
  • Taiwan: Occurs annually
• Virus
  • Family: Picornaviridae
• Clinical syndromes
  • Prodromes
    • Hand, Foot & Mouth disease
    • Herpangina
    • Febrile illness
  • Aseptic meningitis
  • Encephalitis
    • General
      • Decreased consciousness
      • Seizures
    • Brainstem (Rhombencephalitis) (58%)
      • Ataxia
      • Tremor
      • Eye
        • Opsoclonus
        • Gaze paresis
        • Nystagmus
      • Myoclonic jerks
      • Bulbar palsies
      • Respiratory system dysfunction
    • Fatal cases: Early neurologic involvement
  • Acute weakness syndromes
    • Guillain-Barré
    • Poliomyelitis-like paralytic disease
    • Acute flaccid paralysis
      • Clinical
        • Onset
          • Age: Often < 3 years; Range 6 to 109 months
          • Days 3 to 6 of illness
        • Weakness
          • Asymmetric
          • 1 or 2 limbs
        • Autonomic dysfunction
          • Tachypnea
          • Sweating
          • Mottled skin
          • Tachycardia
          • Hypertension
        • Heart failure, Left: LVEF < 40%
        • May precede CNS syndrome
        • Prognosis
          • Complete recovery: 30% to 80%; More with less severe disease
          • Flaccid paralysis duration: Range 1 month to 6 years; Median 6 months
          • Respiratory failure: Occasional
        • Treatment: ? IVIg
      • Laboratory
        • MRI: Brain & Spine
          • May be normal: 25%; Better outcome
          • Dorsal medulla: Increased with disease severity
          • Spinal cord & Medulla: Unfavorable outcome
          • Spinal cord
            • Locations: Cervical; Lumbar or Sacral; Diffuse
            • Paralysis: Anterior horns
          • Root enhancement
        • Diagnostic: Culture or PCR
        • CSF
          • Cells: 21 to 260; Mean 174
          • Protein: Normal or High; Up to 500
    • Differential diagnosis: Viral motor neuron disorders
• Mouse model: Necrotizing myositis

CENTRAL EUROPEAN ENCEPHALITIS ⁸

• Virus
  • Tick-borne
  • Flavivirus
• Epidemiology
  • Poland, Czech, Slovakia, Austria, Bavaria, Hungary, former Russian States
• History
  • Tick bite
  • Residing in endemic area
• Clinical
  • Meningoencephalitis
  • Myelitic & Radiculitic symptoms: Up to 5% of patients
  • Poliomyelitic-like course: Occasional patients
  • Diagnosis: Serologic testing for CEE
  • Prodrome: Nonspecific influenza-like symptoms
  • Cranial nerve change
    • Variable
    • May include III, VII, IX, X, XI or XII
  • Weakness
  • Rapidly progressive
  • Distribution: Proximal & Arm > Distal & Leg
  • Respiratory failure: Diaphragm paralysis
  • Sensory: Normal
  • Course: Death (50%); Persistent weakness
  • Laboratory: Poliomyelitic-like course
    • CSF at initial presentation
      • Cells: 63 to 2133/mL; Lymphocytes (20% to 60%) & Polys (40 to 80%)
      • Protein: 110 to 240 g/L
    • EMG: Consistent with lower motor neuron damage
    • Pathology: 1 Patient
      • Cervicothoracic spinal cord inflammation: Severe
      • Changes mainly in anterior horn cells and roots

PYOMYOSITIS ⁹

Definition Localized regions of infection (abscesses) in muscle Usually not secondary to infection of neighboring tissues Nosology Tropical myositis (Myositis purulenta tropica) Infective myositis (Bacterial myositis) Pyogenic myositis Suppurative myositis Epidemic abscess Associations: Found in 60% of non-tropical patients Immunosuppression HIV Leukemia Medications: Over 30 years of age Drug addiction: Contaminated injections Pre-existing bacterial surface colonization Neutrophil disorders Nutropenia Functional defects Defective cell-mediated immunity Burn patients Diabetes mellitus Liver disease, alcoholic Trauma

Pyomyositis: MRI, Leg

• Epidemiology
  • Geography: Tropical regions more common
  • Ages: Several peaks
    • 2 to 5 years: Associated with malnutrition
    • 35 to 40 years: Often (50%) have underlying disease or immunosuppression
    • Temperate climates: Adolescents & Young adults
    • Range: 0 to 92 years
  • Sex: Slight male predominance
• Common organisms
  • Typical: Staphylococcus aureus 95% in tropical areas, 75% in North America
  • Immunosuppression: Fungal; Yeast; Also see HIV
  • Nigeria: Dracunculus mediensis
  • Actinomycosis
  • Salmonella enteritidus
  • Tuberculosis
  • Streptococcus pyogenes
  • Other
    • Escherichia coli
    • Cryptococcus
    • Histoplasmosis
    • Anaerobic bacteria
      • Clostridia
      • Mycobacteria
      • Fusobacterium necrophorum
    • Nocardia
    • Actinomycosis
• Disease evolution & General features
  • Onset
    • ? Transient bacteremia
    • Lesions more likely to develop in injured muscle
  • Lesion number
    • Single (25%)
    • Multiple (75%)
  • Stages in pyomyositis
    • Onset: Progression over days
      • Adults: 5 to 6 days
      • Children: More acute
      • Immunosuppression: Over weeks
    • Early/Invasive: 1 to 3 weeks
      • Pain: Dull, cramping, progressive pain associated
      • Low-grade fever
      • General malaise: Muscle ache
      • Signs of local inflammaton may be absent
      • Muscle pathology
        • Diffuse induration
        • Enlargement
    • Supperative: Muscle abscess formation
      • Local signs: Tender soft tissue mass (firm & woody)
      • Systemic signs: Fever
      • Muscle pathology
        • Suppurative
        • Localized with drainable pus
        • Polymorphonuclear leukocytes
        • Necrotic cellular debris
        • Rim: Histiocytes + Peripheral neovascularization
    • Late/Systemic
      • High fever
      • Septicemia
      • Muscle: Destruction (Severe)
      • Compartment syndrome
      • Extension into & destruction of adjacent tissue
        • Joints
        • Bone (Osteomyelitis)
      • Systemic abscesses
    • Prognosis: Complete recovery with treatment
  • Muscles involved
    • Common: Quadriceps, Glutei, Psoas, Calf
    • Other: Arm; Axial Scapula, Chest wall, Neck
  • Laboratory
    • CBC: Leukocytosis, Neutrophilic
    • Serum CK: Normal or Mildly high
    • X-ray: Normal muscle; Used to rule out bone lesions
    • CT
      • Central: Fluid
      • Rim: Enhancing
    • MRI
      • Diagnostic test of choice: Especially for axial lesions
      • Hyperintense lesions on T2
      • Gadolinium: Ring lesions enhance + Hypointense central regions
    • Diagnosis: Analysis of abscess material
  • Treatment
    • Appropriate antibiotics
    • Abscess drainage
• Clinical syndromes: Specific infections
  • Staphylococcus aureus
  • Epidemiology
    • Tropical climates: Otherwise healthy children & young adults
    • Temperate climates: Debilitated, elderly patients, often with immunosuppression or diabetes
  • Common organism features
    • Community-acquired
    • Methicillin-resistant Staphylococcus aureus (MRSA)
  • Size of lesions
    • Small abscesses: Temperate countries
    • Large abscesses: Tropical countries; Younger patients
    • Multiple abscesses: Immunosuppression
  • Prodromal factors: History of minor trauma to limb
  • Clinical features
    • Onset
      • Progression over days
      • Pain ± Fever
    • Muscle site: Most commonly thigh; More than 1 muscle in 50%
    • Single or multiple abscesses
    • Muscle signs: Swelling; Tenderness; Pain
    • Systemic
      • Fever
      • Systemic infection with delayed diagnosis
      • Hyperbilirubinemia
    • Diagnosis: Muscle biopsy ± Imaging
    • Association in tropics: Toxicariasis
    • Complications of late, untreated disease: Septicemia
    • Treatment: Surgical drainage; Antibiotics
  • Pathology
    • Zone of damage containing degenerating polymorphnuclear cells
    • Perivascular mononuclear cells at periphery
    • Granulation tissue
    • Burn patient: Linear extension of infection from exposed surface
  • Streptococcal myositis variants
    • Organism: Streptococcus pyogenes (Group A) ⁶²
    • Clinical
      • Pain: Intense; Myalgia
      • High Fever
      • Diffuse muscle swelling ± necrosis: May not develop abscesses
      • Systemic: Fever
      • Course
        • Rapidly progressive
        • Recovery days to weeks
        • Rare recurrence
      • Variant: Orbital inflammatory syndrome
    • Laboratory
      • MRI: Fasciitis
      • Serum CK: Normal
      • ASO: High
      • Sed rate & CRP: High
    • Streptococcus agalactiae
      • Group B
      • Associated with
        • Diabetes
        • Necrotizing fasciitis
  • Salmonella enteritidis: Focal myositis
  • Tuberculosis
    • Especially untreated disease
    • Common muscles: Psoas & Quadriceps
    • Associated with spread from bone or lymph nodes
  • Actinomycosis
  • Epidemiology: Children & adults living in temperate climates
  • Clinical
    • Spread from cervicofacial forms
    • Association: Alcoholism
    • Prodrome: Penetrating wound; Occasional hematogenous spread
    • Abscess: Slowly evolving painless mass; Few systemic signs
    • Treatment: Surgical removal; Penicillin
  • Laboratory: Sedimentation rate high
  • Cryptococcus
• Pyomyositis Variant: Psoas abscess
  • Associations: Tuberculosis; GI or Urinary tract infections
  • Secondary: Caused by local spread of infection (66%)
  • Primary: No anatomically associated lesion
  • Clinical
    • Pain: Deep, diffuse in back, flank, or hip. The patient may
    • Functional: Walk with a limp; Refuse to move the hip
    • Affected thigh held in flexion and external rotation
    • Movements that stretch the iliopsoas muscle group: May elicit pain
    • Tender mass: Flank or just above inguinal ligament; Rectal examination useful
• Also see: Trichinosis

RABIES ¹⁰

History: 1st case reported in pre-Mosaic Eshmuna Code of Babylon, 23rd century B.C Virus Rhabdovirus: Lyssavirus; Single stranded RNA Tissue receptors Canine rabies virus: Viral glycoprotein may bind to nicotinic AChRs on muscle Bat lyssaviruses: Virus may bind to unknown receptors in the epidermis or dermis Eclipse (Latent) phase: Incubation period Rabies-virus antigen & genome may persist up to 2 months after inoculation into muscle Location: Muscle; Cells at NMJ Replication In muscle or neural cells Some bat related viruses replicate in epidermis & fibroblasts: May be portal of entry Further replication after axonal transport to dorsal root ganglia Virulence: Related to Glycoprotein in viral envelope Argine or lysine at position 333 confer virulence Spread to CNS No viremia Transported to CNS via retrograde axonal transport Entry into nerves at NMJs May occur with or without replication in peripheral cells Transport rate: Rapid; 8 to 20 mm/day Interaction between microtubule dynein light chain & viral capsid P protein Only neurons affected Dissemination within CNS Via: Plasma-membrane budding & direct cell-to-cell transmission, or by trans-synaptic propagation G protein is required for attachment to neuronal receptors and for trans-synaptic spread Preferential localization: Brainstem, Thalamus, Basal ganglia, Spinal cord Spread from CNS: Virus may spread centrifugally along nerves Unmyelinated axons To salivary & serous glands of tongue, heart & skin Disease Pathophysiology: ? Associated with immune attack on peripheral nerve or CNS Encephalitic rabies & earlier death T-cell immunity to rabies virus High concentrations of serum IL-2 receptor and IL-6 Paralytic rabies & longer survival Less T-cell immunity Lower serum IL-2 receptor and IL-6 Amount of virus in CNS not strongly related to disease Epidemiology Endemic in most continents Australia with recently identified variant in fruit bats None in Antarctica or UK Animal Reservoirs Only mammals; Non-immunized dogs; Wild carnivores; Bats Eastern US: Raccoon Mid-Western US: Skunk Southwest US: Fox & Coyote Western US: Skunk Transmission Animal bites Most common route Overall risk: 5% to 80% Highest risk of disease & increased severity with bites to head & face Lowest risk of disease with bites to lower extremity Human cases most commonly from Bats & Dogs Thailand: Mostly dog bites US: Bat rabies virus most common Other Scratches: 50x lower risk (0.1% to 1%) than bite Aerosol: Occasionally from caves with large bat populations; Laboratory accident Tissue transplantation: Corneas Transplacental: Rare Prevalence Worldwide: 50,000 deaths per year; Most in India from dog bites US: 1 or 2 human cases & 8,000 animal cases per year Clinical Incubation period Average 1 to 2 months; Range of 1 week to 6 years Bite factors Site of bite: Decreased incubation with more Proximity to the CNS Severity of bite Viral load in bite Longest incubation periods with Australian bat lyssavirus Short incubation periods (< 1 week) Direct inoculation of virus into nervous tissue Example: Brachial-plexus injury from dog bites Patient factors: Age; Immune status Chloroquine treatment may increase likelihood & severity of rabies Prodrome General symptoms: Headache; Fever; Hyperactivity Sensory Paresthesias & Pain Especially at inoculation site spreading over limb Sensations: Burning, numbness, tingling, itching, or pruritus Duration: Few days to week Frequency: Bat bite (75%); Dog related (33%) Virus moves from periphery to dorsal root ganglion Death often occurs in next 2 weeks No loss of sensation Weakness or Spasms: One extremity Encephalopathy (Furious cases): Neurological signs, then coma Frequency: Occurs in 2/3 of patients with classic rabies Clinical Hyperactivity: Hydrophobia or aerophobia; Early in course Spasms Location: Neck, diaphragm & pharyngeal muscles Triggered by sensory stimuli Development of drowsiness & coma: Reduced frequency of typical spasms Inspiratory spasms: May occur without stimulation; May persist during coma Gag reflex: Increased Encephalopathy Agitation; Hallucinations; Myoclonus; Seizures (Late) Mentation: Fluctuations; May be normal early in course Autonomic hyperactivity Fever: May be very high; Common Hyperhidrosis Salivation: Increased Pupils: Poorly reactive; Dilated; May be transient or asymmetric changes Other: Piloerection; Pulmonary edema; Priapism & Spontaneous ejaculation Paralysis: May occur late in course Course: Progressive Coma phase Inspiratory spasms may occur Cardiac: Sinus tachycardia; Nodal rhythms; Reduced ejection fraction Hematemesis (50%): Pre-terminal Death Time: In < 7 days from onset Due to: Respiratory or Circulatory insufficiency Recovery Rare Often with atypical presentation Early prophylaxis with cell-culture vaccine High concentrations of neutralizing antibodies Improvement over months Chronic sequellae common Paralytic (Dumb; Myelitic) rabies: 20% of patients General: Little hyperactivity early in course; Fever common Weakness Onset in bitten extremity Proximal > Distal Progression: Quadriplegia; May involve bulbar & respiratory muscles Percussion myoedema: Chest; Deltoid; Thigh Cranial nerve Pharyngeal Facial: May be unilateral early; Often becomes bilateral Sensory: Paresthesias; No loss of sensation Tendon reflexes: Absent Autonomic: Piloerection Phobic spasms: 50% Urinary incontinence Symptoms of furious rabies Mild; Late-appearing Inspiratory spasms: Pre-terminal More CSF cellularity Course More prolonged than encephalitic rabies Death: May be due to respiratory failure; After ~13 days Variant syndrome Associations: Most common after insectiverous bat bite; Some dog-related Local limb prodromes especially common Local neuropathic pain Choreiform movements of bitten limb during prodrome Often evolves to furious rabies Sensory: Objective loss may occur Face weakness CNS Ataxia Seizures Occasional brainstem features: Anisocoria; Ptosis; Diplopia; Nystagmus; Myoclonus No phobic spasms or autonomic hyperactivity Mortality Reduced by treatment Dog bites: 38% to 57%; Depends on severity + location of wound & saliva virus concentration Other species (wolves): Up to 80% Higher with: Bites on head, face, neck & hand; Bleeding Superficial bat bites: Risk due to viral replication in epidermis & dermis Diagnosis Inoculation of mice with patient saliva Rabies antigen in skin within hairline Saliva PCR Antibodies (Serum & CSF) May only occur late in course Titers high in non-immunized patient Very high titers in previously immunized patient Evaluate animal for rabies: Confinement or Pathological examination Fluorescent examination of brain for rabies antigen: High sensitivity MRI: Increased T2 signal in brainstem, hippocampi, hypothalami, white matter & cortical grey Pathology Distribution: Encephalitis & Myelitis Cellular: Cytoplasmic eosinophilic inclusion bodies (Negri bodies) in neurons External link: CDC Treatment & Prophylaxis Wound care Rabies vaccine Use duck embryo or tissue culture prepared vaccines Course of treatment Neutralizing antibody should be maintained for 1 year 5th dose at 30 days necessary Vaccines prepared in brain or spinal cord may produce Encephalomyelitis Acute demyelinating neuropathy (GBS): Less common in children Uses Post-exposure Prophylactic in high risk groups (Veterinarians): Only 1 or 2 booster doses needed after exposure Experimental: Vaccination of wildlife using recombinant vaccinia vaccine (live) in animal bait Rabies immunoglobulin Skin test first if using equine form Indications: Transdermal bites; Licks over mucosa After disease onset: Symptomatic External link: CDC

CDC Rabies virus

TUBERCULOSIS ¹⁷

Frequency: 1% to 2% of tuberculosis infections in endemic areas Routes of infection Contiguous spread (63%) Lesions in bone or contiguous soft tissues Locations: Chest wall & Paraspinous muscles Hematogenous (29%): Thigh, Pelvis & Arm muscles Traumatic innoculation (9%) Via contaminated instruments Thigh muscles Clinical Onset Age: 1 to 86 years Local lesion with damage to bone & soft tissue Local inflammatory symptoms: 91% Systemic symptoms (Fever, Malaise, Weight loss): 22% Pyomyositis: Distribution 50% in only 1 muscle with hematogenous spread Common muscles: Psoas & Quadriceps Spread from infected site Distribution: Pleura, Joints, Intra-abdominal, Subcutaneous Nodular tuberculous polymyositis Diffuse involvement Weakness & Atrophy Masses in muscle: Tender; Palpable Course Poorer prognosis Muscle involvement develops after steroid treatment Hematogenous spread of infection Death may occur from sepsis Laboratory Imaging Muscle Involved muscles: Swelling & Edema Multiple muscles involved in 50% Common muscle: Quadriceps Differs from pyomyositis No venous thrombosis or cellulitis around affected muscles Other Bone destruction Spine: Vertebral damage Intervertebral disk: Preservation Mediastinal changes: Lymphadenopathy with low central density Chest X-ray: Abnormal in 50% Serum CK Usually normal High Few patients Multiple muscles involved Hematogenous spread Muscle histology Granulomatous reaction Histiocytes Giant cells Lymphocytes Necrosis

G Durante

Treatment

• Anti-tuberculous therapy
• Surgery: Debridement; Drainage

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AFRICAN TICK BITE FEVER ²⁰

• Organism: Rickettsia africae
• Location: Sub-Saharan Africa
• Sub-acute neuropathy
  • Onset: 1-3 months after return from trip ± doxycycline treatment for infection
  • Syndromes: Variable
    • Feet or Posterior calf: Weakness & Paresthesias; Bilateral; Recurrent
    • Arm or Face: Paresthesias & Pain; Unilateral
    • Sensori-Neural hearing loss
  • Course: Often spontaneous resolution; Occasional relapse
  • Laboratory
    • CSF protein: ? Mildly high in some patients

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Dengue Virus ³²

• Epidemiology
  • 96 million symptomatic cases per year
  • Asia (70%), Tropical & Sub-tropical areas
• Virus
  • Arbovirus
  • Mosquito-borne: Aedes
  • Neurological features: Serotypes 2 & 3
• Clinical
  • Forms
    • Dengue fever, Classic (DF)
      • Self-limiting illness
    • Dengue hemorrhagic fever (DHF)
      • After 2nd infection with different serotype: Antibody-dependent enhancement
      • Clinical: More severe
      • Increased vascular permeability
      • Thrombocytopenia & Hemorrhage
  • General features
    • Fever: Onset
    • Headache: Frontal; Retro-orbital pain
    • Skin: Rash
    • Hemorrhage
    • Myalgias
    • Arthralgias
    • Abdominal: Nausea, Vomiting, Pain
    • Treatment: Symptomatic
  • CNS (6%)
    • Encephalitis: Most common; Seizures; Altered consciousness
    • Encephalopathy
    • ADEM
    • Myelitis
      • Acute: Flaccid
      • Chronic: Spastic
      • MRI: Diffuse signal
    • Death: 5%
    • MRI: Cerebral edema; Parenchymal & meningeal lesions
  • PNS (3%)
    • Polyneuropathy: Acute, Immune/GBS-like
      • Female: Male = 2:1
      • Associated disorder: Thrombocytopenia
      • Axonal or Demyelinating
      • Timing: 7 to 14 days or in Recovery phase
    • Neuralgic amyotrophy
    • Mononeuropathies
      • Males: 90%
      • Phrenic (30%)
    • Course: Recovery common
  • Muscle
    • Myositis
      • Onset: Within 3 to 5 days of illness
      • Clinical: Myalgia; Respiratory; Monophasic
      • Laboratory: CK 1,500 to 20,000
      • Muscle: Muscle fiber necrosis; Perivascular mononuclear cells
    • Hypokalemic paralysis
      • Males: 90%
    • Rhabdomyolysis
      • Females: 80%
      • Associated: Fever; GI disorders
      • Timing: Early, within 5 days of disease onset
• Laboratory
  • Hematocrit: Increased
  • Thrombocytopenia
  • Liver enzyme levels: Increased

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Scrub Typhus ³³

• Epidemiology
  • Occupational disease: Rural areas of Asia-Pacific region
    • "tsutsugamushi triangle"
    • North & North-East India
  • Time: Post-monsoon period before winter
• Organism
  • Rickettsia
  • Scrub typhus group: Includes Orientia tsutsugamushi
  • Mite-borne
  • Obligate intracellular gram negative bacterium
  • Carriers: Chiggers of trombiculid mites
    • Infected by feeding on body fluids of small infected mammals (including rodents)
    • Remain infected throughout life & transmit infection to progeny
  • Mitochondria: May have descended from relatives of typhus-causing bacteria
• Clinical
  • Onset: Acute illness with high fever
  • Multi-organ dysfunction
    • Pneumonia
    • Renal failure, acute
    • Liver dysfunction: Hepatomegaly
    • Myocarditis
    • Hematology
      • Bleeding diathesis
      • Lymphadenopathy
    • Meningoencephalitis: Encephalopathy
      • Headache
      • Coma
      • Seizures
    • Muscle (40%)
      • Myalgia (77%)
      • Weakness: May be severe
      • More severe disease
  • Treatment: Doxycycline 200 mg daily for 7 days
  • Course
    • Complete recovery frequent
    • Mortality: 3%
• Laboratory
  • Diagnostic test: Serology (Antibodies)
  • Serum CK: High in 26%; High range 287 to 3166
  • EMG: Small, short, polyphasic potentials
  • NCV: Normal
  • Blood: Thrombocytopenia; Anemia
  • Muscle
    • Inflammation: Pervascular; Perimysium; Endomysium
    • No necrosis

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Chikungunya virus ⁴⁹

• Alphavirus: Togaviviradae family
• Virus properties
  • Single stranded
  • RNA
  • Transmitted to humans by Aedes mosquitoes
  • Intracellular parasite
  • May infect: Skin; Muscle; Joints
  • Infection rates: High
  • Bind to: Sulfated Glycosaminoglycans
  • FHL1 protein
    • Virus host factor
    • Binds to viral nsP3 protein
  • Disease manifestations related to
    • IL6
    • Replication in skeletal muscle
• Epidemiology
  • Outbreaks in developing world
  • Temperate climates
  • Infected humans: Can seed transmission
• Clinical syndrome
  • Fever
  • Pain
    • Muscle & Joint
    • Severe
  • Skin rash
  • Course
    • Often self-limited
    • May persist for months (30%)
• Neuromuscular associations
  • Guillain-Barré syndrome

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Zika virus ³⁶

• Epidemiology
  • Frequency: 42 French-Polynesian patients reported (2013 to 2014)
  • Season: Summer
  • Geography: Africa; Asia; South America; Mexico
  • Mosquito-borne (Aedes)
  • Other possible transmission: Sexual; Perinatal
  • Some patients with evidence of previous Dengue
• Organism
  • Arbovirus, flavivirus genus
  • Single-stranded RNA
  • Neurotropic
  • Similar viruses: Dengue, Yellow fever, Japanese encephalitis, West Nile & Saint-Louis encephalitis
• Clinical
  • Infection Syndrome
    • Symptomatic in 18%
    • Influenza-like
    • Fever: Low-grade
    • Pain: Arthralgia (Small joints of hands & feet), Myalgia, Headache, retroocular
    • Conjunctivitis: More commoin than with Dengue or Chikungunya
    • Skin: Maculopapular rash; Pruritis
    • GI: Abdominal pain, Diarrhea, Constipation
    • Leukopenia: Rare vs Dengue or Chikungunya
    • Mucous membranes: Ulcerations
    • Polyneuritis
    • Post-infection: Asthenia
    • Course: Self limited; Few deaths
  • Associated disorders
    • Zika: Acute Transient Polyneuritis ³⁸
      • Epidemiology: 3 female patients, age 23 to 39
      • Clinical
        • Onset: 1 to 2 days after Zika virus symptom onset
        • Pain: Distal
        • Hypesthesia: Stocking-Glove distribution
        • Weakness: Distal; Hands & Feet; Mild
        • Tendon reflexes: Present
        • Mental status & Cranial nerves: Normal
        • Time to resolution of symptoms: 7 to 10 days
      • Laboratory
        • Ultrasound: Enlarged median nerves, Normalization with improved symptoms
        • NCV: CMAPs & SNAPs normal; Velocities normal
        • CSF: Normal
    • Zika-related Guillain-Barré-like syndrome: AMAN
      • Epidemiology
        • Male (74%)
        • 0·24 per 1000 Zika virus infections
        • Time from infection to weakness: 4 to 10 days
        • Epidemic outbreak: French Polynesia
      • Clinical
        • Onset age: Mean 46 years; Range 26 to 74 years
        • Weakness
          • Limbs
            • Arms & Legs
            • Symmetric
            • Inability to walk (62%)
          • Respiratory
          • Face (31% to 79%): Asymmetric in some
          • Dysphagia (45%)
          • Progression: Rapid over < 1 week
        • Tendon reflexes: Reduced
        • Autonomic: Orthostatic hypotension; Tachycardia
        • Paresthesias (83%)
        • Course: Outcome often good
      • Laboratory
        • CSF: High protein (90%), 3x; Few cells (1 to 7)
        • Serum antibody: Asialo-GM1 ganglioside antibody (46%); No anti-GM1
        • NCV: Motor > Sensory neuropathy
          • Long latency: Distal motor; F-wave
          • Conduction block: Occasional
          • CMAP amplitude: Reduced
          • SNAP amplitude: Normal
          • NCV: Usually normal
          • Distal motor latency: May be very prolonged
    • Zika-related Guillain-Barré-like syndrome: Demyelinating ³⁷
      • Epidemiology: Colombia, 68 patients
      • Prodrome: ZIKA infection symptoms
        • Time: Mean 7 days before GBS onset; Range 3 to 10 days
        • Fever 69%
        • Rash 59%
        • Headache 34%
        • Myalgia 34%
        • Conjunctivitis 25%
        • Arthralgia 22%
      • Clinical
        • Limb weakness 97%
        • Ascending paralysis 82%
        • Paresthesias 76%
        • Bilateral facial nerve paresis 50%
        • Bulbar 22%
        • Cranial nerves III, IV & VI 10%
        • Areflexia or Hyporeflexia 94%
        • Sensory deficit 25%
      • Laboratory
        • CSF: Albuminocytologic dissociation
          • Cells: Usually none
          • Protein: Median 116 mg/dl; Range 67 to 171
        • NCV: AIDP 78%; Inexcitable nerves 7%
        • Zika RT-PCR positive in 40% (Usually urine)
        • Any evidence of recent flavivirus infection 86%
    • Pregnant women
      • Children with microcephaly
• Laboratory: Zika infection
  • Diagnosis
    • RT-PCR
    • Serology with sero-neutralization
  • Infectious antibody
    • Zika virus: IgG (69%) or IgM (93%)
    • May also be positive for Dengue
  • Other serum antibody
    • IgG vs GD3 ganglioside: May occur in acute infection without neurologic signs ³⁹

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COVID-19 (SARS-CoV-2) virus ⁴⁰

Clinical   AIN   Focal PN   Muscle Virus

• Virus
  • Type: β-Coronavirus
  • Enveloped, Positive sense, Single-stranded RNA (+ssRNA) virus
  • Mutation rate: Low
  • Infectivity
    • Interaction between viral spike protein & host cell receptor
    • Receptor: Angiotensin converting enzyme 2 (ACE2) on epithelial cell surfaces
    • Cell target: Endothelial
  • 1st Human infection: November 2019
  • Transmission routes: Respiratory droplets; Direct contact
  • Incubation period: Median 4 days
• Clinical
  • Systemic features
    • Fever: "Chills"
    • Pulmonary: Cough; Failure
    • Diarrhea
    • Fatigue
    • Myalgia
    • Renal failure: Severe disease; Later in disease course
  • Prognosis worse
    • Age: Increased
    • Males
    • Concurrent diseases
      • Diabetes
      • Hypertension
      • COPD
      • Renal failure
      • Neoplasm
  • Neurologic features
    • Frequency: 36%; More frequent with more severe disease
    • Onset time: Early in disease course
    • Symptoms: Headache; Dizziness
    • Sensory: Loss of Taste & Smell
      • Timing: Common at disease onset
      • Possible viral target: Sustentacular cells in olfactory epithelium
    • Cerebrovascular diseases
      • Frequency: 1% to 7%; Mean 2%
      • Risk factor: Hypertension
      • Possible viral target: Endothelial cells, Vascular
      • Types: Cerebrovascular disease, primary, vs Embolic
      • Onset age: 3rd to 7th decade
      • Course: Acute
      • May occur with otherwise mild viral infection syndrome
      • Large vessel lesions: May be multifocal
    • CNS
      • Consciousness Impaired: 2% to 14%
      • Few patients: Ataxia; Seizures
    • Skeletal muscle
      • Injury: 5% to 50% frequency
      • Clinical
        • Myalgia
          • Frequency: 30% to 40%
          • Common at onset
          • May appear or persist for months after infection (5%)
        • Dyspnea
      • Muscle pathology (Autopsy; 49% with diabetes) ⁴⁸
        • Type 2 fiber atrophy
        • Muscle fiber necrosis (20%)
        • Inflammatory cell foci (20%)
        • MHC1 upregulation by some muscle fibers (45%): May be perifascicular or diffuse
        • Capillary MxA (25%)
        • SARS-CoV-2: No staining
      • Serum CK: Normal or High
    • Inflammatory neuropathy
      • Nerve pathology: Epineurial perivascular inflammation
    • Acute immune neuropathy (GBS) in COVID-19 infected patients
      • Epidemiology: Frequency varied
        • UK: Covid-19 not associated with increased GBS incidence ³⁴
        • Spain: Covid-19 is associated with increased GBS incidence (0.15%; OR 6.3) ³⁶
        • Italy: 0.42% (5 of 1,200) ⁴¹
      • Syndromes reported
        • General Clinical
          • Onset time: 5 to 14 days after COVID-19 symptom onset
          • Weakness (80%): Legs & Arms; Often severe
          • Tendon reflexes: Reduced
          • Paresthesias (100%)
          • Olfactory-gustatory disorders
        • General Laboratory
          • CSF: Protein & Cells Normal; SARS-CoV-2 PCR negative
          • MRI: Root or nerve enhancement (60%), or normal
          • Ganglioside antibodies: Negative
          • NCV: Axonal variant (60%); Demyelinating (40%)
        • Demyelinating GBS
        • Axonal variants: AMSAN
        • Miller-Fisher & Cranial nerve syndromes ⁴²
          • VII paresis + Ataxia
          • Polyneuritis cranialis
    • Focal neuropathies ⁴⁴
      • Common location: Upper extremity
      • Association: Prone positioning (90%)
      • Injury type: Axonotmesis (Axon loss with nerve remaining in continuity)
      • Nerves
        • VII ⁴⁹
        • Ulnar (Elbow)
        • Radial (Upper arm)
        • Brachial plexus: Upper or Lower trunk
        • Sciatic
        • Median (Upper arm)
        • Phrenic: Post-pneumonia
      • Prevention
        • Protect: Shoulder; Upper arm; Elbow
        • Arm positioning: Alongside body; Frequent movement
      • Prognosis: Improvement in most
  • External links
    • Guidance for management of concurrent NMJ disorders
• Laboratory
  • WBC
    • Lymphocytes: Low in 83%
    • Neutrophils: High
  • Serum CK
    • High in 30%: Range = Normal to 12,000
    • Association: Increased disease severity & mortality ⁴⁶
  • C-reactive protein: High
  • D-dimer: High
  • Liver enzymes: High
  • Lung CT: Groundglass opacity appearance
  • Renal disorders
  • COVID-19 diagnosis: Nucleic acid testing
  • No evidence of direct infection of nervous system by virus

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Epstein-Barr Virus (EBV)

Virus features

• Herpesvirus family
• Doublestranded deoxyribonucleic acid (DNA) virus
• Infects B lymphocytes
• Uses envelope glycoproteins to attach & enter host cells
• Human infection: 90%

Inflammatory myopathy ⁶¹

• General
  • Occurs as multisystem syndrome
  • During active disease
• Clinical
  • Onset age: Mean 29 years
  • Muscle involvement
    • Generalized
    • Fatigue
    • Myalgias
  • Systemic
    • Limbs: Swelling
    • Fever (82%)
    • Splenomegaly (82%)
    • Hemophagocytic lymphohistiocytosis (55%)
    • Skin rash (18%)
• Laboratory
  • Muscle pathology
    • Inflammation: Lymphocytes with NK cells; Endomysial (82%) & Perimysial (91%); Angiocentric
  • Plasma: EBV DNA
  • Skin: Epstein-Barr virus-encoded RNA in situ hybridization
  • Serum CK: Mildly, transiently high
  • Myositis antibodies: Few patients

Other EBV Associations

• Acute Immune Neuropathies (GBS): Prodrome ⁵⁹
• Rhabdomyolysis ⁶⁰
• Lymphomatoid granulomatosis
• Nasopharyngeal carcinoma
• BACM

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Cryptococcus 52

• Basidiomycetus yeast
• Epidemiology, General
  • Infection
    • Frequency
      • Several 100,000 infections/year
      • 80% of children in urban environments: Usually no clinical features
    • Sources: Avian guano; Rotting vegitation; Soil
    • Often via respiratory tract
    • Many species can be infected
    • Common outcome of infection: Asymptomatic latent state
  • Predator: Amoeba
• Organism types
  • Neoformans
    • Most in Europe (serotype D; var neoformans)
    • Immunocompromised host
  • Gatti
    • Australia, Papua New Guinea, parts of USA & Canada
    • Immunocompetent host
    • Serotypes B & C
• Properties
  • Yeast size: 4 to 6 μM
  • Facultative intracellular pathogen: Within phagocytes & ? endothelial cells
  • Phagocytes may play role in cryptococcus dissemination
• Cryptococcal sub-structures
  • Cell (Plasma) membrane
  • Cell wall
    • Contains: Melanin; Chitin
  • Capsule
    • Size: 0 to 30 μM thick
    • Composition: 2 types of polysaccharide chains
      • Synthesized intracellularly
      • Translocated to surface in vesicles
      • Glucuronoxylomannan (GXM)
        • 90% of polysaccharides
        • T-cell & Immunomodulatory effects
      • Galactoxylomannan (GXM-Gal)
        • 5% to 8% of polysaccharides
        • Activation: TLRs; NF-κB; NO production
        • Antioxidant
        • Inhibition: NETs production in neutrophils
      • General carbohydrate chain functions
        • Stimulation: IL10 production
        • Inhibition: TNF-α; Phagocytosis;
            Macrophage attachment; Lymphocyte proliferation
      • Vesicles
        • Transport capsule components
        • Virulence
  • Other virulence factor: Laccase
    • Required for synthesis of melanin

  Clinical Predisposition Immunocompromise HIV (CD4 < 100) Solid organ transplant Calcineurin inhibitors Anti-GM-CSF antibodies Cirrhosis & Renal disease Diabetes, type 2 Common involvement Pulmonary Lung mass Nodules Diffuse infection Brain 53 Meningitis Mass Muscle: Pyomyositis+ Treatment Induction: Amphotericin B; Flucytosine Consolidation: Fluconazole Anti-malarials Laboratory Stain for organism: Grocott Methenamine Silver 51 Muscle pathology Muscle areas involved: Legs, Paraspinous or Disseminated Within individual muscles: Patchy areas involved Muscle MRI

  Chest CT Cryptococcus, Pulmonary

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Histoplasmosis ⁵⁶

• Histoplasma capsulatum: Dimorphic fungus
• Epidemiology
  • Geography
    • Distributed: Worldwide
    • Most prevalent: Central United States (Mississippi and Ohio River valleys), Caribbean, Central & South America
    • India: Gangetic delta
  • Bird & bat droppings
• Forms
  • Mold (Mycelial) form: Soil temperatures
  • Yeast form: Normal human body temperatures
• Infection
  • Inhaled: Settle in alveoli
  • Ingested by alveolar macrophages
    • Replicate
    • Spread: Regional lymph nodes: Throughout reticuloendothelial system
  • Intracellular mycotic infection of reticuloendothelial system
    • Resides within macrophages
  • Some syndromes: Reactivation of old infection
• Clinical
  • 95% of infections: Subclinical or Benign
  • Symptomatic infection: Immunocompromised host
    • Onset age: Adult
    • Immunomodulating medications: Glucocorticoids
    • HIV
  • Muscle
    • Clinical: Myalgias
    • Pathology
      • Nodular or Pyomyositis: Collections of intracellular organisms in muscle
      • Myofasciitis
      • Histology
        • Morphology: Ovoid, 3–5-μm, yeasts with single, narrow-based buds
        • Gomori-Methenamine-Silver & PAS positive
        • Distribution: Clusters
        • May be associated with necrotizing granulomatous structures
        • External link
    • Systemic patterns
      • Pulmonary
      • Mediastinal
      • Disseminated
  • Diagnosis
    • Active disease: Histoplasma galactomannan antigen tests on urine or serum
    • Molecular confirmation
  • Treatment
    • Itraconazole: Oral
    • Amphotericin B IV: For severe disease

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Candidiasis

• Organism: Candida albicans
  • Yeast
  • Common inhabitant: Oral cavity, GI, Vagina, Penis
  • Syndromes: Mouth (Thrush); Vagina ("Yeast infection")
• Risk factors
  • Neutropenia
  • Broad-spectrum antibiotic use
  • Immunosuppressive drugs
  • Autoimmune polyendocrine syndrome, Type I (APS1; APECED)
  • Sjögren
  • Thymoma
  • Barth syndrome
• Muscle involvement: Usually diffuse
  • Systemic: Tenderness, Fever, Rash
  • Disseminated candidiasis: May produce local muscle mass or abscess
  • Muscle pathology: Abscesses, micro or large; Budding yeast forms & pseudohyphae; Neutrophils
• External reference: StatPearls

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Cysticercosis

• Organism: Cysticercus cellulosae
  • Larval form of pork tapeworm: Taenia solium
  • Endemic: India
  • Affects individuals of low socioeconomic status
    • Poor access to adequate clean water and sanitation
    • Areas that ingest under-cooked meat
  • Taeniasis (infestations by the adult worm): Rarely co-occurs with cysticercosis
  • Infection: Acquired from contaminated food containing ova
  • Ingested ova: Activated by gastric fluid develop into larvae in GI tract
  • Larvae: Penetrate intestinal wall; Disseminate hematogenously
  • Tissue trophism: CNS > Eyes, Muscle, Heart, Peritoneum, Pleura, Subcutaneous
• CNS
  • Frequency: 60% of infections
  • Intracranial lesions
  • Epilepsy
• Muscle invasion
  • Frequency: 5% of cases
  • Encysted
  • Common presentation: Muscle mass
    • Asymmetric
    • Asymptomatic
    • Cyst may contain: Intact larvae
    • May occur as isolated feature or with disseminated infection to CNS
    • Course: Organism death; Cyst degeneration; Calcification
    • Treatment with intact larvae: Surgical removal; Albendazole/praziquantel
  • Some patients
    • Painful local cyst degeneration
    • Histology: Lymphocytes, Eosinophils, Foreign body giant cells
• External reference: StatPearls

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Echinococcosis (Hydatid Cyst) ⁶³

• Organism: Echinococcus granulosus
• General
  • Endemic regions: Tunisia (North Africa) Middle East, South America
  • Presentations
    • Incidentally detected lesion (often calcified) on radiology
    • Mass: Slowly growing
    • Acute onset: Cyst rupture
  • Common locations: Liver; Lungs
  • Cyst contents: "Rock water" fluid
  • Treatment: Surgical excision; Albendazole
  • Outcome: Usually no recurrence
• Muscle
  • Locations: Thigh > Paraspinal, Pelvic (Gluteal), Deltoid, Psoas
  • Frequency: 3% of infections
  • Presentatins: Isolated cyst or with systemic disease

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Also see Infections & Myelopathies
Return to Neuropathy Differential Diagnosis
Return to Neuromuscular home page

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