Infections & NM disease

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INFECTIONS & NEUROMUSCULAR DISORDERS

Botulism Brucellosis Campylobacter jejuni Central European encephalitis Chagas' Cytomegalovirus Diphtheria Erlichiosis: Human Granulocytic Haemophilus influenzae Hepatitis C Herpes Zoster HIV HTLV1 Leprosy	Leptospirosis Lyme disease Polio Pyomyositis Rabies Syphilis Tetanus Tick African Paralysis Trichinosis Tuberculosis West Nile Virus
Myelopathies Myopathy: Inflammatory

LYME DISEASE¹⁵

from CDC

Ixodes dammini

Causative organism
- US: Borrelia burgdorferi
- Europe
  - Borrelia garinii: Associated with common neural involvement
  - Borrelia afzelii
  - B. burgdorferi sensu stricto
- Type of organism: Spirochete
- External link: Pasteur
- 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
  - 10 states extending along the east coast 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
  - Dematogenous dissemiantion
    - Particularly with US strains
    - Often results in a multifocal rash
      - Each focus represents a separate nidus of metastatic infection
    - Other organs may become 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): In 10% to 40% of Borrelia burgdorferi infections
  - Central Nervous System
    - Aseptic meningitis syndrome
    - Encephalomyelitis: Often with focal features & fatigue
      - Spastic paraparesis
      - Bladder dysfunction
  - 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
      - Often bilateral
      - May not involve taste or hyperacusis
      - Full recovery in 85% with treatment
      - Borrelia burgdorferi antigen in CSF
      - May occur early in disease course 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
        Carpal tunnel syndrome
      - Laboratory
        
        CSF: Pleocytosis
        Nerve conduction: Axonal loss
        EMG: Denervation may occur 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 reaction (allodynia) at bony prominences underlying an ACA lesion
        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 myositis²¹
    - 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 remote past
    - False-positive: May occur with
      - Response to microbiologically similar organisms: Relapsing fever; Syphilis
      - Nonspecific B-cell proliferation with systemic inflammation: Bacterial endocarditis; SLE; Vasculitis
      - Western blot: Can verfy US results; European strains with 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

HERPES ZOSTER (Varicella)²

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

Viral properties
- Double-stranded DNA virus
- 1° infection usually in 1st decades
- Establishes latent infection in dorsal root ganglion
- Recurrent disease caused by viral reactivation
- DRG infection confirmed by presence of: Immediate early protein VZV IE62
Disease loci
- Dorsal root ganglion: Especially thoracic & face
- Mucocutaneous
- Occasionally also produces transverse myelitis
- Recurrent activation in same distribution as 1° infection
Epidemiology
- 90 percent of adults in US have serologic evidence of varicella–zoster virus infection
- 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 20%
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 features: Radiculopathy
- Onset: Dermatomal pain; 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: Hyperesthesia or Reduced over affected areas
- 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 syndrome¹⁸
- Epidemiology
  - 12% of unilateral VII nerve palsy
    - 2nd most common cause of non-traumatic VII nerve paralysis
    - More frequent cause ove 6 years of age
  - Onset age: Children & Adults
  - Sex: Male = Female
- Clinical
  - Facial nerve palsy
    - Unilateral
    - Peripheral
    - Severity: May be more severe than Bell's palsy
    - May occcur in absensce 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 severity of VII nerve paralysis
      - Tinnitus
    - Vestibular disorders
      - Vertigo
      - Nausea
      - Nystagmus
  - 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
  - Zoster oticus: Vesicle distribution
    - Hard palate
    - Tongue: Anterior two-thirds
    - Ear: Ipsilateral
  - 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 the geniculate ganglion
  - Diagnosis: PCR of ear scrapings
- Treatment
  - Acyclovir: IV, 5 mg/kg q8h for 7 days; Oral 800 mg 5x/d for 10 days
  - Corticosteroids
Clinical: Other VZV-associated syndromes¹¹
- 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%
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: Systemic¹⁴
  - 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
- ERMM animations: HSV infection; HSV genes & proteins

LEPROSY⁶

Clinical features
Acute
Lepromatous
Tuberculoid
Borderline
Neural
Diagnosis
Epidemiology
Organism
Treatment

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

Causative organism: Mycobacterium leprae
- Organism features
  - Acid fast rod
  - Gram positive
  - Location: Intracellular
- Disease reservoirs
  - Most common: Humans
  - Other: Armadillos; 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
- Frequency of nerve damage in leprosy: 20% to 30%
- Onset age: All; Most common at 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-fold higher risk²²
    - 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
    - LPRS3
      - Chromosome 4q32
      - Toll-like receptors 1 & 2
        
        High expression: Localized disease
        
        Low expression: Disseminated disease
    - 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
    - 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
- Geography
  - 70% of cases in world: India, Indonesia and Myanmar
  - Africa
  - South America: Brazil & Columbia
  - US
    - Endemic foci: Hawaii; Florida; Louisiana & Texas (Near Mexico)
    - Most cases are immigrants (85%)
- Prevalence: Declined over past 50 years due to
  - Shorter treatment regimens
  - Improved nutrition & living conditions
- Incidence world-wide: 500,000 per year
- Most human infection (90%): Develop effective immunity without evidence of disease

Features: General

Clinical
- Early features
  - Due to direct invasion of dermal nerves
  - Pain along nerves: May occur when swollen inflamed nerve is stretched
- Sensory loss progression
  - Temperature affected 1st
  - Then Pain
  - Later: Pressure
- 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
- Early: Evidence of demyelination
  - Distal latencies: Prolonged
  - Conduction velocities
    - Segmental slowing
    - Especially across vulnerable sections: Ulnar nerve at elbow
  - Conduction block: May be found with weakness
- Later: Axonal loss

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
      
      From WHO
      
      Skin lesions
  - 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
  - Nerves affected
    - Sensory
      - Cutaneous: Digital
      - Sural
      - Radial
      - Posterior auricular
    - Motor + Sensory
      - Ulnar
      - Median
      - 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
  
  From: P Bailey
  
  Sensory loss
  - 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
  - Neuropathy
    - Nerve size: Diffusely enlarged nerves
    - Sensory
      - Loss: Distribution
        
        Stocking-glove
        Face (upper & bilateral)
        Ulnar nerves above elbow
        
        From WHO
        
        Enlarged nerves
      - 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
  - 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
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
  - 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
Treatment
- Drugs
  - Paucibacillary disease (2 to 5 skin lesions): WHO regimen
    - Diamino-diphenylsulfone (Dapsone): 100 mg daily
    - Rifampin: 600mg monthly (6 months)
    - Duration: 6 months
  - Paucibacillary (single lesion): WHO regimen
    - Rifampin 600 mg
    - Ofloxacin 400 mg
    - Minocycline 100 mg (ROM)
    - Single dose
  - Paucibacillary (US): Duration 1 year
    - Dapsone 100 mg daily
    - Rifampin 600 mg daily for 12 months
  - Multibacillary (US): Duration 2 years
    - Dapsone 100 mg daily
    - Rifampin 600 mg daily
    - Clofazimine 50 mg daily
  - Other general principles
    - Multibacillary disease add: Clofazimine (B663) 50 mg daily
    - Drug resistance add:
      - Ofloxacin 400 mg daily or
      - Clarithromycin 250 mg bid or
      - Minocycline 100 mg daily
    - Countries with endemic leprosy: Alternative regimen
      - Rifampin 600 mg monthly
      - Ofloxacin 400 mg daily
      - ± Minocycline 100 mg daily
      - Duration: Up to 2 years
  - Contraindications
    - Pregnancy: Clofazimine; Minocycline
    - Children & adolescents: Ofloxacin, relative contraindication
- Duration for disease types
  - Lepromatous: 2 years to life-long; Observe at least 5 years
  - Tuberculoid: At least 6 months; Up to 2 yrs after disease is inactive
- Poor recovery from individual nerve lesions
- 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

HUMAN IMMUNODEFICIENCY VIRUS (HIV)

from CDC

HIV

Muscle
Nerve

General principles

Clinical syndromes occur in specific phases of infection

Early
- ALS-variant syndrome
- Brachial plexopathy
- CIDP
- Guillain-Barré
- Mononeuritis multiplex (Vasculitis)
- Myasthenia gravis
- Neuromyotonia
- Polymyositis
- Nemaline rod myopathy
Advanced

Autonomic neuropathy
Cytomegalovirus
DILS
Mononeuropathies
Sensory motor polyneuropathy
Drug related myopathy
- Zidovudine
- Other
Wasting
Infectious
Carnitine deficiency
Necrotizing myopathy
Adrenal insufficiency

Neuropathy frequency
- Clinical: 10% to 35%
- Pathology: 95% of patients dying of AIDS

HIV & Neuropathies

ALS-variant syndrome
Autonomic
Brachial plexopathy
CIDP
Cytomegalovirus
DILS
Drug-induced
Guillain-Barré
Mononeuritis multiplex
Mononeuropathies
Neuromyotonia
Sensory motor polyneuropathy
VII nerve palsy

Guillain-Barré
- Disease phases
  - Seronegative (Near time of infection)
  - Seropositive (Asymptomatic)
- 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
- Disease phase: ARC & AIDS
- Herpes Zoster
- VII nerve palsy²⁴
  - Disease phase: Often at sero-conversion
  - Unilateral or Bilateral
  - 4.1% to 7.2% incidence in general HIV population
  - HIV in facial paresis in Burkina Faso & Central African Republic: 64% to 100%
  - CSF: Pleocytosis; High protein
  - Course: Often self remitting
Sensory > Motor neuropathy
- Disease phase: AIDS
- Epidemiology
  - Frequency: 35% of patients with AIDS
  - Risk factors
    - Degree of HIV-induced immunosuppression¹³
    - Viral load: Increased frequency with higher viral load
    - May develop in patients with undetectable viral loads after treatment
- Onset
  - Symptoms: Pain & Dysesthesias
  - Distribution: Especially in feet
- Clinical features
  - Sensory loss: Pansensory, sparing 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
- Pathology
  - Axonal loss: Distal
  - ± demyelination
- Rule out
  - Thiamine deficiency
  - Nucleoside drug toxicity
ALS-variant syndromes¹²
- Frequency: Rare; 3/1,000
- Onset age: Mean 34 years; Range 22 to 61 years
- Disease associations
  - Phase: Seropositive; May be presenting syndrome of HIV infection
  - High viral load
  - CD4 counts reduced
- Clinical syndrome
  - Weakness: Variable patterns
    - Monomelic; Distal
    - Diffuse
    - Proximal > Distal
    - Progression: Over weeks
    - Bulbar: Some patients
  - Upper motor neuron signs
    - Tendon reflexes: Brisk
    - Plantar response: Extensor
  - Sensory: Normal
- Laboratory
  - CSF: Protein very high (130 to 1340); Cells 1 to 13
  - EMG: Denervation
  - NCV: Normal conduction velocities; CMAP amplitudes may be normal
  - MRI: Usually non-diagnostic; Some with other CNS disease
- Survival: 3 months to > 3 years
- Treatment
  - Protease inhibitors (AZT +...)
  - Course: Partial or Complete remission
Diffuse infiltrative lymphocytosis syndrome (DILS): Sensory-Motor neuropathy
- Disease associations
  - Phase: Seropositive; Asymptomatic
  - Severity: Fewer opportunisitic infections & longer survival
  - CD8 lymphocytosis
- 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)
- CSF
  - Protein: High
  - Cells: Common
- Pathology
  - CD8-cell infiltration around epi- & endoneurial vessels (Polyclonal)
  - Loss of myelinated fibers: Diffuse, not focal
  - High proviral load in nerve; Not a lymphoma
- 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: CD4 count > 200
  - Monophasic predominantly sensory + CNS in 50%
  - Indolent course
  - May improve without immunosuppressive treatment
  - Pathology: Often salivary gland biopsy
    - Necrotizing vasculitis in epineurium & muscle
    - Mononuclear infilteate
  - 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; but 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%
    - d4T: 15% to 55%
    - Lamivudine (3TC)
  - Dose dependent
  - Pure sensory; Painful
  - Legs > Arms
  - More common with: Pretreatment neuropathy; Later stage disease
  - Axonal loss
- Also see: Nucleoside-associated lactic acidosis
- Other: Vincristine; Isoniazid; Dapsone; Thalidomide
Other syndromes
Neuromuscular syndromes occurring after treatment of AIDS
- Inflammatory myopathy
- Vasculitis: May be severe

HIV & Myopathies

Early HIV
Polymyositis
Nemaline rod
Advanced HIV
Drug related
Zidovudine
Other
Wasting
Infectious
Carnitine deficiency
Necrotizing
Adrenal insufficiency

Early onset: Seropositive
- Polymyositis
  - Syndrome similar to polymyositis in non-HIV patients
    - 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
- Nemaline rod myopathy
  - Clinical
    - Onset: Adult
    - Weakness: Proximal
    - Painless
  - Laboratory
    - Serum CK: High or Normal
    - Muscle pathology
      - Rods in type I muscle fibers
      - Muscle fiber necrosis
      - ± inflammation
    - Treatment: Possible improvement iwth corticosteroids
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
- Necrotizing myopathy
  - Proximal weakness
  - 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)
    - Toxoplasma
- Carnitine deficiency
  - ? Myopathy
  - Risk factors: Especially zidovudine; ? Malnutrition or Malabsorption
  - Muscle pathology: Lipid storage ± Mitochondrial change
- Adrenal insufficiency
- Chronic fatigue
Nucleoside-associated lactic acidosis¹⁹
- 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

Epidemiology: Endemic in Latin America
Causative organism: Trypanosoma cruzi
Tranamission
- Endemic areas: Vector; Feces of Triatoma infestans
- Non-endemic areas: Blood transfusion
Acute infection
- Lymph nodes: Local enlargement; inflammation
- Monophasic in most patients
- Many patients then remain asymptomatic
- Treatment: Nifurtimox; Benznidazole
Chronic disease: Neurological involvment
- Autonomic neuropathy
  - Cardiovascular: Vagal & Sympathetic dysfunction
    - Orthostatic hypotension
    - Bradycardia: Resting
    - Cardiac: Conduction abnormalities; Arrhythmias; Cardiomegaly; Failure
  - Gastrointestinal: Reduced bowel motility
    - Dysphagia
    - Sialorrhea
    - Constipation
    - Megaesophagus
    - Megacolon
- Pathology
  - Inflammatory lesions in muscle, nerve & autonomic ganglia
  - Denervation of intrinsic enteric neurons of submucosal (Meissner) & myenteric (Auerbach) plexuses

SYPHILIS: Tabes dorsalis

from CDC

Treponema pallidum

Joseph Grünpeck, Tractatus de pestilentiali scorra, 1496

Organism: Treponema pallidum
Onset
- 10 to 30 years after initial, often untreated, infection
- May occur in adults or children (Congenital infection)
Clinical features
- Lightning pains: Especially lower extremity & abdomen
- Sensory
  - Joint position & Vibration sense: Reduced
  - Hitzig zones
    - Regions of reduced sensation
    - Locations: Central face; Nipples; Ulnar forearms; Peroneal legs
  - Analgesia: Leads to painless ulcers & Joint damage (Charcot's joints)
- Hyporeflexia
- Pupil disorder: Argyll Robertson pupils
  - Irregular
  - Light: Poor contraction
  - Accomodation: Good contraction
- Autonomic: Impotence; blader dysfunction
- Optic atrophy
- Systemic: Aortitis
- Charcot's joints (Neurogenic osteoarthropathy)
  
  From Bramwell: Diseases of the Spinal Cord
  
  Tabes dorsalis:
  Pallor of posterior columns
  - Onset: Middle aged male
  - Location: Knee ± Other leg joints
  - Fractures common
Serum
- Syphilis: MHA-TP positive; VDRL may be normal
- Also test for HIV
CSF
- Early & Active disease
  - Cells: 10 to 200/μl
  - Protein: ~100 mg/dl
  - IgG: High
- Late: May be normal
Pathology
- Fibrosis & Inflammation
  - Posterior roots & meninges
  - Especially lumbosacral
- Sensory ganglia: Degeneration of neurons
- Posterior columns of spinal cord: Axonal loss
Treatment: Penicillin for active neurosyphilis
External link: Univ Wisconsin-Madison

"Thickening of spinal arachnoid": R Bright 1831

HUMAN GRANULOCYTIC ERLICHIOSIS¹

Causative organism: Erlichia equi
Clinical features: Brachial plexopathy

LEPTOSPIROSIS (Weil's disease)

Causative organisms: Leptospira icterohaemorrhagiae (Rats), pomona (Swine), canicola (Cattle & Dogs)
- Disease phases: Biphasic
  - 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
Epidemiology
- Associations with animals: Farming, Abattoirs, Sewers, Camping & Fishing, Pet dogs
- Human infection: Contact with animal urine
- Temporal: More frequent in summer & early fall
- Male predominance 3:1
- Age: 70% in 10 and 40 years
- Geography: US 50% in Hawaii
- Mortality: Higher in oldest age group; Lowest in children.
Diagnosis: DOT ELISA; PCR
Treatment: ? Anti-microbial, doxycycline or penicillin
Polyneuropathy: Clinical features
- Course: Acute; Occurs in secondary phase of infection
- Sensory-Motor
- Distribution: Lower > Upper extremities; Symmetric
- Axonal loss
- Nerve pathology: Inflammation or hemorrrhage

BRUCELLOSIS

Species: Brucella abortus (cattle), melitensis (sheep & goats), suis (pigs)
Epidemiology
- Most cases in California, Florida, Texas, & Virginia
- Transmitted by:
  - Contact with infected animals, carcassses, or milk
  - Accidental innoculation with live attenuated vaccine
- Risk Groups: Abattoir workers, meat inspectors, animal handlers, veterinarians, and laboratorians.
Clinical syndrome
- Weakness & fatigue
- General
  - Chills, Sweats, Anorexia
  - Aching: Generalized & Headache
  - Fever
- Systemic
  - Enlarged liver (Granulomatous hepatitis), spleen, lymph nodes; Endocarditis
  - Prepatellar bursitis
  - Hematologic: Anemia; Thrombocytopenia; Leukopenia
  - Eye: Uveitis
- CNS: Optic neuritis; Meningitis
Neuropathies: In chronic disease
- VII palsy
- Lumbar radiculopathies & spondylitis
- Acute polyradiculoneuropathy
Treatment
- Rifampicin: 6 months
- Doxycycline: 6 months
- Streptomysin: 3 months

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

From CDC

WEST NILE VIRUS⁷ *

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
- 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
  - US virus distribution: Northeast, South, Midwest, California; Rapid spread
  - Human disease with infection most commonly reported in US & Israel
- Seasonal disease in North America: Especially late summer; Range July to December
- 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%
General clinical features
- Usual infection
  - Asymptomatic in most
  - 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% of symptomatic infections
- May be severe with respiratory failure (10%)
- Reported syndromes
  - West Nile poliomyelitis¹⁶
    - 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; May be in single limb
        
        Face (50%)
        Course
        
        Variable
        Often persists after encephalopthy improves
        
        Prolonged disability: Some weakness may be permanent
      - Sensory involvement: Little or none
      - Tendon reflexes: Increased or Decreased (32%)
    - Laboratory
      - MRI: Enhancement of cauda equina or ventral horn
      - CSF
        
        Pleocytosis
        
        Protein: High
        
        Glucose: Normal
      - CNS Pathology
        
        Motor neuron loss
        
        Gliosis
        
        Perivascular lymphocytes (CD3+)
      - EMG: Denervation
        
        Asymmetric
        
        Present after 2 to 3 weeks
      - NCV
        
        CMAPs: Small after 2 weeks
        Conduction velocity: Normal when corrected for amplitude of CMAP
        
        Some patients with prolonged F-waves or distal latencies
      - Muscle pathology
        
        Scattered necrotic muscle fibers
        
        Perivascular inflammation
    - Flavivirus differential diagnosis: Several may produce motor neuron syndromes
      - St Louis encephalitis
      - Japanese encephalitis
      - Murray Valley encephalitis
      - Russian Spring-Summer: Cervical cord motor neuron involvement; Head drop
  - 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
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: May be normal early; Neutrophils early
  - 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

CENTRAL EUROPEAN ENCEPHALITIS⁸

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
- 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

MRI: Leg

PYOMYOSITIS⁹

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
- Burn patients
- Diabetes mellitus
- Liver disease, alcoholic
Epidemiology
- Geography: Tropical regions more common
- Ages: Several peaks
  - 2 to 5 years: Associated with malnutrition
  - 35 to 40 years: Commonly (50%) have underlying disease or immunosuppression
  - Temperate climates: Adolescents & Young adults
  - Range: 0 to 85 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, Some anaerobic bacteria
Disease evolution & General features
- Onset
  - ? Transient bacteremia
  - Lesions more likely to develop in injured muscle
- Stages in disease syndrome
  - Onset: Progression over days
    - Adults: 5 to 6 days
    - Children: More acute
    - Immunosuppression: Over weeks
  - Early
    - Pain: Dull, cramping, progressive pain associated
    - Low-grade fever
    - General malaise: Muscle ache
    - Signs of local inflammaton may be absent
    - Muscle pathology
      - Diffuse induration
      - Enlarged muscle
  - Muscle abscess formation
    - Local signs: Tender soft tissue mass (firm & woody)
    - Systemic signs: Fever
    - Muscle pathology
      - Suppurative
      - Localized with drainable pus
  - Late
    - 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; Gluteal; Psoas
  - Other: Calf, Arm, Scapula, Chest wall, Neck
- Laboratory
  - CBC: Leukocytosis
  - Serum CK: Normal
  - X-ray: Normal muscle; Used to rule out bone lesions
  - MRI: Diagnostic test of choice
    - Hyperintense lesions on T2
    - Ring lesions with gadolinium
- Treatment
  - Appropriate antibiotics
  - Abscess drainage
Clinical syndromes: Specific infections
- Staphylococcus aureus
- Streptococcal pyomyositis variant
  - Rapidly progressive
  - Intense pain
  - High Fever
  - Diffuse muscle swelling & necrosis: May not develop abscesses
- Tuberculosis
  - Especially untreated disease
  - Common muscles: Psoas & Quadriceps
  - Associated with spread from bone or lymph nodes
- Actinomycosis
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

RABIES¹⁰

CDC
Rabies virus

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

TUBERCULOSIS¹⁷

Inflamatory myopathy

Frequency: 2% of tuberculosis infections in endemic areas
Routes of infection
- Contiguous spread (63%): Lesions in bone or contiguous soft tissues; Chest wall & paraspinous muscles
- Hematogenous (29%): Thigh, Pelvis & Arm muscles
- Traumatic innoculation (9%): Via contaminated instruments; Thigh muscles
Onset
- Age: 1 to 86 years
- Local lesion with damage to bone & soft tissue
Clinical
- 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
    - Swelling & edema of involved muscles
    - Multiple muscles involved in 50%
    - No venous thrombosis or cellulitis surrounding affected muscles: Differs from pyomyositis
  - Other
    - Bone destruction: Spine with vertebral damage but preservation of intervertebral disk
    - Mediastinal changes: Lymphadenopathy with low central density
    - Chest X-ray: Abnormal in 50%
- Serum CK
  - Usually normal
  - High in occasional patient with multiple muscles involved (Hematogenous spread)
- Muscle histology
  - Granulomatous reaction: Histiocytes, Lymphocytes, Giant cells, Necrosis
Treatment
- Anti-tuberculous therapy
- Surgery: Debridement; Drainage

AFRICAN TICK BITE FEVER²⁰

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

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

References

1. Neurology 1996;46:1026-1029
2. NEJM 1996;335:32-42, 2002;347:340-346
3. NEJM 1999;340:300-306
4. Acta Neurologica Scandinavica 2000;101:47-52
5. Medicine 2000;79:47-56, The Neurologist 2008;14:151–156
6. Lancet 1999;353:655-660, Muscle Nerve 2004;30:393–409, Clin Dermatol 2007;25:165-172
7. Neurology 2000;55:144-146, Clin Infect Dis 2000;30:413-418, NEJM 2001;344:1807-1814, Ann Int Med 2002;137:173-179, Lancet Neurol 2007;6:171-181
8. Neurology 2000;55:299-302
9. Am J Med 2000;109:422-425, J Bone Joint Surg 2002;84:2277-2286
10. Curr Opin Neurol 1997;10:260-267, Lancet Neurology 2002;June
11. Neurology 2001;57:351-354
12. Neurology 2001;57:1094-1097, 2001;57:995-1001
13. Neurology 2002;58:1764–1768
14. Neurology 2002;59:1015–1021
15. Muscle Nerve 2003; Online March
16. Ann Neurology 2003;53:703-710
17. Rheumatology 2003;42:836–840, QJM 2007;100:59
18. JNNP 2001;71:149-54, Otolaryngol Head Neck Surg 2003;129:379-381
19. Clinical Infectious Diseases 2002;34:838–846
20. Scandinavian Journal of Infectious Diseases 2006;38:114-118
21. Arthritis Rheumatism 2006;54:2697-2700
22. Clin Vaccine Immunol 2007 Nov 7
23. Journal Neuroimmunol 2007;190:131–138
24. Laryngoscope 2008 Jan 14
25. Neurotherapeutics 2009;6:630-637

10/24/2009

INFECTIONS & NEUROMUSCULAR DISORDERS

LYME DISEASE15

HERPES ZOSTER (Varicella)2

LEPROSY6

HUMAN IMMUNODEFICIENCY VIRUS (HIV)

CHAGAS' DISEASE

SYPHILIS: Tabes dorsalis

HUMAN GRANULOCYTIC ERLICHIOSIS1

LEPTOSPIROSIS (Weil's disease)

BRUCELLOSIS

HEPATITIS C3,5

WEST NILE VIRUS7*

CENTRAL EUROPEAN ENCEPHALITIS8

PYOMYOSITIS9

RABIES10

TUBERCULOSIS17

AFRICAN TICK BITE FEVER20

LYME DISEASE¹⁵

HERPES ZOSTER (Varicella)²

LEPROSY⁶

HUMAN GRANULOCYTIC ERLICHIOSIS¹

HEPATITIS C^3,5

WEST NILE VIRUS⁷ *

CENTRAL EUROPEAN ENCEPHALITIS⁸

PYOMYOSITIS⁹

RABIES¹⁰

TUBERCULOSIS¹⁷

AFRICAN TICK BITE FEVER²⁰