infectious diseases: smh general consult service
TRANSCRIPT
Infectious Myelopathies Raymund R. Razonable, MD, FIDSA, FAST
Professor of Medicine Division of Infectious Diseases
Mayo Clinic College of Medicine and Science Rochester, MN, USA 55905
Overview
• To review the epidemiology and the clinical course of selected infections of the spinal cord
• To discuss methods for diagnosis of selected infectious myelopathy
• To understand treatment options of selected infections of the spinal cord
• To appreciate the prognosis of infectious myelopathy
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In 2014, a cluster of cases of acute limb weakness among children was identified in Colorado MRI had abnormalities of the spinal cord gray matter Most had respiratory or febrile illness before the onset of neurologic symptoms
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What is the causative agent?
A. Treponema pallidum B. Coxsackie virus C. Enterovirus D. Cryptococcus gattii E. I do not know
Trepon
ema p
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m
Coxsa
ckie
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Entero
virus
Crypto
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ii
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ow
0% 0% 0%0%0%
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CDC Case Definition: Acute Flaccid Myelitis A person with onset of acute focal limb weakness, AND MRI showing a spinal cord lesion restricted to gray matter, and spanning one or more spinal segments, OR CSF with pleiocytosis (WBC >5 cells/mm3); CSF protein may or may not be elevated Current investigation: the etiologic agent remains unclear
Could this be due to Enterovirus D68? • Acute flaccid paralysis during an outbreak of enterovirus D68
respiratory illness (pharyngitis, pneumonia, respiratory failure) • Mostly children (median age, 7 years; range: 5m-73y)
• Direct causation not established; clustering supports an association • CSF: only one positive for EV-D68 (negative for other viruses) • Nasopharyngeal swabs: positive for EV-D68 in almost half • Search for etiology is ongoing…..
• Diagnostics:
• MRI: confluent longitudinally extensive T2 hyper-intensity of the cord gray matter, most commonly affecting cervical regions
• Treatment: IVIg, corticosteroids, and plasma exchange
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Many pathogens has been associated with disease of the spinal cord
Class Specific Pathogens (selected)
Bacteria Staphylococcus aureus, Treponema pallidum, Mycobacterium tuberculosis, Mycoplasma sp., Borrelia burdorferri
Viruses Enteroviruses (polio and non-polio viruses [Coxsackievirus, EV-71, EV-68]), flaviviruses (WNV, Zika virus), HIV, HTLV1/II, rabies virus, herpesviruses (HSV 1 and 2, VZV, CMV, EBV, HHV-6)
Parasites Schistosoma haematobium, S. mansoni, Gnathostoma spinigerum, Taenia solium
Fungi Cryptococcus neoformans, Coccidiodes species
Infectious Myelopathy: General Principles • Epidemiologic factors: environmental exposures, travel
history, area of residence, seasonal variation
• Patient characteristics: age, immunologic status, illness and comorbidity
• Clinical presentation: acute, subacute or chronic
• Acute onset: enteroviruses, West Nile, herpes viruses • Subacute onset: transverse myelitis • Chronic: HIV, HTLV-1, syphilis, tuberculosis
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General Principles: Diagnostics • Laboratory profile
• Pathogen-directed testing (serology, molecular methods such as nucleic acid testing, culture)
• Advances in molecular techniques (sequencing) • CSF analysis
• Cell count and differentials, biochemical studies, pathogen testing (conventional/novel methods)
• Radiologic features • MRI is gold standard (centromedullary, extramedullary;
lateral column, dorsal column; mass effect)
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General Principles: Treatment
• Supportive care
• Antimicrobial therapy, if proven and available
• Concomitant steroids and other immunomodulatory treatments, in some cases
• IV immunoglobulin (IVIG), in some cases
• Neurosurgical intervention, in certain settings
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Infectious Myelopathy: Major Mechanisms
• Direct neuronal invasion: direct infection of neural structures
• Para-infectious mechanism: presumed autoimmune pathogenesis
• Compressive myelopathy: involvement of structures adjoining the spinal cord
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Spinal Epidural Abscess • Mechanism: contiguous spread from infection of skin and soft
tissue, complication of spinal surgery and invasive procedures, including indwelling epidural catheters; remote site (bloodstream)
• Pathophysiology: damage to spinal cord - direct compression of neural elements or arterial supply, thrombosis, vasculitis, and inflammation
• Clinical presentation: classic clinical triad of fever, spinal pain, and neurologic deficits
• Risk factors: diabetes, alcoholism, HIV infection • Radiograph: MRI is preferred test; highly sensitive • Diagnosis: cultures of blood and/or aspirate of abscess • Microbiology: Staphylococcus aureus (2/3 of cases), others • Management: surgical decompression/drainage with systemic
targeted antibiotic therapy
Darouiche R. New Eng J Medicine 2006;355;2012
Tuberculosis of the Spinal Cord
Tuberculosis can produce a myelopathy by different mechanisms. 1. Cord compression – tuberculosis of the vertebral body leads to
spondylitis or Pott's disease secondary cord compression. Clinical presentation: back pain over the affected vertebra, low grade fever, weight loss compressive myelopathy
2. Tuberculoma within intramedullary, intradural, extradural space 3. Spinal abscess 4. Arachnoiditis 5. Myelitis
Tuberculosis of the Spinal Cord • Clinical features: insidious onset, accompanied by symptoms of
pulmonary or disseminated TB • Epidemiology, exposures and risk factors
• MRI: extramedullary pattern for spinal cord TB infection • CSF: lymphocytic pleocytosis, hypoglycorrhachia, protein elevation • Laboratory profile: Mycobacterial culture is gold standard
• QuantiFERON-TB to screen prior exposure • TB PCR provides rapid assessment • Search for other focus of infection (CXR, CT chest) • Search for the “exposed” contacts • Antimicrobial susceptibility testing; resistance gene markers
Tuberculosis of the Spinal Cord • Treatment
• Assess for resistance (also epidemiology/exposure) • If susceptible
• Four-drug regimen (INH, RIF, PZA, EMB) for 2 months then two-drug regimen (INH, RIF) for min 7-10 months
• Corticosteroid use? Indicated for TB meningitis
• May be used in TB myelitis • IRIS: paradoxical worsening in symptoms
• Not due to drug resistance • Often seen in HIV-infected individuals (started on CART) or
transplant recipients (reduction in immunosuppression)
• Surgery, if neurologic decline (Pott’s disease, abscess, others)
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Syphilitic Myelopathy
Chilver-Stanier L et al. Neurology. 2009;72(7):673.
• Clinical manifestations: subacute progressive myelopathy • Sensory ataxia, lancinating pains (due to dorsal column and
dorsal nerve root involvement) • MRI: tract-specific pattern on MRI consisting of non-enhancing
longitudinally extensive T2-hyperintense signal changes in the dorsal columns, often with cord atrophy (tabes dorsalis)
• CSF: normal, or elevated protein, lymphocytosis
• Reactive VDRL or treponemal-specific antibody test • Treatment: IV penicillin G (24 million units) for 10-14 days
• Alternatives: Procaine Pen 2.4 mil units IM daily plus probenecid (500 mg PO qid) for 10-14d • Ceftriaxone 2g IV once daily for 10-14 days
Lyme Myelopathy • Borrelia burgdoreferri – most common tickborne illness (US)
• Rarely affects the spinal cord • Myelitis is much less frequently seen than radiculitis and
neuropathies
• Clinical features: acute or subacute presentation early in the course of Lyme disease.
• MRI: centromedullary pattern; may be normal. • MRI features that resemble acute transverse myelitis
have been reported.
Mantienne C, Albucher JF, Catalaa I, Sévely A, Cognard C, Manelfe C Neuroradiology. 2001;43(6):485 Meurs L, Labeye D, Declercq I, Piéret F, Gille M. Eur Neurology 2004;52:186
What is the recommended treatment?
A. Doxycycline B. Ceftriaxone C. Penicillin VK D. Amoxicillin E. Any of the above
Doxyc
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Lyme Myelopathy • Diagnosis:
• Serum and CSF Lyme antibody titers: calculate CSF index to confirm intrathecal antibody production (and not passive transfer)
• CSF: lymphocytic pleocytosis, elevated protein, normal glucose
• Treatment: IV ceftriaxone (IV penicillin G and cefotaxime
as alternatives) for 14-28 day course • Doxycycline has excellent CNS penetration
Mantienne C, Albucher JF, Catalaa I, Sévely A, Cognard C, Manelfe C Neuroradiology. 2001;43(6):485 Meurs L, Labeye D, Declercq I, Piéret F, Gille M. Eur Neurology 2004;52:186
.
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Treatment of Selected Bacterial Myelopathies (summary)
Pathogen Recommended Regimen
Pyogenic Empiric antibiotics: third- or fourth-generation cephalosporin, plus vancomycin; specific antibiotics dictated by culture/susceptibility results
Mycobacterium tuberculosis
Four-drug regimen (rifampin, isoniazid, pyrazinamide, ethambutol) for 2 months, two-drug regimen (isoniazid, rifampin) for 7–10 months minimum; plus steroids
Borrelia species IV ceftriaxone (2 g/d) or IV penicillin G (18–24 million units IV daily divided over every 4 hours) or IV cefotaxime (2 g every 8 hours) for 14–28 days Doxycycline is an alternative
Treponema pallidum
IV penicillin G (18–24 million units daily) for 10–14 days; with or without steroids
Brucella species IV ceftriaxone 2 g/d IV plus rifampin 600-mg orally once daily and doxycycline 100 mg orally twice daily; consider adjunctive steroids
Mycoplasma pneumoniae
Doxycycline 100 mg orally twice daily for 10–14 days (macrolides and quinolones are alternatives); plus adjunctive steroids; consider additional immunotherapy
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Many pathogens has been associated with disease of the spinal cord
Class Specific Pathogens (selected)
Bacteria Staphylococcus aureus, Treponema pallidum, Mycobacterium tuberculosis, Mycoplasma sp., Borrelia burdorferri
Viruses Enteroviruses (polio and non-polio viruses [Coxsackievirus, EV-71, EV-68]), flaviviruses (WNV, Zika virus), HIV, HTLV1/II, rabies virus, herpesviruses (HSV 1 and 2, VZV, CMV, EBV, HHV-6)
Parasites Schistosoma haematobium, S. mansoni, Gnathostoma spinigerum, Taenia solium
Fungi Cryptococcus neoformans, Coccidiodes species
Acute Viral Myelopathy
Two distinct syndromes of spinal cord involvement 1. Acute lower motor neuron disease: involvement of gray matter Enteroviruses: poliovirus, coxsackievirus, enterovirus 71 Flaviviruses: West Nile virus, Japanese encephalitis virus
2. Transverse myelitis Herpesviruses: CMV, VZV, HSV, EBV
Acute Flaccid Myelitis • Enteroviruses are most common causes
• Polio viruses 1, 2 and 3; Coxsackie virus types A and B; Enterovirus 71; Echovirus
• Pathology: predilection to affect the anterior horn cells • Clinical presentation: lower motor neuron weakness, characterized
by flaccid paralysis, fasciculation, areflexia • Sensory and sphincter function often spared.
• MRI: abnormal signal within ventral nerve roots (uni or bilateral) • CSF: neutrophilic lymphocytic pleiocytosis; protein elevation • Diagnosis: enterovirus NAT in CSF; serology (acute, convalescent);
enterovirus culture of stool/NP swab/other samples
• Treatment: supportive care, IVIG may be used in severe cases • No proven antiviral drug effective for enteroviruses
Acute Poliomyelitis • Prototype viral myelitis • Clinical presentation: acute flaccid paralysis due to polio virus
infection of the anterior horn cells • acute to subacute asymmetric weakness • lower extremities > upper extremities • bulbar involvement and autonomic dysfunction may occur • myalgia and muscle spasm • muscle atrophy after several weeks
• Diagnostics: • Serology: CSF IgM for poliovirus; stool culture • MRI: cord signal changes within the ventral horns
• Treatment: supportive • Prognosis: post-polio syndrome - progressive weakness, atrophy,
pain, and fatigue decades after poliovirus infection
• Prevention: worldwide polio eradication program
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What is the treatment of enterovirus myelopathy?
A. Interferon B. Ribavirin C. IVIG D. Prednisone E. Call Infectious
Diseases
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Acute Viral Myelopathy due to Enterovirus 71 • Hand-foot-and-mouth disease and herpangina
• Tropism for motor neurons of brainstem and spinal cord • Outbreaks (most recently, Taiwan, Southeast Asia)
• Clinical presentation:
• Acute flaccid paralysis within 2 to 3 weeks • Tremors, ataxia, or myoclonus may precede flaccid paralysis
• Diagnostics:
• MRI: segmental or extensive T2 signal in ventral horns • Centromedullary/transverse myelitis; rhombencephalitis
• Treatment: supportive care; IVIG may be used • Prognosis: long-term motor and autonomic dysfunction
Acute Herpes Virus Myelopathy • HSV1, HSV2, VZV, EBV, CMV, HHV-6 and HHV-7
• HHV-6, HHV-7 and CMV in immunocompromised patients • Allogeneic HSCT recipients (cord blood, T cell depleted) • Solid organ transplant recipients • Advanced HIV infection
• HSV2 > HSV1 reactivation in DRG Elsberg myeloradiculitis • Clinical presentation:
• Variable patterns of sensory, motor and bladder dysfunction • Diagnostics:
• Etiologic work-up: viral NAT/PCRs in CSF/blood • MRI to demonstrate extent of involvement • CSF: lymphocytic pleiocytosis, mildly elevated protein
• Treatment: IV antivirals with/without steroids • IV acyclovir/valacyclovir: HSV1, HSV2, VZV • IV ganciclovir/valganciclovir or foscarnet: CMV, HHV6
Acute West Nile Virus Myelitis • 5-10% of neuro-invasive disease are associated with myelitis –
“polio-like” illness characterized by acute flaccid paralysis • Clinical presentation:
• Fever, rash, and myalgia • Meningitis or encephalitis may be present • Abrupt onset of progressive asymmetric flaccid weakness • Diminished-absent reflexes; +/- bowel-bladder dysfunction
• Diagnostics: • Etiologic work-up: Blood/CSF WNV serology
• CSF PCR 100% specificity, CSF WNV IgM more sensitive • Note: Not viremic by the time of neuro-invasive disease
• MRI: spinal cord abnormality within ventral cord • CSF: moderate pleiocytosis (may be neutrophilic initially)
• Treatment: supportive; IVIG with high WNV-Ig titers (trial did not show efficacy); interferon-alpha 2b (under investigation)
How do you diagnose Zika infection?
A. PCR of blood B. PCR of CSF C. IgM serology D. Plaque-reduction
neutralization test
PCR of blood
PCR of CSF
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Acute Zika Virus Myelopathy • Zika virus - emerging neurotrophic flavivirus • Clinical manifestations:
• Microcephaly due to congenital infection • Acute flaccid paralysis secondary to Guillain-Barré syndrome
• Epidemiologic link (outbreak of Zika – rise in GBS) • Myelitis (occasional reports)
• Diagnostics: MRI: nonspecific abnormal signal Pathogen-specific testing:
• PCR (Zika-RNA nucleic acid testing) • Trioplex RT-PCR testing (zika, dengue, chik)
• Serology (Zika IgM; false positivity/cross-reactivity) • Plaque-reduction neutralization testing (PRNT)
• Treatment: supportive; steroids (anecdotal)
Carod-Artal. Expert Rev Anti-infect Therapy 2018
What is your diagnosis?
A. HTLV-1 B. Cryptococcus
neoformans C. HIV D. Schistosoma
mansoni
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HIV Vacuolar Myelopathy • Incidence: 10-20% (up to 50% of patients with AIDS at autopsy)
• Most common spinal cord disease in advanced HIV illness • Pathology: vacuolar myelopathy - demyelination of dorsal columns
and dorsal half of lateral columns; prominent vacuoles within myelin sheaths (most often thoracic cord)
• Clinical features: advanced, late-stage AIDS; most patients die within 6 months; co-existing HIV dementia obscures symptoms
Slowly-progressive spastic paresis Loss of vibration and position sense Urinary frequency, urgency, incontinence Erectile dysfunction (early symptoms in male) • MRI: MRI normal; T2 non-enhancing signal in posterior column • CSF: nonspecific abnormalities (may have elevated protein) • Treatment: CART (often not effective, but may lead to improvement)
IVIG may be associated with neurologic improvement (n=17)
Cikurel K et al. AIDS Patient Care STDS 2009; Di Rocco. Semin Neurol 1999;19:151 Geraci A. et al. Neurology. 2000;55(3):440
HTLV-1 Associated Myelopathy
Nagai et al. J Neurovirol 2003;9:228
• Epidemiology: Southern Japan, Caribbean, South America, Papua New Guinea, Middle East, and Africa. Rare in United States.
• Clinical presentation: Slowly progressive spastic paraparesis, sensory impairment, and often with urinary disturbance
• Pathology: inflammation of lateral corticospinal, spinocerebellar, and spinothalamic tracts, with relative sparing of posterior columns. Cerebral, cerebellar, cranial and peripheral nerve involvement.
Immune response contributes to inflammatory process • MRI: Spinal atrophy, particularly thoracic cord (thin spinal cord).
• Brain MRI: subcortical, periventricular white matter lesions. • CSF: mild lymphocytic pleiocytosis, elevated protein • Diagnosis: Anti-HTLV-I antibodies (high CSF/serum ratio).
• Proviral DNA detection by PCR. • Treatment: Steroids (immunomodulators) may slow progression.
NO proven role for antiretroviral drugs (zidovudine/lamivudine). • Debated role of interferon therapy.
Liu W et al. Ann Neurology 2014;76:370
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Treatment of Selected Viral Myelopathies (summary)
Virus Recommended Regimen HSV 1 and 2 IV acyclovir 10 mg/kg q8 hours for min 7 days (longer if immunocompromised);
consider adjunctive steroids
VZV IV acyclovir 10 mg/kg q8 hours for min 7 days (longer if immunocompromised); consider adjunctive steroids (setting of varicella-zoster virus vasculopathy)
CMV IV ganciclovir 5mg/kg q 12 hours for induction, followed oral valganciclovir for maintenance (depending on immunosuppression)
HHV6 IV ganciclovir or foscarnet
Poliovirus Supportive care
Enterovirus 71 Supportive care; consider IVIG
West Nile virus Supportive care; consider IVIG, interferon-alfa
Zika virus Supportive care, consider steroids
HIV Antiretroviral therapy (combination NRTI/NNRTI/PI/integrase inhibitors)
HTLV-1 Supportive care; consider steroids; consider interferon-alfa
Rabies Supportive care; consider Milwaukee protocol (therapeutic coma with ketamine, ribavirin, and amantadine)
©2012 MFMER | 3177424-39
Many pathogens has been associated with disease of the spinal cord
Class Specific Pathogens (selected)
Bacteria Staphylococcus aureus, Treponema pallidum, Mycobacterium tuberculosis, Mycoplasma sp., Borrelia burdorferri
Viruses Enteroviruses (polio and non-polio viruses [Coxsackievirus, EV-71, EV-68]), flaviviruses (WNV, Zika virus), HIV, HTLV1/II, rabies virus, herpesviruses (HSV 1 and 2, VZV, CMV, EBV, HHV-6)
Parasites Schistosoma haematobium, S. mansoni, Gnathostoma spinigerum, Taenia solium
Fungi Cryptococcus neoformans, Coccidiodes species
Parasitic Myelitis
Galiano et al. Int J Infect Dis 2016; 51:19-21
• Neuroschistosomiasis • Schistosoma mansoni • Schistosoma haematobium
• Clinical manifestations: rapidly progressive transverse myelitis,
including lower limb pain, weakness, bowel/bladder dysfunction
• Pathology: embolization of adult worms to spinal cord, subsequent release of eggs leading to inflammatory reaction with local tissue destruction and scarring • Lower thoracic spinal cord is most frequently involved, followed
by lumbar and sacral regions • CSF: pleocytosis and elevated protein; eosinophilia (48%) • MRI: signal change and swelling within the spinal cord.
• Treatment: glucocorticoids and praziquantel
Schistosoma Myeloradiculopathy
Ferrari TC. Medicine (Baltimore). 1999;78(3):176.
A Review of 231 cases • Epidemiology: exposures, usually young male
• Clinical manifestations:
• Spectrum: asymptomatic egg deposition in the spinal cord to devastating myelopathy
• Symptoms: lumbar pain, often radicular in nature, followed by weakness and sensory loss of rapid progression in the lower limbs, with autonomic dysfunction (bladder dysfunction).
• Acute or subacute onset with medullary and radicular involvement.
Schistosoma Myeloradiculopathy
Ferrari TC. Medicine (Baltimore). 1999;78(3):176.
A Review of 231 cases • CSF: mildly-moderately increased protein, lymphocytic pleocytosis.
Eosinophils in CSF of 40.8% patients. • Myelography and computed tomography-myelography were
abnormal in 63%. Filling defect. • MRI: more sensitive, but changes are nonspecific. • Diagnosis: demonstration of eggs in specimen (88.3%).
• Peripheral blood eosinophilia (64.5%) • Detection of anti-Schistosoma antibodies [serum (94.9%) or
CSF (84.8%)]
• Treatment: steroids and anti-schistosoma drugs (praziquantel) have favorable effect on outcome, if administered early. • Praziquantel – damages tegument structure of adult worms –
may lead to host immune reaction
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Treatment of Selected Parasitic Myelopathies (summary)
Parasite Recommended Regimen
Schistosoma species Praziquantel 60 mg/kg divided in 3 doses for 1 day with adjunctive steroids (prednisone 60–80 mg/d, taper over 6 months); possible surgical intervention
Toxoplasma gondii Pyrimethamine, sulfadiazine, and leucovorin
Taenia solium Albendazole, adjunctive steroids
Echinococcus species
Albendazole, surgical removal of hydatid cysts
Gnathostoma spinigerum
Albendazole plus steroids
©2012 MFMER | 3177424-44
Many pathogens has been associated with disease of the spinal cord
Class Specific Pathogens (selected)
Bacteria Treponema pallidum, Mycobacterium tuberculosis, Mycoplasma sp., Staphylococcus aureus, Borrelia burdorferri
Viruses Enteroviruses (polio and non-polio viruses [Coxsackie viruses, EV71, EV68]), Flaviviruses (WNV, Zika), HIV, HTLV1/II, herpesviruses (HSV, VZV, CMV)
Parasites Schistosoma haematobium, S. mansoni Gnathostoma spinigerum, Taenia solium
Fungi Cryptococcus neoformans, Coccidiodes immitis
©2012 MFMER | 3177424-45
Treatment of Selected Fungal Myelopathies (summary)
Fungi Recommended Regimen
Coccidioides immitis, C. posadasii
Fluconazole (minimum of 400–800 mg/d); alternative azole (eg, voriconazole, posaconazole); consider intrathecal or IV amphotericin B if inadequate response; consider short course of adjunctive steroids
Histoplasma capsulatum
Liposomal amphotericin B (5.0mg/kg/d over 4–6weeks), followed by itraconazole (200 mg BID; check levels) for 1 year minimum (follow Histoplasma antigen)
Blastomyces dermatitidis
Liposomal amphotericin B for 4–6 weeks, followed by azole therapy for 1 year minimum
Cryptococcus neoformans
Liposomal amphotericin B plus flucytosine (or fluconazole as alternative) for 4–6 weeks as induction therapy, followed by fluconazole for 1 year minimum
Aspergillus species Liposomal amphotericin B, or voriconazole (or alternative azoles), duration prolonged and guided by clinical and radiologic findings
Conclusions
• Epidemiology and the clinical course of selected bacterial, viral, parasitic and fungal infections of the spinal cord
• Methods for diagnosis: MRI and CSF features; serology, culture, and molecular methods
• Treatment options: pathogen-directed therapy, immune modulators, immunoglobulins and supportive care
• Guarded prognosis with prolonged rehabilitation
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