Systemic Infections with Neurologic Manifestations

Arlene S. Dy-Co, MD, FPPS, FPIDSP

SYSTEMIC INFECTIONS

Infections in the bloodstream

Affecting the entire body

Diverse

Systemic infections with Neurologic Manifestations

Part of CNS syndromes

Systemic manifestations dominate clinical picture

Syndromic approach to diagnosis less effective

Systemic VIRAL infections

Systemic BACTERIAL infections

Systemic PROTOZOAL infections

With Neurologic Manifestations

Systemic viral infections with neurologic manifestations

Measles

Varicella

Dengue

Measles

Rash disease of childhood

Neurologic disease-

community-acquired infection

Fever, cough, diarrhea, rash

Significance

?

Low incidence

Long-term neurologic disabilities

Pathology

Direct viral invasion

Induction of autoimmune response

Neurologic manifestations

Acute disseminated encephalomyelitis

Measles inclusion body encephalitis

Subacute sclerosing panencephalitis

ADEM

• Incidence

Worldwide• Common after measles

1 in 1,000 • Common in children >2 years old• normal immune system

fever 2-7days

after onset of rash

Neurologic manifestations• Seizures • Altered mental

status• Multifocal

neurologic signs

Monophasic course

10-20 daysImprovement few days after

onset

Pathology

Autoimmune demyelinating disease triggered by measles

perivenular demyelinationNo evidence of measles

virus

swelling of cerebral vessels

Mononuclear cell infiltration

autoimmune response to

myelin -unexplained

Diagnosis

clinical MRI –multiple foci of demyelination

CSF –normal or slight increase in protein

EEF non-specific diffuse slowing

Treatment

Treatment not well established• Corticosteroid widely used

Higher mortality in steroid-treated • IVIG, plasma exchange some success

Ziegra SR. Corticosteroid treatment for measles encephalitis. J Pediatrics. 1961; 59:322

Prognosis

Fatality rate- 10-40%

Neurologic residua substantial• Almost always present

Johnson RT, et al. Measles encephalomyelitis –clinical and Immunologic studies. N Engl J med. 1984; 310:137-141

Prevention

To decrease the incidence

Vaccination highly effective

and safe

Varicella

Primary infection with varicella zoster virus

Common, extremely contagious

Generalized vesicular rash

Neurologic manifestations

1-3 per 10,000

Cerebellar ataxia 31%Encephalitis 20%• Transverse myelitis, aseptic meningitis, stroke

www.jwatch.org aug 11,2014

Cerebellar ataxia

1 per 4,000days before to 2 weeks after the

rash

VomitingHeadacheLethargy

ataxia

• Fever• Nuchal

rigidity• Nystagmus• seizures

Pathology

unknown• Lack of necropsy studies

Proposed mechanisms• Direct viral involvement of the cerebellum • Immunologically mediated

Antibodies to VZV in the CSF of patients with neurologic abnormalities

VZV specific DNA in the CSF of 3 children with varicella cerebellitis detected by PCR

Echevarria JM et al. Subclass distribution of the serum and intrathecal IgG antibody response in varicella-zoster virus infection. J Infect Dis 1990

Puchammer E, et al. Detection of VZVDNA by PCR in the CSF of patientsSuffering from neurological complications associated with chickenpox. J Clin Microbiol. 1991; 29:1513.

Diagnosis

Uncomplicated

Clinical presentation

No further evaluation

Complicated

CSF –normal or slight increase

in protein

EEG-diffuse slow wave

Prognosis

Cere

bella

r ata

xia

self-limited

Resolves in 1-3 weeks

Mortality -zero

Encephalitis

Less common

More severe

1-2 per 10,000

Most occur in children

Highest in infants less

than 1 y

Occurs 2 weeks

before up to weeks after

the rashAbrupt or gradual

HeadacheFever

VomitingAltered

sensoriumseizures

AtaxiaHypertonia/hypotonia

HemiparesisSensory changes

Pathology

Role of active viral replication- uncertain

Wide range of histopathologic findings

Diffuse cerebral edema

Diagnosis

CSF

• Frequently abnormal

EEG

• Slow wave activity

CT scan

• Cerebral edema

• Demyelination

Prognosis

Mortality 5-35%

Long-term sequela in 10-20% of survivors

59 cases of varicella with encephalitis -5% mortality

Lehman MD. J Pediatri 2014, Jul 22

Treatment and Prevention

Cerebellar ataxia Encephalitis

No evidence for antiviral therapy Antiviral therapy

Live, attenuated vaccine –effective

and safe

Dengue

4 serotypes

Viral hemorrhagic fever

Dengue

Cause and existence of neurologic manifestations has been a controversy• Neurologic manifestation reported from every

country

strong evidence to support neuroinvasion• non-specific encephalopathy, encephalitis

Soares CN et al. Dengue infection neurologic manifestationsand CSF. J Neurol Sci 2006; 249; 19.

150 CSF samples from fatal cases

Evidence of DENV in 41 CSF out of 84 positive patients

Araujo FMC, et al. CNS involvement in Dengue: a study of fatal cases from a dengue endemic area. Neurology2012,;78:736.

4% with suspected CNS infections were infected with dengue virus

18% of children with encephalitis were confirmed with dengue infection

Solomon, et al. Neurologic manifestations of dengue infection Lancet 2000

Kankirawatana et al. Dengue infection presenting with CNS manifestation J child Neurol 2000

3 types of Neurologic manifestations

Classic signs with

acute infection

Encephalitis with acute

infection

Post-infection disorder

Reduced level of

consciousness

SeizuresProlonged

coma

Other signs of severe dengue

infectionShock

Vascular leakage

hemorrhage

Metabolic disturbances

Diagnosis

CSF

• Moderate lymphocytic pleocytosis

CT/MRI

• Diffuse cerebral edema

CSF

• Viral isolation

trea

tmen

t No effective drugs

Fluid management

prev

entio

n Vaccine not yet available

Vector control

Mortality due to neurologicalInvolvement-low

Systemic bacterial infections with neurologic manifestations

Typhoid fever

Cat-scratch disease

Typhoid fever

Caused by S. ser. typhi

insidious

Incubation period 10-14 daysRelated to inoculum size

Fever malaise anorexia abdominal

pain

Dull, continuous

frontal headacheDrowsy Irritabledelirious

Relative bradycardiaToxic facies

Coated tongueDoughy

abdomenmeningismus

Typhoid with CNS manifestations

27% • Occurring 6 days after fever onset• Lasts for 8 days

Restlessness, confusion, disorientation• Resolution in 4 days

Typhoid delirium

state/toxemia

Specific neurological

complications

Pathogenesis

Not known

Metabolic disturbances, toxemia, hyperpyrexia

Cerebral edema, hemorrhage

Diagnosis

Isolation of Salmonella from cultures•Could not be isolated from

CSF

Relapse rate is 5-10%

Case fatality highest among children

Delay in instituting effective antibiotic

Mortality with neurologic illness 28.9%

encephalitisBhandari et al.Typhoid encephalopahty in children. Indian Journal child health 1990

Severe typhoid feverTreatment

• Parenteral• Ceftriaxone 100mkd OD x 5-7days• ciprofloxacin 20mkd BID x 7 days

• Oral• Cefixime 20mkd OD x 14 days• Ciprofloxacin 20mkd BID x 7 days• Azithromycin 20mkd OD x 7 days

Dexamethasone

Reduces mortality rate from 35-55 % to 10%

For severe typhoid

3mg/kg then 1mg/kg q6 for 48 hours

Control seizure

Manage increased ICP

Prev

entio

n Hand washingCareful food processing

Prev

entio

n Safe waterAppropriate sewage disposal

4 doses>6yo

Single dose>2yo

Oral live attenuated

Parenteral Vi capsular

polysaccharide

VaccinationHigh-risk groups

Cat-scratch diseaseTypical

90%

Cutaneous papule

lymphadenopathy

Atypical

Extranodal

Complicated

CSD with NEUROLOGIC MANIFESTATIONS

Neurologic manifestations

Encephalopathy Neuroretinitis

CSD with Encephalopathy

2-4%May be

fulminantOften

recover fully

Easily overlooked

Follows lymphadenopathy by days to months

Persistent headache

FeverSeizures

Neurologic deficits

Deficits usually self-limited

• Resolution-weeks to months

Death due to CSD encephalitis in 2 healthy children

Neuroretinitis

Seen in association with

bacteremiaAseptic

meningitisencephalopathy

Painless sudden loss of visual

acuityPapilledema

Macular exudates in star

formation

Prognosis goodVitrectomy

rarely indicated

Laboratory studies no

specific positive findings

CNS involvementParenteral

therapy

Short-term anti-

convulsant therapy

Role of antimicrobial

controversial

Neuro-retinitis

Steroid use difficult to evaluate

2 reports of 4yo given steroid

Encepha-lopathy

Systemic protozoal infection with neurologic manifestations

Malaria

Most important parasitic disease

Incidence and prevalence decreasing

Classic symptoms•High fever, chills, sweats

Plasmodium falciparum•Febrile non-specific illness

without localizing signs

Severe disease•Without exposure•young• immunocompromised

P. falciparum

Different clinical syndromes

Cerebral malaria

Cerebral Malaria

Unexplained coma • Patient with malaria parasitemia

Clinical case definition• High sensitivity, low specificity

Disease prodrome

FeverDiaphoresis

chills

Rapidly progresses

to comaBlantyre

scale<2

SeizuresBrainstem

dysfunction

Neurologic manifestations

Generalized seizures

Signs of increased ICP

Confusion, stupor, coma

Sequestration of parasitized RBC in microvasculature

Cytokine abnormalities

Abnormalities of blood-brain barrier

Histologic hallmark

Swollen discolored

brain

Cerebral vessels packed

with parasitized rbc

EEG

Generalized symmetrical

and asymmetrical

slowing

Focal slowing

CSF

Elevated opening pressure

Little cellular response

Treatment

• Antimalarials

• Early detection and treatment of complications

Dosing Schedule of Quinine Dihydrochloride in the Treatment for Severe Plasmodium falciparum Malaria Infection

Age Group Quinine dihydrochloride

Loading Dose Maintenance Dose

Children 8 years to 16 years

15 mg salt/kg IV drip for 4 hours in 10 ml/kg D5W or 0.9 NaCl (infusion rate must not exceed 5mg/kg per hour)

10 mg salt/kg IV drip for 4 hours every 8 hours in D5W or 0.9 NaCl

Children 7 years and younger

10 mg salt/kg in IV drip for 4 hours

10 mg salt/kg IV drip every 12 hours

Parenteral Quinine Dihydrocloride Infusion PLUS Tetracycline/Doxycycline/Clindamycin

Doxycycline3 mg/kg BW once a day (QD) for 7 days

Tetracycline250 mg 4 times a day (QID) for 7 days

Clindamycin10 mg/kg BW twice a day (BID) for 7 days

ICU• No adjunctive therapy decreased

mortality and morbidity

Parenteral therapy• Until parasite density decreases• Able to tolerate oral therapy

Therapy

Glucose correction

fluids

antipyretics

benzodiazepines

phenobarbital

Phenytoin

• fataluntreated

• Coma resolves rapidly

• Mortality 15-25%treated

Acute seizures increase mortality

Long-term neurologicdisability

60 -fold higher odds of adverse neurologic outcome

Prevention

Bed nets

chemoprophylaxis

Vaccine development

chemoprophylaxisDrugs Schedule Dose

Pregnant Adult Pediatric

A. For People Travelling To Endemic Areas

Doxycycline Tablet (100 mg)

Start two to three days prior to travel, daily while in the area and continue up to four weeks upon leaving the area

contraindicated < 8 years: contraindicated> 8 years old:2 mg/kg up to 100 mg daily

MefloquineTablet (250 mg base)

Start 1-2 weeks before travel; take weekly while in the area, and continue up to four weeks upon leaving the area

contraindicated 1 tablet weekly

< 45 kg: 5 mg/kg bw5-10 kg ⅛ tab

10-19 kg ¼ tab

20-30 kg ½ tab

31-45 kg ¾ tab

Choloroquine Start 2 weeks before travel, take weekly while in the area and continue 4 weeks after leaving the area

2 tablets NA < 8 years: 5 mg/kg b.w. > 8 years: 2 tablets

Summary

Systemic infections with Neurologic manifestationsbacterial

protozoal

viral