Fever with CNS Manifestations

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Meningitis: Bacterial, tubercular, viral, fungal

Encephalitis: (i) Epidemic(ii) Sporadic – Herpes, enterovirus, varicella

Others: Parainfections, autoimmune, ADEM

9 month old baby boy

• High fever for last 3 days• Irritability • Poor feeding with occasional vomiting

since yesterday• Has been on oral cephalosporin

• No rash / otorrhea / diarrhea

• Bulging fontanel

• No neck stiffness, meningeal signs absent

• Abdomen soft, hepatomegaly 3cm

Provisional diagnosis

Meningitis

What investigations you will like to do?

LP and CSF examination: Gold standard for diagnosis

• It is should be done in all suspected cases

• CSF to be examined within 30 minutes of LP

• CSF sugar in fluoride vial / bulb

• Collect blood sugar just before LP

CBC, Blood cultures

When should LP be delayed?• Hypotension, shock• Severe respiratory distress• Signs of brainstem herniation such as unequal pupils • Papilledema• Decerebrate posturing

What should be done if LP is delayed?• Send blood cultures and start empirical antibiotics• CNS imaging if possible (Contrast CT is adequate) or

MRI brain

Tests to be done in CSF

Cytology (5-15/mm3)SugarProteinGram stain ( Sensitivity 40-70%, Specificity 97%)CSF cultures (Sensitivity 70-85% in antibiotic naïve)PCR and antibody for viral infectionsCSF lactate, aminoacids in suspected metabolic diseasesIndia ink for suspected fungal meningitis

Interpretation of LP when already on antibiotics

• CSF gram stain and culture negative

• Pleocytosis, elevated protein and reduced glucose persists for several days

• Bacterial antigens have limited role

• PCR may be useful

Parameter (normal)

Pyogenic Aseptic/ Viral

Partially treated pyo meningitis

Early TBM

Cells (<5/ cumm) 100-10,000 Polymorph

10-1000Lympho

5-10,000Lymphos> polys

10-500, polys early and then lymphos

Sugar ( > 60% of BSL)

Low N except mumps

Low Low /Normal

Protein (20-40 mg%) 100-500 mg%

50-200 mg% 100-500 mg% 100-1000

Gram St & C/S Positive Negative Usually Negative

Negative

ADA, Lactate, LDH High N High High

CSF evaluation

Other testsAcute-phase reactants

C-reactive protein (CRP) and serum procalcitonin (PCT):

PCT decreases rapidly (within 24 hours) with appropriate

antibiotic treatment

PCT is not useful in ventriculitis

Petechial fluid

May be utilized for diagnosis meningococcal disease

TB meningitisCBNAAT or GenXpert MTB/RIF (Sensitivity85.7%)

ADA is not recommended in the diagnosis of TBM

Investigation for TB at other sites

Chest X-ray, Mantoux test ,sputum GA for AFB

USG or CT scan abdomen

CECT or MRI Brain

Imaging• Contrast MRI has higher sensitivity than CECT for detection of • Meningeal enhancement• Infarcts • Tuberculomas mainly involving the brainstem• Complications

Mild ventriculo megaly and sulcal effacement

Contrast-enhanced T1w-MRI : leptomeningeal enhancement (arrows) and ventriculomegaly

Slit like ventricle, low attenuation of white matter, obliteration of cysterns

Plain CT Scan

Investigation results in our patientHb11.2 gm/dl, WBC 19600, N75, L21, ESR 55

CRP 46

LP done: Traumatic

Cell count – Plenty of RBC

Protein 124, sugar 34 (blood sugar 96 mg/dl)

Gm stain – Negative, Culture – Pending

Blood culture: Pending

How to Interpret traumatic LPNormal CSF contains no RBC and their presence indicates

traumatic tap

Progressive clearing of blood between the first and the last

samples is suggestive of traumatic LP

• LP at higher interspaces may produce less hemorrhagic

fluid but may contain RBC

• Leucocytes and protein concentration are altered

• Gram stain, culture and glucose may remain unaltered

Empiric antibiotics

IV Ceftriaxone 100mg/kg

Other supportive measures

72 hrs after treatment started

• Patient’s condition not improved: Fever persisting

• CSF culture – No growth• What to do now ?

Emperic Abx following LP (ceftriaxone / cefotaxim)

Poor clinical response - repeat LPAdd vancomycin till sensitivity report

Good response

Review clinical / CSF sensitivityreport; change Abx accordingly

Cont Abx / change accordingto CSF sensitivity report ifneeded

7 days?

Not improving ImprovementCont Abx

Re-investigateConsult neurologist

Repeat LP• Cell count – 180 (lymho > poly)• Protein – 220 mg%, Sugar – 24mg%• Gm stain – Negative

Comment : Partially treated meningitis and not responding to given

antibiotics

• Suspected Penicillin resistant Pneumococci

• Add Vancomycin (60 mg/kg/day in 4 divided doses)

• Continued for at least 7 days (?)

Contrast imaging done – Normal study

How long will you treat?

Duration•Organism not identified – Antibiotics for 10-14 days,

intravenous, no switch to oral•7 days for meningococcus•10-14 days for H. influenzae and pneumococcus

Watch for complications Subdural effusion Hydrocephalus (HC monitoring)

5 year old boy

Monsoon, rural areaFever for 2 daysExcessive somnolenceGeneralized seizure 1 episodeAltered sensorium since then

What are diagnostic possibilities ?• Encephalitis ü Japanese encephalitis ü Herpes simplex encephalitisü Mycoplasmaü Enterovirusü Other viruses –varicella, mumps, measles, rabies,

dengue, chandipuraü Autoimmune encephalitis -Acute disseminated

encephalomyelitis (ADEM)

• Cerebral malaria• Encephalopathy (Reye’s syndrome, metabolic

encephalopathy, epileptic encephalopathy)• Rarely pyogenic meningitis, TBM

Clinical features

• No pallor, icterus, organomegaly• No skin rash• No respiratory signs• Left sided hemiparesis• No abnormal movements, no meningeal signs

What is the likely diagnosis

Encephalitis • Infective• Autoimmune encephalitis• Vasculitis• Collagen vascular disease• Paraneoplastic encephalitis

Etiology

Infective Non Infective

Epidemic Non epidemic Others JE virus Enterovirus Bacteria Para neoplastic

Herpes virus Protozoal Autoimmune

Varicella Parasite Intracranial hge

E B virus Toxin Exposure to drugs

Mumps Chemical and toxins

Autoimmune encephalitis

• Antibodies directed against neuronal cell surface protein and synaptic receptors.

• Not all are uniformly fatal – Some respond to immunotherapy

• Previously those encephalitis termed “idiopathic” or “Encephalitis lethargica”

Epidemiological Clues in etiology

Animal contact Person to person transmission

Birds - JE Herpes simplex

Dog - Rabies Varicella

Pigs - JE Enterovirus

Mouse - Rickettsia Influenza

Insect contact Measles, mumps, rubella

Mosquito – JE, P falciparum M pneumoniae

Ticks - Rickettsia

Diagnosis of JE / AES

• Presence of IgM antibody in serum/CSF to JE

• Fourfold rise in IgG antibody in paired sera

• Antigen detection by immunofluroscence

• Nucleic acid detection by PCR

• Virus isolation from brain tissue

• MRI lesions in thalamus, basal ganglia and mid brain

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High signal intensity lesions in thalamus, basal ganglia, cerebellum, pons, mid brain and occasionally spinal cord. Involvement of basal ganglia almost rules out HSV.

MRI (T2 weighted image) in JE

HSV Encephalitis: Lab Diagnosis

• DNA PCR from CSF • Best 3-10 days following symptoms. • Reduced sensitivity after 2 days of acyclovir• HSV IgM are notoriously unreliable. • Four fold rise in IgG between acute and convalescence

sera• MRI – bilateral temporal lobe involvement is almost

pathognomic

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• Lumber puncture• MRI especially involves

the temporal lobes, which may be associated with generalized swelling of the brain parenchyma

• EEG (focal finding)/PLED

Imaging: Contrast MRI

Left temporal hyper intense lesions diagnosis HSV

encephalitis

How to distinguish between encephalitis and cerebral malaria ?

Cerebral malaria

• Epidemiological setting• Clinical clues – eg. Splenomegaly• Symmetric CNS findings – UMN lesions• Ophthalmoscopy – Malarial retinopathy

Patchy retinal whiteningWhite or orange

discoloration of retinal vessels

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Autoimmune encephalitis

Immune-mediated damage to CNSOften mimics encephalitis – though actually they are encephalopathy

Immune medicated CNS diseaseDiverse presentation a follows :

Presentation in infants and toddlers

Ac onset focal neurologic deficits

Presentation with encephalopathy/behavior disturbance

Seizure as primary manifestation

Movement disorder as primary manifestation.

ADEM

1. Monophasic illness occurring 1-14 days following

vaccine or ≤ 1 week following examthematous fever.

2. Fever usually absent at the onset of neurological

illness.

3. Multifocal neurological signs – Optic nerve, brain and

spinal cord.

4. Disturbed consciousness, stupor and confusion to

coma.

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The lesions of ADEM are best seen in T2 weighted images, FLAIR sequences. There are multiple, bilateral, asymmetric demyelinating lesions of the subcortical white matter.

Periventricular area is spared. Sometimes lesions may show contrast enhancement and may be in gray matter.

The MRI shows the following features of

Acute Demyelinating Encephalo Myelitis (ADEM)

T2 cut at the vent. LevelPatchy hyperintense lesion in deep white matter

Same in flair image. CSF is black, hyperintense lesion

Supraventricular level, symmetrical hyperintensity in centrum semi ovale

What are anti NMDAR encephalitis ?

Anti NMDAR encephalitis

• Starts with psychiatric manifestations

• These may be proceeded by a prodrome of headache, fever and viral like symptoms

• Additional symptoms like consciousness, seizure, abnormal movement and autonomic instability.

• MRI and EEG – usually non specific. • CSF lymphocytic pleocytosis, protein• Diagnosis- by NMDAR antibodies in CSF and

serum