John Lynch MD MPHHarborview Medical Center &

University of Washington

Encephalitis and Meningitis

http://bit.ly/1wb7KOz

Case

25 year old woman with a headache and change in mental status. LP finds WBC 88 per microliter.

Central Nervous System Infections

• Signs and symptoms– Fever– Headache– Altered mental status– Focal neurological findings

• Nonspecific• Infectious and noninfectious etiologies

CNS Infections

• Risk factors– Geographic location, travel– Time of year– Environments (dormitories, barracks)– Concomitant illness (HIV, diabetes, alcoholism)– Medications (immunosuppressants, chemo,

prophylactic medications)

CNS Infections

• Physical examination– Identify contraindications to LP• mass lesion with midline shift• infected lumbar area• disordered coagulation (PLT <50K, INR >1.5)

– Identify concomitant sites of pathology– Define the site and the syndrome

CNS Infection Syndromes

• Acute meningitis• Subacute or chronic meningitis• Acute encephalitis• Chronic encephalitis• Space occupying lesion• Toxin mediated• Encephalopathy with systemic infection• Postinfectious

Case

25 year old woman with a headache and change in mental status. LP finds WBC 88 per microliter, HSV PCR negative. D/c to home, improved on topiramate after 5 days.

Encephalitis

• “Inflammation of the brain”– Pathological diagnosis– +/- neurons infected

• Cardinal features– Altered mental status– Can mimic psychiatric disease

• Other features– Headache, fever, nausea, vomiting– Seizures, focal neurological deficits

Neuroimaging in Encephalitis

• Normal• Focal inflammation• Diffuse inflammation

Encephalitis Etiology

• Infectious– More than 100 infectious etiologies identified– Most commonly viruses

• Para- or post-infectious• Etiology not established in ~50% of cases– Diagnostics not adequate– Emergence of new etiologies

Encephalitis etiology?• Season: late summer, early fall – enteroviruses– parechoviruses–tick and mosquito-borne agents

• Geographic exposure–Relapsing fever vs Borreliosis– JEV in Asia/SE Asia– Consult public health

Encephalitis etiology?Underlying medical problems–HIV: toxoplasmosis (CD4 <200)–Transplant: LCMV, WNV, rabies– Immunosuppression: VZV, HHV6, WNV,

toxoplasmosis

More clues–Rash: VZV, JJV6, WNV, borrelia, erlichia,

anaplasma–Retinitis: WNV, B henselae, syphilis–Parkinsonism: WNV, SLEV, JEV–Flaccid paralysis: WNV, JEV, tick-borne

encephalitis virus

Case

Ongoing abnormal mental status leading to admission to psychiatric floor. Two weeks later develops seizures and is transferred to the neurology service at the local university hospital. Unresponsive, eyes closed, hyperventilating, resists passive eye opening, no response to visual threat.

Case

EEG with EDsHead CT normalCSF

WBC 58 per microliter (all WBCs)Glucose 53 mg/dlProtein 48 mg/dl

Selected Causes of Encephalitis-Viral

Viruses CommentsHSV 1 and 2 Type 1 most common cause of

sporadic encephalitisVZV Elderly and

immunocompromised, rash may be absent

Enteroviruses, Parechoviruses Myelitis, brainstem encephalitisWNV, JEV, SLEV Parkinsonian movement

disorder, flaccid paralysis

Selected Causes of Encephalitis-Bacterial

Viruses CommentsM pneumoniae parainfectiousM tuberculosis immunocompromised,

immigrantsB henselae seizures, retinal diseaseT pallidum imaging may mimic HSVE Rickettsia, Erlichiosis, Anaplasmosis

Geographic distribution

Infectious endocarditis Infarcts in vascular distributions

Selected Causes of Encephalitis- Non-infectious

Viruses CommentsNMDA receptor Young women, movement

disorder, autonomic instability, ovarian teratoma

Leucine rich glioma inactivated-2 (LGI1; VGKC)

Older men, faciobrachial seizures, hyponatremia

Case

Subsequently developed high fever, hypertension, tachycardia

CSF and serum with NMDAR antibodies

Ovarian US showed “dermoid” (teratoma)

Question

What is the most likely diagnosis?A. Herpes encephalitisB. HHV6 encephalitisC. Leucine rich glioma inactivated 1

encephalitisD. Rhomboencephalitis 2nd to L

monocytogenesE. NMDA receptor encephalitis

Anti-NMDAR Encephalitis

Population-based study of encephalitis in England = 4% of all cases

California Encephalitis Project = most common cause of encephalitis in those under 30 years of age

Anti-NMDAR Encephalitis

• 80% of patients are female• Associated with ovarian teratoma– Females >11 yrs– More common in people of African and Asian ancestry

• Prominent psychiatric symptoms early (can resemble phencyclidine or ketamine intox)

• Patients often require ICU care and prolonged hospitalization

Clinical Findings in NMDARE-1

Prodrome–Headache–Fever–Nausea and vomiting–Diarrhea–URI symptoms

Clinical Findings in NMDARE-1

Early– Seizures– Psychiatric symptoms– Short-term memory loss– Language abnormalities

Clinical Findings in NMDARE-1

Late– Involuntary movements– Catatonia– Coma– Autonomic and breathing

instability

Diagnosis NMDARE

• Serum: antibodies to N-terminal domain of NR1 subunit of NMDAR• CSF–Mild to moderate mononuclear

pleocytosis–OCBs in 60%–Antibodies to NMDAR, more sensitive

than serum antibodies

Diagnosis NMDARE

• MRI: non-specific abnormalities• EEG: slowing, electrographic seizures• Pelvic and transvaginal ultrasound:

teratoma

NMDARE Treatment

• Immunotherapy–Corticosteroids–Rituximab +/- cyclophosphamide

• Identification and removal of tumor (empiric oophorectomy)

NMDARE Prognosis

• Recover or mild sequelae ~75%, can take >18 months• Severely disabled ~20%• Die ~4%• Relapse ~20-25%– No tumor identified– Not treated with immunosuppression– Rapid taper of immunosuppression

Case 2

70 yo man with CAD, AF on warfarin. Comes into the ED ill x 3-4 days (fever, MS changes, nausea, vomiting, diarrhea). Neurological examination: confused and left facial weakness

Case 2

70 yo man with CAD, AF on warfarin. Comes into the ED ill x 3-4 days (fever, MS changes, nausea, vomiting, diarrhea). Neurological examination: confused and left facial weakness

WBC 17,000, head CT normalCSF: 28 WBCs (40% polys), glucose 57, protein 56

Question

What is the most likely diagnosis?A. Herpes encephalitisB. HHV6 encephalitisC. Leucine rich glioma inactivate 1 encephalitisD. Rhomboencephalitis due to L monocytogenesE. NMDA receptor encephalitis

HSV Encephalitis

Most common cause of sporadic encephalitis in USOccurs any time of yearBimodal age distribution– 25-30% <20yo– 50-70% >40 yo

Most due to HSV-1– Primary ~30%– Reactivation ~60%

HSV-2 in immunosuppressed (Mollaret’s?)Steroids, TNF-alpha blockers are risk factors

Clinical Findings in HSVE

FeverHeadacheChange in level of consciousnessDysphasiaPersonality changesSeizuresMild or atypical cases in PCR era

HSVE Treatment

Acyclovir 10mg/kg IV q8hrs– 14-21 days course– Continue till CSF HSV PCR negative

Prolonged PO treatment after IV?– Study in adults pending– Study in neonates found better

neurodevelopmental outcomes after 6 months of treatment

HSVE Prognosis

MortalityUntreated 70%Treated 28%

Neurological, neuropsychiatric sequelae in more than 50%

Diagnostic Algorithm

Metabolic Evaluation and Directed Physical Exam

CT FIRST?

YES

CTEmpiric AcyclovirLP

MR

Not OK OK

Continue treatment

NO

Meningitis

Inflammation of the leptomeninges (the pia, arachnoid, and dura mater). Meningitis reflects inflammation of the arachnoid mater and the cerebrospinal fluid (CSF) in both the subarachnoid space and in the cerebral ventricles.

Types of Meningitis

• Bacterial (N meningitidis, S pneumoniae)• Viral (enteroviruses, arbovirus, HSV)• Fungal (cryptococcus, histoplasma)• Parasitic (A cantonensis)• Non-infectious (SLE, vancer, drugs, injury)

Case 3

12 yo male living in Alabama with headache, neck stiffness, nausea, vomiting x 1. Only medical history is sinusitis treated with home remedies. Started on broad empiric antibiotics and acyclovir. The next day he started to hallucinate and soon became unresponsive and died a day later.

Question

What is the most likely etiology?A. S pneumoniaeB. Naegleria fowleriC. N meningococcusD. L monocytogenesE. B henselaeF. MRSA

Primary Amebic Meningoencephalitis (PAM)

• Very rare form of parasitic meningitis (31 US cases/10 yrs)

• The ameba is found worldwide in warm freshwater, hot springs, water heaters and warm industrial waters

• The ameba enters the body through the nose (cannot infect by drinking water)

• Uniformly fatal in 1-12 days

Fungal Meningitis

• Cryptococcus- inhalation of soil contaminated with bird droppings

• Histoplasma- environments with heavy contamination of bird/bat droppings, Ohio and Mississippi Rivers

• Blastomyces- soil with rich decaying matter, northern Midwest

• Coccidioides- SW US, Central and S America (and E Washington), African Americans, Filipinos, pregnant women, immunocompromised at higher risk

• Candida- usually hospital acquired

Viral Meningitis

• Summer and fall months = enteroviruses – Fecal contamination and respiratory secretions– Person to person spread

• Others: mumps, EBV, HSV, VZV, measles, influenza, arboviruses, LCMV

• Risk groups: Infants <1 month old and immunocompromised

HSV-2 Meningitis

More commonly associated with aseptic meningitisCan be recurrent (Mollaret’s syndrome)– Prophylactic valacyclovir RCT– Slightly higher recurrence rates on

tx– 3x higher recurrence after

stopping prophy Aurelius CID 2012

Case 4

20 yo male, sexually active and daily IC drug use, in the ED with 2 days of fever and HA. He has photophobia, mild meningismus and a normal neurological exam.

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Question

What is the most likely etiology?A. S pneumoniaeB. Naegleria fowleriC. N meningococcusD. L monocytogenesE. B henselaeF. MRSA

Causes of Meningitis by AgeAge Group Causes

Newborns Group B Streptococcus, E coli, L monocytogenes

Infants and children S pneumo, N meningitidis, H influenzae type B

Adolescents and young adults N meningitidis, S penumo

Older adults S pneumo, N meningitidis, L monocytogenes

Trends in Meningitis in the USA,1998-2007

Thigpen NEJM 2011

Trends in Meningitis, England 2004-2011

Okike Lancet Infect Disease 2014

Non-CNS Infection Meningitis

• Shiga-toxin-producing E coli outbreak in N Germany in 2011 (3500 people)• ~25% developed HUS, ~100

developed neurological disease (cognitive impairment, aphasia, seizures)

Magnus Brain 2012

Case 5

58 yo man presents with mental status change, fever, headache. CSF with 40 WBCs, mostly lymphocytes, normal glucose and protein.

Case 5

58 yo man presents with mental status change, fever, headache. CSF with 40 WBCs, mostly lymphocytes, normal glucose and protein.

www.eurorad.org

Question

What is the most likely etiology?A. S pneumoniaeB. Naegleria fowleriC. N meningococcusD. L monocytogenesE. B henselaeF. MRSA

Listeria monocytogenes rhomboencephalitis

• Typical biphasic pattern– Non-specific prodrome– Followed by asymmetrical CN palsies, cerebellar

signs and diminished consciousness• Prognosis depends on extent of disease– Abx early, survival ~70%– Even then, ~60% have neurological sequelae

• Though rhomboencephalitis is not specific to Listeria, is must be strongly suspected

Meningitis Prevention

• In developed countries the meningococcal serogroup C vaccine = decrease meningitis and sepsis

• Historically there has been a hole with serogroup B due to similarity to human Ag

• New vaccine: 4CMenB (2012) showed good immunogenicity and good protection (66-91%) in neonates. This is the vaccine used in Princeton and Santa Barbara this year.

Case 6

30 yo woman with left arm, neck and face tingling and numbness, chronic mild bilateral headache and mild difficulty hearing and speaking. Neurological exam was normal.

Naddaf WMJ 2014

Case 6

30 yo woman with left arm, neck and face tingling and numbness, chronic mild bilateral headache and mild difficulty hearing and speaking. Neurological exam was normal.

MRI should a 9x12 mm ring-enhancing lesion in the parietal lobe. An internal soft tissue component was c/w a scolex. The pt had traveled to Mexico multiple times over the last 10 years.

Naddaf WMJ 2014

Taenia solium (neurocysticercosis)

Naddaf WMJ 2014

Brain Abscess

Brouwer NEJM 2014

0.4-0.9/100,000

Brain Abscess

Brouwer NEJM 2014

• Predisposing factors– Underlying disease (ex. HIV infection)– Immunosuppression– Disruption of barriers (surgery, trauma, dental

infection)– Systemic source of infection (bacteremia,

endocarditis)• Contiguous spread ~1/3, hematogenous

spread in ~1/2, rest unk