Meningitis and Encephalitis in the Older Patient Debra

Meningitis and Encephalitis in the Older Patient Debra Bynum, MD Division of Geriatric Medicine University of North Carolina Chapel Hill April 2007

Outline n n n n Cases for thought… Meningitis and Encephalitis: general features and causes Diagnosis: review of CSF findings Meningitis: specific causes Encephalitis: specific causes Zoom in on important arboviruses and tick-borne illnesses Summary of diagnosis and treatment Review of the cases

Cases n 1. Active 78 -y/o man with prior hx of aortic valve replacement years ago, presents with fever, slight confusion, dehydration. Initial concern for SBE, but CSF : TNC of 20. His serum Na 128. All cultures negative. What would the DDX include? n 2. 85 -y/o with severe dementia admitted with fever, ? stiff neck and worsening confusion and lethargy. CXR and U/A are negative. What would you do? n 3. Healthy community living 75 -y/o presents with personality changes, confusion, agitation. She has no fever, no other evidence of infection. What to do? n 4. 80 -year-old man presents with low grade fever and coma after several days of myalgias and viral-like illness. Exam is notable for some Parkinsonian type features… initial concern would be for ?

Meningitis n n Inflammation of the meninges Classic triad: n n Fever Headache n Severe, frontal, photophobia, n/v n Jolt accentuation Meningismus/altered mental status Meningeal signs n n Kernig sign: one leg with hip flexed, pain in back with extension of knee Brudzinski sign: flexion of legs and thighs when neck is flexed

Encephalitis n n n n Inflammation of the cerebral cortex Fever, HA, altered mental status Key: early mental status changes More commonly viruses Obtundation/coma Behavioral or speech problems, neurological signs, seizures Meningoencephalitis Difference from meningitis: less likely fever, more likely personality/behavioral changes

Causes of Meningitis Bacterial n Viral n Fungal: cryptococcus n Mycobacteria: MTB n Parasitic/protozoa: Naegleria fowleri n Noninfectious n n Medications n Paraneoplastic

Acute Bacterial Meningitis Streptococcus pneumoniae n Neisseria meningitidis n Listeria monocytogenes n Haemophilus influenzae: nearly unheard of since vaccinations n Less common: Gram negatives (Klebsiella, E. coli) n History of procedure: Staphylococcus n

Viral Meningitis n n n n n Aseptic meningitis Spectrum with encephalitis, meningoenchephalitis Enteroviruses HSV VZV Arboviruses (arthropod borne viruses) n West Nile, Eastern Equine, Western Equine, St. Louis, California, Japanese Encephalitis HIV Rabies virus Adenovirus CMV, EBV

Encephalitis n Viral n HSV n Arboviruses n VZV, CMV, EBV, HIV, rabies n Enteroviruses n Bacterial n Listeria monocytogenes n Tick-borne illnesses n RMSF: Rickettsia rickettsii n STARI: Borrelia lonestari n Lyme: Borrelia burgdorferi n Ehrlichiosis: Ehrlichia chaffoensis

Meningitis in the Elderly n n n n Decreased total incidence; increased in elderly Increased prevalence of Listeria (25%) 30 -50%: S. pneumoniae Less likely Neisseria and Haemophilus Less likely fever and meningeal signs; more likely neurological symptoms, seizure, coma More often complicated by pneumonia Older patients with neurological impairment: 50% mortality

Meningitis n Risk Factors n Age (bimodal peak) n Prior neurosurgery, alcoholism, malignancy, steroids, HIV, sinusitis, DM n Clinical suspicion n Triad: fever, nuchal rigidity, altered mental status: only seen in 40% elderly n Only 59% of elderly patients with acute bacterial meningitis had fever n Most have at least ONE symptom

The Diagnosis n n LP if suspicion Do not delay antibiotics if suspected! CT prior to LP in patients with focal neurological deficits, seizures, HIV, or elderly MRI: to identify areas of CNS involvement n Temporal involvement with HSV n Basilar meningitis with TB

The Lumbar Puncture: Risks n n Headache: 10 -25% n Typical: appears suddenly upon standing n Decrease CSF pressure with small leak n Decrease risk: small (<20 g) needle, leave patient prone after procedure n Blood patch Infection (small) Local bleeding: traumatic tap to epidural hematoma Brain herniation

The LP n Opening Pressure n Important data n Only in lateral decubitus (not position usually done under radiology) n Xanthochromia n Yellow/orange color of centrifuged CSF n RBC lysis – oxyhemoglobin, bilirubin n Blood in subarachnoid space at least 2 -4 hrs n More likely due to blood in CSF and less likely traumatic tap

CSF Findings Normal WBC (TNC) Bacterial Viral Fungal TB other 0 -5 10010, 000 5 -3000 5 -500 paraneo >50% PMN >50% lymphs Monoclon al, atypia increased Cell type Protein 50 -80 mg/d. L >200 Nl/slight increase Increase Glucose 70 -80 mg/d. L >60% serum <40, <60% of serum glucose Normal normal <40 or nl decrease 60% + Neg 50% india ink + crypto AFB + 25 -35% Inc Nl/inc Gm stain Pressure 75 -200 mm Hg

CSF: Some Catches n n n Protein least specific TB: early neutrophilic predominance Encephalitis, RMSF, tick-borne illnesses: inc CSF WBC Listeria: misread as “contamination”/diphtheroids Listeria: bacterial meningitis that can have significant encephalitis and abscess, and CSF with lymphocytes! RBCs that do not clear: SAH or HSV

CSF: More Pearls n Correction factors for traumatic tap n n n “trauma” and RBCs increase protein and with an increase in RBCs come an increase in WBCs True CSF protein = subtract 1 mg/d. L protein for every 1000 RBC/mm 3 True WBC in CSF: actual WBC in CSF – (WBC in blood x RBC in CSF)/ RBC in blood

Meningitis: Specific Causes

Strep Pneumoniae Meningitis n n n Now most common cause (H flu rare) 30 -50% cases of bacterial meningitis in elderly Otitis 30%, sinusitis 8%, pneumonia 18% Elderly more often have pneumonia (bad) Bad markers: older age, low platelets, dec CSF glucose, no otogenic focus Vaccination: recommended in all over age 65 n Efficacy in elderly/immunocompromised NOT clear n Decrease bacteremia/meningitis

Listeria n n n Food-borne outbreaks Herd animals Common, likely cause of mild GI illnesses Invasive disease with bacteremia and CNS involvement may follow other GI infection (piggy back…) Increased risk with depressed cellular immunity: pregnant women, elderly, AIDS, lymphoma, steroid use, transplant patients

Listeria… n n n n Small, anaerobic gm + baccillus Look like diphtheroids, contaminants Cerebritis, brain abscess Confusion, altered LOC, seizure, movement Mortality 22% in older patients with CNS dz 20% of all cases of bacterial meningitis in patients over age 60 Brain abscess: 10% CNS infections n Usually due to bacteremia n Concomitant meningitis in 25 -40% (rare with other causes of brain abscess)

Listeria… Big Points n n NOT uncommon in elderly Meningitis, encephalitis, focal brain abscess Add Ampicillin Diphtheroids in CSF: listeria unless proven otherwise

TB Meningitis n n n Tuberculous meningitis (most common) Intracranial tuberculomas Spinal tuberculous arachnoiditis n Meningitis: inflammation from rupture of subependymal tubercle into subarachnoid space n Basilar meningitis, CN palsies, hydrocephalus n Subacute or chronic n Initial neutrophilic pattern on CSF n Very high CSF protein may be seen n AFB smears often neg; need HIGH volume sent to lab

Viral Meningitis n n n Aseptic meningitis May be difficult to initially separate from partially treated bacterial meningitis (obligates empiric treatment for bacterial) Differentiate from true aseptic (drug related such as NSAIDs, paraneoplastic)

Viral Meningitis n n Finland study: etiology found in 66% patients with aseptic meningitis Viral encephalitis: etiology only found in 36% cases Viral prodrome, sore throat, myalgias, ill contacts, GI complaints; summer/fall season Most common= enteroviruses (25%) n Echoviruses n Coxsackievirus

Viral Meningitis n Less common causes n Adenoviruses: URI sxs, year round n CMV, EBV, HIV, influenzae n Measles, mumps, rabies, rubella, varicella n ? future avian flu (usually not CNS sxs, more URI/pneumonia/ARDS and DIC)

Encephalitis: Specific Causes

Encephalitis Lethargica… n n The Awakenings… 1916: von Economo described CNS disorder with lethargy and Parkinsonian features following viral syndrome with pharyngitis 1916 -1927 epidemic; now sporadic cases 1918: influenza pandemic, ? connection (? immune mediated process)

Encephalitis n n More likely to be viral Etiology only found in 35% cases n HSV-1: 10% cases (but accounts for over 50% cases in patients over 50) n HSV-2 n VZV (? up to 10% in some series) n Tick or insect borne diseases: 10%

Encephalitis n Acute Viral Encephalitis n Direct viral infection of neuronal cells n Perivascular inflammation n Destruction of gray matter n Post-Infectious Encephalomyelitis n Follows viral or bacterial infection n Demyelination of white matter n ? autoimmune component triggered by infectious agent

HSV Encephalitis n n n 2 -4 cases/million people/year Acute infection or more commonly reactivation of latent infection (trigeminal nerve ganglion) Characteristic site of damage: temporal lobe n MRI findings of necrosis in temporal lobe n Necrosis = RBC s on CSF!

HSV Encephalitis n n n Dysphasia, bizarre behavior, seizures Abnormal EEG High mortality: 30% with treatment Survivors: 10% long term disability Fever +/Treatment: Acyclovir (60 -75% mortality without treatment)

HSV Encephalitis: Big Points n n n Odd behavior, think encephalitis If thinking encephalitis, add acyclovir RBCs on CSF (with xanthochromia or lack of clearing between tube 1 and 4), think HSV Temporal symptoms Temporal necrosis or abnormalities on MRI

Arboviruses and Encephalitis n n n Arbovirus: Arthropod Borne Virus RNA viruses transmitted by mosquitoes or ticks 10 % cases of sporadic encephalitis (? higher in elderly, up to 50% cases during epidemics)

Arboviruses and Encephalitis n Alphavirus family: n Eastern Equine Encephalitis ** n Western Equine Encephalitis n Flavivirus family: n St Louis Encephalitis ** n Japanese Encephalitis n California Encephalitis n West Nile Virus **

West Nile Virus and Encephalitis in the Elderly

West Nile Virus n 1937: West Nile district Uganda (mild cases) n Middle east/ Israel (14% fatality) n 1996: outbreak in Romania (4% fatality) n 1999: NY outbreak (11% fatality) n Subsequent west spread to most states n 2002: 4156 reported cases in US, 284 deaths n 2003: 9858 cases, 262 deaths

West Nile Virus n n n Season: summer Mosquito transmission (currently infects 43/ 174 different types of North American mosquitoes) Other routes n Placenta n Lactation n Transfusion n Organ transplant

West Nile Virus n n n Disease of the elderly Higher mortality in elderly Other risk factors not clear (? maybe HTN and DM leading to better virus entry)

WNV: Predictors n Admission diagnoses: n 30%: aseptic meningitis n 15%: fever n 18%: viral infection n 14%: UTI n 10% pneumonia n 7% : encephalitis n 5%: probable WNV (year 2001) n Mortality rates highest with: Initial diagnosis of encephalitis (35% of those who died), No headache (50% had HA, 7% those that died had HA), and Initial mental status changes n n n

WNV n Presenting symptoms n HA, fever, mental status changes n CN findings, optic neuritis n Myoclonus n Flaccid Paralysis n With or without encephalitis n Asymmetric weakness/paralysis, no sensory loss n Anterior horn cells (polio like) n Absent DTRs

WNV n Movement Disorders n Parkinsonian n Tremors n Bradykinesia n Cogwheel rigidity n Postural instability n Masked facies n 80 -100% will have rest or intention tremor n 30% will have myoclonus

WNV: Diagnosis n n n High index of suspicion CSF: usually 200 TNC; 5 -10% can have over 500 TNC, 5% with < 5 TNC CSF with 50% neutrophils Elevated CSF protein CSF for ab studies: anti WNV ab, and negative SLE Ig. M (up to 40% cross reactivity in earlier studies)

WNV: Treatment n n ? nucleoside analogues (ribavirin – no benefit in Israel) Human Immunoglobulin : protective antibodies (patients from Israel with high titers of anti-WNV ab); if effective, only in early disease ? vaccine development (effective in horses in 2001) ? inactivated JEV vaccine?

Meningitis and Encephalitis: Others

Tick-Borne Diseases RMSF ** n Lyme Disease ** n Ehrlichiosis ** n STARI ** n Tularemia n Babesiosis n Colorado Tick Fever n

Rocky Mountain Spotted Fever n Rickettsia rickettsii n Gm negative intracellular bacteria n Endothelial cells: small vessel vasculitis n Southeast, summer Dog Tick, Wood Tick 2 nd most common tick-borne illness n n n Fever/headache/nausea/rash 80% Rash: blanching maculopapular, palms/soles, spreads centrally, later petechial and purpuric Hyponatremia, thrombocytopenia, inc ALT CSF: inc TNC, inc protein; neg gram stain

RMSF: Diagnosis n n Clinical suspicion Low threshold to empirically treat Rash may be absent in 20% RMSF serologies: initial may be negative; need convalescent titers several weeks later

RMSF: Treatment n n n Doxycycline 100 BID Do not delay ? newer quinolones: probably, but no studies and no recommendations No indication for prophylactic treatment after uncomplicated tick bite Prevention: frequent inspection

RMSF: Big Points n n n Empiric Treatment if even suspected In North Carolina, any fever, HA, neuro syndrome will need treatment First serology titers NOT reliable Hyponatremia, low platelets, elevated LFTs, think RMSF… Do not wait for the rash…

Lyme Disease n n Borrelia burgdorferi Deer Tick (smaller) NE/Great Lakes, but reported in almost all Stages n 1: erythema migrans rash, viral-like syndrome n 2. early disseminated phase, secondary cutaneous n 3. late/chronic: arthritis, cns involvement (CN palsies), myocardial damage

STARI n n Southern Tick Associated Rash Illness Lyme-like infection in North Carolina with negative Lyme serologies Lone Star Tick Borrelia lonestari

Ehrlichia n n n “Rashless” RMSF n Fever, headache n CSF: pleocytosis, neg gm stain, inc protein Hyponatremia, thrombocytopenia, elevated LFTs Lone Star tick, Dog Tick Same treatment as RMSF Serologies and convalescent titers

Overall Picture: Diagnosis n n n Difficult to initially separate meningitis from encephalitis in elderly; both present with mental status changes; elderly with meningitis less likely to have fever Other infections cause delirium in elderly Red flags n Any CNS focality n Behavioral changes/personality changes n Seizures n Lack of other source of infection n Headache, ? nuchal rigidity, ill contacts n Season, outdoor activity n Low threshold to do LP

Overall Picture n Main Players n Strep pneumoniae n Listeria n Viral agents such as enteroviruses n HSV n Arboviruses (including WNV now) n Tick-borne bacteria (RMSF, ehrilchia, STARI)

If things are not adding up… n Less common causes n VZV n Rabies virus n Post-measles, mumps, cmv, ebv n Adenoviruses n TB n Protozoa n Cryptococcus n Gm negatives: klebsiella, e coli

Diagnosis n CSF n Elevated protein least specific n Acute bacterial meningitis usually has high TNC, low glu, unless partially treated or listeria n More than 2 -3 TNC is not normal n Gram stain, culture, PCR for HSV, viral studies for enteroviruses, serologies for arboviruses n Latex agglutination studies: NOT helpful n Serum for RMSF/ehrlichiosis titers: initial and convalescent titers

Treatment n n n Initial empiric treatment OK to shotgun pending culture and test results the first 24 - 48 hours! Risk of s. pneumoniae resistance and high mortality of untreated disease – vancomycin initially

Treatment: Dexamethasone n Acute bacterial meningitis n Decreased mortality/morbidity (20 min prior to abx) n Recommended: proven S. pneumoniae, high opening pressure, pos gm stain n Not clear with other causes, subgroups like elderly n Probably not bad effects with viral causes n Dose: . 4 mg/kg Q 6 hrs for 2 -4 days n ? decrease vancomycin crossing blood-brain barrier

Treatment Summary n n n n Vancomycin Ceftriaxone/cefotaxime Ampicillin Acyclovir Doxycycline ? dexamethasone OK to cover for all for first 24 -48 hours, then narrow based upon CSF results and serologies

CASES n 1. Active 78 -y/o man with prior hx of aortic valve replacement years ago, presents with fever, slight confusion, dehydration. n Initial concern for SBE, but CSF : TNC of 20. n n His serum Na 128. All cultures negative. What would the DDX include?

CASES n 2. 85 -y/o with severe dementia admitted with fever, ? stiff neck and worsening confusion and lethargy. n CXR and U/A are negative. n What would you do?

CASES n n n 3. Healthy community living 75 -y/o presents with personality changes, confusion, agitation. She has no fever, no other evidence of infection. What to do?

CASES n 4. 80 -year-old man presents with low grade fever and coma after several days of myalgias and viral like illness. n Exam is notable for some Parkinsonian type features… n initial concern would be for ?