CNS-infektioner (feber o huvudvärk)

Question 1

1. Vad finns det för CNS-infektioner?

Answer 1

MENINGIT

Meningitis = An inflammation of the meninges, especially the arachnoid mater and the pia mater, often secondary to infection. Edema and inflammatory infiltrates lead to fever, focal neurological deficits, decreased level of consciousness, and seizure.

• Infectious causes can be bacterial, viral, fungal, or parasitic
• While the etiology is usually infectious, ultimately it is the inflammatory changes in the CNS that cause morbidity and mortality
• bakteriell: subaraknoidalrummet, via blod, näraliggande t ex sinus, mellanöra, trauma, 50% S pneumoniae, 12% N meningitidis
• viral: se nedan

HJÄRNABSCESS

• bakteriell, fokal i hjärnparenkymet, oftast omgiven av vaskulariserad kapsel (annars “cerebrit”), via emissarievener från tänder, sinus, öron, hemotgent, trauma; α-strep, anaerober (bacteroides, fusobakterier), S aureus, HI, pseudomonas

ENCEFALIT

MENINGOENCEFALIT

MYELIT = inflammation i ryggmärgen

VIRALA CNS-INFEKTIONER

Lokus kontinuum: meningit - meningoencefalit - encefalit (TBE och HSV1 mer benägna att ge encefalit än övriga)

• olika virus har olika benägenhet att infektera CNS EBV 1%, rabies 100% och varierande preferens för olika lokus; vanligaste: enterovirus, TBE, VZV, HSV1&2, EBV

Question 2

BAKTERIELL MENINGIT

1. Vad är det?
2. Spridningsvägar?
3. Etiologi - vanligaste agens?
4. Vilken är den förväntade etiologin i följande fall:
   
   1. spädbarn, gamla
   2. immunosuppression
   3. sluten skallfraktur
   4. öppen skallfraktur
   5. post neutokirurgi
   6. iv missbruk

Answer 2

BAKTERIELL MENINGIT
= bakteriell infektion i subaraknoidalrummet

Spridningsvägar:

• Hematogent – via kolonisation av övre luftvägar eller avlägset fokus
• Parameningealt fokus – sinus, mellanöra
• Direkt implantation – trauma, neurokirurgi, LP

Vanligaste agens:

1. S pneumoniae – 52 %
2. N meningitidis – 12 %
3. H influenzae – 6 %
4. L monocytogenes – 4 %
5. S aureus – 4 %
6. Betahemolytiska strep 4 %

Pneumococcal infections are caused by Streptococcus pneumoniae, a gram-positive, catalase-negative organism commonly referred to as pneumococcus. S pneumoniae is the most common cause of community-acquired pneumonia (CAP), bacterial meningitis, bacteremia, and otitis media, as well as an important cause of sinusitis, septic arthritis, osteomyelitis, peritonitis, and endocarditis. Complications of each of these diagnoses are common. See the image below. Clinical signs and symptoms and physical examination findings alone cannot distinguish S pneumoniae disease from infections caused by other pathogens.

Epidemiology

S pneumoniae can cause a wide variety of clinical symptoms owing to its ability to cause disease by either direct extension from the nasopharynx into surrounding anatomic structures or vascular invasion with hematogenous spread. Features that should prompt the clinician to consider pneumococcal infection include the following:

• High-risk age groups (children younger than 5 years, particularly aged 2 years or younger; adults older than 55-65 years)
• Conditions that cause immune deficits (eg, HIV infection, malignancy, or diabetes mellitus)
• Conditions associated with decreased pulmonary clearance functions (eg, asthma, chronic bronchitis, or chronic obstructive pulmonary disease [COPD])
• Presentation from late fall to early spring

Conditions that may develop by direct extension of S pneumoniae from the nasopharynx include the following:

• Conjunctivitis
• Otitis media
• Sinusitis
• Acute exacerbations of chronic bronchitis (AECB)
• Pneumonia (which may be complicated by purulent pericarditis)

Conditions that may result from vascular invasion and hematogenous spread of S pneumoniae include the following:

• Meningitis
• Bacteremia (most common manifestation of invasive pneumococcal disease)
• Joint and bone infections (osteomyelitis and septic arthritis)
• Soft tissue infections (eg, myositis, periorbital cellulitis, abscess)
• Peritonitis
• Cardiac infections (eg, endocarditis)

Neisseria meningitidis, often referred to as meningococcus, is a gram negative bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life-threatening sepsis. The bacterium is referred to as a coccus because it is round, and more specifically, diplococcus because of its tendency to form pairs. About 10% of adults are carriers of the bacteria in their nasopharynx.[1] As an exclusively human pathogen it is the main cause of bacterial meningitis in children and young adults, causing developmental impairment and death in about 10% of cases. It causes the only form of bacterial meningitis known to occur epidemically, mainly in Africa and Asia. N. meningitidis is spread through saliva and respiratory secretions during coughing, sneezing, kissing, and chewing on toys. It infects the cell by sticking to it with long thin extensions called pili and the surface-exposed proteins Opa and Opc and has several virulence factors.

All recent contacts of the infected patient over the 7 days before onset should receive medication to prevent them from contracting the infection. This especially includes young children and their child caregivers or nursery-school contacts, as well as anyone who had direct exposure to the patient through kissing, sharing utensils, or medical interventions such as mouth-to-mouth resuscitation. Anyone who frequently ate, slept or stayed at the patient’s home during the 7 days before the onset of symptom, or those who sat beside the patient on an airplane flight or classroom for 8 hours or longer, should also receive chemoprophylaxis. The agent of choice is usually oral rifampicin for a few days.

Meningococcal disease is very serious and can be fatal. In fatal cases, deaths can occur in as little as a few hours. Anyone can get meningococcal disease, but certain groups of people are at increased risk. Although meningococcal disease is found worldwide, the “meningitis belt” of sub-Saharan Africa has the highest rates in the world. In addition to the meningitis belt, travelers to the Hajj pilgrimage in Saudi Arabia are also at risk.

Meningococcal vaccine refers to any of the vaccines used to prevent infection by Neisseria meningitidis.[1] Different versions are effective against some or all of the following types of meningococcus: A, C, W135, and Y. The vaccines are between 85 and 100% effective for at least two years.[1] They result in a decrease in meningitis and sepsis among populations where they are widely used.[2][3] They are given either by injection into a muscleor just under the skin.[1]

The World Health Organization recommends that countries with a moderate or high rate of disease or with frequent outbreaks should routinely vaccinate.[1][4] In countries with a low risk of disease, they recommend that high risk groups should be immunized.[1] In the African meningitis belt efforts to immunize all people between the ages of one and thirty with the meningococcal A conjugate vaccineare ongoing.[4] In Canada and the United States the vaccines effective against all four types of meningococcus are recommended routinely for teenagers and others who are at high risk.[1] They are also required for people travelling to Mecca for Hajj.[1]

Safety is generally good. Some people develop pain and redness at the site of injection.[1] Use in pregnancy appears to be safe.[4]Severe allergic reactions occur in less than one in a million doses.

Förväntad etiologi:

1. Spädbarn, gamla: De vanligaste (= _S. pneumoniae_, Neisseria meningitidis, H. influenzae, L. monocytogenes, S aureus, Betahem strep) + Listeria och gramneg (tex E.coli)
2. Immunosuppression: Listeria, gramneg, TB, opportunister (tex svamp, toxoplasma)
3. Sluten skallfraktur: pnkk (= pneumokocker), HI
4. Öppen skallfraktur: S. aureus
5. Post neurokirurgi: S. aureus, KNS, gramneg
6. I.v. missbruk: S. aureus

• Neonates < 3 mån: Strep B, E coli, Listeria
• Barn: S pneumoniae, N meningitidis, HI typ B
• Vuxna: S pneumoniae, N meningitidis (tillsammans 80 % av alla fall)
• Äldre > 65 år: S pneumoniae, N Meningitidis, Listeria

If no organism can be isolated with routine culture and sensitivity assays of cerebrospinal fluid (CSF), the condition is called aseptic meningitis, and the etiology is likely viral (e.g. Enterovirus, HIV and HSV). Less common etiologies for aseptic meningitis include tuberculous meningitis (Mycobacterium tuberculosis), Lyme disease (Borrelia spp.), parasitic infections (e.g. Taenia solium, Toxoplasma gondii), and malignancy.

Koagulasnegativa stafylokocker (KNS) är en gruppbeteckning för ett antal bakteriearter (varav ett 40-tal inom genus Staphylococcus) som inte producerar enzymet koagulas, vilket skiljer dem från S. aureus. S. epidermidis är vanligaste species och finns i hudens normalflora. Exempel på andra arter är S. cohnii, S. haemolyticus, S. schleiferi subsp schleiferi, S. pettenkoferi och S. warneri. S hyicus (patogen för hästar, boskap) kan ibland vara koagulaspositiv. Sjukdomsframkallande förmågan är låg men infektioner utgående från främmande kroppar förekommer. Sjukhusstammar är ofta antibiotikaresistenta. Vanliga kontaminanter.

Staphylococcus epidermidis är den vanligaste koagulasnegativa stafylokocken i hudens normalflora. Den har låg sjukdomsframkallande förmåga men kan ge infektioner utgående från främmande kroppar. Sjukhusstammar är ofta antibiotikaresistenta. Vanlig kontaminant.

Staphylococcus lugdunensis kan ge abscesser, septikemi, endokardit, graft- och protesinfektioner m.m. Infektionerna har ofta ett mer akut förlopp än man väntar sig av koagulasnegativa stafylokocker. Dock ses långdragna svårbehandlade infektioner av typ hidroadenit, paronyki och mastit.

Staphylococcus saprophyticus kan ge kraftig akut cystit hos kvinnor främst i fertil ålder. Ofta täta miktioner vilket ger låga bakterietal vid urinodling.

Övriga koagulasnegativa stafylokocker

Endast ett fåtal arter av gramnegativa katalaspositiva arter som inte hör till genus Staphylococcus har identifierats som orsak till humana infektioner.

Micrococcus, Arthrobacter, Kytococcus och Kocuria är grampositiva kocker närmast släkt med koagulasnegativa stafylokocker och inbegrips i gruppbeteckningen KNS. De finns i naturen och i huden hos människor och djur. Låg sjukdomsframkallande förmåga, men har associerats med endokardit, pneumoni och sepsis hos immunsupprimerade patienter.

Alloiococcus otitis hör till normal hörselgångsflora och kan möjligen orsaka lokal infektion i öra.

Listeria monocytogenes är en kort, stavformad grampositiv bakterie som är vanligt förekommande i vatten, jord och vegetation. Många djurarter kan vara bärare av listeria.
Livsmedel som förvaras lång tid i kylskåp och sedan förtärs utan föregående tillagning utgör risk för smitta. Detta gäller både färdiglagade köttprodukter, fisk (t ex kallrökt/gravad lax) och dessertostar tillverkade på opastöriserad mjölk.
Trots att listeria är vanligt förekommande i vår miljö, diagnostiseras bara cirka 60-100 personer per år i landet med listerios, varav endast 1-5 drabbar gravida kvinnor.
Sjukdomen är anmälningspliktig. Smittspårning skall utföras. Fråga efter misstänkta livsmedel och djurkontakter. Tänk speciellt på opastöriserad mjölk, dessertostar och andra livsmedel som ej upphettats före förtäring.

KLINIK OCH SYMTOM

• Hos vuxna är sepsis eller meningit vanligast. Det är främst äldre och personer med kortison- eller annan immunosuppressiv behandling som drabbas. Se behandlingsöversikt - “Meningit - bakteriell.
• Gravida kvinnor är också en riskgrupp för listerios och kan insjukna i influensaliknande symptombild. Infektion som leder till missfall är ovanligt.
• Även helt friska personer kan insjukna i listerios (oftast meningit), om smittdosen blir tillräckligt stor.
• Hos nyfödda förekommer två former av listeriainfektion; en tidig form (första levnadsveckan) dominerad av svår septisk sjukdom och en sen form (1-2 veckor efter förlossningen) dominerad av meningitbild. Smittspridning kan ha skett nosokomialt vid den senare formen eftersom det ibland finns fall med tidig sjukdom som fötts på samma förlossningsavdelning. Smittspridningen vid den tidigare formen har sannolikt skett intrauterint.
• Det finns en lindrigare febril, gastrointestinal form av listerios, som även drabbar immunkompetenta individer och som lätt kan förväxlas med viral gastroenterit. Incidensen av denna manifestation är osäker eftersom standardodlingar från faeces inte upptäcker listeria.

Question 3

BAKTERIELL MENINGIT 2

SYMTOM

1. Vilka tre symtom uppträder hos 90 %?
2. Fler symtom?

Answer 3

1. 90 % får huvudvärk, feber, nackstyvhet

2 Fler symtom:

1. Illamående/kräkningar
2. Ljus-/ljudskygghet
3. Symptom från öron/bihålor
4. Kognitiva symptom
5. Medvetandesänkning
6. Kramper
7. Fokal neurologi
8. Septiska symptom
9. Petekier

Clinical features and pathophysiology

Symptom: Chills, rigors

Sign: Fever (T>38°)

Mechanism: Endogenous cytokines (released during the immune response to the invading pathogens) affect the thermoregulatory neurons of the hypothalamus, changing the central regulation of body temperature.

Invading viruses or bacteria produce exogenous substances (pyrogens) that can also re-set the hypothalamic thermal set point.

Symptom: Nuchal rigidity (neck stiffness)

Sign: Brudzinski sign and Kernig sign

Mechanism: Flexion of the spine leads to stretching of the meninges.

In meningitis, traction on the inflamed meninges is painful, resulting in limited range of motion through the spine (especially in the cervical spine).

Symptom: Altered mental status

Sign: Decreased Glasgow Coma Scale (GCS)

Mechanism: ↑ ICP → brain herniation → damage to the reticular formation (structure in the brainstem that governs consciousness)

Symptom: Focal neurological deficits, e.g. vision loss

Sign: Examples: cranial nerve palsies, hemiparesis, hypertonia, nystagmus

Mechanism: Cytotoxic edema and ↑ ICP lead to neuronal damage.

Signs or symptoms depend on the affected area (cerebrum, cerebellum, brainstem, etc.)

Symptom: Seizures

Sign: n/a

Mechanism: Inflammation in the brain alters membrane permeability, lowering the seizure threshold. Exact seizure pathophysiology is unknown.

Symptom: Headache

Sign: Jolt accentuation of headache: headache worse when patient vigorously shakes head

Mechanism: Bacterial exotoxins, cytokines, and ↑ ICP stimulate nociceptors in the meninges (cerebral tissue itself lacks nerve endings that generate pain sensation).

Symptom: Photophobia

Sign: n/a

Mechanism: Due to meningeal irritation. Mechanisms unclear; pathways are thought to involve the trigeminal nerve.

Symptom: Nausea and vomiting

Sign: n/a

Mechanism: ↑ ICP stimulates the area postrema (vomiting centre), causing nausea and vomiting.

Symptom and sign: Petechial rash

Mechanism: Meningococcemia (due to N. meningitidis)

In the pediatric population, all of the above signs and symptoms are applicable. Additional signs and symptoms in children include:

• Bulging fontanelles
  
  • Bones of the skull do not join fully (form sutures) until age 2
  • ↑ ICP → meninges protrude through gaps in skull bones
• Jaundice
  
  • Impaired bilirubin excretion
  • Exact mechanism unclear, associated with sepsis
• Reduced feeds, irritability, lethargy, and toxic appearance
  
  • Fever, shock and cerebral edema can lead to such manifestations in children

​

Question 4

BAKTERIELL MENINGIT 3

Beskriv mekanismerna för uppkomst av hjärnskada vid bakteriell meningit

Answer 4

Question 5

BAKTERIELL MENINGIT 4

Vilken andel blir fullt frisk, dör, resp får men?

Vilka sekvelae förekommer?

Handläggning?

När bör man avvakta med LP?

Vad bedömer GCS? Vilket intervall ligger poängen i?

BEHANDLING: Vilka lkm ges? Motiv?

Answer 5

50 % tillfrisknar helt, 15 % dör, 35 % får sekvelae.

Ex på sekvelae:

hörselnedsättning (18 %), epilepsi, pareser, HV, yrsel, kognitiva besvär, balansrubbning, hydrocefalus

Handläggning

OBS: snabb beh = mindre hjärnskada!!

• Säkra 2 infarter
• Ge syrgas och vätska
• LP m tryckmätning efter grovt neurologiskt status (glöm ej GCS!)
• Odla från likvor, blod, NPH, svalg ev öronsekret
• Ge steroider + antibiotika (beh helst< 30 min!)
• Kem-prover (likvoranalys, blodstatus, CRP, elektrolyter, koagulation…)
• Kompletterande status

Avvakta med LP …

• Vid tecken på kraftigt stegrat ICP :
  
  • medvetslöshet (GCS 8 el lägre)
  • snabbt sjunkande medvetandegrad
  • uttalad psykomotorisk oro

–> Ta övriga odlingar och sätt in beh, kontakta därefter intensivvårdsavd (helst neurokirurgisk) direkt för övertagning

• Vid fokala neurologiska symptom, tex:
  
  • hemipares, dysartri (talstörning pga nedsatt motorisk kontroll), synbortfall

–> Ta övriga odlingar och sätt in beh, uteslut hjärnabscess m DT före LP

• Vid koagulationspåverkan (TPK < 30 [kv: 165-387; män: 145-348], INR > 1,6 [< 1,2])

–> Ta övriga odlingar och sätt in beh, korrigera koagulationsrubbningen och gör därefter LP

• Vid pågående epileptiskt anfall

–> Ta övriga odlingar och sätt in beh, ge antiepileptika och gör därefter LP

OBS:

• Inklämningsrisken är ofta överskattad!
• Ge alltid behandling även om du skjuter upp eller avstår från LP!

GCS: ger 3 - 15 p, bedöm eye opening, verbal response, motor response

Läkemedel: antibiotika + steroider

1. Antibiotika: cefotaxim 3gx4 + ampicillin 3gx4
   (alt: meropenem 2gx3)
2. Steroider:

• Motverkar inflammationspåslaget vid antibiotikainducerad bakteriolys
• ↑ överlevnad ↓ sekvelae – (bevisat för pneumokocker och HI)
• Skall ges till alla m samhällsförvärvad bakteriell meningit
• Ges omedelbart före el i samb. med första antibiotikadosen
• vanligast: betametason – 0,12 mg/kg (max 8 mg) iv x 4 i 4d

****

Treatment (McMaster)

The goal of treatment is to maintain cerebral perfusion pressure by preserving the mean arterial pressure (e.g. fluid resuscitation) and normalizing intracranial pressure (e.g. elevating the head, hyperventilation, controlling seizure activity; hyperventilation causes hypocapnia-mediated cerebral vasoconstriction).

Cerebral perfusion pressure = Mean arterial pressure – ICP

The mainstay of treatment for bacterial meningitis is antibiotics; choice of antibiotic depends on the organism isolated from blood and CNS cultures. Any delay in treatment results in increased morbidity and mortality, so antibiotics are often started empirically based on the age of the patient (see table in Etiology above) and any risk factors they may have (e.g. if they are immunocompromised or have recently had neurosurgery). The antibiotic regimen is then adjusted once the causative organism is known. Corticosteroids can be used adjunctively to reduce inflammation in the brain if the pathogen is Streptococcus pneumoniae.

In viral meningitis, the treatment is supportive. In patients with suspected Herpes Simplex Virus (HSV) infection, empiric antiviral therapy is started to prevent complications of HSV encephalitis.

Distinguishing between viral and bacterial meningitis is done using blood and CSF cultures, as well as lumbar puncture opening pressure (which reflects ICP) and CSF analysis.

Parameter: Opening pressure (N: 8-20 cm H2O)

Bacterial meningitis: Elevated (20-30 cm H2O)

Viral meningitis: Normal or mildly increased

Mechanism: Increased inflammation in bacterial meningitis results a higher ICP and thus a high opening pressure.

Parameter: CSF glucose (N: 2.8-4.4 mmol/L; blood:CSF glucose ratio is normally 0.3-0.9)

Bacterial meningitis: Decreased (<2.2 mmol/L)

Viral meningitis: Normal

Mechanism: In bacterial meningitis, glucose transport from the blood into the CSF is impaired; inflammation of the meninges leads to decreased glucose receptor expression. There is also increased anaerobic glycolysis by leukocytes and brain cells.

Parameter: CSF protein (N: 0.15-0.45 g/L)

Bacterial meningitis: Very high >1.5 g/L

Viral meningitis: Mildly increased 0.5-2 g/L

Mechanism: Bacterial meningitis leads to a more permeable blood brain barrier (due to increased inflammation). Protein leaks into the subarachnoid space from the blood, resulting in markedly increased CSF protein levels.

Surgical management is indicated where there is extremely increased intracranial pressure, infection of an adjacent bony structure (e.g. mastoiditis), skull fracture, or abscess formation.

Internetmedicin om bakteriell meningit och Nationellt vårdprogram för bakteriell meningit

INITIAL HANDLÄGGNING

Den initiala handläggningen är helt avgörande för utgången. Bakteriell meningit är ett akut tillstånd som skall handläggas med stor skyndsamhet. Telefonkontakt tas med närmaste infektionsklinik.

1. Lumbalpunktion (LP) omedelbart! Andra undersökningar som t ex datortomografi av hjärnan skall ej utföras innan LP är gjord. LP bör vara utförd inom 10-15 minuter efter det att patienten kommit till akutmottagningen. Finns kontraindikation mot LP, t ex tecken till inklämning (djup medv.-löshet + ljusstela pupiller, ändrat andn.-mönster, stigande BT + bradykardi eller reaktionslöshet), eller om patienten står på antikoagulationsbehandling, eller om LP misslyckas eller av något annat skäl inte kan utföras, ges antibiotika direkt utan att LP utförs innan patienten skickas vidare.

Om patienten har tecken på intrakraniell tryckstegring kan insättande av ventrikeldrän och aktiv trycksänkande behandling på neurokirurgisk intensivvårdsavdelning (NIVA) vara aktuellt. Sådan behandling är dock inte vetenskapligt validerad på patienter med bakteriell meningit.

Likvor tas för:

a. cellräkning, glukos, albumin, laktat (1 ml)
b. odling och gramfärgning (1-2 ml)
c. extrarör (2-3 ml) för eventuell senare analys

Obs! Vänta inte på svar av likvoranalysen innan antibiotika ges.

2. Blododling, sätt nålar och ta övriga blodprover (Hb, LPK, diff., TPK, elstatus, leverstatus, PTK, APTT, CRP, p-glukos) samtidigt som LP görs. Odla från andra infektionsfokus om möjligt (hörselgång vid perforerad otit, nasopharynx vid pneumoni eller otit).

3. Antibiotika (se nedan)

4. Kortikosteroider, dexametason 0,15 mg/kg x 4 i fyra dygn med max 10 mg/dos alt Betametason 0,12 mg/kg x 4 i fyra dygn - rekommenderas till alla meningitpatienter. Ges före, eller senast samtidigt som första antibiotikadosen med syfte att minska risken för sekvele.

Seponeras tidigare än efter 4 dygn om meningokocker verifieras och kan också sättas ut tidigare hos alla patienter vid snabb klinisk förbättring.

Det är sedan länge känt att den lokala inflammationen i CNS spelar en avgörande roll för skadeutvecklingen vid akut bakteriell meningit. I djurstudier kunde man tidigt visa att bakterielys efter initial antibiotikabehandling gav upphov till förstärkt inflam- matoriskt svar vilket var associerat med förhöjd mortalitet. Adjuvant behandling med glukokortikoid medförde i dessa studier en dämpning av inflammationen i CNS och minskade neurologiska sekvele (1,2). En viktig experimentell observation som gjordes på 80-talet var att steroiden måste ges strax innan eller samtidigt med första antibiotikadosen för att ha någon tydlig antiinflammatorisk verkan. Vid fördröjning en timme uteblev effekten. Orsaken är att det omfattande sönderfall av bakterier som äger rum i samband med den första antibiotikadosen ibland orsakar en kraftig ökning av den inflammatoriska aktiviteten i likvor.

Rekommendation

Arbetsgruppens bedömning är att det finns stöd för adjuvant steroidbehandling av vuxna med ABM i Sverige. Då några negativa effekter inte kunnat påvisas anser vi att adjuvant steroidbehandling bör ges initialt till samtliga vuxna patienter med ABM oavsett sannolik etiologi (BII). Om annan diagnos än pneumokocker framkommer kan man överväga seponering av kortikosteroider.

I samband med, helst före, den första antibiotikadosen inleds iv. steroidbehandling. Det preparat som genom sin höga lipidlöslighet och härigenom goda penetration till CNS bedömts som mest lämpligt och också använts i flertalet kliniska studier är dexametason (Decadron®, Oradexon®). Preparatet är avregistrerat i Sverige men kan fås på licens.

Betametason (Betapred®, Celeston®) uppvisar också god penetration till CNS och är väl beprövat i neurokirurgiska sammanhang och rekommenderas som alternativ då dexametason inte finns tillgängligt.

Steroidbehandlingen kan seponeras tidigare än efter 4 dagar om meningokocketiologi verifieras och/eller efter två dygn vid snabb klinisk förbättring. (Det finns visst särskilt bra stöd för minskad mortalitet vid pneumokock-etiologi.)

Vidare handläggning

• Patienten bör vårdas på intensivvårdsavdelning på infektionsklinik, på neuro-IVA eller på allmän IVA
• Respiratorbehandling ofta nödvändig
• Ibland behandling av samtidig septisk chock (för mer information se separat behandlingsöversikt Sepsis och septisk chock)
• Undvik att ge stora mängder kristalloida lösningar.

ANTIBIOTIKA

Initialt kan antibiotika väljas enligt nedan (modifieras efter odlingssvar). I vårdprogrammet för bakteriella CNS-infektioner från Svenska Infektionsläkarföreningen rekommenderas 4 doser beta-laktam-antibiotika per dygn grundat på beta-laktamernas korta halveringstid. Det finns inga studier som visat att 4 doser per dygn ger bättre resultat än 3 doser. Traditionellt har regimer med 3 doser per dygn använts i Sverige, med mycket goda kliniska resultat. Båda alternativen anges nedan.

Vuxna och barn > 6 mån

Cefotaxim (Claforan) 3 g x 4 i.v. (< 40 kg 75 mg/kg x 3-4) eller ceftriaxon (Rocephalin) 4 g x 1 i.v. (< 40 kg 100 mg/kg x 1)

+ ampicillin (Doktacillin) 3 g x 4 i.v. ( < 40 kg 100 mg/kg x 3-4)

eller meropenem (Meronem) 2 g x 3 i.v. (< 50 kg 40 mg/kg x 3) som ensam terapi.

Vid “allvarlig” penicillinallergi (urticaria, andningspåverkan, anafylaxi): Moxifloxacin (Avelox) 400 mg x 1 i.v. + vankomycin 1 g x 3 i.v. (15 mg/kg x 3) + trimetoprim/sulfametoxazol (Eusaprim, Bactrim) 20 ml x 2 i.v.

Vid ökad risk för bakteriell meningit orsakad av pneumokocker med nedsatt känslighet för penicillin bör den initiala empiriska behandlingen kompletteras med vancomycin (AIII). Vid insjuknande efter vistelse i land med högre förekomst av pneumokockresistens än i Sverige bör därför sådan behandling övervägas.

Mina funderingar:

Apriori-etiologi: Strep pneumoniae 52 %, N meningitidis 12 %, HI 6 %, L monocytogenes 4 %, S aureus 4 %, Betahemolytiska strep 4 %, Övriga 5 %, ? 13 %. (Ecoli o gramnegativa – barn o äldre)

Betalaktamer

• Cefotaxim (eller ekvivalent ceftriaxon) används vid meningit o sepsis med effekt på G+: Strep, S aureus, ej enterokocker; G-: HI, E coli, G- stavar, ej pseudomonas; ej mykoplasma, ej anaerober. N meningitidis, betahemolyserande strep, ej Listeria,
• Ampicillin används vid meningit med effekt på G+: (Strep), ej S aureus, ej enterokocker; G-: HI, ej E coli, ej pseudomonas; ej mykoplasma, ej anaerober, ej G- stavar. N meningitidis. Betahemolyserande strep, Listeria. Om patienten initialt förbättras på behandling med cefotaxim + ampicillin, seponeras i första hand ampicillin om misstanken om Listeria är ringa. Behandlingen fullföljs med cefotaxim.
• Meropenem används vid svår sepsis o resistens med effekt på G+: Strep, S aureus, ej enterokocker; G-: HI, E coli, pseudomonas; ej mykoplasma, effekt på anaerober. Täcker in allt som cefotaxim + ampicillin gör tillsammans.

Övriga AB

• Moxifloxacin (kinolon) används vid svår pneumoni med effekt på G+: Strep**, S aureus, ej enterokocker; G- HI, **E coli, ej pseudomonas; effekt på mykoplasma; ej på anaerober.
• Vankomycin (glykopeptid) används vid MRSA med effekt på G+: Strep, S aureus, ej enterokocker; ej G-, ej mykoplasma, ej anaerober.
• Trimetoprimsulfa (folsyra-antagonist) används vid UVI med effekt på G+: Strep, S aureus, ej enterokocker; G-: HI, E coli, ej pseudomonas; ej mykoplasma; ej anaerober. Kan utgå om Listeria bedöms som mkt osannolikt.

Trimetoprim är ett pyrimidinderivat och sulfametoxazol en sulfonamid. Kombinationen (J01EE01) blockerar bakteriers syntes av folsyra.

Trimetoprim-sulfametoxazol är ett förstahandsmedel vid profylax mot och behandling av infektioner orsakade av Pneumocystis jirovecii och även ett förstahandsmedel vid behandlingskrävande infektioner av Stenotrophomonas maltophilia. Till följd av hög resistensnivå hos Escherichia coli är medlet endast ett alternativt andrahandsmedel vid övre urinvägsinfektion, nedre komplicerad urinvägsinfektion och bakteriell prostatit. Det är också ett alternativt andrahandsmedel vid akut exacerbation av kronisk bronkit.

FARMAKODYNAMIK

Sulfametoxazol är en sulfonamid som kompetitivt hämmar bakteriers syntes av folsyra. Trimetoprim hämmar specifikt mikroorganismernas dihydrofolatreduktas. Kombinationen blockerar två på varandra följande steg i folsyrametabolismen. Kombinationen av trimetoprim och sulfametoxazol, testad in vitro i förhållandet 1/20 vilket är det ungefärliga förhållandet mellan komponenterna som uppnås i serum, är verksam mot grampositiva och gramnegativa bakterier och har då i huvudsak baktericid effekt.

Aktivitet trimetoprim-sulfametoxazol

• God aktivitet: stafylokocker, streptokocker (inklusive pneumokocker) Escherichia coli, Klebsiella, Enterobacter, Proteus, Salmonella och Shiggella, Haemophilus influenzae (trimetoprims effekt), Stenotrophomonas maltophilia, Listeria monocytogenes, Pneumocystis jirovecii.
• Lägre aktivitet (nativ population i I-grupp): enterokocker
• Otillräcklig aktivitet: Pseudomonas spp., anaeroba bakterier.

Fortsatt antibiotikabehandling efter odlingsresultat och resistensbestämning

Behandlingstiden måste alltid ställas i relation till det kliniska förloppet. Nedan anges de behandlingstider som oftast används av författarna till den här översikten. Studier saknas.

Meningokocker:

Bensylpenicillin 3 g x 4 i.v (< 40 kg 100 mg/kg x 3-4) i 5-7 dagar.

Pneumokocker (penicillinkänsliga):

Bensylpenicillin 3 g x 4 i.v, (< 40 kg 100 mg/kg x 3-4) i 10 dagar.

Pneumokocker (penicillinresistenta):

cefotaxim (Claforan) 3 g x 3-4 i.v. (< 40 kg 75 mg/kg x 3-4) + vancomycin 1 g x 3 i.v. i 10 dagar (undvik steroider).

H.influenzae (ampicillinkänslig):

ampicillin (Doktacillin) 3 g x 4 i.v (< 40 kg 100 mg/kg x 3-4) i 10 dagar.

H.influenzae (ampicillinresistent):

cefotaxim (Claforan) 3 g x 3-4 i.v. (< 40 kg 75 mg/kg x 3-4) i 10 dagar eller enligt resistensmönster.

Listeria:

ampicillin (Doktacillin) 3 g x 4 i.v (< 40 kg 100 mg/kg x 3-4) i 10-14 dagar, vid immunosuppression krävs ibland längre behandling.

Ampicillin i kombination med trimetoprim-sulfamethoxazol (BIII) har också använts för att förbättra avdödningen av Listeria. I en okontrollerad studie har denna kombination visat på färre behandlingsmisslyckanden och neurologiska resttillstånd jämfört med en kombination av ampicillin och aminoglykosid (36). Behandling med enbart trimetoprim-sulfamethoxazol uppvisar också bactericid effekt mot Listeria och är bästa alternativ vid svår penicillinallergi (BIII). Meropenem (BIII) och nyare kinoloner, såsom levofloxacin och moxifloxacin, uppvisar god aktivitet in vitro mot Listeria vilket stöds av fallrapporter om god behandlingseffekt vid listeriameningit, men den kliniska erfarenheten är ännu begränsad.

Övriga:

Enligt resistensmönster.

Enterobacteriaceae inkl. Pseudomonas:
Introduktion av 3:e generationens cefalosporiner har revolutionerat behandlingen av meningit orsakad aeroba Gram-negativa tarmbakterier (37,38). En kraftigt minskad mortalitet i storleksordningen 6-22 % ses idag i jämförelse med tidigare dödlighet på 50 % eller mer. Studier som jämfört olika tänkbara behandlingsregimer saknas dock helt men okontrollerade observationer ger belägg för att cefotaxim, ceftriaxon, cefepim, ceftazidim och meropenem är användbara alternativ (AII–AIII). Vid meningit orsakad av Enterobacter, Citrobacter, Acinetobacter samt E coli och Klebsiella med utökad betalaktamas-aktivitet (ESBL- stammar) där cefalosporinresistens utgör ett växande problem, är meropenem ett väsentligt tillskott i behandlingsarsenalen (AIII).

Stafylococcus aureus:

Kloxacillin och dikloxacillin penetrerar på grund av hög proteinbindning dåligt till likvorrummet och är teoretiskt därför inte optimal behandling vid stafylokock- meningit. Jämförande kliniska studier saknas dock mellan olika tänkbara behandlingsalternativ vid meningit orsakad av S aureus. Vid retrospektiva studier av konsekutiva patienter med S. aureus-meningit finns ett flertal olika behandlings- alternativ representerade och dödligheten är vid samhällsförvärvad meningit genomgående mycket hög (>40 %). En association mellan överlevnad och en inledande behandling som täcker stafylokocker har iakttagits liksom en bättre överlevnad hos patienter som fick ett stafylokock-penicillin i kombination med fucidinsyra (41). Den annars i litteraturen mest förespråkade tilläggsbehandlingen vid stafylokockmeningit är rifampicin, vilket teoretiskt också är att föredra eftersom antagonism mellan fucidinsyra och methicillin är beskrivet djurexperimentellt (42).

Värdet av kombinationsbehandling kan ej säkert avgöras men i analogi med situationen vid S. aureus-infektioner med annan för antibiotika svåråtkomlig lokalisation är kombinationsbehandling attraktivt. 3:e generationens cefalosporiner och cefuroxim som kombinerar en bättre likvorpenetration än isoxazolylpenicilliner med god stafylokockeffekt, har framgångsrikt använts vid behandling av meningit orsakad av S. aureus (43). Vid meningit orsakad av S. aureus känslig för methicillin rekommenderas därför i första hand cefuroxim i kombination med rifampicin (BIII). Teoretiskt torde även inledande empirisk behandling med meropenem vara effektivt vid S. aurues-meningit, men klinisk erfarenhet saknas. Till patienter med allvarlig penicillinallergi rekommenderas vancomycin i kombination med rifampicin (BIII).

Vid meningit orsakad av MRSA rekommenderas vancomycin alltid i kombination med rifampicin på grund av vancomycinets dåliga och något oförutsägbara penet- ration till likvor (BIII). Om ventrikeldrän anlagts kan även intraventrikulär behand- ling med vancomycin tillgripas vid uteblivet behandlingssvar (se sida 56-59). I ett flertal fallrapporter och sammanställningar av erfarenheterna vid CNS-infektioner har också linezolid med framgång använts vid methicillinresistent stafylokockmeningit, vid såväl S. aureus som S. epidermidis (44-46).

Linezolid har en god CNS-penetration och har, trots bakteriostatiskt effekt och trots att indikationen varit behandlingssvikt på annan behandling (vanligen vancomycin), resulterat i utläkning i flertalet fall. Linezolid, eventuellt i kombination med andra läkemedel såsom rifampicin eller som tilläggsbehandling, kan därför rekommenderas vid behandlingssvikt på vancomycin och rifampicin, besvärliga resistensförhållanden, biverkningar på given behandling eller allergi (BIII).

Betahemolyserande streptokocker:
Betahemolyserande streptokocker är vanligen höggradigt känsliga för bensylpenicillin, vilket är förstahandsmedel (AIII), men ampicillin (AIII) är likvärdigt. Även inledande empirisk behandling med 3:e generationens cefalosporiner (BIII) eller meropenem kan förväntas ha god effekt på streptokocker även om klinisk erfarenhet är begränsad, i synnerhet för meropenem.

Question 6

Tolkning av likvorfynd

Hur ser följande ut vid bakteriell resp viral infektion?

Ev undantag, kommentarer?

1. Sp-LPK
2. Sp-poly > mono
3. Sp-tryck
4. Sp-albumin/protein
5. Sp-glukos
6. Sp-laktat

Sp som i “spinal”

Answer 6

Question 7

HJÄRNABSCESS

• Vad är det?
• Vad är cerebrit?
• • Spridningsvägar?
• Etiologi? (agens)
• Symtom?
• Utredning?

Answer 7

• Hjärnabscess = Fokal,bakteriell infektion i hjärn- parenkymet, oftast omgiven av en vaskulariserad kapsel.
  
  • Cerebrit= icke inkapslad hjärnabscess

SPRIDNINGSVÄGAR:

• Från infektioner i tänder, bihålor el öron via emissarievener (An emissary vein is one passing through a foramen of the skull anddraining blood from a cerebral sinus into a vessel outside the skull. Because the emissary veins are valveless, they are an important part in selective brain cooling through bidirectional flow of cooler blood from the evaporating surface of the head. In general, blood flow is from external to internal but the flow can be altered by increased intracranial pressure.
• A type of emissary vein goes through the sphenoidal emissary foramen inferior to the zygomatic arch with the cavernous sinus on the inside of the skull.*
• This is an important route for spread of infection because cranial nerve VI and the internal carotidpass through the cavernous sinus, with cranial nerves III, IV, V1, and V2 passing alongside the lateral wall of the sinus. Subsequent infection or inflammation in the cavernous sinus can result in damage to any of the cranial nerves that pass through it or meningitis. Also, rupturing the emissary veins will result in a subdural hematoma which will compress the brain.)*
• Hematogen spridning vid tex endokardit eller pneumoni
• Efter trauma el kirurgi
• Okänt primärfokus i ca 25% av fallen!

ETIOLOGI:

• α-streptokocker (ffa S. milleri)
• anaerober (bacteroides, fusobakterier)
• S. aureus
• HI
• Pseudomonas

SYMTOMATOLOGI

Varierande. Trycksymptom > infektionsymptom. Jfr hjärntumör!

• Huvudvärk (75%)
• fokal neurologi
• Feber (50%)
• Kramper
• Illamående/kräkningar
• Meningitsymptom vid ruptur

UTREDNING

• CT/MR (CT kan vara ua i tidigt skede)
• SR/CRP/LPK kan vara ua!
• Blododling
• Ev stereotaktisk punktion
• Tandläkar-/ÖNH-bedömning
• Ev TEE (transesofageal ekokardiografi)

OBS: LP kontraindicerat! (likvor oftast normal ändå)

Se NHS diagnos nedan: diagnos ställs mha DT/MR samt stereotaktisk punktion för att utröna agens.

BEHANDLING

ANTIBIOTIKA
• cefotaxim + metronidazol

Ev STEROIDER

• (vid hotande inklämning el kraftig medvetandesänkning)

Ev ANTIEPILEPTIKA

KIRURGI

• Reducerar expansiviteten och påskyndar läkningen
• Ger odlingsmöjlighet
• Ger definitiv diagnos

Med alfa-streptokocker (engelska viridans-streptococci) avses ett antal olika arter av aeroba/fakultativt anaeroba grampositiva katalasnegativa kocker med liknande fenotypiska egenskaper som sammanförts till en grupp mer av praktiska än strikt taxonomiska skäl. De växer på blodagar med kolonier med varierande (beta, alfa eller ingen) hemolys, de flesta med alfahemolys.

Alfa-streptokocker är generellt lågvirulenta och hör i flera fall till normal human normal mikroflora. De kan ändå orsaka infektioner i första hand hos immunsupprimerade, efter långvarig antibiotikaterapi eller vid närvaro av främmande kropp. Många av bakterierna orsakar endokardit, men de förekommer också vid andra tillstånd som exempelvis abscesser, sårinfektioner, meningit, luftvägsinfektioner (Gemella), ögoninfektioner (Granulitacella /Abiotrophia) och urinvägsinfektioner (Aerococcus).

NHS: Diagnosing a brain abscess

If a brain abscess is suspected, the diagnosis can be confirmed using a brain scan.

An initial assessment will be made based on your physical symptoms and medical history, such as whether you have had a recent infection or a weakened immune system.

Blood tests can also be carried out to check for the presence of infection. A high level of white blood cells in your blood indicates the presence of a serious infection.

If you are referred to hospital for further tests, you may have either:

a computerised tomography (CT) scan – which involves a series of X-rays to produce a detailed image of the inside of your body

a magnetic resonance imaging (MRI) scan – which uses strong magnetic fields and radio waves to produce a detailed image of the inside of your body.

A CT scan can often detect the presence of the abscess and any associated swelling inside the brain.

A MRI scan can provide a more detailed image than a CT scan, so is sometimes used if the results of the CT scan are inconclusive.

CT-guided aspiration

If an abscess is found, neurosurgeons (doctors who specialise in the treatment of the nervous system and brain) can use a CT scan to guide a needle to the site of the abscess and remove a sample of pus for further testing. This is known as CT-guided aspiration. The sample of pus should indicate the type of germ causing the abscess.

Treatment with broad-spectrum antibiotics will usually begin as soon as possible, even before a CT-guided aspiration is carried out, because it can be dangerous to wait for the results.

Broad-spectrum antibiotics can be used against a wide range of bacteria. They will be used before a specific diagnosis is made, because there is a high chance they will be effective if the infection is caused by bacteria.

If the test reveals the abscess is caused by a fungus, the treatment plan can be changed and antifungal medication given.

Question 8

VIRALA CNS-INFEKTIONER

• Kontinuum: Meningit – meningoencefalit – encefalit
• Varierande benägenhet för olika virus att infektera CNS
  Tex: EBV ca 1% ——- Rabies 100%
• Preferensen för meningier (meningit) och för hjärnparenkym (encefalit, myelit) varierar också stort mellan olika virus

Etiologi

1. Vilka är de fem vanligaste virusen?
2. Vilka två av dem orsakar encefalit i högre utsträckning än de övriga?
3. Vilka andra virus förekommer?

Symtomatologi

1. Meningitsymtom = ?
2. Encefalitsymtom = ?
3. Symtom/fynd relaterade till olika agens - vilka agens ger typiskt …
   
   1. utslag
   2. myalgi
   3. konjunktivit
   4. dubbelinsjuknande
   5. cerebellär ataxi
   6. temporallobsencefalit
   7. pareser i skuldror/proximala överarmar
   8. fästinganamnes
   9. recidiverande meningiter

Diagnostik?

Behandling?

Utredningsalgoritm för alla meningiter?

Answer 8

Etiologi

VANLIGAST

1. Enterovirus
2. TBE*
3. VZV
4. HSV 1* & 2
5. EBV

*Orsakar encefalit i högre utsträckning än de övriga

ÖVRIGA VIRUS:

• Adenovirus • Influensa • CMV • HIV

Ovanliga tack vare vaccin: • Polio • Parotit • Morbilli (mässling - rna, paramyxovirus)

Symtomatologi

MENINGITSYMPTOM • Feber • Huvudvärk • Illamående/kräkningar • Ljus-/ljudskygghet • nackstyvhet

ENCEFALITSYMPTOM • Feber • Huvudvärk • Kramper • Medvetandesänkning • Irritabilitet • Kognitiva symptom • Psykiska symptom • Fokalneurologiska symptom

SYMPTOM/FYND RELATERADE TILL RESPEKTIVE AGENS

1. Utslag — enterovirus, VZV
2. Myalgi — enterovirus, TBE
3. Konjunktivit — enterovirus
4. Dubbelinsjuknande — enterovirus, TBE
5. Cerebellär ataxi — VZV
6. Temporallobsencefalit — HSV1
7. Pareser i skuldror/proximala överarmar — TBE
8. Fästinganamnes — TBE (uppges av 2/3 av pat)
9. Recidiverande meningiter — HSV 2

OBS: Pat m herpesencefalit saknar nästan alltid blåsor!

Diagnostik

OBS: Viktigt att utesluta bakteriell orsak och identifiera pat som bör ha antiviral terapi!

• LP – likvor till kemanalys (cellräkning, etc), odling och virusdiagnostik
• MR vid encefalitmisstanke
• CT el MR före LP vid kontraindicerande symptom
• Ev EEG (typisk bild hos 70% av herpesencefaliter)

VIROLOGISK DIAGNOSTIK

• Likvor-PCR : enterovirus, HSV 1 & 2, VZV, mfl
• IgM-diagnostik på serum vid TBE
• Påvisande av intratekal antikroppsproduktion - för virus som ej kan påvisas med PCR eller för retrospektiv diagnostik när virus inte längre är påvisbart med PCR

Behandling

ANTIVIRAL BEH Acyklovir iv (po går bra vid HSV 2-meningit) i väntan på diagnos TILL

• Alla m susp encefalit!
• VZV-infektion (oavsett meningit el encefalit) hos immundefekta
• HSV2–meningit

SYMPTOMATISK BEH TILL

• Alla som behöver – Ex: - Analgetika - Antiemetika - Dropp

Patient.info

Management of viral meningitis

• The general principles of management for all viral meningitis include supportive therapy - eg, analgesia, antipyretics, nutritional support and hydration.
• Enteroviral meningitis: usually self-limiting and no specific therapy is required unless there is hypogammaglobulinaemia (immunoglobulins required).
• Aciclovir is considered beneficial in treating herpetic viral infections but only if given very early in the course of the infection and evidence for benefit is limited. Intravenous aciclovir should be started immediately if there is any suspicion of herpes simplex encephalitis.
• Ganciclovir is effective for cytomegalovirus (CMV) infections but it has significant renal toxicity and close monitoring is mandatory.

The human enteroviruses are ubiquitous viruses that are transmitted from person to person via direct contact with virus shed from the gastrointestinal or upper respiratory tract. Poliovirus, the prototypical enterovirus, can cause a subclinical or mild illness, aseptic meningitis, or paralytic poliomyelitis. The nonpolio viruses (group A and B coxsackieviruses, echoviruses, enteroviruses) are responsible for a wide spectrum of diseases in persons of all ages, although infection and illness occur most commonly in infants.

Enteroviruses cause a wide range of infections. Poliovirus, the prototypical enterovirus, can cause a subclinical or mild illness, aseptic meningitis, or paralytic poliomyelitis, a disease that has been eradicated in the United States and other developed countries. The nonpolio viruses (group A and B coxsackieviruses, echoviruses, enteroviruses) continue to be responsible for a wide spectrum of diseases in persons of all ages, although infection and illness occur most commonly in infants.

Coxsackievirus infection is the most common cause of viral heart disease. Group A coxsackieviruses may cause flaccid paralysis, while group B coxsackieviruses cause spastic paralysis. Other diseases associated with group A coxsackievirus infections include hand-foot-and-mouth disease (HFMD) and hemorrhagic conjunctivitis, while group B coxsackievirus is associated with herpangina, pleurodynia, myocarditis, pericarditis, and meningoencephalitis. Aseptic meningitis and the common cold are associated with both groups.

Diseases caused by echoviral infections range from the common cold and fever to aseptic meningitis and acute hemorrhagic conjunctivitis (AHC).

Enteroviruses are transmitted predominantly via the fecal-oral route. However, there are some exceptions, including coxsackievirus A21, which is spread mainly by respiratory secretions,[13] and enterovirus 70, which is shed in tears and spread via fingers and fomites.[14]

Upon entry into the oropharynx, the virus replicates in submucosal tissues of the distal pharynx and alimentary tract.[15] Viral particles are shed in the feces and in upper respiratory tract secretions for days prior to symptom onset. The average incubation period is 3-10 days, during which the virus migrates to regional lymphoid tissue and replicates. Minor viremia results, which is associated with the onset of symptoms and viral spread to the reticuloendothelial system (spleen, liver, bone marrow).[16]

Dissemination to target organs follows, and viral replication in target organs produces the major viremia with possible secondary seeding of the CNS. Potential target organs include the skin and CNS. Infectious virus is shed from the upper respiratory tract for 1-3 weeks and from the feces for 3-8 weeks. Enteroviruses undergoes a high rate of mutation during replication in the gastrointestinal tract, where single-site mutations can occur in the 5’ noncoding region of the attenuated polioviruses; this can lead to prolonged excretion and neurovirulence.[17]

The neuropathy of paralytic diseases caused by enteroviruses is due to direct cellular destruction. Neuronal lesions occur mainly in anterior horn cells of the spinal cord. The 3 serotypes of poliovirus all bind to the cell surface receptor CD155.

Viral Infections of the Central Nervous System

Essentials

Viral Meningitis

Enteroviruses are responsible for 80 to 90% and mumps for 10 to 20% of diagnosed cases of viral meningitis, with many other viruses sometimes incriminated with considerable geographical and seasonal variation.

Clinical features and prognosis—typical presentation is with sudden onset of fever, headache, change in conscious level, and (occasionally) a stiff neck and vomiting. The specific cause may be suggested by characteristic signs outside the nervous system, e.g. swelling in the parotid region (mumps). Prognosis is excellent.

Viral Encephalitis

Japanese encephalitis is the commonest cause of encephalitis in Asia: other causes—with considerable geographical and seasonal variation—include dengue viruses, Enteroviruses (EV71) rabies, Nipah virus, herpes simplex, West Nile virus, and mumps.

Clinical features and prognosis—most patients present with the symptoms of meningitis followed by altered consciousness, convulsions, and sometimes focal neurological signs, signs of raised intracranial pressure, or psychiatric symptoms. Some manifestations suggest particular viruses, e.g. temporal lobe features in herpes simplex encephalitis; hydrophobia in rabies; Parkinsonian and extrapyramidal features in Japanese encephalitis. Mortality and morbidity vary according to cause, but are high, e.g. mortality 10 to 40% in Japanese encephalitis, with neurological sequelae in 5 to 75% of survivors.

Viral Myelitis

Viral ‘paralytic’ myelitis is classically caused by poliovirus, which has now been virtually eliminated from the Americas: other causes—with considerable geographical and seasonal variation—include Japanese encephalitis and various coxsackieviruses, echoviruses, enteroviruses and flaviruses.

Clinical features—following a nonspecific episode of influenza-like symptoms, poliomyelitis typically presents with features of viral meningitis preceding or accompanying the development of lower motor neurone (flaccid) paralysis. Respiratory and bulbar paralysis is life-threatening. Mortality in adults is more than 20%.

Investigation

The most important investigation is lumbar puncture to allow examination of the cerebrospinal fluid, with typical findings of (1) pleocytosis—ranging from tens to thousands of cells/µl, with lymphocytes and other mononuclear cells usually predominating; (2) modest increase in protein concentration; (3) normal glucose concentration. Some viruses can be isolated from the cerebrospinal fluid, and viruses can sometimes be cultured from distant sites, but polymerase chain reaction (PCR) technology is now used routinely for diagnosis of viral central nervous system infection.

Treatment

Aside from supportive care, aciclovir is effective in treating herpes simplex encephalitis, and hyperimmune plasma reduces mortality of Argentine haemorrhagic fever (Junin virus) and Congo Crimean haemorrhagic fever, but there is no effective specific treatment for most viral infections of the central nervous system.

Prevention

Prophylactic vaccination is available against poliomyelitis, measles, Japanese encephalitis, and rabies. Postexposure rabies vaccination is effective in preventing rabies encephalitis. Hyperimmune immunoglobulin has been used for prophylaxis of measles, herpes zoster virus, HSV-2, vaccinia, rabies, and some other infections in high-risk groups.

Other neurological disorders in which viruses play a role

These include (1) Reye’s syndrome—an acute encephalopathy affecting children aged 2 to 16 years, associated with use of salicylates during the preceding viral illness. (2) Subacute sclerosing panencephalitis—caused by measles virus; typically presents with very gradual onset of altered behaviour, mild intellectual deterioration, and loss of energy and interest; periodic involuntary movements then appear; further progression is marked by intellectual deterioration, rigidity, spasticity, and increasing helplessness; there is no effective treatment; 40% of patients die within a year. (3) Progressive multifocal leucoencephalopathy—caused by opportunistic infection by papovaviruses, most commonly JC virus and the simian virus SV40; onset is usually with progressive evidence of a focal lesion of one cerebral hemisphere, before gradual development of more widespread signs; there is no effective treatment; most patients die within 6 to 12 months.

Introduction

Viruses invade and damage the central nervous system in two ways: directly, by infecting the leptomeninges, brain, and spinal cord; and, indirectly, by inducing an immunological reaction resulting in para- and postinfectious diseases. In both cases, the terms ‘meningitis’, ‘encephalitis’, and ‘myelitis’ are used alone or in combination. Meningitis implies inflammation of the meninges without alteration of consciousness, convulsions, or the production of focal neurological abnormalities; in encephalitis there is impairment of cerebral function, usually with an altered state of consciousness and often with convulsions and focal neurological signs; while myelitis indicates involvement of the spinal cord. Retroviral and prion diseases of the central nervous system are dealt with elsewhere.

There is considerable geographical and seasonal variation in the kinds of viruses causing meningitis, myelitis, and encephalitis. Vulnerability varies with age and immunocompetence.

Enteroviruses are responsible for 80 to 90% of diagnosed cases of viral meningitis. Almost all the serotypes have been implicated in sporadic cases, and outbreaks have been associated with coxsackieviruses A7 and A9, EV71, all the coxsackievirus B types, and many of the echoviruses, especially 4, 6, 9, 11, 14, 16, and 30. Echovirus 13, a rare type, has caused cases in the United States of America, Australia, and Europe, and there has been an increase in echovirus 30 cases. Mumps is responsible for about 10 to 20% of cases of viral meningitis. Other causes include herpes zoster (HZV), herpes simplex virus (predominantly type 2, HSV-2), measles, adenoviruses, Epstein–Barr virus (EBV), and, in the United States of America, togaviruses, such as St Louis, eastern and western equine encephalitis, and West Nile and bunyaviruses, such as California (La Crosse) encephalitis viruses.

Poliovirus has long been considered the major cause of viral ‘paralytic’ myelitis throughout the world, but has now been virtually eliminated from the Americas. A confusingly similar syndrome of acute flaccid paralysis caused by Japanese encephalitis (JE) has been reported from Vietnam. Coxsackievirus A7 (AB IV) has caused occasional outbreaks, and other coxsackieviruses A and B, echoviruses, enterovirus 71, and flaviruses (tick-borne encephalitis) have all been implicated as causes of flaccid paralysis. HZV, paralytic rabies virus, EBV, and herpesvirus simiae (B virus) can cause myelitis or ascending paralysis, and HSV-2 can cause lumbosacral myeloradiculitis.

Viruses causing encephalitis vary from country to country. JE virus is the major cause of encephalitis in Asia. There are at least 50 000 cases of JE with 15 000 deaths annually (case fatality 0.3 to 60%). The virus is transmitted by culex mosquitoes and is endemic across much of Asia and the Indian subcontinent. Dengue viruses have been implicated as a cause of encephalitis in both south-east Asia and Latin America. Rabies remains an important cause of fatal encephalomyelitis, especially in the Indian subcontinent and Africa (see Chapter 7.5.10).

In 1999 an outbreak of an encephalitic illness among pig farm and abattoir workers was reported from Singapore and Malaysia. There were 258 cases of encephalitis, with a case fatality rate of almost 40%. Subsequently, Nipah has become endemic in Bangladesh. The causative agent was a new paramyxovirus, Nipah virus, closely related to the Hendra and Manangle viruses described in Australia. Nipah virus encephalitis is a zoonosis infecting pigs and flying foxes (Pteropus spp.). Almost all patients infected in this outbreak had direct contact with pigs. Hendra virus has caused a few cases of equine and human encephalitis with a human fatality in Brisbane, Australia in 2008.

In North America, herpes simplex virus is the most common cause of sporadic fatal viral encephalitis, followed by the California encephalitis group, St Louis encephalitis virus, HZV, enteroviruses, mumps, measles, and, most recently, the West Nile virus. In the United States of America, herpes simplex encephalitis has an estimated incidence of 2.3 per million population each year; HSV-1 accounts for 95% of cases; HSV-2 causes encephalitis mainly in neonates and those who are immunosuppressed, such as transplant recipients, and those with HIV infection. In 1999 there was an outbreak of West Nile infection in the eastern United States of America with a cluster of cases of encephalitis in New York and 16 human deaths. West Nile virus is a mosquito-borne flavivirus closely related to JE. It has been known to cause encephalitis in Africa, the Middle East, and southern and eastern Europe, but this was the first appearance of this virus in the New World. In endemic areas, infection with West Nile virus is usually asymptomatic or associated with a mild flu-like illness. Only occasionally does it cause encephalitis, with a case fatality rate for patients admitted to hospital in New York of 12%. The virus has now become established in migrant bird populations across the United States of America and Central America, and in 2008 there were 1370 cases with 37 fatalities in the United States of America reported by the Centers for Disease Control (CDC), Atlanta.

In the United Kingdom, mumps is the most frequently diagnosed viral encephalitis, followed by echoviruses, coxsackieviruses, measles, HSV, HZV, EBV, and adenoviruses (especially adenovirus 7). Louping ill is the only indigenous arthropod (tick)-borne encephalitis in the United Kingdom. In central and eastern Europe and Scandinavia, tick-borne encephalitis virus and Russian spring–summer encephalitis viruses are endemic. Usutu, a flavivirus, has been isolated in birds in Austria. In many developing countries rabies is an important cause of viral encephalitis. Other regional causes are Rift Valley fever virus in Africa and the Middle East, arenaviruses (Junin, Guanarito, Sabiá, Lassa, and Machupo) in Latin America and Africa, Marburg and Ebola viruses in Africa, Colorado tick fever virus in North America, and Murray Valley encephalitis virus in Australia.

Postinfectious encephalomyelitis most commonly follows measles, vaccinia, varicella, rubella, mumps, and influenza. Guillain–Barré syndrome, a sensorimotor polyneuropathy (see Chapter 24.16), has been associated with infections by EBV, cytomegalovirus (CMV), coxsackievirus B, and HZV. The decreasingly used nervous tissue vaccines for rabies may give rise to postvaccinal encephalomyelitis (see below), whereas immunization against influenza, rabies, hepatitis B, measles, and poliomyelitis has been complicated by Guillain–Barré syndrome.

Immunodeficient patients are particularly vulnerable to some viral infections. Those with depressed cell-mediated immunity (Hodgkin’s disease) may develop HZV encephalitis, and CMV may cause a subacute encephalitis in patients with AIDS. In children or adults with hypogammaglobulinaemia, enteroviruses, including live-attenuated polio vaccine, may produce a progressive and fatal meningoencephalitis. Progressive multifocal leucoencephalopathy, a chronic and fatal papovavirus infection in patients with impaired cell-mediated immunity, is described below. HIV infection of the brain and meninges may be responsible for acute meningoencephalitis at the time of seroconversion and for subacute chronic encephalopathies and dementia in patients with AIDS.

Epidemiology

Many viral infections of the central nervous system (CNS) occur in seasonal peaks or as epidemics, whereas others, such as herpes simplex encephalitis, are sporadic. Epidemics of JE occur in the summer or rainy season in northern India, Nepal, northern Thailand, Korea, Taiwan, and China. However, in southern Vietnam, Indonesia, Malaysia, southern India, and the Philippines the disease can occur all the year round, although the peak is at the start of the rainy season. This variation in the incidence of disease is an important consideration when recommending immunization. In endemic areas it is mostly a disease of children, but as the disease spreads to new regions, or nonimmune travellers visit endemic regions, nonimmune adults are also affected. The major vector is Culex tritaeniorhynchus mosquitoes that have been infected by first feeding on the bird (cattle egrets, herons) or mammal reservoir species. Indigenous children and nonimmune (immigrant) adults are most susceptible. Euro-Siberian tick-borne encephalitidese occur in spring and early summer when the ticks are most active but can also be acquired by drinking unpasteurized dairy products, especially goat’s milk. Mumps encephalitis is most common in the late winter or early spring, whereas enterovirus infections occur most often in the summer and early autumn. Rodent-related encephalitides, such as the arenaviruses, are most common when the rodent population is at its peak, either in the fields (Machupo and Junin viruses) or in the home (lymphocytic choriomeningitis virus). Zoonotic viral infections, such as Rift Valley fever, survive periods of cold weather, during which the invertebrate–vertebrate cycle is suspended by ‘overwintering’ in their arthropod vectors (e.g. in the bottom of dried-up ponds) or hibernating vertebrate reservoirs. Rabies, the classic zoonosis (see Chapter 7.5.10), occurs sporadically or in microepidemics although, in Europe, historically the greatest risk of dogs becoming mad with rabies was believed to be associated with the hot weather, the ‘dog days’, when Sirius the dog star was in the ascendant (20 July to 15August).

Invasion of the CNS seems to be a rare event in most viral infections. In the case of some infections, such as JE, there may be only 1 case of encephalitis for every 300 to 500 asymptomatic infections. Eastern equine encephalitis virus produces a much higher proportion of encephalitic cases than other togaviruses.

Infections by many neurotropic viruses are most frequent and severe in children and older people. Herpes simplex encephalitis affects all age groups but shows peaks of incidence in those aged between 5 and 30 years and over 50 years. When HSV-2 invades the CNS it is likely to cause a benign lymphocytic meningitis in adults, but in neonates it usually produces a severe encephalitis. Among mosquito-borne epidemic encephalitides, California encephalitis and JE are most common in children, St Louis and West Nile encephalitis in older people, whereas eastern and western equine encephalitis affect both very young and older people. Postinfectious encephalitis is most frequent in children, because it complicates the common childhood exanthematous viral infections. It is the most common demyelinating disease in the world.

Pathogenesis

Most viral infections reach the CNS from the primary site of infection and multiplication via the bloodstream, but the rabies virus enters peripheral nerves through acetylcholine and other receptors and travels to the CNS in axoplasm, employing the microtubular dynein motor system. Viruses inoculated through the skin include those transmitted by arthropods, rabies virus, herpes simplex virus, herpesvirus simiae (B virus), and lymphocytic choriomeningitis virus. Arthropod-borne viruses are presumed to replicate in local lymph nodes, the vascular endothelium, and circulating fixed macrophages, in order to sustain viraemia. Rabies virus may multiply locally in the cytoplasm of muscle cells before entering peripheral nerves. Viruses that enter through the respiratory tract (e.g. measles, mumps, varicella) or gut (enteroviruses) multiply in local lymphoid tissue before entering the bloodstream. Viraemia is a feature of most viral infections, yet invasion of the CNS is rare in most cases. The explanation for this is not known, but the CNS contains a number of intrinsic physical barriers to infectious agents such as viruses. These include the blood–brain barrier with its ‘tight junctions’, virus-resistant cells, and the absence of lymphatic drainage. Nonspecific mechanisms at or near the site of virus entry, such as gastric acidity and cilia in the respiratory tract, also play a protective role. In the case of rabies, HSV, and HZV, the virus enters the CNS through the peripheral nerves. Although the subarachnoid space surrounding the olfactory nerves projects through the cribriform plate and is directly beneath the nasal mucosa, this route of infection seems to be extremely rare in humans and has been proven only in a few cases of inhaled rabies virus infection and herpes simplex encephalitis. Viruses have been inoculated directly into the CNS by infected corneal transplant grafts (rabies) and prions through infected brain-surface electrodes (Creutzfeldt–Jakob disease). Herpes simplex encephalitis may complicate primary HSV infection in children and young adults, but in most cases of herpes simplex encephalitis the cause is thought to be reactivation of latent virus (HSV-1) in the trigeminal nerve, autonomic nerve roots, or brain.

Some viruses, such as the enteroviruses and mumps, usually infect the meninges rather than the parenchyma of the CNS, whereas others, such as the togaviruses, usually cause encephalitis. Different neural cells are selectively vulnerable to different neurotropic viruses. Examples are the predilection of polioviruses for motor neurons of the anterior horns of the spinal cord, and of rabies for neurons of the limbic system and cerebellar Purkinje cells. The pathological effects of viral infections on the CNS include:

◆ the destruction and phagocytosis of neurons (neuronophagia) as a result of either viral invasion itself or immune lysis

◆ demyelination

◆ inflammatory oedema with the compressive effects of raised intracranial pressure

◆ in some cases, vascular lesions

In rabies, a universally fatal encephalitis, neuronolysis is relatively mild. However, rabies virus may interfere with neurotransmission at central and peripheral synapses. It also produces severe systemic effects, following its centrifugal spread (e.g. myocarditis and cardiac arrhythmias) or its focal effects on vasomotor and respiratory centres in the brainstem and in the temporal lobes and amygdala (compare Klüver–Bucy syndrome)

Postinfectious encephalitis and the Guillain–Barré syndrome are thought to result from sensitization to central and peripheral myelin, respectively. The animal model for the former is experimental allergic encephalomyelitis, which can be produced in a variety of animals after immunization with myelin basic protein. A similar animal model for Guillain–Barré syndrome is known as experimental allergic neuritis. It is uncertain how the preceding viral infection induces this autoimmune response. In the case of postvaccinal encephalomyelitis resulting from old-fashioned nervous tissue antirabies vaccines containing homogenized animal brain, the mechanism is still not clear. The antimyelin basic protein is not always present and is probably not the direct cause of demyelination.

The host’s immune responses to viruses play a crucial role in combating infection. They may be directed against either the virus particle or the virus-infected cell, and may be humorally or cell mediated. An important local immune response at infected surfaces is provided by IgA antibody, which is present in secretions in the gut, saliva, and respiratory tract. This is important, for example, in the early stages of poliovirus infection where the antibody neutralizes the virus by combining with viral surface proteins. The systemic viral infection may also be limited by means of circulating IgG and IgM antibodies, which can neutralize the virus in a variety of different ways. Immune responses may also occur locally within the CNS, where local synthesis of immunoglobulins in response to virus infection, sometimes in an oligoclonal pattern, may be evident. Such antibody elevations may be of considerable diagnostic value (see below). Under certain conditions immune responses to viruses may themselves set in train immunopathological processes leading to disease. This may occur in a number of different ways, such as through the deposition in blood vessels of immune complexes formed between an antiviral antibody and viral antigen. In other cases, such as lymphocytic choriomeningitis virus infection, the induction of virus-specific cytotoxic T lymphocytes is itself responsible for the production of encephalitis.

Pathology

Meningitis

The basal leptomeninges, ependyma, and choroid plexus are infiltrated with mononuclear cells but the parenchyma is normal. In mumps meningitis there may be exfoliation of ependymal cells.

Poliomyelitis

Virus is distributed widely throughout the brain and spinal cord, possibly even in nonparalytic cases, but usually the only cells to suffer chromatolysis and phagocytosis are motor neurons in the anterior horns of the spinal cord, medulla, and grey matter of the precentral gyrus.

Encephalitis

Most viral encephalitides are characterized by lymphocytic infiltration of the meninges and perivascular cuffing (in the Virchow–Robin spaces) in the cortex and underlying white matter, by lymphocytes, plasma cells, histiocytes, and some neutrophils, and proliferation of microglia with the formation of glial nodules. Neuronolysis and demyelination are variable in their degree and location. Infected neurons may show characteristic inclusion bodies in their nuclei (measles, HSV, and adenoviruses) or cytoplasm (Negri’s bodies in rabies). Microhaemorrhages and foci of necrosis may be found.

Herpes simplex encephalitis

Characteristic features of this condition are gross cerebral oedema and severe haemorrhagic and necrotizing encephalitis, which is often asymmetrically localized to the inferior and medial parts of the temporal lobe, the insula, and the orbital part of the frontal lobe. Histological sections show eosinophilic Cowdry type A intranuclear inclusions with margination of chromatin in neurons, oligodendrocytes, and astrocytes, inflammatory and haemorrhagic perivascular reactions, but no demyelination. Cowdry type A inclusions are also found in HZV and CMV encephalitides. The unique cerebral localization of herpes simplex encephalitis has not been satisfactorily explained, but is probably the result of viral spread along specific neural pathways rather than a differential susceptibility of particular cell populations. A popular idea is that HSV spreads along olfactory pathways to the base of the brain and temporal lobes, but it is also possible that virus may spread from the trigeminal ganglia through sensory fibres innervating the dura near these regions. This latter mechanism is consistent with the discovery of latent HSV-1 in the trigeminal, superior cervical, and vagal ganglia in a high proportion of normal individuals, irrespective of whether they have a history of mucocutaneous herpes infections (‘cold sores’). Latent HSV-1 might be reactivated by a variety of stimuli, such as sunlight, fever, trauma, and stress; however, the actual mechanisms underlying its latency and reactivation in the nervous system are not yet fully understood. If herpes simplex encephalitis is caused by the reactivation of latent virus, its rarity, despite ubiquitous asymptomatic infection in humans, is hard to explain.

Japanese encephalitis

Microscopic appearances are typical of other viral encephalitides: there is oedema, congestion, and focal haemorrhages of the brain and meninges, and perivascular cuffing, neuronophagia, and glial nodules of the brain parenchyma. Neuronolysis and neuronophagia are unusually widespread in the thalamus, basal ganglia, brainstem, cerebellum (where there is marked destruction of Purkinje’s cells), and the spinal cord. Viral antigen is localized to neurons, especially in the brainstem, thalamus, and basal ganglia.

Nipah virus encephalitis

Pathological studies on the brains of fatal cases demonstrated that the endothelium of small blood vessels in the CNS was particularly susceptible to infection. This led to disseminated endothelial damage and syncytium formation, vasculitis, thrombosis, ischaemia, and microinfarction. There was also evidence of neuronal infection by the virus that may have contributed to neurological dysfunction.

West Nile virus encephalitis

Pathological changes include varying degrees of neuronal necrosis in the grey matter, with infiltrates of microglia and polymorphonuclear leucocytes, perivascular cuffing, neuronal degeneration, and neuronophagia. Viral antigens were demonstrated in neurons and in areas of necrosis. No antigen was detected in other major organs, including lung, liver, spleen, and kidney. The major pathological lesions were seen in the brainstem and spinal cord.

Enterovirus 71

There is severe perivascular cuffing, parenchymal inflammation, and neuronophagia in the spinal cord, brainstem, and diencephalon, and in focal areas in the cerebellum and cerebrum. Although no viral inclusions were detected, immunohistochemistry showed viral antigen in the neuronal cytoplasm. Inflammation was often more extensive than neuronal infection, suggesting that other indirect factors may be involved in tissue damage in addition to the effects of direct viral invasion.

Tick-borne encephalitis

A feverish illness accompanied by myalgia, headache, and fatigue develops 4 to 28 days after the tick bite. Between 1 and 33 days later, about one-third of the patients will develop meningitis, meningoencephalomyelitis, myelitis, or meningoradiculitis.

Clinical Features

Meningitis

A prodromal influenza-like illness, followed by a brief remission of symptoms, is typical of lymphocytic choriomeningitis viral infection, and some outbreaks of enteroviral meningitis (e.g. echovirus 9), but in most cases of viral meningitis symptoms start suddenly. There is usually fever, headache, change in conscious level, and occasionally a stiff neck, and vomiting, especially in children. Nausea, anorexia, abdominal pain, myalgias, and sore throat are particularly common in enteroviral meningitis. Myalgia is particularly severe with coxsackievirus B infections. As in acute bacterial meningitis, infants usually present with vague irritability and a tense fontanelle, and young children with fever and irritability or lethargy. Conjunctival injection, pharyngitis, and cervical lymphadenopathy may be found. Macular or petechial exanthems or enanthemas are seen with coxsackievirus A and B and echovirus infections (especially echovirus 9). Vesicles on the hands, feet, and mouth have been reported with coxsackievirus A16 and enterovirus 71 infections. By definition, the level of consciousness is normal in simple meningitis. Neurological features include vertigo, nystagmus, cerebellar ataxia, facial spasms, and involuntary movements.

The specific cause of viral meningitis may be suggested by characteristic signs outside the nervous system, such as genital or rectal vesicles in the sexually active age group (HSV-2), HZV skin lesions, swelling in the parotid region (mumps, and occasionally coxsackie-, lymphocytic choriomeningitis, and EBV), orchitis (mumps and lymphocytic choriomeningitis virus), and arthritis (lymphocytic choriomeningitis virus). However, potentially helpful features, such as gastrointestinal symptoms associated with enteroviral infections and parotitis associated with mumps, may be completely absent in patients with meningitis.

Mollaret’s meningitis (benign recurrent aseptic meningitis or benign recurrent lymphocytic meningitis)

This is a sporadic condition presenting between the ages of 5 and 60 years. The symptoms are typical of acute meningitis—malaise, fever, vomiting, neck stiffness, convulsions, and coma. There is complete spontaneous recovery, usually within a few days, and symptom-free intervals lasting from a few days to years. About half the patients develop other neurological disturbances including hallucinations, diplopia, cranial nerve lesions, and signs of an upper motor neuron lesion. Pleocytosis is usually less than 3000/µl, with a predominance of lymphocytes, monocytes, and large endothelial (Mollaret’s) cells, but occasionally neutrophils are in the majority. The protein level in cerebrospinal fluid is mildly increased, with increased gammaglobulin. The cerebrospinal fluid glucose concentration may be decreased. HSV-2 and HSV-1, human herpesvirus 6, and EBV have been implicated by polymerase chain reaction (PCR) detection. However, some argue that the term ‘Mollaret’s meningitis’ should be restricted to idiopathic recurrent aseptic meningitis.

Differential diagnosis of recurrent meningitis

An important differential diagnosis is recurrent purulent meningitis that is often attributable to a congenital or traumatic defect providing access to the subarachnoid space, such as congenital occult spina bifida or fracture of the base of the skull. A cerebrospinal fluid leak may be apparent in about 50% of the cases with post-traumatic recurrent meningitis. The head trauma may have occurred many years earlier and a connection with the subarachnoid space may be clinically inapparent. Rarely, recurrent meningitis may arise from episodes of recurrent sepsis of a parameningeal focus (e.g. sinusitis or mastoiditis) or from a complement deficiency. Deficiency in a number of the components of the complement pathway has been detected in patients with recurrent meningitis. Neisseria meningitidis meningitis caused consecutively by different serogroups is the usual presentation in these cases.

Other causes of recurrent meningitis include Behçet’s syndrome, Vogt–Koyanagi–Harada syndrome, sarcoidosis, and systemic lupus erythematosus, and undiagnosed viral meningitis (e.g. that due to encephalomyocarditis virus).

Paralytic poliomyelitis

Poliomyelitis is acquired by droplet spread from the respiratory tract or by the faecal–oral route. The ‘minor illness’, coinciding with viraemia, is a nonspecific episode of influenza-like symptoms—fever, headache, sore throat, malaise, and mild gastrointestinal symptoms—which resolves in a few days. Most of those infected have no further symptoms but, in a minority, the ‘major illness’ follows, sometimes after a few days’ remission of symptoms. The features are those of viral meningitis: muscle pain, spasms, and sensory disturbances may precede or accompany the development of lower motor neuron (flaccid) paralysis. Any combination of motor unit deficits may be seen. Respiratory and bulbar paralysis is life threatening. Encephalitis is rare. The most common causes of death are aspiration and airway obstruction, resulting from bulbar paralysis and paralysis of respiratory muscles. Disturbances of respiratory and cardiac rhythm, thought to be the result of damage to medullary vasomotor and respiratory centres, are extremely uncommon. Other complications include impaired control of body temperature and blood pressure, gastrointestinal haemorrhage, aspiration pneumonia, and paralysis of the bladder and bowel.

Encephalitis

Most patients with viral encephalitis present with the symptoms of meningitis (fever, headache, neck stiffness, vomiting), followed by altered consciousness, convulsions, and sometimes focal neurological signs, signs of raised intracranial pressure, or psychiatric symptoms.

Herpes simplex encephalitis

This relatively common sporadic encephalitis may occur in any age group. In neonates, it is caused by HSV-2.

As well as the usual clinical features of severe viral encephalitis, patients with herpes simplex encephalitis have symptoms related to the focal nature of the encephalitis (frontal and temporal cortex and limbic system). These include behavioural abnormalities, olfactory and gustatory hallucinations, anosmia, amnesia, expressive aphasia, and temporal lobe seizures. Herpetic skin or mucosal lesions are rarely found, except in the case of acute genital HSV-2 infection, or proctitis, and a past history of ‘cold sores’ does not affect the chances of the infection being due to HSV. Most deaths occur within the first 2 weeks.

Japanese encephalitis

After an incubation period of 7 to 14 days, patients develop nonspecific prodromal symptoms (fever, headache, malaise, and nausea) lasting 2 to 3 days. Neurological symptoms begin with headache, deteriorating level of consciousness, and generalized convulsions, which may result in status epilepticus. Fever persists for 6 to 7 days and, in survivors, neurological symptoms may persist for several weeks. Parkinsonian and extrapyramidal features occur frequently and choreoathetoid movement disorders or severe dystonias can last for many months. The case fatality rate is 30% in those admitted to hospital. Most deaths occur in the first 7 to 10 days from respiratory failure, aspiration pneumonias, intracranial hypertension, and uncontrolled seizures. Up to 50% of survivors suffer from intellectual impairment, psychiatric problems, persistent epilepsy, or a vegetative state with spastic quadriparesis and evidence of basal ganglia involvement, such as dystonia of the limbs and trunk, rigidity, and tremor.

Nipah virus encephalitis

The main clinical features of Nipah virus encephalitis are fever, headache, dizziness, reduced consciousness, and prominent brainstem dysfunction. Distinctive signs included myoclonus, areflexia, hypotonia, hypertension, and tachycardia, suggesting extensive brainstem and spinal cord involvement. MRI during the acute illness shows widespread focal lesions in subcortical and deep white matter and, to a lesser extent, in grey matter on T2-weighted sequences. Long-term sequelae are common in Nipah encephalitis.

West Nile virus encephalitis

The most common clinical features are encephalitis, meningitis, fever, weakness, and headache following an incubation period of 3 to 15 days. Infection usually results in an acute febrile episode with no CNS involvement. In unusual cases or, as in the United States of America, when the virus is introduced into a naïve population, the incidence of encephalitis rises particularly in older people. An erythematous rash of the neck, trunk, and limbs is present in 20% of cases. Patients over 50 years of age were most at risk of developing encephalitis, but all age groups are affected in endemic areas. Muscle weakness, areflexia, and diffuse flaccid paralysis in association with an axonal polyneuropathy were also reported. MRI of the brain demonstrated enhancement of the meninges and periventricular areas. There is no specific treatment.

Enterovirus 71

As the goal of poliomyelitis eradication appears more achievable, another enterovirus is emerging as a significant cause of acute neurological disease in Asia. Enterovirus 71 (EV71) was first recognized in 1969 and is responsible for a variety of clinical manifestations, including: hand, foot, and mouth disease; aseptic meningitis; meningoencephalitis; and acute flaccid paralysis. In an outbreak of hand, foot, and mouth disease in Malaysia, a number of young children developed fatal encephalomyelitis, dying within a few hours of presentation with cardiovascular instability and severe pulmonary oedema. Postmortem examination in four cases revealed major involvement of the brainstem and spinal cord, with EV71 being isolated from brain tissue in all cases; there was no apparent cardiac pathology and the virus was not isolated from the myocardium. Molecular characterization of these four viruses and others isolated concurrently suggest that at least two potentially virulent EV71 strains were circulating during the outbreak. An adenovirus was also thought to have complicated the infection in 60% of the children dying with a similar clinical picture. It is possible that coinfection with the two viruses may have resulted in severe disease.

Postinfectious encephalomyelitis

Sudden convulsions, coma, fever, or pareses appear 10 to 14 days after the start of immunization (vaccinia or nervous tissue rabies vaccine) or after infection with measles, varicella, rubella, mumps, or influenza. In the case of measles, varicella, and rubella, encephalitic symptoms develop 2 to 12 days after the rash has appeared, and in mumps before or after parotid swelling. Involuntary movements, cranial nerve lesions (VII and III), pupillary abnormalities, nystagmus, ataxia, and upper motor neuron signs are common.

Diagnosis

Clinical and epidemiological details

The time of year, known current epidemics, the patient’s age, occupation, animal contacts, and countries or states visited recently may help to narrow down the possibilities. A specific diagnosis may be suggested by distinctive clinical features of the encephalitis itself (e.g. hydrophobia in rabies, temporal lobe features in herpes simplex encephalitis) or of the associated infection (e.g. mumps parotitis, measles rash, skin and mucosal lesions of herpesviruses, and gastrointestinal symptoms associated with enteroviral infections).

Laboratory investigations

These should aim to demonstrate a specific viral agent (particularly important for the potentially treatable herpesvirus infections) or exclude potentially treatable nonviral causes of meningitis or encephalomyelitis. The most important investigation is examination of the cerebrospinal fluid. Contraindications to lumbar puncture are the same as for acute bacterial meningitis. If there are lateralizing neurological signs or evidence of raised intracranial pressure, a CT or MRI scan should be performed to exclude an intracranial mass lesion before contemplating a lumbar puncture. Cerebrospinal fluid pressure is especially increased in herpes simplex encephalitis, where there is intense cerebral oedema. Pleocytosis ranges from tens to thousands of cells per microlitre. Lymphocytes and other mononuclear cells predominate, except in the early stages of some infections (e.g. enteroviruses, herpes simplex encephalitis). The cerebrospinal fluid contains erythrocytes or is xanthochromic in haemorrhagic encephalitides such as herpes simplex encephalitis and acute necrotic leucoencephalitis. Protein concentration is usually increased in the range of 50 to 150 mg/dl with an increasing proportion of IgG as the disease progresses. Leakage of serum IgG into the cerebrospinal fluid and intrathecal IgG synthesis, indicated by a monoclonal band, are responsible. Cerebrospinal fluid glucose concentration is usually normal or increased towards the level in a blood sample taken simultaneously, but low levels are occasionally reported, especially in mumps and lymphocytic choriomeningitis virus infections. Cerebrospinal fluid examination may be misleading if it is normal: as it is at the first examination in 10 to 15% of patients with herpes simplex encephalitis; if there is a predominantly neutrophil pleocytosis; or if the glucose concentration is low.

Question 9

Fall 1

18-årig tidigare väsentligen frisk flicka som går på gymnasiet och bor med föräldrarna.

Hemkom 2/3 med buss från en veckas skidsemester i franska alperna. Delade där rum med 4 kamrater som varit förkylda. Pat var själv rejält förkyld vid hemkomsten.

Den 3/3 debut av tilltagande huvudvärk, dagen efter försämrad med allmän kroppsvärk och feber 38-39C. Försämras under natten med stigande feber och kraftig huvudvärk.

Inkommer med ambulans, puls 135, BT 80/50. Vid ankomsten högfebril, lätt medvetandesänkning GCS 10 (E2 V3 M5). (Eye opening 2=to pain/Verbal response 3 = inappropriate/Motor response= localises to pain)

Vad är Din preliminära bedömning och diagnos av patienten? Motivera!

Vilka undersökningar och åtgärder vidtar Du omedelbart på akuten och i vilken ordning vidtar Du dessa?

Answer 9

Feber, BT, medvetandesänkning –> ? sepsis, meningit

Handläggning:

1. Sätt 2-3 iv infarter + syrgas, vätska (Ringer acetat) + blododling, blodgas (pH, laktat, BE, sat) + AF, odla från NPH, svalg, ev öronsekret

2. grovt neurostatus (inkl GCS, kranialnerver) + nackstyv –> LP m tryckmätning (–> 28 cm) (> 40, 18-21 normalt, 35 vid HV)

Kontraindikationer mot LP: (–> behandla ändå) + DNA-PCR på urin (pneumo, meningo, HI), blododling (pneumo)

• GCS < 8
• waran, PK < 1,6
• fokala neurologiska symtom
• lång anamnes (>= 3 dagar) (hjärnabscess?)

Om man gör LP (likvor o ledvätska: lägg en portion i blododlingsflaska så de inte dör):

–> grumlig likvor –>

cefotaxim 3gx4 + ampicillin 3gx4 eller meropenem 2gx3

+ kortison (ab tros stimulera kinocyter; vanligen betametason - 2-4 dagar, tas bort om meningokocker)

?? Vankomycin + kinolon (ekologisk katastrof):

• mot G-: ciprofloxacin
• mot G+: levo?, moxif? (strep, pneumo, staff)

​

3. Ring IVA –> bedömning av IVA- o narkosläkare (ska med på CT)

Ring infektionsläkare, neurokirurg (ventrikeldrän?)

Proverna visade:

BLOD: CRP 372, LPK 22,9 (3,5-8,8), TPK 100 (kv: 165-387, män: 145-348), krea 69 (kv: < 90, män < 100), Na+ 129 (136-148) - kan ge hjärnödem.

LIKVOR: LPK 9000 (0-5) varav poly 5700, mono 3300, Ery 0, Glu 0,7 (0,15), laktat 8,3, alb 2100 (barriärskada –> vankomycin - stor så kan komma in o verka) – klassisk bakteriell meningit

Normala likvorvärden:

mono < 5, poly < 1, röda < 1 (0), glu > 50% av p-glu, laktat 1,2 - 2,1, albumin < 0,4, tryck < 20 cm vatten

4. Inläggning på avdelning

Kontinuerlig monitorering av medvetande, …

5. Efter 3 dagar: blododling visade meningokocker

–> ta bort doktacillin (ampicillin??). Ge bensylPc iv. Känsliga pt <—-> lång behandling

6. Pt på återbesök efter 1 mån

Restsymtom: trötthet, påverkad 6 - 12 mån

Sequele: nedsatt hörsel; diffusa kogn nedsättningar

7. Cipro till nära kontakter och rumskompisar

Meningokock: - dör ofta; C3-C4 brist i komplement; smittskyddsanmälan

Pneumokock: nej

Dödlighet

Pneumokocker 15 - 25 %

Meningokocker 2 - 10 %

Listeria 20 - 70 %

Mkt ovanliga - om ej vanligt utomlands??: MRB, … MRSA: betydligt sämre - missar ofta i inledningen

Question 10

Fall 2

36-årig kvinna som under semester med familjen i Stockholmstrakten insjuknat 6/7 med hö-sidig frontal huvudvärk. Den 8/7 något sämre och via Järna vårdcentral blivit insatt på Kåvepenin. Den 9/7 ytterligare försämring varför hon söker akut Södertälje sjukhus. På vägen dit får hon ett krampanfall som klingat av vid inkomsten. Sändes efter kontakt med Karolinska Huddinge hit för fortsatt handläggning.

Status
AT: Lätt desorienterad, viss amnesi. Temp 38.5.

MoS: små blödande sår på tungan. Lgl: ua. Cor: RR, 0 biljud. BT: 115/65. Pulm: ua. Buk: mjuk, oöm.

Neurol: ej nackstel, susp anisokori (hö pupill större än vä), felpekning finger-näs, Grassé ua, extremitetsreflexer symmetriska, Laseuge neg, Babinskis tecken saknas.

Kemlab: CRP<10 (< 3), LPK 8,1 (3,5 - 8,8)

Ytterligare uppgifter i anamnes och status kan vara av intresse?

Vad är Din preliminära bedömning och diagnos av patienten? Motivera!

Vilka undersökningar och åtgärder vidtar Du och i vilken ordning?

Answer 10

“Varje timme viktig”

Diff:

encefalit

• TBE (typiskt: dubbelinsjuknande: första skovet: allmänna infektionssymtom, andra skovet: hög feber, svår HV)
• HSV (typiskt: desorientering, kramp, personlighetsförändring) - går att behandla
• entero

hjärnabscess

Handläggning:

• serologi på blod: IgM
• INTE LP (fokala neurosymtom, kramp) (inte heller om det hade varit tecken på kraftigt höjt ICP, koagulationspåverkan, pågående epileptiskt anfall)
• DT (MR - mkt bättre) –> temporala förändringar, inte abscess, inte ICP –>

Tag LP –>

LPK 308 (mono 270, poly 38), glu 4,1 (p-glu 5,0), laktat 4,0 - 5,0, alb 257

(LP –> likvor –> provrör; PCR på HSV 1+2, VZV)

Normala likvorvärden:

mono < 5, poly < 1, röda < 1 (0), glu > 50% av p-glu, laktat 1,2 - 2,1, albumin < 0,4, tryck < 20 cm vatten

–> viral bild

Behandling:

Antag att DT normal, samma LP –> acyklovir (i väntan på diagnos)

(Antiviraler till alla med misstänkt encefalit, VZV-meningit hos immundefekta, HSV2-meningit)

Sequele:

TBE: 30 - 40 % från sequele (någon % dör, ett par % blir helt borta , …, helt friska)

HSV, TBE: neurologisk rehab krävs för alla

***

Patient.info

Encephalitis is inflammation of the brain parenchyma, often caused by viral infections but also by other pathogenic organisms and occasionally by other conditions - eg, toxins, autoimmune disorders. Meningoencephalitis is an inflammatory process, most often due to viral infection, involving both the brain and meninges.

Bacterial causes: tuberculosis (TB), mycoplasma, listeria, Lyme disease, Bartonella henselae (cat scratch fever), leptospira, brucella, legionella, neurosyphilis, all causes of bacterial meningitis.

Rickettsial: Rocky Mountain spotted fever, endemic typhus, epidemic typhus, Q fever, human monocytic ehrlichiosis.

Fungal: cryptococcosis, coccidiomycosis, histoplasmosis, North American blastomycosis, candidiasis.

Parasitic: African trypanosomiasis, toxoplasmosis, echinococcus, schistosomiasis.

Tick-borne encephalitis is a rapidly growing public health problem in Europe and other parts of the world.[4] It is caused by tick-borne encephalitis virus, a member of the family Flaviviridae. See separate Tick-borne Encephalitis and Tick-borne Encephalitis Vaccination article for more information.[5]

Primary amoebic meningoencephalitis is caused by infection from an amoeba such as Naegleria fowleri or Balamuthia mandrillaris.

Question 11

Fall 3 (vanligt på VC, spec i augusti)

7-årig tidigare frisk pojke, nr 4/4 syskon.

Insjuknar den 19/8 med feber ca 38°C samt huvudvärk. Mår bättre 21-23/8 men kommer den 24/8 hem och klagar över huvudvärk, kräks en gång och är väldigt trött och påverkad varför modern tar hem jourhavande läkare. Det framkommer att flera kamrater i området ligger sjuka med huvudvärk, kräkningar och feber.

Status
AT: opåv, klar och orienterad. Temp 39,5°C grader.

MoS: stora oretade tonsiller. Cor: RR, systol biljud över apex.

Neurol: susp nackstel f ö ua.

Kemlab: CRP 25 (< 3), LPK 9,8 (>18 år: 3,5 - 8,8) varav poly 6,9 (1,7 - 9,1).

Ytterligare uppgifter i anamnes och status kan vara av intresse?

Vad är Din preliminära bedömning och diagnos av patienten? Motivera!

Vilka undersökningar och åtgärder vidtar Du?

Answer 11

Epidemiologi: liknande hos kompisar, skärgård, inga fästingbett, varit i naturen, ej vaccinerad

Diff: TBE, enterovirus (typiskt f augusti), bakteriell meningit (farligt men otroligt)

• *Handläggning**
• *1. LP** (lära sig ordentligt) VC eller trol –> sjh; nackstel –> LP obl

–> LPK 623 varav poly 123, mono 500, alb 520, laktat 1,2, glu 2,9, rbc (?) 5

• Normala likvorvärden:*
• mono < 5, poly < 1, röda < 1 (0), glu > 50% av p-glu, laktat 1,2 - 2,1, albumin < 0,4, tryck < 20 cm vatten*

–> serös/viral meningit

Prover –> tror inte HSV –> behöver inte prova

2. Vitalparametrar, prover

Har något av dessa:

1. enterovirus (ger ej sequele): likvor-PCR, NPH, blod
2. borrelia (nej)
3. TBE: IgM på serum

Om pt är dålig: ge AB + acyklovir

Behandling av virala CNS-infektioner:

Enbart meningit –> identifiera agens –> oftast enbart symtomatisk behandling

Encefalit –> CT/MR, ev EEG, akutprov för HSV, TBE, VZV –> acyklovir i väntan på diagnos

ANTIVIRAL BEHANDLING Acyklovir iv (po går bra vid HSV 2 – meningit) TILL

• Alla m susp encefalit!
• VZV-infektion (oavsett meningit el encefalit) hos immundefekta
• HSV2–meningit

SYMPTOMATISK BEH TILL • Alla som behöver Ex: - Analgetika - Antiemetika - Dropp

Diagnostik av virala CNS-infektioner

Uteslut bakteriell orsak o identifiera pt som bör ges antiviraler!

1. LP - kemanalys, odling, virusdiagnostik - PCR för entero, HSV1&2, VZV m fl (CT/MR innan vid kontraindikation)
   1b. IgM på serum vid TBE
   * 1c. Påvisa intratekal AK-prod - för virus som inte kan påvisas med PCR eller inte längre kan påvisas (retrospektivt)*
2. MR om encefalitmisstanke
3. Ev EEG - ger typisk bild hos 70 % av herpesencefaliter

*****

SYMPTOM/FYND RELATERADE TILL RESPEKTIVE AGENS

• Utslag-enterovirus,VZV
• Myalgi–enterovirus,TBE
• Konjunktivit–enterovirus
• Dubbelinsjuknande–enterovirus,TBE
• Cerebellär ataxi–VZV
• Temporallobsencefalit–HSV1
• Pareser i skuldror/proximala övrarmar – TBE
• Fästinganamnes – TBE (uppges av 2/3 av pat)
• Recidiverande meningiter – HSV 2

OBS: Pat m herpesencefalit saknar nästan alltid blåsor!

*****

Medscape:

Viral meningitis is inflammation of the leptomeninges as a manifestation of central nervous system (CNS) infection. Viral names the causative agent, and the term meningitis implies lack of parenchymal and spinal cord involvement (otherwise called encephalitis and myelitis, respectively). Viral meningitis is also often referred to as aseptic meningitis.

In uncomplicated viral meningitis, the clinical course is usually self-limited, with complete recovery in 7-10 days. However, when the viral pathogen causes a more involved meningoencephalitis or meningomyelitis, the course can be significantly more protracted. A magnetic resonance imaging (MRI) scan of a patient with meningoencephalitis is seen below.

Currently, more than 85% of viral meningitis cases are caused by nonpolio enteroviruses. Disease characteristics, clinical manifestations, and epidemiology generally mimic those of enteroviral infections.

Mumps, polio, and lymphocytic choriomeningitis viruses (LCMVs) are now rare offenders in developed countries. However, polio remains a major cause of debilitating myelitis in some regions of the world.

As discussed below, many viruses are capable of causing meningitis. This discussion attempts to simplify the microbiology of each viral family with emphasis on disease manifestations and risk factors. Note that in as many as one third of cases, no causative agents are identified. This number is improving with new testing methodologies.

Enteroviruses

Enteroviruses account for more than 85% of all cases of viral meningitis. They are part of the viral family Picornaviridae (“pico” for small, “rna” for ribonucleic acid) and include echoviruses, coxsackieviruses A and B, polioviruses, and the numbered enteroviruses. Nonpolio enteroviruses are common viruses; they are nearly as prevalent as rhinoviruses (which cause the common cold).[1]

The overwhelming majority of meningitis cases are caused by serotypes of coxsackievirus and echovirus. Coxsackievirus B subgroups alone account for more than 60% of meningitis cases in children younger than age 3 months.

Enteroviruses enter the human host usually via the oral-fecal route, but can also spread through the respiratory route.

Enteroviruses are ubiquitous in the summer and early fall; their propensity to cause infection during the warmer months is the major factor in the higher incidence of aseptic meningitis during that time.

The associated clinical findings in enteroviral infections may include pharyngitis, pleurodynia, rash, and pericarditis.

Expectant mothers infected with coxsackievirus B may remain minimally symptomatic, but their infants can acquire the infection perinatally and develop a potential fatal illness, with the infection targeted mainly toward the heart.

Enteroviruses 70 and 71, which exhibit strong neurotropism, are associated with meningoencephalitis, poliolike paralytic syndromes, and Guillain-Barre syndrome, as well as aseptic meningitis.

Arboviruses

Arboviruses account for about 5% of cases in North America.

Arboviruses consist of more than 500 viruses from different viral families, all given the common name “ar-bo,” for arthropod-borne disease. Blood-sucking arthropods, usually mosquitoes, serve as vectors for transmission.

Because exposure to mosquitoes or ticks is the risk factor for transmission, the number of infections is highest in summer and early fall, in concordance with high mosquito populations.

Some of the important arboviruses include the eastern and western equine encephalitis viruses, from the Togavirus family; St. Louis encephalitis’ West Nile, Japanese B, and Murray Valley viruses, from the Flavivirus family; and California group and Jamestown Canyon viruses, from the Bunyaviridae family. Colorado tick fever is caused by a coltivirus in the western regions of the United States.

The most common clinical manifestation is meningoencephalitis rather than pure meningitis.

Seizures are more common with arboviral meningitis than with any other group of viruses.

Some agents preferentially infect certain age groups, such as St. Louis encephalitis, which affects the extremes of age, and California virus, which infects young children. Children with St. Louis or California group encephalitis viruses may not exhibit any neurologic signs or altered mental status.

St. Louis encephalitis (SLE) virus is the most common cause of arboviral meningitis, and is also the most common mosquito-transmitted disease in the United States. Internationally, Japanese B virus is the biggest offender in this group.

Of the arboviruses, West Nile virus caused much attention, as it was first recognized in the United States only in 1999 and quickly became an epidemic in 2002, with more than 4,000 reported cases. In 2008, 1,356 cases were reported.[2]

Infection with the West Nile virus is usually asymptomatic or manifests as mild symptoms of nonspecific fever, myalgia, and fatigue. However, 1 in 150 cases develop into severe disease involving the nervous system, with encephalitis reported more than meningitis. In 2008, 687 cases of West Nile neuroinvasive disease were reported to the US Centers for Disease Control and Prevention (CDC) from all across the United States.[2]

Neuroinvasive West Nile disease occurs more often in elderly persons.

Mumps

A member of the Paramyxovirus family, mumps virus was one of the first known causative agents of meningitis and meningoencephalitis.[3]

The incidence of mumps in the vaccination era has decreased significantly to 1 per 100,000 population in the United States.

Nonetheless, outbreaks have occurred in vaccinated populations, including a large epidemic in the United Kingdom that peaked in 2005 and several outbreaks in the American Midwest in 2006.[4, 18] In addition, mumps continues to cause 10-20% of meningitis and meningoencephalitis cases in parts of the world where vaccines are not readily accessible.

Males 16-21 years of age are at highest risk for developing this infection, with a 3:1 male/female ratio.

Clusters of cases occur in schools and colleges in the winter months.

Concomitant parotitis is a helpful clinical tool, but it may be absent in as many as half of cases with CNS involvement.

A cohort study of 12,000 unvaccinated children from northern Finland revealed that mumps meningoencephalitis accounted for 40.9% of all viral CNS infections. Mumps also remains an important cause of aseptic meningitis in England and Japan.[15]

In 2003, epidemics of aseptic meningitis following measles, mumps, rubella (MMR) vaccination campaigns in various nations (including Brazil and the UK) prompted the Global Advisory Committee on Vaccine Safety to conduct a review of vaccine-derived mumps meningitis.[5] At the time, the committee stated that certain strains of the mumps vaccine (Urabe, Leningrad-Zagreb, and Leningrad-3 strains) were associated with higher incidences of postvaccination aseptic meningitis.

In 2006, the committee determined that the international literature reviewed was actually inconclusive and that further studies were needed.[6] Even so, replacement mumps components were developed and vaccines were reformulated worldwide.

Herpes family viruses

Herpes simplex virus (HSV)-1, HSV-2, varicella-zoster virus (VZV), Ebstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 collectively cause approximately 4% of cases of viral meningitis, with HSV-2 being the most common offender. The viruses may attack at any time of the year.

Meningitis caused by these viruses is often self-limited. When associated with encephalitis, however, the mortality rate can be high. Early treatment with acyclovir can significantly reduce morbidity.

HSV-1 remains the most common cause of sporadic encephalitis, while HSV-2 infections of CNS mostly are restricted to aseptic meningitis.

HSV-2 genital infection may precede meningitis; sexual contact with actively infected individuals is one of the known risk factors.

In one review, however, only 3 of 23 patients with HSV-2 meningitis had a history of prior genital herpes or had genital lesions noted at the time of presentation.[7] Maternal-fetal transmission of HSV-2 can occur, leading to significant systemic sequelae, including infantile septicemia and death.

EBV, HSV-1, and especially HSV-2 have been associated with Mollaret meningitis, a rare, benign, recurrent meningitis that resolves spontaneously. Mollaret cells (activated monocytes with an atypical appearance of enlarged, bilobed nuclei and amorphous cytoplasm) are found in the CSF usually on the first day of symptoms. Herpesvirus-6, EBV, and the human immunodeficiency virus (HIV; which is not a member of the herpes family) have also been implicated. These viruses are all known to remain latent within the nervous system.

CMV infections occur mostly in immunocompromised hosts. CMV may cause subacute encephalitis in patients with AIDS. Congenital CMV, which is a much more serious form of infection, has significant associated morbidity and mortality.

Childhood or adult chickenpox infections by VZV rarely are complicated by meningitis. Adult zoster involving any dermatome may lead to meningitis or meningoencephalitis.

Lymphocytic choriomeningitis virus

LCMV belongs to the family of arenaviruses. Now a rare cause of meningitis, the virus is transmitted to humans by contact with rodents (eg, hamster, rats, mice) or their excreta. Persons at highest risk of infection are laboratory workers, pet owners, or persons living in nonhygienic areas.

Adenovirus

Adenovirus is a rare cause of meningitis in immunocompetent individuals but a major cause in patients with acquired immunodeficiency syndrome (AIDS). The infection may occur simultaneously with an upper respiratory infection.

Measles

This Morbillivirus is another cause of meningitis that has become rare. The characteristic maculopapular rash aids in the diagnosis. Most cases occur in younger people in schools and colleges. Still a worldwide health threat, measles has the highest attack rate of any infection.

From January 1 through April 24, 2015, the United States experienced 5 outbreaks, with 166 cases reported.[19] Preliminary investigations of a large multistate outbreak that originated in California revealed 45% of the infected were unvaccinated, and 43% had unknown vaccination status.[19]

Eradication of measles is an important goal of the World Health Organization (WHO).

HIV

HIV may be a cause of atypical meningitis characterized by chronicity and recurrence. About the time of seroconversion, patients may present with CSF pleocytosis, elevated protein level and, occasionally, high intracranial pressure.

Reports have suggested that as many as 5-10% of HIV infections can be heralded by meningitis. Aside from the usual meningeal signs, HIV infections may also cause global encephalopathy, seizures, and focal neurologic deficits. Some patients develop chronically abnormal CSF findings with mild or no symptoms. HIV often can be isolated from the CSF.

Nonviral causes of meningitis

Tuberculous, fungal, and mycoplasmal organisms are among the important nonviral causes of aseptic meningitis and should be suspected in the appropriate clinical setting.

For example, Lyme borreliosis causes a significant number of cases of aseptic meningitis in the Northeast and Mid-Atlantic states. The diagnosis is suggested by the history of tick bite or outdoor activity in these areas of endemic disease, and the presence of erythema chronicum migrans at the site of tick bite is pathognomonic. Lyme meningitis has a predilection to cause focal cranial nerve palsies, with the seventh nerve most commonly affected.

Clinicians must consider partially-treated bacterial meningitis as a possible etiology for the aseptic nature of their patient’s disease; for example, patients with bacterial otitis and sinusitis who have been taking antibiotics may present with meningitis and CSF findings identical to those of viral meningitis.

The clinician should also realize that the picture of aseptic meningitis is created not only by infectious agents, but also by chemical irritation (chemical meningitis), neoplasm (meningitis carcinomatous), granulomatous disorders, and other inflammatory conditions. This discussion, however, focuses on meningitis caused by viral agents.

History

Upon presentation, most patients report fever, headache, irritability, nausea, vomiting, stiff neck, rash, or fatigue within the previous 18-36 hours. Constitutional symptoms of vomiting, diarrhea, cough, and myalgias appear in more than 50% of patients.

For several weeks or longer, children may experience irritability, incoordination, and an inability to concentrate.

Headache is almost always present in patients with viral meningitis and is often reported as severe. However, the classic description of abrupt onset of the “worst headache of my life,” attributable to aneurysmal subarachnoid hemorrhage, is uncommon.

History of temperature elevation occurs in 76-100% of patients who come to medical attention. A common pattern is low-grade fever in the prodromal stage and higher temperature elevations at the onset of neurological signs.

Younger children may not report headache and may simply be irritable.

Newborns may present with poor feeding and lethargy.

Some viruses cause rapid onset of the above symptoms, while others manifest as nonspecific viral prodromes, such as malaise, myalgia, and upper respiratory symptoms. In many cases, symptoms have a biphasic pattern; the nonspecific flu-like symptoms and low-grade fever precede neurologic symptoms by approximately 48 hours. With the onset of neck stiffness and headache, the fever usually returns.

Meticulous history taking is essential and must include evaluation of exposure to ill contacts, mosquitoes, ticks, outdoor activity in areas of endemic Lyme disease, travel history with possible exposure to tuberculosis, as well as history of medication use, intravenous drug use, and sexually transmitted disease risk.

An important part of the history is prior antibiotic use, which may alter the clinical picture of bacterial meningitis.

Physical Examination

Some general physical findings in viral meningitis are common to all causative agents.

The classically taught triad of meningitis consists of fever, nuchal rigidity, and altered mental status, but not all patients have all 3 symptoms.

Fever is common (80-100% of cases) and usually ranges from 38°-40°C.

Nuchal rigidity or other signs of meningeal irritation (Brudzinski or Kernig sign) may be seen in more than half of patients, but these symptoms are generally less severe than they are in bacterial meningitis. Pediatric patients, especially neonates, tend not to exhibit nuchal rigidity on examination.

Irritability, disorientation, and altered mentation may be seen.

Severe lethargy or bulging fontanelle in neonates is a sign of increased intracranial pressure but may be absent in more than half of all cases. The neonate may exhibit hypotonia, irritability, and poor feeding. The clinical picture can mimic neonatal bacterial septicemia accompanied by multiple organ system involvement.

Headache is common and is characteristically severe.

Photophobia is relatively common but may be mild. Phonophobia may also be present.

Seizures occur occasionally and are usually a result of the fever, although the involvement of brain parenchyma (encephalitis) should be considered.

Global encephalopathy and focal neurologic deficits are rare but can be present. Deep tendon reflexes are usually normal but may be brisk.

Various signs of specific viral infection can aid in diagnosis. These include the following:

• Pharyngitis and pleurodynia in enteroviral infections
• Skin manifestations, such as zoster eruption from VZV, maculopapular rash from measles and enteroviruses, vesicular eruption from herpes simplex, and herpangina from coxsackievirus A infections
• Pharyngitis, lymphadenopathy, and splenomegaly, which suggest EBV infection
• Immunodeficiency and pneumonia, which should suggest adenovirus, CMV, or HIV as the causative agent
• Parotitis and orchitis (testikelinflammation), from mumps
• Gastroenteritis and rash, which occur with most enteroviral infections

Question 12

Fall 4

23-årig kvinna som söker akuten med feber, huvudvärk och intensivt illamående. På eftermiddagen i går allt intensivare huvudvärk och kände sig stel i nacken.

Har under det senaste året haft 4 liknande episoder.

Vad är Din preliminära bedömning och diagnos av patienten? Motivera!

Vilka undersökningar och åtgärder vidtar Du?

Behandling?

Answer 12

Diff:

• bakteriell meningit
• viral meningit HSV2 (recidiverande - typiskt, ofta genitalt) - hitta i likvor
• vaskulit, SLE

Handläggning

1. LP minst en gång –>

LPK 64 varav mono 62, albumin 350, glu OK

• Normala likvorvärden:*
• mono < 5, poly < 1, röda < 1 (0), glu > 50% av p-glu, laktat 1,2 - 2,1, albumin < 0,4, tryck < 20 cm vatten*

–> serös bild

(Sätt inte ut ab för säkerhets skull - sätt in acyklovir - tills PCR/odling är klara. Kan vara bakteriellt recidiv vid likvorläckage.)

2. Analys

• odling
• PCR HSV1&2, VZV (varför ej andra?)

3. PO acyklovir = Varacidon = Valtrex (R) 3xV

OBS: efter 2-3 dygn är behandlingen ej verksam - lyssna efter prodromalsymtom

Question 13

Fall 5

56-årig gift man, tidigare ljumskbråcksopererad f ö väsentligen frisk.

Söker på Karolinska Huddinge akuten 24/9 då han i ca 2 veckor besvärats av värk från olika delar av kroppen samt trötthet och allmän sjukdomskänsla. Värken började i vänster skuldra men har sista veckan flyttat sig över mot höger sida och strålar nu ut i höger arm. Patienten klagar också över värk lokalt i nacken. Han har inte uppmätt någon feber i hemmet.

Status
AT: blek f ö opåverkad, temp 37,3°C. Cor: RR frekv 104. 0 biljud.

Lgll: mjuka, oömma adeniter bägge axiller.

Pulm: ua. Buk: ua. Neurol: ej nackstel, reflexer ua. Bab neg.

Kem lab: CRP <10 (< 3), LPK 6.7 (3,5 - 8,8). Hb 145 (kv 117 - 153, män: 134 - 170)

Ytterligare uppgifter i anamnes och status kan vara av intresse?

Vad är Din preliminära bedömning och diagnos av patienten? Motivera!

Vilka undersökningar och åtgärder vidtar Du?

Behandling?

Answer 13

Vaccin: ej TBE. Stuga i finska skärgården. ECM = erytema cronica migrans - behöver inte vara runt

Feber, värk

Flera utslag –> systemisk borrelia

Diff:

• neuroborrelios (typiskt m fascialispares)
• cancer
• inklämd nerv

Handläggning

Prov:

blod-serologi –> IgG neg, IgM låg aktivitet (bakgrundsbrus - ej specifikt)

Ny serologi efter 4 - 6 veckor

LP –> LPK 550, varav mono 538; ery ok, glu ok, albumin 1300 (serös meningit - barriärskada), laktat 1,5

Klassiskt neuroborrelios

Diagnos: blod o likvor –> jämför. IgG högre i likvor = intratekal produktion

–> AB:

• Kåvepenin funkar inte pga BBB,
• iv ceftriaxon bara (cefalosporin) 1/dag
• po doxycyklin (tetracyklin) - sparas i skelettben

Återkom om 1 år.

• ingen har visat att kronisk borrelia finns

​Alla CNS-infektioner: ju längre tid desto större risk för neurologiska skador

JANUSINFO

Neuroborrelios

Diagnos

Neuroborrelios yttrar sig som meningit och/el- ler radikulit. Meningiten är påtagligt subakut med obetydlig feber och endast lätt till måttlig huvudvärk. Radikuliten kan vara sensorisk el- ler motorisk, eller båda delarna. Sensorisk ra- dikulit ger svår neuralgisk smärta med varie- rande lokalisation. Motorisk radikulit ger partiell eller total pares. Vanligast är perifer facialispa- res. 15-20 % av facialispareserna under andra halvåret är orsakade av Borrelia. Hos barn är siffran högre, cirka 50 %. Den viktigaste diag- nostiska vägledningen ger anamnesen: 50 % har haft ett föregående bett 2-16 veckor före debut av neurologiska symtom (vanligen 3-8 veckor); 50 % av patienterna har haft ett före- gående erytem.

Serologi

Den kan vara negativ initialt och är 100 % po- sitiv först efter 6-8 veckors sjukdomsduration. Vid t ex facialispares måste man därför ta två serologier med 6-8 veckors mellanrum för att kunna utesluta borreliainfektion. Misstänkta fall bör dessutom verifieras med LP, som nästan alltid visar cellstegring och där man dessutom kan påvisa positiv likvorserologi.

Behandling

Doxycyklin peroralt 200 mg x 1 i 14 dagar till vuxna i öppen vård. Diagnosen bör dock vara noggrant verifierad (innebär oftast LP) före be- handling. I svårare fall, t ex patienter med svåra smärtor och mycket lång sjukdomsduration, bör man inleda med intravenös behandling.

Skåne 2014:

Neuroborrelios-diagnos verifieras mha positiv serologi + likvoranalys

Diagnostik med leukocyter och serologi i liquor ger inte alltid borreliadiagnos (Skogman, PIDJ, 2008)

 Av 177 barn som utretts för klinisk misstänkt neuroborrelios

 Säkerställd neuroborrelios 40%  Möjlig neuroborrelios 25% , Oklar diagnos 35%

Serologisk diagnostik vid neuroborrelios? Vad är problemet?

Subkliniska symtom
 4-8 v (2v-6mån) efter fästingbett

 Positiv serologi i serum 6-8 v efter debut av neurologiska symtom

 Positiv serologi i spinalvätska före serum – intratekal antikroppsproduktion

 Lumbalpunktion (inflammatorisk likvor)

 Antikroppssvaret kvarstår länge (år) aktuell eller gammal infektion??

 Borrelia antikroppar 5-12 (-25)% i befolkningen

 Ingen screening / alltid riktad undersökning

Serologisk diagnostik: När? Jo, om du MISSTÄNKER

 Serum vid misstanke om: sekundära/multipla EM, lymfocytom, artrit, ACA

 Spinalvätska + serum vid misstanke: neuroborrelios

6-8 v efter neurologiska symtom positiv i serum

Serologisk diagnostik Western blot när?

_Uteslut_ borrelios
Korsreagerande antikroppar (falskt positiv ELISA)

IgM: EBV, CMV ledsjukdomar, positiv RF, autoimmuna sjukdomar

IgG: syfilis

PCR för att påvisa borrelia-genmaterial - när?

• Atypiska EM (Likvor)
• Ledvätska, synovia

Internetmedicin

NEUROBORRELIOS

Borreliabakterien kan spridas från fästingen till kroppens nervsystem utan hudinfektion 1-2 veckor efter bettet (ej efter månader till år). Bakterien kan också spridas via hudinfektionen erythema migrans. Tiden mellan bett och neurologiska symtom kan då förlängas.

Smärtor, kranialnervspareser och sensibilitetsrubbningar är vanliga symtom vid neuroborrelios. Insätts antibiotikabehandling efter ett par veckors sjukdom brukar symtomen börja klinga av efter 1 veckas behandling och successivt minska inom ett par veckor till någon månad.
Har sjukdomen pågått under flera månader finns risk för kvarstående neurologiska skador framför allt hos äldre personer, trots att infektionen bekämpats.
Lumbalpunktion är ett viktigt diagnostiskt hjälpmedel. Vid oklar akut smärta under sommar och höst bör lumbalpunktion övervägas. Smärtan beskrivs mest intensiv nattetid. Analys av likvor kan också vara av värde för att bedöma effekt av behandling, om tveksamhet uppstår.

Symtom och klinisk bild
Radikulitsymtom och meningitsymtom förekommer samtidigt eller var för sig.

• Meningitsymtomen yttrar sig som huvudvärk, nackvärk, trötthet, aptitlöshet och ibland kräkningar.
• Radikulitsymtomen kan vara både sensoriska och motoriska. Alla nervsegment kan drabbas, men kranialnerverna och speciellt facialisnerven är typisk lokalisation för radikulit.
• Smärtan dominerar bland sensoriska symtom. Den är neuralgiskt intensiv och svårbehandlad med analgetika.

Beroende på lokalisation misstolkas ibland orsaken till smärta. Exempel på feldiagnoser kan vara lumbago-ischias, gallstenssmärtor, hjärtinfarkt, gastrit-ulcus.

Ensidig facialispares är vanligast bland de motoriska symtomen. Svåra fall av hemipares och tetrapares är sällsynta.

Diagnostik

• Anamnes på fästingbett eller erytem förekommer i knappt hälften av fallen.
• Lumbalpunktion med bestämning av celltal och antikroppshalt skall alltid utföras vid misstanke på neurologisk sjukdom.

I likvor ses förhöjt antal mononukleära celler. Antikroppshalten blir efter en tid positiv i likvor och blod, men kan utvecklas långsamt och dröja 4-8 veckor efter symtomdebut. Om patienten haft mer än 8 veckors oklara neurologiska symtom och det föreligger en negativ IgG-borrelia-titer i serum, kan neuroborrelios uteslutas i majoriteten av fallen.

Ospecifika förhöjda antikroppshalter i serum förekommer i ökad frekvens med stigande ålder i normalpopulationen. Förhöjda IgM-koncentrationer hos vuxna är ofta falskt positiva. Isolerad IgM-stegring och normalt IgG-värde hos patienter med lång anamnes tyder ej på borreliainfektion. Vid tveksamma fall kan en lumbalpunktion behöva utföras för att få säkrare diagnos.

Differentialdiagnos

• Virusmeningit
• Lumbago-ischias och andra smärttillstånd
• Hjärntumör

Behandling

• Vuxna, peroralt doxycyklin (Doxyferm) 100 mg, 2 tabletter 1-2 ggr dagligen i 10-14 dagar. Den kortare tiden, 10 dagar, kan användas vid dosering i det högre intervallet. I dessa fall rekommenderas dosreduktion (300 mg dagligen) vid vikt under 50 kg. Alternativt ceftriaxon (Rocephalin) 2 g x 1 i.v. i 14 dagar.
• Barn > 8 år doxycyklin 4 mg/kg/dygn i 10 dagar.
• Barn < 8 år intravenöst ceftriaxon (Rocephalin) 50-100 mg/kg/dygn i 10 dagar. Vid pc+cefalosporin-allergi rekommenderas oralt doxycyklin även till barn under 8 år. Risken för biverkningar av doxycyklin är sannolikt mycket liten, därför kan det vara ett alternativ även till barn under 8 år som av praktiska eller andra skäl inte vill genomgå intravenös behandling. Nya studier har inte påvisat någon risk för missfärgade tänder när doxycyklin ges i korta kurer till barn, se referens nedan Todd et al 2015.

Många veckors/månaders behandling som praktiseras i en del länder, t ex Tyskland och Norge mot s k kronisk borrelios har ingen vetenskapligt dokumenterad effekt. I de flesta fall är diagnosen fel eller också orsakas symtomen av kvarstående neurologiska skador utan aktiv infektion.

PROFYLAX

Profylax mot borreliainfektioner:

• Vaccin saknas.
• Täckande klädsel vid vistelse i område med fästingar.
• Insektsrepellenter innehållande N,N-diethyl-3metylbenzamide (DEET).

Question 14

Likvorprov - lumbalpunktion

1. Vad är normalvärden?

Answer 14

LIKVOR NORMALVÄRDEN

den mängd likvor som tappas vid en LP återbildas på ungefär en halvtimme

Vita mono < 5, poly < 1 x 10⁶

grumlig om > 200-600 x 10⁶ celler/liter

ofta kraftig stegring av ffa poly vid bakteriell meningit, tidigt i förloppet dock lägre nivåer, ibland med monoövervikt

monocytär pleocytos kan ses hos neuroborrelios, Listeria, tuberkulös meningit eller kryptokockmeningit

virusmeningit (tex enterovirus) kan tidigt i förloppet ha polyövervikt

diskret monocytär cellstegring kan även ses vid inflammatoriska sjukdomar, MS

en blödning kan leda till ökade leukocyter (meningeal retning?)

Röda normalt inga (< 1)

tag flera rör för att skilja stickblödning från SAB/intrakraniell blödning

spektrofotometri kan påvisa intrakraniell blödning (likvor färglös efter centrifugering om stickblödning)

röda kan förekomma även vid inflammatoriska tillstånd

Sp-glukos koncentrationen är normalt 35 % lägre i likvor än i serum (samvarierar)

kvoten > 0,5 (50 % eller mer av b-glc), < 0,5 är patologiskt (sockerkonsumtion)

sänkt vid bakteriell meningit, svampmeningit men även vid maligna tumörer i subarachnoidalrummet och ofta vid subarachblödning

ofta mycket lågt vid tuberkulös meningit

normalt (ibland sänkt) vid viral meningit och encefalit

stickblödning stör analysen

Sp-laktat oberoende av nivån i serum, varierande referensområde, tex 1,2-2,1 mmol/l

ökar vid tillstånd med ökad anaerob glykolys, tex bakteriell meningit (> 3,0, kan ses före cellstegring), akut cerebral infarkt, blödning, meningeal carcinomatos, hypoglykemiskt koma

stickblödning stör analysen

Albuminkvot (blod-hjärnbarriärens funktion) referensområdet för albumin i varierar med ålder och laboratorium, övre gräns ligger omkring 0,3-0,4 g/l

albuminkvot = sp-albumin / s-albumin mått på blod-hjärnbarriärens funktion, kvoten stiger vid infektion, lätt stegring vid inflammatorisk sjukdom, strukturell hjärnskada, ev MS-skov, cerebral infarkt m.m.

vid mycket hög kvot, misstänk avflödeshinder för likvor (spinal tumör, inflammatoriska sjukdomar i ryggmärgen eller nervrötterna)

vid Guillain-Barré ses s.k. “albumin-cytologisk dissociation” (uttalad ökning av albuminkvot men sällan cellökning)

Likvortryck mätes med stigrör/manometer, nollpunkt vid insticksstället (i nivå med skallens medellinje om pat ligger plant på sidan); normalt < 20 cm H₂0

Hygieninstruktioner vid lumbalpunktion

• noggrann huddesinfektion, låt huden torka
• noggrann handdesinfektion
• sterila handskar
• evidens för användande av munskydd saknas vid vanlig LP, men bör användas vid myelografi, spinalanestesi, inläggning av epiduralkatetrar m.m., möjligen om öli hos punktören

Question 15

När bör man vid utredning avvakta med LP?

• Hur gör man i dessa situationer generellt?

Answer 15

• Vid tecken på kraftigt stegrat ICP: medvetslöshet (GCS 8 el lägre) / snabbt sjunkande medvetandegrad /uttalad psykomotorisk oro

☛ Ta övriga odlingar och sätt in beh, kontakta därefter intensivvårdsavd (helst neurokirurgisk) direkt för övertagning

• Vid fokala neurologiska symptom: tex: hemipares, dysartri, synbortfall

☛ Ta övriga odlingar och sätt in beh, uteslut hjärnabscess m DT innan LP

• Koagulationspåverkan (TPK < 30, INR > 1,6)

☛ Ta övriga odlingar och sätt in beh, korrigera koagulationsrubbningen och gör därefter LP

• Pågående epileptiskt anfall

☛ Ta övriga odlingar och sätt in beh, ge antiepileptika och gör därefter LP

OBS:

1: Inklämningsrisken är ofta överskattad!
2: Ge alltid behandling även om du skjuter upp eller avstår från LP!